Association of diet with per- and polyfluoroalkyl substances in plasma and human milk in the New Hampshire Birth Cohort Study.

Per- and polyfluoroalkyl substances (PFAS) are related to various adverse health outcomes, and food is a common source of PFAS exposure. Dietary sources of PFAS have not been adequately explored among U.S. pregnant individuals. We examined associations of dietary factors during pregnancy with PFAS concentrations in maternal plasma and human milk in the New Hampshire Birth Cohort Study. PFAS concentrations, including perfluorohexane sulfonate (PFHxS), perfluorooctane sulfonate (PFOS), perfluorooctanoate (PFOA), perfluorononanoate (PFNA), and perfluorodecanoate (PFDA), were measured in maternal plasma collected at ∼28 gestational weeks and human milk collected at ∼6 postpartum weeks. Sociodemographic, lifestyle and reproductive factors were collected from prenatal questionnaires and diet from food frequency questionnaires at ∼28 gestational weeks. We used adaptive elastic net (AENET) to identify important dietary variables for PFAS concentrations. We used multivariable linear regression to assess associations of dietary variables selected by AENET models with PFAS concentrations. Models were adjusted for sociodemographic, lifestyle, and reproductive factors, as well as gestational week of blood sample collection (plasma PFAS), postpartum week of milk sample collection (milk PFAS), and enrollment year. A higher intake of fish/seafood, eggs, coffee, or white rice during pregnancy was associated with higher plasma or milk PFAS concentrations. For example, every 1 standard deviation (SD) servings/day increase in egg intake during pregnancy was associated with 4.4 % (95 % CI: 0.6, 8.4), 3.3 % (0.1, 6.7), and 10.3 % (5.6, 15.2) higher plasma PFOS, PFOA, and PFDA concentrations respectively. Similarly, every 1 SD servings/day increase in white rice intake during pregnancy was associated with 7.5 % (95 % CI: -0.2, 15.8) and 12.4 % (4.8, 20.5) greater milk PFOS and PFOA concentrations, respectively. Our study suggests that certain dietary factors during pregnancy may contribute to higher PFAS concentrations in maternal plasma and human milk, which could inform interventions to reduce PFAS exposure for both birthing people and offspring.

Machine learning for predicting cognitive deficits using auditory and demographic factors.

IMPORTANCE: Predicting neurocognitive deficits using complex auditory assessments could change how cognitive dysfunction is identified, and monitored over time. Detecting cognitive impairment in people living with HIV (PLWH) is important for early intervention, especially in low- to middle-income countries where most cases exist. Auditory tests relate to neurocognitive test results, but the incremental predictive capability beyond demographic factors is unknown. OBJECTIVE: Use machine learning to predict neurocognitive deficits, using auditory tests and demographic factors. SETTING: The Infectious Disease Center in Dar es Salaam, Tanzania. PARTICIPANTS: Participants were 939 Tanzanian individuals from Dar es Salaam living with and without HIV who were part of a longitudinal study. Patients who had only one visit, a positive history of ear drainage, concussion, significant noise or chemical exposure, neurological disease, mental illness, or exposure to ototoxic antibiotics (e.g., gentamycin), or chemotherapy were excluded. This provided 478 participants (349 PLWH, 129 HIV-negative). Participant data were randomized to training and test sets for machine learning. MAIN OUTCOME(S) AND MEASURE(S): The main outcome was whether auditory variables combined with relevant demographic variables could predict neurocognitive dysfunction (defined as a score of <26 on the Kiswahili Montreal Cognitive Assessment) better than demographic factors alone. The performance of predictive machine learning algorithms was primarily evaluated using the area under the receiver operational characteristic curve. Secondary metrics for evaluation included F1 scores, accuracies, and the Youden's indices for the algorithms. RESULTS: The percentage of individuals with cognitive deficits was 36.2% (139 PLWH and 34 HIV-negative). The Gaussian and kernel naïve Bayes classifiers were the most predictive algorithms for neurocognitive impairment. Algorithms trained with auditory variables had average area under the curve values of 0.91 and 0.87, F1 scores (metric for precision and recall) of 0.81 and 0.76, and average accuracies of 86.3% and 81.9% respectively. Algorithms trained without auditory variables as features were statistically worse (p < .001) in both the primary measure of area under the curve (0.82/0.78) and the secondary measure of accuracy (72.3%/74.5%) for the Gaussian and kernel algorithms respectively. CONCLUSIONS AND RELEVANCE: Auditory variables improved the prediction of cognitive function. Since auditory tests are easy-to-administer and often naturalistic tasks, they may offer objective measures or predictors of neurocognitive performance suitable for many global settings. Further research and development into using machine learning algorithms for predicting cognitive outcomes should be pursued.

Central auditory test performance predicts future neurocognitive function in children living with and without HIV.

Tests of the brain's ability to process complex sounds (central auditory tests) correlate with overall measures of neurocognitive performance. In the low- middle-income countries where resources to conduct detailed cognitive testing is limited, tests that assess the central auditory system may provide a novel and useful way to track neurocognitive performance. This could be particularly useful for children living with HIV (CLWH). To evaluate this, we administered central auditory tests to CLWH and children living without HIV and examined whether central auditory tests given early in a child's life could predict later neurocognitive performance. We used a machine learning technique to incorporate factors known to affect performance on neurocognitive tests, such as education. The results show that central auditory tests are useful predictors of neurocognitive performance and perform as well or in some cases better than factors such as education. Central auditory tests may offer an objective way to track neurocognitive performance in CLWH.

Maternal-Infant Factors in Relation to Extracellular Vesicle and Particle miRNA in Prenatal Plasma and in Postpartum Human Milk.

MicroRNAs (miRNA) in extracellular vesicles and particles (EVPs) in maternal circulation during pregnancy and in human milk postpartum are hypothesized to facilitate maternal-offspring communication via epigenetic regulation. However, factors influencing maternal EVP miRNA profiles during these two critical developmental windows remain largely unknown. In a pilot study of 54 mother-child dyads in the New Hampshire Birth Cohort Study, we profiled 798 EVP miRNAs, using the NanoString nCounter platform, in paired maternal second-trimester plasma and mature (6-week) milk samples. In adjusted models, total EVP miRNA counts were lower for plasma samples collected in the afternoon compared with the morning (p = 0.024). Infant age at sample collection was inversely associated with total miRNA counts in human milk EVPs (p = 0.040). Milk EVP miRNA counts were also lower among participants who were multiparous after delivery (p = 0.047), had a pre-pregnancy BMI > 25 kg/m2 (p = 0.037), or delivered their baby via cesarean section (p = 0.021). In post hoc analyses, we also identified 22 specific EVP miRNA that were lower among participants who delivered their baby via cesarean section (Q < 0.05). Target genes of delivery mode-associated miRNAs were over-represented in pathways related to satiety signaling in infants (e.g., CCKR signaling) and mammary gland development and lactation (e.g., FGF signaling, EGF receptor signaling). In conclusion, we identified several key factors that may influence maternal EVP miRNA composition during two critical developmental windows, which should be considered in future studies investigating EVP miRNA roles in maternal and child health.

A murine model to evaluate immunotherapy effectiveness for human Fanconi anemia-mutated acute myeloid leukemia.

Fanconi anemia (FA)-mutated acute myeloid leukemia (AML) is a secondary AML with very poor prognosis and limited therapeutic options due to increased sensitivity to DNA-damaging agents. PD-1 immune checkpoint inhibitors upregulate T-cell killing of cancer cells and is a class of promising treatment for FA-AML. Here, we developed a novel FA-AML murine model that allows the study of human AML with a humanized immune system in order to investigate immunotherapeutic treatments in vivo. FA-AML1 cells and non-FA-mutated Kasumi-1 cells were injected into 8-10 week old NSG mice. Once leukemic engraftment was confirmed by HLA-DR expression in the peripheral blood, human peripheral blood mononuclear cells (hPBMCs) were injected into the mice. One week post-hPBMCs injection, Nivolumab (PD-1 inhibitor) or PBS vehicle control was administered to the mice bi-weekly. In our Nivolumab treated mice, FA-AML1, but not Kasumi-1-engrafted mice, had significantly prolonged overall survival. Both FA-AML1 and Kasumi-1 engrafted mice had decreased spleen weights. Higher leukemic infiltration into vital organs was observed in FA-AML1 engrafted mice compared to Kasumi-1 engrafted mice. In conclusion, our novel humanized murine model of FA-mutated AML is an attractive tool for supporting further studies and clinical trials using PD-1 inhibitors to treat FA-mutated AML.

Stratification of dissolved organic matter in the upper 5000 m water column in the western Pacific Ocean.

Marine dissolved organic matter (DOM) is a principal reservoir involved in biogeochemical cycles and exerts a pivotal influence on global carbon flux dynamics. In this study, excitation-emission matrix fluorescence spectroscopy combined with parallel factor analysis (EEM-PARAFAC) was conducted on 230 DOM samples collected from 21 sites between February and April 2022 in the Western Pacific Ocean (WPO). We identified five distinct fluorescence peaks (peaks B, T, A, C, and M), predominantly protein-like and humic-like components. These findings, marked by significant differences (p < 0.01) in fluorescence intensities and spectral indices, characterized the transformation of DOM with ocean depth, illustrating a transition from active to recalcitrant forms. Additionally, random forest analysis (RFA) identified depth as a key factor influencing marine dissolved organic carbon (DOC), with a 32.59% importance value. Correlations between hydrological and fluorescent parameters underscored the complexity of DOM sources and influencing processes. Overall, this work broadens our understanding of DOM variability in the upper 5000 m of the WPO, enhancing our knowledge of the marine environment's role in the global carbon cycle.

A Central Auditory Test reveals differences between drug treatment regimens in adults living with HIV.

OBJECTIVE: This exploratory study examined whether central auditory tests show differences between people living with HIV (PLWH) treated with two predominant antiretroviral drug therapy (ART) regimens. DESIGN: Cross-sectional. STUDY SAMPLE: 253 PLWH (mean age 39.8 years) from the Shanghai Public Health Clinical Centre, China. METHODS: The Hearing in Noise Test speech reception threshold (SRT) assessed central auditory function and the Montreal Cognitive Assessment (MoCA) assessed cognition. The relationship between ART regimen and SRT was evaluated with multivariable linear regression incorporating age, HIV duration, and peripheral hearing ability. Multivariable logistic regression was used to ascertain if SRT and ART regimen predicted MoCA impairment. RESULTS: The two predominant ART regimens differed by one drug (zidovudine or tenofovir). Participants taking the zidovudine-containing regimen had poorer SRT performance (p=.012) independent of age and hearing thresholds. MoCA scores did not differ between drug regimens, but a negative relationship was found between SRT and MoCA impairment (p=.048). CONCLUSIONS: ART regimens differed in their association with central auditory test performance likely reflecting neurocognitive changes in PLWH taking the zidovudine-containing regimen. Central auditory test performance also marginally predicted cognitive impairment, supporting further assessment of central auditory tests to detect neurocognitive deficits in PLWH.

Periconceptional and Prenatal Exposure to Metals and Extracellular Vesicle and Particle miRNAs in Human Milk: A Pilot Study.

Human milk is a rich source of microRNAs (miRNAs), which can be transported by extracellular vesicles and particles (EVPs) and are hypothesized to contribute to maternal-offspring communication and child development. Environmental contaminant impacts on EVP miRNAs in human milk are largely unknown. In a pilot study of 54 mother-child pairs from the New Hampshire Birth Cohort Study, we examined relationships between five metals (arsenic, lead, manganese, mercury, and selenium) measured in maternal toenail clippings, reflecting exposures during the periconceptional and prenatal periods, and EVP miRNA levels in human milk. 798 miRNAs were profiled using the NanoString nCounter platform; 200 miRNAs were widely detectable and retained for downstream analyses. Metal-miRNA associations were evaluated using covariate-adjusted robust linear regression models. Arsenic exposure during the periconceptional and prenatal periods was associated with lower total miRNA content in human milk EVPs (PBonferroni < 0.05). When evaluating miRNAs individually, 13 miRNAs were inversely associated with arsenic exposure, two in the periconceptional period and 11 in the prenatal period (PBonferroni < 0.05). Other metal-miRNA associations were not statistically significant after multiple testing correction (PBonferroni ≥ 0.05). Many of the arsenic-associated miRNAs are involved in lactation and have anti-inflammatory properties in the intestine and tumor suppressive functions in breast cells. Our findings raise the possibility that periconceptional and prenatal arsenic exposure may reduce levels of multiple miRNAs in human milk EVPs. However, larger confirmatory studies, which can apply environmental mixture approaches, evaluate potential effect modifiers of these relationships, and examine possible downstream consequences for maternal and child health and breastfeeding outcomes, are needed.

Near-Infrared Spectral Tomography for Predicting Residual Cancer Burden during Early-Stage Neoadjuvant Chemotherapy for Breast Cancer.

PURPOSE: The aim of this study is to investigate whether near-infrared spectral tomography (NIRST) might serve as a reliable prognostic tool to predict residual cancer burden (RCB) in patients with breast cancer undergoing neoadjuvant chemotherapy (NAC) based upon early treatment response measurements. EXPERIMENTAL DESIGN: A total of thirty-five patients with breast cancer receiving NAC were included in this study. NIRST imaging was performed at multiple time points, including: before treatment, at end of the first cycle, at the mid-point, and post-NAC treatments. From reconstructed NIRST images, average values of total hemoglobin (HbT) were obtained for both the tumor region and contralateral breast at each time point. RCB scores/classes were assessed by a pathologist using histologic slides of the surgical specimen obtained after completing NAC. Logistic regression of the normalized early percentage change of HbT in the tumor region (ΔHbT%) was used to predict RCB and determine its significance as an indicator for differentiating cases within each RCB class. RESULTS: The ΔHbT% at the end of the first cycle, as compared with pretreatment levels, showed excellent prognostic capability in differentiating RCB-0 from RCB-I/II/III or RCB-II from RCB-0/I/III (P < 0.001). Corresponding area under the curve (AUC) values for these comparisons were 0.97 and 0.94, and accuracy values were 0.90 and 0.83, respectively. CONCLUSIONS: NIRST holds promise as a potential clinical tool that can be seamlessly integrated into existing clinical workflow within the infusion suite. By providing early assessment of RCB, NIRST has potential to improve breast cancer patient management strategies.

Mean dose rate in ultra-high dose rate electron irradiation is a significant predictor for O2consumption and H2O2yield.

Objective. The objective of this study was to investigate the impact of mean and instantaneous dose rates on the production of reactive oxygen species (ROS) during ultra-high dose rate (UHDR) radiotherapy. The study aimed to determine whether either dose rate type plays a role in driving the FLASH effect, a phenomenon where UHDR radiotherapy reduces damage to normal tissues while maintaining tumor control.Approach. Assays of hydrogen peroxide (H2O2) production and oxygen consumption (ΔpO2) were conducted using UHDR electron irradiation. Aqueous solutions of 4% albumin were utilized as the experimental medium. The study compared the effects of varying mean dose rates and instantaneous dose rates on ROS yields. Instantaneous dose rate was varied by changing the source-to-surface distance (SSD), resulting in instantaneous dose rates ranging from 102to 106Gy s-1. Mean dose rate was manipulated by altering the pulse frequency of the linear accelerator (linac) and by changing the SSD, ranging from 0.14 to 1500 Gy s-1.Main results. The study found that both ΔH2O2and ΔpO2decreased as the mean dose rate increased. Multivariate analysis indicated that instantaneous dose rates also contributed to this effect. The variation in ΔpO2was dependent on the initial oxygen concentration in the solution. Based on the analysis of dose rate variation, the study estimated that 7.51 moles of H2O2were produced for every mole of O2consumed.Significance. The results highlight the significance of mean dose rate as a predictor of ROS production during UHDR radiotherapy. As the mean dose rate increased, there was a decrease in oxygen consumption and in H2O2production. These findings have implications for understanding the FLASH effect and its potential optimization. The study sheds light on the role of dose rate parameters and their impact on radiochemical outcomes, contributing to the advancement of UHDR radiotherapy techniques.

A phase II study of alternating sunitinib and temsirolimus therapy in patients with metastatic renal cell carcinoma.

BACKGROUND: Sunitinib is a multi-target tyrosine kinase inhibitor (TKI) that inhibits VEGF receptor 1, 2, 3 (VEGFRs), platelet-derived growth factor receptor (PDGFR), colony-stimulating factor receptor (CSFR), and the stem cell factor receptor c-KIT. Temsirolimus inhibits mammalian target of rapamycin (mTOR) through binding to intracellular protein FKBP-12. Both agents are approved for the treatment of metastatic renal cell carcinoma (mRCC), have different anticancer mechanisms, and non-overlapping toxicities. These attributes form the scientific rationale for sequential combination of these agents. The primary objective of the study was to investigate the efficacy of alternating sunitinib and temsirolimus therapy on progression-free survival (PFS) in mRCC. METHODS: We undertook a phase II, multi-center, single cohort, open-label study in patients with mRCC. Patients were treated with alternating dosing of 4 weeks of sunitinib 50 mg PO daily, followed by 2 weeks rest, then 4 weeks of temsirolimus 25 mg IV weekly, followed by 2 weeks rest (12 weeks total per cycle). The primary endpoint was PFS. Secondary endpoints included clinical response rate and characterization of the toxicity profile of this combination therapy. RESULTS: Nineteen patients were enrolled into the study. The median observed PFS (n = 13 evaluable for PFS) was 8.8 months (95% CI 6.8-25.2 months). Best responses achieved were five partial response, nine stable disease, and three disease progression according to RECIST 1.1 guidelines (two non-evaluable). The most commonly observed toxicities were fatigue, platelet count decrease, creatinine increased, diarrhea, oral mucositis, edema, anemia, rash, hypophosphatemia, dysgeusia, and palmar-plantar erythrodysesthesia syndrome. CONCLUSION: Alternating sunitinib and temsirolimus did not improve the PFS in patients with mRCC.

Neural oscillations in the ventral striatum reveal differences between the encoding of palatable food and ethanol consumption.

BACKGROUND: Across multiple levels of investigation, there appear to be convergent neuronal processes underlying substance use and other motivated behaviors (i.e., the pursuit and consumption of rewarding substances). The consumption of alcohol and sweet, high-fat food engages many of the same brain regions, especially, the ventral striatum. In the current study, we hypothesized that ventral striatal local field potentials (LFPs) recorded during self-administration sessions could be used to detect when the consumption of 10% ethanol or sweet-fat food (SF) was occurring compared to all other behaviors, including naturalistic controls (i.e., water or house-chow). METHODS: We used an intermittent limited access approach to condition Sprague-Dawley rats to consume either ethanol or SF while we recorded LFPs. We used machine learning and simple logistic regressions to determine whether LFP features could classify when consumption of each substance was occurring, and whether a general model could predict consumption of both substances. We report performance as the average area under the receiver operator characteristic curve (AUROC). RESULTS: Consumption of a single substance was differentiable from all other behaviors, as evidenced by the AUROC (ethanol = 0.84 and SF = 0.83, p < 0.01). Models built from the combined dataset (general) did modestly overall (general → general = 0.68, p < 0.05), and did not detect the consumption of the two substances similarly (general → SF = 0.5 and general → ethanol = 0.63, p > 0.05). CONCLUSIONS: Models successfully classified ethanol and SF consumption versus all other behavior/naturalistic controls. However, the findings highlight differences in how the ventral striatum represents the consumption of ethanol and SF and show that, although there is potential for finding biomarkers related to substance use, it may be difficult to build a model that performs well detecting multiple substances.

Peripheral Auditory Function in Tanzanian Children Living With HIV With Clinically Normal Hearing.

Importance: Despite normal audiometry, adults living with HIV have lower distortion product otoacoustic emissions (DPOAEs) compared with HIV-negative controls, but the degree of these differences in children living with HIV is unknown. If subclinical auditory deficits are present, results could affect developmental outcomes in children living with HIV (CLWH). Objective: To compare DPOAEs and auditory brainstem responses (ABR) between 2 age- and sex-matched groups of younger children with normal audiometry, 1 infected with HIV and the other uninfected. Design, Setting, and Participants: Cohort study in an infectious disease center in Dar es Salaam, Tanzania. Participants included 340 Tanzanian children aged 3 to 9 years with clinically normal hearing, type A tympanograms bilaterally, and air-conduction thresholds of 20 dB HL or less from 0.5 to 8 kHz. Participants in the cohort repeated testing approximately every 6 months (approximately 2.2 sessions per participant) for a total of 744 total observations. Data were analyzed from March 2020 to January 2022. Main Outcomes and Measures: DPOAE amplitudes from 1.5 to 8 kHz using an f2 to f1 ratio of 1.2 and L1/L2 values of 65/55 dB sound pressure level and click-evoked ABR using a slow (21.1/s) and fast (61.1/s) click rate. Results: A total of 141 CLWH (70 female participants [49.3%]; mean [SD] age, 7.24 [1.67] years) and 199 HIV-negative individuals (99 female participants [49.7%]; mean [SD] age, 7.26 [1.44] years) participated in the study. The groups did not differ significantly in age, static immittance, or air-conduction thresholds. HIV status was independently associated with approximately 1.4 dB (95% CI, -3.28 to 0.30 dB) to 3.8 dB (95% CI, 6.03 to -1.99 dB) lower DPOAE amplitudes at 6 and 8 kHz bilaterally and 0.28 µV (95% CI, 0.01 to 0.33 µV) lower ABR wave V amplitudes in the right ear. Conclusions and Relevance: Consistent with previous findings in young adults, CLWH had slightly, but reliably, lower DPOAEs and ABR wave V amplitudes than HIV-negative controls. The magnitude of these differences was small, but results suggest an early and consistent association between HIV infection or treatment and outer hair cell and auditory brainstem responses in children as young as 3 years. These subclinical changes suggest tracking both auditory function and development outcomes in CLWH is warranted.

Umbilical cord blood immune cell profiles in relation to the infant gut microbiome.

During infancy, the interplay between the developing immune system and the microbiome is critical. We examined whether blood immune cell composition at birth in the umbilical cord (inferred by DNA methylation profiling) related to the early infant gut microbiome (assessed by 16S rRNA gene sequencing) among 73 infants in the New Hampshire Birth Cohort Study. We used generalized estimating equations and controlled for false discovery rate to select microbial taxa associated with immune cells. We found associations between the infant gut microbiome and immune cells, including a positive association between B cells and Enterobacter, a negative association between natural killer cells and Bifidobacterium, and a positive association between granulocytes and Bifidobacterium. Our findings give clues that immune profiles at the time of birth as measured in umbilical cord blood are associated with the development of the gut microbiome in early life.

A prospective study of the infant gut microbiome in relation to vaccine response.

BACKGROUND: The establishment of the gut microbiome plays a key symbiotic role in the developing immune system; however, its influence on vaccine response is yet uncertain. We prospectively investigated the composition and diversity of the early-life gut microbiome in relation to infant antibody response to two routinely administered vaccines. METHODS: Eighty-three infants enrolled in the New Hampshire Birth Cohort Study were included in the analysis. We collected blood samples at 12 months of age and assayed the isolated serum to quantify total IgG and measured antibody to pneumococcal capsular polysaccharide and tetanus toxoid. Stool samples were collected from infants at 6 weeks of age and sequenced using 16S rRNA, and a subset of 61 samples were sequenced using shotgun metagenomics sequencing. RESULTS: We observed differences in beta diversity for 16S 6-week stool microbiota and pneumococcal and tetanus IgG antibody responses. Metagenomics analyses identified species and metabolic pathways in 6-week stool associated with tetanus antibody response, in particular, negative associations with the relative abundance of Aeriscardovia aeriphila species and positive associations with the relative abundance of species associated with CDP-diacylglycerol biosynthesis pathways. CONCLUSIONS: The early gut microbiome composition may influence an infant's vaccine response. IMPACT: Early intestinal microbiome acquisition plays a critical role in immune maturation and in both adaptive and innate immune response in infancy. We identified associations between early life microbiome composition and response to two routinely administered vaccines-pneumococcal capsular polysaccharide and tetanus toxoid-measured at approximately 1 year of age. Our findings highlight the potential impact of the gut microbiome on infant immune response that may open up opportunities for future interventions.

Examination of increasing suicide rates among rural Hispanic VA patients.

PURPOSE: Death by suicide is increasing more rapidly among Hispanics than non-Hispanics who use United States Department of Veterans Affairs (VA) health services, and the increase is most rapid among those living in rural areas. Our goal was to identify characteristics of rural Hispanic VA patients that contribute to this emerging disparity. METHODS: We linked electronic medical records from the VA, personnel data from the US Department of Defense, mortality data from the US National Death Index, and data on area characteristics from the US Census Bureau to examine suicide trends among Hispanic VA patients from 2005 through 2019. After identifying the strongest predictors of suicide in the rural and urban Hispanic populations, we examined how those characteristics changed over time. FINDINGS: Age and sex-adjusted suicide mortality rates were consistently higher for rural versus urban Hispanic patients beginning in 2012, with the most recent rolling 5-year average rates being 31.0 per 100,000 for rural compared to 20.3 per 100,000 for urban in 2019. Models to predict suicide had fair performance in the rural (accuracy = 0.62, 95% CI: 0.51, 0.73) and urban (accuracy = 0.67, 95% CI: 0.63, 0.70) groups. Mental health diagnoses were predictive of suicide among rural Hispanic patients, but there was no evidence that mental health diagnoses were increasing more rapidly in rural compared to urban patients. CONCLUSIONS: While we confirmed that there is a higher rate of death by suicide among rural Hispanic VA patients relative to their urban counterparts, we were unable to identify clear drivers of this finding.

Adaptive-mixture-categorization (AMC)-based g-computation and its application to trace element mixtures and bladder cancer risk.

Several new statistical methods have been developed to identify the overall impact of an exposure mixture on health outcomes. Weighted quantile sum (WQS) regression assigns the joint mixture effect weights to indicate the overall association of multiple exposures, and quantile-based g-computation is a generalized version of WQS without the restriction of directional homogeneity. This paper proposes an adaptive-mixture-categorization (AMC)-based g-computation approach that combines g-computation with an optimal exposure categorization search using the F statistic. AMC-based g-computation reduces variance within each category and retains the variance between categories to build more powerful predictors. In a simulation study, the performance of association analysis was improved using categorizing by AMC compared with quantiles. We applied this method to assess the association between a mixture of 12 trace element concentrations measured from toenails and the risk of non-muscle invasive bladder cancer. Our findings suggested that medium-level (116.7-145.5 µg/g) vs. low-level (39.5-116.2 µg/g) of toenail zinc had a statistically significant positive association with bladder cancer risk.

Changes in Alcohol Consumption following Direct-Acting Antiviral Treatment for Hepatitis C in VA Patients with Comorbid Alcohol Use Disorder and PTSD.

OBJECTIVE: To investigate whether direct-acting antivirals (DAA) for hepatitis C viral infection (HCV): glecaprevir/pibrentasvir (GLE/PIB), ledipasvir/sofosbuvir (LDV/SOF), and sofosbuvir/velpatasvir (SOF/VEL) are associated with reduced alcohol consumption among veterans with alcohol use disorder (AUD) and co-occurring post-traumatic stress disorder (PTSD). METHODS: We measured change in Alcohol Use Disorder Identification Test-Consumption Module (AUDIT-C) scores in a retrospective cohort of veterans with PTSD and AUD receiving DAAs for HCV. RESULTS: One thousand two hundred and eleven patients were included (GLE/PIB n = 174, LDV/SOF n = 808, SOF/VEL n = 229). Adjusted frequencies of clinically meaningful improvement were 30.5% for GLE/PIB, 45.5% for LDV/SOF, and 40.5% for SOF/VEL. The frequency was lower for GLE/PIB than for LDV/SOF (OR = 0.59; 95% CI [0.40, 0.87]) or SOF/VEL (OR = 0.66; 95% CI [0.42, 1.04]). CONCLUSIONS: DAA treatment for HCV was associated with a substantial reduction in alcohol use in patients with AUD and co-occurring PTSD. Further exploration of the role of DAAs in AUD treatment is warranted.

A new method for estimating under-recruitment of a patient registry: a case study with the Ohio Registry of Amyotrophic Lateral Sclerosis.

We developed a disease registry to collect all incident amyotrophic lateral sclerosis (ALS) cases diagnosed during 2016-2018 in Ohio. Due to incomplete case ascertainment and limitations of the traditional capture-recapture method, we proposed a new method to estimate the number of cases not recruited by the Registry and their spatial distribution. Specifically, we employed three statistical methods to identify reference counties with normal case-population relationships to build a Poisson regression model for estimating case counts in target counties that potentially have unrecruited cases. Then, we conducted spatial smoothing to adjust outliers locally. We validated the estimates with ALS mortality data. We estimated that 119 total cases (95% CI [109, 130]) were not recruited, including 36 females (95% CI [31, 41]) and 83 males (95% CI [74, 99]), and were distributed unevenly across the state. For target counties, including estimated unrecruited cases increased the correlation between the case count and mortality count from r = 0.8494 to 0.9585 for the total, from 0.7573 to 0.8270 for females, and from 0.6862 to 0.9292 for males. The advantage of this method in the spatial perspective makes it an alternative to capture-recapture for estimating cases missed by disease registries.

The relationship between the gut microbiome and the risk of respiratory infections among newborns.

Background: Emerging evidence points to a critical role of the developing gut microbiome in immune maturation and infant health; however, prospective studies are lacking. Methods: We examined the occurrence of infections and associated symptoms during the first year of life in relation to the infant gut microbiome at six weeks of age using bacterial 16S rRNA V4-V5 gene sequencing (N = 465) and shotgun metagenomics (N = 185). We used generalized estimating equations to assess the associations between longitudinal outcomes and 16S alpha diversity and metagenomics species. Results: Here we show higher infant gut microbiota alpha diversity was associated with an increased risk of infections or respiratory symptoms treated with a prescription medicine, and specifically upper respiratory tract infections. Among vaginally delivered infants, a higher alpha diversity was associated with an increased risk of all-cause wheezing treated with a prescription medicine and diarrhea involving a visit to a health care provider. Positive associations were specifically observed with Veillonella species among all deliveries and Haemophilus influenzae among cesarean-delivered infants. Conclusion: Our findings suggest that intestinal microbial diversity and the relative abundance of key taxa in early infancy may influence susceptibility to respiratory infection, wheezing, and diarrhea.