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Excessive cardiorespiratory responses to CO2 are a hallmark of panic disorder (PD). Female sex and exposure to early life stress are risk factors for PD. Neonatal maternal separation (NMS; 3 h/day, postnatal days 3–12) augments the ventilatory response to CO2 by ∼35% relative to controls; this effect is most notable during pro‐oestrus but is not observed in males. Orexin‐1 receptor (OX1‐R) antagonism attenuates the CO2 response of NMS females. In the limbic system, stress and ovarian hormones influence OX1‐R expression, but the impact of these factors on OX1‐Rs in regions regulating the cardiorespiratory responses to CO2 is unknown. Here, we hypothesised that ovarian hormones and NMS determine OX1‐R expression in structures regulating the CO2 response; we used in situ hybridisation to quantify OX‐1R mRNA expression in the brains of adult NMS and control rats. Brains were harvested from females that were either in pro‐oestrus (high ovarian hormones) or 2 weeks post ovariectomy (OVX; low ovarian hormones); males were included for comparison. Hormonal status influenced the intensity of the OX1‐R signal in the medial amygdala, raphe obscurus (RObs) and the A5 area, but the direction of the changes (increase vs. decrease) was structure‐specific. Significant NMS × hormonal status interactions were noted in the dorsal raphe, the locus coeruleus, the nucleus of the solitary tract and the A5 area; the effects were structure‐specific. As the dorsal raphe was the only structure in which the changes in OX1‐R expression matched the sex‐specific effect of NMS on the CO2 response, this structure likely contributes to respiratory manifestations of PD. What is the central question of this study? Anomalies in orexin signalling are an important mechanism of excessive cardiorespiratory response to CO2, a hallmark of panic disorder (PD): does early life stress and hormonal status (male, female in pro‐oestrus, and ovariectomised females) influence orexin‐1 receptor (OX1‐R) expression in brain regions regulating the cardiorespiratory responses to CO2? What is the main finding and its importance? The effects of stress and hormonal status are structure‐specific. Because the changes in OX1‐Rs observed in the dorsal raphe nucleus match the sex‐specific increase in CO2 response, this structure emerges as a primary candidate in the aetiology of PD.

Ponatinib (PON), a tyrosine kinase inhibitor approved in chronic myeloid leukaemia, has proven cardiovascular toxicity. We assessed mechanisms of sex‐related PON‐induced cardiotoxicity and identified rescue strategies in a murine model. PON+scrambled siRNA‐treated male mice had a higher number of TUNEL‐positive cells (%TdT+6.12 ± 0.17), higher percentage of SA‐β‐gal‐positive senescent cardiac area (%SA‐β‐gal 1.41 ± 0.59) and a lower reactivity degree (RD) for the survival marker Bmi1 [Abs (OD) 5000 ± 703] compared to female (%TdT+3.75 ± 0.35; %SA‐β‐gal 0.77 ± 0.02; Bmi1 [Abs (OD) 8567 ± 2173]. Proteomics analysis of cardiac tissue showed downstream activation of cell death in PON+siRNA scrambled compared to vehicle or PON+siRNA‐Notch1‐treated male mice. Upstream analysis showed beta‐oestradiol activation, and downstream analysis showed activation of cell survival and inhibition of cell death in PON+scrambled siRNA compared to vehicle or PON+siRNA‐Notch1‐treated female mice. PON+scrambled siRNA‐treated mice also had a downregulation of cardiac actin—more marked in males—and vessel density—more marked in females. Female hearts showed greater cardiac fibrosis than their male counterparts at baseline, with no significant change after PON treatment. PON+siRNA‐scrambled mice had less fibrosis than vehicle or PON+siRNA‐Notch1‐treated mice. The left ventricular systolic dysfunction showed by PON+scrambled siRNA‐treated mice (male %EF 28 ± 9; female %EF 36 ± 7) was reversed in both PON+siRNA‐Notch1‐treated male (%EF 53 ± 9) and female mice (%EF 52 ± 8). We report sex‐related differential susceptibility and Notch1 modulation in PON‐induced cardiotoxicity. This can help to identify biomarkers and potential mechanisms underlying sex‐related differences in PON‐induced cardiotoxicity.

Although mitochondrial alterations are implicated in cardiac pathologies, sex‐specific changes following chronic stress and ischemia–reperfusion injury are poorly characterized. Male and female Wistar rats underwent chronic restraint stress (CRS) for 4 weeks versus controls, whereafter ex vivo hearts were subjected to regional ischemia and reperfusion. Post‐reperfusion hearts were dissected into ischemia‐reperfused and non‐ischemic regions with high‐resolution mitochondrial respirometry, and oxidative stress assays performed. CRS males displayed increased routine and fatty acid β‐oxidation respiration in non‐ischemic tissues but lowered ETF‐linked LEAK contributions to overall electron transfer system capacity ratios in ischemia‐reperfused regions versus controls. CRS males exhibited lowered superoxide dismutase activity and increased lipid peroxidation in well‐perfused regions versus controls. Female CRS hearts showed attenuated ETF‐linked LEAK respiration and increased lipid peroxidation versus controls in non‐ischemic tissue but a lowered RE ratio (measure of mitochondrial coupling) with ischemia–reperfusion. Our findings highlight the heart's sexually dimorphic response to chronic stress and ischemic injury, with female hearts showing oxidative damage in non‐ischemic tissues together with relatively intact mitochondrial function in ischemia‐reperfused tissues.

Multiple studies have reported a male bias in incidence and/or prevalence of malaria infection in males compared to females. To test the hypothesis that sex-based differences in host-parasite interactions affect the epidemiology of malaria, we intensively followed Plasmodium falciparum infections in a cohort in a malaria endemic area of eastern Uganda and estimated both force of infection (FOI) and rate of clearance using amplicon deep-sequencing. We found no evidence of differences in behavioral risk factors, incidence of malaria, or FOI by sex. In contrast, females cleared asymptomatic infections at a faster rate than males (hazard ratio [HR]=1.82, 95% CI 1.20 to 2.75 by clone and HR = 2.07, 95% CI 1.24 to 3.47 by infection event) in multivariate models adjusted for age, timing of infection onset, and parasite density. These findings implicate biological sex-based differences as an important factor in the host response to this globally important pathogen.

Traumatic brain injury is a leading cause of injury-related death and morbidity. Multiple clinical and pre-clinical studies have reported various results regarding sex-based differences in TBI. Our accepted rodent model of traumatic brain injury was used to identify sex-based differences in the pathological features of TBI. Male and female Sprague-Dawley rats were subjected to either controlled-cortical impact (CCI) or sham injury; brain tissue was harvested at different time intervals depending on the specific study. Blood-brain barrier (BBB) analysis was performed using infrared imaging to measure fluorescence dye extravasation. Microglia and splenocytes were characterized with traditional flow cytometry; microglia markers such as CD45, P2Y12, CD32, and CD163 were analyzed with t-distributed stochastic neighbor embedding (t-SNE). Flow cytometry was used to study tissue cytokine levels, and supplemented with ELISAs of TNF-⍺, IL-17, and IL-1β of the ipsilateral hemisphere tissue. CCI groups of both sexes recorded a higher BBB permeability at 72 hours post-injury than their respective sham groups. There was significant difference in the integrated density value of BBB permeability between the male CCI group and the female CCI group (female CCI mean = 3.08 x 108 ± 2.83 x 107, male CCI mean = 2.20 x 108 ± 4.05 x 106, p = 0.0210), but otherwise no differences were observed. Traditional flow cytometry did not distinguish any sex-based difference in regards to splenocyte cell population after CCI. t-SNE did not reveal any significant difference between the male and female injury groups in the activation of microglia. Cytokine analysis after injury by flow cytometry and ELISA was limited in differences at the time point of 6 hours post-injury. In our rodent model of traumatic brain injury, sex-based differences in pathology and neuroinflammation at specified time points are limited, and only noted in one specific analysis of BBB permeability.

Previous research has identified possible sex-based differences in restricted and repetitive behaviors in autism spectrum disorder (ASD). However, this finding is mixed, particularly among preschool-aged children. We investigated the presence of sex-based differences in parent-rated ASD symptomatology, using the Autism Spectrum Rating Scale (ASRS). Participants consisted of a large (n = 481,100 female), clinically-referred sample of preschoolers (ages 2–5) diagnosed with ASD (NVIQ: M = 67.11, SD = 21.79). Females had less severe symptoms on the Total, Unusual Behaviors, DSM-5, and Stereotypy scales on the ASRS. The effects were small-to-medium, but statistically significant. There was evidence of differential relationships between nonverbal IQ and ASRS scores among males and females. This study provides additional evidence of sex-based differences in ASD symptoms present from an early age.

In the krill-based ecosystem of the Antarctic, fluctuations in the distribution and abundance of Euphausia superba may have strong impacts on predator populations; thus, it is crucial to observe the feeding ecology of Antarctic predators, especially in the light of climate change and increasing human pressure. We determined the composition of euphausiid species in diet samples collected from Adélie ( Pygoscelis adeliae ), chinstrap ( Pygoscelis antarcticus ) and gentoo ( Pygoscelis papua ) penguins on King George Island (South Shetlands Islands) during a breeding season. For all three penguin species, euphausiids (mainly E. superba ) represented almost the entirety of researched stomach samples (i.e. 99.9% in the case of Adélie and chinstrap penguins), while gentoo penguins also proved to feed on fish (99.4% krill; 0.5% fish). Analysed material differed in the size of eaten E. superba specimens, with the smallest crustaceans consumed by Adélie penguins. Furthermore, we found differences in the ratio of consumed krill and krill size. Such disparities may be a result of sex-based differences and slight differences in feeding areas between the birds. Additionally, we noted some fragments of plastic debris in the investigated penguin diet samples.

Sexual dimorphism has been observed in many physiological and pathological responses, yet few studies incorporate both female and male experimental groups for preclinical work. For the development of biomaterial devices, in vitro studies are essential for design and optimization, and quantitative comparison of female and male cell migratory behavior is a crucial design consideration. In this work, we thoroughly examined sex-based migration on flat controls and aligned nanofiber scaffolds of various diameters using anomalous and random walk models. Male and female cells exhibited significantly different migration on flat substrates, with female cells having increased speed while male cells had higher persistence. Persistence increased with the introduction of aligned fiber topography for female cells, but only affected male cells on the highest fiber diameter. Speed along the axis of alignment differed between sexes on 1.2 and 1.8 µm fibers. Morphological analysis confirmed cell shape was a function of both sex and fiber size. These results provided critical information regarding sex-based cell migration, highlighting the importance of sex within in vitro studies for clinical device design.

BackgroundMuch of our knowledge about inguinal hernias is based on males. Meanwhile, it is established that women have worse outcomes after inguinal hernia repair, with more chronic pain and higher recurrences. Pediatric literature shows inguinal hernias in females are more likely to be bilateral, incarcerated, and carry a stronger genetic predisposition than males. We aimed to evaluate sex-based differences in inguinal hernia factors in adults, to help supplement the paucity of literature in the adult population.MethodsAn institutional database of patients undergoing repair of primary inguinal hernias was queried with focus on preoperative risk factors and operative characteristics. Multivariate analysis was performed looking for independent variables associated with a greater number of hernia defects found intraoperatively.ResultsAmong 494 patients, 202 (40.9%) were female. Number of risk factors among females was significantly higher than males (1.53 vs 1.2, p = 0.003). Females had significantly more constipation, GERD, and asthma and lower BMI than males. Family history of hernias was similar between both sexes. As expected, females had significantly less direct hernias (12.9% vs 32.9%, p < 0.001) and more femoral hernias (38.5% vs 12.2%, p < 0.001) than males. Bilaterality was similar. Females undergoing inguinal hernia repair averaged 1.23 prior deliveries. Regression analysis showed age, sex, BMI, and number of deliveries were not correlated with the number of defects.ConclusionsFemales undergoing primary inguinal hernia repair had more preoperative risk factors for inguinal hernia than males. In our population, there was no higher incidence of bilaterality or significant genetic predisposition in females as noted by family history of hernias. Age, sex, BMI and number of deliveries did not correlate with the number of hernia defects found. Our study promotes awareness of inguinal hernias in females and presents new data to quantify sex-based differences and predispositions to inguinal hernias.

PurposeThe erythema migrans (EM) skin lesion is often the first clinical sign of Lyme disease. Significant variability in EM presenting characteristics such as shape, color, pattern, and homogeneity, has been reported. We studied associations between these presenting characteristics, as well as whether they were associated with age, sex, EM duration, body location, and initiation of antibiotics.MethodsTwo hundred and seventy one adult participants with early Lyme disease who had a physician-diagnosed EM skin lesion of ≥ 5 cm in diameter and ≤ 72 h of antibiotic treatment were enrolled. Participant demographics, clinical characteristics, and characteristics of their primary EM lesion were recorded.ResultsAfter adjusting for potential confounders, EM size increased along with increasing EM duration to a peak of 14 days. Male EM were found to be on average 2.18 cm larger than female EM. The odds of a red (vs blue/red) EM were 65% lower in males compared to females, and were over 3 times as high for EM found on the pelvis, torso, or arm compared to the leg. Age remained a significant predictor of central clearing in adjusted models; for every 10-year increase in age, the odds of central clearing decreased 25%.ConclusionsGiven that EM remains a clinical diagnosis, it is essential that both physicians and the general public are aware of its varied manifestations. Our findings suggest possible patterns within this variability, with implications for prompt diagnosis and treatment initiation, as well as an understanding of the clinical spectrum of EM.