Combined Untargeted and Targeted Fingerprinting by Comprehensive Two-Dimensional Gas Chromatography to Track Compositional Changes on Hazelnut Primary Metabolome during Roasting

This study focuses on the detectable metabolome of high-quality raw hazelnuts (Cory- lus avellana L.) and on its changes after dry-roasting. Informative fingerprinting was obtained by comprehensive two-dimensional gas chromatography with fast-scanning quadrupole mass spectrom- etry (GC×GC-qMS) combined with dedicated data processing. In particular, combined untargeted and targeted (UT) fingerprinting, based on pattern recognition by template matching, is applied to chromatograms from raw and roasted samples of Tonda Gentile Trilobata and Anakliuri hazelnuts harvested in Italy and Georgia. Lab-scale roasting was designed to develop a desirable organoleptic profile matching industrial standards. Results, based on 430 peak features, reveal that phenotype expression is markedly correlated to cultivar and pedoclimatic conditions. Discriminant components between cultivars are amino acids (valine, alanine, glycine, and proline); organic acids (citric, aspartic, malic, gluconic, threonic, and 4-aminobutanoic acids); and sugars and polyols (maltose, xylulose, xylitol, turanose, mannitol, scyllo-inositol, and pinitol). Of these, alanine, glycine, and proline have a high informational role as precursors of 2-acetyl- and 2-propionylpyrroline, two key-aroma com- pounds of roasted hazelnuts. Roasting has a decisive impact on metabolite patterns—it caused a marked decrease (−90%) of alanine, proline, leucine and valine, and aspartic and pyroglutamic acid and a −50% reduction of saccharose and galactose

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

Early mobilisation in critically ill COVID-19 patients: a subanalysis of the ESICM-initiated UNITE-COVID observational study

Background Early mobilisation (EM) is an intervention that may improve the outcome of critically ill patients. There is limited data on EM in COVID-19 patients and its use during the first pandemic wave. Methods This is a pre-planned subanalysis of the ESICM UNITE-COVID, an international multicenter observational study involving critically ill COVID-19 patients in the ICU between February 15th and May 15th, 2020. We analysed variables associated with the initiation of EM (within 72 h of ICU admission) and explored the impact of EM on mortality, ICU and hospital length of stay, as well as discharge location. Statistical analyses were done using (generalised) linear mixed-effect models and ANOVAs. Results Mobilisation data from 4190 patients from 280 ICUs in 45 countries were analysed. 1114 (26.6%) of these patients received mobilisation within 72 h after ICU admission; 3076 (73.4%) did not. In our analysis of factors associated with EM, mechanical ventilation at admission (OR 0.29; 95% CI 0.25, 0.35; p = 0.001), higher age (OR 0.99; 95% CI 0.98, 1.00; p ≤ 0.001), pre-existing asthma (OR 0.84; 95% CI 0.73, 0.98; p = 0.028), and pre-existing kidney disease (OR 0.84; 95% CI 0.71, 0.99; p = 0.036) were negatively associated with the initiation of EM. EM was associated with a higher chance of being discharged home (OR 1.31; 95% CI 1.08, 1.58; p = 0.007) but was not associated with length of stay in ICU (adj. difference 0.91 days; 95% CI − 0.47, 1.37, p = 0.34) and hospital (adj. difference 1.4 days; 95% CI − 0.62, 2.35, p = 0.24) or mortality (OR 0.88; 95% CI 0.7, 1.09, p = 0.24) when adjusted for covariates. Conclusions Our findings demonstrate that a quarter of COVID-19 patients received EM. There was no association found between EM in COVID-19 patients' ICU and hospital length of stay or mortality. However, EM in COVID-19 patients was associated with increased odds of being discharged home rather than to a care facility. Trial registration ClinicalTrials.gov: NCT04836065 (retrospectively registered April 8th 2021)

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

Combined Untargeted and Targeted Fingerprinting by Comprehensive Two-Dimensional Gas Chromatography to Track Compositional Changes on Hazelnut Primary Metabolome during Roasting

This study focuses on the detectable metabolome of high-quality raw hazelnuts (Cory- lus avellana L.) and on its changes after dry-roasting. Informative fingerprinting was obtained by comprehensive two-dimensional gas chromatography with fast-scanning quadrupole mass spectrom- etry (GC×GC-qMS) combined with dedicated data processing. In particular, combined untargeted and targeted (UT) fingerprinting, based on pattern recognition by template matching, is applied to chromatograms from raw and roasted samples of Tonda Gentile Trilobata and Anakliuri hazelnuts harvested in Italy and Georgia. Lab-scale roasting was designed to develop a desirable organoleptic profile matching industrial standards. Results, based on 430 peak features, reveal that phenotype expression is markedly correlated to cultivar and pedoclimatic conditions. Discriminant components between cultivars are amino acids (valine, alanine, glycine, and proline); organic acids (citric, aspartic, malic, gluconic, threonic, and 4-aminobutanoic acids); and sugars and polyols (maltose, xylulose, xylitol, turanose, mannitol, scyllo-inositol, and pinitol). Of these, alanine, glycine, and proline have a high informational role as precursors of 2-acetyl- and 2-propionylpyrroline, two key-aroma com- pounds of roasted hazelnuts. Roasting has a decisive impact on metabolite patterns—it caused a marked decrease (−90%) of alanine, proline, leucine and valine, and aspartic and pyroglutamic acid and a −50% reduction of saccharose and galactose

Validation of a General and Sports Nutrition Knowledge Questionnaire in Italian Early Adolescents

To the best of our knowledge, no specific questionnaires on sports nutrition knowledge (NK) have been validated so far in Italian early adolescents. The aim of the present study was to validate a short (26-item) general and sports NK questionnaire in a group of Italian early adolescents. To this aim, the questionnaire was administered to 264 subjects for analysis of internal consistency, and in a subgroup (n = 39) for evaluating the reliability over time. The questionnaire revealed good overall internal consistency and reliability (Cronbach’s α = 0.684) and a highly significant correlation over time (r = 0.977, p < 0.001). Comparison with other validated questionnaires is tricky, because the previous questionnaires were validated in different populations, such as middle or late adolescents or adults, with a higher number of items compared to our questionnaire. Furthermore, data on adolescent NK in Italy are very limited. This study provides a brief, feasible, and validated questionnaire that can be used for investigating sports NK in young subjects. It could be used for evaluating the efficacy of education on general and sports nutrition in both the general population and athletes, and for investigating the relationship between NK and different sports in early adolescence

Impact of IBD gene candidate ORFs on the THP-1 transcriptome.

(A) Selected example illustrating impact observed on the transcriptome of THP-1 cells following the expression of IRF5. Each dot represents a single detectable gene in the THP-1 transcriptome. The x-axis shows the log2-transformed median expression across all conditions tested (baseline). The y-axis represents the effect of transduction and expression of a given ORF, as the log2-transformed fold-induction compared to baseline. Skyblue dots represent genes with expression value within expected variation (|Z|≤2), orange dots represent genes suggestively outside the range (|Z|>2) and red dots represent genes outside expected range of variation (|Z|>4). Gray dots are genes with expression value below our detection threshold. Additive effect in log2 correspond to multiplicative effect on the original scale. The fold-change equivalent to a given effect log2-effect x is then: FC = 2x. As an example, an effect of 1 correspond to a FC = 2. (B) Correlation of effect of independent set of replicated expression of IRF5 on THP-1 transcriptome. The x-axis (inner color of dots) and y-axis (border color of dots) show the effect of two independent set of replicated ORFs on the transcriptome, as the log2-transformed fold-induction compared to baseline. Variation between sets of replicates includes effect of independent infection dates, RNA extraction, expression arrays and batches. (C) Impact of the transduction and expression of all 42 IBD gene candidate ORFs on the transcriptome of THP-1 cells. ORFs are ordered by their total number of HITS, with the number of up- and down-regulated HITS illustrated by black and gray, respectively (S2 Table & S1 Appendix). Starred ORFs are previously reported IBD candidate causal genes.</p

Proposed model of S100A8/9 induction.

PTGIR and PTGER4 are activated by their ligands (PGI2 and PGE2 respectively) turning on the AC which converts ATP into cAMP; cAMP activates PKA which in turn triggers STAT3 by phosphorylation. STAT3 binds to the promoters (S9 Fig) of S100A8 and S100A9 inducing their expression. TLR4 and when activated by its ligand LPS, activates the JAK2-STAT3 pathway which induces the expression of S100A8/9 and inhibits NF-kB. We have shown the induction of S100A8/9 genes in THP-1 activated by LPS (Fig 5). ZBTB40 could potentially bind directly to the S100A8/9 promoters inducing their expression and/or to the PLA2G1B promoter (by Encode) activating its expression. PLA2G1B encodes an enzyme that initiates the PG synthesis including PGI2 and PGE2 which bind PTGIR and PTGER4 respectively, inducing S100A8/S100A9 (see above). Based on RNAseq data, expression of NFKB1 in THP-1 induces the expression of EBI3 (one of the top 5 HITS) (S3A Table) most likely via direct binding to the EBI3 promoter by RELB subunit. EBI3 encodes the interleukine-27 subunit beta, which can bind to IL27R and activate JAK/STAT3 pathway [55,56]. In addition, NFKB1 induces the expression of PTGIR ((S10 Fig). RELB binds directly to PTGIR promoter (by Encode).</p

S4 Table -

S4A Table: gProfiler enrichment analyses of all the HITS identified in the screen. S4B Table: gProfiler enrichment analyses of the upregulated HITS identified in the screen. S4C Table: gProfiler enrichment analyses of the downregulated HITS identified in the screen. (XLSX)</p