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Continuum of care is a concept that has been widely applied in HIV prevention and treatment studies. However, measuring care continuum can be challenging because it involves multiple stages and multiple components or domains at each stage of care. In this study, we introduced an analytical framework to (1) estimate intervention effects overall and by domain using a multi-level modeling approach, and (2) learn possible patterns of domains over time utilizing a multi-layer heatmap visualization. Longitudinal data from an intervention study conducted among people who use drugs in Vietnam were used to construct Seek, Test, Treat, and Retain (STTR) domain and overall scores. Findings from the adjusted analysis showed that people who use drugs in the intervention exhibited a significantly greater improvement in the overall STTR score than those in the control (p-values < .0001). The multi-layer heatmap revealed different patterns of the individual domains over time and the inter-relationships among the individual domains. This study demonstrates the feasibility of constructing a general fulfillment score and domain specific scores to measure care continuum among people who use drugs. The analytical framework can be readily extended to evaluate service fulfillment outcomes in health services and treatment studies for other key populations.

In the ENSEMBLE randomized, placebo-controlled phase 3 trial (NCT04505722), estimated single-dose Ad26.COV2.S vaccine efficacy (VE) was 56% against moderate to severe-critical COVID-19. SARS-CoV-2 Spike sequences were determined from 484 vaccine and 1,067 placebo recipients who acquired COVID-19. In this set of prespecified analyses, we show that in Latin America, VE was significantly lower against Lambda vs. Reference and against Lambda vs. non-Lambda [family-wise error rate (FWER) p

Human induced pluripotent stem cell (hiPSC) to cardiomyocyte (CM) differentiation has reshaped approaches to studying cardiac development and disease. In this study, we employed a genome-wide CRISPR screen in a hiPSC to CM differentiation system and reveal here that BRD4, a member of the bromodomain and extraterminal (BET) family, regulates CM differentiation. Chemical inhibition of BET proteins in mouse embryonic stem cell (mESC)-derived or hiPSC-derived cardiac progenitor cells (CPCs) results in decreased CM differentiation and persistence of cells expressing progenitor markers. In vivo, BRD4 deletion in second heart field (SHF) CPCs results in embryonic or early postnatal lethality, with mutants demonstrating myocardial hypoplasia and an increase in CPCs. Single-cell transcriptomics identified a subpopulation of SHF CPCs that is sensitive to BRD4 loss and associated with attenuated CM lineage-specific gene programs. These results highlight a previously unrecognized role for BRD4 in CM fate determination during development and a heterogenous requirement for BRD4 among SHF CPCs.

BackgroundDelivering methadone treatment in community health facilities by primary care providers is a task-shifting strategy to expand access to drug use treatment, especially in rural mountainous areas. This study aims to investigate factors related to confidence in providing methadone treatment among primary care providers in Vietnam to inform good practice development.MethodsWe conducted a cross-sectional survey with 276 primary care providers who were physicians, physician assistants, nurses, pharmacists or dispensing staff from 67 communes in a mountainous province in Northern Vietnam. Using self-report scales, we measured providers' confidence in providing methadone treatment, beliefs in harm reduction, perceived work-related support, perceived stigma and risk in working with drug-using patients, and empathy towards this population. We used multiple linear regression analyses to explore factors associated with providers' confidence in providing methadone treatment in the whole sample and to compare two groups of providers who did and did not have experience providing methadone. Potential associated factors were measured at facility and provider levels.Result114 (41.3%) participants had previously experience in providing methadone treatment. Providers with methadone treatment experiences had higher confidence in and more accurate knowledge of methadone treatment, perceived less stigma of working with drug-using patients, and reported more work-related support than those without experiences. Higher medical education is associated with lower confidence in providing methadone treatment among providers without methadone experiences, but higher confidence among providers with methadone experiences. Better methadone knowledge was associated with greater confidence in providing methadone treatment among inexperienced providers but not among those with experiences. Receiving work-related support was associated with greater confidence in providing treatment in both groups, regardless of their past methadone experiences.ConclusionIn rural provinces where methadone treatment has been expanded to primary care clinics, interventions to improve primary care providers' confidence should benefit professionals with diverse experiences in providing methadone treatment. Continued training and support at work for providers is essential to ensuring quality in decentralized methadone treatment.

Ferroptosis is an iron-dependent programmed cell death associated with severe kidney diseases, linked to decreased glutathione peroxidase 4 (GPX4). However, the spatial distribution of renal GPX4-mediated ferroptosis and the molecular events causing GPX4 reduction during ischemia-reperfusion (I/R) remain largely unknown. Using spatial transcriptomics, we identify that GPX4 is situated at the interface of the inner cortex and outer medulla, a hyperactive ferroptosis site post-I/R injury. We further discover OTU deubiquitinase 5 (OTUD5) as a GPX4-binding protein that confers ferroptosis resistance by stabilizing GPX4. During I/R, ferroptosis is induced by mTORC1-mediated autophagy, causing OTUD5 degradation and subsequent GPX4 decay. Functionally, OTUD5 deletion intensifies renal tubular cell ferroptosis and exacerbates acute kidney injury, while AAV-mediated OTUD5 delivery mitigates ferroptosis and promotes renal function recovery from I/R injury. Overall, this study highlights a new autophagy-dependent ferroptosis module: hypoxia/ischemia-induced OTUD5 autophagy triggers GPX4 degradation, offering a potential therapeutic avenue for I/R-related kidney diseases.

BACKGROUND: Epidemiological and experimental evidence suggests that higher folate intake is associated with decreased colorectal cancer (CRC) risk; however, the mechanisms underlying this relationship are not fully understood. Genetic variation that may have a direct or indirect impact on folate metabolism can provide insights into folates role in CRC. OBJECTIVES: Our aim was to perform a genome-wide interaction analysis to identify genetic variants that may modify the association of folate on CRC risk. METHODS: We applied traditional case-control logistic regression, joint 3-degree of freedom, and a 2-step weighted hypothesis approach to test the interactions of common variants (allele frequency >1%) across the genome and dietary folate, folic acid supplement use, and total folate in relation to risk of CRC in 30,550 cases and 42,336 controls from 51 studies from 3 genetic consortia (CCFR, CORECT, GECCO). RESULTS: Inverse associations of dietary, total folate, and folic acid supplement with CRC were found (odds ratio [OR]: 0.93; 95% confidence interval [CI]: 0.90, 0.96; and 0.91; 95% CI: 0.89, 0.94 per quartile higher intake, and 0.82 (95% CI: 0.78, 0.88) for users compared with nonusers, respectively). Interactions (P-interaction < 5×10-8) of folic acid supplement and variants in the 3p25.2 locus (in the region of Synapsin II [SYN2]/tissue inhibitor of metalloproteinase 4 [TIMP4]) were found using traditional interaction analysis, with variant rs150924902 (located upstream to SYN2) showing the strongest interaction. In stratified analyses by rs150924902 genotypes, folate supplementation was associated with decreased CRC risk among those carrying the TT genotype (OR: 0.82; 95% CI: 0.79, 0.86) but increased CRC risk among those carrying the TA genotype (OR: 1.63; 95% CI: 1.29, 2.05), suggesting a qualitative interaction (P-interaction = 1.4×10-8). No interactions were observed for dietary and total folate. CONCLUSIONS: Variation in 3p25.2 locus may modify the association of folate supplement with CRC risk. Experimental studies and studies incorporating other relevant omics data are warranted to validate this finding.

The C allele of rs11136000 variant in the clusterin (CLU) gene represents the third strongest known genetic risk factor for late-onset Alzheimer's disease. However, whether this single-nucleotide polymorphism (SNP) is functional and what the underlying mechanisms are remain unclear. In this study, the CLU rs11136000 SNP is identified as a functional variant by a small-scale CRISPR-Cas9 screen. Astrocytes derived from isogenic induced pluripotent stem cells (iPSCs) carrying the "C" or "T" allele of the CLU rs11136000 SNP exhibit different CLU expression levels. TAR DNA-binding protein-43 (TDP-43) preferentially binds to the "C" allele to promote CLU expression and exacerbate inflammation. The interferon response and CXCL10 expression are elevated in cytokine-treated C/C astrocytes, leading to inhibition of oligodendrocyte progenitor cell (OPC) proliferation and myelination. Accordingly, elevated CLU and CXCL10 but reduced myelin basic protein (MBP) expression are detected in human brains of C/C carriers. Our study uncovers a mechanism underlying reduced white matter integrity observed in the CLU rs11136000 risk "C" allele carriers.

Community health workers (CHW) can play an active role in providing integrated HIV and harm reduction services. We used social media to create a virtual network among Vietnamese CHW. This paper reports CHW's social media engagement and the relationships with other work-related indicators. Sixty CHW participated in an intervention for integrated HIV/drug use service delivery. Following two in-person sessions, Facebook groups were established for CHW to share information, seek consultation, and refer patients. CHW's levels of online engagements were tracked for six months and linked to their service provision confidence, interaction with patients and other providers, and job satisfaction. The CHW made 181 posts, which received 557 comments and 1,607 reactions during the six months. Among the 60 CHW, 22 (36.6%) had three or more posts, 19 (31.7%) had one or two posts, and 19 (31.7%) had no post. Comparing the baseline and 6-month follow-up data, we observed that those who posted three or more times showed better service provision confidence (p = 0.0081), more interaction with providers in other settings (p = 0.0071), and higher job satisfaction (p = 0.0268). Our study suggests using social media to engage CHW in virtual communications to improve service provision in communities.

The ability to sense and respond to changes in cellular oxygen levels is critical for aerobic organisms and requires a molecular oxygen sensor. The prototypical sensor is the oxygen-dependent enzyme PHD: hypoxia inhibits its ability to hydroxylate the transcription factor HIF, causing HIF to accumulate and trigger the classic HIF-dependent hypoxia response. A small handful of other oxygen sensors are known, all of which are oxygen-dependent enzymes. However, hundreds of oxygen-dependent enzymes exist among aerobic organisms, raising the possibility that additional sensors remain to be discovered. This review summarizes known and potential hypoxia sensors among human O2-dependent enzymes and highlights their possible roles in hypoxia-related adaptation and diseases.

Quaternary ammonium compounds (QACs), a large class of chemicals that includes high production volume substances, have been used for decades as antimicrobials, preservatives, and antistatic agents and for other functions in cleaning, disinfecting, personal care products, and durable consumer goods. QAC use has accelerated in response to the COVID-19 pandemic and the banning of 19 antimicrobials from several personal care products by the US Food and Drug Administration in 2016. Studies conducted before and after the onset of the pandemic indicate increased human exposure to QACs. Environmental releases of these chemicals have also increased. Emerging information on adverse environmental and human health impacts of QACs is motivating a reconsideration of the risks and benefits across the life cycle of their production, use, and disposal. This work presents a critical review of the literature and scientific perspective developed by a multidisciplinary, multi-institutional team of authors from academia, governmental, and nonprofit organizations. The review evaluates currently available information on the ecological and human health profile of QACs and identifies multiple areas of potential concern. Adverse ecological effects include acute and chronic toxicity to susceptible aquatic organisms, with concentrations of some QACs approaching levels of concern. Suspected or known adverse health outcomes include dermal and respiratory effects, developmental and reproductive toxicity, disruption of metabolic function such as lipid homeostasis, and impairment of mitochondrial function. QACs' role in antimicrobial resistance has also been demonstrated. In the US regulatory system, how a QAC is managed depends on how it is used, for example in pesticides or personal care products. This can result in the same QACs receiving different degrees of scrutiny depending on the use and the agency regulating it. Further, the US Environmental Protection Agency's current method of grouping QACs based on structure, first proposed in 1988, is insufficient to address the wide range of QAC chemistries, potential toxicities, and exposure scenarios. Consequently, exposures to common mixtures of QACs and from multiple sources remain largely unassessed. Some restrictions on the use of QACs have been implemented in the US and elsewhere, primarily focused on personal care products. Assessing the risks posed by QACs is hampered by their vast structural diversity and a lack of quantitative data on exposure and toxicity for the majority of these compounds. This review identifies important data gaps and provides research and policy recommendations for preserving the utility of QAC chemistries while also seeking to limit adverse environmental and human health effects.

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.

PURPOSE: This study aims to elucidate the electrotaxis response of alveolar epithelial cells (AECs) in direct-current electric fields (EFs), explore the impact of EFs on the cell fate of AECs, and lay the foundation for future exploitation of EFs for the treatment of acute lung injury. METHODS: AECs were extracted from rat lung tissues using magnetic-activated cell sorting. To elucidate the electrotaxis responses of AECs, different voltages of EFs (0, 50, 100, and 200 mV/mm) were applied to two types of AECs, respectively. Cell migrations were recorded and trajectories were pooled to better demonstrate cellular activities through graphs. Cell directionality was calculated as the cosine value of the angle formed by the EF vector and cell migration. To further demonstrate the impact of EFs on the pulmonary tissue, the human bronchial epithelial cells transformed with Ad12-SV40 2B (BEAS-2B cells) were obtained and experimented under the same conditions as AECs. To determine the influence on cell fate, cells underwent electric stimulation were collected to perform Western blot analysis. RESULTS: The successful separation and culturing of AECs were confirmed through immunofluorescence staining. Compared with the control, AECs in EFs demonstrated a significant directionality in a voltage-dependent way. In general, type Ⅰ alveolar epithelial cells migrated faster than type Ⅱ alveolar epithelial cells, and under EFs, these two types of cells exhibited different response threshold. For type Ⅱ alveolar epithelial cells, only EFs at 200 mV/mm resulted a significant difference to the velocity, whereas for, EFs at both 100 mV/mm and 200 mV/mm gave rise to a significant difference. Western blotting suggested that EFs led to an increased expression of a AKT and myeloid leukemia 1 and a decreased expression of Bcl-2-associated X protein and Bcl-2-like protein 11. CONCLUSION: EFs could guide and accelerate the directional migration of AECs and exert antiapoptotic effects, which indicated that EFs are important biophysical signals in the re-epithelialization of alveolar epithelium in lung injury.

IntroductionHarm reduction services, including methadone maintenance therapy (MMT), have been decentralized to Vietnam's community health care settings. This study aims to pilot test an intervention to facilitate decentralized harm reduction service delivery in Vietnam.MethodsThe research team conducted an intervention pilot between August 2020 and May 2021 with six community MMT distribution sites in Thai Nguyen Province of Vietnam. We recruited five commune health workers (CHW) from each center (N = 30). In-person intervention training included content to correct misconceptions about harm reduction and reduce stigmatizing attitudes toward patients who use drugs and teach CHWs to self-examine and improve their service provision process. The study team developed a web-based platform to streamline CHW's patient monitoring and referral efforts. The team assessed intervention outcomes at baseline, 3-, and 6-months. CHWs in the intervention group provided acceptability ratings and feedback on the intervention at 6-months.ResultsCHWs in both intervention and control groups had similar background characteristics and outcome measures at baseline. CHWs in the intervention group, compared to those in the control group, showed a significantly higher level of improvement in adherence to service delivery protocol at 3-months. CHW in the intervention group had a significantly lower level of management-related stress compared to the control group at 6-months, although the intervention effect measured by the difference in change from baseline was not statistically significant. CHWs who participated in the final focus group reported high acceptability of the intervention.ConclusionThis intervention pilot demonstrated acceptability and promising outcomes on community-based harm reduction service delivery. Similar intervention strategies can be applied to enhance the decentralization of other chronic disease treatment services.

BackgroundMethamphetamine use could jeopardize the current efforts to address opioid use disorder and HIV infection. Evidence-based behavioral interventions (EBI) are effective in reducing methamphetamine use. However, evidence on optimal combinations of EBI is limited. This protocol presents a type-1 effectiveness-implementation hybrid design to evaluate the effectiveness, cost-effectiveness of adaptive methamphetamine use interventions, and their implementation barriers in Vietnam.MethodDesign: Participants will be first randomized into two frontline interventions for 12 weeks. They will then be placed or randomized to three adaptive strategies for another 12 weeks. An economic evaluation and an ethnographic evaluation will be conducted alongside the interventions.ParticipantsWe will recruit 600 participants in 20 methadone clinics.Eligibility criteria(1) age 16+; (2) Alcohol, Smoking and Substance Involvement Screening Test (ASSIST) scores ≥ 10 for methamphetamine use or confirmed methamphetamine use with urine drug screening; (3) willing to provide three pieces of contact information; and (4) having a cell phone.OutcomesOutcomes are measured at 13, 26, and 49 weeks and throughout the interventions. Primary outcomes include the (1) increase in HIV viral suppression, (2) reduction in HIV risk behaviors, and (3) reduction in methamphetamine use. COVID-19 response: We developed a response plan for interruptions caused by COVID-19 lockdowns to ensure data quality and intervention fidelity.DiscussionThis study will provide important evidence for scale-up of EBIs for methamphetamine use among methadone patients in limited-resource settings. As the EBIs will be delivered by methadone providers, they can be readily implemented if the trial demonstrates effectiveness and cost-effectiveness.Trial registrationClinicalTrials.gov NCT04706624. Registered on 13 January 2021. https://clinicaltrials.gov/ct2/show/NCT04706624.

Pharmacologic activation of branched-chain amino acid (BCAA) catabolism is protective in models of heart failure (HF). How protection occurs remains unclear, although a causative block in cardiac BCAA oxidation is widely assumed. Here, we use in vivo isotope infusions to show that cardiac BCAA oxidation in fact increases, rather than decreases, in HF. Moreover, cardiac-specific activation of BCAA oxidation does not protect from HF even though systemic activation does. Lowering plasma and cardiac BCAAs also fails to confer significant protection, suggesting alternative mechanisms of protection. Surprisingly, activation of BCAA catabolism lowers blood pressure (BP), a known cardioprotective mechanism. BP lowering occurred independently of nitric oxide and reflected vascular resistance to adrenergic constriction. Mendelian randomization studies revealed that elevated plasma BCAAs portend higher BP in humans. Together, these data indicate that BCAA oxidation lowers vascular resistance, perhaps in part explaining cardioprotection in HF that is not mediated directly in cardiomyocytes.

The high burden of kidney disease, global disparities in kidney care, and the poor outcomes of kidney failure place a growing burden on affected individuals and their families, caregivers, and the community at large. Health literacy is the degree to which individuals and organizations have, or equitably enable individuals to have, the ability to find, understand, and use information and services to make informed health-related decisions and actions for themselves and others. Rather than viewing health literacy as a patient deficit, improving health literacy lies primarily with health care providers communicating and educating effectively in codesigned partnership with those with kidney disease. For kidney policy makers, health literacy is a prerequisite for organizations to transition to a culture that places the person at the center of health care. The growing capability of and access to technology provides new opportunities to enhance education and awareness of kidney disease for all stakeholders. Advances in telecommunication, including social media platforms, can be leveraged to enhance persons' and providers' education. The World Kidney Day declares 2022 as the year of "Kidney Health for All" to promote global teamwork in advancing strategies in bridging the gap in kidney health education and literacy. Kidney organizations should work toward shifting the patient-deficit health literacy narrative to that of being the responsibility of health care providers and health policy makers. By engaging in and supporting kidney health-centered policy making, community health planning, and health literacy approaches for all, the kidney communities strive to prevent kidney diseases and enable living well with kidney disease.

The low-density lipoprotein receptor (LDLR) controls cellular delivery of cholesterol and clears LDL from the bloodstream, protecting against atherosclerotic heart disease, the leading cause of death in the United States. We therefore sought to identify regulators of the LDLR beyond the targets of current therapies and known causes of familial hypercholesterolemia. We found that cold shock domain-containing protein E1 (CSDE1) enhanced hepatic LDLR messenger RNA (mRNA) decay via its 3' untranslated region and regulated atherogenic lipoproteins in vivo. Using parallel phenotypic genome-wide CRISPR interference screens in a tissue culture model, we identified 40 specific regulators of the LDLR that were not previously identified by observational human genetic studies. Among these, we demonstrated that, in HepG2 cells, CSDE1 regulated the LDLR at least as strongly as statins and proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors. In addition, we showed that hepatic gene silencing of Csde1 treated diet-induced dyslipidemia in mice to a similar degree as Pcsk9 silencing. These results suggest the therapeutic potential of targeting CSDE1 to manipulate the posttranscriptional regulation of the LDLR mRNA for the prevention of cardiovascular disease. Our approach of modeling a clinically relevant phenotype in a forward genetic screen, followed by mechanistic pharmacologic dissection and in vivo validation, may serve as a generalizable template for the identification of therapeutic targets in other human disease states.

BackgroundThe use of menopausal hormone therapy (MHT) may interact with genetic variants to influence colorectal cancer (CRC) risk.MethodsWe conducted a genome-wide, gene-environment interaction between single nucleotide polymorphisms and the use of any MHT, estrogen only, and combined estrogen-progestogen therapy with CRC risk, among 28 486 postmenopausal women (11 519 CRC patients and 16 967 participants without CRC) from 38 studies, using logistic regression, 2-step method, and 2- or 3-degree-of-freedom joint test. A set-based score test was applied for rare genetic variants.ResultsThe use of any MHT, estrogen only and estrogen-progestogen were associated with a reduced CRC risk (odds ratio [OR] = 0.71, 95% confidence interval [CI] = 0.64 to 0.78; OR = 0.65, 95% CI = 0.53 to 0.79; and OR = 0.73, 95% CI = 0.59 to 0.90, respectively). The 2-step method identified a statistically significant interaction between a GRIN2B variant rs117868593 and MHT use, whereby MHT-associated CRC risk was statistically significantly reduced in women with the GG genotype (OR = 0.68, 95% CI = 0.64 to 0.72) but not within strata of GC or CC genotypes. A statistically significant interaction between a DCBLD1 intronic variant at 6q22.1 (rs10782186) and MHT use was identified by the 2-degree-of-freedom joint test. The MHT-associated CRC risk was reduced with increasing number of rs10782186-C alleles, showing odds ratios of 0.78 (95% CI = 0.70 to 0.87) for TT, 0.68 (95% CI = 0.63 to 0.73) for TC, and 0.66 (95% CI = 0.60 to 0.74) for CC genotypes. In addition, 5 genes in rare variant analysis showed suggestive interactions with MHT (2-sided P

Pre-exposure prophylaxis (PrEP) is a promising HIV prevention method. However, the rollout of PrEP among men who have sex with men (MSM) is facing challenges. This study sought to understand PrEP acceptability and service use challenges among MSM in China. The study was conducted in 2018 in Guangdong Province using a mixed-methods approach. Among 489 HIV-negative MSM who completed an online survey, 374 (76.5%) had heard of PrEP before. The most common PrEP information sources were internet/social media (32.1%) and community-based organizations (30.4%). Two-thirds (n=328) of the MSM would accept PrEP even the protective efficacy is less than 100%, 60.1% (n=294) expressed willingness to use PrEP once it is approved in China, and 59.3% (n=290) were willing to pay out of pocket. Employment, disclosure of MSM status, and mental health issues were associated with PrEP acceptability. In-depth interviews with 30 MSM revealed that high cost, low accessibility, and stigma in clinic settings were barriers to PrEP using. Primary care-based PrEP services were acceptable, but patients' confidentiality was a concern. PrEP promotion efforts should address social and mental health challenges among MSM and mobilize primary care systems and community-based organizations to achieve the best result.

BackgroundPeople living with HIV who use drugs (PLHWUD) face enormous challenges to access antiretroviral therapy (ART), addiction treatment, and other healthcare services. This study evaluated the effect of a community capacity-building approach on PLHWUD's access to healthcare services.MethodsA cluster randomized controlled trial was conducted in four provinces of Vietnam. Trained commune health workers in the intervention condition were encouraged to provide services to PLHWUD in the community and engage them in HIV/addiction treatment and care using learned knowledge and skills. A total of 241 PLHWUD participated in surveys at the baseline and every three months for one year. The primary outcome was PLHWUD's reported barriers to seeking healthcare. A linear mixed-effects regression model with a difference in difference approach was used to estimate the intervention effect on the primary outcome.ResultsAdjusted analyses indicated that significant intervention effects were observed at the Sixth and ninth month follow-ups for those on ART at the baseline and increased motivation to engage in treatment at the 3-month follow-up (60.2% vs 34.4% for the intervention and control groups, respectively).ConclusionsThe community capacity-building intervention had shown promising yet limited outcomes among a subset of PLHWUD in the community, that is, PLHWUD who had already initiated ART.

Scientific findings and policy guidelines recommend integrating HIV and drug addiction prevention and care into community-based settings. Systematic capacity-building efforts are warranted to provide technical support for community health workers and improve their confidence in the integrated service provision. An intervention trial was conducted between 2018 and 2019 with 120 community health workers (CHW) from 60 communes in Vietnam's four provinces. The 60 intervention CHW received in-person training to enhance their HIV/addiction-related service knowledge and skills. Online support groups were established between trained CHW and local HIV and addiction specialists. The intervention outcomes were assessed using mixed-effects regression models with the data collected at baseline and every 3 months for 1 year. Adjusted analyses showed that intervention CHW reported a significant increase in the interaction with other treatment providers than the control group at 6 months and remained at the 12-month follow-up. The difference in the improvement of confidence in HIV/addiction-related service delivery between the intervention and control groups was significant at 6-month but became insignificant at the 12-month. Male CHW were more confident in providing services than female CHW at baseline, and gender differences in the changing patterns were observed over time. This capacity-building intervention demonstrated promising outcomes on CHW inter-agency collaborations and confidence in service delivery. Gender divides in healthcare professionals should be attended to in future studies.

IntroductionSarcoidosis is a multiorgan granulomatous disorder thought to be triggered and influenced by gene-environment interactions. Sarcoidosis affects 45-300/100 000 individuals in the USA and has an increasing mortality rate. The greatest gap in knowledge about sarcoidosis pathobiology is a lack of understanding about the underlying immunological mechanisms driving progressive pulmonary disease. The objective of this study is to define the lung-specific and blood-specific longitudinal changes in the adaptive immune response and their relationship to progressive and non-progressive pulmonary outcomes in patients with recently diagnosed sarcoidosis.Methods and analysisThe BRonchoscopy at Initial sarcoidosis diagnosis Targeting longitudinal Endpoints study is a US-based, NIH-sponsored longitudinal blood and bronchoscopy study. Enrolment will occur over four centres with a target sample size of 80 eligible participants within 18 months of tissue diagnosis. Participants will undergo six study visits over 18 months. In addition to serial measurement of lung function, symptom surveys and chest X-rays, participants will undergo collection of blood and two bronchoscopies with bronchoalveolar lavage separated by 6 months. Freshly processed samples will be stained and flow-sorted for isolation of CD4 +T helper (Th1, Th17.0 and Th17.1) and T regulatory cell immune populations, followed by next-generation RNA sequencing. We will construct bioinformatic tools using this gene expression to define sarcoidosis endotypes that associate with progressive and non-progressive pulmonary disease outcomes and validate the tools using an independent cohort.Ethics and disseminationThe study protocol has been approved by the Institutional Review Boards at National Jewish Hospital (IRB# HS-3118), University of Iowa (IRB# 201801750), Johns Hopkins University (IRB# 00149513) and University of California, San Francisco (IRB# 17-23432). All participants will be required to provide written informed consent. Findings will be disseminated via journal publications, scientific conferences, patient advocacy group online content and social media platforms.

Higher-order chromatin structure regulates gene expression, and mutations in proteins mediating genome folding underlie developmental disorders known as cohesinopathies. However, the relationship between three-dimensional genome organization and embryonic development remains unclear. Here we define a role for bromodomain-containing protein 4 (BRD4) in genome folding, and leverage it to understand the importance of genome folding in neural crest progenitor differentiation. Brd4 deletion in neural crest results in cohesinopathy-like phenotypes. BRD4 interacts with NIPBL, a cohesin agonist, and BRD4 depletion or loss of the BRD4-NIPBL interaction reduces NIPBL occupancy, suggesting that BRD4 stabilizes NIPBL on chromatin. Chromatin interaction mapping and imaging experiments demonstrate that BRD4 depletion results in compromised genome folding and loop extrusion. Finally, mutation of individual BRD4 amino acids that mediate an interaction with NIPBL impedes neural crest differentiation into smooth muscle. Remarkably, loss of WAPL, a cohesin antagonist, rescues attenuated smooth muscle differentiation resulting from BRD4 loss. Collectively, our data reveal that BRD4 choreographs genome folding and illustrates the relevance of balancing cohesin activity for progenitor differentiation.

Myanmar's continuum of HIV care was surveyed to assess the National AIDS Control Programme's progress; according to its reports, ART coverage was 38% in 2014, 47% in 2015, and 56% in 2016. To evaluate ART coverage and gaps in care, a serial cross-sectional study used the national programme data reported between January 2014 and December 2016, including 228 public and 62 private ART facilities. ART coverage among PLHIV under 15 years old was 89% in 2014, 93% in 2015, and 88% in 2016. Retention in ART care among women was higher than among men, although women were more likely to discontinue care. PLHIV who were enrolled in ART facilities initiated ART at the rates of 60% in 2014, 68% in 2015, and 74% in 2016. Over the 3-year study period, these facilities reported that 2.5-3.7% of PLHIV taking ART had died, and that 3.3-4.8% were lost to follow-up. PLHIV who were tested for viral load were low (2.5-3%). The continuum of HIV care at ART facilities has improved, but more information about attrition and viral suppression are still needed. The reporting system for newly diagnosed PLHIV and facilities for viral load testing need to be strengthened.

In diseased organs, stress-activated signalling cascades alter chromatin, thereby triggering maladaptive cell state transitions. Fibroblast activation is a common stress response in tissues that worsens lung, liver, kidney and heart disease, yet its mechanistic basis remains unclear1,2. Pharmacological inhibition of bromodomain and extra-terminal domain (BET) proteins alleviates cardiac dysfunction3-7, providing a tool to interrogate and modulate cardiac cell states as a potential therapeutic approach. Here we use single-cell epigenomic analyses of hearts dynamically exposed to BET inhibitors to reveal a reversible transcriptional switch that underlies the activation of fibroblasts. Resident cardiac fibroblasts demonstrated robust toggling between the quiescent and activated state in a manner directly correlating with BET inhibitor exposure and cardiac function. Single-cell chromatin accessibility revealed previously undescribed DNA elements, the accessibility of which dynamically correlated with cardiac performance. Among the most dynamic elements was an enhancer that regulated the transcription factor MEOX1, which was specifically expressed in activated fibroblasts, occupied putative regulatory elements of a broad fibrotic gene program and was required for TGFβ-induced fibroblast activation. Selective CRISPR inhibition of the single most dynamic cis-element within the enhancer blocked TGFβ-induced Meox1 activation. We identify MEOX1 as a central regulator of fibroblast activation associated with cardiac dysfunction and demonstrate its upregulation after activation of human lung, liver and kidney fibroblasts. The plasticity and specificity of BET-dependent regulation of MEOX1 in tissue fibroblasts provide previously unknown trans- and cis-targets for treating fibrotic disease.

BackgroundThe literature on associations of circulating concentrations of minerals and vitamins with risk of colorectal cancer is limited and inconsistent. Evidence from randomized controlled trials (RCTs) to support the efficacy of dietary modification or nutrient supplementation for colorectal cancer prevention is also limited.ObjectivesTo complement observational and RCT findings, we investigated associations of genetically predicted concentrations of 11 micronutrients (β-carotene, calcium, copper, folate, iron, magnesium, phosphorus, selenium, vitamin B-6, vitamin B-12, and zinc) with colorectal cancer risk using Mendelian randomization (MR).MethodsTwo-sample MR was conducted using 58,221 individuals with colorectal cancer and 67,694 controls from the Genetics and Epidemiology of Colorectal Cancer Consortium, Colorectal Cancer Transdisciplinary Study, and Colon Cancer Family Registry. Inverse variance-weighted MR analyses were performed with sensitivity analyses to assess the impact of potential violations of MR assumptions.ResultsNominally significant associations were noted for genetically predicted iron concentration and higher risk of colon cancer [ORs per SD (ORSD): 1.08; 95% CI: 1.00, 1.17; P value = 0.05] and similarly for proximal colon cancer, and for vitamin B-12 concentration and higher risk of colorectal cancer (ORSD: 1.12; 95% CI: 1.03, 1.21; P value = 0.01) and similarly for colon cancer. A nominally significant association was also noted for genetically predicted selenium concentration and lower risk of colon cancer (ORSD: 0.98; 95% CI: 0.96, 1.00; P value = 0.05) and similarly for distal colon cancer. These associations were robust to sensitivity analyses. Nominally significant inverse associations were observed for zinc and risk of colorectal and distal colon cancers, but sensitivity analyses could not be performed. None of these findings survived correction for multiple testing. Genetically predicted concentrations of β-carotene, calcium, copper, folate, magnesium, phosphorus, and vitamin B-6 were not associated with disease risk.ConclusionsThese results suggest possible causal associations of circulating iron and vitamin B-12 (positively) and selenium (inversely) with risk of colon cancer.

ImportanceThe prevalence of overweight and obesity is increasing among persons of childbearing age and pregnant persons. In 2015, almost half of all persons began pregnancy with overweight (24%) or obesity (24%). Reported rates of overweight and obesity are higher among Black, Alaska Native/American Indian, and Hispanic women and lower among White and Asian women. Excess weight at the beginning of pregnancy and excess gestational weight gain have been associated with adverse maternal and infant health outcomes such as a large for gestational age infant, cesarean delivery, or preterm birth.ObjectiveThe USPSTF commissioned a systematic review to evaluate the benefits and harms of behavioral counseling interventions to prevent adverse health outcomes associated with obesity during pregnancy and to evaluate intermediate outcomes, including excess gestational weight gain. This is a new recommendation.PopulationPregnant adolescents and adults in primary care settings.Evidence assessmentThe USPSTF concludes with moderate certainty that behavioral counseling interventions aimed at promoting healthy weight gain and preventing excess gestational weight gain in pregnancy have a moderate net benefit for pregnant persons.RecommendationThe USPSTF recommends that clinicians offer pregnant persons effective behavioral counseling interventions aimed at promoting healthy weight gain and preventing excess gestational weight gain in pregnancy. (B recommendation).

ImportanceColorectal cancer is the third leading cause of cancer death for both men and women, with an estimated 52 980 persons in the US projected to die of colorectal cancer in 2021. Colorectal cancer is most frequently diagnosed among persons aged 65 to 74 years. It is estimated that 10.5% of new colorectal cancer cases occur in persons younger than 50 years. Incidence of colorectal cancer (specifically adenocarcinoma) in adults aged 40 to 49 years has increased by almost 15% from 2000-2002 to 2014-2016. In 2016, 26% of eligible adults in the US had never been screened for colorectal cancer and in 2018, 31% were not up to date with screening.ObjectiveTo update its 2016 recommendation, the US Preventive Services Task Force (USPSTF) commissioned a systematic review to evaluate the benefits and harms of screening for colorectal cancer in adults 40 years or older. The review also examined whether these findings varied by age, sex, or race/ethnicity. In addition, as in 2016, the USPSTF commissioned a report from the Cancer Intervention and Surveillance Modeling Network Colorectal Cancer Working Group to provide information from comparative modeling on how estimated life-years gained, colorectal cancer cases averted, and colorectal cancer deaths averted vary by different starting and stopping ages for various screening strategies.PopulationAsymptomatic adults 45 years or older at average risk of colorectal cancer (ie, no prior diagnosis of colorectal cancer, adenomatous polyps, or inflammatory bowel disease; no personal diagnosis or family history of known genetic disorders that predispose them to a high lifetime risk of colorectal cancer [such as Lynch syndrome or familial adenomatous polyposis]).Evidence assessmentThe USPSTF concludes with high certainty that screening for colorectal cancer in adults aged 50 to 75 years has substantial net benefit. The USPSTF concludes with moderate certainty that screening for colorectal cancer in adults aged 45 to 49 years has moderate net benefit. The USPSTF concludes with moderate certainty that screening for colorectal cancer in adults aged 76 to 85 years who have been previously screened has small net benefit. Adults who have never been screened for colorectal cancer are more likely to benefit.RecommendationThe USPSTF recommends screening for colorectal cancer in all adults aged 50 to 75 years. (A recommendation) The USPSTF recommends screening for colorectal cancer in adults aged 45 to 49 years. (B recommendation) The USPSTF recommends that clinicians selectively offer screening for colorectal cancer in adults aged 76 to 85 years. Evidence indicates that the net benefit of screening all persons in this age group is small. In determining whether this service is appropriate in individual cases, patients and clinicians should consider the patient's overall health, prior screening history, and preferences. (C recommendation).

ImportanceThe prevalence of overweight and obesity is increasing among persons of childbearing age and pregnant persons. In 2015, almost half of all persons began pregnancy with overweight (24%) or obesity (24%). Reported rates of overweight and obesity are higher among Black, Alaska Native/American Indian, and Hispanic women and lower among White and Asian women. Excess weight at the beginning of pregnancy and excess gestational weight gain have been associated with adverse maternal and infant health outcomes such as a large for gestational age infant, cesarean delivery, or preterm birth.ObjectiveThe USPSTF commissioned a systematic review to evaluate the benefits and harms of behavioral counseling interventions to prevent adverse health outcomes associated with obesity during pregnancy and to evaluate intermediate outcomes, including excess gestational weight gain. This is a new recommendation.PopulationPregnant adolescents and adults in primary care settings.Evidence assessmentThe USPSTF concludes with moderate certainty that behavioral counseling interventions aimed at promoting healthy weight gain and preventing excess gestational weight gain in pregnancy have a moderate net benefit for pregnant persons.RecommendationThe USPSTF recommends that clinicians offer pregnant persons effective behavioral counseling interventions aimed at promoting healthy weight gain and preventing excess gestational weight gain in pregnancy. (B recommendation).

ImportanceColorectal cancer is the third leading cause of cancer death for both men and women, with an estimated 52 980 persons in the US projected to die of colorectal cancer in 2021. Colorectal cancer is most frequently diagnosed among persons aged 65 to 74 years. It is estimated that 10.5% of new colorectal cancer cases occur in persons younger than 50 years. Incidence of colorectal cancer (specifically adenocarcinoma) in adults aged 40 to 49 years has increased by almost 15% from 2000-2002 to 2014-2016. In 2016, 26% of eligible adults in the US had never been screened for colorectal cancer and in 2018, 31% were not up to date with screening.ObjectiveTo update its 2016 recommendation, the US Preventive Services Task Force (USPSTF) commissioned a systematic review to evaluate the benefits and harms of screening for colorectal cancer in adults 40 years or older. The review also examined whether these findings varied by age, sex, or race/ethnicity. In addition, as in 2016, the USPSTF commissioned a report from the Cancer Intervention and Surveillance Modeling Network Colorectal Cancer Working Group to provide information from comparative modeling on how estimated life-years gained, colorectal cancer cases averted, and colorectal cancer deaths averted vary by different starting and stopping ages for various screening strategies.PopulationAsymptomatic adults 45 years or older at average risk of colorectal cancer (ie, no prior diagnosis of colorectal cancer, adenomatous polyps, or inflammatory bowel disease; no personal diagnosis or family history of known genetic disorders that predispose them to a high lifetime risk of colorectal cancer [such as Lynch syndrome or familial adenomatous polyposis]).Evidence assessmentThe USPSTF concludes with high certainty that screening for colorectal cancer in adults aged 50 to 75 years has substantial net benefit. The USPSTF concludes with moderate certainty that screening for colorectal cancer in adults aged 45 to 49 years has moderate net benefit. The USPSTF concludes with moderate certainty that screening for colorectal cancer in adults aged 76 to 85 years who have been previously screened has small net benefit. Adults who have never been screened for colorectal cancer are more likely to benefit.RecommendationThe USPSTF recommends screening for colorectal cancer in all adults aged 50 to 75 years. (A recommendation) The USPSTF recommends screening for colorectal cancer in adults aged 45 to 49 years. (B recommendation) The USPSTF recommends that clinicians selectively offer screening for colorectal cancer in adults aged 76 to 85 years. Evidence indicates that the net benefit of screening all persons in this age group is small. In determining whether this service is appropriate in individual cases, patients and clinicians should consider the patient's overall health, prior screening history, and preferences. (C recommendation).

ImportanceHypertension is a prevalent condition that affects approximately 45% of the adult US population and is the most commonly diagnosed condition at outpatient office visits. Hypertension is a major contributing risk factor for heart failure, myocardial infarction, stroke, and chronic kidney disease.ObjectiveTo reaffirm its 2015 recommendation, the US Preventive Services Task Force (USPSTF) commissioned a systematic review to evaluate the benefits and harms of screening for hypertension in adults, the accuracy of office blood pressure measurement for initial screening, and the accuracy of various confirmatory blood pressure measurement methods.PopulationAdults 18 years or older without known hypertension.Evidence assessmentUsing a reaffirmation deliberation process, the USPSTF concludes with high certainty that screening for hypertension in adults has substantial net benefit.RecommendationThe USPSTF recommends screening for hypertension in adults 18 years or older with office blood pressure measurement. The USPSTF recommends obtaining blood pressure measurements outside of the clinical setting for diagnostic confirmation before starting treatment. (A recommendation).

ImportanceVitamin D is a fat-soluble vitamin that performs an important role in calcium homeostasis and bone metabolism and also affects many other cellular regulatory functions outside the skeletal system. Vitamin D requirements may vary by individual; thus, no one serum vitamin D level cutpoint defines deficiency, and no consensus exists regarding the precise serum levels of vitamin D that represent optimal health or sufficiency.ObjectiveTo update its 2014 recommendation, the US Preventive Services Task Force (USPSTF) commissioned a systematic review on screening for vitamin D deficiency, including the benefits and harms of screening and early treatment.PopulationCommunity-dwelling, nonpregnant adults who have no signs or symptoms of vitamin D deficiency or conditions for which vitamin D treatment is recommended.Evidence assessmentThe USPSTF concludes that the overall evidence on the benefits of screening for vitamin D deficiency is lacking. Therefore, the balance of benefits and harms of screening for vitamin D deficiency in asymptomatic adults cannot be determined.RecommendationThe USPSTF concludes that the current evidence is insufficient to assess the balance of benefits and harms of screening for vitamin D deficiency in asymptomatic adults. (I statement).

ImportanceVitamin D is a fat-soluble vitamin that performs an important role in calcium homeostasis and bone metabolism and also affects many other cellular regulatory functions outside the skeletal system. Vitamin D requirements may vary by individual; thus, no one serum vitamin D level cutpoint defines deficiency, and no consensus exists regarding the precise serum levels of vitamin D that represent optimal health or sufficiency.ObjectiveTo update its 2014 recommendation, the US Preventive Services Task Force (USPSTF) commissioned a systematic review on screening for vitamin D deficiency, including the benefits and harms of screening and early treatment.PopulationCommunity-dwelling, nonpregnant adults who have no signs or symptoms of vitamin D deficiency or conditions for which vitamin D treatment is recommended.Evidence assessmentThe USPSTF concludes that the overall evidence on the benefits of screening for vitamin D deficiency is lacking. Therefore, the balance of benefits and harms of screening for vitamin D deficiency in asymptomatic adults cannot be determined.RecommendationThe USPSTF concludes that the current evidence is insufficient to assess the balance of benefits and harms of screening for vitamin D deficiency in asymptomatic adults. (I statement).

ImportanceHypertension is a prevalent condition that affects approximately 45% of the adult US population and is the most commonly diagnosed condition at outpatient office visits. Hypertension is a major contributing risk factor for heart failure, myocardial infarction, stroke, and chronic kidney disease.ObjectiveTo reaffirm its 2015 recommendation, the US Preventive Services Task Force (USPSTF) commissioned a systematic review to evaluate the benefits and harms of screening for hypertension in adults, the accuracy of office blood pressure measurement for initial screening, and the accuracy of various confirmatory blood pressure measurement methods.PopulationAdults 18 years or older without known hypertension.Evidence assessmentUsing a reaffirmation deliberation process, the USPSTF concludes with high certainty that screening for hypertension in adults has substantial net benefit.RecommendationThe USPSTF recommends screening for hypertension in adults 18 years or older with office blood pressure measurement. The USPSTF recommends obtaining blood pressure measurements outside of the clinical setting for diagnostic confirmation before starting treatment. (A recommendation).

ImportanceAge-related sensorineural hearing loss is a common health problem among adults. Nearly 16% of US adults 18 years or older report difficulty hearing. The prevalence of perceived hearing loss increases with age. Hearing loss can adversely affect an individual's quality of life and ability to function independently and has been associated with increased risk of falls, hospitalizations, social isolation, and cognitive decline.ObjectiveTo update its 2012 recommendation, the US Preventive Services Task Force (USPSTF) commissioned a systematic review on screening for hearing loss in adults 50 years or older.PopulationAsymptomatic adults 50 years or older with age-related hearing loss.Evidence assessmentBecause of a lack of evidence, the USPSTF concludes that the benefits and harms of screening for hearing loss in asymptomatic older adults are uncertain and that the balance of benefits and harms cannot be determined. More research is needed.RecommendationThe USPSTF concludes that the current evidence is insufficient to assess the balance of benefits and harms of screening for hearing loss in older adults. (I statement).

ImportanceLung cancer is the second most common cancer and the leading cause of cancer death in the US. In 2020, an estimated 228 820 persons were diagnosed with lung cancer, and 135 720 persons died of the disease. The most important risk factor for lung cancer is smoking. Increasing age is also a risk factor for lung cancer. Lung cancer has a generally poor prognosis, with an overall 5-year survival rate of 20.5%. However, early-stage lung cancer has a better prognosis and is more amenable to treatment.ObjectiveTo update its 2013 recommendation, the US Preventive Services Task Force (USPSTF) commissioned a systematic review on the accuracy of screening for lung cancer with low-dose computed tomography (LDCT) and on the benefits and harms of screening for lung cancer and commissioned a collaborative modeling study to provide information about the optimum age at which to begin and end screening, the optimal screening interval, and the relative benefits and harms of different screening strategies compared with modified versions of multivariate risk prediction models.PopulationThis recommendation statement applies to adults aged 50 to 80 years who have a 20 pack-year smoking history and currently smoke or have quit within the past 15 years.Evidence assessmentThe USPSTF concludes with moderate certainty that annual screening for lung cancer with LDCT has a moderate net benefit in persons at high risk of lung cancer based on age, total cumulative exposure to tobacco smoke, and years since quitting smoking.RecommendationThe USPSTF recommends annual screening for lung cancer with LDCT in adults aged 50 to 80 years who have a 20 pack-year smoking history and currently smoke or have quit within the past 15 years. Screening should be discontinued once a person has not smoked for 15 years or develops a health problem that substantially limits life expectancy or the ability or willingness to have curative lung surgery. (B recommendation) This recommendation replaces the 2013 USPSTF statement that recommended annual screening for lung cancer with LDCT in adults aged 55 to 80 years who have a 30 pack-year smoking history and currently smoke or have quit within the past 15 years.

ImportanceAge-related sensorineural hearing loss is a common health problem among adults. Nearly 16% of US adults 18 years or older report difficulty hearing. The prevalence of perceived hearing loss increases with age. Hearing loss can adversely affect an individual's quality of life and ability to function independently and has been associated with increased risk of falls, hospitalizations, social isolation, and cognitive decline.ObjectiveTo update its 2012 recommendation, the US Preventive Services Task Force (USPSTF) commissioned a systematic review on screening for hearing loss in adults 50 years or older.PopulationAsymptomatic adults 50 years or older with age-related hearing loss.Evidence assessmentBecause of a lack of evidence, the USPSTF concludes that the benefits and harms of screening for hearing loss in asymptomatic older adults are uncertain and that the balance of benefits and harms cannot be determined. More research is needed.RecommendationThe USPSTF concludes that the current evidence is insufficient to assess the balance of benefits and harms of screening for hearing loss in older adults. (I statement).

ImportanceLung cancer is the second most common cancer and the leading cause of cancer death in the US. In 2020, an estimated 228 820 persons were diagnosed with lung cancer, and 135 720 persons died of the disease. The most important risk factor for lung cancer is smoking. Increasing age is also a risk factor for lung cancer. Lung cancer has a generally poor prognosis, with an overall 5-year survival rate of 20.5%. However, early-stage lung cancer has a better prognosis and is more amenable to treatment.ObjectiveTo update its 2013 recommendation, the US Preventive Services Task Force (USPSTF) commissioned a systematic review on the accuracy of screening for lung cancer with low-dose computed tomography (LDCT) and on the benefits and harms of screening for lung cancer and commissioned a collaborative modeling study to provide information about the optimum age at which to begin and end screening, the optimal screening interval, and the relative benefits and harms of different screening strategies compared with modified versions of multivariate risk prediction models.PopulationThis recommendation statement applies to adults aged 50 to 80 years who have a 20 pack-year smoking history and currently smoke or have quit within the past 15 years.Evidence assessmentThe USPSTF concludes with moderate certainty that annual screening for lung cancer with LDCT has a moderate net benefit in persons at high risk of lung cancer based on age, total cumulative exposure to tobacco smoke, and years since quitting smoking.RecommendationThe USPSTF recommends annual screening for lung cancer with LDCT in adults aged 50 to 80 years who have a 20 pack-year smoking history and currently smoke or have quit within the past 15 years. Screening should be discontinued once a person has not smoked for 15 years or develops a health problem that substantially limits life expectancy or the ability or willingness to have curative lung surgery. (B recommendation) This recommendation replaces the 2013 USPSTF statement that recommended annual screening for lung cancer with LDCT in adults aged 55 to 80 years who have a 30 pack-year smoking history and currently smoke or have quit within the past 15 years.

This study explores the presence of mental health challenges and related service utilization among MSM in China. An online cross-sectional survey recruited 520 MSM in Guangdong, China, to evaluate the participants' psychiatric symptoms, service fulfillment, and challenges. A high proportion of the participants experienced at least one psychiatric symptom in the past year, but less than half of their mental health service needs were fulfilled. The preferred agencies for mental health services were provincial and city-level general hospitals or primary health centers. Lack of knowledge and misconceptions of mental health services were the primary reasons for not receiving necessary services. Mental health service fulfillment was associated with younger age, lower education, higher income, local residency, cohabitation, and disclosure of MSM status. The high rate of mental health issues and gaps in service seeking indicates an urgent need to increase mental health awareness among MSM.

The tumor microenvironment is a highly complex ecosystem of diverse cell types, which shape cancer biology and impact the responsiveness to therapy. Here, we analyze the microenvironment of esophageal squamous cell carcinoma (ESCC) using single-cell transcriptome sequencing in 62,161 cells from blood, adjacent nonmalignant and matched tumor samples from 11 ESCC patients. We uncover heterogeneity in most cell types of the ESCC stroma, particularly in the fibroblast and immune cell compartments. We identify a tumor-specific subset of CST1+ myofibroblasts with prognostic values and potential biological significance. CST1+ myofibroblasts are also highly tumor-specific in other cancer types. Additionally, a subset of antigen-presenting fibroblasts is revealed and validated. Analyses of myeloid and T lymphoid lineages highlight the immunosuppressive nature of the ESCC microenvironment, and identify cancer-specific expression of immune checkpoint inhibitors. This work establishes a rich resource of stromal cell types of the ESCC microenvironment for further understanding of ESCC biology.

BackgroundGene regulatory networks control tissue homeostasis and disease progression in a cell type-specific manner. Ubiquitously expressed chromatin regulators modulate these networks, yet the mechanisms governing how tissue specificity of their function is achieved are poorly understood. BRD4 (bromodomain-containing protein 4), a member of the BET (bromo- and extraterminal domain) family of ubiquitously expressed acetyl-lysine reader proteins, plays a pivotal role as a coactivator of enhancer signaling across diverse tissue types in both health and disease and has been implicated as a pharmacological target in heart failure. However, the cell-specific role of BRD4 in adult cardiomyocytes remains unknown.MethodsWe combined conditional mouse genetics, unbiased transcriptomic and epigenomic analyses, and classic molecular biology and biochemical approaches to understand the mechanism by which BRD4 in adult cardiomyocyte homeostasis.ResultsHere, we show that cardiomyocyte-specific deletion of Brd4 in adult mice leads to acute deterioration of cardiac contractile function with mutant animals demonstrating a transcriptomic signature characterized by decreased expression of genes critical for mitochondrial energy production. Genome-wide occupancy data show that BRD4 enriches at many downregulated genes (including the master coactivators Ppargc1a, Ppargc1b, and their downstream targets) and preferentially colocalizes with GATA4 (GATA binding protein 4), a lineage-determining cardiac transcription factor not previously implicated in regulation of adult cardiac metabolism. BRD4 and GATA4 form an endogenous complex in cardiomyocytes and interact in a bromodomain-independent manner, revealing a new functional interaction partner for BRD4 that can direct its locus and tissue specificity.ConclusionsThese results highlight a novel role for a BRD4-GATA4 module in cooperative regulation of a cardiomyocyte-specific gene program governing bioenergetic homeostasis in the adult heart.

PurposeIn MONARCH 1 (NCT02102490), single-agent abemaciclib demonstrated promising efficacy activity and tolerability in a population of heavily pretreated women with refractory HR+, HER2- metastatic breast cancer (MBC). To help interpret these results and put in clinical context, we compared overall survival (OS) and duration of therapy (DoT) between MONARCH 1 and a real-world single-agent chemotherapy cohort.MethodsThe real-world chemotherapy cohort was created from a Flatiron Health electronic health records-derived database based on key eligibility criteria from MONARCH 1. The chemotherapies included in the cohort were single-agent capecitabine, gemcitabine, eribulin, or vinorelbine. Results were adjusted for baseline demographics and clinical differences using Mahalanobis distance matching (primary analysis) and entropy balancing (sensitivity analysis). OS and DoT were analyzed using the Kaplan-Meier method and Cox proportional hazards regression.ResultsA real-world single-agent chemotherapy cohort (n = 281) with eligibility criteria similar to the MONARCH 1 population (n = 132) was identified. The MONARCH 1 (n = 108) cohort was matched to the real-world chemotherapy cohort (n = 108). Median OS was 22.3 months in the abemaciclib arm versus 13.6 months in the matched real-world chemotherapy cohort with an estimated hazard ratio (HR) of 0.54. The median DoT was 4.1 months in MONARCH 1 compared to 2.9 months in the real-world chemotherapy cohort with HR of 0.76.ConclusionsThis study demonstrates an approach to create a real-world chemotherapy cohort suitable to serve as a comparator for trial data. These exploratory results suggest a survival advantage and place the benefit of abemaciclib monotherapy in clinical context.

Stigma poses considerable challenges to the mental health of people living with HIV who use drugs (PLHWUD). In this study, we explored factors related to different types of stigma (perceived and internalized) attached to layered stigmatizing characters (HIV and drug use) and their mental health influences on PLHWUD. The study used baseline data of an ongoing randomized controlled trial among 241 PLHWUD recruited between March and December 2018 in Vietnam. A structural equation model was used to assess the relationships among different types and layers of stigma and mental health status. Both perceived and internalized drug-related stigma measures were significantly higher than their corresponding HIV-related stigma. HIV-related stigma was negatively associated with mental health status; however, we did not find a significant relationship between drug-related stigma and mental health. Tailored intervention strategies in consideration of types and layers of stigma are needed to address stigma-related challenges faced by PLHWUD.

IntroductionNearly 40 years into the HIV epidemic, the persistence of HIV stigma is a matter of grave urgency. Discrimination (i.e. enacted stigma) in healthcare settings is particularly problematic as it deprives people of critical healthcare services while also discouraging preventive care seeking by confirming fears of anticipated stigma. We review existing research on the effectiveness of stigma interventions in healthcare settings of low- and middle-income countries (LMIC), where stigma control efforts are often further complicated by heavy HIV burdens, less developed healthcare systems, and the layering of HIV stigma with discrimination towards other marginalized identities. This review describes progress in this field to date and identifies research gaps to guide future directions for research.MethodsWe conducted a scoping review of HIV reduction interventions in LMIC healthcare settings using Embase, Ovid MEDLINE, PsycINFO and Scopus (through March 5, 2020). Information regarding study design, stigma measurement techniques, intervention features and study findings were extracted. We also assessed methodological rigor using the Joanna Briggs Institute checklist for systematic reviews.Results and discussionOur search identified 8766 studies, of which 19 were included in the final analysis. All but one study reported reductions in stigma following the intervention. The studies demonstrated broad regional distribution across LMIC and many employed designs that made use of a control condition. However, these strengths masked key shortcomings including a dearth of research from the lowest income category of LMIC and a lack of interventions to address institutional or structural determinants of stigma. Lastly, despite the fact that most stigma measures were based on existing instruments, only three studies described steps taken to validate or adapt the stigma measures to local settings.ConclusionsCombating healthcare stigma in LMIC demands interventions that can simultaneously address resource constraints, high HIV burden and more severe stigma. Our findings suggest that this will require more objective, reliable and culturally adaptable stigma measures to facilitate meaningful programme evaluation and comparison across studies. All but one study concluded that their interventions were effective in reducing healthcare stigma. Though encouraging, the fact that most studies measured impact using self-reported measures suggests that social desirability may bias results upwards. Homogeneity of study results also hindered our ability to draw substantive conclusions about potential best practices to guide the design of future stigma reduction programmes.

BackgroundService providers are often inadequately compliant with standard precaution protocols. This study used bottleneck analysis to identify the weakest link in standard precaution implementation and its associated challenges in hospitals.MethodsBottleneck analysis was conducted in 12 hospitals in Fujian Province, China. In each hospital, a focus group was organized among the key informants to illustrate the sequential steps of standard precaution implementation graphically. The level of difficulty and the specific challenges associated with each step were discussed.ResultsThe sequential activities of standard precaution implementation generally start with making budget for personal protection equipment (PPE), followed by procurement, storage/inventory, in-hospital distribution, in-department distribution, usage/monitoring, and recycling of PPE. Service providers' improper use of PPE was the primary bottleneck. The reasons for improper use of PPE included high workload, time constraints, the sense of wearing PPE would interfere with clinical judgment, and various misconceptions. Making financial planning, recycling, and procurement of PPE were the secondary bottlenecks.ConclusionsBottleneck analysis is useful to illustrate workflow in healthcare systems and pinpoint constraints in standard precaution implementation. Institutional changes, including targeted provider training, adjustment of providers' workloads, and allocation of budget, are suggested strategies to address the identified bottlenecks in standard precaution.

HCV co-infection is widespread among people living with HIV who use drugs (PLHWUD). However, HCV testing was inconsistently implemented among PLHWUD. The low infection awareness and mental health challenges together impede PLHWUD's treatment-seeking. The study used baseline data of a randomized controlled trial conducted in Vietnam. HCV infection status was collected through self-report and medical record review. A linear mixed-effects regression model was used to examine the relationships between PLHWUD's perceived barriers to seeking healthcare, their depressive symptoms, and the consistencies in HCV status reports. Among the 181 PLHWUD in the study, one-third (64; 35.4%) had inconsistent self-reports and medical records of HIV infection status. The agreement between the two records was fair (Kappa statistics = 0.43). PLHWUD with consistent HCV infection confirmed by both medical records and self-reports perceived lower levels of healthcare-seeking barriers than those with discrepant HCV reports (estimated difference = -1.59, SE = 0.71, P = 0.027). Depressive symptoms were significantly correlated with healthcare-seeking barriers among those with discrepant HCV results (estimate = 0.17, SE = 0.06, P = 0.007). There is an urgent need to extend HCV screening efforts and increase HCV awareness among PLHWUD. Explicit HCV result notification and integrated mental health support are recommended to facilitate patients' access to needed care.

BackgroundBody mass index (BMI) and diabetes are established risk factors for colorectal cancer (CRC), likely through perturbations in metabolic traits (e.g. insulin resistance and glucose homeostasis). Identification of interactions between variation in genes and these metabolic risk factors may identify novel biologic insights into CRC etiology.MethodsTo improve statistical power and interpretation for gene-environment interaction (G × E) testing, we tested genetic variants that regulate expression of a gene together for interaction with BMI (kg/m2 ) and diabetes on CRC risk among 26 017 cases and 20 692 controls. Each variant was weighted based on PrediXcan analysis of gene expression data from colon tissue generated in the Genotype-Tissue Expression Project for all genes with heritability ≥1%. We used a mixed-effects model to jointly measure the G × E interaction in a gene by partitioning the interactions into the predicted gene expression levels (fixed effects), and residual G × E effects (random effects). G × BMI analyses were stratified by sex as BMI-CRC associations differ by sex. We used false discovery rates to account for multiple comparisons and reported all results with FDR

This study compared community health workers' (CHW) stigma towards people living with HIV (PLH) and people who use drugs (PWUD) and explored the relationship between stigma and CHWs' confidence level in providing HIV/drug-related services. Using two sets of identically worded questions, levels of stigma towards PWUD and PLH were measured among 120 CHW from 60 communes in Vietnam. The associations between CHWs' confidence in service provision and stigma towards PWUD and PLH were examined using a linear mixed-effects regression model. The majority of the CHW reported higher levels of stigma towards PWUD than towards PLH. Compared to the CHW reporting higher stigma towards PWUD, those with higher stigma towards PLH were significantly less confident in service provision. Social opprobrium attached to drug-using behaviors can be a major driver behind the overall HIV stigma. CHWs' fear of HIV infection should be tackled to boost their confidence in HIV/drug-related care provision.

ObjectiveService providers' job satisfaction is critical to the stability of the work force and thereby the effectiveness of methadone maintenance treatment (MMT) programs. This study aimed to explore MMT clinic service providers' job satisfaction and associated factors in Jiangsu, China.MethodsThis secondary study used baseline data of a randomized interventional trial implemented in Jiangsu, China. A survey was conducted among 76 MMT service providers using the computer-assisted self-interview (CASI) method. Job satisfaction responses were assessed via a 30-item scale, with a higher score indicating a higher level of job satisfaction. Perceived institutional support and perceived stigma due to working with drug users were measured using a 9-item scale. Correlation and multiple linear regression analyses were performed to identify factors associated with job satisfaction.ResultsCorrelation analyses found a significant association between job satisfaction and having professional experience in the prevention and control of HIV, other sexually transmitted infections, or other infectious diseases (P = 0.046). Multiple regression analyses revealed that working at MMT clinics affiliated with Center for Disease Control and Prevention sites was associated with a lower level of job satisfaction (P = 0.014), and perception of greater institutional support (P = 0.001) was associated with a higher level of job satisfaction.ConclusionJob satisfaction among MMT clinic service providers was moderate in our study. Our findings suggest that institutional support for providers should be improved, and that acquisition of additional expertise should be encouraged.