Trends in Diet Quality Among U.S. Adults From 1999 to 2020 by Race, Ethnicity, and Socioeconomic Disadvantage.

BACKGROUND: Few data have assessed trends in diet quality among U.S. adults. OBJECTIVE: To evaluate trends in diet quality by race, ethnicity, and socioeconomic disadvantage. DESIGN: Repeated cross-sectional study. SETTING: United States. PARTICIPANTS: Noninstitutionalized adults aged 20 years or older who responded to the 1999-2020 National Health and Nutrition Examination Survey (NHANES). MEASUREMENTS: The proportion of participants meeting the targets of the validated American Heart Association (AHA) 2020 continuous diet score (based on higher intake of fruits, vegetables, whole grains, fish and shellfish, and nuts, seeds, and legumes and lower intake of sugar-sweetened beverages, processed meat, saturated fat, and sodium) and the Healthy Eating Index (HEI)-2015, and energy-adjusted consumption of their components and other individual food groups and nutrients. Poor diet was defined as less than 40% adherence to the AHA score, intermediate as 40% to 79.9% adherence, and ideal as at least 80% adherence. RESULTS: A total of 51 703 adults were included. From 1999 to 2020, the proportion of U.S. adults with poor diet quality decreased from 48.8% to 37.4% (difference, -11.4 percentage points [95% CI, -16.8 to -5.96 percentage points]), the proportion with intermediate quality increased from 50.6% to 61.1% (difference, 10.5 percentage points [CI, 5.20 to 16.1 percentage points]), and the proportion with ideal quality increased from 0.66% to 1.58% (difference, 0.93 percentage points [CI, 0.35 to 1.51 percentage points]) (P for trend < 0.001 for each). Persistent or worsening disparities in diet quality were observed by age, sex, race and ethnicity, education, income, food security, Supplemental Nutrition Assistance Program participation, and health insurance coverage. For example, the proportion of adults with poor diet quality decreased from 47.9% to 33.0% among those with food security (P for trend < 0.001) but did not change (51.3% to 48.2%) among those experiencing food insecurity (P for trend = 0.140) (P for interaction = 0.001). Findings were similar for HEI-2015. LIMITATIONS: Self-reported diet; cross-sectional study design. CONCLUSION: Diet quality among U.S. adults improved modestly between 1999 and 2020, but the proportion with poor diet quality remains high, and dietary disparities persist or are worsening. PRIMARY FUNDING SOURCE: National Institutes of Health.

Association of ultra-processed food consumption with muscle mass among young and middle-aged US adults.

INTRODUCTION: Muscle mass is vital for physical activity and fundamental physiological processes supporting long-term health. While aging is inevitable, certain modifiable factors positively influence muscle preservation and overall well-being. However, the relationship between the consumption of ultra-processed foods (UPF) and muscle mass is not yet clear. METHODS: This study included 7,173 men and nonpregnant women aged 20-59 years with valid 24-hour dietary recalls and accessible whole-body dual-energy x-ray absorptiometry (DXA) scans from NHANES 2011-2018. UPFs were identified through the NOVA classification system, and the percentage of energy derived from UPF consumption was evaluated in quintiles. Muscle mass measures were derived from DXA scans and quantified by the total and regional muscle mass index (MMI, kg/m²) and appendicular muscle mass index (AMMI, kg/m²). Multivariable-adjusted generalized linear regression models were applied to investigate the association between consumption of UPFs and muscle mass measures overall and by sociodemographic subgroups. RESULTS: The multivariable-adjusted differences of total MMI from the lowest to highest quintile of UPF consumption were 0 (reference), -0.03 (95% CI, -0.13, 0.07), -0.13 (95%CI, -0.24, -0.04), -0.12 (95% CI, -0.23, -0.01), and - 0.17 (95% CI, -0.27, -0.08) (P for trend < 0.001). Subtotal MMI followed a similar magnitude of associational pattern as total MMI. For trunk MMI, corresponding values from the lowest to highest quintiles of UPF consumption were 0 (reference), -0.02 (95% CI, -0.07, 0.02), -0.05 (95%CI, -0.11, 0.00), -0.07 (95% CI, -0.13, -0.01), and - 0.07 (95% CI, -0.12, -0.01). For AMMI, corresponding values from the lowest to highest quintiles of UPF consumption were 0 (reference), -0.004 (95% CI, -0.07, 0.06), -0.08 (95%CI, -0.14, -0.02), -0.05 (95% CI, -0.11, 0.02), and - 0.10 (95% CI, -0.16, -0.04) (All P for trend < 0.001). While most subgroups maintained similar overall patterns, heterogeneous findings were also observed. For example, the multivariable-adjusted differences in total MMI between the lowest and highest quantile of UPF consumption were - 0.19 (95% CI, -0.32, -0.06) for non-Hispanic Whites, 0.18 (95% CI, 0.01, 0.36) for non-Hispanic Blacks, -0.25 (95%CI, -0.45, -0.04) for Hispanics, -0.25 (95% CI, -0.51, 0.05) for non-Hispanic Asians and - 0.32 (95% CI, -0.75, 0.12) for others (P for interaction < 0.001). CONCLUSION: Higher consumption of UPFs was significantly associated with lower values of total and regional muscle mass. Specifically, comparing the highest quantile of UPF consumption to the lowest, total MMI decreased by 0.93%, trunk MMI decreased by 0.76%, and AMMI decreased by 1.25%. The differences in associational patterns between UPF consumption and muscle mass across sociodemographic subgroups require further investigation.

Long-term survival outcomes and immune checkpoint inhibitor retreatment in patients with advanced cervical cancer treated with camrelizumab plus apatinib in the phase II CLAP study.

BACKGROUND: Camrelizumab plus apatinib have demonstrated robust antitumor activity and safety in patients with advanced cervical cancer (CLAP study; NCT03816553). We herein present the updated long-term results of the CLAP study and explore potential biomarkers for survival. The outcomes of patients who underwent immune checkpoint inhibitor (ICI) retreatment were also reported. METHODS: In this phase II trial, eligible patients received camrelizumab 200 mg intravenously every two weeks and apatinib 250 mg orally once daily in 4-week cycles for up to two years. Treatment was continued until disease progression, unacceptable toxicity, or withdrawal of consent. RESULTS: Between January 21 and August 1, 2019, a total of 45 patients were enrolled. Data were analyzed as of July 31, 2023, representing > 48 months since treatment initiation for all patients. Nine (20.0%) patients completed the 2-year study. The median duration of response (DOR) was 16.6 months, and 45.0% of patients achieved a DOR of ≥ 24 months. The 12-month progression-free survival (PFS) rate was 40.7% (95% confidence interval [CI], 25.2-55.6), with an 18-month PFS rate of 37.8% (95% CI, 22.7-52.8). The median overall survival (OS) was 20.3 months (95% CI, 9.3-36.9), and the 24-month OS rate was 47.8% (95% CI, 31.7-62.3). Age > 50 years, programmed death-ligand 1 (PD-L1) combined positive score (CPS) ≥ 1 (versus [vs.] < 1), CPS ≥ 10 (vs. < 1), high tumor mutational burden, and PIK3CA mutations were associated with improved PFS (hazard ratio [HR] < 1) and longer OS (HR < 1). Eight patients who initially responded in the CLAP trial but later experienced disease progression were retreated with ICIs. Among them, 2 (25.0%) achieved a partial response, while 5 (62.5%) had stable disease. Notably, four patients who received retreatment with ICIs survived for more than 45 months. No new safety signals were identified in the present study. CONCLUSION: Long-term survival follow-up data demonstrated that camrelizumab plus apatinib has robust, sustained, and durable efficacy in patients with advanced cervical cancer who progress after first-line platinum-based chemotherapy. No new safety signals were noted with long-term treatment.

17ß-estradiol promotes myeloid-derived suppressor cells functions and alleviates inflammatory bowel disease by activation of Stat3 and NF-κB signalings.

Inflammatory bowel disease (IBD) describes a group of clinically common autoimmune diseases characterized by chronic intestinal inflammation, with gender differences in prevalence. Estrogen has been previously shown to exert anti-inflammatory action in IBD development, however, the mechanisms remain obscure. Recent research has revealed that myeloid-derived suppressor cells (MDSCs) play a protective role in IBD pathogenesis. To investigate the molecular mechanisms of estrogen steroid 17ß-estradiol (E2) in IBD progression, we established IBD mouse models (DNB-induced) with or without prior ovariectomy (OVX) and E2 implantation. We found that OVX led to worse IBD symptoms and reduced MDSCs frequency, whereas E2 significantly alleviated these effects in vivo. Moreover, in vitro experiments showed that E2 promoted the proliferation and immunosuppressive function of MDSCs through phosphorylation of Stat3 and p65. Mechanistically, E2-mediated Stat3/p65 phosphorylation depends on the interaction between HOTAIR, a long non-coding RNA that are well-known in MDSCs proliferation, and Stat3/p65 respectively. In conclusion, our study revealed that E2 promotes the expansion and immunosuppressive function of MDSCs, and thus diminished the occurrence and development of IBD.

Single-cell BCR and transcriptome analysis reveals peripheral immune signatures in patients with thyroid-associated ophthalmopathy.

Thyroid-associated ophthalmopathy (TAO) is the most prevalent orbital disease in adults caused by an autoimmune disorder, which can lead to disfigurement and vision impairment. Developing effective treatments for this condition presents challenges due to our limited understanding of its underlying immune aberrations. In this study, we profiled the immune components in the peripheral blood of patients with TAO as well as healthy individuals, utilizing single-cell RNA sequencing and B-cell receptor repertoires (BCR) analysis. We observed a significant reduction in the proportions of regulatory B cells (Bregs) and type 2 conventional dendritic cells (DCs) in patients with TAO during the active phase. Conversely, there was a significant increase in the proportion of type 1 DCs. Further analysis of cell differentiation trajectory revealed potential impairment in the transition of B cells towards Breg phenotype during the active phase of TAO. Besides, the activation process of TAO appeared to involve inflammation and immune dysfunction, as indicated by the dynamic changes in the activities of key regulators. The abnormalities in the peripheral immune system, such as the reduced capacity of Bregs to suppress inflammation, were primarily driven by the enhanced interaction among Breg, DCs, and monocytes (i.e., CD22-PTPRC and BTLA-TNFRSF14). Collectively, our findings offer a comprehensive insight into the molecular regulation and cellular reconfiguration during the active phase of TAO at the single-cell level, in order to explore the pathogenesis of TAO and provide new ideas for the future treatment of TAO.

Electrical Conductivities and Conduction Mechanism of Lithium-Doped High-Entropy Oxides at Different Temperature and Pressure Conditions.

Li-doped high-entropy oxides (Li-HEO) are promising electrode materials for Li-ion batteries. However, their electrical conduction in a wide range of temperatures and/or at high pressure is unknown, hindering their applications under extreme conditions. Especially, a clear understanding of the conduction mechanism is needed. In this work, we determined the carrier type of several Li-doped (MgCoNiCuZn)O semiconductor compounds and measured their electrical conduction at temperatures 79-773 K and/or at pressures up to 50 GPa. Three optical band gaps were uncovered from the UV-vis-NIR absorption measurements, unveiling the existence of defect energy levels near the valence band of p-type semiconductors. The Arrhenius-like plot of the electrical conductivity data revealed the electronic conduction in three temperature regions, i.e., the ionization region from 79 to 170 K, the extrinsic region from ∼170 to 300 K, and the intrinsic region at ≥300 K. The closeness of the determined electronic band gap and the second optical band gap suggests that the conduction electrons in the intrinsic region originate from a thermal excitation from the defect energy levels to the conduction band, which determines the electronic conductivity. It was also found that at or above room temperature, ionic conduction coexists with electronic conduction with a comparable magnitude at ambient pressure and that the intrinsic conduction mechanism also operates at high pressures. These findings provide us a fundamental understanding of the band structure and conduction mechanism of Li-HEO, which would be indispensable to their applications in new technical areas.

Mathematical Modeling of PI3K/Akt Pathway in Microglia.

The motility of microglia involves intracellular signaling pathways that are predominantly controlled by changes in cytosolic Ca2+ and activation of PI3K/Akt (phosphoinositide-3-kinase/protein kinase B). In this letter, we develop a novel biophysical model for cytosolic Ca2+ activation of the PI3K/Akt pathway in microglia where Ca2+ influx is mediated by both P2Y purinergic receptors (P2YR) and P2X purinergic receptors (P2XR). The model parameters are estimated by employing optimization techniques to fit the model to phosphorylated Akt (pAkt) experimental modeling/in vitro data. The integrated model supports the hypothesis that Ca2+ influx via P2YR and P2XR can explain the experimentally reported biphasic transient responses in measuring pAkt levels. Our predictions reveal new quantitative insights into P2Rs on how they regulate Ca2+ and Akt in terms of physiological interactions and transient responses. It is shown that the upregulation of P2X receptors through a repetitive application of agonist results in a continual increase in the baseline [Ca2+], which causes the biphasic response to become a monophasic response which prolongs elevated levels of pAkt.

Medical financial hardship between young adult cancer survivors and matched individuals without cancer in the United States.

BACKGROUND: Young adult cancer survivors face medical financial hardships that may lead to delaying or forgoing medical care. This study describes the medical financial difficulties young adult cancer survivors in the United States experience in the post-Patient Protection and Affordable Care Act period. METHOD: We identified 1009 cancer survivors aged 18 to 39 years from the National Health Interview Survey (2015-2022) and matched 963 (95%) cancer survivors to 2733 control individuals using nearest-neighbor matching. We used conditional logistic regression to examine the association between cancer history and medical financial hardship and to assess whether this association varied by age, sex, race and ethnicity, and region of residence. RESULTS: Compared with those who did not have a history of cancer, young adult cancer survivors were more likely to report material financial hardship (22.8% vs 15.2%; odds ratio = 1.65, 95% confidence interval = 1.50 to 1.81) and behavior-related financial hardship (34.3% vs 24.4%; odds ratio = 1.62, 95% confidence interval = 1.49 to 1.76) but not psychological financial hardship (52.6% vs 50.9%; odds ratio = 1.07, 95% confidence interval = 0.99 to 1.16). Young adult cancer survivors who were Hispanic or lived in the Midwest and South were more likely to report psychological financial hardship than their counterparts. CONCLUSIONS: We found that young adult cancer survivors were more likely to experience material and behavior-related financial hardship than young adults without a history of cancer. We also identified specific subgroups of young adult cancer survivors that may benefit from targeted policies and interventions to alleviate medical financial hardship.

Trends and disparities in prevalence of cardiometabolic diseases by food security status in the United States.

BACKGROUND: Previous studies have demonstrated the association between food security and cardiometabolic diseases (CMDs), yet none have investigated trends in prevalence of CMDs by food security status in the United States (US). METHODS: Serial cross-sectional analysis of the US nationally representative data from National Health and Nutrition Examination Survey (1999-2018) was conducted among adults aged 20 years or older. Food security status was defined by the US Household Food Security Survey Module (full, marginal, low, and very low food security). We estimated the age-adjusted prevalence of CMDs including obesity, hypertension, diabetes, and coronary heart disease by food security status. Racial and ethnic disparities in age-adjusted prevalence of CMDs by food security status were also assessed. RESULTS: A total of 49,738 participants were included in this analysis (weighted mean age 47.3 years; 51.3% women). From 1999 to 2018, the age-adjusted prevalence of CMDs was lower in full food secure group as compared with other groups. For example, trends in hypertension decreased from 49.7% (47.5-51.8%) to 45.9% (43.8-48.0%) (P-trend = 0.002) among the full and from 54.2% (49.9-58.5%) to 49.7% (46.8-52.6%) (P-trend = 0.02) among the marginal but remained stable among the low at 49.7% (47.9-51.6%) and among the very low at 51.1% (48.9-53.3%) (P-interaction = 0.02). Prevalence of diabetes increased from 8.85% (8.15-9.60%) to 12.2% (11.1-13.5%) among the full (P-trend < 0.001), from 16.5% (13.2-20.4%) to 20.9% (18.6-23.5%) (P-trend = 0.045) among the marginal and from 14.6% (11.1-19.0%) to 20.9% (18.8-23.3%) (P-trend = 0.001) among the low but remained stable at 18.8% (17.0-20.9) among the very low (P-trend = 0.35) (P-interaction = 0.03). Racial and ethnic differences in prevalence of CMD by food security status were observed. For example, among individuals with full food secure status, the prevalence of diabetes was 9.08% (95% CI, 8.60-9.59%) for non-Hispanic whites, 17.3% (95% CI, 16.4-18.2%) for non-Hispanic blacks, 16.1% (95% CI, 15.0-17.4%) for Hispanics and 14.9% (95% CI, 13.3-16.7%) for others. CONCLUSIONS AND RELEVANCE: Prevalence of CMDs was greatest among those experiencing food insecurity, and food insecurity disproportionately affected racial/ethnic minorities. Disparities in CMD prevalence by food security status persisted or worsened, especially among racial/ethnic minorities.

2024 Heart Disease and Stroke Statistics: A Report of US and Global Data From the American Heart Association.

BACKGROUND: The American Heart Association (AHA), in conjunction with the National Institutes of Health, annually reports the most up-to-date statistics related to heart disease, stroke, and cardiovascular risk factors, including core health behaviors (smoking, physical activity, nutrition, sleep, and obesity) and health factors (cholesterol, blood pressure, glucose control, and metabolic syndrome) that contribute to cardiovascular health. The AHA Heart Disease and Stroke Statistical Update presents the latest data on a range of major clinical heart and circulatory disease conditions (including stroke, brain health, complications of pregnancy, kidney disease, congenital heart disease, rhythm disorders, sudden cardiac arrest, subclinical atherosclerosis, coronary heart disease, cardiomyopathy, heart failure, valvular disease, venous thromboembolism, and peripheral artery disease) and the associated outcomes (including quality of care, procedures, and economic costs). METHODS: The AHA, through its Epidemiology and Prevention Statistics Committee, continuously monitors and evaluates sources of data on heart disease and stroke in the United States and globally to provide the most current information available in the annual Statistical Update with review of published literature through the year before writing. The 2024 AHA Statistical Update is the product of a full year's worth of effort in 2023 by dedicated volunteer clinicians and scientists, committed government professionals, and AHA staff members. The AHA strives to further understand and help heal health problems inflicted by structural racism, a public health crisis that can significantly damage physical and mental health and perpetuate disparities in access to health care, education, income, housing, and several other factors vital to healthy lives. This year's edition includes additional global data, as well as data on the monitoring and benefits of cardiovascular health in the population, with an enhanced focus on health equity across several key domains. RESULTS: Each of the chapters in the Statistical Update focuses on a different topic related to heart disease and stroke statistics. CONCLUSIONS: The Statistical Update represents a critical resource for the lay public, policymakers, media professionals, clinicians, health care administrators, researchers, health advocates, and others seeking the best available data on these factors and conditions.

Familial Hypercholesterolemia Variant and Cardiovascular Risk in Individuals With Elevated Cholesterol.

Importance: Familial hypercholesterolemia (FH) is a genetic disorder that often results in severely high low-density lipoprotein cholesterol (LDL-C) and high risk of premature coronary heart disease (CHD). However, the impact of FH variants on CHD risk among individuals with moderately elevated LDL-C is not well quantified. Objective: To assess CHD risk associated with FH variants among individuals with moderately (130-189 mg/dL) and severely (≥190 mg/dL) elevated LDL-C and to quantify excess CHD deaths attributable to FH variants in US adults. Design, Setting, and Participants: A total of 21 426 individuals without preexisting CHD from 6 US cohort studies (Atherosclerosis Risk in Communities study, Coronary Artery Risk Development in Young Adults study, Cardiovascular Health Study, Framingham Heart Study Offspring cohort, Jackson Heart Study, and Multi-Ethnic Study of Atherosclerosis) were included, 63 of whom had an FH variant. Data were collected from 1971 to 2018, and the median (IQR) follow-up was 18 (13-28) years. Data were analyzed from March to May 2023. Exposures: LDL-C, cumulative past LDL-C, FH variant status. Main Outcomes and Measures: Cox proportional hazards models estimated associations between FH variants and incident CHD. The Cardiovascular Disease Policy Model projected excess CHD deaths associated with FH variants in US adults. Results: Of the 21 426 individuals without preexisting CHD (mean [SD] age 52.1 [15.5] years; 12 041 [56.2%] female), an FH variant was found in 22 individuals with moderately elevated LDL-C (0.3%) and in 33 individuals with severely elevated LDL-C (2.5%). The adjusted hazard ratios for incident CHD comparing those with and without FH variants were 2.9 (95% CI, 1.4-6.0) and 2.6 (95% CI, 1.4-4.9) among individuals with moderately and severely elevated LDL-C, respectively. The association between FH variants and CHD was slightly attenuated when further adjusting for baseline LDL-C level, whereas the association was no longer statistically significant after adjusting for cumulative past LDL-C exposure. Among US adults 20 years and older with no history of CHD and LDL-C 130 mg/dL or higher, more than 417 000 carry an FH variant and were projected to experience more than 12 000 excess CHD deaths in those with moderately elevated LDL-C and 15 000 in those with severely elevated LDL-C compared with individuals without an FH variant. Conclusions and Relevance: In this pooled cohort study, the presence of FH variants was associated with a 2-fold higher CHD risk, even when LDL-C was only moderately elevated. The increased CHD risk appeared to be largely explained by the higher cumulative LDL-C exposure in individuals with an FH variant compared to those without. Further research is needed to assess the value of adding genetic testing to traditional phenotypic FH screening.

Efficacy and safety of sintilimab plus albumin-bound-paclitaxel in recurrent or metastatic cervical cancer: a multicenter, open-label, single-arm, phase II trial.

Background: Sintilimab is an antibody against programmed cell death protein 1. We assessed the efficacy and safety of sintilimab plus albumin-bound (nab)-paclitaxel for the treatment of recurrent or metastatic cervical cancer. Methods: This multicenter, open-label, single-arm, phase II study (ClinicalTrials.gov identifier NCT04341883) enrolled patients with recurrent or metastatic cervical cancer who progressed after at least one line of systemic therapy. The patients received sintilimab 200 mg and nab-paclitaxel 260 mg/m2 body surface area every 3 weeks. The primary endpoint was objective response rate (ORR) assessed by investigators per Response Evaluation Criteria in Solid Tumors version 1.1. Key secondary endpoints were progression-free survival (PFS), overall survival (OS), duration of response (DoR), and safety. Findings: From January 13, 2020 to February 21, 2022, 27 patients were enrolled and received treatment. Median patient age was 50 years (range, 34-68 years). By data cut-off (May 22, 2022), in intention-to-treat population, ORR was 44.4% (95% CI, 24.4%-64.5%). The disease control rate was 88.9% (95% CI, 70.8%-97.6%). Median PFS was 5.2 months (95% CI, 2.7-7.7 months). Median DoR was 3.8 months (95% CI, 0.7-6.9 months), and median OS was 13.1 months (95% CI, 5.8-20.4 months). Treatment-related grade 3 or 4 adverse events (AEs) occurred in 44.4% of the patients, and the most common AEs were decreased neutrophil count (22.2%), decreased white blood cell count (14.8%), and anemia (7.4%). The most common potential immune-related AEs were grade 1-2 hypothyroidism (18.5%), neutropenia (11.1%), and rash (7.4%). Interpretation: Sintilimab plus nab-paclitaxel treatment shows promising antitumor activity and manageable toxicity in patients with advanced cervical cancer. Larger randomized controlled trials are required for validation. Funding: Innovent Biologics Co., Ltd.; Csps Holdings Co., Ltd.

Patient-derived organoids as personalized avatars and a potential immunotherapy model in cervical cancer.

Cervical cancer remains a significant health issue in developing countries. However, finding a preclinical model that accurately reproduces tumor characteristics is challenging. Therefore, we established a patient-derived organoids (PDOs) biobank containing 67 cases of heterogeneous cervical cancer that mimic the histopathological and genomic characteristics of parental tumors. The in vitro response of the organoids indicated their ability to capture the radiological heterogeneity of the patients. To model individual responses to adoptive T cell therapy (ACT), we expanded tumor-infiltrating lymphocytes (TILs) ex vivo and co-cultured them with paired organoids. The PDOs-TILs co-culture system demonstrates clear responses that correspond to established immunotherapy efficiency markers like the proportion of CTLs. This study supports the potential of the PDOs platform to guide treatment in prospective interventional trials in cervical cancer.

Tyrosine catabolism enhances genotoxic chemotherapy by suppressing translesion DNA synthesis in epithelial ovarian cancer.

Amino acid metabolism has been actively investigated as a potential target for antitumor therapy, but how it may alter the response to genotoxic chemotherapy remains largely unknown. Here, we report that the depletion of fumarylacetoacetate hydrolase (FAH), an enzyme that catalyzes the final step of tyrosine catabolism, reduced chemosensitivity in epithelial ovarian cancer (EOC). The expression level of FAH correlated significantly with chemotherapy efficacy in patients with EOC. Mechanistically, under genotoxic chemotherapy, FAH is oxidized at Met308 and translocates to the nucleus, where FAH-mediated tyrosine catabolism predominantly supplies fumarate. FAH-produced fumarate binds directly to REV1, resulting in the suppression of translesion DNA synthesis (TLS) and improved chemosensitivity. Furthermore, in vivo tyrosine supplementation improves sensitivity to genotoxic chemotherapeutics and reduces the occurrence of therapy resistance. Our findings reveal a unique role for tyrosine-derived fumarate in the regulation of TLS and may be exploited to improve genotoxic chemotherapy through dietary tyrosine supplementation.

Development and Validation of the US Diabetes, Obesity, Cardiovascular Disease Microsimulation (DOC-M) Model: Health Disparity and Economic Impact Model.

BACKGROUND: Few simulation models have incorporated the interplay of diabetes, obesity, and cardiovascular disease (CVD); their upstream lifestyle and biological risk factors; and their downstream effects on health disparities and economic consequences. METHODS: We developed and validated a US Diabetes, Obesity, Cardiovascular Disease Microsimulation (DOC-M) model that incorporates demographic, clinical, and lifestyle risk factors to jointly predict overall and racial-ethnic groups-specific obesity, diabetes, CVD, and cause-specific mortality for the US adult population aged 40 to 79 y at baseline. An individualized health care cost prediction model was further developed and integrated. This model incorporates nationally representative data on baseline demographics, lifestyle, health, and cause-specific mortality; dynamic changes in modifiable risk factors over time; and parameter uncertainty using probabilistic distributions. Validation analyses included assessment of 1) population-level risk calibration and 2) individual-level risk discrimination. To illustrate the application of the DOC-M model, we evaluated the long-term cost-effectiveness of a national produce prescription program. RESULTS: Comparing the 15-y model-predicted population risk of primary outcomes among the 2001-2002 National Health and Nutrition Examination Survey (NHANES) cohort with the observed prevalence from age-matched cross-sectional 2003-2016 NHANES cohorts, calibration performance was strong based on observed-to-expected ratio and calibration plot analysis. In most cases, Brier scores fell below 0.0004, indicating a low overall prediction error. Using the Multi-Ethnic Study of Atherosclerosis cohorts, the c-statistics for assessing individual-level risk discrimination were 0.85 to 0.88 for diabetes, 0.93 to 0.95 for obesity, 0.74 to 0.76 for CVD history, and 0.78 to 0.81 for all-cause mortality, both overall and in three racial-ethnic groups. Open-source code for the model was posted at https://github.com/food-price/DOC-M-Model-Development-and-Validation. CONCLUSIONS: The validated DOC-M model can be used to examine health, equity, and the economic impact of health policies and interventions on behavioral and clinical risk factors for obesity, diabetes, and CVD. HIGHLIGHTS: We developed a novel microsimula'tion model for obesity, diabetes, and CVD, which intersect together and - critically for prevention and treatment interventions - share common lifestyle, biologic, and demographic risk factors.Validation analyses, including assessment of (1) population-level risk calibration and (2) individual-level risk discrimination, showed strong performance across the overall population and three major racial-ethnic groups for 6 outcomes (obesity, diabetes, CVD, and all-cause mortality, CVD- and DM-cause mortality)This paper provides a thorough explanation and documentation of the development and validation process of a novel microsimulation model, along with the open-source code (https://github.com/food-price/ DOCM_validation) for public use, to serve as a guide for future simulation model assessments, validation, and implementation.

Spatiotemporal Optimization for the Placement of Automated External Defibrillators Using Mobile Phone Data.

With over 350,000 cases occurring each year, out-of-hospital cardiac arrest (OHCA) remains a severe public health concern in the United States. The correct and timely use of automated external defibrillators (AEDs) has been widely acknowledged as an effective measure to improve the survival rate of OHCA. While general guidelines have been provided by the American Heart Association (AHA) for AED deployment, the lack of detailed instructions hindered the adoption of such guidelines under dynamic scenarios with various time and space distributions. Formulating the AED deployment as a location optimization problem under budget and resource constraints, we proposed an overlayed spatio-temporal optimization (OSTO) method, which accounted for the spatiotemporal heterogeneity of potential OHCAs. To highlight the effectiveness of the proposed model, we applied the proposed method to Washington DC using user-generated anonymized mobile device location data. The results demonstrated that optimization-based planning provided an improved AED coverage level. We further evaluated the effectiveness of adding additional AEDs by analyzing the cost-coverage increment curve. In general, our framework provides a systematic approach for municipalities to integrate inclusive planning and budget-limited efficiency into their final decision-making. Given the high practicality and adaptability of the framework, the OSTO is highly amenable to different healthcare facilities' deployment tasks with flexible demand and resource restraints.

Geographic and Sociodemographic Variations in Prevalence of Mental Health Symptoms Among US Youths, 2022.

Objectives. To assess geographic and sociodemographic variations in prevalence of mental health symptoms among US youths. Methods. We analyzed data from the Household Pulse Survey, phases 3.5 and 3.6, between June 1 and November 14, 2022. The sample included 103 296 households with an estimated 190 017 youths younger than 18 years. We defined mental health symptoms based on parental responses and estimated prevalence by state and subgroups, including race/ethnicity, parental education, household income, housing tenure, household food sufficiency, and health insurance coverage. All analyses incorporated sampling weight. Results. An estimated 34.5% (95% confidence interval [CI] = 33.7%, 35.3%) of youths had parent-reported mental health symptoms. The prevalence of symptoms varied across states, ranging from 27.9% (95% CI = 23.8%, 32.0%) in Florida to 46.4% (95% CI = 41.9%, 50.9%) in New Hampshire. We observed variations by subgroup, with youths in households that did not pay rent reporting a prevalence of 43.8% (95% CI = 39.3%, 48.4%) and those experiencing food insufficiency reporting a prevalence of 56.0% (95% CI = 50.9%, 61.2%). Conclusions. There is an urgent need for attention to mental health challenges among youths, taking into account geographic and sociodemographic variations. (Am J Public Health. 2023;113(10):1116-1119. https://doi.org/10.2105/AJPH.2023.307355).

Role of the tripartite motif (TRIM) family in female genital neoplasms.

The tripartite motif proteins (TRIMs) family represents a class of highly conservative proteins which play a large regulatory role in molecular processes. Recently, increasing evidence has demonstrated a role of TRIMs in female genital neoplasms. Our review thereby aimed to provide an overview of the biological involvement of TRIMs in female genital neoplasms, to provide a better understanding of its role in the development and progression of such diseases, and emphasize its potential as targeted cancer therapy. Overall, our review highlighted that the wide-ranging roles of TRIMs, in not only target protein ubiquitination, tumor migration and/or invasion, epithelial-mesenchymal transition, stemness, cell adhesion, proliferation, cell cycle regulation, and apoptosis, but also in influencing estrogenic, and chemotherapy response.

Obesity-related cardiometabolic indicators modify the associations of personal noise exposure with heart rate variability: A further investigation on the Study among Obese and Normal-weight Adults (SONA).

Elucidating the associations between environmental noise and heart rate variability (HRV) would be beneficial for the prevention and control of detrimental cardiovascular changes. Obese people have been found to manifest heightened susceptibility to the adverse effects of noise on HRV. However, the underlying mechanisms remain unclear. Based on 53 normal-weight and 44 obese young adults aged 18-26 years in Beijing, China, this study aimed to investigate the role of obesity-related cardiometabolic indicators for associations between short-term environmental noise exposure and HRV in the real-world context. The participants underwent personal noise exposure and ambulatory electrocardiogram monitoring using portable devices at 5-min intervals for 24 continuous hours. Obesity-related blood pressure, glucose and lipid metabolism, and inflammatory indicators were subsequently examined. Generalized mixed-effect models were used to estimate the associations between noise exposure and HRV parameters. The C-peptide, homeostasis model assessment of insulin resistance (HOMA-IR), and leptin levels were higher in obese participants compared to normal-weight participants. We observed amplified associations between short-term noise exposure and decreases in HRV among participants with higher C-peptide, HOMA-IR, and leptin levels. For instance, a 1 dB(A) increment in 3 h-average noise exposure level preceding each measurement was associated with changes of -0.20% (95%CI: -0.45%, 0.04%) and -1.35% (95%CI: -1.85%, -0.86%) in standard deviation of all normal to normal intervals (SDNN) among participants with lower and higher C-peptide levels, respectively (P for interaction <0.05). Meanwhile, co-existing fine particulate matter (PM2.5) could amplify the associations between noise and HRV among obese participants and participants with higher C-peptide, HOMA-IR, and leptin levels. The more apparent associations of short-term exposure to environmental noise with HRV and the effect modification by PM2.5 may be partially explained by the higher C-peptide, HOMA-IR, and leptin levels of obese people.

Associations of multiple air pollutants with kidney function in normal-weight and obese adults and effect modification by free fatty acids.

Increasing studies have linked air pollution to kidney dysfunction, however, the associations between the mixture of air pollutants and kidney function and potential effect modifiers remain unclear. We aimed to investigate whether obese adults were more susceptible than normal-weight ones to the joint effects of multiple air pollutants on kidney function and further to explore effect modification by free fatty acids (FFAs). Forty obese and 49 normal-weight adults were recruited from a panel study (252 follow-up visits). Individual exposure levels of air pollutants (PM2.5, PM10, O3, NO2, SO2 and CO) were estimated. Glomerular function (cystatin C (CysC) and estimated glomerular filtration rate (eGFR)) and tubular function (neutrophil gelatinase-associated lipocalin (NGAL) and kidney injury molecule-1) were evaluated. Plasma levels of FFAs including trans fatty acids (TFAs) and essential fatty acids (EFAs) were quantified using targeted metabolomics. Bayesian kernel machine regression model was applied to estimate the associations between the mixture of air pollutants and kidney function. The results showed significant joint effects of air pollutants on kidney function indicators. In the normal-weight group, the mixture of air pollutants was significantly associated with CysC and eGFRcr-cys when the mixture was at or above its 70 percentile compared with the median, where O3 was identified as the key pollutant. In the obese group, a significantly positive association between the pollutant mixture and NGAL was observed in addition to trends in CysC and eGFRcr-cys, mainly driven by SO2. Interaction analysis suggested that the associations of air pollutants with kidney function were augmented by TFAs in both groups and weakened by EFAs in the normal-weight group. This study highlighted the renal adverse effects of air pollutants and modification of FFAs, which has implications for target prevention for kidney dysfunction associated with air pollution, especially among vulnerable populations.