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Objetivo: Relatar três casos clínicos de Hemoglobinúria Paroxística Noturna (HPN) debatendo suas formas de apresentação clínica, clonalidade, cenário diagnóstico e tratamento. Série de casos: C.M.S, feminina, 34 anos, deu entrada no serviço com cefaleia e exames laboratoriais evidenciando hemólise. Apresentava coombs direto positivo, poliespecifico e presença de crioaglutininas. Inicialmente refrataria a corticoesteroides e então a pesquisa de clone HPN foi solicitado. Devido a gravidade do quadro e as informações até o momento, iniciado rituximab. O resultado de clone HPN revelou 46.3% clone tipo III e 20.4% clone tipo II em hemácias. Iniciado tratamento com eculizumab endovenoso apresentando resolução completa da anemia. A.C.S, masculino, 63 anos, com diagnóstico em 2016 de aplasia medular não grave e clone HPN 5%. Em 2018, iniciou tratamento com ciclosporina, que foi suspensa em 2020 devido à nefrotoxicidade e níveis hematimétricos estáveis. Em 2023, apresentou piora da anemia com critérios de hemólise, coombs direto negativo, esplenomegalia e dificuldade de ereção. Repetida pesquisa de clone HPN com achado de 32% clone tipo II e 1% clone tipo III. Estabelecimento diagnóstico de HPN sobreposto à aplasia de medula óssea (MO), iniciou eculizumab com remissão completa dos sintomas e normalização da hemoglobina após 3 semanas. F.A.F, masculino, 24 anos, com anemia aplástica grave diagnosticada em 2019 com imuno-histoquímica de MO acusando 6% de clone HPN. Realizada terapia com prednisona, timoglobulina de coelho e ciclosporina, com boa resposta ao tratamento. Após redução gradativa da dose de ciclosporina, sem citopenias importantes ou necessidade transfusional, foi optado por suspender medicação em 2023 e paciente manteve sem piora da anemia. Durante segmento, apresentava clone HPN de 7.7% em hemácias, sendo 4.16% tipo III e clones acometidos em neutrófilos e monócitos próximos a 30%. Mantem sem necessidade de tratamento com eculizumabe. Discussão: A HPN é condição rara e adquirida onde as células-tronco hematopoiéticas e seus clones possuem mutação no gene PIGA, responsável pela biossíntese de glicosilfosfatidilinositol (GPI) o que causa redução ou ausência de inibidores do sistema complemento na superfície das hemácias (CD55 e CD59). Resulta em hemólise intravascular crônica, trombose arterial e venosa, distonia dos músculos lisos e MO hipocelular ou displásica. Clones tipo I são normais, tipo II apresentam deficiência parcial e tipo III deficiência completa desses inibidores. Embora os clones possam surgir em diversas linhagens celulares os sintomas clássicos se relacionam ao acometimento da linhagem eritrocítica, que resulta em hemólise. Sendo assim hipótese diagnóstica nos casos de anemias hemolíticas em aplasias e outras falências medulares ou em eventos trombóticos sem outra explicação. É caracterizada como anemia hemolítica coombs negativo, mas pode apresentar padrões positivos principalmente em hemólises graves. A distribuição do clone e a diversidade na apresentação clínica podem resultar em atraso no diagnóstico. Conclusão: A variabilidade das expressões clonais assim como a falta do teste de coombs monoespecifico no SUS, tornam o diagnóstico da HPN desafiador. É necessário reforçar a importância do conhecimento clínico sobre a doença para obter o diagnóstico preciso.

Introdução: Mieloma múltiplo é uma doença que afeta as células da medula óssea, particularmente os plasmócitos. A idade média de diagnóstico varia entre 65 e 74 anos. Esta condição é caracterizada por alta morbidade e mortalidade. As manifestações extramedulares são raras, ocorrendo em cerca de 5% dos casos, enquanto o acometimento do sistema nervoso central (SNC) é uma complicação rara, afetando 1% dos pacientes. Neste estudo, é relatado um caso de mieloma múltiplo com infiltração no SNC e seu desfecho clínico. Objetivo: Relatar o caso clínico de Mieloma múltiplo com acometimento do sistema nervoso central de paciente em seguimento no Hospital Estadual Mário Covas (HEMC). Relato de caso: JSM, um paciente masculino de 58 anos, hipertenso, com diagnóstico de mieloma múltiplo de cadeia leve Kappa, apresentou manifestações neurológicas (despertar patológico). Um EEG revelou alentecimento difuso bilateral, enquanto a tomografia computadorizada do crânio não mostrou alterações. A análise do líquor revelou níveis de proteína de 51,8, glicose de 63 e celularidade de 5. A imunofenotipagem do líquor indicou a presença de 0,31% de plasmócitos. Materiais e métodos: Revisão do prontuário do paciente, do acesso ao laudo dos métodos diagnósticos aos quais o paciente foi submetido e de uma revisão de literatura. Discussão: Os sintomas em pacientes com mieloma múltiplo são inespecíficos e cursam com anemia, hipercalcemia, lesão lítica e renal. O acometimento do SNC é raro, mas pode ocorrer por contiguidade ou por via hematogênica. O tratamento da doença, apesar de não curativo e apresentar sobrevida de 5 anos em menos de 60% dos casos, consiste na associação de quimioterapia e corticosteroide. No entanto, em casos de infiltração do SNC, a literatura ainda é escassa em evidências para guiar o tratamento. Conclusão: A apresentação deste caso de mieloma múltiplo com envolvimento do sistema nervoso central destaca a complexidade e gravidade da doença. A rápida progressão e os desafios terapêuticos ressaltam a necessidade de abordagens integradas e vigilância contínua para melhorar os desfechos clínicos. Este relato sublinha a importância da detecção precoce e manejo multidisciplinar para enfrentar os múltiplos aspectos dessa doença.

Objetivo: Relatar um caso de síndrome Rhnull associada à deficiência de G6PD em paciente submetida a esplenectomia que faz seguimento no Hospital Estadual Mário Covas (HEMC). Material e métodos: Realizado revisão de prontuário, análise cronológica de exames laboratoriais, incluindo fenotipagem e sequenciamento genético, assim como revisão de literatura. Relato de caso: DGS, feminino, 59 anos, diabética e hipertensa, iniciou atendimento médico com equipe de cirurgia vascular na emergência do HEMC em abril de 2021 devido à necrose infectada em antepé bilateral associada à anemia hemolítica e história prévia de esferocitose hereditária. A equipe de hematologia iniciou o acompanhamento após solicitado concentrado de hemácias e identificado a presença de Rhnull, aloanticorpos (ANTIs-/jkb/Fya-) e numerosos esferócitos em sangue periférico sem alteração na curva de fragilidade osmótica. Devido à gravidade trombótica da microcirculação, por provável doença hematológicaassociada às comorbidades pré-existentes, em setembro de 2021, optou-se pela amputação transmetatarsiana bilateral. Para maior segurança do procedimento, devido à indisponibilidade de doador compatível para reserva sanguínea, iniciou-se eritropoietina até atingir Hb 7.6%. Após a cirurgia, a paciente manteve seguimento hematológico e apresentava crises hemolíticas recorrentes. Realizada discussão clínica e debatido as evidências literárias de melhora com esplenectomia, o procedimento foi indicado e realizado sem intercorrências em fevereiro de 2023 após preparo adequado. Um mês após a esplenectomia, ela sustentou Hb 14.7%, sem sinais de hemólise e sem uso de medicações de resgate. Para maior esclarecimento do caso e a fim de identificar os genes envolvidos, solicitou-se exoma NGS, que revelou a presença de homozigose para Rhnull e heterozigose para deficiência de G6PD, levando-nos a orientá-la sobre medicações e alimentos a serem evitados para minimizar crises. Discussão: A síndrome Rhnull caracteriza-se pela ausência de antígenos do grupo Rh nos eritrócitos e trata-se de herança autossômica recessiva rara apartir na mutação do gene RHAG. Essa condição faz com que as glicoproteínas do fenótipo Rh estejam reduzidas ou ausentes na membrana plasmática das hemácias acarretando graus variáveis de estomatocitose, esferocitose, aumento da fragilidade osmótica, resultando em anemia hemolítica crônica. Além disso, a paciente apresentava deficiência hereditária de G6PD que resulta em anemia hemolítica aguda quando há aumento da produção de espécies reativas de oxigênio, sendo assim ambas as alterações genéticas encontradas levam a desencadear hemólise. Estudos prévios evidenciaram a melhora significativa e sustentada da hemoglobina nos pacientes submetidos a esplenectomia, conduta adotada nesse caso. É válido ressaltar que a intensificação da hemólise, muitas vezes relacionada a infecções ou quadros inflamatórios, é compatível com a deficiência de G6PD, que também ajuda a justificar a resposta favorável à esplenectomia. Conclusão: Este caso demonstra a importância do diagnóstico genético adequado para doenças raras e reforça a utilidade da esplenectomia no planejamento e tratamento da síndrome Rhnull, em concordância com a literatura.

Accumulating evidence indicates that most female patients with suicidal ideation (SI) experience a dimensional worsening of depressive symptoms and SI in the perimenstrual phase of the menstrual cycle. Experimental trials demonstrate that acute perimenstrual administration of estradiol (E2; with or without progesterone/P4), can prevent these recurring episodes of increased risk. In this archival sample drawn from one of these clinical trials, we examined whether these beneficial E2 effects extend to specific types of cognition. For a double-blind, placebo-controlled experiment, we recruited transdiagnostic psychiatric outpatients with natural menstrual cycles who experienced past-month SI (N(per-protocol sample)=23; N(intent-to-treat sample)=44). In each of two counterbalanced conditions (perimenstrual administration of 0.1mg/d transdermal E2 vs. placebo), participants completed three cognitive tasks in three menstrual cycle phases (mid-luteal, perimenstrual, mid-follicular). Multilevel models revealed a significant interaction of condition and phase: E2 administration prevented mid-luteal-to-perimenstrual drops in working memory (p=.006) and verbal fluency (p=.005) observed under placebo. No effects were found for inhibitory control. In conclusion, we find perimenstrual declines in working memory and verbal fluency in patients with SI, which can be prevented by administering E2. This study contributes to our understanding of the hormone-brain pathways involved in the cyclical worsening of suicidality., 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 © 2024. Published by Elsevier B.V.)

Introduction: Magnetic resonance imaging (MRI) at 7 Telsa (7T) has superior signal-to-noise ratio to 3 Telsa (3T) but also presents higher signal inhomogeneities and geometric distortions. A key knowledge gap is to robustly investigate the sensitivity and accuracy of 3T and 7T MRI in assessing brain morphometrics. This study aims to (a) aggregate a large number of paired 3T and 7T scans to evaluate their differences in quantitative brain morphological assessment using a widely available brain segmentation tool, FreeSurfer, as well as to (b) examine the impact of normalization methods for subject variability and smaller sample sizes on data analysis., Methods: A total of 452 healthy participants aged 29 to 68 were imaged at both 3T and 7T. Structural T1-weighted magnetization-prepared rapid gradient-echo (MPRAGE) images were processed and segmented using FreeSurfer. To account for head size variability, the brain volumes underwent intracranial volume (ICV) correction using the Residual (regression model) and Proportional (simple division to ICV) methods. The resulting volumes and thicknesses were correlated with age using Pearson correlation and false discovery rate correction. The correlations were also calculated in increasing sample size from 3 to the whole sample to estimate the sample size required to detect aging-related brain variation., Results: 352 subjects (210 females) passed the image quality control with 100 subjects excluded due to excessive motion artifacts on 3T, 7T, or both. 7T MRI showed an overall stronger correlation between morphometrics and age and a larger number of significantly correlated brain volumes and cortical thicknesses. While the ICV is consistent between both field strengths, the Residual normalization method shows markedly higher correlation with age for 3T when compared with the Proportional normalization method. The 7T results are consistent regardless of the normalization method used., Conclusion: In a large cohort of healthy participants with paired 3T and 7T scans, we compared the statistical performance in assessing age-related brain morphological changes. Our study reaffirmed the inverse correlation between brain volumes and cortical thicknesses and age and highlighted varying correlations in different brain regions and normalization methods at 3T and 7T. 7T imaging significantly improves statistical power and thus reduces required sample size., Competing Interests: Conflict of interest statement The authors declare no conflict of interest.

Background: Approximately 4% to 8% of pregnant individuals meet the criteria for current posttraumatic stress disorder (PTSD), a known risk factor for a multitude of adverse maternal and child health outcomes. However, PTSD is rarely detected or treated in obstetric settings. Moreover, available prenatal PTSD treatments require in-person services that are often inaccessible due to barriers to care. Thus, web-based interventions offer great potential in extending PTSD treatment to high-risk pregnant individuals by providing affordable, accessible care. However, there are currently no web-based interventions designed specifically for the treatment of PTSD symptoms during pregnancy., Objective: This study aims to develop and pilot a 6-week, web-based, cognitive behavioral therapy intervention for PTSD, SunnysideFlex, in a sample of 10 pregnant women with current probable PTSD. Consistent with established guidelines for developing and testing novel interventions, the focus of this pilot study was to evaluate the initial feasibility and acceptability of the SunnysideFlex intervention and preintervention to postintervention changes in PTSD and depression symptoms. This approach will allow for early refinement and optimization of the SunnysideFlex intervention to increase the odds of success in a larger-scale clinical trial., Methods: The SunnysideFlex intervention adapted an existing web-based platform for postpartum depression, Sunnyside for Moms, to include revised, trauma-focused content. A total of 10 pregnant women in weeks 16 to 28 of their pregnancy who reported lifetime interpersonal trauma exposure (ie, sexual or physical assault) and with current probable PTSD (scores ≥33 per the PTSD checklist for DSM-5) were enrolled in the SunnysideFlex intervention. Assessments took place at baseline and 6 weeks (postintervention)., Results: All participants were retained through the postintervention assessment period. Engagement was high; participants on average accessed 90% of their lessons, logged on to the platform at least weekly, and reported a generally positive user experience. Moreover, 80% (8/10) of participants demonstrated clinically meaningful reductions in PTSD symptoms from baseline to postintervention, and 50% (5/10) of participants no longer screened positive for probable PTSD at postintervention. Most (6/10, 60%) of the participants maintained subclinical depression symptoms from baseline to postintervention., Conclusions: Findings from this small pilot study indicate that SunnysideFlex may be a feasible and acceptable mechanism for delivering PTSD intervention to high-risk, trauma-exposed pregnant women who might otherwise not have opportunities for services. Larger-scale trials of the intervention are necessary to better understand the impact of SunnysideFlex on PTSD symptoms during pregnancy and the postpartum period., (©Katherine C Paltell, Jennifer Duffecy, Pauline M Maki, Shiva Edalatian Zakeri, Anka A Vujanovic, Erin C Berenz. Originally published in JMIR Formative Research (https://formative.jmir.org), 01.11.2024.)

Objectives: Virally-suppressed people with HIV (VS-PWH) show heterogeneity in patterns of cognitive dysfunction. To better understand the relationship between the neuroimmune response and cognition, we used positron emission tomography (PET) to image the translocator protein 18 kDa (TSPO). The study examined HIV-serostatus differences in TSPO as well as associations between regional TSPO and select cognitive processes defined using the Research Domain Criteria (RDoC) framework., Design: Cross-sectional investigation in VS-PWH (n = 25) versus HIV-uninfected individuals (n = 18) of cognitive control and declarative memory, as well as [11C]DPA-713 PET measures of TSPO within cognitive control and declarative memory regions of interest., Methods: Group differences in [11C]DPA-713 binding (VT) in cognitive control or declarative memory regions were examined using linear mixed models. Tests of associations between factor-derived cognitive system measures and PET measures were performed, controlling for TSPO genotype., Results: There were no group differences in any of the four factor-derived cognitive system measures. VS-PWH had higher log [11C]DPA-713 VT across cognitive control regions(unstandardized beta coefficient reflecting mean difference [B] = 0.23, SE = 0.11, 95% confidence interval [CI] 0.01, 0.45, P = 0.04) and declarative memory regions (B = 0.24, SE = 0.11, 95%CI 0.02, 0.45, P = 0.03). Higher log [11C]DPA-713 VT in cognitive control regions related to poorer cognitive control in each group, and to worse self-reported cognitive performance in VS-PWH. Log [11C]DPA-713 VT in each declarative memory region did not associate with measured declarative memory., Conclusions: A localized neuroimmune response marked by high TSPO in brain regions that subserve cognitive control may contribute to poorer cognitive control in VS-PWH., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Objective: Findings concerning the effects of hormone therapy (HT) on cognition and dementia are mixed, with some trials suggesting increased harm at older ages. Personality, like cognition, changes with dementia, but no clinical trials to date have examined the effects of HT on personality traits. This study aimed to determine the effects of HT on personality traits in older men and women., Method: Secondary data analysis was performed from randomized, double-blind, placebo-controlled cross-over studies of menopausal HT in women and testosterone therapy (TT) in men. Participants were community-dwelling cognitively normal adults (mean age = 75.2 years), including 29 men and 22 women. Three months of hormone intervention (for women, 0.625 mg/day conjugated equine estrogen with or without 2.5 mg/day medroxyprogesterone acetate; for men, 200 mg intramuscular testosterone enanthate every 2 weeks) were crossed over with 3 months of identical placebo with a 3-month washout between intervention phases. The main outcome measure was neuroticism and conscientiousness personality domains and facets assessed with the Revised NEO Personality Inventory (NEO-PI-R) after the active and placebo intervention phases., Results: In linear mixed-effect models, HT in women decreased conscientiousness ( p  < 0.01) and the conscientiousness facet of achievement striving ( p  < 0.01), and increased vulnerability, a facet of neuroticism ( p  < 0.05). Testosterone in men decreased conscientiousness ( p  < 0.05) and the conscientiousness facet of dutifulness ( p  < 0.05), and increased vulnerability ( p  < 0.05)., Conclusion: In a preliminary study of healthy older adults, HT and TT formulations produced adverse changes in vulnerability and conscientiousness facets that parallel personality changes in dementia.

Introduction: Although reproductive hormones are implicated in cerebral small vessel disease in women, few studies consider measured hormones in relation to white matter hyperintensity volume (WMHV), a key indicator of cerebral small vessel disease. Even fewer studies consider estrone (E1), the primary postmenopausal estrogen, or follicle-stimulating hormone (FSH), an indicator of ovarian age. We tested associations of estradiol (E2), E1, and FSH to WMHV among women., Methods: Two hundred twenty-two women (mean age = 59) underwent hormone assays (E1, E2, FSH) and 3T brain magnetic resonance imaging. Associations of hormones to WMHV were tested with linear regression., Results: Higher E2 (B[standard error (SE)] = -0.17[0.06], P = 0.008) and E1 (B[SE] = -0.26[0.10], P = 0.007) were associated with lower whole-brain WMHV, and higher FSH (B[SE] = 0.26[0.07], P = 0.0005) with greater WMHV (covariates age, race, education). When additionally controlling for cardiovascular disease risk factors, associations of E1 and FSH to WMHV remained., Discussion: Reproductive hormones, particularly E1 and FSH, are important to women's cerebrovascular health., Highlights: Despite widespread belief that sex hormones are important to women's brain health, little work has considered how these hormones in women relate to white matter hyperintensities (WMH), a major indicator of cerebral small vessel disease. We considered relations of estradiol (E2), estrone (E1), and follicle-stimulating hormone (FSH) to WMH in midlife women. Higher E2 and E1 were associated with lower whole-brain WMH volume (WMHV), and higher FSH with higher whole-brain WMHV. Associations of E1 and FSH, but not E2, to WMHV persisted with adjustment for cardiovascular disease risk factors. Findings underscore the importance of E2 and FSH to women's cerebrovascular health., (© 2024 The Author(s). Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Importance: Safe and effective nonhormonal treatments for menopausal vasomotor symptoms (VMS) are needed., Objective: To evaluate the efficacy and safety of elinzanetant, a selective neurokinin-1,3 receptor antagonist, for the treatment of moderate to severe menopausal vasomotor symptoms., Design, Setting, and Participants: Two randomized double-blind phase 3 trials (OASIS 1 and 2) included postmenopausal participants aged 40 to 65 years experiencing moderate to severe vasomotor symptoms (OASIS 1: 77 sites in the US, Europe, and Israel from August 27, 2021, to November 27, 2023, and OASIS 2: 77 sites in the US, Canada, and Europe from October 29, 2021, to October 10, 2023)., Intervention: Once daily oral elinzanetant, 120 mg, for 26 weeks or matching placebo for 12 weeks followed by elinzanetant, 120 mg, for 14 weeks., Main Outcomes and Measures: Primary end points included mean change in frequency and severity of moderate to severe vasomotor symptoms from baseline to weeks 4 and 12, measured by the electronic hot flash daily diary. Secondary end points included Patient-Reported Outcomes Measurement Information System Sleep Disturbance Short Form 8b total T score and Menopause-Specific Quality of Life questionnaire total score from baseline to week 12., Results: Eligible participants (mean [SD] age, OASIS 1: 54.6 [4.9] years; OASIS 2: 54.6 [4.8] years) were randomized to elinzanetant (OASIS 1: n = 199; OASIS 2: n = 200) or placebo (OASIS 1: n = 197; OASIS 2: n = 200). A total of 309 (78.0%) and 324 (81.0%) completed OASIS 1 and 2, respectively. For the elinzanetant and placebo groups, the baseline mean (SD) VMS per 24 hours were 13.4 (6.6) vs 14.3 (13.9) (OASIS 1) and 14.7 (11.1) v 16.2 (11.2) (OASIS 2). Baseline VMS severity was 2.6 (0.2) vs 2.5 (0.2) (OASIS 1) and 2.5 (0.2) vs 2.5 (0.2) (OASIS 2). Elinzanetant significantly reduced VMS frequency at week 4 (OASIS 1: -3.3 [95% CI, -4.5 to -2.1], P < .001; OASIS 2: -3.0 [95% CI, -4.4 to -1.7], P < .001) and at week 12 (OASIS 1: -3.2 [95% CI, -4.8 to -1.6], P < .001; OASIS 2: -3.2 [95% CI, -4.6 to -1.9], P < .001). Elinzanetant also improved VMS severity at week 4 (OASIS 1: -0.3 [95% CI, -0.4 to -0.2], P < .001; OASIS 2: -0.2 [95 CI, -0.3 to -0.1], P < .001) and week 12 (OASIS 1: -0.4 [95% CI, -0.5 to -0.3], P < .001; OASIS 2: -0.3 [95% CI, -0.4 to -0.1], P < .001). Elinzanetant improved sleep disturbances and menopause-related quality of life at week 12, and the safety profile was favorable., Conclusions and Relevance: Elinzanetant was well tolerated and efficacious for moderate to severe menopausal VMS., Trial Registration: ClinicalTrials.gov Identifier: OASIS 1: NCT05042362, OASIS 2: NCT05099159.

Importance and Objectives: Sleep disturbance is one of the most common and debilitating symptoms experienced by women during the menopause transition. However, there are currently no therapies specifically approved for sleep disturbance associated with the menopause. Here, we consider how to characterize sleep disturbance associated with the menopause and discuss its etiology, including the latest advances in our understanding of the neuronal circuits that regulate reproduction, body temperature, sleep, and mood; and reflect on its impact on women's health and well-being. We also examine the current treatment landscape and look to the future of treatment for this condition., Methods: We conducted a review of the literature and combined this with discussion with experts in the fields of sleep and menopause as well as experiences from our own clinical practices., Discussion and Conclusions: Sleep disturbance associated with the menopause is characterized by frequent night-time awakenings and increased awake time after sleep onset. Its impacts are wide-ranging, negatively affecting health as well as personal and social relationships, productivity, and work performance. There is currently an unmet need for effective, safe, and well-tolerated treatments to address this important symptom, and wider recognition of the association between sleep disturbances and the menopause is needed. Sleep disturbances associated with the menopause can result from hormone changes as well as vasomotor and mood symptoms. Growing research has contributed to our knowledge of the role of hypothalamic estrogen-sensitive kisspeptin/neurokinin B/dynorphin neurons. These neurons are thought to integrate the gonadotropin-releasing hormone pathway and the pathways responsible for the homeostatic control of body temperature and the circadian regulation of sleep-wake cycles. Understanding these neurons offers the potential to create treatments that target a key cause of sleep disturbance associated with the menopause. Further research to understand their etiology and characterize the neuronal circuits responsible could benefit the development of these targeted treatment approaches., Competing Interests: Financial disclosure/conflicts of interest: Pauline Maki has received compensation as a member of the scientific advisory board of Astellas, Bayer, and Johnson & Johnson. She has received compensation from Pfizer for consulting. She serves as a member of the scientific advisory board and has/had equity in Alloy, Estrigenix, and MidiHealth. She has received speaking fees and travel support from Mithra. All her research is supported by the NIH. Nick Panay has undertaken speaker's bureau work for: Abbott, Bayer, Besins, Gedeon Richter, Kora, Meda, MSD, Mylan, Novo Nordisk, SeCur, Shionogi, Theramex, and Viatris and participated in advisory committees for: Abbott, Astellas, Bayer, Besins, Gedeon Richter, LivBio, Meda, Mithra, MSD, Mylan, Novo Nordisk, Kora, SeCur, Serelys, Shionogi, and Viatris. James A. Simon has received grant/research support: AbbVie, Inc, Bayer Healthcare LLC., Dare´ Bioscience, Ipsen, Mylan/Viatris Inc, Myovant Sciences, and Sebela Pharmaceuticals Inc, participated as a consultant or in advisory boards for: Bayer HealthCare Pharmaceuticals Inc, Besins Healthcare, Biote Medical, LLC, California Institute of Integral Studies (CIIS), Dare´ Bioscience, Femasys Inc, Khyria, Madorra Pty Ltd., Mayne Pharma, Inc, Pfizer Inc, and Vella Bioscience Inc, has undertaken speaker's bureau work for: Astellas Pharma, Inc, Mayne Pharma, Inc, Myovant Sciences, Inc, Pfizer Inc, Pharmavite LLC., and Scynexis Inc, and is a stockholder (direct purchase) in: Sermonix Pharmaceuticals., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of The Menopause Society.)

Objective: This study aimed to examine sex differences in factors associated with mood and anxiety in midlife men and women during the COVID-19 pandemic., Methods: During a remote visit, 312 adults aged 40-60 years (167 female; 23.6% perimenopausal) from the Human Connectome Project in Aging completed PROMIS measures of depression, anxiety and anger/irritability; perceived stress; and questions about social support, financial stress and menopause stage. Multivariate linear regression models assessed sex differences in mental health and the association of social support, financial stress and menopause stage with mental health., Results: Anxiety was higher in women than in men ( b  = 2.39, p  = 0.02). For women only, decreased social support was associated with increased anxiety ( b  = -2.26, p  = 0.002), anger/irritability ( b  = -1.89, p  = 0.02) and stress ( b  = -1.67, p  = 0.002). For women only, not having close family was associated with increased depressive symptoms ( b  = -6.60, p  = 0.01) and stress ( b  = -7.03, p  < 0.001). For both sexes, having children was associated with lower depressive symptoms ( b  = -3.08, p  = 0.002), anxiety ( b  = -1.93, p  = 0.07), anger/irritability ( b  = -2.73, p  = 0.02) and stress ( b  = -1.44, p  = 0.07). Menopause stage was unrelated to mental health., Conclusion: Social support, but not financial stress, influenced mental health during the COVID-19 pandemic at midlife, particularly for women.

Objective: Determine associations of endogenous estrogens with memory systems in the postmenopausal brain and evaluate clinical significance., Study Design: In the MsBrain cohort (n=199, mean age 59.3+3.9 years, 83.9% white), we examined the cross-sectional association of serum estradiol and estrone, measured using liquid chromatography-tandem mass spectrometry (LC-MS/MS), during a functional magnetic resonance imaging (fMRI) task of word encoding and recognition. To characterize the clinical significance of those associations, we examined the magnitude of activation in relation to a neuropsychological measures of memory and affect., Results: Endogenous estradiol was positively associated with activation in temporal and frontal cortices during encoding and negatively associated with one prefrontal region during recognition (p<.05). Activation in the left inferior frontal gyrus was associated with memory performance (β(SE)= 0.004(0.002), p<.05), and anxiety (β(SE)= -0.100(0.050), p<.05). The left middle frontal gyrus was associated with memory performance (β(SE)= 0.006(0.002), p<.01), depression, and anxiety. The left superior temporal gyrus (STG) was associated with depression (β(SE)= -0.083(0.036), p<.05) and anxiety (β(SE)= -0.134(0.058), p<.05). Estrone was positively associated with activation in a range of brain areas including bilateral STG and right superior frontal gyrus during encoding (p<.05). Activation of the left insula an precental gyrus were associated with symptoms of depression and anxiety. None related to memory., Conclusion: The function of brain areas critical to memory performance varies with estrogen levels in the postmenopause, even though those levels are low. Higher levels of estradiol may facilitate memory performance through enhanced function of temporal and frontal cortices during encoding of verbal material., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com. See the journal About page for additional terms.)

Background: Women carrying the APOE4 allele are at greater risk of developing Alzheimer's disease (AD) from ages 65-75 years compared to men. To better understand the elevated risk conferred by APOE4 carrier status among midlife women, we investigated the separate and interactive associations of endogenous estrogens, plasma AD biomarkers, and APOE4 carrier status on regional brain volumes in a sample of late midlife postmenopausal women., Methods: Participants were enrolled in MsBrain, a cohort study of postmenopausal women ( n  = 171, mean age = 59.4 years, mean MoCA score = 26.9; race = 83.2% white, APOE4 carriers = 40). Serum estrone (E1) and estradiol (E2) levels were assessed using liquid chromatography-tandem mass spectrometry. APOE genotype was determined using TaqMan SNP genotyping assays. Plasma AD biomarkers were measured using single molecule array technology. Cortical volume was measured and segmented by FreeSurfer software using individual T1w MPRAGE images. Multiple linear regression models were conducted to determine whether separate and interactive associations between endogenous estrogen levels, plasma AD biomarkers (Aβ42/Aβ40, Aβ42/p-tau181), and APOE4 carrier status predict regional brain volume (21 regions per hemisphere, selected a priori ); and, whether significant interactive associations between estrogens and AD biomarkers on brain volume differed by APOE4 carrier status., Results: There was no main effect of APOE4 carrier status on regional brain volumes, endogenous estrogen levels, or plasma AD biomarkers. Estrogens did not associate with regional brain volumes, except for positive associations with left caudal middle frontal gyrus and fusiform volumes. The interactive association of estrogens and APOE4 carrier status on brain volume was not significant for any region. The interactive association of estrogens and plasma AD biomarkers predicted brain volume of several regions. Higher E1 and E2 were more strongly associated with greater regional brain volumes among women with a poorer AD biomarker profile (lower Aβ42/40, lower Aβ42/p-tau181 ratios). In APOE4 -stratified analyses, these interactions were driven by non- APOE4 carriers., Conclusion: We demonstrate that the brain volumes of postmenopausal women with poorer AD biomarker profiles benefit most from higher endogenous estrogen levels. These findings are driven by non- APOE4 carriers, suggesting that APOE4 carriers may be insensitive to the favorable effects of estrogens on brain volume in the postmenopause., Competing Interests: RT reported receiving personal fees from Astellas Pharma, Bayer, Hello Therapeutics, Happify Health, and Vira Health outside the submitted work. HA reported receiving personal fees from Eisai outside the submitted work. PM reported receiving personal fees from Astellas Pharma, Bayer, Estrigenix, Alloy, and MidiHealth outside the submitted work. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Wugalter, Schroeder, Thurston, Wu, Aizenstein, Cohen, Kamboh, Karikari, Derby and Maki.)

Objective: The aim of the study is to identify suitable definitions and patient-reported outcome measures (PROMs) to assess each of the six core outcomes previously identified through the COMMA (Core Outcomes in Menopause) global consensus process relating to vasomotor symptoms: frequency, severity, distress/bother/interference, impact on sleep, satisfaction with treatment, and side effects., Methods: A systematic review was conducted to identify relevant definitions for the outcome of side-effects and PROMs with acceptable measurement properties for the remaining five core outcomes. The consensus process, involving 36 participants from 16 countries, was conducted to review definitions and PROMs and make final recommendations for the measurement of each core outcome., Results: A total of 21,207 publications were screened from which 119 reporting on 40 PROMs were identified. Of these 40 PROMs, 36 either did not adequately map onto the core outcomes or lacked sufficient measurement properties. Therefore, only four PROMs corresponding to two of the six core outcomes were considered for recommendation. We recommend the Hot Flash Related Daily Interference Scale to measure the domain of distress, bother, or interference of vasomotor symptoms and to capture impact on sleep (one item in the Hot Flash Related Daily Interference Scale captures interference with sleep). Six definitions of "side effects" were identified and considered. We recommend that all trials report adverse events, which is a requirement of Good Clinical Practice., Conclusions: We identified suitable definitions and PROMs for only three of the six core outcomes. No suitable PROMs were found for the remaining three outcomes (frequency and severity of vasomotor symptoms and satisfaction with treatment). Future studies should develop and validate PROMs for these outcomes., Competing Interests: Financial disclosure/conflicts of interest: V.P. received past funding from Sigvaris AG. M.P. received institutional funding from University of Melbourne (Internal Grant Schemes), Royal Women's Hospital (Internal grant scheme), and Cancer Council NSW Project Grant RG 21-06, Centre for Research Excellence in Women's Health in Reproductive Life (CREWHiRL) Seed Funding and Project Support Grant, NHMRC (APP1163202), and Royal Children's Hospital Foundation. She received past funding from FertilityIQ webinar honorarium. She has received fee registration fees as an invited speaker by the Pacific Society of Reproductive Medicine 2023 Conference and had subsidized flights and accommodations as an invited speaker for the European Society of Human Reproduction and Embryology 2022 Conference. She was also given free registration as an invited speaker for the Annual Scientific Meeting of Breast Cancer Trials 2021. D.A. has consulted for Evestra, Exeltis, Lupin, Mithra, ObsEva, and TherapeuticsMD, received industry support for research from AbbVie, Mithra, Myovant, and ObsEva, and has stock holdings in Agile Therapeutics, InnovaGyn, Inc. N.A. receives ongoing institutional funding from the National Cancer Institute. J.C. is owner of JSCarpenter, LLC which received scale licensing fees from Mapi Research Trust (2022), consulting fees from the University of Wisconsin (spring 2022), and consulting fees from Simumetrix SMX Health (spring 2022). M.C. has been paid for developing and delivering educational presentations for Alliance Chicago, received fees for an educational video and speaking engagements with Fertility IQ, wrote a White Paper on GSM for Materna (no financial reimbursement), and is a member of The Menopause Society Board of Trustees. M.D. receives current institutional funding from National Institute of Health Research. She serves as a chief investigator on POISE study (research relevant to HRT) and a chief investigator for BLUSH study (research on treatment of menopause). She received past institutional funding from Best Practice & Research Clinical Obstetrics & Gynaecology as editor of volume on menopause management published 2022. She is an elected member of the Medical Advisory Council of the British Menopause Society, is a member of the ESHRE guideline update group on Premature Ovarian Insufficiency, is a member of the British Endocrine Society working group producing clinical guidelines on estrogen treatment, and is a member of the British Gynaecological Cancer Society working group producing clinical guidelines on HRT. T.H. received past funding from Besins and Astellas. M.H. receives ongoing funding from Rightsteps and current funding from Hello Therapeutics. L.K. has lectured and/or acted in an advisory capacity for Gedeon Richter, Dr. KADE Besins and Mithra. P.M. has received compensation as a member of the scientific advisory board of Astellas, Bayer, and Johnson & Johnson; compensation from AbbVie and Pfizer for consulting; and serves as a member of the scientific advisory board and has/had equity in Alloy, Estrigenix, and MidiHealth. She has received speaking fees and travel support from Mithra. R.E.N. has ongoing relationships with Abbott, Astellas, Bayer HealthCare AG, Besins Healthcare, Exeltis, Fidia, Gedeon Richter, HRA Pharma, Merck Healthcare, Novo Nordisk, Shionogi Limited, Theramex, and Viatris. N.P. has lectured and/or acted in an advisory capacity for Abbott, Lawley, Mithra, Novo, SeCur, and Viatris. S.R. has lectured and/or acted in an advisory capacity or conducted studies for Abbott, Bayer, Gedeon Richter, Mylan, Amgen, UCB, Theramex, and Viatris. J.S. receives grant/research support from AbbVie, Inc., Bayer Healthcare LLC., Dare´ Bioscience; Ipsen, Mylan/Viatris Inc., Myovant Sciences, Sebela Pharmaceuticals Inc. He acts as a consultant is on advisory boards for Bayer HealthCare Pharmaceuticals Inc., Besins Healthcare, California Institute of Integral Studies (CIIS), Dare´ Bioscience, Femasys Inc., Khyria, Madorra Pty Ltd., Mayne Pharma, Inc., and Vella Bioscience Inc. He serves on speaker's bureaus for Astellas Pharma, Inc., Mayne Pharma, Inc., Myovant Sciences, Inc., Pfizer Inc., Pharmavite LLC., Scynexis Inc. He is a stockholder (direct purchase) of Sermonix Pharmaceuticals. P.S. has received fees for giving educational presentations, participating in advisory boards and conducting research by Besins Healthcare, Astellas, Mylan, Labatec, Exeltis, Effik, Theramex, and Gedeon-Richter. A.J.V. has received fees for presentations and participation in an advisory board from Besins and Theramex. W.W. has received institutional support with an unrestricted grant from Pfizer and sits on the advisory boards of Pfizer, Lupin, and Biosyent. She has received fees for educational presentations for Lupin, Astellas, Bayer and Pfizer, and Biosyent. She is a board member of the International Menopause Society and the President of the Canadian Menopause Society. M.H. has received funding from Madorra for a study of a device to manage GU symptoms and is a clinical expert for the NICE Menopause Guidelines. J.T.G. is a speaker for NurtureMed Pharma, Bayer Phils, Corbridge Phils, and Zuellig Pharma. P.S. has a research consultancy relationship with Chugai Pharmaceuticals. H.J. receives grant funding from the National Institutes of Health, Merck, and Pfizer and is a consultant to Bayer, Merck, and Hello Therapeutics. She receives in kind support from Sage to her institution (drug provided to support NIH-funded trial), funds from Bayer support a pilot grant program she lead within an NIH-funded Center grant. Her spouse is employed by Arsenal Biosciences and receives equity from Merck Research Labs. N.J. is on the advisory board of Vira Health, UK. All other authors report no conflicts of interest., (Copyright © 2024 by The North American Menopause Society.)

Brain fog, referring to menopause-related subjective cognitive difficulties, is common in midlife women. Longitudinal studies find small but reliable declines in objective memory performance as women transition into perimenopause, and these are not explained by advancing age alone. When memory declines occur, performance levels remain within normal limits for all but a very small number of women. Women's experience of brain fog extends beyond memory complaints, reflecting the negative effect on a broad range of cognitive abilities. Clinicians can counsel women about how menopause symptoms, estrogen, hormone therapy, and modifiable risk factors (eg, hypertension, sedentary lifestyle) can influence cognitive health., (Copyright © 2024 by The Menopause Society.)

Pregnancy alters many physiological systems, including the maternal gut microbiota. Diet is a key regulator of this system and can alter the host immune system to promote inflammation. Multiple perinatal disorders have been associated with inflammation, maternal metabolic alterations, and gut microbial dysbiosis, including gestational diabetes mellitus, pre-eclampsia, preterm birth, and mood disorders. However, the effects of high-inflammatory diets on the gut microbiota during pregnancy have yet to be fully explored. We aimed to address this gap using a system-based approach to characterize associations among dietary inflammatory potential, a measure of diet quality, and the gut microbiome during pregnancy. Forty-seven pregnant persons were recruited prior to 16 weeks of gestation. Participants completed a food frequency questionnaire (FFQ) and provided fecal samples. Dietary inflammatory potential was assessed using the Dietary Inflammatory Index (DII) from the FFQ data. Fecal samples were analyzed using 16S rRNA amplicon sequencing. Differential taxon abundances with respect to the DII score were identified, and the microbial metabolic potential was predicted using PICRUSt2. Inflammatory diets were associated with decreased vitamin and mineral intake and a dysbiotic gut microbiota structure and predicted metabolism. Gut microbial compositional differences revealed a decrease in short-chain fatty acid producers such as Faecalibacterium , and an increase in predicted vitamin B12 synthesis, methylglyoxal detoxification, galactose metabolism, and multidrug efflux systems in pregnant individuals with increased DII scores. Dietary inflammatory potential was associated with a reduction in the consumption of vitamins and minerals and predicted gut microbiota metabolic dysregulation.

Objective: While modern antiretroviral therapy (ART) is highly effective and safe, depressive symptoms have been associated with certain ART drugs. We examined the association between common ART regimens and depressive symptoms in women with HIV (WWH) with a focus on somatic vs. nonsomatic symptoms., Design: Analysis of longitudinal data from the Women's Interagency HIV Study., Methods: Participants were classified into three groups based on the frequency of positive depression screening (CES-D ≥16): chronic depression (≥50% of visits since study enrollment), infrequent depression (<50% of visits), and never depressed (no visits). Novel Bayesian machine learning methods building upon a subset-tree kernel approach were developed to estimate the combined effects of ART regimens on depressive symptoms in each group after covariate adjustment., Results: The analysis included 1538 WWH who participated in 12 924 (mean = 8.4) visits. The mean age was 49.9 years, 72% were Black, and 14% Hispanic. In the chronic depression group, combinations including tenofovir alafenamide and cobicistat-boosted elvitegravir and/or darunavir were associated with greater somatic symptoms of depression, whereas those combinations containing tenofovir disoproxil fumarate and efavirenz or rilpivirine were associated with less somatic depressive symptoms. ART was not associated with somatic symptoms in the infrequent depression or never depressed groups. ART regimens were not associated with nonsomatic symptoms in any group., Conclusions: Specific ART combinations are associated with somatic depressive symptoms in WWH with chronic depression. Future studies should consider specific depressive symptoms domains as well as complete drug combinations when assessing the relationship between ART and depression., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Importance: Posttraumatic stress disorder (PTSD), cardiovascular disease (CVD), and Alzheimer disease are major public health issues, particularly for women. The implications of PTSD for cardiovascular and brain health for women is poorly understood., Objective: To assess whether PTSD symptoms among midlife women are associated with carotid intima media thickness (IMT), an indicator of carotid atherosclerosis; brain white matter hyperintensity volume (WMHV), an indicator of brain small vessel disease; and cognitive performance and to test a modifying role of the APOEε4 genotype., Design, Setting, and Participants: In this cross-sectional study, participants were enrolled between 2016 to 2021 and completed questionnaires (PTSD Checklist-Civilian Version), physical measures, phlebotomy, neuropsychological testing, a carotid ultrasonographic examination, and 3-Tesla brain magnetic resonance imaging. Participants included community-based women ages 45 to 67 years without a history of CVD, stroke, or dementia. Data were analyzed from July 2022 to September 2023., Exposures: PTSD symptoms., Main Outcomes and Measures: Outcomes of interest were associations of PTSD symptoms with carotid IMT, brain WMHV, and cognition, assessed in linear regression models. Interactions by APOEε4 were tested. Covariates included age, race and ethnicity, education, and CVD risk factors., Results: Among 274 participants (mean [SD] age, 59.03 [4.34] years; 6 Asian participants [2.2%]; 48 Black participants [17.5%]; 215 White participants [78.5%]; 5 multiracial participants [1.8%]), 64 participants (24.71%) were APOEε4 genotype carriers. Higher PTSD symptoms were associated with greater carotid IMT (multivariable β = 0.07 [95% CI, 0.01 to 0.13]; P = .03). Associations of PTSD symptoms with neurocognitive outcomes significantly varied by APOEε4 status. Among women with APOEε4, PTSD symptoms were associated with greater whole-brain WMHV (β = 0.96 [95% CI, 0.30 to 1.63]; P = .009), periventricular WMHV (β = 0.90 [95% CI, 0.24 to 1.56]; P = .02), deep WMHV (β = 1.21 [95% CI, 0.23 to 2.20]; P = .01), and frontal WMHV (β = 1.25 [95% CI, 0.05 to 2.45]; P = .04), as well as with poorer cognition, specifically attention and working memory (β = -3.37 [95% CI, -6.12 to -0.62]; P = .02), semantic fluency (β = -6.01 [95% CI, -10.70 to -1.31]; P = .01), perceptual speed (β = -12.73 [95% CI, -20.71 to -4.75]; P = .002), and processing speed (β = -11.05 [95% CI, -17.80 to -4.30]; P = .002) in multivariable models., Conclusions and Relevance: In this cross-sectional study of midlife women, greater PTSD symptoms were associated with higher carotid atherosclerosis and, among women who were APOEε4 carriers, greater brain small vessel disease and poorer cognitive performance. These findings point to the adverse implications of PTSD symptoms for cardiovascular and neurocognitive health among women in midlife, particularly for women who are APOEε4 carriers.

Objective: To assess the rates and feasibility of assessing comorbid mental health disorders and referral rates in low-income urban and rural perinatal patients., Methods: In two urban and one rural clinic serving primarily low-income perinatal patients of color, a computerized adaptive diagnostic tool CAT-MH® was implemented to assess major depressive disorder (MDD), general anxiety disorder (GAD), suicidality (SS), substance use disorder (SUD), and post-traumatic stress disorder (PTSD) at the first obstetric visit and/or 8 weeks postpartum., Results: Of a total of 717 screens, 10.7% (n = 77 unique patients) were positive for one or more disorders (6.1% one, 2.5% two, 2.1% three or more). MDD was the most common disorder (9.6%) and was most commonly comorbid with GAD (33% of MDD cases), SUD (23%), or PTSD (23%). For patients with a positive screen, referral to treatment was 35.1% overall, with higher rates in urban (51.6%) versus rural (23.9%) clinics (p = 0.03)., Conclusion: Mental health comorbidities are common in low-income urban and rural populations, but referral rates are low. Promoting mental health in these populations requires comprehensive screening and treatment approaches for psychiatric comorbidities and dedication to increase the availability of mental health prevention and treatment options., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Introduction: Carotid atherosclerosis may be associated with brain white matter hyperintensities (WMH). Few studies consider women at midlife, a critical time for women's cardiovascular and brain health. We tested the hypothesis that higher carotid intima media thickness (IMT) would be associated with greater WMH volume (WMHV) among midlife women. We explored interactions by apolipoprotein E (APOE) ε4 status., Methods: Two hundred thirty-nine women aged 45 to 67 underwent carotid artery ultrasound, phlebotomy, and magnetic resonance imaging (MRI). One hundred seventy participants had undergone an ultrasound 5 years earlier., Results: Higher IMT was associated with greater whole brain (B[standard error (SE)] = 0.77 [.31], P = 0.01; multivariable) and periventricular (B[SE] = 0.80 [.30], P = 0.008; multivariable) WMHV. Associations were observed for IMT assessed contemporaneously with the MRI and 5 years prior to the MRI. Associations were strongest for APOE ε4-positive women., Discussion: Among midlife women, higher IMT was associated with greater WMHV. Vascular risk is critical to midlife brain health, particularly for APOE ε4-positive women., (© 2023 the Alzheimer's Association.)

Objective: Women with HIV(WWH) are more likely to discontinue/change antiretroviral therapy(ART) due to side effects including neuropsychiatric symptoms. Efavirenz and integrase strand transfer inhibitors(INSTIs) are particularly concerning. We focused on these ART agents and neuropsychiatric symptoms in previously developed subgroups of WWH that differed on key sociodemographic factors as well as longitudinal behavioral and clinical profiles. WWH from the Women's Interagency HIV Study were included if they had ART data available, completed the Perceived Stress Scale-10 and PTSD Checklist-Civilian. Questionnaires were completed biannually beginning in 2008 through 2016. To examine ART-symptom associations, constrained continuation ratio model via penalized maximum likelihood were fit within 5 subgroups of WWH. Data from 1882 WWH contributed a total of 4598 observations. 353 women were previously defined as primarily having well-controlled HIV with vascular comorbidities, 463 with legacy effects(CD4 nadir < 250cells/mL), 274 aged ≤ 45 with hepatitis, 453 between 35-55 years, and 339 with poorly-controlled HIV/substance users. INSTIs, but not efavirenz, were associated with symptoms among key subgroups of WWH. Among those with HIV legacy effects, dolutegravir and elvitegravir were associated with greater stress/anxiety and avoidance symptoms(P's < 0.01); dolutegravir was also associated with greater re-experiencing symptoms(P = 0.005). Elvitegravir related to greater re-experiencing and hyperarousal among women with well-controlled HIV with vascular comorbidities(P's < 0.022). Raltegravir was associated with less hyperarousal, but only among women aged ≤ 45 years(P = 0.001). The adverse neuropsychiatric effects of INSTIs do not appear to be consistent across all WWH. Key characteristics (e.g., age, hepatitis positivity) may need consideration to fully weight the risk-benefit ratio of dolutegravir and elvitegravir in WWH., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Purpose: To investigate the relationships between optic nerve cupping and total and regional brain volumes., Design: Secondary analysis of randomized clinical trial data., Methods: Women 65 to 79 years of age without glaucoma with cup-to-disc ratio (CDR) measurements from the Women's Health Initiative (WHI) Sight Examination study and magnetic resonance imaging (MRI)-based total and regional brain volumes from the WHI Memory Study MRI-1 were included. Large CDR was defined as 0.6 or greater in either eye. Generalized estimating equation models were used to account for intra-brain correlations between the right and left sides. The final analysis was adjusted for demographic and clinical characteristics and for total brain volume (for regional analyses)., Results: Final analyses included 471 women, with the mean age ± SD was 69.2 ± 3.6 years; 92.8% of the subjects were white. Of 471 women, 34 (7.2%) had large CDR. Controlling for total brain volume and for demographic and clinical characteristics, lateral ventricle volume was 3.01 cc larger for subjects with large CDR compared to those without large CDR (95% CI = 0.02 to 5.99; P = .048). Furthermore, frontal lobe volume was 4.78 cc lower for subjects with large CDR compared to those without (95% CI = -8.71, -0.84; P = 0.02), and occipital lobe volume was 1.86 cc lower for those with large CDR compared to those without (95% CI = -3.39, -0.3; P =.02)., Conclusions: Our analysis suggests that in women aged 65 years or more, large CDR is associated with lower relative total brain volume and absolute regional volume in the frontal and occipital lobes. Enlarged CDR in individuals without glaucoma may represent a sign of optic nerve and brain aging, although more longitudinal data are needed., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Objective: Sexual and physical abuse are highly prevalent among women living with HIV (WLWH) and are risk factors for the development of mental health and substance use disorders (MHDs, SUDs), and cognitive and medical comorbidities. We examined empirically derived patterns of trauma, MHD, and SUD, and associations with later cognitive and health outcomes., Methods: A total of 1027 WLWH (average age = 48.6 years) in the Women's Interagency HIV Study completed the World Mental Health Composite International Diagnostic Interview from 2010 to 2013 to identify MHDs, SUDs, and age at onset of sexual and physical abuse. Then, cognitive impairment, cardiovascular/metabolic conditions, and HIV disease outcomes were assessed for up to 8.8 years. Latent class analysis identified patterns of co-occurring trauma, MHDs, and/or SUDs. Generalized estimating equations determined associations between these patterns and midlife cognitive and medical outcomes., Results: Six distinct profiles emerged: no/negligible sexual/physical trauma, MHD, or SUD (39%); preadolescent/adolescent sexual trauma with anxiety and SUD (22%); SUD only (16%); MHD + SUD only (12%); early childhood sexual/physical trauma only (6%); and early childhood sexual/physical trauma with later MHD + SUD (4%). Profiles including early childhood trauma had the largest number of midlife conditions (i.e., cognitive, cardiovascular, HIV-related). Preadolescent/adolescent sexual trauma with anxiety and SUD predicted both global and domain-specific cognitive declines. Only SUD without trauma predicted lower CD4, whereas childhood trauma with MHD + SUD predicted increased CD8., Conclusions: WLWH have complex multisystem profiles of abuse, MHD, and/or SUD that predict midlife cognitive, metabolic/cardiovascular, and HIV outcomes. Understanding the interplay between these factors over time can identify risks and personalize preventative and treatment interventions., (Copyright © 2023 by the American Psychosomatic Society.)

Higher stress during pregnancy associates with negative outcomes and elevated inflammation. The gut microbiota, reflecting environment and social interactions, alongside host immune responses have the potential to better understand perceived stress and identify when stress is excessive in pregnancy. Two U.S. cohorts of 84 pregnant individuals, composed of urban women of color and suburban white women, completed the Perceived Stress Scale-10 (PSS-10) and provided fecal and blood samples at two time points. Confirmatory Factor Analysis assessed the robustness of a two-factor PSS-10 model (Emotional Distress/ED and Self-Efficacy/SE). Gut microbiota composition was measured by 16 S rRNA amplicon sequencing and the immune system activity was assessed with a panel of 21 T-cell related cytokines and chemokines. ED levels were higher in the suburban compared to the urban cohort, but levels of SE were similar. ED and SE levels were associated with distinct taxonomical signatures and the gut microbiota data improved the prediction of SE levels compared with models based on socio-demographic characteristics alone. Integration of self-reported symptoms, microbial and immune information revealed a possible mediation effect of Bacteroides uniformis between the immune system (through CXCL11) and SE. The study identified links between distinct taxonomical and immunological signatures with perceived stress. The data are congruent with a model where gut microbiome and immune factors, both impacting and reflecting factors such as close social relationships and dietary fiber, may modulate neural plasticity resulting in increased SE during pregnancy. The predictive value of these peripheral markers merit further study., (© 2023. The Author(s).)

Midlife women commonly experience changes in their cognitive function as they transition through menopause and express concern about whether these changes represent the initial stages of a more serious cognitive disorder. Health-care practitioners play an important role in counseling women on cognitive changes at midlife and normalizing women's experience. The aim of this commissioned International Menopause Society White Paper on cognition is to provide practitioners with an overview of data informing the clinical care of menopausal women and a framework for clinical counseling and decision-making. Among the topics presented are the specific cognitive changes occurring in menopause, the duration of such changes and their severity. The role of estrogen and menopause symptoms is reviewed. We present talking points for clinical counseling on the effects of hormone therapy on cognition and dementia risk in women, including discussion of absolute risk. Lastly, a brief review of modifiable risk factors for age-related cognitive decline and dementia is presented, with guidance for counseling patients on optimizing their brain health at midlife and beyond.

Background Childhood maltreatment has been associated with arterial stiffness. This relationship has not been examined specifically among women at midlife, a time of increased arterial stiffness in women. This study tested whether childhood maltreatment is associated with arterial stiffness among a cohort of midlife women. Methods and Results A total of 162 nonsmoking perimenopausal and postmenopausal women free of clinical cardiovascular disease (mean age, 54 years; 72% White race, 23% Black race, and 5% Asian/Pacific Islander or Mixed race) completed the Child Trauma Questionnaire at baseline. At a follow-up visit 5 years later, blood pressure and carotid-femoral pulse wave velocity (a measure of arterial stiffness) were assessed. Relationships between childhood maltreatment and carotid-femoral pulse wave velocity were tested in linear regression models, adjusting for time between visits, age, race and ethnicity, education, body mass index, heart rate, hypertension medication, and diastolic blood pressure. Seventy-one women (44% of the sample) met criteria for a history of childhood maltreatment. Women with a history of childhood maltreatment had higher carotid-femoral pulse wave velocity (B [SE]=0.47 [0.21]; P =0.03) than women without this history, controlling for time between visits, age, race and ethnicity, education, body mass index, heart rate, hypertension medication, and diastolic blood pressure. Conclusions Among these midlife women, childhood maltreatment was associated with arterial stiffness, highlighting the potential long-term cardiovascular implications of childhood maltreatment.

Purpose: To investigate if accounting for a cup-to-disc ratio (CDR) genetic risk score (GRS) modified the association between large CDR and cognitive function among women., Design: This was a retrospective study using data from the Women's Health Initiative., Methods: Patients with glaucoma or ocular hypertension were excluded. Large CDR was defined as ≥ 0.6 in either eye. Cognitive function was measured by the Modified Mini-Mental State Examination (3MSE). We used the combined effects from 13 single nucleotide polymorphisms (SNPs) to formulate the GRS for CDR. We used logistic regression to investigate associations between weighted GRS and large CDR, then a linear regression to assess the association between weighted GRS and 3MSE scores, and between weighted GRS, CDR, and 3MSE scores, adjusted for demographic and clinical characteristics., Results: Final analyses included 1,196 White women with mean age of 69.60 ± 3.62 years and 7.27% with large CDR. Mean GRS in women with and without large CDR was 1.51 ± 0.31 vs. 1.41 ± 0.36, respectively (p = 0.004). The odds of large CDR for a one unit increase in GRS was 2.30 (95% CI: (1.22, 4.36), p = 0.011). Adding the CDR GRS in the model with CDR and 3MSE, women with large CDR still had statistically significantly lower 3MSE scores than those without large CDR, yielding a predicted mean difference in 3MSE scores of 0.84 (p = 0.007)., Conclusions: Independent of the CDR GRS, women with large CDR had a lower cognitive function., Competing Interests: The authors have declared that no competing interests exist.

Objective: Alterations in glucocorticoid receptor (GCR) function may be a risk factor for cognitive complications among older people with human immunodeficiency virus (HIV). We evaluated whether HIV serostatus and age modify the GCR function-cognition association among women., Methods: Eighty women with HIV ( n = 40, <40 years of age [younger]; n = 40, >50 years of age [older]) and 80 HIV-uninfected women ( n = 40 older, n = 40 younger) enrolled in the Women's Interagency HIV Study completed a comprehensive neuropsychological test battery. Peripheral blood mononuclear cells collected concurrent with neuropsychological testing were assessed for GCR function. Multivariable linear regression analyses were conducted to examine whether a) HIV serostatus and age were associated with GCR function, and b) GCR function-cognition associations are moderated by HIV serostatus and age adjusting for relevant covariates., Results: Among older women, higher baseline FKBP5 expression level was associated with lower attention/working memory performance among women with HIV ( B = 6.4, standard error = 1.7, p = .0003) but not in women without HIV infection ( B = -1.7, standard error = 1.9, p = .37). There were no significant HIV serostatus by age interactions on dexamethasone (DEX)-stimulated expression of the genes regulated by the GCR or lipopolysaccharide-stimulated tumor necrosis factor α levels (with or without DEX stimulation; p values > .13). HIV serostatus was associated with GC target genes PER1 ( p = .006) and DUSP1 ( p = .02), but not TSC22D3 ( p = .32), after DEX stimulation., Conclusions: Collectively, these data suggest that HIV serostatus and age may modify the influence of the GCR, such that the receptor is likely engaged to a similar extent, but the downstream influence of the receptor is altered, potentially through epigenetic modification of target genes., (Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Psychosomatic Society.)

Objective: Early life trauma (ELT) and HIV are associated with social processing deficits. In people with HIV (PWH), we examined whether facial emotion identification accuracy differs by ELT and whether neuroendocrine factors including cortisol, oxytocin (OT), and arginine vasopressin, and/or immune system measures play a role in the ELT-performance association., Methods: We used secondary data from the placebo condition of a pharmacologic challenge study in PWH. Presence of ELT was measured with the Childhood Trauma Questionnaire (at least moderate experiences of sexual, physical, and/or emotional abuse). Social processing was measured with the Facial Emotion Perception Test (FEPT). Salivary immune system measures and cortisol were sampled across a 5-hour study session. Blood was collected at study session start (12 pm ) to measure OT and arginine vasopressin. We examined the association of ELT with FEPT and five biological moderators (from principal components analysis of 12 biomarkers) of ELT-FEPT associations., Results: Of 58 PWH (42 men; mean [standard deviation] age = 33.7 [8.9] years), 50% endorsed ELT. ELT-exposed PWH demonstrated lower identification accuracy across all emotional expressions (unstandardized β [ B ] = 0.13; standard error [SE] = 0.05; p = .021, d = 0.63) and had higher OT levels compared with ELT-unexposed PWH ( t(1,56) = 2.12, p = .039; d = 0.57). For total accuracy, an OT/C-reactive protein factor moderated the ELT-FEPT association ( B = 0.14; SE = 0.05; p = .014); accuracy was lower in ELT-exposed PWH versus ELT-unexposed PWH when the factor was low but not when high. Similar results were obtained for fearful, neutral, and happy faces ( p values < .05). Regardless of ELT, a myeloid migration (MCP-1/MMP-9) factor was associated with reduced accuracy ( p values < .05)., Conclusions: Our pilot findings suggest that ELT may alter social processing in PWH, and OT and C-reactive protein may be a target for improving social processing in ELT-exposed PWH, and myeloid migration markers may be a target in PWH more generally., (Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Psychosomatic Society.)

The number of people with HIV (PWH) experiencing age-associated comorbidities including those treated with medications and cognitive impairment is increasing. We examined associations between polypharmacy and cognition in older women with HIV (WWH) given their vulnerability to this comorbidity. Cross-sectional analysis capitalizing on Women's Interagency HIV Study data collected between 2014 and 2017. WWH meeting the following criteria were analyzed: age ≥50 years; availability of self-reported non-antiretroviral therapy (ART) medications data; and neuropsychological data. The number of non-ART medications used regularly in the prior 6 months was summed. Polypharmacy was categorized as none/low (0-4), moderate (5-9), or severe (≥10). Multivariable linear regression analyses examined polypharmacy-cognition (T-score) associations in the total sample and among virally suppressed (VS; < 20 copies/mL)-WWH after covariate adjustment for enrollment site, income, depressive symptoms, substance use (smoking, heavy alcohol, marijuana, crack, cocaine, and/or heroin), the Veterans Aging Cohort Study index (indicators of HIV disease and organ system function, hepatitis C virus serostatus), ART use, nadir CD4 count, and specific ART drugs (efavirenz, integrase inhibitors). We included 637 women (median age = 55 years; 72% Black). Ninety-four percent reported ART use in the past 6 months and 75% had HIV RNA <20 copies/mL. Comorbidity prevalence was high (61% hypertension; 26% diabetes). Moderate and severe polypharmacy in WWH were 34% and 24%. In WWH, severe polypharmacy was associated with poorer executive function ( p  = .007) and processing speed ( p  = .01). The same pattern of findings remained among VS-WWH. Moderate polypharmacy was not associated with cognition. Moderate and severe polypharmacy were common and associated with poorer executive function and processing speed in WWH. Severe polypharmacy may be a major contributor to the persistence of domain-specific cognitive complications in older WWH above and beyond the conditions that these medications are used to treat.

Background & Aims: Normal gestation involves a reprogramming of the maternal gut microbiome (GM) that contributes to maternal metabolic changes by unclear mechanisms. This study aimed to understand the mechanistic underpinnings of the GM-maternal metabolism interaction., Methods: The GM and plasma metabolome of CD1, NIH-Swiss, and C57 mice were analyzed with the use of 16S rRNA sequencing and untargeted liquid chromatography-mass spectrometry throughout gestation. Pharmacologic and genetic knockout mouse models were used to identify the role of indoleamine 2,3-dioxygenase (IDO1) in pregnancy-associated insulin resistance (IR). Involvement of gestational GM was studied with the use of fecal microbial transplants (FMTs)., Results: Significant variation in GM alpha diversity occurred throughout pregnancy. Enrichment in gut bacterial taxa was mouse strain and pregnancy time point specific, with the species enriched at gestation day 15/19 (G15/19), a point of heightened IR, being distinct from those enriched before or after pregnancy. Metabolomics revealed elevated plasma kynurenine at G15/19 in all 3 mouse strains. IDO1, the rate-limiting enzyme for kynurenine production, had increased intestinal expression at G15, which was associated with mild systemic and gut inflammation. Pharmacologic and genetic inhibition of IDO1 inhibited kynurenine levels and reversed pregnancy-associated IR. FMT revealed that IDO1 induction and local kynurenine level effects on IR derive from the GM in both mouse and human pregnancy., Conclusions: GM changes accompanying pregnancy shift IDO1-dependent tryptophan metabolism toward kynurenine production, intestinal inflammation, and gestational IR, a phenotype reversed by genetic deletion or inhibition of IDO1. (Gestational Gut Microbiome-IDO1 Axis Mediates Pregnancy Insulin Resistance; EMBL-ENA ID: PRJEB45047. MetaboLights ID: MTBLS3598)., (Published by Elsevier Inc.)

Perinatal depression affects 6.5-12.9% of women, with high rates in women of color and comorbid perinatal anxiety in up to 50% of cases. The Research Domain Criteria (RDoC) provides a translational framework for identifying transdiagnostic psychiatric symptoms, but its application in perinatal affective disorders (PNAD) is yet limited. Here, we identified RDoC-based transdiagnostic features of PNAD in 140 primarily low-income Black and Hispanic women at 272 total longitudinal visits across the perinatal period. Women completed RDoC self-report measures of potential threat and reward valuation-Behavioral Inhibition System/Behavioral Activation System scale (BIS/BAS) and Intolerance of Uncertainty Scale (IUS)-and measures of depression (Patient Health Questionnaire-9; PHQ-9) and anxiety (Generalized Anxiety Disorder-7; GAD-7). Longitudinal mixed effects models assessed associations of between-person ("trait-like") and within-person ("state-like") measures of potential threat (BIS/IUS) and reward valuation (BAS-Drive) with depression and anxiety symptoms. Higher "trait-like" BIS (standardized b = 2.33, p < .001) and IUS (b = 2.97, p < .001) scores, higher "state-like" BIS (b = .71, p < .001), and lower "state-like" BAS-Drive (b =  - .58, p = .04) scores were associated with worse depressive symptoms. Higher "trait-like" BIS (b = 2.22, p < .001) and IUS (b = 2.73, p < .001) and higher "state-like" BIS scores (b = .92, p < .001) were associated with worse anxiety symptoms. Potential threat may be a prominent, transdiagnostic feature of perinatal anxiety and depression, whereas reward valuation may be a non-transdiagnostic, weaker feature of perinatal depression. Potential threat is important as both a "trait-like" feature that is sustained across the perinatal period and a "state-like" feature that varies within a woman across pregnancy. Grounded in RDoC, this work reveals neurobiological targets for translational research into PNAD., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Austria, part of Springer Nature.)

Traumatic experiences have been linked to poor mental and physical health. However, there has been little examination of their relationship to neuroimaging markers of cerebrovascular risk. White matter hyperintensities (WMHs) are markers of brain small vessel disease. WMHs can be detected decades before the onset of dementia and other disorders and can serve as early markers for these brain disorders. We tested whether traumatic experiences were associated with brain WMH volume among midlife women. In the MsBrain study, 145 women (mean age = 59 years) without cardiovascular disease, stroke, or dementia were recruited. Women completed questionnaires [trauma checklist, depression, post-traumatic stress measures]; physical measures [body mass index (BMI), blood pressure (BP)]; phlebotomy; actigraphy sleep measurement, and 3 Tesla magnetic resonance brain imaging for WMHs. Cross-sectional associations between traumatic experiences and WMH volume were assessed in linear regression models. Covariates were age, race/ethnicity, education, BMI, BP, lipids, preeclampsia, sleep, and additionally depressive and post-traumatic stress disorder symptoms. 68% of women endorsed at least one of the traumas assessed. The most common trauma was sexual assault (23% of women). Women with trauma exposure had greater WMH volume than women without trauma [B(SE) = .24 (.09), p = .01, multivariable]. The single trauma most associated with WMH was sexual assault [B(SE) = .25 (.11), p = .02, multivariable]. Results persisted adjusting for depressive or post-traumatic stress symptoms. A trauma history, particularly sexual assault, was associated with greater WMH volume controlling for covariates, including depressive and post-traumatic symptoms. Sexual assault may place women at risk for poor brain health., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Individuals engage in a range of behaviors to maintain close relationships. One behavior is self-silencing or inhibiting self-expression to avoid relationship conflict or loss. Self-silencing is related to poor mental health and self-reported physical health in women but has not been examined in relation to cardiovascular health, particularly using direct measures of the vasculature., Purpose: To test associations between self-silencing and carotid atherosclerosis in midlife women; secondary analyses examined moderation by race/ethnicity., Methods: Women (N = 290, ages 40-60) reported on self-silencing in intimate relationships and underwent physical measurements, blood draw, and ultrasound assessment of carotid intima-media thickness (IMT) and plaque. Associations between self-silencing and mean IMT and plaque index (0, 1, ≥2) were tested in linear regression and multinomial logistic regression models, respectively, followed by interaction terms between self-silencing and race, adjusted for demographic factors, CVD risk factors, partner status, depression, physical activity, and diet., Results: Forty-seven percent of women demonstrated carotid plaque. Greater self-silencing was related to increased odds of plaque index ≥2 (e.g., for each additional point, odds ratio [95% confidence interval] = 1.16 [1.03-1.31], p = .012), relative to no plaque). Moderation analyses indicated that self-silencing was related to odds of plaque index ≥2 in non-white women (1.15 [1.05-1.26], p = .004), but there was no significant relationship in white women (1.01 [0.97-1.06], p = .550). No associations emerged for IMT., Conclusions: Among midlife women, self-silencing was associated with carotid plaque, independent of CVD risk factors, depression, and health behaviors. Emotional expression in relationships may be important for women's cardiovascular health., (© Society of Behavioral Medicine 2021. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Underserved women of color experience high rates of perinatal affective disorders, but most research to date on the natural history of these disorders has been conducted on White women. The present study investigated longitudinal changes in anxiety and depression in a sample of perinatal non-Hispanic Black and Latina women. Categorical (yes/no) measures of positive anxiety and depression screens, as well as total symptom scores, were measured longitudinally across the perinatal period in 178 women (115 non-Hispanic Black, 63 Latina) using the CAT-MH™, a computerized adaptive test. Time (up to 4 visits) and race/ethnicity effects were assessed in linear mixed effects models. Rates of positive anxiety screenings were 13.6%, 3.2%, 8.5%, and 0% in Latina women and 2.6%, 4.2%, 6.1%, and 5.8% in non-Hispanic Black women in the 1 st , 2 nd , and 3 rd trimesters, and postpartum, respectively. Rates of positive anxiety screenings overall were highest in the first trimester (OR = 0.20; 95% CI 0.04-0.98), and there was a significant time-by-race/ethnicity interaction for positive anxiety screens (OR = 8.88; 95% CI 1.42-55.51), as positive screens were most frequent in the first trimester and sharply declined for Latina women, while rates were relatively consistent across the perinatal period in non-Hispanic Black women. Rates of positive depression screens did not change over time, but there was a trend (OR = 1.93; 95% CI 0.93-4.03) for a time-by-race/ethnicity interaction in a direction similar to that seen for anxiety. The odds of positive anxiety screens vary by race/ethnicity and trimester, suggesting that anxiety screening and anxiety interventions may be most resourcefully used in the first trimester for Latina women in particular., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Austria, part of Springer Nature.)

Objective: Self-compassion is a positive psychological construct characterized by extending compassion toward oneself, often during periods of suffering. Whereas self-compassion has been associated with psychological outcomes, research linking self-compassion to physical health is limited. We tested the hypothesis that greater self-compassion would be associated with less subclinical cardiovascular disease (CVD) as assessed by carotid intima-media thickness (IMT). We adjusted for demographics, CVD risk factors and additionally depressive symptoms in these associations., Method: Women (N = 195; M age = 59 years) without CVD were recruited. Women completed questionnaires (Neff Self-Compassion Scale, Center for Epidemiology Studies of Depression Scale); physical measures (body mass index [BMI], blood pressure [BP]); phlebotomy (lipids, insulin resistance); and ultrasound assessments of the carotid artery (mean, maximal IMT). Cross-sectional associations between self-compassion and IMT were assessed in linear regression models covarying for age, race/ethnicity, education, and CVD risk factors (BMI, BP, insulin resistance, lipids, medications), and additionally depressive symptoms., Results: Higher self-compassion was associated with lower mean IMT [B(SE)=-.03 (.01), p = .02], adjusting for demographic factors and CVD risk factors. Associations persisted adjusting for depressive symptoms. When considering self-compassion subscale bifactors, the positive self-compassion bifactor (self-compassion), but not negative self-compassion bifactor (self-coldness), was related to lower IMT., Conclusions: Self-compassion is associated with lower subclinical CVD. Associations were not explained by standard CVD risk factors nor by depressive symptoms. Future research should consider whether enhancing self-compassion improves women's vascular health. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

One sex differences in the perception of emotion is that females, particularly those with high anxiety, often show heightened identification of fearful faces. To better understand the causal role of glucocorticoids in this sex difference, we examine these associations in people with HIV(PWH) where emotion perception is impaired and mental health disorders are frequent. In a double-blind, placebo-controlled, cross-over study, we used a single low-dose of hydrocortisone (10 mg; LDH) as a mechanistic probe of the effects of elevated glucocorticoids on negative emotion perception in 65 PWH (31 women). The primary outcome was accuracy in identifying emotional expressions on the Facial Emotion Perception Test (FEPT). Salivary cortisol, self-reported stress/anxiety, and childhood trauma were also assessed. LDH increased salivary cortisol levels versus placebo. The effect of LDH versus placebo on FEPT accuracy depended on the combined influence of facial expression and sex (P = 0.03). LDH influenced accuracy only for women (P = 0.03), specifically for fearful faces (Cohen's d = 0.44, P = 0.04). Women's enhanced threat detection varied with psychological burden (mood, anxiety, and post-traumatic stress symptoms), more pronounced among those with lower burden and trauma (P < 0.05). This result suggests a role of the HPA axis in sex differences for perception of fearful faces in women with HIV, potentially due to changes in glucocorticoid receptor availability/activity, or improved integration of signals from facial recognition and emotion processing regions. The blunting of this effect in men and in individuals with more severe trauma suggests that the mechanisms underlying threat detection differ by sex and trauma history and warrant further investigation., (© 2021. Journal of NeuroVirology, Inc.)

Progesterone (P4) can be metabolized to two general classes of neuroactive steroids (NAS) -those like allopregnanolone (ALLO) and pregnanolone (PA) which are positive allosteric modulators of the Gamma Aminobutyric Acid type A (GABA A ) receptor and those like isoallopregnanolone (ISOALLO) and epipregnanolone (EPI) which are negative allosteric modulators of the GABA A receptor. While exogenous administration of ALLO is effective in treating postpartum depression, knowledge gaps remain in the dynamic interplay of NAS across the perinatal period. In particular little is known about ALLO and PA in relation to depression earlier in pregnancy, and the role of ISOALLO and EPI in relation to depression at any point in the perinatal period. In a prospective, nested case/control study in low-income women of color, we compared the metabolism of P4 to four NAS (i.e., ratios ALLO:P4, PA:P4, ISOALLO:P4, EPI:P4) in pregnant women with depression at either or both of the first and second trimesters (cases) and women without depression at either time point (controls). Fifty women (36% depressed, 56% Black, 28% Latina) completed depression screening using a computerized adaptive test of mental health (CAT-MH™) and provided blood serum samples in both trimesters. In longitudinal mixed effects models of both trimesters, PND cases showed higher ratios of ALLO:P4 (p = .002) and PA:P4 (p = .03) compared to controls. In regression models of only first trimester data, there was no significant difference in NAS ratios between cases and controls (p > .05). Conversely, in models of the second trimester, ratios of PA:P4 (p = .002) and ISOALLO:P4 (p = .01) were significantly higher in cases compared to controls, and ratios of ALLO:P4 (p = .08) and EPI:P4 (p = .1) also trended higher in cases. The most severe cases, those with depression at both trimesters, showed an increase in ALLO:P4 (p = .06) and EPI:P4 (p < .001) ratios from the first to the second trimester, whereas controls showed a decrease in these ratios. Secondary analyses confirmed higher levels of ALLO (p = .04) and PA (p = .07) overall in cases compared to controls, along with higher levels of PA (p = .005) and ISOALLO (p = .02) in the second trimester alone. This work suggests a dynamic relationship between NAS and PND; whereas low ALLO levels have been previously associated with postpartum depression, earlier in pregnancy a higher metabolism of P4 to ALLO (and higher ALLO levels) is associated with depression. Some women may show a hormone-sensitive depressive response to acute increases in NAS metabolism in early pregnancy., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

There has been a proliferation of studies demonstrating important sex differences in cognitive aging and dementia, and with this an increased interest in the role of menopause and sex steroid hormones in women's brain health. Foundational longitudinal studies of cognitive changes from the premenopause to perimenopause stage have shown reliable declines in verbal memory, with variable findings in processing speed, attention/working memory and verbal fluency. Continued research is needed to advance understanding of the range of cognitive domains affected, the duration of cognitive changes, the generalizability of these changes across cultures, the factors that account for such changes and the factors that can improve cognition at this time. In this article, we briefly review and draw on findings from large longitudinal studies of cognitive changes across the menopause transition to inform the design of future studies on this topic. We focus on key issues such as objective versus subjective cognitive measures; cognitive domains and tests; staging menopause; study design; mediators of cognitive effects (including hormones and menopause symptoms); and consideration of key covariates. We suggest that a more uniform and evidence-based approach to the investigation of these issues can advance the quality of the science in menopause and cognition.

Objective: Perimenopause is associated with declines in attention, working memory and verbal memory; however, there are significant individual differences. Further, the contributions of hormones and menopausal symptoms to domain-specific cognitive functions remain unknown. This longitudinal study aimed to determine whether there were distinct cognitive profiles in perimenopause and to identify factors associated with each profile., Design: In a sample of 85 women evaluated over 400 bi-annual visits, we administered a comprehensive neuropsychological battery, assessed menopausal symptoms and measured 17β-estradiol and follicle stimulating hormone. Multilevel latent profile analysis was used to identify cognitive profiles. Regressions were conducted to determine differences in hormones and symptoms by profile after adjusting for Stages of Reproductive Aging Workshop + 10 (STRAW + 10) stage and demographic factors., Results: Perimenopausal cognitive profiles consisted of cognitively normal (Profile 1; n  = 162), weaknesses in verbal learning and memory (Profile 2; n  = 94), strengths in verbal learning and memory (Profile 3; n  = 98) and strengths in attention and executive function (Profile 4; n  = 61). Profile 2 was differentiated by less hormonal variability and more sleep disturbance than Profile 1 ( p  < 0.05)., Conclusions: There is significant heterogeneity in cognition during perimenopause. While most women do not develop impairments, a significant minority experience weaknesses in verbal learning and memory. Profile analysis may identify at-risk populations and inform interventions.

BACKGROUNDIdentifying a quantitative biomarker of neuropsychiatric dysfunction in people with HIV (PWH) remains a significant challenge in the neuroHIV field. The strongest evidence to date implicates the role of monocytes in central nervous system (CNS) dysfunction in HIV, yet no study has examined monocyte subsets in blood as a correlate and/or predictor of neuropsychiatric function in virally suppressed PWH.METHODSIn 2 independent cohorts of virologically suppressed women with HIV (vsWWH; n = 25 and n = 18), whole blood samples were obtained either in conjunction with neuropsychiatric assessments (neuropsychological [NP] test battery, self-report depression and stress-related symptom questionnaires) or 1 year prior to assessments. Immune cell subsets were assessed by flow cytometry.RESULTSA higher proportion of intermediate monocytes (CD14+CD16+) was associated with lower global NP function when assessing monocytes concurrently and approximately 1 year before (predictive) NP testing. The same pattern was seen for executive function (mental flexibility) and processing speed. Conversely, there were no associations with monocyte subsets and depression or stress-related symptoms. Additionally, we found that a higher proportion of classical monocytes was associated with better cognition.CONCLUSIONAlthough it is widely accepted that lentiviral infection of the CNS targets cells of monocyte-macrophage-microglial lineage and is associated with an increase in intermediate monocytes in the blood and monocyte migration into the brain, the percentage of intermediate monocytes in blood of vsWWH has not been associated with neuropsychiatric outcomes. Our findings provide evidence for a new, easily measured, blood-based cognitive biomarker in vsWWH.FUNDINGR01-MH113512, R01-MH113512-S, P30-AI094189, R01-MH112391, R01-AI127142, R00-DA044838, U01-AI35004, and P30-MH075673.

Objective: Genitourinary symptoms, such as vaginal dryness and pain with sex, are commonly experienced by postmenopausal women. Comparing treatments for these genitourinary symptoms are restricted by the use of different outcome measures in clinical trials and the omission of outcomes, which may be relevant to women. The aim of this project was to develop a Core Outcome Set (COS) to be reported in clinical trials of treatments for genitourinary symptoms associated with menopause., Methods: We performed a systematic review of randomized controlled trials of treatments for genitourinary symptoms associated with menopause and extracted their outcomes. This list was refined and entered into a two-round modified Delphi survey, which was open to clinicians, researchers, and postmenopausal women from November 2019 to March 2020. Outcomes were scored on a nine-point scale from "not important" to "critically important." The final COS was determined following two international consensus meetings., Results: A total of 26 unique outcomes were included in the Delphi process, which was completed by 227 participants of whom 58% were postmenopausal women, 34% clinicians, and 8% researchers. Predefined thresholds were applied to the Delphi scores to categorize outcomes by importance, which informed the e consensus meetings, attended by 43 participants from 21 countries. The final COS includes eight outcomes: (1) pain with sex, (2) vulvovaginal dryness, (3) vulvovaginal discomfort or irritation, (4) discomfort or pain when urinating, (5) change in most bothersome symptom, (6) distress, bother or interference of genitourinary symptoms, (7) satisfaction with treatment, (8) side effects of treatment., Conclusion: These eight core outcomes reflect the joint priorities of postmenopausal women, clinicians, and researchers internationally. Standardized collection and reporting of these outcomes in clinical trials will facilitate the comparison of different treatments for genitourinary symptoms, advance clinical practice, and ultimately improve outcomes for symptomatic women., (Copyright © 2021 by The North American Menopause Society.)

Objective: Vasomotor symptoms (VMS) (hot flashes and night sweats) affect most women over the menopause transition. Comparing the safety and effectiveness of treatments for vasomotor symptoms is limited by the use of inconsistent outcome measures, and uncertainty as to which outcomes are most important to symptomatic women. To address this, we have developed a Core Outcome Set (COS) for use in clinical trials of treatments for VMS., Methods: We systematically reviewed the primary outcomes measured in randomized controlled trials of treatments for VMS. These were refined and entered into a two-round modified Delphi survey completed by clinicians, researchers, and postmenopausal women between November 2019 and March 2020. Outcomes were scored on a nine-point scale from "not important" to "critically important." Two international consensus meetings were held to finalize the COS., Results: Based on the systematic review, 13 separate outcomes were included in the Delphi process. This was completed by 227 participants of whom 58% were postmenopausal women, 34% clinicians, and 8% researchers. Predefined thresholds were applied to categorize importance scores obtained during Round 2 of the Delphi survey. These informed discussions at the consensus meetings which were attended by 56 participants from 28 countries. The final COS includes six outcomes: 1) frequency of VMS, 2) severity of VMS, 3) distress, bother or interference caused by VMS, 4) impact on sleep, 5) satisfaction with treatment, and 6) side-effects of treatment., Conclusion: Implementation of this COS will: better enable research studies to accurately reflect the joint priorities of postmenopausal women, clinicians and researchers, standardize outcome reporting, and facilitate combining and comparing results from different studies, and ultimately improve outcomes for women with bothersome VMS., Competing Interests: Financial disclosure/conflicts of interest: S.L., S.I., M.C., R.B., H.R., K.G., U.J., S.K., B.V.K., J.S., and M.S.H. declare no disclosures/conflicts of interest., (Copyright © 2021 by The North American Menopause Society.)

Background: Integrase strand transfer inhibitors (INSTIs) are first-line regimens for HIV treatment. We aimed to examine their impact on cognitive performance and depressive symptoms in women with HIV (WWH)., Setting: Women's Interagency HIV Study, a multisite, prospective, cohort study., Methods: WWH who started or switched to INSTI-based antiretroviral therapy (ART) and completed neuropsychological testing and the Center for Epidemiological Studies-Depression (CES-D) scale before and after INSTI start/switch were included in the analyses. Primary outcomes were demographically corrected cognitive domain T-scores. Linear mixed-effects models adjusted for relevant covariates were used to examine effects of start/switch of any INSTI and individual INSTI drugs on cognition and CES-D scores., Results: Six hundred thirty-nine WWH, median age 49 (interquartile range 12) years, 66% Black non-Hispanic, had neuropsychological and CES-D scale data before and after INSTI start/switch. Although 14% started INSTI-based ART, the remainder switched to INSTI-based ART from another regimen. Overall, any INSTI use was associated with poorer learning post-INSTI. Specifically, use of dolutegravir and elvitegravir, but not raltegravir, was associated with poorer learning. In analyses restricted to INSTI switch, any INSTI use, and dolutegravir use, was associated with poorer learning. Among those switching from a PI-based regimen, INSTIs overall and dolutegravir remained associated with poorer learning; switching from a nonnucleoside reverse transcriptase inhibitor to dolutegravir was also associated with poorer learning. INSTI start/switch was not related to depressive symptom changes., Conclusions: INSTI use was associated with poorer learning among WWH. These changes were mainly observed in elvitegravir and dolutegravir users, indicating that the impact of INSTI on cognition in WWH may not be a class effect., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.)

Cognitive complications persist in antiretroviral therapy(ART)-treated people with HIV. However, the pattern and severity of domain-specific cognitive performance is variable and may be exacerbated by ART-mediated neurotoxicity. 929 women with HIV(WWH) from the Women's Interagency HIV Study who were classified into subgroups based on sociodemographic and longitudinal behavioral and clinical data using semi-parametric latent class trajectory modelling. Five subgroups were comprised of: 1) well-controlled HIV with vascular comorbidities(n = 116); 2) profound HIV legacy effects(CD4 nadir <250 cells/μL; n = 275); 3) primarily <45 year olds with hepatitis C(n = 165); 4) primarily 35-55 year olds(n = 244), and 5) poorly-controlled HIV/substance use(n = 129). Within each subgroup, we fitted a constrained continuation ratio model via penalized maximum likelihood to examine adjusted associations between recent ART agents and cognition. Most drugs were not associated with cognition. However, among the few drugs, non-nucleoside reverse transcriptase inhibitor (NNRTIs) and protease inhibitors(PIs) were most commonly associated with cognition, followed by nucleoside reverse transcriptase inhibitors(NRTIs) and integrase inhibitors(IIs). Directionality of ART-cognition associations varied by subgroup. Better psychomotor speed and fluency were associated with ART for women with well-controlled HIV with vascular comorbidities. This pattern contrasts women with profound HIV legacy effects for whom poorer executive function and fluency were associated with ART. Motor function was associated with ART for younger WWH and primarily 35-55 year olds. Memory was associated with ART only for women with poorly-controlled HIV/substance abuse. Findings demonstrate interindividual variability in ART-cognition associations among WWH and highlight the importance of considering sociodemographic, clinical, and behavioral factors as an underlying contributors to cognition. Are antiretroviral agents a risk factor for cognitive complications in women with HIV? We examind associations between ART-agents and cognitive function among similar subgroups of women with HIV from the Women's Interagency HIV study. The patterns of associations depended on sociodemographic, clinical, and behavioral characteristics of women.

Antiretroviral therapy (ART) is inconsistently associated with depression. These associations may depend on factors such as biological sex, age, and health status. Identifying such factors may help optimize treatment of HIV and depression. We implemented a novel approach to examine interindividual variability in the association between ART agents and depressive symptoms. 3434 women living with HIV (WLWH) from the Women's Interagency HIV Study (WIHS) were computationally divided into subgroups based on sociodemographic (e.g., age) and longitudinal (from 1995 to 2016) behavioral and clinical profiles (e.g., substance use, HIV RNA, CD4 counts). Five subgroups (n's ranged from 482 to 802) were identified and characterized as those with: controlled HIV/vascular comorbidities; profound HIV legacy effects; younger women [<45 years of age] with hepatitis C; primarily 35-55 year olds; and poorly controlled HIV/substance use. Within each subgroup, we examined associations between ART agents used over the past 6 months and item-level depressive symptoms on the Center for Epidemiologic Studies Depression Scale. Tenofovir (4 of 5 subgroups) followed by efavirenz, emtricitabine, stavudine, lopinavir, etravirine, nelfinavir, ritonavir, and maraviroc were the most common agents associated with depressive symptoms, although the pattern and directionality varied by subgroup. For example, lopinavir was associated with fewer symptoms among the subgroup with a legacy HIV effect but more symptoms among the subgroup with well-controlled HIV/vascular comorbidities. Unexpectedly, dolutegravir and raltegravir were not associated with depressive symptoms among any subgroup. Findings underscore marked interindividual variability in ART agents on depression in WLWH. Sociodemographic, clinical, and behavioral factors are important determinants of the relationship between ART agents and depressive symptoms in WLWH. Graphical Abstract Are antiretroviral agents a risk factor for depressive symptoms in women with HIV? We examined associations between ART-agents and depressive symptoms among similar subgroups of women with HIV from the Women's Interagency HIV Study. The patterns of associations depended on sociodemographic, clinical, and behavioral characteristics of women.

Cognitive impairment remains frequent and heterogeneous in presentation and severity among virally suppressed (VS) women with HIV (WWH). We identified cognitive profiles among 929 VS-WWH and 717 HIV-uninfected women from 11 Women's Interagency HIV Study sites at their first neuropsychological (NP) test battery completion comprised of: Hopkins Verbal Learning Test-Revised, Trail Making, Symbol Digit Modalities, Grooved Pegboard, Stroop, Letter/Animal Fluency, and Letter-Number Sequencing. Using 17 NP performance metrics (T-scores), we used Kohonen self-organizing maps to identify patterns of high-dimensional data by mapping participants to similar nodes based on T-scores and clustering those nodes. Among VS-WWH, nine clusters were identified (entropy = 0.990) with four having average T-scores ≥45 for all metrics and thus combined into an "unimpaired" profile ( n = 311). Impaired profiles consisted of weaknesses in: (1) sequencing ( Profile-1 ; n = 129), (2) speed ( Profile-2 ; n = 144), (3) learning + recognition ( Profile-3 ; n = 137), (4) learning + memory ( Profile-4 ; n = 86), and (5) learning + processing speed + attention + executive function ( Profile-5 ; n = 122). Sociodemographic, behavioral, and clinical variables differentiated profile membership using Random Forest models. The top 10 variables distinguishing the combined impaired vs. unimpaired profiles were: clinic site, age, education, race, illicit substance use, current and nadir CD4 count, duration of effective antiretrovirals, and protease inhibitor use. Additional variables differentiating each impaired from unimpaired profile included: depression, stress-symptoms, income ( Profile-1 ); depression, employment ( Profile 2 ); depression, integrase inhibitor (INSTI) use ( Profile-3 ); employment, INSTI use, income, atazanavir use, non-ART medications with anticholinergic properties ( Profile-4 ); and marijuana use ( Profile-5 ). Findings highlight consideration of NP profile heterogeneity and potential modifiable factors contributing to impaired profiles., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Dastgheyb, Buchholz, Fitzgerald, Xu, Williams, Springer, Anastos, Gustafson, Spence, Adimora, Waldrop, Vance, Milam, Bolivar, Weber, Haughey, Maki and Rubin.)