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Abstract Background Oral immunotherapy (OIT) has become the standard of care for children with food allergy (FA) and has substantially improved their quality of life. The effect of OIT on the quality of life in adults, however, has been studied to a much lesser degree. Methods Patients with food allergy aged ≥ 18 years who underwent OIT at Shamir Medical Center completed the Food Allergy Quality of Life Questionnaire-Adult Form (FAQLQ-AF) before and at the end of treatment. Adults with FA not undergoing OIT who completed the FAQLQ-AF at 2 time points, served as controls. Results A total of 44 adults, median age 23.4 years, who underwent OIT for milk (n = 19), egg (n = 2), peanut (n = 9), sesame (n = 6), and tree nuts (n = 8), and 11 controls were studied. The median OIT starting dose was 23.8 mg protein. 33 patients (75%) reached full desensitization within a median of 10.3 months. The FAQLQ-AF baseline scores were comparable between the study and control groups for all items except for Food Allergy related Health (FAH) item in which the study group had a significantly better score (p = 0.02). At the second time point, the study group had significantly better scores in all items (Allergen Avoidance and Dietary Restrictions (AADR), p = 0.02; and Emotional Impact (EI), Risk of Allergen Exposure (RAE), FAH and the Total Score, p

We thank Frey et al. for their response to our manuscript as we think this provides an excellent opportunity for further dialogue regarding the effects of plague on wildlife populations and the difficulties in interpreting and explaining how this disease system may function under natural conditions. Herein, we will attempt to directly address some of the criticisms of Goldberg et al. 2022b. We may have been remiss in not providing sufficient detail on the history of our experimental design, which could have led to misconceptions. The criticisms helped point out such weaknesses and we are thankful for the opportunity to address them here.

Abstract Pervasive SARS-CoV-2 infections in humans have led to multiple transmission events to animals. While SARS-CoV-2 has a potential broad wildlife host range, most documented infections have been in captive animals and a single wildlife species, the white-tailed deer. The full extent of SARS-CoV-2 exposure among wildlife communities and the factors that influence wildlife transmission risk remain unknown. We sampled 23 species of wildlife for SARS-CoV-2 and examined the effects of urbanization and human use on seropositivity. Here, we document positive detections of SARS-CoV-2 RNA in six species, including the deer mouse, Virginia opossum, raccoon, groundhog, Eastern cottontail, and Eastern red bat between May 2022–September 2023 across Virginia and Washington, D.C., USA. In addition, we found that sites with high human activity had three times higher seroprevalence than low human-use areas. We obtained SARS-CoV-2 genomic sequences from nine individuals of six species which were assigned to seven Pango lineages of the Omicron variant. The close match to variants circulating in humans at the time suggests at least seven recent human-to-animal transmission events. Our data support that exposure to SARS-CoV-2 has been widespread in wildlife communities and suggests that areas with high human activity may serve as points of contact for cross-species transmission.

Introduction: Colorectal cancer is increasingly diagnosed in people aged

Abstract INTRODUCTION Smartphones are proving useful in assessing movement and speech function in Alzheimer's disease and other neurodegenerative conditions. Valid outcomes across different smartphones are needed before population‐level tests are deployed. This study introduces the TapTalk protocol, a novel app designed to capture hand and speech function and validate it in smartphones against gold‐standard measures. METHODS Twenty different smartphones collected video data from motor tests and audio data from speech tests. Features were extracted using Google Mediapipe (movement) and Python audio analysis packages (speech). Electromagnetic sensors (60 Hz) and a microphone acquired simultaneous movement and voice data, respectively. RESULTS TapTalk video and audio outcomes were comparable to gold‐standard data: 90.3% of video, and 98.3% of audio, data recorded tapping/speech frequencies within ± 1 Hz of the gold‐standard measures. DISCUSSION Validation of TapTalk across a range of devices is an important step in the development of smartphone‐based telemedicine and was achieved in this study. Highlights TapTalk evaluates hand motor and speech functions across a wide range of smartphones. Data showed 90.3% motor and 98.3% speech accuracy within +/–1 Hz of gold standards. Validation advances smartphone‐based telemedicine for neurodegenerative diseases.

Abstract Background Dementia prevalence is predicted to triple to 152 million globally by 2050. Alzheimer’s disease (AD) constitutes 70% of cases. There is an urgent need to identify individuals with preclinical AD, a 10–20-year period of progressive brain pathology without noticeable cognitive symptoms, for targeted risk reduction. Current tests of AD pathology are either too invasive, specialised or expensive for population-level assessments. Cognitive tests are normal in preclinical AD. Emerging evidence demonstrates that movement analysis is sensitive to AD across the disease continuum, including preclinical AD. Our new smartphone test, TapTalk, combines analysis of hand and speech-like movements to detect AD risk. This study aims to [1] determine which combinations of hand-speech movement data most accurately predict preclinical AD [2], determine usability, reliability, and validity of TapTalk in cognitively asymptomatic older adults and [3], prospectively validate TapTalk in older adults who have cognitive symptoms against cognitive tests and clinical diagnoses of Mild Cognitive Impairment and AD dementia. Methods Aim 1 will be addressed in a cross-sectional study of at least 500 cognitively asymptomatic older adults who will complete computerised tests comprising measures of hand motor control (finger tapping) and oro-motor control (syllabic diadochokinesis). So far, 1382 adults, mean (SD) age 66.20 (7.65) years, range 50–92 (72.07% female) have been recruited. Motor measures will be compared to a blood-based AD biomarker, phosphorylated tau 181 to develop an algorithm that classifies preclinical AD risk. Aim 2 comprises three sub-studies in cognitively asymptomatic adults: (i) a cross-sectional study of 30–40 adults to determine the validity of data collection from different types of smartphones, (ii) a prospective cohort study of 50–100 adults ≥ 50 years old to determine usability and test-retest reliability, and (iii) a prospective cohort study of ~1,000 adults ≥ 50 years old to validate against cognitive measures. Aim 3 will be addressed in a cross-sectional study of ~200 participants with cognitive symptoms to validate TapTalk against Montreal Cognitive Assessment and interdisciplinary consensus diagnosis. Discussion This study will establish the precision of TapTalk to identify preclinical AD and estimate risk of cognitive decline. If accurate, this innovative smartphone app will enable low-cost, accessible screening of individuals for AD risk. This will have wide applications in public health initiatives and clinical trials. Trial registration ClinicalTrials.gov identifier: NCT06114914, 29 October 2023. Retrospectively registered.

Uhl anomaly is characterized by the morphologic absence of right ventricular myocardium and is an exceedingly rare cause of nonischemic cardiomyopathy. We report the first case of a successful heart transplantation in a 41-year-old patient who presented in cardiogenic shock from Uhl anomaly causing decompensated right ventricular failure.

Abstract Background Some microbiota compositions are associated with negative outcomes, including among others, obesity, allergies, and the failure to respond to treatment. Microbiota manipulation or supplementation can restore a community associated with a healthy condition. Such interventions are typically probiotics or fecal microbiota transplantation (FMT). FMT donor selection is currently based on donor phenotype, rather than the anticipated microbiota composition in the recipient and associated health benefits. However, the donor and post-transplant recipient conditions differ drastically. We here propose an algorithm to identify ideal donors and predict the expected outcome of FMT based on donor microbiome alone. We also demonstrate how to optimize FMT for different required outcomes. Results We show, using multiple microbiome properties, that donor and post-transplant recipient microbiota differ widely and propose a tool to predict the recipient post-transplant condition (engraftment success and clinical outcome), using only the donors’ microbiome and, when available, demographics for transplantations from humans to either mice or other humans (with or without antibiotic pre-treatment). We validated the predictor using a de novo FMT experiment highlighting the possibility of choosing transplants that optimize an array of required goals. We then extend the method to characterize a best-planned transplant (bacterial cocktail) by combining the predictor and a generative genetic algorithm (GA). We further show that a limited number of taxa is enough for an FMT to produce a desired microbiome or phenotype. Conclusions Off-the-shelf FMT requires recipient-independent optimized FMT selection. Such a transplant can be from an optimal donor or from a cultured set of microbes. We have here shown the feasibility of both types of manipulations in mouse and human recipients. Video Abstract

We evaluated the invasion of plague bacteria Yersinia pestis into a population of black-tailed prairie dogs (Cynomys ludovicianus; BTPDs) in South Dakota. We aimed to ascertain if Y. pestis invaded slowly or rapidly, and to determine if vector (flea) control or vaccination of BTPDs assisted in increasing survival rates. We sampled BTPDs in 2007 (before Y. pestis documentation), 2008 (year of confirmed invasion), and 2009 (after invasion). We estimated annual BTPD re-encounter rates on three 9-ha plots treated annually with deltamethrin dust for flea control and three 9-ha plots lacking dust. In 2007 and 2008, approximately half the adult BTPDs live-trapped were injected subcutaneously with either an experimental plague vaccine (F1–V fusion protein) or placebo formulation; the remaining individuals were not inoculated. From 2007 to 2009, we sampled 1559 BTPDs on 2542 occasions. During 2007–2008, the prevalence and intensity of fleas on BTPDs were 69–97% lower on the dusted vs. no dust plots. From 2007 to 2008, the annual re-encounter rate of non-inoculated BTPDs was 150% higher on the dusted vs. no dust plots. During the same interval on the dusted plots, the re-encounter rate was 55% higher for vaccinated adult female BTPDs vs. nonvaccinated adult females, but the annual re-encounter rate was 19% lower for vaccinated adult males. By late August 2008, BTPDs were nearly extirpated from the no dust plots. During 2007–2008 and 2008–2009 on the dusted plots, which persisted, the BTPD re-encounter rate was 41% higher for vaccinated vs. non-vaccinated adult females but 35% lower for vaccinated adult males. Yersinia pestis erupted with vigor as it invaded. Flea control enhanced BTPD survival but did not offer full protection. Flea control and F1–V vaccination seemed to have additive, positive effects on adult females. Annual re-encounter rates were reduced for vaccinated adult males; additional experimentation is needed to further evaluate this trend.

As the emerging field of equity in STEM education continues to grow, debates surrounding how to best serve populations with historically restricted access and successful outcomes within the STEM fields is growing as well. In this article, a group of doctoral students who took a course titled Equity in STEM Education and discusses their takeaways regarding the literature discussed in the course. The topics covered in this article will center around Gutiérrez’s (2007) equity framework of power, identity, access, and achievement. Through the lens of the equity framework, the dimension of power will be used to present discourse on the sociopolitical turn in STEM education. Identity will be used to explore debates on race, poverty, gender, and sexuality within STEM equity and education. Access will be used to examine discussions on students’ ability to achieve STEM equity in rural settings and within specific domains such as computer science. Finally, achievement will be used to explore arguments on both sides of the achievement gap research. To conclude, we urge researchers, educators, and policymakers to listen and act upon the work of contemporary scholars in order to achieve an equitable STEM education system.

We use supervised learning to identify factors that predict the cross-section of returns and maximum drawdown for stocks in the US equity market. Our data run from January 1970 to December 2019 and our analysis includes ordinary least squares, penalized linear regressions, tree-based models, and neural networks. We find that the most important predictors tended to be consistent across models, and that non-linear models had better predictive power than linear models. Predictive power was higher in calm periods than in stressed periods. Environmental, social, and governance indicators marginally impacted the predictive power of non-linear models in our data, despite their negative correlation with maximum drawdown and positive correlation with returns. Upon exploring whether ESG variables are captured by some models, we find that ESG data contribute to the prediction nonetheless.

Nicotine use continues to be a major public health concern, with an alarming recent rise in electronic cigarette consumption. Heritability estimates of nicotine use and abuse range from 40% to 80%, providing strong evidence that genetic factors impact nicotine addiction-relevant phenotypes. Although nicotine use during adolescence is a key factor in the development of addiction, it remains unclear how genetic factors impact adolescent nicotine use and abuse. This review will discuss studies investigating genetic factors impacting nicotine use during adolescence. Evidence from both rodent and human studies will be summarized and integrated when possible. Human adolescent studies have largely included candidate gene studies for genes identified in adult populations, such as genes involved in nicotine metabolism, nicotinic acetylcholine receptor signaling, dopaminergic signaling, and other neurotransmitter signaling systems. Alternatively, rodent studies have largely taken a discovery-based approach identifying strain differences in adolescent nicotine addiction-relevant behaviors. Here, we aim to answer the following three questions by integrating human and rodent findings: (1) Are there genetic variants that uniquely impact nicotine use during adolescence? (2) Are there genetic variants that impact both adolescent and adult nicotine use? and (3) Do genetic factors in adolescence significantly impact long-term consequences of adolescent nicotine use? Determining answers for these three questions will be critical for the development of preventative measures and treatments for adolescent nicotine use and addiction.

In March 2020, the COVID-19 pandemic required capstone design course instructors to transition to online learning. Student project teams were denied access to resources needed to construct and test prototypes scheduled to be delivered to project sponsors and clients at the end of the semester. Face-to-face collaboration was replaced with virtual team meetings. At Marquette University, efforts to identify (1) barriers to completing projects, (2) potential alternate prototyping resources, (3) adjustments to expectations of teams, and (4) changes to course deliverable requirements were completed. The results of these activities, the thought process used to guide students through the search for alternate resources, and final outcomes of student projects along with a discussion of what was learned from this experience are presented.

Abstract Background Advances in genetics and sequencing technologies are enabling the identification of more individuals with inherited cancer susceptibility who could benefit from tailored screening and prevention recommendations. While cancer family history information is used in primary care settings to identify unaffected patients who could benefit from a cancer genetics evaluation, this information is underutilized. System-level population health management strategies are needed to assist health care systems in identifying patients who may benefit from genetic services. In addition, because of the limited number of trained genetics specialists and increasing patient volume, the development of innovative and sustainable approaches to delivering cancer genetic services is essential. Methods We are conducting a randomized controlled trial, entitled Broadening the Reach, Impact, and Delivery of Genetic Services (BRIDGE), to address these needs. The trial is comparing uptake of genetic counseling, uptake of genetic testing, and patient adherence to management recommendations for automated, patient-directed versus enhanced standard of care cancer genetics services delivery models. An algorithm-based system that utilizes structured cancer family history data available in the electronic health record (EHR) is used to identify unaffected patients who receive primary care at the study sites and meet current guidelines for cancer genetic testing. We are enrolling eligible patients at two healthcare systems (University of Utah Health and New York University Langone Health) through outreach to a randomly selected sample of 2780 eligible patients in the two sites, with 1:1 randomization to the genetic services delivery arms within sites. Study outcomes are assessed through genetics clinic records, EHR, and two follow-up questionnaires at 4 weeks and 12 months after last genetic counseling contactpre-test genetic counseling. Discussion BRIDGE is being conducted in two healthcare systems with different clinical structures and patient populations. Innovative aspects of the trial include a randomized comparison of a chatbot-based genetic services delivery model to standard of care, as well as identification of at-risk individuals through a sustainable EHR-based system. The findings from the BRIDGE trial will advance the state of the science in identification of unaffected patients with inherited cancer susceptibility and delivery of genetic services to those patients. Trial registration BRIDGE is registered as NCT03985852 . The trial was registered on June 6, 2019 at clinicaltrials.gov .

Abstract Though elephants are a major cause of savanna tree mortality and threaten vulnerable tree species, managing their impact remains difficult, in part because relatively little is known about how elephant impacts are distributed throughout space. This is exacerbated by uncertainty about what determines the distribution of elephants themselves, as well as whether the distribution of elephants is even informative for understanding the distribution of their impacts. To better understand the factors that underlie elephant impacts, we modeled elephant distributions and their damage to trees with respect to soil properties, water availability, and vegetation in Kruger National Park, South Africa, using structural equation modeling. We found that bull elephants and mixed herds differed markedly in their distributions, with bull elephants concentrating in sparsely treed basaltic sites close to artificial waterholes and mixed herds aggregating around permanent rivers, particularly in areas with little grass. Surprisingly, we also found that the distribution of elephant impacts, while highly heterogeneous, was largely unrelated to the distribution of elephants themselves, with damage concentrated instead in densely treed areas and particularly on basaltic soils. Results underscore the importance of surface water for elephants but suggest that elephant water dependence operates together with other landscape factors, particularly vegetation community composition and historical management interventions, to influence elephant distributions.

Abstract Aims Perioperative blood transfusions are common among patients undergoing left ventricular assist device (LVAD) implantation. The association between blood product transfusion at the time of LVAD implantation and mortality has not been described. Methods and results This was a retrospective cohort study of all patients who underwent continuous flow LVAD implantation at a single, large, tertiary care, academic centre, from 2008 to 2014. We assessed used of packed red blood cells (pRBCs), platelets, and fresh frozen plasma (FFP). Outcomes of interest included all‐cause mortality and acute right ventricular (RV) failure. Standard regression techniques were used to examine the association between blood product exposure and outcomes of interest. A total of 170 patients were included in this study (mean age: 56.5 ± 15.5 years, 79.4% men). Over a median follow‐up period of 11.2 months, for every unit of pRBC transfused, the hazard for mortality increased by 4% [hazard ratio (HR) 1.04; 95% CI 1.02–1.07] and odds for acute RV failure increased by 10% (odds ratio 1.10; 95% CI 1.05–1.16). This association persisted for other blood products including platelets (HR for mortality per unit 1.20; 95% CI 1.08–1.32) and FFP (HR for mortality per unit 1.08; 95% CI 1.04–1.12). The most significant predictor of perioperative blood product exposure was a lower pre‐implant haemoglobin. Conclusions Perioperative blood transfusions among patients undergoing LVAD implantation were associated with a higher risk for all‐cause mortality and acute RV failure. Of all blood products, FFP use was associated with worst outcomes. Future studies are needed to evaluate whether pre‐implant interventions, such as intravenous iron supplementation, will improve the outcomes of LVAD candidates by decreasing need for transfusions.

Abstract In herbivores, survival and reproduction are influenced by quality and quantity of forage, and hence, diet and foraging behavior are the foundation of an herbivore's life history strategy. Given the importance of diet to most herbivores, it is imperative that we know the species of plants they prefer, especially for herbivorous species that are at risk for extinction. However, it is often difficult to identify the diet of small herbivores because: (a) They are difficult to observe, (b) collecting stomach contents requires sacrificing animals, and (c) microhistology requires accurately identifying taxa from partially digested plant fragments and likely overemphasizes less‐digestible taxa. The northern Idaho ground squirrel (Urocitellus brunneus) is federally threatened in the United States under the Endangered Species Act. We used DNA metabarcoding techniques to identify the diet of 188 squirrels at 11 study sites from fecal samples. We identified 42 families, 126 genera, and 120 species of plants in the squirrel's diet. Our use of three gene regions was beneficial because reliance on only one gene region (e.g., only trnL) would have caused us to miss >30% of the taxa in their diet. Northern Idaho ground squirrel diet differed between spring and summer, frequency of many plants in the diet differed from their frequency within their foraging areas (evidence of selective foraging), and several plant genera in their diet were associated with survival. Our results suggest that while these squirrels are generalists (they consume a wide variety of plant species), they are also selective and do not eat plants relative to availability. Consumption of particular genera such as Perideridia may be associated with higher overwinter survival.

IntroductionThis paper details the journey of eight Aboriginal women from Circular Head, a rural and remote area of North-West Tasmania, as they undertook an innovative 2-year program of tertiary studies in dementia to address a documented community need. The Chief Executive Officer of the Circular Head Aboriginal Corporation (CHAC) had identified difficulties being experienced by older members of the community. These difficulties included changes in behavior, memory, and communication, with profound consequences on social engagement and care needs from both individual and community perspectives. The community wished to know if a combined vocational and university program, completed on Country and in community, could serve as a culturally safe education pathway to empower Aboriginal members of a rural and remote area in providing community health and dementia education and care.MethodsThe nationally funded program included a year-long face-to-face vocational Certificate III in Individual Support (Aging, Home, and Community) on Country, including within-community experience with adults with dementia. This face-to-face learning was combined with online study in the award-winning Bachelor of Dementia care offered by the University of Tasmania. Students received a PhD level stipend to support them in their studies and were guided by an Elder from their community.ResultsAll students completed their Certificate III. The number of units they completed toward the eight required for their Diploma of Dementia Care varied. Emergent themes from students' reflections were holistic and relational, highlighting achievements and challenges, the importance of on Country individual connections and community support, and the value of their current and future contributions to the community. Data from this mixed methods approach documented the impact of the innovative coupling of authentic, culturally appropriate experiential learning with broad and deep academic knowledge about dementia and evidence-based care.ConclusionsThis program provided students with a work-related qualification embedded within a university education and increased the capacity and capability of this Aboriginal community to provide care for its members with dementia, a documented concern. The combination of vocational learning on Country with online university study established a pathway to improve students' access to and success in higher education and the professional workforce. This assisted in counteracting the negative influences of racism, stigma, rurality, and socio-economic marginalization on educational opportunity for Aboriginal people. Data showed the need for flexibility with this learning journey, and the strengths and resilience of these women as they learned.

Background The past decade has seen tremendous growth in patients with ambulatory ventricular assist devices. We sought to identify patients that present to the emergency department (ED) at the highest risk of death. Methods and Results This retrospective analysis of ED encounters from the Nationwide Emergency Department Sample includes 2010 to 2017. Using a random sampling of patient encounters, 80% were assigned to development and 20% to validation cohorts. A risk model was derived from independent predictors of mortality. Each patient encounter was assigned to 1 of 3 groups based on risk score. A total of 44 042 ED ventricular assist device patient encounters were included. The majority of patients were male (73.6%),

Background: Many patients with self-reported food allergy are not allergic but suffer from similar burdens. We aimed to characterize young adults with misconceived food allergy. Methods: A cross-sectional study of individuals (n = 12,592) aged 17–18 years, recruited to the Israel Defense Forces (IDF) at a single urban-area recruitment center over a six month-period. All participants underwent a comprehensive medical and psychological evaluation. Cognitive tests were performed and a Combined Intellectual-Education score assigned. Participants who reported food elimination due to allergy were skin-tested and underwent oral food challenges, when indicated. The characteristics, psychological evaluation and cognitive tests of individuals with no reported food allergy (n = 12,444), misconceived food allergy (n = 64) and true food allergy (n = 84) were compared. Findings: The prevalence of atopic co-morbidities was higher in recruits reporting compared to those not reporting food allergy while the rate of other co-morbidities was comparable. Anxiety disorder was diagnosed significantly more in individuals who reported food allergy (4·1%) compared to those who did not (1·7%) (p = 0·04). Further analysis revealed that this diagnosis was concentrated in individuals with misconceived (8/64, 12·5%) compared to true food allergy (2/84, 2·4%), (p = 0·02). Patients with misconceived food allergy were mostly of female sex, had lower Combined Intellectual-Education scores compared to patients with true (p = 0·001) and no reported food allergy (p = 0·01), and required the longest mean evaluation time (147·6 ± 109·4 days). Interpretation: Patients with misconceived food allergy have higher rates of anxiety disorder and are often from a lower educational level and of female sex. Medical and educational attention is required to improve care of this specific population. Funding: The research reported in this publication was supported by the Israel Defense Forces (IDF) Medical Corps and Directorate of Defense Research & Development, Israeli Ministry of Defense (IMOD DDR&D).

Abstract For vector‐borne diseases, the abundance and competency of different vector species and their host preferences will impact the transfer of pathogens among hosts. Sylvatic plague is a lethal disease caused by the primarily flea‐borne bacterium Yersinia pestis. Sylvatic plague was introduced into the western United States in the early 1900s and impacts many species of rodents. Plague may be suppressing populations of the threatened northern Idaho ground squirrel (Urocitellus brunneus) if a competent flea community is allowing plague to be maintained within the few extant sites that support this rare ground squirrel. We collected fleas from four species of sympatric rodents in central Idaho: northern Idaho ground squirrels, Columbian ground squirrels (Urocitellus columbianus), yellow‐pine chipmunks (Tamias amoenus), and deer mice (Peromyscus maniculatus). We evaluated which flea species were present and whether fleas were shared among the rodent community. We documented seven species of fleas among 3356 fleas collected from the four host species of rodents, and all seven species of fleas are known vectors of plague. Three of the seven flea species were detected on all four rodent species, demonstrating potential for spillover of plague (bridge vectors) in the rodent community. We used generalized linear mixed models to evaluate which abiotic and biotic factors influence flea abundance (total number of fleas, regardless of flea species, on each individual host of the four rodent host species). Factors that impacted flea abundance varied among the four host species, but flea abundance: (1) changed over summer depending on host species, (2) was greater on males, and (3) was impacted by summer and winter precipitation depending on host species. Our results suggest this diverse flea community has the capacity to transfer Y. pestis among populations of the four rodents if Y. pestis is present. Furthermore, the disease may be more likely to persist in some locations than others, those that have higher flea abundances, more sympatric hosts, or optimal conditions for fleas, and such high‐risk sites can be identified based on their abiotic and biotic factors.

Variants in a gene cluster upstream-adjacent to TERC on human chromosome 3, which includes genes APRM, LRRC31, LRRC34 and MYNN, have been associated with telomere length in several human populations. Currently, the mechanism by which variants in the TERC gene cluster influence telomere length in humans is unknown. Given the proximity between the TERC gene cluster and TERC (~0.05 Mb) in humans, it is speculated that cluster variants are in linkage disequilibrium with a TERC causal variant. In mice, the Terc gene/Terc gene cluster are also located on chromosome 3; however, the Terc gene cluster is located distantly downstream of Terc (~60 Mb). Here, we initially aim to investigate the interactions between genotype and nicotine exposure on absolute liver telomere length (aTL) in a panel of eight inbred mouse strains. Although we found no significant impact of nicotine on liver aTL, this first experiment identified candidate single nucleotide polymorphisms (SNPs) in the murine Terc gene cluster (within genes Lrrc31, Lrriq4 and Mynn) co-varying with aTL in our panel. In a second experiment, we tested the association of these Terc gene cluster variants with liver aTL in an independent panel of eight inbred mice selected based on candidate SNP genotype. This supported our initial finding that Terc gene cluster polymorphisms impact aTL in mice, consistent with data in human populations. This provides support for mice as a model for telomere dynamics, especially for studying mechanisms underlying the association between Terc cluster variants and telomere length. Finally, these data suggest that mechanisms independent of linkage disequilibrium between the Terc/TERC gene cluster and the Terc/TERC gene mediate the cluster’s regulation of telomere length.

Abstract Background Animal studies have shown that nutritional exposures during pregnancy can modify epigenetic marks regulating fetal development and susceptibility to later disease, providing a plausible mechanism to explain the developmental origins of health and disease. Human observational studies have shown that maternal peri-conceptional diet predicts DNA methylation in offspring. However, a causal pathway from maternal diet, through changes in DNA methylation, to later health outcomes has yet to be established. The EMPHASIS study (Epigenetic Mechanisms linking Pre-conceptional nutrition and Health Assessed in India and Sub-Saharan Africa, ISRCTN14266771) will investigate epigenetically mediated links between peri-conceptional nutrition and health-related outcomes in children whose mothers participated in two randomized controlled trials of micronutrient supplementation before and during pregnancy. Methods The original trials were the Mumbai Maternal Nutrition Project (MMNP, ISRCTN62811278) in which Indian women were offered a daily snack made from micronutrient-rich foods or low-micronutrient foods (controls), and the Peri-conceptional Multiple Micronutrient Supplementation Trial (PMMST, ISRCTN13687662) in rural Gambia, in which women were offered a daily multiple micronutrient (UNIMMAP) tablet or placebo. In the EMPHASIS study, DNA methylation will be analysed in the children of these women (~1100 children aged 5–7 y in MMNP and 298 children aged 7–9 y in PMMST). Cohort-specific and cross-cohort effects will be explored. Differences in DNA methylation between allocation groups will be identified using the Illumina Infinium MethylationEPIC array, and by pyrosequencing top hits and selected candidate loci. Associations will be analysed between DNA methylation and health-related phenotypic outcomes, including size at birth, and children’s post-natal growth, body composition, skeletal development, cardio-metabolic risk markers (blood pressure, serum lipids, plasma glucose and insulin) and cognitive function. Pathways analysis will be used to test for enrichment of nutrition-sensitive loci in biological pathways. Causal mechanisms for nutrition-methylation-phenotype associations will be explored using Mendelian Randomization. Associations between methylation unrelated to supplementation and phenotypes will also be analysed. Conclusion The study will increase understanding of the epigenetic mechanisms underpinning the long-term impact of maternal nutrition on offspring health. It will potentially lead to better nutritional interventions for mothers preparing for pregnancy, and to identification of early life biomarkers of later disease risk.

Chronic liver disease (CLD) is a global health epidemic causing ∼2 million deaths annually worldwide. As the incidence of CLD is expected to rise over the next decade, understanding the cellular and molecular mediators of CLD is critical for developing novel therapeutics. Common characteristics of CLD include steatosis, inflammation, and cholesterol accumulation in the liver. While the lymphatic system in the liver has largely been overlooked, the liver lymphatics, as in other organs, are thought to play a critical role in maintaining normal hepatic function by assisting in the removal of protein, cholesterol, and immune infiltrate. Lymphatic growth, permeability, and/or hyperplasia in non-liver organs has been demonstrated to be caused by obesity or hypercholesterolemia in humans and animal models. While it is still unclear if changes in permeability occur in liver lymphatics, the lymphatics do expand in number and size in all disease etiologies tested. This is consistent with the lymphatic endothelial cells (LEC) upregulating proliferation specific genes, however, other transcriptional changes occur in liver LECs that are dependent on the inflammatory mediators that are specific to the disease etiology. Whether these changes induce lymphatic dysfunction or if they impact liver function has yet to be directly addressed. Here, we will review what is known about liver lymphatics in health and disease, what can be learned from recent work on the influence of obesity and hypercholesterolemia on the lymphatics in other organs, changes that occur in LECs in the liver during disease and outstanding questions in the field.