Arterial tortuosity syndrome (ATS) is a very rare autosomal recessive disorder that affects the connective tissue. The incidence of ATS is not well known and to date only 106 patients have been described in the literature. ATS affects medium and large size arteries, leading to widespread elongation and intensification of the average vessel tortuousness, responsible of several loops and kinks. Like other connective tissue disorders, ATS can present with joint laxity, hernias, pectus excavatum, scoliosis or other musculoskeletal abnormalities, and ocular defects. Due to the extreme variability of clinical symptoms and the fact that ATS has no curative management, prompt diagnosis is of tremendous importance to prevent disease-associated complications. In this situation, imaging techniques have a central role. In this study, we describe a rare case of a male newborn with tortuosity and lengthening of the main arterial and venous medium and large caliber branches with associated aortic coarctation who passed away prematurely. The finding of aortic coarctation in a newborn with ATS has rarely been described in the literature. Arterial tortuosity syndrome  is a very rare autosomal recessive disorder that affects the connective tissue. It was first described in 1967 by Ertugrul.The incidence of ATS is not well known and, to date, only 106 patients have been described in literature, but its incidence is supposed to be even higher due to its very large and difficult-to-identify manifestation spectrum.Specifically, ATS affects medium and large size arteries, leading to widespread elongation and intensification of the average vessel tortuousness, responsible of several loops and kinks, with a predisposition to dissection and aneurysms. CoA in association with ATS is a rare condition, with only a few cases described in the literature.It is necessary to suspect ATS in newborns who present with typical facial features , musculoskeletal alteration with joint laxity 76%), hernia, pectus excavatum (28%), scoliosis or other musculoskeletal abnormalities, and ocular defects, especially if, after imaging examination, an increased vascular tortuosity is evident.%, herniaThe main cardiovascular findings reported in literature are aortic tortuosity (92%), tortuosity of other arteries (80%), aortic root aneurysm (16%), pulmonary artery stenosis 57%), focal stenosis of the aorta (24%), autonomic dysfunction (18%), aortic and arterial aneurysms, stenosis of the aortic valve and pulmonary arteries, and ischemic or hemorrhagic events.7%, focalDue to the generalized abnormalities caused by ATS, early diagnosis is of fundamental importance to try to prevent life-threatening complications.However, the diagnostic criteria are still not well established. Therefore, the diagnostic pathway begins with a strong clinical suspect, continues with advanced imaging multimodality techniques  and ends with genetic research of the SLC2A10 mutation.We describe the rare case of a newborn with typical facial features, increased skin folds, showing typical imaging results of ATS in CTA with aortic coarctation (CoA) that died about 2 months and 15 days from birth due to severe diffuse ischemia.We present the case of a male infant, born at 37 weeks of gestation (W.G.) by urgent cesarean section for growth arrest.The infant's birth weight was 2.250 g (3th percentile), height was 47 cm (10th percentile), and occipitofrontal circumference (OFC) was 34 cm (3th percentile).Family history was unremarkable. The infant was first child to healthy nonconsanguineous parents originating from southern Italy.The patient's prenatal echocardiographic study showed evidence of complex congenital heart disease.At birth, the infant was hemodynamically stable and in spontaneous breathing and was admitted to the neonatal cardiologic intensive care unit at birth for further investigations and appropriate treatment.On physical examination, the newborn presented dysmorphic facial features (wide folded ears and narrow maxilla), increased skin plication, acrocyanosis, minimal chest excavation, joint hypermobility , pronatThe cardiac auscultation displayed a continuous murmur (systolic–diastolic murmur) due to patent ductus arteriosus (PDA).A transthoracic echocardiogram (TTE) was performed and it showed tortuosity at the origins of the great vessels that appeared elongated, with an ill-defined course, patent foramen ovale with bidirectional shunt, no left or right ventricular outflow tract obstruction, mitral valve dysplasia with mild regurgitation and mild aortic regurgitation, left ventricular hypertrophy, pulmonary branches with crossed pulmonary arteries (CPAs), without stenosis on the trunk or branches, and PDA.The aortic arch demonstrated reduced caliber in its extremely tortuous course with evidence of significant turbulence on Doppler and increased caliber of the ascending aorta.In view of these findings, at 4 days of life, a multidetector computed tomography (MDCT) angiography examination was performed with a multidetector CT (GE LightSpeed Plus 16 Slice) and multiplanar reconstruction (MPR). Maximal intensity projection (MIP) and three-dimensional (3D) volume-rendering virtual reality (VR) and surface-rendering (SR) reconstructions were also done.Z-score: +5.08), which also appeared elongated  with early bifurcation  and relative elongation and narrowing of the right and left pulmonary arteries. The left pulmonary artery presented mid-distal narrowing followed by ectasia of the branch itself, which hyper-arborized the distal circles of both the pulmonary arterial districts  limb and SpOInitial DNA analysis was performed from the DNA extracted from the peripheral blood samples from the child. Array comparative genomic hybridization (CGH) was performed to exclude Ehlers–Danlos syndrome. Based on the negative finding, the exons and intronic flanking regions of the SLC2A10 gene were amplified and direct sequencing was performed and the diagnosis of ATS was confirmed. Therefore, heparins therapy was started.Subsequently, at day 17 from birth, two CT scans were performed during the follow-up and following the detection of delayed neurological development of the child and a worsening of clinical symptoms. CT images showed a progressive increase in vessel tortuosity, encephalic ischemia , and maThe newborn died about 2 months and 15 days from birth due to severe picture of diffuse ischemia.ATS is considered a rare  autosomal recessive genetic disease, with a male-to-female ratio of 1:1.The first authors who described this syndrome named it “Ehlers–Danlos syndrome with multiple pulmonary artery stenoses and tortuous systemic arteries,” underlying the similarity between these two conditions, such a pathology in fact enters in differential diagnosis with different connective diseases, for the very similar vascular, connective tissue changes and clinical presentation like Marfan's syndrome, Williams–Beuren syndrome, Ehlers–Danlos syndrome, hereditary cutis laxa syndromes, Loeys–Dietz syndrome (LDS), and lethal syndromic vasculopathy associated with a novel mutation in FBLN4; the latter are associated with greater vascular involvement.Evidence of marked vascular tortuosity in newborn or young adults should lead to an appropriate investigation for inherited arteriopathies. It is of crucial importance to recognize specific findings associated with hereditary arteriopathies, in order to perform a targeted genetic analysis for an early final diagnosis, hoping to influence the outcome of the disease.Z-score and aortic ratio) that allows us to have a quantitative evaluation of the data found, early identification of cases of nonmanifest tortuosity, and screening of family members. It also enables better communication between the different specialists.Imaging is of fundamental importance as it allows us to make a diagnosis, to evaluate the onset of complications, and to complete a preoperative assessment, as often such subjects need to undergo surgery. Two different quantitative methods exist for measuring arterial tortuosity. The most widely used is the tortuosity index (TI) defined as the percent ratio of calculated shortest distance between the end points divided by the actual length of the arterial segment considered. It is fundamental for the radiologist to describe the vascular anatomy, providing the index of tortuosity and a quantitative evaluation of aneurysms dilations  that can help in the recognition of such a pathological condition that we have highlighted in our case.V” sign of pulmonary bifurcation  or inverted “Vsign” of pulmonary bifurcation at axial CT expressed early bifurcation of pulmonary arteries, often with narrowing of the origin.An “aortic elongation sign” at anteroposterior (AP) chest radiography with elongation of the aorta leading to prominent aortic knuckle can be observed in a young patient. The following may also be observed: “meandering vessel sign” , evidenAwareness of early sign of arterial tortuosity and recognition of the described marks lead to early diagnosis of clinically asymptomatic cases of ATS. In this context, MDCT evaluation appears to be the best choice in the investigation of ATS patients.CoA in patients with aortic ATS occurs rarely with only one report of an adult patient described in the literature.Mortality was originally estimated at 40% before the age of 5 years.ATS with CoA is a very rare condition. It is crucial to maintain high diagnostic suspicion because of overlap with other connective tissue disorders.Imaging plays a central role in the diagnosis and detection of complications. Radiologists should be aware of the imaging features of ATS for timely diagnosis. If high vascular tortuosity is found, it is critical to suspect an underlying genetic disorder. Consequently, the use of the TI helps provide a quantitative figure for this parameter. Radiologists must be familiar with the imaging features of ATS for prompt diagnosis.


N-acyl-ethanolamines (NAEs) and gut microbial families were correlated with intakes of vegetables, refined grains, olive oil and meats independently of adiposity and energy intakes. Specifically, higher intakes in vegetables and olive oil were associated with increased relative abundance of Clostridiaceae, Veillonellaceae and Peptostreptococaceae, decreased relative abundance of Acidominococaceae, higher circulating levels of NAEs, and higher HDL and LDL cholesterol levels. Our findings highlight the relative importance of food patterns in determining the gut microbiome–eCBome axis. They emphasize the importance of recognizing the contribution of dietary habits in these systems to develop personalized dietary interventions for preventing and treating metabolic disorders through this axis.The gut microbiota and the endocannabinoidome (eCBome) play important roles in regulating energy homeostasis, and both are closely linked to dietary habits. However, the complex and compositional nature of these variables has limited our understanding of their interrelationship. This study aims to decipher the interrelation between dietary intake and the gut microbiome–eCBome axis using two different approaches for measuring dietary intake: one based on whole food and the other on macronutrient intakes. We reveal that food patterns, rather than macronutrient intakes, were associated with the gut microbiome–eCBome axis in a sample of healthy men and women (n = 195).  Even though many associations have been identified between gut microbiota and metabolic health parameters, the exact mechanisms regulating this complex ecosystem remain difficult to identify. The endocannabinoid (eCB) system, a biological system potentially at the interface of the gut microbiota and host metabolism, includes two bioactive lipids derived from arachidonic acid, N-arachidonoyl-ethanolamine  and 2-arachidonoyl-glycerol (2-AG), the cannabinoid receptors (CB1 and CB2) as well as anabolic and catabolic enzymes of these mediators2. The extension of the eCB system, the endocannabinoidome (eCBome), includes additional eCB congeners derived from long chain fatty acids, notably within the N-acyl-ethanolamines (NAEs) and the 2-monoacyl-glycerols (2-MAGs) families, as well as numerous other enzymes and receptors. This system shares several metabolic functions with the gut microbiota, such as energy metabolism, inflammation, and immunity5. An increasing amount of evidence points to a bidirectional relationship between gut microbiota activity and the host eCBome system. Of note, germ-free mice harbor altered circulating and tissue levels of eCBome mediators compared to conventionally reared mice, while fecal matter transplant reverse most of these changes6. Interestingly, some evidence also highlights the production of endocannabinoid-like mediators by gut bacteria9.Gut microbiota composition and its metabolic activity are increasingly seen as a potential prevention and therapeutic targets to improve cardiometabolic health outcomes of the host. The composition of the gut microbiota is known to be modulated by several factors including, but not limited to, life stages, diseases, environment, and food intake and to have a ubiquitous impact on mostly all human physiology aspects12, NAEs being mainly associated with total fat mass while 2-MAGs seems more closely related to visceral fat mass15. Moreover, circulating eCBome mediators have also been shown to be associated with the fatty acid intakes in cross-sectional cohorts using dietary recalls as well as in the context of dietary interventions18. Indeed, a 2-day Mediterranean diet full-feeding intervention, modulates the relative levels of circulating eCBome mediators in a manner reflecting the fatty acid composition of the diet, which means rich in monounsaturated (MUFA) and polyunsaturated (PUFA) fatty acid and poor in saturated fatty acids19. The profile of dietary fatty acids appeared as a key determinant of the circulating lipidomic profile independently of the increased eCBome tone associated to adiposity. Of note, the Mediterranean diet recommendations are not focused on lipid intakes, but mostly on the consumption of a nutrient rich food such as olive oil, vegetables, fruits, whole grains, legumes, nuts and fish20.The presence of eCBome mediators has been shown in virtually all tissues, especially in the brain, immune cells, adipose tissue and gut. These mediators can also be measured in peripheral circulation, where their origin and physiological significance remain uncertain. Circulating levels of eCBome mediators have been strongly associated with BMI19 and the circulating endocannabinoidome15. However, in a cross-sectional analysis, the macronutrient intake, except fatty acids intake, per se is not related to the circulating endocannabinoidome15. We thus hypothesize that whole-diet food pattern, rather than its macronutrient contents, is associated with gut microbiota and the circulating eCBome. We, therefore, aimed here at deciphering the associations between the dietary intake and the gut microbiome–eCBome axis using two different dietary intake approaches measuring whole food and macronutrient intakes. The results obtained provide novel insight on how the gut microbiome–eCBome axis is modulated by the diet and this new knowledge will pave the way to improving the design of future preventive or therapeutic nutritional strategies for metabolic health.We have previously published that a short-term  adherence to the Mediterranean diet recommendations is sufficient to modulate the relative abundance of several gut microbiota taxa15. All recruitment was performed during the winter and spring of the same year. Individuals with enteropathies, alcohol consumption exceeding the Canadian recommendation for men (> 15) and women (> 10 drinks/week), weight change (± 5 kg) in the last 6 months, having taken antibiotics in the last 3 months and pregnant and/or breastfeeding women were not eligible. Participants who consumed cannabis more than once per week or the week preceding the study (n = 5) were excluded, while current tobacco smokers were not excluded (n = 10). Written informed consent was obtained and the project was approved by the Laval University Ethics Committee (2017-328). Detailed data collecting and sampling procedures have been previously described15.The environment and Microbiota–EndoCannabinoidome Axis (eMECA) cross-sectional clinical trial (NCT03463304) included 102 women and 93 men covering a large range of adiposity phenotypes  validated in this populationN-acylethanolamine (NAEs) and the 2-monoacylglycerol (2-MAGs) were measured using high-performance liquid chromatography coupled to tandem mass spectrometry (LC–MS/MS). The methods23 and the circulating levels of the eCBome mediators in this cohort15 have been published previously.Levels of 15. Diversity indexes were calculated for all samples at an even depth from rarefied OUT table (Vegan R package). For statistical analysis bacterial relative abundances were normalized using Cumulative Sum Scaling  as specified in the result section and figure legends.Stool bacterial DNA was extracted , V3–V4 libraries were prepared  and sequences were processed as previously described for this cohort2), n = 3 variables], Metabolic profile , and Gut microbiota families  factors. Sex and age were included at first in the model, but these variables didn’t contribute and were not included in the final model. Participants were stratified in two clusters according to the Dimension x* coordinate of each individual.Correlation between dietary intakes, gut microbiota composition and eCBome mediators were computed using Spearman’s rank correlations. Multiple factor analysis (MFA), a dimensionality reduction method tailored to handle multiple groups of variables, was performed with the FactoMineR R package (version 2.4) and the factoextra R package (version 1.0.7). Factors, i.e., groups of variables, included in the MFA model were: Adiposity [fat mass (kg), visceral adipose tissue mass (kg) and BMI . Correlation networks were drawn using ggraph R package (version 2.1.0). GraphPad Prism (version 9.3.1) was used to generate the correlation heatmap and boxplot.All experiments and methods were performed in accordance with relevant guidelines and regulations.19. To decipher the complex interrelation between the gut microbiome–eCBome axis with the diet, we have computed a multiple factor analysis (MFA) model including dietary intakes as two independent factors: one with whole foods (Food groups) and the other with macronutrient intakes (Macronutrients).  even though some food group intakes  were associated with diversity indexes . PEA and LEA can respectively bind the G-protein-coupled receptors (GPCR) 55 and 119 and thus improve glucose homeostasis2. It remains difficult to predict the overall metabolic impact of changes in the circulating levels of these eCBome mediators because their origin and role in circulation are poorly documented, and each mediator binds different types of receptors to generate a complex cellular response. Nevertheless, as mentioned earlier, this association is aligned with the respective roles on metabolic health of these members of the eCBome29.This study takes advantage of food groups based on the Mediterranean diet pattern. Consumption of a diet rich in vegetables, fruits, legumes, nuts, whole grains, MUFA-rich oil and fish has proved to provide many beneficial cardiometabolic effectsPeptostreptococcaceae family with eCBome mediators, such as higher levels of this taxon were observed in individuals with higher circulating levels of all NAEs, apart from OEA. To our knowledge, no potential association has been previously reported between the Peptostreptococcaceae family and metabolic health parameters, macronutrients, or whole food consumption. Interestingly, in our analysis this taxon was not directly associated with macronutrient intakes but shared a significant amount of variance with the intakes of food groups and NAEs in the MFA. Indeed, independently of other variables included in the model , the relative abundance of Peptostreptococcaceae family was higher in individuals with elevated levels of circulating NAEs.We highlight novel associations between the relative abundance of the Ruminoccocaceae relative abundance was associated to dietary intakes of whole-grain foods, from which we can infer a higher intake of fibers. While this taxon was not directly associated with LEA and PEA, these eCBome mediators were negatively associated with the intakes in whole-grain foods.We observed that Akkermanciaceae (i.e. Akkermansia muciniphila) relative abundance was found and both variables have been linked to improved metabolic health32. We previously reported that 2-EPG levels are negatively associated with Akkermanciaceae independently of adiposity15. However, when including all groups of variables, i.e., dietary intake, adiposity, clinical parameters, Akkermanciaceae was not a significant contributor to any dimension of the model.An association between fruit consumption and 33, but also by variations in whole food intakes as well as in food patterns35. As the synthesis of different eCB congeners is partly defined by the profile of fatty acids in their phospholipid precursors, we have previously shown that the fatty acid profile of dietary lipids is associated with the profile of the circulating eCBome mediators15. The present analysis fills in the knowledge gap of the most potent measures relating dietary intakes and the gut microbiota-eCBome axis. Indeed, here we show that the consumption of specific food groups related to the Mediterranean diet was more closely related to the gut microbiota composition and to the profile of circulating eCBome mediators than intake of specific macronutrients. It should be kept in mind that intakes of food and of macronutrients are closely interrelated. Indeed, we found that higher consumption of olive oil, an important source of oleic acid, is positively associated with circulating levels of OEA, an oleic acid-derived molecule, even though dietary intakes of oleic acid did not significantly correlate with circulating OEA levels15. This finding suggests that oleic acid derived eCBome mediators may be more closely related to specific food groups and thus points to the existence of interactions with eating habits related to higher consumption of olive oil. Similarly, circulating levels of AEA and 2-AG were positively associated with consumption of food rich in the eCB precursor arachidonic acid, such as poultry and red meat. However, intake of arachidonic acid was not directly associated with circulating AEA and 2-AG levels15. All 2-MAGs congeners were associated with higher consumption of meats, but these associations seem to be secondary to the strong interrelation of these variables with adiposity and the metabolic profile shown in the first dimension of the MFA. Indeed, 2-MAG levels in circulation are strongly associated with visceral adiposity15 and so are, on average, meat and processed meat intakes .39. Therefore, comparing both dietary intake measures, i.e., food groups and macronutrients, was an undeniable strength in this study focused on eCBome mediators and gut microbiota, which are emerging players in energy metabolism. Our analysis enabled us to control for the compositional nature of the data as well as for common confounding variables for the two investigated systems, but these results will necessitate further attention to unravel the nature of this relationship in view of the cross-sectional design of this study.This study was carried out in a well-characterized cross-sectional cohort of men and women with a wide range of adiposity and with food intakes monitored thoroughly with a web-based 24 h recall validated for this population. Previously reported correlations were observed between certain food groups and BMI, fat mass and VAT mass (Supplementary Fig. In conclusion, our findings highlight the relative importance of food patterns, compared to macronutrients per se, in determining the gut microbiome–eCBome axis state. It is crucial to consider the presence of such a complex and concomitant relationship between the gut microbiome–eCBome axis and dietary intakes. Indeed, all these systems and the dietary habits are each tightly associated with obesity and metabolic complications. Therefore, our results emphasize the importance of recognizing the contribution of dietary habits in these systems to develop personalized dietary interventions for preventing and treating metabolic disorders through the gut microbiome–eCBome axis.Supplementary Information.


Efforts to reduce health disparities have been made since a major recognition of health disparities emerged two decades ago, resulting in overtime improvements in population health. Thus far, however, many health disparities have remained and extended in some cases . EvidencThe goal of this Research Topic is to showcase recent studies across different populations relating to impacts of socioeconomic differences in dietary behavior and health disparities.Were et al.), the indicators of socioeconomic status as predictors of animal food consumption , and the age and cohort trends of the impact of socioeconomic status on dietary diversity in older adults . In addition, the papers elaborate the role of food assistance programs in supporting diet quality during the COVID-19 pandemic , the trend of the chronic kidney disease associated with high sodium intake by socio-demographic index (SDI) from 1990 to 2019 , and the socioeconomic determinants and inequalities in exclusive breastfeeding among children (Hernández-Vásquez and Vargas-Fernández).In this Research Topic, the selected papers focus on the extent of socioeconomic differences in food purchasing practices, expenditure, and consumption . Evidently, participation in the safety net programs have increased their food consumption, regardless of healthfulness .In addition, economic and food supply chain shocks during the COVID-19 pandemic have caused substantial increases in the numbers of individuals experiencing food insecurity . Adults Liu et al.).Effective monitoring and management of dietary habits, such as sodium intake, are cost-effective for the prevention and intervention of chronic diseases, including chronic kidney disease (CKD) , 18. RegHernández-Vásquez and Vargas-Fernández, exclusive breastfeeding in Peruvian children 6 to 59 months of age was concentrated among the poorest mothers and the major contributors were residing in the highlands and jungle. Most Peruvian women living in the highlands and jungle regions have low socioeconomic levels, which could be associated with low exposure to advertising and marketing of breast milk substitutes and where cultural practices increase exclusive breastfeeding (Hernández-Vásquez and Vargas-Fernández).Socioeconomic differences also occur in exclusive breastfeeding practices, a healthy practice that improves both maternal and infant wellbeing; the socioeconomic disparities observed for breastfeeding may be one component contributing to differences in health at various points across the life course . In the In summary, socioeconomic status continues to have a major effect on dietary behavior and health status across different populations. Despite all the existing literature and evidence related to this significant topic, the papers in this Research Topic clearly show that many aspects remain to be clarified and understood regarding the associations of socioeconomic differences with dietary behavior and health status across different populations. It is expected that the evidence collected here will be referenced in future food policies to improve diet quality and reduce health disparities.HN wrote the article. All authors contributed to the article and approved the submitted version.


OTOG, MYO7A, and TECTA, previously associated with autosomal dominant and recessive non-syndromic SNHL. These findings suggest a new hypothesis where proteins involved in the extracellular structures in the apical surface of sensory epithelia  and proteins in the stereocilia links would be key elements in the pathophysiology of MD. The ionic homeostasis of the otolithic and tectorial membranes could be critical to suppress the innate motility of individual hair cell bundles. Initially, focal detachment of these extracellular membranes may cause random depolarization of hair cells and will explain changes in tinnitus loudness or trigger vertigo attacks in early stages of MD. With the progression of the disease, a larger detachment will lead to an otolithic membrane herniation into the horizontal semicircular canal with dissociation in caloric and head impulse responses. Familial MD shows different types of inheritance, including autosomal dominant and compound recessive patterns and implementation of genetic testing will improve our understanding of the genetic structure of MD.Meniere disease (MD) is a rare disorder of the inner ear defined by sensorineural hearing loss (SNHL) associated with episodes of vertigo and tinnitus. The phenotype is variable, and it may be associated with other comorbidities such as migraine, respiratory allergies, and several autoimmune disorders. The condition has a significant heritability according to epidemiological and familial segregation studies. Familial MD is found in 10% of cases, the most frequently found genes being  Meniere disease (MD) is a term used to describe patients with an audio-vestibular phenotype that includes episodes of vertigo associated with variable aural symptoms  . The pheThe diagnostic criteria were initially proposed by the Japanese Ménière’s disease study group in 1974. The American Academy of Otolaryngology-Head and Neck Surgery (AAO-HNS) developed guidelines for diagnosis and therapy evaluation of MD in 1972 and revised them in 1985 and 1995 . These cHistopathological studies in human temporal bones have consistently shown an accumulation of endolymph, termed endolymphatic hydrops, in the vestibular end organs (saccule and utricle) and the cochlear duct in most patients with MD , 12. ThiTwo major hypotheses are currently accepted to explain the pathophysiology of MD: a chronic autoinflammatory process defined by a immune dysfunction with high levels of several cytokines and chemokines , 16, andThe purpose of this review is to summarize the evidence that supports the genetic contribution to MD, including familial aggregation and exome sequencing studies. Furthermore, we describe the main genes reported in multiplex familial MD and elaborate a hypothesis regarding the potential role of stereocilia, otolithic membrane (OM), and tectorial membrane (TM) proteins in MD. For this, we conducted a Pubmed search with the following keywords:  AND (meniere disease [Title/Abstract] OR meniere’s disease [Title/Abstract]). The search was filtered by the last 22 years (2000–2022) and limited to publication written in English, including original and review papers.Madeleine Ray Brown was the first that reported two families with MD in 1941. The first family consisted of two sisters and a brother in one French Canadian consanguineous family with paroxysmal vertigo associated with sensorineural hearing loss. All started with tinnitus before the vertigo attacks and the age of onset were 46, 32, and 35 respectively . In the Bernstein described in 1965 seven families in which more than one member had episodic vertigo or hearing loss. Two families had histories of allergy and members of three other families were suffering from migraine headaches .Morrison et al. reported a series of 46 British families with MD. Most of these families showed an autosomal dominant inheritance with reduced penetrance . AnticipFamilial clustering has been reported in about 9% of cases in Spanish population , and in Most MD patients do not report relatives with the same clinical picture; however, it is not uncommon to find relatives with SNHL or episodic vertigo that have not been investigated in detail and could be partial syndromes . For thiSeveral types of inheritance have been reported in FMD, including autosomal dominant (AD) and autosomal recessive (AR) inheritance , 25. MorFAM136A and DTNA genes which were classified as pathogenic [The application of exome sequencing technology to the diagnosis of MD has contributed to decipher the genetics underpinnings of familial MD , 25. Sevthogenic .FAM136A gene leading to a stop codon ; the second variant was an ultrarare missense heterozygous variant found in the DTNA gene  that results in a p.Val715Phe substitution and generates a novel splice-site sequence predicted as a constitutive acceptor [The first variant was a nonsense novel variant in the Thirteen genes have been associated with AD or AR familial MD. Intriguingly, each of these genes has a different function within the inner ear ranging from playing a role in the cytoskeleton structure of cochlear hair cells, the stress oxidative to axonal guidance pathways . The maiOTOG gene [Otog mutant mouse will be needed to confirm the functional effect of these VUS, these findings support that OTOG gene is associated with heterozygous compound recessive inheritance in the 6 families [However, this issue was solved by Roman-Naranjo et al. in 2020, with the report of 6 Spanish families segregating 2 missense variants in the TOG gene . Two hetfamilies .MYO7A gene with other genes including CDH23, PCDH15, and ADGRV1 involved in the mechanoelectric transduction (MET) complex and the interciliary links of the hair cells in several MD families, suggesting a digenic inheritance model [Multiple MD families carrying rare variants in genes encoding proteins involved in the architecture of the hair cells stereocilia and their attachment to the TM have been found . Roman-Nce model  Fig. 1)MYO7A genCDH23 and PCDH15 genes encode for cadherin-23 and protocadherin-15, two calcium-dependent cell adhesion proteins that show a direct interaction in the apical surface of hair cells to form the tip links between stereocilia. These links are required for maintaining the proper organization of the stereocilia bundle of hair cells in the sensory epithelia of the organ of Corti and the vestibular organs during embryonic and early postnatal development [USH1C (harmonin b), USH1G (SANS), CDH23, and MYO7A (myosin-VIIa) that regulate MET in cochlear hair cells [elopment . Furtherelopment . They arir cells , 34.OTOG gene were found in 15 families with MD suggesting multiallelic inheritance, including the 6 families previously mentioned with compound recessive inheritance [TECTA gene within 6 MD families suggests a role of this gene in the pathophysiology of the disease [Moreover, by using a gene burden analysis and applying multiallelic inheritance models in SNHL genes, enrichment of rare missense variants in the eritance . Finally disease .CDH23, PCDH15, or ADGRV1, that encode for stereocilia link proteins [Although familial MD has been associated to several genes, the incomplete penetrance and variable expressivity within families remain unexplained and the role of regulatory elements  in the MD phenotype deserves further research. Several microRNAs and other non-coding elements are known to be associated with SNHL and they are candidate targets for therapy . An epigproteins ; howeverAll these studies point to a complex inheritance model, including digenic and multiallelic inheritance. Genes encoding proteins linking the hair cells stereocilia in the sensory epithelia and proteins in the TM and OM should be considered potential molecular targets associated with the onset of FMD.FAM136A, DTNA, PRKCB, COCH, DPT, SEMA3D, TECTA, GUSB, and SLC6A7 have been reported in autosomal dominant familial MD . Both deletions generate a shorter α-tectorin with a modified C‐terminal region that involves the glycosylphosphatidylinositol (GPI) anchorage signal. This signal peptide is essential to prevent diffusion of secreted TM proteins, and these deletions lead to a random aggregation of collagen fibrils and thinner TM with low tolerance to changes in endolymphatic pressure .COCH is the causal gene for DFNA9, characterized by a progressive high-frequency SNHL with variable progressive vestibular impairment [pairment ; howeverpairment . In the pairment .DTNA encodes α-dystrobrevin, a structural component of the dystrophin-glycoprotein complex, leading to progressive brain oedema in the knockout mouse [ut mouse . Evidencut mouse . Requenaut mouse .However, for the seven remaining genes, pathogenicity is based on bioinformatic predictors and additional evidence from new families segregating rare variants in these genes are required to support the association.HMX2, LSAMP, OTOG, and STRC.Table OTOG which encodes for otogelin Spanish families have compound recessive inheritance in 6% of the cases, but rare VUS or likely pathogenic variants are found in 15% of the families [The most relevant gene in familial MD is families .OTOG gene has a low expression in the adult cochlear supporting cells [Otogelin is a secreted protein related to epithelial mucins required for the anchoring of the OM to the hair cell stereocilia in the sensory epithelia in the vestibule and the organ of Corti . It is ing cells .HMX2 gene in a Finnish family with MD affecting a child and his paternal grandfather [HMX2 gene encodes a highly conserved protein involved in the inner ear development in mice [A novel heterozygous missense variant p.Tyr273Asn was found in the ndfather . The HMX in mice  and zebr in mice .LSAMP) was described in two sisters from a consanguineous Iranian Lur family [The gene encoding the limbic system associated membrane protein  [MYO7A gene have been reported in familial MD [ADGRV1, CDH23, PCDH15, USH1C, or SHROOM2 which also segregated the phenotype, leading to the hypothesis of digenic/polygenic inheritance in familial MD associated with protein in the stereocilia links.The type 1B) . Nine railial MD . Two of 2+ levels around the hair cell stereocilia and MET channel adaptation [2+ ions acting as a reservoir for Ca2+ cations [The TM may contribute to regulating Caaptation . Apparen cations , 57. Sev cations . Since α cations .Moreover, proteins involved in the stereocilia links seems to be also involved in the pathophysiology of MD, including myosin VIIa, cadherin-23, protochadherin-15, or adhesion G-protein coupled receptor V1 (ADGRV1) .The stereocilia in the mature outer hair cells have 2 types of links: the tip links, a filamentous protein formation that connect adjacent stereocilia formed by two cadherin-related proteins, cadherin-23, and protochadherin-15, which is linked to the MET channel , and theThe network of proteins that connects stereocilia, OM, or TM is essential to preserve not only the OM or TM architecture but also the ionic microenvironment in hair cell bundles. The ionic homeostasis of the otolithic and TM could be critical to suppress the innate motility of individual hair cell bundles and focal detachment of these membranes may cause random depolarization of hair cells and explaining the changes in tinnitus loudness or triggering vertigo attacks .With the progression of the disease, a large detachment will lead to an otolithic membrane herniation into the horizontal semicircular canal with dissociation in caloric and head impulse responses . HoweverWe would like to thank the patients with MD and their families for their enthusiastic participation.


Since April 2022, over 1000 children across 35 countries have developed episodes of acute hepatitis of unknown origin. At King’s College Hospital, a total of 65 children were referred with acute hepatitis of unknown etiology, with 10 of these children presenting with acute liver dysfunction leading to acute liver failure. Multiple hypotheses have been proposed and continue to be investigated worldwide. In this review, we explore the current understanding of potential aetiologies for this outbreak. We further characterize the proposed immunological mechanisms of liver injury in these cases. Health alerts have been triggered across multiple countries with regards to reports of severe adenovirus-associated acute hepatitis in previously well children. Multiple hypotheses have been proposed and continue to be investigated worldwide. In this review, we discuss the potential aetiologies and underlying mechanisms of liver injury of this outbreak.  Since April 2022, in the UK and some other countries, there has been an outbreak of children with acute hepatitis of unknown aetiology. By 8 July 2022, the number of probable cases of acute hepatitis in children had risen to 1010, across 35 countries. Of these, 46 children (5%) had liver transplants and 22 deaths (2%) were reported by the World Health Organisation [The affected children were previously well and generally under the age of 5 years . They demonstrated markedly raised liver biochemistry with aspartate aminotransferase (AST) or alanine aminotransferase (ALT) over 500 U/L at presentation . The most common presenting symptoms were jaundice and gastrointestinal symptoms such as vomiting and diarrhoea [definitively establish a causal relationship between this outbreak of acute hepatitis and any potential aetiology. The leading hypothesis continues to involve human adenovirus (HAdV), as the most commonly identified potential pathogen in the UK cohort. Ninety-four percent of patients underwent testing for HAdV in the UK, with 170 cases (65.9%) testing positive for HAdV, necessitating treatment with antivirals like Cidofovir in children with high levels of adenoviraemia. We showed that Cidofovir resulted in a reduction in viral load and non-recurrence of hepatitis in the allograft, with only transient nephrotoxicity as a side effect in our cohort of children presenting with PALF [Multiple hypotheses have been proposed and continue to be investigated worldwide . There rith PALF . Partial0 cases 6.9% testiith PALF .More recently, large amounts of adeno-associated virus type 2 (AAV-2) on metagenomic and PCR analyses of blood and liver tissues have been identified in a subset of the UK cohort. Highly abundant amounts of AAV-2 were found in the five explanted livers and in blood samples of the 11/12 non-transplanted cases, as opposed to infrequent detection in controls . AAV-2 iThe mechanism in which AAV-2 is implicated alongside a co-infection with HAdV infection is possibly through an aberrant immune-mediated host response. This is evidenced by cases of hepatitis described in the early trials of AAV-2, when used as a viral vector for gene therapy, with a possible CD8+ cell-mediated response directed against the AAV-2 viral capsid (VP1) , 12. ChaGenetic susceptibility has also been postulated in this cohort, with HLA typing of 20 Scottish children and 64 controls demonstrating an association of the Class II HLA DRB1*0401 allele in affected cases. Further proteomic data from explanted livers also showed high levels of HLA Class II proteins . TogetheOf the 162 cases tested for SARS-CoV-2 in the UK, only 19 cases tested positive at admission or in the preceding 8 weeks prior to admission (11.6%). There was no statistically significant difference in antibody positivity between hepatitis cases and NHS patient controls. It has also been proposed that SARS-CoV-2 persistence in the gut with immunological sensitization from the spike protein superantigen coupled with adenoviral gut infection, may have potentially led to IFNγ release and IFNγ-mediated hepatocyte apoptosis . It is dWhilst there has been a surge of acute hepatitis cases in children, we believe that this may not be a new association between HadV and PALF. In the five years prior to 2022, we saw between three and six cases per year of PALF of unknown aetiology at our centre, compared to the 10 cases reported in the first half of 2022. Between 2017 and 2019, HAdV was detected in 25–75% of these cases, none in years 2020 and 2021 and 100% in 2022. We believe that this may be a new epidemiological phenomenon in the post-pandemic period, of an already well-described disease of PALF of unknown aetiology, albeit with a higher morbidity rate.It is pivotal that we use this opportunity to better elucidate the pathogenesis and management strategies for PALF of unknown aetiology. One of the key areas of research would be to better characterize the mechanisms of liver injury. Alongside a systemic inflammatory insult, exogenous local triggers including viruses containing pathogen associated molecular patterns (PAMPs) and endogenous local triggers in the form of damage associated molecular patterns (DAMPs) generated from the liver injury itself, are thought to cause ongoing liver inflammation in PALF. This results in the production of stromal cell-derived factor 1 (sdf1) to recruit sinusoidal endothelial cell progenitor cells (sprocs), and subsequently liver regeneration may occur through release of hepatocyte growth factor (HGF). This process may be interrupted further through the overwhelming systemic inflammatory response leading to suppression of the bone marrow and thus inhibition of the release of sprocs . BiorepoInterestingly there appears to be a sudden halt in new patients referred in the UK and to our centre from August 2022, suggesting an epidemiological phenomenon of the increased occurrence of acute liver dysfunction of indeterminate aetiology with population dynamics reset to pre-pandemic levels. Based on recent evidence, AAV-2 alongside a “helper virus” like HadV appears to have played a role in initiating an immune response in genetically susceptible individuals to cause acute hepatitis and PALF, in some. Further pathological investigation will be important in understanding the immunopathologic damage in the liver of these children. As we continue to understand the aetiology of this current outbreak, it is important to make a concerted global effort to map and identify relevant cases. Epidemiological studies will be of paramount importance in disease prevention.


What are the probable health consequences of 3 US Supreme Court decisions in 2022 that invalidated COVID-19 workplace protections, voided state laws on handgun-carry restrictions, and revoked the constitutional right to abortion?In this decision analytical modeling study, the model projected that the Supreme Court ruling to invalidate COVID-19 workplace protections was associated with 1402 deaths in early 2022. The model also projected that the court’s decision to end handgun-carry restrictions will result in 152 additional firearm-related deaths annually, and that its decision to revoke the constitutional right to abortion will result in 6 to 15 deaths and hundreds of cases of peripartum morbidity each year.These findings suggest that over a decade, the 3 Supreme Court decisions examined here will contribute to the loss of nearly 3000 US lives and possibly many more. This decision analytical modeling study evaluates potential public health outcomes associated with 3 Supreme Court decisions in 2022 on COVID-19 workplace protections, handgun-carry restrictions, and constitutional abortion rights. Several recent US Supreme Court rulings have drawn criticism from the medical community, but their health consequences have not been quantitatively evaluated.To model health outcomes associated with 3 Supreme Court rulings in 2022 that invalidated workplace COVID-19 vaccine or mask-and-test requirements, voided state handgun-carry restrictions, and revoked the constitutional right to abortion.National Federation of Independent Business v Department of Labor, Occupational Safety and Health Administration (OSHA), which invalidated COVID-19 workplace protections; (2) New York State Rifle and Pistol Association Inc v Bruen, Superintendent of New York State Police (Bruen), which voided state laws restricting handgun carry; and (3) Dobbs v Jackson Women’s Health Organization (Dobbs), which revoked the constitutional right to abortion. Data analysis was performed from July 1, 2022, to April 7, 2023.This decision analytical modeling study estimated outcomes associated with 3 Supreme Court rulings in 2022: (1) OSHA ruling, multiple data sources were used to calculate deaths attributable to COVID-19 among unvaccinated workers from January 4 to May 28, 2022, and the share of these deaths that would have been prevented by the voided protections. To model the Bruen decision, published estimates of the consequences of right-to-carry laws were applied to 2020 firearm-related deaths (and injuries) in 7 affected jurisdictions. For the Dobbs ruling, the model assessed unwanted pregnancy continuations, resulting from the change in distance to the closest abortion facility, and then excess deaths (and peripartum complications) from forcing these unwanted pregnancies to term.For the OSHA decision was associated with 1402 additional COVID-19 deaths  in early 2022. In addition, the model projected that 152 additional firearm-related deaths  annually will result from the Bruen decision. Finally, the model projected that 30 440 fewer abortions will occur annually due to current abortion bans stemming from Dobbs, with 76 612 fewer abortions if states at high risk for such bans also were to ban the procedure; these bans will be associated with an estimated 6 to 15 additional pregnancy-related deaths each year, respectively, and hundreds of additional cases of peripartum morbidity.The decision model projected that the These findings suggest that outcomes from 3 Supreme Court decisions in 2022 could lead to substantial harms to public health, including nearly 3000 excess deaths (and possibly many more) over a decade. The first ruling, issued in January 2022 in National Federation of Independent Business v Department of Labor, Occupational Safety and Health Administration (OSHA),6 overturned the OSHA emergency temporary standard (ETS) that would have required large employers to implement measures to protect their workers from COVID-19. Subsequently, over the course of 8 days in June 2022, the court issued several decisions with major public health consequences. In New York State Rifle and Pistol Association Inc v Bruen, Superintendent of New York State Police (Bruen),7 the court decision voided laws in 6 states and the District of Columbia restricting the right to carry handguns, a decision likely to increase handgun carrying and possibly undermine other gun regulations.11 In Dobbs v Jackson Women’s Health Organization (Dobbs),12 the court overturned Roe v Wade, which had protected abortion rights since 1973; abortion bans went into effect immediately in several states and more are forthcoming.The US Supreme Court has issued myriad rulings with ramifications for public health and medical care,14 However, none have comprehensively modeled their quantitative impact. We projected the outcomes of these decisions on mortality and other adverse health consequences.Many commentators have criticized these decisions as a threat to public health.CHEERS) for evaluations of health interventions.This decision analytical modeling study relied on deidentified publicly available data and was hence deemed not to be human participant research by the Cambridge Health Alliance Institutional Review Board. We summarize our approach to modeling each decision next, and we present detailed methods in the eMethods in 15 This standard would have obligated employers to implement a requirement that employees either be vaccinated against COVID-19 or they had to mask and test. Robust evidence supports the efficacy of vaccine mandates in improving vaccine uptake,18 and growing evidence supports the association of mandates with respiratory virus outcomes, including from COVID-19.19 The ETS would have been effective on January 4, 2022, near the peak of the first Omicron surge, but was immediately suspended by a federal district court. It was briefly reinstated, before the Supreme Court fully overturned it on January 13, 2022.On November 5, 2021, OSHA issued the COVID-19 ETS applicable to businesses employing 100 or more workers, with some exclusions.OSHA decision invalidating the ETS by building on OSHA estimates of the number of workers who would have been vaccinated as a result of full ETS implementation (18.9 million).20 We modeled 3 scenarios that assumed different dates of implementation: for a lower-bound estimate, we assumed the ETS would be effective by the week ending February 5, 2022; for an upper-bound scenario, we assumed it would have been effective by the week ending January 8, 2022; and for our middle  scenario, we assumed that about half of the ETS impact would be realized in mid-January and the full impact by February 2022.We modeled likely health outcomes of the Supreme Court 21 Because these CDC data were only representative of 71% of the US population, we applied the age-group and week-level ratio of unvaccinated deaths to vaccinated deaths from these calculations to the corresponding age-group and week-level death-certificate–based COVID-19 death counts from the National Center for Health Statistics.22 These calculations produced our week-level national estimates of deaths among the unvaccinated adult population aged 18 to 64 years.To model deaths, we analyzed several sources. First, using 2022 US Centers for Disease Control and Prevention (CDC) data on COVID-19 deaths by vaccination status, we aggregated deaths by week, vaccination status, and age group .23 and calculated the proportion of all unvaccinated individuals aged 18 to 64 years who would have been vaccinated had the OSHA ETS been implemented for each week. We multiplied this weekly percentage by the weekly death count among those aged 18 to 64 years who were unvaccinated and deflated this by 15% (assuming 85% vaccine efficacy against death)24 to arrive at an estimate of the total number of additional weekly deaths due to the Supreme Court OSHA decision. We did not attempt to model the impact of mask-and-test requirements for workers who were not vaccinated, given uncertainties of the effect size of these interventions.25 Finally, we modeled hospitalizations, intensive care unit (ICU) hospitalizations, and mechanical ventilation hospitalizations by applying the month-specific ratio of deaths to each of these 3 hospitalization outcomes drawn from COVID-19–Associated Hospitalization Surveillance Network data26 to our estimates of COVID-19 deaths averted.Next, we analyzed day-level vaccination data from the CDCBruen decision, the Supreme Court ruled that the may-issue handgun concealed-carry permit regulations of 6 named states  and the District of Columbia were unconstitutional. These may-issue provisions gave law enforcement discretion in restricting handgun concealed-carry permits; the decision is widely expected to boost the carrying of firearms outside the home, creating a shall-issue or right-to-carry standard in these jurisdictions.27In the Bruen could attenuate its impact . For a middle scenario, we assumed that state policy would partially offset Bruen, and we projected half the expected outcome (described next) from the implementation of right-to-carry laws in each state. We did not attempt to model expected spillover effects on other states29 or the impact of any broader legal shifts signaled by the decision; consequently, each scenario produced conservative estimates of likely health consequences.The actions of states in response to Next, we estimated the expected mortality outcome of a shall-issue  standard (on any jurisdiction forced to adopt such a standard); eTable 2 in Bruen on firearm-related mortality by applying  each of the 3 state policy scenarios to each of the 3 expected outcomes  used a national data set of abortion facilities, (2) calculated driving time from the centroid of each US county to the nearest abortion facility with and without state abortion bans, and (3) used the causal estimates from Lindo et al32 of abortions foregone as a function of driving distance. We mostly followed this approach for our study, with 3 major modifications. First, the directory of abortion facilities was updated to use the Myers Abortion Facility Database,33 providing exact dates of operation for all US abortion facilities open at any point between May 1, 2022, and March 30, 2023. Second, we used the most current available estimates of the impact of driving distance from Myers.34 Third, we assumed a different set of state abortion bans, under 2 scenarios. In the first scenario, we only assumed that abortion facilities would close in the 13 states enforcing bans on abortion from the moment of conception as of March 30, 2023, as per the Myers database.33 In the second, we assumed abortion facility closures in 10 additional states that the Guttmacher Institute35 judged likely to ban abortion (referred to hereinafter as high-risk states).To estimate the number of deaths associated with mandatory continuation of pregnancies, we first projected the number of foregone abortions consequent to the 36 who calculated the impact of a total national abortion ban on additional pregnancy-related mortality. We assumed, following Stevenson, that each foregone abortion would be associated with an additional 0.8 births in the first full year following the ban, and then multiplied the number of increased births in each state by the state-specific, pregnancy-related mortality rate.37 Again following Stevenson,36 we subtracted the expected number of abortion-related deaths from this estimate. To project increases in postpartum morbidity among patients forced to continue unwanted pregnancies, we assumed a postpartum hemorrhage rate of 3.21%38 and applied this to our estimate of unwanted births.Next, we followed the method of Stevenson,39 While patients with previable or periviable PPROM are typically offered 2 options, either termination of pregnancy or expectant (“wait and see”) management, a large academic medical center offered patients only expectant management after implementation of the Texas 6-week abortion ban and noted high rates of maternal morbidity.39 Moreover, a recent multicenter study by Sklar et al40 found higher rates of morbidity among pregnant patients with periviable PPROM managed expectantly vs with immediate termination of pregnancy. We used these estimates to project the impact of Dobbs on peripartum morbidity and on postpartum hemorrhage related to a shift to initial universal expectant management in abortion ban states.Finally, we examined safety implications of changed obstetrical management associated with abortion bans, which may put facilities at risk for loss of their licenses or even felony charges. Numerous news reports have described changes in the management of dangerous pregnancy-related complications such as ectopic pregnancy, previable premature rupture of membranes (PPROM), and preeclampsia as consequences of the new state abortion bans. We focused on the impact of 1 complication, previable PPROM (or PPROM near the limits of viability), for which changed management as a result of abortion bans was documented in a recent study.31 We did not perform statistical tests for hypothesis testing in this modeling study. Data analysis was performed from July 1, 2022, to April 7, 2023.Data management and analyses were conducted in Stata/SE, version 17 (StataCorp LLC), or Excel, version 16.43 (Microsoft Corp). Detailed statistical methods used in the calculation of foregone abortions were described briefly earlier, and further details are provided in the eMethods in The We estimated that abortion bans would be associated with 30 440 fewer abortions annually in the 13 states that had such bans as of March 30, 2023, related to increased driving distance to the nearest abortion facility . Under aDue to these foregone abortions, we projected an estimated 6 additional pregnancy-related deaths annually in our first scenario and 15 additional yearly deaths if all high-risk states were also to ban abortion . We alsoFinally, we projected an additional 454 cases of peripartum morbidity and 202 cases of hemorrhage associated with changed management of PPROM in our first scenario; we projected 826 and 367 cases, respectively, in a scenario where all high-risk states ban abortion , assuming no outcomes from the OSHA ruling after May 2022 and no outcomes from Bruen or Dobbs in 2022 with stable annual impacts thereafter; that toll would be about 2-fold higher under our high-end, perhaps more realistic assumptions. We also projected approximately 22 830 additional COVID-19 hospitalizations in 2022, as well as 377 additional nonfatal firearm-related injuries, 982 additional cases of postpartum hemorrhage, and 454 cases of maternal morbidity from changes in obstetrical management annually. Given the populations most affected by these decisions , it is probable that the majority of these excess deaths, injuries, and complications will occur among working-age adults and adolescents.In this decision analytical modeling study, we estimated (in our primary scenarios) that the Supreme Court 41 as well as the effectiveness of mandates on vaccine uptake in different settings.42 A previous study by OSHA20 specifically projected outcomes of the proposed ETS on COVID-19–related illness and deaths. Our estimate of 1402 deaths preventable by ETS implementation was substantially lower than the OSHA estimate of 6830 deaths prevented, reflecting our more conservative methods and assumptions. For instance, our primary scenario assumed a lag in outcomes attributable to the ETS owing to decisions by lower courts before the Supreme Court accepted the case. Had we assumed that the ETS was implemented on January 2, 2022, our primary estimate would be closer to the OSHA estimate. Moreover, neither our analysis nor the OSHA primary estimate included potential outcomes of reduced transmission ; a recent analysis examining outcomes of college-level vaccine mandates suggested that such spillover benefits may be substantial.19 Hence, both estimates should be regarded as conservative.Previous studies have examined the impact of vaccination on population-wide COVID-19 mortalityBruen decision were lower than what would be expected from a more comprehensive reversal of gun regulations.43 However, Bruen invalidated only particular regulations (and in only 7 jurisdictions) expanding the Supreme Court’s previous decisions that had already led to substantial firearm deregulation . Still, the impact of Bruen, as some legal scholars have noted, might be broader; it rests on a novel argument  that the court may use to further prioritize gun rights over health outcomes.5 Although Bruen may ultimately “reverberate much more widely”8 and be used by lower courts to invalidate other gun regulations, we modeled only its impacts on right-to-carry policies in 7 jurisdictions. Finally, while it is conceivable that a reduction in firearm-related homicides might result in “substitution” with homicide via other means, recent research suggests that this outcome is negligible or nonexistent.45Our projections of additional firearm-related homicides (and injuries) associated with the 36 previously estimated mortality associated with the repeal of Roe v Wade, projecting 140 additional pregnancy-related deaths in the first full year following a national abortion ban. Our approach emulated some of Stevenson’s methods but posited bans in some, rather than all, states and estimated the number of foregone abortions in those states as a function of changing travel time to abortion facilities. Consequently, our modeling accounted for the fact that some individuals will obtain abortions out of state. However, we elected not to model the effects of congestion at abortion facilities in states without bans, which will likely further delay and reduce abortions  until facilities are able to expand capacity. In addition to pregnancy-related mortality, we examined maternal morbidity  as well as health outcomes attributable to changed obstetrical management of PPROM due to abortion bans. However, our analysis did not address delays due to Dobbs in receipt of abortion. Such delays are likely to increase the proportion of abortions performed in the second trimester, which is associated with more complications (including hemorrhage) relative to earlier abortions. Additionally, we elected not to model the impact of the likely increase in self-managed abortion46 or worsened management of ectopic pregnancy, previable preeclampsia, or miscarriage, given greater uncertainty for these outcomes. Abortion denial is also expected to force some individuals (and their family members) into poverty,47 an important social determinant of ill health that we also did not model. These are important areas for future research.StevensonThis decision analytical modeling study has some additional limitations. Modeling required consideration of studies that often provided a range of plausible effect estimates for a particular policy . Moreover, health outcomes of each Supreme Court decision will be shaped by future executive branch rulemaking, legislative actions, and court decisions as well as other behavioral impacts . Given this complexity, together with variability in the underlying studies we used to estimate policy impacts, we eschewed probabilistic modeling and instead modeled a range of scenarios for each decision, while hewing to an overall conservative approach. Finally, our modeling pertained only to the 3 decisions described and does not speak to health outcomes associated with the Supreme Court’s other 2022 decisions.In this decision analytical model study, we estimate that over a decade, nearly 3000 lives (and likely many more) will be lost due to 3 Supreme Court decisions in 2022. Its conservative reshaping in recent years has yielded decisions with substantial impacts on many aspects of life in the US, including health, as we examine here. The findings of this study suggest that these Supreme Court decisions may harm the health of US citizens for years, and possibly decades, to come.


Ostrya carpinifolia) and downy oak (Quercus pubescens), were positively correlated with TBE emergence (R2 = 0.2) while a multivariate model with both tree species better explained the variation in annual TBE incidence (R2 = 0.34). To the best of our knowledge, this is the first attempt at quantifying the correlation between pollen quantities and the incidence of TBE in human populations. As pollen loads are collected by widespread aerobiological networks using standardized procedures, our study could be easily replicated to test their potential as early warning system for TBE and other tick-borne diseases.Tick-borne encephalitis (TBE) is caused by a flavivirus that infects animals including humans. In Europe, the TBE virus circulates enzootically in natural foci among ticks and rodent hosts. The abundance of ticks depends on the abundance of rodent hosts, which in turn depends on the availability of food resources, such as tree seeds. Trees can exhibit large inter-annual fluctuations in seed production (masting), which influences the abundance of rodents the following year, and the abundance of nymphal ticks two years later. Thus, the biology of this system predicts a 2-year time lag between masting and the incidence of tick-borne diseases such as TBE. As airborne pollen abundance is related to masting, we investigated whether inter-annual variation in pollen load could be directly correlated with inter-annual variation in the incidence of TBE in human populations with a 2-year time lag. We focused our study on the province of Trento , where 206 TBE cases were notified between 1992 and 2020. We tested the relationship between TBE incidence and pollen load collected from 1989 to 2020 for 7 different tree species common in our study area. Through univariate analysis we found that the pollen quantities recorded two years prior for two tree species, hop-hornbeam ( This is particularly true for tick-borne diseases such as Lyme borreliosis, tick-borne relapsing fever, Crimean-Congo haemorrhagic fever and tick-borne encephalitis (TBE).In Europe, zoonoses originating from wildlife reservoirs and/or transmitted by arthropods are expected to rise in the future due to environmental and climatic changes3. The number of human cases of TBE have been increasing from 1995 to 20204 in both endemic5 and in previously unaffected countries, such as Belgium and the United Kingdom8. In Europe, TBE became a notifiable disease since 2012, and it is considered a major public health concern with a total of ~ 3000 human cases reported each year in 25 countries. TBEv is typically distributed in hotspots (foci of infection) characterized by high spatial and temporal variability. Numerous modelling studies have investigated how the presence of suitable habitat, climate conditions, and host availability influence the distribution of ticks and TBEv and the mechanisms of TBEv transmission16.TBE virus (TBEv) is a flavivirus that affects the human and animal central nervous system. This virus is mainly transmitted by the bite of an infected tick. However, TBEv can also be acquired via consumption of infected unpasteurized milk and dairy products and through other non-vectorial routes of transmissionIxodes, and their small mammal hosts (rodents and insectivores). In western Europe, the castor bean tick, Ixodes ricinus, is the most important tick vector. The life cycle of I. ricinus includes four developmental stages , requires three blood meals, and takes an average of three years (varying from two to six). Discrete cohorts of all three ticks stages occur in the environment at the same time. Larval and nymphal ticks feed on small mammals, whereas adult ticks feed on large ungulates. In Ixodes ticks, TBEv has both transovarial transmission (from the mother to the eggs) and transstadial transmission (from one stage to the other). Ticks can acquire TBEv by either systemic transmission or non-systemic transmission . In systemic transmission, the infected host develops a sufficient viremia to transmit TBEv to feeding ticks. In co-feeding transmission, the host acts as a vehicle for the spatio-temporal coincidental feeding of naïve larvae and infected nymphs, and viral transmission occurs at the local skin site level17. Thus, co-feeding transmission requires synchronous questing of larvae and nymphs on the same vertebrate reservoir hosts. Theoretical models based on the basic reproduction number (R0) indicate that co-feeding transmission is most important for the persistence of TBEv in nature18. Hence, the synchronous activity of larvae and nymphs and the presence of rodents are crucial to maintain TBEv in nature19 and may explain the highly focal distribution of this pathogen compared to the wide geographic distribution of both the ticks and vertebrate hosts9.In its natural enzootic cycle, transmission involves ixodid ticks, mainly belonging to the genus 21. Increased resource availability, as a consequence of global changes, is widespread in many ecosystems strongly affecting animal communities22, both in terms of population dynamics and interactions between consumers and resources. Rodents are r-strategy species  that quickly react with functional and numerical responses to environmental changes such as the availability of food resources. Intra-annual seasonal fluctuations in rodent density follow the favorable vegetation period, while inter-annual outbreaks in rodent density are driven by synchronized production of seed crop termed mast28. Mast seeding is a well-known example of pulsed resources in terrestrial ecosystems. The density of granivorous rodents can increase dramatically the year after a mast event and crash two years later. Inter-annual variation in rodent density and their pathogens will influence the zoonotic risk to humans but the timing of increased risk relative to the mast event will differ among pathogens29. Thus, when the pathogen is transmitted by a tick with a multi-year life cycle, high rodent density caused by larger food availability leads to an increase in the number of infected nymphs the following year, and hence a greater incidence of human cases is expected to occur two years after the masting event32.Rodents are also important for feeding the immature stages of ticks (larvae and nymphs). The availability of more hosts increases the chances of larvae to feed and develop into nymphs. If the hosts are competent for TBEv then the pathogen can be amplified, thus increasing the density of infected nymphs and consequently the risk of exposure for susceptible hosts, including humans34 or directly using a masting index to predict the incidence of TBE in humans31. The expected two-year lag between a masting event and the increase in (infected) nymphs density has been confirmed by several studies37. Consistently, other studies highlighted such time lag between masting and the incidence of tick-borne disease including TBE and Lyme borreliosis32. In particular, some modelling efforts considering a beech masting index provided quite reliable predictions for the annual incidence of TBE in humans 2 years later31.The link between tree masting, rodent population dynamics, density of nymphal ticks and eventually the incidence of tick-borne diseases in humans, has been investigated in several studies mainly correlating some climatic variables that regulate the mast event38 and masting index is often obtained from a limited number of forest stands, or limited number of years of observation or dependent on the observer. For some forest tree species, such as beech and oak, airborne pollen amount is a key driver of seed production41, resulting in a link between pollen availability and masting. Since the presence and quantity of pollen in the air has a significant impact on allergies in humans, air quality is monitored at the global level to improve the prevention of allergic diseases. Hence, in this study we tested whether pollen abundance data provides an early warning predictor for TBE infection risk. To this aim, we investigated the correlation between pollen data, derived from a 30-year long term dataset, and TBE incidence in humans in an endemic area in northern Italy.Climatic factors are not the only determinants of mast eventsPollen data were recorded at Fondazione Edmund Mach, in San Michele all’Adige, Province of Trento, Italy , from 1989 to 2020. Airborne pollen was sampled by a Hirst-type sampler and analyzed following conventional techniques and standardized protocols (UNI EN 16868:2019). San Michele all’Adige is located near the center of the province of Trento, the area under study.Ostrya carpinifolia Scop.), beech (Fagus sylvatica L.), spruce (Picea abies L.), pine (Pinus sylvestris L. and P. nigra J. F. Arnold), downy oak (Quercus pubescens Willd.), manna ash (Fraxinus ornus L.) and hazel (Corylus avellana L.).The study area is located in the alpine biogeographical region, and we considered the following forest tree species growing in the area: hop-hornbeam . We denote the number of cases of TBE recorded during year y with 43.TBE is a notifiable disease in Europe since 2012 and in Italy since 2017. The case classification and definition are provided by the European Center for Disease Control44), denoted by PT(y), was calculated for each considered tree species T and each year y, applying a gap filling of missing data built on the basis of the seasonality of the historical database. Overall, only 4.18% of the data was interpolated.Total amount of pollen grains produced during the main pollen season  and sd(PT) represent the mean and the standard deviation of PT(y), respectively  by developing univariate linear models which can be represented by the following equation:0,T,y−n and βT,y−n are the model coefficients (intercept and slope) and T collected during year y−n . Therefore, 21 models (7 taxa and 3 time lags) were evaluated. Afterwards, we built a full model by considering all covariates having a significant slope βT,y-n in the univariate models previously described, after checking for potential collinearity between variables. In case of substantial correlation (Pearson correlation coefficient > 0.746), we considered only the variable having the lowest Akaike Information Criterion (AIC) score in the associated univariate model.We first investigated the association between entclass1pt{minima47 and packages AeRobiology48, EnvStats49, tidyverse50 and car51. Transformed pollen quantities and incidences are presented in Supplementary Table All analysis was carried out using R v4.2.0Between 1992 and 2020, a total of 206 TBE human infections were recorded in the province of Trento. The incidence varied between years, as shown in Fig. We found a significant association between TBE incidence and pollen indicators with a two-year time lag for beech, oak and hop hornbeam , we can note that they were almost always positive (see The coefficients of the selected univariate models (significant regression slopes) are presented in Table tive see .Table 1Ep < 0.001). The model can thus be represented asTaking into account such findings, we built the full model considering entclass1pt{minima2 = 0.34) and, consistently with the previous analysis, both tree species are positively associated with TBE incidence.This model  following a mast event has been repeatedly demonstrated to be correlated with simultaneous56 or postponed35 disease incidence fluctuations in humans. More specifically, it has been highlighted by several studies that tick-borne pathogens’ incidence is expected to be higher two years after a masting event32. For instance, in5 the authors used the beech masting index, among other predictors, to forecast human TBE incidence in Germany, Austria and Switzerland, but also underlined the importance of considering other forest tree species that are food resources for small mammals, such as oak (Quercus spp.) or European spruce (Picea abies). However, measuring seed production in long-lived plants requires direct observations over many years which may differ among countries adding intrinsic uncertainties to this value57. Moreover, such measures often consist of arbitrary categorical observations, which might not be easily compared as they are observer-dependent58.The optimal ecological conditions for TBE viral circulation, and therefore the infection hazard, are not yet completely elucidated, but the abundance of vector ticks and reservoir animals are fundamental59 through national and supranational networks  with standardized databases mostly available and accessible for several tree taxa. The link between pollen amount and acorn production has received a lot of attention because fruiting dynamics dramatically impacts forest regeneration, biodiversity, population dynamics of seed consumers, and ultimately epidemiology of infectious disease. Many tree species, like oak and beech, which dominate temperate forests in Europe, regenerate through synchronized, highly variable fruit production62. Usually in these tree species, hot summer temperatures in the previous year affect flower initiation increasing pollination efficiency64, provided that the plants have enough energy . Regardless of this common feature, oak masting is also driven by pollen dynamics with mechanisms that involve both internal resource allocation and spring weather conditions that affect the amount of airborne pollen released (synchrony hypothesis41). Whatever the mechanism, the pulsed resource availability generated by inter-annual fluctuations in seed production eventually drives the population dynamics of granivore forest rodents25, by increasing the length of the rodent breeding season and enhancing their winter survival. Rodents are the main hosts of larval stages of ticks that will molt into nymphs the following year. This relationship is not always straightforward, although in the majority of the cases rodent density positively affects larval survival and abundance9. As a cascading effect, in forested areas given a certain prevalence of tick-borne pathogens in the host population, the density of infected nymphs and the risk of tick-borne disease transmission will increase.Airborne pollen is measured around the world2 and higher AIC), probably because of the distance of beech forests from the monitoring site, resulting in relatively small quantities of detected pollen, which might also be due to the intrinsic low dispersal capability of beech pollen, which consists of heavy and rapidly falling grains released simultaneously with the emergence of beech leaves66. The ratio of recorded pollen abundances among beech, oak and hop hornbeam were 1:9:61, respectively67. Pollen amounts of hop hornbeam and beech recorded at the sampling station during the study period showed highly synchronized fluctuations, and hop hornbeam was therefore a good proxy indicator for beech pollen and beech seed production.In this study, TBE cases were strongly correlated with the pollen loads of oak, hop hornbeam and beech recorded two years earlier. The association with beech pollen was weaker  between TBE incidence and fructification 2 years prior31.Our findings are consistent with previous studies on the main predictors of tick-borne pathogens transmission in North America and Europe70, with potential effects on the community of seed consumers yet to be determined. A further limitation that prevents more accurate predictions is the lack of extensive data on TBE vaccination coverage among countries, including Italy.It should be noted that future predictions regarding mast seeding may be disrupted by anthropogenic environmental changes59), the results of our small-scale, long-term study could be tested over larger areas. If the relationships are confirmed by further studies, airborne pollen data could be used as an early warning system for the risk of TBE in Europe where rodent dynamics are mostly driven by food availability. Public health agencies would know two years in advance of a potential TBE outbreak, which would give them time to plan preventive measures, such as campaigns aimed at raising public awareness and implementation of vaccination programs. Moreover, the proposed warning system could be tested and applied to other arthropod-borne infections, where pulsed resource availability could be estimated by airborne pollen and seed production.Nevertheless, as pollen data collected using standardized procedures by widespread networks (over 800 monitoring stations in 2018Supplementary Information 1.Supplementary Information 2.


While the cellular interactions and biochemical signaling has been investigated for long and showed to play a major role in the cell’s fate, it is now also evident that mechanical forces continuously applied to the cells in their microenvironment are as important for tissue homeostasis. Mechanical cues are emerging as key regulators of cellular drug response and we aimed to demonstrate in this review that such effects should also be considered vital for the cellular response to radiation. In order to explore the mechanobiology of the radiation response, we reviewed the main mechanoreceptors and transducers, including integrin-mediated adhesion, YAP/TAZ pathways, Wnt/β-catenin signaling, ion channels and G protein-coupled receptors and showed their implication in the modulation of cellular radiosensitivity. We then discussed the current studies that investigated a direct effect of mechanical stress, including extracellular matrix stiffness, shear stress and mechanical strain, on radiation response of cancer and normal cells and showed through preliminary results that such stress effectively can alter cell response after irradiation. However, we also highlighted the limitations of these studies and emphasized some of the contradictory data, demonstrating that the effect of mechanical cues could involve complex interactions and potential crosstalk with numerous cellular processes also affected by irradiation. Overall, mechanical forces alter radiation response and although additional studies are required to deeply understand the underlying mechanisms, these effects should not be neglected in radiation research as they could reveal new fundamental knowledge for predicting radiosensitivity or understanding resistance to radiotherapy. Multicellular life requires a fine regulation to maintain stability of the metazoan tissues and ensure an efficient recovery after the homeostasis dysregulation due to pathological conditions . This reThis intercellular communication has been shown to be a crucial factor of the tissue response to radiation. Although not fully understood yet, the mechanisms behind the bystander effect  have been known to involve gap-junction  or paracHowever, the cells of a tissue or an organ also interact physically with their environment. This mechanical stimulation is sensed by the cells and transformed into a biochemical signal to induce a specific cellular response, in a mechanism commonly referred as mechanotransduction.Among these physical interactions, the most studied is probably the ubiquitous effect of the non-cellular component of a tissue: the extracellular matrix (ECM). The pioneering work in the early 2000 s, made with the emergence of reliable models , highligInterestingly, increased lines of evidence also showed that these mechanical cues alter response to chemotherapeutic drug and induce treatment resistance ,34. For In this review, we will present the main mechanotransducers and show their close link with radiation-modulated cellular pathways, thus suggesting that mechanical cues should not be neglected when studying cell response to radiation. We will discuss the few current evidence demonstrating the direct effect of several mechanical stresses on cellular radiosensitivity and discuss the gaps that need to be addressed by the radiation research community in order to improve the current approach.The interaction between a cell and the ECM occurs through the integrins that are the major metazoan receptors for cell adhesion . These tThe interaction between the integrins and the ECM protein network modulates the cell survival after irradiation in a phenomenon called cell adhesion-mediated radioresistance. Integrins are heterodimers formed from 18 α and 8 β transmembrane subunits . Many prRecently, a study has identified Yorkie-homologues YAP (Yes-associated protein) and TAZ  proteins, the two nuclear effectors of the Hippo signaling pathway, as another major cellular hub of mechanotransduction signaling . In respet al. also showed that YAP activity enhanced cell proliferation, the authors identified that YAP overexpression in medulloblastoma cells prevented complete DNA repair and promote inactivation of the checkpoint regulators ATM and Chk2 leading to the blockade of the activation of the G2/M checkpoint and to a mitosis entry with un-repaired DNA [The versatility of YAP/TAZ pathway led to the investigation of its potential role in the radiation response. Overall, preliminary studies showed that YAP conferred radioresistance in many different cells and that tumors with a high YAP expression level had poor prognosis –66. Its ired DNA . They suired DNA . InteresThe β-catenin–dependent mechanotransduction is a 600 million year regulatory mechanism, identified in many animal mesoderm ,70. SeveIonizing radiation promotes accumulation and translocation of β-catenin into the nucleus, leading to an increased transcriptional activity of β-catenin target genes and up-regulation of proteins in the Wnt/β-catenin pathways . The act+, K+, Ca2+, or Cl− between the extra- and intracellular medium, these channels are vital for cell interaction with the environment and are implicated in many cellular functions such as cell cycle regulation, apoptosis, oxidative defense, metabolism, etc., thus ensuring cellular homeostasis. Ionizing radiation being known to modulate their activity, the role of ion channels in the regulation of cellular radiosensitivity has already been investigated and extensively reviewed by Huber et al [The ion channels present on the cell membrane can sense the external mechanical forces applied to it and thus play a major role in the mechanotransduction . Among ter et al ,91.et al. demonstrated that mechanical stress activated Ang II receptors without the involvement of Ang II but by the association with Janus kinase 2 and translocation of G proteins into the cytosol [et al. demonstrated that the overexpression of G protein-coupled receptor kinase 2 (GRK2) protected human embryonic kidney cell line against radiation [The G-protein-coupled receptors (GPCRs) superfamily is the largest group of membrane receptors in humans. The binding of a ligand to the extracellular domain of the GPCR activates downstream effectors and stimulates signaling pathways inside the cell to trigger a large variety of processes involved in the regulation of the cellular phenotype and response to external stimuli. Early studies reported that mechanical stress promoted the release of small molecules that would bind and activate the GPCRs such as the stretch-induced autocrine secretion of angiotensin II (Ang II) in cardiac myocytes that binds Ang II receptors to act as an initial mediator of the cellular response . However cytosol . New evi cytosol ,95. Rece cytosol ,97. Inte cytosol ,99. Desp cytosol ,101 suggadiation . Specifiadiation .in vitro radiation response of cell lines [et al. investigated deeper the mechanisms involved in this response and observed that both homologous recombination (HR) and non-homologous end joining (NHEJ) pathways were inhibited in low stiffness environment, suggesting that double-strand breaks (DSBs) repair can indeed be regulated by extracellular mechanical signals [The close correlation between the activation of mechanotransducers and the modulation of cellular radiosensitivity described previously could reveal a potential and significant effect of mechanical stress on radiation-induced tissue damage and response. However, to date, few studies have really investigated the direct effect of mechanical cues on cellular response to radiation. Two recent studies have focused on the effect of ECM stiffness on the ll lines ,105  level compared to stiffer substrate [et al. highlighted that stiff ECM induced a tumorigenic phenotype of breast spheroids [in vivo by showing that the irradiation of cells with a low number of nucleosomes produced more DNA breaks [In our opinion, these results should be placed in parallel to the increasing evidence showing the relationship between environmental stiffness, chromatin state and cellular phenotype. Chromatin structure is an important regulator of gene expression and thus dictates many biological processes such as stem cell differentiation . Chromatubstrate . Interespheroids . These cpheroids –116. A rA breaks . The anaA breaks . AltogetA breaks . The decThe observation of a soft environment promoting the formation of a condensed chromatin less susceptible to radiation-induced damages suggests that cells on soft substrate should be more radioresistant and thus contradicts the preliminary results previously described and obtained with hydrogels of different stiffness. Additional investigations are thus required to draw a complete overview of the multiple mechanoresponsive targets, identify their interactions and their respective influence in the cellular response to eventually understand the underlying mechanisms that affect the stiffness-mediated radiosensitivity. Mechanosensing has been mainly studied using two-dimensional (2D) models, and it is now essential to move into a more physiologically relevant 3D context as 3D cellular structures exhibit major mechanoresponsive features such as increased integrins expression and ECM interaction.et al. also investigated the adhesion and migration response to radiation of breast normal (MCF10A) and cancer (MDA-MB-231) cells seeded on physiological (1.3 kPa) and malignant (13 kPa) matrix stiffness [Beyond radiosensitivity, Panzetta tiffness  , this flow generates a significant shear stress (comprised between 0.001–0.01 dyne/cm2) due to the high resistance of the surrounding 3D ECM. This fluidic stress has important roles on cell–cell and cell-ECM signaling driving tissue development and maintenance or pathobiology [However, although less important in magnitude, epithelial cells can also be exposed to shear stress forces when fluid is present. For instance, in the kidney, the flow of glomerular filtrate creates a significant fluid shear stress at the apical surface of the renal tubular epithelial cells . This stobiology ,137. In obiology , also afobiology ,140.et al. showed that a prolonged (24 h) shear stress of 12 dyne/cm2 enhanced the radiation induced cytotoxicity to colon cancer cells [2 is elevated and it is very unlikely that tumor cells are exposed to such high flow stress in vivo. The authors showed that lower shear stress (<3 dyne/cm2) did not affect cell survival after radiation, therefore, it is still to be determined if physiological shear stress can really affect cancer cells radiosensitivity.The mechanotransduction of shear stress shares similarities with the one involved in ECM stiffness response, and several common mechanosensors are triggered in both stresses. Indeed, integrins for example are also activated by shear stress that switches them to an active conformation thus increasing their affinity for ECM proteins . This acer cells   triggered a sustained NF-κB activity), and activated stem cell biology signaling pathways. The extensive investigation of shear stress effect on endothelial cells over the years also highlighted specific mechanoreceptors such as tyrosine kinase receptors (TKRs), G proteins and GPCRs, ion channels, intercellular junction proteins , caveolae, membrane lipids, and glycocalyx [However, high shear stress is encountered in vascular system where it can be comprised between 1 to 6 dynes/cmillaries . Thus, Nothelium   only, and not laminar flow (with a clear direction), led to YAP/TAZ activation in endothelium, suggesting that YAP activation by fluid stress is a fine and complex regulated mechanism and highlighting the need of a better understanding of the role of the mechanoreceptors involved in this mechanotransduction response.Following the discovery of its role in ECM sensing, the role of YAP in shear stress transduction signaling is also now under investigation. Preliminary data showed that fluid shear stress activates ROCK and LIMK. Once activated, LIMK phosphorylates cofilin that inhibits actin depolymerization leading stabilized F-actin filaments. In such circumstances, YAP is dephosphorylated, moves to the nucleus where it interacts with TEAD and acts as a transcription factor for genes promoting motility and survival in cancer cells . To note vessels . Since t vessels  or epith vessels . Importa vessels . Wang etSeveral tissues in the body are subjected to mechanical stretch including lung cells in the alveoli during breathing movement, cardiac tissue during heart beating, blood vessels due to blood flow and the action of blood pressure, muscle during body movement, intestinal cells during intestinal peristalsis or bladder at the time of urination . With th2 [To date, we have not identified any studies that investigated the role of mechanical strain on cellular response to ionizing radiation. However, using mouse fibroblasts seeded on an elastic polydimethylsiloxane (PDMS) membrane, Nagayama and Fukuei showed that 10 % cyclic uniaxial stretch at a frequency of 0.5 Hz for 12 h decreased γH2AX fluorescence compared to non-stretched control after ultraviolet (UV)-C irradiation at 45 J/m2   or by targeting the cell-matrix junctions and the mechanotransduction response , respectively ,182. WheThe permanent discovery of new molecular partners as receptors or transducers of the mechanical response, conjugated with the continuous improvement of bioengineered models should encourage the radiation research community to investigate the role of mechanical cues as such effects might clearly influence tissue radiosensitivity, resistance to treatment and bystander effects, among others radiation-responsive cellular processes. Ultimately, a comprehensive knowledge of these mechanical-modified radiobiological phenomena will allow the emergence of new treatments and alternative strategies in RT that could greatly benefit the patients.