mTOR inhibition in Q175 Huntington's disease model mice facilitates neuronal autophagy and mutant huntingtin clearance.

Huntington's disease (HD) is caused by expansion of the polyglutamine stretch in huntingtin protein (HTT) resulting in hallmark aggresomes/inclusion bodies (IBs) composed of mutant huntingtin protein (mHTT) and its fragments. Stimulating autophagy to enhance mHTT clearance is considered a potential therapeutic strategy for HD. Our recent evaluation of the autophagic-lysosomal pathway (ALP) in human HD brain reveals upregulated lysosomal biogenesis and relatively normal autophagy flux in early Vonsattel grade brains, but impaired autolysosome clearance in late grade brains, suggesting that autophagy stimulation could have therapeutic benefits as an earlier clinical intervention. Here, we tested this hypothesis by crossing the Q175 HD knock-in model with our autophagy reporter mouse TRGL ( T hy-1- R FP- G FP- L C3) to investigate in vivo neuronal ALP dynamics. In the Q175 and/or TRGL/Q175 mice, mHTT was detected in autophagic vacuoles and also exhibited high level colocalization with autophagy receptors p62/SQSTM1 and ubiquitin in the IBs. Compared to the robust lysosomal pathology in late-stage human HD striatum, ALP alterations in Q175 models are also late-onset but milder that included a lowered phospho-p70S6K level, lysosome depletion and autolysosome elevation including more poorly acidified autolysosomes and larger-sized lipofuscin granules, reflecting impaired autophagic flux. Administration of a mTOR inhibitor to 6-mo-old TRGL/Q175 normalized lysosome number, ameliorated aggresome pathology while reducing mHTT-, p62- and ubiquitin-immunoreactivities, suggesting beneficial potential of autophagy modulation at early stages of disease progression.

Stakeholder perspectives of mental healthcare services in Bangladesh, its challenges and opportunities: a qualitative study.

This study explores Bangladesh's mental health services from an individual- and system-level perspective and provides insights and recommendations for strengthening it's mental health system. We conducted 13 in-depth interviews and 2 focus group discussions. Thirty-one participants were recruited using a combination of purposive and snowball sampling methods. All interviews and group discussions were audio-recorded and transcribed, and key findings were translated from Bengali to English. Data were coded manually and analysed using a thematic and narrative analysis approach. Stakeholders perceived scarcity of service availability at the peripheral level, shortage of professionals, weak referral systems, lack of policy implementation and regulatory mechanisms were significant challenges to the mental health system in Bangladesh. At the population level, low levels of mental health literacy, high societal stigma, and treatment costs were barriers to accessing mental healthcare. Key recommendations included increasing the number of mental health workers and capacity building, strengthening regulatory mechanisms to enhance the quality of care within the health systems, and raising awareness about mental health. Introducing measures that relate to tackling stigma, mental health literacy as well as building the capacity of the health workforce and governance systems will help ensure universal mental health coverage.

Understanding the impacts of COVID-19 pandemic on mental health and well-being among university students in Dhaka, Bangladesh: A nested mixed-methods study.

Background: University students are more at risk of mental illness compared with the general population. Declaration of a global COVID-19 pandemic led the Bangladesh government in March 2020 to implement a national lockdown, home quarantining, social distancing measures, and closure of educational institutions. We aimed to explore the impact of lockdown on the mental health and well-being of university students in Bangladesh. Methods: A nested mixed-methods survey design was undertaken using a semi structured questionnaire and in-depth interviews conducted by telephone of 73 university students (mean age of 22 years, range 18 to 26-years-old) attending public and private academic institutions in Dhaka. A questionnaire was developed de-novo and pre-tested. Qualitative, open-ended questions were used to understand experiences regarding students' mental health and well-being, their perceptions of COVID-19, and coping strategies. Results: Fifty nine percent of students reported that lockdown had a significant impact on their mental health and well-being. They described difficulties with social isolation and loneliness, motivation, and interpersonal conflict within families. Students' knowledge of COVID-19 were high with television, newspapers, online, and social media were main sources of information; few relied on government reports. Most pressing concerns were timely graduation and employment (83%), not being able to socialize (46%), being stuck at home (37%), and financial difficulties regarding university fees (29%). Additional underlying stressors included financial insecurity of respondents' households and parental health. Coping strategies included watching television or films, online meetings with friends, social media, as well interactions with family. Conclusion: As a result of Bangladesh's first national lockdown, university students experienced negative effects on their mental health and well-being. There is an urgent need for greater proactive measures within educational settings, such as mental health literacy programmes and diagnosis management that could mitigate and prevent adverse impacts of future lockdowns.

Safeguarding the Caribbean's future: making the case to research the direct and indirect impacts of climate change on youth mental health and wellbeing.

This article makes a call for attention to paid on the development of a research agenda for studying the impact of climatic events on youth mental health in the Caribbean. It details the climate injustices that the region faces and the potential mental health problem which can arise from climatic events. It makes a call for interdisciplinary research and a multi stakeholder approach to dealing with this potential issue.

Differential attainment in specialty training recruitment in the UK: an observational analysis of the impact of psychometric testing assessment in Public Health postgraduate selection.

OBJECTIVES: To determine how current psychometric testing approaches used in selection of postgraduate training in UK Public Health are associated with socioeconomic and sociocultural background of applicants (including ethnicity). DESIGN: Observational study using contemporaneous data collected during recruitment and psychometric test scores. SETTING: Assessment centre of UK national Public Health recruitment for postgraduate Public Health training. The assessment centre element of selection comprises three psychometric assessments: Rust Advanced Numerical Reasoning, Watson-Glaser Critical Thinking Assessment II and Public Health situational judgement test. PARTICIPANTS: 629 applicants completed the assessment centre in 2021. 219 (34.8%) were UK medical graduates, 73 (116%) were international medical graduates and 337 (53.6%) were from backgrounds other than medicine. MAIN OUTCOME MEASURE: Multivariable-adjusted progression statistics in the form of adjusted OR (aOR), accounting for age, sex, ethnicity, professional background and surrogate measures of familial socioeconomic and sociocultural status. RESULTS: 357 (56.8%) candidates passed all three psychometric tests. Candidate characteristics negatively associated with progression were black ethnicity (aOR 0.19, 0.08 to 0.44), Asian ethnicity (aOR 0.35, 0.16 to 0.71) and coming from a non-UK medical graduate background (aOR 0.05, 0.03 to 0.12); similar differential attainment was observed in each of the psychometric tests. Even within the UK-trained medical cohort, candidates from white British backgrounds were more likely to progress than those from ethnic minorities (89.2% vs 75.0%, p=0.003). CONCLUSION: Although perceived to mitigate the risks of conscious and unconscious bias in selection to medical postgraduate training, these psychometric tests demonstrate unexplained variation that suggests differential attainment. Other specialties should enhance their data collection to evaluate the impact of differential attainment on current selection processes and take forward opportunities to mitigate differential attainment where possible.

Differential attainment in public health specialty training recruitment in the United Kingdom: an observational analysis of applicants from 2018 to 2020.

BACKGROUND: Differential attainment has been widely observed in United Kingdom (UK) medical training, with minority ethnicity being associated with reduced success in recruitment and progression through training. Specialty training in Public Health in the UK recruits candidates with medical as well as non-medical backgrounds. At the request of the UK Faculty of Public Health and Health Education England, we sought to examine whether differential attainment may or may not be occurring in the multi-stage recruitment process. METHODS: We analysed 3 years of national recruitment data into Public Health specialty training to identify whether demographic characteristics including age, sex, ethnicity and professional background were associated with successful recruitment. RESULTS: In total 2252 applications between 2018 and 2020 were analysed. Candidates who were older, Asian, black or from backgrounds other than medicine were significantly less likely to progress from the psychometric testing stage than the white British group. Fewer statistically significant differences were observed at the final stage of recruitment involving interviews, group work and a written task. CONCLUSIONS: The findings suggest that older candidates those from some ethnic minority backgrounds and those from backgrounds other than medicine are disadvantaged by the current recruitment process, with differential attainment associated with the psychometric testing stage.

Autophagy is a novel pathway for neurofilament protein degradation in vivo.

How macroautophagy/autophagy influences neurofilament (NF) proteins in neurons, a frequent target in neurodegenerative diseases and injury, is not known. NFs in axons have exceptionally long half-lives in vivo enabling formation of large stable supporting networks, but they can be rapidly degraded during Wallerian degeneration initiated by a limited calpain cleavage. Here, we identify autophagy as a previously unrecognized pathway for NF subunit protein degradation that modulates constitutive and inducible NF turnover in vivo. Levels of NEFL/NF-L, NEFM/NF-M, and NEFH/NF-H subunits rise substantially in neuroblastoma (N2a) cells after blocking autophagy either with the phosphatidylinositol 3-kinase (PtdIns3K) inhibitor 3-methyladenine (3-MA), by depleting ATG5 expression with shRNA, or by using both treatments. In contrast, activating autophagy with rapamycin significantly lowers NF levels in N2a cells. In the mouse brain, NF subunit levels increase in vivo after intracerebroventricular infusion of 3-MA. Furthermore, using tomographic confocal microscopy, immunoelectron microscopy, and biochemical fractionation, we demonstrate the presence of NF proteins intra-lumenally within autophagosomes (APs), autolysosomes (ALs), and lysosomes (LYs). Our findings establish a prominent role for autophagy in NF proteolysis. Autophagy may regulate axon cytoskeleton size and responses of the NF cytoskeleton to injury and disease.

Implementing the English health inequalities agenda: addressing challenges to person-level, cross-sectoral data linkage, access and routine use for local authority public health.

Local authorities are central to the implementation of English Integrated Care Systems' health inequalities agendas, embedding public health into population health management planning. They work with partners to deliver a range of 'health determinant' services and facilities for people in a defined geographic area. This work is substantially premised on the use of cross-sectoral data that is linked at the individual level, readily available, longitudinal and contemporaneous. However, multiple challenges exist to such data availability. This paper elaborates upon these challenges to local authority public health systems and their potential solutions.

Primary health care as a platform for addressing racial discrimination to "leave no one behind" and reduce health inequities.

The health inequities faced by populations experiencing racial discrimination, including indigenous peoples and people of African descent, Roma, and other ethnic minorities, are an issue of global concern. Health systems have an important role to play in tackling these health inequities. Health systems based on comprehensive Primary Health Care (PHC) are best placed to tackle health inequities because PHC encompasses a whole-of-society approach to health. PHC includes actions to address the wider social determinants of health, multisectoral policy and action, intercultural and integrated healthcare services, community empowerment, and a focus on addressing health inequities. PHC can also serve as a platform for introducing specific actions to tackle racial discrimination and can act to drive wider societal change for tackling racial and ethnic health inequities.

Faulty autolysosome acidification in Alzheimer's disease mouse models induces autophagic build-up of Aß in neurons, yielding senile plaques.

Autophagy is markedly impaired in Alzheimer's disease (AD). Here we reveal unique autophagy dysregulation within neurons in five AD mouse models in vivo and identify its basis using a neuron-specific transgenic mRFP-eGFP-LC3 probe of autophagy and pH, multiplex confocal imaging and correlative light electron microscopy. Autolysosome acidification declines in neurons well before extracellular amyloid deposition, associated with markedly lowered vATPase activity and build-up of Aß/APP-ßCTF selectively within enlarged de-acidified autolysosomes. In more compromised yet still intact neurons, profuse Aß-positive autophagic vacuoles (AVs) pack into large membrane blebs forming flower-like perikaryal rosettes. This unique pattern, termed PANTHOS (poisonous anthos (flower)), is also present in AD brains. Additional AVs coalesce into peri-nuclear networks of membrane tubules where fibrillar ß-amyloid accumulates intraluminally. Lysosomal membrane permeabilization, cathepsin release and lysosomal cell death ensue, accompanied by microglial invasion. Quantitative analyses confirm that individual neurons exhibiting PANTHOS are the principal source of senile plaques in amyloid precursor protein AD models.

Educational and Training Interventions Aimed at Healthcare Workers in the Detection and Management of People With Mental Health Conditions in South and South-East Asia: A Systematic Review.

Background: To bridge significant mental health treatment gaps, it is essential that the healthcare workforce is able to detect and manage mental health conditions. We aim to synthesise evidence of effective educational and training interventions aimed at healthcare workers to increase their ability to detect and manage mental health conditions in South and South-East Asia. Methods: Systematic review of six electronic academic databases from January 2000 to August 2020 was performed. All primary research studies were eligible if conducted among healthcare workers in South and South-East Asia and reported education and training interventions to improve detection and management of mental health conditions. Quality of studies were assessed using Modified Cochrane Collaboration, ROBINS-I, and Mixed Methods Appraisal Tools and data synthesised by narrative synthesis. Results are reported according to Preferred Reporting Items for Systematic Reviews and Meta-analysis guidelines. A review protocol was registered with the PROSPERO database (CRD42020203955). Findings: We included 48 of 3,654 screened articles. Thirty-six reported improvements in knowledge and skills in the detection and management of mental health conditions. Training was predominantly delivered to community and primary care health workers to identify and manage common mental health disorders. Commonly used training included the World Health Organization's mhGAP guidelines (n = 9) and Cognitive Behavioural Therapy (n = 8) and were successfully tailored and delivered to healthcare workers. Digitally delivered training was found to be acceptable and effective. Only one study analysed cost effectiveness. Few targeted severe mental illnesses and upskilling mental health specialists or offered long-term follow-up or supervision. We found 21 studies were appraised as low/moderate and 19 as high/critical risk of bias. Interpretation: In low resource country settings, upskilling and capacity building of primary care and community healthcare workers can lead to better detection and management of people with mental health disorders and help reduce the treatment gap. Systematic Review Registration: https://www.crd.york.ac.uk/prospero/, identifier CRD42020203955.

Development and presentation of an objective risk stratification tool for healthcare workers when dealing with the COVID-19 pandemic in the UK: risk modelling based on hospitalisation and mortality statistics compared with epidemiological data.

OBJECTIVES: Healthcare workers have greater exposure to SARS-CoV-2 and an estimated 2.5-fold increased risk of contracting COVID-19 than the general population. We wished to explore the predictive role of basic demographics to establish a simple tool that could help risk stratify healthcare workers. SETTING: We undertook a review of the published literature (including multiple search strategies in MEDLINE with PubMed interface) and critically assessed early reports on preprint servers. We explored the relative risk of mortality from readily available demographics to identify the population at the highest risk. RESULTS: The published studies specifically assessing the risk of healthcare workers had limited demographics available; therefore, we explored the general population in the literature. Clinician demographics: Mortality increased with increasing age from 50 years onwards. Male sex at birth, and people of black and minority ethnicity groups had higher susceptibility to both hospitalisation and mortality. Comorbid disease. Vascular disease, renal disease, diabetes and chronic pulmonary disease further increased risk. Risk stratification tool: A risk stratification tool was compiled using a white female aged <50 years with no comorbidities as a reference. A point allocated to risk factors was associated with an approximate doubling in risk. This tool provides numerical support for healthcare workers when determining which team members should be allocated to patient facing clinical duties compared with remote supportive roles. CONCLUSIONS: We generated a tool that provides a framework for objective risk stratification of doctors and healthcare professionals during the COVID-19 pandemic, without requiring disclosure of information that an individual may not wish to share with their direct line manager during the risk assessment process. This tool has been made freely available through the British Medical Association website and is widely used in the National Health Service and other external organisations.

Educational and training interventions aimed at healthcare workers in the detection and management of people with mental health conditions in South and Southeast Asia: systematic review protocol.

INTRODUCTION: The mental health burden and treatment gap in South and Southeast Asia is high and significant. Capacity building of healthcare workers is essential to support programmes related to the detection and management of patients with mental health conditions. We aim to conduct a systematic review to summarise the research on educational, training and capacity-building interventions aimed at the healthcare workforce in detection and management of mental health conditions in South and Southeast Asia. OBJECTIVE: To synthesise evidence on (1) the types of educational and training interventions that have been used to improve the knowledge, skills and attitudes of healthcare workers in South and Southeast Asian countries in the detection and management of mental health conditions; (2) the effectiveness, including cost-effectiveness of the interventions; and (3) the enabling factors and barriers that influence the effectiveness of these interventions. METHODS AND ANALYSIS: This review will be conducted in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses Extension for Scoping Reviews guidelines. We will search six electronic databases: MEDLINE, EMBASE, PsycINFO, Cochrane Library, Cumulative Index to Nursing and Allied Health Literature, and Global Health for empirical studies published from 1 January 2000 to 31 August 2020. Search results from each database will be combined and uploaded in Covidence library. Title, abstract and full-text screening, and data extraction of each included study will be performed by two independent reviewers. Disagreements between reviewers will be resolved by a third reviewer and study team. Quality of included studies will be assessed by the modified Cochrane Collaboration tool and ROBINS-I tool. Data will be synthesised and if a meta-analysis is not appropriate, a stepwise thematic analysis will be performed. ETHICS AND DISSEMINATION: Ethics approval is not required for this study. Findings will be disseminated through peer-reviewed publications, fact sheets, multimedia press briefings, conferences, seminars and symposia. PROSPERO REGISTRATION NUMBER: CRD42020203955.