Publications by authors named "Ana M Valdes"

186 Publications

Clinical and preclinical evidence for roles of soluble epoxide hydrolase in osteoarthritis knee pain.

Arthritis Rheumatol 2021 Oct 21. Epub 2021 Oct 21.

Pain Centre Versus Arthritis and NIHR Nottingham Biomedical Research Centre, School of Life Sciences, University of Nottingham, UK.

Objective: Chronic pain due to osteoarthritis (OA) is a major clinical problem, existing analgesics often have limited beneficial effects and/or adverse effects, necessitating the development of novel therapies. Epoxyeicosatrienoic acids (EETs) are endogenous anti-inflammatory mediators, rapidly metabolized by soluble epoxide hydrolase (sEH) to dihydroxyeicosatrienoic acids (DHETs). We hypothesized that sEH driven metabolism of the EETs to DHETs plays a critical role in chronic joint pain associated with OA and provides a new target for treatment.

Methods: Potential associations between chronic knee pain in people and single nucleotide polymorphisms (SNPs) in the gene encoding sEH and circulating levels of the EETs and DHETs were investigated. A surgically-induced murine model of OA was used to determine the effects of both acute and chronic selective inhibition of sEH by N-[1-(1-oxopropy)-4-piperidinyl]-N -(trifluoromethoxy)phenyl]urea (TPPU) on weight-bearing asymmetry, hind-paw withdrawal thresholds, joint histology, and circulating concentrations of the EETs and DHETs.

Results: In people with chronic knee pain, 3 pain measures were associated with SNPs of the sEH gene, EPHX2, and in two separate cohorts circulating levels of EETs and DHETs were also associated with 3 pain measures. In the murine OA model, systemic administration of TPPU both acutely and chronically reversed established pain behaviours and decreased circulating levels of 8,9-DHET and 14,15-DHET. The levels of the EETs were unchanged by TPPU administration.

Conclusion: Our novel findings support a role of sEH in OA pain and suggest that inhibition of sEH and protection of endogenous EETs from catabolism represents a potential new therapeutic target for OA pain.
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http://dx.doi.org/10.1002/art.42000DOI Listing
October 2021

Role of the gut microbiome in chronic diseases: a narrative review.

Eur J Clin Nutr 2021 Sep 28. Epub 2021 Sep 28.

Division of Rheumatology, Orthopaedics and Dermatology, School of Medicine, The University of Nottingham, Nottingham, UK.

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http://dx.doi.org/10.1038/s41430-021-00991-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8477631PMC
September 2021

Deciphering osteoarthritis genetics across 826,690 individuals from 9 populations.

Cell 2021 Sep 26;184(18):4784-4818.e17. Epub 2021 Aug 26.

Laboratory for Bone and Joint Diseases, RIKEN Center for Integrative Medical Sciences, Tokyo 108-8639, Japan; Department of Orthopedic Surgery, Shimane University, Shimane 693-8501, Japan.

Osteoarthritis affects over 300 million people worldwide. Here, we conduct a genome-wide association study meta-analysis across 826,690 individuals (177,517 with osteoarthritis) and identify 100 independently associated risk variants across 11 osteoarthritis phenotypes, 52 of which have not been associated with the disease before. We report thumb and spine osteoarthritis risk variants and identify differences in genetic effects between weight-bearing and non-weight-bearing joints. We identify sex-specific and early age-at-onset osteoarthritis risk loci. We integrate functional genomics data from primary patient tissues (including articular cartilage, subchondral bone, and osteophytic cartilage) and identify high-confidence effector genes. We provide evidence for genetic correlation with phenotypes related to pain, the main disease symptom, and identify likely causal genes linked to neuronal processes. Our results provide insights into key molecular players in disease processes and highlight attractive drug targets to accelerate translation.
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http://dx.doi.org/10.1016/j.cell.2021.07.038DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8459317PMC
September 2021

Two doses of the SARS-CoV-2 BNT162b2 vaccine enhance antibody responses to variants in individuals with prior SARS-CoV-2 infection.

Sci Transl Med 2021 09 5;13(609):eabj0847. Epub 2021 Aug 5.

NIHR Nottingham Biomedical Research Centre, Nottingham University Hospitals NHS Trust and University of Nottingham, Queen's Medical Centre, Derby Road, Nottingham NG7 2UH, UK.

[Figure: see text].
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http://dx.doi.org/10.1126/scitranslmed.abj0847DOI Listing
September 2021

Dietary Interventions Reduce Traditional and Novel Cardiovascular Risk Markers by Altering the Gut Microbiome and Their Metabolites.

Front Cardiovasc Med 2021 14;8:691564. Epub 2021 Jul 14.

School of Medicine, University of Nottingham, Nottingham, United Kingdom.

The current study investigates the role of diet in mediating the gut microbiome-cardiovascular association which has not yet been explored in humans. Using a two-arm dietary intervention study in healthy participants ( = 70), we assessed the effects of omega-3 and fibre supplementation on gut microbiome composition and short-chain fatty acid (SCFA) production. We then investigated how changes in gut microbiome composition correlated with changes in traditional cardiovascular risk factors (cholesterol, triglycerides, blood pressure), cytokines, and novel validated markers such as GlycA and ceramides, previously linked to CVD incidence and mortality. Both interventions resulted in significant drops in blood pressure, cholesterol, proinflammatory cytokines, GlycA and ceramides (all < 0.05). Decreases in the atherogenic low-density lipoprotein triglyceride fraction, in total serum cholesterol were correlated with increases in butyric acid-production [β(SE) = -0.58 (0.06), < 0.001; -0.53 (0.04), < 0.001] and nominally associated with increases in some butyrogenic bacteria. Drops in GlycA were linked to increases in [β(SE) = -0.32 (0.04), = 0.02] and other SCFAs including acetic acid [β(SE) = -0.28 (0.04), = 0.02] and propionic acid [β(SE) = -0.3 (0.04), = 0.02]. Additionally, we report for the first-time reductions in specific ceramide ratios that have been shown to predict CVD mortality and major adverse cardiovascular events such as d18:1/16:0, d18:0/24:0, and d18:1/24:1 which were associated with the reduction in the abundance in and increases in and and SCFAs (all < 0.05). Overall, these findings support the potential of using simple dietary interventions to alter validated biomarkers linked to cardiovascular risk via the gut microbiome composition and its metabolic functions.
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http://dx.doi.org/10.3389/fcvm.2021.691564DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8319029PMC
July 2021

Circulating Levels of the Short-Chain Fatty Acid Acetate Mediate the Effect of the Gut Microbiome on Visceral Fat.

Front Microbiol 2021 15;12:711359. Epub 2021 Jul 15.

Department of Twin Research and Genetic Epidemiology, King's College London, London, United Kingdom.

Background: Acetate is a short-chain fatty acid (SCFA) produced by gut bacteria, which has been implicated in cardio-metabolic health. Here we examine the relationships of circulating acetate levels with gut microbiome composition and diversity and with visceral fat in a large population-based cohort.

Results: Microbiome alpha-diversity was positively correlated with circulating acetate levels (Shannon, Beta [95%CI] = 0.12 [0.06, 0.18], = 0.002) after adjustment for covariates. Six serum acetate-associated bacterial genera were also identified, including positive correlations with , , , and and negative correlations were observed with and We also identified a correlation between visceral fat and serum acetate levels (Beta [95%CI] = -0.07 [-0.11, -0.04], = 2.8 × 10) and between visceral fat and (Beta [95%CI] = 0.076 [0.042, 0.11], = 1.44 × 10). Formal mediation analysis revealed that acetate mediates ∼10% of the total effect of on visceral fat. The taxonomic diversity showed that and comprise at least 18 and 9 species, respectively, including novel bacterial species. By predicting the functional capabilities, we found that spp. present pathways involved in acetate production and metabolism of vitamins B, whereas we identified pathways related to the biosynthesis of trimethylamine (TMA) and CDP-diacylglycerol in spp.

Conclusions: Our data indicates that gut microbiota composition and diversity may influence circulating acetate levels and that acetate might exert benefits on certain cardio-metabolic disease risk by decreasing visceral fat. may play an important role in host health by its production of vitamins B and SCFAs, whereas might have an opposing effect by influencing negatively the circulating levels of acetate and being involved in the biosynthesis of detrimental lipid compounds.
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http://dx.doi.org/10.3389/fmicb.2021.711359DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8320334PMC
July 2021

Modest effects of dietary supplements during the COVID-19 pandemic: insights from 445 850 users of the COVID-19 Symptom Study app.

BMJ Nutr Prev Health 2021 19;4(1):149-157. Epub 2021 Apr 19.

Department of Twin Research and Genetic Epidemiology, King's College London, London, UK.

Objectives: Dietary supplements may ameliorate SARS-CoV-2 infection, although scientific evidence to support such a role is lacking. We investigated whether users of the COVID-19 Symptom Study app who regularly took dietary supplements were less likely to test positive for SARS-CoV-2 infection.

Design: App-based community survey.

Setting: 445 850 subscribers of an app that was launched to enable self-reported information related to SARS-CoV-2 infection for use in the general population in the UK (n=372 720), the USA (n=45 757) and Sweden (n=27 373).

Main Exposure: Self-reported regular dietary supplement usage (constant use during previous 3 months) in the first waves of the pandemic up to 31 July 2020.

Main Outcome Measures: SARS-CoV-2 infection confirmed by viral RNA reverse transcriptase PCR test or serology test before 31 July 2020.

Results: In 372 720 UK participants (175 652 supplement users and 197 068 non-users), those taking probiotics, omega-3 fatty acids, multivitamins or vitamin D had a lower risk of SARS-CoV-2 infection by 14% (95% CI (8% to 19%)), 12% (95% CI (8% to 16%)), 13% (95% CI (10% to 16%)) and 9% (95% CI (6% to 12%)), respectively, after adjusting for potential confounders. No effect was observed for those taking vitamin C, zinc or garlic supplements. On stratification by sex, age and body mass index (BMI), the protective associations in individuals taking probiotics, omega-3 fatty acids, multivitamins and vitamin D were observed in females across all ages and BMI groups, but were not seen in men. The same overall pattern of association was observed in both the US and Swedish cohorts.

Conclusion: In women, we observed a modest but significant association between use of probiotics, omega-3 fatty acid, multivitamin or vitamin D supplements and lower risk of testing positive for SARS-CoV-2. We found no clear benefits for men nor any effect of vitamin C, garlic or zinc. Randomised controlled trials are required to confirm these observational findings before any therapeutic recommendations can be made.
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http://dx.doi.org/10.1136/bmjnph-2021-000250DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8061565PMC
April 2021

N-glycosylation of immunoglobulin G predicts incident hypertension.

J Hypertens 2021 Jul 19. Epub 2021 Jul 19.

Faculty of Pharmacy and Biochemistry, University of Zagreb, Zagreb, Croatia Department of Twin Research, Kings College London, London, UK Genos Glycoscience Research Laboratory, Zagreb, Croatia Research Unit of Molecular Epidemiology, Institute of Epidemiology, Helmholtz Zentrum München Research Center for Environmental Health German Center for Diabetes Research (DZD) Institute of Epidemiology, Helmholtz Zentrum München Research Center for Environmental Health LMU Munich, IBE-Chair of Epidemiology, Neuherberg, Germany Department of Public Health, University of Split, School of Medicine, Split, Croatia NIHR Biomedical Research Centre at Guy's and St Thomas' Foundation Trust, London Academic Rheumatology Clinical Sciences Building, Nottingham City Hospital, University of Nottingham, Nottingham University of Glasgow, Glasgow, Scotland, UK.

Objectives: Glycosylation of immunoglobulin G (IgG) is an important regulator of the immune system and has been implicated in prevalent hypertension.The aim of this study is to investigate whether the IgG glycome begins to change prior to hypertension diagnosis by analysing the IgG glycome composition in a large population-based female cohort with two independent replication samples.

Methods: We included 989 unrelated cases with incident hypertension and 1628 controls from the TwinsUK cohort (mean follow-up time of 6.3 years) with IgG measured at baseline by ultra-performance liquid chromatography and longitudinal BP measurement available. We replicated our findings in 106 individuals from the 10 001 Dalmatians and 729 from KORA S4. Cox regression mixed models were applied to identify changes in glycan traits preincident hypertension, after adjusting for age, mean arterial pressure, BMI, family relatedness and multiple testing (FDR < 0.1). Significant IgG-incident hypertension associations were replicated in the two independent cohorts by leveraging Cox regression mixed models in the 10 001 Dalmatians and logistic regression models in the KORA cohort.

Results: We identified and replicated four glycan traits, incidence of bisecting GlcNAc, GP4, GP9 and GP21, that are predictive of incident hypertension after adjusting for confoundes and multiple testing [hazard ratio (95% CI) ranging from 0.45 (0.24-0.84) for GP21 to 2.9 (1.5-5.68) for GP4]. We then linearly combined the four replicated glycans and found that the glycan score correlated with incident hypertension, SBP and DBP.

Conclusion: Our results suggest that the IgG glycome changes prior to the development of hypertension.
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http://dx.doi.org/10.1097/HJH.0000000000002963DOI Listing
July 2021

Meal-induced inflammation: postprandial insights from the Personalised REsponses to DIetary Composition Trial (PREDICT) study in 1000 participants.

Am J Clin Nutr 2021 09;114(3):1028-1038

Department of Nutritional Sciences, King's College London, London, United Kingdom.

Background: Meal-induced metabolic changes trigger an acute inflammatory response, contributing to chronic inflammation and associated diseases.

Objectives: We aimed to characterize variability in postprandial inflammatory responses using traditional (IL-6) and novel [glycoprotein acetylation (GlycA)] biomarkers of inflammation and dissect their biological determinants with a focus on postprandial glycemia and lipemia.

Methods: Postprandial (0-6 h) glucose, triglyceride (TG), IL-6, and GlycA responses were measured at multiple intervals after sequential mixed-nutrient meals (0 h and 4 h) in 1002 healthy adults aged 18-65 y from the PREDICT (Personalised REsponses to DIetary Composition Trial) 1 study, a single-arm dietary intervention study. Measures of habitual diet, blood biochemistry, gut microbiome composition, and visceral fat mass (VFM) were also collected.

Results: The postprandial changes in GlycA and IL-6 concentrations were highly variable between individuals. Participants eliciting an increase in GlycA and IL-6 (60% and 94% of the total participants, respectively) had mean 6-h increases of 11% and 190%, respectively. Peak postprandial TG and glucose concentrations were significantly associated with 6-h GlycA (r = 0.83 and r = 0.24, respectively; both P < 0.001) but not with 6-h IL-6 (both P > 0.26). A random forest model revealed the maximum TG concentration was the strongest postprandial TG predictor of postprandial GlycA and structural equation modeling revealed that VFM and fasting TG were most strongly associated with fasting and postprandial GlycA. Network Mendelian randomization demonstrated a causal link between VFM and fasting GlycA, mediated (28%) by fasting TG. Individuals eliciting enhanced GlycA responses had higher predicted cardiovascular disease risk (using the atherosclerotic disease risk score) than the rest of the cohort.

Conclusions: The variable postprandial increases in GlycA and their associations with TG metabolism highlight the importance of modulating TG in concert with obesity to reduce GlycA and associated low-grade inflammation-related diseases.This trial was registered at clinicaltrials.gov as NCT03479866.
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http://dx.doi.org/10.1093/ajcn/nqab132DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8408875PMC
September 2021

Gut microbiome diversity and composition is associated with hypertension in women.

J Hypertens 2021 09;39(9):1810-1816

Department of Twin Research and Genetic Epidemiology, King's College London, London, UK.

Objectives: Animal studies support a role for the gut microbiota in hypertension development, but large human studies are lacking. Here, we investigated the relationship between hypertension prevalence and gut microbial composition in two cohorts.

Methods: We included 871 unrelated TwinsUK women with faecal microbiome data (16s rRNA gene sequencing). Multivariable linear models adjusted for age, age2 and BMI as well as MiRKAT models, were used to estimate the association of hypertension with alpha- and beta-diversity metrics. To identify taxa associated with hypertension, a generalized additive model for location scale and shape was computed adjusting for covariates and multiple testing. Results were replicated in 448 women from PREDICT-1.

Results: We found that measures of alpha diversity are significantly lower in hypertensive cases [Beta(95% confidence interval, 95% CI) = -0.05 (-0.095 to -0.004), P = 0.03] and a significant association between beta diversity and hypertension (FDR < 0.05). We identified and replicated two genera associated with hypertension. The genus, Ruminiclostridium 6 was less abundant in hypertension cases [meta-analysis (95% CI) = -0.31 (-0.5 to -0.13), P = 1 × 10-3]. The uncultured microbe Erysipelotrichacea-UCG003 was more abundant in hypertensive cases [meta-analysis (95% CI) = 0.46 (0.3-0.62), P = 1 × 10-4]. We genomically analysed the 16 s rRNA sequence and established a 100% identity match with the 16 s rRNA sequence of the genus Faecalibacillus. We functionally annotated Ruminiclostridium, identifying 83 metabolic pathways, including pathways previously linked to blood pressure regulation.

Conclusion: In this large human observation, we show that gut microbiome diversity and composition are associated with hypertension. Our results suggest that targeting the microbiome may be a novel means to prevent or treat hypertension.
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http://dx.doi.org/10.1097/HJH.0000000000002878DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7611529PMC
September 2021

Prior SARS-CoV-2 infection rescues B and T cell responses to variants after first vaccine dose.

Science 2021 Apr 30. Epub 2021 Apr 30.

Department of Infectious Disease, Imperial College London, London, UK.

SARS-CoV-2 vaccine rollout has coincided with the spread of variants of concern. We investigated if single dose vaccination, with or without prior infection, confers cross protective immunity to variants. We analyzed T and B cell responses after first dose vaccination with the Pfizer/BioNTech mRNA vaccine BNT162b2 in healthcare workers (HCW) followed longitudinally, with or without prior Wuhan-Hu-1 SARS-CoV-2 infection. After one dose, individuals with prior infection showed enhanced T cell immunity, antibody secreting memory B cell response to spike and neutralizing antibodies effective against B.1.1.7 and B.1.351. By comparison, HCW receiving one vaccine dose without prior infection showed reduced immunity against variants. B.1.1.7 and B.1.351 spike mutations resulted in increased, abrogated or unchanged T cell responses depending on human leukocyte antigen (HLA) polymorphisms. Single dose vaccination with BNT162b2 in the context of prior infection with a heterologous variant substantially enhances neutralizing antibody responses against variants.
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http://dx.doi.org/10.1126/science.abh1282DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8168614PMC
April 2021

Vaccine side-effects and SARS-CoV-2 infection after vaccination in users of the COVID Symptom Study app in the UK: a prospective observational study.

Lancet Infect Dis 2021 07 27;21(7):939-949. Epub 2021 Apr 27.

Department of Twin Research & Genetic Epidemiology, King's College London, London, UK.

Background: The Pfizer-BioNTech (BNT162b2) and the Oxford-AstraZeneca (ChAdOx1 nCoV-19) COVID-19 vaccines have shown excellent safety and efficacy in phase 3 trials. We aimed to investigate the safety and effectiveness of these vaccines in a UK community setting.

Methods: In this prospective observational study, we examined the proportion and probability of self-reported systemic and local side-effects within 8 days of vaccination in individuals using the COVID Symptom Study app who received one or two doses of the BNT162b2 vaccine or one dose of the ChAdOx1 nCoV-19 vaccine. We also compared infection rates in a subset of vaccinated individuals subsequently tested for SARS-CoV-2 with PCR or lateral flow tests with infection rates in unvaccinated controls. All analyses were adjusted by age (≤55 years vs >55 years), sex, health-care worker status (binary variable), obesity (BMI <30 kg/mvs ≥30 kg/m), and comorbidities (binary variable, with or without comorbidities).

Findings: Between Dec 8, and March 10, 2021, 627 383 individuals reported being vaccinated with 655 590 doses: 282 103 received one dose of BNT162b2, of whom 28 207 received a second dose, and 345 280 received one dose of ChAdOx1 nCoV-19. Systemic side-effects were reported by 13·5% (38 155 of 282 103) of individuals after the first dose of BNT162b2, by 22·0% (6216 of 28 207) after the second dose of BNT162b2, and by 33·7% (116 473 of 345 280) after the first dose of ChAdOx1 nCoV-19. Local side-effects were reported by 71·9% (150 023 of 208 767) of individuals after the first dose of BNT162b2, by 68·5% (9025 of 13 179) after the second dose of BNT162b2, and by 58·7% (104 282 of 177 655) after the first dose of ChAdOx1 nCoV-19. Systemic side-effects were more common (1·6 times after the first dose of ChAdOx1 nCoV-19 and 2·9 times after the first dose of BNT162b2) among individuals with previous SARS-CoV-2 infection than among those without known past infection. Local effects were similarly higher in individuals previously infected than in those without known past infection (1·4 times after the first dose of ChAdOx1 nCoV-19 and 1·2 times after the first dose of BNT162b2). 3106 of 103 622 vaccinated individuals and 50 340 of 464 356 unvaccinated controls tested positive for SARS-CoV-2 infection. Significant reductions in infection risk were seen starting at 12 days after the first dose, reaching 60% (95% CI 49-68) for ChAdOx1 nCoV-19 and 69% (66-72) for BNT162b2 at 21-44 days and 72% (63-79) for BNT162b2 after 45-59 days.

Interpretation: Systemic and local side-effects after BNT162b2 and ChAdOx1 nCoV-19 vaccination occur at frequencies lower than reported in phase 3 trials. Both vaccines decrease the risk of SARS-CoV-2 infection after 12 days.

Funding: ZOE Global, National Institute for Health Research, Chronic Disease Research Foundation, National Institutes of Health, UK Medical Research Council, Wellcome Trust, UK Research and Innovation, American Gastroenterological Association.
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http://dx.doi.org/10.1016/S1473-3099(21)00224-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8078878PMC
July 2021

Longitudinal assessment of symptoms and risk of SARS-CoV-2 infection in healthcare workers across 5 hospitals to understand ethnic differences in infection risk.

EClinicalMedicine 2021 Apr 15;34:100835. Epub 2021 Apr 15.

Barts Heart Centre, St. Bartholomew's Hospital, London, United Kingdom.

Background: : Healthcare workers (HCWs) have increased rates of SARS-CoV-2 infection compared with the general population. We aimed to understand ethnic differences in SARS-CoV-2 seropositivity among hospital healthcare workers depending on their hospital role, socioeconomic status, Covid-19 symptoms and basic demographics.

Methods: A prospective longitudinal observational cohort study. 1364 HCWs at five UK hospitals were studied with up to 16 weeks of symptom questionnaires and antibody testing (to both nucleocapsid and spike protein) during the first UK wave in five NHS hospitals between March 20 and July 10 2020. The main outcome measures were SARS-CoV-2 infection (seropositivity at any time-point) and symptoms. Registration number: NCT04318314.

Findings: 272 of 1364 HCWs (mean age 40.7 years, 72% female, 74% White, ≥6 samples per participant) seroconverted, reporting predominantly mild or no symptoms. Seropositivity was lower in Intensive Therapy Unit (ITU) workers (OR=0.44 95%CI 0.24, 0.77; p=0.0035). Seropositivity was higher in Black (compared to White) participants, independent of age, sex, role and index of multiple deprivation (OR=2.61 95%CI 1.47-4.62 p=0.0009). No association was seen between White HCWs and other minority ethnic groups.

Interpretation: In the UK first wave, Black ethnicity (but not other ethnicities) more than doubled HCWs likelihood of seropositivity, independent of age, sex, measured socio-economic factors and hospital role.
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http://dx.doi.org/10.1016/j.eclinm.2021.100835DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8049191PMC
April 2021

Serum glucose, lactate dehydrogenase and hypertension are mediators of the effect of body mass index on severity of COVID-19.

Endocrinol Diabetes Metab 2021 04 16;4(2):e00215. Epub 2021 Feb 16.

NIHR Nottingham Biomedical Research Centre Nottingham University Hospitals NHS Trust and University of Nottingham Nottingham UK.

Background: COVID-19 has a broad clinical spectrum. We investigated the role of serum markers measured on admission on severity as assessed at discharge and investigated those which relate to the effect of BMI on severity.

Methods: Clinical and laboratory data from 610 COVID-19 cases hospitalized in the province of Zheijang, China were investigated as risk factors for severe COVID-19 (assessed by respiratory distress) compared to mild or common forms using logistic regression methods. Biochemical markers were correlated with severity using spearman correlations, and a ROC analysis was used to determine the individual contribution of each of the biochemical markers on severity. We carried out formal mediation analyses to investigate the extent of the effect of body mass index (BMI) on COVID-19 severity mediated by hypertension, glycemia, Lactose Dehydrogenase (LDH) at the time of hospitalization and C-Reactive Protein levels (CRP), in units of standard deviations.

Results: The individual markers measured on admission contributing most strongly to prediction of COVID-19 severity as assessed at discharge were LDH, CRP and glucose. The proportion of the effect of BMI on severity of COVID-19 mediated by CRP, glycemia or hypertension, we find that glucose mediated 79% (p < .0001), LDH mediated 78% (p < .0001), hypertension mediated 66% (p < .0001); however, only 44% (p < .005) was mediated by systemic inflammation (CRP).

Conclusion: Our data indicate that a larger proportion of the effect of BMI on severity of COVID-19 is mediated by glycemia and LDH levels whereas less than half of it is mediated by systemic inflammation.
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http://dx.doi.org/10.1002/edm2.215DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7994990PMC
April 2021

Postprandial glycaemic dips predict appetite and energy intake in healthy individuals.

Nat Metab 2021 04 12;3(4):523-529. Epub 2021 Apr 12.

Department of Twin Research and Genetic Epidemiology, King's College London, London, UK.

Understanding how to modulate appetite in humans is key to developing successful weight loss interventions. Here, we showed that postprandial glucose dips 2-3 h after a meal are a better predictor of postprandial self-reported hunger and subsequent energy intake than peak glucose at 0-2 h and glucose incremental area under the blood glucose curve at 0-2 h. We explore the links among postprandial glucose, appetite and subsequent energy intake in 1,070 participants from a UK exploratory and US validation cohort, who consumed 8,624 standardized meals followed by 71,715 ad libitum meals, using continuous glucose monitors to record postprandial glycaemia. For participants eating each of the standardized meals, the average postprandial glucose dip at 2-3 h relative to baseline level predicted an increase in hunger at 2-3 h (r = 0.16, P < 0.001), shorter time until next meal (r = -0.14, P < 0.001), greater energy intake at 3-4 h (r = 0.19, P < 0.001) and greater energy intake at 24 h (r = 0.27, P < 0.001). Results were directionally consistent in the US validation cohort. These data provide a quantitative assessment of the relevance of postprandial glycaemia in appetite and energy intake modulation.
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http://dx.doi.org/10.1038/s42255-021-00383-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7610681PMC
April 2021

The role of short-chain fatty acids in the interplay between gut microbiota and diet in cardio-metabolic health.

Gut Microbes 2021 Jan-Dec;13(1):1-24

Department of Twin Research, King's College London, St Thomas' Hospital Campus, London, UK.

The gut microbiota plays an important role in cardio-metabolic diseases with diet being among the strongest modulators of gut microbiota composition and function. Resistant dietary carbohydrates are fermented to short-chain fatty acids (SCFAs) by the gut bacteria. Fiber and omega-3 rich diets increase SCFAs production and abundance of SCFA-producing bacteria. Likewise, SCFAs can improve gut barrier integrity, glucose, and lipid metabolism, regulate the immune system, the inflammatory response, and blood pressure. Therefore, targeting the gut microbiota with dietary strategies leading to increased SCFA production may benefit cardio-metabolic health. In this review, we provide an overview of the association between diet, SCFAs produced by the gut microbiota and cardio-metabolic diseases. We first discuss the association between the human gut microbiota and cardio-metabolic diseases, then investigate the role of SCFAs and finally explore the beneficial effects of specific dietary interventions that can improve cardio-metabolic outcomes through boosting the SCFA production.
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http://dx.doi.org/10.1080/19490976.2021.1897212DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8007165PMC
March 2021

Blue poo: impact of gut transit time on the gut microbiome using a novel marker.

Gut 2021 Sep 15;70(9):1665-1674. Epub 2021 Mar 15.

Diabetes and Nutritional Sciences Division, King's College London, London, UK

Background And Aims: Gut transit time is a key modulator of host-microbiome interactions, yet this is often overlooked, partly because reliable methods are typically expensive or burdensome. The aim of this single-arm, single-blinded intervention study is to assess (1) the relationship between gut transit time and the human gut microbiome, and (2) the utility of the 'blue dye' method as an inexpensive and scalable technique to measure transit time.

Methods: We assessed interactions between the taxonomic and functional potential profiles of the gut microbiome (profiled via shotgun metagenomic sequencing), gut transit time (measured via the blue dye method), cardiometabolic health and diet in 863 healthy individuals from the PREDICT 1 study.

Results: We found that gut microbiome taxonomic composition can accurately discriminate between gut transit time classes (0.82 area under the receiver operating characteristic curve) and longer gut transit time is linked with specific microbial species such as , spp and spp (false discovery rate-adjusted p values <0.01). The blue dye measure of gut transit time had the strongest association with the gut microbiome over typical transit time proxies such as stool consistency and frequency.

Conclusions: Gut transit time, measured via the blue dye method, is a more informative marker of gut microbiome function than traditional measures of stool consistency and frequency. The blue dye method can be applied in large-scale epidemiological studies to advance diet-microbiome-health research. Clinical trial registry website https://clinicaltrials.gov/ct2/show/NCT03479866 and trial number NCT03479866.
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http://dx.doi.org/10.1136/gutjnl-2020-323877DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8349893PMC
September 2021

β-blocker prescription is associated with lower cumulative risk of knee osteoarthritis and knee pain consultations in primary care: a propensity score matched cohort study.

Rheumatology (Oxford) 2021 Mar 12. Epub 2021 Mar 12.

Academic Rheumatology, School of Medicine, University of Nottingham, Nottingham, UK.

Objectives: To examine the association between β-blocker prescription and first primary-care consultation for knee osteoarthritis (OA), hip OA, knee pain and hip pain.

Methods: Data source: Clinical Practice Research Datalink. Participants aged ≥40 years in receipt of new oral β-blocker prescriptions were propensity score (PS) matched to an unexposed control. Cox proportional hazard ratios (HRs) and 95% confidence intervals (CI) were calculated, and adjusted for non-osteoporotic fractures, number of primary-care consultations for knee or hip injury, and, the number of primary-care consultations, out-patient referrals and hospitalizations in the 12-months preceding cohort entry. Analysis was stratified according to β-blocker class and for commonly prescribed drugs. p< 0.05 was statistically significant.  .

Results: 111 718 β-blocker exposed participants were 1:1 PS matched to unexposed controls. β-blocker prescription was associated with reduced cumulative risk of knee OA, knee pain, and hip pain consultations with aHR(95%CI) 0.90(0.83-0.98); 0.88(0.83-0.92), and 0.85(0.79-0.90), respectively. Propranolol and atenolol were associated with a lower incidence of knee OA and knee pain consultations with aHRs between 0.78-0.91. β-blockers were associated with reduced incidence of consultation for large-joint lower-limb OA/pain as a composite outcome, defined as earliest of knee OA, knee pain, hip OA or hip pain consultation (aHR(95%CI) 0.87(0.84-0.90)).

Conclusion: Commonly used β-blockers have analgesic properties for musculoskeletal pain. Atenolol might be a therapeutic option for OA and cardiovascular co-morbidities in which β-blockers are indicated, while propranolol may be suitable for people with co-morbid anxiety. A confirmatory randomised controlled trial is needed before clinical practice is changed.
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http://dx.doi.org/10.1093/rheumatology/keab234DOI Listing
March 2021

Gut Microbial Profile Is Associated With Residential Settings and Not Nutritional Status in Adults in Karnataka, India.

Front Nutr 2021 23;8:595756. Epub 2021 Feb 23.

Nottingham Digestive Diseases Center, School of Medicine, University of Nottingham, Nottingham, United Kingdom.

Undernutrition is a leading contributor to disease and disability in people of all ages. Several studies have reported significant association between nutritional status and gut microbiome composition but other factors such as demographic settings may also influence the adult microbiome. The relationship between undernourishment and gut microbiome in adults has not been described to date. In this study, we compared the gut microbiome in fecal samples of 48 individuals, from two demographic settings (rural and urban slum) in Karnataka, India using 16S rRNA sequencing. Nutritional status was assessed based on BMI, with a BMI of < 18.5 kg/m classified as undernourished, and a BMI in the range 18.5-25 kg/m as nourished. We analyzed 25 individuals from rural settings (12 undernourished and 13 nourished) and 23 individuals from urban slum settings (11 undernourished and 12 nourished). We found no significant difference in overall gut microbial diversity (Shannon and Unweighted UniFrac) between undernourished and nourished individuals in either geographical settings, however, microbial taxa at the phylum level (i.e., Firmicutes and Proteobacteria) and beta diversity (unweighted UniFrac) differed significantly between the rural and urban slum settings. By predicting microbial function from 16S data profiling we found significant differences in metabolic pathways present in the gut microbiota from people residing in different settings; specifically, those related to carbohydrate and lipid metabolism. The weighted sum of the KEGG Orthologs associated with carbohydrate metabolism (Spearman's correlation coefficient, ρ = -0.707, < 0.001), lipid metabolism (Spearman's correlation coefficient, ρ = -0.330, < 0.022) and biosynthesis of secondary metabolites (Spearman's correlation coefficient, ρ = -0.507, < 0.001) were decreased in the urban slum group compared to the rural group. In conclusion, we report that the geographical location of residence is associated with differences in gut microbiome composition in adults. We found no significant differences in microbiome composition between nourished and undernourished adults from urban slum or rural settings in India.
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http://dx.doi.org/10.3389/fnut.2021.595756DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7940358PMC
February 2021

Metabolic signatures of osteoarthritis in urine using liquid chromatography-high resolution tandem mass spectrometry.

Metabolomics 2021 03 3;17(3):29. Epub 2021 Mar 3.

Centre for Analytical Bioscience, Advanced Materials and Healthcare Technologies Division, School of Pharmacy, University of Nottingham, Nottingham, NG7 2RD, UK.

Introduction: Osteoarthritis (OA) is a common cause of disability in older people, but its aetiology is not yet fully understood. Biomarkers of OA from metabolomics studies have shown potential use in understanding the progression and pathophysiology of OA.

Objectives: To investigate possible surrogate biomarkers of knee OA in urine using metabolomics to contribute towards a better understanding of OA progression and possible targeted treatment.

Method: Liquid chromatography-high resolution mass spectrometry (LC-HRMS) was applied in a case-control approach to explore the possible metabolic differences between the urinary profiles of symptomatic knee OA patients (n = 74) (subclassified into inflammatory OA, n = 22 and non-inflammatory OA, n = 52) and non-OA controls (n = 68). Univariate, multivariate and pathway analyses were performed with a rigorous validation including cross-validation, permutation test, prediction and receiver operating characteristic curve to identify significantly altered metabolites and pathways in OA.

Results: OA datasets generated 7405 variables and multivariate analysis showed clear separation of inflammatory OA, but not non-inflammatory OA, from non-OA controls. Adequate cross-validation (RY = 0.874, Q = 0.465) was obtained. The prediction model and the ROC curve showed satisfactory results with a sensitivity of 88%, specificity of 71% and accuracy of 77%. 26 metabolites were identified as potential biomarkers of inflammatory OA using HMDB, authentic standards and/or MS/MS database.

Conclusion: Urinary metabolic profiles were altered in inflammatory knee OA subjects compared to those with non-inflammatory OA and non-OA controls. These altered profiles associated with perturbed activity of the TCA cycle, pyruvate and amino acid metabolism linked to inflammation, oxidative stress and collagen destruction. Of note, 2-keto-glutaramic acid level was > eightfold higher in the inflammatory OA patients compared to non-OA control, signalling a possible perturbation in glutamine metabolism related to OA progression.
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http://dx.doi.org/10.1007/s11306-021-01778-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7925472PMC
March 2021

Effectiveness of Internet-Based Exercises Aimed at Treating Knee Osteoarthritis: The iBEAT-OA Randomized Clinical Trial.

JAMA Netw Open 2021 02 1;4(2):e210012. Epub 2021 Feb 1.

National Institute for Health Research, Nottingham Biomedical Research Centre, School of Medicine, University of Nottingham, Nottingham, United Kingdom.

Importance: Osteoarthritis is a prevalent, debilitating, and costly chronic disease for which recommended first-line treatment is underused.

Objective: To compare the effect of an internet-based treatment for knee osteoarthritis vs routine self-management (ie, usual care).

Design, Setting, And Participants: This randomized clinical trial was conducted from October 2018 to March 2020. Participants included individuals aged 45 years or older with a diagnosis of knee osteoarthritis recruited from an existing primary care database or from social media advertisements were invited. Data were analyzed April to July 2020.

Interventions: The intervention and control group conformed to first-line knee osteoarthritis treatment. For the intervention group, treatment was delivered via a smartphone application. The control group received routine self-management care.

Main Outcomes And Measures: The primary outcome was change from baseline to 6 weeks in self-reported pain during the last 7 days, reported on a numerical rating scale (NRS; range, 0-10, with 0 indicating no pain and 10, worst pain imaginable), compared between groups. Secondary outcomes included 2 physical functioning scores, hamstring and quadriceps muscle strength, the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), and quantitative sensory testing.

Results: Among a total of 551 participants screened for eligibility, 146 were randomized and 105 were analyzed (mean [SD] age, 66.7 [9.2] years, 71 [67.1%] women), including 48 participants in the intervention group and 57 participants in the control group. There were no significant differences in baseline characteristics between the groups. At the 6-week follow-up, the intervention group showed a greater NRS pain score reduction than the control group (between-group difference, -1.5 [95% CI, -2.2 to -0.8]; P < .001). Similarly, the intervention group had better improvements in the 30-second sit-to-stand test (between-group difference, 3.4 [95% CI, 2.2 to 4.5]; P < .001) and Timed Up-and-Go test (between-group difference, -1.8 [95% CI, -3.0 to -0.5] seconds; P = .007), as well as the WOMAC subscales for pain (between-group difference, -1.1 [95% CI, -2.0 to -0.2]; P = .02), stiffness (between-group difference, -1.0 [95% CI, -1.5 to -0.5]; P < .001), and physical function (between-group difference, -3.4 [95% CI, -6.2 to -0.7]; P = .02). The magnitude of within-group changes in pain (d = 0.83) and function outcomes (30 second sit-to-stand test d = 1.24; Timed Up-and-Go test d = 0.76) in the intervention group corresponded to medium to very strong effects. No adverse events were reported.

Conclusions And Relevance: These findings suggest that this internet-delivered, evidence-based, first-line osteoarthritis treatment was superior to routine self-managed usual care and could be provided without harm to people with osteoarthritis. Effect sizes observed in the intervention group corresponded to clinically important improvements.

Trial Registration: ClinicalTrials.gov Identifier: NCT03545048.
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http://dx.doi.org/10.1001/jamanetworkopen.2021.0012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7903254PMC
February 2021

High intake of vegetables is linked to lower white blood cell profile and the effect is mediated by the gut microbiome.

BMC Med 2021 02 11;19(1):37. Epub 2021 Feb 11.

Department of Twin Research and Genetic Epidemiology, King's College London, St Thomas' Hospital Campus, Westminster Bridge Road, London, SE1 7EH, UK.

Background: Chronic inflammation, which can be modulated by diet, is linked to high white blood cell counts and correlates with higher cardiometabolic risk and risk of more severe infections, as in the case of COVID-19.

Methods: Here, we assessed the association between white blood cell profile (lymphocytes, basophils, eosinophils, neutrophils, monocytes and total white blood cells) as markers of chronic inflammation, habitual diet and gut microbiome composition (determined by sequencing of the 16S RNA) in 986 healthy individuals from the PREDICT-1 nutritional intervention study. We then investigated whether the gut microbiome mediates part of the benefits of vegetable intake on lymphocyte counts.

Results: Higher levels of white blood cells, lymphocytes and basophils were all significantly correlated with lower habitual intake of vegetables, with vegetable intake explaining between 3.59 and 6.58% of variation in white blood cells after adjusting for covariates and multiple testing using false discovery rate (q < 0.1). No such association was seen with fruit intake. A mediation analysis found that 20.00% of the effect of vegetable intake on lymphocyte counts was mediated by one bacterial genus, Collinsella, known to increase with the intake of processed foods and previously associated with fatty liver disease. We further correlated white blood cells to other inflammatory markers including IL6 and GlycA, fasting and post-prandial glucose levels and found a significant relationship between inflammation and diet.

Conclusion: A habitual diet high in vegetables, but not fruits, is linked to a lower inflammatory profile for white blood cells, and a fifth of the effect is mediated by the genus Collinsella.

Trial Registration: The ClinicalTrials.gov registration identifier is NCT03479866 .
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http://dx.doi.org/10.1186/s12916-021-01913-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7875684PMC
February 2021

Effects of Environmental Factors on Severity and Mortality of COVID-19.

Front Med (Lausanne) 2020 20;7:607786. Epub 2021 Jan 20.

Central Clinical Hospital of Ministry of the Interior and Administration, Warsaw, Poland.

Most respiratory viruses show pronounced seasonality, but for SARS-CoV-2, this still needs to be documented. We examined the disease progression of COVID-19 in 6,914 patients admitted to hospitals in Europe and China. In addition, we evaluated progress of disease symptoms in 37,187 individuals reporting symptoms into the COVID Symptom Study application. Meta-analysis of the mortality risk in seven European hospitals estimated odds ratios per 1-day increase in the admission date to be 0.981 (0.973-0.988, < 0.001) and per increase in ambient temperature of 1°C to be 0.854 (0.773-0.944, = 0.007). Statistically significant decreases of comparable magnitude in median hospital stay, probability of transfer to the intensive care unit, and need for mechanical ventilation were also observed in most, but not all hospitals. The analysis of individually reported symptoms of 37,187 individuals in the UK also showed the decrease in symptom duration and disease severity with time. Severity of COVID-19 in Europe decreased significantly between March and May and the seasonality of COVID-19 is the most likely explanation.
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http://dx.doi.org/10.3389/fmed.2020.607786DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7855590PMC
January 2021

Microbiome connections with host metabolism and habitual diet from 1,098 deeply phenotyped individuals.

Nat Med 2021 02 11;27(2):321-332. Epub 2021 Jan 11.

Zoe Global Ltd, London, UK.

The gut microbiome is shaped by diet and influences host metabolism; however, these links are complex and can be unique to each individual. We performed deep metagenomic sequencing of 1,203 gut microbiomes from 1,098 individuals enrolled in the Personalised Responses to Dietary Composition Trial (PREDICT 1) study, whose detailed long-term diet information, as well as hundreds of fasting and same-meal postprandial cardiometabolic blood marker measurements were available. We found many significant associations between microbes and specific nutrients, foods, food groups and general dietary indices, which were driven especially by the presence and diversity of healthy and plant-based foods. Microbial biomarkers of obesity were reproducible across external publicly available cohorts and in agreement with circulating blood metabolites that are indicators of cardiovascular disease risk. While some microbes, such as Prevotella copri and Blastocystis spp., were indicators of favorable postprandial glucose metabolism, overall microbiome composition was predictive for a large panel of cardiometabolic blood markers including fasting and postprandial glycemic, lipemic and inflammatory indices. The panel of intestinal species associated with healthy dietary habits overlapped with those associated with favorable cardiometabolic and postprandial markers, indicating that our large-scale resource can potentially stratify the gut microbiome into generalizable health levels in individuals without clinically manifest disease.
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http://dx.doi.org/10.1038/s41591-020-01183-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8353542PMC
February 2021

The prebiotic effects of omega-3 fatty acid supplementation: A six-week randomised intervention trial.

Gut Microbes 2021 Jan-Dec;13(1):1-11

Department of Twin Research and Genetic Epidemiology, King's College London , London, UK.

Prebiotics are compounds in food that benefit health affecting the gut microbiome. Omega-3 fatty acids have been associated with differences in gut microbiome composition and are widely accepted to have health benefits, although recent large trials have been inconclusive. We carried out a 6-week dietary intervention comparing the effects of daily supplementation with 500 mg of omega-3 versus 20 g of a well-characterized prebiotic, inulin. Inulin supplementation resulted in large increases in and Lachnospiraceae. In contrast, omega-3 supplementation resulted in significant increases in . and , and significant decreases in the fatty-liver associated . On the other hand, similar to the results with inulin supplementation which resulted in significant increases in butyrate, iso-valerate, and iso-butyrate ( < .004), omega-3 supplementation resulted in significant increases in iso-butyrate and isovalerate ( < .002) and nearly significant increases in butyrate ( < .053). , which was significantly increased post-supplementation with omega-3, was found to be positively associated with iso-butyric acid (Beta (SE) = 0.69 (0.02), = 1.4 x 10) and negatively associated with triglyceride-rich lipoproteins such as VLDL (Beta (SE) = -0.381 (0.01), = .001) and VLDL-TG (Beta (SE) = -0.372 (0.04), = .001) after adjusting for confounders. Dietary omega-3 alters gut microbiome composition and some of its cardiovascular effects appear to be potentially mediated by its effect on gut microbial fermentation products indicating that it may be a prebiotic nutrient.
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http://dx.doi.org/10.1080/19490976.2020.1863133DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7781624PMC
December 2020

Are facemasks a priority for all staff in theatre to prevent surgical site infections during shortages of supply? A systematic review and meta-analysis.

Surgeon 2021 Oct 7;19(5):e132-e139. Epub 2020 Oct 7.

University of Nottingham, Queens Medical Centre, Nottingham, NG7 2UH, UK.

Background: The provision of facemasks must be prioritised when supplies are interrupted. These include supplies to operating rooms. The aim of this review is to evaluate the available evidence to determine the relative priority for the provision of facemasks in operating rooms to prevent surgical site infection.

Methods: A systematic search of OVID Medline, Embase & Cochrane Central was completed. Candidate full-text articles were identified and analysed by two reviewers who also assessed risk of bias.

Findings: Six studies were identified that described infections with and without facemask usage. The pooled effect of not wearing facemasks was a risk ratio for infection of 0.77 (0.62-0.97) in favour of not wearing masks. Only one case-controlled study evaluated facemask usage in implant surgery and demonstrated an odds ratio for developing infection of 3.34 (95% CI 1.94-5.74) if facemasks were not worn by the operating surgeon. Four studies collected microbiological cultures during periods in surgery with or without facemasks. Two demonstrated an increase in colony forming units in surgery where the wound was directly below the surgeon. One study showed equivocal results when masks were worn, and one was terminated early limiting interpretation.

Conclusion: The use of facemasks by scrubbed staff during implant surgery should be mandatory to prevent infection. We recommend the use of facemasks by all scrubbed staff during other forms of surgery to protect the patient and staff, but the supporting evidence is weak. There is insufficient evidence to show that non-scrubbed staff must wear masks during surgery.
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http://dx.doi.org/10.1016/j.surge.2020.08.014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7539019PMC
October 2021

Role of Drugs Used for Chronic Disease Management on Susceptibility and Severity of COVID-19: A Large Case-Control Study.

Clin Pharmacol Ther 2020 12 5;108(6):1185-1194. Epub 2020 Oct 5.

Division of Rheumatology, Orthopaedics, and Dermatology, School of Medicine, University of Nottingham, Nottingham, UK.

This study aimed to investigate whether specific medications used in the treatment chronic diseases affected either the development and/ or severity of coronavirus disease 2019 (COVID-19) in a cohort of 610 COVID-19 cases and 48,667 population-based controls from Zhejiang, China. Using a cohort of 578 COVID-19 cases and 48,667 population-based controls from Zhejiang, China, we tested the role of usage of cardiovascular, antidiabetic, and other medications on risk and severity of COVID-19. Analyses were adjusted for age, sex, and body mass index and for presence of relevant comorbidities. Individuals with hypertension taking calcium channel blockers had significantly increased risk (odds ratio (OR) = 1.73, 95% confidence interval (CI) 1.2-2.3) of manifesting symptoms of COVID-19, whereas those taking angiotensin receptor blockers and diuretics had significantly lower disease risk (OR = 0.22, 95% CI 0.15-0.30 and OR = 0.30, 95% CI 0.19-0.58, respectively). Among those with type 2 diabetes, dipeptidyl peptidase-4 inhibitors (OR = 6.02, 95% CI 2.3-15.5) and insulin (OR = 2.71, 95% CI 1.6-5.5) were more and glucosidase inhibitors were less prevalent (OR = 0.11, 95% CI 0.1-0.3) among with patients with COVID-19. Drugs used in the treatment of hypertension and diabetes influence the risk of development of COVID-19, but, not its severity.
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http://dx.doi.org/10.1002/cpt.2047DOI Listing
December 2020

IL-15 and IL15RA in Osteoarthritis: Association With Symptoms and Protease Production, but Not Structural Severity.

Front Immunol 2020 23;11:1385. Epub 2020 Jul 23.

Translational Musculoskeletal Research Center & Section of Rheumatology, Corporal Michael J. Crescenz VA Medical Center, Philadelphia, PA, United States.

Interleukin-15 (IL-15) is a pro-inflammatory cytokine that is increased in joint fluids of early-stage osteoarthritis (OA) patients, and has been associated with expression of proteases that can damage cartilage, and the development of neuropathic pain-like symptoms (NP) after nerve injury. The objective of this study was to further explore the role of IL-15 in the pathogenesis of OA cartilage degeneration and test genetic variation in the IL-15 receptor α gene () for an association with OA with radiographic severity and symptoms. Cartilage samples from donors ( = 10) were analyzed for expression of the IL15 receptor α-chain using immunohistochemistry, and for responses to IL-15 using explant cultures. Data from two independent Nottinghamshire-based studies ( = 795 and = 613) were used to test genetic variants in the gene (rs2228059 and rs7097780) for an association with radiographic severity, symptomatic vs. asymptomatic OA and NP. IL-15Rα was expressed in chondrocytes from cartilage obtained from normal and degenerative knees. IL-15 significantly increased the release of matrix metalloproteinase-1 and -3 (MMP-1 and -3), but did not affect loss of proteoglycan from the articular matrix. Genetic variants in the gene are associated with risk of symptomatic vs. asymptomatic OA (rs7097780 OR = 1.48 95% 1.10-1.98 < 0.01) and with the risk of NP post-total joint replacement (rs2228059 OR = 0.76 95% 0.63-0.92 < 0.01) but not with radiographic severity. In two different cohorts of patients, we show an association between genetic variation at the IL15 receptor and pain. Although cartilage explants could respond to IL-15 with increased protease production, we found no effect of IL-15 on cartilage matrix loss and no association between variants and radiographic severity. Together, these results suggest that IL-15 signaling may be a target for pain, but may not impact structural progression, in OA.
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http://dx.doi.org/10.3389/fimmu.2020.01385DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7390829PMC
April 2021
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