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BACKGROUND: Alpha-1 antitrypsin deficiency (A1ATD) is a life-threatening condition caused by the inheritance of the serpin family A member 1 "Z" genetic variant driving alpha-1 antitrypsin (AAT) protein misfolding in hepatocytes. There are no approved medicines for this disease. METHODS: We conducted a high-throughput image-based small molecule screen using patient-derived induced pluripotent stem cell-hepatocytes (iPSC-hepatocytes). Identified targets were validated in vitro using 3 independent patient iPSC lines. The effects of the identified target, leucine-rich repeat kinase 2 (LRRK2), were further evaluated in an animal model of A1ATD through histology and immunohistochemistry and in an autophagy-reporter line. Autophagy induction was assessed through immunoblot and immunofluorescence analyses. RESULTS: Small-molecule screen performed in iPSC-hepatocytes identified LRRK2 as a potentially new therapeutic target. Of the commercially available LRRK2 inhibitors tested, we identified CZC-25146, a candidate with favorable pharmacokinetic properties, as capable of reducing polymer load, increasing normal AAT secretion, and reducing inflammatory cytokines in both cells and PiZ mice. Mechanistically, this effect was achieved through the induction of autophagy. CONCLUSIONS: Our findings support the use of CZC-25146 and leucine-rich repeat kinase-2 inhibitors in hepatic proteinopathy research and their further investigation as novel therapeutic candidates for A1ATD.
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Optimising treatment outcomes for people living with hepatitis B virus (HBV) is key to advancing progress towards international targets for the elimination of viral hepatitis as a public health threat. Nucleos/tide analogue agents (most commonly tenofovir or entecavir) are well-tolerated and suppress viraemia effectively in the majority of those who are offered therapy. However, outcomes are not consistent, and we explore the factors that may contribute to incomplete therapeutic responses. We discuss situations in which therapy is not accessible, affordable or acceptable, reflecting the impact of social, cultural and economic barriers, stigma and discrimination, low awareness, poor access to health systems and comorbidity. These challenges are amplified in certain vulnerable populations, increasing the risk of adverse outcomes-which include liver cirrhosis and hepatocellular carcinoma-among people who already experience marginalisation and health inequities. We also tackle the physiological and biological mechanisms for incomplete virological suppression in individuals receiving HBV treatment, considering the possible impact of inadequate tissue drug levels, poor drug-target avidity and genomic resistance. These factors are interdependent, leading to a complex landscape in which socioeconomic challenges increase the challenge of consistent daily therapy and set the scene for selection of drug resistance. By putting a spotlight on this neglected topic, we aim to raise awareness, prompt dialogue, inform research and advocate for enhanced interventions. As criteria for HBV treatment eligibility relax, the population receiving therapy will expand, and there is a pressing need to optimise outcomes and close the equity gap.
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Antivirais , Vírus da Hepatite B , Tenofovir , Humanos , Antivirais/uso terapêutico , Farmacorresistência Viral , Guanina/análogos & derivados , Guanina/uso terapêutico , Acessibilidade aos Serviços de Saúde , Hepatite B/tratamento farmacológico , Vírus da Hepatite B/efeitos dos fármacos , Hepatite B Crônica/tratamento farmacológico , Tenofovir/uso terapêutico , Resultado do TratamentoRESUMO
OBJECTIVES: Significant disparities exist between different ethnic groups when it comes to participation in colorectal cancer (CRC) screening programmes. A variety of interventions have been proposed to improve participation rates of ethnic minorities for CRC screening. This systematic review aims to appraise the evidence available from published randomised controlled trials (RCTs) and to identify effective interventions aimed at promoting CRC screening amongst underserved ethnic minorities. DESIGN: We searched EmBASE, Medline, PsychInfo, Scopus and CINAHL for RCTs that analysed interventions to promote CRC screening in all ethnic minorities. CRC screening was measured as documented or self-reported screening rates. The protocol of this study was registered prospectively on PROSPERO with the registration number CRD42020216384. RESULTS: We identified 42 relevant RCT articles, out of 1805 articles highlighted by the initial search. All except one were conducted in the US. The most frequently studied ethnic groups were African-Americans (33%), East Asians (30%), and Hispanics/Latinos (23%). In total, 7/42 (16%) RCTs had multiple arms. Interventions mainly intended to educate (52%), provide patient navigation services (21%), or provide a combination of these interventions (19%). We demonstrate that combination methods are most effective. CONCLUSION: Many RCTs, mostly in the US, have trialed interventions aimed to increase CRC screening uptake amongst ethnic minorities to varying success. We conclude that using a combination of methods with patient navigation, education, and cultural tailoring is most effective at increasing CRC screening uptake amongst ethnic minorities. This highlights that multiple factors may hinder CRC screening and finding a one-size-fits-all solution that can be reliably implemented among different cultures and countries may be complex.
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Neoplasias Colorretais , Minorias Étnicas e Raciais , Humanos , Detecção Precoce de Câncer/métodos , Neoplasias Colorretais/diagnóstico , EtnicidadeRESUMO
Background Advances in computer processing and improvements in data availability have led to the development of machine learning (ML) techniques for mammographic imaging. Purpose To evaluate the reported performance of stand-alone ML applications for screening mammography workflow. Materials and Methods Ovid Embase, Ovid Medline, Cochrane Central Register of Controlled Trials, Scopus, and Web of Science literature databases were searched for relevant studies published from January 2012 to September 2020. The study was registered with the PROSPERO International Prospective Register of Systematic Reviews (protocol no. CRD42019156016). Stand-alone technology was defined as a ML algorithm that can be used independently of a human reader. Studies were quality assessed using the Quality Assessment of Diagnostic Accuracy Studies 2 and the Prediction Model Risk of Bias Assessment Tool, and reporting was evaluated using the Checklist for Artificial Intelligence in Medical Imaging. A primary meta-analysis included the top-performing algorithm and corresponding reader performance from which pooled summary estimates for the area under the receiver operating characteristic curve (AUC) were calculated using a bivariate model. Results Fourteen articles were included, which detailed 15 studies for stand-alone detection (n = 8) and triage (n = 7). Triage studies reported that 17%-91% of normal mammograms identified could be read by adapted screening, while "missing" an estimated 0%-7% of cancers. In total, an estimated 185 252 cases from three countries with more than 39 readers were included in the primary meta-analysis. The pooled sensitivity, specificity, and AUC was 75.4% (95% CI: 65.6, 83.2; P = .11), 90.6% (95% CI: 82.9, 95.0; P = .40), and 0.89 (95% CI: 0.84, 0.98), respectively, for algorithms, and 73.0% (95% CI: 60.7, 82.6), 88.6% (95% CI: 72.4, 95.8), and 0.85 (95% CI: 0.78, 0.97), respectively, for readers. Conclusion Machine learning (ML) algorithms that demonstrate a stand-alone application in mammographic screening workflows achieve or even exceed human reader detection performance and improve efficiency. However, this evidence is from a small number of retrospective studies. Therefore, further rigorous independent external prospective testing of ML algorithms to assess performance at preassigned thresholds is required to support these claims. ©RSNA, 2021 Online supplemental material is available for this article. See also the editorial by Whitman and Moseley in this issue.
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Neoplasias da Mama/diagnóstico por imagem , Aprendizado de Máquina , Mamografia/métodos , Interpretação de Imagem Radiográfica Assistida por Computador/métodos , Fluxo de Trabalho , Feminino , Humanos , Sensibilidade e EspecificidadeRESUMO
BACKGROUND AND AIMS: Animal models of human disease are a key component of translational hepatology research, yet there is no consensus on which model is optimal for NAFLD. APPROACH AND RESULTS: We generated a database of 3,920 rodent models of NAFLD. Study designs were highly heterogeneous, and therefore, few models had been cited more than once. Analysis of genetic models supported the current evidence for the role of adipose dysfunction and suggested a role for innate immunity in the progression of NAFLD. We identified that high-fat, high-fructose diets most closely recapitulate the human phenotype of NAFLD. There was substantial variability in the nomenclature of animal models: a consensus on terminology of specialist diets is needed. More broadly, this analysis demonstrates the variability in preclinical study design, which has wider implications for the reproducibility of in vivo experiments both in the field of hepatology and beyond. CONCLUSIONS: This systematic analysis provides a framework for phenotypic assessment of NAFLD models and highlights the need for increased standardization and replication.
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Dieta Hiperlipídica , Modelos Animais de Doenças , Frutose , Síndrome Metabólica/metabolismo , Camundongos , Hepatopatia Gordurosa não Alcoólica/metabolismo , Ratos , Animais , Animais Geneticamente Modificados , Colesterol na Dieta , Dieta , Sacarose Alimentar , Açúcares da Dieta , Dislipidemias/genética , Dislipidemias/metabolismo , Dislipidemias/patologia , Feminino , Humanos , Fígado/patologia , Masculino , Síndrome Metabólica/genética , Síndrome Metabólica/patologia , Hepatopatia Gordurosa não Alcoólica/genética , Hepatopatia Gordurosa não Alcoólica/patologia , Obesidade/genética , Obesidade/metabolismo , Obesidade/patologia , Reprodutibilidade dos TestesRESUMO
BACKGROUND: Despite growing concerns about transmissibility and clinical impact, occult hepatitis B virus (HBV) infection has received little attention in the hepatitis elimination agenda. We aimed to estimate the prevalence of occult HBV infection at a global and regional scale and in specific populations. METHODS: For this systematic review and meta-analysis, we searched the MEDLINE, Embase, Global Health, and Web of Science databases for articles published in any language between Jan 1, 2010, and Aug 14, 2019. We included original articles and conference abstracts of any study design that reported the proportion of HBsAg-negative adults (aged ≥18 years) who are positive for HBV DNA (ie, people with occult HBV infection). The prevalence of occult HBV infection was pooled, using the DerSimonian-Laird random-effects model, in the general population and specific groups defined by the type of study participants (blood donors; other low-risk populations; high-risk populations; and people with advanced chronic liver disease), and stratified by HBV endemicity in each country. We also assessed the performance of anti-HBc as an alternative biomarker to detect occult HBV infection. The study was registered with PROSPERO, CRD42019115490. FINDINGS: 305 of 3962 articles were eligible, allowing a meta-analysis of 140 521 993 individuals tested for HBV DNA. Overall, only two studies evaluated occult HBV infection in the general population, precluding unbiased global and regional estimates of occult HBV infection prevalence. In blood donors, occult HBV infection prevalence mirrored HBV endemicity: 0·06% (95% CI 0·00-0·26) in low-endemicity countries, 0·12% (0·04-0·23) in intermediate-endemicity countries, and 0·98% (0·44-1·72), in high-endemicity countries (p=0·0012). In high-risk groups, occult HBV infection prevalence was substantial, irrespective of endemicity: 5·5% (95% CI 2·9-8·7) in low-endemicity countries, 5·2% (2·5-8·6) in intermediate-endemicity countries, and 12·0% (3·4-24·7) in high-endemicity countries. The pooled sensitivity of anti-HBc to identify occult HBV infection was 77% (95% CI 62-88) and its specificity was 76% (68-83). INTERPRETATION: A substantial proportion of people carry occult HBV infection, especially among high-risk groups across the globe and people living in highly endemic countries. Occult HBV infection should be part of the global viral hepatitis elimination strategy. FUNDING: None.
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Hepatite B Crônica , Hepatite B , Adolescente , Adulto , DNA Viral , Hepatite B/diagnóstico , Hepatite B/epidemiologia , Anticorpos Anti-Hepatite B , Vírus da Hepatite B/genética , Humanos , PrevalênciaRESUMO
The COVID-19 pandemic has brought unprecedented challenges to the medical workforce. This has put them at increased risk of burnout at a time when levels are already worryingly high in the profession, with recent studies consistently showing that around half of doctors meet the validated criteria for burnout. OBJECTIVES: To understand the wider factors influencing and impacting upon hospital doctors' well-being during the COVID-19 pandemic in England. DESIGN: Cross-sectional survey and mixed quantitative-qualitative analysis. SETTING: Acute National Health Service (NHS) Foundation Trust in England. PARTICIPANTS: An online survey was circulated in early June 2020 to all 449 doctors employed by the Trust. 242 doctors completed the survey (54% response rate). PRIMARY OUTCOME MEASURES: Questions assessed occupational details, self-reported changes in physical and mental health, satisfaction with working hours and patterns, availability of personal protective equipment (PPE), medication and facilities, communication and sought to identify areas seen as having a significant effect on doctors' well-being. RESULTS: 96% of respondents requiring PPE were able to access it. Nearly half of the respondents felt that their mental health had deteriorated since the start of the pandemic. Over a third stated that their physical health had also declined. Issues identified as having a negative impact on doctors included increased workload, redeployment, loss of autonomy, personal issues affecting family members, anxiety around recovery plans, inadequate access to changing and storage facilities and to rest areas that allow for social distancing. Doctors appreciated access to 'calm rooms' that were made available for staff, access to clinical psychology support, free drinks and free car parking on site. CONCLUSION: The emerging themes are suggestive of increased burnout risk among doctors during the COVID-19 pandemic and encompass factors well beyond shortage of PPE. Small organisational initiatives and the implementation of changes suggested by survey respondents can have a positive impact on doctors' well-being.
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COVID-19 , Saúde Mental , Pandemias , Equipamento de Proteção Individual , Médicos/psicologia , Estudos Transversais , Inglaterra/epidemiologia , Humanos , Medicina EstatalRESUMO
The classical drug development pipeline necessitates studies using animal models of human disease to gauge future efficacy in humans, however there is a low conversion rate from success in animals to humans. Non-alcoholic fatty liver disease (NAFLD) is a complex chronic disease without any established therapies and a major field of animal research. We performed a meta-analysis with meta-regression of 603 interventional rodent studies (10,364 animals) in NAFLD to assess which variables influenced treatment response. Weight loss and alleviation of insulin resistance were consistently associated with improvement in NAFLD. Multiple drug classes that do not affect weight in humans caused weight loss in animals. Other study design variables, such as age of animals and dietary composition, influenced the magnitude of treatment effect. Publication bias may have increased effect estimates by 37-79%. These findings help to explain the challenge of reproducibility and translation within the field of metabolism.
Obesity and diabetes are increasingly common diseases that can lead to other complications such as fatty liver disease. Fatty liver disease affects one in five people and is caused by a built-up of fat in the liver, which can result in scarring of the liver tissue and other serious complications. There is currently no cure for fatty liver disease. Drugs that have been effective in treating the condition in mice, lack efficacy in humans. To better understand why this is the case, Hunter, de Gracia Hahn, Duret, Im et al. conducted a review of over 5,000 published studies, analysing over 600 experiments. Hunter et al. asked which drugs improved fatty liver in mice the most and if they had the same effect in humans. They also tested whether the age of the mice affected the outcome of the experiments. The analyses revealed that the drugs that work best in mice are different to the ones that show some effect in humans. In mice, many of the drugs reduced their weight or lowered their blood sugar levels, which also improved the fatty liver condition. Moreover, drugs appeared to be less effective the older the mice were. However, most of these drugs do not cause weight loss or lower blood sugar levels in humans, suggesting that factors other than the intended action of these drug could affect the outcome of a mouse study. These findings will help shape future research into obesity, diabetes and fatty liver disease using mice. They highlight that results obtained from studies with mice so far do not predict if a drug will work in humans to treat fatty liver disease. Moreover, weight loss seems to be the most important factor linked to how efficiently a drug treats fatty liver disease.