Experience of Public Health Departments in Implementation of COVID-19 Case Investigation and Contact Tracing Programs.

OBJECTIVE: Case investigation and contact tracing (CI/CT) are fundamental public health efforts widely used during the COVID-19 pandemic to mitigate transmission. This study investigated how state, local, and tribal public health departments used CI/CT during the COVID-19 pandemic, including CI/CT methodology, staffing models, training and support, and efforts to identify or prioritize populations disproportionately affected by COVID-19. METHODS: During March and April 2022, we conducted key informant interviews with up to 3 public health officials from 43 state, local, and tribal public health departments. From audio-recorded and transcribed interviews, we used the framework method to analyze key themes. RESULTS: Major adjustments to CI/CT protocols during the pandemic included (1) prioritizing populations for outreach; (2) implementing automated outreach for nonprioritized groups, particularly during COVID-19 surges; (3) discontinuing contact tracing and focusing exclusively on case investigation; and (4) adding innovations to provide additional support. Key informants also discussed the utility of having backup staffing to support overwhelmed public health departments and spoke to the difficulty in "right-sizing" the public health workforce, with COVID-19 surges leaving public health departments understaffed as case rates rose and overstaffed as case rates fell. CONCLUSIONS: When addressing future epidemics or outbreaks, public health officials should consider strategies that improve the effectiveness of CI/CT efforts over time, such as prioritizing populations based on disproportionate risk, implementing automated outreach, developing models that provide flexible additional staffing resources as cases rise and fall among local public health departments, incorporating demographic data in laboratory reporting, providing community connections and support, and having a system of self-notification of contacts.

Songs tell a story: The Arc of narrative for music.

Research suggests that a core lexical structure characterized by words that define plot staging, plot progression, and cognitive tension underlies written narratives. Here, we investigate the extent to which song lyrics follow this underlying narrative structure. Using a text analytic approach and two publicly available datasets of song lyrics including a larger dataset (N = 12,280) and a smaller dataset of greatest hits (N = 2,823), we find that music lyrics tend to exhibit a core Arc of Narrative structure: setting the stage at the beginning, progressing the plot steadily until the end of the song, and peaking in cognitive tension in the middle. We also observe differences in narrative structure based on musical genre, suggesting different genres set the scene in greater detail (Country, Rap) or progress the plot faster and have a higher rate of internal conflict (Pop). These findings add to the evidence that storytelling exhibits predictable language patterns and that storytelling is evident in music lyrics.

Discovery of Potent Glycosidases Enables Quantification of Smoke-Derived Phenolic Glycosides through Enzymatic Hydrolysis.

When grapes are exposed to wildfire smoke, certain smoke-related volatile phenols (VPs) can be absorbed into the fruit, where they can be then converted into volatile-phenol (VP) glycosides through glycosylation. These volatile-phenol glycosides can be particularly problematic from a winemaking standpoint as they can be hydrolyzed, releasing volatile phenols, which can contribute to smoke-related off-flavors. Current methods for quantitating these volatile-phenol glycosides present several challenges, including the requirement of expensive capital equipment, limited accuracy due to the molecular complexity of the glycosides, and the utilization of harsh reagents. To address these challenges, we proposed an enzymatic hydrolysis method enabled by a tailored enzyme cocktail of novel glycosidases discovered through genome mining, and the generated VPs from VP glycosides can be quantitated by gas chromatography-mass spectrometry (GC-MS). The enzyme cocktails displayed high activities and a broad substrate scope when using commercially available VP glycosides as the substrates for testing. When evaluated in an industrially relevant matrix of Cabernet Sauvignon wine and grapes, this enzymatic cocktail consistently achieved a comparable efficacy of acid hydrolysis. The proposed method offers a simple, safe, and affordable option for smoke taint analysis.

Report from the World Health Organization's immunization and vaccines-related implementation research advisory committee (IVIR-AC) meeting, virtual gathering, 26 February-1 March 2024.

The Immunization and Vaccine-related Implementation Research Advisory Committee (IVIR-AC) is the World Health Organization's key standing advisory body to conduct an independent review of research, particularly of transmission and economic modeling analyses that estimate the impact and value of vaccines. From 26th February-1st March 2024, at its first of two semi-annual meetings, IVIR-AC provided feedback and recommendations across four sessions; this report summarizes the proceedings and recommendations from that meeting. Session topics included modeling of the impact and cost-effectiveness of the R21/Matrix-M malaria vaccine, meta-analysis of economic evaluations of vaccines, a global analysis estimating the impact of vaccination over the last 50 years, and modeling the impact of different RTS,S malaria vaccine dose schedules in seasonal settings.

Representativeness of a national, probability-based panel survey of COVID-19 isolation practices-United States, 2020-2022.

The U.S. Centers for Disease Control and Prevention (CDC) received surveillance data on how many people tested positive for SARS-CoV-2, but there was little information about what individuals did to mitigate transmission. To fill the information gap, we conducted an online, probability-based survey among a nationally representative panel of adults living in the United States to better understand the behaviors of individuals following a positive SARS-CoV-2 test result. Given the low response rates commonly associated with panel surveys, we assessed how well the survey data aligned with CDC surveillance data from March, 2020 to March, 2022. We used CDC surveillance data to calculate monthly aggregated COVID-19 case counts and compared these to monthly COVID-19 case counts captured by our survey during the same period. We found high correlation between our overall survey data estimates and monthly case counts reported to the CDC during the analytic period (r: +0.94; p < 0.05). When stratified according to demographic characteristics, correlations remained high. These correlations strengthened our confidence that the panel survey participants were reflective of the cases reported to CDC and demonstrated the potential value of panel surveys to inform decision making.

Design and Modification of COVID-19 Case Investigation and Contact Tracing Interview Scripts Used by Health Departments Throughout the COVID-19 Pandemic.

OBJECTIVES: We sought to (1) document how health departments (HDs) developed COVID-19 case investigation and contact tracing (CI/CT) interview scripts and the topics covered, and (2) understand how and why HDs modified those scripts. DESIGN: Qualitative analysis of CI/CT interview scripts and in-depth key informant interviews with public health officials in 14 HDs. Collected scripts represent 3 distinct points (initial, the majority of which were time stamped May 2020; interim, spanning from September 2020 to August 2021; and current, as of April 2022). SETTING: Fourteen state, local, and tribal health jurisdictions and Centers for Disease Control and Prevention (CDC). PARTICIPANTS: Thirty-six public health officials involved in leading CI/CT from 14 state, local, and tribal health jurisdictions (6 states, 3 cities, 4 counties, and 1 tribal area). MAIN OUTCOME MEASURE: Interview script elements included in CI/CT interview scripts over time. RESULTS: Many COVID-19 CI/CT scripts were developed by modifying questions from scripts used for other communicable diseases. Early in the pandemic, scripts included guidance on isolation/quarantine and discussed symptoms of COVID-19. As the pandemic evolved, the length of scripts increased substantially, with significant additions on contact elicitation, vaccinations, isolation/quarantine recommendations, and testing. Drivers of script changes included changes in our understanding of how the virus spreads, risk factors and symptoms, new treatments, new variants, vaccine development, and adjustments to CDC's official isolation and quarantine guidance. CONCLUSIONS: Our findings offer suggestions about components to include in future CI/CT efforts, including educating members of the public about the disease and its symptoms, offering mitigation guidance, and providing sufficient support and resources to help people act on that guidance. Assessing the correlation between script length and number of completed interviews or other quality and performance measures could be an area for future study.

The effect of COVID-19 pandemic on healthcare seeking in an urban informal settlement in Nairobi and a rural setting in western Kenya.

The COVID-19 pandemic caused widespread changes and disruptions to healthcare seeking behavior. There are limited studies on the effect of the COVID-19 pandemic on healthcare seeking patterns in low-and middle-income countries (LMICs), especially in settings with inequitable access to healthcare in rural and urban informal settlements. We investigated the effect of the COVID-19 pandemic on reported healthcare seeking at health facilities and chemists using morbidity data from participants in an ongoing population-based infectious disease surveillance platform in Asembo in Siaya County, a rural setting in western Kenya and Kibera, an urban informal settlement in Nairobi County. We described healthcare seeking patterns before (from 1st January 2016 to 12th March 2020) and during the pandemic (from 13th March 2020 to 31st August 2022) by gender and age for any reported illness and select clinical syndromes using frequencies and percentages. We used a generalized estimating equation with an exchangeable correlation structure to assess the effect of the pandemic on healthcare seeking adjusting for gender and age. Overall, there was a 19% (adjusted odds ratio, aOR: 0.81; 95% Confidence Interval, CI: 0.79-0.83) decline in odds of seeking healthcare at health facilities for any illness in Asembo during the pandemic, and a 30% (aOR: 0.70; 95% CI: 0.67-0.73) decline in Kibera. Similarly, there was a decline in seeking healthcare by clinical syndromes, e.g., for ARI, aOR: 0.76; 95% CI:0.73-0.79 in Asembo, and aOR: 0.68; 95% CI:0.64-0.72 in Kibera. The pandemic resulted in increased healthcare seeking at chemists (aOR: 1.23; 95% CI: 1.20-1.27 in Asembo, and aOR: 1.40; 95% CI: 1.35-1.46 in Kibera). This study highlights interruptions to healthcare seeking in resource-limited settings due to the COVID-19 pandemic. The pandemic resulted in a substantial decline in seeking care at health facilities, and an increase of the same at chemists.

HPV DNA Testing and Mobile Colposcopy for Cervical Precancer Screening in HIV Positive Women: A Comparison Between Two Settings in Ghana and Recommendation for Screening.

INTRODUCTION: Women living with HIV (WLHIV) have higher prevalence and persistence rates of high-risk human papillomavirus (hr-HPV) infection with a six-fold increased risk of cervical cancer. Thus, more frequent screening is recommended for WLHIV. OBJECTIVES: This retrospective descriptive cross-sectional study was conducted to investigate and compare the prevalence of hr-HPV infection and abnormal findings on mobile colposcopy in two cohorts of WLHIV following cervical screening in rural and urban settings in Ghana. METHODS: Through the mPharma 10 000 Women Initiative, WLHIV were screened via concurrent hr-HPV DNA testing (MA-6000; Sansure Biotech Inc., Hunan, China) and visual inspection (Enhanced Visual Assessment [EVA] mobile colposcope; MobileODT, Tel Aviv, Israel) by trained nurses. The women were screened while undergoing routine outpatient reviews at HIV clinics held at the Catholic Hospital, Battor (rural setting) and Tema General Hospital (urban setting), both in Ghana. RESULTS: Two-hundred and fifty-eight WLHIV were included in the analysis (rural, n = 132; urban, n = 126). The two groups were comparable in terms of age, time since HIV diagnosis, and duration of treatment for HIV. The hr-HPV prevalence rates were 53.7% (95% CI, 45.3-62.3) and 48.4% (95% CI, 39.7-57.1) among WLHIV screened in the rural vs urban settings (p-value = .388). Abnormal colposcopy findings were found in 8.5% (95% CI, 5.1-11.9) of the WLHIV, with no significant difference in detection rates between the two settings (p-value = .221). Three (13.6%) of 22 women who showed abnormal colposcopic findings underwent loop electrosurgical excision procedure (LEEP), leaving 19/22 women from both rural and urban areas with pending treatment/follow-up results, which demonstrates the difficulty faced in reaching early diagnosis and treatment, regardless of their area of residence. Histopathology following LEEP revealed CIN III in 2 WLHIV (urban setting, both hr-HPV negative) and CIN I in 1 woman in the rural setting (hr-HPV positive). CONCLUSIONS: There is a high prevalence of hr-HPV among WLHIV in both rural and urban settings in this study in Ghana. Concurrent HPV DNA testing with a visual inspection method (colposcopy/VIA) reduces loss to follow-up compared to performing HPV DNA testing as a standalone test and recalling hr-HPV positive women for follow up with a visual inspection method. Concurrent HPV DNA testing and a visual inspection method may also pick up precancerous cervical lesions that are hr-HPV negative and may be missed if HPV DNA testing is performed alone.

Preoperative Function Affects Ability to Achieve One-Year Minimum Clinically Important Difference for Patients Undergoing Total Knee Arthroplasty.

Background: Minimum clinically important difference (MCID) values are commonly used to measure treatment success for total knee arthroplasty (TKA). MCID values vary according to calculation methodology, and prior studies have shown that patient factors are associated with failure to achieve MCID thresholds. The purpose of this study was to determine if anchor-based 1-year Knee Injury and Osteoarthritis Outcome Score Joint Replacement (KOOS-JR) MCID values varied among patients undergoing TKA based on patient-specific factors. Methods: This was a retrospective review of patients undergoing TKA from 2017-2018. Patients without baseline or 1-year KOOS-JR or Patient-Reported Outcome Measurement Information System Global Health data or that underwent procedures other than primary TKA were excluded. MCIDs were calculated and compared between patient groups according to preoperative characteristics. Results: Among the included 976 patients, 1-year KOOS-JR MCIDs were 26.6 for men, 28.2 for women, 30.7 for patients with a diagnosis of anxiety and/or depression, and 26.7 for patients without a diagnosis. One-year MCID values did not differ significantly according to gender (P = .379) or mental health diagnosis (P = .066), nor did they correlate with body mass index (ß = -0.034, P = .822). Preoperative KOOS-JR decile demonstrated an inverse relationship with 1-year MCID values and attainment of MCID. Conclusions: The proportion of patients attaining KOOS-JR MCID values demonstrated an inverse relationship with preoperative baseline function. Future investigation may identify patient factors that allow surgeons to better capture patient satisfaction with their procedure despite failure to attain a 1-year MCID.

Repellent and larvicidal properties of selected indigenous plants in the control of Anopheles mosquitoes.

BACKGROUND OBJECTIVES: Widespread pyrethroid resistance and plastic-feeding behaviour of most malaria vectors across Africa threaten the efficacy of current insecticide-based vector control interventions like Insecticide-Treated Nets (ITNs) and Indoor Residual Spraying (IRS). This study examined the larvicidal activity ofMorinda citrifolia against Anopheles gambiae larvae and the repellent properties of Morinda citrifolia (Noni), Moringa oleifera (Moringa), and Ocimum basilicum (Basil) as complementary vector control tools against Anopheles gambiae sensu lato (s.l.). METHODS: Noni, Basil, and Moringa oil extracts were obtained with the extraction techniques; Soxhlet, steam distillation and maceration respectively, using hexane and ethanol. The effectiveness of the extracts was assessed using the WHO standard larval susceptibility bioassay and guidelines for repellent efficacy. Following bioassays, effective doses (ED) and lethal concentrations (LC) were determined. Gas Chromatography-Mass Spectroscopy analysis was performed to identify the bioactive chemical components of the extracts of Moringa oleifera and Ocimum basilicum. RESULTS: Emulsified Morinda citrifolia seed oil had LC50=68.3, LC90=130.9 and LC99.9=222.5, and ED99. 9=308.3%v/v, the ethanolic extract of Moringa oleifera leaves had ED99.9= 1.25g/ml, and essential oil of Ocimum basilicum leaves had ED99.9=0.28g/ml against Anopheles gambiae. INTERPRETATION CONCLUSION: The results obtained indicated that seed oil of Morinda citrifolia, essential oil of Ocimum basilicum, and crude extract of Moringa oleifera have repellent activity against An. gambiae s.l. The complete protection time (CPT) of Morinda citrifolia, Moringa oleifera, and Ocimum basilicum was 120 min, 72 min and 84 min at ED99.9 respectively. Morinda citrifolia oil exhibited larvicidal effects against the larvae of An. gambiae s.l. The results provide valuable information for the use of the plants as biocides.

DNA binding analysis of rare variants in homeodomains reveals homeodomain specificity-determining residues.

Homeodomains (HDs) are the second largest class of DNA binding domains (DBDs) among eukaryotic sequence-specific transcription factors (TFs) and are the TF structural class with the largest number of disease-associated mutations in the Human Gene Mutation Database (HGMD). Despite numerous structural studies and large-scale analyses of HD DNA binding specificity, HD-DNA recognition is still not fully understood. Here, we analyze 92 human HD mutants, including disease-associated variants and variants of uncertain significance (VUS), for their effects on DNA binding activity. Many of the variants alter DNA binding affinity and/or specificity. Detailed biochemical analysis and structural modeling identifies 14 previously unknown specificity-determining positions, 5 of which do not contact DNA. The same missense substitution at analogous positions within different HDs often exhibits different effects on DNA binding activity. Variant effect prediction tools perform moderately well in distinguishing variants with altered DNA binding affinity, but poorly in identifying those with altered binding specificity. Our results highlight the need for biochemical assays of TF coding variants and prioritize dozens of variants for further investigations into their pathogenicity and the development of clinical diagnostics and precision therapies.

Structure-Based Protein Assembly Simulations Including Various Binding Sites and Conformations.

Many biological functions are mediated by large complexes formed by multiple proteins and other cellular macromolecules. Recent progress in experimental structure determination, as well as in integrative modeling and protein structure prediction using deep learning approaches, has resulted in a rapid increase in the number of solved multiprotein assemblies. However, the assembly process of large complexes from their components is much less well-studied. We introduce a rapid computational structure-based (SB) model, GoCa, that allows to follow the assembly process of large multiprotein complexes based on a known native structure. Beyond existing SB Go̅-type models, it distinguishes between intra- and intersubunit interactions, allowing us to include coupled folding and binding. It accounts automatically for the permutation of identical subunits in a complex and allows the definition of multiple minima (native) structures in the case of proteins that undergo global transitions during assembly. The model is successfully tested on several multiprotein complexes. The source code of the GoCa program including a tutorial is publicly available on Github: https://github.com/ZachariasLab/GoCa. We also provide a web source that allows users to quickly generate the necessary input files for a GoCa simulation: https://goca.t38webservices.nat.tum.de.

Early Parenting Interactions and First-Time Mothers' Postnatal Depression and Parental Competence.

Objectives: Schema Therapy, an approach that integrates cognitive-behavioural and attachment principles, helps us understand the impact of early interactions with caregivers on adult mental health. These early interactions can be assessed through Schema Therapy-informed tools; however, these tools have yet to be used with a postnatal population, which represents a period of vulnerability for new mothers. Therefore, the present study aimed to evaluate the impact of positive and negative early parenting interactions on a first-time mother's mental health and her sense of competence during the postnatal period, using recently revised and newly developed Schema Therapy-informed tools. Design: This is a cross-sectional study. Method: First-time mothers (N = 220) participated in an online survey within 12 months post-birth. Participants completed the Positive Parenting Schema Inventory (PPSI), Young Parenting Inventory-Revised (YPI-R2), Edinburgh Postnatal Depression Scale (EPDS), and Parenting Sense of Competence (PSOC) scale. The data were analysed using hierarchical multiple regression and mediational analysis. Results: Negative early interactions with mothers and fathers led to greater postnatal depressive symptomology, while positive early interactions with mothers led to fewer postnatal depressive symptoms. Mediation analyses revealed that postnatal depressive symptoms mediated early parenting interactions and participants' sense of parenting competence as a new mother. Conclusions: The protective effects of positive early interactions with caregivers can help first-time mothers' postnatal emotional adjustment and their sense of competence through diminished postnatal depressive symptoms. However, the enduring effects of negative early interactions with caregivers can contribute to a first-time mother's risk of developing postnatal depression and negatively affect her sense of parental competence.

Intrawound Vancomycin Powder in Primary Total Hip Arthroplasty: A Prospective Quality Control Study.

BACKGROUND: The purpose of this retrospective analysis of a prospective quality control project was to determine whether the use of intrawound vancomycin powder (IVP) decreases the rate of periprosthetic joint infection (PJI) within 90 days following primary total hip arthroplasty (THA). METHODS: From October 2021 to September 2022, a prospective quality control project was undertaken in which 10 high-volume THA surgeons alternated between using and not using IVP each month while keeping other perioperative protocols unchanged. A retrospective analysis of the project was performed to compare the group of patients who received IVP to the group of patients who did not. The primary outcome was a culture positive infection within 90 days following primary THA. Secondary outcomes included gram-positive culture, overall reoperation rate, wound complications, readmission, and wound complications within 90 days post-operatively. A total of 1,193 primary THA patients were identified for analysis. There were 523 (43.8%) patients who received IVP and were included in the IVP group, while 670 (56.2%) did not and were included in the non-IVP group. Age, body mass index, and sex were similar between the 2 groups (P > .25). RESULTS: The IVP group had a higher rate of culture positive joint infections (1.7 [0.8, 3.2] versus 0.3% [0.04, 1.1], P = .01) than the non-IVP group. All PJI's were found to have gram positive bacteria in both groups. The IVP group had a higher overall reoperation rate than the non-IVP group (6.1 [4.2, 8.5] versus 2.4% [1.4, 3.9], P < .01). The IVP group had a higher reoperation rate for any wound complication compared to non-IVP patients (2.7 [1.5, 4.5] versus 0.7% [0.2, 1.7], P < .01). The overall readmission rate (6.1 [4.2, 8.5] versus 2.8% [1.7, 4.4], P < .01), as well as readmission for suspected infection (2.1 [1.1, 3.7] versus 0.6% [0.02, 1.5], P = .03), were higher in the IVP group. CONCLUSIONS: The use of IVP in primary THA was associated with a higher rate of PJI, overall reoperation, reoperation for wound complications, and readmission in a prospective quality control project. Until future prospective randomized studies determine the safety and efficacy of IVP in THA conclusively, we advocate against its utilization.

The tumor microenvironment of benign and malignant salivary gland tumors.

BACKGROUND: Treatment of salivary gland tumors (SGTs) remains challenging. Little is known about the immune landscape of SGTs. We aimed to characterize the tumor microenvironment in benign and malignant SGTs. METHODS: Eleven benign and nine malignant tumors were collected from patients undergoing curative intent surgery. Specimens were analyzed using mass cytometry by time-of-flight. Immune cell populations were manually gated, and T cells were clustered using the FlowSOM algorithm. Population frequencies were compared between high-grade and low-grade malignancies, corrected for multiple hypothesis testing. RESULTS: There were trends towards increased CD4+ and CD8+ T cells among malignant tumors. High-grade malignancies exhibited trends towards higher frequencies of CD8+ PD-1+ CD39+ CD103+ exhausted T cells, CD4+ FoxP3+ TCF-1+ CD127- Tregs, and CD69+ CD25- CD4+ T cells compared to low-grade malignancies. CONCLUSION: SGTs exhibit significant immunologic diversity. High-grade malignancies tended to have greater infiltration of exhausted CD8+ T cells and Tregs, which may guide future studies for immunotherapy strategies.

Landscape of global urban environmental resistome and its association with local socioeconomic and medical status.

Antimicrobial resistance (AMR) poses a critical threat to global health and development, with environmental factors-particularly in urban areas-contributing significantly to the spread of antibiotic resistance genes (ARGs). However, most research to date has been conducted at a local level, leaving significant gaps in our understanding of the global status of antibiotic resistance in urban environments. To address this issue, we thoroughly analyzed a total of 86,213 ARGs detected within 4,728 metagenome samples, which were collected by the MetaSUB International Consortium involving diverse urban environments in 60 cities of 27 countries, utilizing a deep-learning based methodology. Our findings demonstrated the strong geographical specificity of urban environmental resistome, and their correlation with various local socioeconomic and medical conditions. We also identified distinctive evolutionary patterns of ARG-related biosynthetic gene clusters (BGCs) across different countries, and discovered that the urban environment represents a rich source of novel antibiotics. Our study provides a comprehensive overview of the global urban environmental resistome, and fills a significant gap in our knowledge of large-scale urban antibiotic resistome analysis.

SMARCA4 is a haploinsufficient B cell lymphoma tumor suppressor that fine-tunes centrocyte cell fate decisions.

SMARCA4 encodes one of two mutually exclusive ATPase subunits in the BRG/BRM associated factor (BAF) complex that is recruited by transcription factors (TFs) to drive chromatin accessibility and transcriptional activation. SMARCA4 is among the most recurrently mutated genes in human cancer, including ∼30% of germinal center (GC)-derived Burkitt lymphomas. In mice, GC-specific Smarca4 haploinsufficiency cooperated with MYC over-expression to drive lymphomagenesis. Furthermore, monoallelic Smarca4 deletion drove GC hyperplasia with centroblast polarization via significantly increased rates of centrocyte recycling to the dark zone. Mechanistically, Smarca4 loss reduced the activity of TFs that are activated in centrocytes to drive GC-exit, including SPI1 (PU.1), IRF family, and NF-κB. Loss of activity for these factors phenocopied aberrant BCL6 activity within murine centrocytes and human Burkitt lymphoma cells. SMARCA4 therefore facilitates chromatin accessibility for TFs that shape centrocyte trajectories, and loss of fine-control of these programs biases toward centroblast cell-fate, GC hyperplasia and lymphoma.

Prioritizing Mental Health within HIV and Tuberculosis Services in PEPFAR.

Underprioritization of mental health is a global problem and threatens the decades-long progress of the US President's Emergency Plan for AIDS Relief (PEPFAR) program. In recent years, mental health has become globally recognized as a part of universal healthcare, making this an opportune moment for the global community to integrate mental health services into routine programming. PEPFAR is well positioned to lead by example. We conceptualized 5 key strategies that might help serve as a framework to support mental health programming as part of PEPFAR's current 5-year strategic plan. PEPFAR and the global community have an opportunity to identify mental health service gaps and interweave global mental health priorities with actions to end the HIV and TB epidemics by 2030.

BRG1/BRM inhibitor targets AML stem cells and exerts superior preclinical efficacy combined with BET or menin inhibitor.

ABSTRACT: BRG1 (SMARCA4) and BRM (SMARCA2) are the mutually exclusive core ATPases of the chromatin remodeling BAF (BRG1/BRM-associated factor) complexes. They enable transcription factors/cofactors to access enhancers/promoter and modulate gene expressions responsible for cell growth and differentiation of acute myeloid leukemia (AML) stem/progenitor cells. In AML with MLL1 rearrangement (MLL1r) or mutant NPM1 (mtNPM1), although menin inhibitor (MI) treatment induces clinical remissions, most patients either fail to respond or relapse, some harboring menin mutations. FHD-286 is an orally bioavailable, selective inhibitor of BRG1/BRM under clinical development in AML. Present studies show that FHD-286 induces differentiation and lethality in AML cells with MLL1r or mtNPM1, concomitantly causing perturbed chromatin accessibility and repression of c-Myc, PU.1, and CDK4/6. Cotreatment with FHD-286 and decitabine, BET inhibitor (BETi) or MI, or venetoclax synergistically induced in vitro lethality in AML cells with MLL1r or mtNPM1. In models of xenografts derived from patients with AML with MLL1r or mtNPM1, FHD-286 treatment reduced AML burden, improved survival, and attenuated AML-initiating potential of stem-progenitor cells. Compared with each drug, cotreatment with FHD-286 and BETi, MI, decitabine, or venetoclax significantly reduced AML burden and improved survival, without inducing significant toxicity. These findings highlight the FHD-286-based combinations as a promising therapy for AML with MLL1r or mtNPM1.