Systematic review and meta-analysis of the effects of menopause hormone therapy on cognition.

Introduction: Despite evidence from preclinical studies suggesting estrogen's neuroprotective effects, the use of menopausal hormone therapy (MHT) to support cognitive function remains controversial. Methods: We used random-effect meta-analysis and multi-level meta-regression to derive pooled standardized mean difference (SMD) and 95% confidence intervals (C.I.) from 34 randomized controlled trials, including 14,914 treated and 12,679 placebo participants. Results: Associations between MHT and cognitive function in some domains and tests of interest varied by formulation and treatment timing. While MHT had no overall effects on cognitive domain scores, treatment for surgical menopause, mostly estrogen-only therapy, improved global cognition (SMD=1.575, 95% CI 0.228, 2.921; P=0.043) compared to placebo. When initiated specifically in midlife or close to menopause onset, estrogen therapy was associated with improved verbal memory (SMD=0.394, 95% CI 0.014, 0.774; P=0.046), while late-life initiation had no effects. Overall, estrogen-progestogen therapy for spontaneous menopause was associated with a decline in Mini Mental State Exam (MMSE) scores as compared to placebo, with most studies administering treatment in a late-life population (SMD=-1.853, 95% CI -2.974, -0.733; P = 0.030). In analysis of timing of initiation, estrogen-progestogen therapy had no significant effects in midlife but was associated with improved verbal memory in late-life (P = 0.049). Duration of treatment >1 year was associated with worsening in visual memory as compared to shorter duration. Analysis of individual cognitive tests yielded more variable results of positive and negative effects associated with MHT. Discussion: These findings suggest time-dependent effects of MHT on certain aspects of cognition, with variations based on formulation and timing of initiation, underscoring the need for further research with larger samples and more homogeneous study designs.

Sex-specific associations of serum cortisol with brain biomarkers of Alzheimer's risk.

Emerging evidence implicates chronic psychological stress as a risk factor for Alzheimer's disease (AD). Herein, we examined the relationships between serum cortisol and multimodality brain AD biomarkers in 277 cognitively normal midlife individuals at risk for AD. Overall, higher cortisol was associated with lower total brain volume, lower glucose metabolism (CMRglc) in frontal cortex, and higher ß-amyloid (Aß) load in AD-vulnerable regions; and marginally associated with phosphocreatine to ATP ratios (PCr/ATP) in precuneus and parietal regions. Sex-specific modification effects were noted: in women, cortisol exhibited stronger associations with Aß load and frontal CMRglc, the latter being more pronounced postmenopause. In men, cortisol exhibited stronger associations with gray matter volume and PCr/ATP measures. Higher cortisol was associated with poorer delayed memory in men but not in women. Results were adjusted for age, Apolipoprotein E (APOE) epsilon 4 status, midlife health factors, and hormone therapy use. These results suggest sex-specific neurophysiological responses to stress, and support a role for stress reduction in AD prevention.

Histologic Manifestations of Gastrointestinal Adenovirus Infection After Stem Cell Transplant.

Adenovirus can cause severe disease in hematopoietic stem cell transplant (HSCT) patients. Histopathologic features of this infection in gastrointestinal biopsies and their distinction from graft-versus-host disease (GVHD) have been incompletely studied. We retrospectively identified patients with gastrointestinal adenovirus infection. H&E-stained sections were reviewed and the histologic features were recorded. The extent of immunostaining was determined using a semiquantitative scale and a maximum number of positive cells per high-power field. Information regarding the clinical course and endoscopic findings were obtained from the electronic medical records. The study group included 32 HSCT patients. Most (81%) presented with diarrhea and detectable virus in the serum. Twenty patients had multiorgan involvement in the gastrointestinal tract, mostly in the duodenum (62%) and colon (56%). Characteristic features included apoptotic epithelial cells with nuclear disarray (84%) and tufted aggregates of degenerating epithelial cells (69%), the latter of which was more commonly seen in the study population more than a control group of HSCT patients with GI involvement by GVHD. Viral inclusions were limited to the superficial epithelium in 59% of samples, and the density of viral inclusions within biopsies was variable (grade 1: 40%, grade 2: 38%, and grade 3: 22%). Following therapy, 10 patients (30%) improved and 14 (42%) had progressive disease. Patients with disease progression were often older (64 vs. 36 years, P =0.01) with higher serologic viral loads, prior history of GVHD, multifocal involvement, and increased number and density of immunoreactive nuclei. Adenovirus infection elicits a spectrum of histologic changes that can simulate or occur in combination with gastrointestinal GVHD. Patients with progressive disease are more likely to have high viral loads and more extensive infection of the gastrointestinal tract.

Human Cytomegalovirus mRNA-1647 Vaccine Candidate Elicits Potent and Broad Neutralization and Higher Antibody-Dependent Cellular Cytotoxicity Responses Than the gB/MF59 Vaccine.

BACKGROUND: MF59-adjuvanted gB subunit (gB/MF59) vaccine demonstrated approximately 50% efficacy against human cytomegalovirus (HCMV) acquisition in multiple clinical trials, suggesting that efforts to improve this vaccine design might yield a vaccine suitable for licensure. METHODS: A messenger RNA (mRNA)-based vaccine candidate encoding HCMV gB and pentameric complex (PC), mRNA-1647, is currently in late-stage efficacy trials. However, its immunogenicity has not been compared to the partially effective gB/MF59 vaccine. We assessed neutralizing and Fc-mediated immunoglobulin G (IgG) effector antibody responses induced by mRNA-1647 in both HCMV-seropositive and -seronegative vaccinees from a first-in-human clinical trial through 1 year following third vaccination using a systems serology approach. Furthermore, we compared peak anti-gB antibody responses in seronegative mRNA-1647 vaccinees to that of seronegative gB/MF59 vaccine recipients. RESULTS: mRNA-1647 vaccination elicited and boosted HCMV-specific IgG responses in seronegative and seropositive vaccinees, respectively, including neutralizing and Fc-mediated effector antibody responses. gB-specific IgG responses were lower than PC-specific IgG responses. gB-specific IgG and antibody-dependent cellular phagocytosis responses were lower than those elicited by gB/MF59. However, mRNA-1647 elicited higher neutralization and antibody-dependent cellular cytotoxicity (ADCC) responses. CONCLUSIONS: Overall, mRNA-1647 vaccination induced polyfunctional and durable HCMV-specific antibody responses, with lower gB-specific IgG responses but higher neutralization and ADCC responses compared to the gB/MF59 vaccine. CLINICAL TRIALS REGISTRATION: NCT03382405 (mRNA-1647) and NCT00133497 (gB/MF59).

Systematic review and meta-analysis of the effects of menopause hormone therapy on risk of Alzheimer's disease and dementia.

Introduction: Despite a large preclinical literature demonstrating neuroprotective effects of estrogen, use of menopausal hormone therapy (HT) for Alzheimer's disease (AD) risk reduction has been controversial. Herein, we conducted a systematic review and meta-analysis of HT effects on AD and dementia risk. Methods: Our systematic search yielded 6 RCT reports (21,065 treated and 20,997 placebo participants) and 45 observational reports (768,866 patient cases and 5.5 million controls). We used fixed and random effect meta-analysis to derive pooled relative risk (RR) and 95% confidence intervals (C.I.) from these studies. Results: Randomized controlled trials conducted in postmenopausal women ages 65 and older show an increased risk of dementia with HT use compared with placebo [RR = 1.38, 95% C.I. 1.16-1.64, p < 0.001], driven by estrogen-plus-progestogen therapy (EPT) [RR = 1.64, 95% C.I. 1.20-2.25, p = 0.002] and no significant effects of estrogen-only therapy (ET) [RR = 1.19, 95% C.I. 0.92-1.54, p = 0.18]. Conversely, observational studies indicate a reduced risk of AD [RR = 0.78, 95% C.I. 0.64-0.95, p = 0.013] and all-cause dementia [RR = .81, 95% C.I. 0.70-0.94, p = 0.007] with HT use, with protective effects noted with ET [RR = 0.86, 95% C.I. 0.77-0.95, p = 0.002] but not with EPT [RR = 0.910, 95% C.I. 0.775-1.069, p = 0.251]. Stratified analysis of pooled estimates indicates a 32% reduced risk of dementia with midlife ET [RR = 0.685, 95% C.I. 0.513-0.915, p = 0.010] and non-significant reductions with midlife EPT [RR = 0.775, 95% C.I. 0.474-1.266, p = 0.309]. Late-life HT use was associated with increased risk, albeit not significant [EPT: RR = 1.323, 95% C.I. 0.979-1.789, p = 0.069; ET: RR = 1.066, 95% C.I. 0.996-1.140, p = 0.066]. Discussion: These findings support renewed research interest in evaluating midlife estrogen therapy for AD risk reduction.

Improved Utilization of Serial Testing Without Increased Admissions after Implementation of High-Sensitivity Troponin I: a Controlled Retrospective Cohort Study.

BACKGROUND: Guidelines recommend high-sensitivity cardiac troponin (hs-cTn) for diagnosis of myocardial infarction. Use of hs-cTn is increasing across the U.S., but questions remain regarding clinical and operational impact. Prior studies have had methodologic limitations and yielded conflicting results. OBJECTIVE: To evaluate the impact of transitioning from conventional cardiac troponin (cTn) to hs-cTn on test and resource utilization, operational efficiency, and patient safety. DESIGN: Retrospective cohort study in two New York City hospitals during the months before and after transition from conventional cTn to hs-cTn at Hospital 1. Hospital 2 served as a control. PARTICIPANTS: Consecutive emergency department (ED) patients with at least one cTn test resulted. INTERVENTION: Multifaceted hs-cTn intervention bundle, including a 0/2-h diagnostic algorithm for non-ST-elevation myocardial infarction, an educational bundle, enhancements to the electronic medical record, and nursing interventions to facilitate timed sample collection. MAIN MEASURES: Primary outcomes included serial cTn test utilization, probability of hospital admission, ED length of stay (LOS), and among discharged patients, probability of ED revisit within 72 h resulting in hospital admission. Multivariable regression models adjusted for age, sex, temporal trends, and interhospital differences. KEY RESULTS: The intervention was associated with increased use of serial cTn testing (adjusted risk difference: 48 percentage points, 95% CI: 45-50, P < 0.001) and ED LOS (adjusted geometric mean difference: 50 min, 95% CI: 50-51, P < 0.001). There was no significant association between the intervention and probability of admission (adjusted relative risk [aRR]: 0.99, 95% CI: 0.89-1.1, P = 0.81) or probability of ED revisit within 72 h resulting in admission (aRR: 1.1, 95% CI: 0.44-2.9, P = 0.81). CONCLUSIONS: Implementation of a hs-cTn intervention bundle was associated with an improvement in serial cTn testing, a neutral effect on probability of hospital admission, and a modest increase in ED LOS.

Return of the Flap; The Empire State Mandate: A Multi-decade Multi-institutional Analysis of the 2010 New York State Legislature's Impact on Postmastectomy Immediate Flap-Based Reconstruction.

PURPOSE: Immediate postmastectomy breast reconstruction plays an integral role in patient care because of its psychosocial benefits. New York State (NYS) passed the 2010 Breast Cancer Provider Discussion Law with the aim of increasing patient awareness of reconstructive options through mandating plastic surgery referral at the time of cancer diagnosis. Short-term analysis of the years surrounding implementation suggests the law increased access to reconstruction, especially for certain minority groups. However, given the continued presence of disparities in access to autologous reconstruction, we aimed to investigate the longitudinal effects of the bill on access to autologous reconstruction along various sociodemographic cohorts. METHODS: Retrospective review identified demographic, socioeconomic, and clinical data for patients undergoing mastectomy with immediate reconstruction at Weill Cornell Medicine and Columbia University Irving Medical Center from 2002 to 2019. Primary outcome was receiving implant or autologous-based reconstruction. Subgroup analysis was based on sociodemographic factors. Multivariate logistic regression identified predictors of autologous reconstruction. Interrupted time series modeling analyzed differences in reconstructive trends for subgroups before and after the 2011 implementation of the NYS law. RESULTS: We included 3178 patients; 2418 (76.1%) and 760 (23.9%) patients underwent implant and autologous-based reconstruction, respectively. Multivariate analysis indicated that race, Hispanic status, and income were not predictors of autologous reconstruction. Interrupted time series showed that with each year leading up to 2011 implementation, patients were 19% less likely to receive autologous-based reconstruction. Following implementation, there was a 34% increase in the odds of receiving autologous-based reconstruction with each passing year. Following implementation, Asian American and Pacific Islander patients experienced a 55% greater increase in the rate of flap reconstruction than White patients. Following implementation, the highest-income quartile experienced a 26% greater increase in the rate of autologous-based reconstruction compared with the lowest-income quartile. After implementation, Hispanic patients experienced a 30% greater decrease in the rate of autologous-based reconstruction compared with non-Hispanic patients. CONCLUSIONS: Our data indicate the long-term efficacy of the NYS Breast Cancer Provider Discussion Law in increasing access to autologous-based reconstruction, especially for certain minority groups. These findings underscore the importance of this bill and encourage its adoption into other states.

In vivo Brain Estrogen Receptor Expression By Neuroendocrine Aging And Relationships With Gray Matter Volume, Bio-Energetics, and Clinical Symptomatology.

17ß-estradiol,the most biologically active estrogen, exerts wide-ranging effects in brain through its action on estrogen receptors (ERs), influencing higher-order cognitive function and neurobiological aging. However, our knowledge of ER expression and regulation by neuroendocrine aging in the living human brain is limited. This in vivo multi-modality neuroimaging study of healthy midlife women reveals progressively higher ER density over the menopause transition in estrogen-regulated networks. Effects were independent of age and plasma estradiol levels, and were highly consistent, correctly classifying all women as being post-menopausal or not. Higher ER density was generally associated with lower gray matter volume and blood flow, and with higher mitochondria ATP production, possibly reflecting compensatory mechanisms. Additionally, ER density predicted changes in thermoregulation, mood, cognition, and libido. Our data provide evidence that ER density impacts brainstructure, perfusion and energy production during female endocrine aging, with clinical implications for women's health.

Sex and menopause impact 31P-Magnetic Resonance Spectroscopy brain mitochondrial function in association with 11C-PiB PET amyloid-beta load.

Increasing evidence implicates sex and endocrine aging effects on brain bioenergetic aging in the greater lifetime risk of Alzheimer's disease (AD) in women. We conducted 31Phosphorus Magnetic Resonance Spectroscopy (31P-MRS) to assess the impact of sex and menopause on brain high-energy phosphates [adenosine triphosphate (ATP), phosphocreatine (PCr), inorganic phosphate (Pi)] and membrane phospholipids [phosphomonoesters/phosphodiesters (PME/PDE)] in 216 midlife cognitively normal individuals at risk for AD, 80% female. Ninety-seven participants completed amyloid-beta (Aß) 11C-PiB PET. Women exhibited higher ATP utilization than men in AD-vulnerable frontal, posterior cingulate, fusiform, medial and lateral temporal regions (p < 0.001). This profile was evident in frontal cortex at the pre-menopausal and peri-menopausal stage and extended to the other regions at the post-menopausal stage (p = 0.001). Results were significant after multi-variable adjustment for age, APOE-4 status, midlife health indicators, history of hysterectomy/oophorectomy, use of menopause hormonal therapy, and total intracranial volume. While associations between ATP/PCr and Aß load were not significant, individuals with the highest Aß load were post-menopausal and peri-menopausal women with ATP/PCr ratios in the higher end of the distribution. No differences in Pi/PCr, Pi/ATP or PME/PDE were detected. Outcomes are consistent with dynamic bioenergetic brain adaptations that are associated with female sex and endocrine aging.