Genetics of liver disease in adults.

Chronic liver disease stands as a significant global health problem with an estimated 2 million annual deaths across the globe. Combining the use of next-generation sequencing technologies with evolving knowledge in the interpretation of genetic variation across the human genome is propelling our understanding, diagnosis, and management of both rare and common liver diseases. Here, we review the contribution of risk and protective alleles to common forms of liver disease, the rising number of monogenic diseases affecting the liver, and the role of somatic genetic variants in the onset and progression of oncological and non-oncological liver diseases. The incorporation of genomic information in the diagnosis and management of patients with liver disease is driving the beginning of a new era of genomics-informed clinical hepatology practice, facilitating personalized medicine, and improving patient care.

Almajiri health; a scoping review on disease, health literacy and space for participatory research.

INTRODUCTION: Almajirai are male children in Northern Nigeria and Southern Niger who study Islam in the almajiranci system. Almajiranci has been associated with non-participation in formal education, abuse, poverty, and underdevelopment. However, the peer-reviewed literature around health among almajirai remains limited. We conduct a scoping review around almajiri health to synthesize evidence for health problems, draw links between findings, identify research gaps, indicate areas for intervention, and assess participatory approaches in this literature. METHODS: We searched the academic literature for articles concerning almajiri heath using a framework integrating the biopsychosocial and socio-ecological models of health. We included articles in English and French published between 2000 and 2022. For each study we collected information regarding authorship, study year and location(s), study design and aims, sample characteristics, findings, and almajiri participation in research design, execution, interpretation and dissemination. RESULTS: Of 1,944 studies, 17 were found relevant for data extraction. These included 14 cross-sectional studies, 2 descriptive articles, and one case-control study. All were conducted in Nigeria, though one included Nigerien almajirai. No study engaged almajirai in participatory roles. Domains evaluated included infectious disease (10 studies), oral health (2 studies), workplace injury, nutrition, health status, health determinants, and mental health (1 study each). Almajirai included ranged from 3 to 28 years old. Included studies found high rates of malaria, intestinal parasitosis, urinary tract infection, N. meningitidis, and occupational injury among almajirai. Studies comparing almajirai to controls found significantly higher rates of cholera, urinary schistosomiasis, and psychiatric disorders, lower levels of rabies awareness and poorer oral hygiene among almajirai (p<0.05). One study, concerning nutrition, described an intervention to improve almajiri health, though did not provide health outcomes for that intervention. CONCLUSION: We find that the literature around almajiri health has concerned a broad range of domains, though the number of studies within each domain remains limited. We further note limitations in the geographic scope of this literature, interventions to improve almajiri health, and the consideration of demographic features, like age, that may influence almajiri health. We stress the need for further study in these areas, and for participatory approaches, which may be more likely to effectively improve almajiri health.

Advancing diagnosis and management of liver disease in adults through exome sequencing.

BACKGROUND: Whole-exome sequencing (WES) is an effective tool for diagnosis in patients who remain undiagnosed despite a comprehensive clinical work-up. While WES is being used increasingly in pediatrics and oncology, it remains underutilized in non-oncological adult medicine, including in patients with liver disease, in part based on the faulty premise that adults are unlikely to harbor rare genetic variants with large effect size. Here, we aim to assess the burden of rare genetic variants underlying liver disease in adults at two major tertiary referral academic medical centers. METHODS: WES analysis paired with comprehensive clinical evaluation was performed in fifty-two adult patients with liver disease of unknown etiology evaluated at two US tertiary academic health care centers. FINDINGS: Exome analysis uncovered a definitive or presumed diagnosis in 33% of patients (17/52) providing insight into their disease pathogenesis, with most of these patients (12/17) not having a known family history of liver disease. Our data shows that over two-thirds of undiagnosed liver disease patients attaining a genetic diagnosis were being evaluated for cholestasis or hepatic steatosis of unknown etiology. INTERPRETATION: This study reveals an underappreciated incidence and spectrum of genetic diseases presenting in adulthood and underscores the clinical value of incorporating exome sequencing in the evaluation and management of adults with liver disease of unknown etiology. FUNDING: S.V. is supported by the NIH/NIDDK (K08 DK113109 and R01 DK131033-01A1) and the Doris Duke Charitable Foundation Grant #2019081. This work was supported in part by NIH-funded Yale Liver Center, P30 DK34989.

Provider-identified barriers to performance at seven Nigerian accident & emergency units: A cross-sectional study.

BACKGROUND: Nigeria hosts much of Africa's morbidity and mortality from emergency medical conditions. We surveyed providers at seven Nigerian Accident & Emergency (A&E) units about (i) their unit's ability to manage six major types of emergency medical condition (sentinel conditions) and (ii) barriers to performing key functions (signal functions) to manage sentinel conditions. Here, we present our analysis of provider-reported barriers to signal function performance. METHODS: 503 Health Providers at 7 A&E units, across 7 states, were surveyed using a modified African Federation of Emergency Medicine (AFEM) Emergency Care Assessment Tool (ECAT). Providers indicating suboptimal performance ascribed this performance to any of eight multiple-choice barriers [infrastructural issues, absent and broken equipment, inadequate training, inadequate personnel, requirement of out-of-pocket payment, non-indication of that signal function for the sentinel condition, and hospital-specific policies barring signal function performance] or an open-ended "other" response. The average number of endorsements for each barrier was obtained for each sentinel condition. Differences in barrier endorsement were compared across site, barrier type and sentinel condition using a three-way ANOVA test. Open-ended responses were evaluated using inductive thematic analysis. Sentinel conditions were Shock, Respiratory Failure, Altered Mental Status, Pain, Trauma, and Maternal & Child Health. Study sites were the University of Calabar Teaching Hospital, the Lagos University Teaching Hospital, the Federal Medical Center, Katsina, the National Hospital Abuja, the Federal Teaching Hospital Gombe, the University of Ilorin Teaching Hospital (Kwara), and the Federal Medical Center Owerri (Imo). FINDINGS: Barrier distribution varied widely by study site. Just three study sites shared any one barrier to signal function performance as their most common. The two barriers most commonly endorsed were (i) non-indication of, and (ii) insufficient infrastructure to perform signal functions. A three-way ANOVA test found significant differences in barrier endorsement by barrier type, study site and sentinel condition (p<0.05). Thematic analysis of open-ended responses highlighted (i) considerations disfavoring signal function performance and (ii) lack of experience with signal functions as barriers to signal function performance. Interrater reliability, calculated using Fleiss' Kappa, was found to be 0.5 across 11 initial codes and 0.51 for our two final themes. INTERPRETATION: Provider perspective varied with regards to barriers to care. Despite these differences, the trends seen for infrastructure reflect the importance of sustained investment in Nigerian health infrastructure. The high level of endorsement seen for the non-indication barrier may signal need for better ECAT adaptation for local practice & education, and for improved Nigerian emergency medical education and training. A low endorsement was seen for patient-facing costs, despite the high burden of Nigerian private expenditure on healthcare, indicating limited representation of patient-facing barriers. Analysis of open-ended responses was limited by the brevity and ambiguity of these responses on the ECAT. Further investigation is needed towards better representation of patient-facing barriers and qualitative approaches to evaluating Nigerian emergency care provision.

Genomic analysis of lean individuals with NAFLD identifies monogenic disorders in a prospective cohort study.

Background & Aims: Lean patients with non-alcoholic fatty liver disease (NAFLD) represent 10-20% of the affected population and may have heterogeneous drivers of disease. We have recently proposed the evaluation of patients with lean NAFLD without visceral adiposity for rare monogenic drivers of disease. Here, we aimed to validate this framework in a well-characterised cohort of patients with biopsy-proven NAFLD by performing whole exome sequencing. Methods: This prospective study included 124 patients with biopsy-proven NAFLD and paired liver biopsies who underwent standardised research visits including advanced magnetic resonance imaging (MRI) assessment of liver fat and stiffness. Results: Six patients with lean NAFLD were identified and underwent whole exome sequencing. Two lean patients (33%) were identified to have monogenic disorders. The lean patients with monogenic disorders had similar age, and anthropometric and MRI characteristics to lean patients without a monogenic disorder. Patient 1 harbours a rare homozygous pathogenic mutation in ALDOB (aldolase B) and was diagnosed with hereditary fructose intolerance. Patient 2 harbours a rare heterozygous mutation in apolipoprotein B (APOB). The pathogenicity of this APOB variant (p.Val1856CysfsTer2) was further validated in the UK Biobank and associated with lower circulating APOB levels (beta = -0.51 g/L, 95% CI -0.65 to -0.36 g/L, p = 1.4 × 10-11) and higher liver fat on MRI (beta = +10.4%, 95% CI 4.3-16.5%, p = 8.8 × 10-4). Hence, patient 2 was diagnosed with heterozygous familial hypobetalipoproteinaemia. Conclusions: In this cohort of well-characterised patients with lean NAFLD without visceral adiposity, 33% (2/6) had rare monogenic drivers of disease, highlighting the importance of genomic analysis in this NAFLD subtype. Impact and Implications: Although most people with non-alcoholic fatty liver disease (NAFLD) are overweight or obese, a subset are lean and may have unique genetic mutations that cause their fatty liver disease. We show that 33% of study participants with NAFLD who were lean harboured unique mutations that cause their fatty liver, and that these mutations had effects beyond the liver. This study demonstrates the value of genetic assessment of NAFLD in lean individuals to identify distinct subtypes of disease.

Revisiting the Exhibits-Medical Student Reflections on Changes to the Institutional Portraiture at a US Medical School.

BACKGROUND: Yale School of Medicine's (YSM) Sterling Hall of Medicine (SHM) has historically been lined with large oil paintings of mostly White men, despite over a century of Black and female enrollment. These spaces can be seen as exclusionary to students underrepresented in medicine, and may result in decreased well-being and adversely affect academic performance. Student-led activism has resulted in recent changes to these walls, including the addition of images of women faculty, and artwork by students, faculty, and staff. OBJECTIVE: We aimed to evaluate how recent changes to longstanding historical portraiture in SHM affected students' reflections on being in that space. DESIGN: This was a qualitative study based on semi-structured interviews conducted virtually. PARTICIPANTS: Second- to fourth-year YSM medical students were interviewed. APPROACH: Qualitative interviews were used to gauge students' impressions of how they perceived both the original and updated artwork and portraiture, as well as the overall physical environment. KEY RESULTS: Nine interviews were conducted, with interviewees describing the portraiture as reflective of YSM's institutional values. They related this to other aspects of an exclusionary environment, and noted that they created belonging at YSM within smaller communities. Students recognized and expressed appreciation for the changes to the portraiture, particularly the increase in diverse representation, and they noted stark contrasts to the prior space. While they describe positive attitudes regarding changes in SHM's exhibited portraiture and art, they also expressed skepticism about whether these changes were performative or whether they reflected true commitment to reform. CONCLUSIONS: This study depicts how the portraiture and physical environment of a medical school affects medical students, and that interventions to reform institutional portraiture can have considerable impact on students' attitudes regarding their medical school experiences.

Combinatorial glucose, nicotinic acid and N-acetylcysteine therapy has synergistic effect in preclinical C. elegans and zebrafish models of mitochondrial complex I disease.

Mitochondrial respiratory chain disorders are empirically managed with variable antioxidant, cofactor and vitamin 'cocktails'. However, clinical trial validated and approved compounds, or doses, do not exist for any single or combinatorial mitochondrial disease therapy. Here, we sought to pre-clinically evaluate whether rationally designed mitochondrial medicine combinatorial regimens might synergistically improve survival, health and physiology in translational animal models of respiratory chain complex I disease. Having previously demonstrated that gas-1(fc21) complex I subunit ndufs2-/-C. elegans have short lifespan that can be significantly rescued with 17 different metabolic modifiers, signaling modifiers or antioxidants, here we evaluated 11 random combinations of these three treatment classes on gas-1(fc21) lifespan. Synergistic rescue occurred only with glucose, nicotinic acid and N-acetylcysteine (Glu + NA + NAC), yielding improved mitochondrial membrane potential that reflects integrated respiratory chain function, without exacerbating oxidative stress, and while reducing mitochondrial stress (UPRmt) and improving intermediary metabolic disruptions at the levels of the transcriptome, steady-state metabolites and intermediary metabolic flux. Equimolar Glu + NA + NAC dosing in a zebrafish vertebrate model of rotenone-based complex I inhibition synergistically rescued larval activity, brain death, lactate, ATP and glutathione levels. Overall, these data provide objective preclinical evidence in two evolutionary-divergent animal models of mitochondrial complex I disease to demonstrate that combinatorial Glu + NA + NAC therapy significantly improved animal resiliency, even in the face of stressors that cause severe metabolic deficiency, thereby preventing acute neurologic and biochemical decompensation. Clinical trials are warranted to evaluate the efficacy of this lead combinatorial therapy regimen to improve resiliency and health outcomes in human subjects with mitochondrial disease.

Imeglimin: Current Development and Future Potential in Type 2 Diabetes.

Imeglimin is the first of the "glimins," a new class of drugs developed for the treatment of type 2 diabetes mellitus (T2DM). This review highlights its mechanism of action and its context in the field of T2DM treatment. Preclinical data in multiple rodent models have detailed significant effects on mitochondria, particularly improved mitochondrial bioenergetics. This includes changes favoring complex II and complex III metabolism, a mechanism potentially promoting increased fatty acid oxidation, leading to the decrease in hepatic lipid accumulation observed in these mice. Imeglimin was also shown to increase muscle glucose uptake and decrease hepatic glucose production, both in vitro and in vivo. Though studies have also shown imeglimin to significantly improve insulin secretion and decrease ß-cell death, whether its physiologic effects are purely insulin dependent remains unclear. Early preclinical studies have shown evidence for improvements in cardiac and renal function in rats with metabolic syndrome, effects not conferred by most currently available T2DM drugs. Clinical studies of imeglimin in humans have shown increased insulin secretion, along with decreased fasting plasma glucose and glycated hemoglobin. Its observed efficacy was comparable to that of currently available agents metformin and sitagliptin and was increased when given in combination with either agent. When considered alongside its benign safety profile reported in patients with chronic kidney disease, imeglimin shows true promise to provide a novel mechanism for T2DM treatment, with potential application in a larger, more comprehensive patient population.

Pre-clinical evaluation of cysteamine bitartrate as a therapeutic agent for mitochondrial respiratory chain disease.

Cysteamine bitartrate is a US Food and Drug Administration-approved therapy for nephropathic cystinosis also postulated to enhance glutathione biosynthesis. We hypothesized this antioxidant effect may reduce oxidative stress in primary mitochondrial respiratory chain (RC) disease, improving cellular viability and organismal health. Here, we systematically evaluated the therapeutic potential of cysteamine bitartrate in RC disease models spanning three evolutionarily distinct species. These pre-clinical studies demonstrated the narrow therapeutic window of cysteamine bitartrate, with toxicity at millimolar levels directly correlating with marked induction of hydrogen peroxide production. Micromolar range cysteamine bitartrate treatment in Caenorhabditis elegans gas-1(fc21) RC complex I (NDUFS2-/-) disease invertebrate worms significantly improved mitochondrial membrane potential and oxidative stress, with corresponding modest improvement in fecundity but not lifespan. At 10 to 100 µm concentrations, cysteamine bitartrate improved multiple RC complex disease FBXL4 human fibroblast survival, and protected both complex I (rotenone) and complex IV (azide) Danio rerio vertebrate zebrafish disease models from brain death. Mechanistic profiling of cysteamine bitartrate effects showed it increases aspartate levels and flux, without increasing total glutathione levels. Transcriptional normalization of broadly dysregulated intermediary metabolic, glutathione, cell defense, DNA, and immune pathways was greater in RC disease human cells than in C. elegans, with similar rescue in both models of downregulated ribosomal and proteasomal pathway expression. Overall, these data suggest cysteamine bitartrate may hold therapeutic potential in RC disease, although not through obvious modulation of total glutathione levels. Careful consideration is required to determine safe and effective cysteamine bitartrate concentrations to further evaluate in clinical trials of human subjects with primary mitochondrial RC disease.