Brain volume, energy balance, and cardiovascular health in two nonindustrial South American populations.

Little is known about brain aging or dementia in nonindustrialized environments that are similar to how humans lived throughout evolutionary history. This paper examines brain volume (BV) in middle and old age among two indigenous South American populations, the Tsimane and Moseten, whose lifestyles and environments diverge from those in high-income nations. With a sample of 1,165 individuals aged 40 to 94, we analyze population differences in cross-sectional rates of decline in BV with age. We also assess the relationships of BV with energy biomarkers and arterial disease and compare them against findings in industrialized contexts. The analyses test three hypotheses derived from an evolutionary model of brain health, which we call the embarrassment of riches (EOR). The model hypothesizes that food energy was positively associated with late life BV in the physically active, food-limited past, but excess body mass and adiposity are now associated with reduced BV in industrialized societies in middle and older ages. We find that the relationship of BV with both non-HDL cholesterol and body mass index is curvilinear, positive from the lowest values to 1.4 to 1.6 SDs above the mean, and negative from that value to the highest values. The more acculturated Moseten exhibit a steeper decrease in BV with age than Tsimane, but still shallower than US and European populations. Lastly, aortic arteriosclerosis is associated with lower BV. Complemented by findings from the United States and Europe, our results are consistent with the EOR model, with implications for interventions to improve brain health.

Association of HIV and HCV Infection With Carotid Artery Plaque Echomorphology in the MACS/WIHS Combined Cohort Study.

BACKGROUND: HIV and hepatitis C virus (HCV) are associated with increased risk of carotid artery atherosclerotic plaque and stroke. We examined associations of HIV- and HCV-related factors with echomorphologic features of carotid artery plaque. METHODS: This cross-sectional study included participants from the MACS (Multicenter AIDS Cohort Study)/WIHS (Women's Interagency HIV Study) Combined Cohort Study who underwent high-resolution B-mode carotid artery ultrasound. Plaques were characterized from 6 areas of the right carotid artery. Poisson regression controlling for demographic and cardiometabolic risk factors determined adjusted prevalence ratios (aPRs) and 95% CIs for associations of HIV- and HCV-related factors with echomorphologic features. RESULTS: Of 2655 participants (65% women, median age 44 [interquartile range, 37-50] years), 1845 (70%) were living with HIV, 600 (23%) were living with HCV, and 425 (16%) had carotid plaque. There were 191 plaques identified in 129 (11%) women with HIV, 51 plaques in 32 (7%) women without HIV, 248 plaques in 171 (28%) men with HIV, and 139 plaques in 93 (29%) men without HIV. Adjusted analyses showed that people with HIV and current CD4+ count <200 cells/µL had a significantly higher prevalence of predominantly echolucent plaque (aPR, 1.86 [95% CI, 1.08-3.21]) than those without HIV. HCV infection alone (aPR, 1.86 [95% CI, 1.08-3.19]) and HIV-HCV coinfection (aPR, 1.75 [95% CI, 1.10-2.78]) were each associated with higher prevalence of predominantly echogenic plaque. HIV-HCV coinfection was also associated with higher prevalence of smooth surface plaque (aPR, 2.75 [95% CI, 1.03-7.32]) compared with people without HIV and HCV. CONCLUSIONS: HIV with poor immunologic control, as well as HCV infection, either alone or in the presence of HIV, were associated with different echomorphologic phenotypes of carotid artery plaque.

Microglial TLR4 Mediates White Matter Injury in a Combined Model of Diesel Exhaust Exposure and Cerebral Hypoperfusion.

BACKGROUND: Air pollution particulate matter exposure and chronic cerebral hypoperfusion (CCH) contribute to white matter toxicity through shared mechanisms of neuroinflammation, oxidative stress, and myelin breakdown. Prior studies showed that exposure of mice to joint particulate matter and CCH caused supra-additive injury to corpus callosum white matter. This study examines the role of TLR4 (toll-like receptor 4) signaling in mediating neurotoxicity and myelin damage observed in joint particulate matter and CCH exposures. METHODS: Experiments utilized a novel murine model of inducible monocyte/microglia-specific TLR4 knockout (i-mTLR4-ko). Bilateral carotid artery stenosis (BCAS) was induced surgically to model CCH. TLR4-intact (control) and i-mTLR4-ko mice were exposed to 8 weeks of either aerosolized diesel exhaust particulate (DEP) or filtered air (FA) in 8 experimental groups: (1) control/FA (n=10), (2) control/DEP (n=10), (3) control/FA+BCAS (n=9), (4) control/DEP+BCAS (n=10), (5) i-mTLR4-ko/FA (n=9), (6) i-mTLR4-ko/DEP (n=8), (7) i-mTLR4-ko/FA+BCAS (n=8), and (8) i-mTLR4-ko/DEP+BCAS (n=10). Corpus callosum levels of 4-hydroxynonenal, 8-Oxo-2'-deoxyguanosine, Iba-1 (ionized calcium-binding adapter molecule 1), and dMBP (degraded myelin basic protein) were assayed via immunofluorescence to measure oxidative stress, neuroinflammation, and myelin breakdown, respectively. RESULTS: Compared with control/FA mice, control/DEP+BCAS mice exhibited increased dMBP (41%; P<0.01), Iba-1 (51%; P<0.0001), 4-hydroxynonenal (100%; P<0.0001), and 8-Oxo-2'-deoxyguanosine (65%; P<0.05). I-mTLR4 knockout attenuated responses to DEP/BCAS for all markers. CONCLUSIONS: i-mTLR4-ko markedly reduced neuroinflammation and oxidative stress and attenuated white matter degradation following DEP and CCH exposures. This suggests a potential role for targeting TLR4 signaling in individuals with vascular cognitive impairment, particularly those exposed to substantial ambient air pollution.

Disparities in Care for Low-Income Patients with Cirrhosis: Implementing an Innovative Outpatient Clinic for Refractory Ascites in a Safety Net Hospital.

BACKGROUND: Disparities in life-saving interventions for low-income patients with cirrhosis necessitate innovative models of care. AIM: To implement a novel generalist-led FLuid ASPiration (FLASP) clinic to reduce emergency department (ED) care for refractory ascites. SETTING: A large safety net hospital in Los Angeles. PARTICIPANTS: MediCal patients with paracentesis in the ED from 6/1/2020 to 1/31/2021 or in FLASP clinic or the ED from 3/1/2021 to 4/30/2022. PROGRAM DESCRIPTION: According to RE-AIM, adoption obtained administrative endorsement and oriented ED staff. Reach engaged ED staff and eligible patients with timely access to FLASP. Implementation trained FLASP clinicians in safer, guideline-based paracentesis, facilitated timely access, and offered patient education and support. PROGRAM EVALUATION: After FLASP clinic opened, significantly fewer ED visits were made by patients discharged after paracentesis [rate ratio (RR) of 0.33 (95% CI 0.28, 0.40, p < 0.0001)] but not if subsequently hospitalized (RR = 0.88, 95% CI 0.70, 1.11). Among 2685 paracenteses in 225 FLASP patients, complications were infrequent: 39 (1.5%) spontaneous bacterial peritonitis, 265 (9.9%) acute kidney injury, and 2 (< 0.001%) hypotension. FLASP patients rated satisfaction highly on a Likert-type question. DISCUSSION: Patients with refractory ascites in large safety net hospitals may benefit from an outpatient procedure clinic instead of ED care.

Use of Telehealth Information for Early Detection: Insights From the COVID-19 Pandemic.

Objectives. To examine whether the addition of telehealth data to existing surveillance infrastructure can improve forecasts of cases and mortality. Methods. In this observational study, we compared accuracy of 14-day forecasts using real-time data available to the National Syndromic Surveillance Program (standard forecasts) to forecasts that also included telehealth information (telehealth forecasts). The study was performed in a national telehealth service provider in 2020 serving 50 US states and the District of Columbia. Results. Among 10.5 million telemedicine encounters, 169 672 probable COVID-19 cases were diagnosed by 5050 clinicians, with a rate between 0.79 and 47.8 probable cases per 100 000 encounters per day (mean = 8.37; SD = 10.75). Publicly reported case counts ranged from 0.5 to 237 916 (mean: 53 913; SD = 47 466) and 0 to 2328 deaths (mean = 1035; SD = 550) per day. Telehealth-based forecasts improved 14-day case forecasting accuracy by 1.8 percentage points to 30.9% (P = .06) and mortality forecasting by 6.4 percentage points to 26.9% (P < .048). Conclusions. Modest improvements in forecasting can be gained from adding telehealth data to syndromic surveillance infrastructure. (Am J Public Health. 2024;114(2):218-225. https://doi.org/10.2105/AJPH.2023.307499).

Cerebrovascular reactivity in Alzheimer's disease signature regions is associated with mild cognitive impairment in adults with hypertension.

INTRODUCTION: Vascular risk factors contribute to cognitive decline suggesting that maintaining cerebrovascular health could reduce dementia risk. The objective of this study is to evaluate the association of cerebrovascular reactivity (CVR), a measure of brain blood vessel elasticity, with mild cognitive impairment (MCI) and dementia. METHODS: Participants were enrolled in the Systolic Blood Pressure Intervention Trial Memory and Cognition in Decreased Hypertension (SPRINT-MIND) magnetic resonance imaging substudy. Baseline CVR in Alzheimer's disease (AD) signature regions were primary variables of interest. The occipital pole and postcentral gyrus were included as control regions. RESULTS: Higher AD composite CVR was associated with lower MCI risk. No significant associations between inferior temporal gyrus, occipital pole, or postcentral gyrus CVR and MCI risk, or any regional CVR-combined risk associations were observed. DISCUSSION: CVR in AD signature regions is negatively associated with occurrence of MCI, implicating CVR in AD signature regions as a potential mechanism leading to cognitive impairment.

Associations of ApoE4 status and DHA supplementation on plasma and CSF lipid profiles and entorhinal cortex thickness.

Apolipoprotein ε allele 4 (APOE4) influences the metabolism of polyunsaturated fatty acids (PUFAs) such as docosahexaenoic acid (DHA). The entorhinal cortex (EC) in the brain is affected early in Alzheimer's disease and is rich in DHA. The purpose of this study is to identify the effect of APOE4 and DHA lipid species on the EC. Plasma and cerebrospinal fluid (CSF) lipidomic measurements were obtained from the DHA Brain Delivery Pilot, a randomized clinical trial of DHA supplementation (n = 10) versus placebo (n = 12) for six months in nondemented older adults stratified by APOE4 status. Wild-type C57B6/J mice were fed a high or low DHA diet for 6 months followed by plasma and brain lipidomic analysis. Levels of phosphatidylcholine DHA (PC 38:6) and cholesterol ester DHA (CE 22:6) had the largest increases in CSF following supplementation (P < 0.001). DHA within triglyceride (TG) lipids in CSF strongly correlated with corresponding plasma TG lipids, and differed by APOE4, with carriers having a lower increase than noncarriers. Changes in plasma PC DHA had the strongest association with changes in EC thickness in millimeters, independent of APOE4 status (P = 0.007). In mice, a high DHA diet increased PUFAs within brain lipids. Our findings demonstrate an exchange of DHA at the CSF-blood barrier and into the brain within all lipid species with APOE having the strongest effect on DHA-containing TGs. The correlation of PC DHA with EC suggests a functional consequence of DHA accretion in high density lipoprotein for the brain.

Particulate matter exposure and chronic cerebral hypoperfusion promote oxidative stress and induce neuronal and oligodendrocyte apoptosis in male mice.

Chronic cerebral hypoperfusion (CCH) may amplify the neurotoxicity of nanoscale particulate matter (nPM), resulting in white matter injury. This study characterized the joint effects of nPM (diameter ≤ 200 nm) and CCH secondary to bilateral carotid artery stenosis (BCAS) exposure on neuronal and white matter injury in a murine model. nPM was collected near a highway and re-aerosolized for exposure. Ten-week-old C57BL/6 male mice were randomized into four groups: filtered air (FA), nPM, FA + BCAS, and nPM + BCAS. Mice were exposed to FA or nPM for 10 weeks. BCAS surgeries were performed. Markers of inflammation, oxidative stress, and apoptosis were examined. nPM + BCAS exposure increased brain hemisphere TNFα protein compared to FA. iNOS and HNE immunofluorescence were increased in the corpus callosum and cerebral cortex of nPM + BCAS mice compared to FA. While nPM exposure alone did not decrease cortical neuronal cell count, nPM decreased corpus callosum oligodendrocyte cell count. nPM exposure decreased mature oligodendrocyte cell count and increased oligodendrocyte precursor cell count in the corpus callosum. nPM + BCAS mice exhibited a 200% increase in cortical neuronal TUNEL staining and a 700% increase in corpus callosum oligodendrocyte TUNEL staining compared to FA. There was a supra-additive interaction between nPM and BCAS on cortical neuronal TUNEL staining (2.6× the additive effects of nPM + BCAS). nPM + BCAS exposure increased apoptosis, neuroinflammation, and oxidative stress in the cerebral cortex and corpus callosum. nPM + BCAS exposure increased neuronal apoptosis above the separate responses to each exposure. However, oligodendrocytes in the corpus callosum demonstrated a greater susceptibility to the combined neurotoxic effects of nPM + BCAS exposure.

Comparison of Cardiovascular Disease Risk Factors Between 2 Subclinical Atherosclerosis Measures in Healthy Postmenopausal Women: Carotid Artery Wall Thickness and Echogenicity: Carotid Artery Wall Thickness and Echogenicity.

OBJECTIVES: Although carotid artery intima media thickness (CIMT) is a widely used determinant of subclinical atherosclerosis, gray-scale median of the intima-media complex (IM-GSM) of the common carotid artery is a relatively novel measure of echogenicity reflecting composition of the arterial wall. It is important to compare cardiovascular disease (CVD) risk factor correlates across CIMT and IM-GSM to determine whether these measures reflect distinct aspects of atherosclerosis. METHODS: Baseline information from a completed randomized clinical trial of 643 healthy postmenopausal women without clinically apparent CVD was included in this cross-sectional study. The women were on average ± SD 61 ± 7 years old, and predominantly non-Hispanic White. CIMT and IM-GSM were measured by high-resolution B-mode ultrasonogram in the far wall of the right common carotid artery. CVD risk factors including age, race, body mass index (BMI), smoking, weekly hours of physical activity, systolic (SBP) and diastolic blood pressure (DBP), lipids, glucose, and inflammatory markers were measured at baseline. Linear regression models were used to assess associations of CVD risk factors with CIMT and IM-GSM. Multivariable models included groups of risk factors added one at a time with and withoutbasic demographic factors (age, race, BMI, physical activity) with model R2 values compared between CIMT and IM-GSM. RESULTS: In multivariable analysis, age, Black race, BMI, SBP, and DBP were associated with CIMT (all P < .05), whereas age, Hispanic race, BMI, SBP, physical activity, LDL-cholesterol, and leptin were correlates of IM-GSM (all P < .05). Adjusted for age, race, BMI, and physical activity, the R2 value for SBP was greater for CIMT association, whereas R2 values for lipids, glucose, inflammatory markers, and adipokines were greater for IM-GSM associations. CONCLUSIONS: CIMT and IM-GSM assess different attributes of subclinical atherosclerosis. Integrating both measures may provide improved assessment of atherosclerosis in asymptomatic individuals.

Combined protein and transcript single-cell RNA sequencing in human peripheral blood mononuclear cells.

BACKGROUND: Cryopreserved peripheral blood mononuclear cells (PBMCs) are frequently collected and provide disease- and treatment-relevant data in clinical studies. Here, we developed combined protein (40 antibodies) and transcript single-cell (sc)RNA sequencing (scRNA-seq) in PBMCs. RESULTS: Among 31 participants in the Women's Interagency HIV Study (WIHS), we sequenced 41,611 cells. Using Boolean gating followed by Seurat UMAPs (tool for visualizing high-dimensional data) and Louvain clustering, we identified 50 subsets among CD4+ T, CD8+ T, B, NK cells, and monocytes. This resolution was superior to flow cytometry, mass cytometry, or scRNA-seq without antibodies. Combined protein and transcript scRNA-seq allowed for the assessment of disease-related changes in transcriptomes and cell type proportions. As a proof-of-concept, we showed such differences between healthy and matched individuals living with HIV with and without cardiovascular disease. CONCLUSIONS: In conclusion, combined protein and transcript scRNA sequencing is a suitable and powerful method for clinical investigations using PBMCs.

Information fraction estimation: Strategies for a phase 3 non-inferiority maximum duration design with time to event outcome.

There is considerable debate surrounding the choice of methods to estimate information fraction for futility monitoring in a randomized non-inferiority maximum duration trial. This question was motivated by a pediatric oncology study that aimed to establish non-inferiority for two primary outcomes. While non-inferiority was determined for one outcome, the futility monitoring of the other outcome failed to stop the trial early, despite accumulating evidence of inferiority. For a one-sided trial design for which the intervention is inferior to the standard therapy, futility monitoring should provide the opportunity to terminate the trial early. Our research focuses on the Total Control Only (TCO) method, which is defined as a ratio of observed events to total events exclusively within the standard treatment regimen. We investigate its properties in stopping a trial early in favor of inferiority. Simulation results comparing the TCO method with alternative methods, one based on the assumption of an inferior treatment effect (TH0), and the other based on a specified hypothesis of a non-inferior treatment effect (THA), were provided under various pediatric oncology trial design settings. The TCO method is the only method that provides unbiased information fraction estimates regardless of the hypothesis assumptions and exhibits a good power and a comparable type I error rate at each interim analysis compared to other methods. Although none of the methods is uniformly superior on all criteria, the TCO method possesses favorable characteristics, making it a compelling choice for estimating the information fraction when the aim is to reduce cancer treatment-related adverse outcomes.

Short-term outcomes from a pilot randomized controlled trial evaluating a virtual culturally adapted parenting intervention among Filipino parents of school-age children.

BACKGROUND: Filipino youth in the United States have significant behavioral health problems, including high rates of depression and suicidal behavior. Evidence-based parenting groups promote positive parenting practices and improve child behavior, yet few have been implemented online. OBJECTIVES: This study tested the short-term effects of a culturally adapted hybrid version of the Incredible Years School Age Basic and Advance Programs when delivered online among groups of parents of Filipino children and estimated intervention effect sizes. METHOD: Forty-nine parents of children aged 8-12 years recruited from schools, clinics, community organizations, and social media were randomly assigned to intervention or a wait-list control group that received literature from the American Academy of Pediatrics' Bright Futures program. The intervention consisted of 12 weekly 2-hr sessions. Parent perceptions of child behavior, parenting practices, and parenting stress as well as child surveys of anxiety and depression symptoms using validated assessments were obtained at baseline and 3-month postintervention follow-up. RESULTS: Forty parents completed both baseline and follow-up surveys with a mean attendance of 9.35 out of 12 sessions (n = 18). Analysis of covariance comparing 3-month (pre-/postintervention) changes revealed that the program had a statistically significant positive impact on parenting practices (positive verbal discipline, praise and incentives, and clear expectations); parent perceptions of their child's internalizing symptoms; and child-reported anxiety and depression symptoms. CONCLUSIONS: Results support the feasibility and potential effectiveness of offering an online evidence-based parenting program to promote positive parenting and decrease child anxiety and depression. This multigenerational approach to mental health prevention could potentially help address the growing mental health epidemic among youth. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Prevalence of dementia and mild cognitive impairment in indigenous Bolivian forager-horticulturalists.

INTRODUCTION: We evaluated the prevalence of dementia and mild cognitive impairment (MCI) in indigenous Tsimane and Moseten, who lead a subsistence lifestyle. METHODS: Participants from population-based samples ≥ 60 years of age (n = 623) were assessed using adapted versions of the Modified Mini-Mental State Examination, informant interview, longitudinal cognitive testing and brain computed tomography (CT) scans. RESULTS: Tsimane exhibited five cases of dementia (among n = 435; crude prevalence = 1.2%, 95% confidence interval [CI]: 0.4, 2.7); Moseten exhibited one case (among n = 169; crude prevalence = 0.6%, 95% CI: 0.0, 3.2), all age ≥ 80 years. Age-standardized MCI prevalence was 7.7% (95% CI: 5.2, 10.3) in Tsimane and 9.8% (95% CI: 4.9, 14.6) in Moseten. Cognitive impairment was associated with visuospatial impairments, parkinsonian symptoms, and vascular calcification in the basal ganglia. DISCUSSION: The prevalence of dementia in this cohort is among the lowest in the world. Widespread intracranial medial arterial calcifications suggest a previously unrecognized, non-Alzheimer's disease (AD) dementia phenotype.

Sonographic reference values for median nerve cross-sectional area: A meta-analysis of data from healthy individuals.

Objective: Establish median nerve CSA reference values and identify patient-level factors impacting diagnostic thresholds. Methods: Studies were identified through a robust search of multiple databases, and quality assessment was conducted using a modified version of the National Institute of Health Study Quality Assessment Tool for Observational Cohort and Cross-Sectional Studies. A meta-analysis was performed to identify normative values stratified by anatomic location. A meta-regression was conducted to examine heterogeneity effects of age, sex, and laterality. Results: The meta-analysis included 73 studies; 41 (56.2%) were high quality. The median nerve CSA [95% CI] was 6.46mm2 [6.09-6.84], 8.68mm2 [8.22-9.13], and 8.60mm2 [8.23-8.97] at the proximal forearm, the carpal tunnel inlet, and the proximal carpal tunnel, respectively. Age was positively associated with CSA at the level of proximal carpal tunnel (ß=0.03mm2, p=0.047). Men (9.42mm2, [8.06-10.78]) had statistically larger proximal tunnel CSA (p = 0.03) as compared to women (7.71mm2, [7.01-8.42]). No difference was noted in laterality. Conclusion: A reference value for median nerve CSA in the carpal tunnel is 8.60mm2. Adjustments may be required in pediatrics or older adults. The diagnostic threshold of 10.0mm2 for male patients should be cautiously applied as the upper limit of normative averages surpasses this threshold.

Lifetime personal cigarette smoking and risk of young-onset breast cancer by subtype among non-Hispanic Black and White women in the Young Women's Health History Study.

PURPOSE: To evaluate the association between lifetime personal cigarette smoking and young-onset breast cancer (YOBC; diagnosed <50 years of age) risk overall and by breast cancer (BC) subtype, and whether risk varies by race or socioeconomic position (SEP). METHODS: Data are from the Young Women's Health History Study (YWHHS), a population-based case-control study of non-Hispanic Black (NHB) and White (NHW) women, ages 20-49 years (n = 1812 cases, n = 1381 controls) in the Los Angeles County and Metropolitan Detroit Surveillance, Epidemiology, and End Results (SEER) registry areas, 2010-2015. Lifetime personal cigarette smoking characteristics and YOBC risk by subtype were examined using sample-weighted, multivariable-adjusted polytomous logistic regression. RESULTS: YOBC risk associated with ever versus never smoking differed by subtype (Pheterogeneity = 0.01) with risk significantly increased for Luminal A (adjusted odds ratio [aOR] 1.34; 95% confidence interval [CI] 1.06-1.68) and HER2-type (aOR 1.97; 95% CI 1.23-3.16), and no association with Luminal B or Triple Negative subtypes. Additionally, ≥30 years since smoking initiation (versus never) was statistically significantly associated with an increased risk of Luminal A (aOR 1.55; 95% CI 1.07-2.26) and HER2-type YOBC (aOR 2.77; 95% CI 1.32-5.79), but not other subtypes. In addition, among parous women, smoking initiated before first full-term pregnancy (versus never) was significantly associated with an increased risk of Luminal A YOBC (aOR 1.45; 95% CI 1.11-1.89). We observed little evidence for interactions by race and SEP. CONCLUSION: Findings confirm prior reports of a positive association between cigarette smoking and Luminal A YOBC and identify a novel association between smoking and HER2-type YOBC.

A Systematic Review and Meta-Analysis of Smoking and Circulating Sex Hormone Levels Among Premenopausal Women.

INTRODUCTION: It is established that higher prediagnostic circulating androgen and estrogen levels are associated with increased breast cancer risk in premenopausal and postmenopausal women. Pooled analyses in postmenopausal women report higher androgen and estrogen levels in current heavy cigarette smokers compared to nonsmokers. However, evidence among premenopausal women has been inconsistent. AIMS AND METHODS: We conducted a systematic review and meta-analysis to estimate differences in standardized mean hormone levels among current premenopausal smokers compared to nonsmokers. We reviewed and collated publications with sex hormone levels by smoking status among healthy, premenopausal women who were nonusers of exogenous hormones, including oral contraceptives, using PubMed through December 2019. A random effects meta-analysis was conducted to combine the standardized mean differences (SMD) and 95% confidence intervals (CIs) for estradiol, progesterone, testosterone, dehydroepiandrosterone, dehydroepiandrosterone-sulfate, and sex hormone-binding globulin by smoking status. Findings were summarized by menstrual cycle phase and overall. RESULTS: Nineteen published peer-reviewed articles were included. Significantly increased testosterone levels among smokers compared to nonsmokers were identified from cross-sectional studies with varied menstrual phase timing (SMD 0.14; 95% CI 0.0005, 0.29) and significantly increased dehydroepiandrosterone-sulfate levels were found over all phases (SMD 0.12; 95% CI 0.01, 0.22). However, substantial heterogeneity existed in these studies. CONCLUSIONS: This meta-analysis suggests that smoking may increase blood androgen levels in healthy premenopausal women which may increase breast cancer risk; however, the differences were modest. Larger and covariate-adjusted studies with standardized collection over the menstrual cycle are needed to better understand this relationship and to reduce heterogeneity. IMPLICATIONS: Existing research has described associations between high prediagnostic estradiol and androgen levels with breast cancer risk among premenopausal women and has established active smoking as a breast cancer risk factor. However, the smoking and circulating sex hormone associations among premenopausal women remain inadequately studied. In this meta-analysis, we identified an association between smoking and higher mean testosterone and dehydroepiandrosterone-sulfate levels with consideration of menstrual phase, providing additional information on smoking's potential pathway to premenopausal breast cancer.

Parental Perspectives on Immunizations: Impact of the COVID-19 Pandemic on Childhood Vaccine Hesitancy.

Childhood vaccine hesitancy has been studied extensively before the COVID-19 pandemic. The pandemic presented new barriers to pediatric vaccinations. Furthermore, the development of COVID-19 vaccines has complicated factors underlying vaccine hesitancy. We performed a cross-sectional mobile phone-based survey at Children's Hospital Los Angeles querying parents regarding perspectives on vaccines before and during the pandemic. Our primary aim was to understand the impact of the pandemic on routine childhood vaccine hesitancy. Secondarily, we examined intent to vaccinate, COVID-19 vaccine hesitancy, and key contributing demographic factors. Among 252 participants, we found overall increased childhood vaccine hesitancy (p = 0.006), increased risk perception (p = 0.006), and unchanged vaccine confidence during the COVID-19 pandemic. Increased hesitancy did not translate into decreased intent to vaccinate with routine childhood vaccines or influenza vaccines. During the pandemic, households with higher income (50-99 K, > 100 K) correlated with decreased routine childhood vaccine hesitancy, while Hispanic ethnicity and African American race had increased risk perception. For COVID-19 vaccine hesitancy, households with higher income (> 100 K) correlated with decreased hesitancy, while non-White ethnicity and race had increased risk perception. We found that routine childhood vaccine hesitancy increased during the COVID-19 pandemic, mainly due to increased risk perception. Key contributing demographic factors behind both childhood vaccine hesitancy and COVID-19 vaccine hesitancy included household income and race. Understanding factors behind routine childhood vaccine hesitancy is crucial to maintaining pediatric vaccination rates and promoting vaccine confidence during and after the COVID-19 pandemic.

Development of shoulder pain with job-related repetitive load: mechanisms of tendon pathology and anxiety.

BACKGROUND: The paucity of longitudinal clinical studies limits our understanding of the development of shoulder pain with repetitive shoulder tasks, and its association with underlying mind and body mechanisms. Tendon thickening characterizes painful shoulder supraspinatus tendinopathy, and the perception of pain can be affected by the presence of psychological factors such as anxiety and depression. This study determined the incidence of shoulder pain in novice individuals exposed to repetitive shoulder tasks, and the associated change in outcomes of supraspinatus tendon morphology and measures of anxiety and depression. METHODS: We recruited dental hygiene (DH) students (n = 45, novice and exposed to shoulder repetitive tasks) and occupational therapy (OT) students (n = 52, novice, but not exposed to shoulder repetitive tasks), following them over their first year of training. We measured shoulder pain, supraspinatus morphology via ultrasonography, and psychosocial distress via the Hospital Anxiety and Depression Scale. We compared the incidence of shoulder pain (defined as a change of visual analog scale for pain score greater than the minimal clinically important difference) between DH and OT students using Fisher exact test. We used mixed effects models to longitudinally compare the change in outcomes between 3 groups: DH students who develop and did not develop shoulder pain, and OT students. RESULTS: The incidence of shoulder pain is higher in DH students (relative risk = 4.0, 95% confidence interval [CI] 1.4, 11.4). After 1 year, DH students with pain had the greatest thickening of the supraspinatus (0.7 mm, 95% CI 0.4, 0.9). The change in supraspinatus thickness of DH students with pain was greater than both DH students with no pain (0.4 mm, 95% CI 0.1, 0.8) and OT students (0.9 mm, 95% CI 0.5, 1.2). Anxiety score increased 3.8 points (95% CI 1.6, 5.1) in DH students with pain, and 43% of DH students with pain had abnormal anxiety score at 1 year (relative risk = 2.9, 95% CI 1.0, 8.6). CONCLUSION: Our results provide support for the theoretical model of repetitive load as a mechanism of tendinopathy. The supraspinatus tendon thickens in the presence of repetitive tasks, and it thickens the most in those who develop shoulder pain. Concurrently, anxiety develops with shoulder pain, indicating a potential maladaptive central mechanism that may impact the perception of pain.

Gut microbiome in people living with HIV is associated with impaired thiamine and folate syntheses.

People living with HIV have a high incidence of cardiovascular and neurological diseases as comorbid disorders that are commonly linked to inflammation. While microbial translocation can augment inflammation during HIV infection, functional microbiome shifts that may increase pro-inflammatory responses have not been fully characterized. In addition, defining HIV-induced microbiome changes has been complicated by high variability among individuals. Here we conducted functional annotation of previously-published 16S ribosomal RNA gene sequences of 305 HIV positive and 249 negative individuals, with adjustment for geographic region, sex, sexual behavior, and age. Metagenome profiles were inferred from these individuals' 16S data. HIV infection was associated with impaired microbial vitamin B synthesis; around half of the gene families in thiamine and folate biosynthesis pathways were significantly less abundant in the HIV positive group than the negative control. These results are consistent with the high prevalence of thiamine and folate deficiencies in HIV infections. These HIV-induced microbiota shifts have the potential to influence cardiovascular and neurocognitive diseases, given the documented associations between B-vitamin deficiencies, inflammation, and these diseases. We also observed that most essential amino acid biosynthesis pathways were downregulated in the microbiome of HIV-infected individuals. Microbial vitamin B and amino acid synthesis pathways were not significantly recovered by antiretroviral treatment when we compared 262 ART positive and 184 ART negative individuals. Our meta-analysis provides a new outlook for understanding vitamin B and amino acid deficiencies in HIV patients, suggesting that interventions for reversing HIV-induced microbiome shifts may aid in lessening the burdens of HIV comorbidities.

Cytokine measurements add value to clinical variables in predicting outcomes for Staphylococcus aureus bacteremia.

BACKGROUND: We demonstrated that an early dysregulated cytokine response [high interleukin-10 to tissue necrosis factor (IL-10/TNF) ratio] predicted poor outcomes in patients with Staphylococcus aureus bacteremia (SAB). However, high interpatient variability in cytokine levels were observed. We grouped cytokine measurements in quartiles and assessed their additive value to clinical variables for predicting bacterial persistence and 30-day mortality in patients with SAB. METHODS: A multicenter observational study was conducted in hospitalized patients with SAB. Medical charts were reviewed for relevant information. Blood samples were obtained for cytokine measurements by ELISA: interferon-gamma (IFNγ), interleukin (IL-1ß, IL-6, IL-8, IL-10, IL-17) and tissue necrosis factor (TNF). Cytokine measurements were grouped into quartiles. Significant predictors for bacterial persistence and 30-day mortality were determined by multivariable logistic regression analysis. Area under the ROC curve (AUC) analysis was performed and predictive performance was compared between models with and without cytokine quartiles. RESULTS: Among 606 patients with SAB, a subset of patients (n = 239) had Day 1 cytokine measurements and clinical data collected; of those, 53 (22%) had persistent bacteremia. Accounting for septic shock, the addition of either IL-10 (AUC 0.708) or TNF (AUC 0.714) quartiles measured on Day 1 improved model performance for predicting bacterial persistence. All patients had Day 4 cytokine measurements; 52 patients (8.5%) died within 30-days of SAB onset. Inclusion of either IL-10 (AUC 0.873) or TNF (AUC 0.879) quartiles, but not both, measured on Day 4 to the significant clinical predictors (coronary artery disease, Pitt bacteremia score ≥ 4, and septic shock) improved model performance for mortality. CONCLUSIONS: IL-10 or TNF levels falling within the range in the upper quartiles, when combined with clinical variables, improved model performance for predicting outcomes, and may potentially be used to support aggressive management and biomarker-guided studies to evaluate the benefit of adjunctive immunotherapy for SAB in the future.