Probiotics for people with hepatic encephalopathy

Background Hepatic encephalopathy is a disorder of brain function as a result of liver failure or portosystemic shunt or both. Both hepatic encephalopathy (clinically overt) and minimal hepatic encephalopathy (not clinically overt) significantly impair patient’s quality of life and daily functioning, and represent a significant burden on healthcare resources. Probiotics are live micro‐organisms, which when administered in adequate amounts, may confer a health benefit on the host. Objectives To determine the beneficial and harmful effects of probiotics in any dosage, compared with placebo or no intervention, or with any other treatment for people with any grade of acute or chronic hepatic encephalopathy. This review did not consider the primary prophylaxis of hepatic encephalopathy. Search methods We searched The Cochrane Hepato‐Biliary Group Controlled Trials Register, CENTRAL, MEDLINE, Embase, Science Citation Index Expanded, conference proceedings, reference lists of included trials, and the World Health Organization International Clinical Trials Registry Platform until June 2016. Selection criteria We included randomised clinical trials that compared probiotics in any dosage with placebo or no intervention, or with any other treatment in people with hepatic encephalopathy. Data collection and analysis We used standard methodological procedures expected by The Cochrane Collaboration. We conducted random‐effects model meta‐analysis due to obvious heterogeneity of participants and interventions. We defined a P value of 0.05 or less as significant. We expressed dichotomous outcomes as risk ratio (RR) and continuous outcomes as mean difference (MD) with 95% confidence intervals (CI). Main results We included 21 trials with 1420 participants, of these, 14 were new trials. Fourteen trials compared a probiotic with placebo or no treatment, and seven trials compared a probiotic with lactulose. The trials used a variety of probiotics; the most commonly used group of probiotic was VSL#3, a proprietary name for a group of eight probiotics. Duration of administration ranged from 10 days to 180 days. Eight trials declared their funding source, of which six were independently funded and two were industry funded. The remaining 13 trials did not disclose their funding source. We classified 19 of the 21 trials at high risk of bias. We found no effect on all‐cause mortality when probiotics were compared with placebo or no treatment (7 trials; 404 participants; RR 0.58, 95% CI 0.23 to 1.44; low‐quality evidence). No‐recovery (as measured by incomplete resolution of symptoms) was lower for participants treated with probiotic (10 trials; 574 participants; RR 0.67, 95% CI 0.56 to 0.79; moderate‐quality evidence). Adverse events were lower for participants treated with probiotic than with no intervention when considering the development of overt hepatic encephalopathy (10 trials; 585 participants; RR 0.29, 95% CI 0.16 to 0.51; low‐quality evidence), but effects on hospitalisation and change of/or withdrawal from treatment were uncertain (hospitalisation: 3 trials, 163 participants; RR 0.67, 95% CI 0.11 to 4.00; very low‐quality evidence; change of/or withdrawal from treatment: 9 trials, 551 participants; RR 0.70, 95% CI 0.46 to 1.07; very low‐quality evidence). Probiotics may slightly improve quality of life compared with no intervention (3 trials; 115 participants; results not meta‐analysed; low‐quality evidence). Plasma ammonia concentration was lower for participants treated with probiotic (10 trials; 705 participants; MD ‐8.29 μmol/L, 95% CI ‐13.17 to ‐3.41; low‐quality evidence). There were no reports of septicaemia attributable to probiotic in any trial. When probiotics were compared with lactulose, the effects on all‐cause mortality were uncertain (2 trials; 200 participants; RR 5.00, 95% CI 0.25 to 102.00; very low‐quality evidence); lack of recovery (7 trials; 430 participants; RR 1.01, 95% CI 0.85 to 1.21; very low‐quality evidence); adverse events considering the development of overt hepatic encephalopathy (6 trials; 420 participants; RR 1.17, 95% CI 0.63 to 2.17; very low‐quality evidence); hospitalisation (1 trial; 80 participants; RR 0.33, 95% CI 0.04 to 3.07; very low‐quality evidence); intolerance leading to discontinuation (3 trials; 220 participants; RR 0.35, 95% CI 0.08 to 1.43; very low‐quality evidence); change of/or withdrawal from treatment (7 trials; 490 participants; RR 1.27, 95% CI 0.88 to 1.82; very low‐quality evidence); quality of life (results not meta‐analysed; 1 trial; 69 participants); and plasma ammonia concentration overall (6 trials; 325 participants; MD ‐2.93 μmol/L, 95% CI ‐9.36 to 3.50; very low‐quality evidence). There were no reports of septicaemia attributable to probiotic in any trial. Authors' conclusions The majority of included trials suffered from a high risk of systematic error (‘bias’) and a high risk of random error (‘play of chance’). Accordingly, we consider the evidence to be of low quality. Compared with placebo or no intervention, probiotics probably improve recovery and may lead to improvements in the development of overt hepatic encephalopathy, quality of life, and plasma ammonia concentrations, but probiotics may lead to little or no difference in mortality. Whether probiotics are better than lactulose for hepatic encephalopathy is uncertain because the quality of the available evidence is very low. High‐quality randomised clinical trials with standardised outcome collection and data reporting are needed to further clarify the true efficacy of probiotics

Almanac: Retrieval-Augmented Language Models for Clinical Medicine

Large-language models have recently demonstrated impressive zero-shot capabilities in a variety of natural language tasks such as summarization, dialogue generation, and question-answering. Despite many promising applications in clinical medicine, adoption of these models in real-world settings has been largely limited by their tendency to generate incorrect and sometimes even toxic statements. In this study, we develop Almanac, a large language model framework augmented with retrieval capabilities for medical guideline and treatment recommendations. Performance on a novel dataset of clinical scenarios (n = 130) evaluated by a panel of 5 board-certified and resident physicians demonstrates significant increases in factuality (mean of 18% at p-value < 0.05) across all specialties, with improvements in completeness and safety. Our results demonstrate the potential for large language models to be effective tools in the clinical decision-making process, while also emphasizing the importance of careful testing and deployment to mitigate their shortcomings

Burden of injury along the development spectrum: associations between the Socio-demographic Index and disability-adjusted life year estimates from the Global Burden of Disease Study 2017

Background The epidemiological transition of non-communicable diseases replacing infectious diseases as the main contributors to disease burden has been well documented in global health literature. Less focus, however, has been given to the relationship between sociodemographic changes and injury. The aim of this study was to examine the association between disability-adjusted life years (DALYs) from injury for 195 countries and territories at different levels along the development spectrum between 1990 and 2017 based on the Global Burden of Disease (GBD) 2017 estimates. Methods Injury mortality was estimated using the GBD mortality database, corrections for garbage coding and CODEm-the cause of death ensemble modelling tool. Morbidity estimation was based on surveys and inpatient and outpatient data sets for 30 cause-of-injury with 47 nature-of-injury categories each. The Socio-demographic Index (SDI) is a composite indicator that includes lagged income per capita, average educational attainment over age 15 years and total fertility rate. results For many causes of injury, age-standardised DALY rates declined with increasing SDI, although road injury, interpersonal violence and self-harm did not follow this pattern. Particularly for self-harm opposing patterns were observed in regions with similar SDI levels. For road injuries, this effect was less pronounced. Conclusions The overall global pattern is that of declining injury burden with increasing SDI. However, not all injuries follow this pattern, which suggests multiple underlying mechanisms influencing injury DALYs. There is a need for a detailed understanding of these patterns to help to inform national and global efforts to address injury-related health outcomes across the development spectrum

Burden of injury along the development spectrum : associations between the Socio-demographic Index and disability-adjusted life year estimates from the Global Burden of Disease Study 2017

Background The epidemiological transition of non-communicable diseases replacing infectious diseases as the main contributors to disease burden has been well documented in global health literature. Less focus, however, has been given to the relationship between sociodemographic changes and injury. The aim of this study was to examine the association between disability-adjusted life years (DALYs) from injury for 195 countries and territories at different levels along the development spectrum between 1990 and 2017 based on the Global Burden of Disease (GBD) 2017 estimates. Methods Injury mortality was estimated using the GBD mortality database, corrections for garbage coding and CODEm-the cause of death ensemble modelling tool. Morbidity estimation was based on surveys and inpatient and outpatient data sets for 30 cause-of-injury with 47 nature-of-injury categories each. The Socio-demographic Index (SDI) is a composite indicator that includes lagged income per capita, average educational attainment over age 15 years and total fertility rate. Results For many causes of injury, age-standardised DALY rates declined with increasing SDI, although road injury, interpersonal violence and self-harm did not follow this pattern. Particularly for self-harm opposing patterns were observed in regions with similar SDI levels. For road injuries, this effect was less pronounced. Conclusions The overall global pattern is that of declining injury burden with increasing SDI. However, not all injuries follow this pattern, which suggests multiple underlying mechanisms influencing injury DALYs. There is a need for a detailed understanding of these patterns to help to inform national and global efforts to address injury-related health outcomes across the development spectrum.Peer reviewe

Global age-sex-specific mortality, life expectancy, and population estimates in 204 countries and territories and 811 subnational locations, 1950–2021, and the impact of the COVID-19 pandemic: a comprehensive demographic analysis for the Global Burden of Disease Study 2021

Background: Estimates of demographic metrics are crucial to assess levels and trends of population health outcomes. The profound impact of the COVID-19 pandemic on populations worldwide has underscored the need for timely estimates to understand this unprecedented event within the context of long-term population health trends. The Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2021 provides new demographic estimates for 204 countries and territories and 811 additional subnational locations from 1950 to 2021, with a particular emphasis on changes in mortality and life expectancy that occurred during the 2020–21 COVID-19 pandemic period. Methods: 22 223 data sources from vital registration, sample registration, surveys, censuses, and other sources were used to estimate mortality, with a subset of these sources used exclusively to estimate excess mortality due to the COVID-19 pandemic. 2026 data sources were used for population estimation. Additional sources were used to estimate migration; the effects of the HIV epidemic; and demographic discontinuities due to conflicts, famines, natural disasters, and pandemics, which are used as inputs for estimating mortality and population. Spatiotemporal Gaussian process regression (ST-GPR) was used to generate under-5 mortality rates, which synthesised 30 763 location-years of vital registration and sample registration data, 1365 surveys and censuses, and 80 other sources. ST-GPR was also used to estimate adult mortality (between ages 15 and 59 years) based on information from 31 642 location-years of vital registration and sample registration data, 355 surveys and censuses, and 24 other sources. Estimates of child and adult mortality rates were then used to generate life tables with a relational model life table system. For countries with large HIV epidemics, life tables were adjusted using independent estimates of HIV-specific mortality generated via an epidemiological analysis of HIV prevalence surveys, antenatal clinic serosurveillance, and other data sources. Excess mortality due to the COVID-19 pandemic in 2020 and 2021 was determined by subtracting observed all-cause mortality (adjusted for late registration and mortality anomalies) from the mortality expected in the absence of the pandemic. Expected mortality was calculated based on historical trends using an ensemble of models. In location-years where all-cause mortality data were unavailable, we estimated excess mortality rates using a regression model with covariates pertaining to the pandemic. Population size was computed using a Bayesian hierarchical cohort component model. Life expectancy was calculated using age-specific mortality rates and standard demographic methods. Uncertainty intervals (UIs) were calculated for every metric using the 25th and 975th ordered values from a 1000-draw posterior distribution. Findings: Global all-cause mortality followed two distinct patterns over the study period: age-standardised mortality rates declined between 1950 and 2019 (a 62·8% [95% UI 60·5–65·1] decline), and increased during the COVID-19 pandemic period (2020–21; 5·1% [0·9–9·6] increase). In contrast with the overall reverse in mortality trends during the pandemic period, child mortality continued to decline, with 4·66 million (3·98–5·50) global deaths in children younger than 5 years in 2021 compared with 5·21 million (4·50–6·01) in 2019. An estimated 131 million (126–137) people died globally from all causes in 2020 and 2021 combined, of which 15·9 million (14·7–17·2) were due to the COVID-19 pandemic (measured by excess mortality, which includes deaths directly due to SARS-CoV-2 infection and those indirectly due to other social, economic, or behavioural changes associated with the pandemic). Excess mortality rates exceeded 150 deaths per 100 000 population during at least one year of the pandemic in 80 countries and territories, whereas 20 nations had a negative excess mortality rate in 2020 or 2021, indicating that all-cause mortality in these countries was lower during the pandemic than expected based on historical trends. Between 1950 and 2021, global life expectancy at birth increased by 22·7 years (20·8–24·8), from 49·0 years (46·7–51·3) to 71·7 years (70·9–72·5). Global life expectancy at birth declined by 1·6 years (1·0–2·2) between 2019 and 2021, reversing historical trends. An increase in life expectancy was only observed in 32 (15·7%) of 204 countries and territories between 2019 and 2021. The global population reached 7·89 billion (7·67–8·13) people in 2021, by which time 56 of 204 countries and territories had peaked and subsequently populations have declined. The largest proportion of population growth between 2020 and 2021 was in sub-Saharan Africa (39·5% [28·4–52·7]) and south Asia (26·3% [9·0–44·7]). From 2000 to 2021, the ratio of the population aged 65 years and older to the population aged younger than 15 years increased in 188 (92·2%) of 204 nations. Interpretation: Global adult mortality rates markedly increased during the COVID-19 pandemic in 2020 and 2021, reversing past decreasing trends, while child mortality rates continued to decline, albeit more slowly than in earlier years. Although COVID-19 had a substantial impact on many demographic indicators during the first 2 years of the pandemic, overall global health progress over the 72 years evaluated has been profound, with considerable improvements in mortality and life expectancy. Additionally, we observed a deceleration of global population growth since 2017, despite steady or increasing growth in lower-income countries, combined with a continued global shift of population age structures towards older ages. These demographic changes will likely present future challenges to health systems, economies, and societies. The comprehensive demographic estimates reported here will enable researchers, policy makers, health practitioners, and other key stakeholders to better understand and address the profound changes that have occurred in the global health landscape following the first 2 years of the COVID-19 pandemic, and longer-term trends beyond the pandemic

Classification of Chemical Chaperones Based on Their Effect on Protein Folding Landscapes

Various small molecules present in biological systems can assist protein folding <i>in vitro</i> and are known as chemical chaperones. <i>De novo</i> design of chemical chaperones with higher activity than currently known examples is desirable to ameliorate protein misfolding and aggregation in multiple contexts. However, this development has been hindered by limited knowledge of their activities. It is thought that chemical chaperones are typically poor solvents for a protein backbone and hence facilitate native structure formation. However, it is unknown if different chemical chaperones can act differently to modulate folding energy landscapes. Using a model slow folding protein, double-mutant Maltose-binding protein (DM-MBP), we show that a canonical chemical chaperone, trimethylamine-N-oxide (TMAO), accelerates refolding by decreasing the flexibility of the refolding intermediate (RI). Among a number of small molecules that chaperone DM-MBP folding, proline and serine stabilize the transition state (TS) enthalpically, while trehalose behaves like TMAO and increases the rate of barrier crossing through nonenthalpic processes. We propose a two-group classification of chemical chaperones based upon their thermodynamic effect on RI and TS, which is also supported by single molecule Förster resonance energy transfer (smFRET) studies. Interestingly, for a different test protein, the molecular mechanisms of the two groups of chaperones are not conserved. This provides a glimpse into the complexity of chemical chaperoning activity of osmolytes. Future work would allow us to engineer synergism between the two classes to design more efficient chemical chaperones to ameliorate protein misfolding and aggregation problems

Tuberculosis Risk among Medical Trainees, Pune, India

During 2012–2013, at a public hospital in Pune, India, 26 (3.9%) cases of tuberculosis were reported among 662 medical trainees, representing an estimated incidence of 3,279 cases/100,000 person-years. Three of these infections were isoniazid-resistant, 1 was multidrug-resistant, and 1 occurred in a trainee who had fulminant hepatitis after starting treatment for TB