Enhanced Monocyte Response and Decreased Central Memory T Cells in Children with Invasive Staphylococcus aureus Infections

Staphylococcus aureus has emerged as a significant pathogen causing severe invasive disease in otherwise healthy people. Despite considerable advances in understanding the epidemiology, resistance mechanisms, and virulence factors produced by the bacteria, there is limited knowledge of the in vivo host immune response to acute, invasive S. aureus infections. Herein, we report that peripheral blood mononuclear cells from patients with severe S. aureus infections demonstrate a distinctive and robust gene expression profile which is validated in a distinct group of patients and on a different microarray platform. Application of a systems-wide modular analysis framework reveals significant over-expression of innate immunity genes and under-expression of genes related to adaptive immunity. Simultaneous flow cytometry analyses demonstrated marked alterations in immune cell numbers, with decreased central memory CD4 and CD8 T cells and increased numbers of monocytes. CD14+ monocyte numbers significantly correlated with the gene expression levels of genes related to the innate immune response. These results demonstrate the value of applying a systems biology approach that reveals the significant alterations in the components of circulating blood lymphocytes and monocytes in invasive S. aureus infections

Large expert-curated database for benchmarking document similarity detection in biomedical literature search

Document recommendation systems for locating relevant literature have mostly relied on methods developed a decade ago. This is largely due to the lack of a large offline gold-standard benchmark of relevant documents that cover a variety of research fields such that newly developed literature search techniques can be compared, improved and translated into practice. To overcome this bottleneck, we have established the RElevant LIterature SearcH consortium consisting of more than 1500 scientists from 84 countries, who have collectively annotated the relevance of over 180 000 PubMed-listed articles with regard to their respective seed (input) article/s. The majority of annotations were contributed by highly experienced, original authors of the seed articles. The collected data cover 76% of all unique PubMed Medical Subject Headings descriptors. No systematic biases were observed across different experience levels, research fields or time spent on annotations. More importantly, annotations of the same document pairs contributed by different scientists were highly concordant. We further show that the three representative baseline methods used to generate recommended articles for evaluation (Okapi Best Matching 25, Term Frequency-Inverse Document Frequency and PubMed Related Articles) had similar overall performances. Additionally, we found that these methods each tend to produce distinct collections of recommended articles, suggesting that a hybrid method may be required to completely capture all relevant articles. The established database server located at https://relishdb.ict.griffith.edu.au is freely available for the downloading of annotation data and the blind testing of new methods. We expect that this benchmark will be useful for stimulating the development of new powerful techniques for title and title/abstract-based search engines for relevant articles in biomedical research.Peer reviewe

Effect of Hydrocortisone on Mortality and Organ Support in Patients With Severe COVID-19: The REMAP-CAP COVID-19 Corticosteroid Domain Randomized Clinical Trial.

Importance: Evidence regarding corticosteroid use for severe coronavirus disease 2019 (COVID-19) is limited. Objective: To determine whether hydrocortisone improves outcome for patients with severe COVID-19. Design, Setting, and Participants: An ongoing adaptive platform trial testing multiple interventions within multiple therapeutic domains, for example, antiviral agents, corticosteroids, or immunoglobulin. Between March 9 and June 17, 2020, 614 adult patients with suspected or confirmed COVID-19 were enrolled and randomized within at least 1 domain following admission to an intensive care unit (ICU) for respiratory or cardiovascular organ support at 121 sites in 8 countries. Of these, 403 were randomized to open-label interventions within the corticosteroid domain. The domain was halted after results from another trial were released. Follow-up ended August 12, 2020. Interventions: The corticosteroid domain randomized participants to a fixed 7-day course of intravenous hydrocortisone (50 mg or 100 mg every 6 hours) (n = 143), a shock-dependent course (50 mg every 6 hours when shock was clinically evident) (n = 152), or no hydrocortisone (n = 108). Main Outcomes and Measures: The primary end point was organ support-free days (days alive and free of ICU-based respiratory or cardiovascular support) within 21 days, where patients who died were assigned -1 day. The primary analysis was a bayesian cumulative logistic model that included all patients enrolled with severe COVID-19, adjusting for age, sex, site, region, time, assignment to interventions within other domains, and domain and intervention eligibility. Superiority was defined as the posterior probability of an odds ratio greater than 1 (threshold for trial conclusion of superiority >99%). Results: After excluding 19 participants who withdrew consent, there were 384 patients (mean age, 60 years; 29% female) randomized to the fixed-dose (n = 137), shock-dependent (n = 146), and no (n = 101) hydrocortisone groups; 379 (99%) completed the study and were included in the analysis. The mean age for the 3 groups ranged between 59.5 and 60.4 years; most patients were male (range, 70.6%-71.5%); mean body mass index ranged between 29.7 and 30.9; and patients receiving mechanical ventilation ranged between 50.0% and 63.5%. For the fixed-dose, shock-dependent, and no hydrocortisone groups, respectively, the median organ support-free days were 0 (IQR, -1 to 15), 0 (IQR, -1 to 13), and 0 (-1 to 11) days (composed of 30%, 26%, and 33% mortality rates and 11.5, 9.5, and 6 median organ support-free days among survivors). The median adjusted odds ratio and bayesian probability of superiority were 1.43 (95% credible interval, 0.91-2.27) and 93% for fixed-dose hydrocortisone, respectively, and were 1.22 (95% credible interval, 0.76-1.94) and 80% for shock-dependent hydrocortisone compared with no hydrocortisone. Serious adverse events were reported in 4 (3%), 5 (3%), and 1 (1%) patients in the fixed-dose, shock-dependent, and no hydrocortisone groups, respectively. Conclusions and Relevance: Among patients with severe COVID-19, treatment with a 7-day fixed-dose course of hydrocortisone or shock-dependent dosing of hydrocortisone, compared with no hydrocortisone, resulted in 93% and 80% probabilities of superiority with regard to the odds of improvement in organ support-free days within 21 days. However, the trial was stopped early and no treatment strategy met prespecified criteria for statistical superiority, precluding definitive conclusions. Trial Registration: ClinicalTrials.gov Identifier: NCT02735707

31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016) : part two

Background The immunological escape of tumors represents one of the main ob- stacles to the treatment of malignancies. The blockade of PD-1 or CTLA-4 receptors represented a milestone in the history of immunotherapy. However, immune checkpoint inhibitors seem to be effective in specific cohorts of patients. It has been proposed that their efficacy relies on the presence of an immunological response. Thus, we hypothesized that disruption of the PD-L1/PD-1 axis would synergize with our oncolytic vaccine platform PeptiCRAd. Methods We used murine B16OVA in vivo tumor models and flow cytometry analysis to investigate the immunological background. Results First, we found that high-burden B16OVA tumors were refractory to combination immunotherapy. However, with a more aggressive schedule, tumors with a lower burden were more susceptible to the combination of PeptiCRAd and PD-L1 blockade. The therapy signifi- cantly increased the median survival of mice (Fig. 7). Interestingly, the reduced growth of contralaterally injected B16F10 cells sug- gested the presence of a long lasting immunological memory also against non-targeted antigens. Concerning the functional state of tumor infiltrating lymphocytes (TILs), we found that all the immune therapies would enhance the percentage of activated (PD-1pos TIM- 3neg) T lymphocytes and reduce the amount of exhausted (PD-1pos TIM-3pos) cells compared to placebo. As expected, we found that PeptiCRAd monotherapy could increase the number of antigen spe- cific CD8+ T cells compared to other treatments. However, only the combination with PD-L1 blockade could significantly increase the ra- tio between activated and exhausted pentamer positive cells (p= 0.0058), suggesting that by disrupting the PD-1/PD-L1 axis we could decrease the amount of dysfunctional antigen specific T cells. We ob- served that the anatomical location deeply influenced the state of CD4+ and CD8+ T lymphocytes. In fact, TIM-3 expression was in- creased by 2 fold on TILs compared to splenic and lymphoid T cells. In the CD8+ compartment, the expression of PD-1 on the surface seemed to be restricted to the tumor micro-environment, while CD4 + T cells had a high expression of PD-1 also in lymphoid organs. Interestingly, we found that the levels of PD-1 were significantly higher on CD8+ T cells than on CD4+ T cells into the tumor micro- environment (p < 0.0001). Conclusions In conclusion, we demonstrated that the efficacy of immune check- point inhibitors might be strongly enhanced by their combination with cancer vaccines. PeptiCRAd was able to increase the number of antigen-specific T cells and PD-L1 blockade prevented their exhaus- tion, resulting in long-lasting immunological memory and increased median survival

Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570

Lower serum osteocalcin is associated with more severe metabolic syndrome in elderly men from the MINOS cohort

International audienceBACKGROUND: Bone has emerged as an endocrine organ regulating energy metabolism through secretion of osteocalcin. In epidemiological studies, presence of metabolic syndrome (MetS) was associated with lower osteocalcin level. OBJECTIVES: We evaluated whether osteocalcin level was associated with MetS severity in men and whether it was more strongly associated with MetS compared with N-terminal propeptide of type I procollagen (PINP), bone-specific alkaline phosphatase (BAP), and C-terminal telopeptide of type I collagen (betaCTX). METHODS: We included 798 men aged 51-85 years for total osteocalcin measurement. Number of MetS criteria was used to define severity. We used polytomous logistic regression to assess the relationship between MetS severity and osteocalcin level. RESULTS: Thirty percent of men had MetS. In patients with MetS, the higher the number of MetS traits were present, the lower was the average osteocalcin level (0-2 criteria: 551 men: 19.5+/-6.7 ng/ml, three criteria: 155 men: 19.3+/-7.4 ng/ml, four criteria: 72 men: 17.3+/-5.7 ng/ml, and five criteria: 20 men: 15.0+/-5.1 ng/ml; P for trend=0.002).In the polytomous logistic regression model, an increase in osteocalcin level of 10 ng/ml was associated with lower prevalence of severe MetS: three criteria (odds ratio (OR)=0.93 (0.70-1.24)), four criteria (OR=0.54 (0.34-0.84)), and five criteria (OR=0.28 (0.10-0.82)) in comparison with no MetS (P for trend=0.008).After adjustment, using stepwise analysis of the polytomous logistic regression model, we observed that osteocalcin, age, and apparent free testosterone entered in the model but not other bone markers (PINP, betaCTX, and BAP). CONCLUSION: In older Caucasian men, total osteocalcin level was associated with MetS severity. Osteocalcin was more strongly associated with MetS severity than other bone turnover markers

Has sclerostin a true endocrine metabolic action complementary to osteocalcin in older men?

International audienceUNLABELLED: The reported association between sclerostin and diabetes mellitus or abdominal fat may be biased by body size and bone mass. In older men, the association between serum sclerostin levels and metabolic syndrome lost significance after adjustment for bone mass. The association between sclerostin and energy metabolism needs further clarification. INTRODUCTION: Sclerostin is associated with abdominal fat, but this relationship may be biased since both are associated with body size and bone mass. Osteocalcin is a bone-derived hormone regulating energy metabolism. We assessed the association between serum sclerostin and metabolic syndrome (MetS) accounting for whole body mineral content (BMC) and osteocalcin. METHODS: We studied 694 men aged 51-85 who had serum osteocalcin and sclerostin measurements. RESULTS: Sclerostin was higher in 216 men with MetS compared with those without MetS (p \textless 0.005). Average sclerostin level increased significantly across the increasing number of MetS components. In multivariable models, higher sclerostin was associated with higher odds of MetS (odds ratio (OR) = 1.24/1 standard deviation (SD) increase [95 % confidence interval (95 % CI), 1.01-1.51]; p \textless 0.05). After further adjustment for BMC, the association of MetS with sclerostin lost significance, whereas that with osteocalcin remained significant. Men who were simultaneously in the highest sclerostin quartile and the lowest osteocalcin quartile had higher odds of MetS (OR = 2.14 [95 % CI, 1.15-4.18]; p \textless 0.05) vs. men being in the three lower sclerostin quartiles and three upper osteocalcin quartiles. After adjustment for whole body BMC, the association lost significance. CONCLUSIONS: Higher sclerostin level is associated with MetS severity; however, this association may be related to higher whole body BMC. The adjustment for BMC had no impact on the association between MetS and osteocalcin. Clinical cross-sectional studies do not elucidate the potential role of sclerostin in the regulation of energy metabolism and direct experimental approach is necessary

Policies for an Ageing Society: Recent Measures and Areas for Further Reform

This paper provides a synthesis of age-related developments and policies for a range of OECD countries, drawing on recent OECD work. It describes the expected impact of ageing on expenditure and fiscal pressures taking into account the current configuration of age-related policies. Since later retirement appears to be a key policy to easing the burden of ageing, it looks at indicators of the incentives for early retirement via pension systems and other transfer programmes permitting early withdrawal from the labour market for those approaching retirement. The report discussed the different types of age-related reforms undertaken up to now and areas where further reforms appear needed ... Ce document présente une synthèse des évolutions et des politiques liées au vieillissement pour un ensemble de pays de l’OCDE, basée sur des travaux récents de l’OCDE. Il décrit l’impact prévu du vieillissement sur les dépenses et les pressions budgétaires en tenant compte de la configuration actuelle des politiques liées au vieillissement. Dans la mesure où le recul de l’âge de la retraite est un moyen essentiel pour alléger le poids du vieillissement, ce papier examine certains indicateurs d’incitation à la retraite anticipée par le biais de systèmes de retraite et d’autres programmes de transferts sociaux permettant aux individus approchant de la retraite de quitter plus tôt le marché du travail. Ce rapport étudie les différents types de réformes liées au vieillissement mises en place jusqu’à présent, ainsi que les domaines dans lesquels des réformes supplémentaires seraient nécessaires ...fiscal implications of ageing, retirement incentives, pension system reforms, care for the elderly, implications fiscales liées au vieillissement, réforme du système de retraite, incitations de départ à la retraite, aide et soins des personnes âgées

Hydrophobic distal pocket affects NO-heme geminate recombination dynamics in dehaloperoxidase and H64V myoglobin

International audienceThe recombination dynamics of NO with dehaloperoxidase ( DHP) from Amphitrite ornata following photolysis were measured by femtosecond time- resolved absorption spectroscopy. Singular value decomposition ( SVD) analysis reveals two important basis spectra. The first SVD basis spectrum reports on the population of photolyzed NO molecules and has the appearance of the equilibrium difference spectrum between the deoxy and NO forms of DHP. The first basis time course has two kinetic components with time constants of tau(11) approximate to 9 ps and tau(12) approximate to 50 ps that correspond to geminate recombination. The fast geminate process tau(11) arises from a contact pair with the heme iron in a bound state with S) 3/2 spin. The slow geminate process tau(12) corresponds to the recombination from a more remote docking site > 3 angstrom from the heme iron with the greater barrier corresponding to a S) 5/ 2 spin state. The second SVD basis spectrum represents a time- dependent Soret band shift indicative of heme photophysical processes and protein relaxation with time constants of tau(21) approximate to 3 ps and tau(22) approximate to 17 ps, respectively. A comparison between the more rapid rate constant of the slow geminate phase in DHP- NO and horse heart myoglobin ( HHMbNO) or sperm whale myoglobin ( SWMbNO) suggests that protein interactions with photolyzed NO are weaker in DHP than in the wild- type MbNOs, consistent with the hydrophobic distal pocket of DHP. The slower protein relaxation rate tau(22) in DHP- NO relative to HHMbNO implies less effective trapping in the docking site of the distal pocket and is consistent with a greater yield for the fast geminate process. The trends observed for DHP- NO also hold for the H64V mutant of SWMb ( H64V MbNO), consistent with a more hydrophobic distal pocket for that protein as well. We examine the influence of solution viscosity on NO recombination by varying the glycerol content in the range from 0% to 90% ( v/ v). The dominant effect of increasing viscosity is the increase of the rate of the slow geminate process, tau(12), coupled with a population decrease of the slow geminate component. Both phenomena are similar to the effect of viscosity on wild- type Mb due to slowing of protein relaxation resulting from an increased solution viscosity and protein surface dehydration