Development of a (Poly)phenol Metabolic Signature for Assessing (Poly)phenol-Rich Dietary Patterns.

The objective assessment of habitual (poly)phenol-rich diets in nutritional epidemiology studies remains challenging. This study developed and evaluated the metabolic signature of a (poly)phenol-rich dietary score (PPS) using a targeted metabolomics method comprising 105 representative (poly)phenol metabolites, analyzed in 24 h of urine samples collected from healthy volunteers. The metabolites that were significantly associated with PPS after adjusting for energy intake were selected to establish a metabolic signature using a combination of linear regression followed by ridge regression to estimate penalized weights for each metabolite. A metabolic signature comprising 51 metabolites was significantly associated with adherence to PPS in 24 h urine samples, as well as with (poly)phenol intake estimated from food frequency questionnaires and diaries. Internal and external data sets were used for validation, and plasma, spot urine, and 24 h urine samples were compared. The metabolic signature proposed here has the potential to accurately reflect adherence to (poly)phenol-rich diets, and may be used as an objective tool for the assessment of (poly)phenol intake.

The impact of incident stroke on cognitive trajectories in later life.

BACKGROUND: Cognitive impairment is common after stroke, and a large proportion of stroke patients will develop dementia. However, there have been few large prospective studies which have assessed cognition both prior to and after stroke. This study aims to determine the extent to which incident stroke impacts different domains of cognitive function in a longitudinal cohort of older community-dwelling individuals. METHODS: 19,114 older individuals without cardiovascular disease or major cognitive impairment were recruited and followed over a maximum 11 years. Stroke included ischaemic and haemorrhagic stroke and was adjudicated by experts. Cognitive function was assessed regularly using Modified Mini-Mental State Examination (3MS), Hopkins Verbal Learning Test-Revised (HVLT-R), Symbol Digit Modalities Test (SDMT), and Controlled Oral Word Association Test (COWAT). Linear mixed models were used to investigate the change in cognition at the time of stroke and decline in cognitive trajectories following incident stroke. RESULTS: During a median follow-up period of 8.4 [IQR: 7.2, 9.6] years, 815 (4.3%) participants experienced a stroke. Over this time, there was a general decline observed in 3MS, HVLT-R delayed recall, and SDMT scores across participants. However, for individuals who experienced a stroke, there was a significantly greater decline across all cognitive domains immediately after the event immediately after the event (3MS: -1.03 [95%CI: -1.45, -0.60]; HVLT-R: -0.47 [-0.70, -0.24]; SDMT: -2.82 [-3.57, -2.08]; COWAT: -0.67 [-1.04, -0.29]) and a steeper long-term decline for three of these domains (3MS -0.62 [-0.88, -0.35]; COWAT: -0.30 [-0.46, -0.14]); HVLT-R: -0.12 [95%CI, -0.70, -0.24]). However individuals with stroke experienced no longer-term decline in SDMT compared to the rest of the participants. CONCLUSIONS: These findings highlight the need for comprehensive neuropsychology assessments for ongoing monitoring of cognition following incident stroke; and potential early intervention.

An undue emphasis on rural older adults in the Chief Medical Officer's annual report 2023?

The Chief Medical Officer's annual report 2023 presents an incomplete and skewed picture of the geography of older people in England. We show that there are higher absolute numbers of older people in urban areas in England and Wales, in contrast to key messages from the CMO report which suggest greater need in rural areas based on relative metrics. The absolute size of the urban-rural difference in the population of older people is projected to grow by 2043. Older adults in urban areas are much more likely to live in deprived areas than older adults in rural areas. The absolute number and prevalence of older adults in poorer health is also higher in urban areas, leading to greater healthcare needs. Policy-makers need to consider both absolute and relative demographic trends as well as making use of direct measures of health when planning how healthcare services for older adults are distributed geographically in England.

Symptoms before and after COVID-19: a population and case-control study using prospective data.

BACKGROUND: Some individuals experience prolonged illness after acute COVID-19. We assessed whether pre-infection symptoms affected post-COVID illness duration. METHODS: Survival analysis was performed in adults (n=23 452) with community-managed SARC-CoV-2 infection prospectively self-logging data through the ZOE COVID Symptom Study app, at least weekly, from 8 weeks before to 12 weeks after COVID-19 onset, conditioned on presence versus absence of baseline symptoms (4-8 weeks before COVID-19). A case-control study was performed in 1350 individuals with long illness (≥8 weeks, 906 [67.1%] with illness ≥12 weeks), matched 1:1 (for age, sex, body mass index, testing week, prior infection, vaccination, smoking, index of multiple deprivation) with 1350 individuals with short illness (<4 weeks). Baseline symptoms were compared between the two groups; and against post-COVID symptoms. RESULTS: Individuals reporting baseline symptoms had longer post-COVID symptom duration (from 10 to 15 days) with baseline fatigue nearly doubling duration. Two-thirds (910 of 1350 [67.4%]) of individuals with long illness were asymptomatic beforehand. However, 440 (32.6%) had baseline symptoms, versus 255 (18.9%) of 1350 individuals with short illness (p<0.0001). Baseline symptoms increased the odds ratio for long illness (2.14 [CI: 1.78; 2.57]). Prior comorbidities were more common in individuals with long versus short illness. In individuals with long illness, baseline symptomatic (versus asymptomatic) individuals were more likely to be female, younger, and have prior comorbidities; and baseline and post-acute symptoms and symptom burden correlated strongly. CONCLUSIONS: Individuals experiencing symptoms before COVID-19 have longer illness duration and increased odds of long illness. However, many individuals with long illness are well before SARS-CoV-2 infection.

Effect of gut microbiome modulation on muscle function and cognition: the PROMOTe randomised controlled trial.

Studies suggest that inducing gut microbiota changes may alter both muscle physiology and cognitive behaviour. Gut microbiota may play a role in both anabolic resistance of older muscle, and cognition. In this placebo controlled double blinded randomised controlled trial of 36 twin pairs (72 individuals), aged ≥60, each twin pair are block randomised to receive either placebo or prebiotic daily for 12 weeks. Resistance exercise and branched chain amino acid (BCAA) supplementation is prescribed to all participants. Outcomes are physical function and cognition. The trial is carried out remotely using video visits, online questionnaires and cognitive testing, and posting of equipment and biological samples. The prebiotic supplement is well tolerated and results in a changed gut microbiome [e.g., increased relative Bifidobacterium abundance]. There is no significant difference between prebiotic and placebo for the primary outcome of chair rise time (ß = 0.579; 95% CI -1.080-2.239 p = 0.494). The prebiotic improves cognition (factor score versus placebo (ß = -0.482; 95% CI,-0.813, -0.141; p = 0.014)). Our results demonstrate that cheap and readily available gut microbiome interventions may improve cognition in our ageing population. We illustrate the feasibility of remotely delivered trials for older people, which could reduce under-representation of older people in clinical trials. ClinicalTrials.gov registration: NCT04309292.

Systematic identification of the role of gut microbiota in mental disorders: a TwinsUK cohort study.

Mental disorders are complex disorders influenced by multiple genetic, environmental, and biological factors. Specific microbiota imbalances seem to affect mental health status. However, the mechanisms by which microbiota disturbances impact the presence of depression, stress, anxiety, and eating disorders remain poorly understood. Currently, there are no robust biomarkers identified. We proposed a novel pyramid-layer design to accurately identify microbial/metabolomic signatures underlying mental disorders in the TwinsUK registry. Monozygotic and dizygotic twins discordant for mental disorders were screened, in a pairwise manner, for differentially abundant bacterial genera and circulating metabolites. In addition, multivariate analyses were performed, accounting for individual-level confounders. Our pyramid-layer study design allowed us to overcome the limitations of cross-sectional study designs with significant confounder effects and resulted in an association of the abundance of genus Parabacteroides with the diagnosis of mental disorders. Future research should explore the potential role of Parabacteroides as a mediator of mental health status. Our results indicate the potential role of the microbiome as a modifier in mental disorders that might contribute to the development of novel methodologies to assess personal risk and intervention strategies.

Diet patterns and cognitive performance in a UK Female Twin Registry (TwinsUK).

BACKGROUND: Plant-based diets may provide protection against cognitive decline and Alzheimer's disease, but observational data have not been consistent. Previous studies include early life confounding from socioeconomic conditions and genetics that are known to influence both cognitive performance and diet behaviour. This study investigated associations between Mediterranean (MED) diet and MIND diets and cognitive performance accounting for shared genotype and early-life environmental exposures in female twins. METHODS: Diet scores were examined in 509 female twins enrolled in TwinsUK study. The Cambridge Neuropsychological Test Automated Battery was used to assess cognition at baseline and 10 years later (in n = 275). A co-twin case-control study for discordant monozygotic (MZ) twins examined effects of diet on cognitive performance independent of genetic factors. Differences in relative abundance of taxa at 10-year follow-up were explored in subsamples. RESULTS: Each 1-point increase in MIND or MED diet score was associated with 1.75 (95% CI: - 2.96, - 0.54, p = 0.005 and q = 0.11) and 1.67 (95% CI: - 2.71, - 0.65, p = 0.002 and q = 0.02) fewer respective errors in paired-associates learning. Within each MZ pair, the twin with the high diet score had better preservation in spatial span especially for MED diet (p = 0.02). There were no differences between diet scores and 10-year change in the other cognitive tests. MIND diet adherence was associated with higher relative abundance of Ruminococcaceae UCG-010 (0.30% (95% CI 0.17, 0.62), q = 0.05) which was also associated with less decline in global cognition over 10 years (0.22 (95% CI 0.06, 0.39), p = 0.01). CONCLUSIONS: MIND or MED diets could help to preserve some cognitive abilities in midlife, particularly episodic and visuospatial working memory. Effects may be mediated by high dietary fibre content and increased abundance of short-chain fatty acid producing gut bacteria. Longer follow-up with repeated measures of cognition will determine whether diet can influence changes in cognition occurring in older age.

Cardiovascular Disease Risk Scores and Incident Dementia and Cognitive Decline in Older Men and Women.

INTRODUCTION: Risk factors for cardiovascular disease (CVD) also increase the risk of dementia. However, whether commonly used CVD risk scores are associated with dementia risk in older adults who do not have a history of CVD, and potential gender differences in this association, remains unclear. The aim of this study was to determine whether CVD risk scores are prospectively associated with cognitive decline and dementia in initially healthy older men and women. METHODS: A total of19,114 participants from a prospective cohort of individuals aged 65+ years without known CVD or dementia were recruited. The atherosclerotic cardiovascular disease risk score (ASCVDRS), Systematic Coronary Risk Evaluation 2-Older Persons (SCORE2-OP), and the Framingham risk score (FRS) were calculated at baseline. Risk of dementia (according to DSM-IV criteria) and cognitive decline (defined as a >1.5 standard deviation decline in global cognition, episodic memory, psychomotor speed, or verbal fluency from the previous year) were assessed using hazard ratio. RESULTS: Over a median follow-up of 6.4 years, 850 individuals developed dementia and 4,352 cognitive decline. Men and women in the highest ASCVDRS tertile had a 41% (95% CI 1.08, 1.85) and 45% (1.11, 1.89) increased risk of dementia compared to the lowest tertile, respectively. Likewise, men and women in the highest SCORE2-OP tertile had a 64% (1.24, 2.16) and 60% (1.22, 2.11) increased risk of dementia compared to the lowest tertile, respectively. Findings were similar, but the risk was slightly lesser when examining risk of cognitive decline for both ASCVDRS and SCORE2-OP. However, FRS was only associated with the risk of cognitive decline among women (highest vs. lowest tertiles: 1.13 [1.01-1.26]). CONCLUSION: These findings suggest the utility of the ASCVDRS and SCORE2-OP in clinical practice, to not only assess future risk of CVD, but also as potential early indicators of cognitive impairment, even in relatively healthy older men and women.

The relationship between weight-related indicators and depressive symptoms during adolescence and adulthood: results from two twin studies.

BACKGROUND: The association between weight and depressive symptoms is well established, but the direction of effects remains unclear. Most studies rely on body mass index (BMI) as the sole weight indicator, with few examining the aetiology of the association between weight indicators and depressive symptoms. METHODS: We analysed data from the Twins Early Development Study (TEDS) and UK Adult Twin Registry (TwinsUK) (7658 and 2775 twin pairs, respectively). A phenotypic cross-lagged panel model assessed the directionality between BMI and depressive symptoms at ages 12, 16, and 21 years in TEDS. Bivariate correlations tested the phenotypic association between a range of weight indicators and depressive symptoms in TwinsUK. In both samples, structural equation modelling of twin data investigated genetic and environmental influences between weight indicators and depression. Sensitivity analyses included two-wave phenotypic cross-lagged panel models and the exclusion of those with a BMI <18.5. RESULTS: Within TEDS, the relationship between BMI and depression was bidirectional between ages 12 and 16 with a stronger influence of earlier BMI on later depression. The associations were unidirectional thereafter with depression at 16 influencing BMI at 21. Small genetic correlations were found between BMI and depression at ages 16 and 21, but not at 12. Within TwinsUK, depression was weakly correlated with weight indicators; therefore, it was not possible to generate precise estimates of genetic or environmental correlations. CONCLUSIONS: The directionality of the relationship between BMI and depression appears to be developmentally sensitive. Further research with larger genetically informative samples is needed to estimate the aetiological influence on these associations.

Diversity of symptom phenotypes in SARS-CoV-2 community infections observed in multiple large datasets.

Variability in case severity and in the range of symptoms experienced has been apparent from the earliest months of the COVID-19 pandemic. From a clinical perspective, symptom variability might indicate various routes/mechanisms by which infection leads to disease, with different routes requiring potentially different treatment approaches. For public health and control of transmission, symptoms in community cases were the prompt upon which action such as PCR testing and isolation was taken. However, interpreting symptoms presents challenges, for instance, in balancing the sensitivity and specificity of individual symptoms with the need to maximise case finding, whilst managing demand for limited resources such as testing. For both clinical and transmission control reasons, we require an approach that allows for the possibility of distinct symptom phenotypes, rather than assuming variability along a single dimension. Here we address this problem by bringing together four large and diverse datasets deriving from routine testing, a population-representative household survey and participatory smartphone surveillance in the United Kingdom. Through the use of cutting-edge unsupervised classification techniques from statistics and machine learning, we characterise symptom phenotypes among symptomatic SARS-CoV-2 PCR-positive community cases. We first analyse each dataset in isolation and across age bands, before using methods that allow us to compare multiple datasets. While we observe separation due to the total number of symptoms experienced by cases, we also see a separation of symptoms into gastrointestinal, respiratory and other types, and different symptom co-occurrence patterns at the extremes of age. In this way, we are able to demonstrate the deep structure of symptoms of COVID-19 without usual biases due to study design. This is expected to have implications for the identification and management of community SARS-CoV-2 cases and could be further applied to symptom-based management of other diseases and syndromes.

Activin type I receptor polymorphisms and body composition in older individuals with sarcopenia-Analyses from the LACE randomised controlled trial.

BACKGROUND: Ageing is associated with changes in body composition including an overall reduction in muscle mass and a proportionate increase in fat mass. Sarcopenia is characterised by losses in both muscle mass and strength. Body composition and muscle strength are at least in part genetically determined, consequently polymorphisms in pathways important in muscle biology (e.g., the activin/myostatin signalling pathway) are hypothesised to contribute to the development of sarcopenia. METHODS: We compared regional body composition measured by DXA with genotypes for two polymorphisms (rs10783486, minor allele frequency (MAF) = 0.26 and rs2854464, MAF = 0.26) in the activin 1B receptor (ACVR1B) determined by PCR in a cross-sectional analysis of DNA from 110 older individuals with sarcopenia from the LACE trial. RESULTS: Neither muscle mass nor strength showed any significant associations with either genotype in this cohort. Initial analysis of rs10783486 showed that males with the AA/AG genotype were taller than GG males (174±7cm vs 170±5cm, p = 0.023) and had higher arm fat mass, (median higher by 15%, p = 0.008), and leg fat mass (median higher by 14%, p = 0.042). After correcting for height, arm fat mass remained significantly higher (median higher by 4% padj = 0.024). No associations (adjusted or unadjusted) were seen in females. Similar analysis of the rs2854464 allele showed a similar pattern with the presence of the minor allele (GG/AG) being associated with greater height (GG/AG = 174±7 cm vs AA = 170 ±5cm, p = 0.017) and greater arm fat mass (median higher by 16%, p = 0.023). Again, the difference in arm fat remained after correction for height. No similar associations were seen in females analysed alone. CONCLUSION: These data suggest that polymorphic variation in the ACVR1B locus could be associated with body composition in older males. The activin/myostatin pathway might offer a novel potential target to prevent fat accumulation in older individuals.

Accurate phenotypic classification and exome sequencing allow identification of novel genes and variants associated with adult-onset hearing loss.

Adult-onset progressive hearing loss is a common, complex disease with a strong genetic component. Although to date over 150 genes have been identified as contributing to human hearing loss, many more remain to be discovered, as does most of the underlying genetic diversity. Many different variants have been found to underlie adult-onset hearing loss, but they tend to be rare variants with a high impact upon the gene product. It is likely that combinations of more common, lower impact variants also play a role in the prevalence of the disease. Here we present our exome study of hearing loss in a cohort of 532 older adult volunteers with extensive phenotypic data, including 99 older adults with normal hearing, an important control set. Firstly, we carried out an outlier analysis to identify genes with a high variant load in older adults with hearing loss compared to those with normal hearing. Secondly, we used audiometric threshold data to identify individual variants which appear to contribute to different threshold values. We followed up these analyses in a second cohort. Using these approaches, we identified genes and variants linked to better hearing as well as those linked to worse hearing. These analyses identified some known deafness genes, demonstrating proof of principle of our approach. However, most of the candidate genes are novel associations with hearing loss. While the results support the suggestion that genes responsible for severe deafness may also be involved in milder hearing loss, they also suggest that there are many more genes involved in hearing which remain to be identified. Our candidate gene lists may provide useful starting points for improved diagnosis and drug development.

ACE I/D genotype associates with strength in sarcopenic men but not with response to ACE inhibitor therapy in older adults with sarcopenia: Results from the LACE trial.

BACKGROUND: Angiotensin II (AII), has been suggested to promote muscle loss. Reducing AII synthesis, by inhibiting angiotensin converting enzyme (ACE) activity has been proposed as a method to inhibit muscle loss. The LACE clinical trial was designed to determine whether ACE inhibition would reduce further muscle loss in individuals with sarcopenia but suffered from low recruitment and returned a negative result. Polymorphic variation in the ACE promoter (I/D alleles) has been associated with differences in ACE activity and muscle physiology in a range of clinical conditions. This aim of this analysis was to determine whether I/D polymorphic variation is associated with muscle mass, strength, in sarcopenia or contributed to the lack of response to treatment in the LACE study. METHODS: Sarcopenic individuals were recruited into a 2x2 factorial multicentre double-blind study of the effects of perindopril and/or leucine versus placebo on physical performance and muscle mass. DNA extracted from blood samples (n = 130 72 women and 58 men) was genotyped by PCR for the ACE I/D polymorphism. Genotypes were then compared with body composition measured by DXA, hand grip and quadriceps strength before and after 12 months' treatment with leucine and/or perindopril in a cross-sectional analysis of the influence of genotype on these variables. RESULTS: Allele frequencies for the normal UK population were extracted from 13 previous studies (I = 0.473, D = 0.527). In the LACE cohort the D allele was over-represented (I = 0.412, D = 0.588, p = 0.046). This over-representation was present in men (I = 0.353, D = 0.647, p = 0.010) but not women (I = 0.458, D = 0.532, p = 0.708). In men but not women, individuals with the I allele had greater leg strength (II/ID = 18.00 kg (14.50, 21.60) vs DD = 13.20 kg (10.50, 15.90), p = 0.028). Over the 12 months individuals with the DD genotype increased in quadriceps strength but those with the II or ID genotype did not. Perindopril did not increase muscle strength or mass in any polymorphism group relative to placebo. CONCLUSION: Our results suggest that although ACE genotype was not associated with response to ACE inhibitor therapy in the LACE trial population, sarcopenic men with the ACE DD genotype may be weaker than those with the ACE I/D or II genotype.

The effects of COVID-19 on cognitive performance in a community-based cohort: a COVID symptom study biobank prospective cohort study.

Background: Cognitive impairment has been reported after many types of infection, including SARS-CoV-2. Whether deficits following SARS-CoV-2 improve over time is unclear. Studies to date have focused on hospitalised individuals with up to a year follow-up. The presence, magnitude, persistence and correlations of effects in community-based cases remain relatively unexplored. Methods: Cognitive performance (working memory, attention, reasoning, motor control) was assessed in a prospective cohort study of participants from the United Kingdom COVID Symptom Study Biobank between July 12, 2021 and August 27, 2021 (Round 1), and between April 28, 2022 and June 21, 2022 (Round 2). Participants, recruited from the COVID Symptom Study smartphone app, comprised individuals with and without SARS-CoV-2 infection and varying symptom duration. Effects of COVID-19 exposures on cognitive accuracy and reaction time scores were estimated using multivariable ordinary least squares linear regression models weighted for inverse probability of participation, adjusting for potential confounders and mediators. The role of ongoing symptoms after COVID-19 infection was examined stratifying for self-perceived recovery. Longitudinal analysis assessed change in cognitive performance between rounds. Findings: 3335 individuals completed Round 1, of whom 1768 also completed Round 2. At Round 1, individuals with previous positive SARS-CoV-2 tests had lower cognitive accuracy (N = 1737, ß = -0.14 standard deviations, SDs, 95% confidence intervals, CI: -0.21, -0.07) than negative controls. Deficits were largest for positive individuals with ≥12 weeks of symptoms (N = 495, ß = -0.22 SDs, 95% CI: -0.35, -0.09). Effects were comparable to hospital presentation during illness (N = 281, ß = -0.31 SDs, 95% CI: -0.44, -0.18), and 10 years age difference (60-70 years vs. 50-60 years, ß = -0.21 SDs, 95% CI: -0.30, -0.13) in the whole study population. Stratification by self-reported recovery revealed that deficits were only detectable in SARS-CoV-2 positive individuals who did not feel recovered from COVID-19, whereas individuals who reported full recovery showed no deficits. Longitudinal analysis showed no evidence of cognitive change over time, suggesting that cognitive deficits for affected individuals persisted at almost 2 years since initial infection. Interpretation: Cognitive deficits following SARS-CoV-2 infection were detectable nearly two years post infection, and largest for individuals with longer symptom durations, ongoing symptoms, and/or more severe infection. However, no such deficits were detected in individuals who reported full recovery from COVID-19. Further work is needed to monitor and develop understanding of recovery mechanisms for those with ongoing symptoms. Funding: Chronic Disease Research Foundation, Wellcome Trust, National Institute for Health and Care Research, Medical Research Council, British Heart Foundation, Alzheimer's Society, European Union, COVID-19 Driver Relief Fund, French National Research Agency.

SARS-CoV-2 infection following booster vaccination: Illness and symptom profile in a prospective, observational community-based case-control study.

BACKGROUND: Booster COVID-19 vaccines have shown efficacy in clinical trials and effectiveness in real-world data against symptomatic and severe illness. However, some people still become infected with SARS-CoV-2 following a third (booster) vaccination. This study describes the characteristics of SARS-CoV-2 illness following a third vaccination and assesses the risk of progression to symptomatic disease in SARS-CoV-2 infected individuals with time since vaccination. METHODS: This prospective, community-based, case-control study used data from UK-based, adult (≥18 years) users of the COVID Symptom Study mobile application, self-reporting a first positive COVID-19 test between June 1, 2021 and April 1, 2022. To describe the characteristics of SARS-CoV-2 illness following a third vaccination, we selected cases and controls who had received a third and second dose of monovalent vaccination against COVID-19, respectively, and reported a first positive SARS-CoV-2 test at least 7 days after most recent vaccination. Cases and controls were matched (1:1) based on age, sex, BMI, time between first vaccination and infection, and week of testing. We used logistic regression models (adjusted for age, sex, BMI, level of social deprivation and frailty) to analyse associations of disease severity, overall disease duration, and individual symptoms with booster vaccination status. To assess for potential waning of vaccine effectiveness, we compared disease severity, duration, and symptom profiles of individuals testing positive within 3 months of most recent vaccination (reference group) to profiles of individuals infected between 3 and 4, 4-5, and 5-6 months, for both third and second dose. All analyses were stratified by time period, based on the predominant SARS-CoV-2 variant at time of infection (Delta: June 1, 2021-27 Nov, 2021; Omicron: 20 Dec, 2021-Apr 1, 2022). FINDINGS: During the study period, 50,162 (Delta period) and 162,041 (Omicron) participants reported a positive SARS-CoV-2 test. During the Delta period, infection following three vaccination doses was associated with lower odds of long COVID (symptoms≥ 4 weeks) (OR=0.83, CI[0.50-1.36], p < 0.0001), hospitalisation (OR=0.55, CI[0.39-0.75], p < 0.0001) and severe symptoms (OR=0.36, CI[0.27-0.49], p < 0.0001), and higher odds of asymptomatic infection (OR=3.45, CI[2.86-4.16], p < 0.0001), compared to infection following only two vaccination doses. During the Omicron period, infection following three vaccination doses was associated with lower odds of severe symptoms (OR=0.48, CI[0.42-0.55], p < 0.0001). During the Delta period, infected individuals were less likely to report almost all individual symptoms after a third vaccination. During the Omicron period, individuals were less likely to report most symptoms after a third vaccination, except for upper respiratory symptoms e.g. sneezing (OR=1.40, CI[1.18-1.35], p < 0.0001), runny nose (OR=1.26, CI[1.18-1.35], p < 0.0001), sore throat (OR=1.17, CI[1.10-1.25], p < 0.0001), and hoarse voice (OR=1.13, CI[1.06-1.21], p < 0.0001), which were more likely to be reported. There was evidence of reduced vaccine effectiveness during both Delta and Omicron periods in those infected more than 3 months after their most recent vaccination, with increased reporting of severe symptoms, long duration illness, and most individual symptoms. INTERPRETATION: This study suggests that a third dose of monovalent vaccine may reduce symptoms, severity and duration of SARS-CoV-2 infection following vaccination. For Omicron variants, the third vaccination appears to reduce overall symptom burden but may increase upper respiratory symptoms, potentially due to immunological priming. There is evidence of waning vaccine effectiveness against progression to symptomatic and severe disease and long COVID after three months. Our findings support ongoing booster vaccination promotion amongst individuals at high risk from COVID-19, to reduce severe symptoms and duration of illness, and health system burden. Disseminating knowledge on expected symptoms following booster vaccination may encourage vaccine uptake.

Metabolomic and gut microbiome profiles across the spectrum of community-based COVID and non-COVID disease.

Whilst most individuals with SARS-CoV-2 infection have relatively mild disease, managed in the community, it was noted early in the pandemic that individuals with cardiovascular risk factors were more likely to experience severe acute disease, requiring hospitalisation. As the pandemic has progressed, increasing concern has also developed over long symptom duration in many individuals after SARS-CoV-2 infection, including among the majority who are managed acutely in the community. Risk factors for long symptom duration, including biological variables, are still poorly defined. Here, we examine post-illness metabolomic profiles, using nuclear magnetic resonance (Nightingale Health Oyj), and gut-microbiome profiles, using shotgun metagenomic sequencing (Illumina Inc), in 2561 community-dwelling participants with SARS-CoV-2. Illness duration ranged from asymptomatic (n = 307) to Post-COVID Syndrome (n = 180), and included participants with prolonged non-COVID-19 illnesses (n = 287). We also assess a pre-established metabolomic biomarker score, previously associated with hospitalisation for both acute pneumonia and severe acute COVID-19 illness, for its association with illness duration. We found an atherogenic-dyslipidaemic metabolic profile, including biomarkers such as fatty acids and cholesterol, was associated with longer duration of illness, both in individuals with and without SARS-CoV-2 infection. Greater values of a pre-existing metabolomic biomarker score also associated with longer duration of illness, regardless of SARS-CoV-2 infection. We found no association between illness duration and gut microbiome profiles in convalescence. This highlights the potential role of cardiometabolic dysfunction in relation to the experience of long duration symptoms after symptoms of acute infection, both COVID-19 as well as other illnesses.

Profiling post-COVID-19 condition across different variants of SARS-CoV-2: a prospective longitudinal study in unvaccinated wild-type, unvaccinated alpha-variant, and vaccinated delta-variant populations.

BACKGROUND: Self-reported symptom studies rapidly increased understanding of SARS-CoV-2 during the COVID-19 pandemic and enabled monitoring of long-term effects of COVID-19 outside hospital settings. Post-COVID-19 condition presents as heterogeneous profiles, which need characterisation to enable personalised patient care. We aimed to describe post-COVID-19 condition profiles by viral variant and vaccination status. METHODS: In this prospective longitudinal cohort study, we analysed data from UK-based adults (aged 18-100 years) who regularly provided health reports via the Covid Symptom Study smartphone app between March 24, 2020, and Dec 8, 2021. We included participants who reported feeling physically normal for at least 30 days before testing positive for SARS-CoV-2 who subsequently developed long COVID (ie, symptoms lasting longer than 28 days from the date of the initial positive test). We separately defined post-COVID-19 condition as symptoms that persisted for at least 84 days after the initial positive test. We did unsupervised clustering analysis of time-series data to identify distinct symptom profiles for vaccinated and unvaccinated people with post-COVID-19 condition after infection with the wild-type, alpha (B.1.1.7), or delta (B.1.617.2 and AY.x) variants of SARS-CoV-2. Clusters were then characterised on the basis of symptom prevalence, duration, demography, and previous comorbidities. We also used an additional testing sample with additional data from the Covid Symptom Study Biobank (collected between October, 2020, and April, 2021) to investigate the effects of the identified symptom clusters of post-COVID-19 condition on the lives of affected people. FINDINGS: We included 9804 people from the COVID Symptom Study with long COVID, 1513 (15%) of whom developed post-COVID-19 condition. Sample sizes were sufficient only for analyses of the unvaccinated wild-type, unvaccinated alpha variant, and vaccinated delta variant groups. We identified distinct profiles of symptoms for post-COVID-19 condition within and across variants: four endotypes were identified for infections due to the wild-type variant (in unvaccinated people), seven for the alpha variant (in unvaccinated people), and five for the delta variant (in vaccinated people). Across all variants, we identified a cardiorespiratory cluster of symptoms, a central neurological cluster, and a multi-organ systemic inflammatory cluster. These three main clusers were confirmed in a testing sample. Gastrointestinal symptoms clustered in no more than two specific phenotypes per viral variant. INTERPRETATION: Our unsupervised analysis identified different profiles of post-COVID-19 condition, characterised by differing symptom combinations, durations, and functional outcomes. Our classification could be useful for understanding the distinct mechanisms of post-COVID-19 condition, as well as for identification of subgroups of individuals who might be at risk of prolonged debilitation. FUNDING: UK Government Department of Health and Social Care, Chronic Disease Research Foundation, The Wellcome Trust, UK Engineering and Physical Sciences Research Council, UK Research and Innovation London Medical Imaging & Artificial Intelligence Centre for Value-Based Healthcare, UK National Institute for Health Research, UK Medical Research Council, British Heart Foundation, UK Alzheimer's Society, and ZOE.

Accurate phenotypic classification and exome sequencing allow identification of novel genes and variants associated with adult-onset hearing loss.

Adult-onset progressive hearing loss is a common, complex disease with a strong genetic component. Although to date over 150 genes have been identified as contributing to human hearing loss, many more remain to be discovered, as does most of the underlying genetic diversity. Many different variants have been found to underlie adult-onset hearing loss, but they tend to be rare variants with a high impact upon the gene product. It is likely that combinations of more common, lower impact variants also play a role in the prevalence of the disease. Here we present our exome study of hearing loss in a cohort of 532 older adult volunteers with extensive phenotypic data, including 99 older adults with normal hearing, an important control set. Firstly, we carried out an outlier analysis to identify genes with a high variant load in older adults with hearing loss compared to those with normal hearing. Secondly, we used audiometric threshold data to identify individual variants which appear to contribute to different threshold values. We followed up these analyses in a second cohort. Using these approaches, we identified genes and variants linked to better hearing as well as those linked to worse hearing. These analyses identified some known deafness genes, demonstrating proof of principle of our approach. However, most of the candidate genes are novel associations with hearing loss. While the results support the suggestion that genes responsible for severe deafness may also be involved in milder hearing loss, they also suggest that there are many more genes involved in hearing which remain to be identified. Our candidate gene lists may provide useful starting points for improved diagnosis and drug development.

Interplay between the (Poly)phenol Metabolome, Gut Microbiome, and Cardiovascular Health in Women: A Cross-Sectional Study from the TwinsUK Cohort.

BACKGROUND: Dietary (poly)phenol consumption is inversely associated with cardiovascular disease (CVD) risk in epidemiological studies, but little is known about the role of the gut microbiome in this relationship. METHODS: In 200 healthy females, aged 62.0 ± 10.0 years, from the TwinsUK cohort, 114 individual (poly)phenol metabolites were measured from spot urine using ultra-high-performance liquid chromatography-mass spectrometry. The associations between metabolites, the gut microbiome (alpha diversity and genera), and cardiovascular scores were investigated using linear mixed models adjusting age, BMI, fibre, energy intake, family relatedness, and multiple testing (FDR < 0.1). RESULTS: Significant associations were found between phenolic acid metabolites, CVD risk, and the gut microbiome. A total of 35 phenolic acid metabolites were associated with the Firmicutes phylum, while 5 metabolites were associated with alpha diversity (FDR-adjusted p < 0.05). Negative associations were observed between the atherosclerotic CVD (ASCVD) risk score and five phenolic acid metabolites, two tyrosol metabolites, and daidzein with stdBeta (95% (CI)) ranging from -0.05 (-0.09, -0.01) for 3-(2,4-dihydroxyphenyl)propanoic acid to -0.04 (-0.08, -0.003) for 2-hydroxycinnamic acid (FDR-adjusted p < 0.1). The genus 5-7N15 in the Bacteroidetes phylum was positively associated with the same metabolites, including 3-(3,5-dihydroxyphenyl)propanoic acid, 3-(2,4-dihydroxyphenyl)propanoic acid, 3-(3,4-dihydroxyphenyl)propanoic acid), 3-hydroxyphenylethanol-4-sulfate, and 4-hydroxyphenylethanol-3-sulfate)(stdBeta (95% CI): 0.23 (0.09, 0.36) to 0.28 (0.15, 0.42), FDR-adjusted p < 0.05), and negatively associated with the ASCVD score (stdBeta (95% CI): -0.05 (-0.09, -0.01), FDR-adjusted p = 0.02). Mediation analysis showed that genus 5-7N15 mediated 23.8% of the total effect of 3-(3,4-dihydroxyphenyl)propanoic acid on the ASCVD score. CONCLUSIONS: Coffee, tea, red wine, and several vegetables and fruits, especially berries, are the most abundant food sources of phenolic acids that have the strongest associations with CVD risk. We found that the gut microbiome, particularly the genus 5-7N15, partially mediates the negative association between urinary (poly)phenols and cardiovascular risk, supporting a key role of the gut microbiome in the health benefits of dietary (poly)phenols.