Mosaicism-independent mechanisms contribute to Pcdh19-related epilepsy and repetitive behaviors in Xenopus.

Protocadherin19 (PCDH19)-related epilepsy syndrome is a rare disorder characterized by early-onset epilepsy, intellectual disability, and autistic behaviors. PCDH19 is located on the X chromosome and encodes a calcium-dependent single-pass transmembrane protein, which regulates cell-to-cell adhesion through homophilic binding. In human, 90% of heterozygous females, containing PCDH19 wild-type and mutant cells due to random X inactivation, are affected, whereas mutant males, containing only mutant cells, are typically not. The current view, the cellular interference, is that the altered interactions between wild-type and mutant cells during development, rather than loss of function itself, are responsible. However, studies using Pcdh19 knockout mice showed that the complete loss of function also causes autism-like behaviors both in males and females, suggesting that other functions of PCDH19 may also contribute to pathogenesis. To address whether mosaicism is required for PCDH19-related epilepsy, we generated Xenopus tropicalis tadpoles with complete or mosaic loss of function by injecting antisense morpholino oligonucleotides into the blastomeres of neural lineage at different stages of development. We found that either mosaic or complete knockdown results in seizure-like behaviors, which could be rescued by antiseizure medication, and repetitive behaviors. Our results suggest that the loss of PCDH19 function itself, in addition to cellular interference, may also contribute to PCDH19-related epilepsy.

An accessory prefrontal cortex-thalamus circuit sculpts maternal behavior in virgin female mice.

The ability to care for the young is innate and readily displayed by postpartum females after delivery to ensure offspring survival. Upon pup exposure, rodent virgin (nulliparous) females also develop parental behavior that over time becomes displayed at levels equivalent to parenting mothers. Although maternal behavior in postpartum females and the associated neurocircuits are well characterized, the neural mechanisms underlying the acquisition of maternal behavior without prior experience remain poorly understood. Here, we show that the development of maternal care behavior in response to first-time pup exposure in virgin females is initiated by the activation of the anterior cingulate cortex (ACC). ACC activity is dependent on feedback excitation by Vglut2+ /Galanin+ neurons of the centrolateral nucleus of the thalamus (CL), with their activity sufficient to display parenting behaviors. Accordingly, acute bidirectional chemogenetic manipulation of neuronal activity in the ACC facilitates or impairs the attainment of maternal behavior, exclusively in virgin females. These results reveal an ACC-CL neurocircuit as an accessory loop in virgin females for the initiation of maternal care upon first-time exposure to pups.

Electroencephalography findings in menstrually-related mood disorders: A critical review.

The female reproductive years are characterized by fluctuations in ovarian hormones across the menstrual cycle, which have the potential to modulate neurophysiological and behavioral dynamics. Menstrually-related mood disorders (MRMDs) comprise cognitive-affective or somatic symptoms that are thought to be triggered by the rapid fluctuations in ovarian hormones in the luteal phase of the menstrual cycle. MRMDs include premenstrual syndrome (PMS), premenstrual dysphoric disorder (PMDD), and premenstrual exacerbation (PME) of other psychiatric disorders. Electroencephalography (EEG) non-invasively records in vivo synchronous activity from populations of neurons with high temporal resolution. The present overview sought to systematically review the current state of task-related and resting-state EEG investigations on MRMDs. Preliminary evidence indicates lower alpha asymmetry at rest being associated with MRMDs, while one study points to the effect being luteal-phase specific. Moreover, higher luteal spontaneous frontal brain activity (slow/fast wave ratio as measured by the delta/beta power ratio) has been observed in persons with MRMDs, while sleep architecture results point to potential circadian rhythm disturbances. In this review, we discuss the quality of study designs as well as future perspectives and challenges of supplementing the diagnostic and scientific toolbox for MRMDs with EEG.

Obesogenic diet induces sex-specific alterations of contextual fear memory and associated hippocampal activity in mice.

In addition to metabolic and cardiovascular disorders, obesity is associated with cognitive deficits in humans and animal models. We have previously shown that obesogenic high-fat and sugar diet intake during adolescence (adoHFSD) impairs hippocampus (HPC)-dependent memory in rodents. These results were obtained in males only and it remains to evaluate whether adoHFSD has similar effect in females. Therefore, here, we investigated the effects of adoHFSD consumption on HPC-dependent contextual fear memory and associated brain activation in male and female mice. Exposure to adoHFSD increased fat mass accumulation and glucose levels in both males and females but impaired contextual fear memory only in males. Compared with females, contextual fear conditioning induced higher neuronal activation in the dorsal and ventral HPC (CA1 and CA3 subfields) as well as in the medial prefrontal cortex in males. Also, adoHFSD-fed males showed enhanced c-Fos expression in the dorsal HPC, particularly in the dentate gyrus, and in the basolateral amygdala compared with the other groups. Finally, chemogenetic inactivation of the dorsal HPC rescued adoHFSD-induced memory deficits in males. Our results suggest that males are more vulnerable to the effects of adoHFSD on HPC-dependent aversive memory than females, due to overactivation of the dorsal HPC.

Sex differences in treatment of familial hypercholesterolaemia: a meta-analysis.

BACKGROUND AND AIMS: Familial hypercholesterolaemia (FH) is a highly prevalent monogenic disorder characterized by elevated LDL cholesterol (LDL-C) levels and premature atherosclerotic cardiovascular disease. Sex disparities in diagnosis, lipid-lowering therapy, and achieved lipid levels have emerged worldwide, resulting in barriers to care in FH. A systematic review was performed to investigate sex-related disparities in treatment, response, and lipid target achievement in FH (PROSPERO, CRD42022353297). METHODS: MEDLINE, Embase, The Cochrane library, PubMed, Scopus, PsycInfo, and grey literature databases were searched from inception to 26 April 2023. Records were eligible if they described sex differences in the treatment of adults with FH. RESULTS: Of 4432 publications reviewed, 133 met our eligibility criteria. In 16 interventional clinical trials (eight randomized and eight non-randomized; 1840 participants, 49.4% females), there were no differences between males and females in response to fixed doses of lipid-lowering therapy, suggesting that sex was not a determinant of response. Meta-analysis of 25 real-world observational studies (129 441 participants, 53.4% females) found that females were less likely to be on lipid-lowering therapy compared with males (odds ratio .74, 95% confidence interval .66-.85). Importantly, females were less likely to reach an LDL-C < 2.5 mmol/L (odds ratio .85, 95% confidence interval .74-.97). Similarly, treated LDL-C levels were higher in females. Despite this, male sex was associated with a two-fold greater relative risk of major adverse cardiovascular events including myocardial infarction, atherosclerotic cardiovascular disease, and cardiovascular mortality. CONCLUSIONS: Females with FH were less likely to be treated intensively and to reach guideline-recommended LDL-C targets. This sex bias represents a surmountable barrier to clinical care.

Exercise training alters skeletal muscle microvascular endothelial cell properties in recent postmenopausal females.

The present study examined and compared the impact of exercise training on redox and molecular properties of human microvascular endothelial cells derived from skeletal muscle biopsies from sedentary recent (RPF, ≤ 5 years as postmenopausal) and late (LPF, ≥ 10 years as postmenopausal) postmenopausal females. Resting skeletal muscle biopsies were obtained before and after 8 weeks of intense aerobic exercise training for isolation of microvascular endothelial cells and determination of skeletal muscle angiogenic proteins and capillarisation. The microvascular endothelial cells were analysed for mitochondrial respiration and production of reactive oxygen species (ROS), glycolysis and proteins related to vascular function, redox balance and oestrogen receptors. Exercise training led to a reduced endothelial cell ROS formation (∼50%; P = 0.009 and P = 0.020 for intact and permeabilized cells (state 3), respectively) in RPF only, with no effect on endothelial mitochondrial capacity in either group. Basal endothelial cell lactate formation was higher (7%; P = 0.028), indicating increased glycolysis, after compared to before the exercise training period in RPF only. Baseline endothelial G protein-coupled oestrogen receptor (P = 0.028) and muscle capillarisation (P = 0.028) was lower in LPF than in RPF. Muscle vascular endothelial growth factor protein was higher (32%; P = 0.002) following exercise training in LPF only. Exercise training did not influence endothelial cell proliferation or skeletal muscle capillarisation in either group, but the CD31 level in the muscle tissue, indicating endothelial cell content, was higher (>50%; P < 0.05) in both groups. In conclusion, 8 weeks of intense aerobic exercise training reduces ROS formation and enhances glycolysis in microvascular endothelial cells from RPF but does not induce skeletal muscle angiogenesis. KEY POINTS: Late postmenopausal females have been reported to achieve limited vascular adaptations to exercise training. There is a paucity of data on the effect of exercise training on isolated skeletal muscle microvascular endothelial cells (MMECs). In this study the formation of reactive oxygen species in MMECs was reduced and glycolysis increased after 8 weeks of aerobic exercise training in recent but not late postmenopausal females. Late postmenopausal females had lower levels of G protein-coupled oestrogen receptor in MMECs and lower skeletal muscle capillary density at baseline. Eight weeks of intense exercise training altered MMEC properties but did not induce skeletal muscle angiogenesis in postmenopausal females.

Racial and Ethnic Disparities in Hepatitis C Care in Reproductive-Aged Women With Opioid Use Disorder.

BACKGROUND: In the United States, hepatitis C virus (HCV) diagnoses among reproductive-aged women are increasing amidst the ongoing opioid and drug overdose epidemic. While previous studies document racial and ethnic disparities in HCV testing and treatment in largely male populations, to our knowledge no national studies analyze these outcomes in reproductive-aged women with opioid use disorder (OUD). METHODS: We analyzed data from a cohort of reproductive-aged women (aged 15-44 years) with diagnosed OUD captured in the TriNetX Research Network, a network of electronic health records from across the United States. Using a log-binomial model, we assessed differences in achieving HCV cascade of care stages (HCV antibody testing, HCV infection [positive HCV RNA test result], linkage to care, and HCV treatment) by race and ethnicity. RESULTS: From 2014 to 2022, 44.6% of the cohort were tested for HCV antibody. Asian and black/African American individuals had a lower probability of having an HCV antibody test than white individuals (risk ratio, 0.77 [95% confidence interval, .62-.96] and 0.76 [.63-.92], respectively). Among those with HCV infection, only 9.1% were treated with direct-acting antivirals. Hispanic/Latinx individuals had a higher probability of treatment than non-Hispanic/Latinx individuals (risk ratio, 1.63 [95% confidence interval, 1.01-2.61]). CONCLUSIONS: Few reproductive-aged women with OUD are tested or treated for HCV. Disparities by race and ethnicity in HCV testing further exacerbate the risk of perinatal transmission and disease progression among minoritized communities. Interventions are needed to improve overall rates of and equity in HCV screening and treatment for reproductive-aged women.

Estradiol and progesterone in female reward-learning, addiction, and therapeutic interventions.

Sex steroid hormones like estradiol (E2) and progesterone (P4) guide the sexual organization and activation of the developing brain and control female reproductive behavior throughout the lifecycle; importantly, these hormones modulate functional activity of not just the endocrine system, but most of the nervous system including the brain reward system. The effects of E2 and P4 can be seen in the processing of and memory for rewarding stimuli and in the development of compulsive reward-seeking behaviors like those seen in substance use disorders. Women are at increased risk of developing substance use disorders; however, the origins of this sex difference are not well understood and therapeutic interventions targeting ovarian hormones have produced conflicting results. This article reviews the contribution of the E2 and P4 in females to functional modulation of the brain reward system, their possible roles in origins of addiction vulnerability, and the development and treatment of compulsive reward-seeking behaviors.

Exercise testing unmasks exaggerated blood pressure independent of fibrinolytic response in Black but not White postmenopausal females.

Exercise testing unmasks more exaggerated systolic blood pressure responses (SBP) in Black compared with White male adults. Such responses, if translatable to females, may detect racial disparities particularly relevant during menopause. Given the endothelial involvement in BP regulation and as a source of fibrinolytic markers, it follows that fibrinolytic and BP response to exercise could be linked. Thus, we examined BP and fibrinolytic responses to exercise testing in Black and White postmenopausal females. Postmenopausal females (Black = 40; White = 41; 51-70 yr) performed maximal treadmill exercise. BP and blood draws were conducted before and immediately after exercise. Plasma samples, using minimal stasis, were analyzed for tissue plasminogen activator (tPA) and plasminogen activator inhibitor 1 (PAI-1) activity and antigen, respectively. Resting SBP and fibrinolytic potential were similar between races. Black females exhibited greater increases in SBP during exercise [change (d)=75, 95% CI: 64-86 mmHg, P < 0.001] than White females (d = 60, 95% CI: 48-71 mmHg, P < 0.001). Black compared with White females had smaller changes in tPA (d = 3.27, 95% CI: 2.28-4.27 IU/mL, P < 0.001 vs. d = 5.55, 95% CI: 4.58-6.53, P < 0.001) and PAI-1 (d = -2.89, 95% CI: -4.39 to -1.40 IU/mL, P < 0.001 vs. d = -5.08, 95% CI: -6.59 to -3.61, P < 0.001) activities after exercise. SBP exercise-induced changes were not associated with tPA (r = -0.10, P = 0.42) or PAI-1 (r = 0.13, P = 0.30), without any influence of race (P > 0.05). Our findings show that maximal exercise unmasks risk factors for cardiovascular disease in Black postmenopausal females.NEW & NOTEWORTHY Exaggerated SBP responses to exercise testing are more frequent in Black than in White male adults. Such responses, if translatable to females, may detect early racial disparities arriving during menopause. Because the endothelium regulates BP and fibrinolytic responses, these could be linked during exercise. At peak exercise, Black but not White postmenopausal females had more exaggerated SPB responses regardless of reduced fibrinolytic potential. Maximal exercise unmasked risk factors for cardiovascular disease in Black postmenopausal females.

A pre-existing Toxoplasma gondii infection exacerbates the pathophysiological response and extent of brain damage after traumatic brain injury in mice.

Traumatic brain injury (TBI) is a key contributor to global morbidity that lacks effective treatments. Microbial infections are common in TBI patients, and their presence could modify the physiological response to TBI. It is estimated that one-third of the human population is incurably infected with the feline-borne parasite, Toxoplasma gondii, which can invade the central nervous system and result in chronic low-grade neuroinflammation, oxidative stress, and excitotoxicity-all of which are also important pathophysiological processes in TBI. Considering the large number of TBI patients that have a pre-existing T. gondii infection prior to injury, and the potential mechanistic synergies between the conditions, this study investigated how a pre-existing T. gondii infection modified TBI outcomes across acute, sub-acute and chronic recovery in male and female mice. Gene expression analysis of brain tissue found that neuroinflammation and immune cell markers were amplified in the combined T. gondii + TBI setting in both males and females as early as 2-h post-injury. Glutamatergic, neurotoxic, and oxidative stress markers were altered in a sex-specific manner in T. gondii + TBI mice. Structural MRI found that male, but not female, T. gondii + TBI mice had a significantly larger lesion size compared to their uninfected counterparts at 18-weeks post-injury. Similarly, diffusion MRI revealed that T. gondii + TBI mice had exacerbated white matter tract abnormalities, particularly in male mice. These novel findings indicate that a pre-existing T. gondii infection affects the pathophysiological aftermath of TBI in a sex-dependent manner, and may be an important modifier to consider in the care and prognostication of TBI patients.

Mpox outbreak in Rio de Janeiro, Brazil: A translational approach.

Mpox is a zoonotic disease historically reported in Africa. Since 2003, limited outbreaks have occurred outside Africa. In 2022, the global spread of cases with sustained interhuman transmission and unusual disease features raised public health concerns. We explore the mpox outbreak in Rio de Janeiro (RJ) state, Brazil, in an observational study of mpox-suspected cases from June to December 2022. Data collection relied on a public healthcare notification form. Diagnosis was determined by MPXV-PCR. In 46 confirmed cases, anti-OPXV IgG was determined by ELISA, and seven MPXV genomes were sequenced. A total of 3095 cases were included, 816 (26.3%) with positive MPXV-PCR results. Most positive cases were men in their 30 s and MSM. A total of 285 (34.9%) MPXV-PCR+ patients live with HIV. Eight were coinfected with varicella-zoster virus. Anogenital lesions and adenomegaly were associated with the diagnosis of mpox. Females and individuals under 18 represented 9.4% and 5.4% of all confirmed cases, respectively, showing higher PCR cycle threshold (Ct) values and fewer anogenital lesions compared to adult men. Anti-OPXV IgG was detected in 29/46 (63.0%) patients. All analyzed sequences belonged to clade IIb. In RJ state, mpox presented a diverse clinical picture, represented mainly by mild cases with low complication rates and prominent genital involvement. The incidence in females and children was higher than usually reported. The observation of a bimodal distribution of Ct values, with few positive results, may suggest the need to review the diagnostic criteria in these groups.

Women are Underrepresented in Non-small Cell Lung Cancer Clinical Trials: A Systematic Review.

PURPOSE: To perform a systematic review of clinical trials examining non-small cell lung cancer (NSCLC) to better understand the equity afforded to women in the study of lung cancer. METHODS: An electronic search was conducted for all NSCLC clinical trials published between 2010 and 2020 with included words "carcinoma, non-small cell, lung" and "non-small cell lung cancer." Studies from PubMed, Cochrane, and SCOPUS were included and were uploaded into Covidence to assist with systematic review. All articles were screened by two separate individuals and reviewed for location, study type, cancer stage, field of study of the research team, and percentage of females included. Student's t-test was used to compare the means of males and females. RESULTS: Across the 269 studies that met inclusion criteria, fewer females than males were enrolled (38.7% vs. 61.1%; p < 0.0001). Compared with studies from 2010 to 2015, those from 2016 to 2020 had greater representation of females (36.7% vs. 41.4%, p = 0.0091, respectively). Both nonsurgical and surgical studies enrolled fewer female than male patients (38.1% vs. 61.7%, p < 0.0001; 43.1% vs. 57.2%, p = 0.0002, respectively). Clinical trials from the USA had the least difference between sexes with an average of 46.7% females enrolled. Less females compared with males were enrolled in early-stage NSCLC (37.6% female vs. 62.6% male, p < 0.0001) and late-stage NSCLC trials (37.6% female vs. 62.0% male, p < 0.0001). CONCLUSIONS: Despite recent improvement, there continues to be significant underrepresentation of females compared with males in NSCLC clinical trials.

Cardiac implantable electronic devices in female patients: Esthetic, breast implant, and anatomic considerations.

INTRODUCTION: The implantation of a cardiac implantable electronic device (CIED) can have esthetic and psychological consequences on patients. We explore a heart team model for care coordination and discuss esthetic approaches for improved cosmetic outcomes in patients undergoing (CIED)-related procedures or de novo implantation. METHODS: Patients undergoing CIED surgery for approved indications between June 2015 and June 2022 were identified. Patients were included when surgical care was provided by a collaborative relationship between the primary electrophysiologist and the plastic surgeon. Patient demographics, details of the surgical procedure, information on breast implants, complications, and outcomes related to cosmesis were recorded. RESULTS: Twenty-two female patients were included in this study. The mean age was 50.2 ± 18.2 years. The mean follow-up duration was 2.2 ± 5.5 months. The top two indications for the procedure included CIED generator change (n = 9, 41%) and implantable cardioverter-defibrillator (ICD) implantation (n = 7, 32%). The most common reasons for involving plastic surgery in the procedure included surgery near breast implants (n = 10, 45%) and device displacement or discomfort (n = 8, 36%). CIED pocket position was prepectoral in 10 cases (45%), subpectoral in 11 patients (50%), and intramuscular in one patient (4.5%). The majority of the patients (20, 91%) had cosmetically acceptable results postprocedure. One patient (4.5%) had breast asymmetry on the CIED side, and another continued to have skin erosion over the CIED and leads. CONCLUSION: A heart team approach incorporating the expertize of cardiac electrophysiology and plastic surgery is essential for providing optimal care for patients with breast implants and patients requesting esthetic appeal.

Perspectives of carriers of X-linked retinal diseases on genetic testing and gene therapy: A global survey.

Female carriers of X-linked inherited retinal diseases (IRDs) are burdened with potentially passing their disease-causing variant to future generations, as well as exhibiting signs of retinal disease themselves. This study aimed to investigate carriers' experiences of genetic testing, emotions relating to having affected children, and their knowledge regarding genetic testing and gene therapy. An online survey was advertised to self-identified carriers worldwide. Two hundred and twenty-eight carriers completed the survey with mean age of 51 years (SD ± 15.0). A majority of respondents resided in the United States of America (51%), Australia (19%), and the United Kingdom (14%). Most carriers identified with feelings of guilt (70%), concern (91%), and anxiety (88%) for their child. Female carriers who had given birth to children had significantly greater gene therapy knowledge compared to carriers who had not (p < 0.05). Respondents agreed that their eyecare provider and general practitioner helped them understand their condition (63%), however, few carriers reported receiving psychological counselling (9%) or family planning advice (5%). Most respondents (78%) agreed that gene therapy should be available to carriers. This study emphasises the importance of providing appropriate counselling to female carriers and illustrates the motivation of many to participate in emerging treatment options, such as gene therapy.

Sex differences in the association between insulin resistance and non-fatal myocardial infarction across glycaemic states.

BACKGROUND: Females are generally less prone to cardiovascular (CV) events than males, but this protection is trumped by diabetes. The mechanism behind the increased relative risk in females with diabetes is not fully understood. Insulin resistance (IR) is suggested to be a more important contributor to CV morbidity in females than in males. We aim to investigate differences in the association between IR indexes (Homeostatic Model Assessment of IR - HOMA-IR, visceral adiposity index - VAI, and triglycerides/high-density lipoprotein-cholesterol - TG/HDL-C index), and a first non-fatal myocardial infarction (MI) across different glycaemic states. METHODS: IR indexes were calculated in a population with (n = 696) and without (n = 707) a first non-fatal MI, free from known diabetes. MI cases were investigated at least six weeks after the event. All participants were categorized by an oral glucose tolerance test as having normal glucose tolerance, impaired fasting glucose, impaired glucose tolerance, or newly diagnosed diabetes. Comparison of proportion of glycaemic states by sex was tested by chi-square test. The associations between sex, a first non-fatal MI, IR indexes, and traditional CV risk factors were analysed by multivariate logistic regression models. Continuous variables were logarithmically transformed. RESULTS: Of the total population 19% were females and 81% males, out of whom 47% and 50% had a first non-fatal MI, respectively. Compared with males, females were older, less often smokers, with lower body mass index and higher total cholesterol and high-density lipoprotein cholesterol levels. The proportion of glycaemic states did not differ between the sexes (p = 0.06). Females were less insulin resistant than males, especially among cases and with normal glucose tolerance. In logistic regression models adjusted for major CV risk factors including sex, the associations between VAI and TG/HDL-C index and a first non-fatal MI remained significant only in females (odds ratios and 95% confidence intervals: 1.7, 1.0-2.9, and 1.9, 1.1-3.4 respectively). CONCLUSIONS: These results support the assumption that IR indexes based on anthropometrics and lipid panel, i.e., VAI and TG/HDL-C, could be a better measure of IR and CV-predictor for non-fatal MI in females, even without glycaemic perturbations.

Reproductive factors and risk of lung cancer among 300,000 Chinese female never-smokers: evidence from the China Kadoorie Biobank study.

BACKGROUND: Lung cancer is the leading cause of cancer mortality among Chinese females despite the low smoking prevalence among this population. This study assessed the roles of reproductive factors in lung cancer development among Chinese female never-smokers. METHODS: The prospective China Kadoorie Biobank (CKB) recruited over 0.5 million Chinese adults (0.3 million females) from 10 geographical areas in China in 2004-2008 when information on socio-demographic/lifestyle/environmental factors, physical measurements, medical history, and reproductive history collected through interviewer-administered questionnaires. Cox proportional hazard regression was used to estimate adjusted hazard ratios (HRs) of lung cancer by reproductive factors. Subgroup analyses by menopausal status, birth year, and geographical region were performed. RESULTS: During a median follow-up of 11 years, 2,284 incident lung cancers occurred among 282,558 female never-smokers. Ever oral contraceptive use was associated with a higher risk of lung cancer (HR = 1.16, 95% CI: 1.02-1.33) with a significant increasing trend associated with longer duration of use (p-trend = 0.03). Longer average breastfeeding duration per child was associated with a decreased risk (0.86, 0.78-0.95) for > 12 months compared with those who breastfed for 7-12 months. No statistically significant association was detected between other reproductive factors and lung cancer risk. CONCLUSION: Oral contraceptive use was associated with an increased risk of lung cancer in Chinese female never-smokers. Further studies are needed to assess lung cancer risk related to different types of oral contraceptives in similar populations.

Daily Dietary Protein Distribution Does Not Influence Changes in Body Composition During Weight Loss in Women of Reproductive Years with Overweight or Obesity: A Randomized Controlled Trial.

BACKGROUND: Preservation of fat-free mass (FFM) during intentional weight loss is challenging yet important to maintain a resting metabolic rate. A balanced protein distribution of 25-30 g per meal improves 24-h muscle protein synthesis, which may promote FFM maintenance and greater reductions in fat mass (FM) during weight loss in women. OBJECTIVES: We aimed to determine whether the daily dietary protein distribution pattern during energy restriction influences changes in body composition in women of reproductive age. We hypothesized that evenly distributing protein across meals compared with the usual intake pattern of consuming most of the protein at the dinner meal would be superior in preserving FFM while reducing FM during weight loss. METHODS: Healthy women (n = 43) aged 20-44 y with a BMI of 28-45 kg/m2 completed a randomized parallel feeding study testing 2 patterns of daily protein intake (even distribution across all meals compared with a skewed distribution with most protein consumed at the evening meal). Participants completed an 8-wk controlled 20% energy restriction (all foods provided), followed by an 8-wk self-choice phase in which participants were asked to maintain a similar diet and dietary pattern when purchasing and consuming their own foods. Body composition was measured at baseline, week 8, and week 16. Data were analyzed using mixed models. Statistical significance was set at P < 0.05. Data are presented as differences in least squares means ± SE. RESULTS: No significant main effects of group or group-by-time interactions were observed. All measures exhibited the main effect of time (P < 0.001). Overall, body weight, FFM, FM, and body fat percentage decreased 5.6 ± 0.4, 1.0 ± 0.2, 4.6 ± 0.4 kg, and 2.3 ± 0.2%, respectively, during this 16-wk study. CONCLUSION: Daily dietary protein distribution at a fixed protein level does not appear to influence changes in body composition during weight loss in women of reproductive age. CLINICAL TRIAL REGISTRY NUMBER AND WEBSITE WHERE IT WAS OBTAINED: NCT03202069 https://classic. CLINICALTRIALS: gov/ct2/show/NCT03202069.

A systematic review and meta-analysis comparing the severity of core symptoms of attention-deficit hyperactivity disorder in females and males.

In the past decade, there have been substantial changes in diagnostic nomenclature. This study investigated sex differences in attention-deficit/hyperactivity disorder (ADHD) symptom severity based on Diagnostic and Statistical Manual of Mental Disorders (DSM)-IV, DSM-IV(TR), and DSM-5 criteria, separating rating scale and clinical interview data in children and adults with ADHD. PubMed, PsycINFO, and Scopus were searched for published studies (1996-2021) reporting severity of attention, and hyperactivity/impulsivity in males and females. We compared data: (1) across the entire lifespan aggregating rating scale and clinical interview data (51 studies), (2) drawing solely on rating scale data (18 studies), and (3) drawing solely on clinical interview data (33 studies). Fifty-two studies met inclusion criteria comparing data for females (n = 8423) and males (n = 9985) with ADHD across childhood and/or adulthood. In total, 15 meta-analyses were conducted. Pooled data across the lifespan aggregating both rating scale and clinical diagnostic interview data, showed males had significantly more severe hyperactivity/impulsivity symptoms than females. Rating scale data were similar; boys had significantly more severe hyperactivity/impulsivity than girls. In adulthood, men were rated to have significantly more severe inattention than women with no difference in the hyperactivity/impulsivity dimension. All significant differences were of small effect size. No significant sex differences in the severity of symptoms emerged for clinical interview data for children or adults, in contrast. Possible reasons for the discrepancy in findings between rating scales and clinical diagnostic interviews are discussed.

Evolution of mate harm resistance in females from Drosophila melanogaster populations selected for faster development and early reproduction.

Interlocus sexual conflict is predicted to result in sexually antagonistic coevolution between male competitive traits, which are also female-detrimental, and mate harm resistance (MHR) in females. Little is known about the connection between life-history evolution and sexually antagonistic coevolution. Here, we investigated the evolution of MHR in a set of experimentally evolved populations, where mate-harming ability has been shown to have substantially reduced in males as a correlated response to the selection for faster development and early reproduction. We measured mortality and fecundity of females of these populations and those of their matched controls, under different male exposure conditions. We observed that the evolved females were more susceptible to mate harm - suffering from significantly higher mortality under continuous exposure to control males within the twenty-day assay period. Though these evolved females are known to have shorter lifespan, substantially higher mortality was not observed under virgin and single-mating conditions. We used fecundity data to show that this higher mortality in the experimentally evolved females was not due to the cost of egg production, and hence can only be attributed to reduced MHR. Further analysis indicated that this decreased MHR is unlikely to be due purely to the smaller size of these females. Instead, it is more likely to be an indirect experimentally evolved response attributable to the changed breeding ecology, and/or male trait evolution. Our results underline the implications of changes in life history traits, including lifespan, to the evolution of MHR in females.

Experience with cascade screening: A comprehensive family pedigree analysis of two index patients with Fabry disease.

The wide range of clinical symptoms observed in patients with Fabry disease (FD) often leads to delays in diagnosis and initiation of treatment. Delayed initiation of therapy may result in end-organ damage, such as chronic renal failure, hypertrophic cardiomyopathy, and stroke. Although some tools are available to identify undiagnosed patients, new comprehensive screening methods are needed. In this study, the outcomes of the cascade screening applied to three index cases with FD from 2 familes were investigated. In the pedigree analysis, 280 individuals were included; out of them, 131 individuals underwent genetic testing and cascade screening for FD. During the screening program, a total of 45 individuals were diagnosed, with a diagnostic ratio of 1:15. The average age at diagnosis for all individuals was 30.9 ± 17.7 years, and %25 were pediatric cases (mean age 9.5 ± 5.9 years). Thirty affected relatives were diagnosed from the two index cases in Family 1 and 15 individuals were diagnosed from one index case in Family 2. There were 13 consanguineous marriages observed among 2 pedigres, in two both spouses  were affected, leading to two homozygous affected daughters in one couple. In regions where there is a high prevalence of consanguineous marriages, implementing the cascade screening approach to identify all individuals at risk can be beneficial for patients with FD, specifically women and children.