the first Italian Cheese Café opened in Milan where cheese is celebrated in all its declinations The venue is located in the Garibaldi area at Via Tocqueville, 10 Cool area with a varied offer of really interesting little places Gòodurie Soresina will enrich the neighborhood with its cheesy and tasty proposals Recipes with the products of the famous Soresina dairy whose mission is to transform raw material into Italian excellence Which of course will be found on the restaurant’s menu Gòodurie Soresina goes very well with the neighborhood in which it is inserted à la page that has evolved a lot over time Very convenient to reach it presents different services: food Gòodurie Soresina will give an extra touch of glam cheese is the main ingredient in all its versions where products can be purchased to become the ingredients of the most imaginative recipes along with ready-to-eat take-away delights The excellences of the territory, collected in the “cheese card,” offer a fine selection of PDO cheeses , including lactose-free ones, which can be enjoyed pure or in original, healthy and tasty recipes. Each dish is a gastronomic journey, from brunch to aperitif “Irresistibles” include polenta with porcini mushrooms and Caciotta with truffles and codfish mantecato with Stracciatella and sun-dried tomatoes; “Las Lasciati Stuzzicare” includes tempting proposals such as Trusdel: potato and leek strudel with smoked Caciocavallo and pumpkin and the legendary Emilian erbazzone; “Energy Food” includes gourmet recipes for the energy-hungry; “Adorate Salads” when vegetable garden meets cheese; and “Good 4 Kids” to make children love cheese Plus great classics such as taglieri and pan brioche with Parma ham A varied and tasty choice that satisfies a little of every palate Gòodurie Soresina is the place to discover the true flavor of Italy The deal will create a business with a combined turnover of more than EUR500m ($540.8m) Italian dairy cooperative Latteria Soresina plans to acquire gorgonzola cheese maker Fratelli Oioli Dairy based in Soresina in the province of Cremona in Italy’s Lombardy region said in a statement yesterday (16 January) it expects to close the deal in the “next few days” Latteria Soresina is buying the Cavaglietto-based business from the Oioli brother owners The combined businesses will have a turnover of more than EUR500m (US$540.8m) Fratelli Oioli generated EUR14m in turnover Latteria Soresina will add a third cheese of Italian protected designation of origin (DOP) to its portfolio which currently includes grana padano and parmigiano reggiano carrying that status The company also produces provolone cheese said the transaction “is a strategic operation aimed at adding an important DOP such as gorgonzola a cheese that lends itself to being produced with the milk of our members” Don’t let policy changes catch you off guard Stay proactive with real-time data and expert analysis He added: “The union between Latteria Soresina and the skills of Oioli will therefore allow us to offer the market a product of absolute excellence supported by a robust corporate structure and supply chain opening up further opportunities both in Italy but above all towards exports.” one of the brothers whose father Giovanni founded the business in 1992 said: “We believe that becoming part of a large and solid group such as Latteria Soresina will allow the company to continue to grow on the market as it has done in recent years in which it has managed to safely overcome both the problems of the pandemic and those of the energy crisis and availability of raw materials which are still heavily influencing the market.” Nominations are now open for the prestigious Just Food Excellence Awards - one of the industry's most recognised programmes celebrating innovation This is your chance to showcase your achievements Don't miss the opportunity to be honoured among the best - submit your nomination today Give your business an edge with our leading industry insights View all newsletters from across the GlobalData Media network. Autoimmune and Autoinflammatory Disorders : Autoimmune Disorders Volume 15 - 2024 | https://doi.org/10.3389/fimmu.2024.1497921 Inborn errors of immunity (IEI) are rare diseases that affect the immune system According to the latest International Union of Immunological Societies (IUIS) classification Even if increased susceptibility to infections is the best-known symptom IEI are no longer defined by the higher likelihood of infections alone Immune dysregulation with autoimmune disease and hyperinflammation and malignancy are common manifestations and could be the only symptoms of IEI that must be recognized An exclusive focus on infection-centered warning signs would miss around 25% of patients with IEI who initially present with other manifestations Timely and appropriate diagnosis and treatment are essential to enhance the quality of life (QoL) and as patients are susceptible to life-threatening infections or autoimmunity the advantage of early diagnosis in IEI with immune dysregulation (i.e activated phosphoinositide 3-kinase delta syndrome -APDS-) is the initiation of targeted therapies with precise re-balancing of the dysregulated immune pathways (i.e. selective inhibitors) or definitive therapy (i.e. The group of Inborn Errors of Immunity (IEI) currently comprises 485 disorders of immune function and/or regulation, most of them with a specific monogenetic cause (1). These conditions are classified into 10 categories according to their clinical and immunologic phenotypes by the International Union of Immunological Societies (IUIS) (1) IEI are inherited immune system disorders with a broad spectrum of manifestations, starting with an increased susceptibility to infections, but also often including immune dysregulation and malignancy. Earlier diagnosis helps ensure that the patient is prescribed the most appropriate therapeutic intervention, improving prognosis (2) and decreasing the risk of infection and inappropriate vaccinations (3, 4) Recent discoveries in the field of IEI enabled the better characterization of the non-infectious manifestations of IEI In some patients autoimmune or autoinflammatory may be the only indicators of IEIs (5). These cases may be categorized as “diseases of immune dysregulation” according to the most recent classification from the International Union of Immunological Societies (IUIS) 2022 (1). Other types of IEIs include immune dysregulation as part of a wider clinical phenotype (6) The latest IUIS lists “Diseases of immune dysregulation” as an independent category of IEI (1) including familial haemophagocytic lymphohistiocytosis (FHL syndromes) autoimmunity with or without lymphoproliferation autoimmune lymphoproliferative syndrome (ALPS Canale-Smith syndrome) and susceptibility to EBV and lymphoproliferative conditions Patients with these diseases may suffer from immune dysregulation alone or with a combined manifestation of immune deficiency lymphoproliferation and even predisposition to malignancy However, overlap between immunodeficiency and autoimmunity is commonly observed in patients with other various IEI (7) (Figure 1) Clinical spectrum of Inborn Errors of Immunity as a continuum autoimmune lymphoproliferative syndrome; APDS Activated Phosphoinositide 3-kinase-d-syndrome; CVID Mechanisms preventing adequate response against pathogens also affect self-tolerance and immune regulation (8) As described by Fischer et al. (9) immune dysregulation is associated with virtually all IEI and is observed in a significant group of patients with IEI These manifestations occurred throughout the patient’s lifetime and have a prognostic significance Immunoregulatory disorders are at least 10 times more frequent in patients with IEI than in the general population (9). This increase in risk is extremely high for autoimmune cytopenia (by a factor of 120), but also with the 80-fold increased risk of inflammatory bowel disease, and the 40-fold increased risk of arthritis (9) suggesting that patients presenting with immune dysregulation should be screened for IEI Although autoimmune manifestations occurred in patients with all types of IEI and are a significant component of the clinical presentation of all types of IEI, those with T-cell defects or common variable immunodeficiency (CVID) tended to have the highest risk for autoimmunity (10) As described by Thalhammer et al., even if infection is the most frequent initial presenting manifestation of IEI, 18% of patients present with immune dysregulation as the first symptom (5) Individual IEI disorders are rare, but IEI as a collective account for a significant group of diseases, affecting around 1 in 2000 people (11–13) Considering the first presenting symptoms in relation to the age of onset, at early onset age (6-25 years) immune dysregulation was the initial presentation of IEI in approximately 25% of patients, associated or not with infection. However, beyond age 30 infection without immune dysregulation was the dominant initial presentation in around 80% of patients with IEI (5) Analysis of the ESID registry indicates there are more male than female patients (56 vs 44% respectively), suggested to be explained by the X-linked inheritance of many IEI. This, plus the early onset before age 6 leads to a particular predominance in males within the first years of life which predictably shifts to a female predominance with increasing age, most evident after 50 years (5) There is also a significant change observed in the sex ratio of patients presenting with immune dysregulation with increasing age. In patients under 10 years of age, more than 60% with immune dysregulation as only or concomitant initial manifestation were boys, whereas male/female ratios were similar between age 10-30 years. It is only beyond 30 that females predominated, reaching up to 70% after age 40 (5) Considering all these data, there is growing awareness that autoimmune disorders may precede infections among patients with IEI, especially those with primary immune regulatory diseases (PIRD) (5). Therefore, initiatives are critical to expedite a diagnosis and repurpose mechanism-based biologics for targeted therapies (14) Immune dysregulation accounts for a large proportion of manifestations in IEI patients, resulting in a worse prognosis in patients with immune dysregulation compared to those with only high infection susceptibility (9) autoimmune cytopenias are often dominant in the initial clinical presentation but patients may eventually progress to autoimmune enteropathy ITP and AHIA often present as the first symptom in adults too. Most children with AHIA, ITP, and AIN have a mild to moderate clinical course of the disease, often requiring only observation and treatment with first-line therapies (17) if a patient does not respond to first-line therapy Currently, there are no specific diagnostic biomarkers to identify the patients at risk of IEI among those presenting with autoimmune cytopenia, but unusual age at disease onset (early chronic immune thrombocytopenia, late onset of autoimmune neutropenia), positive family history for IEI or immune dysregulation, chronic disease course, and refractory disease should be considered as elements of interest. In these cases, immunological investigations are always recommended (18) In AIC patients with IEI, cytopenias affecting multiple blood lineages or those associated with adenopathy and/or hepatomegaly/splenomegaly or corresponding infections are characteristic traits (21) (Figure 2) Critical approach to patients with autoimmune cytopenias AIC patients with IEI often do not respond to first-line therapy and further investigation into best practice for these patients still needs to be understood (18) the ability to obtain a definitive molecular diagnosis may present new opportunities for targeted therapeutic options as seen in LRBA and CTLA-4 deficiencies One specific class of disorders, non-malignant pediatric lymphoproliferative disorders (PLPD) which can be characterized by the presence of proliferating clonal or polyclonal lymphoid cells, can occur in response to immune stimuli and can indicate underlying immune dysregulation (15) Clinical presentations include chronic (>3 months) or recurrent lymphadenopathy or symptoms secondary to organ infiltration by lymphoid cells PLPD has also been noted to be linked to an increased incidence of lymphoma and other haematopoetic malignancies (22) Lymphadenopathy can create diagnostic challenges when it is the first presenting symptom of an immune system disorder, particularly in children, resulting in delayed diagnosis (22) Lymphadenopathy is common during childhood and it poses a significant diagnostic dilemma when it represents the first sign of a disorder of the immune system, leading to a consequently delayed diagnosis. While transient lymphadenopathy in children is often benign, long-standing lymphoproliferation may reflect underlying immune dysregulation, increase the risk for developing malignant disease, and/or drive life-threatening lymphoproliferative disease (23) When lymphadenopathy is identified in patients who have been diagnosed with immunodeficiency, it should be considered a red flag to consider differential diagnosis between benign lymphoproliferation and malignancy (24) Lymphadenopathy as well as hepatosplenomegaly can be part of the clinical spectrum of several IEI, including diseases with immune dysregulation and autoinflammatory disorders, as the clinical expression of benign polyclonal lymphoproliferation, granulomatous disease or lymphoid malignancy (24) Although several inherited diseases of immune dysregulation have been associated with PLPD frequency and distribution of PLPD in children with IEIs are unknown Errors in more than 400 genes are now ascribed to IEI and a significant number of these conditions present with clinical features consistent with PLPD (22) (Figure 3) Inborn errors of immunity associated with non-malignant pediatric lymphoproliferative disorders The figure was generated using Python and the NetworkX library The mechanisms underlying lymphoproliferation in the different immune system disorders are multiple and have yet to be completely understood However, recent advances in genetic techniques will allow for increased opportunities to identify new disorders, which in turn will allow genotype-phenotype connections to be made, resulting in improved treatment and follow-up. Forbes et al., noted the identification of pathogenic gene variants implicated in PLPD were able to allow use of targeted therapies and to reduce mortality (22) The signs and symptoms of most rheumatic diseases are classified in international ACR or EULAR criteria Rheumatologic disorders are considered complex diseases with partial genetic origin with a heterogeneous genetic background and variable phenotypic presentation An increase in research into the genetics behind these diseases has led to the detection of several genetic mutations that are linked to the immune dysregulation seen in many rheumatic diseases In recent years, the increased interest in identification of single-gene causes of the rheumatologic diseases, has resulted in identification of several genetic mutations that underlie immune dysregulation and subsequently rheumatological manifestation (25) A high degree of overlap exists between autoimmune diseases and inborn errors of immunity in terms of genetic associations and causes (7) There is a significant increase in autoimmune and autoinflammatory complications in IEI patients, especially in common variable immunodeficiency (CVID) and combined immunodeficiency (CID). Patients with these complications have a shorter life expectancy or increased mortality (9) From a genetic point of view, rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) are the two best-studied rheumatic diseases. Different genes associated with IEI and involved in immune regulation are relevant to rheumatic diseases (Table 1) Inborn errors of immunity resulting in rheumatologic disease rheumatologic diseases presenting within a multisystem disease spectrum as well as therapy resistance may alert clinicians considering IEI as a possible diagnosis the case of early-onset connective tissue disease should raise the suspicion of a potentially underlying IEI The association between endocrine autoimmune diseases and IEI is currently well known when endocrinopathies represent the main symptom or develop before the patient has experienced recurrent infections an underlying IEI may be missed and its diagnosis delayed for years Clinical clues that a patient with endocrinopathy may have an underlying IEI are early disease onset the development of autoimmune processes affecting multiple organ systems and the positive familial history for endocrine disorders and autoimmunity Autoimmune thyroid diseases or other endocrinopathies Even though autoimmune polyendocrine syndrome 1 (APS-1) represents the paradigm of the immune disorder associated with endocrinopathy other disorders such as immune dysregulation IEI resulting in monogenic IBD are disorders involving the intestinal epithelial barrier Consequences of the breakdown of the immune system are strongly reflected in the gastrointestinal tract and often result in disease at an especially young age Monogenic IBD is predominantly identified in patients diagnosed prior to 6 years old, known as very early onset IBD (VEO-IBD) (28) (Table 2) Monogenic causes of IBD that are concurrent IEI Among patients with monogenic IBD, employing conventional therapeutics is oftentimes inadequate. Indeed, biologics are only effective in 25.5% of patients with monogenic IBD (28) Moreover, among VEO-IBD patients, monogenic disease is a driver of disease severity, including death (29) Given the growing number of IEI that occur with IBD Understanding the mechanisms driving intestinal inflammation reveals pathways of importance that merit evaluation for therapeutic targeting facilitating personalized therapeutic options and optimizing prognosis Allergy develops on account of disturbed function of the immune system The immune system depends on a complex balance of activation to differentiate between self and non-self Allergic manifestations depend on exaggerated immune responses against specific non-self-antigens, known as allergens (30). Frequent allergic symptoms include eczema, allergic rhinitis, asthma, and food allergy, associated with increased serum immunoglobulin (Ig) E and peripheral blood eosinophilia. It is now known that allergic manifestations can be the main symptoms of IEI (31, 32) (Table 3) Six different phenotypes of IEI associated with allergies In particular, the allergic triad defined by increased IgE, eosinophilia, and eczema is shared by different IEI that may be misdiagnosed as common allergic diseases (32) Patients affected by IEI with atopic phenotypes usually present with distinguishing associated clinical manifestations and laboratory findings that need to be promptly identified it is fundamental to assess the presence or absence of a familiarity for IEI and/or consanguinity Common features of IEI associated with atopic phenotypes are: usually at birth or in the first months of life usually not responsive to standard therapy Associated susceptibility to fungal or bacterial infections In general, red flags of IEI that the clinician should recognize are the presence of neonatal erythroderma, congenital ichthyosis, serum total IgE >2000 kU/L, especially in the first 3 months of life, and atopic manifestations associated with recurrent/severe bacterial or viral infections, autoimmunity, cytopenias, chronic diarrhea and/or failure to thrive (30) Granulomas are inflammatory infiltrates, which can occur in different tissues as a self-limited or severe condition that can persist for years. Granulomas represent the result of an immune response induced by an encounter between antigen presenting cells (predominantly monocytes and macrophages) and T cells (both CD4 + and CD8+ T cells) (33) Granulomas can be associated with infectious or inflammatory diseases, and it is hypothesized that they occur as a result of antigen persistence or immune dysregulation. Granulomas are more common in adults than children with IEI (34), and non-infectious granulomatous inflammation is common patients with chronic granulomatous disease (CGD), ataxia telangiectasia (AT), CVID, and severe combined immunodeficiency (SCID) (35, 36) The spectrum of manifestations of IEI is continually expanding Among the various presenting symptoms of these diseases we must not forget the neurological manifestations Although central nervous system involvement and vasculopathies are present only in a minority of patients systemic and central nervous system vasculitis and also vascular malformations and MoyaMoya syndrome have recently been reported as presenting or accompanying symptoms in some IEI neurological involvement is present in almost 30% of cases ranging from forms of autoimmune encephalitis to inflammatory disorders optic neuritis and lymphoproliferative diseases with infiltration of the central nervous system Neurological involvement in CTLA-4 deficiency represents the presenting symptom in approximately 5% of patients The identification of this form of congenital defect of immunity underlying the neurological manifestations also justifies the use of target therapy with abatacept which was also effective in controlling neurological symptoms (37) The involvement of the central nervous system may be present in the form of vascular alterations (aneurysms thrombotic events) also in Hyper-IgE Syndromes In those caused by loss of function mutation of DOCK8, nervous involvement most often occurs in form of CNS vasculitis and Moyamoya syndrome (38) Neurological involvement is also present in up to 75% of cases in DADA2 deficiency. Neurological manifestations can be an initial symptom of the disease and can recur, typically presenting in the form of ischemic strokes, but also as central or peripheral neuropathy (37) Renal, intestinal, pulmonary, but also cerebral vasculitis is a well-known, and sometimes fatal, complication of Wiskott-Aldrich Syndrome (39) The literature lacks sufficient evidence regarding vasculitis of the central nervous system associated with IEI and shared consensus regarding treatment the identification of a causative immune defect allow an important consideration regarding the treatment of patients with CNS vasculitis is the risk they have of developing stroke due to inflammation and stenosis of the involved vessels Recognizing these symptoms as early as possible allows aggressive management of the initial inflammation in order to control the progression of the disease there has been a rapid growth of IEI discoveries and a deeper understanding of their mechanisms It has come to our knowledge that IEI does not only mean higher susceptibility to infections Those patients with a combination of several types of autoimmune or inflammatory diseases should be considered for a scan of IEI Identifying an underlying IEI in a heterogeneous group of patients with a variety of autoimmune disorders requires an immune evaluation in the initial workup to get a specific diagnosis of highly vulnerable patients with genetic immune deficiency disease (10) The modern diagnostics of IEI include various diagnostic measures, such as a simple blood count with particular attention paid to the total absolute lymphocyte count, the serum immunoglobulin levels, and the complete sequencing of the exome or genome (40) Current guidelines recommend performing advanced immunological diagnostics of suspected IEI patients before molecular testing (41) Genetic sequencing is the current standard for confirming the presence of IEI. This is done via predefined panels of sequenced genes or whole exome sequencing (WES). In addition, whole genome sequencing (WGS) can be performed in addition to, or in replacement of a panel or exome approach (42) As individually diagnosed IEI are considered rare, it is challenging to conduct large-scale studies and thus it is difficult to treat such conditions with limited available data. The advancements in WES and WDS approaches have helped to improve the identification of the causative mutations for IEI, resulting in a doubling of identified mutations between 2009-2019 (43) Early detection of genetic diagnoses in immune dysregulatory disorders informs mechanisms of pathogenesis and allows potential therapeutic targets and/or definitive HSCT potentially avoiding the morbidity and mortality associated with uncontrolled disease and broad immunosuppression Therapeutic strategies for IEI affected patients are mainly symptomatic, with the goal of avoiding complications using antibiotics, immunoglobulin replacement, corticosteroids, and immunosuppressive agents, depending on the underlying IEI (17) Control of immune dysregulation with immunosuppressive therapies should be balanced against the increased risk of infection posed by the underlying defect and accumulated end-organ damage (44) understanding the molecular basis of IEI disorders enables the physicians to exploit the molecular defect with targeted therapies An improved understanding of the pathophysiology of these disorders has led to the development of mechanism-based therapeutic strategies. Small molecules and biologics are effective in reversing clinical manifestations of primary immune deficiencies and as a bridge treatment to hematopoietic stem cell transplantation (45) (Table 4) Therapeutic strategies in IEI associated with immune dysregulation For example, in IEI caused by hyperactivation of a specific protein, the use of small molecules to inhibit activity and return it to baseline levels has been studied for activated phosphoinositide 3-kinase-d syndrome (46) anti-CD-28); Anakinra (anti-IL-1 receptor); Baricitinib (JAK 1/2 inhibitor); Belatacept (CTLA-4 fusion protein); Infliximab (anti-TNF); IVIG (intravenous immunoglobulin); Leniolisib (PI3Kδ inhibitor); MMF (mycophenolate mofetil); Rituximab (anti-CD20); Ruxolitinib (JAK 1/2 inhibitor); Sirolimus (m-TOR inhibitor); Tocilizumab (anti-IL-6 receptor) APDS is a very rare disease due to monogenic defects that cause constitutive T cell activation. It is an autosomal-dominant (AD) IEI caused by point mutations or deletions in one of the two genes encoding the two phosphoinositide 3-kinase δ (PI3Kδ) subunits. Heterozygous gain-of-PI3Kd-activity variants in PIK3CD or PIK3R1 cause APDS1 and APDS2, respectively, which show large phenotypic overlap (47, 48) (49–51) APDS often presents early in life with an association of recurrent infections, lymphoproliferation, and autoimmune disease (i.e. autoimmune cytopenias, colitis, arthritis, and granulomatous skin lesions), deteriorating, later in life, in decrease lung function or lymphoma (52) Additional nonimmunological features such as neurodevelopmental delay or neuropsychiatric disorders, are more frequent in APDS-2 than APDS-1 patients (53, 54) In APDS, both humoral and cell-mediated immune defenses are affected. Immunological characteristics that should lead to suspected APDS are represented by increased IgM serum levels with concomitant decreased to normal IgG and IgA levels, progressive B cell lymphopenia associated with a relative expansion of transitional B cells and plasmablasts, decrease of naïve T cell subsets with relative expansion of central and effector memory T cells (52, 55) To date, there is no standard of care for treating APDS patients. Currently, the majority of treatments do not target the underlying pathogenesis of APDS and immune deficiency is treated with prophylactic antimicrobials and immunoglobulin replacement therapy (IRT), while immune dysregulation is generally treated with immunomodulatory therapies such as corticosteroids or the mTOR inhibitor rapamycin (52) (52) Haematopoietic stem cell transplantation may represent a curative option. While HSCT has the potential to decrease the frequency of infections or severity of lymphoproliferation (56, 57) it may not correct non-immune/extra-haematopoietic manifestations Moreover, HSCT carries the risk of serious complications, including increased rates of graft rejection. In the literature, HSCT-related events represent the second most common cause of death in APDS patients (51) As APDS is known to be caused by PI3Kδ overactivity PI3Kδ inhibitors such as nemiralisib have been studied as potential treatment options in limited patient populations In the absence of easy ways to measure cellular PI3K activity it is difficult to know whether PI3Kδ activity is completely normalized A commercially accessible method to monitor pAKT or other markers of pathway activity or inhibition would be helpful The effects of leniolisib on pediatric populations requires further study For APDS, early onset predicts a severe disease course, calling for specific treatment studies in younger patients (54) and a pediatric trial is now recruiting (NCT05438407) Abatacept is superior to immunosuppressants in controlling disease manifestations over the long term, especially when started early, and it may provide a safe and effective therapeutic alternative to transplantation (62) Patients with IEI are susceptible to developing a severe infection-related clinical phenotype, but the clinical consequences of this phenotype could represent the first sign in a significant percentage of patients. Early diagnosis of IEI is therefore essential to help identify suitable treatments that may delay or prevent irreversible organ damage (40) The so-called “warning signs” of IEI (56) may help identify immunologic disorders these do not include signs of immune dysregulation Our purpose is to underline the need for early identification of common features of IEI and red flags to suspect IEI in the context of immune dysregulation for every patient. These new red flags, encompassing autoimmune cytopenias, chronic lymphoproliferation, cancer predisposition, allergies, endocrinopathies, enteropathy and vasculitis, should be considered as further warning signs to suspect a IEI (63) In fact, identification of an underlying genetic diagnosis in immune dysregulation disorders is the prerequisite for disease-specific therapies, which are increasingly available for IEI (64) The global initiative of the Jeffrey (65) Modell Foundation involving over 1,300 patients reported that genetic screening that interrogated a panel of 407 genes associated with IEI led to an alteration of clinical diagnosis and treatment in over 35% of patients (45) Improvement in genetic testing has led to more specific diagnosis and delineation of immune dysregulation syndromes targeted therapies are available or show promise for the treatment of different IEIs Writing – review & editing The author(s) declare financial support was received for the research Autoinflammatory and Autoimmune Diseases (ERN-RITA) This study was supported in part by Ministero della Salute (PNRR-MR1-2022-12376594) and by unconditioned support by Pharming to RB Medical writing and editorial assistance was provided by Julie Howard Ph.D in accordance with Good Publications Practice guidelines Several of the authors are members of the European Reference Network 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 The author(s) declared that they were an editorial board member of Frontiers This had no impact on the peer review process and the final decision 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 Human inborn 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RIPK1-mediated neuroinflammation in CNS diseases PubMed Abstract | Crossref Full Text | Google Scholar Soresina A and Badolato R (2024) Unmasking inborn errors of immunity: identifying the red flags of immune dysregulation Received: 18 September 2024; Accepted: 04 December 2024;Published: 19 December 2024 Copyright © 2024 Cortesi, Dotta, Cattalini, Lougaris, Soresina and Badolato. 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: Manuela Cortesi, Y29ydGVzaW1hbnVlbGE5MUBnbWFpbC5jb20= 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 Categories Weather Report At least 7 tornadoes were reported by storm chasers and the public across the Po Valley this afternoon A tornado outbreak has developed under a well-defined upper low moving across the northern Mediterranean and the Alps producing a number of isolated supercell thunderstorms It has been a pretty wild year with severe weather and tornadoes reported in various parts of Europe over the last few months, including the destructive tornado in Hodonin, Czech Republic on June 25th several areas across the large plain of northern Italy – known as the Po Valley Plain – have been hit by damaging tornadoes Today’s event is one of the tornado outbreaks with the highest number of tornadoes in recent years Let’s see further details about the event and the general weather pattern over this part of Europe this weekend The ongoing general weather pattern over Europe reveals a deep upper low strengthening over eastern Europe locked-in with the strong blocking High across northern Europe and the Arctic region Together they are resulting in a significant cold outbreak into the Baltic region and eastern Europe another shallow but well-defined upper-level low is moving across the northern Mediterranean and the Alps This is the featured system that has resulted in a tornado outbreak across the Po Valley in the northern Italy plains today The upper low that can be seen moving across North Italy has been rounded with powerful winds aloft a strong westerly jet stream is providing the favorable upper-level support for vigorous thunderstorm development over the region This jet stream also separates warm/hot air mass over the Mediterranean from the cooler weather to the north of the Alps This large upper-level low is also well-visible on the water vapor and visible satellite imagery – see the attached image below The upper low is centered over northwestern Italy Sunday afternoon (marked with a white circle) while the blue arrows represent the jet stream aloft A pronounced dry intrusion that provides a boost to the thunderstorm activity is marked with yellow around penetrating into the upper low from the west-southwest underneath the jet stream aloft – the left-exit jet region.  Marked with small yellow circles are those isolated supercell thunderstorms that produced tornadoes or severe thunderstorm events These cells were generally moving east-northeast and brought quite some damaging severe weather Isolated supercell thunderstorms were also perfectly visible on the radar imagery Some of these storms were also hinting at the hook-echo radar signature that is usually found with tornadic supercells Tornadoes were reported from Settimo Milanese (MI) Castiglione dello Stiviere (MN) and Medole/Castel Goffredo The chaser reports hint that some of those were landspouts while a few of those tornado reports were mesocyclonic tornadoes The environment across the Po Valley is often in the prime position for an outbreak of severe thunderstorms when a frontal system or an upper low enters the region from the northwest The North Italian Plains are placed to the south of the Alps which leads to a formation of a secondary Lee low behind the Alpine mountain chain This means that surface pressure deepens in the Plains creating a unique environment trapped with the Alps to the North and the northern Apennines to its south this classic environment occurred again with unstable air mass over the Plains thanks to the advection of very moist air mass from the east – from the warmer Adriatic Sea the mid-level winds that are normally rounding the base of the upper low This usually leads to a formation of a dryline (a drier air mass mixing down from the mountains) into the central Po Valley plains Above: Video of a supercell and tornadoes near Soresina and Carpenedolo, Italy by Luca Vezzosi The severe weather outbreak has started in the early afternoon as a few isolated supercell thunderstorms initiated near the dryline bulge from the Apennines while the upper-level low was emerging into the northern Mediterranean from the west Activity has then been spread further north-northeast until the evening hours Healthy moisture across the Po Valley plains has provided moderately strong instability to support the rather explosive nature of thunderstorms The strongly unstable air mass spread across the Po Valley has then been overlapped with the powerful jet stream aloft allowing storms to quickly become severe and supercellular Above: Photograph of a supercell thunderstorm near Verona, Italy by Luca Vezzosi Italian storm chasers were out chasing some of these supercells Revealing a majestic structure of mesocyclones that can be often found in the Tornado Alley in the United States.  Above: Photograph of a supercell thunderstorm with a tornado near Carpendolo by Luca Vezzosi Above: Spectacular photograph of a supercell thunderstorm with a developing tornado near Castiglione dello Stiviere (MN) by Samuele / Tornado in Italia Above: Sigificant tornado damage in Carpendolo (BS) Italy by Montichiari è in un click di Marzia Borzi Here are now a couple of video reports of supercells and tornadoes from the Po Valley: there are about 300 and 500 tornado reports collected into the European Severe Weather Database – ESWD on average Those reports also include waterspouts that are most often reported across the Mediterranean Sea there is quite a good track of tornado reports but many tornadoes still get unreported as they hit sparsely populated rural areas and no storm chasers or locals see and report them The Mediterranean region has the highest number of tornadoes in the autumn and winter month while most of continental Europe sees the maximum of tornado reports during the summer months from May through August or early September Italy and Greece see the highest tornado activity thanks to the warm Mediterranean Sea that also extends the thunderstorm activity into the autumn months There is also a quite high number of fatalities caused by tornadoes in Europe averaging between 10 and 15 on average each year And most fatalities are often caused by the F2/F3 or stronger tornadoes The European Severe Storms Laboratory has investigated that: From 2010 until 2020 3827 tornadoes have occurred over land in and around Europe The deadliest tornado since 1950 occurred in Ivanovo Above: Tornadoes in Europe between 1950 and 2020 You can learn more about tornado climatology in Europe in this article: A Climatology of Tornadoes in Europe: Results from the European Severe Weather Database Note: This is breaking news of the tornado report so some further details or corrections will be added as they appear in the coming hours and tonight ***Images used in this article were provided by Windy and Pivotal Weather Fall 2021 Forecast: La Nina will grip the weather in North America while Europe Autumn will show its influence later in the season Volcano in La Palma erupts in a spectacular fashion after 50 years RSS Feed “Follow severe weather as it happens. Anywhere. Any time.” © Severe Weather Europe 2023 Stream PBS SoCal and your favorite PBS programs to your TV and devices wherever, whenever. Celebrate AAPI Month on PBS SoCal all May with exclusive programs. Find full episodes and educational games from Curious George, Wild Kratts and other PBS KIDS shows. Support PBS SoCal and watch full seasons of your favorite shows. [Editor's note: This commentary is prompted by a rancher's move to kill one of the Santa Monica Mountains' beleaguered mountain lions after one or more of those lions killed ten alpacas and a goat. As we published this piece, the owner of the unfortunate livestock was reportedly negotiating an alternative, non-lethal response to the puma depredation. We will update this story as necessary.] The cats that Soresina was after were not mountain lions, but African lions, and she wasn't driving around the Santa Monica Mountains, but Tanzania's Tarangire National Park. At first, Soresina blamed the hunting blocks that lied just outside the park's boundaries. Lions born inside the park would eventually wander onto private property where they became fair game for a wealthy trophy hunter. It's a compelling way to explain the males with their impressive manes who would disappear. But why were the females disappearing just as often? Many of the lions tracked by Soresina ultimately met their end when confronted with the tip of a Maasai spear. Others were poisoned. Despite some reports, this is not aberrant behavior, but altogether predictable. "Mountain lions don't discern much of a difference between an alpaca and a deer—just that penned animals are much easier to catch," said Beth Pratt-Bergstrom, California Director for the National Wildlife Federation. Which means any mountain lion in the area, during the period the permit is active, is fair game. Whether or not that particular lion was responsible. This detail makes it clear that the goal is not to eliminate any future predation events by one guilty lion, but rather to mitigate the grief and anger experienced by the property owner. Though they couldn't be more different in wealth and privilege, the Malibu-dwelling alpaca rancher and the Maasai pastoralist have something in common: bloodlust. Revenge. Hatred. Fear. When the needs of humans and their property collide with the needs of wild animals with which many genuinely hope to coexist, what can be done? In some places, effective predator conservation builds upon economic incentives. Rather than allowing an aggrieved property-owner to kill a predator, they are offered a small monetary reimbursement to offset the loss of their livestock. It turns out that scientists have some good ideas about this as well.  Just this week, CDFW and NPS are co-teaching a workshop to help those who live in mountain lion country learn how to best protect themselves, their pets, their livestock, and their property. The best defense, after all, is a strong offense. But providing tips for avoiding negative interactions alone simply serves to highlight the potential downsides of living alongside predators, and actually reduces tolerance for the carnivores with their big, sharp teeth and long, scary claws. PBS SoCal is a 501(c)(3) nonprofit organization.Tax ID: 95-2211661 Background and aims: Primary immunodeficiencies (PID) are characterized by recurrent infections and increased risk of malignancies because of the reduced immunological surveillance against cancer cells and oncogenic viruses. Methods: We report the incidence of tumors among 690 patients with PID, diagnosed from 1990 until 2017 in Brescia. Volume 7 - 2019 | https://doi.org/10.3389/fped.2019.00232 This article is part of the Research TopicThe Relationship between Cancer Predisposition and Primary Immunodeficiency View all 18 articles Background and aims: Primary immunodeficiencies (PID) are characterized by recurrent infections and increased risk of malignancies because of the reduced immunological surveillance against cancer cells and oncogenic viruses Methods: We report the incidence of tumors among 690 patients with PID 8 patients suffered from common variable immunodeficiency (CVID) 1 from severe combined immunodeficiency (SCID) The age at diagnosis ranged from 1 to 52 years The time between the diagnosis of PID and onset of tumor was short often <1 year between diagnosis and the appearance of cancer in the case of CID the diagnosis of cancer was made before the diagnosis of PID so cancer was the onset clinical manifestation Hematological malignancies were prevalent (22/33 66.7%) with a minority of solid tumors (11/33 In particular Non-Hodgkin lymphomas were the most frequent (16/33 In total 13 patients survived (52%) and tumor was the main cause of death (7 cases) Two patients underwent BMT once the disease was in remission the correct management of tumors that arise in patients with primitive immunodeficiency still represents a challenge in the pediatric field For this reason now it is mandatory to collect in a unique international registry the cases of malignancies in PID that could lead to a better understanding of the etiopathogenesis and of the biological and clinical characteristics of these tumors with the aim of defining adequate preventive measures and guaranteeing an early diagnosis which also creating a shared and specific therapeutic strategy with the prospect of obtaining a better prognosis for these patients Primary immunodeficiencies (PID) represent a heterogeneous group of congenital diseases characterized by an alteration of the functionality of the immune system. These diseases are considered rare, in fact in Italy the incidence of these forms is variable, ranging from 1:500 for the most frequent forms to 1:500 000 for other rare forms. The overall incidence of PID can be calculated around 1:20001 The classification of these diseases is very complex and constantly evolving in relation to genetic mutations and the etiopathogenetic mechanisms that are identified progressively over the years Depending on the component of the immune system that is altered they can be divided into two main groups: the deficiencies of innate immunity and the deficiencies of adaptive immunity the latter group includes the deficits of humoral immunity the immune deficiencies associated with syndromes These diseases are characterized by an increased susceptibility to infections by the frequent development of autoimmune diseases and by a predisposition toward the onset of neoplasia This particular case became even more evident in recent years since the development of drugs for the prophylaxis and the treatment of opportunistic infections made it possible to have an increase of the life expectancy of these patients providing the necessary time for neoplastic development tumors are currently the second leading cause of death for patients with PID after infections these mechanisms are joined by the tendency to acquire frequent genetic mutations the result of genomic instability that characterizes some PID This condition occurs in the following cases: • presence of defects in DNA damage repair (Ataxia-telangectasia) (7) • presence of defects of apoptosis that, causing cellular immortalization, allow cells to survive even in the presence of irreversible damage to the genome (Autoimmune Lymphoproliferative Syndrome) (6) • presence of deficiencies in the cell cycle check-points for which the cell cycle, fundamental to allow a correct repair of the damage, is missing (Cartilage-hair hypoplasia) (8) • defects in the cytokinesis which, by hindering cell division, lead to the formation of genetically unstable tetraploid cells (Neutropenia X linked and Wiskott-Aldrich syndrome) (9) We decided to carry out a retrospective analysis at the Brescia Children's Hospital (Italy) reporting the incidence of tumors among 690 patients with a diagnosis of PID diagnosed between 1990 and 2017 in Brescia The study was approved by the Ethical Committee of the Spedali Civili of Brescia The study has the main purpose of reporting the experience of an Italian Pediatric Children's Hospital with patients suffering from PID who developed an oncological pathology during their lifetime trying to report their characterizing elements Out of 690 patients, 25 patients (3.6%) developed 33 tumors. They were treated differently depending on the tumor and the immunodeficiency: in particular, for solid tumors surgery was performed, with or without chemotherapy, while for hematological tumors, the treatment was based on National or International therapeutic protocols (Figures 1, 2) making the comparison of data obtained from studies on different populations even more complex It is also important to say that SCID and WAS are currently treated early with bone marrow transplantation which has the advantage of ensuring a complete reconstitution of the functionality of the immune system and which could justify the small number of cases of cancer found in our records (1 out of 123 patients with SCID and 2 out of 52 patients with WAS) in recent years the tendency of our Center is to rapidly perform a bone marrow transplant even in patients with CID since experience has shown that executing of this procedure only after the development of a hematological tumor may be insufficient in the control of these neoplasms (two patients presented with tumor relapse despite bone marrow transplant) in the next few years we expect a reduction in cancer cases in these patients too Another interesting finding is about the two patients with HSP2, who are two siblings, who both developed Hodgkin's lymphoma, a neoplasm that had never previously been identified in this immunodeficiency. In fact, before now, this syndrome was known only to determine a predisposition to the development of skin tumors (in our case a Dermatofibroma was detected) (18) Among the cases we analyzed, patients who developed cancer were mostly male: 17 males (68%) and 8 females (32%). These data appear to be discordant with what emerges from the major studies in the literature. In fact, in two of these a distribution of cases of similar cancer was found in males and females (16, 17), while in one of them the females appeared more affected than males (17) it is clear that the most common (non-Hodgkin's lymphoma and stomach tumors) have been presented with equal frequency in males and females and that the excess of cases present in the female subjects is attributable to the high number of cases of breast cancer (20% of all cancers) the most frequent occurrence of cases in males which was highlighted in the present study is probably the consequence of the fact that the cohort of patients with PID in our center is characterized by a clear male prevalence (435 male patients out of 690 total which can at least partially be explained by the fact that many of these diseases (XLA and 60% of CGD cases) have an X-linked transmission and These divergences explain the heterogeneity of the distribution of immunodeficiencies and tumors in the different populations and the consequent difficulty in studying the general characteristics of this phenomenon In other PID the age of onset of the first neoplasia was very variable: in XLA at 1 and 37 years and 29 years and in HSP2 at 8 and 10 years Tumors in pediatric age (<18 years) We also evaluated the latency time between the diagnosis of PID and the appearance of the first tumor which was very different from case to case (from 1 month to 29 years) there was a short latency (in 5 patients <1 year) between the diagnosis of SCID/CID and the subsequent appearance of cancer in two cases of CID the tumor was diagnosed even before the underlying immunodeficiency constituting the clinical manifestation of onset This finding has already been reported in the literature, in particular in those PIDs that present a delayed onset and/or a mild clinical manifestation (4) the wide variability that was found did not allow to identify either an age or a time of homogeneous latency of presentation of the neoplasms screening investigations for the most frequent tumors in these patients should be performed early The presence of a marked predisposition to the development of neoplasms is suggested in our study by the number of tumors: 25 patients showed 33 tumors of which two were synchronous and one bilateral Most of the tumors were malignant (30 cases only 3 cases (9.1%) were non-invasive tumors (non-infiltrative intraepithelial neoplasia of the stomach The neoplasms were mostly hematological (22 cases 66.67%): 21 cases of lymphomas (5 cases of Hodgkin's lymphomas and 16 cases of Non-Hodking's lymphomas) Non-Hodgkin's lymphomas were the most frequent tumors (16/33 We identified the different subtypes: 8 diffuse large cell lymphomas These lymphomas presented peculiar characteristics: (1) frequent extranodal onset (12/15 cases); (2) Prevalence of B phenotype (12/15); (3) Majority of diffuse large cell Lymphoma B (8/15). These results also appeared to be aligned with those present in the literature and this is fundamental, since it is thanks to the knowledge of the common characteristics of these tumors that it is possible to make a diagnostic plan aimed at their early identification (15) There was a minority of solid tumors (11 cases which appeared to be very heterogeneous both by histotype and by localization: 3 cases of skin tumors (1 dermatofibroma 1 squamous cell carcinoma in situ and 1 basalioma) 2 cases of thyroid tumors (papillary thyroid carcinoma) 2 gastric tumors (1 diffuse gastric carcinoma and 1 non-infiltrative intraepithelial neoplasia of the stomach) 1 case of surrenalic tumor (leiomyosarcoma) 1 case of duodenal tumor (gastrointestinal stromal tumor 1 case of breast cancer (lobular breast cancer) and 1 case of renal tumor (clear cell renal cell carcinoma) Moreover, in our study in various situations, the anatomo-pathological evaluation allowed to identify microbial agents in the tumor microenvironment: EBV, HP, and HPV, confirming their role in the etiopathogenesis of these neoplasms. Therefore, it is important to identify and treat these infections early, with the aim of preventing related cancers Figure 5 In the period considered, 12 patients died (48%) in total and the tumor was the leading cause of death (7 cases). In particular, in our experience among patients who developed cancer at pediatric age, 7/11 patients (63.6%) survived 5 years after diagnosis, a number that appears lower than the general population of patients with cancer of the same age, in which the 5-year survival is 82% (20) This discrepancy could be due to the appearance in these patients of rapidly progressive tumors in pediatric patients who died for the spreading of the tumor death occurred in all cases a short time after the diagnosis (from 3 to 13 months) This condition does not seem to be due to the presence of tumors that are more resistant to treatment but it is more likely the consequence of inadequate therapeutic management in the absence of randomized clinical trials performed on these patients the currently available chemotherapy treatment does not differ from that of immunocompetent patients except for an individual modulation of the chemotherapeutic dosage and for the execution of a tight anti-infective prophylaxis our experience has often shown a non-optimal response as well as the appearance of disease progression during the treatment of chemotherapy in 3 cases and relapses in 6 patients they have all been successfully treated and relapse has not occurred The only exception was the case of gastric adenocarcinoma which however appeared already metastatic at onset to the point of contraindicating any treatment Our descriptive study certainly has the advantage of a very large number of cases (690) for a single Center considering the rarity of these diseases a very long observation period (27 years) and good expertise in PID The limits are instead represented by the difficulty of finding all the blood tests of older patients above all because in many cases some immunological tests were not yet carried out such a long observation time helps to highlight the importance of monitoring patients with PID in order to recognize and treat tumors early the correct management of tumors that arise in patients with PID still represents a challenge in the pediatric field The datasets generated for this study are available on request to the corresponding author and LN contributed conception and design of the study AL was involved in the manipulation of stem cells of transplant patients and has coordinated the activities of the stem cell laboratory wrote the first draft of the manuscript and sections of the manuscript All authors contributed to manuscript revision 1. ^Document drawn up by AIEOP (Italian association of pediatric oncohematology) https://www.aieop.org/web/famiglie/schede-malattia/immunodeficienze/ Cellular and Humoral Aspects of Hypersensitivity Google Scholar Cancer immunoediting: form imunosurveillance to tumor escape CrossRef Full Text | Google Scholar Development of cancer in patients with primary immunodeficiencies Lymphoproliferative disorders related to immunodeficiencies Google Scholar PubMed Abstract | Google Scholar Dna repair: the link between primary immunodeficiency and cancer Cartilage-hair hypoplasia: molecular basis and heterogeneity of the immunological phenotype Unregulated actin polymerization by WASp causes defects of mitosis and cytokinesis in X-linked neutropenia Are antibody deficiency disorders associated with narrower range of cancers than other forms of immunodeficiency Primary immunodeficiency diseases and cancer: the immunodeficiency-cancer registry Malignancies in the setting of primary immunodeficiency: implications for hematologists/oncologists Genetic predisposition and hematopoietic malignancies in children: primary immunodeficiency Therapy for non-Hodgkin lymphoma in children with primary immunodeficiency: analysis of 19 patients from the BFM trials doi: 10.1002/(SICI)1096-911X(199912)33:6<536::AID-MPO3>3.0.CO;2-Z Cancer in primary immunodeficiency diseases: an analysis of cancer incidence in the United States immunodeficiency network (USINET) registry Primary immunodeficiencies in the Netherlands: national patient data demonstrate the increased risk of malignancy Dermatologic manifestations of hermansky-pudlak syndrome Google Scholar Google Scholar Lanfranchi A and Porta F (2019) Primary Immunodeficiencies and Oncological Risk: The Experience of the Children's Hospital of Brescia Received: 21 February 2019; Accepted: 22 May 2019; Published: 19 June 2019 Copyright © 2019 Maffeis, Notarangelo, Schumacher, Soncini, Soresina, Lanfranchi and Porta. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY) *Correspondence: Marianna Maffeis, bWFyaWRvbmRhQGhvdG1haWwuaXQ= Please enable JS and disable any ad blocker A serious accident at work led to the death of a 35-year-old worker in Soresina A tragic accident at work has shaken the community of Soresina where a 35-year-old worker lost his life in dramatic circumstances an Egyptian crane operator living in the province of Brescia he accidentally activated the bucket of his Bobcat perhaps made in an attempt to recover an object inside the passenger compartment continuing its downward movement without anyone being able to intervene in time to stop the mechanical arm The impact was fatal and the man died instantly leaving an unfillable void among his loved ones and colleagues including the Carabinieri of Soresina and Cremona together with the inspectors of the ATS Val Padana are currently investigating the dynamics of the accident It is essential to clarify the circumstances that led to this tragedy to prevent similar events from happening again in the future The investigators are collecting testimonies and evidence to reconstruct what happened and verify whether there were violations of safety regulations at work is subject to strict regulations to ensure the safety of workers incidents like this one raise questions about the actual application of these rules and the effectiveness of controls and every fatal accident represents a collective failure to protect workers This tragic event brings attention to the importance of training and prevention in the workplace especially those who operate heavy machinery receive adequate training and are constantly updated on safety procedures Companies must invest in the safety of their employees but also to protect the life and health of those who work every day The community of Soresina gathers around the worker's family expressing their condolences for such a tragic loss so that similar accidents never happen again and a safe working environment can be guaranteed for all Notizie.it is a newspaper registered with the Court of Milan n.68 on 01/03/2018 Impara come descrivere lo scopo dell'immagine (si apre in una nuova scheda) Lascia vuoto se l'immagine è puramente decorativa A 35-year-old worker lost his life in a dramatic accident at work that occurred on a construction site in Soresina he accidentally activated the bucket of an excavator perhaps taken in an attempt to recover an object inside the passenger compartment the worker inadvertently activated the machinery This tragic event has not only shocked the local community but has also raised questions about safety on construction sites and the adequacy of worker protection measures Incidents like the one in Soresina highlight the importance of ensuring a safe work environment Statistics show an increase in fatal accidents on construction sites highlighting the need for more training and more rigorous controls It is essential that companies adopt effective safety protocols and that workers are adequately trained to operate machinery safely The tragedy in Soresina must serve as a warning to everyone to do more to prevent similar events in the future