Longitudinal Outcomes Associated With Metabolic Dysfunction-Associated Steatotic Liver Disease: A Meta-analysis of 129 Studies.

BACKGROUND & AIMS: The progression of metabolic dysfunction-associated steatotic liver disease (MASLD) has been found to manifest in a series of hepatic and extrahepatic complications. A comprehensive meta-analysis of the longitudinal outcomes associated with MASLD has yet to be conducted. METHODS: To investigate the longitudinal outcomes associated with MASLD, Medline and Embase databases were searched to identify original studies that evaluated the longitudinal risks of incident clinical outcomes among MASLD patients compared with non-MASLD individuals. DerSimonian Laird random-effects meta-analysis was performed. Pooled effect estimates were calculated, and heterogeneity among studies was evaluated. RESULTS: One hundred twenty-nine studies were included in the meta-analysis. Meta-analysis revealed a significant increase in the risk of cardiovascular outcomes (hazard ratio [HR], 1.43; 95% confidence interval [CI], 1.27-1.60; P < .01), various metabolic outcomes such as incident hypertension (HR, 1.75; 95% CI, 1.46-2.08; P < .01), diabetes (HR, 2.56; 95% CI, 2.10-3.13; P < .01), pre-diabetes (HR, 1.69; 95% CI, 1.22-2.35; P < .01), metabolic syndrome (HR, 2.57; 95% CI, 1.13-5.85; P = .02), chronic kidney disease (HR, 1.38; 95% CI, 1.27-1.50; P < .01), as well as all cancers (HR, 1.54; 95% CI, 1.35-1.76; P < .01) among MASLD patients compared with non-MASLD individuals. By subgroup analysis, MASLD patients with advanced liver disease (HR, 3.60; 95% CI, 2.10-6.18; P < .01) were also found to be associated with a significantly greater risk (P = .02) of incident diabetes than those with less severe MASLD (HR, 1.63; 95% CI, 1.0-2.45; P = .02) when compared with non-MASLD. CONCLUSIONS: The present study emphasizes the association between MASLD and its clinical outcomes including cardiovascular, metabolic, oncologic, and other outcomes. The multisystemic nature of MASLD found in this analysis requires treatment targets to reduce systemic events and end organ complications.

Donor Diabetes and Steatosis Affects Recipient Survival Following Liver Transplantation Based on Etiology of Liver Cirrhosis.

BACKGROUND: Liver transplantation (LT) offers patients with decompensated cirrhosis the best chance at long-term survival. With the rising prevalence of diabetes, further clarity is needed on the impact of receiving a liver allograft from a donor with diabetes on post-LT outcomes. This study aims to evaluate the impact of donor diabetes on clinical outcomes after LT. METHODS: This is a retrospective analysis of the United Network for Organ Sharing registry data of LT recipients from January 1, 2000, to December 31, 2021. Outcomes analysis was performed using Cox proportional model for all-cause mortality and graft failure. Confounding was reduced by coarsened exact matching causal inference analysis. RESULTS: Of 66 960 donors identified, 7178 (10.7%) had diabetes. Trend analysis revealed a longitudinal increase in the prevalence of donor diabetes ( P < 0.001). Importantly, donor diabetes was associated with increased all-cause mortality (hazard ratio [HR]: 1.13; 95% confidence interval [CI], 1.07-1.19; P < 0.001) and graft failure (HR: 1.16; 95% CI, 1.11-1.22; P < 0.001). Receiving donor organ with diabetes reduced graft survival in patients who received LT for nonalcoholic steatohepatitis cirrhosis (HR: 1.26; 95% CI, 1.13-1.41; P < 0.001) but not other etiologies of cirrhosis. CONCLUSIONS: Donor diabetes was associated with worse outcomes post-LT, particularly in patients receiving LT for nonalcoholic steatohepatitis cirrhosis. Future studies are needed to better understand the mechanism underlying this association to develop better risk stratification and clinical practice to improve the outcomes of the transplanted patients.

Proton Pump Inhibitors Increases Longitudinal Risk of Mortality, Decompensation, and Infection in Cirrhosis: A Meta-Analysis.

BACKGROUND/AIMS: Proton pump inhibitors (PPIs) are frequently prescribed to cirrhotic patients, but there is limited longitudinal evidence regarding their effects. This study aimed to assess the impact of PPIs on adverse events in cirrhotic patients. METHODS: A comprehensive search was conducted using the Medline and Embase databases to identify relevant articles. Pooled hazard ratios (HRs) using DerSimonian and Laird random-effects model were calculated to evaluate the risk of adverse events such as long-term mortality, hepatic decompensation, hepatic encephalopathy (HE), spontaneous bacterial peritonitis (SBP), and overall infection in cirrhotic patients with PPI use. RESULTS: The analysis included 28 studies with 260,854 cirrhotic patients. The prevalence of PPI use among cirrhotic patients was 55.93%. The use of PPIs was not significantly associated with short-term mortality in cirrhotic patients. However, long-term mortality (HR 1.321, 95% CI 1.103-1.581, P = 0.002), decompensation (HR 1.646, 95% CI 1.477-1.835, P < 0.001), HE (HR 1.968, 95% CI 1.372-2.822, P < 0.001), SBP (HR 1.751, 95% CI 1.649-1.859, P < 0.001), and infection (HR 1.370, 95% CI 1.148-1.634, P < 0.001) were significantly associated with PPI use. Sensitivity analysis with prospective studies yielded similar results. CONCLUSION: PPIs should be reserved for appropriate indications at lowest effective dose for cirrhotic patients due to the potential harm.

Survival Trends in Sorafenib for Advanced Hepatocellular Carcinoma: A Reconstructed Individual Patient Data Meta-Analysis of Randomized Trials.

Background: Emerging data suggest that outcomes for advanced hepatocellular carcinoma (HCC) treated with sorafenib may have improved over time. We aimed to provide robust, time-to-event estimates of survival outcomes for sorafenib in advanced HCC. Summary: In this systematic review and individual patient data meta-analysis of randomized-controlled trials (RCTs), we searched MEDLINE and Embase from inception till September 2022 for RCTs that provided data for overall survival (OS) and progression-free survival (PFS) for sorafenib monotherapy as first-line systemic therapy for advanced HCC. We performed a pooled analysis using reconstructed individual participant data from published Kaplan-Meier curves to obtain robust estimates for OS and PFS. Of 1,599 articles identified, 29 studies (5,525 patients) met the inclusion criteria. Overall, the median OS was 10.4 (95% CI: 9.6-11.4) months. Median OS increased over time, from 9.8 (95% CI: 8.8-10.7) months in studies before 2015 to 13.4 (95% CI: 11.03-15.24) months in studies from 2015 onwards (p < 0.001). OS did not differ by trial phase, geographical region, or study design. The overall median PFS was 4.4 (95% CI: 3.9-4.8) months, but PFS did not improve over time. Sensitivity analysis of studies from 2015 and onwards to account for the introduction of direct-acting antivirals determined that hepatitis C virus was associated with reduced mortality (p < 0.001). There was minimal heterogeneity in the estimates for OS (all I2 ≤ 33). Key Messages: Survival outcomes for sorafenib in advanced HCC have improved over time. These data have important implications for clinical trial design.

Patterns in Cancer Incidence Among People Younger Than 50 Years in the US, 2010 to 2019.

Importance: Emerging data suggest that the incidence of early-onset cancers, defined as cancers diagnosed in people younger than 50 years, is increasing, but updated data are limited. Objective: To characterize the patterns in the incidence of early-onset cancers in the US from 2010 to 2019 and provide granular data on the cancers with the fastest-growing incidence rates. Design, Setting, and Participants: This population-based cohort study analyzed data from 17 National Cancer Institute Surveillance, Epidemiology, and End Results registries from January 1, 2010, to December 31, 2019. Age-standardized incidence rates per 100 000 people were extracted for early-onset cancers, with rates age adjusted to the US standard population. A total of 562 145 patients with early-onset cancer between 2010 and 2019 were identified and included. Data were analyzed from October 16, 2022, to May 23, 2023. Main Outcomes and Measures: Primary outcomes were incidence rates and descriptive epidemiological data for people younger than 50 years with cancer. The annual percentage change (APC) of the age-standardized incidence rate was estimated using the Joinpoint regression program. Results: Among 562 145 patients (324 138 [57.7%] aged 40-49 years; 351 120 [62.5%] female) with early-onset cancer, 4565 (0.8%) were American Indian or Alaska Native, 54 876 (9.8%) were Asian or Pacific Islander, 61 048 (10.9%) were Black, 118 099 (21.0%) were Hispanic, 314 610 (56.0%) were White, and 8947 (1.6%) were of unknown race and/or ethnicity. From 2010 to 2019, the age-standardized incidence rate of early-onset cancers increased overall (APC, 0.28%; 95% CI, 0.09%-0.47%; P = .01) and in female individuals (APC, 0.67%; 95% CI, 0.39%-0.94%; P = .001) but decreased in male individuals (APC, -0.37%; 95% CI, -0.51% to -0.22%; P < .001). In contrast, the age-standardized incidence rate of cancers in individuals aged 50 years and older decreased over the study period (APC, -0.87%; 95% CI, -1.06% to -0.67%; P < .001). In 2019, the highest number of incident cases of early-onset cancer were in the breast (n = 12 649). From 2010 to 2019, gastrointestinal cancers had the fastest-growing incidence rates among all early-onset cancer groups (APC, 2.16%; 95% CI, 1.66%-2.67%; P < .001). Among gastrointestinal cancers, those with the fastest-growing incidence rates were in the appendix (APC, 15.61%; 95% CI, 9.21%-22.38%; P < .001), intrahepatic bile duct (APC, 8.12%; 95% CI, 4.94%-11.39%; P < .001), and pancreas (APC, 2.53%; 95% CI, 1.69%-3.38%; P < .001). Conclusions and Relevance: In this cohort study, the incidence rates of early-onset cancer increased from 2010 to 2019. Although breast cancer had the highest number of incident cases, gastrointestinal cancers had the fastest-growing incidence rates among all early-onset cancers. These data may be useful for the development of surveillance strategies and funding priorities.

Trial watch: immunotherapeutic strategies on the horizon for hepatocellular carcinoma.

The use of immune checkpoint inhibitors (ICIs) targeting PD-L1/PD-1 and CTLA-4 has transformed the oncology practice of hepatocellular carcinoma. However, only 25-30% of the patients with advanced HCC treated with atezolizumab-bevacizumab or tremelimumab-durvalumab (STRIDE) respond initially, and mechanistic biomarkers and novel treatment strategies are urgently needed for patients who present with or acquire resistance to first-line ICI-based therapies. The recent approval of the STRIDE regimen has also engendered new questions, such as patient selection factors (e.g. portal hypertension and history of variceal bleed) and biomarkers, and the optimal combination and sequencing of ICI-based regimens. Triumphs in the setting of advanced HCC have also galvanized considerable interest in the broader application of ICIs to early- and intermediate-stage diseases, including clinical combination of ICIs with locoregional therapies. Among these clinical contexts, the role of ICIs in liver transplantation - which is a potentially curative strategy unique to HCC management - as a bridge to liver transplant in potential candidates or in the setting of post-transplant recurrence, warrants investigation in view of the notable theoretical risk of allograft rejection. In this review, we summarize and chart the landscape of seminal immuno-oncology trials in HCC and envision future clinical developments.

Meta-analysis: Prevalence of significant or advanced fibrosis in adults with alpha-1-antitrypsin deficiency.

BACKGROUND: The prevalence of liver fibrosis detected by non-invasive imaging in alpha-1-antitrypsin (AAT) deficiency has not been systematically assessed. AIMS: We conducted a systematic review and meta-analysis to determine the prevalence of significant fibrosis and advanced fibrosis in AAT deficiency based on non-invasive imaging. METHODS: Medline and Embase electronic databases were searched for studies from inception to 13 November 2022 that provided data for the prevalence of fibrosis in adults with AAT deficiency. A generalised linear mixed model with Clopper-Pearson intervals was used to pool single-arm outcomes. RESULTS: Of the 214 records identified, 8 studies were included. Five studies assessed fibrosis using vibration-controlled transient elastography. The prevalence of significant fibrosis (defined as ≥7.1 kPA) in Z homozygosity, Z heterozygosity and non-carrier status was 22.10% (five studies, 95% CI: 17.07-28.12), 9.24% (three studies, 95% CI: 4.68-17.45) and 5.38% (one study, 95% CI: 3.27-8.73), respectively, p < 0.0001, and the prevalence of advanced fibrosis (defined as ≥9.5 kPa) was 8.13% (five studies, 95% CI: 4.60-13.96), 2.96% (three studies, 95% CI: 1.49-5.81) and 1.08% (one study, 95% CI: 0.35-3.28), respectively, p = 0.003. There were limited data regarding the use of magnetic resonance elastography or acoustic radiation force impulse to assess for fibrosis. CONCLUSION: More than one in five adult individuals with AAT deficiency and Z homozygosity harbour significant fibrosis, and nearly 1 in 10 harbours advanced fibrosis. The risk of fibrosis increases incrementally with the frequency of Pi*Z mutations.

Examining the interim proposal for name change to steatotic liver disease in the US population.

BACKGROUND AND AIMS: Fatty liver is the commonest liver condition globally and traditionally associated with NAFLD. A consensus meeting was held in Chicago to explore various terminologies. Herein, we explore the proposed changes in nomenclature in a population data set from the US. APPROACH AND RESULTS: Statistical analysis was conducted using survey-weighted analysis. Assessment of fatty liver was conducted with vibration-controlled transient elastography. A controlled attenuation parameter of 288 dB/m was used to identify hepatic steatosis. Patients were classified into nonalcoholic steatotic liver disease, alcohol-associated steatotic liver disease, and viral hepatitis steatotic liver disease. Liver stiffness measures at ≥8.8, ≥11.7, and ≥14 kPa were used to identify clinically significant fibrosis, advanced fibrosis, and cirrhosis, respectively. A total of 5102 individuals were included in the analysis. Using a survey-weighted analysis, a total of 25.43%, 6.95%, and 0.73% of the population were classified as nonalcoholic steatotic liver disease, alcohol-associated steatotic liver disease, and viral hepatitis steatotic liver disease, respectively. A sensitivity analysis at controlled attenuation parameter of 248 dB/m and fatty liver index found similar distribution. In a comparison between nonalcoholic steatotic liver disease, alcohol-associated steatotic liver disease, and viral hepatitis steatotic liver disease, there was no significant difference between the odds of advanced fibrosis and cirrhosis between groups. However, viral hepatitis steatotic liver disease individuals were found to have a significantly higher odds of clinically significant fibrosis (OR: 3.76, 95% CI, 1.27-11.14, p =0.02) compared with nonalcoholic steatotic liver disease. CONCLUSIONS: The current analysis assessed the proposed changes based on discussions from the consensus meeting. Although the definitions are an interim analysis of discussions, steatotic liver disease respects the underlying liver etiology and reduces stigma while increasing awareness of FL among viral and alcohol-associated steatosis/steatohepatitis.

Alternative medicine and doping in sports.

Athletes are high achievers who may seek creative or unconventional methods to improve performance. The literature indicates that athletes are among the heaviest users of complementary and alternative medicine (CAM) and thus may pioneer population trends in CAM use. Unlike non-athletes, athletes may use CAM not just for prevention, treatment or rehabilitation from illness or injuries, but also for performance enhancement. Assuming that athletes' creative use of anything unconventional is aimed at "legally" improving performance, CAM may be used because it is perceived as more "natural" and erroneously assumed as not potentially doping. This failure to recognise CAMs as pharmacological agents puts athletes at risk of inadvertent doping.The general position of the World Anti-Doping Authority (WADA) is one of strict liability, an application of the legal proposition that ignorance is no excuse and the ultimate responsibility is on the athlete to ensure at all times whatever is swallowed, injected or applied to the athlete is both safe and legal for use. This means that a violation occurs whether or not the athlete intentionally or unintentionally, knowingly or unknowingly, used a prohibited substance/method or was negligent or otherwise at fault. Athletes are therefore expected to understand not only what is prohibited, but also what might potentially cause an inadvertent doping violation. Yet, as will be discussed, athlete knowledge on doping is deficient and WADA itself sometimes changes its position on prohibited methods or substances. The situation is further confounded by the conflicting stance of anti-doping experts in the media. These highly publicised disagreements may further portray inconsistencies in anti-doping guidelines and suggest to athletes that what is considered doping is dependent on the dominant political zeitgeist. Taken together, athletes may believe that unless a specific and explicit ruling is made, guidelines are open to interpretation. Therefore doping risk-taking behaviours may occur because of the potential financial, social and performance gains and the optimistically biased interpretation (that trying alternatives is part of the "spirit of sport") and doping risk-taking behaviours may occur.This discussion paper seeks to situate the reader in a world where elite level sports and CAM intersects. It posits that an understanding of the underlying motivation for CAM use and doping is currently lacking and that anti-doping rules need to be repositioned in the context of the emerging phenomenon and prevalence of CAM use.

Epidemiology and control of hand, foot and mouth disease in Singapore, 2001-2007.

INTRODUCTION: We reviewed the epidemiology of hand, foot and mouth disease (HFMD) in Singapore after the 2000 epidemic caused by Enterovirus 71 (EV71), with particular reference to the cyclical pattern, predominant circulating enteroviruses and impact of prevention and control measures in preschool centres. MATERIALS AND METHODS: We analysed the epidemiological data from all clinical cases and deaths of HFMD diagnosed by medical practitioners and notified to the Ministry of Health, as well as laboratory data on enteroviruses detected among HFMD patients maintained by the Department of Pathology, Singapore General Hospital, and the Microbiology Laboratory, KK Women's and Children's Hospital from 2001 to 2007. RESULTS: The incidence rate was highest in the 0 to 4 years old age group, with males being predominant. Three deaths were reported between January and February 2001. Nationwide epidemics occurred periodically; the predominating circulating virus was Coxsackievirus A16 (CA16) in the 2002, 2005 and 2007 epidemics, and EV71 in the 2006 epidemic. During the epidemic years between 2005 and 2007, 2 peaks were observed. The number of institutional outbreaks had increased 10-fold from 167 in 2001 to 1723 in 2007, although most of these outbreaks were rapidly brought under control with an attack rate of less than 10%. CONCLUSION: HFMD remains an important public health problem in Singapore with the annual incidence rate per 100,000 population increasing from 125.5 in 2001 to 435.9 in 2007, despite stringent measures taken in preschool centres to prevent the transmission of infection. A high degree of vigilance should be maintained over the disease situation, in particular, surveillance of EV 71 which continues to cause severe complications and deaths in the region.

The 2005 dengue epidemic in Singapore: epidemiology, prevention and control.

INTRODUCTION: We investigated the 2005 outbreak of dengue fever (DF)/dengue haemorrhagic fever (DHF) to determine its epidemiological, virological and entomological features to further understand the unprecedented resurgence. MATERIALS AND METHODS: All physician-diagnosed, laboratory-confirmed cases of DF/DHF notified to the Ministry of Health, Singapore during the outbreak as well as entomological and virological data were analysed retrospectively. RESULTS: A total of 14,006 cases of DF/DHF comprising 13,625 cases of DF and 381 cases of DHF, including 27 deaths were reported, giving an incidence rate of 322.6 per 100,000 and a case-fatality rate of 0.19%. The median age of the cases and deaths were 32 and 59.5 years, respectively. The incidence rate of those living in compound houses was more than twice that of residents living in public and private apartments. The distribution of DF/DHF cases was more closely associated with Aedes aegypti compared to Aedes albopictus breeding sites and the overall Aedes premises index was 1.15% (2.28% in compound houses and 0.33% to 0.8% in public and private apartments). The predominant dengue serotype was DEN-1. A significant correlation between weekly mean temperature and cases was noted. The correlation was strongest when the increase in temperature preceded rise in cases by a period of 18 weeks. CONCLUSION: The resurgence occurred in a highly densely populated city-state in the presence of low Aedes mosquito population. Factors contributing to this resurgence included lower herd immunity and change in dominant dengue serotype from DEN-2 to DEN-1. There was no evidence from gene sequencing of the dengue viruses that the epidemic was precipitated by the introduction of a new virulent strain. The current epidemiological situation is highly conducive to periodic dengue recurrences. A high degree of vigilance and active community participation in source reduction should be maintained.

Migration psychosis and homicide in Singapore: a five year study.

Psychiatric research into violent offences, particularly murder, have been scant in the South East Asian region, with the last major review of homicides in Singapore and their association with psychiatric disorders being as far back as 1985. This study seeks to update the psychiatric community on individuals charged with murder in Singapore from 1997 to 2001 and particularly to further investigate the phenomenon of 'migration psychosis' in relation to foreigners in this sample who have committed homicide. One hundred and ten individuals in Singapore were charged with murder between 1997 and 2001. Socio-demographic data, psychiatric diagnoses, offence and victim profiles and court outcomes were obtained. The group consisting of offenders who were Singapore citizens or permanent residents was compared with those offenders who were foreigners. Analysis was done using the statistical package, SPSS. The proportion of foreigners in this study who committed homicide is significantly higher than the proportion of citizens/permanent residents in the general population. Foreigners who commit homicide also appear to (i) suffer from the more serious psychiatric illnesses of mood and psychotic disorders compared with locals, (ii) be less likely to have a known history of violence or a past forensic history and (iii) be more likely to be new to psychiatric services compared with the local homicide offenders. Compared with locals, foreigners appear to have a higher risk for committing homicide. Yet, they are less likely to appear early enough before mental health services. Some form of basic education to employers of foreigners as well as to the foreigners themselves on the early signs of mental illness is recommended.

Epidemiology and control of SARS in Singapore.

Severe acute respiratory syndrome (SARS) was imported into Singapore in late February 2003 by a local resident who returned from a holiday in Hong Kong and started an outbreak in the hospital where she was admitted on 1 March 2003. The disease subsequently spread to 4 other healthcare institutions and a vegetable wholesale centre. During the period between March and May 2003, 238 probable SARS cases, including 8 imported cases and 33 deaths, were reported. Transmission within the healthcare and household settings accounted for more than 90% of the cases. Factors contributing to the spread of infection included the failure to recognise the high infectivity of this novel infection, resulting in a delay in isolating initial cases and contacts and the implementation of personal protective measures in healthcare institutions; and the super-spreading events by 5 index cases, including 3 with co-morbid conditions presenting with atypical clinical manifestations of SARS. Key public health measures were directed at prevention and control within the community and hospitals, and the prevention of imported and exported cases. An isolated laboratory-acquired case of SARS was reported on 8 September 2003. Based on the lessons learnt, Singapore has further strengthened its operational readiness and laboratory safety to respond to SARS, avian flu and other emerging diseases.