Jacobs Institute of Women's Health
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Burnout, Belonging, and Mental Well-Being: Predictors of Turnover Intent Among Local Public Health Professionals
No full textWe analyzed a nationally representative sample of local public health professionals (LPHPs) from varying jurisdiction sizes across the United States who responded to the 2024 Public Health Workforce Interests and Needs Survey (PH WINS). Our goal was to explore experiences of burnout; perceived belonging within an agency; self-rated mental and emotional well-being; and intentions to leave an organization. Results showed that burnout was negatively associated with and perceived belonging within an agency was positively associated with ratings of mental and emotional health. Each of these 3 variables were associated with an intent to leave an organization in the next year. We discuss implications to-and recommendations for mitigating-attrition of the nation\u27s local public health workforce after the size of the LPHP workforce rebounded following over a decade of decline
Discovering the unexpected: Insights into the dynamics of mouse neural tube closure revealed by time-lapse imaging
No full textThe use of time-lapse imaging to study neural tube closure in mouse embryos has provided unexpected insights into the complex morphogenetic processes involved. When neural tube closure is disrupted, it leads to neural tube defects (NTDs), which are among the most common structural birth defects in humans, associated with long-term disabilities and death. This review explores the growing body of research on time-lapse imaging experiments conducted in mice, emphasizing discoveries of the dynamic cellular movements and changes that enable neural tube formation. Advances in mouse embryo culture and live imaging techniques have enabled visualization of dynamic cellular movements and shape changes during neural tube formation, allowing researchers to observe abnormal cell behaviors in genetic mouse models with neural tube closure defects. These studies use transgenic reporters, conditional mouse genetics, and various physical and pharmacological interventions to track tissue and cell behavior and elucidate the underlying molecular and biophysical mechanisms as neural folds rise and fuse at the dorsal midline. Observing neural tube closure in real time has led to important findings, including revealing the crucial role of the surface ectoderm in supporting neural fold elevation and fusion. The coordination of apical constriction with cell cycle progression and apoptosis helps shape the neural plate. Analyzing convergent extension shows that oriented neighbor exchanges-requiring planar cell polarity signaling-drive polarized protrusive activity and actomyosin contractility, along with coordinated apical constriction to elevate and bring the neural folds together. Future innovations are expected to improve the measurement of biomechanical forces during neural tube formation and visualization of deep tissues to clarify mechanisms of cranial mesenchyme morphogenesis during cranial neural fold elevation
Bridging the gap: Artificial intelligence knowledge, confidence, and education needs in clinical practice
No full textAssociations of endocrine disrupting chemical biomarkers and their mixture with vitamin D biomarker concentrations in childhood: The HOME Study
No full textBACKGROUND: Children are universally exposed to endocrine disrupting chemicals (EDCs) which may disrupt the vitamin D system through several mechanisms, including competitive receptor binding. Current epidemiologic evidence is limited, especially in children. We cross-sectionally investigated the short-term associations of 24 EDC biomarkers with 3 vitamin D biomarkers measured at ages 8 and 12 years. METHODS: Among 236 children from the Health Outcomes and Measures of the Environment Study, we quantified serum concentrations of 4 per-/poly-fluoroalkyl substances (PFAS), 5 polybrominated diphenyl ethers (PBDEs), and 3 vitamin D biomarkers and urinary metabolites of 4 organophosphate esters (OPE), 9 phthalates/replacements, and 2 environmental phenols at ages 8 (n = 180) and 12 (n = 187) years. Using linear regression models with generalized estimating equations, we estimated cross-sectional covariate-adjusted associations of interquartile range (IQR)-scaled log2 EDCs with vitamin D biomarkers. We used g-computation models to estimate effects of class-based and overall mixtures. RESULTS: A simultaneous IQR increase in all 24 EDCs was associated with 6.6 ng/mL (95% CI: 2.7, 10.6) higher total 25-dihydroxyvitamin D [total 25(OH)D]. Class-based mixtures of PFAS (β: 3.1; 95% CI: 1.3, 5.0), PBDEs (β: 2.1; 95% CI: 0.3, 3.9) and OPEs (β: 2.6; 95% CI: 0.3, 4.8) were associated with higher total 25(OH)D whereas environmental phenols (β: 0.8; 95% CI: -0.8, 2.4) and phthalates/replacements (β: -0.8; 95% CI: -3.3, 1.8) were not. Results for 24,25-dihydroxyvitamin D were similar. The PBDE mixture was associated with 4.0 pg/mL (95% CI: 0.4, 7.6) higher 1α,25-dihydroxyvitamin D. DISCUSSION: Findings suggest that EDCs may alter the childhood vitamin D system. Associations with higher vitamin D biomarker levels may indicate competitive receptor binding and altered cellular transport with potential adverse downstream health impacts
Identification of Distinct Subtypes in Immune Tolerance after Hematopoietic Cell Transplantation Using the Prospective ABLE1.0 Pediatric Study Cohort
No full textBACKGROUND: The lack of immune tolerance after hematopoietic cell transplantation (HCT) can result in chronic graft-versus-host-disease (cGvHD), which is the primary non-relapse limitation on a successful HCT. OBJECTIVES: To date, immune tolerance has been considered as a single biologic entity, but we hypothesized that post-HCT immune tolerance could develop through multiple pathways. STUDY DESIGN: Using the ABLE network database, which comprises measurements of 75 cell populations, 10 cytokines and chemokines, lymphocyte population telomere length, KREC and TREC, and 132 metabolites from the largest pediatric cGvHD cohort (N = 241), we applied clustering analysis to the primary immune tolerance (PIT; no acute GvHD or cGvHD) and secondary immune tolerance (SIT; previous acute GvHD and no cGvHD) patients to test whether subtypes could be identified. RESULTS: Evaluation of PIT found three subtypes. PIT-1, associated with post-pubertal age and lower thymic output, and increased ST2 compared to PIT-2 and PIT-3, was effector memory T cell-predominant. PIT-2, associated with prepubertal age, normal thymic output, increased B cell development, longer lymphocyte telomeres, had a naïve T cell-predominant pattern. PIT-3, associated with post-puberty, higher thymic output, and malignancy, was dominated by increased PD1 T and helper T cells and decreased long chain acylcarnitine. We partially replicated these PIT subtypes using metabolomic data from a separate pediatric cohort of the COG trial ASCT0031 (24 PIT patients). Previously resolved acute GvHD had minimal impact on the overall patterns of SIT-1 and SIT-2 compared to PIT-1 and PIT-2, except for time delays in expansion of some immune cells. PIT-3 and SIT-3 were dominated by a late increase in phosphatidylcholines (lysophosphatidylcholines precursors) and long chain lysophosphatidylcholines (LYSOC20:4 and LYSOC16:2), respectively. CONCLUSIONS: This is the first time that distinct biologic patterns of immune reconstitution after HCT are identified, which upon validation, could potentially aid future strategies for tolerance induction
The role of 7-dehydrocholesterol in inducing ER stress and apoptosis of head and neck squamous cell carcinoma
No full textAlterations of metabolic pathways that sustain cancer cell survival often offer promising therapeutic avenues. Here, we show that enhanced de novo cholesterol biosynthesis is crucial for the survival of head and neck squamous cell carcinoma (HNSCC). Transcriptomic analysis of HNSCC tissues identified profound dysregulation in steroid and cholesterol metabolism compared to normal tissues. Inhibition of two key enzymes, DHCR7 and DHCR24, which mediate cholesterol biosynthesis, induced apoptosis in HNSCC cells, even when cholesterol levels were restored. Metabolomic profiling revealed the accumulation of 7-dehydrocholesterol (7-DHC) upon DHCR7 or DHCR24 inhibition, triggering endoplasmic reticulum (ER) stress and promoting further cell death. These findings suggest that HNSCC cells adapt to ER stress by modulating 7-DHC levels through enhancing DHCR7 and DHCR24 levels, highlighting a metabolic vulnerability in HNSCC and demonstrating a direct link between cholesterol metabolism and ER stress in cancer cell viability
RNA Polymerase III Regulates HIV Replication and Latency
No full textThe elimination of HIV latent reservoirs is an extremely challenging task due to the interplay of multiple mechanisms regulating latency. Thus, we need to identify novel strategies to target heterogeneous reservoirs uniformly. Recent reports have provided intriguing evidence for the novel antiviral function of RNA Polymerase III (RNAP III), which remains to be further explored. In this study, we evaluated the role of RNA Pol III in regulating HIV latency and replication. We first demonstrated that the pharmacological inhibition of RNAP III can lead to a strong reactivation of latency in cell lines representing both T and monocytic cellular reservoirs. Next, we investigated the involvement of RNA Pol III in regulating HIV-1 replication using HIV-1 pseudotyped (DuoFluo) virus and HIV-1-Bal in THP-1 and Sup-T1 cells. We show that the pharmacological inhibition of RNAP III significantly induced HIV transcription. These findings were further confirmed in physiologically relevant primary CD4 T cells, and a consistent increase in HIV transcription was observed up to 72 h. Collectively, our study suggests that inhibition of RNAP III can increase the rate of HIV transcription, while the total HIV DNA remains unchanged. Overall, our study identifies a previously unknown role of RNA Pol III in restricting HIV transcription and advocates that targeting RNAP III-driven mechanisms could be a novel strategy to reactivate HIV latent reservoirs
Safety and immunogenicity of SpiN-Tec, a T-cell based RBD-Nucleocapsid chimeric vaccine for COVID-19
No full textThe SpiN-Tec MCTI UFMG is a chimeric recombinant protein (SpiN) containing the RBD region from the Spike protein (S) fused with the Nucleocapsid protein (N), adjuvanted with a squalene-based emulsion (CTVad1), which was developed as booster COVID-19 vaccine. This is a phase I clinical trial to evaluate safety and reactogenicity. Thirty-six healthy adults aged 18-54, previously vaccinated with two doses of CoronaVac™ (Sinovac) and a booster with the Comirnaty™ Bivalent BA.4/BA.5 (Pfizer-BioNTech), were randomized to receive either SpiN-Tec (20 μg, 60 μg, or 100 μg) or CoviShield™(AstraZeneca). SpiN-Tec was safe and showed a reactogenic profile comparable to CoviShield. Immunogenicity results showed a dose-dependent increase in IgG levels against N and SpiN, peaking at day 28 post-vaccination and declining by day 180. Neutralizing antibody levels against both the Wuhan ancestral and BA1.88 strains showed similar curves presenting no differences between SpiN-Tec and CoviShield. Importantly, SpiN-Tec induced robust IFN-γ production up to 270 days, particularly by CD4 effector memory T cells, indicating a durable immune response memory. These results indicate the potential of SpiN-Tec as a viable COVID-19 booster vaccine
Definitive Local Therapy in cM1 Major Salivary Gland Cancer
No full textOBJECTIVE: To investigate the impact of surgical resection and radiotherapy on overall survival (OS) in clinically distantly metastatic (cM1) major salivary gland cancer (MSGC). STUDY DESIGN: Retrospective cohort study. SETTING: The 2006 to 2020 hospital-based National Cancer Database. METHODS: The 2006 to 2020 National Cancer Database was queried for patients with cM1 MSGC undergoing chemotherapy. Kaplan-Meier and Cox proportional hazards regression models were implemented. RESULTS: Of 700 patients satisfying inclusion criteria, 219 (37.8%) underwent chemotherapy alone (ie, no local therapy), 159 (27.4%) underwent low-dose chemoradiotherapy (CRT), 56 (9.7%) underwent high-dose CRT, 47 (8.1%) underwent surgical resection + chemotherapy, 47 (8.1%) underwent surgical resection + low-dose CRT, and 52 (9.0%) underwent surgical resection + high-dose CRT; 5-year OS was 10%, 12%, 34%, 25%, 23%, and 28%, respectively (P \u3c .001). Patients undergoing surgical resection underwent high-dose radiotherapy more frequently (N = 53, 36.1% vs N = 56, 12.9%) but multiple-agent chemotherapy less frequently (N = 105, 62.5% vs N = 363, 75.3%) than those not undergoing surgical resection (P \u3c .005). Compared with chemotherapy alone, surgical resection + chemotherapy (aHR 0.67, 95% confidence interval [CI] 0.53-0.86), high-dose CRT (aHR 0.55, 95% CI 0.41-0.73), and immunotherapy (aHR 0.49, 95% CI 0.35-0.69) were associated with higher OS on multivariable Cox regression (P \u3c .01). CONCLUSIONS: A minority of patients with cM1 MSGC underwent surgical resection or high-dose CRT. Despite the high rate of PSM, surgical resection was associated with higher OS than chemotherapy alone. High-dose CRT was associated with the highest OS. Definitive local therapy may benefit select patients with cM1 MSGC. LEVEL OF EVIDENCE: IV
Cost-effectiveness and health equity improvements from excluding sugar-sweetened beverages from the Supplemental Nutrition Assistance Program
No full textINTRODUCTION: Excluding sugar-sweetened beverages (SSBs) from eligible purchases in the Supplemental Nutrition Assistance Program (SNAP) has been proposed as a strategy to improve diet quality and health. This study estimates the cost-effectiveness of this policy and its potential impact on health equity. METHODS: The Childhood Obesity Intervention Cost Effectiveness Study (CHOICES) microsimulation and systematic review process was used in 2024 to estimate the potential impact of excluding SSBs from SNAP-eligible purchases over a ten-year period (2023-2032) for the U.S. POPULATION: Health outcomes related to excess weight, costs, and relative changes in obesity prevalence by income, race, and ethnicity group in 2032 were estimated. RESULTS: The policy is projected to be cost-saving, prevent 279,000 cases of obesity (95% UI: 149,000-446,000), and contribute 115,000 (95% UI: 60,100-187,000) quality-adjusted life years gained over ten years among SNAP participants. The policy could save an estimated 3.35 in healthcare cost savings per dollar spent on implementation. Reductions in obesity prevalence were estimated to be 3.5 times greater among individuals with income ≤130% of the federal poverty level compared to the overall mean, and 3-3.5 times greater among non-Hispanic Black and Hispanic individuals compared to non-Hispanic white individuals. CONCLUSIONS: Excluding SSBs from SNAP-eligible purchases could be a cost-saving strategy to improve health and health equity between income, racial, and ethnic groups. The U.S. Department of Agriculture could use pilot studies to test the real-world effects of excluding SSBs from SNAP