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The cellular response to SARS-CoV-2 vaccination and infection in allogeneic hematopoietic stem cell transplant (HSCT) recipients is not yet clear. In the current study, HSCT recipients prior to and post vaccination were tested for SARS-CoV-2-specific humoral and cellular immunity. Antibodies against spike (S) 1 were assessed by Anti-SARS-CoV-2 IgG ELISA (Euroimmun). Cellular immunity was analyzed by an in house interferon-gamma ELISpot and T-SPOT.COVID (Oxford Immunotec), using altogether seven SARS-CoV-2-specific antigens. In 117 HSCT patients vaccinated twice, SARS-CoV-2 IgG antibodies were significantly higher than in HSCT controls pre vaccination (p < 0.0001). After the second vaccination, we observed a median antibody ratio of 4.7 and 68% positive results, whereas 35 healthy controls reached a median ratio of 9.0 and 100% positivity. ELISpot responses in patients were significantly (p < 0.001) reduced to ≤33% of the controls. After the second vaccination, female HSCT patients and female healthy controls showed significantly higher antibody responses than males (6.0 vs. 2.1 and 9.2 vs. 8.2, respectively; p < 0.05). Cellular immunity was diminished in patients irrespective of sex. In conclusion, especially male HSCT recipients showed impaired antibody responses after SARS-CoV-2 vaccination. Changing the vaccine schedule or composition could help increase vaccine responses.

BackgroundOutcome of aneurysmal subarachnoid hemorrhage (SAH) depends strongly on occurrence of symptomatic vasospasm (SV) leading to delayed cerebral ischemia (DCI). Various demographic, radiographic, and clinical predictors of SV have been reported so far, partially with conflicting results. The aim of this study was to analyze the role of patients’ age and sex on SV/DCI risk, especially to identify age and sex-specific risk groups.MethodsAll patients admitted with acute SAH during a 14-year-period ending in 2016 were eligible for this study. The study endpoints were the following: SV requiring spasmolysis, occurrence of DCI in follow-up computed tomography scans and unfavorable outcome at 6 months (modified Rankin scale > 2).ResultsNine hundred ninety-four patients were included in this study. The majority was female (666; 67%). SV, DCI, and unfavorable outcomes were observed in 21.5, 21.8, and 43.6% of the patients, respectively. Younger age (p < 0.001; OR = 1.03 per year decrease) and female sex (p = 0.025; OR = 1.510) were confirmed as independent predictors of SV. Regarding the sex differences, there were three age groups for SV/DCI risk ≤ 54, 55–74, and ≥ 75 years. Male patients showed earlier decrease in SV risk (at ≥ 55 vs. ≥ 75 years in females). Therefore, SAH females aged between 55 and 74 years were at the highest risk for DCI and unfavorable outcome, as compared to younger/older females (p = 0.001, OR = 1.77/p = 0.001, OR = 1.80). In contrast, their male counterparts did not show these risk alterations (p = 0.445/p = 0.822).ConclusionAfter acute SAH, female and male patients seem to show different age patterns for the risk of SV and DCI. Females aged between 55 and 74 years are at particular risk of vasospasm-related SAH complications, possibly due to onset of menopause.Clinical trial registration numberDRKS, Unique identifier: DRKS00008749

Background Inhibition of irrelevant responses is an important aspect of cognitive control of a goal-directed behavior. Females and males show different levels of susceptibility to neuropsychological disorders such as impulsive behavior and addiction, which might be related to differences in inhibitory brain functions. Methods We examined the effects of ‘practice to inhibit’, as a model of rehabilitation approach, and ‘music’, as a salient contextual factor in influencing cognition, on the ability of females and males to perform a stop-signal task that required inhibition of initiated or planned responses. In go trials, the participants had to rapidly respond to a directional go cue within a limited time window. In stop trials, which were presented less frequently, a stop signal appeared immediately after the go-direction cue and the participants had to stop their responses. Results We found a significant difference between females and males in benefiting from practice in the stop-signal task: the percentage of correct responses in the go trials increased, and the ability to inhibit responses significantly improved, after practice in females. While listening to music, females became faster but males became slower in responding to the go trials. Both females and males became slower in performing the go trials following an error in the stop trials; however, music significantly affected this post-error slowing depending on the sex. Listening to music decreased post-error slowing in females but had an opposite effect in males. Conclusionc Here, we show a significant difference in executive control functions and their modulation by contextual factors between females and males that might have implications for the differences in their propensity for particular neuropsychological disorders and related rehabilitation approaches.

The Artemis missions will establish a sustainable human presence on the Moon, serving as a crucial steppingstone for future Mars exploration. Astronauts on these ambitious missions will have to successfully complete complex tasks, which will frequently involve rapid and effective decision making under unfamiliar or high-pressure conditions. Exposure to low doses of space radiation (SR) can impair key executive functions critical to decision making. This study examined the effects of exposure to 10 cGy of Galactic Cosmic Ray simulated radiation (GCRsim) on decision-making performance in male and female rats with a naturally low predisposition for risk-taking (RTP) prior to exposure. Rats were assessed at monthly intervals following SR exposure and the RTP performance contrasted with that observed during the prescreening process. Exposure to 10 cGy of GCRsim impaired decision making in both male and female rats, with sex-dependent outcomes. By 30 days after SR exposure, female rats became more risk-prone, making less profitable decisions, while male rats retained their decision-making strategies but took significantly longer to make selections. However, continued practice in the RTP tasks appeared to reduce/reverse these performance deficits. This study has expanded our understanding of the range of cognitive processes impacted by SR to include decision making.

Males are more susceptible to neurodevelopmental cognitive deficits in their perception of visual information. Subliminally-presented visual stimuli might be subconsciously perceived and consequently influence upcoming decisions, however it is still unclear whether subconscious perception differs between males and females. In this study, young adults performed a two-choice target detection task. In the Baseline condition (trials), participants relied only on their ability to detect the target. In the Cued-conscious condition, a visual cue (information) was presented (250 ms) on the same side of an upcoming target and indicated its location (left/right). In the Subliminal-same condition, a briefly presented (~16 ms) cue correctly indicated the target location, however in the Subliminal-opposite condition the cue was shown on the opposite side of the upcoming target and provided incorrect information. Participants’ performance in the Cued-conscious condition was significantly higher than the Baseline and subliminal conditions. In both females and males, performance in the Subliminal-same and Subliminal-opposite conditions was higher and lower than the Baseline condition respectively; indicating that the subliminal cues (information) affected upcoming decisions. However, the effects were significantly larger in males, suggesting males express heightened sensitivity to subliminal visual information, compared to age- and education-matched females. In both males and females, background acoustic stimuli (Music, White noise or Silence) influenced conscious and subconscious visual information processing. Autonomic nervous system activity, assessed through event-related electrodermal activity, was also differentially modulated by supraliminal and subliminal visual information. Our findings indicate remarkable sex dependency in the effects of subliminal visual information on cognitive functions.

Hematopoietic stem cell transplant (HSCT) recipients have a high risk of developing primary varicella-zoster virus (VZV) infection and reactivation. VZV vaccination may prevent infection and reactivation. In the current study, recipients of allogeneic HSCT (34 females, 45 males) were vaccinated with adjuvanted, recombinant zoster vaccine Shingrix™, which contains the VZV glycoprotein E. Cellular immunity against various VZV antigens was analyzed by interferon-gamma ELISpot. Peripheral blood mononuclear cells (PBMC) of recipients with versus without prior shingles (n = 36 and n = 43, respectively) showed approximately twofold higher VZV-specific responses prior to and post vaccination. After the first and second vaccination, ELISpot responses towards the glycoprotein E were significantly higher in males versus females (median of spots increment 18 versus 1 and 17 versus 4, respectively, p ≤ 0.02 each). Multivariate analysis showed that shingles and sex both impacts significantly on VZV immunity. Whereas vaccination-induced changes could hardly be detected after stimulation with a whole VZV antigen, there was a significant increase in responses towards glycoprotein E after vaccination (p < 0.005). These data indicate that vaccination with Shingrix™ augmented cellular, VZV-specific immunity in HSCT recipients. Shingles and male sex could both be identified as factors leading to increased immunity.

Context-dependent execution or inhibition of a response is an important aspect of executive control, which is impaired in neuropsychological and addiction disorders. Transcranial direct current stimulation (tDCS) of the dorsolateral prefrontal cortex (DLPFC) has been considered a remedial approach to address deficits in response control; however, considerable variability has been observed in tDCS effects. These variabilities might be related to contextual differences such as background visual-auditory stimuli or subjects' sex. In this study, we examined the interaction of two contextual factors, participants' sex and background acoustic stimuli, in modulating the effects of tDCS on response inhibition and execution. In a sham-controlled and cross-over (repeated-measure) design, 73 participants (37 females) performed a Stop-Signal Task in different background acoustic conditions before and after tDCS (anodal or sham) was applied over the DLPFC. Participants had to execute a speeded response in Go trials but inhibit their response in Stop trials. Participants' sex was fully counterbalanced across all experimental conditions (acoustic and tDCS). We found significant practice-related learning that appeared as changes in indices of response inhibition (stop-signal reaction time and percentage of successful inhibition) and action execution (response time and percentage correct). The tDCS and acoustic stimuli interactively influenced practice-related changes in response inhibition and these effects were uniformly seen in both males and females. However, the effects of tDCS on response execution (percentage of correct responses) were sex-dependent in that practice-related changes diminished in females but heightened in males. Our findings indicate that participants' sex influenced the effects of tDCS on the execution, but not inhibition, of responses. Highlights In a fully counterbalanced (for sex and all experimental conditions), sham-controlled cross-over study, we examined the effects of tDCS over the left DLPFC in the context of Stop-Signal task. The effects of tDCS on response inhibition was uniform across both males and females. The effects of tDCS on response execution differed in males and females. The tDCS mainly modulated the practice-related (learning-related) changes in participants’ performance, but these effects of tDCS were different between males and females. These findings highlight the need to adequately control for participants' sex and the need to develop sex-specific tDCS protocols in clinical settings.

Background Obesity is a global health challenge that can lead to various complications, such as metabolic syndrome, diabetes mellitus, and cardiovascular diseases. Heat shock proteins are evolutionarily conserved chaperones that help maintain cellular protein homeostasis. Their expression is dysregulated in various chronic diseases, including diabetes mellitus and hyperlipidemia, and they also regulate inflammatory processes. Therefore, the present study aimed to investigate the effects of a small heat shock protein, HSPB1, on the comorbidities and complications of obesity in a transgenic mouse model. Methods Male and female human apolipoprotein B-100 (APOB) transgenic mice fed with a high-fat diet (HFD) from months 3–10 of age were used as a model of metabolic syndrome (MetS). To study whether HSPB1 influences the development of MetS, APOB animals were crossed with HSPB1-overexpressing mice. Age and sex-matched wild-type and human HSPB1-overexpressing mice were used as controls. Changes in cardiac morphology and function were assessed by transthoracic echocardiography at month 9. At month 10, serum triglyceride and cholesterol concentrations were determined by enzymatic colorimetric assays. Pathological changes in the liver were studied on hematoxylin–eosin-stained sections. Expression levels of genes involved in inflammation and metabolism were measured by quantitative real-time polymerase chain reaction in the liver, left ventricle, and visceral white adipose tissue (vWAT). Results The body weight and serum LDL-cholesterol levels were significantly higher in the APOB animals than in the wild-type mice in both sexes. Notably, HSPB1 overexpression further increased weight gain in female APOB animals. Conversely, in APOB males, HSPB1 overexpression decreased LDL-cholesterol levels without significantly affecting body weight. Furthermore, in APOB females, HSPB1 overexpression elevated Fgf-21 expression in the vWAT, restored Lpl levels, and reduced the expression of several cytokines in the liver. APOB males developed left ventricular hypertrophy (LVH) with diastolic dysfunction. HSPB1 overexpression induced LVH without cardiac dysfunction in the wild-type animals. Conclusions Both sexes of APOB animals developed MetS. APOB males presented LVH with preserved ejection fraction (EF); however, APOB females showed enlarged left ventricular end-systolic volume (LVESV). In APOB animals, HSPB1 overexpression exerted a sex-dependent influence on obesity-related alterations, including weight gain, hypercholesterolemia, and hepatic and vWAT gene expression. Highlights • Overexpression of human HSPB1 led to further weight gain in HFD-fed APOB-100 females, while the body weights of HFD-fed APOB-100 males were unaffected by human HSPB1. • Human HSPB1 overexpression significantly decreased the LDL-cholesterol levels in HFD-fed APOB-100 males. • mRNA level of fibroblast growth factor 21 was elevated in the vWAT of HFD-fed APOB-100 females in response to human HSPB1 overexpression. • Increased gene expression level of lipoprotein lipase was restored by human HSPB1 overexpression in the liver of HFD-fed APOB-100 females. • Overexpression of human HSPB1 failed to restore hyperlipidemia-related cardiac morphological alterations found in HFD-fed APOB-100 males, while it induced LVH in the wild-type animals of both sexes. Plain English Summary Representing the primary risk factor for several chronic diseases, including non-alcoholic fatty liver disease, type 2 diabetes mellitus, and cardiovascular diseases, obesity is a global health challenge nowadays. Cells defend themselves against various stress and disease conditions by inducing a stress response characterized by the activation of heat shock proteins. However, the levels of these proteins and the inducibility of the cellular stress response are altered in chronic metabolic diseases, such as diabetes or hyperlipidemia. Here, we aimed to analyze whether a small molecular weight heat shock protein, HSPB1, has an effect on MetS using a mouse model. We found that HSPB1 overexpression led to a further increase in weight gain and blood LDL-cholesterol concentration in female disease model animals. Conversely, in males, HSPB1 overexpression led to a decrease in LDL cholesterol levels without any significant impact on body weight. However, despite the higher body weight, none of the investigated comorbidities, such as inflammation, hepatic steatosis, or cardiac dysfunction, were worsened in the disease model females in response to HSPB1 overexpression, supported by the sex-specific alterations in the gene expression pattern in these tissues. These results suggest that HSPB1 may have a complex regulatory role in obesity-related comorbidities. Although the restoration of the heat shock response and levels of heat shock proteins may be an effective therapeutic strategy in metabolic disorders, it is important to consider sex-based differences to ensure optimal outcomes.

Solid organ transplant recipients have an up to ninefold higher risk of varicella–zoster virus (VZV) reactivation than the general population. Due to lifelong immunosuppressive therapy, vaccination against VZV may be less effective in kidney transplant (KTX) recipients. In the current study, twelve female and 17 male KTX recipients were vaccinated twice with the adjuvanted, recombinant zoster vaccine Shingrix™, which contains the VZV glycoprotein E (gE). Cellular immunity against various VZV antigens was analyzed with interferon-gamma ELISpot. We observed the strongest vaccination-induced changes after stimulation with a gE peptide pool. One month after the second vaccination, median responses were 8.0-fold higher than the responses prior to vaccination (p = 0.0006) and 4.8-fold higher than responses after the first vaccination (p = 0.0007). After the second vaccination, we observed an at least twofold increase in ELISpot responses towards gE peptides in 22 out of 29 patients (76%). Male sex, good kidney function, early time point after transplantation, and treatment with tacrolimus or mycophenolate were correlated significantly with higher VZV-specific cellular immunity, whereas diabetes mellitus was correlated with impaired responses. Thus, our data indicate that vaccination with Shingrix™ significantly augmented cellular, VZV gE-specific immunity in KTX recipients, which was dependent on several covariates.

Chronic obstructive pulmonary disease (COPD) is a major cause of chronic morbidity and mortality worldwide, and its epidemiological, clinical, and socioeconomic impact is progressively increasing. A first estimate of the economic burden of COPD in Italy was conducted in 2008 (the SIRIO [Social Impact of Respiratory Integrated Outcomes] study). The aim of the present study is to provide an updated picture of the COPD economic burden in Italy. Sequential patients presenting at the specialist center for the first time during the period 2008-2012 and with record file complete (demographic, clinical, lung function, and therapeutic data; health care resources consumed in the 12 months before the enrollment and for the 3 subsequent years) were selected from the institutional database. Two hundred and seventy-five COPD patients fitting the inclusion criteria were selected (226 males; mean age: 70.9 years [standard deviation: ±8.4 years]; 45.8% were from the north, 25.1% from central Italy, and 29.1% from south Italy). COPD-related average costs per patient in the 12 months before enrollment were as follows: hospitalization: €1,970; outpatient care: €463; pharmaceutical: €499; and indirect costs: €358. Average direct costs and total societal costs were €2,932 and €3,291, respectively. Direct cost was €2,461 (hospitalization: €1,570; outpatient: €344; and pharmaceutical: €547) in the first year of follow-up, while total societal cost was €2,707. No significant difference was reported in any cost category between sexes. The therapeutic approach followed in a specialist center, based on the application of clinical guidelines, has been shown to be a highly effective investment for the long-term management of COPD. A small increase of pharmaceutical costs per year allowed a substantial saving in terms of hospitalizations, costs related to outpatient services, and indirect costs.