Lack of awareness and ethnic polarity is a major cause of metabolic associated fatty liver disease in high-risk diabetes population in South London.

Background: Metabolic associated fatty liver disease (MAFLD) stands as the leading cause of chronic liver disease globally. Notably, individuals with metabolic risk factors, such as diabetes and obesity, exhibit a staggering prevalence of MAFLD, with estimates reaching up to 70%. However, despite its widespread occurrence, there's a noticeable gap in understanding and awareness about MAFLD among these high-risk groups. Objectives: The main objective of this study was to assess the awareness and prevalence of MAFLD among diabetic patients who regularly receive secondary care focusing particularly on how multiethnic backgrounds and associated lifestyle preferences influence these health outcomes. Design: Cross-sectional study. Methods: Patients with type 2 diabetes (T2D) who regularly attend Lambeth Diabetes Intermediate Care Team clinics were invited to undergo MAFLD screening using FibroScan. Those who agreed to participate were provided with structured questionnaires on diet, physical activity, and MAFLD knowledge by a hepatologist. For each participant, anthropometric data, medical history, liver stiffness measurement, and controlled attenuation parameter (CAP) were documented. Steatosis was identified with a CAP value of ⩾275 dB/m, and advanced fibrosis was flagged at values of ⩾8 kPa. Results: The FibroScan data was valid in 96.4% (215), 53.5% (115/215) had steatosis and 26.2% (58/215) had liver fibrosis in this multiethnic high-risk group. Awareness of MAFLD was notably low at 30.9%. Alarmingly, 69% of patients diagnosed with liver fibrosis were unfamiliar with the condition. Additionally, understanding of MAFLD showed variation among different ethnic groups with highest levels were demonstrated in the Caucasian/White population (46%). Majority (96%) of these subjects were receiving specific lifestyle advice from healthcare professionals due to metabolic conditions and comorbidities. However, most patients preferred diets that were rich in carbohydrates (65.8%) and only 43% subjects performed moderate exercise daily highlighting lack of understanding regarding MAFLD and lifestyle management. Conclusion: There's a pressing need for increased awareness of MAFLD, especially in multiethnic high-risk groups. Additionally, the development of cost-effective strategies to stratify risk is essential to address this growing health concern.

Ethnic differences and lack of awareness increase fatty liver disease risk in South London diabetics Metabolic associated fatty liver disease (MAFLD) or more commonly fatty liver disease is the leading cause of chronic liver disease globally, particularly affecting individuals with diabetes and obesity. This study focuses on patients with type 2 diabetes in South London who regularly receive secondary care, examining the awareness and prevalence of MAFLD, especially across different ethnic groups. Participants, all with Type 2 Diabetes, attended clinics run by the Diabetes Intermediate Care Team where they underwent MAFLD screening using Fibroscan. This tool measures liver stiffness (fibrosis) and fat levels. In addition to the scans, participants answered questions about their diet, physical activity, and knowledge of MAFLD. Key findings include a low overall awareness of MAFLD, with only about 30.9% of patients aware of the disease. Among those diagnosed with liver fibrosis, 69% were unfamiliar with the condition, indicating a significant awareness gap. Interestingly, awareness levels varied among ethnic groups, with Caucasian/white patients showing the highest awareness at 46%. Despite receiving lifestyle advice from health professionals, many participants preferred carbohydrate-rich diets and only a minority engaged in daily moderate exercise. This behaviour highlights a general lack of understanding about MAFLD and its management through lifestyle changes. The study concludes that there is a critical need to raise awareness about MAFLD among high-risk, multi-ethnic groups in South London. It also highlights the necessity for developing cost-effective strategies to better identify and manage this growing health concern.

Social network enhanced behavioral interventions for diabetes and obesity: A 3 arm randomized trial with 2 years follow-up in Jordan.

While obesity and diabetes are rising pandemics, few low-cost and effective prevention and management strategies exist, especially in the Middle East. Nearly 20% of adults in Jordan suffer from diabetes, and over 75% are overweight or obese. Social network-based programs have shown promise as a viable public health intervention strategy to address these growing crises. We evaluated the effectiveness of the Microclinic Program (MCP) via a 6-month multi-community randomized trial in Jordan, with follow-up at 2 years. The MCP leverages existing social relationships to propagate positive health behaviors and information. We recruited participants from 3 community health centers in Amman, Jordan. Participants were eligible for the study if they had diabetes, pre-diabetes, or possessed ≥1 metabolic risk factor along with a family history of diabetes. We randomized participants into three trial arms: (A Group) received the Full MCP with curriculum-activated social network interactions; (B Group) received Basic MCP educational sessions with organic social network interactions; or (C Group-Control) received standard care coupled with active monitoring and parallel screenings. Groups of individuals were randomized as units in a 3:1:1 ratio, with resulting group sizes of n = 540, 186, and 188 in arms A, B, and C, respectively. We assessed the overall changes in body weight, fasting glucose, hemoglobin A1c (HbA1c) and mean arterial blood pressure between study arms in multiple evaluations across 2 years (including at 6-months and 2-years follow-up). We investigated the effectiveness of Full and Basic MCP social network interventions using multilevel models for longitudinal data with hierarchical nesting of individuals within MCP classrooms, within community centers, and within temporal cohorts. We observed significant overall 2-year differences between all 3 groups for changes in body weight (P = 0.0003), fasting blood glucose (P = 0.0015), and HbA1c (P = 0.0004), but not in mean arterial blood pressure (P = 0.45). However, significant changes in mean arterial pressure were observed for Full MCP versus controls (P = 0.002). Weight loss in the Full MCP exceeded (-0.97 kg (P<0.001)) the Basic MCP during the intervention. Furthermore, both Full and Basic MCP yielded greater weight loss compared to the control group at 2 years. The Full MCP also sustained a superior fasting glucose change over 2 years (overall P<0.0001) versus the control group. For HbA1c, the Full MCP similarly led to greater 6-month reduction in HbA1c versus the control group (P<0.001), with attenuation at 2 years. For mean arterial blood pressure, the Full MCP yielded a greater drop in blood pressure versus control at 6 months; with attenuation at 2 years. These results suggest that activated social networks of classroom interactions can be harnessed to improve health behaviors related to obesity and diabetes. Future studies should investigate how public health policies and initiatives can further leverage social network programs for greater community propagation. Trial registration. ClinicalTrials.gov Identifier: NCT01818674.

Switching Tenofovir Disoproxil Fumarate (TDF) to Tenofovir Alafenamide Fumarate (TAF) in Hepatitis B/HIV Co-Infection: A Feasibility Study.

PURPOSE: Tenofovir alafenamide (TAF) delivers the active metabolite more efficiently to target cells compared with tenofovir disoproxil fumarate (TDF). Recent studies suggest that TAF is efficacious in treatment naïve individuals who are co-infected with HBV/HIV and may have superior effects on HBV e antigen (HBeAg) seroconversion in this setting. The primary objective of this study was to explore the feasibility of switching from TDF to TAF in HBV/HIV co-infection. METHODS: In this single-arm, multicenter, open-label study, we recruited patients (n = 20) who were on stable TDF-based antiviral therapy for at least 12 months. All participants had undetectable HIV RNA and HBV DNA levels at the time of screening and were converted to a TAF-based treatment regimen (TAF + emtricitabine + third agent) for 48 weeks. FINDINGS: Twenty-seven individuals were invited to take part in the screening process; 3 met the exclusion criteria and a further 4 withdrew consent prior to enrolment. The remaining participants were predominantly male (70%), non-cirrhotic (95%) and of Afro-Caribbean ethnicity (60%). All were co-infected with HIV-1 and established on long-term antiretroviral treatment prior to enrolment (median 6.5 years). No adverse events related to the study drug were observed, and most patients (89.5%) maintained undetectable HIV RNA and HBV DNA throughout the follow-up period. IMPLICATIONS: Switching from TDF to TAF in HBV/HIV co-infection was safe, well tolerated and maintained virological suppression in most patients. Additional studies are needed to confirm these findings in larger cohorts and explore other endpoints.

Overview of New Targets for Hepatitis B Virus: Immune Modulators, Interferons, Bifunctional Peptides, Therapeutic Vaccines and Beyond.

Nucleos(t)ide analogs are the cornerstone of treatment against hepatitis B virus; however, they have no direct effect on its transcriptional template (ie, covalently closed circular DNA) and so functional cure is rarely achieved. Over recent years, there has been a significant improvement in our understanding of the viral life cycle and its mechanisms of immune evasion. In this review article, we will explore novel therapeutic targets, discuss the latest data from clinical trials, and highlight future research priorities.

Correction: Ramadan fasting and weight change trajectories: Time-varying association of weight during and after Ramadan in low-income and refugee populations.

[This corrects the article DOI: 10.1371/journal.pgph.0000371.].

Model-based clustering for random hypergraphs.

A probabilistic model for random hypergraphs is introduced to represent unary, binary and higher order interactions among objects in real-world problems. This model is an extension of the latent class analysis model that introduces two clustering structures for hyperedges and captures variation in the size of hyperedges. An expectation maximization algorithm with minorization maximization steps is developed to perform parameter estimation. Model selection using Bayesian Information Criterion is proposed. The model is applied to simulated data and two real-world data sets where interesting results are obtained.

The 'nuclear option' revisited: Confirmation of Ss-daf-12 function and therapeutic potential in Strongyloides stercoralis and other parasitic nematode infections.

Mechanisms governing morphogenesis and development of infectious third-stage larvae (L3i) of parasitic nematodes have been likened to those regulating dauer development in Caenorhabditis elegans. Dauer regulatory signal transduction comprises initial G protein-coupled receptor (GPCR) signaling in chemosensory neurons of the amphidial complex that regulates parallel insulin- and TGFß-like signaling in the tissues. Insulin- and TGFß-like signals converge to co-regulate steroid signaling through the nuclear receptor (NR) DAF-12. Discovery of the steroid ligands of DAF-12 opened a new avenue of small molecule physiology in C. elegans. These signaling pathways are conserved in parasitic nematodes and an increasing body of evidence supports their function in formation and developmental regulation of L3i during the infectious process in soil transmitted species. This review presents these lines of evidence for G protein-coupled receptor (GPCR), insulin- and TGFß-like signaling in brief and focuses primarily on signaling through parasite orthologs of DAF-12. We discuss in some depth the deployment of sensitive analytical techniques to identify Δ7-dafachronic acid as the natural ligand of DAF-12 homologs in Strongyloides stercoralis and Haemonchus contortus and of targeted mutagenesis by CRISPR/Cas9 to assign dauer-like regulatory function to the NR Ss-DAF-12, its coactivator Ss-DIP-1 and the key ligand biosynthetic enzyme Ss-CYP-22a9. Finally, we present published evidence of the potential of Ss-DAF-12 signaling as a chemotherapeutic target in human strongyloidiasis.

Review article: novel biomarkers in hepatitis B infection.

BACKGROUND: Chronic hepatitis B remains a global health problem with an estimated 296 million people affected worldwide. Individuals are at risk of serious complications such as cirrhosis and hepatocellular carcinoma and accurately predicting these clinical endpoints has proven difficult. However, several viral biomarkers have recently been developed, including quantitative HBV surface antigen (qHBsAg), hepatitis B RNA (HBV RNA) and core-related antigen (HBcrAg), and shown promise in a range of clinical settings. AIMS: To critically appraise these novel biomarkers, exploring their potential uses, availability of assays and areas for future development. METHODS: We performed a literature search of PubMed, identifying articles published in the field of hepatitis B biomarkers between 2010 and 2022. RESULTS: Novel biomarkers such as HBcrAg, HBV RNA and qHBsAg may be useful in predicting treatment outcomes, stratifying the risk of future complications and estimating off-treatment viral reactivation. Furthermore, HBV RNA and HBcrAg titres may accurately reflect cccDNA transcriptional activity, and this is particularly informative in the context of nucleoside analogue therapy. On a cautionary note, most studies have been performed in Caucasian or Asian populations, and methods for detecting HBV RNA lack standardisation. CONCLUSION: Novel viral biomarkers have the potential to provide additional insights into the natural history of infection and allow a more bespoke, cost-effective framework of care. However, access remains limited, and further efforts are needed to validate their use in ethnically diverse populations, confirm predictive cut-off values, and establish their role in the era of novel antiviral therapies.

A case of HBV-induced liver failure in the REEF-2 phase II trial: Implications for finite treatment strategies in HBV 'cure'.

Nucleoside analogues are the mainstay of treatment for patients with chronic HBV infection but have no direct effect on covalently closed circular DNA. Long-term HBV viral suppression is now routine, but the desirable endpoint of functional cure is rarely achieved. Newer therapies, targeting other aspects of the replicative life cycle of HBV, present opportunities to deliver finite therapy and HBV 'cure'. This is an area of keen focus for the HBV community. We describe a severe case of hepatitis B reactivation, occurring shortly after the withdrawal of a nucleoside analogue within the protocol of a clinical trial (REEF-2). Despite best supportive care and prompt re-introduction of tenofovir, the patient developed subacute liver failure, requiring emergency orthotopic liver transplantation. As we strive to achieve HBV cure, this case highlights the potential risks of finite therapy and highlights the need for improved biomarker-driven strategies and re-evaluation of study protocols.

Ramadan fasting and weight change trajectories: Time-varying association of weight during and after Ramadan in low-income and refugee populations.

Obesity is a significant driver of the global burden of non-communicable diseases. Fasting is one approach that has been shown to improve health outcomes. However, the effects of Ramadan fasting differ in that the type, frequency, quantity, and time of food consumption vary. This phenomenon requires in-depth evaluation considering that 90% of Muslims (~2 billion people) fast during Ramadan. To address this issue, we evaluated the pattern of weight change during and following Ramadan for a total of 52 weeks. The study was conducted in Amman, Jordan. Between 2012 and 2015, 913 participants were recruited as part of a trial investigating the efficacy of a weight loss intervention among those with or at risk for diabetes. Weight was measured weekly starting at the beginning of Ramadan, and changes were analyzed using discrete and spline models adjusted for age, sex, and trial group. Results show slight weight gain within the first two weeks and weight loss in the subsequent weeks. During the first week of Ramadan, the estimate for a weight increase was 0·427 kg, (95% CI: -0·007, 0·861) relative to baseline, compared to an estimated weight reduction of 0·55kg (95% CI: 0·05, 1·05) by the 8th week relative to baseline. There was clear evidence of gradual weight gain from week 8 until week 26 with an estimated weight gain of 2.547 kg (95% CI: 1.567, 3.527) at week 26 relative to baseline. A sharp drop of 2.66kg in weight was observed between the 26th and 28th week before it stabilized. Our results show that weight changes occurred during and after Ramadan. Weight fluctuations may affect health risks, and thus, findings from this study can inform interventions. Public health agencies could leverage this period of dietary change to sustain some of the benefits of fasting. The authors (DEZ, EFD) acknowledge the Mulago Foundation, the Horace W. Goldsmith Foundation, Robert Wood Johnson Foundation, and the World Diabetes Foundation. TRIAL REGISTRATION. Clinicaltrials.gov registry identifier: NCT01596244.

Characterization of the endogenous DAF-12 ligand and its use as an anthelmintic agent in Strongyloides stercoralis.

A prevalent feature of Strongyloides stercoralis is a life-long and potentially lethal infection that is due to the nematode parasite's ability to autoinfect and, thereby, self-replicate within its host. Here, we investigated the role of the parasite's nuclear receptor, Ss-DAF-12, in governing infection. We identified Δ7-DA as the endogenous Ss-DAF-12 ligand and elucidated the hormone's biosynthetic pathway. Genetic loss of function of the ligand's rate-limiting enzyme demonstrated that Δ7-DA synthesis is necessary for parasite reproduction, whereas its absence is required for the development of infectious larvae. Availability of the ligand permits Ss-DAF-12 to function as an on/off switch governing autoinfection, making it vulnerable to therapeutic intervention. In a preclinical model of hyperinfection, pharmacologic activation of DAF-12 suppressed autoinfection and markedly reduced lethality. Moreover, when Δ7-DA was administered with ivermectin, the current but limited drug of choice for treating strongyloidiasis, the combinatorial effects of the two drugs resulted in a near cure of the disease.

Weighted stochastic block model.

We propose a weighted stochastic block model (WSBM) which extends the stochastic block model to the important case in which edges are weighted. We address the parameter estimation of the WSBM by use of maximum likelihood and variational approaches, and establish the consistency of these estimators. The problem of choosing the number of classes in a WSBM is addressed. The proposed model is applied to simulated data and an illustrative data set.

Screening for Hepatocellular Carcinoma in Chronic Hepatitis B: An Update.

(1) Background: Hepatocellular carcinoma (HCC) is an important cause of mortality in individuals with chronic hepatitis B infection, with screening of high-risk groups recommended in all major international guidelines. Our understanding of the risk factors involved has improved over time, encouraging researchers to develop models that predict future risk of HCC development. (2) Methods: A literature search of the PubMed database was carried out to identify studies that derive or validate models predicting HCC development in patients with chronic hepatitis B. Subsequently, a second literature search was carried out to explore the potential role of novel viral biomarkers in this field. (3) Results: To date, a total of 23 models have been developed predicting future HCC risk, of which 12 have been derived from cohorts of treatment-naïve individuals. Most models have been developed in Asian populations (n = 20), with a smaller number in Caucasian cohorts (n = 3). All of the models demonstrate satisfactory performance in their original derivation cohorts, but many lack external validation. In recent studies, novel viral biomarkers have demonstrated utility in predicting HCC risk in patients with chronic hepatitis B, amongst both treated and treatment-naïve patients. (4) Conclusion: Several models have been developed to predict the risk of HCC development in individuals with chronic hepatitis B infection, but many have not been externally validated outside of the Asian population. Further research is needed to refine these models and facilitate a more tailored HCC surveillance programme in the future.

Transgenic expression of a T cell epitope in Strongyloides ratti reveals that helminth-specific CD4+ T cells constitute both Th2 and Treg populations.

Helminths are distinct from microbial pathogens in both size and complexity, and are the likely evolutionary driving force for type 2 immunity. CD4+ helper T cells can both coordinate worm clearance and prevent immunopathology, but issues of T cell antigen specificity in the context of helminth-induced Th2 and T regulatory cell (Treg) responses have not been addressed. Herein, we generated a novel transgenic line of the gastrointestinal nematode Strongyloides ratti expressing the immunodominant CD4+ T cell epitope 2W1S as a fusion protein with green fluorescent protein (GFP) and FLAG peptide in order to track and study helminth-specific CD4+ T cells. C57BL/6 mice infected with this stable transgenic line (termed Hulk) underwent a dose-dependent expansion of activated CD44hiCD11ahi 2W1S-specific CD4+ T cells, preferentially in the lung parenchyma. Transcriptional profiling of 2W1S-specific CD4+ T cells isolated from mice infected with either Hulk or the enteric bacterial pathogen Salmonella expressing 2W1S revealed that pathogen context exerted a dominant influence over CD4+ T cell phenotype. Interestingly, Hulk-elicited 2W1S-specific CD4+ T cells exhibited both Th2 and Treg phenotypes and expressed high levels of the EGFR ligand amphiregulin, which differed greatly from the phenotype of 2W1S-specific CD4+ T cells elicited by 2W1S-expressing Salmonella. While immunization with 2W1S peptide did not enhance clearance of Hulk infection, immunization did increase total amphiregulin production as well as the number of amphiregulin-expressing CD3+ cells in the lung following Hulk infection. Altogether, this new model system elucidates effector as well as immunosuppressive and wound reparative roles of helminth-specific CD4+ T cells. This report establishes a new resource for studying the nature and function of helminth-specific T cells.

Strongyloides stercoralis and HTLV-1 coinfection in CD34+ cord blood stem cell humanized mice: Alteration of cytokine responses and enhancement of larval growth.

Viral and parasitic coinfections are known to lead to both enhanced disease progression and altered disease states. HTLV-1 and Strongyloides stercoralis are co-endemic throughout much of their worldwide ranges resulting in a significant incidence of coinfection. Independently, HTLV-1 induces a Th1 response and S. stercoralis infection induces a Th2 response. However, coinfection with the two pathogens has been associated with the development of S. stercoralis hyperinfection and an alteration of the Th1/Th2 balance. In this study, a model of HTLV-1 and S. stercoralis coinfection in CD34+ umbilical cord blood hematopoietic stem cell engrafted humanized mice was established. An increased level of mortality was observed in the HTLV-1 and coinfected animals when compared to the S. stercoralis infected group. The mortality was not correlated with proviral loads or total viral RNA. Analysis of cytokine profiles showed a distinct shift towards Th1 responses in HTLV-1 infected animals, a shift towards Th2 cytokines in S. stercoralis infected animals and elevated TNF-α responses in coinfected animals. HTLV-1 infected and coinfection groups showed a significant, yet non-clonal expansion of the CD4+CD25+ T-cell population. Numbers of worms in the coinfection group did not differ from those of the S. stercoralis infected group and no autoinfective larvae were found. However, infective larvae recovered from the coinfection group showed an enhancement in growth, as was seen in mice with S. stercoralis hyperinfection caused by treatment with steroids. Humanized mice coinfected with S. stercoralis and HTLV-1 demonstrate features associated with human infection with these pathogens and provide a unique opportunity to study the interaction between these two infections in vivo in the context of human immune cells.