Search

Obinna O Oleribe,1,2 Andrew W Taylor-Robinson,3,4 Okey C Nwanyanwu,5 Marsha Y Morgan,6 Simon D Taylor-Robinson7,8 1Office of the Director-General, Nigerian Institute for Medical Research, Lagos, Nigeria; 2Best Health Consult Limited Liability Company, Orange, CA, USA; 3College of Health Sciences, VinUniversity, Hanoi, Vietnam; 4Center for Global Health, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA; 5Fast Forward Africa Limited Liability Company, Austin, TX, USA; 6Division of Medicine, Royal Free Campus, University College London, London, UK; 7Departments of Medicine & Public Health, Busitema University, Mbale, Uganda; 8Department of Surgery and Cancer, Imperial College London, St Mary’s Hospital Campus, London, UKCorrespondence: Simon D Taylor-Robinson, Email str338333@gmail.comAbstract: Four years after the first case of COVID-19, the world is still determining how best to prevent and control the long-term effects of SARS-CoV-2 infection. Non-pharmaceutical interventions (NPIs) were employed at the start of the pandemic as the only available options, prior to effective vaccines and antiviral agents. The World Health Organization recommended dual vaccination for 70% worldwide as the threshold for a return to “normal” community life. Immunization rates needed to increase in all global regions, irrespective of socioeconomic status, necessitating more equitable access. During the pandemic, wealthier countries hoarded vaccine supplies even when their citizens were immunized. This highlights the already enormous difficulties in healthcare provision faced by low-income sub-Saharan African countries, which remain at risk as industrialized nations have progressed to a post-pandemic era. Thus, in addition to redoubling vaccination efforts public health policymakers should consider ongoing and future use of NPIs. In this narrative account, we advocate that various NPI practices should not be shelved; rather, more research is needed to evaluate their impact in parallel with booster vaccination. This especially applies to so-called “long COVID”. Lessons learned from implementing best practices in resource-limited settings should be incorporated into preparedness guidelines for future infectious disease outbreaks.Keywords: sub-Saharan Africa, COVID-19, health inequality, non-pharmaceutical interventions, pandemic, vaccination

Simon D Taylor-Robinson,1,2 Marsha Y Morgan3 1Department of Surgery and Cancer, Imperial College London, London, UK; 2Department of Public Health, Busitema University and Mbale Clinical Research Institute, Mbale, Uganda; 3UCL Institute for Liver & Digestive Health, Division of Medicine, Royal Free Campus, University College London, London, UKCorrespondence: Simon D Taylor-Robinson, Department of Surgery and Cancer, St Mary’s Hospital Campus, Imperial College London, London, SW7 2AZ, United Kingdom, Email str338333@gmail.comAbstract: Although the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) primarily attacks the respiratory system, other organs, such as the liver, are also affected. In this overview, the effects of SARS-CoV-2 infection on the liver in both healthy people and in those with pre-existing liver disease are documented; the relationship between coronavirus disease 19 (COVID-19) vaccination and liver injury is examined; the mechanism of SARS-CoV-2-associated liver injury is explored; and the long-term consequences of COVID-19 are delineated, both in people with and without pre-existing liver disease.Keywords: COVID-19, COVID-19 liver disease, pathophysiology, SARS-CoV-2

Abstract Background Sarcopenia, an age‐related loss of muscle mass, is a critical factor that affects the health of the older adults. The SOD1KO mouse is deficient of Cu/Zn superoxide dismutase, used as an accelerated aging model. We previously showed that NT‐3 improves muscle fibre size by activating the mTOR pathway, suggesting a potential for attenuating age‐related muscle loss. This study assessed the therapeutic efficacy of AAV1.NT‐3 in this accelerated aging model. Methods Twelve 6 months old SOD1KO mice were injected intramuscularly with a 1 × 1011 vg dose of AAV1.tMCK.NT‐3, and 13 age‐matched SOD1KO mice were used as controls. The treatment effect was evaluated using treadmill, rotarod and gait analyses as well as histological studies assessing changes in muscle fibre, and fibre type switch, in tibialis anterior, gastrocnemius, and triceps muscles, and myelin thickness by calculating G ratio in sciatic and tibial nerves. Molecular studies involved qPCR experiments to analyse the expression levels of mitochondrial and glycolysis markers and western blot experiments to assess the activity of mTORC1 pathway. Results Treatment resulted in a 36% (154.9 vs. 114.1; P

Limb girdle muscular dystrophy (LGMD) 2A/R1, caused by mutations in the CAPN3 gene and CAPN3 loss of function, is known to play a role in disease pathogenicity. In this study, AAVrh74.tMCK.CAPN3 was delivered systemically to two different age groups of CAPN3 knockout (KO) mice; each group included two treatment cohorts receiving low (1.17 × 1014 vg/kg) and high (2.35 × 1014 vg/kg) doses of the vector and untreated controls. Treatment efficacy was tested 20 weeks after gene delivery using functional (treadmill), physiological (in vivo muscle contractility assay), and histopathological outcomes. AAV.CAPN3 gene therapy resulted in significant, robust improvements in functional outcomes and muscle physiology at low and high doses in both age groups. Histological analyses of skeletal muscle showed remodeling of muscle, a switch to fatigue-resistant oxidative fibers in females, and fiber size increases in both sexes. Safety studies revealed no organ tissue abnormalities; specifically, there was no histopathological evidence of cardiotoxicity. These results show that CAPN3 gene replacement therapy improved the phenotype in the CAPN3 KO mouse model at both doses independent of age at the time of vector administration. The improvements were supported by an absence of cardiotoxicity, showing the efficacy and safety of the AAV.CAPN3 vector as a potential gene therapy for LGMDR1.

BACKGROUND: The impact of disease on health-related quality of life is now well recognized, as is the importance of this variable as a measure of treatment efficacy. METHODS: Patients from five European countries were enrolled in an open, multicenter, prospective study designed to observe outcome in dependent drinkers treated for 6 months with acamprosate and psychosocial support. Version 1 of the 36-item Short Form Health Profile (SF-36v1) questionnaire was administered at inclusion and at 3 and 6 months. Responses were described as handicaps compared with an appropriately matched, healthy reference population. One-way fixed ANOVA and simultaneous stepwise linear regression analysis were used to identify potential predictors of quality of life at baseline and after treatment. RESULTS: Baseline SF-36v1 data were obtained from 1216 patients (mean age, 43 +/- 9 years; 77% male). Mean values for all SF-36v1 dimensions were significantly lower in the patient population than in the normative reference population; the most important deficits were observed in physical and emotional role limitations and in social functioning. The most important predictors of baseline quality of life were severity of alcohol dependence, employment status, psychiatric history, quantity and frequency of alcohol consumption, attendance at Alcoholics Anonymous, global alcohol health status, age, gender, and education. SF-36v1 data were obtained from 686 patients at 3 months and from 497 at 6 months. Significant improvements were observed in all SF-36v1 dimensional and summary scores after 3 months of treatment (p < 0.001); further marginal improvements were observed between 3 and 6 months. The most important predictors of quality of life following treatment were the SF-36v1 profile at baseline, followed by abstinence duration; patients who completed the trial and remained abstinent throughout showed the greatest improvement. CONCLUSIONS: Health-related quality of life is severly impaired in dependent drinkers. Treatment with acamprosate and psychosocial support, by promoting abstinence, improves the quality of life profile to levels comparable to those observed in healthy individuals. [ABSTRACT FROM AUTHOR]

BACKGROUND: A number of clinical trials have been undertaken to determine the efficacy of acamprosate in the maintenance of abstinence in alcohol-dependent individuals. However, the reported differences in patient populations, treatment duration, and study endpoints make comparisons difficult. An assessment of the efficacy of treatment with acamprosate was, therefore, undertaken using meta-analytical techniques. METHODS: All randomized, placebo-controlled trials (RCTs) that fulfilled predetermined criteria were identified using (1) a language unrestricted search of 10 electronic databases; (2) a manual search of relevant journals, symposia, and conference proceedings; (3) cross-referencing of all identified publications; (4) personal communications with investigators; and (5) scrutiny of Merck-Sante's internal reports of all European trials. Study quality was assessed, independently, by three blinded workers. Key outcome data were identified; some outcome variables were recalculated to ensure consistency across trials. The primary outcome measure was continuous abstinence at 6 months; abstinence rates were determined by estimating Relative Benefit (RB). RESULTS: A total of 19 published 1 unpublished RCTs were identified that fulfilled the selection criteria; 3 were excluded because the documentation available was insufficient to allow adequate assessment. The remaining 17 studies, which included 4087 individuals, 53% of whom received active drug, were of good quality and were otherwise reasonably comparable. There was no evidence of publication bias. Continuous abstinence rates at 6 months were significantly higher in the acamprosate-treated patients (acamprosate, 36.1%; placebo, 23.4%; RB, 1.47; [95% confidence intervals (CI): 1.29-1.69]; p < 0.001). This effect was observed independently of the method used for assigning missing data. The effect sizes in abstinent rates at 3, 6, and 12 months were 1.33, 1.50, and 1.95, respectively. At 12 months, the overall pooled difference in success rates between acamprosate and placebo was 13.3% (95% CI, 7.8-18.7%; number needed to treat, 7.5). Acamprosate also had a modest but significant beneficial effect on retention (6.01%; [95% CI, 2.90-8.82]; p = 0.0106). CONCLUSION: Acamprosate has a significant beneficial effect in enhancing abstinence in recently detoxified, alcohol-dependent individuals. [ABSTRACT FROM AUTHOR]

BACKGROUND: A multicenter, prospective study was conducted in five European countries to observe outcome in alcohol misusers treated for 24 weeks with acamprosate and various psychosocial support techniques, within the setting of standard patient care. METHODS: Patients diagnosed as alcohol dependent using DSM-III-R criteria were treated, for 24 weeks, with acamprosate and appropriate psychosocial support. Potential predictor variables were recorded at inclusion. Drinking behavior was monitored throughout; the proportion of cumulative abstinence days was the principal outcome measure. The influence of baseline clinical and demographic variables on outcome was assessed using multiple regression analysis. Adverse events were recorded systematically. RESULTS: A total of 1289 patients were recruited; 1230 took at least one dose of the drug and provided at least one set of follow-up data; 543 (42.1%)patients were observed for the full 24-week period. The overall proportion of cumulative abstinence days was 0.48. Multiple physical and psychiatric comorbidities and a history of drug addiction were negatively correlated with outcome, as were, to a lesser extent, multiple previous episodes of detoxification, unemployment, and living alone. Older age and stable employment were positively associated with outcome. The difference in the unadjusted proportion of cumulative abstinence days between countries was significant ( < 0.001) but less so when adjusted for the predictive factors identified in the multivariate model ( < 0.019). Overall, outcome was not influenced by the nature of the psychosocial support provided. Adverse events were generally mild, with gastrointestinal disorders, which occurred in 21.5% of patients, being the most frequent. CONCLUSIONS: This open-label study confirms the efficacy and safety of acamprosate in the treatment of alcohol dependence in the setting of standard patient care. Treatment benefit was observed irrespective of the nature of the psychosocial support provided. Predictors of the response to treatment were identified; their heterogeneous distribution within the study population explained, at least in part, the differences in outcome between countries. [ABSTRACT FROM AUTHOR]

1. Serum and salivary concentrations of caffeine (1,3,7- trimethylxanthine) and its dimethylxanthine metabolites were measured in 10 healthy control subjects and in 19 patients with cirrhosis, for up to 96 h following a 400 mg oral caffeine load. 2. Serum and salivary caffeine concentrations correlated significantly (r = 0.954; P less than 0.001) and no significant differences were observed in the pharmacokinetic data derived from the respective concentration-time curves. 3. In the control subjects, basal salivary caffeine concentrations did not exceed 0.4 mg l-1. The median (range) basal salivary caffeine concentrations in patients with compensated cirrhosis (n = 10), 0.2 (0-0.7) mg l-1 and decompensated cirrhosis (n = 9), 0.7 (0-5.8) mg l-1, were not significantly different from control values, although three patients with decompensated cirrhosis had basal salivary caffeine values above 2.0 mg l-1. 4. In the patients with compensated cirrhosis, the median peak salivary caffeine concentration, 10.9 (8.2- 16.5) mg l-1 was significantly greater than in controls, 7.1 (4.7-11.8) mg l-1 (P less than 0.01) and the median apparent volume of distribution was significantly reduced, 0.38 (0.19-0.49) vs 0.41 (0.23- 0.63) l kg-1 (P less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS) [ABSTRACT FROM AUTHOR]

Abstract Background Canada’s diverse society and statutory commitment to multiculturalism means that the synthesis of knowledge related to the health care experiences of immigrants is essential to realize the health potential for future Canadians. Although concerns about the maternity experiences of immigrants in Canada are relatively new, recent national guidelines explicitly call for tailoring of services to user needs. We are therefore assessing the experiences of immigrant women in Canada accessing maternity-care services. We are focusing on: 1) accessibility and acceptability (as an important dimension of access) to maternity-care services as perceived and experienced by immigrant women, and 2) the birth and postnatal outcomes of these women. Methods The aim of this study is to use a narrative synthesis, incorporating both a systematic review using narrative synthesis of reports of empirical research (qualitative, quantitative, and mixed-method designs), and a literature review of non-empirically based reports, both of which include ‘grey’ literature. The study aims to provide stakeholders with perspectives on maternity-care services as experienced by immigrant women. To achieve this, we are using integrated knowledge translation, partnering with key stakeholders to ensure topic relevancy and to tailor recommendations for effective translation into future policy and practice/programming. Two search phases and a three-stage selection process are being conducted (database search retrieved 1487 hits excluding duplicates) to provide evidence to contribute jointly to both the narrative synthesis and the non-empirical literature review. The narrative synthesis will be informed by the previous framework published in 2006 by Popay et al., using identified tools for each of its four elements. The non-empirical literature review will build upon the narrative-synthesis findings and/or identify omissions or gaps in the empirical research literature. The integrated knowledge translation plan will ensure that key messages are delivered in an audience-specific manner to optimize their effect on policy and practice change throughout the health service, and the public health, immigration and community sectors. Discussion Narrative-synthesis methods of systematic review facilitate understanding and acknowledgement of the broader influences of theoretical and contextual variables, such as race, gender, socioeconomic status, and geographical location. They also enable understanding of the shaping of differences between reported outcomes and study designs related to childbearing populations, and the development and implementation of maternity services and health interventions across diverse settings. PROSPERO registration Number 2185.

Abstract Background Black minority ethnic groups in the UK have relatively low rates of deceased donation and report a higher prevalence of beliefs that are regarded as barriers to donation. However there is little data from migrants' countries of origin. This paper examines community attitudes to deceased kidney donation in Barbados and compares the findings with a survey conducted in a disadvantaged multi-ethnic area of south London. Methods Questionnaires were administered at four public health centres in Barbados and at three private general practices. Adjusted odds ratios were calculated to compare attitudinal responses with a prior survey of 328 Caribbean and 808 White respondents in south London. Results Questionnaires were completed by 327 respondents in Barbados (93% response); 42% men and 58% women, with a mean age of 40.4 years (SD 12.6). The main religious groups were Anglican (29%) and Pentecostal (24%). Educational levels ranged from 18% not completing 5th form to 12% with university education. Attitudes to the notion of organ donation were favourable, with 73% willing to donate their kidneys after their death and only 5% definitely against this. Most preferred an opt-in system of donation. Responses to nine attitudinal questions identified 18% as having no concerns and 9% as having 4 or more concerns. The highest level of concern (43%) was for lack of confidence that medical teams would try as hard to save the life of a person who has agreed to donate organs. There was no significant association between age, gender, education or religion and attitudinal barriers, but greater knowledge of donation had some positive effect on attitudes. Comparison of attitudes to donation in south London and Barbados (adjusting for gender, age, level of education, employment status) indicated that a significantly higher proportion of the south London Caribbean respondents identified attitudinal barriers to donation. Conclusions Community attitudes in Barbados are favourable to deceased donation based on a system of informed consent. Comparison with south London data supports the hypothesis that the relatively high prevalence of negative attitudes to deceased donation among disadvantaged ethnic minorities in high income countries may reflect feelings of marginalisation and lack of belonging.

Abstract Background Kidney transplantation is associated with greater long term survival rates and improved quality of life compared with dialysis. Continuous growth in the number of patients with kidney failure has not been matched by an increase in the availability of kidneys for transplantation. This leads to long waiting lists, higher treatment costs and negative health outcomes. Discussion Misunderstandings, public uncertainty and issues of trust in the medical system, that limit willingness to be registered as a potential donor, could be addressed by community dissemination of information and new family practice initiatives that respond to individuals' personal beliefs and concerns regarding organ donation and transplantation. Summary Tackling both personal and public inertia on organ donation is important for any community oriented kidney donation campaign.

Abstract Background In Greece, there is limited research on issues related to organ donation, and the low rate of registration as donors requires explanation. This study reports the findings of a survey of knowledge and attitudes to kidney donation among primary care patients in rural Crete, Greece. Methods Two rural primary care settings in the island of Crete, Anogia Health Centre and Vrachasi Practice, were involved in a questionnaire survey. This was conducted among primary care patients (aged 18 years and over) with routine appointments, to assess their knowledge and attitudes to kidney donation. General practitioners (GPs) recruited patients and questionnaires were completed following the patients' medical consultation. Pearson's chi square tests were used and crude odds ratios (OR) with 95% confidence intervals (95% CI) were calculated in order to investigate into the possible associations between the respondents' knowledge, attitudes and specific concerns in relation to their socio-demographic features. Logistic regression analyses were used to examine differences by geographical location. Results The 224 (92.5%) of the 242 primary care attenders who were approached agreed to participate. Only 2.2% (5/224) of the respondents carried a donor card. Most participants (84.4%, 189/224) did not feel well informed about registering as a kidney donor. More than half of the respondents (54.3%, 121/223) were unwilling to register as a kidney donor and donate kidneys for transplant after death. Over a third of respondents (35.4%, 79/223) were not confident that medical teams would try as hard as possible to save the life of a person who has agreed to donate organs. People with a higher level of education were more likely to be willing to register as kidney donors [(OR: 3.3; 95% CI: 1.8–6.0), p < 0.001)] and to be less worried about their kidneys being removed after death [(OR: 0.3; 95% CI: 0.1–0.5), p < 0.001)] than those having a lower level of education. Conclusion Lack of knowledge and information regarding organ donation and negative attitudes related to registration as donors were the main findings of this study. Efforts should be based on targeting the attitudes to organ donation of individuals and population groups.

Background: Polygenic Risk Scores (PRS) based on results from genome-wide association studies offer the prospect of risk stratification for many common and complex diseases. We developed a PRS for alcohol-associated cirrhosis by comparing single-nucleotide polymorphisms among patients with alcohol-associated cirrhosis (ALC) versus drinkers who did not have evidence of liver fibrosis/cirrhosis., Methods: Using a data-driven approach, a PRS for ALC was generated using a meta-genome-wide association study of ALC (N=4305) and an independent cohort of heavy drinkers with ALC and without significant liver disease (N=3037). It was validated in 2 additional independent cohorts from the UK Biobank with diagnosed ALC (N=467) and high-risk drinking controls (N=8981) and participants in the Indiana Biobank Liver cohort with alcohol-associated liver disease (N=121) and controls without liver disease (N=3239)., Results: A 20-single-nucleotide polymorphisms PRS for ALC (PRSALC) was generated that stratified risk for ALC comparing the top and bottom deciles of PRS in the 2 validation cohorts (ORs: 2.83 [95% CI: 1.82 -4.39] in UK Biobank; 4.40 [1.56 -12.44] in Indiana Biobank Liver cohort). Furthermore, PRSALC improved the prediction of ALC risk when added to the models of clinically known predictors of ALC risk. It also stratified the risk for metabolic dysfunction -associated steatotic liver disease -cirrhosis (3.94 [2.23 -6.95]) in the Indiana Biobank Liver cohort -based exploratory analysis., Conclusions: PRSALC incorporates 20 single-nucleotide polymorphisms, predicts increased risk for ALC, and improves risk stratification for ALC compared with the models that only include clinical risk factors. This new score has the potential for early detection of heavy drinking patients who are at high risk for ALC., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Association for the Study of Liver Diseases.)

Introduction: While progress has been made in determining the genetic basis of antisocial behaviour, little progress has been made for antisocial personality disorder (ASPD), a condition that often co-occurs with other psychiatric conditions including substance use disorders, attention deficit hyperactivity disorder (ADHD), and anxiety disorders. This study aims to improve the understanding of the genetic risk for ASPD and its relationship with other disorders and traits., Methods: We conducted a genome-wide association study (GWAS) of the number of ASPD diagnostic criteria data from 3217 alcohol-dependent participants recruited in the UK (UCL, N = 644) and the USA (Yale-Penn, N = 2573)., Results: We identified rs9806493, a chromosome 15 variant, that showed a genome-wide significant association ( Z -score = -5.501, P = 3.77 × 10 -8 ) with ASPD criteria. rs9806493 is an eQTL for SLCO3A1 (Solute Carrier Organic Anion Transporter Family Member 3A1), a ubiquitously expressed gene with strong expression in brain regions that include the anterior cingulate and frontal cortices. Polygenic risk score analysis identified positive correlations between ASPD and smoking, ADHD, depression traits, and posttraumatic stress disorder. Negative correlations were observed between ASPD PRS and alcohol intake frequency, reproductive traits, and level of educational attainment., Conclusion: This study provides evidence for an association between ASPD risk and SLCO3A1 and provides insight into the genetic architecture and pleiotropic associations of ASPD., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Background: The influence of genetic factors on survival following a diagnosis of hepatocellular carcinoma (HCC) remains unclear., Aim: To assess whether genetic polymorphisms influencing the susceptibility to develop HCC are also associated with HCC prognosis., Methods: We included United Kingdom Biobank (UKB) participants diagnosed with HCC after study enrolment. The primary outcome was all-cause mortality. Patients were followed from the date of HCC diagnosis to death or the registry completion date. Five HCC susceptibility loci were investigated: rs738409 (PNPLA3), rs58542926 (TM6SF2); rs72613567 (HSD17B13); rs2242652 (TERT) and rs708113 (WNT3A). The associations between these genetic variants and HCC mortality risk were assessed using Cox regression, adjusted for age, sex, ethnicity, aetiology, severity of the underlying liver disease and receipt of curative HCC treatment., Results: The final sample included 439 patients; 74% had either non-alcoholic fatty liver disease or alcohol-related liver disease. There were 321 deaths during a mean follow-up of 1.9 years per participant. Kaplan-Meier survival estimates at 1, 3 and 5 years were 53.2%, 31.2% and 22.6% respectively. In multivariate analysis, rs72613567:TA (HSD17B13) was the only genetic susceptibility variant significantly associated with all-cause mortality risk (aHR: 0.74; 95% CI: 0.61-0.90; p = 0.003). Other associated factors were Baveno stage 3-4 (aHR: 1.65; 95% CI: 1.05-2.59; p = 0.03) and HCC treatment with curative intent (aHR: 0.25; 95% CI: 0.17-0.37; p < 0.001)., Conclusions: The rs72613567:TA polymorphism in HSD17B13 is not only associated with a reduction in the risk of developing HCC but with a survival benefit in HCC once established. Therapeutic inhibition of HSD17B13 may augment survival in individuals with HCC., (© 2023 The Authors. Alimentary Pharmacology & Therapeutics published by John Wiley & Sons Ltd.)

Background: Hepatic encephalopathy describes the spectrum of neuropsychiatric changes that may complicate the course of cirrhosis and detrimentally affect outcomes. Ammonia plays a key role in its development. Rifaximin is a non-absorbable antibiotic that inhibits urease-producing bacteria and reduces absorption of dietary and bacterial ammonia., Objectives: To evaluate the beneficial and harmful effects of rifaximin versus placebo, no intervention, or non-absorbable disaccharides for: (i) the prevention of hepatic encephalopathy, and (ii) the treatment of minimal and overt hepatic encephalopathy, in people with cirrhosis, both when used alone and when combined with a non-absorbable disaccharide., Search Methods: We searched the Cochrane Hepato-Biliary Group Clinical Trials Register, CENTRAL, MEDLINE, Embase, three other databases, the reference lists of identified papers, and relevant conference proceedings. We wrote to authors and pharmaceutical companies for information on other published, unpublished, or ongoing trials. Searches were performed to January 2023., Selection Criteria: We included randomised clinical trials assessing prevention or treatment of hepatic encephalopathy with rifaximin alone, or with a non-absorbable disaccharide, versus placebo/no intervention, or a non-absorbable disaccharide alone., Data Collection and Analysis: Six authors independently searched for studies, extracted data, and validated findings. We assessed the design, bias risk, and participant/intervention characteristics of the included studies. We assessed mortality, serious adverse events, health-related quality of life, hepatic encephalopathy, non-serious adverse events, blood ammonia, Number Connection Test-A, and length of hospital stay., Main Results: We included 41 trials involving 4545 people with, or at risk for, developing hepatic encephalopathy. We excluded 89 trials and identified 13 ongoing studies. Some trials involved participants with more than one type of hepatic encephalopathy or more than one treatment comparison. Hepatic encephalopathy was classed as acute (13 trials), chronic (7 trials), or minimal (8 trials), or else participants were considered at risk for its development (13 trials). The control groups received placebo (12 trials), no/standard treatment (1 trial), or a non-absorbable disaccharide (14 trials). Eighteen trials assessed rifaximin plus a non-absorbable disaccharide versus a non-absorbable disaccharide alone. We classified 11 trials as at high risk of overall bias for mortality and 28 for non-mortality outcomes, mainly due to lack of blinding, incomplete outcome data, and selective reporting. Compared to placebo/no intervention, rifaximin likely has no overall effect on mortality (risk ratio (RR) 0.83, 95% confidence interval (CI) 0.50 to 1.38; P = 48, I 2 = 0%; 13 trials, 1007 participants; moderate-certainty evidence), and there may be no overall effect when compared to non-absorbable disaccharides (RR 0.99, 95% CI 0.49 to 1.97; P = 0.97, I 2 = 0%; 10 trials, 786 participants; low-certainty evidence). However, there is likely a reduction in the overall risk of mortality when comparing rifaximin plus a non-absorbable disaccharide to a non-absorbable disaccharide alone (RR 0.69, 95% CI 0.55 to 0.86; number needed to treat for an additional beneficial outcome (NNTB) = 22; P = 0.001, I 2 = 0%; 14 trials, 1946 participants; moderate-certainty evidence). There is likely no effect on the overall risk of serious adverse events when comparing rifaximin to placebo/no intervention (RR 1.05, 95% CI 0.83 to 1.32; P = 68, I 2 = 0%; 9 trials, 801 participants; moderate-certainty evidence) and there may be no overall effect when compared to non-absorbable disaccharides (RR 0.97, 95% CI 0.66 to 1.40; P = 85, I 2 = 0%; 8 trials, 681 participants; low-certainty evidence). However, there was very low-certainty evidence that use of rifaximin plus a non-absorbable disaccharide may be associated with a lower risk of serious adverse events than use of a non-absorbable disaccharide alone (RR 0.66, 95% CI 0.45 to 0.98; P = 0.04, I 2 = 60%; 7 trials, 1076 participants). Rifaximin likely results in an overall effect on health-related quality of life when compared to placebo/no intervention (mean difference (MD) -1.43, 95% CI -2.87 to 0.02; P = 0.05, I 2 = 81%; 4 trials, 214 participants; moderate-certainty evidence), and may benefit health-related quality of life in people with minimal hepatic encephalopathy (MD -2.07, 95% CI -2.79 to -1.35; P < 0.001, I 2 = 0%; 3 trials, 176 participants). The overall effect on health-related quality of life when comparing rifaximin to non-absorbable disaccharides is very uncertain (MD -0.33, 95% CI -1.65 to 0.98; P = 0.62, I 2 = 0%; 2 trials, 249 participants; very low-certainty evidence). None of the combined rifaximin/non-absorbable disaccharide trials reported on this outcome. There is likely an overall beneficial effect on hepatic encephalopathy when comparing rifaximin to placebo/no intervention (RR 0.56, 95% CI 0.42 to 0.77; NNTB = 5; P < 0.001, I 2 = 68%; 13 trials, 1009 participants; moderate-certainty evidence). This effect may be more marked in people with minimal hepatic encephalopathy (RR 0.40, 95% CI 0.31 to 0.52; NNTB = 3; P < 0.001, I 2 = 10%; 6 trials, 364 participants) and in prevention trials (RR 0.71, 95% CI 0.56 to 0.91; NNTB = 10; P = 0.007, I 2 = 36%; 4 trials, 474 participants). There may be little overall effect on hepatic encephalopathy when comparing rifaximin to non-absorbable disaccharides (RR 0.85, 95% CI 0.69 to 1.05; P = 0.13, I 2 = 0%; 13 trials, 921 participants; low-certainty evidence). However, there may be an overall beneficial effect on hepatic encephalopathy when comparing rifaximin plus a non-absorbable disaccharide to a non-absorbable disaccharide alone (RR 0.58, 95% CI 0.48 to 0.71; NNTB = 5; P < 0.001, I 2 = 62%; 17 trials, 2332 participants; low-certainty evidence)., Authors' Conclusions: Compared to placebo/no intervention, rifaximin likely improves health-related quality of life in people with minimal hepatic encephalopathy, and may improve hepatic encephalopathy, particularly in populations with minimal hepatic encephalopathy and when it is used for prevention. Rifaximin likely has no overall effect on mortality, serious adverse events, health-related quality of life, or hepatic encephalopathy compared to non-absorbable disaccharides. However, when used in combination with a non-absorbable disaccharide, it likely reduces overall mortality risk, the risk of serious adverse events, improves hepatic encephalopathy, reduces the length of hospital stay, and prevents the occurrence/recurrence of hepatic encephalopathy. The certainty of evidence for these outcomes is very low to moderate; further high-quality trials are needed., (Copyright © 2023 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.)

Objective: Hepatocellular carcinoma (HCC) often develops in patients with alcohol-related cirrhosis at an annual risk of up to 2.5%. Some host genetic risk factors have been identified but do not account for the majority of the variance in occurrence. This study aimed to identify novel susceptibility loci for the development of HCC in people with alcohol related cirrhosis., Design: Patients with alcohol-related cirrhosis and HCC (cases: n=1214) and controls without HCC (n=1866), recruited from Germany, Austria, Switzerland, Italy and the UK, were included in a two-stage genome-wide association study using a case-control design. A validation cohort of 1520 people misusing alcohol but with no evidence of liver disease was included to control for possible association effects with alcohol misuse. Genotyping was performed using the InfiniumGlobal Screening Array (V.24v2, Illumina) and the OmniExpress Array (V.24v1-0a, Illumina)., Results: Associations with variants rs738409 in PNPLA3 and rs58542926 in TM6SF2 previously associated with an increased risk of HCC in patients with alcohol-related cirrhosis were confirmed at genome-wide significance. A novel locus rs2242652(A) in TERT (telomerase reverse transcriptase) was also associated with a decreased risk of HCC, in the combined meta-analysis, at genome-wide significance (p=6.41×10 -9 , OR=0.61 (95% CI 0.52 to 0.70). This protective association remained significant after correction for sex, age, body mass index and type 2 diabetes (p=7.94×10 -5 , OR=0.63 (95% CI 0.50 to 0.79). Carriage of rs2242652(A) in TERT was associated with an increased leucocyte telomere length (p=2.12×10 -44 )., Conclusion: This study identifies rs2242652 in TERT as a novel protective factor for HCC in patients with alcohol-related cirrhosis., Competing Interests: Competing interests: JT has received speaking and/or consulting fees from Versantis, Gore, Bayer, Alexion, Norgine, Grifols and CSL Behring., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY. Published by BMJ.)

Aims: Wernicke-Korsakoff syndrome (WKS) is commonly associated with chronic alcohol misuse, a condition known to have multiple detrimental effects on thiamine metabolism. This study was conducted to identify genetic variants that may contribute to the development of WKS in individuals with alcohol dependence syndrome through alteration of thiamine transport into cells., Methods: Exome sequencing data from a panel of genes related to alcohol metabolism and thiamine pathways were analysed in a discovery cohort of 29 individuals with WKS to identify possible genetic risk variants associated with its development. Variant frequencies in this discovery cohort were compared with European frequencies in the Genome Aggregation Database browser, and those present at significantly higher frequencies were genotyped in an additional cohort of 87 alcohol-dependent cases with WKS and 197 alcohol-dependent cognitively intact controls., Results: Thirty non-synonymous variants were identified in the discovery cohort and, after filtering, 23 were taken forward and genotyped in the case-control cohort. Of these SLC19A1:rs1051266:G was nominally associated with WKS. SLC19A1 encodes the reduced folate carrier, a major transporter for physiological folate in plasma; rs1051266 is reported to impact folate transport. Thiamine pyrophosphate (TPP) efflux was significantly decreased in HEK293 cells, stably transfected with rs1051266:G, under thiamine deficient conditions when compared with the efflux from cells transfected with rs1051266:A (P = 5.7 × 10-11)., Conclusion: This study provides evidence for the role of genetic variation in the SLC19A1 gene, which may contribute to the development of WKS in vivo through modulation of TPP transport in cells., (© The Author(s) 2022. Medical Council on Alcohol and Oxford University Press. All rights reserved.)

Background & Aims: Malnutrition is associated with adverse clinical outcomes in patients with cirrhosis. Accurate assessment of energy requirements is needed to optimize dietary intake. Resting energy expenditure (REE), the major component of total energy expenditure, can be measured using indirect calorimetry (mREE) or estimated using prediction equations (pREE). This study assessed the usefulness of predicted estimates of REE in this patient population., Methods: Individual mREE data were available for 900 patients with cirrhosis (mean [±1 SD] age 55.7±11.6 years-old; 70% men; 52% south-east Asian) and 282 healthy controls (mean age 36.0±12.8 years-old; 52% men; 18% south-east Asian). Metabolic status was classified using thresholds based on the mean ± 1 SD of the mREE in the healthy controls. Comparisons were made between mREE and pREE estimates obtained using the Harris-Benedict, Mifflin, Schofield and Henry equations. Stepwise regression was used to build 3 new prediction models which included sex, ethnicity, body composition measures, and model for end-stage liver disease scores., Results: The mean mREE was significantly higher in patients than controls when referenced to dry body weight (22.4±3.8 cf. 20.8±2.6 kcal/kg/24 hr; p <0.001); there were no significant sex differences. The mean mREE was significantly higher in Caucasian than Asian patients (23.1±4.4 cf. 21.7±2.9 kcal/kg/24 hr; p <0.001). Overall, 37.1% of Caucasian and 25.3% of Asian patients were classified as hypermetabolic. The differences between mREE and pREE were both statistically and clinically relevant; in the total patient population, pREE estimates ranged from 501 kcal/24 hr less to 548 kcal/24 hr more than the mREE. Newly derived prediction equations provided better estimates of mREE but still had limited clinical utility., Conclusions: Prediction equations do not provide useful estimates of REE in patients with cirrhosis. REE should be directly measured., Lay Summary: People with cirrhosis are often malnourished and this has a detrimental effect on outcome. Provision of an adequate diet is very important and is best achieved by measuring daily energy requirements and adjusting dietary intake accordingly. Prediction equations, which use information on age, sex, weight, and height can be used to estimate energy requirements; however, the results they provide are not accurate enough for clinical use, particularly as they vary according to sex and ethnicity., Competing Interests: Conflicts of interest None of the authors report a conflict of interest in relation to this work. Please refer to the accompanying ICMJE disclosure forms for further details., (Copyright © 2022 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)