Sex Differences In Response Research Articles

Abstract P3111: Sex Differences In The Proteomic Response To Chronic Myocardial Ischemia In Swine

Intro: There are known sex differences in response to ischemic insult yet the mechanisms behind these differences have not been fully elucidated. Previous work in our lab has demonstrated female sex confers a relative protective effect on CO in the setting of chronic ischemia. The aim of this study was to use total proteomic analysis in order to uncover the mechanisms behind sex specific responses to myocardial ischemia in a porcine model. Methods: Eight 11-week old pigs (3 female, 5 male) underwent surgical placement of an ameroid constrictor to the left circumflex artery via left thoracotomy in order to induce chronic myocardial ischemia. After seven weeks, pigs were euthanized and myocardial tissue was harvested for total proteomic analysis. Results: When compared with non-ischemic male tissue non-ischemic female tissue demonstrated upregulation of two variants of LMOD2 and down regulation of five variants of ACADS (Figure 1A). However, when comparing ischemic female tissue with ischemic male tissue there were 626 upregulated proteins and 194 down regulated proteins (Figure 1B). Enrichment analysis revealed upregulation of certain metabolic pathways including the citric acid cycle and glycolysis/gluconeogenesis (Figure 1C) while there was down regulation in pathways involved in cardiac muscle contraction and dilated cardiomyopathy (Figure 1D). There was no difference in serum glucose, HDL, LDL, or total cholesterol (P > 0.05 for all) (Figure 1E). Conclusion: There were clear sex differences in response to chronic cardiac ischemia. Proteins involved in metabolic pathways and myocyte function appear to be particularly affected.

Studying sex differences in responses to fibroblast growth factor 21 administration in obese mice consuming a sweet-fat diet.

In animals, obesity caused by consumption of a sweet-fat diet (SFD) is the most adequate mouse model of human diet-induced obesity. Fibroblast growth factor 21 (FGF21) reduces body weight, beneficially affects taste preferences, and corrects glucose metabolism in obese mice. Sex is known to influence FGF21 effects in different models of diet-induced and hereditary obesity. In mice with SFD-induced obesity, the effects of FGF21 have been studied only in males. The aim of this study was to compare the effects of FGF21 on body weight, food preferences and glucose and lipid metabolism in C57Bl/6J male and female mice with SFD-induced obesity. Mice were fed with a diet consisting of standard chow, lard and cookies for 10 weeks, then they were injected with FGF21 (1 mg per 1 kg) or vehicle for 7 days. Body weight, weights of different types of food, blood parameters, glucose tolerance, gene and protein expression in the liver, gene expression in the white, brown adipose tissues, and the hypothalamus were assessed. FGF21 administration reduced body weight, did not alter total energy consumption, and activated orexigenic pathways of hypothalamus in mice of both sexes. However, sex dimorphism was found in the realization of the orexigenic FGF21 action at the transcriptional level in the hypothalamus. Metabolic effects of FGF21 were also sex-specific. Only in males, FGF21 exerted beneficial antidiabetic action: it reduced fatty acid and leptin plasma levels, improved glucose-tolerance, and upregulated hepatic expression of Ppargc1, Fasn, Accα, involved in lipid turnover, gene Insr and protein glucokinase, involved in insulin action. Only in obese females, FGF21 induced preference of standard diet to sweet food. Thus, in mouse model of obesity induced by consumption of a sweet-fat diet, the catabolic effect of FGF21 was not sex-specific and hormonal, transcriptional and behavioral effects of FGF21 were sex-specific. These data suggest elaboration of different approaches to use FGF21 analogs for correction of metabolic consequences of obesity in different sexes.

Sex-dependent effects of acute stress on amyloid-β in male and female mice.

The risk of developing Alzheimer's disease is mediated by a combination of genetics and environmental factors, such as stress, sleep abnormalities and traumatic brain injury. Women are at a higher risk of developing Alzheimer's disease than men, even when controlling for differences in lifespan. Women are also more likely to report high levels of stress than men. Sex differences in response to stress may play a role in the increased risk of Alzheimer's disease in women. In this study, we use in vivo microdialysis to measure levels of Aβ in response to acute stress in male and female mice. We show that Aβ levels are altered differently between female and male mice (APP/PS1 and wild-type) in response to stress, with females showing significantly increased levels of Aβ while most males do not show a significant change. This response is mediated through β-arrestin involvement in Corticotrophin Releasing Factor receptor signalling pathway differences in male and female mice as male mice lacking β-arrestin show increase in Aβ in response to stress similar to females.

The stress of losing sleep: Sex-specific neurobiological outcomes

Sleep is a vital and evolutionarily conserved process, critical to daily functioning and homeostatic balance. Losing sleep is inherently stressful and leads to numerous detrimental physiological outcomes. Despite sleep disturbances affecting everyone, women and female rodents are often excluded or underrepresented in clinical and pre-clinical studies. Advancing our understanding of the role of biological sex in the responses to sleep loss stands to greatly improve our ability to understand and treat health consequences of insufficient sleep. As such, this review discusses sex differences in response to sleep deprivation, with a focus on the sympathetic nervous system stress response and activation of the hypothalamic-pituitary-adrenal (HPA) axis. We review sex differences in several stress-related consequences of sleep loss, including inflammation, learning and memory deficits, and mood related changes. Focusing on women's health, we discuss the effects of sleep deprivation during the peripartum period. In closing, we present neurobiological mechanisms, including the contribution of sex hormones, orexins, circadian timing systems, and astrocytic neuromodulation, that may underlie potential sex differences in sleep deprivation responses.

Sex differences in the erythropoietin response to hot tub treatment and carbon monoxide inhalation

The kidney increases erythropoietin (EPO) when oxygen delivery is reduced, and when reductions in oxygen delivery are sustained, increased EPO results in increased red blood cell (RBC) production. More recently, carbon monoxide (CO) and heat have been used chronically to increase RBC production and therefore hemoglobin (Hb) mass. However, studies examining the acute effects of these interventions are limited, and no studies have examined these interventions in women. The purpose of this study was to examine the effects of CO inhalation and heat treatment alone and in combination on circulating EPO and determine if there are sex differences in these responses. 11 healthy subjects completed the study (6 women). Baseline blood was drawn to measure iron, ferritin, and transferrin concentrations. Hb mass was measured via the 10-minute CO-rebreathe method. Subjects completed three interventions – CO inhalation (carboxyhemoglobin 13.01±2.5%) hot tub immersion (40 degrees C for 45 minutes), and combined CO and hot tub – in a randomized crossover design. Renal blood velocity (RBV) was measured via ultrasound during all interventions. Venous blood was drawn at baseline and every hour for 6 hours post-intervention for measurements of EPO. All interventions reduced renal oxygen delivery (Δ47.5±21mL O2/min), and there were no sex differences in the reduction in oxygen delivery. All three treatments similarly increased EPO from baseline to peak concentration (Δ4.94±5.6mIU/mL). Women had a significantly greater increase in EPO than men to all three interventions (Δwomen 8.22±5.6mIU/mL; Δmen 1±2.06mIU/mL). The degree of EPO increase on all three days negatively correlated with Hb mass (R2=0.64) and positively correlated with transferrin (R2=0.73). Women may respond better to these interventions aimed to increase EPO, but the degree of responsiveness may depend on baseline Hb mass as well as transferrin concentrations. Wu-Tsai Human Performance Alliance at Oregon This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Sex Differences in Gut Microbiota Fatty Acid Metabolism in Human Salt Sensitivity of Blood Pressure

Salt sensitivity is a trait in which high dietary sodium (Na+) intake causes an increase in blood pressure. We previously demonstrated that in the gut, elevated dietary Na+ causes dysbiosis. The mechanistic interplay between excess dietary Na+-induced alteration in the gut microbiome and sex differences is less understood. The goal of this study was to identify novel metabolites in salt sensitivity and sex differences in response to a high dietary Na+ intake. We hypothesized that excess dietary salt-induced dysbiosis is associated with distinct metabolomic changes in men and women. We performed plasma metabolomics analysis and measured blood pressure of human volunteers who completed a validated 3-day food record to estimate dietary Na+ intake. Based on the recommendations by the American Heart Association, we classified daily Na+ intake of <2.3g as normal salt and high salt for subjects consuming ≥ 2.3g Na+. Spearman correlation was used to assess the relationship between Na+ intake and blood pressure. We also performed RNA sequencing on human (N=11) monocytes treated with high salt in vitro. The relationship between dietary Na+ intake and mean arterial pressure was different in women (r=0.3422, p=0.0022, N=81) and men (r=0.4552, p=0.0010, N=49). Network analysis of human plasma untargeted metabolome revealed fatty acids as top subnetworks differentially changed with salt intake. In subjects consuming a high Na+ diet, levels of linoleate (1.211 ± 0.330 vs. 0.869 ± 0.170; p<0.001); palmitate (1.155 ± 0.292 vs. 0.924 ± 0.233; p= 0.003); arachidonic acid (1.119 ± 0.242 vs. 0.965 ± 0.201; p=0.015); and 12-hydroxyeicosatetraenoic acid (1.329 ± 0.925 vs. 0.902 ± 0.520; p=0.0469) were higher in women (28) than men (25). In contrast, we observed no sex differences in these parameters between men and women consuming a normal salt diet. RNA sequencing analysis revealed that exposure of human monocytes to high salt in vitro upregulated transcription of fatty acid receptors and arachidonic acid-related genes. Specifically, ALOX12 (277.8 ± 13.8 vs. 169.5 ± 16.7, p<0.0001) which encodes for arachidonate 12-lipoxygenase, ALOX5AP (6459 ± 1553 vs. 2598 ± 30, p=0.0310) which encodes for 5-lipoxygenase activating protein, and FFR2 (418.1 ± 97.8 vs. 115.9 ± 29.4, p=0.0078) which encodes for free fatty acids receptor 2 were increased in human monocytes, and this was associated with a pro-inflammatory phenotype. These findings suggest that excess dietary Na+ is associated with fatty acid metabolism dysregulation, and that the arachidonic acid pathway may potentially play a role in sex differences of salt-sensitive hypertension. This work was supported by American Heart Association grants POST9034281 (to JAI) and 15SDG24890015 (to JFF) and NIH grants K01HL130497 (to AK) as well as Venture Pilot Funding (to AK) from Vanderbilt Microbiome Initiative and Vanderbilt Institute for Infection, Immunology, and Inflammation (VI4) and a P&F award (to JFF) from Vanderbilt University Medical Center's Digestive Disease Research Center supported by NIH grant P30DK058404. This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Sex differences in body fluid composition in humans with obstructive sleep apnea before and after CPAP therapy.

Obstructive sleep apnea (OSA) is common in heart and kidney disease, both conditions prone to fluid retention. Nocturnal rostral fluid shift contributes to the pathogenesis of OSA in men more than women, suggesting a potential role for sex differences in body fluid composition in the pathogenesis of OSA, with men having a predisposition to more severe OSA due to an underlying volume expanded state. Continuous positive airway pressure (CPAP) increases intraluminal pressure in the upper airway and mitigates the rostral fluid shift; this, in turn, may prevent fluid redistribution from other parts of the body to the upper airway. We sought to determine the impact of CPAP on sex differences in body fluid composition. Twenty-nine (10 women, 19 men) incident, sodium replete, otherwise healthy participants who were referred with symptomatic OSA (oxygen desaturation index >15/h) were studied pre- and post-CPAP (>4 h/night × 4 weeks) using bioimpedance analysis. Bioimpedance parameters including fat-free mass (FFM, %body mass), total body water (TBW, %FFM), extracellular and intracellular water (ECW and ICW, %TBW), and phase angle (°) were measured and evaluated for sex differences before and after CPAP. Pre-CPAP, despite TBW being similar between sexes (74.6 ± 0.4 vs. 74.3 ± 0.2%FFM, p = 0.14; all values women vs. men), ECW (49.7 ± 0.7 vs. 44.0 ± 0.9%TBW, p < 0.001) was increased, while ICW (49.7 ± 0.5 vs. 55.8 ± 0.9%TBW, p < 0.001) and phase angle (6.7 ± 0.3 vs. 8.0 ± 0.3°, p = 0.005) were reduced in women compared to men. There were no sex differences in response to CPAP (∆TBW -1.0 ± 0.8 vs. 0.7 ± 0.7%FFM, p = 0.14; ∆ECW -0.1 ± 0.8 vs. -0.3 ± 1.0%TBW, p = 0.3; ∆ICW 0.7 ± 0.4 vs. 0.5 ± 1.0%TBW, p = 0.2; ∆Phase Angle 0.2 ± 0.3 vs. 0.0 ± 0.1°, p = 0.7). Women with OSA had baseline parameters favoring volume expansion (increased ECW, reduced phase angle) compared to men. Changes in body fluid composition parameters in response to CPAP did not differ by sex.

Sex impacts pain behaviour but not emotional reactivity of lambs following ring tail docking.

Studies in humans have shown sex differences in response to painful events, however, little is known in relation to sex differences in sheep. Understanding sex differences would enable improved experimental design and interpretation of studies of painful procedures in sheep. To examine sex differences in response to pain, 80 lambs were tested across five cohorts of 16. The lambs were penned in groups containing two male and two female lambs with their respective mothers. Lambs were randomly allocated from within each block to one of four treatment groups; FRing-Female lamb, ring tail docked without analgesia, MRing-Male lamb, ring tail docked without analgesia, FSham-Female lamb, tail manipulated and MSham-Male lamb, tail manipulated. Following treatment, lambs were returned to their pen and were video recorded for 45 mins for behavioural observations of acute pain and posture. An hour after treatment, lambs then underwent an emotional reactivity test that consisted of three phases: Isolation, Novelty and Startle. Following treatment, Ring lambs displayed more abnormal postures (mean = 2.5±0.5) compared to Sham lambs (mean = 0.05±0.4, P=0.0001). There was an effect of sex on the display of acute pain-related behaviours in lambs that were tail docked (P<0.001), with female lambs displaying more acute behaviours (mean count = +2.2). This difference in behaviour between sexes was not observed in Sham lambs. There was no effect of sex on display of postures related to pain (P=0.99). During the Novelty and Startle phase of the emotional reactivity test, Ring lambs tended to (P=0.084) or did (P=0.018) show more fear related behaviours, respectively. However, no effect of sex was observed. The results of this study indicate that a pain state may alter the emotional response of lambs to novel objects and potential fearful situations. It was also demonstrated that female lambs display increased sensitivity to the acute pain caused by tail docking compared to males.

Differences in phytohormone and flavonoid metabolism explain the sex differences in responses of Salix rehderiana to drought and nitrogen deposition.

Due to global warming and the increase in nitrogen oxide emissions, plants experience drought and nitrogen (N) deposition. However, little is known about the acclimation to drought and N deposition of Salix species, which are dioecious woody plants. Here, an investigation into foliar N deposition combined with drought was conducted by assessing integrated phenotypes, phytohormones, transcriptomics, and metabolomics of male and female Salix rehderiana. The results indicated that there was greater transcriptional regulation in males than in females. Foliar N deposition induced an increase in foliar abscisic acid (ABA) levels in males, resulting in the inhibition of stomatal conductance, photosynthesis, carbon (C) and N accumulation, and growth, whereas more N was assimilated in females. Growth as well as C and N accumulation in drought-stressed S. rehderiana females increased after N deposition. Interestingly, drought decreased flavonoid biosynthesis whereas N deposition increased it in females. Both drought and N deposition increased flavonoid methylation in males and glycosylation in females. However, in drought-exposed S. rehderiana, N deposition increased the biosynthesis and glycosylation of flavonoids in females but decreased glycosylation in males. Therefore, foliar N deposition affects the growth and drought tolerance of S. rehderiana by altering the foliar ABA levels and the biosynthesis and modification of flavonoids. This work provides a basis for understanding how S. rehderiana may acclimate to N deposition and drought in the future.

Sex differences in response to lifestyle intervention among children and adolescents: Systematic review and meta-analysis.

Little is known about sex differences in response to lifestyle interventions among pediatric populations. The purpose of this analysis was to evaluate sex differences in adiposity following lifestyle interventions among children and adolescents with overweight or obesity aged 6 to 18 years old. Searches were conducted in PubMed, Web of Science, and MEDLINE (from inception to March 2021), and references from included articles were examined. Eligibility criteria included children and adolescents aged 6 to 18 years with overweight or obesity, randomization to a lifestyle intervention versus a control group, and assessment of at least one adiposity measure. Corresponding authors were contacted to obtain summary statistics by sex (n=14/49). Of 89 full-text articles reviewed, 49 (55%) were included, of which 33 (67%) reported statistically significant intervention effects on adiposity. Only two studies (4%) evaluated sex differences in response to lifestyle intervention, reporting conflicting results. The results of the meta-regression models demonstrated no significant differences in the treatment effect between male and female youth for weight (beta=-0.05, SE=0.18, z=-0.28, p=0.8), BMI (beta=0.03, SE=0.14, z=0.19, p=0.85), BMI z score (beta=-0.04, SE=0.18, z=-0.23, p=0.82), percentage body fat (beta=-0.11, SE=0.16, z=-0.67, p=0.51), and waist circumference (beta=-0.30, SE=0.25, z=-1.18, p=0.24). The meta-analysis revealed that youth with overweight or obesity do not demonstrate a differential response to lifestyle intervention in relation to adiposity-related outcomes.

The 2018 California wildfires: examining sex differences in response to crisis communication and underlying processes

ABSTRACT A sizable body of research has explored information seeking processes during crises and disasters, including the ways in which people seek mediated information to help make sense of the event and take action. Much of this research has postulated that information seeking is used as a mechanism for stress reduction, and that sex differences exist in terms of information seeking and risk perceptions. The current study attempted to explicate these links in the context of the 2018 California wildfires. While evidence was found for differential patterns of information seeking across sex and degree of risk perception, evidence did not support the notion that aggregate information seeking leads to a reduction in stress. Alternative theoretical explanations for sex differences in crisis information seeking and stress responses are proposed and discussed, as are implications for crisis managers and emergency responders.

COVID-19: Understanding the impact of anti-hypertensive drugs and hydroxychloroquine on the ACE1 and ACE2 in lung and adipose tissue in SHR and WKY rats.

Hypertensive individuals taking anti-hypertensive drugs from renin-angiotensin system inhibitors may exhibit a more severe evolution of the disease when contracting the SARS-CoV-2 virus (COVID-19 disease) due to potential increases in ACE2 expression. The study investigated ACE1 and ACE2 axes and hydroxychloroquine in the lungs and adipose tissue of male and female normotensive Wistar Kyoto (WKY) and spontaneously hypertensive rats (SHRs). SHRs were treated with losartan (10mg/kg/day) or captopril (10mg/kg/day) for 14 days or 7 days with hydroxychloroquine (200 mg/kg/day) in drinking water. WKY rats were also treated for 7 days with hydroxychloroquine. Blood pressure (BP), protein, and mRNA expression of ACE1 and ACE2 were analyzed in serum, adipose, and lung tissues. Losartan and captopril reduced BP in both sexes in SHR, whereas hydroxychloroquine increased BP in WKY rats. Losartan reduced ACE2 in serum and lungs in both sexes and in adipose tissue of male SHRs. Captopril decreased ACE2 protein in the lung of females and in adipose tissue in both sexes of SHRs. Hydroxychloroquine decreased ACE1 and ACE2 proteins in the lungs in both sexes and adipose tissue in male SHRs. In female WKY rats, ACE2 protein was lower only in the lungs and adipose tissue. Losartan effectively inhibited ACE2 in male and captopril in female SHRs. Hydroxychloroquine inhibited ACE2 in male SHRs and female WKY rats. These results further our understanding of the ACE2 mechanism in patients under renin-angiotensin anti-hypertensive therapy and in many trials using hydroxychloroquine for COVID-19 treatment and potential sex differences in response to drug treatment.

Effects of sex and pro-inflammatory cytokines on context discrimination memory

In learning and memory tasks, immune overactivation is associated with impaired performance, while normal immune activation is associated with optimal performance. In one specific domain of memory, context discrimination memory, peripheral immune stimulation has been shown to impair performance on the context-object discrimination memory task in male rats. In order to evaluate potential sex differences in this task, as well as potential mechanisms for the memory impairment, we evaluated the ability of peripheral immune stimulation to impair task performance in both males and females. Next, we examined whether treatment with interleukin-1 receptor antagonist (IL-1ra), a receptor antagonist for the pro-inflammatory cytokine interleukin (IL)−1β, was able to rescue the memory deficit. We examined microglial morphology in the hippocampus and cytokine mRNA and protein expression in the hippocampus and the periphery. Male rats displayed memory impairment in response to LPS, and this impairment was not rescued by IL-1ra. Female rats did not have significant memory impairments and IL-1ra administration improved memory following inflammation. A subset of cytokines and chemokines were increased only in LPS-treated males. Inflammation alone did not alter microglia morphology, but IL-1ra did in certain sub-regions of the hippocampus. Together, these results indicate that sex differences exist in the ability of a peripheral immune stimulus to influence context discrimination memory and specific cytokine signals may be altered in impaired males. This study highlights the importance of sex differences in response to inflammatory challenges, especially related to memory impairments in context discrimination memory.

Sex Differences in Response to Administration of Heparin During Non-Cardiac Arterial Procedures

Females are more prone to complications during non-cardiac arterial procedures (NCAPs) than males. The current study investigated the difference in the effect of peri-procedural prophylactic heparin in males and females, using the activated clotting time (ACT). This was a retrospective analysis of a prospective multicentre cohort study.

Getting a handle on rat familiarization: The impact of handling protocols on classic tests of stress in Rattus norvegicus.

Experimenter familiarization with laboratory rodents through handling prior to experimentation is an important practice in neurobehavioral research and is implicated in stress, study variability, and replicability. Unfortunately, different handling protocols have not been thoroughly examined. Determining optimal experimenter familiarization protocols is expected to reduce animal stress and thus improve welfare and data consistency. The impact of different handling protocols was determined through behavioral assessments (i.e. elevated plus maze, light/dark box, open field) as well as via analysis of fecal boli counts, ultrasonic vocalizations, and blood corticosterone. Male and female Sprague Dawley rats were distributed among three groups: never handled, picked-up, and handled for 5 min once daily over five days. Handled and picked-up rats spent more time in open arms and less time in closed arms of the elevated plus maze and more time in the center and less time at the perimeter of the open field compared to rats that were never handled, indicating that handled and picked-up rats were less anxious than those that were never handled. Male rats consistently defecated more frequently throughout the handling process and throughout behavioral testing, whereas females showed greater concentrations of blood corticosterone. Female rats were found to emit more 50-kHz calls and fewer 22-kHz calls compared to males. The results observed suggest that picking animals up may suffice as a handling method compared to time-intensive handling procedures, and that there are significant sex differences in response to handling.

Sex differences of burosumab in children with X-linked hypophosphataemic rickets.

The severity of X-linked hypophosphataemic rickets (XLH) may be affected by genotype and sex. However, burosumab, a fully humanized monoclonal antibody against fibroblast growth factor 23, has the same pediatric dose recommendation for both sexes (0.8mg/kg every 2weeks). In a retrospective cohort study, we describe the burosumab response differences by sex in children with XLH. We treated 10 children (5 females, mean age at initiation 4.2 ± 3.5years) with XLH with burosumab. Initial mean serum phosphate was 0.69 ± 0.18mmol/L in males and 0.86 ± 0.22mmol/L in females (p = 0.108). The mean ratio of tubular maximum reabsorption rate of phosphate to glomerular filtration rate (TmP/GFR) was 0.55 ± 0.11mmol/L in males and 0.76 ± 0.23mmol/L in females (p = 0.06). The mean starting dose of burosumab was 0.83 ± 0.19mg/kg subcutaneously every 14days (males: 0.79 ± 0.19mg/kg; females: 0.87 ± 0.21mg/kg, n.s.). Two weeks after starting burosumab, serum phosphate differed significantly between males (0.90 ± 0.21mmol/L) and females (1.27 ± 0.25mmol/L) (p = 0.018). All males required a dose increase to try to normalize serum phosphate. On day 140 after starting, the average dose in males increased further to 1.24 ± 0.41mg/kg to achieve a phosphate of 0.87 ± 0.11mmol/L while females had a normal phosphate and alkaline phosphatase on the starting dose. After a mean of 458 ± 79days, the mean burosumab dose/kg in males was 1.68 ± 0.61mg/kg, mean serum phosphate was 1.08 ± 0.23mmol/L, mean TmP/GFR was 1.01 ± 0.20, mean alkaline phosphatase had normalized to 303.6 ± 40.7U/L, and mean 1.25(OH)2 vitamin D level was 186.4 ± 16.6nmol/L. Our findings may suggest a sex difference in response to burosumab in XLH patients. Our data suggest that males may require higher doses.

Sex Differences in Response to Marek's Disease: Mapping Quantitative Trait Loci Regions (QTLRs) to the Z Chromosome.

Marek's Disease (MD) has a significant impact on both the global poultry economy and animal welfare. The disease pathology can include neurological damage and tumour formation. Sexual dimorphism in immunity and known higher susceptibility of females to MD makes the chicken Z chromosome (GGZ) a particularly attractive target to study the chicken MD response. Previously, we used a Hy-Line F6 population from a full-sib advanced intercross line to map MD QTL regions (QTLRs) on all chicken autosomes. Here, we mapped MD QTLRs on GGZ in the previously utilized F6 population with individual genotypes and phenotypes, and in eight elite commercial egg production lines with daughter-tested sires and selective DNA pooling (SDP). Four MD QTLRs were found from each analysis. Some of these QTLRs overlap regions from previous reports. All QTLRs were tested by individuals from the same eight lines used in the SDP and genotyped with markers located within and around the QTLRs. All QTLRs were confirmed. The results exemplify the complexity of MD resistance in chickens and the complex distribution of p-values and Linkage Disequilibrium (LD) pattern and their effect on localization of the causative elements. Considering the fragments and interdigitated LD blocks while using LD to aid localization of causative elements, one must look beyond the non-significant markers, for possible distant markers and blocks in high LD with the significant block. The QTLRs found here may explain at least part of the gender differences in MD tolerance, and provide targets for mitigating the effects of MD.

Temple cooling increases parasympathetic activity and decreases pressure pain on the hand.

Applying an ice cube to the temple (the conditioning stimulus) inhibits electrically evoked pain in the forearm. The present study aimed to determine whether temple cooling also inhibits pressure- and heat-pain test stimuli in the upper limb and, if so, to investigate the intra-session test-retest reliability of this response. Additional aims were to establish whether pain inhibition evoked by temple cooling was associated with parasympathetic activity; and to explore sex differences in response. The sample consisted of 40 healthy adults (24 females). Heart rate was recorded continuously throughout the session. An ice cube (3× 4cm contact area) was applied for 1 min to the temple on the dominant side. Before and immediately afterwards, the pressure pain threshold was measured from the dorsal hand and sensitivity to heat (individually adjusted at baseline to elicit moderate pain) was measured from the ventral forearm. The procedures were repeated 15min later. Temple cooling inhibited pressure pain on the hand but not heat pain on the forearm. However, test-retest reliability of pressure pain inhibition was poor. Heart rate decreased during temple cooling, consistent with a "diving" reflex. Males had stronger pressure pain inhibition, lower heart rate and higher overall autonomic activity than females. However, cardiac parasympathetic activation during temple cooling was comparable in both sexes and was unrelated to pain inhibition. These findings indicate that temple cooling evokes pain inhibition that is stronger in males than in females. Cardiac parasympathetic activity does not appear to mediate this response. The conditioning stimulus in the conditioned pain modulation paradigm is often applied to the upper or lower limbs. This may confound pain-inhibitory effects in people with peripheral neuropathy who typically have enhanced or diminished sensation in the extremities. Applying an ice cube at the temple area induces pain-inhibitory effects on the upper limb after the ice is removed. Future research examining pain modulation in people with peripheral neuropathy may consider adopting temple cooling as the conditioning stimulus.

Female Sex, Age, and Unfavorable Response to Tumor Necrosis Factor Inhibitors in Patients With Axial Spondyloarthritis: Results of Statistical and Artificial Intelligence-Based Data Analyses of a National Multicenter Prospective Registry.

Real-world studies are needed to identify factors associated with response to biologic therapies in patients with axial spondyloarthritis (SpA). The objective was to assess sex differences in response to tumor necrosis factor inhibitors (TNFi) and to explore possible risk factors associated with TNFi efficacy. A total of 969 patients with axial SpA (315 females, 654 males) enrolled in the BIOBADASER registry (2000-2019) who initiated a TNFi (first, second, or further lines) were studied. Statistical and artificial intelligence (AI)-based data analyses were used to explore the association of sex differences and other factors to TNFi response, using the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), to calculate the BASDAI50, with an improvement of at least 50% of the BASDAI score, and using the Ankylosing Spondylitis Disease Activity Score, calculated using the C-reactive protein level (ASDAS-CRP). Females had a lower probability of reaching a BASDAI50 response with a first line TNFi treatment at the second year of follow-up (P=0.018) and a lesser reduction of the ASDAS-CRP at this time point. The logistic regression model showed lower BASDAI50 responses to TNFi in females (P=0.05). Other factors, such as older age (P=0.004), were associated with unfavorable responses. The AI data analyses reinforced the idea that age at the beginning of the treatment was the main factor associated with an unfavorable response. The combination of age with other clinical characteristics (female sex or cardiovascular risk factors and events) potentially contributed to an unfavorable response to TNFi. In this national multicenter registry, female sex was associated with less response to a first-line TNFi by the second year of follow-up. A higher age at the start of the TNFi was the main factor associated with an unfavorable response to TNFi.

Limited sex differences in plastic responses suggest evolutionary conservatism of thermal reaction norms: A meta-analysis in insects.

Temperature has a profound effect on the growth and development of ectothermic animals. However, the extent to which ecologically driven selection pressures can adjust thermal plastic responses in growth schedules is not well understood. Comparing temperature-induced plastic responses between sexes provides a promising but underexploited approach to evaluating the evolvability of thermal reaction norms: males and females share largely the same genes and immature environments but typically experience different ecological selection pressures. We proceed from the idea that substantial sex differences in plastic responses could be interpreted as resulting from sex-specific life-history optimization, whereas similarity among the sexes should rather be seen as evidence of an essential role of physiological constraints. In this study, we performed a meta-analysis of sex-specific thermal responses in insect development times, using data on 161 species with comprehensive phylogenetic and ecological coverage. As a reference for judging the magnitude of sex specificity in thermal plasticity, we compared the magnitude of sex differences in plastic responses to temperature with those in response to diet. We show that sex-specific responses of development times to temperature variation are broadly similar. We also found no strong evidence for sex specificity in thermal responses to depend on the magnitude or direction of sex differences in development time. Sex differences in temperature-induced plastic responses were systematically less pronounced than sex differences in responses induced by variations in larval diet. Our results point to the existence of substantial constraints on the evolvability of thermal reaction norms in insects as the most likely explanation. If confirmed, the low evolvability of thermal response is an essential aspect to consider in predicting evolutionary responses to climate warming.