White matter hyperintensity volume modifies the association between CSF vascular inflammatory biomarkers and regional FDG-PET along the Alzheimer's disease continuum.

In older adults with abnormal levels of Alzheimer's disease neuropathology, lower cerebrospinal fluid (CSF) vascular endothelial growth factor (VEGF) levels are associated with lower [¹8F]-fluorodeoxyglucose positron emission tomography (FDG-PET) signal, but whether this association is (1) specific to VEGF or broadly driven by vascular inflammation, or (2) modified by vascular risk (e.g., white matter hyperintensities [WMHs]) remains unknown. To address this and build upon our past work, we evaluated whether 5 CSF vascular inflammation biomarkers (vascular cell adhesion molecule 1, VEGF, C-reactive protein, fibrinogen, and von Willebrand factor)-previously associated with CSF amyloid levels-were related to FDG-PET signal and whether WMH volume modified these associations in 158 Alzheimer's Disease Neuroimaging Initiative participants (55-90 years old, 39 cognitively normal, 80 mild cognitive impairment, 39 Alzheimer's disease). We defined regions both by cortical boundary and by the 3 major vascular territories: anterior, middle, and posterior cerebral arteries. We found that WMH volume had interactive effects with CSF biomarkers (VEGF and C-reactive protein) on FDG-PET throughout the cortex in both vascular territories and conventionally defined regions of interest.

Midlife body mass index, central adiposity and neuropsychological performance over 10 years in women living with and without HIV.

Background and objective: Observations of overweight and obesity in association with neuropsychological performance (NP) vary over the adult life course depending on baseline levels, biological sex, age, race, temporality of measurements, and other factors. Therefore, similar published analyses across cohorts are inconsistent. In our sample of women living with HIV (WLWH) and women without HIV (WWOH), we conducted comparable analyses as those published in men with and without HIV. We examined cross-sectional and longitudinal associations between body mass index (BMI) and waist circumference (WC) and NP. Methods: Four hundred thirty two 432 virologically-suppressed WLWH and 367 WWOH, ≥40 years in the Women's Interagency HIV Study (WIHS) with anthropometry and NP assessments every two years from 2009-2019 were included in the study. Demographically-adjusted T-scores were calculated for six NP domains: learning, memory, executive function, processing speed, attention and working memory, and motor function. Multivariable linear regression models stratified by HIV status were used to examine cross-sectional associations of BMI and WC by NP domain; repeated measures analyses assessed baseline BMI and WC in association with longitudinal change in NP. Covariates included sociodemographic, behavioral, and HIV-related characteristics. Results: At baseline among all women, the median age was 45 years, 65% were Non-Latinx Black women, and 45% were obese women. Obese WLWH (BMI≥30.0 kg/m2) had poorer executive function (ß=-2.27, 95%CI [-4.46, -0.07]) versus WLWH with healthy BMI (18.5-24.9 kg/m2). Longitudinally over ~8 years, obese versus overweight WWOH improved on memory (ß=2.19, 95%CI [0.13, 4.26]), however overweight versus healthy WWOH experienced declining memory (ß= -2.67, 95%CI [-5.40, -0.07]). Increasing WC was associated with declining executive, processing speed, and motor function (p's<0.05); an at-risk WC was associated with improved memory (ß=1.81, 95%CI [0.19, 3.44]) among WWOH. Among WLWH, increasing BMI was associated with improved learning (ß=0.07, 95%CI [0.00, 0.15]. Conclusion: Our cross-sectional and longitudinal analyses evaluating the associations of BMI and WC and NP were mixed compared to previous reports. This illustrates the importance of sociodemographic characteristics, baseline levels of exposures and outcomes, HIV status, temporality of measurements, and other factors when evaluating aging HIV epidemiology study results.

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.

Factors Associated With Agreement Between Parent and Childhood Cancer Survivor Reports on Child's Health Related Quality of Life.

Pediatric Health Related Quality of Life (HRQoL) among childhood cancer survivors (CCS) measures the impact of illness and treatment from the patient's perspective. However, parents often serve as proxies when the child cannot provide information directly. Studies of agreement between parents' proxy assessment and child's self-report have shown discrepancies. Understanding the reasons for discrepancies is under studied. Thus, this study examined the agreement of 160 parent-CCS dyads on the child's domains of HRQoL by mean difference, intra-class correlation coefficients, and Bland-Altman plots. Differences in agreement were assessed by patients' age, ethnicity, and whether or not they lived with their parents. Overall, the Physical Function Score showed good agreement between parents and CCS (ICC = 0.62), while the Social Function Score had fair agreement (ICC = 0.39). CCS were more likely to rate their Social Function Score higher than their parent. The lowest agreement for the Social Function Score was found for 18-20 years old's (ICC = .254) versus younger or older CCS, and among non-Hispanic whites (ICC = 0.301) versus Hispanics. Differences in agreement varied by patient age and ethnicity, suggesting that other factors, including emotional, familial, and cultural factors, may influence parental awareness of CCS HRQoL.

HIV infection and cardiovascular disease have both shared and distinct monocyte gene expression features: Women's Interagency HIV study.

Persistent inflammation contributes to the development of cardiovascular disease (CVD) as an HIV-associated comorbidity. Innate immune cells such as monocytes are major drivers of inflammation in men and women with HIV. The study objectives are to examine the contribution of circulating non-classical monocytes (NCM, CD14dimCD16+) and intermediate monocytes (IM, CD14+CD16+) to the host response to long-term HIV infection and HIV-associated CVD. Women with and without chronic HIV infection (H) were studied. Subclinical CVD (C) was detected as plaques imaged by B-mode carotid artery ultrasound. The study included H-C-, H+C-, H-C+, and H+C+ participants (23 of each, matched on race/ethnicity, age and smoking status), selected from among enrollees in the Women's Interagency HIV Study. We assessed transcriptomic features associated with HIV or CVD alone or comorbid HIV/CVD comparing to healthy (H-C-) participants in IM and NCM isolated from peripheral blood mononuclear cells. IM gene expression was little affected by HIV alone or CVD alone. In IM, coexisting HIV and CVD produced a measurable gene transcription signature, which was abolished by lipid-lowering treatment. In NCM, versus non-HIV controls, women with HIV had altered gene expression, irrespective of whether or not they had comorbid CVD. The largest set of differentially expressed genes was found in NCM among women with both HIV and CVD. Genes upregulated in association with HIV included several potential targets of drug therapies, including LAG3 (CD223). In conclusion, circulating monocytes from patients with well controlled HIV infection demonstrate an extensive gene expression signature which may be consistent with the ability of these cells to serve as potential viral reservoirs. Gene transcriptional changes in HIV patients were further magnified in the presence of subclinical CVD.

Malignancy Risk of Thyroid Nodules That Are Not Classifiable by the American Thyroid Association Ultrasound Risk Stratification System: A Systematic Review and Meta-Analysis.

Background: Sonographic evaluation is fundamental to thyroid nodule assessment. The American Thyroid Association (ATA) ultrasound risk stratification system (USRSS) is widely used, but the appearance of some nodules has been considered nonclassifiable (NC-ATA). The risk of malignancy (RoM) of NC-ATA nodules varies widely between studies, leading to uncertainty in clinical management. The aim of this study was to comprehensively evaluate the prevalence and malignancy risk of NC-ATA nodules. Methods: A systematic review was performed searching PubMed/MEDLINE and EMBASE to identify original studies of thyroid nodules classified using the ATA USRSS from 2016 to 2022 and reporting the outcome of NC-ATA nodules. Meta-analysis was conducted to obtain pooled RoM estimates and meta-regression sensitivity analyses were used to explore sources of between-study heterogeneity. Results: Of 6377 screened studies, 135 underwent full-text review, and 16 studies reporting 21,271 nodules were included. Within these, the pooled prevalence of NC-ATA nodules was 7.8% (1872 nodules; [confidence interval; CI 5.1-11.1]). The pooled RoM estimate for NC-ATA nodules was 20.3% [CI 13.0-28.7] and there was significant heterogeneity between studies (I2 = 92.8%, p < 0.001). NC-ATA nodule RoM estimates were significantly different by study type: single-center versus multicenter studies (24.8% vs. 12.3%, respectively, p = 0.031) and study design: retrospective versus prospective studies (25.1% vs. 8.5%, respectively, p = 0.003). No significant difference was observed in RoM based on inclusion of <1 cm nodules or geographic region. Meta-regression analysis showed study design and use of surgical histology for diagnostic criteria contributed significantly to differences in the reported RoM estimates. Conclusion: In this first meta-analysis comprehensively assessing the RoM of NC-ATA nodules, the malignancy risk was found to be comparable with the current ATA USRSS intermediate suspicion category. Significant heterogeneity was observed between studies and limits the interpretation of these results. In future iterations of the ATA USRSS that seek into incorporate categorization of NC-ATA nodules, these meta-analysis data may help to inform proper malignancy risk stratification. The study protocol was registered on PROSPERO, the international prospective register of systematic reviews (CRD42020182498), on July 14, 2020.

Long-term outcomes with the pulmonary autograft inclusion technique in adults with bicuspid aortic valves undergoing the Ross procedure.

OBJECTIVE: To compare outcomes with wrapped (pulmonary autograft inclusion) versus unwrapped techniques in adults with bicuspid aortic valves undergoing the Ross procedure. METHODS: Between 1992 and 2019, 129 adults with bicuspid aortic valves (aged ≥18 years) underwent the Ross procedure by a single surgeon. Patients were divided into those without autograft inclusion (unwrapped, n = 71) and those with autograft inclusion (wrapped, n = 58). Median follow-up was 10.3 years (interquartile range, 3.0-16.8 years). Need for autograft reintervention was analyzed using competing risks. RESULTS: Pre- and intraoperative characteristics as well as 30-day morbidity or mortality did not differ between cohorts. Survival at 1, 5, and 10 years, respectively, was 97.2%, 97.2%, and 95.6% in the unwrapped cohort and 100%, 100%, and 100% in the wrapped cohort (P = .15). Autograft valve failure occurred in 25 (35.2%) of the unwrapped and 3 (5.2%) of the wrapped patients. Competing risks analysis demonstrated the wrapped cohort to have a lower need for autograft reintervention (subhazard ratio, 0.28, 95% confidence interval, 0.08-0.91; P = .035). The cumulative incidence of autograft reintervention (death as a competing outcome) at 1, 5, and 10 years, respectively, was 10.2%, 14.9%, and 26.8% in the unwrapped cohort and 4.0%, 4.0%, and 4.0% in the wrapped cohort. CONCLUSIONS: In adults with bicuspid aortic valves, the Ross procedure with pulmonary autograft inclusion stabilizes the aortic root preventing dilatation and reduces the need for reoperation. The autograft inclusion technique allows the Ross procedure to be performed in this population with excellent long-term outcomes.

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.

Higher baseline levels of CSF inflammation increase risk of incident mild cognitive impairment and Alzheimer's disease dementia.

Introduction: Few studies have investigated how neuroinflammation early in the disease course may affect Alzheimer's disease (AD) progression over time despite evidence that neuroinflammation is associated with AD. Methods: Research participants with cerebrospinal fluid (CSF) biomarkers from the Alzheimer's Disease Neuroimaging Initiative (ADNI) were included in this study. Cox models were used to investigate whether baseline CSF neuroinflammation was associated with incident mild cognitive impairment (MCI) or AD. Moderating effects of sex and apolipoprotein E (APOE) ε4 were also examined. Results: Elevated levels of tumor necrosis factor α (TNF-α), interleukin (IL)-9, and IL-12p40 at baseline were associated with higher rates of conversion to MCI/AD. Interactions with sex and APOE ε4 were observed, such that women with elevated TNF-α and all APOE ε4 carriers with elevated IL-9 levels had shorter times to conversion. In addition, TNF-α mediated the relationship between elevated IL-12p40 and IL-9. Discussion: Elevated neuroinflammation markers are associated with incident MCI/AD, and the factors of sex and APOE ε4 status modify the time to conversion.

Neurotoxicity of Diesel Exhaust Particles.

BACKGROUND: Air pollution particulate matter (PM) is strongly associated with risks of accelerated cognitive decline, dementia and Alzheimer's disease. Ambient PM batches have variable neurotoxicity by collection site and season, which limits replicability of findings within and between research groups for analysis of mechanisms and interventions. Diesel exhaust particles (DEP) offer a replicable model that we define in further detail. OBJECTIVE: Define dose- and time course neurotoxic responses of mice to DEP from the National Institute of Science and Technology (NIST) for neurotoxic responses shared by DEP and ambient PM. METHODS: For dose-response, adult C57BL/6 male mice were exposed to 0, 25, 50, and 100µg/m3 of re-aerosolized DEP (NIST SRM 2975) for 5 h. Then, mice were exposed to 100µg/m3 DEP for 5, 100, and 200 h and assayed for amyloid-ß peptides, inflammation, oxidative damage, and microglial activity and morphology. RESULTS: DEP exposure at 100µg/m3 for 5 h, but not lower doses, caused oxidative damage, complement and microglia activation in cerebral cortex and corpus callosum. Longer DEP exposure for 8 weeks/200 h caused further oxidative damage, increased soluble Aß, white matter injury, and microglial soma enlargement that differed by cortical layer. CONCLUSION: Exposure to 100µg/m3 DEP NIST SRM 2975 caused robust neurotoxic responses that are shared with prior studies using DEP or ambient PM0.2. DEP provides a replicable model to study neurotoxic mechanisms of ambient PM and interventions relevant to cognitive decline and dementia.

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.

Effect of menopausal hormone therapy on methylation levels in early and late postmenopausal women.

BACKGROUND: Cardiovascular disease (CVD) remains the leading cause of death among postmenopausal women but standard primary prevention strategies in women are not as effective as in men. By comparison, the Early versus Late Intervention Trial with Estradiol (ELITE) study demonstrated that hormone therapy (HT) was associated with significant reduction in atherosclerosis progression in women who were within six years of menopause compared to those who were 10 or more years from menopause. These findings are consistent with other studies showing significant reductions in all-cause mortality and CVD with HT, particularly when initiated in women younger than 60 years of age or within 10 years since menopause. To explore the biological mechanisms underlying the age-related atheroprotective effects of HT, we investigated changes in methylation of blood cells of postmenopausal women who participated in ELITE. RESULTS: We first validated the epigenetic data generated from blood leukocytes of ELITE participants by replicating previously known associations between smoking and methylation levels at previously identified CpG sites, such as cg05575921 at the AHRR locus. An epigenome-wide association study (EWAS) evaluating changes in methylation through interactions with time-since-menopause and HT revealed two significantly associated CpG sites on chromosomes 12 (cg19552895; p = 1.1 × 10-9) and 19 (cg18515510; p = 2.4 × 10-8). Specifically, HT resulted in modest, but significant, increases in methylation levels at both CpGs but only in women who were 10 or more years since menopause and randomized to HT. Changes in carotid artery intima-media thickness (CIMT) from baseline to 36 months after HT were not significantly correlated with changes in methylation levels at either cg19552895 or cg18515510. Evaluation of other previously identified CpG sites at which methylation levels in either blood or vascular tissue were associated with atherosclerosis also did not reveal any differences in methylation as a function of HT and time-since-menopause or with changes in CIMT. CONCLUSIONS: We identified specific methylation differences in blood in response to HT among women who were 10 or more years since menopause. The functional consequence of these change with respect to atherosclerosis progression and protective effects of HT remains to be determined and will require additional studies.

Effect of the ABCA1 agonist CS-6253 on amyloid-ß and lipoprotein metabolism in cynomolgus monkeys.

BACKGROUND: Inducing brain ATP-binding cassette 1 (ABCA1) activity in Alzheimer's disease (AD) mouse models is associated with improvement in AD pathology. The purpose of this study was to investigate the effects of the ABCA1 agonist peptide CS-6253 on amyloid-ß peptides (Aß) and lipoproteins in plasma and cerebrospinal fluid (CSF) of cynomolgus monkeys, a species with amyloid and lipoprotein metabolism similar to humans. METHODS: CS-6253 peptide was injected intravenously into cynomolgus monkeys at various doses in three different studies. Plasma and CSF samples were collected at several time points before and after treatment. Levels of cholesterol, triglyceride (TG), lipoprotein particles, apolipoproteins, and Aß were measured using ELISA, ion-mobility analysis, and asymmetric-flow field-flow fractionation (AF4). The relationship between the change in levels of these biomarkers was analyzed using multiple linear regression models and linear mixed-effects models. RESULTS: Following CS-6253 intravenous injection, within minutes, small plasma high-density lipoprotein (HDL) particles were increased. In two independent experiments, plasma TG, apolipoprotein E (apoE), and Aß42/40 ratio were transiently increased following CS-6253 intravenous injection. This change was associated with a non-significant decrease in CSF Aß42. Both plasma total cholesterol and HDL-cholesterol levels were reduced following treatment. AF4 fractionation revealed that CS-6253 treatment displaced apoE from HDL to intermediate-density- and low density-lipoprotein (IDL/LDL)-sized particles in plasma. In contrast to plasma, CS-6253 had no effect on the assessed CSF apolipoproteins or lipids. CONCLUSIONS: Treatment with the ABCA1 agonist CS-6253 appears to favor Aß clearance from the brain.

Menopausal Hormone Replacement Therapy and Reduction of All-Cause Mortality and Cardiovascular Disease: It Is About Time and Timing.

ABSTRACT: The totality of evidence indicates menopausal hormone replacement therapy (HRT) effects are determined by timing of initiation according to age and/or time since menopause, underlying health of target tissue, and duration of therapy. Initiated in women at younger than 60 years and/or at or near menopause, HRT significantly reduces all-cause mortality and cardiovascular disease (CVD), whereas other primary CVD prevention therapies such as lipid-lowering fail to do so. The magnitude and type of HRT-associated risks, including breast cancer, stroke, and venous thromboembolism, are rare (<10 events/10,000 women), not unique to HRT, and comparable with other medications. Hormone replacement therapy is a sex-specific and time-dependent primary CVD prevention therapy that concomitantly reduces all-cause mortality, as well as other aging-related diseases with an excellent risk profile. Keeping in mind that prevention strategies must be personalized, health care providers and patients can use cumulated HRT data in making clinical decisions concerning chronic disease prevention including CVD and mortality reduction.

Effect of menopausal hormone therapy on arterial wall echomorphology: Results from the Early versus Late Intervention Trial with Estradiol (ELITE).

OBJECTIVE: To evaluate the effect of hormone therapy (HT) on arterial wall composition by ultrasound. BACKGROUND: The effect of HT on the progression of subclinical atherosclerosis has been well-described using measurements of common carotid artery (CCA) wall thickness. However, it is unknown whether the change in arterial wall anatomic structure is accompanied by an effect of HT on arterial wall composition. METHODS: A total of 643 healthy postmenopausal women divided into two strata according to the time since menopause (<6 years, the early-postmenopause group; or >10 years, the late-postmenopause group) were randomized to receive either active treatment or placebo. For hysterectomized women, the active treatment was oral micronized 17ß-estradiol 1 mg/day; for women with a uterus, 4% vaginal micronized progesterone gel 45 mg/day for 10 days each month was added to the estradiol regimen. Gray-scale median of the CCA intima-media complex (IM-GSM), a (unitless) measurement of arterial wall composition based on echogenicity, was determined by high-resolution B-mode ultrasonography. Lower IM-GSM, or less echogenicity, indicates more atherosclerosis. IM-GSM and serum estradiol (E2) concentration were assessed every 6 months over a median 4.8-year trial period. Linear mixed effects regression models were used for all analyses. RESULTS: Overall, IM-GSM progression/year had a negative trajectory, reflecting reduction in echogenicity over time (worsening atherosclerosis). HT effects on IM-GSM progression/year differed by postmenopause strata (interaction p-value = 0.02). IM-GSM progression/year (95% CI) in the early postmenopause group randomized to HT was -0.50 (-0.82, -0.18)/year compared with -1.47 (-1.81, -1.13)/year among those randomized to placebo (p-value <0.0001). In the late postmenopause group, the annual IM-GSM progression rate did not significantly differ between HT and placebo (p = 0.28). Higher mean on-trial E2 (pg/ml) levels were associated with higher IM-GSM progression, indicating less atherosclerosis progression in all women (ß (95% CI) = 0.006 (0.0003, 0.01), p = 0.04). For each pg/dl E2, IM-GSM progression/year was 0.007 ((-0.0002, 0.01), p = 0.056) in the early and 0.003 ((-0.006, 0.01), p = 0.50) in the late postmenopause group (interaction p-value = 0.51). CIMT progression rate (µm/year) was significantly inversely associated with the IM-GSM progression (ß (95% CI) = -4.63 (-5.6, -3.7), p < 0.001). CONCLUSIONS: HT, primarily with oral estradiol, reduced atherogenic progression of arterial wall composition in healthy postmenopausal women who were within 6 years from menopause. TRIAL REGISTRATION NUMBER: NCT01553084.

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.

Concentrations of endogenous sex steroid hormones and SHBG in healthy postmenopausal women.

Studies reporting age-specific reference ranges of endogenous sex steroid hormones in postmenopausal women are relatively scarce. If levels differ by age, dosing and treatment regimens should vary among postmenopausal women accordingly. Our objective was to establish reference ranges for sex steroid hormones and sex hormone binding globulin (SHBG) by age group and overall, and to investigate their association with demographic characteristics. Serum samples were obtained from 1207 healthy postmenopausal women aged 41-92, not using hormone therapy, at the baseline visit of 3 clinical trials. Estrone (E1), estradiol (E2), and total testosterone (T) were measured by radioimmunoassay with preceding purification steps; SHBG was measured by direct chemiluminescent immunoassay. Free T (FT) was calculated. Women were categorized by 5-year age groups. There was little change in the mean estrogen levels among the different age groups (E2: 9-12 pg/mL; E1: 33-35 pg/mL). Mean total T levels increased gradually with age from 19.9-26.2 ng/dL, but FT mean levels were relatively constant (3.7-4.6 pg/mL). Mean SHBG levels increased with age from 43-68 nmol/L. A generalized linear model tested the association of each demographic characteristic with the hormones and SHBG. A significant association was derived. Our study provides valuable insight into the profiles of serum sex steroid hormones and SHBG in different healthy postmenopausal women aged 41-92 years.

Resident education in congenital heart surgery does not compromise outcomes.

OBJECTIVE: Most of all congenital cardiac surgical programs participate in public outcomes reporting. The primary end point is transparency. In this era, academic programs with surgical residents face the challenge of producing outstanding results while allowing residents to learn by doing. We sought to understand the effect of education on our surgical outcomes. METHODS: We collected data for all American Board of Thoracic Surgery index cases done at our institution over a 10-year period. We identified 3406 cases and categorized them into 2 groups according to primary surgeon: attending (2269) versus resident (1137). In a multivariable logistic regression model we examined the effect of operating surgeon on in-hospital mortality, major morbidity, and length of stay. We used propensity score matching subsequently to balance differences between cohorts, and multivariable logistic regression was repeated. RESULTS: Using the entire cohort, multivariable logistic regression model adjusted for age, sex, weight, lack of preoperative comorbidity, presence of preoperative respiratory failure, The Society of Thoracic Surgeons--European Association for Cardio-Thoracic Surgery category, and need for deep hypothermic circulatory arrest, showed a higher odds of survival in the resident cohort (odds ratio, 1.484; 95% confidence interval, 0.998-2.206; P = .05). Propensity score matching identified 1137 pairs of attending and resident cases with well-balanced preoperative variables. Logistic regression modeling using the matched cohort showed equivalent 30-day mortality, 30-day major morbidity, and length of stay. CONCLUSIONS: There was no difference in mortality, major morbidity, or length of stay when similar cases were compared that were operated on by attendings versus those by a resident. Effectively educating congenital heart surgeons without compromising an operation's quality requires thoughtful approach, including case selection and graded responsibility.

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.

Telemedicine in Otolaryngology During COVID-19: Patient and Physician Satisfaction.

OBJECTIVE: To examine patient and physician satisfaction with telemedicine in otolaryngology during COVID-19 and identify associated factors. STUDY DESIGN: Prospective cohort study. SETTING: Tertiary care center. METHODS: Patient satisfaction was rated by patients (age ≥18 years) who had encounters from May to July 2020 (n = 407). Physician satisfaction was rated by 15 otolaryngologists for specific encounters delivered from May to June 2020 (n = 1011). Patient satisfaction was measured with a Press Ganey questionnaire and a Telemedicine Satisfaction Questionnaire. Mean Press Ganey satisfaction scores of telemedicine encounters during COVID-19 were compared with the pre-COVID-19 Press Ganey scores from in-person encounters (n = 3059) to test a noninferiority hypothesis. Physician satisfaction was measured with a Provider Satisfaction Questionnaire. RESULTS: The mean Press Ganey patient satisfaction score for telemedicine encounters was 94.5 (SD, 8.8), no worse than that for in-person encounters prior to COVID-19 at 93.7 (SD, 15.5; Δ = 0.8 [95% CI, -0.5 to 2.1, excluding the noninferiority margin of -1]). Encounters with videoconference (vs telephone) and patients reporting higher income were associated with higher Telemedicine Satisfaction Questionnaire scores. Physician satisfaction scores during COVID-19 with telemedicine encounters were overall high at 83.3 (95% CI, 77.5-89.1), slightly lower when compared with the scores with in-person encounters at 88.4 (95% CI, 82.5-94.3; Δ = -5.2 [95% CI, -6.6 to -3.8]). Encounters with videoconference (vs telephone) and patients with English as a preferred language and follow-up visits were associated with higher Provider Satisfaction Questionnaire scores. CONCLUSIONS: Telemedicine is a feasible alternative format in otolaryngology during COVID-19 with overall high patient and physician satisfaction. Patient satisfaction with telemedicine encounters during COVID-19 was no worse than in-person encounters prior to the pandemic. Physician satisfaction with telemedicine was relatively lower in comparison with in-person encounters.