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- The clinical course of schizophrenia in women and men—a nation-wide cohort study
- Sex differences in immune responses that underlie COVID-19 disease outcomes
- Nature, Man and Woman
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The clinical course of schizophrenia in women and men—a nation-wide cohort study
However, whether immune responses against severe acute respiratory syndrome coronavirus SARS-CoV-2 differ between sexes, and whether such differences correlate with the sex difference in the disease course of COVID, is currently unknown.
Here we examined sex differences in viral loads, SARS-CoVspecific antibody titres, plasma cytokines and blood-cell phenotyping in patients with moderate COVID who had not received immunomodulatory medications.
Male patients had higher plasma levels of innate immune cytokines such as IL-8 and IL along with more robust induction of non-classical monocytes. By contrast, higher levels of innate immune cytokines were associated with worse disease progression in female patients, but not in male patients. These findings provide a possible explanation for the observed sex biases in COVID, and provide an important basis for the development of a sex-based approach to the treatment and care of male and female patients with COVID A growing body of evidence reveals that male sex is a risk factor for a more severe disease, including death.
Past studies have shown that sex has a considerable effect on the outcome of infections and has been associated with underlying differences in immune responses to infection 9 , For example, the prevalence of hepatitis A and tuberculosis are notably higher in men that in women Viral loads are consistently higher in male patients with hepatitis C virus and human immunodeficiency virus HIV 12 , By contrast, women mount a more robust immune response to vaccines These findings collectively suggest a more robust ability among women to control infectious agents.
However, the mechanism by which SARS-CoV-2 causes more severe disease in male patients than in female patients remains unknown. To determine the immune responses against SARS-CoV-2 infection in male and female patients, we performed detailed analyses on the sex differences in immune phenotypes by the assessment of viral loads, levels of SARS-CoVspecific antibodies, plasma cytokines or chemokines, and blood-cell phenotypes. The detailed demographics and clinical characteristics of these 98 participants are shown in Extended Data Table 1.
Freshly isolated PBMCs were stained and analysed by flow cytometry To compare the immune phenotypes between sexes, two sets of data analyses were performed in parallel—baseline and longitudinal, as described below.
Demographics and background information for the HCW group and the demographics of HCWs for cytokine assays and flow cytometry assays for the primary analyses are in Extended Data Table 1. Demographic data, time-point information of the samples defined by the days from the symptom onset DFSO in each patient, treatment information, and raw data used to generate figures and tables is in Supplementary Table 1. This patient group, cohort A, consisted of 39 patients 17 male and 22 female Extended Data Tables 1 , 2.
Intersex and transgender individuals were not represented in this study. Figures 1 — 4 represent analyses of baseline raw values obtained from patients in cohort A. ND, not detected. The cut-off values for positivity are shown by the dotted lines. P values were determined by unpaired two-tailed t -test a or one-way analysis of variance ANOVA with Bonferroni multiple comparison test b , c. The results of all the cytokines or chemokines measured can be found in Extended Data Fig. Numbers in red indicate the percentages of each population in the parent monocyte gate.
P values were determined by one-way ANOVA with Bonferroni multiple comparison test a , c or unpaired two-tailed t -test d. Dotted lines in the viral concentration and anti-S1-IgG panels indicate the detection limit and cut-off value for positivity, respectively. For viral RNA concentrations and cytokine or chemokine levels, log-transformed values were used for the calculation of the correlations.
As parallel secondary analyses, we performed longitudinal analysis on a total patient cohort cohort B to evaluate the difference in immune response over the course of the disease between male and female patients. Cohort B included all patient samples from cohort A including several time-point samples from the cohort A patients as well as an additional 59 patients who did not meet the inclusion criteria for cohort A. This analysis included several time-point samples from 98 participants in total.
Data from cohort B were analysed for sex differences in immune responses among patients using longitudinal analysis, controlling for potential confounding by age, BMI, receipt of immunomodulatory treatment tocilizumab or corticosteroids , DFSO and ICU status. We first compared the concentrations of viral RNA of male and female patients. For both cohorts A and B, there was no difference by sex in terms of the viral RNA concentrations in nasopharyngeal swab and saliva Fig.
Thus, at baseline and during the course of the disease, there were no clear differences in the amount of IgG or IgM generated against the S1 protein between male and female patients.
Next, we analysed the levels of 71 cytokines and chemokines in the plasma. In line with previous reports, levels of inflammatory cytokine or chemokine were generally higher in patients than in controls Fig. The levels of many cytokines, chemokines and growth factors were increased in patients compared to HCWs in both sexes, and the levels between sexes were comparable Fig. In adjusted analyses of cohort B, although we did not see significant sex differences in the levels of IL-8 and IL, we found significantly higher levels of CCL5 in male patients than in female patients over the course of the disease Extended Data Table 4 and significantly increased levels of CCL5 in male patients compared to male HCWs than in female patients compared to female HCWs Extended Data Table 5 , difference-in-differences.
These data indicated that, although levels of most of the innate inflammatory cytokines and chemokines were comparable, there were a few factors that are more robustly increased at the baseline IL-8 and IL and during the course of the disease CCL5 in male patients than in female patients. Next, we examined the immune cell phenotype by flow cytometry.
Consistent with a previous report on a decrease in T cells in patients 16 , in cohort A, the proportion of T cells in the live cells was significantly lower in patients, whereas the proportion of B cells was higher in both male and female patients than in HCWs Fig. There was no difference in the numbers of B cells across all groups, but the numbers of T cells were lower in patients of both sexes data not shown.
By contrast, in cohort B, we found that male patients had significantly lower numbers of T cells, both total counts and as a proportion of live cells, over the course of the disease than female patients Extended Data Table 4. Next, we found higher populations of monocytes in both sexes in cohort A Fig. These differences were observed in age- and BMI-adjusted analyses, too, but were not significant Extended Data Table 3.
In addition, we found a significant correlation between CCL5 levels and abundance in non-classical monocytes only in male patients Fig. These findings suggest that the progression from classical to non-classical monocytes may be arrested at the intermediate stage in female patients, and that increased innate inflammatory cytokines and chemokines are associated with more robust activation of innate immune cells at the baseline as well as more robust longitudinal T cell decrease in male patients.
In parallel, PD and TIMpositive terminally differentiated T cells were more prevalent among female patients than male patients Fig. Levels of these cytokines were higher in patients than in controls, and were generally comparable between sexes in the patients Extended Data Fig.
Analyses of T cell phenotypes in cohort B did not reveal any significant differences between sexes Extended Data Tables 4 and 5. Therefore, female patients with COVID had more abundant activated and terminally differentiated T cell populations than male patients at baseline in unadjusted analyses. We investigated whether certain immune phenotypes were correlated with disease trajectory, and whether these phenotypes and factors differed between the sexes.
To this end, we evaluated the disease course of patients in cohort A. The clinical scores at the first sample collection C 1 were 1 or 2 for all of the patients in cohort A. We first examined age, BMI, viral loads and titres of anti-S1-IgG antibodies between the stabilized and deteriorated groups in a sex-aggregated manner. We found that the deteriorated group had on average a higher BMI than the stabilized group.
Although the age was not statistically different, the stabilized group spanned a larger age range than the deteriorated group, who were generally of a more advanced age. The viral load and antibody titres were comparable Fig. The levels of antibodies were comparable between the deteriorated and stabilized groups both in male and female, but stabilized female tended to have higher antibody levels Fig. We further investigated whether the key factors identified in the previous analyses correlated with disease progression in male and female patients.
In the age- and DFSO-adjusted analysis of cohort A, we also found that CCL5 was only increased in female patients that progressed to worse disease compared to the stabilized patients, but no such correlation was found in male patients Extended Data Table 6.
However, in female patients, the deteriorated group had similar levels of these types of CD8 T cells compared with the stabilized group Fig. The correlation matrix showed that in female patients, higher levels of innate immunity cytokines, such as TNFSF10 and IL, were positively correlated with disease progression, whereas there was no association between CD8 T cell status and deterioration Fig.
These differences seemed to highlight the differences between the sexes in the immune responses against SARS-CoV-2 as well as the difference of the potential prognostic or predictive factors for clinical deterioration of COVID Our results revealed key differences in immune responses during the disease course of SARS-CoV-2 infection in male and female patients.
First, we found that the levels of several important pro-inflammatory innate immunity chemokines and cytokines such as IL-8, IL at baseline and CCL5 longitudinal analysis were higher in male patients, which correlated with higher non-classical monocytes at baseline.
Second, we observed a more robust T cell response among female patients than male patients at baseline. In particular, activated CD8 T cells were significantly increased only in female patients but not in male patients compared with healthy volunteers. Analysis of their clinical trajectory showed that, although poor T cell responses were associated with future progression of disease in male patients, higher levels of innate immune cytokines were associated with worsening of COVID disease in female patients.
These data indicate key differences in the baseline immune capabilities in male and female patients during the early phase of SARS-CoV-2 infection, and suggest a potential immunological underpinning of the distinct mechanisms of disease progression between sexes. These analyses also provide a potential basis for taking sex-dependent approaches to prognosis, prevention, care, and therapy for patient with COVID Although our study provides a strong basis for further investigation into how COVID disease dynamics may differ between male and female patients, it is important to note that there are some limitations to the analyses presented in this Article.
First, we acknowledge that the healthy HCWs used as the control population were not matched to patients on the basis of age, BMI or underlying risk factors. To account for this, we performed adjusted analyses for the baseline and longitudinal comparisons between patients cohort A and the full patient population, cohort B and HCWs, controlling for age and BMI. However, we cannot rule out residual confounding due to underlying risk factors not available for the HCW controls.
Collectively, these data suggest that vaccines and therapies to increase T cell immune responses to SARS-CoV-2 might be warranted for male patients, whereas female patients might benefit from therapies that dampen innate immune activation early during disease. No statistical methods were used to predetermine sample size. The experiments were not randomized.
Investigators were blinded during experiments in terms of the sex or other clinical background information, with the sample labels having de-identified patient IDs that did not contain any of this information.
Informed consent was obtained from all enrolled patients and healthcare workers. All patients necessitated hospitalization for their symptoms and had an WHO score 17 of at least 3 at admission denoting hospitalized, mild disease.
Only after the confirmation of PCR-positivity, the patients were enrolled and the first time point samples for this study were collected for each patient. The first time point samples were collected at Among these patients, we could obtain whole blood for flow cytometry analysis using fresh PBMCs, plasma for cytokine or chemokine measurements, anti-S1 antibody measurements and nasopharyngeal swab and saliva from total of 98 individuals for the present study.
Detailed demographic information for the entire cohort 98 cohort B patients, and several time-point samples from 54 patients among them and of cohort A 39 patients are shown in Extended Data Tables 1 — 3.
Among total patients enrolled in IMPACT study in this period, we obtained whole blood, nasopharyngeal swabs or saliva samples from 98 patients for the present study. Individuals with active chemotherapy against cancers, pregnant patients, patients with background haematological abnormalities, patients with autoimmune diseases and patients with a history of organ transplantation and on immunosuppressive agents, were excluded from this study.
For the control group, the PBMCs and plasma analysis were done when both tests were negative. That is, if either or both of these tests were positive, these samples were excluded from the analyses.
In some HCWs, samples were collected for the assays at up to two time points. In these cases, if the data for a certain type of assay were available for both of these time points, only the first time point data were used and otherwise data for either time point were used in the main analyses with cohort A. Virus RNA copies were quantified using a tenfold dilution standard curve of RNA transcripts that we previously generated
Sex differences in immune responses that underlie COVID-19 disease outcomes
Aristotle's views on women influenced later Western thinkers , who quoted him as an authority until the end of the Middle Ages , influencing women's history. In his Politics , Aristotle saw women as subject to men, but as higher than slaves, and lacking authority; he believed the husband should exert political rule over the wife. Among women's differences from men were that they were, in his view, more impulsive, more compassionate, more complaining, and more deceptive. He gave the same weight to women's happiness as to men's, and in his Rhetoric stated that society could not be happy unless women were happy too. Whereas Plato was open to the potential equality of men and women, stating both that women were not equal to men in terms of strength and virtue, but were equal to men in terms of rational and occupational capacity, and hence in the ideal Republic should be educated and allowed to work alongside men without differentiation, Aristotle appears to have disagreed.
Nature, Man and Woman
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До смерти напуганный, Двухцветный замотал головой: - Нет. - Viste el anillo. Ты видел кольцо. Двухцветный замер.
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Когда двери автобуса открылись, молодые люди быстро вскочили внутрь. Беккер напряг зрение. Сомнений не .
Grazie! - просиял итальянец. Он швырнул Беккеру ключи от веспы, затем взял свою девушку за руку, и они, смеясь, побежали к зданию клуба. - Aspetta! - закричал Беккер.
Росио попробовала закричать, но в легких не было воздуха. Он вот-вот задавит. Уже теряя сознание, она рванулась к свету, который пробивался из приоткрытой двери гостиничного номера, и успела увидеть руку, сжимающую пистолет с глушителем. Яркая вспышка - и все поглотила черная бездна. ГЛАВА 40 Стоя у двери Третьего узла, Чатрукьян с безумным видом отчаянно пытался убедить Хейла в том, что с ТРАНСТЕКСТОМ стряслась беда.
Конечно. Алгоритм, не подающийся грубой силе, никогда не устареет, какими бы мощными ни стали компьютеры, взламывающие шифры. Когда-нибудь он станет мировым стандартом.
Подобно своим природным аналогам они преследуют одну цель - внедриться в организм и начать размножаться. В данном случае организмом является ТРАНСТЕКСТ. Чатрукьяна всегда изумляло, что АНБ никогда прежде не сталкивалось с проблемой вирусов. Сквозь строй - надежная система, но ведь АНБ - ненасытный пожиратель информации, высасывающий ее из разнообразнейших источников по всему миру. Поглощение огромных объемов информации сродни беспорядочным половым связям: какие меры предосторожности ни принимай, рано или поздно подхватишь какую-нибудь гадость.