UV irradiation remodels the specificity landscape of transcription factors.

Somatic mutations are highly enriched at transcription factor (TF) binding sites, with the strongest trend being observed for ultraviolet light (UV)-induced mutations in melanomas. One of the main mechanisms proposed for this hypermutation pattern is the inefficient repair of UV lesions within TF-binding sites, caused by competition between TFs bound to these lesions and the DNA repair proteins that must recognize the lesions to initiate repair. However, TF binding to UV-irradiated DNA is poorly characterized, and it is unclear whether TFs maintain specificity for their DNA sites after UV exposure. We developed UV-Bind, a high-throughput approach to investigate the impact of UV irradiation on protein-DNA binding specificity. We applied UV-Bind to ten TFs from eight structural families, and found that UV lesions significantly altered the DNA-binding preferences of all the TFs tested. The main effect was a decrease in binding specificity, but the precise effects and their magnitude differ across factors. Importantly, we found that despite the overall reduction in DNA-binding specificity in the presence of UV lesions, TFs can still compete with repair proteins for lesion recognition, in a manner consistent with their specificity for UV-irradiated DNA. In addition, for a subset of TFs, we identified a surprising but reproducible effect at certain nonconsensus DNA sequences, where UV irradiation leads to a high increase in the level of TF binding. These changes in DNA-binding specificity after UV irradiation, at both consensus and nonconsensus sites, have important implications for the regulatory and mutagenic roles of TFs in the cell.

Improving integrated depression and non-communicable disease care in Malawi through engaged leadership and supportive implementation climate.

BACKGROUND: Low- and middle-income countries often lack access to mental health services, leading to calls for integration within other primary care systems. In sub-Saharan Africa, integration of depression treatment in non-communicable disease (NCD) settings is feasible, acceptable, and effective. However, leadership and implementation climate challenges often hinder effective integration and quality of services. The aim of this study was to identify discrete leadership strategies that facilitate overcoming barriers to the integration of depression care in NCD clinics in Malawi and to understand how clinic leadership shapes the implementation climate. METHODS: We conducted 39 in-depth interviews with the District Medical Officer, the NCD coordinator, one NCD provider, and the research assistant from each of the ten Malawian NCD clinics (note one District Medical Officer served two clinics). Based on semi-structured interview guides, participants were asked their perspectives on the impact of leadership and implementation climate on overcoming barriers to integrating depression care into existing NCD services. Thematic analysis used both inductive and deductive approaches to identify emerging themes and compare among participant type. RESULTS: The results revealed how engaged leadership can fuel a positive implementation climate where clinics had heightened capacity to overcome implementation barriers. Effective leaders were approachable and engaged in daily operations of the clinic and problem-solving. They held direct involvement with and mentorship during the intervention, providing assistance in patient screening and consultation with treatment plans. Different levels of leadership utilized their respective standings and power dynamics to influence provider attitudes and perceptions surrounding the intervention. Leaders acted by informing providers about the intervention source and educating them on the importance of mental healthcare, as it was often undervalued. Lastly, they prioritized teamwork and collective ownership for the intervention, increasing provider responsibility. CONCLUSION: Training that prioritizes leadership visibility and open communication will facilitate ongoing Malawi Ministry of Health efforts to scale up evidence-based depression treatment within NCD clinics. This proves useful where extensive and external monitoring may be limited. Ultimately, these results can inform successful strategies to close implementation gaps to achieve integration of mental health services in low-resource settings through improved leadership and implementation climate. TRIAL REGISTRATION: These findings are reported from ClinicalTrials.gov, NCT03711786. Registered on 18/10/2018. https://clinicaltrials.gov/ct2/show/NCT03711786 .

Intimate Partner Violence and Immigration in the United States: A Systematic Review.

This systematic review sought to describe the prevalence of intimate partner violence (IPV) victimization among immigrants in the United States (U.S.) and the prevalence of IPV perpetration among immigrants in the U.S. PsycInfo, PubMed, Global Health and Scopus databases were searched for peer-reviewed literature that quantitatively examined IPV in relation to immigration. Twenty-four articles were included in the final review. Past-year IPV victimization rates among immigrants ranged from 3.8% to 46.9% and lifetime IPV victimization rates ranged from 13.9% to 93%; past-year IPV perpetration rates ranged from 3.0% to 24.8% and the one lifetime IPV perpetration rate was 12.8%. Estimates varied widely by country of origin, type of violence measured, and measure used to quantify IPV. Reliance on small convenience samples is problematic when trying to determine the true prevalence of IPV among immigrants. Epidemiological research is needed to improve the accuracy and representativeness of findings.

Implementation strategies to build mental health-care capacity in Malawi: a health-economic evaluation.

BACKGROUND: Depression is a major contributor to morbidity and mortality in sub-Saharan Africa. Due to low system capacity, three in four patients with depression in sub-Saharan Africa go untreated. Despite this, little attention has been paid to the cost-effectiveness of implementation strategies to scale up evidence-based depression treatment in the region. In this study, we investigate the cost-effectiveness of two different implementation strategies to integrate the Friendship Bench approach and measurement-based care in non-communicable disease clinics in Malawi. METHODS: The two implementation strategies tested in this study are part of a trial, in which ten clinics were randomly assigned (1:1) to a basic implementation package consisting of an internal coordinator acting as a champion (IC-only group) or to an enhanced package that complemented the basic package with quarterly external supervision, and audit and feedback of intervention delivery (IC + ES group). We included material costs, training costs, costs related to project-wide meetings, transportation and medication costs, time costs related to internal champion activities and depression screening or treatment, and costs of external supervision visits if applicable. Outcomes included the number of patients screened with the patient health questionnaire 2 (PHQ-2), cases of remitted depression at 3 and 12 months, and disability-adjusted life-years (DALYs) averted. We compared the cost-effectiveness of both packages to the status quo (ie, no intervention) using a micro-costing-informed decision-tree model. FINDINGS: Relative to the status quo, IC + ES would be on average US$10 387 ($1349-$17 365) more expensive than IC-only but more effective in achieving remission and averting DALYs. The cost per additional remission would also be lower with IC + ES than IC-only at 3 months ($119 vs $223) and 12 months ($210 for IC + ES; IC-only dominated by the status quo at 12 months). Neither package would be cost-effective under the willingness-to-pay threshold of $65 per DALY averted currently used by the Malawian Ministry of Health. However, the IC + ES package would be cost-effective in relation to the commonly used threshold of three times per-capita gross domestic product per DALY averted. INTERPRETATION: Investing in supporting champions might be an appropriate use of resources. Although not currently cost-effective by Malawian willingness-to-pay standards compared with the status quo, the IC + ES package would probably be a cost-effective way to build mental health-care capacity in resource-constrained settings in which decision makers use higher willingness-to-pay thresholds. FUNDING: National Institute of Mental Health.

Multiplexed Live-Cell Imaging for Drug Responses in Patient-Derived Organoid Models of Cancer.

Patient-derived organoid (PDO) models of cancer are a multifunctional research system that better recapitulates human disease as compared to cancer cell lines. PDO models can be generated by culturing patient tumor cells in extracellular basement membrane extracts (BME) and plating them as three-dimensional domes. However, commercially available reagents that have been optimized for phenotypic assays in monolayer cultures often are not compatible with BME. Herein, we describe a method to plate PDO models and assess drug effects using an automated live-cell imaging system. In addition, we apply fluorescent dyes that are compatible with kinetic measurements to quantify cell health and apoptosis simultaneously. Image capture can be customized to occur at regular time intervals over several days. Users can analyze drug effects in individual Z-plane images or a Z Projection of serial images from multiple focal planes. Using masking, specific parameters of interest are calculated, such as PDO number, area, and fluorescence intensity. We provide proof-of-concept data demonstrating the effect of cytotoxic agents on cell health, apoptosis, and viability. This automated kinetic imaging platform can be expanded to other phenotypic readouts to understand diverse therapeutic effects in PDO models of cancer.

Multiplexed live-cell imaging for drug responses in patient-derived organoid models of cancer.

Patient-derived organoid (PDO) models of cancer are a multifunctional research system that better recapitulates human disease as compared to cancer cell lines. PDO models can be generated by culturing patient tumor cells in extracellular basement membrane extracts (BME) and plating as three-dimensional domes. However, commercially available reagents that have been optimized for phenotypic assays in monolayer cultures often are not compatible with BME. Herein we describe a method to plate PDO models and assess drug effects using an automated live-cell imaging system. In addition, we apply fluorescent dyes that are compatible with kinetic measurements to simultaneously quantitate cell health and apoptosis. Image capture can be customized to occur at regular time intervals over several days. Users can analyze drug effects in individual Z-plane images or a Z Projection of serial images from multiple focal planes. Using masking, specific parameters of interest are calculated, such as PDO number, area, and fluorescence intensity. We provide proof-of-concept data demonstrating the effect of cytotoxic agents on cell health, apoptosis and viability. This automated kinetic imaging platform can be expanded to other phenotypic readouts to understand diverse therapeutic effects in PDO models of cancer.

DigiKnowIt News: Educating youth about pediatric clinical trials using an interactive, multimedia educational website.

Pediatric clinical trials allow for the testing of appropriate and effective treatments for children. However, some challenges exist with recruitment. This study examined the effectiveness of DigiKnowIt News, an interactive, multimedia website (which includes activities, videos, and comic books) designed to educate children about clinical trials. A randomized controlled trial was conducted in 2018 with 91 participants (M age = 10.92 years; SD = 2.06). Participants were randomly assigned to intervention or wait-list control groups and completed questionnaires at pretest and posttest (1 week later) about their knowledge, attitudes, beliefs about clinical trials, and self-efficacy for participating in clinical trials. Participants in the intervention group received access to DigiKnowIt News between pretest and posttest and completed a satisfaction questionnaire at posttest. At the end of the study, participants in the wait-list control group were offered the option to use the website and complete a satisfaction questionnaire. At posttest, participants in the intervention group, compared to participants in the wait-list control group, had more knowledge about clinical trials and more reported confidence for participating in clinical trials. Participants reported high levels of satisfaction with DigiKnowIt News. The findings suggest that an educational website can improve factors related to increasing rates of participation in clinical trials.