Volume 10 - 2022 | <a class="ArticleLayoutHeader__info__doi" href="https://doi.org/10.3389/fped.2022.847434">https://doi.org/10.3389/fped.2022.847434</a>
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Worries related to the COVID-19 pandemic are associated with mental health problems and reduced life satisfaction
the association between different types of worries about COVID-19 and adolescent mental health is unclear
there is a lack of information about whether certain groups of adolescents are more vulnerable to the adverse effects of worries and how social support may moderate these effects
Adolescents (N = 12,686) completed a survey during the lockdown in spring 2020 in Oslo
The results showed that adolescent worries could be categorized into worries related to infection and those related to the general negative effects of the pandemic
Multivariate regression analyses showed that both types of worries were negatively related to positive affect and life satisfaction and positively related to depressive symptoms
Interaction analyses indicated that some associations with positive affect and depressive symptoms were stronger among adolescents with non-migrant backgrounds
and high reported levels of social support and physical contact during the pandemic
The findings suggest that COVID-19 worries may have negative effects on mental health and inform strategies to increase tailored psychological interventions to mitigate the effect of worry on adolescents&#x00027; mental health and life satisfaction
knowledge about factors associated with mental health and life satisfaction is required to reduce the negative impact of COVID-19 on adolescents
research is still limited regarding the different content of worries and their relation to adolescent mental health
it is unknown whether these sociodemographic characteristics moderate the association between COVID-19 worries and adolescent mental health and life satisfaction
social support and the source of social contact may moderate the relationship between worry about COVID-19 and adolescent mental health and life satisfaction
the current study aims to better understand the relationship between COVID-19-related worries and adolescent mental health and life satisfaction
and to distinguish the role of sociodemographic variables (gender
perceived social support (support from peers and family) and type of contact (physical and online) for these associations
We hypothesize that: (1) higher levels of COVID-19-related worries are associated with poorer mental health and lower life satisfaction; (2) this association remains when controlling for gender
and social contact; (3) the association of COVID-19-related worries with mental health and life satisfaction is stronger among girls
adolescents with a migrant background and adolescents with lower family SES
we do not predict a specific direction of interactions with social support and type of contact
Results showed that the proportion of girls in the present sample was higher than in the population (56% vs
whereas the proportion of adolescents with migrant background was lower (30% vs
The study was anonymous and exempt from approval by the Regional Committee of Medical and Health Research Ethics
Students received written information outlining the study objectives and stating that the study was anonymous
Parents were informed in advance about the study
Similar to studies that analyzed COVID-19 worries from a bidimensional perspective among adults (i.e., worry about dangerousness of COVID-19 and about socio-economic impact) (<a href="#B11">11</a>)
COVID-19-related worries were conceptualized as worries related to infection (3-items: worry about own illness
and illness of family members or friends; Cronbach&#x00027;s alpha = 0.73) and worries about academic and economic consequences of COVID-19 (3-items: worries about family economic situation
and the country&#x00027;s economy; Cronbach&#x00027;s alpha = 0.56)
Response options ranged from not worried at all (1) to very worried (4)
We conducted confirmatory factor analyses to analyze the latent structure of the items
a one-factor solution was modeled with all items loading on one factor; however
this model did not show satisfactory fit (&#x003C7;2(9) = 2013.99
p &#x0003C; 0.001; CFI = 0.85; RMSEA = 0.137; SRMR = 0.068)
a two-factor solution was modeled with correlated latent factors
The three items related to worries about COVID-19 infection loaded onto one factor
whereas the remaining three items about academic and economic consequences loaded onto a second factor
This model showed satisfactory fit (&#x003C7;2(8) = 298.07
p &#x0003C; 0.001; CFI = 0.98; RMSEA = 0.055; SRMR = 0.025)
The two latent worry factors were positively correlated (r = 0.52
with response options ranging from worst possible life (0) to best possible life (10)
Gender, age (i.e., school grade) and migrant background (i.e., at least one parent born abroad) were assessed by self-report. Family socio-economic status was assessed by a composite score comprising the number of books at home, level of education of parents, and four items from Family Affluence Scale II (<a href="#B27">27</a>)
which include frequency of traveling for family holidays in the previous year
number of computers and cars in the family
and the participant having an individual room at home
Peer social support was measured using one item: &#x0201C;Do you have at least one friend who you completely trust and to whom you can reveal everything?&#x0201D; Response options were yes, certainly (4), yes, I think, (3) I don&#x00027;t think so (2), I don&#x00027;t have anyone I would call a friend, these days (1). Family social support was assessed using three items from a short version of the Parental Bonding Instrument (Cronbach&#x00027;s alpha = 0.68) (<a href="#B28">28</a>)
with higher scores indicating higher social support
Physical and online contact were assessed using two questions: &#x0201C;How many of the previous 7 days have you been physically together with friends or a boyfriend/girlfriend?,&#x0201D; and &#x0201C;How many of the previous 7 days have you been in contact with friends or a boyfriend/girlfriend via the Internet or a mobile phone?.&#x0201D; Higher scores indicated higher levels of contact
A significance level of p &#x0003C; 0.01 was used
adolescents worried more about infecting others (M = 2.90; SD = 0.93) and their families or friends getting infected (M = 2.54; SD = 0.96) than about being infected themselves (M = 1.69; SD = 0.76)
worries about the impact of the pandemic on their academic grades (M = 2.39; SD = 0.99) and the economy of the country (M = 2.20; SD = 0.89) were more common than worries about the family&#x00027;s financial situation (M = 1.74; SD = 0.90)
adolescents showed a moderate level for worry about COVID-19 infection (M = 2.38; SD = 0.72) and academic and economic consequences of the pandemic (M = 2.11; SD = 0.68)
Descriptive statistics are presented in <a href="#T1">Table 1</a>
Both types of worries were positively associated with being female
Higher social support from peers was negatively related to worries about the academic and economic consequences of COVID-19
but not to worries about COVID-19 infection
positive relation to worries about infection
but was negatively related to worries about academic and economic consequences
Physical contact showed negative associations with both types of worry
positive association only with worries about consequences
standard deviations and correlations between all study variables (N = 12,686)
Regression results for worries about infection are displayed in <a href="#T2">Table 2</a>
worry about COVID-19 infection predicted negatively positive affect
The association remained significant when adjusting for covariates
Adjusted analyses also showed that being male
and physical contact with friends predicted higher positive affect
Models that included the interaction terms of worry about COVID-19 infection and moderators showed significant moderation effects by migrant background
Simple-slope analyses indicated that worry about infection predicted significantly positive affect only among those adolescents with a non-migrant background (B = &#x02212;0.09
more social support from peers (B = &#x02212;0.08
and more physical contact with friends (B = &#x02212;0.08
compared to adolescents with a migrant background (B = &#x02212;0.01
less social support from peers (B = &#x02212;0.04
p = 0.01) and less physical contact with friends (B = &#x02212;0.01
Regression analyses for the association between worries about COVID-19 infection on adolescents&#x00027; mental health and life satisfaction
For models with depressive symptoms as the outcome
higher levels of worry about COVID-19 infection predicted higher levels of depressive symptoms
both with and without adjustment for covariates
having more social support from peers and family
and having less physical contact also predicted higher levels of depressive symptoms
Models with interaction terms indicated a moderation effect of migrant background
the relationship between worry about COVID-19 infection and depressive symptoms was stronger among adolescents with a non-migrant background (B = 0.23
and high levels of social support from peers (B = 0.23
compared to adolescents with a migrant background (B = 0.14
and less social support from peers (B = 0.16
high levels of worry about COVID-19 infection predicted low life satisfaction in models both with and without covariate adjustment
and having migrant background predicted higher levels of life satisfaction
and physical contact with friends predicted life satisfaction
Results from moderation analyses showed no statistically significant interaction effects for any of the potential moderators
Regression models for worry about COVID-19&#x00027;s academic and economic consequences are presented in <a href="#T3">Table 3</a>
worries about the academic and economic consequences were negatively related to positive affect both with and without covariates
There were similar associations between the covariates and positive affect as observed in the models with worry about COVID-19 infection
Moderation analyses did not show any significant interactions
Regression analyses for the association between worries about COVID-19&#x00027;s academic and economic consequences on adolescents&#x00027; mental health and life satisfaction
For models including depressive symptoms as the outcome
worries about COVID-19&#x00027;s academic and economic consequences predicted higher levels of depressive symptoms in both unadjusted and adjusted models
Covariates had similar associations with depressive symptoms as with worry about COVID-19 infection
but higher levels of online contact also predicted more depressive symptoms
Interaction analyses demonstrated that the relationship between worries about COVID-19&#x00027;s academic and economic consequences and depressive symptoms was stronger among adolescents with a non-migrant background (B = 0.43
p &#x0003C; 0.001) and with higher social support from peers (B = 0.41
compared to adolescents with a migrant background (B = 0.37
p &#x0003C; 0.001) and lower support from peers (B = 0.37
greater worries about COVID-19&#x00027;s academic and economic consequences predicted lower life satisfaction in both unadjusted and adjusted models
Covariates had similar relations to life satisfaction as in models investigating worry about COVID-19 infection
Results from moderation analyses showed no significant interaction effects
This study analyzed the relationships between worries about the COVID-19 pandemic and adolescent mental health and life satisfaction and assessed whether these relationships were moderated by socio-demographic variables and social support
Results indicated that COVID-19 worries comprised two main dimensions: worries about COVID-19 infection and worries about COVID-19&#x00027;s academic and economic consequences
Findings also revealed that both types of worries predicted poor mental health (i.e.
lower positive affect and higher depressive symptoms) and life satisfaction
our findings suggested that the relationships between worries and mental health were stronger among adolescents with non-migrant backgrounds
and high levels of social support or contact from peers
the relationships between both types of worry on life satisfaction were not moderated by any variables included in the models
our results underline the importance of addressing the impact of both school-related stress and the economic situation on adolescents&#x00027; worries
As expected, higher levels of worries about COVID-19 were negatively related to both positive affect and life satisfaction, and positively depressive symptoms. These associations were also found when accounting for covariates. These findings are in accordance with previous studies indicating that COVID-19-related worries were associated with adolescent mental health and life satisfaction (<a href="#B8">8</a>, <a href="#B9">9</a>)
our results extend previous literature by demonstrating that the relationship between adolescent worries and mental health should be considered from a dimensional perspective including various worries
not only about infection but also about the academic and economic consequences of the pandemic
Adolescents from high SES backgrounds may as such have had more experience of and knowledge about the adverse consequences of COVID-19 infections
which may have strengthened the association between COVID-19 worries and mental health outcomes in this group of adolescents
Future longitudinal studies that investigate the change in worries and their resulting impact on mental health during COVID-19 may help to better understand these relationships
these adolescents may share their concerns and fears related to COVID-19 to a greater degree with their peers
thus increasing the negative effect of these worries on their mental health
when types of social contact were analyzed
the negative association between worry about COVID-19 infection and mental health was stronger among those with higher levels of in-person contact
it is possible that adolescents may worry about infecting others through in-person contact
These worries may change in the post-pandemic period; however
future studies should explore the longitudinal influences of in-person and online contact on adolescent mental health in order to develop better infection control strategies and
Strengths of this study include the use of a large
population-based sample of adolescents (N = 12,686) and multidimensional assessment of worries
the results should be interpreted in the context of some limitations
the cross-sectional design limits the potential to uncover causal relationships between the variables
Future studies should include longitudinal designs
measures may be affected by the limitations of self-report questionnaires
so future research would benefit from multimethod assessment
the bidimensional structure of the measure of COVID-19 worries may be a result of the selection of the six items used to assess this construct in the present study
A more comprehensive instrument with a wider item selection of potential worries may have resulted in a more multifaceted measure
we did not examine whether having experienced a coronavirus infection was related to COVID-19 worries and mental health outcomes
as the survey did not include items on infections
Such information would have provided valuable information about the psychological consequences of an infection and should be examined in future studies
although confirmatory factor analyses showed adequate model fit for a two-factor solution for COVID-19 related worries
this study is the first to use this instrument to assess COVID-19 worries in adolescents
Future studies should explore if the bidimensional solution on worries stands
the 37% rate response in this study and the underrepresentation of boys and adolescents with migrant background may to some degree influence the estimates of prevalence of COVID-19 worries and associations between COVID-19 worries and mental health outcomes
it is unclear whether the present study results are generalizable to adolescents from countries other than Norway with different welfare systems
research examining the effects of worry about COVID-19 in other countries would be beneficial
The current study enhances knowledge about the relationship between different types of worries about COVID-19 and mental health and life satisfaction among adolescents
Adolescents with higher SES and higher perceived social support levels may be more vulnerable to the association between high levels of worry about COVID-19 and poorer mental health
Future studies should monitor specific worries during the COVID-19 pandemic to reduce the risk of the development of mental health problems related to the pandemic
this study helps to inform therapeutic and prevention strategies that aim to reduce adolescents&#x00027; worries about the COVID-19 pandemic and its continuous influence on adolescent mental health and life satisfaction
The data used in this study is available from the corresponding author upon reasonable request and with the permission of Norwegian Social Research (NOVA)
Written informed consent from the participants&#x00027; legal guardian/next of kin was not required to participate in this study in accordance with the national legislation and the institutional requirements
RR-C and LC-G: writing&#x02014;original draft preparation
All authors contributed in conceptualization
and agreed to the published version of the manuscript
This study was supported by grants from the Research Council of Norway (Project nos
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations
Any product that may be evaluated in this article
or claim that may be made by its manufacturer
is not guaranteed or endorsed by the publisher
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Received: 02 January 2022; Accepted: 08 March 2022; Published: 25 April 2022
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Spaniard ruled out of action following crash on Saturday's penultimate stage
There was plenty of suffering to go around on stage 5 of the <a data-analytics-id="inline-link" href="https://www.cyclingnews.com/uae-tour/" data-before-rewrite-localise="https://www.cyclingnews.com/uae-tour/">UAE Tour</a> with five riders leaving the race before Saturday's penultimate stage due to crashes and pre-existing ailments
The misfortune at the race did not end with Dylan Groenewegen's concussion or the crashes suffered by Paul Seixas and Fernando Gaviria
Stage 6, a pan-flat 165km day in the saddle, brought bad news for Ineos Grenadiers and <a data-analytics-id="inline-link" href="https://www.cyclingnews.com/riders/carlos-rodriguez-cano/" data-before-rewrite-localise="https://www.cyclingnews.com/riders/carlos-rodriguez-cano/">Carlos Rodr&iacute;guez.</a>
Sunday morning brought the news that the Spaniard
who didn't make it to the finish of the previous day's stage
Rodr&iacute;guez figured to be a major player in Sunday's final stage up to the summit finish at Jebel Hafeet. He lay in 21st overall, some 1:46 adrift of race leader (now race champion) <a data-analytics-id="inline-link" href="https://www.cyclingnews.com/riders/tadej-pogacar/" data-before-rewrite-localise="https://www.cyclingnews.com/riders/tadej-pogacar/">Tadej Poga&#269;ar</a>
but the 24-year-old will have hoped to bounce back from an anonymous 17th place on Jebel Jais
Rodr&iacute;guez comes away from the UAE with nothing to show for his efforts
while he now faces a multi-week layoff as the calendar turns to the spring
His Ineos Grenadiers team confirmed the news on Sunday morning ahead of the UAE Tour's concluding <a data-analytics-id="inline-link" href="https://www.cyclingnews.com/races/uae-tour-2025/stage-7/results/" data-before-rewrite-localise="https://www.cyclingnews.com/races/uae-tour-2025/stage-7/results/">stage 7</a>
won by Poga&#269;ar in a dominant display ahead of Giulio Ciccone and Pello Bilbao
Carlos Rodr&iacute;guez has not started after hospital tests revealed he suffered a collarbone fracture in a crash on stage 6," the team announced in a social media post
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his team's first WorldTour triumph of the new season
the team will be hoping that Laurens De Plus can convert his third place overall into a final podium spot at the Volta ao Algarve as the Belgian rider faces up to the 19.6km closing time trial on Sunday afternoon
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What&#x27;s Happening with James Rodríguez at Rayo Vallecano?The Colombian international has been shining with his national team
Here’s the current state of his situation.Since James Rodríguez’s arrival at Rayo Vallecano
with high expectations that he would become one of the most significant summer signings
that promise has yet to materialize on the pitch.&nbsp;
as he has shown during his recent appearances with the Colombian national team
James has only played 30 minutes across two games
the Colombian midfielder did not see any action
as head coach Íñigo Pérez kept him on the bench for the full 90 minutes
Pérez explained that he chose players with different attributes to manage what he described as a game that was "hanging by a thread." His decision has sparked debate and criticism
especially from Colombian supporters who express frustration over James' limited minutes
being a standout player during South American World Cup qualifiers
where he both assisted and scored a decisive penalty
Rayo Vallecano’s fans appear to be more understanding of Pérez’s decisions
The fan group Bukaneros even displayed a banner at Vallecas Stadium stating
no one is more important than anyone else,” reinforcing the idea that players must earn their place on the field
Íñigo Pérez has emphasized that James is still in the process of adapting to the team
He missed the preseason and was away for a few weeks due to his international duty with Colombia
which has delayed his full integration into the squad
Pérez has also pointed out that Rayo's starting lineup has not been set in stone
with rotations seen in the team’s seven matches thus far
not with a fixed lineup sheet," Pérez remarked
making it clear that his decision to bench James is purely based on tactical considerations
he will need to continue adapting and demonstrate his value in the opportunities he gets
Despite the external pressure and criticism
confident in making decisions that he believes are best for the team
"I am a coach who does not interfere in signings because there are people in the club doing very well
and I focus on my role in transforming players to reach their level
but I believe he comes from a long period of inactivity
and I choose the best to win every match," he confessed
assistant professor of marketing at McNeese State University
has been named interim dean of the College of Business
provost and vice president for academic affairs and enrollment management at McNeese
who has been serving as interim dean since August 2017
Cano received her Doctorate in Business Administration in marketing
her Master of Accounting degree and her Bachelor of Science degree in accounting from the University of South Florida
“It is my honor and pleasure to serve in an administrative role for the College of Business
I must recognize and voice my appreciation to the outstanding faculty and staff that have been so supportive of my appointment,” said Cano
Cano teaches at both the graduate and undergraduate level
including marketing core courses and electives
Cano taught for 16 years at universities and colleges in Georgia and Florida
including as associate professor of marketing at Georgia College and State University
assistant professor of marketing at Augusta State University and visiting scholar in residence at the University of South Florida
authored numerous articles and made several presentations at professional conferences
She is a member of the Marketing Management Association and the PhD Project in Marketing
Cano is the president-elect of the Society for Marketing Advance
where she previously served as treasurer and member of the Board of Governors
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Chrononutrition studies the relation between diet, circadian rhythms and metabolism, which may alter the metabolic intrauterine environment, influencing infant fat-mass (FM) development and possibly increasing obesity risk.
To evaluate the association of chrononutrition in pregnancy and infant FM at 6 months.
Maternal nighttime eating is associated with higher adiposity in 6 month infants.
Volume 11 - 2024 | <a class="ArticleLayoutHeader__info__doi" href="https://doi.org/10.3389/fnut.2024.1364722">https://doi.org/10.3389/fnut.2024.1364722</a>
This article is part of the Research TopicChrononutrition and Health<a class="Link Link--linkType Link--maincolor Link--medium Link--icon Link--chevronRight Link--right" aria-label="View all 8 articles" href="https://www.frontiersin.org/research-topics/57861/chrononutrition-and-health/magazine" target="_self" data-event="customLink-linkType-a_viewAll8Articles">View all 8 articles</a>
Introduction: Chrononutrition studies the relation between diet
which may alter the metabolic intrauterine environment
influencing infant fat-mass (FM) development and possibly increasing obesity risk
Aim: To evaluate the association of chrononutrition in pregnancy and infant FM at 6&#x2009;months
Methods: Healthy pregnant women and term-babies (n&#x2009;=&#x2009;100pairs) from the OBESO cohort (2017&#x2013;2023) were studied
Maternal registries included pregestational body-mass-index (BMI)
1 each trimester) and sleep-schedule (first and third trimesters) were evaluated computing fasting (hours from last&#x2013;first meal)
breakfast and dinner latencies (minutes between wake up-breakfast and dinner-sleep
meal skipping (&#x02265;1 main meal/d on three recalls) and nighttime eating (from 9:00&#x2009;pm&#x2013;5:59&#x2009;am on three recalls)
%; air-displacement plethysmography) was measured
and FM index (FMI&#x2014;kgFM/length2) computed
Exclusive breastfeeding (EBF) was recorded
Multiple linear regression models evaluated the association between chrononutrition and 6&#x2009;month infant FM
Results: Mean fasting was 11.7&#x2009;&#x000B1;&#x2009;1.3&#x2009;h; breakfast
dinner latency were 87.3&#x2009;&#x000B1;&#x2009;75.2
99.6&#x2009;&#x000B1;&#x2009;65.6&#x2009;min
Average meals/day were 3.0&#x2009;&#x000B1;&#x2009;0.5
Meal skipping was reported in 3% (n&#x2009;=&#x2009;3) of women and nighttime eating in 35% (n&#x2009;=&#x2009;35)
mothers engaged in nighttime-eating had infants with higher %FM (p =&#x2009;0.019)
Regression models (R2&#x2009;&#x02265;&#x2009;0.308
p&#x2009;&#x02264;&#x2009;0.001) showed that nighttime eating was positively associated with %FM (B: 2.7
When analyzing women without complications/medications (n&#x2009;=&#x2009;80)
nighttime eating was associated with higher FM [%FM
Infant sex and weight (6&#x2009;months) were significant
Conclusion: Maternal nighttime eating is associated with higher adiposity in 6&#x2009;month infants
Generating evidence in this area is imperative as it could facilitate the implementation of simple strategies targeting sleeping and eating schedules for pregnant women
In non-pregnant adults, disturbances in biological rhythms can alter homeostasis and metabolic processes which have been linked to chronic conditions such as obesity, diabetes, and cardiovascular disease (<a href="#ref9">9</a>, <a href="#ref15">15</a>). Some chronotypes, particularly the evening type, have been associated with suboptimal glycemic control, higher risk of mortality, and even higher risk of eating disorders (<a href="#ref9">9</a>)
The mechanisms explaining the intricate connection between the timing of food consumption throughout the day and regulating the biological clock still need to be clarified
This study aimed to evaluate if certain chrononutrition behaviors in pregnancy are associated with infant adiposity at 6&#x2009;months of life
The study was reviewed and approved by the institutional Ethics and Research committees (Project No
The women&#x2019;s participation was voluntary
and those who agreed to participate signed the written consent
we included adult pregnant women with singleton pregnancies (recruited between 11.0&#x2013;13.6&#x2009;weeks of gestation) with a pregestational body mass index (BMI) &#x02265;18.5
without previous comorbidities (type 2 diabetes
HPV-) or chronic use of medications (affecting carbohydrate or lipid metabolism or markers of inflammation/oxidative stress)
Exclusion criteria included findings of congenital/structural malformations in the fetus or abnormal fetal karyotype
maternal/fetal infections (chorioamnionitis)
We eliminated women without complete follow-up (&#x0003C;3 prenatal visits)
those with preterm delivery (&#x0003C;37&#x2009;weeks
with a nighttime shift or missing three dietary assessments
as well as those with implausible energy intake (&#x0003C;500 or &#x0003E;3,500&#x2009;kcal/d)
Infants without anthropometric or fat mass (FM) measurements at birth or 6&#x2009;months were eliminated
Prescribed medications (metformin/insulin)
the presence of pregnancy complications (gestational diabetes
and preterm birth were obtained from the institutional clinical records
In each trimester (for a total of 3 evaluations)
a trained and experienced nutrition professional conducted dietary assessment using a multiple-pass 24&#x2009;h recall methodology
having food replicas and standardized measuring cups and spoons to assist in estimating portion sizes
The 24&#x2009;h recall documented the meal times of the day
The Food Processor SQL software (version 14.0
United States) was used to obtain nutrition analysis
The software was previously loaded with standardized local recipes and foods (using food labels or Mexican tables of nutritional value) in its database
The average of the three dietary assessments was computed for each diet component
The evaluation of chrononutrition behaviors included:
&#x02022; Fasting (hours): due to the limitation of collecting only one diet recall in each trimester of pregnancy
it was not possible to accurately compute an overnight fasting window between consecutive days
we approximated a fasting window by computing the time difference between the final eating occasion and the first eating occasion within a single diet recall
which assumes that the first eating occasion is consistent across days among participants
The average of the approximated fasting hours in the three trimesters was obtained
&#x02022; Number of main meals: the count of main meals was determined based on the occasions when food/drinks &#x0003E;250&#x2009;kcal were consumed in each 24&#x2009;h recall
The average number of main meals reported across the three visits was also calculated
&#x02022; Meal skipping (Yes/No): the classification of meal skipping was established when there were &#x0003C;3 main meals reported in all three of the 24&#x2009;h recalls
&#x02022; Nighttime eating (Yes/No): women who
reported food consumption outside the daylight period (&#x02265;21:00&#x2009;h and &#x0003C;6:00&#x2009;h of the next day)
The time criteria are established based on local sunset and sunrise times year-round in Mexico
&#x02022; Breakfast latency (min): calculated as the time difference in minutes between the moment of waking up (from nighttime sleep duration reported) and the time of the first meal recorded in the 24&#x2009;h recall
The average of the minutes from the two measurements (first and third trimester) was determined
&#x02022; Dinner latency (min): calculated as the time difference in minutes between the last meal consumed in the 24&#x2009;h recall and bedtime (from nighttime sleep duration reported)
The average of the minutes from the two measurements (first and third trimester) was established
the classification of exclusive breastfeeding (EBF) was determined through interviews with mothers regarding the feeding practices of their infants during the first 6&#x2009;months
EBF included the consumption of breast milk
Non-EBF infants received any amount of formula
whether in combination with breastmilk or as the sole source of feeding
Descriptive statistics were employed to present the population&#x2019;s characteristics (socioeconomic
clinical data) and the description of the maternal diet
Bivariate analyses were performed: correlations of continuous variables (Pearson/Spearman); mean differences between groups (Student&#x2019;s t-test/U-Mann Whitney test
one-way ANOVA/Kruskal Wallis test); and the difference between two proportions (Chi-square test)
These analyses aimed to explore chrononutrition behaviors and infant FM according to maternal socioeconomic and clinical characteristics
and nutrient consumption according to chrononutrition behaviors
and to assess the association between the different chrononutrition habits (independently) and infant FM
To study the influence of individual chrononutrition behaviors (fasting hours
we performed multiple linear regression models
Each model incorporated confounding variables for adjustment
selected based on (1) their recognized influence on fat mass according to existing literature and (2) previous bivariate analyses
These confounding variables encompassed maternal pregestational BMI
The strength of the models was assessed through R2 values
Normal distribution of residuals was verified to ensure the assumptions of the regression models
considering other potential maternal influences on infant FM (e.g.
Variables without significant impact on the models (no change in R2 or p-value) were excluded
A p-value &#x0003C;0.05 was considered statistically significant
All statistical analyses were performed using the SPSS software version 26.0 (IBM
Out of the 502 women enrolled in the OBESO cohort
44 were excluded due to the presence of chronic or uncontrolled diseases (20 with type 2 diabetes
183 women were eliminated as they did not attend at least three prenatal visits
Eighty-six women had incomplete dietary information
and one of them was excluded because of a nighttime shift
No woman exhibited an implausible energy intake (&#x0003C;500 or &#x0003E;3,500&#x2009;kcal/d)
88 infants were eliminated from the analysis because they lacked FM measurement (non-attendance at visit
A total of 100 mother-infant pairs were included in the final analysis
<a href="#tab1">Table 1</a> shows the maternal characteristics of our population
Pregnancy complications and the use of metformin/insulin were observed in only a small percentage of the sample
Sleep had a minimum duration of 1.64&#x2009;h and a maximum of 10&#x2009;h
More than a third of women presented short sleep
Maternal characteristics according to nighttime eating during pregnancy
Most women had three main meals per day (2.0&#x2013;5.67 meals); only 3% (n&#x2009;=&#x2009;3) of them reported meal skipping during pregnancy
n&#x2009;=&#x2009;35) presented nighttime eating during gestation
The mean breakfast and dinner latency duration were 87.3&#x2009;&#x000B1;&#x2009;75.2&#x2009;min and 99.6&#x2009;&#x000B1;&#x2009;65.6
with a wide distribution (breakfast range: 0 to 320&#x2009;min
The mean night fasting duration was 11.7&#x2009;&#x000B1;&#x2009;1.3&#x2009;h (6.52 to 14.75&#x2009;h)
Nulliparous women showed a shorter duration of breakfast latency (min
p&#x2009;=&#x2009;0.009) and longer sleep hours (hr
No other differences in chrononutrition behaviors were found based on clinical (pregestational BMI
GWG) or maternal socioeconomic variables (occupation
Maternal age exhibited a positive correlation with the number of main meals per day (r&#x2009;=&#x2009;0.201
p&#x2009;=&#x2009;0.045) and a negative correlation with hours of fasting (r&#x2009;=&#x2009;&#x02212;0.292
p&#x2009;=&#x2009;0.003) and sleeping (r&#x2009;=&#x2009;&#x02212;0.286
No additional correlations were observed between pregestational BMI and chrononutrition behaviors
<a href="#tab2">Table 2</a> describes the mean consumption of energy and macronutrients during pregnancy
Women with pregestational obesity presented a lower consumption of carbohydrates (grams
Normal: 286.8&#x2009;&#x000B1;&#x2009;69.8
Overweight: 260.2&#x2009;&#x000B1;&#x2009;58.7
Obesity: 246.9&#x2009;&#x000B1;&#x2009;57.0
p&#x2009;=&#x2009;0.034) and saturated fat (grams
Overweight: 20.3&#x2009;&#x000B1;&#x2009;7.1
No energy or nutrient consumption differences were identified according to GWG
Sleep hours did not correlate with energy or nutrient intake
Energy and nutrient consumption during pregnancy according to nighttime eating
Some consumption differences were identified based on chrononutrition behaviors
there was a significantly higher intake of protein (grams
p&#x2009;=&#x2009;0.033) and a trend of higher energy (kcals
p&#x2009;=&#x2009;0.078) and total fat intake (grams
The mean gestational age of newborns was 38.9&#x2009;&#x000B1;&#x2009;1.0&#x2009;weeks, with 52% (n&#x2009;=&#x2009;52) of female infants. Anthropometric measurements at birth and 6&#x2009;months and adiposity indicators are detailed in <a href="#tab3">Table 3</a>
Most infants were classified with normal BMI/age at birth
and 8% (n&#x2009;=&#x2009;8) and 3% (n&#x2009;=&#x2009;3) presented overweight risk and overweight
respectively; no case of obesity was detected
No differences in anthropometric measurements or BMI/age classification were observed at birth based on sex
12% (n&#x2009;=&#x2009;12) of infants were at risk of overweight and 2% (n&#x2009;=&#x2009;2) were classified as overweight; there were no cases of obesity detected
p&#x2009;=&#x2009;0.032) compared to girls
but no difference in BMI/age classification at 6&#x2009;months
Thirty percent (n&#x2009;=&#x2009;30) of infants received EBF for the first 6&#x2009;months of life
there were no differences in anthropometric or adiposity measurements at 6&#x2009;months
there were no differences in infant anthropometric measurements or BMI/age classification at 6&#x2009;months
Description of newborn and infant anthropometric measurements and infant FM according to maternal nighttime eating
infants born to mothers with pregestational obesity exhibited lower FM (p&#x2009;&#x0003C;&#x2009;0.05)
No other differences in adiposity indicators according to GWG
or any maternal socioeconomic characteristics were found
Infants born to nighttime-eating mothers had higher %FM (p&#x2009;=&#x2009;0.019) and FMI (p&#x2009;=&#x2009;0.046) and a tendency towards higher kgFM (p&#x2009;=&#x2009;0.067) (<a href="#tab3">Table 3</a>)
No differences in anthropometry or adiposity were identified based on main meal skipping
A negative correlation between breakfast latency and infant weight (r&#x2009;=&#x2009;&#x02212;0.258
p&#x2009;=&#x2009;0.009) and length (r&#x2009;=&#x2009;&#x02212;0.317
p&#x2009;=&#x2009;0.001) was observed at 6&#x2009;months
No other differences were found between infant anthropometric or adipositymeasurements and chrononutrition behaviors
In the multiple linear regression models, the only significant model (R2: 0.311, p&#x2009;&#x0003C;&#x2009;0.001) was for maternal nighttime eating, which was associated with a significantly higher %FM and a trend towards higher kgFM and FMI (<a href="#tab4">Table 4</a>)
Infant sex and weight at 6&#x2009;months were also found to be associated factors
These associations were independent of maternal pregestational BMI
Association of nighttime eating during pregnancy and infant fat at 6&#x2009;months of life
After excluding women with pregnancy complications and medication use (n&#x2009;=&#x2009;20), multiple linear regression models showed that having a mother engaged in nighttime consumption during pregnancy was associated with a higher %FM, kgFM, and FMI at 6&#x2009;months, as well as being female or having a higher infant body weight (<a href="#tab5">Table 5</a>)
saturated and monounsaturated fat did not modify the models
None of the models performed for the other chrononutrition behaviors were significant for this subgroup of women
Association of nighttime eating during pregnancy in women without pregnancy complications or medication use and infant fat at 6&#x2009;months of life
This is one of the first prospective studies that describe chrononutrition behaviors during pregnancy (meal skipping
and nighttime eating) and shows some influence on maternal nutrient consumption (protein
Our findings suggest a potential link between maternal nighttime eating during pregnancy and higher infant adiposity at 6&#x2009;months
There is an intricate interplay between circadian rhythm
underlying the need for further research in this complex area
Manipulating meal timing may be a potential strategy to manage glucose homeostasis
Breakfast and dinner latencies represent novel elements scarcely studied within the chrononutrition field
These aspects could be associated with alterations in consumption and metabolic issues related to light/dark periods
Our results show that the shorter time between waking up and having breakfast was associated with higher consumption of omega-3 fatty acids
Exploring these timing factors and their association with maternal-infant health is essential
promoting breastfeeding should be a priority
Maternal obesity is recognized as a factor that predisposes the offspring to alterations in fetal growth (<a href="#ref62">62</a>), with excessive and insufficient growth associated with higher adiposity later in life (<a href="#ref63">63</a>)
we found a lower FM in infants born to mothers with gestational obesity
pregestational BMI was not associated with FM in our multiple regression models examining the association between maternal nighttime eating and adiposity
This study presents some limitations that warrant consideration
the absence of a specific dietary assessment method to evaluate chrononutrition behaviors prospectively may have introduced error and different biases in the estimation of our indicators
The fact that we analyzed information from each recall and used the average for computing chrononutrition variables is an indirect assessment
especially regarding the approximated overnight fasting duration used in our analysis
the study design did not allow us to assess or consider differences in chrononutrition behaviors across pregnancy trimesters
It is possible that the behaviors described in this study are not representative of all stages of pregnancy
Although we were able to assess usual sleeping schedule
the retrospective nature of the questionnaire is not ideal
a more comprehensive evaluation of episodes of night eating could have included the proportion of calories or a macronutrient analysis
providing a more detailed understanding of dietary patterns
It is also possible that women under or overreported energy/macronutrient consumption
The lack of FM measurement at birth is another limitation
as having this variable could have allowed for better adjustment in our models or facilitated a longitudinal analysis
it may somehow decrease the reliability and precision of our findings
The results of this study may not be applicable for the general population
socioeconomic status and that women receiving prenatal care in our hospital are classified as &#x201C;high-risk&#x201D; pregnancies
Even though we established strict inclusion criteria in this cohort for reducing variability
Using data from a prospective cohort enabled the assessment of maternal variables throughout pregnancy and early infancy
This longitudinal approach allowed for considering various influential factors on adiposity in our statistical models
The ability to evaluate dietary consumption longitudinally
allowed a better characterization of chrononutrition behaviors throughout pregnancy
Air-displacement plethysmography is a well-validated method to assess FM in this early stage of life
Our outcome variable included different indicators of adiposity such as a percentage (relative)
and FMI (relative to length) to have a broader analysis with better indicators of body composition
The temporal aspects of feeding should be included when evaluating dietary patterns in pregnant women
could affect the intake of nutrients and may indicate different nutrition and metabolic imbalances
Maternal nighttime eating is associated with higher infant adiposity at 6&#x2009;months of age
Chrononutrition behavior modification could represent an innovative and feasible strategy that may be incorporated into nutritional counseling during pregnancy for improving nutrient intake and promoting metabolic health
The raw data supporting the conclusions of this article will be made available by the authors
The studies involving humans were approved by Ethics and Research committees&#x2014;Instituto Nacional de Perinatolog&#x000ED;a (Project No
The studies were conducted in accordance with the local legislation and institutional requirements
The participants provided their written informed consent to participate in this study
The author(s) declare that financial support was received for the research
Project financially supported by the DGPIS (#FPIS2023-INPER-4257; #INPer: 2023-1-31)
financed by the Instituto Nacional de Perinatolog&#x000ED;a (No
and AR-C are speakers of the Nestle Nutrition Institute
OP-P and ER-M are speakers of Exeltis Pharma Mexico
The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest
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Estrada-Gutierrez G and Perichart-Perera O (2024) Nighttime eating during pregnancy and infant adiposity at 6&#x2009;months of life
Received: 02 January 2024; Accepted: 25 June 2024; Published: 10 July 2024
Copyright &#x000A9; 2024 Rodr&#x000ED;guez-Cano, Medel-Canchola, Gonz&#x000E1;lez-Ludlow, Rodr&#x000ED;guez-Hern&#x000E1;ndez, Reyes-Mu&#x000F1;oz, Schiffman-Selechnik, Estrada-Gutierrez and Perichart-Perera. This is an open-access article distributed under the terms of the <a rel="license" href="http://creativecommons.org/licenses/by/4.0/" target="_blank">Creative Commons Attribution License (CC BY)</a>
&#x0002A;Correspondence: Otilia Perichart-Perera, <a id="encmail">b3RpbGlhcGVyaWNoYXJ0QGlucGVyLmdvYi5teA==</a>
ESPN Sunday Night Baseball analyst <a href="https://elitesportsny.com/tag/alex-rodriguez" target="_blank" rel="noopener">Alex Rodriguez</a> was asked about PED use again
but this time it was regarding his former teammate and friend
Cano was banned for 80 games <a href="https://elitesportsny.com/2018/05/15/mlb-news-robinson-cano-suspended-for-violating-joint-drug-agreement/" target="_blank" rel="noopener">after he tested positive for Furosemide</a>
There are probably more questions you could ask A-Rod about Cano’s situation. <a href="https://t.co/pDiRAEZIn5">https://t.co/pDiRAEZIn5</a>
&mdash; Andrew Marchand (@AndrewMarchand) <a href="https://twitter.com/AndrewMarchand/status/998526052443082752?ref_src=twsrc%5Etfw">May 21, 2018</a>
Talking about the Cano suspension, Rodriguez made sure <a href="https://elitesportsny.com/2018/05/17/new-york-yankees-robinson-canos-suspension-not-surprising-to-mark-teixeira/" target="_blank" rel="noopener">not to bash Cano</a>
He talked about what he believes Cano may be going through right now
and what lies ahead for the Seattle Mariners&#8217; second baseman
&#8220;It will be a long road back, a tough road back, but I’m confident that Robinson Cano is going to come back and continue his spectacular career and I hope at the same time he can learn a great lesson and make his life even better,” said Rodriguez reported by <a href="https://nypost.com/2018/05/20/alex-rodriguez-breaks-silence-on-robinson-canos-ped-ban/?utm_campaign=iosapp&amp;utm_source=twitter_app" target="_blank" rel="noopener">Joseph Staszewki</a> of the New York Post
as the Indians faced the Astros on Sunday on ESPN
was suspended by the MLB for the entire 2014 season due to PED use
The Yankee slugger went on to play two more seasons with New York then retired
Robinson Cano now lies in the same spot as Rodriguez did back in 2014
He has the numbers to make it into Cooperstown
but he is now held in the &#8220;PED&#8217; era of Major League Baseball
where he will be looked at as a cheater in the sport today
A tough thing to break away as many players can attest to
Though a selection to the Baseball Hall of fame is outside the realm of possibility
Rodriguez has regenerated his identity and career
He currently is a baseball broadcaster for both ESPN and Fox Sports
His new career has set aside his baseball PED use
as he now is able to talk to fans with his great knowledge and descriptive skill of the game of baseball
Fans will see if Cano has the ability to bounce back much later on this season
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Rodriguez passed from this life Friday August 2
Ruben is preceded in death by his parents Magdaleno and Dolores Rodriguez
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Ineos Grenadiers place three riders in top ten overall
Talented young Spaniard Carlos Rodriguez remains well within sight of the podium in the <a data-analytics-id="inline-link" href="https://www.cyclingnews.com/vuelta-a-espana/" data-before-rewrite-localise="https://www.cyclingnews.com/vuelta-a-espana/">Vuelta a Espa&ntilde;a</a> after punching above expectations again with a strong fourth in Tuesday&rsquo;s crucial individual time trial
The 21-year-old started out relatively slowly on the <a data-analytics-id="inline-link" href="https://www.cyclingnews.com/races/vuelta-a-espana-2022/stage-10/results/" data-before-rewrite-localise="https://www.cyclingnews.com/races/vuelta-a-espana-2022/stage-10/results/">flat Alicante course</a>
clocking the twelfth fastest time at the opening checkpoint
30 seconds down on stage winner and noted specialist Remco Evenepoel (QuickStep-AlphaVinyl).&nbsp;
But then he went from strength to strength
moving up to sixth at 56 seconds at the second checkpoint and concluding just out of the podium placings for the stage
In the process, <a data-analytics-id="inline-link" href="https://www.cyclingnews.com/riders/carlos-rodriguez-cano/" data-before-rewrite-localise="https://www.cyclingnews.com/riders/carlos-rodriguez-cano/">Rodriguez</a> has clawed back nearly 30 seconds on compatriot Enric Mas (Movistar) and is now trailing Mas
was the top performer in the squad both on the day and remains best-placed Ineos rider overall too
despite being by far the least experienced in Grand Tour racing of all the squad's GC contenders in the Vuelta a Espa&ntilde;a
Rodriguez repeatedly said afterwards he was delighted to finish so close behind riders of the calibre of an Olympic Champion like Primo&#382; Rogli&#269;
who beat him by the comparatively small margin of just over 30 seconds
But he also underlined his main objective remained to stay focussed on enjoying the short-term successes and letting the longer goals take care of themselves
but started the stage pretty conservatively because I didn&rsquo;t want to risk going into the red zone,&rdquo; Rodriguez told reporters at the line shortly after finishing
I&rsquo;ve never done such a good time trial as this
&ldquo;I was very keen to see how I got on in comparison to the rest
but the important thing is to enjoy it as much as I can and to go on doing that.&rdquo;
Sivakov confirmed that the team&rsquo;s strategy for himself and other Ineos riders had been to take the first part of the TT relatively calmly because "we heard a lot of the guys had been overpacing it
&ldquo;We&rsquo;ve worked a lot on my TT position and I think that paid off today as well
but not as much as a lot of the other guys.&rdquo;
saying &ldquo;I don&rsquo;t know what to expect further down the line and we&rsquo;ll see how it goes
Now it&rsquo;s time to recover and take a cold shower because it was very hot out there.&rdquo;&nbsp;
the important thing was that in general he is &ldquo;back in the race and that&rsquo;s great for the confidence." Rodriguez
may have stayed where he was overall on GC on Tuesday
that represents another notable step forward.&nbsp;
Volume 11 - 2024 | <a class="ArticleLayoutHeader__info__doi" href="https://doi.org/10.3389/fmed.2024.1339428">https://doi.org/10.3389/fmed.2024.1339428</a>
This article is part of the Research TopicPrecision Treatments for Patients with Obesity<a class="Link Link--linkType Link--maincolor Link--medium Link--icon Link--chevronRight Link--right" aria-label="View all 6 articles" href="https://www.frontiersin.org/research-topics/52268/precision-treatments-for-patients-with-obesity/magazine" target="_self" data-event="customLink-linkType-a_viewAll6Articles">View all 6 articles</a>
myo-inositol and micronutrients) in pregnant women with obesity on the prevention of GDM
and neurodevelopment compared to usual care
Given the absence of established nutritional guidelines for managing obesity during pregnancy
there is a pressing need to develop and implement new nutritional programs to enhance perinatal outcomes
Neurodevelopmental alterations in children have also been documented as complications of pregnancies with obesity. In a systematic review (36 cohort studies), a higher risk of attention deficit disorder, autism, developmental delay, and/or emotional and behavioral problems was observed in infants born from women with pregestational overweight or obesity (<a href="#B18">18</a>)
studies have failed to demonstrate effectiveness in multiple perinatal outcomes or adiposity later in life
Early nutrition interventions are affordable
and represent a particular chance to prevent obesity and related health problems
The possibility of preventing negative perinatal results and improving fetal growth and nutritional status of this high-risk group
by recommending a healthy dietary pattern and an individualized nutrient supplementation scheme
is an opportunity to decrease the risks of diseases in the future
The present study aims to assess the effect of a multi-component nutrition intervention (intensive nutrition counseling and multiple nutrient supplementation) for women with pregestational obesity during pregnancy
examining its influence on the risk of GDM and other perinatal outcomes
We propose an open-label randomized clinical trial (<a href="#T1">Table 1</a>) (<a href="#B42">42</a>) to evaluate an intensive nutrition therapy and supplementation intervention within the prospective cohort OBESO (by its acronym in Spanish &#x0201C;Origen Bioqu&#x000ED;mico y Epigen&#x000E9;tico del Sobrepeso y la Obesidad&#x0201D;)
This protocol was submitted for evaluation by the Ethics and Research Committees within our institution (Provisional number: 2023&#x02013;1-5) and in the UMIN Clinical Trials Registry (UMIN000052753)
All procedures will be conducted according to the Helsinki Declaration
The OBESO cohort (Instituto Nacional de Perinatolog&#x000ED;a &#x02013;INPer&#x02013;
since 2017) follows women from the first trimester of pregnancy and through the first two years of their infant&#x00027;s life
and its main aim is to study different factors (biochemical
Pregnant women between 11 and 13.6 weeks of gestation are recruited at the Maternal-Fetal Medicine department
Table 1. Description of blinding in the study (<a style="color:grey;" href="#B42">42</a>)
We used Precis-2 in the design, a 10 domain tool to disclose individual explanatory vs. pragmatic components in our trial (<a href="#B43">43</a>). The mean score for this study is 2.7 (<a href="#SM1">Supplementary Table</a>)
all OBESO participants will be invited to participate
Each woman will decide voluntarily whether to participate in the project
without this having any impact on their current care
The signing of the written informed consent will be required
Women will be selected following the inclusion criteria: adult women without previous diseases
pregnancies with only one fetus (no congenital malformations)
and pregestational BMI (pBMI) &#x02265;30 (using pregestational weight -self-reported- and height -measured with a digital stadiometer-)
Women will be excluded if they have pregestational diabetes mellitus
or if take medications influencing the metabolism of the endocrine system (insulin
All women will have an oral glucose tolerance test (OGTT) at the first prenatal care visit
according to Institutional GDM screening procedures
Women with 2 or more altered values or those classified with pregestational diabetes mellitus will be excluded
and considering a superiority trial with a dichotomous outcome (GDM incidence: control group 30% and intervention group 10%)
we will study 136 women in total (68 participants per group)
Considering the current number of patients recruited in the OBESO cohort, the recruitment phase of this study will end in approximately 24 months. The last follow-up is expected 12 months after the last recruitment (<a href="#T2">Table 2</a>)
all participants will be randomized (Simple randomization: with a list of random numbers and files numbered sequentially) to one of two groups (parallel design): Group 1-Nutrition intervention
Group 2-Control group (usual prenatal care)
Allocation will be performed with envelopes (darkened and sealed) which will have the assigned study group
an external researcher will retrieve the appropriate envelope containing the group assignment
Recruitment and randomization will be performed by clinical staff from the OBESO cohort
who will not be involved with the intervention proposed
Group 1 (intervention group): Women in this group will receive medical prenatal care by an assigned attending obstetrician who will follow institutional guidelines and intensive MNT by a clinical nutritionist
Nutrition goals will be to encourage the adoption of a healthy dietary pattern throughout pregnancy and achieve adequate micronutrient intakes
Nutrition intervention will be delivered in the context of intensive counseling
Educational main themes will include &#x0201C;My Healthy Eating Plate&#x0201D; in pregnancy
adapted from the Harvard Healthy Eating Plate (which includes Mexican
smart food choices from each group (high-quality carbohydrates and fats)
the importance of a healthy diet on later health
Breastfeeding education and promotion will be carried out
the dietitian will inquire women about their perception of adherence to dietary recommendations based on a scale of 0%&#x02212;100%
Barriers and motivators to follow dietary recommendations will be discussed and considered for individual dietary strategies
Intensive multiple-nutrient supplementation will be recommended to all women in the intervention group. Daily nutrient doses are presented in <a href="#T3">Table 3</a>
as well as the contribution to daily intake recommendations
This supplementation scheme represents taking 4 capsules daily: 1 multivitamin capsule
Two capsules of vitamin D3 will be taken weekly
with AM and PM divisions) will be given to each woman
Counted pills will be distributed in the containers and will be reviewed in the follow-up visit to evaluate adherence in taking the supplements
Nutrient supplementation scheme for pregnant women with obesity in the intervention group
Calcium supplementation is also recommended for the prevention of preeclampsia in women at high risk of developing this condition or with low calcium intake (<a href="#B28">28</a>)
Women in this study will have a higher risk of preeclampsia
but calcium supplementation will not be routinely recommended for this group
The obstetrician will decide if calcium supplementation is needed and the individualized doses (minimum 1 g/d)
Group 2: control group (usual care): Participants within this group will be provided with identical medical prenatal care as the intervention group
Nutrient supplementation in this group will consist in a multivitamin containing folic acid (400 mcg/d)
and other micronutrients (meeting &#x02264;100% of recommended intake)
In this group omega 3 fatty acids and myo-inositol will not be supplemented
Calcium supplementation (1&#x02013;2 g/d) will be recommended in some women (as in the intervention group)
The attending obstetrician will prescribe this supplementation scheme
The schedule for prenatal care appointments will include monthly visits from the first visit (11&#x02013;13.6 weeks) until the 32nd week of pregnancy
bi-weekly visits from the 33rd to the 36th week
and weekly appointments from the 36th to the 40th week of gestation
intrauterine growth restriction (IUGR) and fetal growth will be evaluated according to maternal fetal medicine ultrasound assessments in each trimester
urine tests and vaginal swabs will be performed in each trimester or at a higher frequency based on clinical necessity
Blood pressure will be measured in the morning in each visit with an ambulatory device (Spacelabs Healthcare
If the obstetrician in charge considers that a patient has a high risk of preeclampsia
If a patient is detected with a high risk of preterm birth
200 mg/d of progesterone will be indicated
The obstetrician will determine the delivery method based on the clinical obstetric background of participants
Table 4. Schedule of enrolment, intervention, and maternal and infant assessment (<a style="color:grey;" href="#B58">58</a>)
For this study, the primary outcome is to compare GDM incidence in both groups. For this, a 75 g 2-h OGTT will be performed at 24&#x02013;28 weeks of gestation. GDM will be stablished if at least one glucose value is altered: fasting &#x02265; 92 mg/dL, 1-h &#x02265; 180 mg/dL and 2-h &#x02265; 153 mg/dL, according to the International Association of Diabetes and Pregnancy Study Groups criteria (<a href="#B59">59</a>)
All women (in both groups) who develop GDM will be referred to the Institutional Diabetes in Pregnancy Program for multidisciplinary care
including endocrinology treatment and intensive MNT
&#x02022; Preterm birth: Live birth before 37 weeks of gestation
The first-trimester ultrasound measurement will be the basis for establishing gestational age
&#x02022; Fetal and neonatal death: The death of a fetus in utero at any stage of pregnancy and the death at birth or within the first 28 days after birth
&#x02022; Mode of delivery: Either vaginal birth or cesarean delivery
Maternal weight retention (kg) will be considered the difference between postpartum and pregestational self-reported weight
It will be measured by ELISA (MBS266722; MyBiosource
Two experienced and trained research nutritionists will perform anthropometric and body composition measurements in the newborn at birth and in the infant at 1 and 6 months
Neurodevelopment assessment will be applied to infants at 1 and 6 months by licensed pediatric psychologists
A birthweight &#x0003C;2500 g and &#x0003E;4000 g will define LBW and macrosomia
Newborns categorized as SGA or LGA will be identified based on a weight below the 10th percentile or above the 90th percentile for their gestational age
nutritional indices will be computed and interpreted: weight/age
The WHO reference growth criteria will be used for term infants
and the Intergrowth reference (birth and postnatal) for preterm infants
Energy intake from all ultra-processed foods consumed will be computed in each trimester as a percentage of the total energy intake
&#x02022; Adherence to the intervention: The number of MNT visits and self-reported perceived adherence to dietary recommendations (0&#x02013;10 scale) will be used to evaluate adherence to MNT
&#x02022; Adherence to supplementation: The percentage of pills taken each month (pills taken vs
total pills recommended &#x000D7;100) will be recorded to evaluate adherence to supplementation
Each woman will receive a 30-day pill container with daily distribution of recommended supplements
The container will be reviewed during each MNT visit
&#x02022; Pharmacological treatment: Any medication (corticosteroids
among others) the women take during pregnancy will be recorded
&#x02022; Physical activity: The International Physical Activity Questionnaire-Short version (<a href="#B73">73</a>) will be applied in the first and the last trimester of gestation
The total metabolic equivalent of task (METs) will be quantified per hour/week
&#x02022; Sleep quality: The Pittsburgh Sleep Quality Index scale (<a href="#B74">74</a>) will be applied during the initial and the final trimester of pregnancy
and women will be classified as having good quality sleep or bad quality sleep
Established procedures of the institutional committees contemplate periodic audits for active research projects
in addition to submitting quarterly reports on the progress and eventualities in the implementation of the protocol
Monthly evaluations of the adverse effects form of each participant will be performed
it will be turned to the research and ethics committee for its evaluation
it will be decided by the aforementioned committees
While there is increasing evidence showing that gestational obesity and metabolic derangements are risk factors for perinatal complications, and that these conditions have long-term implications for mother and infant health, there are still inconsistencies about what prevention and intervention strategies should be implemented at the clinical level (<a href="#B85">85</a>)
There is a lack of standardized and effective interventions to reduce perinatal risk and improve the metabolic health of the next generation
there are no clinical guidelines to manage obesity in pregnancy
and medical nutrition therapy is not integrated into primary prenatal care
our group started an institutional cohort to study early determinants of adiposity
and neurodevelopment by studying pregnant women
The Instituto Nacional de Perinatolog&#x000ED;a in Mexico City is a major governmental tertiary hospital in Mexico that offers clinical care to women without social security in the gynecology
It is also a research (72 researchers) and training hospital (300 students)
The OBESO cohort follows-up women during pregnancy and their infants until 2 years old
and environmental factors are being studied
We have examined 520 women from 2017 to 2023
with different baseline metabolic and clinical risk status
one-third of them subsequently presented excessive gestational weight gain
17% of infants were classified as at risk of overweight
The feasibility of this study is supported by the Instituto Nacional de Perinatolog&#x000ED;a
a National Health Institute focused on addressing complex perinatal health issues on a national scale
The institute conducts diverse research&#x02014;basic
and sociomedical&#x02013;to create care models for pregnant women and their infants
Our institute has an annual attendance of 3,500 births and is the regional reference in perinatal medicine
so it is our role to generate knowledge that will help develop an evidence-based clinical practice guideline to provide optimal prenatal care in this high-risk population
Our results will be the basis for designing and implementing new nutrition programs and policies to improve perinatal outcomes and palliate the adverse metabolic and neurodevelopmental programming associated with obesity in pregnancy
Part of the strengths of this protocol is the experience we have acquired during the last 8 years within the OBESO cohort, in addition to our experience in conducting RCTs with nutrition interventions (<a href="#B98">98</a>&#x02013;<a href="#B100">100</a>)
combined with our available human resources
enables us to enroll women and systematically assess various outcomes throughout pregnancy efficiently
Our infrastructure comprises medical facilities for maternal-fetal medicine
specialized nutrition and metabolic laboratories
Our laboratory participates in an external quality control program
and control samples are sent monthly to evaluate intra-assay variation
Quality control performance is validated each year
We also have a specialized area for maternal nutritional assessment equipped with food replicas for portion estimation
as well as a bioelectrical impedance equipment for pregnancy and postpartum follow-up
we have equipment for anthropometric measurement (infantometer
and an air displacement plethysmography (PEAPOD) in the hospital settings
we have a body composition area equipped with an additional PEAPOD equipment and a separate set of anthropometric tools in the research facility
Research nutritionist in charge of anthropometrical measurements
are experienced and well-trained professionals who collaborate in international studies
Another strength is the independence among researchers
which may reduce bias toward one study group
Pregnant women receiving prenatal care at our hospital are classified as high-risk
where only women without any diagnosed disease will be included
we have been able to recruit women with these characteristics in our cohort
the measurement of adherence to this intervention is complicated and we included subjective and more objective methodologies
People with obesity tend to sub-report dietary intake
The design of this study does not allow to assess the independent effect of each supplemented nutrient on the study outcomes; however
our aim is to evaluate the global effect of multiple strategies associated with different benefits in pregnancies complicated with obesity
Women in the control group who develop GDM will receive multidisciplinary treatment
which possibly will benefit infant outcomes; however we can statistically measure the effect of treatment by including different variables in the multivariate models
We also recognize that implementing the intervention may prove difficult (low pragmatic attitude)
particularly in typical prenatal care settings in regions like Mexico and other low to middle-income countries
test and ensuring the presence of a nutrition expert on-site could be challenging
the nature of usual prenatal care suggests a higher likelihood of desertion
which could impede the completion and efficacy of the intervention
These limitations underscore the need for careful consideration and adaptation of strategies to address resource constraints and participant adherence challenges in future studies
Interventions in early stages have a high potential for preventing different health conditions
where nutrition strategies stand out for being cost-effective
The proposed multi-component nutrition intervention includes many of the nutrition strategies that have been proven effective in some studies
Our institution is the regional reference in perinatal medicine
so it is our role to generate knowledge that will help develop an evidence-based clinical practice guideline to provide optimal prenatal care for these women prone to preventable perinatal complications
Our results will offer a basis for designing and implementing new nutrition programs and policies to improve perinatal outcomes and palliate adverse metabolic and neurodevelopmental programming
This study was submitted for evaluation and reviewed and approved by the Research and Ethics Committees within our institution (Provisional Number: 2023-1-5)
All procedures were conducted according to the Helsinki Declaration
The patients provided their written informed consent to participate in this study
Writing &#x02013; review &#x00026; editing
The author(s) declare financial support was received for the publication of this article from the Instituto Nacional de Perinatolog&#x000ED;a
The supplement that will be used for this study will be a donation from Exeltis Pharma Mexico
Exeltis Pharma Mexico has not participated in the methodological design
and publication this article; and will not be involved in data analysis and future publication of the results
This study will receive primary funding from the Instituto Nacional de Perinatolog&#x000ED;a (&#x00023;INPer: 2023-1-31)
and AR-C are speakers of Nestle Nutrition Institute
The Supplementary Material for this article can be found online at: <a href="https://www.frontiersin.org/articles/10.3389/fmed.2024.1339428/full#supplementary-material">https://www.frontiersin.org/articles/10.3389/fmed.2024.1339428/full#supplementary-material</a>
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Received: 16 November 2023; Accepted: 18 March 2024; Published: 12 April 2024
&#x0002A;Correspondence: Guadalupe Estrada-Gutierrez, <a id="encmail">Z3Blc3RyYWRAZ21haWwuY29t</a>
&#x02020;These authors share first authorship
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The use of carbon-based materials as catalyst supports for Fischer&#x02013;Tropsch synthesis (FTS) is thoroughly reviewed
The main factors to consider when using a carbonaceous catalyst support for FTS are first discussed
the most relevant and recent literature on the topic from the last 2&#x000a0;decades is reviewed
classifying the different examples according to the carbon structure and shape
Some aspects such as the carbon textural properties
carbon support modification (functionalization and doping)
and the catalyst performance for FTS are summarized and discussed
and perspectives of using carbon catalyst supports for FTS are outlined
Hydrocarbons are the most widely used chemicals and fuels and are the main driving force of occidental social well-being
The major part of hydrocarbons on earth are produced from crude oil
which provide approximately 33% of the current world&#x02019;s primary energy requirements
followed by coal (27%) and natural gas (24%)
oil consumption has grown globally by an average of 1.1% (1.1 million barrels per day)
Asia being the region that has shown the highest growth
the global proved oil reserves account only for around 45 years at the current consumption ratio
whereas the estimates of the extent of available reserves of natural gas and coal seem to be around 50 and 132 years
and the implementation of a more stringent environmental legislation on liquid fuels boost the use of alternative and sustainable hydrocarbon sources
but only in the area of research because they have not yet been used at an industrial level
Evolution of the literature reported for different carbon-based supports for FT catalysts in the last 2&#x000a0;decades
The values in parenthesis in the legend indicate the percentage of research papers dedicated to each carbon support
B and D are adapted from (A) Valero&#x02010;Romero
Hierarchical porous carbons by liquid phase impregnation of zeolite templates with lignin solution
Carbon nanotubes and nanofibers in catalysis
Effect of type and localization of nitrogen in graphene nanoflake support on structure and catalytic performance of Co-based Fischer&#x02010;Tropsch catalysts
TEM image C was derived from (Valero&#x02010;Romero et al.
some challenges and future perspectives about the industrial feasibility of carbon-based supported FT catalysts are also considered
particularly those under severe oxidizing conditions
may cause the partial destruction of the pore structure of the carbon material due to their gasification to CO2 (and CO)
Carbon surface oxygen (A) and nitrogen functional groups (B)
The chemical and thermal stability of a particular carbon-based catalyst depends on several aspects
catalyst stability measurements during reduction for each individual carbon-based catalyst should be addressed in order to determine the optimum reduction temperature
carbon materials can be used as support of cobalt catalysts if harsh preparation conditions responsible for the formation of cobalt carbides are avoided
High pore volume and high mean pore size have been reported to be important parameters to control metal particle size and dispersion on carbon materials for the FTS process (<a href="#B5">Ahn et al., 2016</a>)
A carbon support with a well-developed mesoporous and macroporous structure would have excellent advantages in FT reaction
because larger pores benefit the diffusion of the reactants and hydrocarbon products to and from the catalytic active reaction sites
enhancing the production for longer hydrocarbon chains
The earlier studies on carbon-supported catalysts for the FTS process focused on the use of AC, black carbon, and glassy carbon as supports. These works were dedicated to study how to achieve small metal particles, and hence a high metal dispersion, and to study the metal-support interactions (<a href="#B137">Xiong et al., 2015</a>)
ACs have been mostly studied as model catalyst supports for the FTS reaction
with the purpose of analyzing the effect of the carbon nature and porous texture as compared with other supports and with the aim of analyzing the effect of metal promoters on the FTS catalyst performance
Textural parameter range values and metal content range for Fe- and Co-supported carbon catalysts used in FTS
Summary of FTS performance of cobalt and iron catalysts supported on AC
who also compared the preparation of iron catalysts on ACs and different inorganic supports
the former presented a higher selectivity to C5&#x0002b; hydrocarbons and a lower selectivity to methane
The most commonly used promoters for Fe/AC catalysts are K, Mn, and Mo. On the other hand, K, Zr, Ce, Cr, Na, and Mn have been studied as catalyst promoters for Co/AC catalysts. <a href="#F4">Figure 4</a> represents the increase in the CO conversion and selectivity to the main reaction products values for some Co- and Fe-supported catalyst on AC in comparison with those for the unpromoted counterpart
0.5 m3&#x000a0;kg&#x02212;1&#x000a0;h&#x02212;1; Cr
3 m3&#x000a0;kg&#x02212;1&#x000a0;h&#x02212;1; Mn&#x0002b;K
3,000&#x000a0;h&#x02212;1; and Mo&#x0002b;Cu&#x0002b;K
3 m3&#x000a0;kg&#x02212;1&#x000a0;h&#x02212;1
These differences in CO conversion were attributed to the magnetite particle size formed in each catalyst
The authors claimed that the alkalinization of the AC
increased the number of oxygen-containing groups on the AC surface
giving rise to the formation of more nucleation centers for Fe3&#x0002b; ions and consequently
smaller magnetite particles were formed when K was firstly loaded on the AC
the selectivity to main reaction products were also affected by the promoters
being observed an increase of a 46% in the C2-C4 selectivity and a decrease of a 44% in the C5&#x0002b; selectivity
with respect to those of the unpromoted catalyst
the O/P ratio outstandingly increased from 0.65 for the unpromoted catalyst to 4.88 for the promoted one
The promotion effect of Mn was associated to the synergistic effect of MnO and H&#x000e4;gg carbides in enhancing CO adsorption and dissociation and K helped to form iron carbides on the AC surface
K promotion of Fe-based catalysts resulted in the increase of the CO conversion
when it was loaded in certain controlled amounts
and an enhancement of the activity for WGS
the olefin/paraffin ratio and the C5&#x0002b; selectivity values were increased
Mn and K promotion enhanced the CO conversion value and gave rise to a higher C2-C4 olefin production
the addition of Mo as a promoter has been shown to lower the initial activity but also to enhance the catalyst stability
<a href="#B76">Ma et al. (2004)</a> studied the effect of Zr, K, and Ce as promoters for Co/AC catalysts. K acted as a strong poison for the catalyst, decreasing syngas conversion and methane selectivity, as compared to the unpromoted catalyst (<a href="#F4">Figure 4</a>)
which was attributed to the possible coverage of cobalt active sites by K
both Zr and Ce had a positive impact in the catalytic activity
Zr promoted CO conversion without largely modifying the hydrocarbon selectivity values and the activity for WGS
Ce enhanced both syngas conversion and activity for WGS and increased the methane and C2-C4 selectivity values
The positive effects of Zr and Ce as promoters were attributed to the improvements found in cobalt dispersion and to the enhanced interaction between cobalt and the oxygen surface groups resulting from the addition of Zr and Ce to the AC
the O/P ratio was lower after Cr promotion
The authors attributed these catalytic features to the higher H2-rich surface environment caused by Cr promotion in the catalyst
which facilitated the &#x003b1;-hydrogen addition step and suppressed the &#x003b2;-hydride elimination and CO insertion steps
the O/P ratio experienced a noticeable increase
from 0.65 for the catalyst promoted with Mn to 1.54
when using together Na and Mn as promoters
Another feature observed in this work was the capacity of Na to enhance the WGS reaction activity in cobalt catalysts
<a href="#B61">Knox et al. (1986)</a> were pioneers in reporting the preparation of OMCs by the hard-template method. Among the reported OMC, CMK-3, a hexagonally structured OMC, is the most commonly used OMC support for FTS catalysts. This material was first synthetized by <a href="#B53">Jun et al. (2000)</a>
using SBA-15 as the hard template and sucrose and H2SO4 in water solution as the carbon source
An outstanding O/P ratio value of 10 was attributed to the efficient promotion of the catalyst with S
Metal particle size is a highly important Fischer&#x02013;Tropsch catalyst feature
different catalyst synthesis strategies have been proposed to control the size of the active phase on OMC supports
More recently, <a href="#B144">Yang et al. (2014)</a> carried out a study to control the cobalt particle size of FTS catalysts using an N-doped OMC as catalyst support
Nitrogen incorporation was carried out by a postsynthetic route using cyanamide
The metal loading was carried out by IWI using cobalt nitrate in acetone solution
The authors found that the higher the N content in the support
This fact was associated to the capacity of N of improving dispersion of cobalt metal species and forming more uniform particles
The TOF values and the catalytic activity increased with increasing the cobalt particle size up to a 10&#x000a0;nm
but a decrease in the catalytic activity was observed
The O/P ratio showed an outstanding value of 10 in both promoted catalysts studied
Given that CNTs and CNFs are relatively inert materials
it is necessary to modify their nature by introducing surface functional groups in order to attain high stabilization and dispersion of the metal particles on their surface
these materials have been considered as model supports in the FTS reaction process
the effect of CNT and CNF functionalization
and the incorporation of metal promoters on the catalysts structure and FTS performance have been investigated
It appeared that sonication in a short time (10&#x000a0;s) resulted in Co/FCNTs-10 catalyst with a remarkably narrow cobalt particle size distribution
FIGURE 5. Amount of oxygen measured by XPS and increase of BET surface area, CO conversion, C5&#x0002b; yield, and Co particle growth during FTS for Co/CNT catalysts when CNTs were oxidized with HNO3 for 1, 3, 9, and 15&#x000a0;h with respect to the catalyst supported on pristine CNTs. Data were adapted from ref. (<a href="#B23">Chernyak et al., 2016</a>)
The different catalytic performance was ascribed to the low crystalline metallic Co content on oxidized CNTs than on pristine CNTs
They claimed that it was possible to partially remove the oxygen-containing functional groups from the surface of CNTs by controlling the thermal treatment temperature
while keeping the integrity of inner CNT walls and thus controlling the preferential encapsulation of cobalt clusters (80% for Co/CNTs-650) with optimal size (5&#x02013;10&#x000a0;nm) inside the CNTs
Fe supported on N-doped CNTs presents the highest metal-time yield (MTY) operating at HT-FTS conditions
FT performance of unpromoted Co and Fe catalysts supported on CNTs and CNFs after different catalyst preparation methods
The comparison of Co/CNT prepared by IWI (Co/CNT-IM) and the HDP method (Co/CNT-DP), using urea as the precipitation agent, showed that the catalysts prepared by IWI were 2.6 times more active, which was attributed to lower cobalt particle size and improved metal dispersion on the latter case (entries 3 and 4, <a href="#T3">Table 3</a>) (<a href="#B138">Xiong et al., 2011</a>)
The modification of the Co and Fe/CNT FTS catalysts by thermal treatments was also investigated. <a href="#B21">Chernyak et al. (2020)</a> studied the effect of sintering temperature (800&#x02013;1,200&#x000b0;C) on the structure and FTS catalytic performance of Co and Fe CNT-supported catalyst prepared by IWI via the spark plasma sintering approach (Co800 and Fe800, entries 9 and 17, <a href="#T3">Table 3</a>)
The sintered catalysts presented higher activity and selectivity to C5&#x0002b; liquid hydrocarbons during FTS
as compared to those nonthermally treated catalysts and without the application of a prereduction step
The main reason was the presence of carbon-encapsulated metallic nanoparticles embedded in the CNT framework
In the case of the sintered Fe/CNT catalyst
the close contact between the metallic site and the carbon material after the sintering approach facilitated the formation of the active iron carbide phase
It should be also highlighted the calculated TOF values for Co800 (0.10 s&#x02212;1) and for Fe800 (&#x0223c;1.0 s&#x02212;1)
which were remarkably high as compared to other unpromoted FTS catalysts
CNT pore confinement of the FT active phase and the effect of the support pore size have also shown to influence the activity and selectivity of the catalysts for FTS
the pore size of the CNTs can be associated to both the inner diameter of the tube or to aggregated pores caused by CNT interaction
The effects of pore diameters of Fe catalysts supported on CNT on the FTS reaction rates and product selectivity were also studied. <a href="#B2">Abbaslou et al. (2010)</a> showed that both the selectivity to C5&#x0002b; hydrocarbons and the CO conversion were improved for Fe/CNT catalysts with the narrower pore structure
Deposition of iron inside the nanotubes (&#x0223c;80% according to the TEM images) with narrower pore structure resulted in smaller metal particle size (12&#x000a0;nm compared to 17&#x000a0;nm of Fe/wp-CNT catalyst with wider pore structure) and better metal dispersion
These features conferred the catalyst a better extent of reduction and an improved catalytic performance
FIGURE 6. TEM images of the fresh confined and nonconfined Fe catalysts: (A) Fe/CNT-out, (B) Fe/CNT-in. Reprinted from <a href="#B43">Gu et al., 2019</a>
Synergy of nanoconfinement and promotion in the design of efficient supported iron catalysts for direct olefin synthesis from syngas
This behavior was attributed to the modified redox properties of the confined iron catalysts and to the trapping effect of the reaction intermediates inside the CNTs
which was suggested to increase their contact time with iron catalysts
favoring the growth of longer chain hydrocarbons
FTS activity of Fe-in-CNT (filled symbols) and Fe-out-CNT (open symbols) at 270&#x000b0;C as a function of pressure
Square symbols represent CO conversion and circles the space-time yield of C5&#x0002b; hydrocarbons
Effect of confinement in carbon nanotubes on the activity of Fischer-Tropsch iron catalyst
The influence of cobalt particle size on (A) FT synthesis activity normalized to cobalt loading (220&#x000b0;C
1&#x000a0;bar) and (B) the C5&#x0002b; selectivity measured at 35&#x000a0;bar
data markers in black at 210&#x000b0;C and in gray at 250&#x000b0;C
Figure reprinted with permission from (Bezemer
Cobalt Particle Size Effects in the Fischer&#x02010;Tropsch Reaction Studied with Carbon Nanofiber Supported Catalysts
exhibited the highest selectivity toward C10-C20 (60%) and TOF for CO conversion at 260&#x000b0;C
a significant selectivity to C5&#x0002b; hydrocarbon and lower selectivity to CH4 were obtained for the bimetallic catalyst
The authors attributed this behavior to the role of iron enhancing the distribution of cobalt species over the carbon support
have recently proposed a promising and novel Co/Mn bimetallic center supported on N-doped CNTs as an efficient FTS catalytic system for the production of long-chain hydrocarbons
It was found a remarkable selectivity to C2-C4 olefins (50.3%) and higher CO conversion than FeMnK/CNT catalyst prepared by the coimpregnation method using CNTs as support
This was associated to the small-sized and narrow nanoparticle distribution
Combined promotion of Fe/CNF catalysts with 0.1&#x000a0;wt% Na and 0.2&#x000a0;wt% S was shown to improve the selectivity to light olefins at low conversions operating at HT-FTS conditions (<a href="#F9">Figure 9</a> and entry 15, <a href="#SM1">Supplementary Table S5</a>) (<a href="#B134">Xie et al., 2016</a>)
The comparison with the unpromoted Fe/CNF revealed a notable enhanced iron carburization and higher initial catalytic activities over the promoted iron catalysts with Na and S
More recently, professor Khodakov and collaborators (<a href="#B44">Gu et al., 2018</a>; <a href="#B43">Gu et al., 2019</a>) found extremely strong promotion effect of Bi and Pb on the catalytic performance of Fe/CNT catalysts. Compared to the unpromoted catalysts, a significant increase in FT reaction rate and a higher selectivity to the C2-C4 olefins (55&#x02013;60%) at 10&#x000a0;bar were obtained (<a href="#F9">Figure 9</a> and entries 16 and 17, <a href="#SM1">Supplementary Table S5</a>)
The promoting effects of Bi and Pb on iron catalysts have been reinforced by their preferential localization at the surface of iron carbide nanoparticles leading to the formation of core-shell structures
the presence of Bi enhanced the catalyst reducibility and facilitated carburization of iron nanoparticles
the FeTY was 82 &#x000d7; 10&#x02013;5 molCO gFe&#x02212;1 s&#x02212;1 for the FePb/CNT-in catalyst at 350&#x000b0;C
and SV of 17 m3&#x000a0;kg&#x02212;1&#x000a0;h&#x02212;1
which is one of the best results for unpromoted and promoted iron-based FTS catalysts available so far in the literature
To sum up, from <a href="#F8">Figure 8</a>
it can be concluded that promotion with MnO to Co/CNTs catalysts produced a very significant increase of CoTY with respect to the unpromoted catalyst
whereas promotion of Bi and Pb enhanced considerably the FeTY in Fe/CNT catalysts
it should be remarked that promotion with K&#x0002b;Cu and Na enhanced selectively C5&#x0002b; formation over Fe/CNT catalytic systems with respect to the unpromoted catalysts compared under very similar FeTY values
and promoters on the FTS performance of Fe- and Co-supported CSs have been investigated
In the case that hollow carbon spheres (HCSs) were used as supports
the effect of catalyst confinement was studied
CSs prepared by the CVD process are characterized for exhibiting a high carbon purity and an inert surface chemistry
In order to achieve a high metal dispersion when using these carbon materials as catalyst supports
CSs have to be functionalized with different oxygen and/or nitrogen surface groups
CSs obtained by the HTC approach usually do not require functionalization due to their hydrophilic shell with abundant oxygen functional groups
The remarkable catalytic activity and stability was associated to the favorable formation of iron carbides during H2 activation
which were embedded into the carbonaceous matrix
Functionalization using nitric acid or KMnO4 showed comparable catalytic activity and C5&#x0002b; hydrocarbon selectivity
More recently, <a href="#B62">Kuang et al. (2019)</a> prepared Co/CS catalysts by thermal decomposition (TD)
The preparation of the CS support was carried out by the hydrothermal approach using an aqueous glucose solution followed by carbonization at 800&#x000b0;C in N2
The catalyst prepared by the TD method (CoO/C-TD) presented the highest metal dispersion and
remarkably higher CO conversion (21%) and selectivity to C5&#x0002b; hydrocarbons (81.9%) during LT-FTS
<a href="#B31">Dlamini et al. (2015)</a> prepared a series of Fe-Co bimetallic-supported CS catalysts and investigated their use in the FTS reaction. The addition of small amounts of Fe to Co-based catalyst resulted in an enhancement of the CO conversion, being its maximum for the catalyst containing 0.5&#x000a0;wt% Fe and 9.5&#x000a0;wt% Co (entry 17, <a href="#SM1">Supplementary Table S6</a>)
Fe/Co alloy formation was detected upon reduction above 450&#x000b0;C
but its relative amount was not correlated with higher C5&#x0002b; selectivity
The bimetallic catalysts with iron content higher than 2&#x000a0;wt% showed the highest C5&#x0002b; selectivity (87%) at a CO conversion of 21%
<a href="#B151">Zhang et al. (2015)</a> carried out a deep study on the effect of different promoters (Na
and Zn) over Fe-supported CSs prepared through one pot solvothermal method and their use in the FTS process
and Zn promotion resulted in an enhancement of the CO conversion values as compared to that of the unpromoted catalyst
Mn promotion resulted in the decrease of the CO conversion
The FTS results revealed that Na was the one enhancing the catalytic performance to the most
Na promotion strongly decreased the methane generation
producing more C5&#x0002b; hydrocarbons and enhancing the O/P ratio
In this line, K- and Mn-promoted Fe-supported spherical mesoporous carbons (Fe/SMCs) were reported by <a href="#B13">Chen et al. (2018)</a>
These authors prepared spherical mesoporous carbons by a SiO2 template assisted sol&#x02013;gel procedure in water-in-oil emulsions
using resorcinol and formaldehyde as carbon sources
High iron loadings were achieved (30&#x02013;50&#x000a0;wt%)
and the BET surface area was very high (397&#x000a0;m2/g for an iron loading of 40&#x000a0;wt%)
2.5&#x000a0;wt% K promotion decreased the FeTY and TOF values
whereas the presence of 5&#x000a0;wt% of Mn enhanced them
CO2 generation was diminished by the presence of Mn but enhanced by K
The presence of the metal promoters increased the selectivity to C5&#x0002b; hydrocarbons following the order: Na &#x0003e; K &#x0003e; Li
A further study on the effect of Na content revealed that the CO conversion value was maximum for a Na load of 1&#x000a0;wt%
whereas the highest selectivity to C5&#x0002b; hydrocarbons was achieved for the catalyst with 2&#x000a0;wt% of Na
alkali metals result in the enhancement of the CO conversion
and the C5&#x0002b; selectivity values when they are used as promoters in Fe/CS catalysts
K promotion resulted in the decrease of the catalytic activity
Mn has been shown as a useful promoter for olefin generation purposes in Fe-supported CS catalysts
CNTs as support for FT catalysts have the advantage of allocating the catalytic active phase either inside or outside the nanotube. This phenomenology was also studied with HCSs. HCSs used as supports for FTS catalysts were prepared by coating a carbon precursor onto either SiO2 (<a href="#B94">Phaahlamohlaka et al., 2017</a>; <a href="#B113">Teng et al., 2018</a>) or polystyrene (<a href="#B93">Phaahlamohlaka et al., 2020</a>) spheres as hard and soft templates
followed by a pyrolysis stage and removal of the template
The SiO2 template spheres were removed by NaOH or HF treatments
whereas polystyrene was easily removed by heat treatment under an inert environment
The authors attributed these differences to the confinement effect of the Co and Ru nanoparticles inside the hollow carbon structure
which gave rise to a hydrogen richer environment
In other work, <a href="#B113">Teng et al. (2018)</a> reported a highly efficient Fe-contained hollow CS catalyst with highly dispersed Fe2C sites embedded within the carbon matrix and successfully tested it in the HT-FTS reaction
SiO2 spheres were used as hard templates with different diameter sizes (150 and 260&#x000a0;nm) and resorcinol and formaldehyde as carbon sources
Iron loading was carried out prior to the pyrolysis of the polymer at different temperatures (500
Lower carbon thickness and higher iron particle size was evidenced from TEM when increasing the pyrolysis temperature
It was found that the catalyst calcinated at 600&#x000b0;C exhibited the highest selectivity to lower olefins (30.1% in a CO2-free basis) and the highest O/P ratio (4.8)
they found a higher methane formation and lower O/P ratio when using the larger template
which was also associated to the H2 enrichment effect taking place inside the hollow structure of the catalyst
being it higher when increasing the cavity size of the CS catalyst
To the best of our knowledge, there is only one work of Co-loaded powdered oxidized diamond catalyst tested in the FTS reaction (<a href="#B48">Honsho et al., 2012</a>)
The authors used a commercial powdered diamond having a surface area of 24&#x000a0;m2/g
which was oxidized in air prior to cobalt deposition by IWI
The catalysts showed a high CO conversion of 44.5% and selectivity to C5&#x0002b; hydrocarbons of 62.7%
This CO conversion was significantly higher than those obtained for Co-loaded on SiO2 (38.4%)
and powdered oxidized graphite catalysts (2.8%) with higher surface areas
The weaker interaction between the O-DIA surface and cobalt oxide contributed to the better FTS results
Regarding the use of graphene as supports for FTS catalysts, <a href="#B84">Moussa et al. (2014)</a> investigated the chemical reduction of graphene oxide in water in the presence of nitrates of iron and potassium under microwave irradiation resulting in Fe15K5-G catalyst (15&#x000a0;wt% of Fe and 5&#x000a0;wt% of K)
It should be highlighted that graphene oxide does not require a prefunctionalization of the support due to the presence of epoxy groups on the surface
which act as anchoring sites for the metal catalysts
The FTS catalyst was tested under HT-FTS and compared with K-promoted Fe/CNT catalyst
It was observed that the graphene oxide-supported catalyst exhibited an excellent stability
and selectivity to C8&#x0002b; hydrocarbons (86.7%)
The authors attributed the good FTS performance of the Fe15K5-G catalyst to the presence or defects within the graphene lattice
which acted as favorable nucleation sites to anchor the metal nanoparticles
<a href="#B58">Karimi et al. (2015a)</a> and <a href="#B59">Karimi et al. (2015b)</a> performed a comparative study of 15Co/graphene (602&#x000a0;m2/g) and 15Co/CNT (372&#x000a0;m2/g) catalysts for the FTS reaction
The FTS rate and CO conversion percentage obtained by 15Co/graphene were significantly larger than that obtained using 15Co/CNT catalyst
The selectivity to C5&#x0002b; hydrocarbons was also higher for 15Co/graphene (87.1%) than for 15Co/CNTs (83.9%) at isoconversion conditions (around 60% of CO conversion)
the CO conversion dropped only by 22% over 15Co/graphene after 480&#x000a0;h
whereas it dropped by 34% for the 15Co/CNT catalyst
which was caused in both cases by cobalt sintering
Co-supported graphene outperformed to Co-supported CNTs catalyst under the preparation and reaction conditions used
In this line, <a href="#B45">Hajjar et al. (2017)</a> compared the FTS performance of cobalt catalysts supported on graphene oxide and nanoporous graphene with BET surface areas of 290 and 700&#x000a0;m2/g
The nanoporous graphene material was first oxidized in a mixture of sulfuric and nitric acids
graphene oxide did not require functionalization
The resulting catalysts (15Co/GO and 15Co/NPG) were evaluated in the FTS reaction
The carbon nanostructured graphene-based catalysts exhibited higher CO conversion of around 65% and lower deactivation rate compared to 15Co/GO
the selectivity to C5&#x0002b; hydrocarbon was also significantly higher when using Co/NPG (87.4%)
which was evident from the higher surface area and pore volume
greatly higher TOF and selectivity to short-chain hydrocarbons (C2-C4) were obtained for Co/N-GNFox
whereas higher CO conversion and CH4 selectivity was obtained for Co/GNFox
The presence of smaller cobalt oxide crystallites found in Co/N-GNFox and the higher resistance to particle sintering during catalyst activation could explain these results
their C5&#x0002b; selectivity values were quite low (20&#x02013;43%) due to the presence of very narrow pores on these samples (less than 1&#x000a0;nm)
which hindered CO diffusion and increased H2 intrapore concentration
On the other hand, a high surface area graphite material (399&#x000a0;m2/g) has been used as support of cesium-promoted Ru catalysts and tested for FT reaction (entries 8 and 9, <a href="#SM1">Supplementary Table S7</a>). In this work, <a href="#B35">Eslava et al. (2018)</a> claimed that the presence of Cs2O in the catalysts prepared with CSNO3 as promoter precursor was responsible of a high selectivity to CO2 during reaction
the metal loading and catalyst preparation procedure also influenced the textural characteristics and surface chemistry of the resultant catalysts
blocking part of support porosity and creating specific oxygen surface groups
To compare the effect of carbon support structure of Co- and Fe-based catalysts on their activity for the FTS reaction, the weight specific activity (cobalt- and iron-time yield, CoTY and FeTY, respectively) and surface-specific activity (turnover frequency, TOF) were plotted for each type of carbon-based supported catalyst under similar reaction condition range, and the results are shown in <a href="#F11">Figure 11</a> and <a href="#SM1">Supplementary Figure S1</a>
and stable FT catalysts than that of iron dispersion
This behavior was attributed to the closer contact of the promoters with Fe inside the tubes due to the nanoconfinement effect
The use of carbon-based supports derived from lignocellulosic biomass in FTS has been less studied
the presence of inorganic species in biomass-derived carbon supports might play an important role in enhancing the activity in FTS
Such studies would help to identify suitable biomass sources and natural and cheap promoters from the extensive and heterogeneous diversity of the biomass materials
In the light of all the aforementioned results
one can conclude that carbon materials exhibit a huge potential not only in terms of reducing metal-support interactions and providing a high metal dispersion and FTS catalyst activity
but also for the enhancement of the heat and mass transfer inside the reactor
allowing for a better reactor temperature control and a higher catalytic performance
Fischer&#x02013;Tropsch synthesis (FTS) is an important industrial process in the transformation of nonpetroleum carbon resources
and lignocellulosic biomass into clean hydrocarbon fuels and valuable chemicals
The FTS catalysts are required to be preferably supported
and carbon-based materials have been recognized as an interesting alternative to conventional metal oxides
we have described the use of different carbon-based materials as supports for Co
and in a lesser extent Ru-based FT catalysts (promoted and unpromoted) over the past 2&#x000a0;decades
carbon nanotubes and nanofibers (CNTs and CNFs)
Some general conclusions can be drawn from these studies: (1) the carbon surface modification (functionalization and doping) with oxygen and nitrogen functional groups
especially in the case of carbon supports prepared at high carbonization temperature
is crucial to produce catalysts with a high dispersion
and enhanced selectivity; (2) the extent of reduction of FT metal-carbon catalysts is generally high due to the low metal-support interactions; (3) the proximity between carbon and supported iron can facilitate the formation of the active iron carbides
thus leading to a higher concentration of active sites on the catalyst surface; (4) the morphology and structure of the carbon are crucial aspects to modify the metal-support interactions
metal catalyst confinement inside the pores of CNTs has shown an outstanding behavior as compared to those of catalytic systems presenting metal nanoparticles supported on the outer CNT surface; (5) larger pores in the support
resulted in larger metal phase crystallites formed inside and
higher metal reducibility and lower metal dispersion
the hydrocarbon diffusion and the formation of long-chain hydrocarbons; (6) an optimum metal promoter loading and a close proximity between the promoter and the FT metal catalyst seem to be essential factors to increase the FT catalyst reducibility and
to improve the FTS activity and selectivity; (7) it has been demonstrated that the carbon support improves the catalyst heat-transfer properties during the highly exothermic FTS reaction and
there are also some challenges to be addressed and future perspectives regarding the use of carbon-based materials as FTS catalyst supports from an industrial-scale point of view
One of these issues is the low density and
the insufficient mechanical strength of carbon-based materials
Most of FT reactors used in industry are fixed-bed reactors and slurry reactors
the catalyst requires to have an appropriate size and shape and therefore they need to be pelletized in order to facilitate intraparticle mass transfer and avoid high-pressure drops
problems derived from the catalyst abrasion and product-catalyst separation are remarkable
Carbon-supported catalysts have been less evaluated on a slurry reactor
One important disadvantage is related to the high costs of the nanostructured carbon materials as compared to conventional oxide supports
Although the industrial production of CNTs
the production of metal-doped carbons is currently not available on a large industrial scale
petroleum-derived carbon sources are used for the preparation of the carbon-based materials
the use of biomassic sources has been explored as raw material
most of the catalysts studied have been prepared using commercially available AC supports
Much research is still necessary in this direction
besides being used for the production of liquid fuels via gasification and further conversion of the produced syngas
could be used for the production of the FT catalyst supports
resulting in both a positive environmental and an economic impact
it would be possible to minimize greenhouse gas emissions and to achieve a significant reduction of fossil fuel dependency
the simulation of syngas from the gasification of biomass as feedstock to the FTS reactor operating at both low- and high-temperature (LT-FTS and LT-FTS) processes
process intensification and catalyst engineering are both crucial steps necessary to be investigated and optimized for the successful implementation of the biomass-to-liquid technology and the use of carbon-based catalyst supports for FTS at large scale
JR-M and TC conceived and designed the structure of the review
and JP contributed with the literature analysis
All authors contributed to the manuscript revision and approved the submitted version
The authors acknowledge the Spanish Ministry of Science
and Universities (MICIU) and FEDER (Project RTI2018-097555-B-I00) and Junta de Andaluc&#x000ed;a (Project UMA18-FEDERJA-110)
MJVR acknowledges MICIU for her Juan de la Cierva-Incorporaci&#x000f3;n postdoctoral fellowship (IJC2019-041222-I)
and MARC thanks MICIU for his FPU predoctoral fellowship (FPU18/02796)
The Supplementary Material for this article can be found online at: <a href="https://www.frontiersin.org/articles/10.3389/fmats.2020.617432/full#supplementary-material">https://www.frontiersin.org/articles/10.3389/fmats.2020.617432/full&#x00023;supplementary-material</a>
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Rodr&#x000ed;guez-Mirasol J and Cordero T (2021) Carbon-Based Materials as Catalyst Supports for Fischer&#x02013;Tropsch Synthesis: A Review
Received: 14 October 2020; Accepted: 30 November 2020;Published: 04 February 2021
Copyright &#x000a9; 2021 Valero-Romero, Rodr&#x000ed;guez-Cano, Palomo, Rodr&#x000ed;guez-Mirasol and Cordero. This is an open-access article distributed under the terms of the <a rel="license" href="http://creativecommons.org/licenses/by/4.0/" target="_blank">Creative Commons Attribution License (CC BY).</a> The use
&#x0002a;Correspondence: Mar&#x000ed;a Jos&#x000e9; Valero-Romero, <a id="encmail">bWp2YWxlcm9AdW1hLmVz</a>; Jos&#x000e9; Rodr&#x000ed;guez-Mirasol, <a id="encmail">bWlyYXNvbEB1bWEuZXM=</a>
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who is a former professional golfer for the Ladies Professional Golf Association and a San Antonio native
began her tenure as the men’s head coach in April 2020
“Getting to come home and…start a program from the very beginning is something that was definitely appealing,” Cano said about her decision to take the job
“It’s just an exciting opportunity to give back to San Antonio.”
Cano explained the difficulties of being a head coach early on because of the pandemic
“Going into the position…you’re already knowing that there’s going to a lot more unknowns,” she said
“We just had to be resilient and patient…and know that things we’re going to change sometimes for the better…sometimes for the worse.” 
From winning the San Antonio Women’s Amateur Championship
Big XII Championship at Oklahoma State University
and the Texas Women’s Open on the LPGA tour
Cano believes the experience she gained from playing golf all her life helped her transition to coaching
“It’s something I really enjoy doing,” she said
“I feel like I had a lot of experience that I wanted to share with student-athletes.”
A strong culture needs to be learned from the beginning
“I want players that are going to come in and create a competitive…team-oriented culture,” she said
hardworking and coachable…those are the type of players we want on the team.” 
Cano has seen that establishment and recognition have interested more players to play golf for A&amp;M-San Antonio
“We’re getting 50 to 100 kids every year trying to join the team,” she said
being a smaller team…you’re turning away 95% of the students (that) inquire about being on the team.”
A&amp;M-San Antonio received $10 million from the Bexar County Commissioners Court to expand athletics facilities
Cano said she sees how important funding will be for the university and for the Southside community
“To be able to receive that tells us that the city’s committed to seeing us grow and be successful,” she said
“Whenever the leadership is on your side…it shows that the future success of athletics is here
“That’s the first step to where we’re going to be in the near future…being a nationally ranked program in different sports.” 
Finishing in the top five and top 10 in the National Association of Intercollegiate Athletics tournaments
the Jags have made leaps and bounds with players such as junior Jordan Hardin and freshman Jacob Pena cracking top 25 finishes individually
Cano wants people to know that her players have taken care of business both on and off the course
“Our academic is solid with a 3.4 GPA,” she said
“We’re not just here to play sports…we’re here to build futures for the student athletes.”
A&amp;M-San Antonio Men’s golf team is preparing to compete in the Red River Athletic Conference Championship April 17-19 in Victoria
For more information about the men’s golf team, visit their social media account on Instagram, @<a href="https://www.instagram.com/tamusamensgolf/">tamusamensgolf</a>. Team coverage can be found at @<a href="https://www.instagram.com/tamusasports/">tamusasports</a> on all other social media platforms.
First of all, nobody likes a cheater.  Sports, however, have proven to be the land of second, third, and fourth chances. The <a href="https://empirewritesback.com/new-york-mets/">New York Mets</a> have acquired just this type of guy
Cano was on top of the world playing and winning in New York
A lot has happened since he was hoisting the World Series trophy alongside <a href="https://www.baseball-reference.com/players/j/jeterde01.shtml?utm_campaign=Linker&amp;utm_source=direct&amp;utm_medium=linker-" target="_blank" rel="nofollow noopener">Derek Jeter</a> and <a href="https://www.baseball-reference.com/players/r/rodrial01.shtml?utm_campaign=Linker&amp;utm_source=direct&amp;utm_medium=linker-" target="_blank" rel="nofollow noopener">Alex Rodriguez</a>
 Cano signed a massive ten-year deal with the Seattle Mariners worth $240 million; his agent at the time was Van Wagenen
The team failed to make the playoffs during his time there
Cano’s final season with Seattle ended even earlier when he was banned 80 games for testing positive for the diuretic Furosemide
he can be a learning lesson to some of the young players on the Mets roster
Alonso has been a highly touted prospect for the team and it is not by accident that his locker is next to the oldest guy on the team.  Outfielder <a href="https://www.baseball-reference.com/players/c/confomi01.shtml?utm_campaign=Linker&amp;utm_source=direct&amp;utm_medium=linker-" target="_blank" rel="nofollow noopener">Michael Conforto</a> spoke about the team signing Cano
It’s great to see the Mets embrace Cano as he also embraces them.  During a news conference, he admitted that he wants to go out and act like he is “<a href="http://www.espn.com/mlb/story/_/id/26018560/robinson-cano-says-feels-25-not-36-reports-mets">competing for a job</a>“
It should please Mets’ executives to see Cano come in and not expect anything to be handed to him.  The Mets had <a href="https://www.baseball-reference.com/players/m/mcneije01.shtml?utm_campaign=Linker&amp;utm_source=direct&amp;utm_medium=linker-" target="_blank" rel="nofollow noopener">Jeff McNeil</a> play second base last season and while he had some great offensive production
he is likely to be used as a utility player
Speaking about what Cano brings to the team, manager <a href="https://www.baseball-reference.com/players/c/callami01.shtml?utm_campaign=Linker&amp;utm_source=direct&amp;utm_medium=linker-" target="_blank" rel="nofollow noopener">Mickey Callaway</a> glowed about his ability to hit against the shift <a href="https://nypost.com/2019/02/24/pete-alonso-robinson-cano-provide-glimpse-of-what-could-be/">saying</a>
The Mets have struggled with situational hitting for years so to hear that is a sigh of relief for fans
 Having a guy in the middle of the lineup who can get the hit and keep the line moving is exactly what the Mets have been lacking
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A lot has happened since he was hoisting the World Series trophy alongside <a href=\"https://www.baseball-reference.com/players/j/jeterde01.shtml?utm_campaign=Linker&amp;utm_source=direct&amp;utm_medium=linker-\" target=\"_blank\" rel=\"nofollow noopener\">Derek Jeter</a> and <a href=\"https://www.baseball-reference.com/players/r/rodrial01.shtml?utm_campaign=Linker&amp;utm_source=direct&amp;utm_medium=linker-\" target=\"_blank\" rel=\"nofollow noopener\">Alex Rodriguez</a>
Alonso has been a highly touted prospect for the team and it is not by accident that his locker is next to the oldest guy on the team.  Outfielder <a href=\"https://www.baseball-reference.com/players/c/confomi01.shtml?utm_campaign=Linker&amp;utm_source=direct&amp;utm_medium=linker-\" target=\"_blank\" rel=\"nofollow noopener\">Michael Conforto</a> spoke about the team signing Cano
It’s great to see the Mets embrace Cano as he also embraces them.  During a news conference, he admitted that he wants to go out and act like he is “<a href=\"http://www.espn.com/mlb/story/_/id/26018560/robinson-cano-says-feels-25-not-36-reports-mets\">competing for a job</a>“
It should please Mets’ executives to see Cano come in and not expect anything to be handed to him.  The Mets had <a href=\"https://www.baseball-reference.com/players/m/mcneije01.shtml?utm_campaign=Linker&amp;utm_source=direct&amp;utm_medium=linker-\" target=\"_blank\" rel=\"nofollow noopener\">Jeff McNeil</a> play second base last season and while he had some great offensive production
Speaking about what Cano brings to the team, manager <a href=\"https://www.baseball-reference.com/players/c/callami01.shtml?utm_campaign=Linker&amp;utm_source=direct&amp;utm_medium=linker-\" target=\"_blank\" rel=\"nofollow noopener\">Mickey Callaway</a> glowed about his ability to hit against the shift <a href=\"https://nypost.com/2019/02/24/pete-alonso-robinson-cano-provide-glimpse-of-what-could-be/\">saying</a>
Alonso working hard to live up to the hype
Volume 11 - 2024 | <a class="ArticleLayoutHeader__info__doi" href="https://doi.org/10.3389/fmed.2024.1497756">https://doi.org/10.3389/fmed.2024.1497756</a>
This article is part of the Research TopicStudy on Immune Mechanism and Immune Intervention in Connective Tissue Diseases<a class="Link Link--linkType Link--maincolor Link--medium Link--icon Link--chevronRight Link--right" aria-label="View all 10 articles" href="https://www.frontiersin.org/research-topics/62146/study-on-immune-mechanism-and-immune-intervention-in-connective-tissue-diseases/articles" target="_self" data-event="customLink-linkType-a_viewAll10Articles">View all 10 articles</a>
Background: Difficult-to-treat rheumatoid arthritis (D2T RA) refers to a subset of patients who fail to achieve adequate disease control after the use of two or more biological or targeted synthetic disease-modifying antirheumatic drugs (b/tsDMARDs) with different mechanisms of action
while maintaining active inflammatory disease
This presents a therapeutic challenge and highlights the need to explore contributing factors such as the potential role of the gut microbiota
the aim of this study was to analyze the gut microbiota and inflammation in patients with D2T RA in comparison to patients with easy-to-treat RA (E2T RA)
Objective: To analyze the gut microbiota and inflammation in patients with D2T RA
Methods: We performed an observational study of a prospective cohort between 2007 and 2011 and analyzed the gut microbiota
we identified 2 extreme patient phenotypes: (1) D2T RA
which was defined as failure of &#x02265;2 biological or targeted synthetic disease-modifying antirheumatic drugs (b/tsDMARDs) (with different mechanisms of action) plus signs of active disease; and (2) easy-to-treat RA (E2T RA)
stable disease managed with a single treatment
The gut microbiota was analyzed using 16S rRNA gene sequencing; bioinformatics analysis was performed using QIIME2
and its functionality was inferred through PICRUSt
A Cox multivariate analysis was performed to identify factors related to D2T RA
Results: The study population comprised 39 patients: 13 (33%) with D2T RA and 26 (66%) with E2T RA
The families Lachnospiraceae and Pasteurellaceae
and their genera Coprococcus and Haemophilus were more abundant in E2T RA patients
while the genus Megasphaera was more abundant in D2T RA patients
The Firmicutes/Bacteroidetes ratio decreased in D2T RA patients
The metabolic profile of the gut microbiota was characterized by differences in Degradation/Utilization/Assimilation pathway and the Biosynthesis pathway
The factors associated with D2T RA were inflammatory activity according to DAS28-ESR (HR
and the Firmicutes/Bacteroidetes ratio (HR
Conclusion: The composition of the gut microbiota of patients with D2T RA differed from that of E2T RA patients
According to the &#x201C;European Alliance of Associations for Rheumatology&#x201D; (EULAR) (<a href="#ref3">3</a>)
patients with RA are considered D2T if at least 2 biological or targeted synthetic disease-modifying antirheumatic drugs (b/tsDMARDs) (with different mechanisms of action) have failed after previous failure of a csDMARD (unless contraindicated)
the patient must have signs of active/progressive disease in which management of signs and/or symptoms is problematic for the rheumatologist and/or doctor
and no studies to date have specifically evaluated the gut microbiota of patients with D2T
no evidence is available on whether there is an association between continuously high inflammatory activity and high levels of proinflammatory cytokines in patients with D2T RA
the primary objective of the present study was to compare the gut microbiota
and other clinical characteristics between patients with D2T RA and patients who respond well to therapy in order to identify microbial profiles and other factors associated with D2T RA
The data for this controlled cross-sectional study came from a prospective cohort of incident cases recruited between 2007 and 2011 in the Department of Rheumatology, Hospital Universitario Regional de M&#x000E1;laga, M&#x000E1;laga, Spain (<a href="#ref9">9</a>). All the patients were aged &#x02265;18&#x202F;years, fulfilled the 2010 criteria of the American College of Rheumatology/European League Against Rheumatism for RA (<a href="#ref14">14</a>)
and had been diagnosed and treated for the first time during the 12&#x202F;months after onset of their disease
All participants provided their written informed consent before inclusion
The study was conducted according to the principles of the Declaration of Helsinki
and the study protocol was approved by the Ethics Committee of M&#x000E1;laga (Project identification code 4/2016
Since the creation of the prospective cohort (2007&#x2013;2011)
all patients have been followed up at the outpatient clinic every 3&#x2013;6&#x202F;months by a rheumatologist using a systematic clinical data collection protocol
The data collected included inflammatory activity and physical function throughout follow-up
all the patients in the cohort consented to a relevant modification to the protocol aimed at new
Peripheral venous blood samples were collected after overnight fast
and fecal samples were refrigerated immediately and transported to the laboratory
where they were stored at &#x02212;80&#x000B0;C for subsequent analysis
At the last visit in 2022 (final visit in the present study)
we identified 2 groups of patients with extreme RA phenotypes: (1) a group comprising patients with difficult-to-treat RA (D2T RA); and (2) a group of easy-to-treat RA (E2T RA) patients at a 2:1 ratio
active/progressive disease was defined as &#x02265;1 of the following: at least moderate disease activity (according to validated composite measures including 28-joint Disease Activity Score for Rheumatoid Arthritis with erythrocyte sedimentation rate [DAS28-ESR] &#x0003E;3.2)
signs and/or symptoms suggestive of active disease
inability to taper glucocorticoid treatment (below 7.5&#x202F;mg/day prednisone or equivalent)
and symptoms that diminish quality of life
including comorbid conditions associated with traditional cardiovascular risk factors (smoking
Similarly, on the index date, we evaluated inflammatory activity at the visit and calculated the cumulative activity. Activity was estimated as an arithmetic mean of all the values collected regularly since diagnosis (time-averaged disease activity). Inflammatory activity was measured using the DAS28-ESR (range, 0&#x2013;9.4) (<a href="#ref15">15</a>)
A DAS28-ESR value &#x0003E;3.2 was considered high and &#x02264;3.2 was considered low
The erythrocyte sedimentation rate (ESR; mm/h) was measured
High-sensitivity C-reactive protein (hsCRP; mg/L) was measured for all participants using nephelometry (MMAGE-Immunochemistry Systems
Physical function on the index date was assessed (average value) using the Health Assessment Questionnaire (HAQ)
Inflammatory mediators such as TNF-&#x03B1;
and IL-6 in plasma were quantified using enzyme-linked immunosorbent assay (ELISA) Quantiglo kits (R&#x00026;D Systems Inc.
United States) according to the manufacturer&#x2019;s instructions
Plasma levels of insulin-like growth factor I were analyzed using ELISA (Mediagnost GmbH.
Malondialdehyde-oxidized low-density lipoprotein (LDL) was also measured in plasma using an ELISA kit (Biomedica GmbH.
DNA was extracted using the QIAamp DNA Stool Mini Kit (Qiagen
Germany) according to the manufacturer&#x2019;s instructions
The concentration and purity of DNA were determined using a Nanodrop spectrophotometer (Nanodrop Technologies
Ribosomal 16S RNA (16S rRNA) gene sequences were amplified from DNA using the Ion 16S Metagenomics Kit (Thermo Fisher Scientific
The kit includes 2 primer sets (V2-4-8 and V3&#x2013;6
7&#x2013;9) that selectively amplify the corresponding hypervariable regions of the 16S region in bacteria
Libraries were built with the Ion Plus Fragment Library kit (Thermo Fisher Scientific)
Barcodes were added to each sample using the Ion Xpress&#x02122; Barcode Adapters kit (Thermo Fisher Scientific)
Emulsion PCR and sequencing of the amplicon libraries were performed on an Ion 530 chip (Ion 530&#x02122; Chip Kit) using the Ion Chef System and Ion Torrent S5&#x02122; system (Ion 510&#x02122;/520&#x02122;/530&#x02122; Kit-Chef
according to the manufacturer&#x2019;s instructions
A descriptive analysis of the main outcome measures was performed
Values are expressed as frequencies and percentages or as mean (standard deviation [SD]) or median (interquartile range [IQR])
Normality was assessed using the Kolmogorov&#x2013;Smirnov test
We compared clinical and laboratory characteristics and inflammatory activity between patients with D2T RA and patients with E2T RA using the Pearson &#x03C7;2 test or the t test
to identify factors associated with D2T RA adjusted for disease duration
The variables entered into the models were those that proved to be significant in the bivariate analysis and of clinical interest
Statistical significance was set at p&#x202F;&#x0003C;&#x202F;0.05
The statistical analyzes were performed using IBM SPSS Statistics for Windows
of whom 13 (33%) were D2T RA and 26 (66%) were E2T RA
with a mean (SD) age of 55.1 (11.6) years on the index date
all D2T RA patients had been treated with at least 2 different lines of biologic therapy
whereas E2T RA patients had only received treatment with methotrexate
except for 1 patient who was treated with leflunomide owing to intolerance to methotrexate at 10&#x202F;mg/wk
However, at the final visit (see <a href="#tab2">Table 2</a>)
most of the 13 patients with D2T RA were receiving rituximab (30.8%) or tofacitinib (23.1%) after a mean (SD) of 2.6 (1.3) switches of biologics
with a mean (SD) retention period of 95.8 (56.3) months
the main reason for switching biological or targeted synthetic disease-modifying antirheumatic drugs (b/tsDMARDs) was loss of efficacy (18/34 treatments used [52%])
followed by insufficient response (11/34 [32%]) and nonserious adverse events (5/34 [14%])
the 26 E2T RA patients maintained the same csDMARDs throughout follow-up
a larger number of patients with D2T RA were receiving glucocorticoids on the index date (p&#x202F;=&#x202F;0.018) and at a higher median dose than the E2T RA patients (p&#x202F;=&#x202F;0.040)
Of the 39 patients included, 28 (71.8%) were in remission or with low disease activity at the index date according to their DAS28-ESR values, and 30 (76.9) had maintained an average DAS28-ESR value indicating low activity. D2T RA patients had higher average DAS28-ESR values at the cut-off than the E2T RA patients (<a href="#tab3">Table 3</a>)
The same was true of physical functioning according to the HAQ
laboratory values were generally similar for both groups
such as homocysteine (p&#x202F;=&#x202F;0.010) and CRP (p&#x202F;=&#x202F;0.029)
D2T RA patients had higher levels of IL-6 (p&#x202F;=&#x202F;0.031)
and numerically higher levels of TNF-&#x03B1; (p&#x202F;=&#x202F;0.085)
In the case of lipoproteins and human growth factors
the values remained similar in both groups
D2T RA patients were similar to those with E2T in their adherence to the Mediterranean diet (69.2% vs
Diversity of gut microbiota between E2T RA and D2T RA patients
(A) Alpha diversity indexes: Pielou-evenness
and the Shannon index were compared between the 2 groups
Values are presented as mean&#x202F;&#x000B1;&#x202F;SD
(B) Principal coordinates analysis (PCoA) corresponding to the Bray&#x2013;Curtis dissimilarity index (beta diversity)
The statistical analysis used permutational multivariate analysis of variance (PERMANOVA
Green dots indicate the D2T RA patients; red dots the E2T RA patients
easy-to-treat rheumatoid arthritis; D2T RA
Gut microbiota analysis at the phylum level in E2T RA and D2T RA patients
(A) The distribution of gut microbiota at the phylum level in both RA groups
(B) The absolute abundance in Log10 of the phyla Bacteroidetes and Firmicutes in both RA groups
&#x0002A; Indicates significant differences between groups (p&#x202F;&#x0003C;&#x202F;0.05)
(A) Cladogram and (B) linear discriminant analysis (LDA) scores were used to determine differences in the abundance of microbes in E2T RA and D2T RA patients
LDA&#x202F;&#x0003E;&#x202F;2; p&#x202F;&#x0003C;&#x202F;0.05
Heatmap of differentially abundant Metacyc pathways identified in the study groups (E2T RA and D2T RA patients)
The values of color in the heatmap represent the normalized relative abundance of Metacyc pathways
<a href="#tab4">Table 4</a> shows the results of the Cox multivariate analysis (DV: D2T RA)
in which 39 patients with RA were included over a mean (SD) follow-up of 103.8 (37.8) months
The multivariate analysis showed that the Firmicutes/Bacteroidetes ratio was associated with a reduced risk of D2T RA (HR
0.092&#x2013;0.907; p&#x202F;=&#x202F;0.033)
whereas the variables associated with a greater probability of D2T RA were greater average inflammatory activity according to the DAS28-ESR (HR
1.225&#x2013;5.732; p&#x202F;=&#x202F;0.013) and treatment with prednisone on the index date (HR
1.098&#x2013;10.990; p&#x202F;=&#x202F;0.008)
for each 0.1-point increase in the Firmicutes/Bacteroidetes ratio
the risk of D2T RA decreased by approximately 71%
the present study compares the gut microbiota profile
and other severity-related factors between patients with D2T RA and patients with E2T RA in order to identify the intestinal microbiota profile and other factors associated with this major problem
Non-responder patients do not achieve adequate control with any treatment
while D2T RA patients have failed to respond to two or more biologics or targeted synthetic DMARDs
highlighting their clinical profile and the need for tailored therapeutic strategies
this could be one of the factors affecting the inadequate response to treatment in patients with RA in our study
The findings reported may provide insight into how gut microbiota composition and metabolic activity differ between patients who respond and do not respond to treatment
This in turn could prove useful for developing targeted therapies and improving our understanding of disease mechanisms
which serves as a basis for most published studies
While we acknowledge that including a healthy control group would strengthen our findings
our study primarily focused on comparing D2T and E2T RA patients
the higher proportion of female participants in our cohort may introduce confounding factors
such as hormonal influences on disease activity
although we did not assess dietary components in detail
we observed that a high percentage of patients in both groups adhered to the Mediterranean diet
it is important to remember that other factors may affect D2T RA and have not been the object of this study
metabolic differences between conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) and biological or targeted synthetic disease-modifying antirheumatic drugs (b/tsDMARDs) or adherence to treatment
the association between microbiota-related factors and D2T RA by combining these findings with other clinical characteristics
This study found that the gut microbiota profile differs between D2T RA and E2T RA patients
patients with D2T RA were characterized by enrichment of the phylum Bacteroidetes and the genus Megasphaera
the family Pasteurellaceae and its genus Haemophilus
and the family Lachnospiraceae and its genus Coprococcus were more abundant
The Firmicutes/Bacteroidetes ratio was lower in patients with D2T RA
an increase in this ratio was seen to be an independent factor for reduced risk of D2T RA
suggesting that gut dysbiosis plays a role in nonresponse to treatment
the above-mentioned metabolic pathway analysis revealed differences in the pathways involved in degradation of aromatic compounds
and fatty acids between D2T RA and E2T RA patients
Greater inflammatory activity and use of prednisone were associated with D2T RA
The identification of new factors associated with D2T RA is a relevant finding that enhances our knowledge of patients with this disease
which is currently a severe problem with high social and health care costs
A more individualized approach including these factors can improve outcomes and reduce the risk of adverse effects of medication
The datasets presented in this article are not readily available because according to the data regulations and ethical considerations
the datasets generated and analyzed during our study cannot be made public due to the fact participants only provided their consent to the original team of investigators for the use of their data
and this information may compromise their consent to participate in the study
Requests to access the datasets should be directed to the corresponding author
The studies involving humans were approved by Research Ethics Committee of Hospital Regional Universitario de M&#x000E1;laga (HRUM) (Project identification code 4/2016
This work was supported by Instituto Salud Carlos III (grants cofunded by ERDF) (PI18/00824)
&#x201C;Redes de Investigaci&#x000F3;n Cooperativa Orientadas a Resultados en Salud (RICORS)
Red de Enfermedades Inflamatorias (REI) (RD21/0002/0037)&#x201D;: fondos de Next Generation EU
que financian las actuaciones del Mecanismo para la Recuperaci&#x000F3;n y la 4 Resiliencia (MRR)
PR-L was supported by a &#x201C;Miguel Servet&#x201D; postdoctoral contract (CP22/00096) by the ISCIII-Madrid (Spain) and cofunded by the European Union
IM-I was supported by the &#x201C;Miguel Servet Type II&#x201D; program (CPII21/00013) of the ISCIII-Madrid
AM was supported by a &#x201C;Sara Borrell&#x201D; postdoctoral contract (CD23/00082) by ISCIII and co-funded by the European Union
JL-M was supported by PFIS predoctoral contract (FI23/00084) by ISCIII and co-funded by the European Union
The authors thank the Spanish Foundation of Rheumatology for providing medical writing/editorial assistance during the preparation of the manuscript (FERBT2024)
The research groups thanks for its support of the CIBER-IBIMA-Metagenomics platform
especially Pablo Rodr&#x000ED;guez and M&#x000AA; Jos&#x000E9; Garc&#x000ED;a-L&#x000F3;pez
Biological disease-modifying antirheumatic drugs; DAS28-ESR
28-joint Disease Activity Score for Rheumatoid Arthritis with erythrocyte sedimentation rate; D2T
European Alliance of Associations for Rheumatology; HAQ
Linear discriminant analysis Effect Size; PERMANOVA
Permutational multivariate analysis of variance; PICRUSt2
Phylogenetic Investigation of Communities by Reconstruction of Unobserved States plugin; QIIME2
Quantitative Insights into Microbial Ecology software; RA
Conventional synthetic disease-modifying antirheumatic drugs; SCFA
Statistical Analysis of Metagenomics Profiles; tsDMARDs
Targeted synthetic disease-modifying antirheumatic drugs
1. <a class="footnotetextanchor" href="#xfn0001" title="">^</a><a href="http://huttenhower.sph.Harvard.edu/galaxy/">http://huttenhower.sph.Harvard.edu/galaxy/</a>
Expansion of rare and harmful lineages is associated with established rheumatoid arthritis
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<a href="https://pubmed.ncbi.nlm.nih.gov/26600968" target="_blank">PubMed Abstract</a> | <a href="https://doi.org/10.4291/wjgp.v6.i4.110" target="_blank">Crossref Full Text</a> | <a href="http://scholar.google.com/scholar_lookup?author=CK+Chakraborti&#x00026;publication_year=2015&#x00026;title=New-found+link+between+microbiota+and+obesity&#x00026;journal=World+J+Gastrointest+Pathophysiol&#x00026;volume=6&#x00026;pages=110-9" target="_blank">Google Scholar</a>
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Tinahones FJ and Fern&#x000E1;ndez-Nebro A (2025) Gut dysbiosis is associated with difficult-to-treat rheumatoid arthritis
Received: 17 September 2024; Accepted: 17 December 2024; Published: 16 January 2025
Copyright &#x000A9; 2025 Ruiz-Lim&#x000F3;n, Mena-V&#x000E1;zquez, Moreno-Indias, Lisbona-Monta&#x000F1;ez, Mucientes, Manrique-Arija, Redondo-Rodriguez, Cano-Garc&#x000ED;a, Tinahones and Fern&#x000E1;ndez-Nebro. This is an open-access article distributed under the terms of the <a rel="license" href="http://creativecommons.org/licenses/by/4.0/" target="_blank">Creative Commons Attribution License (CC BY)</a>
&#x0002A;Correspondence: Natalia Mena-V&#x000E1;zquez, <a id="encmail">bmF0YWxpYW1lbmF2YXpxdWV6QGdtYWlsLmNvbQ==</a>
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Numerous questionnaires are available on Knowledge
and Practices (KAP) towards antibiotics' use by adults
but none of these questionnaires is fully validated
We undertook an exhaustive literature review to design a comprehensive KAP questionnaire concerning the personal use of antibiotics in Galicia
The Item Content Validity Index (I-CVI) and modified Kappa statistic (K*)
confirmed the content validity of the questions (0.78 ≤ I-CVI ≤ 1.00 and 0.78 ≤ K* ≤ 1.00)
The S-CVI statistic showed the content validity of the scale (S-CVI/Ave: 0.95)
the Test–Retest Reliability in a sample of 145 adults confirmed the reliability of the questions
We carried out Confirmatory Factor Analysis using cross loadings and modification indices to choose the most adequate model in data collected from 844 adults
We estimated the indicators of model fit and demonstrated that the selected model has a good to excellent fit
The final version of the questionnaire was highly accepted by the general adult population as reflected by the response rate (95.85%) and the low percentage of unanswered questions (0.4–2.7%)
Our fully validated questionnaire could prove useful for research as it permits generating high quality data and reducing measurement error
we aimed in the present study to design and validate a questionnaire for the assessment of Knowledge and Attitude related to Practices of personal use of antibiotics in the general population
We describe the development process of this questionnaire and report the assessment of its face
We also examine the questionnaire reliability
</a>Flow diagram describing the steps followed to develop and validate the KAP questionnaire
All the 30 adults who participated in the pilot testing answered the questionnaire in its totality
Two participants reported that they misunderstood 0 and 10 being the lowest and highest levels of agreement
added an additional indication using arrows to help the participants remember the direction of agreement
We also provided an answered example (“practicing sports benefits health”) to facilitate the understanding of the 0–10 Likert Scale concept
One participant declared that it was not clear whether the Knowledge and Attitudes items should be answered in case the respondent did not use antibiotics
we added this statement “Please evaluate the below statements REGARDLESS of whether you are using antibiotics OR NOT”
“The last time you had to take antibiotics
did you complete the course of treatment?”
the participants suggested adding one additional answer (“still using them”)
The questionnaire took 8–10 min to be completed
and the participants showed satisfaction about the questionnaire length
Since low ICC could be due to lack of sample heterogeneity for these items
we calculated their Spearman´s correlation coefficient in order to explore further their reliability
Spearman coefficient showed that answers in the first and second rounds are weakly correlated for Q5 (Spearman regression coefficient
rs = 0.193; p = 0.022) and moderately correlated for Q10 (rs = 0.433; p &lt; 0.0001) and Q11 (rs = 0.405; p &lt; 0.0001)
Q8 did not load significantly in the Knowledge factor
Q17” loaded negatively in the Attitude factor
These five attitude items dealt with the patient-health care provider relationship and therefore they were attributed to a new factor (Attitude-Healthcare provider)
The new model (Model 1.0) included “Q1, Q2, Q4, Q6, Q7, Q8 and Q11” in the Knowledge factor; “Q3, Q5, Q9, Q12, Q14” in Attitude-Personal factor and “Q10, Q13, Q15, Q16, Q17” in Attitude-Healthcare provider factor. Model 1.0 showed better fit than Model 0, however it still was not acceptable (Table <a data-track="click" data-track-label="link" data-track-action="table anchor" href="/articles/s41598-020-77769-6#Tab2">2</a>)
</a>Representation of the model selected by CFA analysis (Model 1.1)
Attitude-Personal and Attitude-Healthcare provider) is represented with its corresponding standardized items loadings and their residuals
“Knowledge” includes items the explore the knowledge of the adults towards antibiotics
“Attitude-Personal” encompasses statements about attitudes towards the personal use of antibiotics
“Attitude-Healthcare provider” involves phrases about the patient-healthcare provider relationship with respect to antibiotics
The double-sided arrows represent correlations between the variables
Q1–Q7 and Q9–Q17 are items of the Knowledge and Attitude construct (Q8 was deleted in a previous step)
The single headed arrows represent the correlation of the items and their respective factors
The indicators of the goodness of fit assessment of the Model 1.1 showed an adequate fit. (Table <a data-track="click" data-track-label="link" data-track-action="table anchor" href="/articles/s41598-020-77769-6#Tab2">2</a>). The χ2 difference test between Model 1.0 and Model 1.1 showed that they are statistically different (Δ χ2 = 331.97, Δdf = 22, p = 0.0001) (Table <a data-track="click" data-track-label="link" data-track-action="table anchor" href="/articles/s41598-020-77769-6#Tab2">2</a>)
we adopted Model 1.1 for this questionnaire
Knowledge was significantly positively correlated with Attitude-Personal factor (r = 0.56, p &lt; 0.0001), whereas it was not correlated with Attitude-Healthcare provider (r = 0.04, p = 0.417). Attitude-Personal and Attitude-Healthcare provider were weakly negatively correlated (r = − 0.11, p = 0.023) (Fig. <a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/articles/s41598-020-77769-6#Fig1">1</a>)
According to the findings from the validation steps mentioned above, we provide the final version of the questionnaire which consists of three blocks (see Supplementary Information <a data-track="click" data-track-label="link" data-track-action="supplementary material anchor" href="/articles/s41598-020-77769-6#MOESM1">S1</a>)
The first block encompasses the 16 retained items after the CFA analysis and that underlie 3 factors: Knowledge about antibiotics
Attitude towards the personal use of antibiotics and Attitude towards health care providers
The second block includes a series of 11 questions that intend to measure the different practices of personal misuse of antibiotics
The third block entails the demographic characteristics and consists of seven questions
The questions of the second and the third blocks are responded by selecting one or several answers from a list of possible answers
except for “age” which is introduced as a number by the participants
The overall reliability was reflected by the Cronbach's alpha of 0.62
which is deemed acceptable given that our questionnaire assesses distinct dimensions uncorrelated with each other
844 out of 879 participants accepted answering the questionnaire
The percentage of missing or blank answers was between 0.4% and 2.7%
These figures indicate high acceptability of the questionnaire by the population
we designed and validated the psychometric properties of a KAP questionnaire about antibiotics’ use by the adult general population
The content and the scale validity indices confirmed the content validity of our questionnaire
the test–retest reliability and the confirmatory factor analysis proved the reliability and the construct validity of the questionnaire
the questionnaire was accepted by the general population as reflected by the high response rate and the low percentage of unanswered questions
The availability of a reliable and construct-valid instrument is fundamental for epidemiological studies that aim to measure associations between Knowledge
and Practices toward the personal use of antibiotics
as the use of a non-validated questionnaire may induce measurement error in the exposure and the outcome
the availability of a validated KAP questionnaire is crucial for the design of interventions aimed at improving the Knowledge and modifying Attitudes and Practices towards a proper use of antibiotics
where the overwhelming majority of the population answered by 0 (totally disagree) in the two test rounds
an extremely large proportion of participants showed disagreement with the statement Q5
item Q5 is likely to be reliable and should be retained in the questionnaire
Testing these associations in other populations would further validate our findings
an assessment of past intake of antibiotics relies on the memory of the participants
to decrease the risk of recall bias we have included a time limit in the design of the “Practice” questions by asking about the use in the past two months
The questionnaire encompasses 11 questions that are elaborated to determine any aspect of misuse
the provided choices of answers were based on an extensive literature review to include any possible answer
and therefore avoid leaving questions unanswered
The questionnaire was designed to measure the participants’ Knowledge and Attitudes regardless of their consumption of antibiotics in the last 2 months
our questionnaire could prove useful in obtaining data both from users and non-users of antibiotics
which represent a crucial issue in epidemiologic studies involving Knowledge
The translated versions were also pilot tested
This favors the application of the questionnaire in non-English speaking populations
an important step in the validation process involves comparing the results obtained from the questionnaire being validated to a superior method
a gold standard to assess the proper use or the misuse of antibiotics does not exist and therefore
our instrument could not be compared against any previous reference method
we consider that the present questionnaire is reliable and has construct validity
but future research is needed to provide a gold standard for KAP questionnaire about antibiotics
Another limitation of our validation study is that the construct was validated in the Spanish population only
therefore our questionnaire needs to be further tested in different settings and populations
This study presents a step forward towards the validation of a knowledge
and practice questionnaire about the personal use of antibiotics
taking into consideration the inconsistent reporting of validation methodologies across studies and the abuse of the term validation
as well as the exhaustive review of the methodology carried out in the current manuscript
we believe that this study would help validating KAP pharmacologic studies on other drugs than antibiotics
We comprehensively reviewed the literature to identify published KAP questionnaires about the personal use of antibiotics in the general population
We applied the following search syntax in Medline from inception until September 2018: (("Anti-Bacterial Agents"[Mesh] OR "Anti-Bacterial Agents" [Pharmacological Action]) AND ("Surveys and Questionnaires"[Mesh]) AND ("Attitude to Health"[Mesh] OR "Health Knowledge
Practice"[Mesh] OR "Knowledge"[Mesh] OR beliefs OR perception OR "Health Behavior"[Mesh] OR "Awareness"[Mesh]) AND (misuse or overuse or use or abuse))
We also searched conference papers in the Conference Proceedings Citation Index-Science (CPCI-S) as well as the reference list of relevant studies
we reviewed reports about the determinants of self-medication with antibiotics as well as aspects of medicine’s misuse
we generated a pool of 1591 published items (questions or statements) about 3 dimensions: knowledge
After removing duplicated or very similar questions
we selected 27 items based on their relevancy to the topic
We also created 11 additional KAP questions in order to draft a comprehensive questionnaire on the mentioned dimensions
We included seven questions about demographic characteristics
The 45-item questionnaire was originally written in English and then forward and backward translated to Spanish/Galician language by bilingual researchers
The translated version of the questionnaire was then reviewed by a native language specialist
The questionnaire was designed using OMR Remark Office software (Remark Office OMR 2014
and B.T.) subjectively checked the face validity of the questionnaire by reviewing the clarity and the completeness of the questions to measure the target outcome
The questionnaire was then tested in a sample of 30 adults from the general population who were not related to the medical field
We asked the participants to provide feedback about the clarity and the understandability of the questions
the ease of answering and finally on the time taken to answer the questionnaire
Since Knowledge and Attitudes are considered stable characteristics over time
we examined the stability of these domains by conducting a test–retest reliability assessment in a sample of 145 adults
The participants were randomly recruited from the administrative staff at the University of Santiago de Compostela
Participants were unrelated to the health or medical fields
We administered the same questionnaire to the same participants within a 4-week time interval
The participants were informed about the study objective and they agreed to answer the questionnaire on the two occasions
This step is carried out when the construct of the questionnaire is intended to measure more than one dimension
The Knowledge and Attitude construct was designed to comprise two dimensions of 17 items
These variables were measured in a 0–10 Likert Scale
We carried out a Confirmatory Factor Analysis (CFA) to test the construct validity of the questionnaire
CFA assesses the relationships between the items and their corresponding factor
We distributed the questionnaire in a population of 879 adult individuals from the general population
The participants consisted of subjects accompanying a next-of-kin to primary care consultations at the University Hospital of Santiago de Compostela
All subjects visiting the consultations during the recruitment period that took place between May and December 2019 were contacted
They were informed that the questions are about personal use of antibiotics
We started by distributing the 17 items of the construct into two factors
Items that tested the knowledge about antibiotics’ role and specificity were assigned to the Knowledge factor
Items that inspected the agreement of the participants about certain attitudes towards the use of antibiotics and patient-health care provider relationship were placed in the Attitude factor
Subsequently we tested the correlation of the items with their corresponding factors
Standardized factor loadings represent the correlation between an item and its corresponding factor
We ran three CFA and compared the fit of the models against each other
The flow diagram of the full validation procedure is summarized in Fig. <a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/articles/s41598-020-77769-6#Fig1">1</a>
Our study was approved by the ethics committee of the University of Santiago de Compostela (R00002
It was also authorized by the Spanish Agency for Medication and Healthcare Products (AEMPS
The study was conducted in compliance with the general requirements of the ethics committee and with the General Data Protection Regulation (Regulation (EU) 2016/679 and Organic Law 3/2018)
Written informed consent form was obtained from the participants and the data were anonymized before analysis
The dataset generated and analysed during the current study is available in the (FigShare) repository, (<a href="https://figshare.com/s/d8bbd91b657d9a468aaa">https://figshare.com/s/d8bbd91b657d9a468aaa</a>)
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The authors would like to thank the experts who reviewed the questionnaire for their valuable comments: Francisco Caamaño
This work was funded by a grant from the Regional Ministry of Education
Ruben Rodriguez-Cano is supported by the Cancer Prevention and Research Institute of Texas (CPRIT) Postdoctoral Fellowship in Cancer Prevention (RP 170259) and by MD Anderson’s Cancer Center Support Grant (CA016672) funded by the National Cancer Institute
Centro de Investigación Biomédica en Red de Epidemiología y Salud Pública (CIBER-ESP)
The University of Texas MD Anderson Cancer Center
Health Research Institute of Santiago de Compostela (IDIS)
supervised data analysis and interpretation
All authors reviewed and revised the manuscript and counted responsible for its content
The authors declare no competing interests
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Longitudinal study of 100 healthy pregnant women and their neonates. Conventional biochemical tests were performed and maternal organokine concentrations were measured by ELISA. Neonatal percent fat mass was determined using the PEA POD system, and weight and length were measured using a soft tape measure and a baby scale. Multiple linear regression models were made to predict neonatal anthropometric measurements and adiposity.
Maternal PGRN, AFABP, and BDNF concentrations, but not FGF21, vary throughout pregnancy. These organokines and maternal characteristics can be useful in the prediction of neonatal weight, length, and percentage fat mass.
Volume 15 - 2024 | <a class="ArticleLayoutHeader__info__doi" href="https://doi.org/10.3389/fendo.2024.1423950">https://doi.org/10.3389/fendo.2024.1423950</a>
Aims: To evaluate the relation between maternal concentrations of progranulin (PGRN)
adipocyte fatty acid-binding protein (AFABP)
and fibroblast growth factor 21 (FGF21) throughout pregnancy with neonatal weight and length at birth and at one month of age
as well as with the percentage of fat mass at one month of age
we evaluated the association between maternal organokine concentrations with pregestational nutritional status and gestational weight gain (GWG)
Methods: Longitudinal study of 100 healthy pregnant women and their neonates
Conventional biochemical tests were performed and maternal organokine concentrations were measured by ELISA
Neonatal percent fat mass was determined using the PEA POD system
and weight and length were measured using a soft tape measure and a baby scale
Multiple linear regression models were made to predict neonatal anthropometric measurements and adiposity
PGRN concentrations significantly increased as pregnancy progressed
while AFABP concentrations increased until the third trimester and the highest BDNF concentrations were observed in the second trimester of pregnancy
FGF21 concentrations did not change during pregnancy
Only maternal obesity was associated with some differences in AFABP and FGF21 concentrations
maternal age and third-trimester PGRN concentrations predicted weight (gestational age at birth: &#x3b2;=0.11; maternal age: &#x3b2;=-0.033; PGRN: &#x3b2;=0.003
together with first-trimester BDNF concentrations
length (gestational age at birth: &#x3b2;=0.76; maternal age: &#x3b2;=-0.21; PGRN: &#x3b2;=0.24; BDNF: &#x3b2;=0.06
Maternal age and third-trimester BDNF concentrations predicted one-month-old neonate length (maternal age: &#x3b2;=-1.03; BDNF: &#x3b2;=0.45
and third-trimester AFABP concentrations predicted neonatal fat mass percentage (pBMI: &#x3b2;=-0.58; GWG: &#x3b2;=-0.32; FGF21: &#x3b2;=-0.004; AFABP: &#x3b2;=-1.27
These organokines and maternal characteristics can be useful in the prediction of neonatal weight
Emerging evidence suggests that dysregulation in the crosstalk between organs such as the liver, muscle, adipose tissue, and placenta, through the production of protein messengers called organokines (including myokines, adipokines, and hepatokines), may participate in the relationship between maternal weight and neonatal anthropometric outcomes (<a href="#B8">8</a>&#x2013;<a href="#B11">11</a>)
and FGF21 regulate maternal glucose and lipid metabolism
which may ultimately influence nutrient availability to the developing fetus
This may result in a relation between the circulating concentrations of these organokines and neonatal anthropometry and adiposity
it is possible that the concentrations of these organokines are associated with pregestational nutritional status and GWG
To further investigate the potential role of these organokines in the relationship between maternal weight and neonatal anthropometric outcomes
the aim of the present study was to evaluate the relation between maternal concentrations of PGRN
and BDNF throughout pregnancy with neonatal weight and length at birth and at one month of age
we evaluated the association between maternal organokine concentrations with pregestational maternal weight and GWG
This study derives from the OBESO (Origen Bioqu&#xed;mico y Epigen&#xe9;tico del Sobrepeso y la Obesidad) perinatal cohort conducted at the Instituto Nacional de Perinatolog&#xed;a in Mexico City
The research protocol was approved by the Institutional Research and Ethics Review Board (3300-11402-01-575-17 and 2019-1-20)
The study was conducted in accordance with the Declaration of Helsinki ethical principles for human research
and all participants signed an informed consent form
Maternal blood samples were obtained after an 8-hour fast at enrollment and follow-up
Blood samples were centrifuged at 400 g for 15 minutes
and serum was frozen at -70&#xb0;C until assayed
and triglyceride concentrations were measured by enzymatic colorimetric methods utilizing an automated analyzer (ISE Echo Lory 2000) and commercial kits (DiaSys Diagnostic Systems GmbH
Hemoglobin A1c (HbA1c) measurement was performed by turbidimetric immunoassay using an automated analyzer (InnovaStar) and commercial kits (DiaSys Diagnostic Systems GmbH
Insulin was measured on an ARCHITECT i1000SR Clinical Chemistry Analyzer (Abbot Diagnostics
Insulin resistance was determined by applying the homeostasis model assessment formula: HOMA-IR = [fasting insulin (&#xb5;U/ml) &#xd7; fasting plasma glucose (mg/dl)]/405
and BDNF maternal concentrations were determined utilizing DuoSet ELISA kits (R&amp;D Systems
Weight and length were measured at birth and one month later using a soft tape measure and a baby scale. The neonate was classified as small for gestational age (SGA), adequate for gestational age (AGA), or large for gestational age (LGA) based on Intergrowth-21 parameters (<a href="#B30">30</a>)
Low birth weight was defined as any birth weight &lt;2.5 kg
the percent fat mass was determined by qualified personnel using air displacement pletismography (PEA POD system
Statistical analysis was performed with the IBM SPSS Statistics 27.0 program (IBM SPSS Inc.
Data distribution was assessed using the Kolmogorov-Smirnov test
For variables that deviated significantly from normality
rank-based inverse normal transformations were applied
Quantitative variables are presented as mean &#xb1; standard deviation
Repeated measures ANOVA was used to compare biochemical and organokine measurements among trimesters of pregnancy
One-way ANOVA with post-hoc Tukey was used to compare these same variables between women classified by pBMI and GWG
Pearson&#x2019;s test was used to calculate bivariate correlations
Stepwise multiple linear regression models were performed to determine which variables were independently associated with neonatal anthropometrics and adiposity
Categorical variables are presented as counts and percentages
The Chi-square test was used for the bivariate analysis of the categorical variables
p &lt;0.05 was defined as statistically significant
One hundred mother-neonate dyads were studied. <a href="#T1">Table&#xa0;1</a> shows the clinical characteristics of the participants. As expected, there were significant differences in pBMI according to pregestational nutritional status. In women with normal weight, maternal weight was found to be significantly higher in the first trimester than self-reported weight (<a href="#hsm">Supplementary Table&#xa0;1</a>)
As this could introduce bias the GWG classification in this group
GWG classification was performed using self-reported weight
GWG and one-month-old neonate weight were lower in women with obesity than in women with normal weight
Clinical characteristics of the study population
Biochemical changes characteristic of pregnancy were observed in all women, including increased insulin concentrations, heightened insulin resistance, and increased lipid concentrations toward the end of pregnancy (<a href="#T2">Table&#xa0;2</a>). No significant differences in biochemical variables were observed according to pre-pregnancy nutritional status or GWG classification (<a href="#hsm">Supplementary Tables&#xa0;2</a>, <a href="#hsm">3</a>)
Biochemical characteristics of the study population
Regarding organokines, PGRN concentrations significantly increased as pregnancy progressed, while AFABP concentrations increased until the third trimester and the highest BDNF concentrations were observed in the second trimester. In contrast, FGF21 concentrations did not change during pregnancy (<a href="#f1">Figure&#xa0;1</a>)
Organokine concentrations throughout pregnancy in all participants
adipocyte-specific fatty acid-binding protein; FGF21
According to pregestational nutritional status, first- and second-trimester AFABP concentrations were higher in women with obesity than in normal-weight and overweight women, and third-trimester FGF21 concentrations were lower in women with obesity than in normal-weight women (<a href="#hsm">Supplementary Table&#xa0;4</a>). No significant differences were observed in organokine concentrations based on GWG classification (<a href="#hsm">Supplementary Table&#xa0;5</a>)
birth weight positively correlated with GWG (r=0.237
p=0.024) and negatively with third-trimester AFABP concentration (r=-0.265
Birth length positively correlated with third-trimester PGRN concentration (r=0.229
One-month-old neonate weight positively correlated with second- and third-trimester PGRN concentrations (r=0.274
The percentage of one-month-old neonate fat mass negatively correlated with pBMI (r=-0.268
Models with maternal clinical variables and organokine concentrations that significantly predicted neonatal characteristics are shown in <a href="#T3">Table&#xa0;3</a>
Third-trimester PGRN concentration contributed to the prediction of weight and length at birth
while first- and third-trimester BDNF concentrations contributed to the prediction of birth length and one-month old neonate length
Second-trimester FGF21 concentrations and third-trimester AFABP concentrations contributed to the prediction of one-month-old neonate fat mass percentage
Multiple regression analysis for neonatal outcomes
This is the first study to describe changes in maternal PGRN and AFABP concentrations throughout pregnancy
and FGF21 significantly predict neonatal weight
maternal obesity and excessive gestational weight gain had no significant effect on the concentrations of these organokines
with the exception of AFABP in the first and second trimesters
which presented higher levels in women with pregestational obesity
This can be attributed to the observation that these groups exhibited moderate metabolic alterations
as evidenced by the biochemical results and the absence of severe maternal and neonatal complications
Further research is needed to elucidate these aspects
first- and third-trimester BDNF concentrations positively contribute to the prediction of birth length and neonatal adiposity
our understanding of the underlying mechanisms of these observations is limited
It has been reported that in healthy pregnant women FGF21 concentrations are significantly higher in the third trimester than in the first and second trimesters. In our study, we observed that the concentrations of this organokine did not differ throughout pregnancy (<a href="#B41">41</a>)
This inconsistency may be due to differences in the study population
sample size (100 vs 52 participants in the previous study)
or the marked difference in the range established for third-trimester gestational age (28-34 vs
We observed that second-trimester FGF21 negatively contribute to the prediction of neonatal fat mass percentage
we currently lack the necessary information to explain the impact of this maternal organokine on neonatal adiposity
Although our findings are consistent with other studies on the correlations of maternal organokines and neonatal birth weight
its design does not allow for the establishment of causal relationships among maternal organokine concentrations with neonatal anthropometry and adiposity
for the secondary analyses according to pBMI and GWG
our findings should be interpreted cautiously as they must be validated in a wider range of birth weight that includes a larger number of SGA and LGA neonates
The strength of our study design is that it is a longitudinal study of women with complete clinical follow-up and without any metabolic disease beyond excessive maternal weight
Our findings open a new field of research on the role of maternal organokines in fetal programming
The original contributions presented in the study are included in the article/<a href="#hsm">Supplementary Material</a>
Further inquiries can be directed to the corresponding author
The studies involving humans were approved by Research and Ethics Committees of the Instituto Nacional de Perinatolog&#xed;a
This study was funded by Instituto Nacional de Perinatolog&#xed;a (INPer; grant numbers: 2019-1-20 and 2024-1-14)
JV-O has a postdoctoral fellowship from the Direcci&#xf3;n General de Asuntos del Personal Acad&#xe9;mico (DGAPA)
Universidad Nacional Aut&#xf3;noma de M&#xe9;xico
OP-P is a speaker of Nestle Nutrition Institute and Exeltis Pharma Mexico
No relationship of any kind exists regarding this manuscript
The Supplementary Material for this article can be found online at: <a href="https://www.frontiersin.org/articles/10.3389/fendo.2024.1423950/full#supplementary-material">https://www.frontiersin.org/articles/10.3389/fendo.2024.1423950/full#supplementary-material</a>
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Received: 26 April 2024; Accepted: 05 November 2024;Published: 04 December 2024
Copyright &#xa9; 2024 Valencia-Ortega, Galicia-Hern&#xe1;ndez, Castillo-Santos, Moler&#xe9;s-Ordu&#xf1;a, Arceo-Cerna, Perichart-Perera, Rodr&#xed;guez-Cano, Rodr&#xed;guez-Hern&#xe1;ndez, Estrada-Gutierrez, Camacho-Arroyo and Solis-Paredes. This is an open-access article distributed under the terms of the <a rel="license" href="http://creativecommons.org/licenses/by/4.0/" target="_blank">Creative Commons Attribution License (CC BY)</a>
*Correspondence: Juan Mario Solis-Paredes, <a id="encmail">anVhbi5zb2xpc0BpbnBlci5nb2IubXg=</a>
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Histone modifications reflect gene activity
but the relationship between cause and consequence of transcriptional control is heavily debated
Recent developments in rewriting local histone codes of endogenous genes elucidated instructiveness of certain marks in regulating gene expression
Maintenance of such repressive epigenome editing is controversial
while stable reactivation is still largely unexplored
Here we demonstrate sustained gene re-expression using two types of engineered DNA-binding domains fused to a H3K4 methyltransferase
Local induction of H3K4me3 is sufficient to allow re-expression of silenced target genes in various cell types
Maintenance of the re-expression is achieved
but strongly depends on the chromatin microenvironment (that is
We further identify H3K79me to be essential in allowing stable gene re-expression
confirming its role in epigenetic crosstalk for stable reactivation
Our approach uncovers potent epigenetic modifications to be directly written onto genomic loci to stably activate any given gene
Identifying the conditions that drive transcriptional changes is critical to understanding how cell identity is established and how genes become permanently dysregulated in human diseases
the sustainability of this overexpression has not been documented yet
To fully exploit the potentials of epigenome editing
it is necessary to understand how the chromatin microenvironment affects mitotic stability of reprogrammed gene expression patterns
we examined the role of H3K4me3 in upregulating the expression of several model genes in different chromatin contexts
We also identified potential reinforcing marks to achieve stable gene activation
our study identified H3K4me3 and H3K79me as well as the absence of DNA methylation to be critical in allowing sustained re-expression of epigenetically silenced genes
</a>(a) Schematic representation of the targeted genes and the (overlapping) locations where the ZFs and gRNAs bind (the letter or number of each region refers to the name of the ZF or gRNA
for the regions marked with * a ZF as well as a gRNA were designed)
The yellow bars represent the location of the CpG islands
(b) Schematic of dCas9-VP64 targeting sense and antisense strands of DNA
and dCas9 and ZF fused to the epigenetic editor PRDM9 to locally induce H3K4me3
(c) Relative messenger RNA (mRNA) expression of ICAM1
RASSF1a and EpCAM in HEK293T and A549 cells
by the indicated dCas9 fusion protein co-transfected with a combination gRNAs targeted to each promoter region
(n=3 independent experiments; error bars±s.d.)
</a>(a) Relative messenger RNA (mRNA) expression of ICAM1
A549 and A2780 cells determined by qRT–PCR
induced by the indicated ZF fusion protein after retroviral transduction
the letter of each ZF corresponds to the same region where a gRNA binds at the promoter
(b) H3K4me3 ChIP–qPCR enrichment at the promoter region of EpCAM and RASSF1a in HEK293T
A549 and A2780 after retroviral transduction with ZF-PRDM9 and ZF-MutPRDM9 (two-tailed unpaired t-test
n=3 independent experiments; error bars±s.d
</a>(a) Schematic representation of the stable doxycycline inducible system and the experimental timeline set-up
(b) Relative EpCAM messenger RNA (mRNA) expression
at each specific time point using two different ZFs targeting the promoter region
(c) H3K4me3 ChIP–qPCR enrichment at the promoter region of EpCAM at each specific time point
</a>(a) Schematic representation of the stable doxycycline inducible system and the two regions targeted by the ZF protein fusions
(b) Relative PLOD2 messenger RNA (mRNA) expression
(c) H3K4me3 ChIP–qPCR enrichment at the promoter region of PLOD2 at each specific time point
</a>(a) Relative EpCAM messenger RNA (mRNA) expression
at each specific time point after using the inhibitor of DNA demethyltransferases 5′aza for 3 days
(b) H3K4me3 ChIP–qPCR enrichment at the promoter region of EpCAM 10 days after demethylation and ZF fusion protein expression
(c) DNA methylation levels at the EpCAM promoter determined by pyrosequencing
black-dot line represents mean methylation levels of untreated cells
(d) H3K79me2 ChIP–qPCR enrichment at the promoter region of EpCAM 3 and 10 days after demethylation and ZF fusion protein expression
(e) H3K79me2 ChIP–qPCR enrichment at the promoter region of PLOD2 3 and 10 days after ZF fusion protein expression
which urged us to address the role of H3K79me in allowing stability of H3K4me
</a>(a) Graphical representation of the process of gene transcription with the main epigenetic players; RNA polymerase II recruits the ubiquitin-conjugating and -ligating enzyme via PAF to monoubiquitinate H2B
this ubiquitination is required for H3K4me3 and H3K79me
after co-transfection of dCas9 fusions and a combination of gRNAs
(c) H3K4me3 and H3K79me3 ChIP–qPCR enrichment at the promoter region of PLOD2 (around TSS and 750 bp upstream
after co-transfection in HeLa cells of dCas9 fusions and a combination of gRNAs
after co-transfection in HeLa cells of dCas9 fusions and a combination of gRNAs and 5′aza treatment
after co-transfection in C33a cells of dCas9 fusions and a combination of gRNAs
(g) H3K4me3 and H3K79me3 ChIP–qPCR enrichment at the promoter region of PLOD2 20 days after seeding cells around TSS and 750 bp upstream (two-tailed unpaired t-test
This enrichment was evaluated at two different regions (close to TSS and 750 bp upstream)
While H3K4me3 preferentially associated close to the TSS
H3K79me3 was also enriched at the upstream region
Targeting of DOT1L to EpCAM induced expression levels with similar kinetics as targeting PRDM1
when we used 5′aza in combination with a mix of dCas9-PRDM9 and dCas9-DOT1L (MIX)
an effective EpCAM re-expression was obtained and the onset of repression of was delayed
Given the tight association of H3K4me3 and promoter activity
we set out to induce permanent gene re-expression by local enrichment of this mark
We clearly established a causative role of H3K4me3 in instructing gene transcription
our results suggest that gene re-expression achieved by epigenetic editing can be maintained in DNA hypomethylated loci
we neatly indicate that the chromatin microenvironment affects the long-term effects of epigenome editing
which in turn allows for higher levels of transcription
</a>(a) Stable gene reactivation is achieved by targeting H3K4 methyltransferases to a non-hypermethylated locus
(b) Gene reactivation is not achieved by targeting H3K4 methyltransferases to a hypermethylated locus
(c) Co-targeting different epigenetic editors to achieve sustained reactivation at hypermethylated locus
Histone crosstalk is an important mechanism required for gene transcription as described above
Here we demonstrate the crosstalk between H3K4me and H3K79me to play a role in the stability and maintenance of gene transcription
By targeting epigenetic effector domains to promoters
we provide for the first time functional evidence supporting the intrinsic roles of H3K4me3 and/or H3K79me marks in causing transcription
Elucidating the mechanisms whereby histone modifications might be involved in cellular regulation is of fundamental importance in biology
due to the complexity of chromatin and the lack of knowledge in understanding the dynamic process of transcription
We used targeted epigenome editing to unravel the epigenetic mechanisms important for gene transcription
Our system establishes minimal epigenetic requirements to achieve long-term gene re-expression
Several technologies make use of gene expression modulation to change transcription
Manipulating gene expression at will is critical to achieve cellular reprogramming
which can be catalyst to improve different molecular biology and therapeutic applications
Sustained gene reprogramming of diseases with aberrant gene expression patterns can fulfil the promise of the curable genome
our study presents other epigenetic effector domains
to be added to the available tool set for effective epigenome editing
To replace VP64 with the catalytic domains
we used sticky-end ligation after digestion with fast-digest restriction enzymes MluI and PacI (Thermo Scientific)
Each ZF effector domain construct contains a nuclear localization signal and a terminal haemagglutinin (HA) decapeptide tag
We verified all PCR-cloned constructs by DNA Sanger sequencing (Baseclear
The enzymatically inactive pMX-ZFA-MutPRDM9 mutant (G278 to A278) was obtained by site-directed mutagenesis on wild-type pMX-ZFA-PRDM9
The enzymatically inactive dCas9-MutDOT1L mutant (NN241–242 to AD241–242) was obtained by site-directed mutagenesis on wild-type dCas9-DOT1L
Human embryonic kidney cells HEK293T (ATCC: CRL-3216)
and HeLa (ATCC: CCL-2) and C33a (ATCC: HTB-31) cervical cancer cells were cultured in DMEM (BioWhittaker
USA) supplemented with 10% fetal bovine serum (FBS)
2 mM L-glutamine and 50 μg ml−1 gentamycine sulfate
Cells were cultured in a humidified atmosphere at 37 °C supplemented with 5% CO2
All cell lines have been tested for mycoplasma contamination and authenticated using short tandem repeats (STR) profiling
HEK293T cells were co-transfected with the retroviral vector pMX-IRES-GFP along with VSV-G viral envelope (pMD2.G) and the gag/pol proteins (pMDLg/pRRE) using CaPO4
Forty-eight hours and 72 h after transfection
the viral supernatant was used to transduce host cells supplemented with FBS and 5 μg ml−1 polybrene (Sigma
Cells were collected for further experiments 3 days after the last transduction
Transfections were performed in triplicate using Lipofectamine LTX (Life Technologies)
A total of 500,000 cells were seeded into six-well plates the day before transfection
a total of 1 μg of a combination of gRNA plasmids and 1 μg of the plasmid encoding either dCas9-VP64
dCas9-Empty (no effector domain) or (a combination of dCas9-epi-editor(s)
were co-transfected using 2 μl PLUS reagent and 4 μl Lipofectamine LTX
GFP positivity of cells was assessed on a Calibur Flow Cytometer (Beckton Dickenson Biosciences)
Retroviral particles from pRetroX-Tet-On-Advanced (pTet-On; CloneTech
USA) were generated using conventional CaPO4 transfection of HEK293T
Virus-containing supernatant was collected 48 and 72 h post transfection
supplemented with FBS and 5 μg ml−1 polybrene
cells were selected with 1 μg ml−1 geneticin (Gibco/Invitrogen) for 5 days and individual clones were subcultured for testing using the pRetroX-Tight-Luc-Pur
The clone with the highest expression of luciferase after induction was chosen for subsequent use
The coding regions of the fusion proteins of ZFA
PRDM9 and mutPRDM9 were subcloned into the expression vector pRetroX-Tight-Pur (CloneTech) using the BamHI/NotI restriction sites
Retroviral transduction of the plasmids was carried out as described previously using the stable pTet-On HeLa and C33a cells
cells were selected with 1 μg ml−1 geneticin (Gibco/Invitrogen) for 10 days
Expression of the fusion proteins was induced using Dox (100 μg ml−1) for 72 h
Cells were then collected and divided for RNA
Expression of the RASSF1A and PLOD2 genes was assessed using ABsolute qPCR SYBR Green (Thermo Scientific)
In order to achieve a signal with the qRT–PCR
Fold change in messenger RNA expression above control untreated cells was calculated based on the cycle threshold (ΔΔCt) method after normalization to GAPDH expression
The % input was expressed as AE (Ct input−Ct ChIP) × Fd × 100%
where Fd is a dilution compensatory factor and AE represents the primer efficiency
Cells were lysed in RIPA buffer (25 mM Tris–HCl (pH 7.6)
1% sodium deoxycholate and 0.1% SDS; Thermo Scientific) supplemented with Protease Inhibitor Cocktail (Sigma)
An amount of 50 μg of total protein was prepared in 5 × loading buffer supplemented with 10% β-mercaptoethanol and heated for 10 min at 95 °C
Proteins were subjected to SDS–polyacrylamide gel electrophoresisusing 10% polyacrylamide gels
Transfer onto the nitrocellulose membranes was followed by probing with mouse anti-HA antibody (Abcam) at a 1:5,000 dilution
Detection of effector domains was performed with horseradish peroxidase-conjugated anti-mouse secondary antibody at a dilution of 1:5,000
followed by incubation with enhanced chemiluminescence (Amersham)
Statistical tests were performed using the Graphpad Prism 5 software (GraphPad Software)
All experiments were performed at least three times
Relevant comparisons were evaluated by unpaired
A P value of &lt;0.05 was considered statistically significant
The authors declare that all data supporting the findings of this study are available within the article and its <a data-track="click" data-track-label="link" data-track-action="supplementary material anchor" href="/articles/ncomms12284#MOESM748">Supplementary Information</a> files
Writing of H3K4Me3 overcomes epigenetic silencing in a sustained but context-dependent manner
Charting histone modifications and the functional organization of mammalian genomes
An integrated encyclopedia of DNA elements in the human genome
Integrative analysis of 111 reference human epigenomes
The diverse functions of histone lysine methylation
Histone modifications: signalling receptors and potential elements of a heritable epigenetic code
The histone modification pattern of active genes revealed through genome-wide chromatin analysis of a higher eukaryote
Chromatin modifications by methylation and ubiquitination: implications in the regulation of gene expression
The n-SET domain of set1 regulates H2B ubiquitylation-dependent H3K4 methylation
Histone crosstalk: H2Bub and H3K4 methylation
The adjustable nucleosome: an epigenetic signaling module
Combinatorial patterning of chromatin regulators uncovered by genome-wide location analysis in human cells
Tunable and multifunctional eukaryotic transcription factors based on CRISPR/Cas
CRISPR-mediated modular RNA-guided regulation of transcription in eukaryotes
Cas9 effector-mediated regulation of transcription and differentiation in human pluripotent stem cells
Genome-scale transcriptional activation by an engineered CRISPR-Cas9 complex
CRISPR RNA–guided activation of endogenous human genes
synergistic regulation of human gene expression using TALE activators
RNA-guided gene activation by CRISPR-Cas9–based transcription factors
Multiplexed activation of endogenous genes by CRISPR-on
an RNA-guided transcriptional activator system
Functional validation of putative tumor suppressor gene C13ORF18 in cervical cancer by artificial transcription factors
Suppression of breast tumor growth and metastasis by an engineered transcription factor
In vivo selection of combinatorial libraries and designed affinity maturation of polydactyl zinc finger transcription factors for ICAM-1 provides new insights into gene regulation
Prolonged re-expression of the hypermethylated gene EPB41L3 using artificial transcription factors and epigenetic drugs
Targeted silencing of the oncogenic transcription factor SOX2 in breast cancer
Bidirectional modulation of endogenous EpCAM expression to unravel its function in ovarian cancer
Reprogramming epigenetic silencing: artificial transcription factors synergize with chromatin remodeling drugs to reactivate the tumor suppressor mammary serine protease inhibitor
Epigenetic editing: targeted rewriting of epigenetic marks to modulate expression of selected target genes
Epigenome engineering in cancer: fairytale or a realistic path to the clinic
Brave new epigenomes: the dawn of epigenetic engineering
Synthetic epigenetics-towards intelligent control of epigenetic states and cell identity
Epigenome editing by a CRISPR-Cas9-based acetyltransferase activates genes from promoters and enhancers
Induced DNA demethylation by targeting ten-eleven translocation 2 to the human ICAM-1 promoter
Targeted DNA demethylation and activation of endogenous genes using programmable TALE-TET1 fusion proteins
Specific transcriptional enhancement of inducible nitric oxide synthase by targeted promoter demethylation
Using targeted chromatin regulators to engineer combinatorial and spatial transcriptional regulation
Manipulation of prostate cancer metastasis by locus-specific modification of the CRMP4 promoter region using chimeric TALE DNA methyltransferase and demethylase
Towards sustained silencing of HER2/neu in cancer by epigenetic editing
Highly specific epigenome editing by CRISPR-Cas9 repressors for silencing of distal regulatory elements
Epigenetic reprogramming of cancer cells via targeted DNA methylation
Stable oncogenic silencing in vivo by programmable and targeted de novo DNA methylation in breast cancer
Optical control of mammalian endogenous transcription and epigenetic states
Locus-specific editing of histone modifications at endogenous enhancers
Targeted epigenome editing of an endogenous locus with chromatin modifiers is not stably maintained
Modeling gene expression using chromatin features in various cellular contexts
Molecular Basis for the Regulation of the H3K4 Methyltransferase Activity of PRDM9
PRDM9 is a major determinant of meiotic recombination hotspots in humans and mice
Linking DNA methylation and histone modification: patterns and paradigms
Impaired recruitment of the histone methyltransferase DOT1L contributes to the incomplete reactivation of tumor suppressor genes upon DNA demethylation
H3K4me3 interactions with TAF3 regulate preinitiation complex assembly and selective gene activation
Structural insight into the recognition of the H3K4me3 mark by the TFIID subunit TAF3
DNA targeting specificity of RNA-guided Cas9 nucleases
Genome-wide binding of the CRISPR endonuclease Cas9 in mammalian cells
Nucleosomes impede Cas9 access to DNA in vivo and in vitro
Genome-wide mapping of nucleosome positioning and DNA methylation within individual DNA molecules
Reducing lysil hydroxylase 2 expression in a fibrotic environment by introducing repressive epigenetic marks in the PLOD2 promoter
<a data-track="click" data-track-action="download citation references" data-track-label="link" rel="nofollow" href="https://citation-needed.springer.com/v2/references/10.1038/ncomms12284?format=refman&amp;flavour=references">Download references</a>
We kindly acknowledge Dr Steven de Jong for providing the Tera-1 cDNA. The gene encoding the ICAM1-targeted ZF protein was provided by C. Barbas, III. This work was supported by Samenwerkingsverband Noord-Nederland SNN-4D22C-T2007. Networking activities were financially supported by H2020 COST CM1406 ( <a href="http://www.EpiChemBio.eu">www.EpiChemBio.eu</a>)
Department of Pathology and Medical Biology
wrote the manuscript with contributions by all the authors
The authors declare no competing financial interests
Supplementary Tables 1-6 and Supplementary Note 1 (PDF 726 kb)
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Volume 10 - 2019 | <a class="ArticleLayoutHeader__info__doi" href="https://doi.org/10.3389/fmicb.2019.00689">https://doi.org/10.3389/fmicb.2019.00689</a>
This article is part of the Research TopicManufacturing, Formulation And Delivery Issues For Phage Therapy To Become A Reality<a class="Link Link--linkType Link--maincolor Link--medium Link--icon Link--chevronRight Link--right" aria-label="View all 6 articles" href="https://www.frontiersin.org/research-topics/8588/manufacturing-formulation-and-delivery-issues-for-phage-therapy-to-become-a-reality/magazine" target="_self" data-event="customLink-linkType-a_viewAll6Articles">View all 6 articles</a>
This study sheds light on the biodistribution of orally administered
and their transcytosis through intestinal cell layers
Fluorochrome-labeled bacteriophages were used together with a non-invasive imaging methodology in the in vivo visualization of bacteriophages in the stomach and intestinal tract of mice
phage encapsulation resulted in a significant increase of the labeled phages in the mouse stomach
and without a decrease in their concentration
the visualization of encapsulated and non-encapsulated phages in the intestine were similar
Our in vivo observations were corroborated by culture methods and ex vivo experiments
which also showed that the percentage of encapsulated phages in the stomach remained constant (50%) compared to the amount of initially administered product
the use of conventional microbiological methods
which employ bile salts to break down liposomes
prevented the detection of encapsulated phages in the intestine
The ex vivo data showed a higher concentration of non-encapsulated than encapsulated phages in liver
and even muscle up to 6 h post-administration
Encapsulated bacteriophages were able to reach the liver
which persisted over the course of the experiment
Confocal laser scanning microscopy of an in vitro co-culture of human Caco-2/HT29/Raji-B cells revealed that Vybrant-Dil-stained liposomes containing labeled bacteriophages were preferably embedded in cell membranes
No transcytosis of encapsulated phages was detected in this in vitro model
whereas SYBR-gold-labeled non-encapsulated bacteriophages were able to cross the membrane
Our work demonstrates the prolonged persistence of liposome-encapsulated phages in the stomach and their adherence to the intestinal membrane
These observations could explain the greater long-term efficacy of phage therapy using liposome-encapsulated phages
in the present work we studied the adherence of liposome-encapsulated phages to the intestinal barrier and the ability of those phages to cross the barrier
we investigated the in vivo and ex vivo biodistribution of orally administered
liposome-encapsulated bacteriophages using a non-invasive imaging methodology
the presence of bacteriophages in ex vivo organs was determined using culture methods
Phage transcytosis was examined using an in vitro model of the human intestinal barrier
consisting of a triple co-culture of Caco-2 and HT29 intestinal cells with Raji-B lymphocytes
The phages were then washed several times with 10 mM MgSO4 under the same conditions
The final concentration of the purified phage lysate was 1&#x2013;3 &#x00D7; 1012 pfu/mL
The medium was supplemented with 10% fetal bovine serum (FBS)
1% non-essential amino acids (NEAA; PAA Laboratories GmbH
The cell cultures were incubated at 37&#x00B0;C in a humidified atmosphere of 5% CO2 and 95% air
the Caco-2 and HT29 cell lines were sub-cultured once a week with 1% trypsin-EDTA (PAA Laboratories GmbH) at 7.5 &#x00D7; 105 cells/75 cm2 flask and 4 &#x00D7; 105 cells/75 cm2 flask
One mL of each sample was measured without dilution
The mean diameter was the median of three different measurements
The encapsulation efficiency was obtained from three independent encapsulation experiments
the values come from triplicate plates of each dilution
The stained-bacteriophage concentration was also calculated by titration with test strain LB5000
Stained bacteriophage was encapsulated in the liposome mixture as described for the in vivo distribution study
The biodistribution of liposome-encapsulated and non-encapsulated labeled UAB_Phi20 bacteriophage was evaluated in vivo and ex vivo in 5-week-old athymic nude female mice (Mus musculus
The mice were housed in quarantine rooms during an acclimatization period of 8 days and inspected by a veterinarian
The mice were then randomly housed under specific-pathogen-free (SPF) conditions in autoventilated racks
Both liposome-encapsulated and non-encapsulated stained bacteriophages were orally administered by oral gavage of a single dose of 1.3 &#x00D7; 1013 pfu/kg mouse body weight; the dosing volume was 22.4 mL/kg
a non-treated mouse was included as an autofluorescence control of background tissue-fluorescence levels
the whole-body biodistribution of the bacteriophages was measured non-invasively in the mice by VTS-750 fluorescence image monitoring
and blood samples were collected from four animals and bacteriophage accumulation in the respective tissues was determined by ex vivo VTS-750 fluorescence monitoring
all tissues were transferred to MgSO4 buffer (10 mM)
The animals were euthanized by cervical dislocation while still anesthetized
following standard procedures for euthanasia
In vivo and ex vivo FLI was determined using the IVIS Spectrum imaging system (PerkinElmer <a style="color:gray;" href="https://scicrunch.org/resolver/RRID:SCR_012163">RRID:SCR_012163</a>)
Ex vivo FLI values were calculated by measuring the RE of both the dorsal and ventral view of each organ and then considering the weight of each organ
transforming the RE values to the RE per gram of tissue
The in vivo experiments were performed using ICTS &#x201C;NANBIOSIS,&#x201D; specifically, the CIBER-BBN in vivo experimental platform of the Functional Validation &#x0026; Preclinical Research (FVPR) area<a id="note1a"></a><a class="footnoteanchor" href="#note1">1</a> and Laboratory Animal Service (LAS) of Vall d&#x2019;Hebron Institut de Recerca (VHIR; Barcelona)
The animals were treated in compliance with the guidelines of the Ethics Commission (Comit&#x00E9; &#x00C9;tico de Experimentaci&#x00F3;n Animal [CEEA]) of the VHIR
The study was approved and assigned the authorization number 69/15
the transepithelial electrical resistance (TEER) of the cell monolayers was measured using an ohmmeter (Millicell ERS-2 Voltohmmeter; Merck Millipore
Only values >300 &#x03A9;/cm2 were accepted in the analysis
1 &#x00D7; 1010 and 1 &#x00D7; 107 pfu/mL) in DMEM with FBS medium was inoculated on the apical side of the Transwell
bacteriophages from the apical and basolateral sides of the Transwell were quantified on lawns of strain LB5000
the basolateral volume (1.5 mL) was removed and replaced with fresh FBS-containing DMEM
The TEER was measured after each transcytosis test to ensure the integrity and polarization of the cell cultures
Liposome-encapsulated UAB_Phi20 bacteriophage (5 &#x00D7; 109 pfu/well) was assayed at the same time points and under the same conditions but in DMEM without FBS because the presence of FBS resulted in aggregation of the liposomes
Liposome-encapsulated phage was examined by cryogenic transmission electron microscopy (cryo-TEM) using a JEOL JEM-1400 microscope (JEOL, Japan). The samples were prepared as detailed in previous publications (<a href="#B9">Colom et al., 2015</a>; <a href="#B11">Cort&#x00E9;s et al., 2018</a>)
The cell monolayers were observed in a JEOL JEM-1400 microscope (JEOL
Switzerland) software to visualize the confocal stacks and to obtain three-dimensional cross-section images with merged labels
The results are expressed as the mean and SD. A Kolmogorov-Smirnov test was used to check the normality of the samples, and a repeated measure two-way ANOVA and Tukey&#x2019;s multiple comparisons test were performed as appropriate, using GraphPad Prism version 6.00 (GraphPad Prism, <a style="color:gray;" href="https://scicrunch.org/resolver/RRID:SCR_002798">RRID:SCR_002798</a>)
The term &#x201C;the product of phage encapsulation&#x201D; (PPE) is used in the following to refer to this mixture
the RE of dilutions of VTS-750-stained UAB_Phi20 (5.8 &#x00D7; 1011 to 1.1 &#x00D7; 109 pfu/mL) was measured using the IVIS&#x00AE; Spectrum imaging system
Measurements of the same dilutions of PPE and VTS-750-stained UAB_Phi20 showed that
although a quenching effect occurred at higher bacteriophage concentrations
the correlations between fluorescence and the bacteriophage concentration were linear between 4.5 &#x00D7; 109 and 3.6 &#x00D7; 1010 pfu/mL for UAB_Phi20 phage and between 2.3 &#x00D7; 109 and 1.8 &#x00D7; 1010 pfu/mL for PPE
The FLI of the bacteriophage was higher (3.4 &#x00B1; 1.1 times) than that of PPE
indicating that liposome encapsulation resulted in fluorescence attenuation
which was considered in subsequent in vivo measurements
Similar results were achieved following PPE administration
the presence of phages in other tissues was not detected by in vivo fluorescence imaging
In vivo fluorescence images of the biodistribution in mice of VTS-750-stained UAB_Phi20: non-encapsulated phages (A,C) and the products of phage encapsulation (PPE) (B,D)
The ventral side of each mouse was imaged 2.5 h (A,B) and 5.5 h (C,D) after oral administration of the phage preparations (n = 4 mice per group)
The pseudocolor scale bars are consistent for each corresponding view and show the relative changes over time
the FLI in mice treated with UAB_Phi20 and PPE indicated a generally low and variable accumulation of the phages among replicates
attributable to the limit of detection of the imaging technique
at a concentration of stained bacteriophages &#x2264; 7 log10 pfu/g
the imaging methodology did not allow discrimination between the autofluorescence of the mouse tissues and the fluorescence of the stained phages (data not shown)
Ex vivo fluorescence of bacteriophages and PPE in the mouse stomach (A) and intestine (B) 3 and 6 h post-administration
Pseudocolor scale bars are located on the right for each corresponding set of images
(C) Fluorescence accumulation (RE) per tissue weight (g) in the stomach and intestine 3 h (solid) and 6 h (dotted) after the administration of non-encapsulated phages (white) or PPE (gray)
Values of RE/g of PPE were obtained after taking into account the fluorescence attenuation (3.4-fold) observed in the in vitro experiment
The significance of the RE/g values of the encapsulated vs
non-encapsulated phage is shown: &#x2217;&#x2217;&#x2217;P &#x003C; 0.001 and &#x2217;P &#x003C; 0.05
Bacteriophage concentrations in ex vivo organs obtained from mice orally administered bacteriophages and the products of phage encapsulation (PPE)
All tissues from the untreated animals were negative for bacteriophages
It should be noted that encapsulated bacteriophages were not found in the basolateral compartment at any of the sampling times
the percentage of encapsulated phages in the apical section did not change during the experiment
regardless of the initially applied concentration (data not shown)
Transcytosis of non-encapsulated phage (A&#x2013;C) and PPE (D) across an intestinal epithelial monolayer
The bacteriophage concentration was quantified 2
and 48 h post-inoculation by titration of the contents of the apical (black &#x25CF;
DMEM supplemented with FBS was used to study the non-encapsulated bacteriophages (A,B) and serum-free DMEM to compare the transcytosis of non-encapsulated phages (C) and PPE (D)
The concentrations applied in the apical chamber were 1 &#x00D7; 1010 pfu/mL (circles) and 1 &#x00D7; 107 pfu/mL (squares)
Scatter plots show the means; error bars represent the 95% confidence intervals
The phage concentration in the basolateral chamber is the sum of the values obtained at each time point
and z scans of the in vitro Caco-2/HT29/Raji-B lymphocytes co-culture model
The results obtained with the non-treated (A)
bacteriophage-treated (B) and PPE (C) treated cultures at 2 h are shown
Cell nuclei were stained with Hoechst 33242 (blue)
The plasma membrane was stained with CellMask DeepRed (gray)
Red squares indicate the regions where the stained phages (B) or PPE (C) were visualized
Three-dimensional images of a cross-section of the intestinal barrier model based on a Caco-2/HT29/Raji-B lymphocytes co-culture treated with bacteriophages (A) and PPE (B&#x2013;D)
(A) Non-encapsulated phages (green) are seen inside the cells
(B) Only encapsulated phages (green) are shown inside the cells (gray
(C) Merging of all labels with the liposomes (red) covering the encapsulated phages detailed in (B)
The white square indicates the non-encapsulated phages (A)
(D) A detail of the basolateral side of the intestinal barrier (sited in the upper side of the image) shows the presence of liposomes (red) inside the cells
The enlarged image shows phages released from the liposomes
The purpose of this work was to investigate the adherence of encapsulated phages in liposomes to the intestinal barrier and the ability of the phages to cross this barrier
The behavior of the encapsulated phages was studied in an athymic nude mouse model using a non-invasive methodology based on the visualization of fluorophore-labeled bacteriophages administered orally in a single dose
Although our original intent was to determine the biodistribution of encapsulated phages in chickens
technical problems related to the autofluorescence of the down of the chicks prevented the development of this model
We thus hypothesized a high retention capacity of encapsulated bacteriophages in the stomach that enabled the slow delivery and continuous presence of the bacteriophages in the intestine
thereby contributing to prolonged and successful oral phage therapy
The in vivo and ex vivo data presented herein provide further support for this hypothesis
the results of those studies demonstrated the utility of molecular imaging to track phages within living systems
the phages were administered by intraperitoneal injection
which may account for the differences compared to our study
The in vivo and ex vivo results obtained in our mouse model indicated the preferential accumulation of encapsulated bacteriophages in the stomach
at least during the first 6 h post-administration
and that after reaching the intestine they translocated to other organs and tissues
Translocation seems to be a rapid process because encapsulated phages were not found in the intestine as early as 3 h after their oral administration
the continued presence of encapsulated bacteriophages in the intestine cannot be ruled out because homogenization of the intestinal tissue in MgSO4
breaks the phage capsules in a process mediated by the intestinal bile salts of the host mice
encapsulated bacteriophages were found in internal organs
the model used in this study can be employed in other investigations of phage transcytosis
The percentage of bacteriophages that crossed the membrane following PPE administration was also low (<a href="#F3">Figure 3D</a>) and encapsulated bacteriophages could not be detected using conventional microbiological methods (data not shown). Nevertheless, in this model, liposome capsules were seen adhering to the cell surface as aggregates, embedded in the cell membrane, and even present inside the cells (<a href="#F5">Figures 5C,D</a>)
These observations and the detection of bacteriophages inside the liposomes together suggest that liposomes protect phages against their elimination from the intestinal tract by excretion
Following the eventual release of these phage from the liposomes
these results could not be compared with those obtained in our in vivo model because the Transwell membrane obviously does not reproduce the open system of the intestinal tract
This study is the first to demonstrate the biodistribution and transcytosis of orally administered
In a murine model based on a non-invasive methodology
labeled phages were visualized in the mouse stomach and intestine
conventional culture methods revealed the additional presence of liposome-encapsulated phages in the stomach and other internal organs
The adherence of liposome-containing phages to human intestinal cells
and the transcytosis of the phages was evidenced by CLSM
Our results contribute to the development of treatment options based on oral phage therapy
further efforts are required to improve bacteriophage labeling or in vivo imaging in order to track the dissemination of liposome-encapsulated phages
The in vivo experiments were performed by in the ICTS &#x201C;NANBIOSIS,&#x201D; specifically, by the CIBER-BBN&#x2019;s in vivo experimental platform of the Functional Validation &#x0026; Preclinical Research (FVPR) area (<a href="http://www.nanbiosis.es/portfolio/u20-in-vivo-experimental-platform/">http://www.nanbiosis.es/portfolio/u20-in-vivo-experimental-platform/</a>) and Laboratory Animal Service (LAS) of Vall d&#x2019;Hebron Institut de Recerca (VHIR; Barcelona)
The animals were treated in agreement with the guidelines of the Ethics Commission [Comit&#x00E9; &#x00C9;tico de Experimentaci&#x00F3;n Animal (CEEA)] of the VHIR
JO executed most of the bacteriophage experiments
including the ex vivo experiments using conventional microbiology methods
AG-R assisted in establishing and maintaining the intestinal cell cultures
MC-S assisted in bacteriophage encapsulation
PC and ML contributed to the design of the study
All authors read and approved the final version of the manuscript
This work was supported by the Ministerio de Econom&#x00ED;a
Industria y Competitividad in Spain grant BIO2016&#x2013;77011-R
JO and AG-R received predoctoral fellowships from the UAB
ICN2 is supported by the Severo Ochoa program from Spanish MINECO (Grant No
PC and ML are the inventors in patent application EP2750519
We are grateful to the Servei de Microsc&#x00F2;pia of the UAB for their support
Colom for his assistance in carrying out preliminary experiments in the in vivo biodistribution studies
Ruiz for their excellent technical assistance
The Supplementary Material for this article can be found online at: <a href="https://www.frontiersin.org/articles/10.3389/fmicb.2019.00689/full#supplementary-material">https://www.frontiersin.org/articles/10.3389/fmicb.2019.00689/full#supplementary-material</a>
FIGURE S1 &#x007C;(A) Cryo-TEM image of liposome-encapsulated UAB_Phi20; (B) 3D confocal images of SYBR gold-labeled UAB_Phi20 encapsulated into fluorescent Dil-labeled liposome (red)
3D image of liposome surface is shown on the left and its cross-section images on the right
FIGURE S2 &#x007C; Epithelial cell monolayer TEM images after 48 h of incubation with the non-encapsulated bacteriophage
Tight junctions are indicated by a white ellipse
TABLE S1 &#x007C; Determination of the encapsulation yield (%) of UAB_Phi20 after three independent experiments
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*Correspondence: Pilar Cort&#x00E9;s, <a id="encmail">bWFyaWFwaWxhci5jb3J0ZXNAdWFiLmNhdA==</a>
Stage 17 of the 2023 Tour de France was a momentous occasion for <a href="https://www.flobikes.com/people/10162238-felix-gall" rel="noopener noreferrer" target="_blank">Felix Gall</a>
who claimed his first stage win in his inaugural Tour
The 27-year-old AG2R-Citroen rider lands at the eighth spot in the general standings.&nbsp;
Cyclists rolled into Courchevel, France on July 19, and while Gall won the stage, defending champion <a href="https://www.flobikes.com/people/7074685-jonas-vingegaard" rel="noopener noreferrer" target="_blank">Jonas Vingegaard</a> kept his dominant lead in the race.&nbsp;
Vingegaard has controlled the yellow jersey for the majority of the 2023 Tour de France
On stage 17&nbsp;he showed his competitors exactly why he has such a strong hold in the general standings.&nbsp;
He flew up the final ascent and faced the steep climbs alone
finishing stage 17 in fourth-place but continuing his top rank in the general classification.&nbsp;
Here are the Tour de France 2023 general standings and stage 17 results:
A live broadcast will be available on NBC and Peacock
and behind-the-scenes coverage throughout the entire event
FloBikes will provide a live broadcast for Canadian audiences
The Tour de France begins July 1 and finishes July 23 at the Champ-Elyees
The complete route is divided into 21 stages featuring different types of terrain and distance
<a href="https://www.flobikes.com/events/8209007-2023-tour-de-france/schedule" rel="noopener noreferrer" target="_blank">Here is the full Tour de France schedule.</a>
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Schizophrenia may represent a trade-off in the evolution of human-specific ontogenetic mechanisms that guide neurodevelopment
Human Accelerated Regions (HARs) are evolutionary markers functioning as neurodevelopmental transcription enhancers that have been associated with brain configuration
we have investigated the influence of HARs’ polygenic load on neuroanatomical measures through a case-control approach (128 patients with schizophrenia and 115 controls)
we have calculated the global schizophrenia Polygenic Risk Score (Global PRSSZ) and that specific to HARs (HARs PRSSZ)
We have also estimated the polygenic burden restricted to the HARs linked to transcriptional regulatory elements active in the foetal brain (FB-HARs PRSSZ) and the adult brain (AB-HARs PRSSZ)
We have explored the main effects of the PRSs and the PRSs x diagnosis interactions on brain regional cortical thickness (CT) and surface area (SA)
The results indicate that a higher FB-HARs PRSSZ is associated with patients’ lower SA in the lateral orbitofrontal cortex
the pars triangularis and the paracentral lobule
While noHARs-derived PRSs show an effect on the risk
our neuroanatomical findings suggest that the human-specific transcriptional regulation during the prenatal period underlies SA variability
highlighting the role of these evolutionary markers in the schizophrenia genomic architecture
while the foundations of this multifactorial and complex disorder are not entirely understood
multiple pieces of evidence straightforwardly point towards a neurodevelopmental and evolutionary origin
HARs modulation of brain measures in SZ has been scarcely explored
and further studies using brain-based phenotypes to assess their role in the disorder are necessary
based on the evidence of HARs’ role in neurodevelopment
brain configuration and susceptibility for SZ
we aimed to investigate the modulatory effect of HARs’ polygenic load on neuroanatomical measures through a neuroimaging genetics approach in healthy controls and patients with SZ
We generated different PRSs summarising HARs’ genetic variability
specifically including HARs SNPs related to active regulatory elements in the foetal and adult brain
We explored whether the PRSs modulated CT and SA differently depending on the health/disease condition
Our findings point to a specific effect of HARs linked to foetal brain regulatory elements on patients’ cortical SA
emphasising the importance of human-specific changes in early neurodevelopment and in the structural changes associated with the disorder
When examining the extent to which the four PRSs modulated CT and SA measures of each cortical region, we detected that no PRS estimate influenced the CT in HC or patients with SZ. Along the same line, the PRSs x diagnosis interactions on CT did not evidence significant effects (Supplementary Data <a data-track="click" data-track-label="link" data-track-action="supplementary material anchor" href="/articles/s42003-023-05356-2#MOESM3">2</a>)
</a>Brain plots include the lateral and medial sagittal views for the right hemisphere
The coloured regions are the ones with significant FB-HARs PRSSZ effect on surface area (SA)
and the unstandardised SA residuals (estimated regressing out the covariates)
These  plots evidence the negative correlation between the two measures (black solid line and black dashed lines representing the regression line and the 95% confidence intervals
Each region is numerically labelled as follows: (1) superior temporal cortex; (2) lateral orbitofrontal cortex; (3) pars triangularis; and (4) paracentral lobule
</a>Functional annotation results derived from FUMA (<a href="https://fuma.ctglab.nl/">https://fuma.ctglab.nl/</a>) in Gene Ontology (GO) categories for biological processes (a)
followed by the proportion of the overlapping genes
the associated p-value after FDR correction (Enrichment P-value)
our study is the first to assess the effect of HARs genetic variability on brain cortical measures in patients with SZ and healthy controls
These analyses provide evidence of the impact of foetal active regulatory HARs on the cortical surface area of different brain regions in patients with SZ
These findings highlight the importance of human-specific genetic changes guiding human brain cortical architecture
particularly those affecting the gene-expression machinery active during prenatal stages
that joint analysis of common and rare variants can help disentangling the role of HARs variability on the susceptibility for the disorder and its specific phenotypes
other genetic evolutionary markers could be more suitable for inspecting the evolutionary traces of CT
our study adds evidence on the role of the genetic variability within HARs guiding foetal neurodevelopment and shaping cortical surface area configuration in patients with SZ
The biological plausibility of our findings highlights the importance of HARs in the early developmental gene regulatory machinery and suggests that these regions may contribute to bridging together the neurodevelopmental and evolutionary hypotheses in schizophrenia
All participants met the same exclusion criteria
which included suffering from major medical illness
conditions affecting cognitive or brain function
history of head trauma with loss of consciousness and present or history of drug abuse or dependence
exclusion criteria also included personal or family history of psychiatric service contact or treatment
A group matching procedure was conducted to minimise the differences across diagnostic groups while maximising the sample size. Therefore, the analyses were conducted in a sample of 115 HC and 128 patients diagnosed with SZ with no age and sex differences between them (Table <a data-track="click" data-track-label="link" data-track-action="table anchor" href="/articles/s42003-023-05356-2#Tab2">2</a>)
All subjects signed a written consent after being fully informed about the procedures and implications of the study
approved by the Germanes Hospitalàries Research Ethics Committee
and performed following its guidelines and in accord with the Declaration of Helsinki
All ethical regulations relevant to human research participants were followed
Genomic DNA was extracted from buccal mucosa through cotton swabs or peripheral blood cells using Realpure Saliva or Blood kits (Durviz
A MAF value of &gt;1% and an imputation quality of R2 &gt; 0.3 were required for the inclusion of the variants into further analyses
our final SNP dataset included 7,606,397 genetic markers
This method is defined as the sum of allele counts
weighted by estimated effect sizes obtained from the GWAS
after two filtering steps: LD clumping (based on the European population from phase 3 of the 1000 Genomes Project reference panel) and p-value thresholding
we calculated the whole-genome PRS (Global PRSSZ)
The LD filtering was conducted by including the most significant SNP from any pair showing an LD r2 &gt; 0.015 within 1000 kb windows
resulting in a set of informative linkage-disequilibrium independent markers (98,121 SNPs)
we considered a range of thirteen p-value thresholds: p &lt; 5 × 10−8
we established the best threshold in p &lt; 5 × 10−3 as the better predictor of the diagnosis status based on Nagelkerke’s pseudo-R2 (p = 4.75 × 10−12
The MRI neuroimaging data were obtained from two scanners: 58% (70 HC
72 patients) of the sample was scanned in a 1.5 T GE Sigma scanner (General Electrical Medical Systems
56 patients) in a 3 T Philips Ingenia scanner (Philips Medical Systems
The Netherlands) at Hospital Sant Joan de Déu (Barcelona
High-resolution structural-T1 MRI data in the 1.5 T scanner was obtained using the following acquisition parameters: matrix size 512 × 512; 180 contiguous axial slices; voxel resolution 0.47 × 0.47 × 1 mm3; echo time (TE) = 3.93 ms
repetition time (TR) = 2000 ms; and flip angle = 15°
structural T1-weighted sequences were acquired as follows: matrix size 320 × 320 × 250; voxel resolution 0.75 × 0.75 × 0.80 mm3; TE = 3.80 ms
All images were visually inspected to exclude those with artefacts and movement
mean values of CT and SA were quantified for each individual
the global mean CT and the total SA were also considered
Demographic and clinical data were processed and analysed using SPSS (IBM SPSS Statistics
To assess whether PRSs modulate patients’ clinical profiles
we tested the effect of the four PRSs estimations on age at onset
and antipsychotic medication dose by means of linear regression models (controlled by sex)
to determine if the detected anatomical changes were related to the clinical profiles of patients
we analysed whether the SA changes impacted their age at onset
and PANSS scores by means of linear regression models
we regressed the SA residuals from the four significant cortical regions of interest (obtained after regressing age
and antipsychotic medication) on the clinical phenotypes (controlling for age
The positional mapping parameters were left as default
The eQTL mapping was conducted in PsychENCODE
ComminMind and BRAINEAC tissues filtering by PsychENCODE and brain open chromatin atlas annotations
The 3D chromatin interaction mapping was built-in PsychENCODE and Hi-C adult and foetal cortex
dorsolateral and hippocampus and neural progenitor cells data
filtered by PsychENCODE and brain open chromatin atlas annotations
The p-values from each of the before mentioned statistical tests were adjusted using the false discovery rate (FDR) method
precisely the Benjamini-Hochberg procedure
to control for multiple comparisons at level q = 0.05
only those results with a corrected FDR-pval&lt;0.05 are reported as statistically significant
Further information on research design is available in the <a data-track="click" data-track-label="link" data-track-action="supplementary material anchor" href="/articles/s42003-023-05356-2#MOESM4">Nature Portfolio Reporting Summary</a> linked to this article
The data supporting the findings of this study are available from the corresponding authors upon reasonable request
The custom code used for the analyses of this study is available from the corresponding authors upon reasonable request
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This study received project funding from the Brain &amp; Behavior Research Foundation (NARSAD Young Investigator Award) to MF-V (grant ID 26206)
Researchers were supported by: (i) Instituto de Salud Carlos III (ISCIII) through the contracts FI19/0352 to MG-R
and CP20/00072 to MF-V (co-funded by European Regional Development Fund (ERDF)/European Social Fund “Investing in your future”); (ii) la “Caixa” Foundation through the Junior Leader Fellowship contract LCF/BQ/PR22/11920017 to PF-C; (iii) the Swiss National Science Ambizione grant PZ00P2_185814 to EJC-R; (iv) Júlia Gil Pineda Research Fellowship to ER-C
We thank the Comissionat per a Universitats i Recerca del DIUE of the Generalitat de Catalunya (Agència de Gestio d’Ajuts Universitaris i de Recerca (AGAUR
CeGen PRB3 is supported by grant PT17/0019 of the PE I + D + i 2013–2016
These authors jointly supervised this work: Edith Pomarol-Clotet
FIDMAG Germanes Hospitalàries Research Foundation
Edith Pomarol-Clotet &amp; Mar Fatjó-Vilas
CIBERSAM (Biomedical Research Network in Mental Health; Instituto de Salud Carlos III)
Institute of Psychiatric Phenomics and Genomics (IPPG)
École Polytechnique Fédérale de Lausanne (EPFL)
conducted the DNA extraction and sample normalisation for genotyping
pre-processed and segmented the MRI images
conducted the recruitment and/or the clinical evaluation
conducted the formal statistical analyses and graphical representations with the help of C.A.-P.
wrote the first and subsequent drafts of the paper
supervised the study activity planning and execution
All the authors reviewed and approved the final manuscript
Communications Biology thanks Noriyoshi Usui
reviewer(s) for their contribution to the peer review of this work
Primary Handling Editors: Karli Montague-Cardoso and Christina Karlsson Rosenthal
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations
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DOI: https://doi.org/10.1038/s42003-023-05356-2
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Bastille Day fell on stage 13 of the <a href="http://Tour%20de%20France" rel="noopener noreferrer" target="_blank">2023 Tour de France</a>.&nbsp;
On July 14, 167 cyclists set off from Châtillon-Sur-Chalaronne to face the Grand Colombier finale. They started on a relatively flat route, but the final kilometers comprised one of the most challenging Hors Catégorie of this year’s Tour de France, the <a href="https://www.flobikes.com/articles/11125095-bastille-day-stage-could-spark-fireworks-in-tour-de-france-duel" rel="noopener noreferrer" target="_blank">Col du Grand Colombier.&nbsp;</a>
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The finish line for this stage lies right at the crest of the summit
and it was a furious fight for the stage win.&nbsp;
<a href="https://www.flobikes.com/people/6717119-adam-yates" rel="noopener noreferrer" target="_blank">Adam Yates</a> went for a massive attack in the final 2 kilometers and finished in 10th place behind his brother
The UAE Team Emirates rider now stands in 5th for the general classification
<a href="https://www.flobikes.com/people/6716980-tadej-pogacar" rel="noopener noreferrer" target="_blank">Tadej Pogača</a>r waited until the absolute last moment to attack past <a href="https://www.flobikes.com/people/7074685-jonas-vingegaard" rel="noopener noreferrer" target="_blank">Jonas Vingegaard</a>
crossing the line four seconds ahead of him.&nbsp;
Pogačar is still in second place for the general classifications.&nbsp;
<a href="https://www.flobikes.com/search?q=Kwiatkowski&amp;page=1" rel="noopener noreferrer" target="_blank">Michal Kwiatkowski</a> was the leader in the last 10 kilometers
with the general classification riders close behind
He was too fast for the chasing group and rode solo across the finish line
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Sixty participants with SCID-5 confirmed DSM-5 diagnosis related with paranoid thinking and without mood symptoms were recruited. In order to test the existence of a two continua model of mental health (CSMH), we conducted a parallel analysis and an exploratory factor analysis. To test our hypothesis regarding the partially mediating role of doubt between paranoid thinking and patients’ well-being, we conducted a biased corrected bootstrapping procedure.
As expected, two different unipolar dimensions emerged from the measures used to assess paranoid thinking and positive health (two continua model of mental health). When patients received metacognitive and pharmacological treatment, more paranoid thinking led to more doubt in all thoughts, which in turn affected well-being. The analyses carried out confirmed the partial mediating role of doubt.
Despite the efficacy shown by both metacognitive therapies and antipsychotics, it seems that they not only reduce pathological confidence, but can also affect other thoughts not linked to delirium. This effect of generalization of doubt in all thoughts negatively affected patients’ well-being and quality of life.
Volume 10 - 2019 | <a class="ArticleLayoutHeader__info__doi" href="https://doi.org/10.3389/fpsyg.2019.02099">https://doi.org/10.3389/fpsyg.2019.02099</a>
Introduction: Pathological confidence in one&#x2019;s thoughts is a key mechanism of chronic paranoid thinking
many of the current therapies focus on trying to reduce it
haloperidol) work seems to be through the induction of doubt
Because of the impact of these pathological thoughts on positive health
studying the well-being of people who experience paranoid thoughts is fundamental
The first objective of this research is to apply the Complete State Model of Health (CSMH) to a sample of patients characterized by the presence of paranoid thinking
Our second objective is to evaluate the impact of therapies based on reducing pathological confidence on patients&#x2019; well-being
Methods: Sixty participants with SCID-5 confirmed DSM-5 diagnosis related with paranoid thinking and without mood symptoms were recruited
In order to test the existence of a two continua model of mental health (CSMH)
we conducted a parallel analysis and an exploratory factor analysis
To test our hypothesis regarding the partially mediating role of doubt between paranoid thinking and patients&#x2019; well-being
we conducted a biased corrected bootstrapping procedure
two different unipolar dimensions emerged from the measures used to assess paranoid thinking and positive health (two continua model of mental health)
When patients received metacognitive and pharmacological treatment
more paranoid thinking led to more doubt in all thoughts
The analyses carried out confirmed the partial mediating role of doubt
Conclusion: Despite the efficacy shown by both metacognitive therapies and antipsychotics
it seems that they not only reduce pathological confidence
but can also affect other thoughts not linked to delirium
This effect of generalization of doubt in all thoughts negatively affected patients&#x2019; well-being and quality of life
Although it is especially interesting to apply the CSMH in the study of disorders related to paranoid thinking, to the best of our knowledge there are no studies that have proven the existence of two axes in these disorders. There is just one study in which the CSMH has been applied in the study of schizophrenia spectrum disorders (<a href="#B13">Chan et al., 2018</a>)
but in that study the existence of two-dimensions related to mental illness and positive mental health was not examined
the first objective of the present research is to apply the CSMH to a sample of patients with paranoid thinking to explore the two different unipolar dimensions: paranoid thinking and positive mental health (i.e.
we expect that paranoid thinking and positive mental health will be correlated
Finally, our second objective is to study how metacognitive and pharmacological therapies influence confidence in thoughts of people with paranoid thinking. Based on previous research (<a href="#B50">Moritz et al., 2014a</a>; <a href="#B22">Eichner and Berna, 2016</a>) our next hypothesis is that therapies will reduce pathological confidence
we also expect that these therapies will generate extreme doubt in all thoughts
and not only the ones associated with delirium
Given that confidence is a key element of positive functioning
this adverse metacognitive effect of generalization of doubt would affect patients&#x2019; positive health (i.e.
we expect doubt to partially mediate the effect of paranoid thinking on patients&#x2019; well-being
for a complete description of the therapy)
patients received 562 min of metacognitive therapy (SD = 51 min)
The study was approved by the ethics committee of the &#x201C;Universidad de Castilla &#x2013; La Mancha&#x201D; (UCLM) and the HGUCR (Comit&#x00E9; &#x00C9;tico de Investigaci&#x00F3;n Cl&#x00ED;nica HGUCR-UCLM)
All participants were informed that all collected information was confidential and anonymous
To avoid possible order effects of the two sets of scales
half of the participants first completed the PIQ
the Positive Affect Scale and the Psychological Well-being Scales
The other half first completed the well-being scales and
Participants were asked to rate each item on a 5-point scale ranging from 0 (certainly false) to 4 (certainly true)
The evaluations of well-being scales and semi-structured interviews converged for 58 patients (96.7%)
we used the result of the semi-structured interview
To assess participants&#x2019; subjective feeling of doubt in general thoughts two items anchored at not at all (1) and extremely (9) asking how much doubt they had in their general thoughts and how invalid they considered their general thoughts
Ratings were highly intercorrelated (r = 0.87)
so they were averaged to create a composite doubt index
Higher values on this index indicated more doubt in general thoughts
Some factors can produce spurious associations
particularly in a non-experimental study such as the present one
and DSM-5 diagnosis were introduced as covariates in mediation analysis
The psychological well-being scales were all significantly correlated with PIQ
PADS-P and PADS-D (with the exception of the correlation between Personal Growth and PIQ)
the autonomy scale showed stronger relation to paranoid thinking than the rest of the scales
the subjective well-being scales showed a weak relationship with paranoid thinking
Only the relationship between life satisfaction and PIQ was significant
and Cronbach alpha coefficients (&#x03B1;) of paranoid thinking
Exploratory factor analysis of paranoid thinking scales and well-being measures
Pearson&#x2019;s correlations and 95% confidence intervals of paranoid thinking scales and well-being measures
Contingency table of mental disorder diagnosis and positive health
Doubt in one&#x2019;s thoughts as a mediator between Paranoid Thinking and Well-being
&#x2013;0.28) is the direct effect of Paranoid Thinking on Well-being while accounting for the effect through the indirect path (&#x2217;p &#x003C; 0.05)
the induction of doubt is also one of the effects of antipsychotic drugs
the main objective of this research was to analyze the effect of doubt (vs
confidence) caused by this type of therapies (i.e.
metacognitive and pharmacological based on antipsychotics) on patients&#x2019; well-being and quality of life
Future studies could explore if this &#x201C;sleeper&#x201D; effect is related to the recovery of confidence in thoughts not related to delirium
to improve patients&#x2019; well-being and quality of life
it seems interesting to design interventions to increase confidence in thoughts not related to delirium
we found a significant relationship between the duration of metacognitive treatment and doubt in general thoughts
Future investigations should further explore this question
This effect of generalization of doubt in all thoughts must be controlled
given that it negatively affects patient&#x2019;s well-being and quality of life
The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request
This study was part of a research project funded by the Spanish Ministry of Education and Science
and was approved by the ethics committee of the &#x201C;Universidad de Castilla &#x2013; La Mancha&#x201D; (UCLM) and the HGUCR (&#x201C;Comit&#x00E9; &#x00C9;tico de Investigaci&#x00F3;n Cl&#x00ED;nica
All participants completed an informed consent form
assuring them that all information they provided would remain confidential and anonymous
and TR-C contributed to the critical revisions of the manuscript
and approved the final version of the manuscript for submission
This research was supported by the Ministry of Economy and Competitiveness &#x2013; Government of Spain (PSI2017-83303-C2-2-P)
The Supplementary Material for this article can be found online at: <a href="https://www.frontiersin.org/articles/10.3389/fpsyg.2019.02099/full#supplementary-material">https://www.frontiersin.org/articles/10.3389/fpsyg.2019.02099/full#supplementary-material</a>
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Copyright &#x00A9; 2019 Asensio-Aguerri, Beato-Fern&#x00E1;ndez, Stavraki, Rodr&#x00ED;guez-Cano, Bajo and D&#x00ED;az. This is an open-access article distributed under the terms of the <a rel="license" href="http://creativecommons.org/licenses/by/4.0/" target="_blank">Creative Commons Attribution License (CC BY)</a>
*Correspondence: Dar&#x00ED;o D&#x00ED;az, <a id="encmail">ZGFyaW8uZGlhekB1Y2xtLmVz</a>
Alzheimer&#39;s Disease and Related Dementias
Volume 15 - 2023 | <a class="ArticleLayoutHeader__info__doi" href="https://doi.org/10.3389/fnagi.2023.1162747">https://doi.org/10.3389/fnagi.2023.1162747</a>
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Being overweight and obesity are world health problems
defined as abnormal or excessive fat accumulation that increases the risk of chronic diseases
generating hypertrophic adipocytes that produce various pro-inflammatory molecules
These molecules cause chronic low-intensity inflammation
affecting the organism&#x2019;s functioning and the central nervous system (CNS)
The neuroinflammatory response during obesity occurs in different structures of the CNS involved in memory and learning
Here we analyzed how obesity-related peripheral inflammation can affect CNS physiology
generating neuroinflammation and promoting cellular senescence establishment
Since some studies have shown an increase in senescent cells during aging
we proposed that cellular senescence participation may contribute to the cognitive decline in an obesity model of middle-aged female Wistar rats
The inflammatory state of 6 and 13&#x2009;months-old female Wistar rats fed with a hypercaloric diet was measured in serum and CNS (cortex and hippocampus)
Memory was evaluated using the novel object recognition (NOR) test; the presence of senescent markers was also determined
Our data suggest that the systemic inflammation generated by obesity induces a neuroinflammatory state in regions involved in learning and memory
thus proposing senescence as a potential participant in the negative consequences of obesity in cognition
Moreover, clinical studies have shown that obesity increases the risk of developing mild cognitive impairment in short-term memory and executive function (<a href="#ref41">Nguyen et al., 2014</a>); however
In addition, it has been reported that organisms fed with high-fat diets present an accumulation of senescent cells in tissues such as the prostate, heart, and adipose tissue with implications for the inflammatory state (<a href="#ref67">Wang et al., 2009</a>; <a href="#ref63">Tikoo et al., 2017</a>). Recently, <a href="#ref8">Bussian et al. (2018)</a> reported that the accumulation of senescent astrocytes and microglia increased neurodegeneration and cognitive decline
They observed that eliminating senescent cells prevented reactive gliosis and neurodegeneration in the cortex and hippocampus
Two tumor suppressor pathways establish the CS, p53/p21, and p16INK4a/pRB, which can be used as proteins to validate the senescent state (<a href="#ref36">McHugh and Gil, 2018</a>). Animal models, mainly rodents, have been advantageous in studying obesity. Dietary manipulations through high-calorie intake are the most used for maintaining a more remarkable similarity with the establishment of obesity in humans (<a href="#ref66">Von Diemen et al., 2006</a>)
The objective of this study was to determine the effect of systemic inflammation produced by the chronic consumption of a hypercaloric diet on the establishment of senescence in the brain and its impact on cognitive deterioration in the obesity model of female Wistar rats
All chemicals and reagents were purchased from Sigma Chemical Co
The reagents obtained from other sources are detailed throughout the text
Sixty-four female Wistar rats (Rattus norvegicus) we used in this study
The animal was provided by the closed breeding colony at the Universidad Aut&#x000F3;noma Metropolitana-Iztapalapa (UAM-I)
They were housed four-per-cage in polycarbonate cages in a 12&#x2009;h light&#x2013;dark cycle and had free access to water and food
The animals&#x2019; health status was constantly evaluated
A good state of health was considered when the animals did not have tumors
or ear infections and when they ate and drank properly
Rats with tumors and those that went blind were discarded from the study
All animal procedures were strictly carried out according to Mexican Official Ethics Standard NOM-062-ZOO-1999 and the Standard for the disposal of biological waste (NOM-087-ECOL-1995)
the 64 rats were randomly distributed into two groups: the Standard Diet (SD) group (n&#x2009;=&#x2009;32) and the hypercaloric diet (HD) group (n&#x2009;=&#x2009;32)
The animals were euthanized at 13&#x2009;months of age
HD diet was prepared following the protocols previously reported (<a href="#ref4">Bautista et al., 2017</a>; <a href="#ref64">Toledo-P&#x000E9;rez et al., 2021</a>)
The HD is based on an obesogenic diet with 23.5% protein
The rats started consuming HD after weaning (at 21&#x2009;days old) until they were euthanized at 13&#x2009;months of age
The SD groups were fed an Abene BDL-7100 diet containing 23% protein
The results represent the consumption per box divided by the number of animals per box
Animals were weighed and measured monthly to obtain the morphometric dimensions. The weight and naso-rectal length were used to obtain the Lee index to diagnose obesity in small animals, and those with an index greater than 0.30 were considered obese animals (<a href="#ref61">Su&#x000E1;rez Rom&#x000E1;n et al., 2013</a>)
Rats were weighed with a digital scale 0SX40-SMART (Torrey
the tissue was homogenized using a polytron PTMR2100 7,549 (Omni International)
As reported previously, the NOR test was used to evaluate short-term and working memory in SD and HD groups at 6 and 13&#x2009;months of age (<a href="#ref2">Antunes and Biala, 2012</a>; <a href="#ref56">Sant&#x000ED;n-M&#x000E1;rquez et al., 2021</a>)
The NOR test was performed using a 45&#x2009;&#x000D7;&#x2009;45&#x2009;&#x000D7;&#x2009;45&#x2009;cm acrylic box
Each rat was introduced into the box for 5&#x2009;min daily over three consecutive days as a training period
Two random objects with different geometric shapes were placed in the box
and the animals explored them for 5&#x2009;min
The exploration time for each object was recorded
The objects were changed and cleaned with 70% vol/vol ethanol before and between use
the test was performed by placing one of the objects previously presented along with a novel one
The animals were then allowed to explore for 5&#x2009;min
and the interaction time and the number of interactions with the old and new objects were recorded
The Novel preference index was calculated by dividing the time spent exploring the novel object by the total exploration time multiplied by 100 to obtain a percentage value
Proteins (30&#x2009;&#x03BC;g) from each fraction protein were separated on 12% SDS-PAGE
transferred to polyvinylidene difluoride membranes (Inmobilon-P
and incubated with specific primary antibodies against anti-&#x03B2;actin (sc-47,778)
Membranes were washed three times with TBS-Tween and incubated with a horseradish peroxidase-conjugated secondary antibody dilution (1:1000; Santa Cruz Biotechnology
the blots were developed using a commercial chemiluminescence reagent
The proportion of these proteins was quantified by densitometric analysis using Kodak Molecular Imaging Software (v.4.5.1)
Rats were perfused transcardially with 4% paraformaldehyde in PBS and drop-fixed in 4% paraformaldehyde for 24&#x2009;h
The brains were rapidly dissected and immersed in PBS/30% sucrose for 24&#x2009;h
The brains were washed with PBS and embedded in tissue-tek (4,583 Sakura finetek
Brain coronal sections (24&#x2009;&#x03BC;m) from the frontal cortex were mounted serially
The &#x03B2;-galactosidase activity was analyzed following the protocol described previously [26]
Brain sections were fixed with 4% paraformaldehyde
and stained with a solution containing 20&#x2009;mg/ml of X-gal (V394A
0:2 M citric acid/sodium phosphate buffer pH&#x2009;=&#x2009;6
Sections were incubated for 12&#x2009;h at 37&#x000B0; C
All data were analyzed and graphed with Prism 8 (GraphPad Software)
Specific tests were performed according to each experimental design and are indicated in each figure
the length increased in both groups over time
with 6% growth in the SD group and 9% in the HD group
no significant differences were found between them
indicating that the physical development of the animals was similar regardless of the diet
Animal body weight was evaluated monthly (n&#x2009;=&#x2009;17 SD and n&#x2009;=&#x2009;15 HD)
The data represent the mean&#x2009;&#x000B1;&#x2009;standard deviation (SD) and were analyzed by ANOVA and post hoc Holm-Sidak
The p-values are indicated in the graph&#x0003C;0.05
The significant differences between groups compared to the HD are marked with &#x0002A;
The Lee index was determined using the data of body weight and naso-rectal length. <a href="#tab1">Table 1</a> shows that the Lee index in the HD group increased by 8% at 6&#x2009;months of age and by 13% at 13&#x2009;months of age compared to the SD group
confirming that HD animals were obese from 6&#x2009;months of age
Food consumption was evaluated monthly (<a href="#SM1">Supplementary Figure 1</a>). In the third month, the SD group consumed 35% more food (measured in g) compared to the HD group, and from month 5 to month 10, there was an increase and then a decrease in food intake (32, 42, 36, 37, 35, and 25% respectively). However, as seen in <a href="#SM1">Supplementary Figure 1B</a>
the monthly kcal intake in the HD group was higher than in the SD group over time
The increase in calorie consumption in the HD group was 24% at month 4
but no differences were found between the groups (data not shown)
The biochemical parameters, including the GOT/GPT ratio, triglycerides, creatinine, glucose, cholesterol, high-density lipoprotein (HDL), atherogenic index, and low-density lipoprotein (LDL), are shown in <a href="#tab2">Table 2</a>
Some parameters significantly increased in the HD group compared to the SD group
an 11-fold increase in triglyceride levels was observed in the HD group at 13&#x2009;months of age (86&#x2009;mg/dl) compared to levels in the same group at 6&#x2009;months (7.8&#x2009;mg/dl)
Augmented glucose levels were observed in both groups at 13&#x2009;months of age compared to the values obtained at 6&#x2009;months
A 1.30-fold increase in glucose levels was observed in the SD group and a 1.68-fold increase in the HD group
the SD group showed increased levels compared to the HD group at 6&#x2009;months; however
the HD group increased their cholesterol levels by 1.40 times compared to the values obtained at 6&#x2009;months
a 2.4-fold increase was observed in the HD group compared to the SD group at 6&#x2009;months
HDL concentrations were higher in the SD group compared to the HD group at 6&#x2009;months of age
this parameter did not significantly change at 13&#x2009;months of age
despite finding differences in some evaluated parameters
none of these values were outside the clinical parameter limits established for Wistar laboratory rats
IL-6 levels increased 2.18 times at 6&#x2009;months and 1.36 times at 13&#x2009;months compared to the SD
an augment in this cytokine was also associated with age since it increased 1.58-fold at 13&#x2009;months compared to 6&#x2009;months
and IL10 (E) were determined by ELISA (n&#x2009;=&#x2009;6 SD and n&#x2009;=&#x2009;6 HD)
The data represent the mean&#x2009;&#x000B1;&#x2009;standard deviation and were analyzed by two-way ANOVA
The significant differences between groups with respect to the SD are marked with &#x02217;
and differences at different ages are marked with &#x00026; p&#x2009;&#x0003C;&#x2009;0.05
The serum concentration of monocyte chemoattractant protein 1 (MCP-1) shown in <a href="#fig2">Figure 2C</a> presented the same behavior as IL-1&#x03B2;
both HD groups increased MCP-1 concentration compared to the SD groups (1.33 times at 6&#x2009;months and 1.63 times at 13&#x2009;months of age)
<a href="#fig2">Figure 2D</a> shows that TNF-&#x03B1; concentration in the HD group significantly increased by 2.36% at 6&#x2009;months and 2.55% at 13&#x2009;months of age compared to the SD group
both 13 moth-old groups decreased TNF-&#x03B1; concentration at month 13 of age
SD group significantly decreased by 2.06-fold and the HD group by 1.91-fold; the HF rats showed a higher TNF-&#x03B1; concentration
IL-10 concentration was quantified to assess the anti-inflammatory response. <a href="#fig2">Figure 2E</a> shows that the HD group significantly increased by 1.33-fold at 6&#x2009;months; however
being more remarkable in the HD group (2.20 decrease fold) compared to the SD group (1.68-fold)
TNF-&#x03B1; levels in the HD group were significantly higher compared to the SD group at 6&#x2009;months of age (1.77-fold increase) and 13&#x2009;months of age (3.02-fold increase)
and IL10 (E) were analyzed by ELISA (n&#x2009;=&#x2009;6 SD and n&#x2009;=&#x2009;6 HD)
The data represent the mean&#x2009;&#x000B1;&#x2009;SD and were analyzed by two-way ANOVA
The significant differences between groups compared to the SD are marked with &#x02217; p&#x2009;&#x0003C;&#x2009;0.05
a 1.27-fold increase in IL-10 concentrations was observed in the SD group at 13&#x2009;months compared to the 6&#x2009;months group
followed by a Tukey&#x2019;s post hoc test
The significant differences between groups compared to the SD are marked with &#x02217;
BDNF concentrations diminished in the HD group compared to the SD group at 6 and 13&#x2009;months
BDNF increased in both groups (SD and HD) at 13&#x2009;months
and hippocampus (C) were determined by ELISA (n&#x2006;=&#x2006;6 SD and n&#x2006;=&#x2006;6 HD)
and differences at different ages are marked with &#x00026; p&#x2006;&#x0003C;&#x2006;0.05
The NOR test was performed to determine the possible detrimental effects of neuroinflammation on cognition; the NOR test was performed at 6 and 13&#x2009;months of age following the scheme shown in <a href="#fig6">Figure 6A</a>. The interaction time with the novel object is shown in <a href="#fig6">Figure 6B</a>; the rats in the SD and HD groups spent more time exploring the novel object at 6&#x2009;months than at 13
the SD group did not differentiate between the familiar and the novel object
equaling the exploration time between the objects
(A) Schematic representation of protocol for a novel object recognition test
Familiar and novel object interaction time (B)
and recognition index (D) determined in rats fed with SD and HD at 6 and 13&#x2009;months of age (n&#x2009;=&#x2009;12 SD and n&#x2009;=&#x2009;12 HD)
Each bar represents the mean&#x2009;&#x000B1;&#x2009;SD
The data were analyzed by two-way ANOVA and Tukey&#x2019;s post hoc test
When evaluating the number of interactions with each object, the SD group at 6 and 13&#x2009;months interacted similarly with both objects (<a href="#fig6">Figure 6C</a>). With an evident decrease in the recognition index, the HD rats did not discriminate the novel object from the familiar object at 6&#x2009;months, as seen in <a href="#fig6">Figure 6D</a>
being more pronounced in both groups at 13&#x2009;months of age
which presented a more significant deficit in recognizing novel objects
To evaluate the participation of senescence in cognitive deterioration, GLB, p21, and &#x03B3;H2AX were determined in the Cx and Hc at 6 and 13&#x2009;months of age. <a href="#fig7">Figure 7A</a> shows a significant increase of 1.12 times in GLB expression in the Cx of the 13-month-old HD group compared to the SD group at the same age
where no changes in the expression of this enzyme were observed throughout life
changes were observed in the HD group at 13&#x2009;months of age
with an increment of 2.12 times compared to 6&#x2009;months
No differences were observed in GLB expression in this region at 6&#x2009;months old
Expression of molecular markers of senescence in brain
Representative Western blot analysis of GLB in the Cx (A) and Hc (B); p21 in the Cx (C) and Hc (D); and &#x03B3;H2AX in the Cx (E) and Hc (F)
The graphs show the densitometric protein expression analysis from six animals per age group (each dot represents an animal; n&#x2009;=&#x2009;6 SD and n&#x2009;=&#x2009;6 HD)
The data represent the mean&#x2009;&#x000B1;&#x2009;SD
the data were compared using the two-way ANOVA and Tukey&#x2019;s post hoc test
The significant differences between groups compared to the SD are marked with &#x0002A;
a significant increase of 1.82 times was found in the HD group at 13&#x2009;months of age compared to the SD group
No changes in the expression of this histone were found at 6&#x2009;months between both groups
Senescent cells in the Cx and Hc were only evaluated at 13&#x2009;months in SD and HD groups because we only found changes in all the senescence markers at this age
The presence of senescent cells is more evident in the HD group in both areas analyzed in concordance with the increase of senescent markers previously shown
(A) Anatomic diagram to locate the regions analyzed
(B) Representative images of different regions with cells with senescence features accumulate in the Cx and Hc in animals with HD at 13&#x2009;months (n&#x2009;=&#x2009;6 SD and n&#x2009;=&#x2009;6 HD)
The percentage of SA-&#x03B2;-gal positive cells per area in each brain section in cortex (C) and hippocampus (D)
The average of three brains per group is graphed
The significant differences between groups compared to the SD are marked with &#x02217; and differences at different ages are marked with &#x00026; p&#x2009;&#x0003C;&#x2009;0.05
Confocal fluorescence micrographs are 20&#x000D7; magnification
<a href="#fig8">Figures 8C</a>,<a href="#fig8">D</a> show the quantification of the SA-&#x03B2;-gal positive cells in the Cx and Hc
there was an increase of 30% in SA-&#x03B2;-gal positive cells in the Cx and 14% in the Hc compared to the SD group
These results suggest a higher number of senescent cells in subjects in the HD group compared to those in the SD group
as a mechanism for removing excess cholesterol from peripheral tissues and redistributing it or removing it from the body by the gallbladder
Since the Cx has a higher number of neurons and fewer astrocytes and microglia than the Hc
these differences in cell composition could contribute to the observed differences in response to HD and obesity
These mechanisms highlight the complex interplay between obesity-induced inflammation and brain function
Research on animal models of obesity has suggested a link between obesity-induced inflammation and the development of cognitive alterations (<a href="#ref58">Schmitt and Gaspar, 2023</a>)
Our results using the NOR test showed that rats in the HD group significantly decreased their ability to discriminate between the new and the familiar object at 6&#x2009;months
That was more evident at 13&#x2009;months of age
rats in the SD group also diminished their ability to discriminate the objects with age
These results suggest that both diet-induced obesity and normal aging can impair the ability to discriminate a new object
which is an indicator of hippocampal-dependent learning and memory
The decline in performance could be due to the negative impact of obesity on the integrity of the Hc and other brain regions
as well as the changes in synaptic plasticity and dendritic spine density associated with neuroinflammation and BDNF dysregulation
These findings highlight the importance of considering obesity and aging as risk factors for cognitive decline
Further research is needed to understand the exact mechanisms by which senescent cells contribute to cognitive decline in obesity
Targeting senescence is a promising strategy to prevent obesity-related neuropsychiatric diseases
The animal study was reviewed and approved by COMISI&#x000D3;N ACAD&#x000C9;MICA DE ETICA DE LA DIVISI&#x000D3;N DE CIENCIAS BIOL&#x000D3;GICAS Y DE LA SALUD
VS-V was involved in the design of the study
AL-L and AC were involved in the analysis and interpretation of the data
and NL-D were involved in the design of the study
MK and NL-D also supervised the investigation
All authors contributed to the article and approved the submitted version
This work was supported by the Consejo Nacional de Ciencia y Tecnolog&#x000ED;a (CONACyT) grant FORDECYT-PRONACES/263957/2020
and CONACYT Ciencia de Frontera 2019 (1783)
as well as Direcci&#x000F3;n General de Asuntos del Personal Acad&#x000E9;mico
Universidad Nacional Aut&#x000F3;noma de M&#x000E9;xico (UNAM)
The authors would like to thank &#x000C1;ngeles Guerrero-Aguilera from UAM-I for animal supply
The Supplementary material for this article can be found online at: <a href="https://www.frontiersin.org/articles/10.3389/fnagi.2023.1162747/full#supplementary-material">https://www.frontiersin.org/articles/10.3389/fnagi.2023.1162747/full#supplementary-material</a>
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&#x0002A;Correspondence: Norma Edith L&#x000F3;pez-D&#x000ED;azguerrero, <a id="encmail">bmVsZGlhemdyb0Bob3RtYWlsLmNvbQ==</a>
Is Robinson Cano more like David Wright or more like Alex Rodriguez
Both players are stars and both play in New York
but they get paid very differently and that is complicating the talks between Cano and the Yankees
While both the <a href="https://www.pinstripealley.com/" class="sbn-auto-link">Yankees</a> and Robinson Cano remain eager to work out a long term contract that will keep the star second baseman in pinstripes far into the future, the talks have not progressed much and sizable gap may separate the two sides, <a href="http://www.cbssports.com/mlb/blog/jon-heyman/22145024/looming-questionshould-cano-be-closer-in-contract-to-wright-or-arod">according to Jon Heyman of CBS Sports. </a> 
Heyman reports that since leaving agent Scott Boras for rap star Jay-Z and his new division at CAA
Robinson Cano is being represented primarily by CAA’s baseball division co-head Brodie Van Wagenen
Jay-Z is unable to represent the Yankee slugger until his is certified as an agent
it appears that Van Wagenen and Yankee GM Brian Cashman have pushed talks to a date sometime in the future and the two sides are still separated by a significant gap in their desired price
Heyman cites sources inside the game who believe that two different deals for star players in New   York are currently at the center of the division between Cano and the Yankees
Cano’s side is reportedly looking for a deal comparable to the ten-year/ $275M contract that the Yankees gave third baseman Alex Rodriguez prior to the 2008 season
With $114M remaining on that deal (including Rodriguez’s $28M salary for 2013) and A-Rod out for at least half of this season and showing significant decline in production
it isn’t surprising that the Yankees want to reference the more modest eight-year/ $138M deal their cross-town rivals gave David Wright
Wright signed that eight-year extension with the <a href="https://www.amazinavenue.com/" class="sbn-auto-link">Mets</a> this off-season after hitting .306/.391/.492 at the age of 30 and it was generally acknowledged to be a team-friendly deal
The Mets star is a career .301/.382/.506 hitter over ten seasons in the majors
Cano is 30 years old this season and he has been a .309/.352/.505 over nine seasons
Alex Rodriguez had hit .305/.386/.573 over thirteen seasons
winning two MVP awards and a batting title
There are a number of other long term extension that could be used as a comparison as the two sides work toward an agreement
including those contracts signed by stars like Prince Fielder
but Heyman’s sources indicate that the deals for Rodriquez and Wright are currently framing the talks
The prevailing belief around the game is that a contract between the two sides will get done
Many people believe that Cano’s decision to leave Boras was largely based on his desire to remain with the Yankess and to avoid entering the free agent market if at all possible
he will almost certainly be the top player available
With a number of aging stars coming back from injuries right
the Yankees are getting a clear reminder of how much they depend on Cano right now
His .319/.374/.626 line this season gives him the second highest OPS on the club
Given his age and his importance to the team
New York may not want to chance a bidding for his services this off-season
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<a href="https://www.flobikes.com/people/6716980-tadej-pogacar" rel="noopener noreferrer" target="_blank">Tadej Pogačar</a> rose to the occasion and won his first stage of the <a href="https://www.flobikes.com/events/8209007-2023-tour-de-france" rel="noopener noreferrer" target="_blank">2023 Tour de France&nbsp;</a>on July 6.&nbsp;
The 2-time Tour de France winner has only worn white jerseys so far in the race. But Pogačar rode closely behind defending champion, <a href="https://www.flobikes.com/people/7074685-jonas-vingegaard" rel="noopener noreferrer" target="_blank">Jonas Vingegaard</a>
waiting for the perfect moment to attack.&nbsp;
With only 2 kilometers left to the finish line Pogačar exploded into a 60-meter lead but there was only a 24-second gap between the two by the time Vingegaard finished.&nbsp;
Pogačar will keep wearing his <a href="https://www.flobikes.com/articles/11078135-tour-de-france-jersey-color-guide" rel="noopener noreferrer" target="_blank">white jersey</a>
but Vingegaard took the yellow jersey from Jai Hindley
who won stage 5 but now is in third-place in the Tour
<a href="https://www.flobikes.com/live/58762/signup" rel="noopener noreferrer" target="_blank">Subscribe to Flobkes to Stay Up to Date with the Tour de France 2023!</a>
Here is the full <a href="https://www.flobikes.com/events/8209007-2023-tour-de-france/schedule" rel="noopener noreferrer" target="_blank">Tour de France schedule</a>.
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Robinson Cano is one of the best baseball players the MLB has to offer
In eight seasons with the New York Yankees
the second baseman has put up incredible numbers
Cano is set to become a free agent after the 2013 season and conventional thinking was that the negotiations would be long and strenuous
But the whole process is about to change a bit
It was announced yesterday that <a class="af gz" href="http://www.nytimes.com/2013/04/03/sports/baseball/robinson-cano-leaves-scott-boras-for-jay-zs-agency.html?_r=0" rel="noopener ugc nofollow" target="_blank">Cano is joining forces with Roc Nation Sports</a>
an entertainment company founded by the rapper Jay-Z
Roc Nation Sports will be partnering with Creative Artists Agency (CAA)
who represents baseball players Ryan Braun
Buster Posey and Ryan Zimmerman among other athletes
CAA will be handling Cano’s upcoming negotiations and Cano will be Jay-Z’s first sports client
This move has dramatic implications for Cano’s upcoming free agency
was notorious for dragging out free agency and milking every last dollar in negotiations
Just look at these contracts: Jayson Werth- 7 years
he is expected to command a contract around 9–10 years upwards of $200 million
this albatross has come at a price to his reputation
it was announced during Game 7 of the 2007 World Series that Rodriguez would be opting out of his then-record-setting contract
Rodriguez contacted the Yankees directly and
Rodriguez is close with Cano and it is possible that Cano wanted to avoid the same experience that has dogged his teammate
This is big plus for Jay-Z. Aside from his allegiances to the Yankees as a fan, this move extends his already large network into another area of sports, as he is a part owner of the Brooklyn Nets and owns a sports bar in the city. <a class="af gz" href="http://espn.go.com/new-york/mlb/story/_/id/9124684/robinson-cano-new-york-yankees-switching-scott-boras-jay-z" rel="noopener ugc nofollow" target="_blank">He plans to become a certified agent</a> in baseball
then he will be required to give up his share in the Nets to avoid a conflict of interests
do everything possible to keep Cano in New York
There is no knowing what will happen between the Yankees and Robinson Cano
While it behooves the team to sign their second baseman to a long-term contract
it is feasible that they will decide to go in a different direction
this development might mitigate what was potentially going to be one of the most interesting contract negotiations in recent history
Cano might now be more inclined to stay in the concrete jungle where dreams are made of and remain one of the faces of the Yankees
<a class="af gz" href="http://espn.go.com/new-york/mlb/story/_/id/9124684/robinson-cano-new-york-yankees-switching-scott-boras-jay-z" rel="noopener ugc nofollow" target="_blank">[Image via]</a>
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Letting A-Rod go after 2007 was the original plan
and the ripples would still be affecting today’s Yankees
that’s just chapter one of A-Rod’s story with the Yankees
what would have happened in a universe in which the Yankees acquire Rodriguez in 2004
His original contract included an opt-out after the 2007 season
one that he was wise to exercise after what was perhaps his finest season at age 31
the owner of the largest contract in sports history at the time
The problem was how Rodriguez went about his business
He announced his opt-out in the middle of the 2007 World Series in what was viewed as a selfish move
Hank Steinbrenner certainly thought as much
declaring that the Yankees would not try to keep Rodriguez:
“It’s a shame, but we are all in agreement: myself, my dad, my brother, all the baseball people. If you don’t want to be a Yankee and paid what you’re being paid, we don’t want you, that’s the bottom line,” Steinbrenner <a href="https://www.nytimes.com/2007/10/29/sports/baseball/29arod.html">said</a>
“You’d be hard-pressed to argue that point
If you don’t understand the magnitude of being a Yankee and understand what that means
and being the highest-paid player in baseball
“If we’re going to make you rich and we’re going to give you the privilege of being a Yankee
you’ve got to show us you want to be here.”
but the Yankees ultimately caved when faced with the possibility of losing the best hitter in baseball smack in his prime
The Yankees originally wanted to let Rodriguez go in part because of the massive investment in his later
but the team decided to bite the bullet and re-sign A-Rod for 10 more years at $275 million
This is where evaluating Rodriguez’s Yankees legacy gets tough
Rodriguez was still worth it for at least the first three years of the deal before his injuries and a lengthy PED suspension
the Yankees do not win the 2009 World Series without him
If you measure contract success by championships
even if the next few years got quite messy and the end involved massively overpaying a 40-year-old designated hitter
It looked like the Yankees were ready to move on after 2007
the Yankees as we know them today would still be affected
and the Yankees came running back to A-Rod
What if the Yankees had actually followed through and gotten Cabrera
They’d have gotten a player who became the equivalent of 2001-2007 Rodriguez
the best right-handed-hitter in the league
instead of the 2008-2016 version of Rodriguez the Yankees overpaid for
If the Yankees had acquired Cabrera after letting Rodriguez walk
the Yankees would still win the 2009 World Series and maybe get to one more
The Yankees ultimately weren’t willing to trade any of their “Big Three” starting pitching prospects
making Cabrera in pinstripes just a pipe dream
where else could they have gone at third base to replace Rodriguez
the team could have eventually trusted the hot corner to Eduardo Nunez
although he profiled better as a shortstop
which could have been filled with Beltre through a trade or free agency at this point
there are also long-term impacts to Rodriguez being let go after 2007
That honor would have been passed onto Robinson Cano
who would certainly have been re-signed after 2013
and the team never trades for Gleyber Torres
having committed to Cano and Didi Gregorius in the middle infield
Those 2013-2016 Yankees teams would have performed better
and may not have gotten the chance to draft Aaron Judge
the real-life Yankees had two title windows (2009-2012 and 2017-present) with a reloading period in the middle
that title window probably becomes one big one from 2009-2015
but the team subsequently declines and has to rebuild around 2016
they’d be going through real-life 2013-2016 now
only without the promise of Torres and Judge in the future
the Yankees won one World Series with Rodriguez over his second contract
and I think that statement remains the same if they had let him go and replaced him effectively
the future of the team in 2020 and beyond is brighter in the current scenario
I think the Yankees made the right choice by re-signing Alex Rodriguez
the Yankees wouldn’t be in the spot they’re enjoying right now
.st1{fill-rule:evenodd;clip-rule:evenodd;fill:#2a2a2a}By <a class="byline__authorLink" href="https://www.nj.com/staff/mcarig/posts.html" title="Marc Carig/The Star-Ledger">Marc Carig/The Star-Ledger</a>Greg Fiume/Getty ImagesThough his work at the plate garners plenty of attention
Yankees second baseman Robinson Cano has enjoyed a strong season in the field as well.TORONTO -- For all of his offensive exploits
Robinson Cano has always set his sights on winning a Gold Glove award
this could be the season he reaches that goal
Cano has vaulted his name into the conversation for A.L
MVP honors with the best overall season of his career
which includes the work he&#x27;s done at second base
Yankees manager Joe Girardi said Cano is worthy of a Gold Glove
&quot;You see some of the plays he makes,&quot; Girardi said
you just kind of go &#x27;wow.&#x27; I think he is a Gold Glove candidate
Girardi pointed at Cano&#x27;s franchise record 81-game errorless streak at second base
Yankees third baseman Alex Rodriguez said Cano has the most accurate arm he&#x27;s ever seen from a second baseman
Cano has put his arm strength on display several times this season
making powerful off-balance throws after fielding balls up the middle
very underrated defensively,&quot; said Rodriguez
who called Cano the best defensive second baseman in baseball
Defensive metrics rank the Twins&#x27; Orlando Hudson as the best defensive second baseman in the game
But those same metrics rank Cano among the best
Cano&#x27;s Ultimate Zone Rating of 3.2 ranks fourth in baseball and second to Hudson&#x27;s big-league leading 8.8 rating
Cano also ranks fourth in the majors according to Fielding Bible statistics
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Yankees fans have seen their share of sweet swings 
Nothing compares to the beauty of a silky smooth swing
The Yankees have had plenty of great power strokes over the years
and fans can boast that their own Babe Ruth possessed the first true home run stroke in baseball history
you can still appreciate the beauty of the Babe’s swing through fuzzy black and white
Maybe none of the guys listed below have the same pure swing that Ken Griffey Jr
but there have been plenty of pinstriped sluggers whose swings were nothing short of a work of art
We’ll keep this list confined to the past few decades due to the volume of phenomenal hitters that the Yanks have had over their history
but there are still plenty of memorable swings to choose from
Let’s begin with the best hitter on this list
Rodriguez is the greatest hitter I have ever seen
and his power stroke to all fields has a lot to do with that
Rodriguez leaves the best for last with one of the sexiest follow-throughs I have ever seen
holding the bat above his head for a brief second before dropping it at his feet to begin his home run trot
If I were to teach my kid how to swing a bat
I would immediately bring up Rodriguez highlights
Oh how I miss seeing this swing in the Bronx
Cano sometimes made his swing look effortless during his Yankees tenure
while making the right field seats his own personal playground for home runs
What is amazing about Cano is his ability to square up a pitch regardless of its location
Cano gets his hands through the zone at lightning speed and seems to drop his bat before his swing is even finished
Strawberry is another example of a Yankee with lightning-quick hands
at times it looked like he was generating his power from just his hands and wrists
The former Yankee always kept his elbow up before beginning his swing
His landing spot on his leg kick was always perfect and many of the balls he hit found landing spots in the outfield seats
Gary Sanchez is the talk of the Baby Bombers (and for good reason)
but Bird’s swing will be catching my eye in 2017
He wastes no motion when awaiting the pitch and you will rarely see his hands drift on a breaking ball
Hopefully the shoulder has fully recovered and Bird will be back to using his pretty swing to generate plenty of home runs for the Yanks this year
I just love this swing for the exact opposite reasons as the others on this list
Everything from Sheffield’s stance to his swing were so violent yet he seemed in perfect control all the time
His 400th career home run captures the incredible essence of his fierce stroke
Volume 11 - 2020 | <a class="ArticleLayoutHeader__info__doi" href="https://doi.org/10.3389/fpsyg.2020.590097">https://doi.org/10.3389/fpsyg.2020.590097</a>
This article is part of the Research TopicChild-to-Parent Violence: Challenges and Perspectives in the Current Society<a class="Link Link--linkType Link--maincolor Link--medium Link--icon Link--chevronRight Link--right" aria-label="View all 10 articles" href="https://www.frontiersin.org/research-topics/12107/child-to-parent-violence-challenges-and-perspectives-in-the-current-society/magazine" target="_self" data-event="customLink-linkType-a_viewAll10Articles">View all 10 articles</a>
The relationship between child-to-parent violence (CPV) and the perceived parental warmth dimension has been well established
it is necessary to further investigate the nature of this relationship considering the involvement of other variables
The objective of this study was to analyze the role of cognitive (hostile attribution)
and social variables (deviant peer group and drug use) in the relationship between the perceived parental warmth dimension (warmth-communication and criticism-rejection) and CPV motivated by reactive or instrumental reasons
The community sample consisted of 1,599 Spanish adolescents (54.8% girls) between the ages of 12 and 18 years (Mage = 14.6
SD = 1.6 years) from different secondary schools in Ja&#x00E9;n (75.3%) and Oviedo (24.7%) (Spain)
Each participant completed the Child-to-Parent Violence Questionnaire (CPV-Q)
the Social Information Processing (SIP) in Child-to-parent Conflicts Questionnaire and Deviant Peers and Drug Use Questionnaires
The results indicate that perceived parental warmth is negatively correlated with hostile attribution
while perceived parental criticism is positively linked to these variables
hostile attribution and adolescent anger are positively linked to reactive CPV
Relationship with a deviant peer group is associated with drug use
which also predicts both reactive and instrumental CPV
a lack of perceived parental warmth has important repercussions in the form of the psychological and social maladjustment of children
which in turn is differentially correlated with reactive or instrumental CPV
prevention and intervention programs for CPV should consider
working with parents on parental practices that incorporate parental warmth as a fundamental element and
taking into account the different motivations for this type of violence
which refers to the use of control and supervision
From the combination of these two dimensions
four parenting styles emerge: authoritarian
it has been considered more useful at the empirical level to focus on specific parental dimensions or practices
This has significant negative effects on the psychological adjustment of children and on their behavior and relationships with others
The results also indicate that the relationships are slightly but significantly stronger in mothers than in fathers
perceived parental rejection is one of the main causes of behavioral problems in childhood and adolescence
and it could have these effects through cognitive and emotional variables
The literature also reveals a close relationship between a deviant peer group and drug use during adolescence (e.g., <a href="#B29">Fergusson et al., 2002</a>; <a href="#B25">Duan et al., 2009</a>; <a href="#B43">Kendler et al., 2014</a>). Regarding CPV, in Spain, it has been observed recently that a deviant peer group predicts drug use, which in turn is linked to violent behavior toward parents (<a href="#B22">Del Hoyo-Bilbao et al., 2020</a>)
there is an indirect effect of the deviant peer group on CPV through drug use
these authors found that affiliation with a deviant peer group was influenced by family variables such as a lack of parental support or parental inefficiency
The sample was made up of 1,599 Spanish adolescents (54.8% girls) aged between 12 and 18 years (Mage = 14.6
SD = 1.6 years) from a community population and they were recruited from eight public and private secondary schools in Ja&#x00E9;n (75.3%) and Oviedo (24.7%) (Spain)
Previously, the minimal sample size was calculated at 95% confidence level, with a 5% confidence interval at 80% of statistical power. The estimated minimum sample size was 385. According to <a href="#B38">Hair et al. (2010)</a>
the general rule to calculate the minimum sample size for factor treatment in a survey is to have a minimum of 5 observations per variable (5:1)
so the minimum for the factorial treatment would be 690
The information on the validity and reliability of all assessment instruments in this study is described in the &#x201C;Results&#x201D; section
The Child-to-Parent Violence Questionnaire (CPV-Q) (<a href="#B11">Contreras et al., 2019</a>)
The CPV-Q consists of 14 parallel items (for the father and for the mother) that measure psychological (four items)
together with behaviors of control and dominion over their parents (four items)
The CPV-Q asks the adolescents to indicate the frequency of the behaviors against their parents in the past year using a 4-points scale: 0 (never)
It also includes a scale with 8 items on the reasons for the aggressions
3 items referring reactive reasons (RR) and 5 items to instrumental reasons (RR)
Higher scores indicate more CPV and more frequency of RR an IR
The Warmth Scale (WS), adolescents&#x2019; version (<a href="#B31">Fuentes et al., 1999</a>)
divided into two factors: (a) Warmth-communication and (b) Criticism-rejection by parents toward their children
Each factor consists of 10 items rated on a scale ranging from 1 (never) to 5 (always)
Higher scores indicate more warmth-communication and more criticism-rejection
The Social Information Processing (SIP) in Child-to-parent Conflicts Questionnaire (<a href="#B6">Calvete et al., 2015</a>)
The anger and hostile attribution scales were used for this study
Adolescents were asked to imagine three scenes of different conflicts with their parents
and they had to respond to each item on a 5-point response scale ranging from 0 (not at all) to 4 (to a great extent): (a) hostile attribution
which included the attribution of negative intentions and positive emotions in parents (2 items per scene
6 items in total); (b) anger (1 item per scene
Higher scores indicate more anger and hostile attributions
This instrument was designed ad hoc for this study
It has a total of four items with which adolescents are asked to indicate if their friends have been involved in criminal activities
The response scale is 1 (none of them) to 4 (all)
Higher scores indicate more frequency of relationship with deviant peer groups
Adolescents were asked to indicate how often they have used different drugs (tobacco
Higher scores indicate more frequency of drug use
the favorable report of the Ethics Committee of the University of Ja&#x00E9;n (Spain) to conduct this study was obtained (Ref
authorizations by the Public Administration in Education and the secondary schools&#x2019; directors were also obtained
The secondary schools were previously selected by the Provincial Delegations of Education according to their representativeness
Eight secondary schools were invited to participate and they were given detailed information of the objectives of the research
The parents&#x2019; informed consent for us to assess their children and the adolescent&#x2019;s informed consent were also requested
Those schools that confirmed their availability and willingness to take part in the research provided the informed consent in paper to both parents and children
Adolescents received the same information as their parents and they participated in the study once they have signed the informed consent
they participated in the assessment only if they had given their informed consent and that of their parents
Each participant received an identification code and no incentive was offered in exchange for participation
The questionnaires in paper were administered in a group setting in their classrooms
The evaluation time was approximately one hour
who were specifically trained for this protocol
Data collection was conducted during 2017 and 2018
The inclusion criteria were to be aged between 12 and 18 years old and to have the informed consent from parents to participate in the study
Participants under 12 years and above 18 were excluded
This is a survey descriptive study using cross-sectional research design (<a href="#B55">Montero and Le&#x00F3;n, 2007</a>)
The diagonal weighted least squares (DWLS) estimator was used for CFA due to the non-normal multivariate distribution of the data
The fit indices used in CFA were Comparative Fit Index (CFI)
Standardized Root Mean Square Residual (SRMS)
and Root Mean Square Error of Approximation (RMSEA) with 90% of Confident interval
The latent variables that constituted the different elements in the SEM model were computed by multiplying the observed variables that comprised them
maximum likelihood estimation with robust standard errors and the Satorra-Bentler scaled test (Maximum Likelihood Method
Cronbach&#x2019;s alpha and McDonald &#x03C9; were used to assess reliability of each subscale
Of all the possible answers given by the participants on the different questionnaires
The multivariate normality of the data was analyzed using the Mardian test
and the results showed that the data did not have a multivariate normal distribution (Zkurtosis 811.98
No item showed multicollinearity (r &#x003E; 0.90) or singularity (r &#x003E; 0.95)
Data screening showed that the data did not violate the assumption of linearity
or homoscedasticity (the residuals of the false regression were mostly distributed between &#x2212;2 and +2)
Before analyzing the proposed SEM model, the validity and reliability of the questionnaires used in the present study were calculated (see <a href="#T1">Table 1</a>). To do this, a CFA of all the questionnaires was performed. The results showed that the goodness of fit determined by the CFA was between good and excellent for each questionnaire (<a href="#B38">Hair et al., 2010</a>)
The CFA showed an excellent fit (&#x03C7;273 = 80.474, p = 0.257; see <a href="#T1">Table 1</a> for more details)
standardized root mean squared residual (SRMR) = 0.066
root mean square error of approximation (RMSEA) = 0.008 (RMSEA 90% CI [0.000,0.017])
and reliability indices of &#x03B1; = 0.820 and &#x03C9; = 0.837
The CFA showed an excellent fit (&#x03C7;273 = 84.204, p = 0.174; see <a href="#T1">Table 1</a> for more details)
RMSEA = 0.010 (RMSEA 90% CI [0.000,0.018])
and reliability indices of &#x03B1; = 0.822 and &#x03C9; = 0.843
The CFA showed a good fit (&#x03C7;219 = 82.111, p &#x003C; 0.001; see <a href="#T1">Table 1</a> for more details)
RMSEA = 0.046 (RMSEA 90% CI [0.036,0.052])
and reliability indices of &#x03B1; = 0.718 and &#x03C9; = 0.747 for the overall scale and &#x03B1; = 0.668 and &#x03C9; = 0.618 for RR and &#x03B1; = 0.704 and &#x03C9; = 0.703 for IR
The CFA showed an excellent fit (&#x03C7;2169 = 503.235, p &#x003C; 0.001; see <a href="#T1">Table 1</a> for more details)
RMSEA = 0.035 (RMSEA 90% CI [0.032,0.039])
and reliability indices of &#x03B1; = 0.500 and &#x03C9; = 0.714 for the overall scale and &#x03B1; = 0.919
&#x03C9; = 0.920 for the Warmth-Communication dimension
and &#x03B1; = 0.887 and &#x03C9; = 0.889 for the Criticism-Rejection dimension
The CFA showed an excellent fit (&#x03C7;2169 = 381.024, p &#x003C; 0.001; see <a href="#T1">Table 1</a> for more details)
RMSEA = 0.028 (RMSEA 90% CI [0.024,0.032])
and reliability indices of &#x03B1; = 0.417 and &#x03C9; = 0.634 for the overall scale
&#x03B1; = 0.887 and &#x03C9; = 0.889 for the Warmth-Communication dimension
and &#x03B1; = 0.843 and &#x03C9; = 0.842 for the Criticism-Rejection dimension
The CFA showed a good fit (&#x03C7;226 = 175.659, p &#x003C; 0.001; see <a href="#T1">Table 1</a> for more details)
RMSEA = 0.060 (RMSEA 90% CI [0.052,0.023])
and reliability indices of &#x03B1; = 0.800 and &#x03C9; = 0.811 for the overall scale
&#x03B1; = 0.720 and &#x03C9; = 0.712 for hostile attribution
and &#x03B1; = 0.745 and &#x03C9; = 0.745 for anger
The CFA showed a good fit (&#x03C7;22 = 16.456, p &#x003C; 0.001; see <a href="#T1">Table 1</a> for more details)
RMSEA = 0.067 (RMSEA 90% CI [0.040,0.099])
and reliability indices of &#x03B1; = 0.647 and &#x03C9; = 0.648
The CFA showed an excellent fit (&#x03C7;29 = 16.771, p = 0.052; see <a href="#T1">Table 1</a> for more details)
RMSEA = 0.023 (RMSEA 90% CI [0.000,0.040])
and reliability indices of &#x03B1; = 0.721 and &#x03C9; = 0.665
In both models all the relationships (except between warmth-mother and anger) were significant
Both models (Father and Mother) show similar factor loadings between the relationships of the different components of the model
SEM theoretical model for Child-to-Parent Violence (CPV)
The circles represent the latent variables
and the arrows indicate the regression between variables
Regression factors from structural equation modeling for father
Regression factors from structural equation modeling for mother
The solid arrows represent significant relationships whereas the dotted arrows indicate non-significant relationships
The numbers indicate the standardized value of the factor load of each variable in the model
The model for fathers is presented in the upper panel A
and the model for mothers is presented on the panel B
The objective of this study was to further investigate the relationship between perceived parental warmth and CPV
it looked into the role of cognitive (hostile attribution)
and social variables (deviant peer group and drug use) in the relationship between perceived parental warmth-communication and criticism-rejection and CPV motivated by reactive and instrumental reasons
who found that family coercive interactions led to coercive relationships with peers and thus to violent behavior
although some studies have previously analyzed hostile attribution and anger in the context of CPV
our data further delve into the relationship between these variables and this type of family violence
showing its specific relationship with reactive CPV toward both fathers and mothers
it is not clear if peer groups promote CPV behaviors or violence in general or simply support the antisocial lifestyles that adolescents who abuse their parents typically show
the present study indicates the complexity of this parental dimension in the explanation of CPV and the need to further investigate the mechanisms involved in this relationship
the lack of perceived parental warmth has important repercussions in the form of psychological maladjustment of children
generating cognitive and emotional problems
which in turn lead to CPV motivated by reactive reasons
Perceived parental criticism-rejection is also correlated with a greater likelihood of association with deviant peer groups
with CPV motivated by both reactive and instrumental reasons
the data correspond to a sample of Spanish adolescents from the community population
which should be taken into account in the generalization of the data
Future studies could replicate the results with other types of samples
It is also important that future studies analyze the differences between boys and girls in the proposed model as well as to include an analysis of other variables that may mediate or moderate the relationship between parental practices and CPV
the findings of the present study are in line with these CPV programs that incorporates the intervention on cognitive
it is important to keep in mind the different motivations that this type of violence can have
The therapeutic approach depends on whether the violence is reactive in nature or of instrumental use
The raw data supporting the conclusion of this article will be made available by the authors
The studies involving human participants were reviewed and approved by the Ethics Committee of the University of Ja&#x00E9;n (Spain) (Ref
Written informed consent to participate in this study was provided by the participants&#x2019; legal guardian/next of kin
MC-L and LC: conceptualization and methodolgy
and LC: writing&#x2014;original draft preparation; MC-L
editing and funding adquisition; MC-L: project administration
This study was part of the Project I+D+i &#x201C;Child-to-parent violence: An emergent social problem
Study of prevalence and psychosocial variables involved,&#x201D; funded by the Ministry of Economy and Competitiveness of Spain and the European Union through the European Regional Development Fund
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*Correspondence: M. Carmen Cano-Lozano, <a id="encmail">bWNjYW5vQHVqYWVuLmVz</a>
WORCESTER - North High School held its graduation services Friday at the DCU Center
 Telegram & Gazette Student Achievement Award: Daniela Fraga Alvarez
 Massachusetts Association Of School Superintendent’s Certificate Of Academic Excellence: Daniela Fraga Alvarez
Clifford Memorial Scholarship From The Class Of 2007 (Given to a graduating Senior from North High who is interested in furthering her studies in the health careers and who represents everything that Ms
true school spirit and a good heart and soul): Alyxandra Peloquin
 Bay State Savings Bank Scholarship: Favio Velasquez
 Hanover Insurance Group Avid Scholarship: Taiwo Abegunde
 Worcester Latino Dollars For Scholars: Beatriz Da Silva
 John & Abigail Adams Scholarship (This scholarship is based on a student’s excellent performance on the English Language Arts and Mathematics assessments of MCAS): Kehinde Abegunde
Having spent nine seasons together in the Bronx, <a href="https://www.sportskeeda.com/player/alex-rodriguez" target="_blank" rel="noopener noreferrer" data-is-sponsored="false">Alex Rodriguez</a>, <a href="https://www.sportskeeda.com/player/derek-jeter" target="_blank" rel="noopener noreferrer" data-is-sponsored="false">Derek Jeter</a>
with each capable of deciding a ballgame by themselves on their day
The trio enjoyed an extremely decorated time together
racking up a total of 18 All-Star selections
four Gold Glove awards and 13 Silver Slugger awards between them
They three also won baseball's biggest prize
As the major leagues celebrated Jackie Robinson Day on Tuesday
Alex Rodriguez shared an image on his Instagram story
all sported the iconic #42 on their jerseys to celebrate the big day back in 2011
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The <a href="https://www.sportskeeda.com/team/new-york-yankees" target="_blank" rel="noopener noreferrer" data-is-sponsored="false">Yankees</a> went on to enjoy quite a successful 2011 regular season
their hopes for another World Series title were dashed by a resilient Detroit Tigers outfit
who beat them 3-2 in a nail-biting ALDS clash
Alex Rodriguez has become quite a successful businessman
the 49-year-old makes shrewd investments in real estate and promising companies
while also co-owning NBA and WNBA franchises the Minnesota Timberwolves and Minnesota Lynx
As a result of his extensive knowledge about both sport and business
who has now been a keynote speaker for five years
looked back on the 'incredible journey' he has enjoyed so far in an Instagram post on Friday
Alongside all the aforementioned work he gets done
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