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Larry W Hunter,1 Jon E Charlesworth,2 Sam Yu,3,4 John C Lieske,5,6 Virginia M Miller1,7 1Department of Surgery, 2Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, MN, USA; 3Lincoln University, Christchurch, New Zealand; 4Izon Science Ltd., Christchurch, New Zealand; 5Department of Internal Medicine, Division of Nephrology and Hypertension; 6Department of Laboratory Medicine and Pathology; 7Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, MN, USA Background: Nano-sized complexes of calcium phosphate mineral and proteins (calcifying nanoparticles [CNPs]) serve as mineral chaperones. Thus, CNPs may be both a result and cause of soft tissue calcification processes. This study determined if CNPs could augment calcification of arterial vascular smooth muscle cells in vitro. Methods: CNPs 210 nm in diameter were propagated in vitro from human serum. Porcine aortic smooth muscle cells were cultured for up to 28 days in medium in the absence (control) or presence of 2 mM phosphate ([P] positive calcification control) or after a single 3-day exposure to CNPs. Transmission electron-microscopy was used to characterize CNPs and to examine their cellular uptake. Calcium deposits were visualized by light microscopy and von Kossa staining and were quantified by colorimetry. Cell viability was quantified by confocal microscopy of live-/dead-stained cells and apoptosis was examined concurrently by fluorescent labeling of exposed phosphatidylserine. Results: CNPs, as well as smaller calcium crystals, were observed by transmission electron-microscopy on day 3 in CNP-treated but not P-treated cells. By day 28, calcium deposits were visible in similar amounts within multicellular nodules of both CNP- and P-treated cells. Apoptosis increased with cell density under all treatments. CNP treatment augmented the density of apoptotic bodies and cellular debris in association with mineralized multicellular nodules. Conclusion: Exogenous CNPs are taken up by aortic smooth muscle cells in vitro and potentiate accumulation of smooth-muscle-derived apoptotic bodies at sites of mineralization. Thus, CNPs may accelerate vascular calcification. Keywords: biomineralization, hydroxyapatite, vascular calcification, protein-mineral complex

Objectives:While global measures of cardiovascular (CV) risk are used to guide prevention and treatment decisions, these estimates fail to account for the considerable interindividual variability in pre-clinical risk status. This study investigated heterog

Observational and epidemiological studies suggest that menopausal hormone therapy (MHT) reduces cardiovascular disease (CVD) risk. However, results from prospective trials showed neutral or adverse effects most likely due to differences in participant demographics, such as age, timing of initiation of treatment, and preexisting cardiovascular disease, which reflected in part the lack of basic science information on mechanisms of action of hormones on the vasculature at the time clinical trials were designed. The Kronos Early Estrogen Replacement Study (KEEPS) is a prospective, randomized, controlled trial designed, using findings from basic science studies, to test the hypothesis that MHT when initiated early in menopause reduces progression of atherosclerosis. KEEPS participants are younger, healthier, and within 3 years of menopause thus matching more closely demographics of women in prior observational and epidemiological studies than women in the Women's Health Initiative hormone trials. KEEPS will provide information relevant to the critical timing hypothesis for MHT use in reducing risk for CVD.

Background: Atherogenic processes increase in women after menopause, when the risk of cardiovascular adverse events approaches that observed in age-matched men. In experimental animals, ovariectomy increases the platelet content of mitogenic cytokines, such as platelet-derived growth factor (PDGF), which when released into the blood or site of vascular injury, contribute to atherogenic processes. Objective: Experiments were designed to assess the sex distribution of inflammatorychemokines/cytokines, which may be released from platelets in the serum of middle-aged women and men in whom the extent of atherosclerotic coronary disease was defined by coronary arterial calcification (CAC). Methods: Blood was obtained from healthy white individuals recruited from the Mayo Clinic database. CAC was assessed by 64-slice computed tomography. Plasma cholesterol, lipids, and high-sensitivity C-reactive protein were analyzed by the Mayo Clinic Department of Laboratory Medicine and Pathology. Serum cytokines were determined using cytokine arrays. Cytokine expression was measured using dot blot analysis. Results: Of the 16 individuals (11 women, 5 men) who agreed to participate in the study, 1 woman was premenopausal, 1 was taking oral contraceptives, and 1 was receiving menopausal hormone therapy. One woman had an active infection and was eliminated from the study. CAC was detected in only 2 of the 11 women (scores of 46 and 56 Agatston units [AU]) but in 3 of the 5 men (scores of 3, 123, and 609 AU). Correcting for all other risk factors, expression of the chemokine RANTES (regulated on activation, normal, T-cell expressed and secreted; CCL5 [CC chemokine ligand 5]) was 100.98% greater in women than in men, and PDGF-BB was 55.30% greater in women than in men. Conclusions: This small pilot study found that the circulating chemokines/cytokines RANTES and PDGF-BB showed sex-disparate distribution between the women and men studied, and did not appear related to the degree of CAC. [ABSTRACT FROM AUTHOR]

Background: Although exogenous estrogenic therapies increase the risk of thrombosis, the effects of estrogen on formed elements of blood are uncertain.Objective: This article examines the genomic and nongenomic actions of estrogen on platelet phenotype that may contribute to increased thrombotic risk.Methods: To determine aggregation, secretion, protein expression, and thrombin generation, platelets were collected from experimental animals of varying hormonal status and from women enrolled in the Kronos Early Estrogen Prevention Study.Results: Estrogen receptor beta predominates in circulating platelets. Estrogenic treatment in ovariectomized animals decreased platelet aggregation and adenosine triphosphate (ATP) secretion. However, acute exposure to 17beta-estradiol did not reverse decreases in platelet ATP secretion invoked by lipopolysaccharide. Thrombin generation was positively correlated to the number of circulating microvesicles expressing phosphatidylserine.Conclusion: Assessing the effect of estrogen treatments on blood platelets may lead to new ways of identifying women at risk for adverse thrombotic events with such therapies. [ABSTRACT FROM AUTHOR]

Menopause is associated with vascular dysfunction. During the menopausal transition, endogenous oestradiol concentrations diminish. Oestradiol is vasoprotective because it has direct and indirect effects on the vasculature. The present study aimed to determine the effect of acute exogenous oestradiol on endothelium-dependent, endothelium independent and β 2 -adrenergic receptor-induced vasodilatation in females. Forearm blood flow (venous occlusion plethysmography) was measured during brachial intraarterial infusions of ACh (endothelium-dependent agonist), sodium nitroprusside (endothelium independent agonist) and terbutaline (β 2 -adrenergic receptor agonist) with and without concurrent infusion of 17β-oestradiol. Nine young premenopausal (age: 26 ± 4 years) and nine postmenopausal (PM, age: 58 ± 4 years, 8 ± 1 years post-menopause) females completed the study. Concurrent oestradiol infusion augmented the vasodilatory response to ACh, sodium nitroprusside and terbutaline in young premenopausal (all P < 0.05) but not older postmenopausal (all P > 0.05), females. Local infusion of exogenous 17β-oestradiol augmented endothelial and smooth muscle microvascular vasodilatation in premenopausal but not postmenopausal, females. KEY POINTS: Menopause is associated with vascular dysfunction. Because oestradiol has vasoprotective effects, the menopause-associated drop in oestradiol concentrations is hypothesized to contribute to vascular dysfunction during the menopause transition. The present study shows that local infusion of exogenous oestradiol augmented microvascular vasodilatation in premenopausal but not postmenopausal females., (© 2025 The Author(s). The Journal of Physiology published by John Wiley & Sons Ltd on behalf of The Physiological Society.)

Background: Our objective was to investigate patient-reported maternal and perinatal outcomes and survival among women undergoing aortic valve and/or aortic root replacement (AVR/ARR). Methods: This was a single-center observational study of U.S. women identified in our surgical/obstetric databases who underwent AVR/ARR between 1967 and 2019. Available, consenting patients participated in a telephone survey detailing patient-reported outcomes. The status of remaining individuals was verified through the Alabama Department of Public Health. Date of death, immediate and underlying cause of death, and death location were abstracted from death certificates. Results: Of 317 patients, 72 were confirmed living, 86 were deceased, and 159 were of unknown status. Mean age at first aortic valve replacement was 43 years. Of patients with known status ( n = 158), 33% were Black, and the majority received a mechanical valve (58%). Of 57 participants completing the survey, reported complications included miscarriage (30%), preterm birth (12%), preeclampsia (14%), antepartum maternal intensive care unit admissions (6%), and congenital heart disease in the neonate (8%). Most pregnancies preceded AVR (78%). Among 86 decedents, the average age of death was 52.5 years; the average time from AVR/ARR to death was 7 years. Of those who died, a higher proportion were Black (75%) and had aortic insufficiency (72%). Conclusions: Patients who underwent aortic valve surgery report high rates of maternal and perinatal complications, and death certificate data confirm high rates of racial disparities and death within a decade of surgery. Interventions are urgently needed to improve maternal and perinatal outcomes in individuals with aortic valve disease and to eliminate preventable racial disparities.

Objective: To assess the association of systolic and diastolic blood pressure (SBP and DBP) in recently menopausal women with white matter hyperintensity (WMH) volume later in life and determine whether short-term menopausal hormone therapy (mHT) modifies these associations., Methods: Kronos Early Estrogen Prevention Study (KEEPS) was a multicenter, randomized, double-blinded, placebo-controlled 4-year mHT trial (oral conjugated equine estrogens or transdermal 17β-estradiol). KEEPS continuation was an observational follow-up of the participants 10 years after the end of mHT. The associations between KEEPS baseline blood pressure (BP) with KEEPS continuation WMH volume were examined adjusting for covariates in model 1 (age, total intracranial volume, study site, mHT type) and model 2 (additionally conventional CVD risk factors). Interaction terms (BP × mHT type) were added into the linear regression models., Results: The mean ± SD ages of participants were 53 (±2) years at KEEPS baseline and 67 (±2) years at KEEPS continuation. Elevated BP at KEEPS baseline was associated with greater WMH volume measured 14 years later (model 1: SBP: β = 0.01 [95% CI, 0.001-0.01] and DBP: β = 0.01 [95% CI, 0.003-0.03]) and after additionally adjusting for CVD risk factors (model 2). We did not find any evidence that mHT versus placebo modified these associations. Topographically, higher BP was associated with greater periventricular WMH in the frontal and parietal lobes., Conclusion: Our findings suggest the importance of maintaining normal BP in recently postmenopausal women with low CVD risk, irrespective of short-term mHT usage, to potentially reduce the risk of WMH later in life., Competing Interests: Financial disclosure/conflicts of interest: K.K. served on the data safety monitoring board of Pfizer Inc. and Takeda Global Research & Development Center, Inc. She received research support from Avid Radiopharmaceuticals and Eli Lilly. She consults for Biogen. L.P. is a member of the advisory board for Flo Health, and receives ongoing funding from Win Fertility and Wolters Kluwer. C.G.S. reports receiving research funds from the NIH. M.L.S. reports receiving research funds from the DoD. J.A.F. receives ongoing institutional funding from the NIH. V.J.L. receives ongoing institutional funding from Siemens Healthcare, current institutional funding from Avid Pharmaceuticals, and past funding from PEERview, Inc. M.M.-A. receives ongoing funding from Biomedical Research Alliance of New York. M.I.C. receives institutional funding from the NIH and funding from UptoDate and American Society of Reproductive Medicine—Presidential Chain. F.N.N. receives funding from e-Bio Copr. (regulation of uterine contractility) and Interactome Biotherapeutics Corp. (exosome-related). E.K. receives ongoing funding from Mithra Pharma, current funding from Womaness, and past funding from Astellas Pharma. N.S. receives ongoing funding from Astellas, Amazon project Ember, and Ansch Labs, and is a member of the Menogenix scientific advisory board. The other authors have nothing to disclose., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of The Menopause Society.)

Background: Findings from Kronos Early Estrogen Prevention Study (KEEPS)-Cog trial suggested no cognitive benefit or harm after 48 months of menopausal hormone therapy (mHT) initiated within 3 years of final menstrual period. To clarify the long-term effects of mHT initiated in early postmenopause, the observational KEEPS Continuation Study reevaluated cognition, mood, and neuroimaging effects in participants enrolled in the KEEPS-Cog and its parent study the KEEPS approximately 10 years after trial completion. We hypothesized that women randomized to transdermal estradiol (tE2) during early postmenopause would show cognitive benefits, while oral conjugated equine estrogens (oCEE) would show no effect, compared to placebo over the 10 years following randomization in the KEEPS trial., Methods and Findings: The KEEPS-Cog (2005-2008) was an ancillary study to the KEEPS (NCT00154180), in which participants were randomized into 3 groups: oCEE (Premarin, 0.45 mg/d), tE2 (Climara, 50 μg/d) both with micronized progesterone (Prometrium, 200 mg/d for 12 d/mo) or placebo pills and patch for 48 months. KEEPS Continuation (2017-2022), an observational, longitudinal cohort study of KEEPS clinical trial, involved recontacting KEEPS participants approximately 10 years after the completion of the 4-year clinical trial to attend in-person research visits. Seven of the original 9 sites participated in the KEEPS Continuation, resulting in 622 women of original 727 being invited to return for a visit, with 299 enrolling across the 7 sites. KEEPS Continuation participants repeated the original KEEPS-Cog test battery which was analyzed using 4 cognitive factor scores and a global cognitive score. Cognitive data from both KEEPS and KEEPS Continuation were available for 275 participants. Latent growth models (LGMs) assessed whether baseline cognition and cognitive changes during KEEPS predicted cognitive performance at follow-up, and whether mHT randomization modified these relationships, adjusting for covariates. Similar health characteristics were observed at KEEPS randomization for KEEPS Continuation participants and nonparticipants (i.e., women not returning for the KEEPS Continuation). The LGM revealed significant associations between intercepts and slopes for cognitive performance across almost all domains, indicating that cognitive factor scores changed over time. Tests assessing the effects of mHT allocation on cognitive slopes during the KEEPS and across all years of follow-up including the KEEPS Continuation visit were all statistically nonsignificant. The KEEPS Continuation study found no long-term cognitive effects of mHT, with baseline cognition and changes during KEEPS being the strongest predictors of later performance. Cross-sectional comparisons confirmed that participants assigned to mHT in KEEPS (oCEE and tE2 groups) performed similarly on cognitive measures to those randomized to placebo, approximately 10 years after completion of the randomized treatments. These findings suggest that mHT poses no long-term cognitive harm; conversely, it provides no cognitive benefit or protective effects against cognitive decline., Conclusions: In these KEEPS Continuation analyses, there were no long-term cognitive effects of short-term exposure to mHT started in early menopause versus placebo. These data provide reassurance about the long-term neurocognitive safety of mHT for symptom management in healthy, recently postmenopausal women, while also suggesting that mHT does not improve or preserve cognitive function in this population., Competing Interests: K.K. served on the data safety monitoring board for Pfizer Inc. and Takeda Global Research & Development Center, Inc. She received research support from Avid. MM-A received consulting fees from the Biomedical Research Alliance of New York. Radiopharmaceuticals, Eli Lilly. She consults for Biogen., (Copyright: This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.)

Objective: This study aimed to determine long-term cardiometabolic effects of hormone therapies initiated within 3 years of onset of menopause after a 14-year follow-up study of participants of the Kronos Early Estrogen Prevention Study (KEEPS)., Methods: KEEPS was a multisite clinical trial that recruited recently menopausal women with good cardiovascular health for randomization to oral conjugated equine estrogens (Premarin, 0.45 mg/d) or transdermal 17β-estradiol (Climara, 50 μg/d) both with micronized progesterone (Prometrium, 200 mg/d) for 12 d/mo, or placebo pills and patch for 4 years. KEEPS continuation recontacted KEEPS participants 14 years after randomization and 10 years after the completion of the 4-year clinical trial to attend in-person clinic visits., Results: Participants of KEEPS continuation (n = 299 of the 727 KEEPS participants; 41%) had an average age of 67 years (range, 58-73 y). Measurements of systolic and diastolic blood pressures, waist-to-hip ratio, fasting levels of glucose, insulin, lipid profiles, and homeostasis model assessment of insulin resistance were not different among the treatment groups at either KEEPS baseline or at KEEPS continuation visits, or for change between these two visits. The frequency of self-reported diabetes ( P = 0.007) and use of diabetes medications was higher in the placebo than the oral conjugated equine estrogens ( P = 0.045) or transdermal 17β-estradiol ( P = 0.02) groups, but these differences were not supported by the laboratory measurements of glycemia or insulin resistance., Conclusions: There was no evidence of cardiovascular and/or metabolic benefits or adverse effects associated with 4 years use of oral or transdermal forms of hormone therapy by recently menopausal women with good cardiovascular health after 10 years., Competing Interests: Financial disclosure/conflicts of interest: Dr Kantarci served on the data safety monitoring board for Pfizer Inc. and Takeda Global Research & Development Center, Inc. She received research support from Avid Radiopharmaceuticals, Eli Lilly. She consults for Biogen. Dr Santoro is a member of the Scientific Advisory Boards for Astellas, Que Oncology, Amazon (Ember), and Menogenix, Inc. She is a consultant for Ansh Labs and has received grant support (to her institution) from Menogenix, Inc. Dr Kapoor is funded in part by the National Institute on Aging (NIA grant U54 AG044170). Dr Kapoor has no conflicts of interest directly related to the subject of this manuscript. However, over the past 36 months, she has had the following conflicts of interest: She has been a consultant for Astellas and Mithra Pharmaceuticals, Scynexis, and Womaness. She receives grant support form Mithra Pharmaceuticals. She has received payment for development of educational content from Med Learning Group and Academy of Continued Healthcare Learning. She has received honoraria for CME activity from PriMed and OBG Management. Dr Pal is a member of advisory board for Flo Health, receives ongoing funding from Springer, and has received funding in the past from Ferring. Dr Fields receives institutional grant funding from the National Institute of Health for three additional projects. Dr Malek-Ahmadi receives grant funding from Biomedical Research Alliance of New York, LLC. The other authors have nothing to disclose., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of The Menopause Society.)

Standard Palm Oil (SPO) is widely used as a food ingredient partially due to its unique thermophysical properties. However, the American Heart Association recommends a saturated fat consumption of <5% of the caloric intake per day. The OxG Palm hybrid yields oil known as "palm oil with a higher content of oleic acid" (HOPO), with <35% SFA and >50% oleic acid. Characterizing novel high oleic oils is the starting point to find processes that can functionalize them such as oleogelation. This study compared the thermophysical properties of HOPO to SPO using Differential Scanning Calorimetry, shear rheology, polarized light microscopy, and texture analysis to characterize the differences between these oils. HOPO had a lower onset crystallization temperature (Δ7 °C) and its rheological behavior followed similar trends to SPO; however, large viscosity offsets were observed and were correlated to differences in crystallization temperatures. The maximum peak force of SPO was an order of magnitude higher than that of HOPO. Overall similar trends between the oils were observed, but differences in firmness, crystal morphology, and viscosity were not linearly correlated with the offset in crystallization temperature. This study quantified differences between these oils that will better enable industry to use HOPO in specific applications.

Objective: The severity of menopause-related symptoms varies considerably among women. The determinants of this variation are incompletely understood. The aim of this study was to assess the association between genetic variation in estrogen metabolism and transport pathways and the severity of menopause symptoms., Methods: This was a cross-sectional study of 60 peri- and postmenopausal women in the Mayo Clinic RIGHT study (which involved sequencing of genes involved in drug metabolism and transport), who had also been evaluated in the Women's Health Clinic at Mayo Clinic in Rochester, MN. All participants completed the Menopause Rating Scale (MRS) for assessment of menopause symptoms, including hot flashes. The association between severity of menopause symptoms and the variation in genes encoding 8 enzymes and transporters involved in estrogen metabolism was evaluated., Results: Lower CYP3A4 activity and higher COMT activity were associated with lower severity of somatic menopause symptoms (p = 0.04 and 0.06, respectively). These associations did not persist after adjustment for hormone therapy use. No differences in MRS scores or hot flash severity were noted among other genetic variant groups. Age at natural menopause was not affected by variations in the genes studied., Conclusion: The current study did not show an association between genetic variation in estrogen metabolism and transport pathways and the severity of menopause symptoms. Further studies with larger sample sizes may be required to understand this potentially complex association., Competing Interests: Declaration of competing interest Dr. Kapoor is funded in part by the National Institute on Aging (NIA grant U54 AG044170). Dr. Kapoor has no conflicts of interest directly related to the subject of this manuscript. However, over the past 36 months she has had the following conflicts of interest: She has been a consultant for Astellas and Mithra Pharmaceuticals, Scynexis and Womaness. She receives grant support form Mithra Pharmaceuticals. She has received payment for development of educational content from Med Learning Group and Academy of Continued Healthcare Learning. She has received honoraria for CME activity from PriMed and OBG Management. JMK: Prior consulting for Proctor and Gamble, Triangle Insights Group. Medical editor for Everyday Health. All other authors have no financial relationships with any organizations that might have an interest in the submitted work in the previous 3 years, and no other relationships or activities that could appear to have influenced the submitted work. The content of this article is solely the responsibility of the authors and does not represent the official views of the National Institutes of Health (NIH), or of the Mayo Clinic., (Copyright © 2023 Elsevier B.V. All rights reserved.)

The rapid advancements in artificial intelligence (AI) technology in recent years have led to its integration into biomedical publishing. However, the extent to which AI has contributed to developing biomedical literature is unclear. This study aimed to identify trends in AI-generated content within peer-reviewed biomedical literature. We first tested the sensitivity and specificity of commercially available AI-detection software (Originality.AI, Collingwood, Ontario, Canada). Next, we conducted a MEDLINE (Medical Literature Analysis and Retrieval System Online) search to identify randomized controlled trials with available abstracts indexed between January 2020 and March 2023. We randomly selected 30 abstracts per quarter during this period and pasted the abstracts into the AI detection software to determine the probability of AI-generated content. The software yielded 100% sensitivity, 95% specificity, and excellent overall discriminatory ability with an area under the receiving operating curve of 97.6%. Among the 390 MEDLINE-indexed abstracts included in the analysis, the prevalence with a high probability (≥ 90%) of AI-generated text increased during the study period from 21.7% to 36.7% (p=0.01) based on a chi-square test for trend. The increasing prevalence of AI-generated text during the study period was also observed in various sensitivity analyses using AI probability thresholds ranging from 50% to 99% (all p≤0.01). The results of this study suggest that the prevalence of AI-assisted publishing in peer-reviewed journals has been increasing in recent years, even before the widespread adoption of ChatGPT (OpenAI, San Francisco, California, United States) and similar tools. The extent to which natural writing characteristics of the authors, utilization of common AI-powered applications, and introduction of AI elements during the post-acceptance publication phase influence AI detection scores warrants further study., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2023, Miller et al.)

Background The availability of large language models such as Chat Generative Pre-trained Transformer (ChatGPT, OpenAI) has enabled individuals from diverse backgrounds to access medical information. However, concerns exist about the accuracy of ChatGPT responses and the references used to generate medical content. Methods This observational study investigated the authenticity and accuracy of references in medical articles generated by ChatGPT. ChatGPT-3.5 generated 30 short medical papers, each with at least three references, based on standardized prompts encompassing various topics and therapeutic areas. Reference authenticity and accuracy were verified by searching Medline, Google Scholar, and the Directory of Open Access Journals. The authenticity and accuracy of individual ChatGPT-generated reference elements were also determined. Results Overall, 115 references were generated by ChatGPT, with a mean of 3.8±1.1 per paper. Among these references, 47% were fabricated, 46% were authentic but inaccurate, and only 7% were authentic and accurate. The likelihood of fabricated references significantly differed based on prompt variations; yet the frequency of authentic and accurate references remained low in all cases. Among the seven components evaluated for each reference, an incorrect PMID number was most common, listed in 93% of papers. Incorrect volume (64%), page numbers (64%), and year of publication (60%) were the next most frequent errors. The mean number of inaccurate components was 4.3±2.8 out of seven per reference. Conclusions The findings of this study emphasize the need for caution when seeking medical information on ChatGPT since most of the references provided were found to be fabricated or inaccurate. Individuals are advised to verify medical information from reliable sources and avoid relying solely on artificial intelligence-generated content., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2023, Bhattacharyya et al.)

The aim of this study is to demonstrate the safety and advantages of a multidisciplinary approach to surgical resection of mediastinal masses in children. Eight patients underwent resection of a mediastinal mass by a team involving both a pediatric general surgeon and pediatric cardiothoracic surgeon. One patient required rapid initiation of cardiopulmonary bypass to complete the tumor resection and repair an aortic injury that occurred when removing adherent tumor from the structure. Perioperative outcomes were excellent for all patients. This series shows that a multidisciplinary surgical approach can be potentially life saving.

Single ventricle (SV) cardiac lesions and tetralogy of Fallot (TOF) are both common forms of cyanotic congenital heart disease. With advances in perioperative care and longitudinal follow-up, survival of these patients has dramatically improved and the majority survive to adulthood. This study compares health-related quality of life (HRQoL) of adult SV and TOF patients to each other and the general population. HRQoL of all surviving, non-transplanted SV and TOF patients 21 years of age and older at our institution was assessed with the SF-36 questionnaire via phone. Additional data including demographic parameters and information related to comorbidities and healthcare utilization were also analyzed. Among 81 eligible SV patients and 207 TOF patients, 33 (41%) and 75 (36%) completed the SF-36 phone survey, respectively. The mean age of SV patients was 32 vs. 38 years in the TOF group (p=0.01). SV patients reported more hepatic, pulmonary, and renal comorbidities. TOF patients were more likely to complete advanced degrees and more likely to have children (p=0.03). SV physical functioning scores were worse compared to TOF. In other domains of the SF-36 questionnaire, SV and TOF scores were similar. Compared to the general population, both groups reported worse bodily pain and mental health, but other aspects of psychosocial and general health were comparable. Overall HRQoL is good for both SV and TOF patients through early and mid-adulthood. Some QoL metrics were modestly worse in the SV patients. While these patients may have some physical limitations, psychosocial wellbeing appears preserved., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Objectives: To examine associations of pituitary-ovarian hormone levels with cognition before and after different formulations of hormone therapy (HT) or placebo independent of treatment group., Methods: Recently menopausal, healthy women were randomized to 0.45 mg/day oral conjugated equine estrogens (o-CEE, n = 109), 50 μg/day transdermal 17β (tE2, n = 107) or placebo pills and patches (n = 146); women on active treatment received oral 200 mg/day micronized progesterone for 12 days per month. Levels of estrone, 17β-estradiol, follicle stimulating hormone, luteinizing hormone, androstenedione, and testosterone were determined prior to and after 48 months of study participation. Neuropsychological testing was administered at baseline, and months 18, 36 and 48. Latent growth curve models controlling for education level, age, APOE allele status, waist circumference, and treatment examined the trajectories of each cognitive domain after accounting for the effect of hormone levels at baseline and months 18, 36 and 48. A linear multivariate mixed model examined the effect of changes in hormone levels on changes in trajectories of complex attention tasks with varying degrees of difficulty., Results: All women were adherent to treatment at month 48. Higher baseline estrone levels were associated with poorer global cognition, auditory attention and working memory, visual attention, and executive function, but not working memory. Higher levels of baseline 17β-E2 were associated with poorer cognitive performance, with marginal significance at baseline in speeded language and mental flexibility (p = 0.013). Other hormone levels were not associated with cognition. Controlling for all treatments, hormone levels at baseline and at month 48 did not have any significant correlation with cognitive trajectories over time., Summary: In healthy, recently menopausal women, baseline estrone levels were inversely associated with selected cognitive factors independent of two types of HT or placebo during 4 years of follow-up. Baseline levels of the other pituitary-ovarian hormones studied were not associated with baseline cognition, nor were changes in any hormones associated with changes in cognition during the study. The marginal association between estradiol levels and cognitive factors warrants further investigation., Gov Numbers: NCT00154180, NCT00623311., Competing Interests: Kejal Kantarci serves on the data safety monitoring board for Takeda Global Research and Development Center, Inc.; receives research support from Avid Radiopharmaceuticals, Eli Lilly, the NIH, and the Alzheimer's Drug Discovery Foundation. Juliana M. Kling has been a prior consultant to Proctor & Gamble and Triangle Insights Group. Lubna Pal is on advisory board for Ferring and serves as a consultant to Flo Health. Other authors have no competing interests to disclose., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Aim: TransCon CNP is a novel prodrug designed to provide sustained release of C-type natriuretic peptide (CNP) for once-weekly therapy, addressing the pathology leading to aberrant skeletal development in achondroplasia. This phase 1 trial was initiated to assess the safety, tolerability, pharmacodynamics (PD) and pharmacokinetics (PK) of TransCon CNP., Methods: This randomized, placebo-controlled, single-ascending dose phase 1 trial was performed at two sites in Australia and enrolled 45 healthy adult males. Subjects received placebo or TransCon CNP (single-ascending dose cohorts [3, 10, 25, 75 or 150 μg CNP/kg]). The primary endpoint was frequency of adverse events and other safety outcomes. Other endpoints included PK and PD measured by cyclic guanosine-monophosphate (cGMP) and amino-terminal propeptide of CNP (NTproCNP)., Results: TransCon CNP provided continuous systemic exposure to CNP over at least 7 days post-dose. Plasma and urine levels of cGMP were significantly increased in subjects administered TransCon CNP at 75-150 μg CNP/kg, indicating target engagement of active CNP at the natriuretic peptide receptor-B (NPR-B) for at least 1 week post-dose. TransCon CNP was well-tolerated, with no serious treatment-emergent adverse events or discontinuations. Extensive cardiac safety assessments did not reveal any clinically relevant effects on electrocardiogram parameters, including heart rate, PR, QRS and QTcF intervals., Conclusions: Safety and PD data from this phase 1 trial support that TransCon CNP is well tolerated, with a PK profile compatible with a once-weekly dosing regimen. Further studies are ongoing to evaluate the potential of TransCon CNP to positively impact abnormal endochondral ossification in children with achondroplasia., (© 2022 The Authors. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)

Background: Intratumoral (IT) delivery of toll-like receptor (TLR) agonists has shown encouraging anti-tumor benefit in preclinical and early clinical studies. However, IT delivery of TLR agonists may lead to rapid effusion from the tumor microenvironment (TME), potentially limiting the duration of local inflammation and increasing the risk of systemic adverse events., Methods: To address these limitations, TransCon ™ TLR7/8 Agonist-an investigational sustained-release prodrug of resiquimod that uses a TransCon linker and hydrogel technology to achieve sustained and predictable IT release of resiquimod-was developed. TransCon TLR7/8 Agonist was characterized for resiquimod release in vitro and in vivo, in mice and rats, and was assessed for anti-tumor efficacy and pharmacodynamic activity in mice., Results: Following a single IT dose, TransCon TLR7/8 Agonist mediated potent tumor growth inhibition which was associated with sustained resiquimod release over several weeks with minimal induction of systemic cytokines. TransCon TLR7/8 Agonist monotherapy promoted activation of antigen-presenting cells in the TME and tumor-draining lymph nodes, with evidence of activation and expansion of CD8 + T cells in the tumor-draining lymph node and TME. Combination of TransCon TLR7/8 Agonist with systemic immunotherapy further promoted anti-tumor activity in TransCon TLR7/8 Agonist-treated tumors. In a bilateral tumor setting, combination of TransCon TLR7/8 Agonist with systemic IL-2 potentiated tumor growth inhibition in both injected and non-injected tumors and conferred protection against tumor rechallenge following complete regressions., Conclusions: Our findings show that a single dose of TransCon TLR7/8 Agonist can mediate sustained local release of resiquimod in the TME and promote potent anti-tumor effects as monotherapy and in combination with systemic immunotherapy, supporting TransCon TLR7/8 Agonist as a novel intratumoral TLR agonist for cancer therapy. A clinical trial to evaluate the safety and efficacy of TransCon TLR7/8 Agonist, as monotherapy and in combination with pembrolizumab, in cancer patients is currently ongoing (transcendIT-101; NCT04799054)., (© 2022. The Author(s).)

Objective: The relationships between cardiometabolic indices and cognition were examined in recently menopausal women., Methods: Cross-sectional analysis of baseline data from the KEEPS (Kronos Early Estrogen Prevention Study)-Cognitive ancillary study (n = 621). Cognitive performance was assessed by the Modified Mini Mental Status (3MS) score (primary outcome). Physical cardiometabolic indices included body mass index (BMI), waist circumference (WC), waist-to-hip ratio (WHR), and blood pressure (BP). Biochemical cardiometabolic indices included serum levels of high sensitivity C-reactive protein (hs-CRP), total cholesterol (TC), low-density lipoprotein (LDL-C), high-density lipoprotein (HDL-C), non-HDL (non-HDL-C), triglycerides (TG), fasting serum glucose (FSG), and insulin resistance (HOMA-IR). Socio-demographic variables included age, race/ethnicity, education, and lifestyle (physical activity, smoking). Central adiposity was defined as WC > 88 cm (>35 in) and WHR > 0.8. Separate stepwise multivariable analyses (GLM, ordinal logistic regression and logistic regression) assessed relationships between 3MS scores (as continuous, in tertiles and dichotomized at 90 respectively) with the measures of central adiposity (predictor variables); socio-demographic variables (age, time since menopause, race, educational status and lifestyle) and cardiometabolic variables (BP, lipids, FSG, HOMA-IR and hs-CRP) were examined as covariates. The final multivariable models included time since menopause, race, ethnicity, educational status, strenuous exercise, BMI ≥30 kg/m 2 , non-HDL-C and hs-CRP as covariates. Due to the high collinearity between the two indices of central adiposity, within each analytic strategy, separate models examined the respective associations of WC > 88 cm and WHR > 0.8 with 3MS score., Results: On adjusted analyses, indices of central adiposity were independent predictors of significantly lower 3MS scores (p < 0.05). Consistency in this relationship was observed across the three different multivariable regression analytic approaches (GLM, ordinal and logistic regression)., Conclusions: Among recently menopausal women, WC > 88 cm and WHR > 0.8 were associated with significantly lower cognitive function, as reflected by lower 3MS scores. The mechanisms that might explain the observed negative implications of central adiposity for cognitive function warrant further study., Competing Interests: LP-Consultant and advisory board member, Flo Health.GNP-Scientific and advisory board member, Astellas Pharmaceutical; research grant Merck Scientific.HST-Research grant, Abbvie.KM, MFS, JEM, MIC, EAB, RL, GNP, MSH, TTJ, CEG have nothing to disclose., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Background: Recombinant interleukin-2 (IL-2, aldesleukin) is an approved cancer immunotherapy but causes severe toxicities including cytokine storm and vascular leak syndrome (VLS). IL-2 promotes antitumor function of IL-2Rβ/γ + natural killer (NK) cells and CD8 + , CD4 + and gamma delta (γδ) T cells. However, IL-2 also potently activates immunosuppressive IL-2Rα + regulatory T cells (Tregs) and IL-2Rα + eosinophils and endothelial cells, which may promote VLS. Aldesleukin is rapidly cleared requiring frequent dosing, resulting in high C max likely potentiating toxicity. Thus, IL-2 cancer immunotherapy has two critical drawbacks: potent activation of undesired IL-2Rα + cells and suboptimal pharmacokinetics with high C max and short half-life., Methods: TransCon IL-2 β/γ was designed to optimally address these drawbacks. To abolish IL-2Rα binding yet retain strong IL-2Rβ/γ activity, IL-2 β/γ was created by permanently attaching a small methoxy polyethylene glycol (mPEG) moiety in the IL-2Rα binding site. To improve pharmacokinetics, IL-2 β/γ was transiently attached to a 40 kDa mPEG carrier via a TransCon (transient conjugation) linker creating a prodrug, TransCon IL-2 β/γ, with sustained release of IL-2 β/γ. IL-2 β/γ was characterized in binding and primary cell assays while TransCon IL-2 β/γ was studied in tumor-bearing mice and cynomolgus monkeys., Results: IL-2 β/γ demonstrated selective and potent human IL-2Rβ/γ binding and activation without IL-2Rα interactions. TransCon IL-2 β/γ showed slow-release pharmacokinetics with a low C max and a long (>30 hours) effective half-life for IL-2 β/γ in monkeys. In mouse tumor models, TransCon IL-2 β/γ promoted CD8 + T cell and NK cell activation and antitumor activity. In monkeys, TransCon IL-2 β/γ induced robust activation and expansion of CD8 + T cells, NK cells and γδ T cells, relative to CD4 + T cells, Tregs and eosinophils, with no evidence of cytokine storm or VLS. Similarly, IL-2 β/γ enhanced proliferation and cytotoxicity of primary human CD8 + T cells, NK cells and γδ T cells., Summary: TransCon IL-2 β/γ is a novel long-acting prodrug with sustained release of an IL-2Rβ/γ-selective IL-2. It has remarkable and durable pharmacodynamic effects in monkeys and potential for improved clinical efficacy and tolerability compared with aldesleukin. TransCon IL-2 β/γ is currently being evaluated in a Phase 1/2 clinical trial (NCT05081609)., Competing Interests: Competing interests: All authors are or were employees and/or stockholders of Ascendis Pharma and declare competing financial interests., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: There have been limited large scale studies assessing sex disparities in the outcomes of cardiac arrest (CA) complicating acute myocardial infarction (AMI)., Methods and Results: Using the National Inpatient Sample (2000-2017), we identified adult admissions (≥18 years) with AMI and CA. Outcomes of interest included sex disparities in coronary angiography (early [hospital day zero] and overall), time to angiography, percutaneous coronary angiography (PCI), mechanical circulatory support (MCS) use, in-hospital mortality, hospitalization costs, hospital length of stay and discharge disposition. In the period between January 1, 2000-December 31, 2017, 11,622,528 admissions for AMI were identified, of which 584,216 (5.0%) were complicated by CA. Men had a higher frequency of CA compared to women (5.4% vs. 4.4%; p < 0.001). Women were on average older (70.4 ± 13.6 vs 65.0 ± 13.1 years), of black race (12.6% vs 7.9%), with higher comorbidity, presenting with non-ST-segment-elevation AMI (36.4% vs 32.3%) and had a non-shockable rhythm (47.6% vs 33.3%); all p < 0.001. Women received less frequent coronary angiography (56.0% vs 66.2%), early coronary angiography (32.0% vs 40.2%), PCI (40.4% vs 49.7%), MCS (17.6% vs 22.0%), and CABG (8.3% vs 10.8%), with a longer median time to angiography (all p < 0.001). Women had higher in-hospital mortality (52.6% vs 40.6%, adjusted odds ratio 1.13 [95% confidence interval 1.11-1.14]; p < 0.001), shorter length of hospital stays, lower hospitalization costs and less frequent discharges to home., Conclusion: Despite no difference in guideline recommendations for men and women with AMI-CA, there appears to be a systematic difference in the use of evidence-based care that disadvantages women., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Despite significant progress in the care of patients suffering from cardiovascular disease, there remains a persistent sex disparity in the diagnosis, management, and outcomes of these patients. These sex disparities are seen across the spectrum of cardiovascular care, but, are especially pronounced in acute cardiovascular care. The spectrum of acute cardiovascular care encompasses critically ill or tenuous patients with cardiovascular conditions that require urgent or emergent decision-making and interventions. In this narrative review, the disparities in the clinical course, management, and outcomes of six commonly encountered acute cardiovascular conditions, some with a known sex-predilection will be discussed within the basis of underlying sex differences in physiology, anatomy, and pharmacology with the goal of identifying areas where improvement in clinical approaches are needed., (© The Author(s) 2021. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Context: For children with growth hormone deficiency (GHD), treatment burden with daily somatropin injections [human growth hormone (hGH)] is high, which may lead to poor adherence and suboptimal overall treatment outcomes. Lonapegsomatropin (TransCon hGH) is an investigational long-acting, once-weekly prodrug for the treatment of GHD., Objective: The objective of this study was to evaluate the efficacy and safety of once-weekly lonapegsomatropin vs daily somatropin., Design: The heiGHt trial was a randomized, open-label, active-controlled, 52-week Phase 3 trial (NCT02781727)., Setting: This trial took place at 73 sites across 15 countries., Patients: This trial enrolled and dosed 161 treatment-naïve, prepubertal patients with GHD., Interventions: Patients were randomized 2:1 to receive lonapegsomatropin 0.24 mg hGH/kg/week or an equivalent weekly dose of somatropin delivered daily., Main Outcome Measure: The primary end point was annualized height velocity (AHV) at week 52. Secondary efficacy end points included change from baseline in height SD scores (SDS)., Results: Least squares (LS) mean (SE) AHV at 52 weeks was 11.2 (0.2) cm/year for lonapegsomatropin vs 10.3 (0.3) cm/year for daily somatropin (P = 0.009), with lonapegsomatropin demonstrating both noninferiority and superiority over daily somatropin. LS mean (SE) height SDS increased from baseline to week 52 by 1.10 (0.04) vs 0.96 (0.05) in the weekly lonapegsomatropin vs daily somatropin groups (P = 0.01). Bone age/chronological age ratio, adverse events, tolerability, and immunogenicity were similar between groups., Conclusions: The trial met its primary objective of noninferiority in AHV and further showed superiority of lonapegsomatropin compared to daily somatropin, with similar safety, in treatment-naïve children with GHD., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Endocrine Society.)

Biological sex, fluctuations in sex steroid hormones throughout life and gender as a social construct all influence every aspect of health and disease. Yet, for decades, most basic and clinical studies have included only male individuals. As modern health care moves towards personalized medicine, it is clear that considering sex and hormonal status in basic and clinical studies will bring precision to the development of novel therapeutics and treatment paradigms. To this end, funding, regulatory and policy agencies now require inclusion of female animals and women in basic and clinical studies. However, inclusion of female animals and women often does not mean that information regarding potential hormonal interactions with pharmacological treatments or clinical outcomes is available. All sex steroid hormones can interact with receptors for drug targets, metabolism and transport. Genetic variation in receptors or in enzymatic function might contribute to sex differences in therapeutic efficacy and adverse drug reactions. Outcomes from clinical trials are often not reported by sex, and, if the data are available, they are not translated into clinical practice guidelines. This Review will provide a historical perspective for the current state of research related to hormone trials and provide concrete strategies that, if implemented, will improve the health of all people., (© 2021. Springer Nature Limited.)

Differences in patient characteristics, including age, sex, and race influence the safety and effectiveness of drugs, biologic products, and medical devices. Here we provide a summary of the topics discussed during the opening panel at the 2018 Johns Hopkins Center for Excellence in Regulatory Science and Innovation symposium on Assessing and Communicating Heterogeneity of Treatment Effects for Patient Subpopulations: Challenges and Opportunities. The goal of this session was to provide a brief overview of FDA-regulated therapeutics, including drugs, biologics and medical devices, and some of the major sources of heterogeneity of treatment effects (HTE) related to patient demographics, such as age, sex and race. The panel discussed the US Food and Drug Administration's role in reviewing and regulating drugs, devices, and biologic products and the challenges associated with ensuring that diverse patient populations benefit from these therapeutics. Ultimately, ensuring diverse demographic inclusion in clinical trials, and designing basic and clinical research studies to account for the intended patient population's age, sex, race, and genetic factors among other characteristics, will lead to better, safer therapies for diverse patient populations., (© 2021 John Wiley & Sons Ltd. This article has been contributed to by US Government employees and their work is in the public domain in the USA.)

Background: Although the overall gender gap in medicine is narrowing, significant gender disparities remain in the cardiothoracic surgery (CTS) field; women represent only 7% of practicing surgeons and 20% of residents. The purpose of this study was to identify gender differences in CTS exposure and interest among fourth year medical students applying to general surgery residency., Methods: An anonymous survey was emailed to general surgery residency applicants at a major academic program for the 2019 and 2020 application cycles. Data were stratified by gender and analyzed using the χ 2 and t tests., Results: Of the 303 responders to the survey, 44% were women. A total of 58% of women were unlikely to be interested in or were definitely not interested in pursuing a career in CTS compared with 35% of men (P < .05). Men were 2.5 times more likely than women to be interested in CTS (odds ratio, 2.5; 95% confidence interval, 1.5 to 4.1). More men had rotated through CTS (55% vs 44%; P = .04) and shadowed a cardiothoracic surgeon (41% vs 29%; P = .03). More than 30% of women interested in CTS reported mentorship as the most important factor in their decision. Mentorship and CTS rotations were both independently associated with CTS interest after adjusting for gender., Conclusions: Interest in CTS is disappointingly low among women and represents a troublesome disparity that must be addressed. Early exposure to CTS and more mentorship from cardiothoracic surgeons are critical to reverse the current trend. Further studies are necessary to determine factors limiting female exposure to CTS rotations and dissuading female applicants from pursuing careers in CTS., (Copyright © 2021 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Objectives: Sex as a biological variable affects response to opioids. However, few reports describe the prevalence of specific adverse reactions to commonly prescribed opioids in men and women separately. A large cohort was used to investigate sex differences in type and occurrence of adverse reactions associated with use of codeine, tramadol, oxycodone and hydrocodone., Design: Retrospective cohort study., Setting: Participants in the Right Drug, Right Dose, Right Time (RIGHT) Study., Participants: The medical records of 8457 participants in the RIGHT Study who received an opioid prescription between 1 January 2004 and 31 December 2017 were reviewed 61% women, 94% white, median age (Q1-Q3)=58 (47-66)., Primary and Secondary Outcome Measures: Adverse reactions including gastrointestinal, skin, psychiatric and nervous system issues were collected from the allergy section of each patient's medical record. Sex differences in the risk of adverse reactions due to prescribed opioids were modelled using logistic regression adjusted for age, body mass index, race and ethnicity., Results: From 8457 participants (of which 449 (5.3%) reported adverse reactions), more women (6.5%) than men (3.4%) reported adverse reactions to at least one opioid (OR (95% CI)=2.3 (1.8 to 2.8), p<0.001). Women were more likely to report adverse reactions to tramadol (OR (95% CI)=2.8 (1.8 to 4.4), p<0.001) and oxycodone (OR (95% CI)=2.2 (1.7 to 2.9), p<0.001). Women were more likely to report gastrointestinal (OR (95% CI)=3.1 (2.3 to 4.3), p<0.001), skin (OR (95% CI)=2.1 (1.4 to 3.3), p=0.001) and nervous system issues (OR (95% CI)=2.3 (1.3 to 4.2), p=0.004)., Conclusions: These findings support the importance of sex as a biological variable to be factored into pain management studies., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Purpose: The depth and breadth of clinical data within electronic health record (EHR) systems paired with innovative machine learning methods can be leveraged to identify novel risk factors for complex diseases. However, analysing the EHR is challenging due to complexity and quality of the data. Therefore, we developed large electronic population-based cohorts with comprehensive harmonised and processed EHR data., Participants: All individuals 30 years of age or older who resided in Olmsted County, Minnesota on 1 January 2006 were identified for the discovery cohort. Algorithms to define a variety of patient characteristics were developed and validated, thus building a comprehensive risk profile for each patient. Patients are followed for incident diseases and ageing-related outcomes. Using the same methods, an independent validation cohort was assembled by identifying all individuals 30 years of age or older who resided in the largely rural 26-county area of southern Minnesota and western Wisconsin on 1 January 2013., Findings to Date: For the discovery cohort, 76 255 individuals (median age 49; 53% women) were identified from which a total of 9 644 221 laboratory results; 9 513 840 diagnosis codes; 10 924 291 procedure codes; 1 277 231 outpatient drug prescriptions; 966 136 heart rate measurements and 1 159 836 blood pressure (BP) measurements were retrieved during the baseline time period. The most prevalent conditions in this cohort were hyperlipidaemia, hypertension and arthritis. For the validation cohort, 333 460 individuals (median age 54; 52% women) were identified and to date, a total of 19 926 750 diagnosis codes, 10 527 444 heart rate measurements and 7 356 344 BP measurements were retrieved during baseline., Future Plans: Using advanced machine learning approaches, these electronic cohorts will be used to identify novel sex-specific risk factors for complex diseases. These approaches will allow us to address several challenges with the use of EHR., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objectives: To compare antimicrobial and resource utilization with T2 Magnetic Resonance (T2MR) versus blood culture (BC) in patients with suspected bloodstream infection. Methods: We systematically searched MEDLINE, EMBASE, and CENTRAL for randomized trials or observational controlled studies of patients with suspected bloodstream infection receiving a diagnosis with T2MR or BC. Using an inverse variance meta-analysis model, we reported mortality using the risk ratio (RR) and the remaining outcomes as the mean difference (MD). Results: Fourteen studies were included in the meta-analysis. Time to detection (MD = -81 hours; p < 0.001) and time to species identification (MD = -77 hours; p < 0.001) were faster with T2MR. Patients testing positive on T2MR received targeted antimicrobial therapy faster (-42 hours; p < 0.001) and patients testing negative on T2MR were de-escalated from empirical therapy faster (-7 hours; p = 0.02) vs. BC. Length of intensive care unit stay (MD = -5.0 days; p = 0.03) and hospital stay (MD = -4.8 days; p = 0.03) were shorter with T2MR. Mortality rates were comparable between T2MR and BC (28.9% vs. 29.9%, RR = 1.02, p = 0.86). Conclusion: Utilization of T2MR for identification of bloodstream pathogens provides faster time to detection, faster transition to targeted microbial therapy, faster de-escalation of empirical therapy, shorter ICU and hospital stay, and with comparable mortality rate versus BC.

The Kronos Early Estrogen Prevention Study (KEEPS) was a randomized, double-blind, placebo-controlled trial designed to determine the effects of hormone treatments (menopausal hormone treatments [MHTs]) on the progression of carotid intima-medial thickness (CIMT) in recently menopausal women. Participants less than 3 years from menopause and without a history of overt cardiovascular disease (CVD), defined as no clinical CVD events and coronary artery calcium < 50 Agatston units, received either oral conjugated equine estrogens (0.45 mg/day) or transdermal 17β-estradiol (50 µg/day), both with progesterone (200 mg/day for 12 days/month), or placebo pills and patches for 4 years. Although MHT did not decrease the age-related increase in CIMT, KEEPS provided other important insights about MHT effects. Both MHTs versus placebo reduced the severity of menopausal symptoms and maintained bone density, but differed in efficacy regarding mood/anxiety, sleep, sexual function, and deposition of β-amyloid in the brain. Additionally, genetic variants in enzymes for metabolism and uptake of estrogen affected the efficacy of MHT for some aspects of symptom relief. KEEPS provides important information for use of MHT in clinical practice, including type, dose, and mode of delivery of MHT recently after menopause, and how genetic variants in hormone metabolism may affect MHT efficacy on specific outcomes.

Hormone therapy improves sleep in menopausal women and recent data suggest that transdermal 17β-estradiol may reduce the accumulation of cortical amyloid-β. However, how menopausal hormone therapies modify the associations of amyloid-β accumulation with sleep quality is not known. In this study, associations of sleep quality with cortical amyloid-β deposition and cognitive function were assessed in a subset of women who had participated in the Kronos early estrogen prevention study. It was a randomized, placebo-controlled trial in which recently menopausal women (age, 42-58; 5-36 months past menopause) were randomized to (1) oral conjugated equine estrogen (n = 19); (2) transdermal 17β-estradiol (tE2, n = 21); (3) placebo pills and patch (n = 32) for 4 years. Global sleep quality score was calculated using Pittsburgh sleep quality index, cortical amyloid-β deposition was measured with Pittsburgh compound-B positron emission tomography standard uptake value ratio and cognitive function was assessed in four cognitive domains 3 years after completion of trial treatments. Lower global sleep quality score (i.e., better sleep quality) correlated with lower cortical Pittsburgh compound-B standard uptake value ratio only in the tE2 group (r = 0.45, P = 0.047). Better global sleep quality also correlated with higher visual attention and executive function scores in the tE2 group (r = -0.54, P = 0.02) and in the oral conjugated equine estrogen group (r = -0.65, P = 0.005). Menopausal hormone therapies may influence the effects of sleep on cognitive function, specifically, visual attention and executive function. There also appears to be a complex relationship between sleep, menopausal hormone therapies, cortical amyloid-β accumulation and cognitive function, and tE2 formulation may modify the relationship between sleep and amyloid-β accumulation., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Objective: To examine the association of adverse childhood experiences (ACEs) with overall menopausal symptom burden in midlife women., Study Design: This was a cross-sectional study of women between the ages of 40 and 65 years who were seen for specialty consultation in the Menopause and Women's Sexual Health Clinic, Mayo Clinic, Rochester, MN between May 1, 2015 and December 31, 2016., Main Outcome Measures: Participants completed the ACE questionnaire to assess childhood abuse and neglect, the Menopause Rating Scale (MRS) to assess menopausal symptom burden, the Patient Health Questionnaire (PHQ-9) to assess depression, the Generalized Anxiety Disorder questionnaire (GAD-7) to assess anxiety, and provided information on current abuse (physical, sexual and verbal/emotional)., Results: Women meeting inclusion criteria (N = 1670) had a median age of 53.7 years (interquartile range: 49.1, 58.0). Of these women, 977 (58.5 %) reported any ACE and 288 (17.2 %) reported ≥4 ACEs. As menopausal symptoms increased in severity from the first to fourth quartile, the odds ratio of ACE 1-3 (vs. 0) increased from 1 to 2.50 (trend p < 0.01), and the odds ratio of ACE ≥ 4 (vs. 0) increased from 1 to 9.61 (trend p < 0.01), a pattern that was consistent across all menopausal symptom domains. The association between severe menopausal symptoms and higher childhood adversity (ACE score 1-3 or ≥4 vs. ACE = 0) remained significant after adjusting for age, partner status, education, employment, depression, anxiety, and hormone therapy use (OR 1.84 and 4.51, p < 0.01)., Conclusion: In this large cross-sectional study, there was a significant association between childhood adversity and self-reported menopausal symptoms that persisted even after adjustment for multiple confounders. These associations highlight the importance of screening women with bothersome menopausal symptoms for childhood adversity, and of offering appropriate management and counseling for the adverse experiences, when indicated., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Background: The identification of blood-borne biomarkers for the diagnosis and prognosis of Alzheimer's disease and related dementias is more feasible at the population level than obtaining cerebrospinal fluid or neuroimaging markers., Objective: This study determined the association of blood microvesicles, derived from cells of the neurovascular unit, with brain amyloid-β deposition in menopausal women., Methods: A subset of women from the Kronos Early Estrogen Prevention Study underwent brain amyloid-β positron emission tomography three years following cessation of study treatment with placebo (PL, n = 29), transdermal 17β-estradiol (tE2; n = 21), or oral conjugated equine estrogen (oCEE; n = 17). Isolated peripheral venous blood microvesicles were analyzed by digital flow cytometry using fluorophore conjugated antibodies directed toward total tau, amyloid-β 1-42 (Aβ1-42), neuron specific class III β-tubulin (Tuj1), microglia ionized calcium -binding adaptor molecule 1(Iba1), glial fibrillary acid protein (GFAP), and low density lipoprotein receptor-related protein1 (LRP1). Principal components analysis reduced the dimensionality of these selected six markers to two principal components (PCs). Proportional odds ordinal logistic regression analysis was used with amyloid-β deposition regressed on these PCs., Results: Only the number of microvesicles positive for Aβ1-42 differed statistically among prior treatment groups (median [IQR]: 6.06 [2.11, 12.55] in PL; 2.49 [0.73, 3.59] in tE2; and 4.96 [0.83, 10.31] in oCEE; p = 0.032). The joint association between the 2 PCs and brain amyloid-β deposition was significant (p = 0.045)., Conclusion: Six selected markers expressing peripheral blood microvesicles derived from cells of the neurovascular unit, when summarized into two principal components, were associated with brain amyloid-β deposition.

Background: There are limited data on how sex influences the outcomes of acute myocardial infarction-cardiogenic shock (AMI-CS) in young adults., Methods: A retrospective cohort of AMI-CS admissions aged 18 to 55 years, during 2000 to 2017, was identified using the National Inpatient Sample. Use of coronary angiography, percutaneous coronary intervention, mechanical circulatory support and noncardiac interventions was identified. Outcomes of interest included in-hospital mortality, use of cardiac interventions, hospitalization costs, and length of stay., Results: A total 90 648 AMI-CS admissions ≤55 years of age were included, of which 26% were women. Higher rates of CS were noted in men (2.2% in 2000 to 4.8% in 2017) compared with women (2.6% in 2000 to 4.0% in 2017; P <0.001). Compared with men, women with AMI-CS were more frequently of Black race, from a lower socioeconomic status, with higher comorbidity, and admitted to rural and small hospitals (all P <0.001). Women had lower rates of ST-segment elevation presentation (73.0% versus 78.7%), acute noncardiac organ failure, cardiac arrest (34.3% versus 35.7%), and received less-frequent coronary angiography (78.3% versus 81.4%), early coronary angiography (49.2% versus 54.1%), percutaneous coronary intervention (59.2% versus 64.0%), and mechanical circulatory support (50.3% versus 59.2%; all P <0.001). Female sex was an independent predictor of in-hospital mortality (23.0% versus 21.7%; adjusted odds ratio, 1.11 [95% CI, 1.07-1.16]; P <0.001). Women had lower hospitalization costs ($156 372±$198 452 versus $167 669±$208 577; P <0.001) but comparable lengths of stay compared with men., Conclusions: In young AMI-CS admissions, women are treated less aggressively and experience higher in-hospital mortality than men.

Background: Studies demonstrate an association between aortic hemodynamics and cognitive function. The impact of pregnancy history on this association is unknown., Methods: Postmenopausal women (age 59 ± 5 years; years since last pregnancy 35 ± 3) with either a history of preeclampsia (PE; n = 34) or a history of a normotensive pregnancy (NP; n = 30) underwent cognitive testing: Letter-Number Sequencing, Digit Span, Trail Making Test, and letter and category fluency. Applanation tonometry was used to derive aortic systolic and diastolic blood pressure and augmentation index., Results: Distribution of cognitive scores and aortic hemodynamic measures was similar between the PE and NP groups. Principal component (PC) analysis was used to reduce the 3 aortic hemodynamic measures and the 5 cognitive variables to single summary indices, each representing a weighted average of their respective constituent variables. Using a multivariable linear model based on these PCs that adjusted for pregnancy history and body mass index, the composite index of aortic hemodynamics was associated with the summary cognitive index, whether taking into account a potential interaction with pregnancy history (P = 0.035) or not (P = 0.026) (interaction P = 0.178). Multivariable modeling of individual cognitive tests revealed a differential association for letter fluency by pregnancy history (test for interaction P = 0.023); this score correlated with the aortic hemodynamic index in the PE (partial R2 = 0.20), but not the NP (partial R2 = 0.00) group., Conclusions: Elevated aortic hemodynamics may negatively impact cognitive function in postmenopausal women with specific executive functions, such as letter fluency, being impacted more by a pregnancy history of PE., (© The Author(s) 2020. Published by Oxford University Press on behalf of American Journal of Hypertension, Ltd.)