Diagnostic value of cutaneous manifestation of SARS-CoV-2 infection.

BACKGROUND: One of the challenging aspects of SARS-CoV-2 infection is its diverse multisystemic disease presentation. OBJECTIVES: To evaluate the diagnostic value of cutaneous manifestations of SARS-CoV-2 infection and investigate their duration and timing in relation to other COVID-19 symptoms. METHODS: We used data from 336 847 UK users of the COVID Symptom Study app to assess the diagnostic value of body rash or an acral rash in SARS-CoV-2 infection, and data from an independent online survey of 11 544 respondents to investigate skin-specific symptoms and collect their photographs. RESULTS: Using data from the app, we show significant association between skin rashes and a positive swab test result (odds ratio 1·67, 95% confidence interval 1·42-1·97). Strikingly, among the respondents of the independent online survey, we found that 17% of SARS-CoV-2-positive cases reported skin rashes as the first presentation, and 21% as the only clinical sign of COVID-19. Together with the British Association of Dermatologists, we have compiled a catalogue of images of the most common skin manifestations of COVID-19 from 400 individuals (https://covidskinsigns.com), which we have made publicly available to assist clinicians in recognition of this early clinical feature of COVID-19. CONCLUSIONS: Skin rashes cluster with other COVID-19 symptoms, are predictive of a positive swab test, and occur in a significant number of cases, either alone or before other classical symptoms. Recognizing rashes is important in identifying new and earlier cases of COVID-19.

Cross-Sectional Associations Between Dietary Antioxidant Vitamins C, E and Carotenoid Intakes and Sarcopenic Indices in Women Aged 18-79 Years.

The prevalence of sarcopenia is increasing in aging populations, so prevention is critical. Vitamins (A, C, E and carotenoids) modify skeletal muscle via protein and collagen synthesis and anti-inflammatory activities. Previous studies have not investigated intake of these vitamins in relation to sarcopenic indices in both younger and older-aged women. Indices of skeletal muscle mass (as fat-free mass (FFM) relative to body size) were measured using DXA and leg explosive power (LEP) using the Nottingham Power Rig in 2570 women aged 18-79 years. Adjusted measures of skeletal muscle were calculated according to quintiles of vitamin C, E, retinol and carotenoid intake, derived from Food Frequency Questionnaires, after stratification by age. Higher vitamin C intake was associated with significantly higher indices of FFM and LEP, (Q5-Q1 = 2.0-12.8%, P < 0.01-0.02). Intakes of total and individual carotenoids were significantly associated with indices of FFM and LEP (Q5-Q1 = 1.0-7.5%). Vitamin E was significantly associated with FFM% and FFMBMI only. In mutually adjusted analysis with vitamin C, total carotene, vitamin E and protein in the model, the strongest associations were with vitamin C. These associations were stronger in younger women (< 65 years). For the first time, our research shows higher dietary intakes of antioxidant vitamins, particularly vitamin C, is associated with higher skeletal muscle mass and power in free-living women. These findings have relevance for the treatment and prevention of frailty and sarcopenia throughout adulthood.

Gut microbiome diversity and high-fibre intake are related to lower long-term weight gain.

BACKGROUND: Cross-sectional studies suggest that the microbes in the human gut have a role in obesity by influencing the human body's ability to extract and store calories. The aim of this study was to assess if there is a correlation between change in body weight over time and gut microbiome composition. METHODS: We analysed 16S ribosomal RNA gene sequence data derived from the faecal samples of 1632 healthy females from TwinsUK to investigate the association between gut microbiome measured cross-sectionally and longitudinal weight gain (adjusted for caloric intake and baseline body mass index). Dietary fibre intake was investigated as a possible modifier. RESULTS: Less than half of the variation in long-term weight change was found to be heritable (h2=0.41 (0.31, 0.47)). Gut microbiota diversity was negatively associated with long-term weight gain, whereas it was positively correlated with fibre intake. Nine bacterial operational taxonomic units (OTUs) were significantly associated with weight gain after adjusting for covariates, family relatedness and multiple testing (false discovery rate <0.05). OTUs associated with lower long-term weight gain included those assigned to Ruminococcaceae (associated in mice with improved energy metabolism) and Lachnospiraceae. A Bacterioides species OTU was associated with increased risk of weight gain but this appears to be driven by its correlation with lower levels of diversity. CONCLUSIONS: High gut microbiome diversity, high-fibre intake and OTUs implicated in animal models of improved energy metabolism are all correlated with lower term weight gain in humans independently of calorie intake and other confounders.

Untangling the relationship between diet and visceral fat mass through blood metabolomics and gut microbiome profiling.

BACKGROUND/OBJECTIVES: Higher visceral fat mass (VFM) is associated with an increased risk for developing cardio-metabolic diseases. The mechanisms by which an unhealthy diet pattern may influence visceral fat (VF) development has yet to be examined through cutting-edge multi-omic methods. Therefore, our objective was to examine the dietary influences on VFM and identify gut microbiome and metabolite profiles that link food intakes to VFM. SUBJECTS/METHODS: In 2218 twins with VFM, food intake and metabolomics data available we identified food intakes most strongly associated with VFM in 50% of the sample, then constructed and tested the 'VFM diet score' in the remainder of the sample. Using linear regression (adjusted for covariates, including body mass index and total fat mass), we investigated associations between the VFM diet score, the blood metabolomics profile and the fecal microbiome (n=889), and confirmed these associations with VFM. We replicated top findings in monozygotic (MZ) twins discordant (⩾1 s.d. apart) for VFM, matched for age, sex and the baseline genetic sequence. RESULTS: Four metabolites were associated with the VFM diet score and VFM: hippurate, alpha-hydroxyisovalerate, bilirubin (Z,Z) and butyrylcarnitine. We replicated associations between VFM and the diet score (beta (s.e.): 0.281 (0.091); P=0.002), butyrylcarnitine (0.199 (0.087); P=0.023) and hippurate (-0.297 (0.095); P=0.002) in VFM-discordant MZ twins. We identified a single species, Eubacterium dolichum to be associated with the VFM diet score (0.042 (0.011), P=8.47 × 10-5), VFM (0.057 (0.019), P=2.73 × 10-3) and hippurate (-0.075 (0.032), P=0.021). Moreover, higher blood hippurate was associated with elevated adipose tissue expression neuroglobin, with roles in cellular oxygen homeostasis (0.016 (0.004), P=9.82x10-6). CONCLUSIONS: We linked a dietary VFM score and VFM to E. dolichum and four metabolites in the blood. In particular, the relationship between hippurate, a metabolite derived from microbial metabolism of dietary polyphenols, and reduced VFM, the microbiome and increased adipose tissue expression of neuroglobin provides potential mechanistic insight into the influence of diet on VFM.

Measurements of skeletal muscle mass and power are positively related to a Mediterranean dietary pattern in women.

The age-related loss of skeletal muscle and function are risk factors for osteoporosis and fractures. We found that higher adherence to the Mediterranean diet score was significantly associated with greater fat-free mass and leg explosive power suggesting a role for the Mediterranean Diet in prevention of loss of muscle outcomes. INTRODUCTION: The loss of skeletal muscle mass, strength, and function with age are contributing risk factors for the onset of sarcopenia, frailty, osteoporosis, fractures, and mortality. Nutrition may affect the progression and trajectory of these changes in skeletal muscle but the role of the micronutrient-rich Mediterranean diet (MD) has hardly been investigated in relation to these muscle outcomes. METHODS: We examined associations between the MD score (MDS) and FFM% (fat-free mass / weight × 100), FFMI (fat-free mass/height2), hand grip strength, and leg explosive power (LEP, watts/kg) in a cross-sectional study in 2570 women aged 18-79 years from the TwinsUK study. Measurements of body composition were made using dual-energy X-ray absorptiometry and dietary intake assessed by a food frequency questionnaire. FFM%, FFMI, grip strength, and LEP were compared across quartiles of the MDS after adjustment for covariates, with CRP measured in a subgroup (n = 1658). RESULTS: Higher adherence to the MDS was positively associated with measurements of muscle outcomes, with significant differences of 1.7 % for FFM% and 9.6 % for LEP (P trend <0.001), comparing extreme quartiles of intake, but not with grip strength or CRP concentrations. CONCLUSIONS: For the first time in a northern European population, we have observed significant positive associations between the MDS and FFM% and LEP in healthy women that are potentially clinically relevant, independent of the factors known to influence muscle outcomes. Our findings emphasize the potential role for overall diet quality based on the MD in the prevention of age-related loss of skeletal muscle outcomes.

Host Genotype Links to Salivary and Gut Microbiota by Periodontal Status.

Limited evidence describing how host genetic variants affect the composition of the microbiota is currently available. The aim of this study was to assess the associations between a set of candidate host genetic variants and microbial composition in both saliva and gut in the TwinsUK registry. A total of 1,746 participants were included in this study and provided stool samples. A subset of 1,018 participants also provided self-reported periodontal data, and 396 of those participants provided a saliva sample. Host DNA was extracted from whole-blood samples and processed for Infinium Global screening array, focusing on 37 selected single-nucleotide polymorphisms (SNPs) previously associated with periodontitis. The gut and salivary microbiota of participants were profiled using 16S ribosomal RNA amplicon sequencing. Associations between genotype on the selected SNPs and microbial outcomes, including α diversity, ß diversity, and amplicon sequence variants (ASVs), were investigated in a multivariate mixed model. Self-reported periodontal status was also compared with microbial outcomes. Downstream analyses in gut microbiota and salivary microbiota were carried out separately. IL10 rs6667202 and VDR 2228570 SNPs were associated with salivary α diversity, and SNPs in IL10, HSA21, UHRF2, and Fc-γR genes were associated with dissimilarity matrix generated from salivary ß diversity. The SNP that was associated with the greatest number of salivary ASVs was VDR 2228570 followed by IL10 rs6667202, and that of gut ASVs was NPY rs2521364. There were 77 salivary ASVs and 39 gut ASVs differentially abundant in self-reported periodontal disease versus periodontal health. The dissimilarity between saliva and gut microbiota within individuals appeared significantly greater in self-reported periodontal cases compared to periodontal health. IL10 and VDR gene variants may affect salivary microbiota composition. Periodontal status may drive variations in the salivary microbiota and possibly, to a lesser extent, in the gut microbiota.

Optimal symptom combinations to aid COVID-19 case identification: Analysis from a community-based, prospective, observational cohort.

OBJECTIVES: Diagnostic work-up following any COVID-19 associated symptom will lead to extensive testing, potentially overwhelming laboratory capacity whilst primarily yielding negative results. We aimed to identify optimal symptom combinations to capture most cases using fewer tests with implications for COVID-19 vaccine developers across different resource settings and public health. METHODS: UK and US users of the COVID-19 Symptom Study app who reported new-onset symptoms and an RT-PCR test within seven days of symptom onset were included. Sensitivity, specificity, and number of RT-PCR tests needed to identify one case (test per case [TPC]) were calculated for different symptom combinations. A multi-objective evolutionary algorithm was applied to generate combinations with optimal trade-offs between sensitivity and specificity. FINDINGS: UK and US cohorts included 122,305 (1,202 positives) and 3,162 (79 positive) individuals. Within three days of symptom onset, the COVID-19 specific symptom combination (cough, dyspnoea, fever, anosmia/ageusia) identified 69% of cases requiring 47 TPC. The combination with highest sensitivity (fatigue, anosmia/ageusia, cough, diarrhoea, headache, sore throat) identified 96% cases requiring 96 TPC. INTERPRETATION: We confirmed the significance of COVID-19 specific symptoms for triggering RT-PCR and identified additional symptom combinations with optimal trade-offs between sensitivity and specificity that maximize case capture given different resource settings.

Optimal symptom combinations to aid COVID-19 case identification: analysis from a community-based, prospective, observational cohort.

OBJECTIVES: Diagnostic work-up following any COVID-19 associated symptom will lead to extensive testing, potentially overwhelming laboratory capacity whilst primarily yielding negative results. We aimed to identify optimal symptom combinations to capture most cases using fewer tests with implications for COVID-19 vaccine developers across different resource settings and public health. METHODS: UK and US users of the COVID-19 Symptom Study app who reported new-onset symptoms and an RT-PCR test within seven days of symptom onset were included. Sensitivity, specificity, and number of RT-PCR tests needed to identify one case (test per case [TPC]) were calculated for different symptom combinations. A multi-objective evolutionary algorithm was applied to generate combinations with optimal trade-offs between sensitivity and specificity. FINDINGS: UK and US cohorts included 122,305 (1,202 positives) and 3,162 (79 positive) individuals. Within three days of symptom onset, the COVID-19 specific symptom combination (cough, dyspnoea, fever, anosmia/ageusia) identified 69% of cases requiring 47 TPC. The combination with highest sensitivity (fatigue, anosmia/ageusia, cough, diarrhoea, headache, sore throat) identified 96% cases requiring 96 TPC. INTERPRETATION: We confirmed the significance of COVID-19 specific symptoms for triggering RT-PCR and identified additional symptom combinations with optimal trade-offs between sensitivity and specificity that maximize case capture given different resource settings.

The Urinary Tract Microbiome in Older Women Exhibits Host Genetic and Environmental Influences.

The urinary microbiome is a relatively unexplored niche that varies with gender. Urinary microbes, especially in aging populations, are associated with morbidity. We present a large-scale study exploring factors defining urinary microbiome composition in community-dwelling older adult women without clinically active infection. Using 1,600 twins, we estimate the contribution of genetic and environmental factors to microbiome variation. The urinary microbiome is distinct from nearby sites and unrelated to stool microbiome with more Actinobacteria, Fusobacteria and Proteobacteria, but fewer Bacteroidetes, Firmicutes and Verrumicrobia. A quarter of variants had heritability estimates greater than 10% with most heritable microbes having potential clinical relevance, including Escherichia-Shigella linked to urinary tract infections. Age, menopausal status, prior UTI, and host genetics were top factors defining the urobiome with increased microbial diversity tending to associate with older age. These findings highlight the distinct composition of the urinary microbiome and significant contributions of host genetics.

Plasma protein biomarkers of Alzheimer's disease endophenotypes in asymptomatic older twins: early cognitive decline and regional brain volumes.

There is great interest in blood-based markers of Alzheimer's disease (AD), especially in its pre-symptomatic stages. Therefore, we aimed to identify plasma proteins whose levels associate with potential markers of pre-symptomatic AD. We also aimed to characterise confounding by genetics and the effect of genetics on blood proteins in general. Panel-based proteomics was performed using SOMAscan on plasma samples from TwinsUK subjects who are asymptomatic for AD, measuring the level of 1129 proteins. Protein levels were compared with 10-year change in CANTAB-paired associates learning (PAL; n = 195), and regional brain volumes (n = 34). Replication of proteins associated with regional brain volumes was performed in 254 individuals from the AddNeuroMed cohort. Across all the proteins measured, genetic factors were found to explain ~26% of the variability in blood protein levels on average. The plasma level of the mitogen-activated protein kinase (MAPK) MAPKAPK5 protein was found to positively associate with the 10-year change in CANTAB-PAL in both the individual and twin difference context. The plasma level of protein MAP2K4 was found to suggestively associate negatively (Q < 0.1) with the volume of the left entorhinal cortex. Future studies will be needed to assess the specificity of MAPKAPK5 and MAP2K4 to eventual conversion to AD.