Blood-brain barrier-associated pericytes internalize and clear aggregated amyloid-β42 by LRP1-dependent apolipoprotein E isoform-specific mechanism

Table S1. Demographic and clinical features of human subjects used in this study. Figure S1. Aβ deposition in microvessels in AD patients and APPSw/0 mice. Figure S2. Biochemical analysis of Aβ42 aggregates. Figure S3. Cy3-Aβ42 cellular uptake in wild type mouse brain slices within 30 min. Figure S4. Pericyte coverages in Lrp1lox/lox and Lrp1lox/lox; Cspg4-Cre mice. Figure S5.. LRP1 and apoE suppression with siRNA. (DOCX 1454 kb

Characterising Kenyan hospitals' suitability for medical officer internship training: a secondary data analysis of a cross-sectional study

Objective To characterise the capacity of Kenya internship hospitals to understand whether they are suitable to provide internship training for medical doctors. Design A secondary data analysis of a cross-sectional health facility assessment (Kenya Harmonized Health Facility Assessment (KHFA) 2018). Setting and population We analysed 61 out of all 74 Kenyan hospitals that provide internship training for medical doctors. Outcome measures Comparing against the minimum requirement outlined in the national guidelines for medical officer interns, we filtered and identified 166 indicators from the KHFA survey questionnaire and grouped them into 12 domains. An overall capacity index was calculated as the mean of 12 domain-specific scores for each facility. Results The average overall capacity index is 69% (95% CI 66% to 72%) for all internship training centres. Hospitals have moderate capacity (over 60%) for most of the general domains, although there is huge variation between hospitals and only 29 out of 61 hospitals have five or more specialists assigned, employed, seconded or part-time-as required by the national guideline. Quality and safety score was low across all hospitals with an average score of 40%. As for major specialties, all hospitals have good capacity for surgery and obstetrics-gynaecology, while mental health was poorest in comparison. Level 5 and 6 facilities (provincial and national hospitals) have higher capacity scores in all domains when compared with level 4 hospitals (equivalent to district hospitals). Conclusion Major gaps exist in staffing, equipment and service availability of Kenya internship hospitals. Level 4 hospitals (equivalent to district hospitals) are more likely to have a lower capacity index, leading to low quality of care, and should be reviewed and improved to provide appropriate and well-resourced training for interns and to use appropriate resources to avoid improvising

Tools for measuring medical internship experience: a scoping review.

BACKGROUND: Appropriate and well-resourced medical internship training is important to ensure psychological health and well-being of doctors in training and also to recruit and retain these doctors. However, most reviews focused on clinical competency of medical interns instead of the non-clinical aspects of training. In this scoping review, we aim to review what tools exist to measure medical internship experience and summarize the major domains assessed. METHOD: The authors searched MEDLINE, Embase, PsycINFO, ERIC, and the Cochrane Library for peer-reviewed studies that provided quantitative data on medical intern's (house officer, foundation year doctor, etc.) internship experience and published between 2000 and 2019. Three reviewers screened studies for eligibility with inclusion criteria. Data including tools used, key themes examined, and psychometric properties within the study population were charted, collated, and summarized. Tools that were used in multiple studies, and tools with internal validity or reliability assessed directed in their intern population were reported. RESULTS: The authors identified 92 studies that were included in the analysis. The majority of studies were conducted in the US (n = 30, 32.6%) and the UK (n = 20, 21.7%), and only 14 studies (15.2%) were conducted in low- and middle-income countries. Major themes examined for internship experience included well-being, educational environment, and work condition and environment. For measuring well-being, standardized tools like the Maslach Burnout Inventory (for measuring burnout), Patient Health Questionnaire-9 (depression), General Health Questionnaire-12 or 30 (psychological distress) and Perceived Stress Scale (stress) were used multiple times. For educational environment and work condition and environment, there is a lack of widely used tools for interns that have undergone psychometric testing in this population other than the Postgraduate Hospital Educational Environment Measure, which has been used in four different countries. CONCLUSIONS: There are a large number of tools designed for measuring medical internship experience. International comparability of results from future studies would benefit if tools that have been more widely used are employed in studies on medical interns with further testing of their psychometric properties in different contexts

A Biomechanical Model of the Inner Ear: Numerical Simulation of the Caloric Test

Whether two vertical semicircular canals can receive thermal stimuli remains controversial. This study examined the caloric response in the three semicircular canals to the clinical hot caloric test using the finite element method. The results of the developed model showed the horizontal canal (HC) cupula maximally deflected to the utricle side by approximately 3 μm during the hot supine test. The anterior canal cupula began to receive the caloric stimuli about 20 s after the HC cupula, and it maximally deflected to the canal side by 0.55 μm. The posterior canal cupula did not receive caloric stimuli until approximately 40 s after the HC cupula, and it maximally deflected to the canal side by 0.34 μm. Although the endolymph flow and the cupular deformation change with respect to the head position during the test, the supine test ensures the maximal caloric response in the HC, but no substantial improvement for the responses of the two vertical canals was observed. In conclusion, while the usual supine test is the optimum test for evaluating the functions of the inner ear, more irrigation time is needed in order to effectively clinically examine the vertical canals

'We were treated like we are nobody': a mixed-methods study of medical doctors' internship experiences in Kenya and Uganda

OBJECTIVE: Medical interns are an important workforce providing first-line healthcare services in hospitals. The internship year is important for doctors as they transition from theoretical learning with minimal hands-on work under supervision to clinical practice roles with considerable responsibility. However, this transition is considered stressful and commonly leads to burn-out due to challenging working conditions and an ongoing need for learning and assessment, which is worse in countries with resource constraints. In this study, we provide an overview of medical doctors' internship experiences in Kenya and Uganda. METHODS: Using a convergent mixed-methods approach, we collected data from a survey of 854 medical interns and junior doctors and semistructured interviews with 54 junior doctors and 14 consultants. Data collection and analysis were guided by major themes identified from a previous global scoping review (well-being, educational environment and working environment and condition), using descriptive analysis and thematic analysis respectively for quantitative and qualitative data. FINDINGS: Most medical interns are satisfied with their job but many reported suffering from stress, depression and burn-out, and working unreasonable hours due to staff shortages. They are also being affected by the challenging working environment characterised by a lack of adequate resources and a poor safety climate. Although the survey data suggested that most interns were satisfied with the supervision received, interviews revealed nuances where many interns faced challenging scenarios, for example, poor supervision, insufficient support due to consultants not being available or being 'treated like we are nobody'. CONCLUSION: We highlight challenges experienced by Kenyan and Ugandan medical interns spanning from burn-out, stress, challenging working environment, inadequate support and poor quality of supervision. We recommend that regulators, educators and hospital administrators should improve the resource availability and capacity of internship hospitals, prioritise individual doctors' well-being and provide standardised supervision, support systems and conducive learning environments

Knowledge structure and hotspots research of glioma immunotherapy: a bibliometric analysis

BackgroundGlioma is the most common primary brain tumor. Traditional treatments for glioma include surgical resection, radiotherapy, chemotherapy, and bevacizumab therapy, but their efficacies are limited. Immunotherapy provides a new direction for glioma treatment. This study aimed to summarize the knowledge structure and research hotspots of glioma immunotherapy through a bibliometric analysis.MethodPublications pertaining to glioma immunotherapy published during the period from 1st January 1990 to 27th March 2023 were downloaded from the Web of Science Core Collection (WoSCC). Bibliometric analysis and visualization were performed using the CiteSpace, VOSviewer, Online Analysis Platform of Literature Metrology, and R software. The hotspots and prospects of glioma immunotherapy research were illustrated via analyzing the countries, institutions, journals, authors, citations and keywords of eligible publications.ResultsA total of 1,929 publications pertaining to glioma immunotherapy in 502 journals were identified as of 27th March 2023, involving 9,505 authors from 1,988 institutions in 62 countries. Among them were 1,285 articles and 644 reviews. Most of publications were produced by the United States. JOURNAL OF NEURO-ONCOLOGY published the majority of publications pertaining to glioma immunotherapy. Among the authors, Lim M contributed the largest number of publications. Through analyzing keyword bursts and co-cited references, immune-checkpoint inhibitors (ICIs) were identified as the research focus and hotspot.ConclusionUsing a bibliometric analysis, this study provided the knowledge structure and research hotspots in glioma immunotherapy research during the past 33 years, with ICIs staying in the current and future hotspot. Our findings may direct the research of glioma immunotherapy in the future

Brain-Specific Phosphorylation of MeCP2 Regulates Activity-Dependent Bdnf Transcription, Dendritic Growth, and Spine Maturation

Mutations or duplications in MECP2 cause Rett and Rett-like syndromes, neurodevelopmental disorders characterized by mental retardation, motor dysfunction, and autistic behaviors. MeCP2 is expressed in many mammalian tissues and functions as a global repressor of transcription; however, the molecular mechanisms by which MeCP2 dysfunction leads to the neural-specific phenotypes of RTT remain poorly understood. Here, we show that neuronal activity and subsequent calcium influx trigger the de novo phosphorylation of MeCP2 at serine 421 (S421) by a CaMKII-dependent mechanism. MeCP2 S421 phosphorylation is induced selectively in the brain in response to physiological stimuli. Significantly, we find that S421 phosphorylation controls the ability of MeCP2 to regulate dendritic patterning, spine morphogenesis, and the activity-dependent induction of Bdnf transcription. These findings suggest that, by triggering MeCP2 phosphorylation, neuronal activity regulates a program of gene expression that mediates nervous system maturation and that disruption of this process in individuals with mutations in MeCP2 may underlie the neural-specific pathology of RTT

TAMEP are brain tumor parenchymal cells controlling neoplastic angiogenesis and progression

Aggressive brain tumors like glioblastoma depend on support by their local environment and subsets of tumor parenchymal cells may promote specific phases of disease progression. We investigated the glioblastoma microenvironment with transgenic lineage-tracing models, intravital imaging, single-cell transcriptomics, immunofluorescence analysis as well as histopathology and characterized a previously unacknowledged population of tumor-associated cells with a myeloid-like expression profile (TAMEP) that transiently appeared during glioblastoma growth. TAMEP of mice and humans were identified with specific markers. Notably, TAMEP did not derive from microglia or peripheral monocytes but were generated by a fraction of CNS-resident, SOX2-positive progenitors. Abrogation of this progenitor cell population, by conditional Sox2-knockout, drastically reduced glioblastoma vascularization and size. Hence, TAMEP emerge as a tumor parenchymal component with a strong impact on glioblastoma progression

Health sector spending and spending on HIV/AIDS, tuberculosis, and malaria, and development assistance for health: progress towards Sustainable Development Goal 3

Sustainable Development Goal (SDG) 3 aims to “ensure healthy lives and promote well-being for all at all ages”. While a substantial effort has been made to quantify progress towards SDG3, less research has focused on tracking spending towards this goal. We used spending estimates to measure progress in financing the priority areas of SDG3, examine the association between outcomes and financing, and identify where resource gains are most needed to achieve the SDG3 indicators for which data are available. Methods We estimated domestic health spending, disaggregated by source (government, out-of-pocket, and prepaid private) from 1995 to 2017 for 195 countries and territories. For disease-specific health spending, we estimated spending for HIV/AIDS and tuberculosis for 135 low-income and middle-income countries, and malaria in 106 malaria-endemic countries, from 2000 to 2017. We also estimated development assistance for health (DAH) from 1990 to 2019, by source, disbursing development agency, recipient, and health focus area, including DAH for pandemic preparedness. Finally, we estimated future health spending for 195 countries and territories from 2018 until 2030. We report all spending estimates in inflation-adjusted 2019 US$, unless otherwise stated. Findings Since the development and implementation of the SDGs in 2015, global health spending has increased, reaching$7·9 trillion (95% uncertainty interval 7·8–8·0) in 2017 and is expected to increase to $11·0 trillion (10·7–11·2) by 2030. In 2017, in low-income and middle-income countries spending on HIV/AIDS was$20·2 billion (17·0–25·0) and on tuberculosis it was $10·9 billion (10·3–11·8), and in malaria-endemic countries spending on malaria was$5·1 billion (4·9–5·4). Development assistance for health was $40·6 billion in 2019 and HIV/AIDS has been the health focus area to receive the highest contribution since 2004. In 2019,$374 million of DAH was provided for pandemic preparedness, less than 1% of DAH. Although spending has increased across HIV/AIDS, tuberculosis, and malaria since 2015, spending has not increased in all countries, and outcomes in terms of prevalence, incidence, and per-capita spending have been mixed. The proportion of health spending from pooled sources is expected to increase from 81·6% (81·6–81·7) in 2015 to 83·1% (82·8–83·3) in 2030. Interpretation Health spending on SDG3 priority areas has increased, but not in all countries, and progress towards meeting the SDG3 targets has been mixed and has varied by country and by target. The evidence on the scale-up of spending and improvements in health outcomes suggest a nuanced relationship, such that increases in spending do not always results in improvements in outcomes. Although countries will probably need more resources to achieve SDG3, other constraints in the broader health system such as inefficient allocation of resources across interventions and populations, weak governance systems, human resource shortages, and drug shortages, will also need to be addressed

Development and validation of a new measurement instrument to assess internship experience of medical doctors in low-income and middle-income countries

Routine surveys are used to understand the training quality and experiences of junior doctors but there are lack of tools designed to evaluate the training experiences of interns in low-income and middle-income countries (LMICs) where working conditions and resource constraints are challenging. We describe our process developing and validating a 'medical internship experience scale' to address this gap, work involving nine LMICs that varied in geographical locations, income-level and internship training models. We used a scoping review of existing tools, content validity discussions with target populations and an expert panel, back-and-forth translations into four language versions and cognitive interviews to develop and test the tool. Using data collected from 1646 interns and junior medical doctors, we assessed factor structure and assessed its reliability and validity. Fifty items about experiences of medical internship were retained from an initial pool of 102 items. These 50 items represent 6 major factors (constructs): (1) clinical learning and supervision, (2) patient safety, (3) job satisfaction, (4) stress and burnout, (5) mental well-being, and (6) fairness and discrimination. We reflect on the process of multicountry scale development and highlight some considerations for others who may use our scale, using preliminary analyses of the 1646 responses to illustrate that the tool may produce useful data to identify priorities for action. We suggest this tool could enable LMICs to assess key metrics regarding intern straining and initial work experiences and possibly allow comparison across countries and over time, to inform better internship planning and management