Exploring heterogeneity: a dive into preclinical models of cancer cachexia.

Cancer cachexia (CC) is a multifactorial and complex syndrome experienced by up to 80% of patients with cancer and implicated in ∼40% of cancer-related deaths. Given its significant impact on patients' quality of life and prognosis, there has been a growing emphasis on elucidating the underlying mechanisms of CC using preclinical models. However, the mechanisms of cachexia appear to differ across several variables including tumor type and model and biologic variables such as sex. These differences may be exacerbated by variance in experimental approaches and data reporting. This review examines literature spanning from 2011 to March 2024, focusing on common preclinical models of CC, including Lewis Lung Carcinoma, pancreatic KPC, and colorectal colon-26 and Apcmin/+ models. Our analysis reveals considerable heterogeneity in phenotypic outcomes, and investigated mechanisms within each model, with particular attention to sex differences that may be exacerbated through methodological differences. Although searching for unified mechanisms is critical, we posit that effective treatment approaches are likely to leverage the heterogeneity presented by the tumor and pertinent biological variables to direct specific interventions. In exploring this heterogeneity, it becomes critical to consider methodological and data reporting approaches to best inform further research.

A preclinical systematic review and meta-analysis assessing the effect of biological sex in lipopolysaccharide-induced acute lung injury.

It is unclear what effect biological sex has on outcomes of acute lung injury (ALI). Clinical studies are confounded by their observational design. We addressed this knowledge gap with a preclinical systematic review of ALI animal studies. We searched MEDLINE and Embase for studies of intratracheal/intranasal/aerosolized lipopolysaccharide administration (the most common ALI model) that reported sex-stratified data. Screening and data extraction were conducted in duplicate. Our primary outcome was histological tissue injury and secondary outcomes included alveolar-capillary barrier alterations and inflammatory markers. We used a random-effects inverse variance meta-analysis, expressing data as standardized mean difference (SMD) with 95% confidence intervals (CIs). Risk of bias was assessed using the Systematic Review Centre for Laboratory Animal Experimentation (SYRCLE) tool. We identified six studies involving 132 animals across 11 independent experiments. A total of 41 outcomes were extracted, with the direction of effect suggesting greater severity in males than females in 26/41 outcomes (63%). One study reported on lung histology and found that male mice exhibited greater injury than females (SMD: 1.61, 95% CI: 0.53-2.69). Meta-analysis demonstrated significantly elevated albumin levels (SMD: 2.17, 95% CI: 0.63-3.70) and total cell counts (SMD: 0.80, 95% CI: 0.27-1.33) in bronchoalveolar lavage fluid from male mice compared with female mice. Most studies had an "unclear risk of bias." Our findings suggest sex-related differences in ALI severity. However, these conclusions are drawn from a small number of animals and studies. Further research is required to address the fundamental issue of biological sex differences in LPS-induced ALI.

Understanding the relationship between gender and mental health in adolescence: the Gender Adherence Index (GAI).

Half of all mental health disorders appear during adolescence, although it is still far from clear how they relate to gender (not sex) criteria. This study aims both to analyse the relationship between gender and adolescent mental health and to propose an index: the Gender Adherence Index (GAI). We used cross-sectional, secondary data from 3888 adolescents (aged 13-19) from the FRESC Health Survey on Adolescence in Barcelona. We analysed the interaction among sex, age and socio-economic status with several mental health indices. Additionally, we computed a Gender Adherence Index (GAI) to transcend the information-poor binary sex label, and thus assess to what extent mental health can be predicted by the gender expression of adolescents irrespective of their biological sex. We found that older age and lower economic status have a greater impact on the emotional distress of girls, who reported lower self-perceived mental health than boys. Nevertheless, girls obtained higher scores regarding their prosocial behaviour, which is protective against mental health problems. The GAI was retained in all statistical models stressing it as a relevant metric to explain the variability of adolescent emotional distress. Young people who showed adherence to normative femininity in their lifestyles showed higher prosocial behaviour but did not tend to present more emotional distress. Despite its limitations, this is a novel attempt to explore the relationship between gender expression and mental health. Better defined indices of gender adherence could help us to improve our predictive capacity of mental health disorders during adolescence.

Variation in Demographics, Hospital, and Patient-Reported Outcomes Following Total Hip Arthroplasty According to Biological Sex.

BACKGROUND: The effect of biological sex on the outcomes of total hip arthroplasty (THA) remains unclear. Accounting for biological sex in research is crucial for reproducibility and accuracy. Average combined data may mask sex-related variation and obscure clinically relevant differences in outcomes. The aim of this study is to investigate hospital and patient-reported outcome measures (PROMs) after THA by biological sex to elucidate differences and ultimately provide more equitable care. METHODS: We performed a retrospective review of patients undergoing primary THA at a single large academic center between January 2013 and August 2020. Demographics, operative variables, hospital outcomes, and PROMs were compared between men and women patients. The PROMs included preoperative, 6-weeks, 6-months, and 1-year Single Assessment Numeric Evaluation, Visual Analog Scale, Hip Disability and Osteoarthritis Outcome Score Joint Replacement, University of California, Los Angeles, and Patient-Reported Outcomes Measurement Information System mental and physical scores, as well as satisfaction scores. RESULTS: A total of 6,418 patients were included (55% women). Women were older (P < .001), had a lower body mass index (P < .001), and were more likely to have public insurance (P < .001). Fewer women were discharged to home or self-care (P < .001). Women had higher rates of cementation (P < .001) and fracture within 90 days (P < .001), and these associations remained significant with adjusted multivariable analyses. Women had significantly higher pain and lower functional scores preoperatively; postoperatively, most PROMs were equivalent. CONCLUSIONS: Important differences were observed in several areas. Demographic parameters differed, and a variable effect of biological sex was observed on surgical and hospital outcomes. Women had an increased incidence of cemented femoral components (indicated for osteoporotic bone) and postoperative fractures. Women's PROMs demonstrated globally lower functional scores and higher pain preoperatively. Differences attributed to sex should continue to be investigated and accounted for in risk-stratification models. Future studies are needed to elucidate the underlying causes of observed biological sex differences and are essential for equitable arthroplasty care.

Ensuring accountability for consideration of sex as a biological variable in research.

The National Institute of Health (NIH) policy, Consideration of Sex as a Biological Variable (SABV) in NIH-funded Research (2015), focuses on the expectation that researchers account for the influence of SABV in vertebrate animal and human studies and provide a strong justification for single-sex investigations. When SABV is considered in the research design, data analyses, and reporting, the rigor and reproducibility of the research are elevated and inform best practices and precision health for all people. Additional recommendations include the appropriate use of terminology, integration into curricula, intersection with social determinants of health, and application of sex and gender equity guidelines when disseminating research. This paper is a "call to action" for nurse researchers to lean into and apply this policy's principles and our recommendations, from the bench to the bedside, to advance the equity and health of all people.

Temporal changes in the microglial proteome of male and female mice after a diffuse brain injury using label-free quantitative proteomics.

Traumatic brain injury (TBI) triggers neuroinflammatory cascades mediated by microglia, which promotes tissue repair in the short-term. These cascades may exacerbate TBI-induced tissue damage and symptoms in the months to years post-injury. However, the progression of the microglial function across time post-injury and whether this differs between biological sexes is not well understood. In this study, we examined the microglial proteome at 3-, 7-, or 28-days after a midline fluid percussion injury (mFPI) in male and female mice using label-free quantitative proteomics. Data are available via ProteomeXchange with identifier PXD033628. We identified a reduction in microglial proteins involved with clearance of neuronal debris via phagocytosis at 3- and 7-days post-injury. At 28 days post-injury, pro-inflammatory proteins were decreased and anti-inflammatory proteins were increased in microglia. These results indicate a reduction in microglial clearance of neuronal debris in the days post-injury with a shift to anti-inflammatory function by 28 days following TBI. The changes in the microglial proteome that occurred across time post-injury did not differ between biological sexes. However, we did identify an increase in microglial proteins related to pro-inflammation and phagocytosis as well as insulin and estrogen signaling in males compared with female mice that occurred with or without a brain injury. Although the microglial response was similar between males and females up to 28 days following TBI, biological sex differences in the microglial proteome, regardless of TBI, has implications for the efficacy of treatment strategies targeting the microglial response post-injury.

Differential Viral Dynamics by Sex and Body Mass Index During Acute SARS-CoV-2 Infection: Results from a Longitudinal Cohort Study.

BACKGROUND: There is evidence of an association of severe COVID-19 outcomes with increased body mass index (BMI) and male sex. However, few studies have examined the interaction between sex and BMI on SARS-CoV-2 viral dynamics. METHODS: Participants conducted RT-PCR testing every 24-48 hours over a 15-day period. Sex and BMI were self-reported, and Ct values from E-gene were used to quantify viral load. Three distinct outcomes were examined using mixed effects generalized linear models, linear models, and logistic models, respectively: all Ct values (Model 1); nadir Ct value (model 2); and strongly detectable infection (at least one Ct value ≤28 during their infection) (Model 3). An interaction term between BMI and sex was included, and inverse logit transformations were applied to quantify the differences by BMI and sex using marginal predictions. RESULTS: In total, 7,988 participants enrolled in this study, and 439 participants (Model 1) and 309 (Model 2 and 3) were eligible for these analyses. Among males, increasing BMI was associated with lower Ct values in a dose-response fashion. For participants with BMIs greater than 29, males had significantly lower Ct values and nadir Ct values than females. In total, 67.8% of males and 55.3% of females recorded a strongly detectable infection; increasing proportions of men had Ct values <28 with BMIs of 35 and 40. CONCLUSIONS: We observed sex-based dimorphism in relation to BMI and COVID-19 viral load. Further investigation is needed to determine the cause, clinical impact, and transmission implications of this sex-differential effect of BMI on viral load.

The time-course of cancer cachexia onset reveals biphasic transcriptional disruptions in female skeletal muscle distinct from males.

BACKGROUND: Cancer-cachexia (CC) is a debilitating condition affecting up to 80% of cancer patients and contributing to 40% of cancer-related deaths. While evidence suggests biological sex differences in the development of CC, assessments of the female transcriptome in CC are lacking, and direct comparisons between sexes are scarce. This study aimed to define the time course of Lewis lung carcinoma (LLC)-induced CC in females using transcriptomics, while directly comparing biological sex differences. RESULTS: We found the global gene expression of the gastrocnemius muscle of female mice revealed biphasic transcriptomic alterations, with one at 1 week following tumor allograft and another during the later stages of cachexia development. The early phase was associated with the upregulation of extracellular-matrix pathways, while the later phase was characterized by the downregulation of oxidative phosphorylation, electron transport chain, and TCA cycle. When DEGs were compared to a known list of mitochondrial genes (MitoCarta), ~ 47% of these genes were differently expressed in females exhibiting global cachexia, suggesting transcriptional changes to mitochondrial gene expression happens concomitantly to functional impairments previously published. In contrast, the JAK-STAT pathway was upregulated in both the early and late stages of CC. Additionally, we observed a consistent downregulation of Type-II Interferon signaling genes in females, which was associated with protection in skeletal muscle atrophy despite systemic cachexia. Upregulation of Interferon signaling was noted in the gastrocnemius muscle of cachectic and atrophic male mice. Comparison of female tumor-bearing mice with males revealed ~ 70% of DEGs were distinct between sexes in cachectic animals, demonstrating dimorphic mechanisms of CC. CONCLUSION: Our findings suggest biphasic disruptions in the transcriptome of female LLC tumor-bearing mice: an early phase associated with ECM remodeling and a late phase, accompanied by the onset of systemic cachexia, affecting overall muscle energy metabolism. Notably, ~ 2/3 of DEGs in CC are biologically sex-specific, providing evidence of dimorphic mechanisms of cachexia between sexes. Downregulation of Type-II Interferon signaling genes appears specific to CC development in females, suggesting a new biological sex-specific marker of CC not reliant on the loss of muscle mass, that might represent a protective mechanism against muscle loss in CC in female mice.

Sex representation in neurodegenerative and psychiatric disorders' preclinical and clinical studies.

Many studies show the importance of biological sex for the onset, progression, and response to treatment in brain disorders. In line with these reports, health agencies have requested that all trials, both at the clinical and preclinical level, use a similar number of male and female subjects to correctly interpret the results. Despite these guidelines, many studies still tend to be unbalanced in the use of male and female subjects. In this review we consider three neurodegenerative disorders: Alzheimer's disease, Parkinson's disease, Amyotrophic lateral sclerosis, and three psychiatric disorders: Depression, Attention Deficit Hyperactivity Disorder, and Schizophrenia. These disorders were chosen because of their prevalence and their recognized sex-specific differences in onset, progression, and response to treatment. Alzheimer's disease and Depression demonstrate higher prevalence in females, whereas Parkinson's Disease, Amyotrophic lateral sclerosis, Attention Deficit Hyperactivity Disorder, and schizophrenia show higher prevalence in males. Results from preclinical and clinical studies examining each of these disorders revealed sex-specific differences in risk factors, diagnostic biomarkers, and treatment response and efficacy, suggesting a role for sex-specific therapies in neurodegenerative and neuropsychiatric disorders. However, the qualitative analysis of the percentage of males and females enrolled in clinical trials in the last two decades shows that for most of the disorders, there is still a sex bias in the patients' enrolment.

Older females but not males exhibit increases in cerebral blood velocity, despite similar pulsatility increases after high-intensity resistance exercise.

Sex differences in resting cerebral hemodynamics decline with aging. Given that acute resistance exercise (RE) is a hypertensive challenge, it may reveal sex-dependent abnormalities in cerebral hemodynamics. Thus, we hypothesized that cerebral blood velocity and pulsatility responses to RE would be sex-dependent in older adults. Fourteen older females and 11 males (50-68 yr) completed a high-intensity unilateral isokinetic knee flexion/extension exercise. Measurements were collected at baseline, immediately, 5- and 30-min post-RE. Blood pressure was measured via finger photoplethysmography. Mean middle cerebral artery blood velocity (MCAv) and pulsatility were assessed via transcranial Doppler ultrasound. Carotid pulsatility was obtained via duplex ultrasound. MCAv increased immediately after RE in older females [mean difference (d) = 6.02, 95% CI: 1.66 to 10.39 cm/s, P < 0.001] but not in males (d = -0.72, 95% CI: -3.83 to 5.27 cm/s, P = 0.99), followed by similar reductions 5-min post-RE in older females (d = -4.40, 95% CI: -8.81 to -0.10 cm/s, P = 0.045) and males (d = -6.41, 95% CI: -11.19 to -1.62 cm/s, P = 0.003). MCAv pulsatility increased similarly in older females (d = 0.24, 95% CI: 0.11 to 0.40, P < 0.001) and males (d = 0.38, 95% CI: 0.20 to 0.53, P < 0.001), persisting 5-min post-RE. Older females showed smaller increases in carotid pulsatility immediately after RE (d = 0.18, 95% CI: 0.03 to 0.38, P = 0.01) than males (d = 0.48, 95% CI: 0.26 to 0.68, P < 0.001). An exercise-mediated hypertensive stimulus revealed differential sex responses in MCAv and carotid pulsatility but not in cerebral pulsatility. Cerebral pulsatility findings suggest a similar sex susceptibility to cerebrovascular abnormalities following exercise-mediated hypertensive stimulus in older adults.NEW & NOTEWORTHY Sex differences in resting cerebral hemodynamics decline with advancing age as females experience larger reductions in cerebral blood velocity and steeper pulsatility increases than males. However, an exercise-mediated hypertensive stimulus might reveal sex differences in cerebral hemodynamics not apparent at rest. Following high-intensity resistance exercise, older females but not males exhibit increases in cerebral blood velocity, despite similar increases in cerebral pulsatility. The susceptibility to cerebrovascular abnormalities following exercise-mediated hypertensive stimulus appears similar between sexes.

EEG microstates in early-to-middle childhood show associations with age, biological sex, and alpha power.

Electroencephalographic (EEG) microstates can provide a unique window into the temporal dynamics of large-scale brain networks across brief (millisecond) timescales. Here, we analysed fundamental temporal features of microstates extracted from the broadband EEG signal in a large (N = 139) cohort of children spanning early-to-middle childhood (4-12 years of age). Linear regression models were used to examine if participants' age and biological sex could predict the temporal parameters GEV, duration, coverage, and occurrence, for five microstate classes (A-E) across both eyes-closed and eyes-open resting-state recordings. We further explored associations between these microstate parameters and posterior alpha power after removal of the 1/f-like aperiodic signal. The microstates obtained from our neurodevelopmental EEG recordings broadly replicated the four canonical microstate classes (A to D) frequently reported in adults, with the addition of the more recently established microstate class E. Biological sex served as a significant predictor in the regression models for four of the five microstate classes (A, C, D, and E). In addition, duration and occurrence for microstate E were both found to be positively associated with age for the eyes-open recordings, while the temporal parameters of microstates C and E both exhibited associations with alpha band spectral power. Together, these findings highlight the influence of age and sex on large-scale functional brain networks during early-to-middle childhood, extending understanding of neural dynamics across this important period for brain development.

Sexually dimorphic extracellular vesicle responses after chronic spinal cord injury are associated with neuroinflammation and neurodegeneration in the aged brain.

BACKGROUND: Medical advances have made it increasingly possible for spinal cord injury (SCI) survivors to survive decades after the insult. But how SCI affects aging changes and aging impacts the injury process have received limited attention. Extracellular vesicles (EVs) are recognized as critical mediators of neuroinflammation after CNS injury, including at a distance from the lesion site. We have previously shown that SCI in young male mice leads to robust changes in plasma EV count and microRNA (miR) content. Here, our goal was to investigate the impact of biological sex and aging on EVs and brain after SCI. METHODS: Young adult age-matched male and female C57BL/6 mice were subjected to SCI. At 19 months post-injury, total plasma EVs were isolated by ultracentrifugation and characterized by nanoparticle tracking analysis (NTA). EVs miR cargo was examined using the Fireplex® assay. The transcriptional changes in the brain were assessed by a NanoString nCounter Neuropathology panel and validated by Western blot (WB) and flow cytometry (FC). A battery of behavioral tests was performed for assessment of neurological function. RESULTS: Transcriptomic changes showed a high number of changes between sham and those with SCI. Sex-specific changes were found in transcription networks related to disease association, activated microglia, and vesicle trafficking. FC showed higher microglia and myeloid counts in the injured tissue of SCI/Female compared to their male counterparts, along with higher microglial production of ROS in both injured site and the brain. In the latter, increased levels of TNF and mitochondrial membrane potential were seen in microglia from SCI/Female. WB and NTA revealed that EV markers are elevated in the plasma of SCI/Male. Particle concentration in the cortex increased after injury, with SCI/Female showing higher counts than SCI/Male. EVs cargo analysis revealed changes in miR content related to injury and sex. Behavioral testing confirmed impairment of cognition and depression at chronic time points after SCI in both sexes, without significant differences between males and females. CONCLUSIONS: Our study is the first to show sexually dimorphic changes in brain after very long-term SCI and supports a potential sex-dependent EV-mediated mechanism that contributes to SCI-induced brain changes.

Development of skeletal muscle fibrosis in a rodent model of cancer cachexia.

Cachexia is characterized by losses in lean body mass and its progression results in worsened quality of life and exacerbated outcomes in cancer patients. However, the role and impact of fibrosis during the early stages and development of cachexia in under-investigated. The purpose of this study was to determine if fibrosis occurs during cachexia development, and to evaluate this in both sexes. Female and male C57BL6/J mice were injected with phosphate-buffered saline or Lewis Lung Carcinoma (LLC) at 8-week of age, and tumors were allowed to develop for 1, 2, 3, or 4 weeks. 3wk and 4wk female tumor-bearing mice displayed a dichotomy in tumor growth and were reassigned to high tumor (HT) and low tumor (LT) groups. In vitro analyses were also performed on cocultured C2C12 and 3T3 cells exposed to LLC conditioned media. Immunohistochemistry and quantitative polymerase chain reaction (qPCR) analysis were used to investigate fibrosis and fibrosis-related signaling in skeletal muscle. Collagen deposition in skeletal muscle was increased in the 1wk, LT, and HT groups in female mice. However, collagen deposition was only increased in the 4wk group in male mice. In general, female mice displayed earlier alterations in extracellular matrix (ECM)-related genes beginning at 1wk post-LLC injection. Whereas this was not seen in males. While overall tumor burden is tightly correlated to cachexia development in both sexes, fibrotic development is not. Male mice did not exhibit early-stage alterations in ECM-related genes contrary to what was noted in female mice.

Do Anxiety Symptoms Mediate the Association Between Cannabis Use Frequency and Psychotic-Like Experiences in Emerging Adult Undergraduates?

OBJECTIVE: Cannabis is commonly used by Canadian emerging adults (ages 18-25 years), many of whom attend post-secondary institutions. Frequent cannabis use is linked with psychotic-like experiences (PLEs); however, the exact nature of this association remains unclear. Anxiety symptoms may mediate this association, as they are prevalent in emerging adults and have been independently linked with both cannabis use and PLEs. Past work found that anxiety mediated the association between cannabis use frequency and attenuated positive psychotic symptoms (further along the psychosis continuum than PLEs), however this research had yet to be validated in the Canadian population, and trait rather than state anxiety (frequency of anxiety symptoms) was studied. Thus, our primary objective was to examine if anxiety symptoms mediated the association between cannabis use frequency and PLEs in Canadian emerging adult undergraduates. Despite known sex differences in cannabis use, expression of anxiety, and PLEs, past work did not evaluate the potential impact of biological sex on the anxiety-mediated model, and thus is the secondary objective of the present study. METHODS: 1,266 first-/second-year emerging adult undergraduates from five Canadian universities provided cross-sectional, self-report survey data in fall 2021 semester. Validated measures of cannabis use frequency, anxiety, and PLEs were administered. RESULTS: Path analyses supported mediation from cannabis use to PLEs through anxiety (b = 0.07, P < 0.001, 95% bootstrap CI [0.03, 0.10]). No direct effect was found (P = 0.457), suggesting that the cannabis-to-PLEs association was mediated by anxiety. Mediation did not depend on biological sex (i.e., bootstrapped 95% CIs crossed zero). CONCLUSIONS: Anxiety symptoms mediated the association between cannabis use and PLEs in emerging adults regardless of their biological sex. Assuming replication in prospective research, results highlight anxiety as an important intervention target in frequent cannabis-using emerging adults, to potentially prevent development/worsening of PLEs, and in turn psychotic illness.

Layer-Specific Tensile Strength of the Human Aorta: Segmental Variations.

Knowledge of the failure properties of the aorta is essential to understand the mechanisms of dissection and rupture. Limited information is, however, available in humans or experimental animals about the layer-specific properties and their segmental variations have not been determined. In this paper, the failure properties of the intima, media, and adventitia were studied in nine consecutive aortic segments and two principal directions. Detailed biomechanical tests were performed with a tensile-testing device on 756 layer strips, harvested from fourteen cadaveric subjects aged 21-82 years. Intimal and medial strength in either direction remained invariant along the aorta, and their extensibility longitudinally decreased, whereas adventitial strength and extensibility longitudinally increased, explaining why the preferential sites for the development of aortic dissection or traumatic rupture are in the proximal aorta. The media was stronger circumferentially than longitudinally in all segments, accounting for the typically transverse tearing in dissection/rupture. The adventitial properties were significantly higher than the intimal and medial in most segments. Still, the intima had similar strength but lower extensibility compared to the media in both directions, and higher maximum stiffness longitudinally in several segments. The rupture surface of all layers was not perpendicular to the loading axis, more so in the circumferential strips compared to longitudinal ones. Aging impaired the extensibility and strength of all layers, particularly the media, but did not affect the maximum stiffness and rupture-surface direction. Females were rarely associated with different failure properties compared to age-matched males.

Positive and Negative Life Events in Association with Psychopathology: An Examination of Sex Differences in Early Adolescence.

Negative life events (NLEs) are associated with psychopathology in older adolescents and adults, particularly for women. However, less is known about the association between positive life events (PLEs) and psychopathology. This study examined associations between NLEs, PLEs, and their interaction, and sex differences in associations between PLEs and NLEs on internalizing and externalizing psychopathology. Youth completed interviews about NLEs and PLEs. Parents and youth reported on youth internalizing and externalizing symptoms. NLEs were positively associated with youth-reported depression and anxiety and parent-reported youth depression. Female youth had stronger positive associations between NLEs and youth-reported anxiety than male youth. Interactions between PLEs and NLEs were non-significant. Findings for NLEs and psychopathology are extended to earlier in development.

Mitochondrial bioenergetics of astrocytes in Fragile X syndrome: new perspectives on culture conditions and sex effects.

Fragile X syndrome (FXS) is a genetic disorder that is characterized by a range of cognitive and behavioral deficits, including mild-moderate intellectual disability. The disease is characterized by an X-linked mutation of the Fmr1 gene, which causes silencing of the gene coding for fragile X mental retardation protein (FMRP), a translational regulator integral for neurodevelopment. Mitochondrial dysfunction has been recently associated with FXS, with reports of increases in oxidative stress markers, reactive oxygen species, and lipid peroxidation being present in the brain tissue. Astrocytes, a prominent glial cell within the central nervous system (CNS), play a large role in regulating oxidative homeostasis within the developing brain and dysregulation of astrocyte redox balance in FXS, which may contribute to oxidative stress. Astrocyte function and mitochondrial bioenergetics are significantly influenced by oxygen availability and circulating sex hormones; yet, these parameters are rarely considered during in vitro experimentation. Given that the brain normally develops in a range of hypoxic conditions and FXS is a sex-linked genetic disorder, we investigated how different oxygen levels (normoxic vs. hypoxic) and biological sex affected mitochondrial bioenergetics of astrocytes in FXS. Our results demonstrate that both mitochondrial respiration capacity and reactive oxygen species emission are altered with Fmr1 deletion in astrocytes and these changes were dependent upon both sexual dimorphism and oxygen availability.

Impact of Tamoxifen on Vorinostat-Induced Human Immunodeficiency Virus Expression in Women on Antiretroviral Therapy: AIDS Clinical Trials Group A5366, The MOXIE Trial.

BACKGROUND: Biological sex and the estrogen receptor alpha (ESR1) modulate human immunodeficiency virus (HIV) activity. Few women have enrolled in clinical trials of latency reversal agents (LRAs); their effectiveness in women is unknown. We hypothesized that ESR1 antagonism would augment induction of HIV expression by the LRA vorinostat. METHODS: AIDS Clinical Trials Group A5366 enrolled 31 virologically suppressed, postmenopausal women on antiretroviral therapy. Participants were randomized 2:1 to receive tamoxifen (arm A, TAMOX/VOR) or observation (arm B, VOR) for 5 weeks followed by 2 doses of vorinostat. Primary end points were safety and the difference between arms in HIV RNA induction after vorinostat. Secondary analyses included histone 4 acetylation, HIV DNA, and plasma viremia by single copy assay (SCA). RESULTS: No significant adverse events were attributed to study treatments. Tamoxifen did not enhance vorinostat-induced HIV transcription (between-arm ratio, 0.8; 95% confidence interval [CI], .2-2.4). Vorinostat-induced HIV transcription was higher in participants with increases in H4Ac (fold increase, 2.78; 95% CI, 1.34-5.79) vs those 9 who did not (fold increase, 1.04; 95% CI, .25-4.29). HIV DNA and SCA plasma viremia did not substantially change. CONCLUSIONS: Tamoxifen did not augment vorinostat-induced HIV RNA expression in postmenopausal women. The modest latency reversal activity of vorinostat, postmenopausal status, and low level of HIV RNA expression near the limits of quantification limited assessment of the impact of tamoxifen. This study is the first HIV cure trial done exclusively in women and establishes both the feasibility and necessity of investigating novel HIV cure strategies in women living with HIV. CLINICAL TRIALS REGISTRATION: NCT03382834.

The effects of biological sex and cardiovascular disease on COVID-19 mortality.

Cardiovascular disease (CVD) is a common comorbidity observed in patients with coronavirus disease 2019 (COVID-19), which is associated with increased severity and mortality. However, the effects of biological sex on CVD-associated mortality in patients with COVID-19 are poorly established, particularly among Hispanic/Latin Americans. We examined the association of preexisting CVD with COVID-19 mortality in hospitalized Latin American men and women. This multicenter study included Mexican patients hospitalized with a positive diagnosis of COVID-19. The main outcome was in-hospital mortality. Multivariable regression analyses were used to calculate the adjusted odds ratio with 95% confidence interval for mortality in women and men. Of 81,400 patients with a positive diagnosis for SARS-CoV-2 infection, 28,929 (35.54%) hospitalized patients were evaluated. Of these, 35.41% (10,243) were women. In-hospital death was higher in men than in women. In relation to CVD between the sexes, women had a higher incidence of CVD than men (4.69 vs. 3.93%, P = 0.0023). The adjusted logistic regression analyses showed that CVD was significantly associated with COVID-19 mortality in women but not men. We then stratified by sex according to age <52 and ≥52 yr old. Similar significant association was also found in prespecified analysis in women ≥52 yr old but not in men of similar age. We conclude that CVD's effect on mortality among patients hospitalized with COVID-19 is dependent on biological sex and age in this Latin American cohort. These results suggest that therapeutic strategies for Latin American women with CVD and COVID-19 should include particular attention to their cardiovascular health.NEW & NOTEWORTHY CVD's effect on COVID-19 mortality is dependent on biological sex and age. CVD in women but not men with COVID-19 is associated with significantly unfavorable outcomes.

Variability in energy expenditure is much greater in males than females.

In mammals, trait variation is often reported to be greater among males than females. However, to date, mainly only morphological traits have been studied. Energy expenditure represents the metabolic costs of multiple physical, physiological, and behavioral traits. Energy expenditure could exhibit particularly high greater male variation through a cumulative effect if those traits mostly exhibit greater male variation, or a lack of greater male variation if many of them do not. Sex differences in energy expenditure variation have been little explored. We analyzed a large database on energy expenditure in adult humans (1494 males and 3108 females) to investigate whether humans have evolved sex differences in the degree of interindividual variation in energy expenditure. We found that, even when statistically comparing males and females of the same age, height, and body composition, there is much more variation in total, activity, and basal energy expenditure among males. However, with aging, variation in total energy expenditure decreases, and because this happens more rapidly in males, the magnitude of greater male variation, though still large, is attenuated in older age groups. Considerably greater male variation in both total and activity energy expenditure could be explained by greater male variation in levels of daily activity. The considerably greater male variation in basal energy expenditure is remarkable and may be explained, at least in part, by greater male variation in the size of energy-demanding organs. If energy expenditure is a trait that is of indirect interest to females when choosing a sexual partner, this would suggest that energy expenditure is under sexual selection. However, we present a novel energetics model demonstrating that it is also possible that females have been under stabilizing selection pressure for an intermediate basal energy expenditure to maximize energy available for reproduction.