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Background: We aim to investigate the proportion of patients (pts) with long-term cognitive outcomes (CO) of PACC and identify associated features. Methods: We assessed participants through a neuropsychological assessment. The chi-square test was used for comparisons according with time of NPA (within or beyond 6 months since COVID19) and with previously hospitalization status (hospitalized patients, PH; not hospitalized patients, nPH). Results: 520 participants: mean age 54 years (SD 12), 53 % female, 14 years of education (SD 3.4), 35 % with >1 comorbidity, 48 % previously hospitalized. Overall, we found CO in 89 % of pts, in particular 88 % evaluated in w6M and 89 % in b6M (p = 0.801) while 90 % and 87 % in nPH and PH, respectively (p = 0.239). By fitting multivariable analysis, PH for COVID19 and female gender were associated with an increased risk of an altered PSQI [Odd Ratio, OR 2.48, 95 % CI 1.54 to 3.99, p

Bu çalışma, ortaokul öğrencilerinin sosyal katılım becerilerinin spora yönelik tutumları üzerindeki etkisini kapsamlı bir şekilde incelemeyi amaçlamaktadır. Bu bağlamda, sosyal katılım becerileri ile spora yönelik tutumlar arasındaki etki, ortaokul öğrencileri özelinde derinlemesine ele alınarak değerlendirilmiştir. Bu çalışma, özellikle gençlerin fiziksel aktiviteye katılımlarını artırmaya yönelik stratejiler geliştirilmesine katkı sağlamayı amaçlamaktadır. Çalışmanın evrenini, Çorum ili Sungurlu (Türkiye) ilçesinde ortaokul düzeyinde eğitim gören 2256 öğrenci oluşturmaktadır. Araştırma, 12-14 yaş aralığındaki 342 öğrenci üzerinde gerçekleştirilmiştir. Katılımcılardan elde edilen veriler, “Ortaokul Öğrencilerinin Sosyal Katılım Ölçeği” ve “Spora Yönelik Tutum Ölçeği” kullanılarak toplanmıştır. Çalışma bulgularına göre, öğrencilerin aile gelir düzeyleri, spor yapma alışkanlıkları, lisanslı spor yapma durumları, okul sporlarına katılımları ve sportif başarı düzeyleri ile sosyal katılım becerileri ve spora yönelik tutumları arasında anlamlı bir ilişki olduğu tespit edilmiştir. Gelir düzeyi yüksek olan, düzenli spor yapan ve okul sporlarına katılan öğrencilerin sosyal katılım becerileri ve spora yönelik tutumlarının daha olumlu olduğu görülmektedir. Ayrıca, düzenli spor yapan öğrencilerin sosyal katılım becerilerinin daha gelişmiş olduğu ve spora yönelik tutumlarının daha olumlu olduğu belirlenmiştir. Bu çalışma, sosyal katılım becerileri ile spora yönelik tutumlar arasındaki etkinin anlaşılmasına katkı sağlamayı ve gelecekteki araştırmalara yol göstermeye katkıda bulunacağı söylenebilir.

Recently reported links between rhythm and grammar processing have opened new perspectives for using rhythm in clinical interventions for children with developmental language disorder (DLD). Previous research using the rhythmic priming paradigm has shown improved performance on language tasks after regular rhythmic primes compared to control conditions. However, this research has been limited to effects of rhythmic priming on grammaticality judgments. The current study investigated whether regular rhythmic primes could also benefit sentence repetition, a task requiring proficiency in complex syntax--an area of difficultly for children with DLD. Regular rhythmic primes improved sentence repetition performance compared to irregular rhythmic primes in children with DLD and with typical development--an effect that did not occur with a non-linguistic control task. These findings suggest processing overlap for musical rhythm and linguistic syntax, with implications for the use of rhythmic stimulation for treatment of children with DLD in clinical research and practice.

Tumor cells reprogram their metabolism to meet the increased demand for nucleotides and other molecules necessary for growth and proliferation. In fact, cancer cells are characterized by an increased “de novo” synthesis of purine nucleotides. Therefore, it is not surprising that specific enzymes of purine metabolism are the targets of drugs as antineoplastic agents, and a better knowledge of the mechanisms underlying their regulation would be of great help in finding new therapeutic approaches. The mammalian target of the rapamycin (mTOR) signaling pathway, which is often activated in cancer cells, promotes anabolic processes and is a major regulator of cell growth and division. Among the numerous effects exerted by mTOR, noteworthy is its empowerment of the “de novo” synthesis of nucleotides, accomplished by supporting the formation of purinosomes, and by increasing the availability of necessary precursors, such as one-carbon formyl group, bicarbonate and 5-phosphoribosyl-1-pyrophosphate. In this review, we highlight the connection between purine and mitochondrial metabolism, and the bidirectional relation between mTOR signaling and purine synthesis pathways.

Summary: Background: Pre-exposure vaccination with MVA-BN has been widely used against mpox to contain the 2022 outbreak. Many countries have defined prioritized strategies, administering a single dose to those historically vaccinated for smallpox, to achieve quickly adequate coverage in front of low supplies. Using epidemiological models, real-life effectiveness was estimated at approximately 36%–86%, but no clinical trials were performed. Few data on MVA-BN immunogenicity are currently available, and there are no established correlates of protection. Immunological response in PLWH in the context of the 2022 outbreak was also poorly described. Methods: Blood samples were collected from participants eligible for pre-exposure MVA-BN vaccination before (T1) receiving a full course of vaccine (single-dose for vaccine-experienced or smallpox-primed and two-dose for smallpox vaccine-naïve or smallpox non-primed) and one month after the last dose (T2 and T3, respectively). MPXV-specific IgGs were measured by in-house immunofluorescence assay, using 1:20 as screening dilution, MPXV-specific nAbs by 50% plaque reduction neutralization test (PRNT50, starting dilution 1:10), and IFN-γ-producing specific T cells to MVA-BN vaccine, by ELISpot assay. Paired or unpaired t-test and Wilcoxon or Mann–Whitney test were used to analyse IgG and nAbs, and T-cell response, as appropriate. The probability of IgG and nAb response in vaccine-experienced vs. vaccine-naïve was estimated in participants not reactive at T1. The McNemar test was used to evaluate vaccination's effect on humoral response both overall and by smallpox vaccination history. In participants who were not reactive at T1, the proportion of becoming responders one month after full-cycle completion by exposure groups was compared by logistic regression and then analysed by HIV status strata (interaction test). The response was also examined in continuous, and the Average Treatment Effect (ATE) of the difference from baseline to schedule completion according to previous smallpox vaccination was estimated after weighting for HIV using a linear regression model. Self-reports of adverse effects following immunization (AEFIs) were prospectively collected after the first MVA-BN dose (T1). Systemic (S-AEFIs: fatigue, myalgia, headache, GI effects, chills) and local (L-AEFIs: redness, swelling, pain) AEFIs were graded as absent (grade 0), mild (1), moderate (2), or severe (3). The maximum level of severity for S-AEFIs and L-AEFIs ever experienced over the 30 days post-dose by vaccination exposure groups were analysed using a univariable multinomial logistic regression model and after adjusting for HIV status; for each of the symptoms, we also compared the mean duration by exposure group using an unpaired t-test. Findings: Among the 164 participants included, 90 (54.8%) were smallpox vaccine-experienced. Median age was 49 years (IQR 41–55). Among the 76 (46%) PLWH, 76% had a CD4 count >500 cells/μL. There was evidence that both the IgG and nAbs titers increased after administration of the MVA-BN vaccine. However, there was no evidence for a difference in the potential mean change in humoral response from baseline to the completion of a full cycle when comparing primed vs. non-primed participants. Similarly, there was no evidence for a difference in the seroconversion rate after full cycle vaccination in the subset of participants not reactive for nAbs at T1 (p = 1.00 by Fisher's exact test). In this same analysis and for the nAbs outcome, there was some evidence of negative effect modification by HIV (interaction p-value = 0.17) as primed people living with HIV (PLWH) showed a lower probability of seroconversion vs. non-primed, and the opposite was seen in PLWoH. When evaluating the response in continuous, we observed an increase in T-cell response after MVA-BN vaccination in both primed and non-primed. There was evidence for a larger increase when using the 2-dose vs. one-dose strategy with a mean difference of −2.01 log2 (p ≤ 0.0001), after controlling for HIV. No evidence for a difference in the risk of developing any AEFIs of any grade were observed by exposure group, except for the lower risk of grade 2 (moderate) fatigue, induration and local pain which was lower in primed vs. non-primed [OR 0.26 (0.08–0.92), p = 0.037; OR 0.30 (0.10–0.88), p = 0.029 and OR 0.19 (0.05–0.73), p = 0.015, respectively]. No evidence for a difference in symptom duration was also detected between the groups. Interpretation: The evaluation of the humoral and cellular response one month after the completion of the vaccination cycle suggested that MVA-BN is immunogenic and that the administration of a two-dose schedule is preferable regardless of the previous smallpox vaccination history, especially in PLWH, to maximize nAbs response. MVA-BN was safe as well tolerated, with grade 2 reactogenicity higher after the first administration in vaccine-naïve than in vaccine-experienced individuals, but with no evidence for a difference in the duration of these adverse effects. Further studies are needed to evaluate the long-term duration of immunity and to establish specific correlates of protection. Funding: The study was supported by the National Institute for Infectious Disease Lazzaro Spallanzani IRCCS “Advanced grant 5 × 1000, 2021” and by the Italian Ministry of Health “Ricerca Corrente Linea 2”.

In 2018 we celebrated 25 years of development of radar altimetry, and the progress achieved by this methodology in the fields of global and coastal oceanography, hydrology, geodesy and cryospheric sciences. Many symbolic major events have celebrated these developments, e.g., in Venice, Italy, the 15th (2006) and 20th (2012) years of progress and more recently, in 2018, in Ponta Delgada, Portugal, 25 Years of Progress in Radar Altimetry. On this latter occasion it was decided to collect contributions of scientists, engineers and managers involved in the worldwide altimetry community to depict the state of altimetry and propose recommendations for the altimetry of the future. This paper summarizes contributions and recommendations that were collected and provides guidance for future mission design, research activities, and sustainable operational radar altimetry data exploitation. Recommendations provided are fundamental for optimizing further scientific and operational advances of oceanographic observations by altimetry, including requirements for spatial and temporal resolution of altimetric measurements, their accuracy and continuity. There are also new challenges and new openings mentioned in the paper that are particularly crucial for observations at higher latitudes, for coastal oceanography, for cryospheric studies and for hydrology. The paper starts with a general introduction followed by a section on Earth System Science including Ocean Dynamics, Sea Level, the Coastal Ocean, Hydrology, the Cryosphere and Polar Oceans and the “Green” Ocean, extending the frontier from biogeochemistry to marine ecology. Applications are described in a subsequent section, which covers Operational Oceanography, Weather, Hurricane Wave and Wind Forecasting, Climate projection. Instruments’ development and satellite missions’ evolutions are described in a fourth section. A fifth section covers the key observations that altimeters provide and their potential complements, from other Earth observation measurements to in situ data. Section 6 identifies the data and methods and provides some accuracy and resolution requirements for the wet tropospheric correction, the orbit and other geodetic requirements, the Mean Sea Surface, Geoid and Mean Dynamic Topography, Calibration and Validation, data accuracy, data access and handling (including the DUACS system). Section 7 brings a transversal view on scales, integration, artificial intelligence, and capacity building (education and training). Section 8 reviews the programmatic issues followed by a conclusion.

In 2018 we celebrated 25 years of development of radar altimetry, and the progress achieved by this methodology in the fields of global and coastal oceanography, hydrology, geodesy and cryospheric sciences. Many symbolic major events have celebrated these developments, e.g., in Venice, Italy, the 15th (2006) and 20th (2012) years of progress and more recently, in 2018, in Ponta Delgada, Portugal, 25 Years of Progress in Radar Altimetry. On this latter occasion it was decided to collect contributions of scientists, engineers and managers involved in the worldwide altimetry community to depict the state of altimetry and propose recommendations for the altimetry of the future. This paper summarizes contributions and recommendations that were collected and provides guidance for future mission design, research activities, and sustainable operational radar altimetry data exploitation. Recommendations provided are fundamental for optimizing further scientific and operational advances of oceanographic observations by altimetry, including requirements for spatial and temporal resolution of altimetric measurements, their accuracy and continuity. There are also new challenges and new openings mentioned in the paper that are particularly crucial for observations at higher latitudes, for coastal oceanography, for cryospheric studies and for hydrology. The paper starts with a general introduction followed by a section on Earth System Science including Ocean Dynamics, Sea Level, the Coastal Ocean, Hydrology, the Cryosphere and Polar Oceans and the “Green” Ocean, extending the frontier from biogeochemistry to marine ecology. Applications are described in a subsequent section, which covers Operational Oceanography, Weather, Hurricane Wave and Wind Forecasting, Climate projection. Instruments’ development and satellite missions’ evolutions are described in a fourth section. A fifth section covers the key observations that altimeters provide and their potential complements, from other Earth observation measurements to in situ data. Section 6 identifies the data and methods and provides some accuracy and resolution requirements for the wet tropospheric correction, the orbit and other geodetic requirements, the Mean Sea Surface, Geoid and Mean Dynamic Topography, Calibration and Validation, data accuracy, data access and handling (including the DUACS system). Section 7 brings a transversal view on scales, integration, artificial intelligence, and capacity building (education and training). Section 8 reviews the programmatic issues followed by a conclusion.

Abstract Background After the acute phase, symptoms or sequelae related to post-COVID-19 syndrome may persist for months. In a population of patients, previously hospitalized and not, followed up to 12 months after the acute infection, we aim to assess whether and to what extent post-COVID-19 syndrome may have an impact on health-related quality of life (HRQoL) and to investigate influencing factors. Methods We present the cross-sectional analysis of a prospective study, including patients referred to the post-COVID-19 service. Questionnaires and scales administered at 3, 6, 12 months were: Short-Form 36-item questionnaire (SF-36); Visual Analogue Scale of the EQ5D (EQ-VAS); in a subgroup, Beck Anxiety Inventory (BAI), Beck Depression Inventory (BDI-II) and Pittsburgh Sleep Quality Index (PSQI). Linear regression models were fitted to identify factors associated with HRQoL. Results We considered the first assessment of each participant (n = 572). The mean scores in SF-36 and in EQ-VAS were significantly lower than the Italian normative values and remained stable over time, except the mental components score (MCS) of the SF-36 and EQ-VAS which resulted in lower ratings at the last observations. Female gender, presence of comorbidities, and corticosteroids treatment during acute COVID-19, were associated with lower scores in SF-36 and EQ-VAS; patients previously hospitalized (54%) reported higher MCS. Alterations in BAI, BDI-II, and PSQI (n = 265)were associated with lower ratings in SF-36 and EQ-VAS. Conclusions This study provides evidence of a significantly bad perception of health status among persons with post-COVID-19 syndrome, associated with female gender and, indirectly, with disease severity. In case of anxious-depressive symptoms and sleep disorders, a worse HRQoL was also reported. A systematic monitoring of these aspects is recommended to properly manage the post-COVID-19 period.

Human and viral microRNAs (miRNAs) are involved in the regulation of gene transcription, and the establishment of their profiles in acute (AHI) and chronic (CHI) HIV infections may shed light on the pathogenetic events related to different phases of HIV disease. Next-generation sequencing (NGS) of miRNA libraries was performed, and the reads were used to analyze miRNA differential expression in the plasma with AHI and CHI. Functional analysis was then undertaken to investigate the biological processes characterizing the two phases of HIV infection. Except for hsa-miR-122-5p, which was found in 3.39% AHI vs. 0.18% CHI, the most represented human miRNAs were similarly represented in AHI and CHI. However, when considering the overall detected miRNAs in AHI and CHI, 15 displayed differential expression (FDR p < 0.05). Functional analysis identified 163 target mRNAs involved in promoting angiogenesis activation in AHI versus CHI through the action of hsa-miR10b-5p, hsa-miR1290, hsa-miR1-3p, and hsa-miR296-5p. The viral miRNAs detected, all belonging to herpesviruses, accounted for only 0.014% of total reads. The present data suggest that AHI patients exhibit strong innate immune activation through the upregulation of hsa-miR-122-5p and early activation of angiogenesis. More specific investigations are needed to study the role of viral miRNAs in HIV pathogenesis.

Therapeutic Area: ASCVD/CVD in Women Background: Women with obstructive coronary artery disease (CAD) have a relatively lower quality of life (QoL) compared to men but our understanding of sex differences in QoL in ischemia with no obstructive coronary artery disease (INOCA) is limited. Methods: We conducted a survey of patient members of INOCA International with an assessment of self-reported health measures. Functional capacity was retrospectively estimated using the Duke Activity Status Index (DASI) assessing levels of activities performed before and after INOCA symptom onset. Results: Of the 1579 patient members of INOCA International, the overall survey completion rate was 21%. Women represented 91% of the respondents. Estimated functional capacity, expressed as metabolic equivalents (METs), was higher before compared to after INOCA diagnosis for comparably for both women (8.6±1.8 METs vs. 5.6±1.8 METs respectively, p

Myocarditis is an inflammatory disease of the heart that may occur because of infections, immune system activation, or exposure to drugs. The diagnosis of myocarditis has changed due to the introduction of cardiac magnetic resonance imaging. We present an expert consensus document aimed to summarize the common terminology related to myocarditis meanwhile highlighting some areas of controversies and uncertainties and the unmet clinical needs. In fact, controversies persist regarding mechanisms that determine the transition from the initial trigger to myocardial inflammation and from acute myocardial damage to chronic ventricular dysfunction. It is still uncertain which viruses (besides enteroviruses) cause direct tissue damage, act as triggers for immune-mediated damage, or both. Regarding terminology, myocarditis can be characterized according to etiology, phase, and severity of the disease, predominant symptoms, and pathological findings. Clinically, acute myocarditis (AM) implies a short time elapsed from the onset of symptoms and diagnosis (generally

Abstract In a murine model of acute ischemic stroke, SIRT6 knockdown resulted in larger cerebral infarct size, worse neurological outcome, and higher mortality, indicating a possible neuro-protective role of SIRT6. In this study, we aimed at evaluating the prognostic value of serum SIRT6 levels in patients with acute ischemic stroke (AIS). Serum levels of SIRT6, collected within 72 h from symptom-onset, were measured in 317 consecutively enrolled AIS patients from the COSMOS cohort. The primary endpoint of this analysis was 90-day mortality. The independent prognostic value of SIRT6 was assessed with multivariate logistic and Cox proportional regression models. 35 patients (11%) deceased within 90-day follow-up. After adjustment for established risk factors (age, NIHSS, heart failure, atrial fibrillation, and C reactive protein), SIRT6 levels were negatively associated with mortality. The optimal cut-off for survival was 634 pg/mL. Patients with SIRT6 levels below this threshold had a higher risk of death in multivariable Cox regression. In this pilot study, SIRT6 levels were significantly associated with 90-day mortality after AIS; these results build on previous molecular and causal observations made in animal models. Should this association be confirmed, SIRT6 could be a potential prognostic predictor and therapeutic target in AIS.

Introduction: The purpose of the study was to investigate the age-related anthropometric and motor performance changes over time and their contributions to swimming style-specific performance in young different chronological age swimmers. Material and Methods: The study was conducted on a total of forty swimmers who were divided into 2 groups. The anthropometric measurements were executed from 12 body parts, and body composition analysis was determined by using the skinfold method. The motor performance tests were performed for the assessment of standing horizontal jump, handgrip strength, flexed-arm hang strength, sit-up, flexibility, aerobic endurance, speed, agility, and balance. Simple Linear Regression analysis was performed to build the models for each of the swimming styles. Results: All the models indicated that aerobic endurance was a significantly predictive variable on all swimming styles (p < 0.001). The results indicated that the anthropometric and motor performance predictors changed depending upon the age progression in each swimming style (p < 0.001). Conclusions: The effect of many variables on swimming performance is seen to be more evident in the following periods based on the increase of age. Aerobic endurance is a common variable that shows effectiveness on swimming performance for both all age groups and swimming styles.

Background Previous randomized control trials showed mixed results concerning the effect of omega‐3 fatty acids (n‐3 FAs) on atrial fibrillation (AF). The associations of n‐3 FA blood levels with heart rhythm in patients with established AF are unknown. The goal of this study was to assess the associations of total and individual n‐3 FA blood levels with AF type (paroxysmal versus nonparoxysmal), heart rate (HR), and HR variability in patients with AF. Methods and Results Total n‐3 FAs, eicosapentaenoic acid, docosahexaenoic acid, docosapentaenoic acid, and alpha‐linolenic acid blood levels were determined in 1969 patients with known AF from the SWISS‐AF (Swiss Atrial Fibrillation cohort). Individual and total n‐3 FAs were correlated with type of AF, HR, and HR variability using standard logistic and linear regression, adjusted for potential confounders. Only a mild association with nonparoxysmal AF was found with total n‐3 FA (odds ratio [OR], 0.97 [95% CI, 0.89–1.05]) and docosahexaenoic acid (OR, 0.93 [95% CI, 0.82–1.06]), whereas other individual n‐3 FAs showed no association with nonparoxysmal AF. Higher total n‐3 FAs (estimate 0.99 [95% CI, 0.98–1.00]) and higher docosahexaenoic acid (0.99 [95% CI, 0.97–1.00]) tended to be associated with slower HR in multivariate analysis. Docosapentaenoic acid was associated with a lower HR variability triangular index (0.94 [95% CI, 0.89–0.99]). Conclusions We found no strong evidence for an association of n‐3 FA blood levels with AF type, but higher total n‐3 FA levels and docosahexaenoic acid might correlate with lower HR, and docosapentaenoic acid with a lower HR variability triangular index.

Inundation is one of the major natural hazards in Europe. The evaluation of the flood hazard and risk is not straightforward mainly due to the monitoring system that is poor or not uniformly distributed in the territory. The ESA Earth Observation Program, including a series of satellites, Sentinels, for the operative observation of the natural phenomenon, e.g. the inundations, can potentially reduce the gap. Sentinel-1 (SAR: synthetic aperture radar) and Sentinel-2 (optical) have been demonstrated to be suitable for mapping flooded areas, but despite the medium–high spatial and temporal resolution of the sensors, the mapping of inundated territories is often partial or missing. The objective of this study is to evaluate through a synthetic study the effectiveness of Sentinel-1 and Sentinel-2 in the systematic assessment of floods in Europe, where the flood events have durations ranging from some hours to a few days. To reach the target, we analysed 10 years of river discharge data over almost 2000 sites in Europe, and we extracted flood events over some established thresholds as proxies of riverine inundations. Based on the revisit time of the satellite constellations and cloud coverage, we derived the percentage of potential inundation events that Sentinel-1 and Sentinel-2 could be able to observe. Results show that assuming the configuration of a constellation of two satellites for each mission and considering the ascending and descending orbit, on average 58 % of flood events are potentially observable by Sentinel-1 and only 28 % by Sentinel-2 due to the cloud coverage.

Background: One of the main challenges in the management of COVID-19 patients is to early assess and stratify them according to their risk of developing severe pneumonia. The alveolar–arterial oxygen gradient (D(A-a)O2) is defined as the difference between the alveolar and arteriolar concentration of oxygen, an accurate index of the ventilatory function. The aim of this study is to evaluate D(A-a)O2 as a marker for predicting severe pneumonia in COVID-19 patients, in comparison to the PaO2/FiO2. Methods: This retrospective, multicentric cohort study included COVID-19 patients admitted to two Italian hospitals between April and July 2020. Clinical and laboratory data were retrospectively collected at the time of hospital admission and during hospitalization. The presence of severe COVID-19 pneumonia was evaluated, as defined by the Infectious Diseases Society of America (IDSA) criteria for community-acquired pneumonia (CAP). Patients were divided in severe and non-severe groups. Results: Overall, 53 COVID-19 patients were included in the study: male were 30/53 (57%), and 10/53 (19%) had severe pneumonia. Patients with severe pneumonia reported dyspnea more often than non-severe patients (90% vs. 39.5%; p = 0.031). A history of chronic obstructive pulmonary disease (COPD) was recalled by 5/10 (50%) patients with severe pneumonia, and only in 6/43 (1.4%) of non-severe cases (p = 0.023). A ROC curve, for D(A-a)O2 >60 mmHg in detecting severe pneumonia, showed an area under the curve (AUC) of 0.877 (95% CI: 0.675–1), while the AUC of PaO2/FiO2 < 263 mmHg resulted 0.802 (95% CI: 0.544–1). D(A-a)O2 in comparison to PaO2/FiO2 had a higher sensibility (77.8% vs. 66.7%), positive predictive value (75% vs. 71.4%), negative predictive value (94% vs. 91%), and similar specificity (94.4% vs. 95.5%). Conclusions: Our study suggests that the D(A-a)O2 is more appropriate than PaO2/FiO2 to identify COVID-19 patients at risk of developing severe pneumonia early.

Summary: Background: Among interleukin-6 inhibitors suggested for use in COVID-19, there are few robust evidences for the efficacy of sarilumab. Herein, we evaluated the efficacy and safety of sarilumab in severe COVID-19. Methods: In this phase 3, open-labeled, randomized clinical trial, conducted at 5 Italian hospitals, adults with severe COVID-19 pneumonia (excluding mechanically ventilated) were randomized 2:1 to receive intravenous sarilumab (400 mg, repeatable after 12 h) plus standard of care (SOC) (arm A) or to continue SOC (arm B). Randomization was web-based. As post-hoc analyses, the participants were stratified according to baseline inflammatory parameters. The primary endpoint was analysed on the modified Intention-To-Treat population, including all the randomized patients who received any study treatment (sarilumab or SOC). It was time to clinical improvement of 2 points on a 7-points ordinal scale, from baseline to day 30. We used Kaplan Meier method and log-rank test to compare the primary outcome between two arms, and Cox regression stratified by clinical center and adjusted for severity of illness, to estimate the hazard ratio (HR). The trial was registered with EudraCT (2020-001390-76). Findings: Between May 2020 and May 2021, 191 patients were assessed for eligibility, of whom, excluding nine dropouts, 176 were assigned to arm A (121) and B (55). At day 30, no significant differences in the primary endpoint were found (88% [95% CI 81–94] in arm A vs 85% [74–93], HR 1.07 [0.8–1.5] in arm B; log-rank p = 0.50). After stratifying for inflammatory parameters, arm A showed higher probability of improvement than B without statistical significance in the strata with C reactive protein (CRP)

Abstract Elevated circulating levels of nutrient-derived trimethylamine N-oxide (TMAO) have been associated with the onset and progression of cardiovascular disease by promoting athero-thrombosis. However, in conditions like bariatric surgery (Roux-en-Y gastric bypass, RYGB), stable increases of plasma TMAO are associated with improved endothelial function and reduced cardiovascular morbidity and mortality, thus questioning whether a mechanistic relationship between TMAO and endothelial dysfunction exists. Herein, we translationally assessed the effects of acute TMAO exposure on endothelial dysfunction, thrombosis and stroke. After RYGB, fasting circulating levels of TMAO increased in patients and obese rats, in parallel with an improved gluco-lipid profile and higher circulating bile acids. The latter enhanced FXR-dependent signalling in rat livers, which may lead to higher TMAO synthesis post RYGB. In lean rats, acute TMAO injection (7 mg kg−1) 1.5-h before sacrifice and ex-vivo 30-min incubation of thoracic aortas with 10−6 M TMAO did not impair vasodilation in response to acetylcholine (Ach), glucagon-like peptide 1, or insulin. Similarly, in lean WT mice (n = 5–6), TMAO injection prior to subjecting mice to ischemic stroke or arterial thrombosis did not increase its severity compared to vehicle treated mice. Endothelial nitric oxide synthase (eNOS) activity and intracellular stress-activated pathways remained unaltered in aorta of TMAO-injected rats, as assessed by Western Blot. Pre-incubation of human aortic endothelial cells with TMAO (10−6 M) did not alter NO release in response to Ach. Our results indicate that increased plasmatic TMAO in the near-physiological range seems to be a neutral bystander to vascular function as translationally seen in patients after bariatric surgery or in healthy lean rodent models and in endothelial cells exposed acutely to TMAO.

The Copernicus Sentinel-3 Surface Topography Mission (STM) Land Altimetry provides valuable surface elevation information over inland waters, sea ice, and land ice, thanks to its synthetic aperture radar (SAR) altimeter and its orbit that covers high-latitude polar regions. To ensure that these measurements are reliable and to maximise the return on investment, adequate validation of the geophysical retrieval methods, processing algorithms, and corrections must be performed using independent observations. The EU-ESA project St3TART (started July 2021) aims to generalise the concept of Fiducial Reference Measurements (FRMs) for the Copernicus Sentinel-3 STM. This work has gathered existing data, made new observations during field campaigns, and ensured that these observations meet the criteria of FRM standards so that they can be used to validate Sentinel-3 STM Land Altimetry products operationally. A roadmap for the operational provision of the FRM, including the definition, consolidation, and identification of the most relevant and cost-effective methods and protocols to be maintained, supported, or implemented, has been developed. The roadmap includes guidelines for SI traceability, definitions of FRM measurement procedures, processing methods, and uncertainty budget estimations.

Torquetenovirus (TTV) is the most abundant component of the human blood virome and its replication is controlled by a functioning immune system. In this study, TTV replication was evaluated in 21 people with acute HIV infection (AHI) and immune reconstitution following antiretroviral therapy (ART). PBMC-associated TTV and HIV-1 DNA, as well as plasma HIV-1 RNA, were measured by real-time PCR. CD4 and CD8 differentiation, activation, exhaustion, and senescence phenotypes were analyzed by flow cytometry. Thirteen healthy donors (HD) and twenty-eight chronically infected HIV individuals (CHI), late presenters at diagnosis, were included as control groups. TTV replication in AHI seems to be controlled by the immune system being higher than in HD and lower than in CHI. During ART, a transient increase in TTV DNA levels was associated with a significant perturbation of activation and senescence markers on CD8 T cells. TTV loads were positively correlated with the expansion of CD8 effector memory and CD57+ cells. Our results shed light on the kinetics of TTV replication in the context of HIV acute infection and confirm that the virus replication is strongly regulated by the modulation of the immune system.

BackgroudThe aim of this study was to assess the prognostic association of plasma levels of N-terminal prohormone of brain natriuretic peptide (NT-proBNP) with clinical outcomes of patients with microvascular angina (MVA). Methods: In this international prospective cohort study of MVA by the Coronary Vasomotor Disorders International Study (COVADIS) group, we examined the association between plasma NT-proBNP levels and the incidence of major adverse cardiovascular events (MACE), including cardiovascular death, non-fatal myocardial infarction, non-fatal stroke, and hospitalization due to heart failure or unstable angina. Results: We examined a total of 226 MVA patients (M/F 66/160, 61.9 ± 10.2 [SD] yrs.) with both plasma NT-proBNP levels and echocardiography data available at the time of enrolment. The median level of NT-proBNP level was 94 pg/ml, while mean left ventricular ejection fraction was 69.2 ± 10.9 % and E/e’ 10.7 ± 5.2. During follow-up period of a median of 365 days (IQR 365–482), 29 MACEs occurred. Receiver-operating characteristics curve analysis identified plasma NT-proBNP level of 78 pg/ml as the optimal cut-off value. Multivariable logistic regression analysis revealed that plasma NT-proBNP level ≥ 78 pg/ml significantly correlated with the incidence of MACE (odds ratio (OR) [95 % confidence interval (CI)] 3.11[1.14–8.49], P = 0.001). Accordingly, Kaplan-Meier survival analysis showed a significantly worse prognosis in the group with NT-proBNP ≥ 78 (log-rank test, P

Determining the spatiotemporal variability in the annual streamflow volume plays a relevant role in hydrology with regard to improving and implementing sustainable and resilient policies and practices of water resource management. This study investigates annual streamflow volume trends in a newly assembled, consolidated, and validated data set of daily mean river flow records from more than 3000 stations which cover near-natural basins in more than 40 countries across Europe. Although the data set contains streamflow time series from 1900 to 2013 in some stations, the statistical analyses were carried out by including observations from 1950 to 2013 in order to have a consistent and reliable data set over the continent. Trends were detected by calculating the slope of the Theil–Sen line over the annual anomalies of streamflow volume. The results show that annual streamflow volume trends have emerged at European scale, with a marked negative tendency in Mediterranean regions, with about -1×103 m3/(km2 yr−2), and a generally positive trend in northern ones, with about 0.5×103 m3/(km−2 yr−2). The annual streamflow volume trend patterns appear to be in agreement with the continental-scale meteorological observations in response to climate change drivers. In the Mediterranean area, the decline of annual streamflow volumes started in 1965, and since the early 1980s, volumes have consistently been lower than the 1950–2013 average. The spatiotemporal annual streamflow volume patterns observed in this work can help to contextualize short-term trends and regional studies already available in the scientific literature, as well as to provide a valid benchmark for further accurate quantitative analysis of annual streamflow volumes.

Agricultural droughts are extreme events which are often a result of interplays between multiple hydro-meteorological processes. Therefore, assessing drought occurrence, extent, duration and intensity is complex and requires the combined use of multiple variables, such as temperature, rainfall, soil moisture (SM) and vegetation state. The benefit of using information on SM and vegetation state is that they integrate information on precipitation, temperature and evapotranspiration, making them direct indicators of plant available water and vegetation productivity. Microwave remote sensing enables the retrieval of both SM and vegetation information, and satellite-based SM and vegetation products are available operationally and free of charge on a regional or global scale and daily basis. As a result, microwave remote sensing products play an increasingly important role in drought monitoring applications. Here, we provide an overview of recent developments in using microwave remote sensing for large-scale agricultural drought monitoring. We focus on the intricacy of monitoring the complex process of drought development using multiple variables. First, we give a brief introduction on fundamental concepts of microwave remote sensing together with an overview of recent research, development and applications of drought indicators derived from microwave-based satellite SM and vegetation observations. This is followed by a more detailed overview of the current research gaps and challenges in combining microwave-based SM and vegetation measurements with hydro-meteorological data sets. The potential of using microwave remote sensing for drought monitoring is demonstrated through a case study over Senegal using multiple satellite- and model-based data sets on rainfall, SM, vegetation and combinations thereof. The case study demonstrates the added-value of microwave-based SM and vegetation observations for drought monitoring applications. Finally, we provide an outlook on potential developments and opportunities.

Cellular purine nucleotides derive mainly from de novo synthesis or nucleic acid turnover and, only marginally, from dietary intake. They are subjected to catabolism, eventually forming uric acid in humans, while bases and nucleosides may be converted back to nucleotides through the salvage pathways. Inborn errors of the purine salvage pathway and catabolism have been described by several researchers and are usually referred to as rare diseases. Since purine compounds play a fundamental role, it is not surprising that their dysmetabolism is accompanied by devastating symptoms. Nevertheless, some of these manifestations are unexpected and, so far, have no explanation or therapy. Herein, we describe several known inborn errors of purine metabolism, highlighting their unexplained pathological aspects. Our intent is to offer new points of view on this topic and suggest diagnostic tools that may possibly indicate to clinicians that the inborn errors of purine metabolism may not be very rare diseases after all.

Objectives: To investigate the association between sex hormones and the severity of coronavirus disease 2019 (COVID-19). Furthermore, associations between sex hormones and systemic inflammation markers, viral shedding and length of hospital stay were studied. Design and methods: This case–control study included a total of 48 male patients with COVID-19 admitted to an Italian reference hospital. The 24 cases were patients with PaO2/FiO2 300 mmHg at all times and who may have required low-flow oxygen supplementation during hospitalization (mild COVID-19). For each group, sex hormones were evaluated on hospital admission. Results: Patients with severe COVID-19 (cases) had a significantly lower testosterone level compared with patients with mild COVID-19 (controls). Median total testosterone (TT) was 1.4 ng/mL in cases and 3.5 ng/mL in controls (P = 0.005); median bioavailable testosterone (BioT) was 0.49 and 1.21 in cases and controls, respectively (P = 0.008); and median calculated free testosterone (cFT) was 0.029 ng/mL and 0.058 ng/mL in cases and controls, respectively (P = 0.015). Low TT, low cFT and low BioT were correlated with hyperinflammatory syndrome (P = 0.018, P = 0.048 and P = 0.020, respectively) and associated with longer length of hospital stay (P = 0.052, P = 0.041 and P = 0.023, respectively). No association was found between sex hormone level and duration of viral shedding, or between sex hormone level and mortality rate. Conclusions: A low level of testosterone was found to be a marker of clinical severity of COVID-19.

Background: Limited data are available about the predictors and outcomes associated with prolonged SARS-CoV-2 RNA shedding (VS). Methods: A retrospective study including COVID-19 patients admitted to an Italian hospital between March 1 and July 1, 2020. Predictors of viral clearance (VC) and prolonged VS from the upper respiratory tract were assessed by Poisson regression and logistic regression analyses. The causal relation between VS and clinical outcomes was evaluated through an inverse probability weighted Cox model. Results: The study included 536 subjects. The median duration of VS from symptoms onset was 18 days. The estimated 30-day probability of VC was 70.2%. Patients with comorbidities, lymphopenia at hospital admission, or moderate/severe respiratory disease had a lower chance of VC. The development of moderate/severe respiratory failure, delayed hospital admission after symptoms onset, baseline comorbidities, or D-dimer >1000 ng/mL at admission independently predicted prolonged VS. The achievement of VC doubled the chance of clinical recovery and reduced the probability of death/mechanical ventilation. Conclusions: Respiratory disease severity, comorbidities, delayed hospital admission and inflammatory markers negatively predicted VC, which resulted to be associated with better clinical outcomes. These findings highlight the importance of prompt hospitalization of symptomatic patients, especially where signs of severity or comorbidities are present.

Future climate scenarios for the Mediterranean region indicate a possible decrease in annual precipitation associated with an intensification of extreme rainfall events in the coming years. A major challenge in this region is to evaluate the impacts of changing precipitation patterns on extreme hydrological events such as droughts and floods. For this, it is important to understand the impact of climate change on soil moisture since it is a proxy for agricultural droughts, and the antecedent soil moisture condition plays a key role on runoff generation. This study focuses on 10 sites, located in southern France, with available soil moisture, temperature, and precipitation observations for a 10-year time period. Soil moisture is simulated at each site at the hourly time step using a model of soil water content. The sensitivity of the simulated soil moisture to different changes in precipitation and temperature is evaluated by simulating the soil moisture response to temperature and precipitation scenarios generated using a delta change method for temperature and a stochastic model (the Neyman–Scott rectangular pulse model) for precipitation. Results show that soil moisture is more impacted by changes in precipitation intermittence than precipitation intensity and temperature. Overall, increased temperature and precipitation intensity associated with more intermittent precipitation leads to decreased soil moisture and an increase in the annual number of days with dry soil moisture conditions. In particular, a temperature increase of +4 ∘C combined with a decrease of annual rainfall between 10 % and 20 %, corresponding to the current available climate scenarios for the Mediterranean, lead to a lengthening of the drought period from June to October with an average of +28 d of soil moisture drought per year.

Myocardial infarction with nonobstructed coronary arteries (MINOCA) can be triggered by intense emotions. We report 5 cases of emotional stress–related death where forensic examination attributed myocardial infarction to a coronary spasm, with the ultimate cause of death being arrhythmias in 4 cases and cardiac rupture in the fifth. (Level of Difficulty: Beginner.)

Sirtuin 1 (SIRT1) is a histone deacetylase belonging to the family of Sirtuins, a class of nicotinamide adenine dinucleotide (NAD+)-dependent enzymes with multiple metabolic functions. SIRT1 localizes in the nucleus and cytoplasm, and is implicated in the regulation of cell survival in response to several stimuli, including metabolic ones. The expression of SIRT1 is associated with lifespan and is reduced with aging both in animal models and in humans, where the lack of SIRT1 is regarded as a potential mediator of age-related cardiovascular diseases. In this review, we will summarize the extensive evidence linking SIRT1 functional and quantitative defects to cellular senescence and aging, with particular regard to their role in determining endothelial dysfunction and consequent cardiovascular diseases. Ultimately, we outline the translational perspectives for this topic, in order to highlight the missing evidence and the future research steps.

Hypertrophic cardiomyopathy (HCM) is the most common genetic cardiomyopathy. The molecular mechanisms determining HCM phenotypes are incompletely understood. Myocardial biopsies were obtained from a group of patients with obstructive HCM (n = 23) selected for surgical myectomy and from 9 unused donor hearts (controls). A subset of tissue-abundant myectomy samples from HCM (n = 10) and controls (n = 6) was submitted to laser-capture microdissection to isolate cardiomyocytes. We investigated the relationship among clinical phenotype, cardiac myosin proteins (MyHC6, MyHC7, and MyHC7b) measured by optimized label-free mass spectrometry, the relative genes (MYH7, MYH7B and MYLC2), and the MyomiR network (myosin-encoded microRNA (miRs) and long-noncoding RNAs (Mhrt)) measured using RNA sequencing and RT-qPCR. MyHC6 was lower in HCM vs. controls, whilst MyHC7, MyHC7b, and MyLC2 were comparable. MYH7, MYH7B, and MYLC2 were higher in HCM whilst MYH6, miR-208a, miR-208b, miR-499 were comparable in HCM and controls. These results are compatible with defective transcription by active genes in HCM. Mhrt and two miR-499-target genes, SOX6 and PTBP3, were upregulated in HCM. The presence of HCM-associated mutations correlated with PTBP3 in myectomies and with SOX6 in cardiomyocytes. Additionally, iPSC-derived cardiomyocytes, transiently transfected with either miR-208a or miR-499, demonstrated a time-dependent relationship between MyomiRs and myosin genes. The transfection end-stage pattern was at least in part similar to findings in HCM myectomies. These data support uncoupling between myosin protein/genes and a modulatory role for the myosin/MyomiR network in the HCM myocardium, possibly contributing to phenotypic diversity and providing putative therapeutic targets.

Summary: Aging is a major risk factor for cardiovascular diseases, including thrombotic events. The gut microbiota has been implicated in the development of thrombotic risk. Plant-derived omega-3 fatty acid ɑ-linolenic acid (ALA) confers beneficial anti-platelet and anti-inflammatory effects. Hence, antithrombotic activity elicited by ALA may be partly dependent on its interaction with gut microbiota during aging. Here, we demonstrate that lifelong dietary ALA decreases platelet hyperresponsiveness and thrombus formation in aged mice. These phenotypic changes can be partly attributed to alteration of microbial composition and reduction of its metabolite trimethylamine N-oxide and inflammatory mediators including TNF-α, as well as the upregulated production of short-chain fatty acid acetate. ALA-rich diet also dampens secretion of increased procoagulant factors, tissue factor and plasminogen activator inhibitor-1, in aged mice. Our results suggest long-term ALA supplementation as an attractive, accessible, and well-tolerated nutritional strategy against age-associated platelet hyperreactivity and thrombotic potential.

Adenosine, acting both through G-protein coupled adenosine receptors and intracellularly, plays a complex role in multiple physiological and pathophysiological processes by modulating neuronal plasticity, astrocytic activity, learning and memory, motor function, feeding, control of sleep and aging. Adenosine is involved in stroke, epilepsy and neurodegenerative pathologies. Extracellular concentration of adenosine in the brain is tightly regulated. Adenosine may be generated intracellularly in the central nervous system from degradation of AMP or from the hydrolysis of S-adenosyl homocysteine, and then exit via bi-directional nucleoside transporters, or extracellularly by the metabolism of released nucleotides. Inactivation of extracellular adenosine occurs by transport into neurons or neighboring cells, followed by either phosphorylation to AMP by adenosine kinase or deamination to inosine by adenosine deaminase. Modulation of the nucleoside transporters or of the enzymatic activities involved in the metabolism of adenosine, by affecting the levels of this nucleoside and the activity of adenosine receptors, could have a role in the onset or the development of central nervous system disorders, and can also be target of drugs for their treatment. In this review, we focus on the contribution of 5′-nucleotidases, adenosine kinase, adenosine deaminase, AMP deaminase, AMP-activated protein kinase and nucleoside transporters in epilepsy, cognition, and neurodegenerative diseases with a particular attention on amyotrophic lateral sclerosis and Huntington’s disease. We include several examples of the involvement of components of the adenosine metabolism in learning and of the possible use of modulators of enzymes involved in adenosine metabolism or nucleoside transporters in the amelioration of cognition deficits.

Background: Patients with signs and symptoms of myocardial ischemia and non-obstructive coronary artery disease (CAD) frequently have coronary functional abnormalities, including coronary microvascular dysfunction. Those with the latter are grouped under the term “microvascular angina” (MVA). Although diagnostic criteria exist for MVA, as recently proposed by our COVADIS (COronary VAsomotor Disorders International Study) group and the condition has been increasingly recognized in clinical practice, the clinical characteristics and long-term prognosis of MVA patients in the current era remain to be fully elucidated. Aims: In the present study, we aimed to prospectively assess the clinical characteristics and long-term prognosis of MVA subjects in the current era in an international, multicenter, observational, and prospective registry study. Methods: A total of 15 medical centers across 7 countries (USA, UK, Germany, Spain, Italy, Australia, and Japan) enrolled subjects fulfilling the COVADIS diagnostic criteria for MVA as follows; (1) signs and/or symptoms of myocardial ischemia, (2) absence of obstructive CAD, and (3) objective evidence of myocardial ischemia and/or coronary microvascular dysfunction. The primary endpoint was the composite of major cardiovascular events (MACE), including cardiovascular death, non-fatal myocardial infarction, non-fatal stroke, hospitalization due to heart failure or unstable angina. Between July 2015 and December 2018, a total of 706 subjects with MVA (M/F 256/450, 61.1 ± 11.8 [SD] yrs.) were registered. Subjects will be followed for at least 1 year. Summary: The present study will provide important information regarding the clinical characteristics, management, and long-term prognosis of MVA patients in the current era.

The optimal therapeutic approach for primary HIV infection (PHI) is still debated. We aimed to compare the viroimmunological response to a four- versus a three-drug regimen, both INSTI-based, in patients with PHI. This was a monocentric, prospective, observational study including all patients diagnosed with PHI from December 2014 to April 2018. Antiretroviral therapy (ART) was started, before genotype resistance test results, with tenofovir/emtricitabine and either raltegravir plus boosted darunavir or dolutegravir. Cumulative probability of virological suppression [VS] (HIV-1 RNA< 40 cp/mL), low-level HIV-1 DNA [LL-HIVDNA] (HIV-1 DNA < 200 copies/106PBMC), and CD4/CD8 ratio ≥1 were estimated using Kaplan–Meier curves. Factors associated with the achievement of VS, LL-HIVDNA, and CD4/CD8 ≥ 1 were assessed by a Cox regression model. We enrolled 144 patients (95.8% male, median age 34 years): 110 (76%) started a four-drug-based therapy, and 34 (24%) a three-drug regimen. Both treatment groups showed a comparable high probability of achieving VS and a similar probability of reaching LL-HIVDNA and a CD4/CD8 ratio ≥1 after 48 weeks from ART initiation. Higher baseline HIV-1 RNA and HIV-1 DNA levels lowered the chance of VS, whereas a better preserved immunocompetence increased that chance. Not statistically significant factors associated with LL-HIVDNA achievement were found, whereas a higher baseline CD4/CD8 ratio predicted the achievement of immune recovery. In PHI patients, the rapid initiation of either an intensified four-drug or a standard three-drug INSTI-based regimen showed comparable responses in terms of VS, viral reservoir size, and immunological recovery.

Platelet adhesion to the sub-endothelial matrix and damaged endothelium occurs through a multi-step process mediated in the initial phase by glycoprotein Ib binding to von Willebrand factor (vWF), which leads to the subsequent formation of a platelet plug. The plant-derived ω-3 fatty acid α-linolenic acid is an abundant alternative to fish-derived n-3 fatty acids and has anti-inflammatory and antithrombotic properties. In this study, we investigated the impact of α-linolenic acid on human platelet binding to vWF under high-shear flow conditions (mimicking blood flow in stenosed arteries). Pre-incubation of fresh human blood from healthy donors with α-linolenic acid at dietary relevant concentrations reduced platelet binding and rolling on vWF-coated microchannels at a shear rate of 100 dyn/cm2. Depletion of membrane cholesterol by incubation of platelet-rich plasma with methyl-β cyclodextrin abrogated platelet rolling on vWF. Analysis of glycoprotein Ib by applying cryo-electron tomography to intact platelets revealed local clusters of glycoprotein Ib complexes upon exposure to shear force: the formation of these complexes could be prevented by treatment with α-linolenic acid. This study provides novel findings on the rapid local rearrangement of glycoprotein Ib complexes in response to high-shear flow and highlights the mechanism of in vitro inhibition of platelet binding to and rolling on vWF by α-linolenic acid.