partner in the Litigation and Agribusiness areas of TozziniFreire Advogados partner in Litigation and Agribusiness at TozziniFreire Advogados lawyer in the area of ​​Litigation at TozziniFreire Advogados It is undeniable that global warming has had several impacts on the planet’s climate and we were surprised by some extreme weather events such as intense heat in winter and the visit of cold fronts and even polar air masses in warm months Frosts arise as an effect of these weather events and consist of the formation of thin layers of ice on plants which often ends up killing entire crops and damaging crops with direct impacts on the agribusiness economy Southeast and Center-West regions of Brazil and directly impacted agricultural production in the country This is because the agribusiness chain is complex and has several agents involved there are specific contracts and legal transactions each with its own singularities and autonomous rules it is questioned whether the aforementioned phenomenon of nature can be understood as a hypothesis of “act of God” or “force majeure” – concepts provided for in the Brazilian Civil Code which can rule out the civil liability of the parties involved due to the damage caused by the occurrence of certain unavoidable circumstances Still in this scenario of possible contractual discussions due to extreme weather events another thesis capable of removing the responsibility of farmers for any damages resulting from frost is the so-called “theory of unpredictability” through which the undoing or revision is understood to be possible when the provision becomes excessively onerous to one of the parties as a result of these unpredictable and extraordinary events of nature In addition to the effective impact of these weather events on the contracts – which would authorize the application of these possible theses of exclusion of liability – it is also necessary to observe the general rules for interpreting the contracts These general rules of hermeneutics guide that legal transactions must be analyzed from the perspective of certain principles such as those of contractual freedom and the obligation of contractual effects the social function of the contract and the private autonomy of the parts how do I know if I will have to bear the damage caused by frost or other events in nature it is worth following how jurisprudence has been positioning itself our courts have already discarded the theory of unpredictability and default due to acts of God and force majeure considering objective aspects of the practical cases analyzed in cases where the unpredictable circumstances were duly proven there are examples of judgments that considered it possible to apply the aforementioned theses of exclusion of liability according to the Superior Court of Justice (STJ) responsible for standardizing the interpretation of federal law throughout Brazil the hypotheses of acts of God and force majeure have currently been understood by jurisprudence as species of the external acts of God in addition to being unpredictable and inevitable needs to be foreign to the organization of the company “despite also being unpredictable and inevitable being inserted in the business structure” (REsp 1.450.434) the superior court understands that only in the event of external fortuitous it will be possible to apply the liability exclusion it is observed that an important aspect considered by our courts when judging cases related to breach of contract due to events of nature would be precisely the predictability of the harmful event there are judgments in the sense that droughts droughts and climate change cannot be considered as unpredictable or extraordinary factors capable of authorizing the application of the theory of unpredictability insofar as which would be inherent risks to rural activity there are also judgments in the opposite direction and it is always necessary to analyze the situation in the specific case considering the occurrence of natural events the various agribusiness agents have at their disposal a wide arsenal of legal arguments that can be explored they may use a variety of dispute settlement methods – such as negotiation arbitration or the judiciary – to defend their respective interests in situations related to the impacts of climate change in the country The rainy season in Brazil began early in November 2021 including the passage of a subtropical cyclone over Bahia on 7 December 2021 caused flooding and landslides in southeastern Brazil The Brazilian Red Cross (BRC) launched this IFRC-DREF operation to respond to humanitarian needs in the state of Bahia and further rains affected other areas of the country (Petrópolis At the close of this operation a total of 174 municipalities in Bahia have declared a state of emergency In the period from November 2021 to May 2022 26people were killed and 520 injured by floods and rockslides According to the report of the Bahia State Superintendence of Protection and Civil Defence (Sudec) approximately 815,769 people have been affected by the floods in Bahia The main affected areas in the far south are in the municipalities of Medeiros Neto where the Brazilian Red Cross (CRB) carried out its response at the close of the operation and since the beginning of April a total of 449 of the 853 municipalities in Minas Gerais declared a state of emergency with a total of 24 deaths and more than 70,000 people displaced by the emergency In Petrópolis (city located in a valley mountainous region) 260 mm of water fell in only two hours causing landslides with 2,917 people affected rains affected the cities of Angra dos Reis and Paraty where the rainfall zone lies between forested mountains and the seacoast In neighbouring Angra dos Reis there were 11 deaths conducted damage assessments and needs analysis over the weekend of 10 December 2021 in Bahia and 17 January 2022 in Minas Gerais In Psychosocial support sessions for children each state and municipal institutions are working Bahia - Source: Brazilian Red Cross together on assistance and early recovery actions Emergency Operations Centres (EOC) established in Bahia and Minas Gerais have been actively involved in the EOC in Itamarajú in Bahia This IFRC-DREF allocation is covering the National Society's response actions and complementing the Federal Government's overall action plan Brazilian Red Cross response teams also responded in the newly affected areas through support to the Rio de Janeiro branch both Bahia and Minas Gerais have already emerged from the state of alert and all people have returned to their homes The usual services have been regularised and the roads are accessible The families whose houses had been totally destroyed have not returned to their homes; some are staying with relatives and friends while others are now living with the support of their State Governments in the form of "social rent" All the houses that were inspected and liberated have already received their families back there is a movement of reconstruction and repair of the houses in both the States of Bahia and Minas Gerais Metrics details An Author Correction to this article was published on 26 May 2022 This article has been updated One of the main categories of Neglected Tropical Diseases (NTDs) are arboviruses of which Dengue and Chikungunya are the most common Arboviruses mainly affect tropical countries Brazil has the largest absolute number of cases in Latin America This work presents a unified data set with clinical and laboratorial data on confirmed patients of Dengue and Chikungunya as well as patients ruled out of infection from these diseases The data is based on case notification data submitted to the Brazilian Information System for Notifiable Diseases from Portuguese Sistema de Informação de Agravo de Notificação (SINAN) The original data set comprised 13,421,230 records and 118 attributes a final data set of 7,632,542 records and 56 attributes was generated The data presented in this work will assist researchers in investigating antecedents of arbovirus emergence and transmission more generally it can be used to train and test machine learning models for differential diagnosis and multi-class classification “only approximately 23% were tested in reference laboratories” Given that Brazil is hyper-endemic for arboviruses the amount of patient data collected is very large almost 1.5 million cases of Dengue were reported to Brazilian Information System for Notifiable Diseases from Portuguese Sistema de Informacao de Agravo de Notificacao (SINAN) in 2020 this represents a significant source of information for both epidemiological analysis as well as training and optimising machine learning models for health purposes The objective of this work is to make available a Brazilian national data set with clinical and socio-demographic data on both confirmed and inconclusive cases of Dengue and Chikungunya so that this data can be used for future research such as the development of machine learning model that helps to correctly classify these patients A high-level epidemiological analysis of the data set is also presented no individually identifiable health information is made available in the data set Figure 1 presents the preprocessing steps used for cleaning the data set. First, the SINAN data from all states were aggregated resulting in 13,421,230 notifications and 118 attributes. The records were grouped into three distinct groups by the CLASSI_FIN attribute: Chikungunya: Patients with confirmed Chikungunya; and Discarded/Inconclusive: Patients who tested negative or inconclusive for Dengue or Chikungunya following laboratory tests. Pre-processing steps performed to build the final data set the data set consisted of 4,307,513 records for Dengue and 2,100,029 records for the Discarded/Inconclusive category Number of records in the data set by category (Dengue Discarded/Inconclusive) in Brazil per year Age structure of individuals in cases of Dengue Occurrence of confirmed cases of Dengue by Brazilian state. Occurrence of confirmed cases of Chikungunya by Brazilian state. Occurrence of discarded/inconclusive cases of Dengue and Chikungunya by Brazilian state This data raises questions regarding the quality of the surveillance system in these areas greater numbers of discarded/inconclusive cases in certain areas may indicate that the health and surveillance infrastructure in these areas is inferior to those in other states most of these categories of cases are located in the cities of SP and MG SP is the state with the highest number of cases in 2015 Socio-demographic data (Table 2) includes age Symptoms relate to specific physical features which can indicate the existence of a disease. As per Table 3 Comorbidities are preexisting conditions in the patient. Table 4 presents the clinical data with information about comorbidities Table 5 presents the attributes for laboratory data This data comprises results from serological and other tests It also contains data on whether the patient was hospitalised as well as the final patient classification The general and disease baseline characteristics are shown in Table 6 Baseline characteristics show an overall mean (SD) age over 30 years and a predominance of women for each arboviral disease and myalgia (34%) were the most frequent symptoms It is important to highlight that in confirmed cases of Chikungunya the absence of symptoms in the records directly affect the percentage of these symptoms in general All data presented in this work can be corroborated by reports published by the Ministry of Health of Brazil This city has a temperate climate and experienced an increase in Dengue cases and virus circulation from 2009 Santa Fé experienced the largest outbreak in Argentina to date The intention of the authors of both papers was to support further research in understanding the factors and patterns of arboviruses emergence and transmission it can provide data develop (low cost) decision support tools for the differential diagnosis of these diseases this data may be used as both training and test data sets for machine learning and deep learning models for binary and multi-class classification and prediction The code used to pre-process the data set presented in this paper is available at: https://github.com/dotlab-brazil/arbovirus-dataset-brazil A Correction to this paper has been published: https://doi.org/10.1038/s41597-022-01397-0 Global risk mapping for major diseases transmitted by aedes aegypti and aedes albopictus International Journal of Infectious Diseases 67 Cavany, S. M., España, G., Vazquez-Prokopec, G. M., Scott, T. W. & Perkins, T. A. Pandemic-associated mobility restrictions could cause increases in dengue virus transmission. PLOS Neglected Tropical Diseases 15, 1–19, https://doi.org/10.1371/journal.pntd.0009603 (2021) WHO Region of the Americas records highest number of dengue cases in history; cases spike in other regions (2019) Plisa health information platform for the americas - dengue cases (2021) Plisa health information platform for the americas - chikungunya cases (2021) The endless challenges of arboviral diseases in brazil (2020) Emerging arboviruses and public health challenges in brazil Oliveira, T. et al. Arbovirus clinical data, brazil, 2013–2020. Mendeley Data https://doi.org/10.17632/2d3kr8zynf.4 (2021) Arboviroses de importância epidemiológica no brasil (2018) Arboviroses emergentes no brasil: desafios para a clnica e implicações para a saúde pública Chikungunya in brazil: rheumatologists on the front line Co-circulation and misdiagnosis led to underestimation of the 2015–2017 zika epidemic in the americas Simple clinical and laboratory predictors of chikungunya versus dengue infections in adults Arbovirus emergence in the temperate city of córdoba Dengue emergence in the temperate argentinian province of santa fe Download references This work was partially funded by Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) - Finance Code 001 Fundação de Amparo a Ciência e Tecnologia do Estado de Pernambuco (FACEPE) an entity of the Government of the State of Pernambuco focused on the promotion of teaching These authors contributed equally: Sebastião Rogério da Silva Neto Programa de Pós-Graduação em Engenharia da Computação Leonides Medeiros Neto & Patricia Takako Endo The authors declare no competing interests Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations Download citation DOI: https://doi.org/10.1038/s41597-022-01312-7 Anyone you share the following link with will be able to read this content: a shareable link is not currently available for this article Sign up for the Nature Briefing newsletter — what matters in science neither of the two competitors being able to throw it was hard but in the end it was Keito Kihara who won the world title as Luka Javakhishvili was disqualified for applying a forbidden technique Hansoku make was deserved as was the title for Kihara It was a hard day in the office for him but with a beautiful conclusion In a particularly hotly contested category which has shown throughout the season that many athletes could claim the podium Samariddin Muxibiddinov (UZB) and Joshua De Lange (NED) offered themselves an opportunity to climb on to the podium but De Lange never really entered the match catapulted to the floor by a massive ura-nage It was a bronze medal for Samariddin Muxibiddinov In the match for the second bronze medal we found Antonio Medeiros Neto (BRA) and Giorgi Mishvelidze (GEO) ready to earn a medal as his opponent had two shido to his name and the third was synonymous with disqualification but again In golden score it was eventually Mishvelidze who scored ippon with a counterattack at just the right moment 2022 / Day 3 of the Cadet World Championships in Sarajevo .. 2022 / Florin Daniel Lascau is an instrumental figure in world .. 2022 / The last category of the day and the last of the individual .. 2022 / The category was especially spectacular right from .. 2022 / We have been repeating it for several days: being seeded .. 2022 / Today’s review comes from someone whose perspective .. The concession is for four 500kV transmission lines across the states of Bahia French utility Engie has won an auction arranged by Brazilian regulator Agência Nacional de Energia Elétrica (ANEEL), to build more than 1,000km of electric power transmission lines in the country Please check your mail inbox to download the buyer's guide you acknowledge that GlobalData UK Limited may share your information with our partners/sponsors who may contact you directly with information on their products and services Tick here to opt out of curated industry news Don’t let policy changes catch you off guard Stay proactive with real-time data and expert analysis Visit our Privacy Policy for more information about our services including information on your rights in respect of your personal data and how you can unsubscribe from future marketing communications Our services are intended for corporate subscribers and you warrant that the email address submitted is your corporate email address The company received a 30-year concession to design build and provide operations and maintenance of the electricity transmission lines in the states of Bahia The total estimated investment in the transmission lines is BRL2.67bn ($557m) Engie will develop four transmission lines between Morro do Chapéu and Poções Medeiros Neto and João Neiva and João Neiva and Viana All the transmission lines will have a capacity of 500kV The transmission lines will help meet the demand for the flow of electricity generated from resources in the north-east region to the south-east region this project is expected to create nearly 5,000 direct jobs Engie executive vice-president and networks activities in charge Cécile Prévieu said: “This success is an important step in the development of Engie’s electric power transmission activities a key country for the Group for over 25 years “While contributing to the security of supply and resilience of the country’s energy system this project will also enable better integration of renewable energies thereby helping to accelerate the energy transition.” Engie has deployed more than 2,700km of new power transmission lines in Brazil since 2017 In January 2020, the company acquired a 30-year greenfield concession project in the country via a tender launched by Sterlite Give your business an edge with our leading industry insights View all newsletters from across the GlobalData Media network TrendingSouth FloridaAMore owners sue Chateau Beach developers Two additional unit owners are suing the developer contractor and a subcontractor of Chateau Beach Residences a luxury condo tower completed last year in Sunny Isles Beach seeking millions of dollars in damages tied to a gas explosion on the top floor of the building last year Arer Investments LLC and Saltwater Trading Corp filed the suit in Miami-Dade Circuit Court on Wednesday against Chateau Beach LLC Coastal Construction of South Florida and Professional Plumbing according to a copy of the complaint obtained by The Real Deal They allege that the explosion, which injured six in October 2015, has damaged the value of their units and the 34-story image of the building, referred to in the lawsuit as “Chateau Boom.” Chateau Group delivered the project at 17475 Collins Avenue a month before the explosion the city of Sunny Isles Beach revoked the condominium tower’s certificate of occupancy The building continued to be “unsafe for occupancy” while repairs were being made until June 2016 a Delaware corporation controlled by Silvino Faustino Medeiros Neto Both entities allege that the eight-month period when they couldn’t access the building coupled with the “complete loss of value of the units” caused them to incur almost $10 million in combined damages told TRD it would be difficult for her clients to sell their units now that the building is “stigmatized” by the explosion and subsequent effects A final certificate of occupancy has not been issued “All of the unit owners in the building have been affected.” SIGN UPIn August, the owners of units 1103, 1003 “and all similarly situated unit owners” also sued the developer and Coastal over nearly identical allegations Naghshineh said the developers have been helpful but called their settlement offers insulting “Forty thousand [dollars] here or there is not going to compensate someone who paid so much for their unit,” she told TRD said through a spokesperson that the company has not had a chance to review the complaint in detail and is occupied and fully operational,” Murphy said The Chateau Group, led by Manuel Grosskopf, did not immediately respond to a request for comment. Chateau completed Fendi Chateau Residences in Surfside in September “My clients don’t want this to go on for years,” Naghshineh said The 7 December 2021 passage of a subtropical cyclone and related flooding continues to impact the health and wellbeing of the people in the extreme south and south regions of Bahia state in Brazil With more than 700 mm of rain in less than three days flood waters remain in many locations in the extreme south of the state The principal affected areas in the extreme south are in the municipalities of Medeiros Neto the southern region in Bahia state also is registering heavy rains The main affected areas in this region are in the cities of Itapetinga and Itabuna Scattered rains are forecast for throughout the extreme south and south in Bahia The Bahia branch of the Superintendency of Civil Protection and Defence (SUDEC) estimates that at least 471,786 people are affected by floods and heavy rains in Bahia state continue to conduct damage assessments and needs analysis SUDEC has reported that 42,929 people have been displaced and 34,163 are homeless SUDEC has reported 358 people injured and 21 deaths The most recent figures from the Emergency Operations Centre (EOC) established in Itamarajú indicate that at least 19,082 people have permanently or temporarily lost their homes in the extreme south of Bahia state The state's federal and local institutions the Government of Bahia’s organisms and firefighters from several states are leading the assistance and early recovery actions from the two EOCs located in Itamarajú and Ilheus The BRC actively participates in the EOC in Itamarajú where daily coordination meetings are held Humanitarian actors have identified the urgent need for safe and clean water menstrual hygiene products and food for the affected population the Brazilian Red Cross team in the field reports additional information by sector: Shelter: The water has not subsided from the homes in the cities of Itapetinga and Itabuna locations where water levels were over 2 metres and where the level of destruction and structural risk are high Challenges remain to repair and rehabilitate the most affected homes some families in less affected areas have been returning to clean and repair their homes Affected people in collective centres lack bedding materials sanitation and hygiene: Due to the damage to the water and sanitation system the provision of safe and clean water and hygiene are prioritised While service providers are repairing the system water quality and quantity continues to be deficient Efforts are underway to increase the provision of water in collective centres Health: The multi-institutional relief teams are providing first aid to injured people with the primary consultations due to traumatisms and incidents with poisonous animals The federal health system has registered cases of flood-related diarrhoea in some areas and there is concern about the increase of cases The Ministry of Health is promoting contingency and prevention measures Local health services are not currently overwhelmed in their response capacity although there is a structural deficit of health facilities in the affected areas Livelihoods: Local commercial centres have been affected with the suspension of economic activities in still flooded areas particularly in the cities of Itapetinga and Itabuna agricultural activities (day labourers and rural workers) are one of the main sources of income generation The level of affectation is considerable in agricultural fields Food security: The Federal Government of Brazil and the municipalities in the area are distributing basic family food baskets A food production and distribution centre has been established for use in the collective centres The Brazilian Red Cross is coordinating with other humanitarian actors for the distribution of donations received for the floods in Bahia Metrics details Venous thromboembolism (VTE) is a leading cause of death among cancer patients Khorana score (KS) is the most studied tool to predict cancer-related VTE Several single-nucleotide polymorphisms (SNPs) have been associated with VTE risk in the general population but whether they are predictors of cancer-related VTE is a matter of discussion little is known about VTE in the setting of cervical cancer (CC) and whether thrombogenesis-related polymorphisms could be valuable biomarkers in patients with this neoplasia This study aims to analyse the effect of VTE occurrence on the prognosis of CC patients explore the predictive capability of KS and the impact of thrombogenesis-related polymorphisms on CC-related VTE incidence and patients’ prognosis regardless of VTE A retrospective hospital-based cohort study was conducted with 400 CC patients under chemoradiotherapy SNP genotyping was carried on by using TaqMan® Allelic Discrimination methodology Time to VTE occurrence and overall survival were the two measures of clinical outcome evaluated The results indicated that VTE occurrence (8.5%) had a significant impact on the patient’s survival (log-rank test PROCR rs10747514 and RGS7 rs2502448 were significantly associated with the risk of CC-related VTE development (P = 0.021 and P = 0.006 respectively) and represented valuable prognostic biomarkers regardless of VTE (P = 0.004 and P = 0.010 thrombogenesis-related genetic polymorphisms may constitute valuable biomarkers among CC patients allowing a more personalized clinical intervention the present study was designed to analyse the incidence of VTE following CC diagnosis and its impact on the outcome of patients with this malignancy from the Northern Region of Portugal the predictive ability of KS was investigated as well as the predictive and prognostic value (regardless of VTE status) of thrombogenesis-related genetic polymorphisms previously identified in the general population The mean follow-up was 155.3 months (standard deviation (SD) = 7.6 months) This study was approved by the ethics committee at IPOP (CES IPO: 287A/014) A written consent according to the principles of the Helsinki Declaration was obtained from each patient before their enrolment in this study Peripheral venous blood samples of each patient were obtained using a standard technique and collected in ethylenediaminetetraacetic acid (EDTA)-containing tubes genomic Deoxyribonucleic Acid (DNA) was extracted using GRS Genomic DNA Kit—Blood & Cultured Cells from Grisp Research Solutions® as indicated by the manufacturer’s instructions eight SNPs were selected: Protein C receptor (PROCR) rs10747514 Regulator of G Protein Signalling 7 (RGS7) rs2502448 Glutathione-Disulfide Reductase (GSR) rs3779647 Coagulation factor 11 (F11) rs4253417 and Contactin 6 (CNTN6) rs6764623 The thermal cycling conditions for DNA amplification were the following: (1) 95 °C for 10 min (activation of Taq DNA Polymerase) (2) 45 cycles of 95 °C for 15 s (denaturation of DNA chains) and (3) 60 °C for 1 min (primers pairing and extension) Data of DNA amplification were analysed using StepOne Software (version 2.3 Applied Biosystems) Negative controls (without DNA) were included in each RT-PCR reaction to prevent false positives a double sampling for at least 10% of randomly selected DNA samples was performed Genotyping results were evaluated by two researchers with no previous knowledge concerning VTE status demographic and clinicopathological data of the patients included in the study Data analysis was carried on by using the computer software IBM® SPSS® Statistics software package Version: 28.0.0.0 Associations of the genetic variants with VTE status and patient’s demographic and clinicopathological factors were assessed using the chi-square test (χ2) for categorical variables while the student’s t-test or the Mann–Whitney U test was employed for continuous variables depending on their distribution (normal and not normal distribution The distribution was assessed using the Kolmogorov–Smirnov test given the large cohort size All tests conducted were two-sided and a 5% level of significance was established The genotype distribution of each selected SNP and the respective TaqMan assay are represented in Table 2 there were no significant statistical differences between the different genotypes of each variant and the patient’s demographic and clinicopathological characteristics (data not shown) ≥ 50 years) and histological subtype (adenocarcinoma/others vs The distribution of RGS7 rs2502448 genotypes among the different histological subtypes was statistically different (χ2 most patients with squamous cell carcinoma had the variant C allele (63.55%; n = 203) while most of those with other histological subtypes had the TT genotype (56.25%; n = 48) cancer histology was not a predictor of CC-related VTE nor a prognostic factor (P > 0.05) 10-year overall survival (OS) by Kaplan–Meier and Log-rank test for CC patients (n = 400) Patients with VTE had a lower 10-year OS compared to the ones without clinical evidence of VTE (P < 0.001) VTE patients had a mean 10-year OS of 60.9 months (SD = 8.8 months) while their counterparts presented a mean 10-year OS of 92.3 months (SD = 2.3 months) The disease frequency was 14% and 22% among the former and the latter KS was found to be only marginally associated with time to VTE occurrence (P = 0.078) Stratified analyses according to FIGO stage (III/IV vs ≥ 50 years) also did not reveal a significant predictive impact on the score KS showed a prognostic value among the 90 patients (log-rank test patients with a score ≥ 3 had a lower 10-year OS compared to the ones with a score < 3 (mean 10-year OS of 33.4 months (SD = 5.9 months) and 48.2 months (SD = 2.0 months) As it was only possible to determine the score for 90 patients and given its poor performance further analyses integrating the score were not conducted Considering the entire cohort of CC patients no statistically significant association with the time to VTE occurrence and patient’s prognosis was observed (P > 0.05) PROCR rs10747514 and RGS7 rs2502448 polymorphisms were shown to have a significant impact (a) Time to VTE occurrence by Kaplan–Meier and Log-rank test for CC patients Patients with the AA genotype presented a lower time to VTE development compared to the G allele carriers (mean time to VTE of 113.7 months (SD = 8.8 months) and 100.8 months (SD = 1.7 months) (b) 10-year overall survival (OS) by Kaplan–Meier and Log-rank test for CC patients Patients with the AA genotype presented a lower 10-year OS compared to the G allele carriers (mean 10-year OS of 73.7 months (SD = 10 8 months) and 95.3 months (SD = 2.8 months) (c) 10-year overall survival (OS) by Kaplan–Meier and Log-rank test for CC patients without clinical evidence of VTE according to PROCR rs10747514 genotypes (n = 250) Patients with the AA genotype had a lower 10-year OS compared to patients with the G allele (mean 10-year OS of 68.8 months (SD = 11.4 months) and 98.2 months (SD = 2.8 months) (d) 10-year overall survival (OS) by Kaplan–Meier and Log-rank test for young CC patients (< 50 years) without clinical evidence of VTE according to PROCR rs10747514 genotypes (n = 136) Patients with the AA genotype had a lower 10-year OS compared to patients with the G allele (mean 10-year OS of 62.1 (SD = 15.4 months) and 99.2 (SD = 3.8 months) respectively; log-rank test (e) 10-year overall survival (OS) by Kaplan–Meier and Log-rank test for CC patients at FIGO I/II stages and without clinical evidence of VTE according to PROCR rs10747514 genotypes (n = 188) Patients with the AA genotype had a lower 10-year OS compared to carriers of G allele genotypes (mean OS of 70.6 months (SD = 11.9 months) and 101.0 months (SD = 3.0 months) according to RGS7 rs2502448 genotypes (n = 254) Patients with the C allele had a lower time to VTE occurrence compared to patients with the TT genotype (mean time to VTE of 118.8 months (SD = 2.9 months) and 108.5 months (SD = 1.2 months) Patients with the C allele had a higher 10-year OS compared to patients with the TT genotype (mean 10-year OS of 97.1 months (SD = 3.5 months) and 86.0 months (SD = 4.9 months) according to RGS7 rs2502448 genotypes (n = 238) Patients with the C allele genotypes had a higher 10-year OS compared to patients with the TT genotype (mean 10-year OS of 102.2 months (SD = 3.4 months) and 85.7 months (SD = 4 (d) 10-year overall survival (OS) by Kaplan–Meier and Log-rank test for young CC patients (< 50 years) and without clinical evidence of VTE according to RGS7 rs2502448 genotypes (n = 128) Patients with the C allele had a higher 10-year OS compared to TT genotype carriers (mean OS of 105.2 months (SD = 4.4 months) and 84.4 months (SD = 6.7 months) (e) 10-year overall survival (OS) by Kaplan–Meier and Log-rank test for CC patients at FIGO I/II disease stages and without clinical evidence of VTE according to RGS7 rs2502448 genotypes (n = 182) Patients with the C allele genotypes had a higher 10-year OS compared to patients with the TT genotype (mean 10-year OS of 104.7 months (SD = 3.6 months) and 85.9 months (SD = 5.4 months) Given the observed predictive and prognostic value of PROCR rs10747514 and RGS7 rs2502448, multivariate analyses considering both polymorphisms were conducted adjusted for FIGO stage (III/IV vs. I/II) and age (< 50 vs. ≥ 50 years) (Table 5) The two polymorphisms had an addictive impact on CC-related VTE and patient survival VTE patients had a lower 10-year OS compared to their counterparts (log-rank test those with VTE presented almost a threefold increase in the risk of death compared to the ones without clinical evidence of the disease (HR 2.522; 95% CI 1.530–4.159; P < 0.001) suggesting that VTE significantly deteriorates CC patients’ prognosis (log-rank test thromboembolism is known to negatively affect the prognosis of cancer patients tumour cells are known to hijack haemostatic components present in the surrounding microenvironment to fuel their progression towards metastasis meanwhile disturbing the haemostatic imbalance towards thrombogenesis Given the negative impact of VTE on the prognosis of CC patients better thromboprophylaxis measures need to be explored which also demands an improvement of VTE risk prediction models required to validate these findings among CC patients particularly in larger cohorts and considering other treatments AG/GG; HR 2.578; 95% CI 1.308–5.083; P = 0.006) and multivariate Cox regression analysis adjusted for FIGO stage (AA vs AG/GG; aHR 2.612; 95% CI 1.322–5.161; P = 0.006) confirmed the prognostic value of PROCR rs10747514 in the cohort of CC patients without clinical evidence of VTE patients carrying the AA genotype had a threefold increase in 10-year risk of death compared to their counterparts in both analyses it was hypothesized that the AA genotype might be associated with higher EPCR levels and/or activity thereby promoting tumorigenesis and deteriorating the CC patients’ clinical outcome the prothrombotic effect of the AA genotype observed in this study (AA vs AG/GG; aHR 4.273; 95% CI 1.342–13.601; P = 0.014) seems to oppose this hypothesis Although future functional studies are required to elucidate the underlying biological processes one possible explanation could be an increased EPCR expression and/or activity paralleling with PC trapping by EPCR thus impairing the anticoagulation pathway while promoting cancer progression through coagulation-independent mechanisms in individuals without symptomatic VTE PROCR rs10747514 may be a useful biomarker to predict VTE among CC patients and assess their prognosis even in the absence of venous thrombogenesis the RGS7 rs2502448 C allele was associated with a lower time to VTE indicating a prothrombotic effect of this allele among CC patients (log-rank test This observation was further confirmed by both univariate (CT/CC vs TT; HR 10.062; 95% CI 1.329–76.179; P = 0.025) and multivariate Cox regression analysis adjusted for FIGO stage (CT/CC vs TT; aHR 10.672; 95% CI 1.409–80.813; P = 0.022) patients carrying the C allele genotypes had a tenfold increase in the 10-year risk of VTE compared to their counterparts RGS7 rs2502448 seems to be a valuable tool to predict VTE among CC patients and assess their prognosis even in the absence of the disease data concerning the use of anticoagulants or antiaggregating agents prior to cancer diagnosis were also unavailable and given that no active screening of VTE is included in the clinical routine procedures asymptomatic VTE events are not accounted for which could partially explain the poor performance of KS the distribution of patients with and without VTE could be different which represents an intrinsic limitation in this study Another important data missing was the specific cause of death among these patients which prevented the assessment of cancer specific survival as well as a possible VTE-related mortality information on the discontinuation of antineoplastic treatment due to VTE the temporal gap regarding the patients’ recruitment (February 2002 to October 2009 and May 2017 to October 2021) due to the requirement of biological samples may have led to selection bias the primary effort of investigation on cancer-related VTE should be focusing on the disease prevention the results of the present study corroborate the detrimental effect VTE has on the survival of CC patients and suggest that the genetic variants PROCR rs10747514 and RGS7 rs2502448 could be useful predictive biomarkers of thrombogenesis in these patients in addition to serving as potential tools for prognosis assessment regardless of VTE status the KS was only marginally associated with CC-related VTE the present study highlights the need for a more tailored thromboprophylaxis among oncological patients and better and more personalized cancer management considering the role of haemostatic components in tumorigenesis thrombogenesis-associated genetic polymorphisms might be the bridge to connect both worlds as this is a preliminary study with limitations additional investigation in larger cohorts and considering other relevant factors are required to validate the results Prospective studies with active screening of VTE are also a must to better explore the role of PROCR rs10747514 and RGS7 rs2502448 and assess the 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Clinical Pathology SV/ RISE@CI-IPOP (Health Research Network) Portuguese Oncology Institute of Porto (IPO Porto) / Porto Comprehensive Cancer Centre (Porto.CCC) Abel Salazar Institute for the Biomedical Sciences Portuguese Institute of Oncology of Porto (IPOP) José Brito da Silva & Deolinda Pereira Centro Hospitalar de Trás-os-Montes e Alto Douro (CHTMAD) Portuguese League Against Cancer (NRNorte) All authors had a significant contribution to the study Joana Liz-Pimenta has received a research Grant from GESCAT-Grupo de Estudos de Cancro e Trombose This institution had no role in the decision to write and publish this manuscript The remaining authors have no relevant affiliations with any organization with a conflict with the subject matter discussed in this manuscript and thus they declare no conflict of interest No writing assistance was required during the production of this manuscript Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations Download citation DOI: https://doi.org/10.1038/s41598-023-36161-w Sorry, a shareable link is not currently available for this article. 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Volume 8 - 2021 | https://doi.org/10.3389/fmed.2021.553280 This article is part of the Research TopicEmerging and Re-emerging Vector-borne and Zoonotic DiseasesView all 10 articles Visceral Leishmaniasis (VL) is a severe parasitic disease that has emerged as an important opportunistic condition in HIV-infected patients and whose control is impaired by inaccurate identification This is mainly due to the serological tests used for VL having a reduced performance in cases of VL-HIV coinfection due to a low humoral response a positive test has even greater diagnostic value when combined with the clinical status This study aimed to evaluate the application and performance of flow cytometry to detect anti-Leishmania infantum antibodies in HIV-infected patients characterized using “gold standard” techniques were compared with sera from healthy controls plus sera from HIV-infected individuals The flow cytometry results were expressed as levels of IgG reactivity based on the percentage of positive fluorescent parasites (PPFP) A ROC curve analysis of a serum titration indicated a PPFP of 1.26% as being the cutoff point to segregate positive and negative results flow cytometry showed greater sensitivity in relation to the serological tests evaluated flow cytometry was the only assay that positively identified all VL-HIV patients with quantified HIV load these findings suggest that flow cytometry may be used as an alternative serological approach for VL identification and as a tool to characterize the humoral response against Leishmania infantum in HIV-infected patients the aim of this study was to evaluate the performance and to verify the possible application of an alternative diagnostic method using flow cytometry to detect anti-L infantum antibodies in HIV-infected patients The study population was defined by the convenience of the sample size from two states from Northeastern Brazil (Pernambuco and Piaui) The sera used were from 18 VL-HIV coinfected (diagnosed by Leishmania positive bone marrow aspirate and rapid HIV test) and 18 VL negative-HIV positive patients as well as 18 healthy control individuals with VL negative sera confirmed using conventional serological tests (rK39 rapid test and DAT) eight patients (five from Pernambuco and three from Piaui) had been more thoroughly investigated prior to this study during their clinical evaluation with more detailed immunological records available (CD4 T cell count and viral load) All serum samples were collected in vacutainer tubes (BD Biosciences) inactivated by heating (30 min at 56°C) and centrifuged at 4°C the supernatants were aliquoted and kept at −20°C until further use This study was approved by the Ethics Committees from the Federal University of Piauí (0116/2005) and from the Aggeu Magalhães Institute Oswaldo Cruz Foundation (CAEE 51603115.7.0000.5190) The IFAT test was performed with an in-house protocol infantum promastigote antigenic suspension were applied to the delimited region of IFAT slides (PERFECTLAB The slides were then coated with 10 μl of the patients' serum Two control sera (positive and negative) were incubated in a humid chamber for 30 min at 37°C the slides were washed three times through immersion in PBS Anti-human IgG conjugated to fluorescein isothiocyanate-FITC (Sigma Chemical Corp. MO) prepared in Evans blue (40 mg) in PBS (previously diluted at 1:10 ratio in the same buffer) was added to the slides in a 1:50 dilution and incubated under the same conditions as mentioned before The slides were then washed three times for 10 min in PBS and left at room temperature The assembly was made with buffered glycerin pH 8.5 and the slides then observed under a fluorescence microscope Sera were considered positive from the dilution 1:40 The ELISA test was performed as described by Oliveira et al. (21) infantum antigen assayed with the various sera diluted 1:900 followed by incubation with the peroxidase-conjugated anti-IgG (Calbiochem After enzymatic detection with o-phenylenediamine (OPD) and H2O2 the reaction was quenched by adding 2M H2SO4 (50 μl/well) and the plates read at 490 nm (Spectra Max 190 Positive and negative controls were added to each 96-well plate to standardize the readings and variations The cutoff point between non-reagent and reagent samples was calculated as the mean of the negative controls plus two standard deviations The optimal serum dilution and PPFP cutoff point were then selected to gather the IgG reactivity data with the best performance indexes The values obtained were plotted as the mean of the PPFP related to the inverse dilution of the evaluated sera in addition to the FITC-conjugated internal control unlabeled controls in quadruplicates and negative (a pool of negative sera) and positive (a pool of positive sera) controls were included to validate the assay The graphs were generated by the GraphPad Prism version 7.0 (GraphPad Prism Inc. a sera dilution curve ranging from 1:64 to 1:8,192 The difference between the reactivity of positive and negative samples (Δ) showed that the best performance in segregating these groups was at the dilution of 1:2,048 we used this dilution to better define the optimal PPFP value for VL diagnosis IgG antibody titration curve of anti-fixed Leishmania infantum promastigotes defected by flow cytometry with sera from the two stratified groups assayed here The gray rectangle corresponds to the titration of 1:2,048 which was the region of greatest separation between groups Percentage of Positive Fluorescent Parasites Δ = difference seen for the reacitivity between groups The tests' global accuracy determined by the area under the ROC curve (AUC) with a confidence interval (CI) between 0.85 and 1.0] flow cytometry displayed 89% of sensitivity (CI 95% = 65–99%) and 83% of specificity (CI 95% = 67–94%) The mean PPFP values was 36% (CI 95% = 22–50%) for the VL-HIV coinfection group 1.4% (CI 95% = 0.9–1.8%) for the healthy controls and 0.2% (CI 95% = 0.1–0.35%) for the mono-infected HIV group ROC curve analysis of the performance indexes The ROC curve was applied to confirm the best cutoff point which was able to discriminate PPFP values from positive and negetive samples and to indicate the area under the curve (AUC = global accuracy) ROC curve of the samples at dilution 1:2,048 indicating a cutoff point of 1.26 Aiming to evaluate the global performance of flow cytometry, we used the same serum panel with serological tests conventionally used for the diagnosis of VL (DAT, rK39 rapid test, ELISA, and IFAT). Flow cytometry had the best values in terms of sensitivity and negative predictive value (89 and 94%, respectively), however, the other tests were more specific (100%) when compared to flow cytometry, which had a specificity of 83% (Table 1) When the different tests were individually compared to flow cytometry we could identify a substantial agreement between DAT and ELISA tests (κ > 0.6; agreement > 80%) and a moderate agreement between rK39 rapid test and IFAT (κ <0.6; agreement <80) and accuracy of the serological tests used for the diagnosis of VL-HIV coinfection (N = 54)* Eight of the VL-HIV coinfected sera were derived from patients whose immune statuses had been evaluated and the HIV viral load quantified (Table 2) We observed that flow cytometry was able to positively identify all of these sera including those with a more severe immunossupression with CD4+ T cell counts below 200 cells/mm3 and even taking into account the very large variations in HIV viral load Although the various conventional tests evaluated also gave positive results even in the patients with the most severe immunosuppressions all the other tests had at least one negative result for the series of cases analyzed with IFAT having the worst performance (three false negative results) no clear correlation between immunosuppression viral load and positivity in the assays was observed for the any of these tests Laboratorial findings of eight cases of the VL-HIV/AIDS coinfected group although in relation to the conventional tests used for comparison the sensitivity of flow cytometry was greater the technique is even more relevant for the diagnosis of VL in cases of VL-HIV co-infections The rk39 rapid test and IFAT are the serological tests most used for the diagnosis of VL, but they show the lowest sensitivity (<60%) in VL-HIV coinfected individuals (6) Our results showed higher sensitivity levels for these tests than previously reported but with a performance still inferior to flow cytometry and DAT Indeed, among the serological tests conventionally used for the VL diagnosis in coinfected individuals, DAT stands out as having the highest sensitivities in multiple studies: 89% (29), 81% (6), 82.3–89.7% (30), 91.3% (31), 89.5% (32), and 90% (33) This performance was also corroborated by our study Both DAT and flow cytometry use serial dilutions that allow the identification of antibodies in low serum concentrations even in immunosuppressive conditions (CD4+ T cells <200 cells/mm3) flow cytometer uses photomultiplier detectors and its quantitative assessment excludes the operator subjectivity which exists in DAT flow cytometry shows the potential to be an alternative serological method for VL detection in HIV-infected patients has diagnostic value when combined with the clinical case definition our results emphasize that flow cytometry can contribute to the correct identification of cases being a useful tool to characterize the humoral response to Leishmania in HIV-infected patients we encourage the evaluation of this technique in a larger number of samples and in other regions such as those affected by Leishmania donovani The raw data supporting the conclusions of this article will be made available by the authors The studies involving human participants were reviewed and approved by Aggeu Magalhães Institute The patients/participants provided their written informed consent to participate in this study All authors read and approved the final manuscript This work was supported by a Brazilian grant from MCTI/CNPq/MS SCTIE—DECIT N° 40/2012—Research in Neglected Diseases from FACEPE—PROEP (APQ-1712- 4.01/15) and from CNPq (400729/2019-9) 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 We would like to thank Camila Queiroz from the Aggeu Magalhães Institute The Supplementary Material for this article can be found online at: 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serodiagnosis of canine visceral leishmaniasis Non-conventional flow cytometry approaches to detect anti-Trypanosoma cruzi immunoglobulin G in the clinical laboratory A brief chronicle of CD4 as a biomarker for HIV/AIDS: a tribute to the memory of John L doi: 10.1615/ForumImmunDisTher.2016014169.A Diagnostic accuracy of direct agglutination test rk39 elisa and six rapid diagnostic tests among visceral leishmaniasis patients with and without hiv coinfection in ethiopia de Medeiros ZM and Pereira VRA (2021) A Flow Cytometry-Based Serological Assay to Detect Visceral Leishmaniasis in HIV-Infected Patients Received: 18 April 2020; Accepted: 08 April 2021; Published: 30 April 2021 Copyright © 2021 da Silva, de Oliveira, Pereira, Guedes, de Melo Neto, Costa, de Medeiros and Pereira. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY) distribution or reproduction in other forums is permitted provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited in accordance with accepted academic practice distribution or reproduction is permitted which does not comply with these terms *Correspondence: Elis D. da Silva, ZGlvbmlzaW8uZWxpc0BnbWFpbC5jb20= Disclaimer: 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 94% of researchers rate our articles as excellent or goodLearn more about the work of our research integrity team to safeguard the quality of each article we publish Please press and hold the button until it turns completely green If you believe this is an error, please contact our support team 147.45.197.102 : bdd247ad-0581-4ce7-86ba-3d8a1885 New Bedford Evening Extension School held its graduation on Tuesday MASSACHUSETTS HIGH SCHOOL EQUIVALENCY CREDENTIAL: Mandi M Metrics details Isolated TSH deficiency leading to hypothyroidism seems to be a rare condition escaping the diagnosis by neonatal screening programs which are based on the primary determination of TSH This is the first report of a case with an autosomal recessive TSH defect caused by a homozygous mutation of the βTSH gene that was diagnosed in the early neonatal period Hypothyroidism in the first child of apparently unrelated parents was suspected because of the classical symptoms of congenital hypothyroidism which were fully expressed already on the 11th day of life Routine neonatal TSH-screening on the 4th day of life had been normal but subsequent determination of serum thyroid hormone levels revealed almost undetectable levels and thyroid hormone substitution was immediately started Because there was no indication for other pituitary hormone deficiencies sequence analysis of the βTSH gene was initiated A homozygous T deletion in codon 105 was found resulting in a change of a highly conserved cysteine to valine followed by eight altered amino acids and a premature stop codon due to the frame-shift This altered βTSH is a biologically inactive peptide Because of the early development of severe symptoms it is possible that this altered TSH suppresses the physiologic constitutive activity of the unliganded TSH receptor Rapid molecular diagnosis in this patient clarified the diagnosis without additional endocrine and imaging studies and it is concluded that symptoms of hypothyroidism in the neonatal period should result always in an immediate comprehensive work-up of thyroid function including molecular genetic studies irrespective of the screening result The clinical diagnosis of hypothyroidism in all of these patients was made after the newborn period and molecular genetic studies were performed only in later life because these patients belonged to consanguineous kindreds with a multiple occurrence of central hypothyroidism We describe the first case of nonfamilial congenital βTSH deficiency in which rapid molecular genetic analysis enabled the diagnosis already in the newborn period and made extensive endocrine and imaging studies unnecessary Besides this useful application of molecular genetic techniques by the presence of severe symptoms and hypoplasia of the thyroid gland already in the neonate indicates that some forms of isolated TSH deficiency can result in severe congenital hypothyroidism and subsequent mental retardation The patient is the first child of unrelated parents without any history of thyroid disease in the families of both parents He was born after 40 wk of an uneventful pregnancy with a birth weight of 3435 g and a length of 51 cm The mother was not given iodine during pregnancy and no iodine-containing drugs were used perinatally in the mother or the newborn He was discharged at the 7th day of life from the maternity ward despite documented hyperbilirubinemia and feeding became increasingly difficult because he was very sleepy The general pediatrician suspected hypothyroidism and asked for the result of the determination of TSH in dried blood spots of the 4th day of life which had given a normal result of 1.3 mU/L The patient was referred to the neonatology unit on the 14th day of life to rule out infectious or other metabolic diseases On admission the newborn presented with the typical symptoms of congenital hypothyroidism: prolonged jaundice (bilirubin 172 µmol/L) and wide open anterior and posterior fontanels and cortisol were measured using specific radioimmunoassays (Pharmacia and neonatal TSH in filter-paper blood were measured by fluoroimmunoassay (Delfia TSH was also measured by an automated ELISA (Boehringer Mannheim Genomic DNA was prepared from peripheral white blood cells of the patient and family using a DNA extraction kit (QIAamp Blood Kit The second and third exons of the human βTSH gene were amplified using polymerase chain reaction (PCR) with 0.5 µg of genomic DNA as template and the following pairs of oligonucleotides: Exon 2: forward 5′ GCA TGA TCA TAT GCA TTG GG 3′ Exon 3: forward 5′ GTC CTG TCA CAT TAT GCT CTC 3′ reverse 5′ GGC AAG CAC ATT TAA CCA AAT TG 3′ Sequencing was performed with BigDye Terminator Cycle Sequencing Ready Reaction Kit (Perkin Elmer The sequencing reactions were analyzed with an automatic sequencer (ABI 373 The deletion of a T at codon 105 creates a new restriction site for SnaBI in this fragment Restriction analysis of exon 3 was performed at 37°C for 2 h and afterward separated on a 2% agarose gel The determination of thyroid hormone levels in serum after hospital admission on the 14th day of life revealed an almost undetectable low total T4 of 10.2 nmol/L and T3 level of 0.46 nmol/L The TG level was in the low normal range (17.5 µg/L) which were taken every 4 h during the first 24 h after admission were at normal levels (3.6-4.1 mmol/L) and baseline cortisol and growth hormone levels were in the normal range ruling out multiple pituitary hormone deficiencies All other biochemical findings were in the normal range besides a still elevated free serum bilirubin of 172 µmol/L There was no indication for an infectious cardiovascular or metabolic disease Thyroid hormone replacement was started on the 15th day of life and a control examination given after 1 wk showed normal results for T4 with 248.4 nmol/L and T3 with 1.9 nmol/L and an unmeasurable TSH of < 0.01 mU/L as assessed by x-ray and ultrasound of the knee and ankle was significantly retarded being only 35 wk at an age of 43 wk of gestation The association of severe symptoms of congenital hypothyroidism low circulating thyroid hormone concentrations and a low TSH level strongly suggested a TSH deficiency as the cause for hypothyroidism Because no other pituitary hormone deficiencies were detected a search for mutations in the βTSH gene of the patient was started immediately Amino acid sequence of the mutated and wild-type βTSH gene The deleted nucleotide at codon 105 is marked and the resulting nucleotide and amino acid sequence of the mutant from codon 105 to 114 is indicated in italic The corresponding nucleotide and amino acid sequence of the wild-type βTSH is shown Mutation analysis of exon 3 of the βTSH gene (B) The T deletion in codon 105 creates a new unique restriction side for SnaBI PCR of exon 3 of the βTSH gene of the patient and grandmothers was performed as described under "Patient" and "Methods." PCR products were digested with SnaBI and separated on a 2% agarose gel The patient is homozygous for this mutation all other family members studied are heterozygous A control sample of exon 3 was not cut by SnaBI The DNA analysis of both parents and grandmothers who are not related and originate from different parts in Germany showed that they all are heterozygous for this mutation Although there was no familial history of hypothyroidism the cause for TSH deficiency in this newborn was clarified within 4 wk The integrity of the α- and βTSH-subunit conformation is necessary for the interaction with the TSHR of the thyroid cell In vitro findings have shown a decreased biologic activity of the C105ΔT βTSH mutant inasmuch as the cAMP production was reduced compared with the wild type it was shown that the loss of biologic activity was solely due to the loss of cysteine and not to the loss of the following amino acids (3) Important conclusions have to be drawn from this study Molecular genetic studies are a valuable tool to clarify the diagnosis of pituitary hypothyroidism within a short period of time and to avoid invasive and costly imaging studies and endocrine function tests this is the first case without a family history of hypothyroidism in which homozygosity for a mutation of the βTSH gene has been demonstrated and who was already diagnosed and treated in the newborn period inherited βTSH defects can lead to severe neonatal hypothyroidism with the risk of mental retardation solely due to hypothyroidism if symptoms of hypothyroidism are present in the newborn period that occur despite a normal TSH measurement in newborn screening an immediate and comprehensive work-up of thyroid function including molecular genetic studies has to be initiated because central hypothyroidism is not detectable by TSH-screening we were able to identify the C105ΔT mutation in two additional newborns with severe symptoms of congenital hypothyroidism born in 1998 Therefore this mutation seems to be frequent in patients with severe congenital hypothyroidism owing to an isolated TSH deficiency and a rapid molecular diagnosis with PCR and restriction enzyme analysis is recommended to verify the diagnosis LaFranchi SH 1986 Detection of congenital hypopituitary hypothyroidism: ten year experience in the northwest regional screening program Dracopoli NC 1990 Familial hypothyroidism caused by a nonsense mutation in the thyroid-stimulating hormone beta-subunit gene biologically inactive thyrotropin caused by a mutation in the beta subunit gene Matsubara KJ 1989 Thyroid-stimulating hormone (TSH) deficiency caused by a single base substitution in the CAGYC region of the beta-subunit school and occupational performance in patients with idiopathic hypothalamo-hypopituitary hypothyroidism Vassart G 1996 Differential effects of NaCl concentration on the constitutive activity of the thyrotropin and the luteinizing hormone/chorionic gonadotropin receptors Nohara Y 1980 Familial transient hypothyroidism due to maternal TSH-binding inhibitory immunoglobulins Heinrichs C 1997 Familial congenital hypothyroidism due to inactivating mutation of the thyrotropin receptor causing profound hypoplasia of the thyroid gland Güters A 1996 Earliest prevention of endemic goiter by iodine supplementation during pregnancy Weintraub BD 1988 Cloning of the human thyrotropin β-subunit gene and transient expression of biologically active human thyrotropin after gene transfection Szkudlinski MW 1997 Novel insights into the molecular mechanisms of human thyrotropin action: structural and therapeutic implications for the glycoprotein hormone family Ingraham HA 1991 Mutations of the POU specific domain of pit-1 and hypopituitarism without pituitary hypoplasia Rosenfeld MG 1998 Mutations of the prop-1 gene cause familial combined pituitary hormone deficiency Download references The authors thank Katrin Huhne for skillful technical assistance Klaus-Peter Liesenkötter & Annette Grüters This study was supported by grants from the Sonnenfeld-Stiftung Download citation DOI: https://doi.org/10.1203/00006450-199908000-00007 Journal of Endocrinological Investigation (2002)