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San Francisco implemented one of the most intensive, comprehensive, multipronged COVID-19 pandemic responses in the United States using 4 core strategies: (1) aggressive mitigation measures to protect populations at risk for severe disease, (2) prioritization of resources in neighborhoods highly affected by COVID-19, (3) timely and adaptive data-driven policy making, and (4) leveraging of partnerships and public trust. We collected data to describe programmatic and population-level outcomes. The excess all-cause mortality rate in 2020 in San Francisco was half that seen in 2019 in California as a whole (8% vs 16%). In almost all age and race and ethnicity groups, excess mortality from COVID-19 was lower in San Francisco than in California overall, with markedly diminished excess mortality among people aged >65 years. The COVID-19 response in San Francisco highlights crucial lessons, particularly the importance of community responsiveness, joint planning, and collective action, to inform future pandemic response and advance health equity.

T cell antigen receptor stimulation induces tyrosine phosphorylation of downstream signaling molecules and the phosphatidylinositol, Ras, MAPK, and PI3 kinase pathways, leading to T cell activation. Previously, we reported that the G-protein-coupled human muscarinic receptor could bypass tyrosine kinases to activate the phosphatidylinositol pathway and induce interleukin-2 production in Jurkat leukemic T cells. Here, we demonstrate that stimulating G-protein-coupled muscarinic receptors (M1 and synthetic hM3Dq) can activate primary mouse T cells if PLCβ1 is coexpressed. Resting peripheral hM3Dq+PLCβ1 (hM3Dq/β1) T cells did not respond to clozapine, an hM3Dq agonist, unless they were preactivated by TCR and CD28 stimulation which increased hM3Dq and PLCβ1 expression. This permitted large calcium and phosphorylated ERK responses to clozapine. Clozapine treatment induced high IFN-γ, CD69, and CD25 expression, but surprisingly did not induce substantial IL-2 in hM3Dq/β1 T cells. Importantly, costimulation of both muscarinic receptors plus the TCR even led to reduced IL-2 expression, suggesting a selective inhibitory effect of muscarinic receptor costimulation. Stimulation of muscarinic receptors induced strong nuclear translocation of NFAT and NFκB and activated AP-1. However, stimulation of hM3Dq led to reduced IL-2 mRNA stability which correlated with an effect on the IL-2 3'UTR activity. Interestingly, stimulation of hM3Dq resulted in reduced pAKT and its downstream pathway. This may explain the inhibitory impact on IL-2 production in hM3Dq/β1T cells. Moreover, an inhibitor of PI3K reduced IL-2 production in TCR-stimulated hM3Dq/β1 CD4 T cells, suggesting that activating the pAKT pathway is critical for IL-2 production in T cells.

IntroductionDecentralising methadone maintenance treatment to primary care improves patients' access to care and their drug and HIV treatment outcomes. However, primary care providers (PCP), especially those working in limited-resource settings, are facing great challenges to provide quality methadone treatment. This study explores the challenges perceived by PCP providing methadone treatment at commune health centres in a mountainous region in Vietnam.MethodWe conducted in-depth interviews with 26 PCP who worked as program managers, physicians, counsellors, pharmacists and medication dispensing staff at the methadone programs of eight commune health centres in Dien Bien, Vietnam, in November and December 2019. We used the health-care system framework in developing the interview guides and in summarising data themes.ResultsParticipants identified major challenges in providing methadone treatment in commune health centres at the individual, clinic and environmental levels. Individual-level challenges included a lack of confidence and motivation in providing methadone treatment. Clinic-level factors included inadequate human resources, lack of institutional support, insufficient technical support, lack of referral resources and additional support for patients. Environment-level factors comprised a lack of reasonable policies on financial support for providers at commune health centres for providing methadone treatment, lack of regulations and mechanisms to ensure providers' safety in case of potential violence by patients and to share responsibility for overdose during treatment.Discussion and conclusionPCP in Vietnam faced multi-level challenges in providing quality methadone treatment. Supportive policies and additional resources are needed to ensure the effectiveness of the decentralisation program.

Nghiên cứu tách chiết protein thủy phân từ gelatin da cá rô phi được thực hiện nhằm xác định chế độ thủy phân gelatin bằng enzyme Thermoase GL30 để thu được protein thủy phân có chất lượng tốt. Bột gelatin được thủy phân bằng enzyme Thermoase GL30 nồng độ 0,3% ở 60°C trong 1 giờ, protein thủy phân thu được có độ nhớt, hiệu suất thu hồi và độ sáng lần lượt là 16,8 mPa.s; 96,4% và L*= 93,1. Protein thủy phân từ gelatin da cá rô phi có hàm lượng amino acid kỵ nước là 596 đơn vị/1.000 đơn vị tương ứng với hoạt tính chống oxy hóa (DPPH) 73,2%. Bên cạnh đó, phổ FTIR cho thấy mối quan hệ chặt chẽ giữa số bước sóng trong vùng amide I và vùng amide III đặc biệt là sự ổn định của cấu trúc xoắn bậc ba. Kết quả nghiên cứu cho thấy có thể tận dụng da cá rô phi để sản xuất protein thủy phân chất lượng cao.

Associations between human genetic variation and clinical phenotypes have become a foundation of biomedical research. Most repositories of these data seek to be disease-agnostic and therefore lack disease-focused views. The Type 2 Diabetes Knowledge Portal (T2DKP) is a public resource of genetic datasets and genomic annotations dedicated to type 2 diabetes (T2D) and related traits. Here, we seek to make the T2DKP more accessible to prospective users and more useful to existing users. First, we evaluate the T2DKP's comprehensiveness by comparing its datasets with those of other repositories. Second, we describe how researchers unfamiliar with human genetic data can begin using and correctly interpreting them via the T2DKP. Third, we describe how existing users can extend their current workflows to use the full suite of tools offered by the T2DKP. We finally discuss the lessons offered by the T2DKP toward the goal of democratizing access to complex disease genetic results.

Polygenic scores (PGSs) combine the effects of common genetic variants1,2 to predict risk or treatment strategies for complex diseases3-7. Adding rare variation to PGSs has largely unknown benefits and is methodically challenging. Here, we developed a method for constructing rare variant PGSs and applied it to calculate genetically modified hemoglobin A1C thresholds for type 2 diabetes (T2D) diagnosis7-10. The resultant rare variant PGS is highly polygenic (21,293 variants across 154 genes), depends on ultra-rare variants (72.7% observed in fewer than three people) and identifies significantly more undiagnosed T2D cases than expected by chance (odds ratio = 2.71; P = 1.51 × 10-6). A PGS combining common and rare variants is expected to identify 4.9 million misdiagnosed T2D cases in the United States-nearly 1.5-fold more than the common variant PGS alone. These results provide a method for constructing complex trait PGSs from rare variants and suggest that rare variants will augment common variants in precision medicine approaches for common disease.

BackgroundThe extent to which vaccinated persons diagnosed with coronavirus disease 2019 (COVID-19) can transmit to other vaccinated and unvaccinated persons is unclear.MethodsUsing data from the San Francisco Department of Public Health, this report describes outcomes of household contact tracing during 29 January-2 July 2021, where fully vaccinated patients with COVID-19 were the index case in the household.ResultsAmong 248 fully vaccinated patients with breakthrough infections, 203 (82%) were symptomatic and 105 were identified as the index patient within their household. Among 179 named household contacts, 71 (40%) contacts tested, over half (56%) were fully vaccinated and the secondary attack rate was 28%. Overall transmission from a symptomatic fully vaccinated patient with breakthrough infection to household contacts was suspected in 14 of 105 (13%) of households. Viral genomic sequencing of samples from 44% of fully vaccinated patients showed that 82% of those sequenced were infected by a variant of concern or interest and 77% by a variant carrying mutation(s) associated with resistance to neutralizing antibodies.ConclusionsTransmission from fully vaccinated symptomatic index patients to vaccinated and unvaccinated household contacts can occur. Indoor face masking and timely testing of all household contacts should be considered when a household member receives a positive test result in order to identify and interrupt transmission chains.

Policymakers use results from randomized controlled trials to inform decisions about whether to implement treatments in target populations. Various methods - including inverse probability weighting, outcome modeling, and Targeted Maximum Likelihood Estimation - that use baseline data available in both the trial and target population have been proposed to generalize the trial treatment effect estimate to the target population. Often the target population is significantly larger than the trial sample, which can cause estimation challenges. We conduct simulations to compare the performance of these methods in this setting. We vary the size of the target population, the proportion of the target population selected into the trial, and the complexity of the true selection and outcome models. All methods performed poorly when the trial size was only 2% of the target population size or the target population included only 1,000 units. When the target population or the proportion of units selected into the trial was larger, some methods, such as outcome modeling using Bayesian Additive Regression Trees, performed well. We caution against generalizing using these existing approaches when the target population is much larger than the trial sample and advocate future research strives to improve methods for generalizing to large target populations.

Melanoma brain metastasis (MBM) frequently occurs in patients with advanced melanoma; yet, our understanding of the underlying salient biology is rudimentary. Here, we performed single-cell/nucleus RNA-seq in 22 treatment-naive MBMs and 10 extracranial melanoma metastases (ECMs) and matched spatial single-cell transcriptomics and T cell receptor (TCR)-seq. Cancer cells from MBM were more chromosomally unstable, adopted a neuronal-like cell state, and enriched for spatially variably expressed metabolic pathways. Key observations were validated in independent patient cohorts, patient-derived MBM/ECM xenograft models, RNA/ATAC-seq, proteomics, and multiplexed imaging. Integrated spatial analyses revealed distinct geography of putative cancer immune evasion and evidence for more abundant intra-tumoral B to plasma cell differentiation in lymphoid aggregates in MBM. MBM harbored larger fractions of monocyte-derived macrophages and dysfunctional TOX+CD8+ T cells with distinct expression of immune checkpoints. This work provides comprehensive insights into MBM biology and serves as a foundational resource for further discovery and therapeutic exploration.

This article examines international English-medium students' language aspirations in relation to social mobility as they are studying in a (Mandarin) Chinese-dominant context. It focuses specifically on Vietnamese students in Taiwan and their perspectives on how English and Chinese are related to their present and future life opportunities. Data were obtained from interviews with students from five different Taiwanese universities. Findings suggest that for these students, English and Chinese were highly mobile languages, which could provide them with the possibility to mobilise across imagined geographical, cultural, educational, work and peer communities of lower and higher scales. Both languages were, as a result, seen by them as a vehicle for their trans-contextual Anglo-Sino social mobility. Their imagination about mobility opportunities associated with the languages, however, may not always be achieved. Implications for supporting international students to enhance their multilingual skills and to contextualise the question of language competence in relation to mobility are then suggested.

Purpose: The aim of this paper is to elaborate on the opportunities and challenges to the application of portfolios as an assessment tool in English as a Foreign Language (EFL) classrooms at different educational levels in Vietnam, as explicitly and implicitly reported in the literature. Design: This study is a combination of a narrative review, synthesising educational documents during 2014-2021, and a systematic review, resulting in 26 empirical studies during 1999-2021 to be included. The adopted approach to data analysis was inductive, deductive and thematic. Data extracting and coding were conducted manually with the aid of Microsoft Word tools. Findings: The results indicate that enabling factors for the use of assessment portfolios included governmental documents; teachers' and/or students' awareness, attitudes and beliefs; available application of assessment portfolios and their benefits. However, practicality, reliability, validity and accuracy might pose certain challenges to this use. Value: This study adds further insights into our current understandings of the opportunities and challenges to the use of assessment portfolios in international EFL contexts.