We sequenced the genomes of 200 individuals from 41 families multiply affected with bipolar disorder (BD) to identify contributions of rare variants to genetic risk. We initially focused on 3,087 candidate genes with known synaptic functions or prior evidence from genomewide association studies. BD pedigrees had an increased burden of rare variants in genes encoding neuronal ion channels, including subunits of GABA A receptors and voltage-gated calcium channels. Four uncommon coding and regulatory variants also showed significant association, including a missense variant in GABRA6. Targeted sequencing of 26 of these candidate genes in an additional 3,014 cases and 1,717 controls confirmed rare variant associations in ANK3, CACNA1B, CACNA1C, CACNA1D, CACNG2, CAMK2A, and NGF. Variants in promoters and 5′ and 3′ UTRs contributed more strongly than coding variants to risk for BD, both in pedigrees and in the case-control cohort. The genes and pathways identified in this study regulate diverse aspects of neuronal excitability. We conclude that rare variants in neuronal excitability genes contribute to risk for BD. by episodes of mania and depression (1). Episodes of mania are marked by elevated or alternatively irritable mood, grandiosity, racing thoughts, rapid speech, diminished need for sleep, and risk-taking behavior. Depression includes sadness, low energy and motivation, decreased ability to experience pleasure, insomnia, and appetite changes. Psychosis with hallucinations and delusions can occur in either state. BD affects 1-2% of the US population, and if untreated, up to 15% of patients die from suicide. Twin and family studies suggest that heritable causes explain 60-80% of lifetime risk for BD (2), with an approximate eightfold relative risk in the siblings of BD probands (3). Several common genetic markers have shown significant and replicable associations in genome-wide association studies (GWASs), including a region near a voltage-gated calcium channel, CACNA1C, and another near a synaptic scaffolding gene, ANK3 (4). Additive effects of common loci detectable on commercially available genomic arrays may be used to predict about 25% of the risk for BD (5), but typically the function and exact location of the causative variants linked to these loci is unknown.Rare variants may explain additional risk for BD. It is possible that one or a few rare variants of large effect dramatically increase disease risk, resulting in an inheritance model resembling monogenic inheritance in a given family. However, four exomesequencing and whole-genome sequencing (WGS) studies of BD pedigrees have detected few, if any, plausible variants of large effect (6-9). An alternative oligogenic model posits that different combinations of several uncommon or rare variants of moderate effect cluster in affected individuals and collectively cause disease.To test the hypothesis that rare variants contribute to risk for BD, we sequenced the genomes of 200 individuals from 41 multiply affected BD pedigrees of European ancestry. We seque...

ObjectiveThe aim of this review, conducted in April 2020, is to examine available national primary care guidelines for COVID-19 and to explore the ways in which these guidelines support primary care facilities in responding to the demands of the COVID-19 pandemic.DesignRapid review and narrative synthesis.Data sourcesPubMed, Embase and Google, as well as the websites of relevant national health departments, were searched from 1 January 2020 to 24 April 2020.Eligibility criteriaDocuments included must be issued by a national health authority, must be specific to COVID-19 care, directed at healthcare workers or managers, and must refer to the role of primary care in the COVID-19 response.ResultsWe identified 17 documents from 14 countries. An adapted framework on primary care challenges and responses to pandemic influenza framed our analysis. Guidelines generally reported on COVID-19 service delivery and mostly made specific recommendations for ensuring continued delivery of essential primary care services through telehealth or other virtual care modalities. Few offered guidance to support surveillance as a public health function. All offered guidance on implementing outbreak control measures, largely through flexible and coordinated organisational models with partners from various sectors. There was a lack of guidance to support supply chain management and practice resilience in primary care, and lack of personal protective equipment represents a serious threat to the provision of quality care during the pandemic.ConclusionsCurrent national primary care guidelines for COVID-19 provide guidance on infection control and minimising the risk of spread in primary care practices, while supporting the use of new technology and coordinated partnerships. However, to ensure primary care practice resilience and quality of care are upheld, guidelines must offer recommendations on supply chain management and operational continuity, supported by adequate resources.

BackgroundRecognizing the growing demand from medical students and residents for more comprehensive global health training, and the paucity of explicit curricula on such issues, global health and curriculum experts from the six Ontario Family Medicine Residency Programs worked together to design a framework for global health curricula in family medicine training programs.MethodsA working group comprised of global health educators from Ontario's six medical schools conducted a scoping review of global health curricula, competencies, and pedagogical approaches. The working group then hosted a full day meeting, inviting experts in education, clinical care, family medicine and public health, and developed a consensus process and draft framework to design global health curricula. Through a series of weekly teleconferences over the next six months, the framework was revised and used to guide the identification of enabling global health competencies (behaviours, skills and attitudes) for Canadian Family Medicine training.ResultsThe main outcome was an evidence-informed interactive framework http://globalhealth.ennovativesolution.com/ to provide a shared foundation to guide the design, delivery and evaluation of global health education programs for Ontario's family medicine residency programs. The curriculum framework blended a definition and mission for global health training, core values and principles, global health competencies aligning with the Canadian Medical Education Directives for Specialists (CanMEDS) competencies, and key learning approaches. The framework guided the development of subsequent enabling competencies.ConclusionsThe shared curriculum framework can support the design, delivery and evaluation of global health curriculum in Canada and around the world, lay the foundation for research and development, provide consistency across programmes, and support the creation of learning and evaluation tools to align with the framework. The process used to develop this framework can be applied to other aspects of residency curriculum development.

SUMMARY We present a systems strategy that facilitated the development of a molecular signature for glioblastoma (GBM), composed of 33 cell-surface transmembrane proteins. This molecular signature, GBMSig was developed through the integration of cell-surface proteomics and transcriptomics from patient tumors in the REMBRANDT (n=228) and TCGA datasets (n=547) and can separate GBM patients from controls with an MCC value of 0.87 in a lock-down-test. Functionally, 17/33 GBMSig proteins are associated with TGFβ signaling pathways, including: CD47, SLC16A1, HMOX1 and MRC2. Knockdown of these genes impaired GBM invasion, reflecting their role in disease-perturbed changes in GBM. ELISA assays for a subset of GBMSig (CD44, VCAM1, HMOX1, and BIGH3) on 84 plasma specimens from multiple clinical sites revealed a high degree of separation of GBM patients from healthy controls (AUC 0.98 in ROC). Additionally, a classifier based on these four proteins differentiated the blood of pre- and post-tumor resections, demonstrating potential clinical value as biomarkers.

PURPOSE To identify and prioritize the needs for new research evidence for primary health care (PHC) in low-and middle-income countries (LMICs) about organization, models of care, and financing of PHC. METHODS Three-round expert panel consultation of LMIC PHC practitioners and academics sampled from global networks, via web-based surveys. Iterative literature review conducted in parallel. Round 1 (pre-Delphi survey) elicited possible research questions to address knowledge gaps about organization and models of care and about financing. Round 2 invited panelists to rate the importance of each question, and in round 3 panelists provided priority ranking. RESULTS One hundred forty-one practitioners and academics from 50 LMICs from all global regions participated and identified 744 knowledge gaps critical to improving PHC organization and 479 for financing. Four priority areas emerged: effective transition of primary and secondary services, horizontal integration within a multidisciplinary team and intersectoral referral, integration of private and public sectors, and ways to support successfully functioning PHC professionals. Financial evidence priorities were mechanisms to drive investment into PHC, redress inequities, increase service quality, and determine the minimum necessary budget for good PHC. CONCLUSIONS This novel approach toward PHC needs in LMICs, informed by local academics and professionals, created an expansive and prioritized list of critical knowledge gaps in PHC organization and financing. It resulted in research questions, offering valuable guidance to global supporters of primary care evaluation and implementation. Its source and context specificity, informed by LMIC practitioners and academics, should increase the likelihood of local relevance and eventual success in implementing research findings.

BackgroundHigh quality primary care is fundamental to achieving health for all. Research priority setting is a key facilitator of improving how research activity responds to concrete needs. There has never before been an attempt to identify international primary care research priorities, in order to guide resource allocation and to enhance global primary care. This study aimed to identify a list of top 10 primary care research priorities, as identified by members of the public, health professionals working in primary care, researchers, and policymakers.MethodsWe adapted the James Lind Alliance Priority Setting Partnership process, to conduct multiple rounds of stakeholder recruitment and prioritization. The study included an online survey conducted in three languages, followed by an in-person priority setting exercise involving primary care stakeholders from 13 countries.FindingsParticipants identified a list of top 10 international primary care research priorities. These were focused on diverse topics such as enhancing use of information and communication technology, and improving integration of indigenous communities’ knowledge in the design of primary care services. The main limitations of the study related to challenges in engaging an adequate diversity and number of appropriate stakeholders, particularly members of the public, in aggregating the diverse set of responses into coherent categories representative of the participants’ perspectives and in adequately representing the diversity of submitted responses while ensuring research priorities on the final list are sufficiently actionable to guide resource allocation.ConclusionsThe top 10 identified research priorities have the potential to guide research resource allocation, supporting funding agencies and initiatives to promote global primary care research and practice.

BackgroundAlthough a growing number of collaborative mental health care models have been developed, targeting specific populations, few studies have utilized such interventions among homeless populations. This quasi-experimental study compared the outcomes of two shelter-based collaborative mental health care models for men experiencing homelessness and mental illness: (1) an integrated multidisciplinary collaborative care (IMCC) model and (2) a less resource intensive shifted outpatient collaborative care (SOCC) model.MethodsIn total 142 participants, 70 from IMCC and 72 from SOCC were enrolled and followed for 12 months. Outcome measures included community functioning, residential stability, and health service use. Multivariate regression models were used to compare study arms with respect to change in community functioning, residential stability, and health service use outcomes over time and to identify baseline demographic, clinical or homelessness variables associated with observed changes in these domains.ResultsWe observed improvements in both programs over time on measures of community functioning, residential stability, hospitalizations, emergency department visits and community physician visits, with no significant differences between groups over time on these outcome measures.ConclusionsOur findings suggest that shelter-based collaborative mental health care models may be effective for individuals experiencing homelessness and mental illness. Future studies should seek to confirm these findings and examine the cost effectiveness of collaborative care models for this population.

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