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The need for concerted global health collaboration predated the foundation of the World Health Organization (WHO). With the emergence of international trading and travel in the 1800s, deadly cholera epidemics necessitated a mechanism of international cooperation for disease prevention and control. Conferences such as the International Sanitary Convention in Paris in 1851 were examples of initial collaborative efforts to manage disease that crossed international borders. At the end of World War II (WW2) in 1945, there was a resolve to establish an organisation dedicated to global health. In 1948, at the International Health Conference in New York, 51 members of the United Nations and 10 other nations finalised the constitution for a WHO. This constitution still guides the WHO today.

Microglia, the innate immune cells of the brain, influence Alzheimer’s disease (AD) progression and are potential therapeutic targets. However, microglia exhibit diverse functions, the regulation of which is not fully understood, complicating therapeutics development. To better define the transcriptomic phenotypes and gene regulatory networks associated with AD, we enriched for microglia nuclei from 12 AD and 10 control human dorsolateral prefrontal cortices (7 males and 15 females, all aged >60 years) before single-nucleus RNA sequencing. Here we describe both established and previously unrecognized microglial molecular phenotypes, the inferred gene networks driving observed transcriptomic change, and apply trajectory analysis to reveal the putative relationships between microglial phenotypes. We identify microglial phenotypes more prevalent in AD cases compared with controls. Further, we describe the heterogeneity in microglia subclusters expressing homeostatic markers. Our study demonstrates that deep profiling of microglia in human AD brain can provide insight into microglial transcriptional changes associated with AD.

Alzheimer’s disease (AD) is the predominant dementia globally, with heterogeneous presentation and penetrance of clinical symptoms, variable presence of mixed pathologies, potential disease subtypes, and numerous associated endophenotypes. Beyond the difficulty of designing treatments that address the core pathological characteristics of the disease, therapeutic development is challenged by the uncertainty of which endophenotypic areas and specific targets implicated by those endophenotypes to prioritize for further translational research. However, publicly-funded consortia driving large-scale open science efforts have produced multiple omic analyses that address both disease risk relevance and biological process involvement of genes across the genome. Here we report the development of an informatic pipeline that draws from genetic association studies, predicted variant impact, and linkage with dementia associated phenotypes to create a genetic risk score. This is paired with a multi omic risk score utilizing extensive sets of both transcriptomic and proteomic studies to identify systems level changes in expression associated with AD. These two elements combined constitute our target risk score that ranks AD risk genomewide. The ranked genes are organized into endophenotypic space through the development of 19 biological domains associated with AD in the described genetics and genomics studies and accompanying literature. The biological domains are constructed from exhaustive gene ontology (GO) term compilations, allowing automated assignment of genes into objectively defined disease-associated biology. This rank and organize approach, performed genome-wide, allows the characterization of aggregations of AD risk across biological domains. The top AD-risk associated biological domains are Synapse, Immune Response, Lipid Metabolism, Mitochondrial Metabolism, Structural Stabilization, and Proteostasis, with slightly lower levels of risk enrichment present within the other 13 biological domains. This provides an objective methodology to localize risk within specific biological endophenotypes, and drill down into the most significantly associated sets of GO-terms and annotated genes for potential therapeutic targets.

Microglia contribute to Alzheimer’s Disease (AD) progression and are candidate therapeutic targets for disease modulation. Single cell transcriptomics demonstrate microglia adopt multiple phenotypes. However, identifying the human AD microglia profile was limited by small numbers. We employed fluorescence activated nuclei sorting prior to single-nucleus RNA-seq on human prefrontal cortices boosting the number of microglia analyzed per subject. We observed microglia subpopulations previously unrecognized in human brain and mapped their transcriptomic relationships by trajectory inference. We identified three clusters enriched for endolysosomal pathways, one of which showed differential expression of AD GWAS genes, in addition to genes implicated in nucleic acid detection and interferon signaling. We histologically demonstrated a microglia subpopulation with cytosolic nucleic acid and altered endolysosome morphology in AD tissue. Analysis of the “homeostatic” microglia cluster revealed a uniquely AD subpopulation. Our study demonstrates the value of deeply profiling microglia to explore the biological implications of microglia transcriptomic diversity.

Objectives: A vital component of the coronavirus response is care of the dying COVID-19 patient. We document the demographics, symptoms experienced, medications required, effectiveness observed, and challenges to high-quality holistic palliative care in 31 patients. This will aid colleagues in primary and secondary care settings anticipate common symptoms and formulate management plans. Methods: A retrospective survey was conducted of patients referred to the hospital palliative care service in a tertiary hospital, south east of England between March 21 and April 26, 2020. Patients included had a confirmed laboratory diagnosis of COVID-19 via reverse transcription polymerase chain reaction nasopharyngeal swab for SARS-Cov-2 or radiological evidence of COVID-19. Results: The thirty-one patients included were predominantly male (77%), elderly (median [interquartile range]: 84 [76-89]), and had multiple (4 [3-5]) comorbidities. Referral was made in the last 2 [1-3] days of life. Common symptoms were breathlessness (84%) and delirium (77%). Fifty-eight percent of patients received at least 1 “as required” dose of an opioid or midazolam in the 24 hours before death. Sixty percent of patients needed a continuous subcutaneous infusion and the median morphine dose was 10 mg S/C per 24 hours and midazolam 10 mg S/C per 24 hours. Nineteen percent of our cohort had a loved one or relative present when dying. Conclusion: We provide additional data to the internationally reported pool examining death arising from infection with SARS-CoV-19. The majority of patients had symptoms controlled with low doses of morphine and midazolam, and death was rapid. The impact of low visitation during dying needs exploring.

Background: Genetics play an important role in late-onset Alzheimer’s Disease (AD) etiology and dozens of genetic variants have been implicated in AD risk through large-scale GWAS meta-analyses. However, the precise mechanistic effects of most of these variants have yet to be determined. Deeply phenotyped cohort data can reveal physiological changes associated with genetic risk for AD across an age spectrum that may provide clues to the biology of the disease.Methods: We utilized over 2000 high-quality quantitative measurements obtained from blood of 2831 cognitively normal adult clients of a consumer-based scientific wellness company, each with CLIA-certified whole-genome sequencing data. Measurements included: clinical laboratory blood tests, targeted chip-based proteomics, and metabolomics. We performed a phenome-wide association study utilizing this diverse blood marker data and 25 known AD genetic variants, adjusting for sex, age, vendor (for clinical labs), and the first four genetic principal components; sex-SNP interactions were also assessed.Results: We observed statistically significant SNP-analyte associations for five genetic variants after correction for multiple testing (for SNPs in or near NYAP1, ABCA7, INPP5D, and APOE), with effects detectable from early adulthood. The ABCA7 SNP and the APOE2 and APOE4 encoding alleles were associated with lipid variability, as seen in previous studies; in addition, six novel proteins were associated with the e2 allele. The most statistically significant finding was between the NYAP1 variant and PILRA and PILRB protein levels, supporting previous functional genomic studies in the identification of a putative causal variant within the PILRA gene. Sex modified the effects of four genetic variants, with multiple interrelated immune-modulating effects associated with the PICALM variant. In post-hoc analysis, sex-stratified GWAS results from an independent AD case-control meta-analysis supported sex-specific disease effects of the PICALM variant, highlighting the importance of sex as a biological variable.Conclusions: Known AD genetic variation influenced lipid metabolism and immune response systems in a population of non-AD individuals, with associations observed from early adulthood onward. Further research is needed to determine whether and how these effects are implicated in early-stage biological pathways to AD. These analyses aim to complement ongoing work on the functional interpretation of AD-associated genetic variants.

Microglia-mediated neuroinflammation is hypothesized to contribute to disease progression in neurodegenerative diseases such as Alzheimer9s Disease (AD). Microglia demonstrate heterogeneous states in health and disease, with proposed beneficial, harmful, and disease specific subtypes. Defining the spectrum of microglia phenotypes is an important step in rational design of neuroinflammation modulating therapies. To facilitate improved phenotype resolution and group comparisons based on disease state we performed single-nucleus RNA-seq on more than 120,000 microglia nuclei from AD and control dorsolateral prefrontal cortex. We identify clusters of microglia enriched for biological pathways implicating defined myeloid roles. We detected several previously unrecognized microglia populations in human AD brain, including three internalization and trafficking subtypes that were heterogeneous in their metabolic and inflammatory signatures. One of these endolysosomal subtypes is larger in AD individuals and was uniquely enriched for genes involved in nucleic acid detection and activation of interferon signaling. This inflammatory endolysosomal cluster also differentially regulated expression of genes associated with AD risk by genome wide association studies. We also identified a cluster of microglia with upregulated cell cycle and DNA repair genes that is proportionately larger in control individuals. Within cluster comparisons demonstrate that in AD brain, homeostatic microglia subpopulations upregulate inflammatory gene expression. These results highlight the heterogenous nature of the microglia response to AD pathology and will inform efforts to target specific subtypes of microglia in the development of novel AD therapies.

Background: COVID-19 has tragically resulted in over 2.5 million deaths globally. Despite this, there is a lack of research on how to care for patients dying of COVID-19, specifically pharmacological management of symptoms. Aim: The aim was to determine the dose ranges of pharmacological interventions commonly used to manage symptoms in adult patients dying of COVID-19, establish how effectiveness of these interventions was measured, and whether the pharmacological interventions were effective. Design: This was a rapid systematic review with narrative synthesis of evidence, prospectively registered on PROSPERO (ID: CRD42020210892). Data sources: We searched MEDLINE, EMBASE, CINAHL via the NICE Evidence Health Databases Advanced Search interface; medRxiv; the Cochrane COVID-19 Study Register; and Google Scholar with no date limits. We included primary studies which documented care of patients dying of COVID-19 under the care of a specialist palliative care team. Results: Seven studies, documenting the care of 493 patients met the inclusion criteria. Approximately two thirds of patients required a continuous subcutaneous infusion with median doses of 15 mg morphine and 10 mg midazolam in the last 24 h of life. Four studies described effectiveness by retrospective review of documentation. One study detailed the effectiveness of individual medications. Conclusions: A higher proportion of patients required continuous subcutaneous infusion than is typically encountered in palliative care. Doses of medications required to manage symptoms were generally modest. There was no evidence of a standardised yet holistic approach to measure effectiveness of these medications and this needs to be urgently addressed.

Deeply phenotyped cohort data can elucidate differences associated with genetic risk for common complex diseases across an age spectrum. Previous work has identified genetic variants associated with Alzheimer’s disease (AD) risk from large-scale genome-wide association study meta-analyses. To explore effects of known AD-risk variants, we performed a phenome-wide association study on ~2000 clinical, proteomic, and metabolic blood-based analytes obtained from 2,831 cognitively normal adult clients of a consumer-based scientific wellness company. Results uncovered statistically significant SNP-analyte associations for five genetic variants after correction for multiple testing (for SNPs in or nearNYAP1, ABCA7, INPP5D, andAPOE). These effects were detectable from early adulthood. Sex modified the effects of four genetic variants, with multiple interrelated immune-modulating effects associated with thePICALMvariant. Sex-stratified GWAS results from an independent AD case-control meta-analysis supported sexspecific disease effects of thePICALMvariant, highlighting the importance of sex as a biological variable. These analyses support evidence from previous functional genomics studies in the identification of a causal variant within thePILRAgene. Taken together, this study highlights clues to the earliest effects of AD genetic risk variants in individuals where disease symptoms have not (yet) arisen.

The temporal molecular changes that lead to disease onset and progression in Alzheimer’s disease (AD) are still unknown. Here we develop a temporal model for these unobserved molecular changes with a manifold learning method applied to RNA-Seq data collected from human postmortem brain samples collected within the ROS/MAP and Mayo Clinic RNA-Seq studies. We define an ordering across samples based on their similarity in gene expression and use this ordering to estimate the molecular disease stage–or disease pseudotime-for each sample. Disease pseudotime is strongly concordant with the burden of tau (Braak score, P = 1.0 × 10−5), Aβ (CERAD score, P = 1.8 × 10−5), and cognitive diagnosis (P = 3.5 × 10−7) of late-onset (LO) AD. Early stage disease pseudotime samples are enriched for controls and show changes in basic cellular functions. Late stage disease pseudotime samples are enriched for late stage AD cases and show changes in neuroinflammation and amyloid pathologic processes. We also identify a set of late stage pseudotime samples that are controls and show changes in genes enriched for protein trafficking, splicing, regulation of apoptosis, and prevention of amyloid cleavage pathways. In summary, we present a method for ordering patients along a trajectory of LOAD disease progression from brain transcriptomic data., The limited understanding of the temporal molecular changes in late-onset Alzheimer’s disease hinder the development of therapeutic treatment. The authors use manifold learning to develop a molecular model for disease progression from RNASeq data from human postmortem brain samples.

© 2017 The Authors. Addiction published by John Wiley & Sons Ltd on behalf of Society for the Study of Addiction. Background and Aims: The Cochrane Tobacco Addiction Group (TAG) conducts systematic reviews of the evidence for tobacco cessation and prevention interventions. In 2016 TAG conducted a priority-setting, stakeholder engagement project to identify where further research is needed in the areas of tobacco control and smoking cessation. Design: The project comprised two surveys and a workshop. A range of stakeholders participated, including members of the public (smokers and ex-smokers), clinicians, researchers, research funders, health-care commissioners and public health organizations. The first survey phase identified unanswered research questions in the field of tobacco control. The second phase asked participants to rank these, with overall rankings calculated by combining scores across participants. The workshop allowed attendees to discuss prioritization of topics and questions in more depth. Workshop discussions were transcribed and analysed thematically, and a final voting activity at the close of the workshop allowed participants to choose topics to prioritize and to de-prioritize. Findings: A total of 304 stakeholders (researchers, health professionals, smokers and ex-smokers, guideline developers, research funders and policymakers, representing 28 countries) identified 183 unanswered research questions. These were categorized into 15 research categories. A total of 175 participants prioritized categories and questions in the second survey phase, with ‘electronic cigarettes’; ‘addressing inequalities’; and ‘mental health and other substance abuse’ prioritized as the top three categories. Forty-three stakeholders attended the workshop and discussed reasons for and against category prioritization. Prioritized research categories largely mirrored those in the survey stage, although ‘treatment delivery’ also emerged as a key category. Five cross-cutting themes emerged: efficacy; relative efficacy; cost effectiveness; addressing inequalities; and different types of evidence. Conclusions: There are many unanswered questions in the field of tobacco control. Stakeholders highlighted electronic cigarettes, addressing inequalities and mental health and other substance abuse as key areas for further research, and efficacy, relative efficacy, cost-effectiveness and use of non-randomized studies as important themes cutting across research areas. Future prioritization work would benefit from targeting non-US and non-UK stakeholders explicitly and from examining where priorities may differ based on stakeholder group.

Lichen planus is a chronic, T-cell-mediated, inflammatory disease of the skin and mucous membranes. Its classic presentation is as violaceous, flat-topped macules and papules, which favour the extremities and flexor creases. When considering the diagnosis of lichen planus, take a thorough drug history to determine whether there is an underlying drug cause before diagnosing ‘idiopathic’ lichen planus. Mucosal surfaces and nails should also be examined in all patients, as the disease commonly also affects these sites. This article explores the clinical presentation, investigations and management of this condition from a primary care perspective.

Biological age (BA), derived from molecular and physiological measurements, has been proposed to better predict mortality and disease than chronological age (CA). In the present study, a computed estimate of BA was investigated longitudinally in 3,558 individuals using deep phenotyping, which encompassed a broad range of biological processes. The Klemera–Doubal algorithm was applied to longitudinal data consisting of genetic, clinical laboratory, metabolomic, and proteomic assays from individuals undergoing a wellness program. BA was elevated relative to CA in the presence of chronic diseases. We observed a significantly lower rate of change than the expected ~1 year/year (to which the estimation algorithm was constrained) in BA for individuals participating in a wellness program. This observation suggests that BA is modifiable and suggests that a lower BA relative to CA may be a sign of healthy aging. Measures of metabolic health, inflammation, and toxin bioaccumulation were strong predictors of BA. BA estimation from deep phenotyping was seen to change in the direction expected for both positive and negative health conditions. We believe BA represents a general and interpretable “metric for wellness” that may aid in monitoring aging over time.

The temporal molecular changes that lead to disease onset and progression in Alzheimer's disease (AD) are still unknown. Here we develop a temporal model for these unobserved molecular changes with a manifold learning method applied to RNA-Seq data collected from human postmortem brain samples collected within the ROS/MAP and Mayo Clinic RNA-Seq studies. We define an ordering across samples based on their similarity in gene expression and use this ordering to estimate the molecular disease stage-or disease pseudotime-for each sample. Disease pseudotime is strongly concordant with the burden of tau (Braak score, P = 1.0 × 10

© The Author(s) 2016. Published by Oxford University Press on behalf of the Society for Research on Nicotine and Tobacco. All rights reserved. Cochrane is a global organization committed to carrying out high-standard systematic reviews and meta-analyses to inform health care and those associated with it, from patients to providers. The Cochrane Tobacco Addiction Group (TAG) has been reviewing the evidence for interventions to treat and prevent tobacco addiction for 20 years. During this time, the group has published over 70 reviews in the area, which have had substantial impacts on health care guidance and treatment provision. This has coincided with a reduction in smoking prevalence in the United Kingdom. One of the groups' key objectives is to move with the times, and it does this not only by updating historical reviews with the most up-to-date evidence but also by commissioning or accepting requests for new reviews in novel areas, such as electronic cigarettes and plain packaging. This review paper highlights the previous important work that the group has done and its impacts, what is happening within the group more currently, and also describes where Cochrane TAG wish to go in the future and the work being done to solidify aims. Part of this is a prioritization project being carried out to mark the 20th anniversary of the group, which is using stakeholder engagement to inform an action plan to inform the outputs and aid dissemination to ensure Cochrane TAG's work is relevant and maximizes impact for the next 20 years. Implications: This review provides an overview of the work of Cochrane TAG. Readers will gain an insight into the origins of the group, its impact on evidence-based medicine relating to tobacco addiction, and the goals of the group moving forward. This supports the group's aim to encourage knowledge of Cochrane's work within the field, and thereby the wider use of and contribution to highquality systematic reviews and meta-analyses of the literature to improve policy and clinical practice.

The current health system aims to cope with the epidemic of chronic pain. The narrative urgently needs to be reset to one that strives for excellence. This reflection illustrates what excellence may look like and also highlights where system biases are preventing positive change from occurring.

Biological age (BA) has been shown to be a better predictor of mortality and disease than chronological age (CA). Aging’s diverse effects are visible across many data types. We investigated BA from deep phenotyping of 3558 wellness program participants and controls. The Klemera-Doubal BA estimation algorithm was applied to genetic and longitudinal clinical laboratory, metabolomic, and proteomic assay data. BA trajectories were calculated using Generalized Estimating Equations. BA of individuals with Type-2 Diabetes averaged 6+ years greater than CA. Wellness program participation decreased individuals’ rate of aging (coefficient: -0.16, 95% CI: -0.45, 0.19), with effects dependent on sex, initial BA, and CA. Measures of metabolic health, inflammation, and toxin bioaccumulation were strong predictors across data types and sex. Deep phenotyping enabled calculation of a BA measure and a wellness program improved BA, either in absolute terms or relative to CA, showing it is modifiable.

OBJECTIVES To determine whether antidepressant use is associated with dementia risk. DESIGN Prospective cohort study. SETTING Kaiser Permanente Washington (KPWA), an integrated healthcare delivery system. PARTICIPANTS Community‐dwelling individuals aged 65 and older without dementia and with 10 years or more of KPWA enrollment at baseline (N=3,059). MEASUREMENTS Primary exposures were selective serotonin reuptake inhibitors (paroxetine vs other), tricyclic antidepressants, and serotonin antagonist and reuptake inhibitors. Using health plan pharmacy data, we calculated cumulative medication exposure, defined as total standardized daily doses (TSDDs), over rolling 10‐year windows. Exposure in the most recent year was excluded to avoid use related to prodromal symptoms. The Cognitive Abilities Screening Instrument was administered every 2 years; low scores triggered clinical evaluation and consensus diagnosis procedures. Dementia risk was estimated according to medication use using Cox proportional hazards models. RESULTS During a mean follow‐up of 7.7 years, 775 participants (25%) developed dementia; 659 (22%) developed possible or probable Alzheimer's disease. Individual antidepressant classes were not associated with differences in dementia risk, although paroxetine use was associated with higher risk of dementia for all TSDD categories than no use (0–90 TSDDs: hazard ratio (HR)=1.69, 95% confidence interval (CI)=1.18–2.42; 91–365 TSDDs: HR=1.40, 95% CI=0.88–2.23; 366–1095 TSDDs: HR=2.13, 95% CI=1.32–3.43; ≥1095 TSDDs: HR=1.42, 95% CI=0.82–2.46). CONCLUSION Most commonly prescribed nonanticholinergic depression medications used in late life do not appear to be associated with dementia risk. Paroxetine and other anticholinergic antidepressants may be exceptions in older individuals. Future studies are warranted to improve scientific understanding of potential associations in other settings and populations.

Background Huntington's disease (HD) is a fatal progressive neurodegenerative disease characterized by chorea, cognitive impairment and psychiatric symptoms. Retinal examination of HD patients as well as in HD animal models have shown evidence of retinal dysfunction. However, a detailed retinal study employing clinically available measurement tools has not been reported to date in HD. Objective The goal of this study was to assess retinal responses measured by electroretinogram (ERG) between HD patients and controls and evaluate any correlation between ERG measurements and stage of disease. Methods Eighteen patients and 10 controls with inclusion criteria of ages 18-70 years (average age HD subjects: 52.1 yrs and control subjects: 51.9 yrs) were recruited for the study. Subjects with previous history of retinal or ophthalmologic disease were excluded. Retinal function was examined by full-field ERG in both eyes of each subject. Amplitudes and latencies to increasing flash intensities in both light- and dark-adaptation were measured in all subjects. Statistical analyses employed generalized estimating equations, which account for repeated measures per subject. Results We analyzed the b-wave amplitudes of ERG response in all flash intensities and with 30 Hz flicker stimulation. We found statistically significant increased amplitudes in HD patients compared to controls at light-adapted (photopic) 24.2 and 60.9 cd.sec/m2 intensities, dark-adapted (scotopic, red flash) 0.22 cd.sec/m2 intensity, and a trend toward significance at light-adapted 30 Hz flicker. Furthermore, we found a significant increase in light-adapted ERG response from female compared to male HD patients, but no significant difference between gender amongst controls. We also noted a positive association between number of CAG repeats and ERG response at the smallest light adapted intensity (3.1 cd.sec/m2). Conclusions ERG studies revealed significantly altered retinal responses at multiple flash intensities in subjects with an HD expansion allele compared to controls. Significant differences were observed with either light-adapted tests or the dark-adapted red flash which suggests that the enhanced responses in HD patients is specific to the cone photoreceptor pathway.

Background Mother-to-child transmission of human immunodeficiency virus-type 1 (HIV-1) poses a serious health threat in developing countries, and adequate interventions are as yet unrealized. HIV-1 infection is frequently initiated by a single founder viral variant, but the factors that influence particular variant selection are poorly understood. Results Our analysis of 647 full-length HIV-1 subtype C and G viral envelope sequences from 22 mother–infant pairs reveals unique genotypic and phenotypic signatures that depend upon transmission route. Relative to maternal strains, intrauterine HIV transmission selects infant variants that have shorter, less-glycosylated V1 loops that are more resistant to soluble CD4 (sCD4) neutralization. Transmission through breastfeeding selects for variants with fewer potential glycosylation sites in gp41, are more sensitive to the broadly neutralizing antibodies PG9 and PG16, and that bind sCD4 with reduced cooperativity. Furthermore, experiments with Affinofile cells indicate that infant viruses, regardless of transmission route, require increased levels of surface CD4 receptor for productive infection. Conclusions These data provide the first evidence for transmission route-specific selection of HIV-1 variants, potentially informing therapeutic strategies and vaccine designs that can be tailored to specific modes of vertical HIV transmission. Electronic supplementary material The online version of this article (doi:10.1186/s12977-017-0331-z) contains supplementary material, which is available to authorized users.