COVID-19 symptoms at hospital admission vary with age and sex: results from the ISARIC prospective multinational observational study

Background: The ISARIC prospective multinational observational study is the largest cohort of hospitalized patients with COVID-19. We present relationships of age, sex, and nationality to presenting symptoms. Methods: International, prospective observational study of 60 109 hospitalized symptomatic patients with laboratory-confirmed COVID-19 recruited from 43 countries between 30 January and 3 August 2020. Logistic regression was performed to evaluate relationships of age and sex to published COVID-19 case definitions and the most commonly reported symptoms. Results: ‘Typical’ symptoms of fever (69%), cough (68%) and shortness of breath (66%) were the most commonly reported. 92% of patients experienced at least one of these. Prevalence of typical symptoms was greatest in 30- to 60-year-olds (respectively 80, 79, 69%; at least one 95%). They were reported less frequently in children (≤ 18 years: 69, 48, 23; 85%), older adults (≥ 70 years: 61, 62, 65; 90%), and women (66, 66, 64; 90%; vs. men 71, 70, 67; 93%, each P < 0.001). The most common atypical presentations under 60 years of age were nausea and vomiting and abdominal pain, and over 60 years was confusion. Regression models showed significant differences in symptoms with sex, age and country. Interpretation: This international collaboration has allowed us to report reliable symptom data from the largest cohort of patients admitted to hospital with COVID-19. Adults over 60 and children admitted to hospital with COVID-19 are less likely to present with typical symptoms. Nausea and vomiting are common atypical presentations under 30 years. Confusion is a frequent atypical presentation of COVID-19 in adults over 60 years. Women are less likely to experience typical symptoms than men

Preventable or potentially inappropriate psychotropics and adverse health outcomes in older adults: systematic review and meta-analysis

International audienceObjective : To systematically review and quantitatively synthetize evidence on the use of PIPs linked to adverse health outcomes in older adults.Methods : A Medline, Embase1 and Opengrey libraries search was conducted from 2004 to February 2021, using the PICO model: older people, psychotropic drugs, inappropriate prescribing, and adverse drug events. Fixed-effects and random-effects meta-analysis were performed from 3 eligible studies using an inverse-variance method.Results : Of the 1943 originally identified abstracts, 106 met the inclusion criteria and 7 studies were included in this review. All were of good quality. The number of participants ranged from 318 to 383,150 older adults (54.5–74.4% women). Associations were found between PIPs use and decreased personal care activities of daily living (ADL), unplanned hospitalizations, falls and mortality. In the pooled analysis, association with falls was confirmed (1.23 [95%CI: 1.15;1.32]).Conclusions : Participants of 65 years and older treated with PIPs were more at risk of adverse health outcomes than those using no PIPs, including greater risks of falls, functional disabilities, unplanned hospitalizations, and mortality. Results of the present systematic review and meta-analysis provide additional evidence for an appropriate and safe use of psychotropics in older adults

Non-photoinduced biological properties of Verteporfin

International audienc

Molecular Features of the YAP Inhibitor Verteporfin: Synthesis of Hexasubstituted Dipyrrins as Potential Inhibitors of YAP/TAZ, the Downstream Effectors of the Hippo Pathway

International audiencePorphyrin derivatives, in particular verteporfin (VP), a photosensitizer initially designed for cancer therapy, have been identified as inhibitors of the YAP–TEAD interaction and transcriptional activity. Herein we report the efficient convergent synthesis of the dipyrrin half of protoporphyrin IX dimethyl ester (PPIX‐DME), in which the sensitive vinyl group was created at the final stage by a dehydroiodination reaction. Two other dipyrrin derivatives were synthesized, including dipyrrin 19 [(Z)‐2‐((3,5‐dimethyl‐4‐vinyl‐2H‐pyrrol‐2‐ylidene)methyl)‐3,5‐dimethyl‐4‐vinyl‐1H‐pyrrole], containing two vinyl groups. We found that VP and dipyrrin 19 showed significant inhibitory effects on TEAD transcriptional activity in MDA‐MB‐231 human breast cancer cells, whereas other compounds did not show significant changes. In addition, we observed a marked decrease in both YAP and TAZ levels following VP treatment, whereas dipyrrin 19 treatment primarily decreased the levels of YAP and receptor kinase AXL, a downstream target of YAP. Together, our data suggest that, due to their chemical structures, porphyrin‐ and dipyrrin‐related derivatives can directly target YAP and/or TAZ proteins and inhibit TEAD transcriptional activity

Vitamin D Supplementation Associated to Better Survival in Hospitalized Frail Elderly COVID-19 Patients: The GERIA-COVID Quasi-Experimental Study

Background. The objective of this quasi-experimental study was to determine whether bolus vitamin D supplementation taken either regularly over the preceding year or after the diagnosis of COVID-19 was effective in improving survival among hospitalized frail elderly COVID-19 patients. Methods. Seventy-seven patients consecutively hospitalized for COVID-19 in a geriatric unit were included. Intervention groups were participants regularly supplemented with vitamin D over the preceding year (Group 1), and those supplemented with vitamin D after COVID-19 diagnosis (Group 2). The comparator group involved participants having received no vitamin D supplements (Group 3). Outcomes were 14-day mortality and highest (worst) score on the ordinal scale for clinical improvement (OSCI) measured during COVID-19 acute phase. Potential confounders were age, gender, functional abilities, undernutrition, cancer, hypertension, cardiomyopathy, glycated hemoglobin, number of acute health issues at admission, hospital use of antibiotics, corticosteroids, and pharmacological treatments of respiratory disorders. Results. The three groups (n = 77; mean ± SD, 88 ± 5 years; 49% women) were similar at baseline (except for woman proportion, p = 0.02), as were the treatments used for COVID-19. In Group 1 (n = 29), 93.1% of COVID-19 participants survived at day 14, compared to 81.2% survivors in Group 2 (n = 16) (p = 0.33) and 68.7% survivors in Group 3 (n = 32) (p = 0.02). While considering Group 3 as reference (hazard ratio (HR) = 1), the fully-adjusted HR for 14-day mortality was HR = 0.07 (p = 0.017) for Group 1 and HR = 0.37 (p = 0.28) for Group 2. Group 1 had longer survival time than Group 3 (log-rank p = 0.015), although there was no difference between Groups 2 and 3 (log-rank p = 0.32). Group 1, but not Group 2 (p = 0.40), was associated with lower risk of OSCI score ≥5 compared to Group 3 (odds ratio = 0.08, p = 0.03). Conclusions. Regular bolus vitamin D supplementation was associated with less severe COVID-19 and better survival in frail elderly

Vitamin D Supplementation Associated to Better Survival in Hospitalized Frail Elderly COVID-19 Patients: The GERIA-COVID Quasi-Experimental Study

International audienceBackground. The objective of this quasi-experimental study was to determine whether bolus vitamin D supplementation taken either regularly over the preceding year or after the diagnosis of COVID-19 was effective in improving survival among hospitalized frail elderly COVID-19 patients. Methods. Seventy-seven patients consecutively hospitalized for COVID-19 in a geriatric unit were included. Intervention groups were participants regularly supplemented with vitamin D over the preceding year (Group 1), and those supplemented with vitamin D after COVID-19 diagnosis (Group 2). The comparator group involved participants having received no vitamin D supplements (Group 3). Outcomes were 14-day mortality and highest (worst) score on the ordinal scale for clinical improvement (OSCI) measured during COVID-19 acute phase. Potential confounders were age, gender, functional abilities, undernutrition, cancer, hypertension, cardiomyopathy, glycated hemoglobin, number of acute health issues at admission, hospital use of antibiotics, corticosteroids, and pharmacological treatments of respiratory disorders. Results. The three groups (n = 77; mean ± SD, 88 ± 5 years; 49% women) were similar at baseline (except for woman proportion, p = 0.02), as were the treatments used for COVID-19. In Group 1 (n = 29), 93.1% of COVID-19 participants survived at day 14, compared to 81.2% survivors in Group 2 (n = 16) (p = 0.33) and 68.7% survivors in Group 3 (n = 32) (p = 0.02). While considering Group 3 as reference (hazard ratio (HR) = 1), the fully-adjusted HR for 14-day mortality was HR = 0.07 (p = 0.017) for Group 1 and HR = 0.37 (p = 0.28) for Group 2. Group 1 had longer survival time than Group 3 (log-rank p = 0.015), although there was no difference between Groups 2 and 3 (log-rank p = 0.32). Group 1, but not Group 2 (p = 0.40), was associated with lower risk of OSCI score ≥5 compared to Group 3 (odds ratio = 0.08, p = 0.03). Conclusions. Regular bolus vitamin D supplementation was associated with less severe COVID-19 and better survival in frail elderly

Fatty acid isotopic fractionation in the diatom Chaetoceros muelleri

Carbon isotopic fractionation was studied during the development of the diatom Chaetoceros muelleri grown in batch culture with 13C-depleted CO2 addition. Cellular and growth parameters and isotopic composition of dissolved inorganic carbon and particulate organic carbon were monitored every two days, while the content and isotopic composition of individual fatty acid in polar lipid and neutral lipid were measured on the 5th day (end of exponential phase), 10th and 14th days (stationary phase). Continuous addition of petrochemical CO2 to the algae led to a rapid and strong modification of dissolved inorganic carbon isotopic composition with cascading effects on particulate organic carbon and fatty acid isotopic compositions. Carbon isotope fractionation in Chaetoceros muelleri ranged from 17‰ to 25‰ and changed according to culture ages. Isotopic fractionation into fatty acids, overall, was similar between polar and neutral lipids, and was systematically higher than in particulate organic carbon. At the end of the exponential growth phase, the isotopic composition of individual fatty acids varied from −51.3‰ to −58.4‰. At this culture age, large differences in the isotopic compositions between fatty acids were observed. Polyunsaturated fatty acids such as 16:3n-4, 18:4n-3, and 20:5n-3 were more strongly 13C-depleted than other fatty acids such as 14:0, 16:0, 16:1n-7 or 18:1n-9. These results showed how isotopic effects occur during the desaturation and elongation phases. Such isotopic effects were also supported by the lower δ13C of averaged δ13C of saturated fatty acids and monounsaturated fatty acids as compared to those of polyunsaturated fatty acids. However, during the stationary phase, fatty acid isotopic compositions were less variable and closer to particulate organic carbon, while saturated and monounsaturated fatty acids were more depleted than polyunsaturated fatty acids. Our study underlined the importance of consideration of phytoplankton physiological status when conducting ecological and biogeochemical studies as they appeared to strongly control phytoplankton carbon isotopic composition

Different particle sources in a bivalve species of a coastal lagoon: evidence from stable isotopes, fatty acids, and compound-specific stable isotopes

International audienceThe trophic fate of various food sources is of central interest for ecologists, yet not well understood in coastal lagoon food webs. In this field study, fatty acids (FA), stable isotopes (SI), and compound-specific isotopic analysis (CSIA) on FA were used to investigate how diets from oceanic and local sources are retained in a bivalve species (Spondylus crassisquama; Lamarck 1819) along a transect in the Ojo de Liebre lagoon (BCS, Mexico). Results from SI and FA indicated the contribution of oceanic diatoms at the entrance of the lagoon, through 15N enrichment, and higher proportions of 16:1n-7 and 20:5n-3 in digestive glands. In the inner bay, higher abundance of 18-carbon FA (18:1n-9, 18:3n-3, 18:4n-3) suggested a higher contribution of microheterotrophs, including (dino)flagellates and ciliates, to the diet of this bivalve derived from local production. Significant spatial differences for the δ13C of FA highlighted changes in the origin of food sources. Indeed, a 13C depletion was observed in the δ13C of heterotrophic flagellates biomarkers in individuals from the innermost station, revealing that their origin in the diet of bivalves differs within the lagoon, highlighting the importance of local processes (sediment resuspension, remineralization) in the trophic functioning of the lagoon. The δ13C values of FA considered as diatoms biomarkers (16:1n-7 and 20:5n-3) were consistent, which suggests that diatoms assimilated have very similar origins throughout the lagoon. The complementary of the tracers used here allowed for a better understanding of the trophic functioning of this coastal lagoon submitted to oceanic influences

Fatty acid isotopic fractionation in the diatom Chaetoceros muelleri

International audienceCarbon isotopic fractionation was studied during the development of the diatom Chaetoceros muelleri grown in batch culture with 13C-depleted CO2 addition. Cellular and growth parameters and isotopic composition of dissolved inorganic carbon and particulate organic carbon were monitored every two days, while the content and isotopic composition of individual fatty acid in polar lipid and neutral lipid were measured on the 5th day (end of exponential phase), 10th and 14th days (stationary phase). Continuous addition of petrochemical CO2 to the algae led to a rapid and strong modification of dissolved inorganic carbon isotopic composition with cascading effects on particulate organic carbon and fatty acid isotopic compositions. Carbon isotope fractionation in Chaetoceros muelleri ranged from 17‰ to 25‰ and changed according to culture ages. Isotopic fractionation into fatty acids, overall, was similar between polar and neutral lipids, and was systematically higher than in particulate organic carbon. At the end of the exponential growth phase, the isotopic composition of individual fatty acids varied from −51.3‰ to −58.4‰. At this culture age, large differences in the isotopic compositions between fatty acids were observed. Polyunsaturated fatty acids such as 16:3n-4, 18:4n-3, and 20:5n-3 were more strongly 13C-depleted than other fatty acids such as 14:0, 16:0, 16:1n-7 or 18:1n-9. These results showed how isotopic effects occur during the desaturation and elongation phases. Such isotopic effects were also supported by the lower δ13C of averaged δ13C of saturated fatty acids and monounsaturated fatty acids as compared to those of polyunsaturated fatty acids. However, during the stationary phase, fatty acid isotopic compositions were less variable and closer to particulate organic carbon, while saturated and monounsaturated fatty acids were more depleted than polyunsaturated fatty acids. Our study underlined the importance of consideration of phytoplankton physiological status when conducting ecological and biogeochemical studies as they appeared to strongly control phytoplankton carbon isotopic composition

Toward the Discovery of a Novel Class of YAP–TEAD Interaction Inhibitors by Virtual Screening Approach Targeting YAP–TEAD Protein–Protein Interface

International audienceIntrinsically disordered protein YAP (yes-associated protein) interacts with TEADs transcriptional factors family (transcriptional enhancer associated domain) creating three interfaces. Interface 3, between the Ω-loop of YAP and a shallow pocket of TEAD was identified as the most important TEAD zone for YAP-TEAD interaction. Using the first X-ray structure of the hYAP 50-71-hTEAD1 209-426 complex (PDB 3KYS) published in 2010, a protein-protein interaction inhibitors-enriched library (175,000 chemical compounds) was screened against this hydrophobic pocket of TEAD. Four different chemical families have been identified and evaluated using biophysical techniques (thermal shift assay, microscale thermophoresis) and in cellulo assays (luciferase activity in transfected HEK293 cells, RTqPCR in MDA-MB231 cells). A first promising hit with micromolar inhibition in the luciferase gene reporter assay was discovered. This hit also decreased mRNA levels of TEAD target genes