Incorporation of oxygen into the succinate co-product of iron(II) and 2-oxoglutarate dependent oxygenases from bacteria, plants and humans.

The ferrous iron and 2-oxoglutarate (2OG) dependent oxygenases catalyse two electron oxidation reactions by coupling the oxidation of substrate to the oxidative decarboxylation of 2OG, giving succinate and carbon dioxide coproducts. The evidence available on the level of incorporation of one atom from dioxygen into succinate is inconclusive. Here, we demonstrate that five members of the 2OG oxygenase family, AlkB from&nbsp;Escherichia coli, anthocyanidin synthase and flavonol synthase from&nbsp;Arabidopsis thaliana, and prolyl hydroxylase domain enzyme 2 and factor inhibiting hypoxia-inducible factor-1 from&nbsp;Homo sapiens&nbsp;all incorporate a single oxygen atom, almost exclusively derived from dioxygen, into the succinate co-product.<br /

Effect of multivitamin and multimineral supplementation on cognitive function in men and women aged 65 years and over : a randomised controlled trial

Background: Observational studies have frequently reported an association between cognitive function and nutrition in later life but randomised trials of B vitamins and antioxidant supplements have mostly found no beneficial effect. We examined the effect of daily supplementation with 11 vitamins and 5 minerals on cognitive function in older adults to assess the possibility that this could help to prevent cognitive decline. Methods: The study was carried out as part of a randomised double blind placebo controlled trial of micronutrient supplementation based in six primary care health centres in North East Scotland. 910 men and women aged 65 years and over living in the community were recruited and randomised: 456 to active treatment and 454 to placebo. The active treatment consisted of a single tablet containing eleven vitamins and five minerals in amounts ranging from 50–210 % of the UK Reference Nutrient Intake or matching placebo tablet taken daily for 12 months. Digit span forward and verbal fluency tests, which assess immediate memory and executive functioning respectively, were conducted at the start and end of the intervention period. Risk of micronutrient deficiency at baseline was assessed by a simple risk questionnaire. Results: For digit span forward there was no evidence of an effect of supplements in all participants or in sub-groups defined by age or risk of deficiency. For verbal fluency there was no evidence of a beneficial effect in the whole study population but there was weak evidence for a beneficial effect of supplementation in the two pre-specified subgroups: in those aged 75 years and over (n 290; mean difference between supplemented and placebo groups 2.8 (95% CI -0.6, 6.2) units) and in those at increased risk of micronutrient deficiency assessed by the risk questionnaire (n 260; mean difference between supplemented and placebo groups 2.5 (95% CI -1.0, 6.1) units). Conclusion: The results provide no evidence for a beneficial effect of daily multivitamin and multimineral supplements on these domains of cognitive function in community-living people over 65 years. However, the possibility of beneficial effects in older people and those at greater risk of nutritional deficiency deserves further attention.Peer reviewedPublisher PD

Multi-level, cross-sectional study of workplace social capital and smoking among Japanese employees

<p>Abstract</p> <p>Background</p> <p>Social capital is hypothesized to be relevant to health promotion, and the association between community social capital and cigarette smoking has been examined. Individual-level social capital has been found to be associated with smoking cessation, but evidence remains sparse on the contextual effect of social capital and smoking. Further, evidence remains sparse on the association between smoking and social capital in the workplace, where people are spending an increasing portion of their daily lives. We examined the association between workplace social capital and smoking status among Japanese private sector employees.</p> <p>Methods</p> <p>We employed a two-stage stratified random sampling procedure. Of the total of 1,800 subjects in 60 companies, 1,171 (men/women; 834/337) employees (65.1%) were identified from 46 companies in Okayama in 2007. Workplace social capital was assessed in two dimensions; trust and reciprocity. Company-level social capital was based on inquiring about employee perceptions of trust and reciprocity among co-workers, and then aggregating their responses in order to calculate the proportion of workers reporting mistrust and lack of reciprocity. Multilevel logistic regression analysis was conducted using Markov Chain Monte Carlo methods to explore whether individual- and company-level social capital was associated with smoking. Odds ratios (ORs) and 95% credible intervals (CIs) for current smoking were obtained.</p> <p>Results</p> <p>Overall, 33.3% of the subjects smoked currently. There was no relationship between individual-level mistrust of others and smoking status. By contrast, one-standard deviation change in company-level mistrust was associated with higher odds of smoking (OR: 1.25, 95% CI: 1.06-1.46) even after controlling for individual-level mistrust, sex, age, occupation, educational attainment, alcohol use, physical activity, body mass index, and chronic diseases. No clear associations were found between lack of reciprocity and smoking both at the individual- and company-level.</p> <p>Conclusions</p> <p>Company-level mistrust is associated with higher likelihood of smoking among Japanese employees, while individual perceptions of mistrust were not associated. The link between lack of reciprocity and smoking was not supported either at the individual- or company-level. Further studies are warranted to examine the possible link between company-level trust and smoking cessation in the Japanese workplace.</p

Dimethyl fumarate in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial

Dimethyl fumarate (DMF) inhibits inflammasome-mediated inflammation and has been proposed as a treatment for patients hospitalised with COVID-19. This randomised, controlled, open-label platform trial (Randomised Evaluation of COVID-19 Therapy [RECOVERY]), is assessing multiple treatments in patients hospitalised for COVID-19 (NCT04381936, ISRCTN50189673). In this assessment of DMF performed at 27 UK hospitals, adults were randomly allocated (1:1) to either usual standard of care alone or usual standard of care plus DMF. The primary outcome was clinical status on day 5 measured on a seven-point ordinal scale. Secondary outcomes were time to sustained improvement in clinical status, time to discharge, day 5 peripheral blood oxygenation, day 5 C-reactive protein, and improvement in day 10 clinical status. Between 2 March 2021 and 18 November 2021, 713 patients were enroled in the DMF evaluation, of whom 356 were randomly allocated to receive usual care plus DMF, and 357 to usual care alone. 95% of patients received corticosteroids as part of routine care. There was no evidence of a beneficial effect of DMF on clinical status at day 5 (common odds ratio of unfavourable outcome 1.12; 95% CI 0.86-1.47; p = 0.40). There was no significant effect of DMF on any secondary outcome

Multiorgan MRI findings after hospitalisation with COVID-19 in the UK (C-MORE): a prospective, multicentre, observational cohort study

Introduction: The multiorgan impact of moderate to severe coronavirus infections in the post-acute phase is still poorly understood. We aimed to evaluate the excess burden of multiorgan abnormalities after hospitalisation with COVID-19, evaluate their determinants, and explore associations with patient-related outcome measures. Methods: In a prospective, UK-wide, multicentre MRI follow-up study (C-MORE), adults (aged ≥18 years) discharged from hospital following COVID-19 who were included in Tier 2 of the Post-hospitalisation COVID-19 study (PHOSP-COVID) and contemporary controls with no evidence of previous COVID-19 (SARS-CoV-2 nucleocapsid antibody negative) underwent multiorgan MRI (lungs, heart, brain, liver, and kidneys) with quantitative and qualitative assessment of images and clinical adjudication when relevant. Individuals with end-stage renal failure or contraindications to MRI were excluded. Participants also underwent detailed recording of symptoms, and physiological and biochemical tests. The primary outcome was the excess burden of multiorgan abnormalities (two or more organs) relative to controls, with further adjustments for potential confounders. The C-MORE study is ongoing and is registered with ClinicalTrials.gov, NCT04510025. Findings: Of 2710 participants in Tier 2 of PHOSP-COVID, 531 were recruited across 13 UK-wide C-MORE sites. After exclusions, 259 C-MORE patients (mean age 57 years [SD 12]; 158 [61%] male and 101 [39%] female) who were discharged from hospital with PCR-confirmed or clinically diagnosed COVID-19 between March 1, 2020, and Nov 1, 2021, and 52 non-COVID-19 controls from the community (mean age 49 years [SD 14]; 30 [58%] male and 22 [42%] female) were included in the analysis. Patients were assessed at a median of 5·0 months (IQR 4·2–6·3) after hospital discharge. Compared with non-COVID-19 controls, patients were older, living with more obesity, and had more comorbidities. Multiorgan abnormalities on MRI were more frequent in patients than in controls (157 [61%] of 259 vs 14 [27%] of 52; p&lt;0·0001) and independently associated with COVID-19 status (odds ratio [OR] 2·9 [95% CI 1·5–5·8]; padjusted=0·0023) after adjusting for relevant confounders. Compared with controls, patients were more likely to have MRI evidence of lung abnormalities (p=0·0001; parenchymal abnormalities), brain abnormalities (p&lt;0·0001; more white matter hyperintensities and regional brain volume reduction), and kidney abnormalities (p=0·014; lower medullary T1 and loss of corticomedullary differentiation), whereas cardiac and liver MRI abnormalities were similar between patients and controls. Patients with multiorgan abnormalities were older (difference in mean age 7 years [95% CI 4–10]; mean age of 59·8 years [SD 11·7] with multiorgan abnormalities vs mean age of 52·8 years [11·9] without multiorgan abnormalities; p&lt;0·0001), more likely to have three or more comorbidities (OR 2·47 [1·32–4·82]; padjusted=0·0059), and more likely to have a more severe acute infection (acute CRP &gt;5mg/L, OR 3·55 [1·23–11·88]; padjusted=0·025) than those without multiorgan abnormalities. Presence of lung MRI abnormalities was associated with a two-fold higher risk of chest tightness, and multiorgan MRI abnormalities were associated with severe and very severe persistent physical and mental health impairment (PHOSP-COVID symptom clusters) after hospitalisation. Interpretation: After hospitalisation for COVID-19, people are at risk of multiorgan abnormalities in the medium term. Our findings emphasise the need for proactive multidisciplinary care pathways, with the potential for imaging to guide surveillance frequency and therapeutic stratification

Dimethyl fumarate in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial

Dimethyl fumarate (DMF) inhibits inflammasome-mediated inflammation and has been proposed as a treatment for patients hospitalised with COVID-19. This randomised, controlled, open-label platform trial (Randomised Evaluation of COVID-19 Therapy [RECOVERY]), is assessing multiple treatments in patients hospitalised for COVID-19 (NCT04381936, ISRCTN50189673). In this assessment of DMF performed at 27 UK hospitals, adults were randomly allocated (1:1) to either usual standard of care alone or usual standard of care plus DMF. The primary outcome was clinical status on day 5 measured on a seven-point ordinal scale. Secondary outcomes were time to sustained improvement in clinical status, time to discharge, day 5 peripheral blood oxygenation, day 5 C-reactive protein, and improvement in day 10 clinical status. Between 2 March 2021 and 18 November 2021, 713 patients were enroled in the DMF evaluation, of whom 356 were randomly allocated to receive usual care plus DMF, and 357 to usual care alone. 95% of patients received corticosteroids as part of routine care. There was no evidence of a beneficial effect of DMF on clinical status at day 5 (common odds ratio of unfavourable outcome 1.12; 95% CI 0.86-1.47; p = 0.40). There was no significant effect of DMF on any secondary outcome

Hydrogen Bonding and Electron Transfer between Dimetal Paddlewheel Compounds Containing Pendant 2-Pyridone Functional Groups

The compounds M2(TiPB)3(HDON) (TiPB = 2,4,6-triisopropylbenzoic acid; H2DON = 2,7-dihdroxy-1,8-napthyridine; M = Mo (1a) or W (1b)) and Mo2(TiPB)2(O2CCH2Cl)(HDON) (1c) which contain a pendant 2-pyridone functional group have been prepared. These compounds are capable of forming self-complementary hydrogen bonds, resulting in the formation of “dimers of dimers” ([1a–c]2) in CH2Cl2 solutions. Electrochemical studies reveal two successive one-electron redox processes for [1a–c]2 in CH2Cl2 solutions that correspond to successive oxidations of the dimetal core, indicating stabilization of the mixed-valence state. Only small changes in the value of Kc are observed upon changing the ancillary ligand or metal, implying that proton coupled mixed valency is responsible for the stabilization. Dimethylsulfoxide (DMSO) disrupts the hydrogen bonding interactions in these compounds, and a single oxidation process is observed in DMSO which shifts to lower potential as the number of HDON ligands increases. Further substitution of carboxylate ligands with HDON leads to the formation of Mo2(TiPB)2(HDON)2 (2) and Mo2(HDON)4 (3), which adopt trans-1,1 and cis-2,2 regioisomers in the solid-state. 1H NMR spectroscopy indicates that there are at least two regioisomers present in solution for both compounds. The lowest energy transition in the electronic absorption spectra of these compounds corresponds to a M2-δ → HDON-π* transition. The electrochemical, spectroscopic and structural results were rationalized with the aid of density functional theory (DFT) calculations