Unravelling mechanistic insights in the platinum-catalysed dihydroalkoxylation of allenes

The mechanism of the platinum-catalysed dihydroalkoxylation of allenes to give acetals has been studied experimentally and by computational methods. Our findings further explain divergent reactivity encountered for platinum- and gold-vinyl intermediates after the first nucleophilic attack onto the coordinated allene, as well as provide new details on the catalytic cycle with platinum, uncovering enol ethers as resting states of the catalytic cycle, a S(E)Ox process via Pt(V)-H as the final protodemetallation step after the second nucleophilic attack when neutral platinum complexes are used, and a fast acid promoted addition of methanol to enol ethers when cationic platinum complexes are employed

The EPICTER score: a bedside and easy tool to predict mortality at 6 months in acute heart failure

Aims: Estimating the prognosis in heart failure (HF) is important to decide when to refer to palliative care (PC). Our objective was to develop a tool to identify the probability of death within 6 months in patients admitted with acute HF. Methods and results: A total of 2848 patients admitted with HF in 74 Spanish hospitals were prospectively included and followed for 6 months. Each factor independently associated with death in the derivation cohort (60% of the sample) was assigned a prognostic weight, and a risk score was calculated. The accuracy of the score was verified in the validation cohort. The characteristics of the population were as follows: advanced age (mean 78 years), equal representation of men and women, significant comorbidity, and predominance of HF with preserved ejection fraction. During follow-up, 753 patients (26%) died. Seven independent predictors of mortality were identified: age, chronic obstructive pulmonary disease, cognitive impairment, New York Heart Association class III-IV, chronic kidney disease, estimated survival of the patient less than 6 months, and acceptance of a palliative approach by the family or the patient. The area under the ROC curve for 6 month death was 0.74 for the derivation and 0.68 for the validation cohort. The model showed good calibration (Hosmer and Lemeshow test, P value 0.11). The 6 month death rates in the score groups ranged from 6% (low risk) to 54% (very high risk). Conclusions: The EPICTER score, developed from a prospective and unselected cohort, is a bedside and easy-to-use tool that could help to identify high-risk patients requiring PC

The discovery BPD (D-BPD) program: Study protocol of a prospective translational multicenter collaborative study to investigate determinants of chronic lung disease in very low birth weight infants

Background: Premature birth is a growing and serious public health problem affecting more than one of every ten infants worldwide. Bronchopulmonary dysplasia (BPD) is the most common neonatal morbidity associated with prematurity and infants with BPD suffer from increased incidence of respiratory infections, asthma, other forms of chronic lung illness, and death (Day and Ryan, Pediatr Res 81: 210-213, 2017; Isayama et la., JAMA Pediatr 171:271-279, 2017). BPD is now understood as a longitudinal disease process influenced by the intrauterine environment during gestation and modulated by gene-environment interactions throughout the neonatal and early childhood periods. Despite of this concept, there remains a paucity of multidisciplinary team-based approaches dedicated to the comprehensive study of this complex disease. Methods: The Discovery BPD (D-BPD) Program involves a cohort of infants < 1,250 g at birth prospectively followed until 6 years of age. The program integrates analysis of detailed clinical data by machine learning, genetic susceptibility and molecular translation studies. Discussion: The current gap in understanding BPD as a complex multi-trait spectrum of different disease endotypes will be addressed by a bedside-to-bench and bench-to-bedside approach in the D-BPD program. The D-BPD will provide enhanced understanding of mechanisms, evolution and consequences of lung diseases in preterm infants. The D-BPD program represents a unique opportunity to combine the expertise of biologists, neonatologists, pulmonologists, geneticists and biostatisticians to examine the disease process from multiple perspectives with a singular goal of improving outcomes of premature infants. Trial registration: Does not apply for this study.Fil: Ofman, Gaston. University of Alabama at Birmingahm; Estados UnidosFil: Caballero, Mauricio Tomás. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Álvarez Paggi, Damián Jorge. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Marzec, Jacqui. National Institute of Environmental Health Sciences; Estados UnidosFil: Nowogrodzki, Florencia. No especifíca;Fil: Cho, Hye Youn. National Institute of Environmental Health Sciences; Estados UnidosFil: Sorgetti, Mariana. No especifíca;Fil: Colantonio, Guillermo. No especifíca;Fil: Bianchi, Alejandra. No especifíca;Fil: Prudent, Luis M.. Fundación para la Salud Materno Infantil; ArgentinaFil: Vain, Néstor Eduardo. Fundación para la Salud Materno Infantil; Argentina. Sanatorio de la Trinidad Palermo.; ArgentinaFil: Mariani, Gonzalo Luis. Hospital Italiano; ArgentinaFil: Digregorio, Jorge. Sanatorio de la Trinidad Palermo.; ArgentinaFil: Lopez Turconi, Elba. No especifíca;Fil: Osio, Cristina. Sanatorio "Otamendi y Miroli S. A."; ArgentinaFil: Galletti, Maria Fernanda. Hospital Italiano; ArgentinaFil: Quiros, Mariangeles. Clinica y Maternidad Suizo Argentina; ArgentinaFil: Brum, Andrea. Sanatorio de la Trinidad Palermo.; ArgentinaFil: Lopez Garcia, Santiago. No especifíca;Fil: Garcia, Silvia. Sanatorio "Otamendi y Miroli S. A."; ArgentinaFil: Bell, Douglas. National Institute of Environmental Health Sciences; Estados UnidosFil: Jones, Marcus H.. Pontificia Universidade Católica do Rio Grande do Sul; BrasilFil: Tipple, Trent E.. University of Alabama at Birmingahm; Estados UnidosFil: Kleeberger, Steven R.. National Institute of Environmental Health Sciences; Estados UnidosFil: Polack, Fernando Pedro. University of Alabama at Birmingahm; Estados Unido

Cabbage and fermented vegetables : From death rate heterogeneity in countries to candidates for mitigation strategies of severe COVID-19

Large differences in COVID-19 death rates exist between countries and between regions of the same country. Some very low death rate countries such as Eastern Asia, Central Europe, or the Balkans have a common feature of eating large quantities of fermented foods. Although biases exist when examining ecological studies, fermented vegetables or cabbage have been associated with low death rates in European countries. SARS-CoV-2 binds to its receptor, the angiotensin-converting enzyme 2 (ACE2). As a result of SARS-CoV-2 binding, ACE2 downregulation enhances the angiotensin II receptor type 1 (AT(1)R) axis associated with oxidative stress. This leads to insulin resistance as well as lung and endothelial damage, two severe outcomes of COVID-19. The nuclear factor (erythroid-derived 2)-like 2 (Nrf2) is the most potent antioxidant in humans and can block in particular the AT(1)R axis. Cabbage contains precursors of sulforaphane, the most active natural activator of Nrf2. Fermented vegetables contain many lactobacilli, which are also potent Nrf2 activators. Three examples are: kimchi in Korea, westernized foods, and the slum paradox. It is proposed that fermented cabbage is a proof-of-concept of dietary manipulations that may enhance Nrf2-associated antioxidant effects, helpful in mitigating COVID-19 severity.Peer reviewe

Nrf2-interacting nutrients and COVID-19 : time for research to develop adaptation strategies

There are large between- and within-country variations in COVID-19 death rates. Some very low death rate settings such as Eastern Asia, Central Europe, the Balkans and Africa have a common feature of eating large quantities of fermented foods whose intake is associated with the activation of the Nrf2 (Nuclear factor (erythroid-derived 2)-like 2) anti-oxidant transcription factor. There are many Nrf2-interacting nutrients (berberine, curcumin, epigallocatechin gallate, genistein, quercetin, resveratrol, sulforaphane) that all act similarly to reduce insulin resistance, endothelial damage, lung injury and cytokine storm. They also act on the same mechanisms (mTOR: Mammalian target of rapamycin, PPAR gamma:Peroxisome proliferator-activated receptor, NF kappa B: Nuclear factor kappa B, ERK: Extracellular signal-regulated kinases and eIF2 alpha:Elongation initiation factor 2 alpha). They may as a result be important in mitigating the severity of COVID-19, acting through the endoplasmic reticulum stress or ACE-Angiotensin-II-AT(1)R axis (AT(1)R) pathway. Many Nrf2-interacting nutrients are also interacting with TRPA1 and/or TRPV1. Interestingly, geographical areas with very low COVID-19 mortality are those with the lowest prevalence of obesity (Sub-Saharan Africa and Asia). It is tempting to propose that Nrf2-interacting foods and nutrients can re-balance insulin resistance and have a significant effect on COVID-19 severity. It is therefore possible that the intake of these foods may restore an optimal natural balance for the Nrf2 pathway and may be of interest in the mitigation of COVID-19 severity

Goodbye Hartmann trial: a prospective, international, multicenter, observational study on the current use of a surgical procedure developed a century ago

Background: Literature suggests colonic resection and primary anastomosis (RPA) instead of Hartmann's procedure (HP) for the treatment of left-sided colonic emergencies. We aim to evaluate the surgical options globally used to treat patients with acute left-sided colonic emergencies and the factors that leading to the choice of treatment, comparing HP and RPA. Methods: This is a prospective, international, multicenter, observational study registered on ClinicalTrials.gov. A total 1215 patients with left-sided colonic emergencies who required surgery were included from 204 centers during the period of March 1, 2020, to May 31, 2020. with a 1-year follow-up. Results: 564 patients (43.1%) were females. The mean age was 65.9 ± 15.6&nbsp;years. HP was performed in 697 (57.3%) patients and RPA in 384 (31.6%) cases. Complicated acute diverticulitis was the most common cause of left-sided colonic emergencies (40.2%), followed by colorectal malignancy (36.6%). Severe complications (Clavien-Dindo ≥ 3b) were higher in the HP group (P &lt; 0.001). 30-day mortality was higher in HP patients (13.7%), especially in case of bowel perforation and diffused peritonitis. 1-year follow-up showed no differences on ostomy reversal rate between HP and RPA. (P = 0.127). A backward likelihood logistic regression model showed that RPA was preferred in younger patients, having low ASA score (≤ 3), in case of large bowel obstruction, absence of colonic ischemia, longer time from admission to surgery, operating early at the day working hours, by a surgeon who performed more than 50 colorectal resections. Conclusions: After 100&nbsp;years since the first Hartmann's procedure, HP remains the most common treatment for left-sided colorectal emergencies. Treatment's choice depends on patient characteristics, the time of surgery and the experience of the surgeon. RPA should be considered as the gold standard for surgery, with HP being an exception

Genetic mechanisms of critical illness in COVID-19.

Host-mediated lung inflammation is present1, and drives mortality2, in the critical illness caused by coronavirus disease 2019 (COVID-19). Host genetic variants associated with critical illness may identify mechanistic targets for therapeutic development3. Here we report the results of the GenOMICC (Genetics Of Mortality In Critical Care) genome-wide association study in 2,244 critically ill patients with COVID-19 from 208 UK intensive care units. We have identified and replicated the following new genome-wide significant associations: on chromosome 12q24.13 (rs10735079, P = 1.65 × 10-8) in a gene cluster that encodes antiviral restriction enzyme activators (OAS1, OAS2 and OAS3); on chromosome 19p13.2 (rs74956615, P = 2.3 × 10-8) near the gene that encodes tyrosine kinase 2 (TYK2); on chromosome 19p13.3 (rs2109069, P = 3.98 ×  10-12) within the gene that encodes dipeptidyl peptidase 9 (DPP9); and on chromosome 21q22.1 (rs2236757, P = 4.99 × 10-8) in the interferon receptor gene IFNAR2. We identified potential targets for repurposing of licensed medications: using Mendelian randomization, we found evidence that low expression of IFNAR2, or high expression of TYK2, are associated with life-threatening disease; and transcriptome-wide association in lung tissue revealed that high expression of the monocyte-macrophage chemotactic receptor CCR2 is associated with severe COVID-19. Our results identify robust genetic signals relating to key host antiviral defence mechanisms and mediators of inflammatory organ damage in COVID-19. Both mechanisms may be amenable to targeted treatment with existing drugs. However, large-scale randomized clinical trials will be essential before any change to clinical practice

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 &lt; 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

Unravelling mechanistic insights in the platinum-catalysed dihydroalkoxylation of allenes

The mechanism of the platinum-catalysed dihydroalkoxylation of allenes to give acetals has been studied experimentally and by computational methods. Our findings further explain divergent reactivity encountered for platinum- and gold-vinyl intermediates after the first nucleophilic attack onto the coordinated allene, as well as provide new details on the catalytic cycle with platinum, uncovering enol ethers as resting states of the catalytic cycle, a S(E)Ox process via Pt(V)-H as the final protodemetallation step after the second nucleophilic attack when neutral platinum complexes are used, and a fast acid promoted addition of methanol to enol ethers when cationic platinum complexes are employed