To investigate how water and food insecurity were associated in nationally representative samples of individuals from 25 low- and middle-income countries.We used data from the 2020 World Gallup Poll in which the Individual Water Insecurity Experiences Scale and the Food Insecurity Experience Scale had been administered to 31 755 respondents. These scales measure insecurity experiences in the previous 12 months. We classified individuals as water insecure if their score was ≥ 12 and food insecure if the Rasch probability parameter was ≥ 0.5. For estimating the proportions, we used projection weights. We estimated the relationships between binary and continuous measures of water insecurity and food insecurity for individuals within each country and region using multivariable logistic and linear regression models, adjusting for key socioeconomic characteristics including income, gender, age and education.Among the 18.3% of respondents who experienced water insecurity, 66.8% also experienced food insecurity. The likelihood of experiencing moderate-to-severe food insecurity was higher among respondents also experiencing water insecurity . Similar odds were found in Asia , Latin America , North Africa  and sub-Saharan Africa .Our results suggest that water insecurity should be considered when developing food and nutrition policies and interventions. However, more research is needed to understand the paths between these insecurities. For example, researchers have shown positive associations between household food insecurity scores and time required to fetch water,,A further limitation in our understanding of the relationships between water insecurity and food insecurity is that disparities by individual characteristics such as gender, age and health status have gone unmeasured. Knowing where and among which individuals water and food insecurities coexist, and whether this coexistence is independent of socioeconomic factors, could offer more precise insights than household-level indicators. These insights could be used for developing appropriately targeted interventions and policies to mitigate food insecurity that are not undermined by concurrent problems with water.–Finally, most studies have been site-specific and not nationally representative. The few studies that have used nationally representative samples measured water in terms of access to an improved water source or distance between the home and water source.Therefore, we investigated how water access, use and stability related to individual food insecurity in 25 low- and middle-income countries, using a national representative survey. We sought to (i) describe the extent to which water insecurity and food insecurity were concurrently experienced in these countries; (ii) test if the likelihood of being moderately to severely food insecure was higher among those who were water insecure when controlling for socioeconomic confounders by both country and region; and (iii) test if the severity of water insecurity predicted the severity of food insecurity when controlling for socioeconomic confounders.,We used data from the 2020 Gallup World Poll, an annual cross-sectional survey administered to nationally representative samples of non-institutionalized individuals 15 years or older. Stratified sampling procedures were used to randomly select respondents, and probability sampling weights were generated to adjust for non-response and helped ensure estimates were representative of the civilian adult population in each country. Details on the sampling frame and methods used by Gallup World Poll to construct sampling weights are described elsewhere,Water insecurity was assessed by Gallup using the Individual Water Insecurity Experiences Scale, which has been established as a reliable, cross-context equivalent and valid scale.In-country partners in 31 low and middle-income countries administered the Individual Water Insecurity Experiences module of the 2020 Gallup World Poll. Details on the translation and implementation procedures used for administering the module have been published elsewhere.,,The survey assessed food insecurity among the same individuals in 27 of the 31 countries using the Food Insecurity Experience Scale (online repository).,The analytic protocol of Food Insecurity Experience Scale data is based on the Rasch model.,,,To account for potential confounding, we adjusted for socioeconomic factors that may be common causes of both water insecurityWe conducted descriptive analyses and regression models using Stata, version 17 . We used Stata’s survey commands to account for sampling weights and regional stratification (online repository).To describe the extent to which water insecurity and food insecurity were concurrently experienced, we examined the proportion of individuals classified as water insecure who also experienced moderate-to-severe food insecurity during the same time. We then used logistic regression models to test how the odds of experiencing moderate-to-severe food insecurity varied by water insecurity status when adjusting for confounders in each country, region and the overall sample.To understand how individuals’ severity of food insecurity covaried in relation to their severity of water insecurity, we built linear regression models regressing Rasch-estimated equated food insecurity severity parameters (expressed as a transformed logit metric) on Individual Water Insecurity Experiences score (modelled continuously) for each country, region and the overall sample.To examine the degree to which socioeconomic factors confound the relationship between water insecurity and food insecurity, we compared unadjusted and fully adjusted coefficients for all logistic and linear regression models. To do this, we first built country models with no covariate adjustment and regional and overall sample models adjusted for only country fixed effects; we then added all socioeconomic covariates to those models.Of the 27 countries surveyed with both the Individual Water Insecurity Experiences and Food Insecurity Experience modules, we had a base sample of 38 189 individuals. For individuals missing responses to one to three questions about water insecurity , we imputed the data to calculate their water insecurity experiences score. We excluded 166 respondents who were missing data for more than three items of the Individual Water Insecurity Experiences module. We also excluded 611 respondents missing data for any item on the Food Insecurity Experience Scale. We excluded all 997 respondents from Zimbabwe due to unreliable income data; all 3468 respondents from China were excluded due to questions on COVID-19 pandemic-related life disruptions not being permitted in the China survey. Finally, 1241 respondents with missing or do not know responses to any of the covariate items were excluded (flowchart available in online repository).Of the 18.3% of respondents who experienced water insecurity in the preceding 12 months, more than half (66.8%) experienced moderate-to-severe food insecurity ; Fig. 1.In the unadjusted model, the likelihood of experiencing moderate-to-severe food insecurity was higher when also experiencing water insecurity in most countries except for Gabon and Uganda, where no relationships were observed . PositivThe severity of food insecurity was positively associated with water insecurity severity in adjusted models in all but two countries, Bangladesh and Gabon . This poThe concurrence of water and food insecurities was common in nationally representative samples from 25 low- and middle-income countries. In most countries and in all regions, these two forms of resource insecurities were strongly associated; this association was independent of income, financial difficulty, personal impact of the COVID-19 pandemic and demographic factors.,,,,These results at the individual level corroborate findings of smaller, non-nationally representative studies. For example, a few studies demonstrated positive linear relationships between household food insecurity scores and the Household Water Insecurity Experiences Scale,,,,,,,,These findings have important public health implications in light of theories and evidence that water insecurity and food insecurity may have mutually exacerbating effects on physiological and mental health.Future research should examine the paths through which water insecurity affects food insecurity, nutritional intake and other food-related behaviours across different settings, and whether relationships are causal. The role that food insecurity may play in exacerbating water insecurity should also be examined. The relationships between water and food insecurities likely differ depending on food production and preparation strategies, climate and climate-change-related alterations in precipitation patterns, infrastructure and other conditions. Elucidating these paths will help explain why water insecurity and food insecurity were occasionally unrelated. Investigation of these relationships in additional low- and middle-income countries, as well as high-income countries, will extend understanding of the extent to which water and food insecurities are experienced concurrently around the globe.Strengths of this study include the use of the first cross-context equivalent scale for a more holistic measurement of water insecurity than is permitted by other global indicators such as water stress or water infrastructure. This study also concurrently measured experiences of water and food insecurity among the same individuals in nationally representative samples. The variety of countries included, spanning four regions, and the large sample size are additional strengths.Our study has some limitations. First, because the data we used are cross-sectional, we cannot determine causality or rule out the possibility that the relationship is bidirectional. Second, other unmeasured material-need insecurities and/or effects of the COVID-19 pandemic on availability and acquisition of resources could confound the results. There may be bidirectional relationships between impacts of the pandemic and water and food insecurities. Future analyses should evaluate if the relationship between water and food insecurity vary by individual characteristics, including sex and age; in the current analyses, we only controlled for these characteristics. Finally, the survey did not collect data on factors that might explain why the relationship between water insecurity and food insecurity was stronger in some countries than in others, such as respondents’ diet, water source and climate-related factors.,Here we provide evidence that water and food need to be considered together, an opinion expressed in a 2020 report by the United Nations (UN) Standing Committee on NutritionAlthough international, governmental and nongovernmental agencies and institutions have different responsibilities, priorities and expertise, the interdependencies of food and water insecurities could help to spur coordination between these entities to ensure that both are considered together where appropriate. Furthermore, the identical recall periods used at the individual level for the Food Insecurity Experience Scale and Individual Water Insecurity Experiences Scale may make it easier to bridge sectors using common measures and indicators. Evidence that improving one type of resource insecurity requires amelioration of the other would further motivate collaboration. For example, failure to consider the role of water issues in food insecurity could lead to less effective policies and interventions; provisioning of food without ensuring access to water to prepare that food could be an incomplete solution. Hence, our findings highlight the importance of measuring, monitoring and addressing water insecurity alongside food insecurity and other nutrition outcomes.


Modulators of skeletal muscle hypertrophy: Mechanisms to Lifestyle Strategies” as a Research Topic of interest. In this Frontiers Research Topic, authors from around the globe have tackled unique aspects of these major challenges, providing cutting edge original research studies and comprehensive review articles.The central importance of skeletal muscle mass and strength as key determinants of overall health, longevity, disease survival, functional independence, and quality of life is now well established. Understanding the basic molecular and cellular mechanisms that regulate skeletal muscle hypertrophy, as well as the effect of various pharmacological and non-pharmacological (including lifestyle) strategies to build muscle mass may ultimately lead to better interventions to maintain or improve muscle size and strength across the life span. For this reason, we focused on the “Zeng et al.). The authors knocked out the Myh4 gene (encoding the murine fast-twitch myosin heavy chain IIb protein) and demonstrated impaired postnatal growth of the gastrocnemius muscle during the transition from slow to fast fiber phenotype. By overexpressing PGC-1α or feeding mice the AMPK agonist AICAR, the authors showed that forcing a more oxidative fiber type profile could partially protect against muscle loss resulting from the ablation of the myosin heavy chain IIb protein. On the other hand, traditional genetic (myostatin deficiency) and pharmacological (clenbuterol treatment) stimulators of muscle hypertrophy had little impact on muscle of mice lacking a functional Myh4 gene. These results suggest that promoting oxidative metabolism may be a therapeutic strategy to mitigate muscle loss in conditions where glycolytic myofibers are preferentially affected such as age-associated muscle wasting (sarcopenia).Two investigations in this Research Topic utilized genetically modified mouse models to better understand the underlying mechanisms of postnatal muscle growth. Zeng and colleagues tested the hypothesis that the muscle fiber type transition (from slow to fast) which normally occurs in early life is required for muscle hypertrophy (Pak1 gene (encoding the p21-activated kinase 1 protein) as a potential mediator of the hypertrophic actions of myostatin deficiency on skeletal muscle from various transcriptomic datasets using different experimental strategies to inhibit myostatin activity . Local expression of Pak1 was shown to be markedly increased in response to myostatin inhibition and positively associated with ensuing muscle hypertrophy in these mouse models. However, genetically deleting the Pak1 gene did not affect muscle hypertrophy in response to myostatin inhibition. Given the existence of different members of the PAK protein family, in particular PAK2, it is possible that some redundancy exists regarding muscle metabolism between PAK1 and PAK2, given that simultaneous deletion of both genes was previously shown to result in muscle atrophy . The authors demonstrated that the size of fast-twitch (type II) myofibers but not slow-twitch (type I) myofibers increased in active male participants that performed 12-weeks of either endurance, resistance, or alternate day concurrent training. Interestingly no changes were observed in satellite cell content in either fiber type, and significant changes in myonuclear number were only observed in type I, but not type II myofibers. Nonetheless, the authors noted that the magnitude of increase in fiber type specific cross-sectional area was positively correlated with the changes in myonuclear number in both fiber types. This data adds to the growing body of evidence questioning whether or not myonuclear accretion via satellite cell fusion is a prerequisite to changes in myofiber hypertrophy in humans.Resistance training promotes skeletal muscle growth by myofiber hypertrophy. However, the underlying mechanisms are not fully understood in humans yet. Resident muscle stem cells termed satellite cells are often cited as a main mechanism of myofiber hypertrophy in response to resistance training Fox et al.). The potential for preferential hypertrophy of myofibrillar or sarcoplasmic cellular fractions of skeletal muscle cells has been a topic of enthusiastic debate in recent years . In this thought-provoking investigation, Fox et al. provide data to corroborate the notion that different resistance exercise training protocols might differentially affect myofibrillar and cytosolic compartments in resistance trained men. An increased myofibrillar spacing i.e., the non-contractile portion of muscle cell, seems to be associated with 8-weeks of a higher volume-training load, at least in muscle biopsy samples obtained 4 days following the last bout of resistance exercise. Whether these adaptations persist or are resolved warrants further investigation. Nevertheless, the study by Fox et al. highlights that myofiber hypertrophy induced by resistance training may partly occur due to expansion of the cytosolic subcellular fraction.Talking about questioning preexisting paradigms, Fox and colleagues investigated whether frequent manipulation of resistance training variables in human volunteers might result in different adaptations to the myofibrillar or sarcoplasmic protein pools in skeletal muscle . In this double-blinded randomized controlled study, the authors demonstrated that the group of postmenopausal women that received transdermal estrogen therapy displayed significantly greater increases in muscle cross-sectional area, whole-body fat-free mass, and handgrip strength compared to the control group following 12 weeks of resistance exercise training. These clinically relevant results show that transdermal estrogen therapy leading to increased circulating estradiol levels can greatly benefit postmenopausal women during resistance training.Dam and colleagues aimed to determine whether transdermal estrogen therapy might improve muscle adaptation to resistance exercise in postmenopausal women, given that the decline in estrogen levels is accompanied with loss of muscle mass at this period (Viecelli and Aguayo). In this detailed review of the literature, Viecelli and Aguayo summarize the latest evidence on the resistance training variables affecting muscle adaptation relevant to the general population, with important directions to training prescription.Finally, Viecelli and Aguayo discuss the state-of-the-art of the research of resistance exercise variables, including volume, intensity, rest interval, frequency, range of motion, and muscle failure, on muscle hypertrophy and muscular strength (Knowledge of the adaptations to resistance training and the lifestyle interventions that affect such responses are of utmost importance to create and apply novel strategies to improve overall health as the population in most countries ages. The studies in this Research Topic not only provide new important data to improve our current understanding of skeletal muscle physiology, but also poses new questions and provokes reanalysis of previously established paradigms. Whether myonuclear accretion resulting from satellite cell fusion is important for muscle hypertrophy and whether sarcoplasmic hypertrophy is a true physiological adaptation to resistance training will still be debated, but the studies presented herein and future work they stimulate will help solve these puzzles. As demonstrated in this Research Topic, mechanistic investigations in pre-clinical mouse models will continue to be invaluable in improving our understanding of the basic mechanisms regulating skeletal muscle hypertrophy. However equally important are clinically relevant human trials which bring the basic science of muscle biology from bench-to-bedside and will ultimately help health practitioners and physicians chose the best interventions to promote muscle hypertrophy during resistance training throughout the life course. We, the editors, are extremely pleased to see the investigations published in this Frontiers Research Topic, the relevance that they will have to our understanding to the field of skeletal muscle physiology, and excited by the groundwork the empirical studies have laid for further research investigations to build upon.


Intense transmission of syphilis has emerged in some Canadian Arctic communities despite screening and prevention efforts. The remoteness of most communities and limited diagnostic infrastructure yield long delays (≥14 days) between screening and treatment of cases. These hamper syphilis control efforts and may contribute to sustained transmission. Syphilis rapid diagnostic tests (RDTs) have been developed to make screening more accessible and to inform clinical decision-making within the same clinical encounter. These RDTs have been successfully deployed in several countries, but not yet in Canada.“Stopping Syphilis Transmission in Arctic Communities Through Rapid Diagnostic Testing” (STAR) study, wherein the clinical and epidemiological impact of deploying a dual syphilis RDT in the context of ongoing transmission in Nunavut and Nunavik will be evaluated. In this prospective multisite field evaluation, sexually active individuals aged ≥14 years at risk for syphilis will be offered screening by an RDT at the point-of-care by non-laboratory trained registered nurses. Whole blood and serum specimens will be concurrently collected, when feasible, for rapid testing with an RDT containing both treponemal and non-treponemal components (Chembio DPP®Syphilis Screen & Confirm) and compared to laboratory-based reference testing according to a reverse sequence algorithm. The diagnostic accuracy of the RDT, using both whole blood and centrifuged serum specimens, will be validated under real-world conditions in remote Northern settings, outside of specialized laboratories. Additionally, screening-to-treatment time, case detection rates, and the number of infectious contacts averted by using the RDT relative to reference testing will be estimated. The impact of both diagnostic approaches on syphilis transmission dynamics will also be modeled.We describe the methodology of the This study will provide much needed evidence for strengthening rapid responses to emerging syphilis outbreaks in remote Arctic regions, by supplementing traditional diagnostic strategies with an RDT to rapidly triage patients likely in need of treatment. These results will also inform the development and tailoring of future diagnostic strategies and public health responses to emerging outbreaks in the North. Treponema pallidum, subspecies pallidum which, if left untreated, leads to a myriad of serious health consequences, including congenital syphilis [Syphilis is a sexually transmitted infection (STI) caused by the bacterium syphilis ,2. In sosyphilis . Since tsyphilis . Rates osyphilis . In the syphilis . DespiteThe presence of syphilis in Nunavut and Nunavik is of particular concern because these are regions with extremely high rates of other STIs such as chlamydia and gonorrhea, and have among the highest birth rates in Canada ,5–7. Altit takes 2 weeks to get your results… that’s two Fridays!”. The resulting long intervals between screening and subsequent treatment of infectious syphilis cases facilitates continued transmission within sexual networks and between communities. Using the contact tracing investigation records in our region, we estimate that up to half of all infectious sexual contacts may occur while screened patients are awaiting test results. Reducing the time between screening and treatment of infectious syphilis cases is therefore a key priority in these Arctic communities.Complicating disease control efforts, the remoteness of most communities in Nunavut and Nunavik hampers timely access to diagnostic testing, which is required to initiate treatment in most cases. In fact, many communities only have a nursing station without a diagnostic laboratory. As a result, the turnaround time between specimen collection and result reporting using current approaches that rely on referral to distant laboratories is typically 6 to 19 days, and is frequently longer due to additional logistical obstacles. Numerous attempts to optimize pre-analytical processes have failed to substantially reduce this interval, which is largely outside the control of the laboratory. Once positive results are reported, further delays to treatment are incurred by having to arrange a follow-up visit with newly identified cases. As outlined by a youth participant of the Consultative Committee on Sexual Health in Nunavik, “Rapid diagnostic tests (RDTs) intended to screen for syphilis have been developed to bridge this gap and have been successfully deployed in several countries, but not yet in Canada ,11. SyphDeployment of point-of-care (POC) or near-care rapid diagnostic testing would facilitate expansion of screening efforts in Arctic communities where transmission risk is identified to increase identification of cases outside of known contact networks, as no laboratory equipment or facilities are required. The current article describes our protocol that aims to evaluate the clinical and epidemiological impact of deploying a syphilis RDT in the context of ongoing transmission in Nunavut and Nunavik to inform policy for syphilis disease-control in remote Arctic settings.Evaluate the diagnostic accuracy of a syphilis RDT when used in real-world conditions in remote Arctic communities.Chembio DPP®Syphilis Screen & Confirm Assay  [The accuracy of RDTs in real-world conditions can vary substantially from that observed with the same test in laboratory settings . This stbio RDT) . Previoubio RDT) –18. The bio RDT) ,20. FurtEstimate the number of cases averted when using the Chembio RDT relative to standard diagnostic algorithms and to model the impact of both diagnostic approaches on disease transmission dynamics.Since the Chembio RDT will be used in parallel with current standard laboratory-based reference tests and diagnostic pathways, and not as a replacement, we can directly compare the impact of these two approaches. Specifically, we will quantify the added clinical value  of deploying this RDT as compared to traditional laboratory-based diagnostic testing. We hypothesize that the Chembio RDT with its shorter turnaround time between specimen collection and availability of results , will lead to the detection of cases at earlier clinical stages, and will facilitate prompt initiation of appropriate treatment within the same clinical encounter. Early identification of asymptomatic cases through increased screening and timely treatment may interrupt the progression of syphilis and reduce of the duration of infectiousness .Sexually active individuals aged ≥14 years at risk for syphilis will be offered screening by both the RDT and standard laboratory diagnostic testing, according to local public health protocols in place.The Chembio RDT will be implemented in (i) the sexual health clinics in two communities in Nunavik (Communities A and B) and in (ii) a nursing station in Nunavut (Community C). These clinics will provide same-day turnaround times and treatment (if required) for patients within these communities.If new syphilis cases are detected among individuals from other communities with no previously documented syphilis transmission, or for new index cases without links to other known cases, intensified case-finding may be deployed in collaboration with local public health authorities. In such cases, dedicated and trained personnel will be deployed from Community A, B or C to perform screening in the affected communities using the RDT in parallel with a laboratory-based algorithm.In both regions, the inclusion criteria are as follows: i) sexually active with possible syphilis  or exposure to syphilis , or ii) STI screening based on public health policies in place, or iii) STI screening requested by the patient, and iv) availability of adequate specimen volume to allow for testing via both diagnostic methods. All individuals screened for syphilis by both diagnostic approaches will be eligible for inclusion regardless of their test results. Individuals aged <14 years will not be eligible for inclusion in the study as they are unable to provide informed consent in accordance with local laws ,23. TherThe research ethics board of the Research Institute of the McGill University Health Centre has approved this study (# 2020–5834) as well as the Nunavut Research Institute (Nunavut Research License: 0300520N-M).® Syphilis Screen & Confirm Assay in Canada has been obtained through Health Canada’s Special Access Program, after a robust lab-based verification of the test’s accuracy at the Quebec provincial laboratory [Authorization for use of the Chembio DPPboratory , validatboratory , and CE There will be no financial compensation or reimbursement offered to participants. Serum specimens will be collected in all cases for standard testing for syphilis, as is currently the standard of care. For the rapid test, a positive test result indicating active syphilis infection will provide a preliminary positive result for syphilis. Participants will be treated before confirmatory testing because the Chembio RDT’s reported specificity is high, syphilis is highly infectious, and transmission is completely preventable with treatment.Following broad community consultations, the following approach to obtaining informed consent for whole blood specimen testing was requested by the respective communities:In Nunavut, study participants will be read a verbal consent script listed in In Nunavik, study participants will be read the verbal consent script and will not be asked to sign the written informed consent form as the local Health and Wellness Committee felt strongly that doing so would discourage syphilis testing in the community.This study will be conducted in accordance with the latest Seoul revision of the Declaration of Helsinki (section K6b), the Medical Research Involving Human Subjects Act, the ICH Good Clinical Practice, and local regulatory requirements.μL drop of venous blood collected immediately upon removal of the butterfly needle used to obtain the serum specimen for routine-care analyses.A serum specimen will be collected from all those undergoing syphilis screening. This is the same specimen that would normally be collected for routine testing. Participants will be asked to provide an additional single venous whole blood specimen for rapid testing. This additional specimen will consist of a 10Following initial on-site screening with the Chembio RDT, all remaining serum specimens will be stored in dedicated coolers and transported from individual villages to diagnostic laboratories according to routine local protocols. These serum specimens will then be stored at -20°C pending shipment on dry ice to their routine designated reference laboratory via airplane for standard syphilis diagnostic testing. Specimens from symptomatic and asymptomatic individuals will be tested in real-time to optimize clinical care and will be done in accordance with routine testing procedures. Specimens positive for active syphilis will be reported, as per public health law, to local public health authorities and to the relevant healthcare practitioners to guide clinical care.In all participating communities, initial screening with the Chembio RDT will be performed during the patient clinical encounter using a venous whole blood specimen. In addition, serum specimens will be brought to the medical laboratory, or designated testing area in communities without a laboratory, and tested as soon as possible with the Chembio RDT. Results will be reported to the requesting physician and/or public health nurse and patients will be contacted (and treated if required) on the same day. Documentation and clinical follow-up of results will be integrated into routine care algorithms, under the responsibility of a designated registered nurse at participating sites.® Syphilis Screen & Confirm Assay is designed for accurate diagnosis at the POC  according to a reverse sequence algorithm ,26.We will evaluate the diagnostic accuracy of the Chembio RDT when used under real-world conditions in remote Northern settings. In communities where screening is taking place, we will estimate the sensitivity and specificity of the Chembio RDT when used with serum specimens, against the reference-standard diagnostic laboratory-based reference tests that are part of the routine provincial testing algorithm.Secondary outcomes will include (i) the positive and negative predictive values as well as the positive and negative likelihood ratios of the Chembio RDT relative to the standard laboratory-based tests; and (ii) the sensitivity and specificity of the Chembio RDT when performed using venous whole blood at the POC, as compared to the performance of the same test with serum specimens in a community-based laboratory or designated testing area.The clinical and epidemiological impact of both diagnostic approaches  on syphilis transmission dynamics in Nunavut and Nunavik will be modeled. The model will enable us to assess the population-level consequences of identifying cases at earlier clinical stages and immediate treatment initiation, thereby resulting in shorter periods of infectiousness, with potentially important consequences on overall transmission dynamics.With an estimated sensitivity of 95% for the purpose of the calculation, and a precision of 5% for both syphilis components of the Chembio RDT , we aim to recruit a minimum of 73 cases of confirmed syphilis. Given that most screened individuals will have negative results, the resulting precision around the estimate of specificity will be much higher. However, if the observed field sensitivity of the RDT falls below that observed in a pilot laboratory-based study we performed , we willP-value of <0.05 will be considered statistically significant. The field diagnostic accuracy of the Chembio RDT will also be described . The diagnostic performance for the RDT will also be stratified by rapid plasma regain titre  if sample size in each stratum allows.Descriptive analyses will be used to characterize cases overall and by region. In particular, the proportion of cases identified, the pattern of sexual contacts, and communities affected will be described for Nunavut and Nunavik. The statistical methods to compare outcomes between regions and/or between cases and non-cases may include chi-square test, Fisher’s exact test for categorical outcomes and unpaired t-test or Wilcoxon rank sum test for continuous data, as appropriate. A Syphilis is a notifiable disease by law across Canada. As such, public health authorities in Nunavut and Nunavik closely monitor all those identified with active syphilis infection and conduct detailed patient histories and STI risk assessments . When poThe clinical and epidemiological impact of both diagnostic approaches  on syphilis transmission dynamics in Nunavut and Nunavik will be modeled. Mathematical models of disease transmission–computer simulations of epidemics–enable investigators to capture the indirect benefits of this intervention. These indirect effects consider the longer-term public health benefits accrued at the population level by averting long chains of syphilis transmission through potentially more rapid diagnosis and treatment. Specifically, we will develop, parameterize, and calibrate a dynamic age-stratified model of syphilis transmission dynamics. The model will simulate syphilis transmission among sexually active individuals in small  communities, the infection’s natural history (and infection-induced immunity against re-infection), sexual mixing characteristics, and the testing and treatment cascade . The modHence, the model will enable us to assess the population-level consequences of identifying cases at earlier clinical stages and immediate treatment initiation, thereby resulting in shorter periods of infectiousness, with potentially important consequences on overall transmission dynamics. Developing a mathematical model will provide us with a more in-depth understanding of the impact of deploying the syphilis RDT in terms of the number of potential cases averted relative to the current routine diagnostic algorithm. The model will additionally provide us with insights into the number of individuals treated due to false positives and those that were missed by the rapid test.This study aims to collect data on a notifiable infection. Relevant variables about cases and contacts are already collected by public health authorities. Thus, study data for analysis will be obtained from these sources. All unique identifiers  will be removed prior to data analysis. Anonymized data  prescribed, number of sexual contacts) will be collected and managed using REDCap electronic data capture tools hosted at the Research Institute of the McGill University Health Centre ,30.This study is ongoing. Participant recruitment began January 16, 2020 and as of January 21, 2022, a total of 176 individuals have been recruited (144 from Nunavik and 32 from Nunavut) of which 46 new cases of syphilis have been identified. We anticipate recruitment will end in late 2022, after which data analysis and modeling will begin.This project will provide much needed insight into the clinical and epidemiological impact of implementing rapid diagnostic testing in parallel with traditional laboratory-based diagnostic algorithms in response to a novel syphilis outbreak as well as in regions where syphilis has emerged/resurged in the Canadian Arctic. Our study builds upon the current evidence-base and addresses critical knowledge gaps by estimating the diagnostic accuracy and impact of the Chembio RDT on syphilis management and transmission in a population that is woefully underserved by existing literature. Accordingly, this project offers a better understanding of the exceptional challenges associated with diagnostics in the Arctic and proposes a promising solution to mitigate such difficulties.This study will provide a strong basis in evidence for rapid responses to emerging syphilis outbreaks in remote northern regions, by supplementing traditional diagnostic strategies with an RDT to rapidly triage patients likely in need of treatment. The addition of a rapid test provides an opportunity for same-day testing and treatment in order to halt ongoing transmission to benefit individual patients and communities alike. This study will contribute the necessary evidence to inform the development and tailoring of future diagnostic strategies and public health responses to emerging outbreaks in the North as well as to improve current diagnostic responses in remote Arctic regions and beyond where syphilis is currently endemic.S1 Appendix(DOCX)Click here for additional data file.S2 Appendix(DOCX)Click here for additional data file.


Despite considerable improvements in terms of prevention, management, and regulation, air pollution remains a leading environmental health issue worldwide. In 2019, the World Health Organization (WHO) estimated that 99 out of 100 people breathe polluted air and live in places where air quality levels exceed the limits set out by the WHO [2 concentrations  and all-cause mortality for adults living in low-socioeconomic-status areas [However, most studies have either focused on estimating the relationship between pollution and health or the health benefits arising from reduced air pollution. Less attention has been paid to the differential health consequences of air pollution exposure according to socioeconomic status, whether measured at individual and/or neighborhood levels, or over a different lifespan. Yet, it is now well established that social inequalities combined with environmental exposure can increase health risks through two main mechanisms. Firstly, the exposure differential means that the most deprived populations (or people living in deprived areas) are exposed to a higher number of environmental nuisances. Secondly, the vulnerability differential refers to the increasing sensitivity of the most deprived populations when exposed to environmental nuisances (including ambient air pollution exposure). More specifically, it means that socioeconomic status can modify the health consequences of air pollution exposure as a result of either poorer living conditions or reduced access to the healthcare system. In Paris in 2015, Deguen et al. demonstrated a strong association between short-term variations in NOus areas .Alongside this, national plans covering multiple domains  that aim to improve the population’s health fail to consider the health risk differential relating to individual socioeconomic status or the socioeconomics of residential areas. Specifically, the translation of national plans into actions does not integrate differences in implementation according to social disadvantages that could lead to increased social health inequalities. This means that even when an intervention reducing air pollution does lead to health benefits, these benefits are not equally distributed across the population in terms of socio-economic status. Health inequalities are also linked to the organization, management and the use of space , marked by a segmentation that is directly linked to land value and the price of houses. Due to the absence of deliberate social mixing policies, socially segregated blocks are created. These gradually shift towards social invisibility because of social groups’ unequal ability to articulate and assert their interests.x), including NO2, and fine particles (PM10 and PM2.5). Less frequently, other pollutants were used . Only two studies evaluated health interventions as well as environmental impacts [Quantitative Health Impact Assessments (HIAs) stand out as one of the best decision-making policy guidance tools for the design of interventions that support environmental policies aiming to tackle air pollution. HIAs can provide useful and valuable information regarding the future health effects of a potential plan or policy. Several worldwide interventions that aim to reduce air pollution have been implemented and quantitatively evaluated for health impacts. In a recent systematic review of the literature, Burns et al.  identifi impacts . The hea impacts  and mortIn addition, without being based on any actual intervention or action, many other studies have estimated the reduction in premature mortality resulting from a hypothetical reduction in air pollution: a decrease of 1–2% in total annual all-cause mortality in the urban area of Lausanne-Morges in Switzerland  and a deThis Special Issue aims to summarize the current state of affairs in studies quantifying the health benefit of air pollution reduction by population subgroups, according to their socio-economic status. This constitutes the preliminary step that is necessary for the production of a robust dose–response function in socio-economic groups, followed by estimation of health benefits by group.


The Hippo signaling pathway is an evolutionarily conserved network that regulates organ size and tissue homeostasis in mammals. This pathway controls various cell functions, such as growth, proliferation, survival, apoptosis, and stemness by switching 'on' or 'off' its inhibitory and/or transcriptional module, thereby regulating target gene(s) expression. Altered Hippo signaling has been implicated in various forms of cancers. Increasing evidence suggests cross-talk between the Hippo signaling pathway and non-coding RNAs, in particular circular RNAs (circRNAs). In this context, the current review presents the mechanistic interplay between the Hippo pathway and related circRNAs in various forms of cancers, along with the capabilities of these circRNAs to function either as tumor suppressors or oncogenes through miRNA sponging or protein binding mechanisms. Furthermore, we discuss the constraints and limitations in circRNA mechanistic studies while highlighting some outstanding questions regarding the roles of circRNAs associated with the Hippo-YAP pathway in cancer. Finally, we delineate the potential of these circRNAs to be employed as diagnostic and prognostic biomarkers, as well as molecular hotspots for cancer therapy. An evolutionary perspective has shown organ size control as a principal inquisition in the domain of biology since its inception. Despite the substantial research carried out so far, our understanding about how organ sizes are maintained through the course of human development is still fragmented. Progress in addressing this enigma has been made since the discovery of the role of the Hippo pathway in control of organ size, primary cellular processes and auxiliary regulatory mechanisms Drosophila melanogaster, the Hippo pathway is an evolutionary conserved network that regulates organ sizes and tissue homeostasis in mammals Contrary to the conventional ligand-receptor binding observed in many cellular signaling pathways, the Hippo pathway is triggered in response to a wide variety of physical, mechanical and biochemical signals, thus regulating diverse biological processes. First discovered in Non-coding RNAs, including microRNA (miRNA), long-chain non-coding RNA (lncRNA), small interference RNA (siRNA), and circular RNA (circRNA) are known to make up more than 75% of the genome transcripts and regulate various physiological processes during development and tumorigenesis Circular RNAs are largely pre-mRNAs derivatives that are formed as a result of back splicing, unlike linear RNAs that follow the standard canonical splicing process Circular RNAs have been shown to impart functions by regulating various signaling cascades during tumorigenesis Circular RNAs are single-stranded circularized RNA molecules that are generated from linear mRNA as a consequence of back-splicing Likewise, these circularized transcripts have also been found to reciprocally interact with the Hippo-YAP signaling pathway, especially during cancer development and progression The regulatory module of the Hippo signaling pathway consists of kinases, including sterile 20 like kinase 1 and 2 (MST1/ MST2), Large Tumor Suppressor 1 and 2 (LATS1/ LATS2), Salvador homolog 1 (SAV1) and MOB Kinase activator 1A and 1B (MOB1A/ MOB1B) Circular RNAs are known to impart either tumor suppressive The transcriptional module is composed of two closely associated molecular entities i.e., transcriptional co-activator (TAZ) and Yes associated protein (YAP) In cervical cancer, hsa_circ_0023404 has been reported to play an oncogenic role by sponging miR-136 and subsequently modulating YAP1 expression Furthermore, circPVT1 was found to be upregulated in head and neck squamous cell carcinoma. It was also observed to function through miR-497-5p sponging mechanism by targeting YAP/TEAD transcription complex To date, circRNAs have been proposed to function through several molecular mechanisms, including (i) miRNA sponging, (ii) mRNA regulation at both translational and transcriptional levels, (iii) interacting with proteins to form circRNA-protein complexes, and (iv) translation into a peptide or a protein Regulation of genes at the translational level is an important aspect of cancer initiation and progression, which typically involves mRNA circularization and binding of RBPs to the translation initiation complex on mRNA MicroRNAs (miRNAs) are small noncoding RNAs that are usually 22 nucleotides in length. In the cytoplasm, these small non-coding RNAs bind to target mRNAs and induce post-transcriptional silencing Due to the advantages of RNA-sequencing techniques and the advancements of new computational schemes specifically designed for circRNA analysis, increasing studies have screened out circRNA candidates that are potentially functional, and more experiments are in the pipeline to elucidate the roles of circRNAs in various pathologies, including cancer During the past decade, there has been a surge in circRNA-based studies, however, only a limited number of studies reported the cross-talk between the Hippo-YAP signaling pathway and circRNAs in the domain of cancer. Out of these, more than 90% of studies have proposed miRNA sponging for Hippo-YAP regulation by circRNAs in cancer Table . Owing tDysregulated expression of circRNAs has been systematically explored in cervical cancer in vitro as well as in vivo studies Current high-throughput approaches have unveiled a number of circRNAs that are dysregulated in colon cancer tissues Differential expression of various circRNAs has been investigated in various forms of liver related pathologies In vivo functional studies also validated the regulatory function of circCDYL/miR-1180/YAP axis and its potential to be exploited as a therapeutic target in multiple myeloma patients Heterogeneous expression of circRNAs has been explored in multiple myeloma and associated with their diagnostic as well as prognostic potential in vitro and in vivo study models showed a decrease in tumor characteristics, including tumor growth, invasion, and migration. circFAT1 was examined to bind to miR-375, acting as a miRNA sponge to modulate YAP1 expression. Therefore, circFAT1 could potentially be used as a therapeutic target for osteosarcoma Osteogenic differentiation of bone marrow stem cells has been revealed to involve differential expression of circRNAs Circular RNAs have been shown to exert functions during tumor growth, proliferation, invasion, migration, and chemo-sensitivity in Head and Neck Squamous Cell Carcinoma (HNSCC) Thus far, a small number of reports addressing expressional dysregulation of various circRNAs in cholangiosarcoma have been published Studies have outlined the role of numerous circRNAs in regulation of gastric cancer (GC) in vitro and in vivo OSCC models, in which it suppressed proliferation, migration, and invasion while increased apoptosis. Further, circRNA_0000140 was found to carry out these functions by targeting LATS2, a critical component of the inhibitory module of the Hippo signaling pathway, via miR-31 sponging Oral squamous cell carcinoma (OSCC) is one of the most prevalent form of Head and Neck Cancer with reduced overall survival across the globe Being the most prevalent form of cancer in women, crucial roles of different circRNAs have been recognized in breast cancer In the last two decades, a large pool of studies has informed us about the roles of circRNAs in different types of cancers, whereby dysregulated expression of these circRNAs is reported to regulate various molecular entities as well as complex cell signaling cascades During the course of cancer development, histopathological characteristics are predominantly altered as a consequence of changes at molecular levels. Although the functional mechanisms of circRNAs in disease pathogenesis are yet to be completely elucidated, their potential to be used as biomarkers for early cancer diagnosis/prognosis cannot be undervalued. Owing to high tissue specificity and sensitivity, circRNAs may be regarded as promising biomarkers for diagnosis and predicting prognosis in cancer patients. Similarly, various studies have revealed the prognostic power of circRNAs associated with Hippo-YAP pathway and their application as biomarkers in different cancer types where the dysregulated circRNAs have been shown to impact survival outcomes in cancer patients, as depicted in Figure Circular RNAs are resistant to exonuclease digestion owing to the unavailability of 5' and 3' ends in their structure, therefore presenting a longer half-life in comparison to their linear counterparts in vivo testing for subsequent development of circRNA based therapies.For adequate cancer management, the choice of therapeutic regimen primarily relies on the type and/or severity of the cancer. Due to increased diversity, heterogeneity and complex underlying molecular mechanisms, personalized therapies (such as targeted therapies or precision medicine) are essentially needed. Numerous inhibitors targeting YAP, a major oncoprotein of the Hippo pathway, have been described earlier. Nonetheless, whether the Hippo-YAP-interacting circRNAs can serve as potential therapeutic agents or targets is still conditional to the findings of the translational studies in progress, and requires extensive Since circRNAs present altered expression profiles in different pathological states in humans, their expression levels can help emphasize their value as therapeutic modulators Over the span of the last few decades, there have been thorough studies on the Hippo signaling pathway in mammals, specifically in humans. Intense research has generated a large amount of data about the Hippo-YAP axis and its interplay with various other signaling pathways, as well as regulatory molecular entities, including non-coding RNAs. Of these, there is emerging evidence for the mechanistic regulation of the Hippo signaling pathway by a relatively new class of non-coding RNAs, circRNAs, in the sphere of cancer biology. The current review outlined the functional mechanisms of circRNAs associated with the Hippo pathway in cancer and how these circularized transcripts have the potential to regulate various pathway components that constitute its regulatory (inhibitory) and transcriptional modules. Still, there are a multitude of dimensions that have yet to be explored and several important concerns that have yet to be addressed, as discussed below.First discovered in 2013, hundreds of circRNAs have been profiled for their miRNA sponging capabilitiesin silico to support this idea of interactive networking between circRNA and miRNA.Concerning circRNA binding to target miRNA, the primary constraint that comes up with this mechanism is lack of copy number measurements for both circRNA and miRNA prior to investigating plausible functions. Being already informed about the higher copy number of miRNAs as compared to the circRNAs, it would be imperative to assess circRNA to miRNA ratio in order to add to the authenticity of miRNA sponging as a potential mechanism for circRNA function. Furthermore, the number of binding sites in the target miRNA must also be taken into consideration to validate miRNA sponging as the proposed mechanism for circRNA activity. This is because if the circRNA expression level is low, it might not be able to occupy all the miRNA binding sites to act as a sponge in true sense. Also, if there exist only few binding sites in the target miRNA for the respective circRNA, the circRNA might still not function as a true sponge. In this regard, more precise yet valid methods of elucidating circRNA functions are highly required. However, some questions are highly intriguing and still need further research to be answered satisfactorily. (i) Can miRNA binding efficiently degrade circRNA and affect its half-life? (ii) How significant is the influence of miRNA on circRNA and vice versa? Since miRNA driven circRNA cleavage requires high sequence complementarity between the two, the number of binding sites and circRNA structure may determine the extent of circRNA degradation upon miRNA binding, and thus its half-life. Therefore, it would be interesting to study as to what extent can this regulatory pattern between circRNA and miRNA affect gene expression? These concerns add an additional level of complexity in circRNA-miRNA target-based interaction complexes. Therefore, more analyses are required to be performed experimentally as well as Apart from the interactions based on the number of binding sites, efficiency to sponge with the target miRNA is also influenced by the tertiary structure of a circRNA. Extensive computational analyses have revealed sequence complementarity to be of utmost importance in regard to circRNA binding with the miRNAs, therefore, determining the stability of the interaction, thus formed. Owing to distinctive tertiary structure formed by the circRNAs, their ability to sponge with the target miRNA can actually be more intricate than what has been described earlier. A circRNA may display various tertiary structures in a cell/tissue specific manner. Within a tertiary structure, these circRNAs may appear to be consisting of a stem loop at one point and/or an imperfectly paired RNA duplex at another, whereby, the binding sites present in the circRNA can exhibit highly diverse sequences with varying complementary. Likewise, single stranded fragment of circRNA may facilitate miRNA sponging to a larger degree as compared to the segment which is already double stranded. Therefore, in order to discern miRNA sponging as a capable mechanism for circRNA function, it is critical to elucidate as to (i) Which part of the circRNA tertiary structure does a complementary miRNA sequence specifically bind to? (ii) How and to what extent does a circRNA tertiary structure affect circRNA-miRNA interaction? (iii) If this complementary binding between miRNA-circRNA forms a stable interaction? (iv) Does circRNA sponging with miRNA explicitly rely on number of binding sites, circRNA tertiary structure, or both? (v) Can a miRNA have multiple varying complementary sequences in the binding circRNA partner? (vi) Can circRNA junctions serve as potential regions of complementary miRNA binding? and (vii) How enriched are circRNAs for miRNA binding sites and vice versa? In order to address these concerns, identification of the circRNA fragment with the highest sequence complementarity for its miRNA binding partner is an aspect that necessitates further research in the field of circRNA biology. Regarding this, we propose the use of RNA pull down technology to bring the circRNA down and the miRNAs that can potentially bind to that circRNA. Nevertheless, this may also pull down various other miRNAs with partial or incomplete complementarity to the circRNA. Therefore, use of adequate controls may help optimize the experimental procedures in a way that enhances the specificity of the RNA-pull down assay and makes circRNA 3D structural dynamics apprehensible.CircRNAs can perform different regulatory functions depending on their presence in the cytoplasm or nucleus. Nuclear circRNAs can play roles in controlling the first part of the central dogma i.e., transcription, while cytoplasmic circRNAs can regulate its second component i.e., translation and post-translation. The following subsections discuss the importance of circRNAs related to Hippo-YAP axis in regulating transcription, translocation, and translation, while highlighting relevant considerations and outstanding questions.Besides miRNA sponging, circRNAs can also efficiently bind to RNA Binding Proteins (RBPs). This binding may not only halt protein function but also induce conformational changes in protein structure, thus modulating their activities. Our lab previously reported the capability of circFOXO3 to bind to p21 and CDK2 proteins, forming a ternary structure that retards cell cycle progression Circular RNAs have been demonstrated to regulate both transcription and translation. Unlike other non-coding RNAs, these circularized transcripts can usually exert their transcriptional effects at cis-domain YAP/TAZ nucleo-cytoplasmic shuttling is a crucial event in Hippo pathway activity. Since circRNAs have been reported to regulate protein translocation, they could also be implicated in modulating YAP/TAZ function serving as an intermediary for nucleus and cytoplasm in tumorigenesis. Generally, nuclear transportation is carried out by importins and requires a protein to have a NLS . Thus, the question arises if there are any circRNAs that possess the potential to regulate YAP/TAZ nucleo-cytoplasmic shuttling? If yes, (i) What underlying mechanisms do these circRNAs follow that allow them to interact with the protein and bring about its translocation? (ii) Does circRNA mediated YAP/YAZ nuclear translocation occur through importins as well? and (iii) Does this circRNA arbitrated shuttling of YAP into the nucleus require the NLS label? These are some of the research questions that need to be rigorously investigated in future studies.6-methyladenosines (m6A)-mediated cap-independent translation in-vivo are the major limitations discerned so far. Moreover, there are only nominal reports to have profiled circRNA translation into peptides under natural conditions. These questions, if answered adequately, would assist in understanding the translation of circRNAs and their protein functions within the cell in a more comprehensive manner.Until recently, circRNAs were always considered to be non-coding molecular entities. During the course of last few years, however, studies have indicated the potential of circRNAs to be effectively translated into distinguishable peptides Thus far, the review paper has primarily emphasized the regulation of the Hippo pathway by associated circRNAs in driving tumorigenesis through intricate molecular mechanisms. Meanwhile, if there is any potential mechanism of feedback regulation of these circRNAs or any other endogenous circRNAs by the Hippo signaling pathway is a niche that still remains to be elucidated in cancers and in general. Mechanistic implications of the Hippo pathway components in regulating circRNA expression and function in disease development and progression are discussed in the following section:Initially, circRNAs were considered as by-products of erroneous splicing and hardly caught the due scientific attention until the advancement of RNA sequencing and computational technologies. Currently, they are no longer considered as mere spliced out intronic sequences but can contain exonic sequences as well. In fact, some circRNAs are abundantly expressed. Since circRNAs exhibit cell- and tissue-specific expression It is through the transcriptional loop that the Hippo pathway exerts its functional activities Although there has been convincing evidence on the modulation of the Hippo signaling pathway by these circRNAs in cancer, nevertheless, expanded research is still necessitated to be carried out on the role of circRNAs in the Hippo pathway regulation. Moreover, there are a number of concerns that must be addressed in future studies. Firstly, additional research is required to be carried out to unveil novel circRNAs associated with the Hippo-YAP signaling pathway in cancer. Thus far, few studies have examined the interplay between circRNAs and the Hippo signaling pathway. Secondly, more work is needed to address the functional mechanisms of circRNAs in various forms of cancer.Elucidation of functional mechanisms of the host gene in conjunction with their circRNAs is lacking in specific forms of cancer. Therefore, cell/ tissue specificity of both the circRNA and its host gene must also be assessed in parallel to describe any possible function in specific cancer types. Furthermore, the Hippo signaling pathway is an extremely important developmental pathway associated with organogenesis and tissue homeostasis. Thus, any circRNA associated with this vital pathway may hold varying functions during different stages of organ development or cancer progression. Therefore, long term studies involving the assessment of circRNA expression and its subsequent function at different time points should be done to acquire insight into circRNA activity during cancer progression. Additionally, the regulatory feedback loops between the upstream signals/ downstream Hippo pathway components and the related circRNAs also require investigation.Moreover, YAP/TAZ have also been shown to induce epigenetic modifications and regulate chromatin remodeling by interacting with various proteins, thus altering chromatic structure in different pathological states, including cancer. Knowing that circRNAs are the epigenetic signatures associated with cancer progression, it would be interesting to study their possible interactions with YAP/TAZ in bringing about or mitigating their chromatin remodeling effects in cancer. Also, circRNAs have been reported to be methylated. It would, therefore, be intriguing to study the epigenetics status of these circRNAs associated with the Hippo signaling pathway and uncover their mechanistic potential in driving carcinogenesis in humans.Given that circRNAs are readily detectable in biological specimens from cancer patients, they have the potential to be used as prognostic/ diagnostic markers and therapeutic targets or agents in cancer. However, off-targeting is a limitation of using circRNAs as therapeutic modulators in cancer, as a particular circRNA might be therapeutic in one tissue type while pathogenic in the other.Moreover, there are several studies that assess the functions of various Hippo pathway related circRNAs in other forms of diseases. Investigating the role of these circRNAs in different types of cancer may also uncover a novel mechanism for circRNA function in tumorigenesis. There are several circRNAs that have been widely implicated in cancer progression, however, these have not been studied in regards to their possible interplay with the Hippo signaling pathway. Discovering these molecular cross-talks and bringing new insights into circRNA-mediated Hippo pathway regulation or Hippo signaling modulation of circRNA function can help in understanding the role of these circRNAs from structural as well as functional perspectives.in vivo validation through translational studies. Considering the regulatory potential of circRNAs, it would be imperative to use these circRNAs as therapeutic modulators. We speculate that circRNAs that act through miRNA sponging might not be efficacious in therapeutic management of cancer owing to their off-targeting effects. However, the circRNAs that follow protein binding mechanism for their activity or act as translational regulators may serve as potential targets for controlling protein expression and function. Additionally, the circRNAs that play role as transcriptional regulators, and are associated with the gene promoter region can be thought of as the most reasonable targets due to their ability to bind to mRNA directly. Furthermore, we presume that using small oligonucleotides that target and bind to circRNA is relatively more appropriate and less complicated than discovering a whole new molecule that retards protein function.As of now, there are quite a few inhibitors/ therapeutic modulators available that target components of the Hippo signaling pathway, nonetheless, if the circRNAs associated with the pathway can be exploited as a subtle therapeutic approach in combating cancer, still requires lot of research and


Broad repertoire autoreactivity may reflect the chances of generating autoreactivity by stochastic use of germline immunoglobulin gene segments or active mechanisms may select autoreactive cells during egress to the naïve peripheral B cell pool. Likewise, it is unclear why in some individuals autoreactive B cell clones become activated and drive pathophysiologic changes in autoimmune diseases. Both of these remain central questions in the study of the immune system(s). In most individuals, autoimmune diseases arise from complex interplay of genetic risk factors and environmental influences. Advances in genome sequencing and increased statistical power from large autoimmune disease cohorts has led to identification of more than 200 autoimmune disease risk loci. It has been observed that autoantibodies are detectable in the serum years to decades prior to the diagnosis of autoimmune disease. Thus, current models hold that genetic defects in the pathways that control autoreactive B cell tolerance set genetic liability thresholds across multiple autoimmune diseases. Despite the fact these seminal concepts were developed in animal  models of autoimmune disease, some perceive a disconnect between human risk alleles and those identified in murine models of autoimmune disease. Here, we synthesize the current state of the art in our understanding of human risk alleles in two prototypical autoimmune diseases – systemic lupus erythematosus (SLE) and type 1 diabetes (T1D) along with spontaneous murine disease models. We compare these risk networks to those reported in murine models of these diseases, focusing on pathways relevant to anergy and central tolerance. We highlight some differences between murine and human environmental and genetic factors that may impact autoimmune disease development and expression and may, in turn, explain some of this discrepancy. Finally, we show that there is substantial overlap between the molecular networks that define these disease states across species. Our synthesis and analysis of the current state of the field are consistent with the idea that the same molecular networks are perturbed in murine and human autoimmune disease. Based on these analyses, we anticipate that murine autoimmune disease models will continue to yield novel insights into how best to diagnose, prognose, prevent and treat human autoimmune diseases.Most B cells produced in the bone marrow have some level of autoreactivity. Despite efforts of central tolerance to eliminate these cells, many escape to periphery, where in healthy individuals, they are rendered functionally non-responsive to restimulation through their antigen receptor  Upwards of 75% of bone marrow produced B cells express B cell antigen receptors (BCRs) that bind self-antigen –8. SeverThere are obvious (and non-obvious) differences and drawbacks inherent in extrapolating principles to human pathologies from animal model systems . NeverthHere we synthesize the recent advances in our understanding of the complex genetic basis of two paradigmatic human B-cell dependent autoimmune diseases: Systemic Lupus Erythematosus (SLE) and Type 1 Diabetes Mellitus (T1D). SLE is the prototypical protean multi-system autoimmune disease, whereas type 1 diabetes is the prototypical organ-specific autoimmune disease invariably leading to pancreatic beta-cell destruction. Importantly, both of these disease states have long been modeled with mouse strains that spontaneously develop disease features that closely resemble several of the key phenotypes and pathophysiologies of the human diseases being modeled. Because of the long history of investigation of the cellular and molecular mechanisms of these models, we expect that models of these two diseases are likely to have a more complete list of the genetic contributors and understanding of the relevant cellular and molecular mechanisms leading to murine autoimmune disease.To address this overlap, we also synthesize what is known regarding the function of putative causal genes across murine models of both systemic autoimmune pathologies (SLE and T1D) and autoreactive B cell tolerance. We discuss several plausible potential explanations for the non-monotonic relationship between currently known human and murine autoimmune risk alleles. Through this analysis, we show that the molecular networks comprised of putative human and murine risk alleles for B-cell dependent autoimmunity and autoimmune pathology substantially overlap. Finally, we propose a framework for steps toward more successful translation of findings from murine model systems to clinical application in humans.at most 40-50% but likely substantially lower for both diseases (In humans both SLE and T1D have heritable component with sibling recurrence risk ratios (lambda S) indicating a substantive genetic contribution  . Both ardiseases . Thus, fdiseases  and in Tdiseases .In terms of epidemiology, SLE is both more prevalent and more severe in several populations of predominately non-European ancestry than in populations with European ancestry . A recenIn terms of epidemiology, T1D is reported to be more prevalent in persons who self-identify as non-Hispanic white, followed by non-Hispanic black, Hispanic and other racial/ethnic identities (0.35 to 2.55 per 1 000) with approximately equal prevalence in boys and girls in the US (1.93 per 1 000) . T1D incWhen taken together with the observations that different geographies have different rates of autoimmune diseases  and autoSeveral environmental factors have been associated with SLE, including smoking, silica exposure, exogenous sex hormones and infection, especially prior Epstein-Barr virus infection , 97. SimIn sum, both SLE and T1D in humans are complex diseases where both genetic and environmental factors contribute both to disease development and disease manifestations.Both SLE and autoimmune type 1 diabetes pose practical challenges in disease definition, diagnosis and classification that should be considered when evaluating the utility and applicability of any disease model. One cannot evaluate whether a model recapitulates human disease pathogenesis if the definition of disease is unclear.The particular nomenclature of autoimmune type 1 diabetes may strike the reader as oddly redundant, but it makes the point that type 1 diabetes is a clinical diagnosis. This diagnosis is made in part through typical seropositive autoimmunity to several pancreatic islet expressed proteins   in the sBy the same token, SLE is a clinical diagnosis. In order to develop homogeneous patient populations for clinical studies, several iterations of classification criteria have been developed –115. TheC4A & C4B) gene copy number  and they each have a small effect, then selective pressure would not be expected to be strong in individuals with polygenic autoimmune disease. By way of analogy, being related to someone who wins the lottery does not make winning the lottery more likely for you, unless you buy more lottery tickets. On the other hand, many monogenic disease genes represent either de novo mutations or recent founder effects. Therefore, monogenic mutations have not had a very long to be subject to natural selection. These observations when combined with theoretical frameworks describing the balance between host collateral damage from immune responses and microbe clearance  in the n vitro , but wasn vitro –226. WhiSeveral criticisms of mouse models of human autoimmune pathologies specifically and human disease writ large  have been raised . SOne major criticism that has been raised for why mouse models of human autoimmune disease are ‘lousy’ is failures in translation from experimental autoimmune/allergic encephalomyelitis into successful therapy for multiple sclerosis. However, we would submit that careful attention to both the details of the murine and human pathology and careful reexamination of models in light of the clinical, phenotypic, cellular and molecular features of the human diseases we seek to model would have predicted successful therapeutic targets even in this ‘lousiest’ of autoimmune disease models.vice versa has an aggregate effect of reducing the influence of potential confounders. In so doing this approach would be expected to lead to a more accurate model autoimmune etiopathogeneis than either approach would have been able to do on its own  that are central regulators of T lymphocyte development in monogenic T1D. Close inspection of these networks shows that they do not overlap at AIRE. This lack of overlap highlights one of the drawbacks of the automated, algorithmic approach to putative causal gene definition. A rare variation in AIRE, rs74203920, was recently reported in a large GWAS of human autoimmune type 1 diabetes , BCR signaling , tolerance response to nucleic acid , tolerance to self-nucleic acid and control of viral infection. These overlaps serve as unifying pathways in these models of autoimmune pathology , TLR7 isOne question that arises is whether these associations represent an increase over what would be expected by chance. Indeed, overlap between the gene networks in type 2 diabetes  and osteWhat are the explanations for challenges in translatability of autoimmune disease mouse models?We have discussed spontaneous, induced and humanized murine autoimmune disease models above in general terms. Here we focus on key potential differences that in our estimation are likely to affect several spontaneous models of lupus, such as those derived from the NZB/NZW F1 (BW) mice and the NOD mouse model of type 1 diabetes.Nnt, the gene encoding for the nicotinamide nucleotide transhydrogenase  and URAT1 and important renal uric acid transporter. As this system non-redundantly regulates blood pressure, it stands to reason that changes across similarly complex immune networks could have also developed differences in some critical regulatory genes. Indeed, many immune phenotypes that diverge between mice and humans have been described . Two selh humans .While humans are housed in varied circumstances, housing of mice is somewhat uniform. Environmental enrichment (EE) makes mouse housing more “fun” and leads to reductions in a variety of depressive/anxious behaviors and indicators of stress response in mice . At the When given the option, mice, like humans tend to inhabit places with comfortable ambient temperature or change their environment to maintain their own core temperature in the thermoneutral zone. Humans do this by wearing clothes, whereas mice tend to fill their burrows with bedding and insulation. Observation of mice in the wild indicates that during their light cycle, mice tend to maintain a thermoneutral zone of 30-32 degrees Celsius. For historical reasons and for the comfort of clothed humans, most mouse facilities house mice at room temperature 19-25 degrees Celsius. Thus, mice are subjected to chronic “cold stress” which carries with it attendant increased sympathetic nervous system/beta-adrenergic tone and changes in whole organism metabolism and physiology . RemovalMice are typically handled in the vivarium during daylight hours, a period during which they commonly sleep in the wild. Several autoimmune diseases are associated with sleep disturbance  due to ivice versa. This may be another important meta-genomic divergence that leads to non-correspondence of murine models of human disease  all distinguish human from murine skin , EBV infection in humans is associated with SLE. There are mechanistic links implicating molecular mimicry by EBNA-1  and subsIn this section we point out some differences to consider when interpreting murine model data in light of human autoimmune pathology. There are several features of humans that make modeling an inherently error-prone process. These complicating features are in addition to the potential intractability of understanding gene X environment interactions, if the omnigenic model proves true. Despite these drawbacks, murine models of autoimmune diseases have advanced our understanding of the gene networks that regulate autoimmune pathologies. At the same time, efforts at translation require both careful attention to potential confounders and continual reexamination of our models in light of the clinical, phenotypic, cellular and molecular features of the human diseases we seek to model.Simply put, the need for improved understanding and more diverse and less toxic therapeutic options for SLE and Type 1 diabetes is dire. The discrepant severity of SLE outcomes between populations simply cannot be accepted in a just society. To the extent that our lack of understanding contributes to this discrepancy, it needs to be corrected. In a similar manner, Type 1 diabetes disproportionately afflicts some of the most vulnerable members of our society with a burden of chronic disease and a concomitant burden of co-morbidity and mortality. Despite life-saving advances in therapy in the prior decades, the incidence of this disease is rising. So, we must better understand its genesis in order to more effectively intervene.We need to understand disease mechanisms and define causal genetic immunophenotypes in humans. For this understanding to be certain regarding causal relationships, parallel understanding of mechanism in model systems is required for effective trial design. Mice have proven to be excellent sacrificial companions on our collective journey of disease deconstruction for both SLE and T1D. They have facilitated perturbations of genes and environmental triggers, allowing assessment of the impacts on murine intermediate immune cellular and molecular phenotypes and correlates of pathology. It continues to be prudent to advance therapies that can prove efficacy in these model systems along the path toward clinical application. However, careful attention to the details of both the model system and the disease processes being modeled is necessary to fully evaluate both therapeutic candidate successes and failures. Nearly 90% of trialed pharmaco-therapeutic candidates do not advance to the FDA approval . These rin vitro (cell lines), ex vivo (primary cells) or in vivo (hu-mice) reductionist model systems and shown to return the cellular/molecular phenotypes and pathologic correlates move to a healthier status with any therapeutic lead. Therapies that pass this bar could be trialed in first in human trials after primate evaluation or if repurposing , moved directly to phase 3 trials. Human trials based on the cellular, molecular and pathologic frameworks derived from model systems would need to include assessment of correlates of the postulated mechanism. Additionally, evaluation of any competing mechanisms would assist post-hoc evaluation of whether a given trial represented a true trial of therapy. Indeed, two recent (the first two since the 1950s) FDA-approved therapies for SLE, belimumab (anti-BAFF) and anifrolumab (anti-IFNAR1), both took approaches similar to the approach that we lay out. Following identification of antigen-presentation by B cells  Project was supported by the Common Fund of the Office of the Director of the National Institutes of Health, and by NCI, NHGRI, NHLBI, NIDA, NIMH, and NINDS. The data used to support the claim that BLK eQTLs occur in fibroblasts were obtained from the GTEx Portal resource , human presource  was usedIH is partly funded by the Pfizer Global Grants Foundation Rheumatology program #51849703, but those funds did not support his work on this project.The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.The contents of this manuscript do not represent the views of the U.S. Department of Veterans Affairs or the United States Government.


The violent nature of generalized tonic-clonic seizures puts individuals at risk of a large number of potential injuries. These can occur due both to the profound muscular contractions that accompany these episodes as well as falls and other traumatic events that occur due to the period of loss of consciousness that occurs during generalized seizures. While injuries such as soft tissue contusions, tongue biting, dental injuries, and facial lacerations resulting from falls from standing predominate, bony injuries are not uncommon. We present a case of bilateral scapular fractures that occurred in an otherwise healthy 32-year male who presented with shoulder and back pain and inability to perform any significant movement of his upper arms secondary to pain after experiencing an apparent first-time generalized tonic-clonic seizure. The presence of unilateral and bilateral scapular fractures, while uncommonly described, should be considered as an additional potential orthopedic injury that may occur secondary to a generalized tonic-clonic seizure. In the absence of observed significant forceful traumatic injury, this injury is unusual, and its presence noted in a patient experiencing sudden loss of consciousness should raise heightened concern of seizures as the potential etiology. There exists the potential for injury accompanying generalized tonic-clonic seizure activity due to both the strong muscular contractions that define these episodes in addition to the lack of natural protective behaviors one might typically rely upon to lessen injuries occurring from falls during this period of loss of consciousness. Loss of shoulder mobility following a generalized tonic-clonic seizure should lead clinicians to evaluate for the potential for anterior as well as the classically described posterior shoulder dislocation. In the absence of a glenohumeral dislocation, other injuries involving the shoulder girdle, including scapular fracture, should be considered. We present a case of bilateral scapular fractures in an otherwise healthy young male following a new onset generalized seizure.A 32-year-old male with a history of depression, taking solely bupropion, presented to the Emergency Department (ED) due to an episode of loss of consciousness and inability to lift his arms. He was communicating via computer with others when he sensed a brief uneasy feeling followed by abrupt loss of consciousness. Individuals conversing with him online described retching sounds, fast and irregular breathing, and then absent patient communication for approximately thirty minutes. After this time, he was described to have slurred and nonsensical speech followed by a gradual return to his baseline mental status. Upon regaining consciousness, the patient noted he was on the floor next to his ground level chair. While able to use his hands to operate his phone, he had otherwise limited range of motion and significant pain and limited range of motion of his upper extremities.Upon ED presentation, he demonstrated a clear sensorium and complained solely of severe bilateral shoulder and upper back pain. Vital signs included a temperature of 98.9 Fahrenheit, blood pressure of 160/89 mmHg, pulse of 107 beats per minute, and a pulse oximetry of 96%. There was no external evidence of trauma aside from a small contusion under his left eye. Shoulder range of motion was limited due to pain. Upper extremity sensation, peripheral pulses, and forearm and hand strength were normal. Laboratory studies including a urine drug screen were unremarkable. Plain radiographs of the shoulders showed an intact glenohumeral joint with a suspected left-sided scapular body fracture . A subseTraumatic injuries in patients with epilepsy are not uncommon, occurring in 23% of individuals within the first 2 years of their diagnosis . LongituThe significant musculature contraction occurring during the tonic phases of seizures is of greatest force in the axial and proximal extremity muscle groups that may lead to fractures that occur unrelated to those occurring from direct impact trauma. These common injuries include anterior and posterior shoulder dislocations and fractures, thoracic and lumbar compression fractures, and proximal femur and acetabular fractures . While pWhile seizures are the etiology for nearly one-third of posterior shoulder dislocations, unilateral and bilateral scapular fractures are infrequently reported outside of the setting of high energy trauma. A review of 17 patients with bilateral scapular fractures described 6 patients without associated high impact trauma of which 2 were due to seizure and 4 were secondary to electrical shock –10. AssoPlain radiographs may be considered initially for those patients in which glenohumeral dislocation is considered the most likely diagnosis. However, identifying scapular fractures on plain film radiography may be challenging, missing up to 43% of fractures in patients suffering from traumatic injuries . SeizureScapular fractures should be considered as a potential etiology for shoulder and upper back pain following seizure activity. Additionally, the presence of this injury following loss of consciousness in the absence of significant trauma should prompt the clinician to consider seizures as a precipitant event.


Enabling individual and collective participation or vulnerable people in health and social care is fundamental to achieving equitable, people-centered care. However, for vulnerable groups and clients, unfolding opportunities for participation in their care is closely related with experiences of empowerment and disempowerment. The workshop focuses on primary health and long-term care, as those are the pillars of resilient health care systems able to meet the complex care needs of vulnerable people. From a public health perspective, the facets of participation range from providing access to comprehensive services for people in need, to developing a shared understanding between clients and health professionals regarding clients’ everyday and care preferences, to sharing decision-making on health and care matters. In this workshop, we will discuss how helpful public health interventions between individual, professional and systemic-structural approaches should or could be designed, to (better) enable participation of vulnerable groups in primary and long-term care. The workshop presentations draw on empirical research with members of vulnerable groups, health professionals and key informants in care policy and practice conducted in Brazil, Germany, India, and Spain. By focusing on different primary and long-term care settings as well as vulnerable groups  we will address and discuss the following questions:• What ideas can we find to strengthen participation of vulnerable groups in primary and long-term care settings?• Which opportunities and barriers are involved?• How can individual, professional, and structural approaches ‘fit together’ to enable greater participation of vulnerable groups in their (self-)care?• Practitioners’ efforts to enable participation have to be accompanied by qualification- and governance-oriented public health approaches to achieve patient oriented health and social care systems.• Present barriers and opportunities for vulnerable groups are instructive indicators for broader challenges towards comprehensive people-centered care.


Acute myeloid leukaemia (AML) is a highly proliferative cancer characterised by infiltration of immature haematopoietic cells in the bone marrow (BM). AML predominantly affects older people and outcomes, particularly in this difficult to treat population remain poor, in part due to inadequate response to therapy, and treatment toxicity. Normal haematopoiesis is supported by numerous support cells within the BM microenvironment or niche, including adipocytes, stromal cells and endothelial cells. In steady state haematopoiesis, haematopoietic stem cells (HSCs) primarily acquire ATP through glycolysis. However, during stress-responses HSCs rapidly transition to oxidative phosphorylation, enabled by mitochondrial plasticity. Historically it was thought that cancer cells preferentially used glycolysis for ATP production, however recently it has become evident that many cancers, including AML primarily use the TCA cycle and oxidative phosphorylation for rapid proliferation. AML cells hijack the stress-response pathways of their non-malignant counterparts, utilising mitochondrial changes to drive expansion. In addition, amino acids are also utilised by leukaemic stem cells to aid their metabolic output. Together, these processes allow AML cells to maximise their ATP production, using multiple metabolites and fuelling rapid cell turnover which is a hallmark of the disease. This review of AML derived changes in the BM niche, which enable enhanced metabolism, will consider the important pathways and discuss future challenges with a view to understanding how AML cells are able to hijack metabolic pathways and how we may elucidate new targets for potential therapies. AML is characterised by the malignant transformation of haematopoietic cells, which reside in the BM and ‘take over’ the environment of healthy haematopoietic stem and progenitor cells . AML is One area of study is the metabolic changes that occur in the leukaemic BM niche. The BM is a structurally complex organ of blood vessels and a heterogeneous population of haematopoietic cells as well numerous support cells, including mesenchymal stromal cells (MSC), adipocytes, endothelial cells and osteoblasts . This crA key function of HSCs is their ability to rapidly respond to external stress such as bleeding or infection and to increase their energy production in order to support rapid HSC expansion and production of mature blood cells. To achieve this, HSCs can transition rapidly to oxidative phosphorylation (OXPHOS) by acquiring mitochondria from BM stromal cells and increasing the uptake of other metabolites such as free fatty acids (FFA) and amino acids –12. We aHaematopoiesis occurs within the BM niche, a supportive microenvironment that helps to regulate maintenance of HSCs and progenitor populations as well as blood cell production . Blood cThe complexity of the supportive BM niche is illustrated in via the transfer of mitochondria from BM stromal cells to HSCs via Connexin 43 Gap Junctions  and was supported by the NNUH charitable fund. The work was supported from the MRC project grant SAR (MR/T02934X/1).The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.