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BACKGROUND AND OBJECTIVES: Previous randomized controlled trials and longitudinal studies have indicated that ongoing antihypertensive use in late life reduces all-cause dementia risk, but the specific impact on Alzheimer dementia (AD) and non-AD risk remains unclear. This study investigates whether previous hypertension or antihypertensive use modifies AD or non-AD risk in late life and the ideal blood pressure (BP) for risk reduction in a diverse consortium of cohort studies. METHODS: This individual participant data meta-analysis included community-based longitudinal studies of aging from a preexisting consortium. The main outcomes were risk of developing AD and non-AD. The main exposures were hypertension history/antihypertensive use and baseline systolic BP/diastolic BP. Mixed-effects Cox proportional hazards models were used to assess risk and natural splines were applied to model the relationship between BP and the dementia outcomes. The main model controlled for age, age2, sex, education, ethnoracial group, and study cohort. Supplementary analyses included a fully adjusted model, an analysis restricting to those with >5 years of follow-up and models that examined the moderating effect of age, sex, and ethnoracial group. RESULTS: There were 31,250 participants from 14 nations in the analysis (41% male) with a mean baseline age of 72 (SD 7.5, range 60-110) years. Participants with untreated hypertension had a 36% (hazard ratio [HR] 1.36, 95% CI 1.01-1.83, p = 0.0406) and 42% (HR 1.42, 95% CI 1.08-1.87, p = 0.0135) increased risk of AD compared with "healthy controls" and those with treated hypertension, respectively. Compared with "healthy controls" both those with treated (HR 1.29, 95% CI 1.03-1.60, p = 0.0267) and untreated hypertension (HR 1.69, 95% CI 1.19-2.40, p = 0.0032) had greater non-AD risk, but there was no difference between the treated and untreated groups. Baseline diastolic BP had a significant U-shaped relationship (p = 0.0227) with non-AD risk in an analysis restricted to those with 5-year follow-up, but otherwise there was no significant relationship between baseline BP and either AD or non-AD risk. DISCUSSION: Antihypertensive use was associated with decreased AD but not non-AD risk throughout late life. This suggests that treating hypertension throughout late life continues to be crucial in AD risk mitigation. A single measure of BP was not associated with AD risk, but DBP may have a U-shaped relationship with non-AD risk over longer periods in late life.

Asunto(s)

Enfermedad de Alzheimer , Antihipertensivos , Presión Sanguínea , Demencia , Hipertensión , Humanos , Enfermedad de Alzheimer/epidemiología , Enfermedad de Alzheimer/tratamiento farmacológico , Antihipertensivos/uso terapéutico , Hipertensión/tratamiento farmacológico , Hipertensión/epidemiología , Hipertensión/complicaciones , Anciano , Presión Sanguínea/efectos de los fármacos , Demencia/epidemiología , Masculino , Femenino , Anciano de 80 o más Años , Estudios Longitudinales , Factores de Riesgo

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The impact of gestational diabetes mellitus (GDM) on maternal or infant microbiome trajectory remains poorly understood. Utilizing large-scale longitudinal fecal samples from 264 mother-baby dyads, we present the gut microbiome trajectory of the mothers throughout pregnancy and infants during the first year of life. GDM mothers had a distinct microbiome diversity and composition during the gestation period. GDM leaves fingerprints on the infant's gut microbiome, which are confounded by delivery mode. Further, Clostridium species positively correlate with a larger head circumference at month 12 in male offspring but not females. The gut microbiome of GDM mothers with male fetuses displays depleted gut-brain modules, including acetate synthesis I and degradation and glutamate synthesis II. The gut microbiome of female infants of GDM mothers has higher histamine degradation and dopamine degradation. Together, our integrative analysis indicates that GDM affects maternal and infant gut composition, which is associated with sexually dimorphic infant head growth.

Asunto(s)

Diabetes Gestacional , Heces , Microbioma Gastrointestinal , Femenino , Humanos , Diabetes Gestacional/microbiología , Embarazo , Masculino , Lactante , Heces/microbiología , Cabeza/microbiología , Adulto , Recién Nacido , Clostridium/crecimiento & desarrollo , Efectos Tardíos de la Exposición Prenatal/microbiología

RESUMEN

Associations between the gut microbiome and autism spectrum disorder (ASD) have been investigated although most studies have focused on the bacterial component of the microbiome. Whether gut archaea, fungi and viruses, or function of the gut microbiome, is altered in ASD is unclear. Here we performed metagenomic sequencing on faecal samples from 1,627 children (aged 1-13 years, 24.4% female) with or without ASD, with extensive phenotype data. Integrated analyses revealed that 14 archaea, 51 bacteria, 7 fungi, 18 viruses, 27 microbial genes and 12 metabolic pathways were altered in children with ASD. Machine learning using single-kingdom panels showed area under the curve (AUC) of 0.68 to 0.87 in differentiating children with ASD from those that are neurotypical. A panel of 31 multikingdom and functional markers showed a superior diagnostic accuracy with an AUC of 0.91, with comparable performance for males and females. Accuracy of the model was predominantly driven by the biosynthesis pathways of ubiquinol-7 or thiamine diphosphate, which were less abundant in children with ASD. Collectively, our findings highlight the potential application of multikingdom and functional gut microbiota markers as non-invasive diagnostic tools in ASD.

Asunto(s)

Trastorno del Espectro Autista , Bacterias , Biomarcadores , Heces , Microbioma Gastrointestinal , Humanos , Microbioma Gastrointestinal/genética , Trastorno del Espectro Autista/microbiología , Trastorno del Espectro Autista/diagnóstico , Femenino , Masculino , Niño , Preescolar , Adolescente , Heces/microbiología , Biomarcadores/análisis , Lactante , Bacterias/genética , Bacterias/clasificación , Bacterias/aislamiento & purificación , Bacterias/metabolismo , Metagenómica/métodos , Aprendizaje Automático , Archaea/genética , Archaea/metabolismo , Archaea/clasificación , Archaea/aislamiento & purificación , Hongos/genética , Hongos/clasificación , Hongos/aislamiento & purificación , Virus/genética , Virus/aislamiento & purificación , Virus/clasificación , Metagenoma

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The gut fungi play important roles in human health and are involved in energy metabolism. This study aimed to examine gut mycobiome composition in obese subjects in two geographically different regions in China and to identify specific gut fungi associated with obesity. A total of 217 subjects from two regions with different urbanization levels [Hong Kong (HK): obese, n = 59; lean, n = 59; Kunming (KM): obese, n = 50; lean, n = 49. Mean body mass index (BMI) for obesity = 33.7] were recruited. We performed deep shotgun metagenomic sequencing on fecal samples to compare gut mycobiome composition and trophic functions in lean and obese subjects across these two regions. The gut mycobiome of obese subjects in both HK and KM were altered compared to those of lean subjects, characterized by a decrease in the relative abundance of Nakaseomyces, Schizosaccharomyces pombe, Candida dubliniensis and an increase in the abundance of Lanchanceathermotolerans, Saccharomyces paradox, Parastagonospora nodorum and Myceliophthorathermophila. Reduced fungal - bacterial and fungal - fungal correlations as well as increased negative fungal-bacterial correlations were observed in the gut of obese subjects. Furthermore, the anti-obesity effect of fungus S. pombe was further validated using a mouse model. Supplementing high-fat diet-induced obese mice with the fungus for 12 weeks led to a significant reduction in body weight gain (p < 0.001), and an improvement in lipid and glucose metabolism compared to mice without intervention. In conclusion, the gut mycobiome composition and functionalities of obese subjects were altered. These data shed light on the potential of utilizing fungus-based therapeutics for the treatment of obesity. S. pombe may serve as a potential fungal probiotic in the prevention of diet-induced obesity and future human trials are needed.

Asunto(s)

Heces , Hongos , Microbioma Gastrointestinal , Micobioma , Obesidad , Obesidad/microbiología , Humanos , Animales , Hongos/clasificación , Hongos/aislamiento & purificación , Hongos/genética , Masculino , Ratones , China , Femenino , Heces/microbiología , Adulto , Bacterias/clasificación , Bacterias/aislamiento & purificación , Bacterias/genética , Persona de Mediana Edad , Ratones Endogámicos C57BL , Índice de Masa Corporal

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BACKGROUND & AIMS: Post-acute COVID-19 syndrome (PACS) is associated with sleep disturbance, but treatment options are limited. The etiology of PACS may be secondary to alterations in the gut microbiome. Here, we report the efficacy of fecal microbiota transplantation (FMT) in alleviating post-COVID insomnia symptoms in a nonrandomized, open-label prospective interventional study. METHODS: Between September 22, 2022, and May 22, 2023, we recruited 60 PACS patients with insomnia defined as Insomnia Severity Index (ISI) ≥8 and assigned them to the FMT group (FMT at weeks 0, 2, 4, and 8; n = 30) or the control group (n = 30). The primary outcome was clinical remission defined by an ISI of <8 at 12 weeks. Secondary outcomes included changes in the Pittsburgh Sleep Quality Index, Generalized Anxiety Disorder-7 scale, Epworth Sleepiness Scale, Multidimensional Fatigue Inventory, blood cortisol and melatonin, and gut microbiome analysis on metagenomic sequencing. RESULTS: At week 12, more patients in the FMT than the control group had insomnia remission (37.9% vs 10.0%; P = .018). The FMT group showed a decrease in ISI score (P < .0001), Pittsburgh Sleep Quality Index (P < .0001), Generalized Anxiety Disorder-7 scale (P = .0019), Epworth Sleepiness Scale (P = .0057), and blood cortisol concentration (P = .035) from baseline to week 12, but there was no significant change in the control group. There was enrichment of bacteria such as Gemmiger formicilis and depletion of microbial pathways producing menaquinol derivatives after FMT. The gut microbiome profile resembled that of the donor in FMT responders but not in nonresponders at week 12. There was no serious adverse event. CONCLUSIONS: This pilot study showed that FMT could be effective and safe in alleviating post-COVID insomnia, and further clinical trials are warranted. CLINICALTRIALS: gov, Number: NCT05556733.

RESUMEN

To investigate the association of attention-deficit/hyperactivity disorder (ADHD) with the 48-base pair (bp) variable number of tandem repeats (VNTR) in exon 3 of the dopamine receptor D4 (DRD4) gene, we genotyped 240 ADHD patients and their parents from Hong Kong. The 4R allele was most common, followed by 2R. We examined association between the 2R allele (relative to 4R) and ADHD by Transmission Disequilibrium Test (TDT). The odds ratio (OR) (95% confidence interval) was 0.90 (0.64-1.3). The p-value was 0.6. Examining subgroups revealed nominally significant association of 2R with inattentive ADHD: OR = 0.33 (0.12-0.92) and p = 0.03. Because our study used TDT analysis, we meta-analyzed the association of 2R with ADHD in Asians (1329 patient alleles), revealing results similar to ours: OR = 0.97 (0.80-1.2) and p = 0.8. To examine the association of 2R with inattentive ADHD, we meta-analyzed all studies (regardless of analysis type or ethnicity, in order to increase statistical power): 702 patient alleles, 1420 control alleles, OR = 0.81 (0.57-1.1) and p = 0.2. Overall, there is no evidence of association between ADHD and the 2R allele, but the suggestive association with the inattentive type warrants further investigation.

Asunto(s)

Alelos , Trastorno por Déficit de Atención con Hiperactividad , Exones , Repeticiones de Minisatélite , Receptores de Dopamina D4 , Humanos , Trastorno por Déficit de Atención con Hiperactividad/genética , Receptores de Dopamina D4/genética , Masculino , Femenino , Niño , Hong Kong , Genotipo , Desequilibrio de Ligamiento , Adolescente , Predisposición Genética a la Enfermedad

RESUMEN

The mechanisms underlying the many phenotypic manifestations of post-acute COVID-19 syndrome (PACS) are poorly understood. Herein, we characterized the gut microbiome in heterogeneous cohorts of subjects with PACS and developed a multi-label machine learning model for using the microbiome to predict specific symptoms. Our processed data covered 585 bacterial species and 500 microbial pathways, explaining 12.7% of the inter-individual variability in PACS. Three gut-microbiome-based enterotypes were identified in subjects with PACS and associated with different phenotypic manifestations. The trained model showed an accuracy of 0.89 in predicting individual symptoms of PACS in the test set and maintained a sensitivity of 86% and a specificity of 82% in predicting upcoming symptoms in an independent longitudinal cohort of subjects before they developed PACS. This study demonstrates that the gut microbiome is associated with phenotypic manifestations of PACS, which has potential clinical utility for the prediction and diagnosis of PACS.

Asunto(s)

COVID-19 , Microbioma Gastrointestinal , Aprendizaje Automático , Fenotipo , Síndrome Post Agudo de COVID-19 , SARS-CoV-2 , Humanos , COVID-19/microbiología , Masculino , Femenino , Persona de Mediana Edad , Adulto , Bacterias/clasificación , Bacterias/aislamiento & purificación , Bacterias/genética , Anciano , Heces/microbiología , Heces/virología , Estudios de Cohortes , Estudios Longitudinales

RESUMEN

The host-microbiota relationship has evolved to shape mammalian physiology, including immunity, metabolism, and development. Germ-free models are widely used to study microbial effects on host processes such as immunity. Here, we find that both germ-free and T cell-deficient mice exhibit a robust sebum secretion defect persisting across multiple generations despite microbial colonization and T cell repletion. These phenotypes are inherited by progeny conceived during in vitro fertilization using germ-free sperm and eggs, demonstrating that non-genetic information in the gametes is required for microbial-dependent phenotypic transmission. Accordingly, gene expression in early embryos derived from gametes from germ-free or T cell-deficient mice is strikingly and similarly altered. Our findings demonstrate that microbial- and immune-dependent regulation of non-genetic information in the gametes can transmit inherited phenotypes transgenerationally in mice. This mechanism could rapidly generate phenotypic diversity to enhance host adaptation to environmental perturbations.

Asunto(s)

Microbiota , Fenotipo , Linfocitos T , Animales , Ratones , Linfocitos T/inmunología , Linfocitos T/metabolismo , Masculino , Femenino , Ratones Endogámicos C57BL

RESUMEN

Background: The disruption of the neurovascular unit (NVU), which maintains the integrity of the blood brain barrier (BBB), has been identified as a critical mechanism in the development of cerebrovascular and neurodegenerative disorders. However, the understanding of the pathophysiological mechanisms linking NVU dysfunction to the disorders is incomplete, and reliable blood biomarkers to measure NVU dysfunction are yet to be established. This systematic review and meta-analysis aimed to identify biomarkers associated with BBB dysfunction in large vessel disease, small vessel disease (SVD) and vascular cognitive disorders (VCD). Methods: A literature search was conducted in PubMed, EMBASE, Scopus and PsychINFO to identify blood biomarkers related to dysfunction of the NVU in disorders with vascular pathologies published until 20 November 2023. Studies that assayed one or more specific markers in human serum or plasma were included. Quality of studies was assessed using the Newcastle-Ottawa Quality Assessment Scale. Effects were pooled and methodological heterogeneity examined using the random effects model. Results: A total of 112 studies were included in this review. Where study numbers allowed, biomarkers were analysed using random effect meta-analysis for VCD (1 biomarker; 5 studies) and cerebrovascular disorders, including stroke and SVD (9 biomarkers; 29 studies) while all remaining biomarkers (n = 17 biomarkers; 78 studies) were examined through qualitative analysis. Results of the meta-analysis revealed that cerebrospinal fluid/serum albumin quotient (Q-Alb) reliably differentiates VCD patients from healthy controls (MD = 2.77; 95 % CI = 1.97-3.57; p < 0.0001) while commonly measured biomarkers of endothelial dysfunction (VEGF, VCAM-1, ICAM-1, vWF and E-selectin) and neuronal injury (NfL) were significantly elevated in vascular pathologies. A qualitative assessment of non-meta-analysed biomarkers revealed NSE, NfL, vWF, ICAM-1, VCAM-1, lipocalin-2, MMP-2 and MMP-9 levels to be upregulated in VCD, although these findings were not consistently replicated. Conclusions: This review identifies several promising biomarkers of NVU dysfunction which require further validation. A panel of biomarkers representing multiple pathophysiological pathways may offer greater discriminative power in distinguishing possible disease mechanisms of VCD.

RESUMEN

BACKGROUND: Post-acute COVID-19 syndrome (PACS) affects over 65 million individuals worldwide but treatment options are scarce. We aimed to assess a synbiotic preparation (SIM01) for the alleviation of PACS symptoms. METHODS: In this randomised, double-blind, placebo-controlled trial at a tertiary referral centre in Hong Kong, patients with PACS according to the US Centers for Disease Control and Prevention criteria were randomly assigned (1:1) by random permuted blocks to receive SIM01 (10 billion colony-forming units in sachets twice daily) or placebo orally for 6 months. Inclusion criterion was the presence of at least one of 14 PACS symptoms for 4 weeks or more after confirmed SARS-CoV-2 infection, including fatigue, memory loss, difficulty in concentration, insomnia, mood disturbance, hair loss, shortness of breath, coughing, inability to exercise, chest pain, muscle pain, joint pain, gastrointestinal upset, or general unwellness. Individuals were excluded if they were immunocompromised, were pregnant or breastfeeding, were unable to receive oral fluids, or if they had received gastrointestinal surgery in the 30 days before randomisation. Participants, care providers, and investigators were masked to group assignment. The primary outcome was alleviation of PACS symptoms by 6 months, assessed by an interviewer-administered 14-item questionnaire in the intention-to-treat population. Forward stepwise multivariable logistical regression was performed to identify predictors of symptom alleviation. The trial is registered with ClinicalTrials.gov, NCT04950803. FINDINGS: Between June 25, 2021, and Aug 12, 2022, 463 patients were randomly assigned to receive SIM01 (n=232) or placebo (n=231). At 6 months, significantly higher proportions of the SIM01 group had alleviation of fatigue (OR 2·273, 95% CI 1·520-3·397, p=0·0001), memory loss (1·967, 1·271-3·044, p=0·0024), difficulty in concentration (2·644, 1·687-4·143, p<0·0001), gastrointestinal upset (1·995, 1·304-3·051, p=0·0014), and general unwellness (2·360, 1·428-3·900, p=0·0008) compared with the placebo group. Adverse event rates were similar between groups during treatment (SIM01 22 [10%] of 232 vs placebo 25 [11%] of 231; p=0·63). Treatment with SIM01, infection with omicron variants, vaccination before COVID-19, and mild acute COVID-19, were predictors of symptom alleviation (p<0·0036). INTERPRETATION: Treatment with SIM01 alleviates multiple symptoms of PACS. Our findings have implications on the management of PACS through gut microbiome modulation. Further studies are warranted to explore the beneficial effects of SIM01 in other chronic or post-infection conditions. FUNDING: Health and Medical Research Fund of Hong Kong, Hui Hoy and Chow Sin Lan Charity Fund, and InnoHK of the HKSAR Government. TRANSLATION: For the Chinese translation of the abstract see Supplementary Materials section.

Asunto(s)

COVID-19 , Complicaciones Infecciosas del Embarazo , Simbióticos , Embarazo , Femenino , Humanos , SARS-CoV-2 , Síndrome Post Agudo de COVID-19 , Hong Kong/epidemiología , Método Doble Ciego , Trastornos de la Memoria , Resultado del Tratamiento

RESUMEN

Importance: The utility of antihypertensives and ideal blood pressure (BP) for dementia prevention in late life remains unclear and highly contested. Objectives: To assess the associations of hypertension history, antihypertensive use, and baseline measured BP in late life (age >60 years) with dementia and the moderating factors of age, sex, and racial group. Data Source and Study Selection: Longitudinal, population-based studies of aging participating in the Cohort Studies of Memory in an International Consortium (COSMIC) group were included. Participants were individuals without dementia at baseline aged 60 to 110 years and were based in 15 different countries (US, Brazil, Australia, China, Korea, Singapore, Central African Republic, Republic of Congo, Nigeria, Germany, Spain, Italy, France, Sweden, and Greece). Data Extraction and Synthesis: Participants were grouped in 3 categories based on previous diagnosis of hypertension and baseline antihypertensive use: healthy controls, treated hypertension, and untreated hypertension. Baseline systolic BP (SBP) and diastolic BP (DBP) were treated as continuous variables. Reporting followed the Preferred Reporting Items for Systematic Review and Meta-Analyses of Individual Participant Data reporting guidelines. Main Outcomes and Measures: The key outcome was all-cause dementia. Mixed-effects Cox proportional hazards models were used to assess the associations between the exposures and the key outcome variable. The association between dementia and baseline BP was modeled using nonlinear natural splines. The main analysis was a partially adjusted Cox proportional hazards model controlling for age, age squared, sex, education, racial group, and a random effect for study. Sensitivity analyses included a fully adjusted analysis, a restricted analysis of those individuals with more than 5 years of follow-up data, and models examining the moderating factors of age, sex, and racial group. Results: The analysis included 17 studies with 34 519 community dwelling older adults (20 160 [58.4%] female) with a mean (SD) age of 72.5 (7.5) years and a mean (SD) follow-up of 4.3 (4.3) years. In the main, partially adjusted analysis including 14 studies, individuals with untreated hypertension had a 42% increased risk of dementia compared with healthy controls (hazard ratio [HR], 1.42; 95% CI 1.15-1.76; P = .001) and 26% increased risk compared with individuals with treated hypertension (HR, 1.26; 95% CI, 1.03-1.53; P = .02). Individuals with treated hypertension had no significant increased dementia risk compared with healthy controls (HR, 1.13; 95% CI, 0.99-1.28; P = .07). The association of antihypertensive use or hypertension status with dementia did not vary with baseline BP. There was no significant association of baseline SBP or DBP with dementia risk in any of the analyses. There were no significant interactions with age, sex, or racial group for any of the analyses. Conclusions and Relevance: This individual patient data meta-analysis of longitudinal cohort studies found that antihypertensive use was associated with decreased dementia risk compared with individuals with untreated hypertension through all ages in late life. Individuals with treated hypertension had no increased risk of dementia compared with healthy controls.

Asunto(s)

Demencia , Hipertensión , Humanos , Femenino , Anciano , Masculino , Presión Sanguínea , Antihipertensivos/uso terapéutico , Estudios Longitudinales , Hipertensión/tratamiento farmacológico , Hipertensión/epidemiología , Demencia/epidemiología

RESUMEN

BACKGROUND: Faecal microbiota transplantation (FMT) has been shown to improve symptoms in a proportion of patients with irritable bowel syndrome (IBS). AIM: We performed a randomised trial to assess the efficacy of FMT in patients with IBS. METHODS: We randomised 56 patients with diarrhoea-predominant IBS 1:1 to FMT or placebo via the duodenal route at baseline and week 4. The primary outcome was > 50 points decrease in IBS severity scoring system (IBS-SSS) score at week 12. Secondary outcomes were improvement in bloating and change in gut microbiota at week 12. After 12-week follow-up, those in the placebo group were assigned to receive open-label FMT. RESULTS: At week 12, 57.1% in the FMT group and 46.4% in the placebo group achieved the primary endpoint (p = 0.42). More patients receiving FMT than placebo had improvement in bloating (72% vs 30%; p = 0.005). In an open-label extension, 65.2% and 82.4% of patients achieved, respectively, the primary endpoint and improvement in bloating. Faecal microbiome of patients in the FMT group showed a reduction in bacteria like Ruminococcus gnavus and enrichment of bacteria such as Lawsonibacter at week 12, while no change in the placebo group. Functional analyses showed that the hydrogen sulphide-producing pathway decreased in patients who had FMT (p < 0.05) accompanied by a reduction in contributing bacteria. There were no serious adverse events related to FMT. CONCLUSION: FMT performed twice at an interval of four weeks did not significantly reduce IBS-SSS score. However, more patients had improvement in abdominal bloating, which was associated with a reduction in hydrogen sulphide-producing bacteria. (ClinicalTrials.gov NCT03125564).

Asunto(s)

Sulfuro de Hidrógeno , Síndrome del Colon Irritable , Humanos , Síndrome del Colon Irritable/microbiología , Trasplante de Microbiota Fecal/efectos adversos , Diarrea/terapia , Diarrea/etiología , Heces/microbiología , Resultado del Tratamiento

RESUMEN

BACKGROUND: This UK Biobank study uses a mendelian randomization approach to mitigate the variability and confounding that has affected previous analyses of the relationship between measured blood pressure (BP) and cognition and thus delineate the true association between the two. METHODS: Systolic BP (SBP) and diastolic BP polygenic risk scores (PRSs) were calculated using summary statistics from the International Consortium of Blood Pressure-Genome Wide Association Study (n=299 024). Adjusted nonlinear mixed-effects regression models were used, including a natural splines term for BP-PRS with outcomes of fluid intelligence, reaction time (RT), and composite attention score. Moderating effects of age, sex, and antihypertensive use were assessed in separate models. RESULTS: There were 448 575 participants (mean age, 56.3 years; age range, 37-72 years) included in the analysis after genetic and neurological disease exclusions. Genetic propensity for high SBP had an approximately linear association with worsened fluid intelligence (P=0.0018). This relationship was significantly moderated by age (P<0.0001). By contrast, genetic propensity for high and low SBP and diastolic BP predicted worse attention function (P=0.0099 and P=0.0019), with high PRSs predicting worse function than low PRSs. Genetic propensity for low SBP and diastolic BP was associated with considerably worse RTs, while for high SBP-PRSs, the RT plateaued (P<0.0001). The relationships between RT and the PRSs were significantly moderated by sex (P<0.0001) and antihypertensive use (P<0.0001). CONCLUSIONS: Genetic propensity for high and low BP impacts on midlife cognition in subtle ways and differentially affects cognitive domains. While a genetic propensity to low BP may preserve nontimed tests in midlife, it may come at a trade-off with worsened attention scores and RT.

Asunto(s)

Antihipertensivos , Hipotensión , Humanos , Adulto , Persona de Mediana Edad , Anciano , Presión Sanguínea/genética , Antihipertensivos/uso terapéutico , Bancos de Muestras Biológicas , Estudio de Asociación del Genoma Completo , Cognición , Reino Unido/epidemiología

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INTRODUCTION: Previous meta-analyses have linked social connections and mild cognitive impairment, dementia, and mortality. However, these used aggregate data from North America and Europe and examined a limited number of social connection markers. METHODS: We used individual participant data (N = 39271, Mage  = 70.67 (40-102), 58.86% female, Meducation  = 8.43 years, Mfollow-up  = 3.22 years) from 13 longitudinal ageing studies. A two-stage meta-analysis of Cox regression models examined the association between social connection markers with our primary outcomes. RESULTS: We found associations between good social connections structure and quality and lower risk of incident mild cognitive impairment (MCI); between social structure and function and lower risk of incident dementia and mortality. Only in Asian cohorts, being married/in a relationship was associated with reduced risk of dementia, and having a confidante was associated with reduced risk of dementia and mortality. DISCUSSION: Different aspects of social connections - structure, function, and quality - are associated with benefits for healthy aging internationally. HIGHLIGHTS: Social connection structure (being married/in a relationship, weekly community group engagement, weekly family/friend interactions) and quality (never lonely) were associated with lower risk of incident MCI. Social connection structure (monthly/weekly friend/family interactions) and function (having a confidante) were associated with lower risk of incident dementia. Social connection structure (living with others, yearly/monthly/weekly community group engagement) and function (having a confidante) were associated with lower risk of mortality. Evidence from 13 longitudinal cohort studies of ageing indicates that social connections are important targets for reducing risk of incident MCI, incident dementia, and mortality. Only in Asian cohorts, being married/in a relationship was associated with reduced risk of dementia, and having a confidante was associated with reduced risk of dementia and mortality.

Asunto(s)

Disfunción Cognitiva , Demencia , Humanos , Femenino , Anciano , Masculino , Estudios Longitudinales , Demencia/epidemiología , Demencia/psicología , Estudios de Cohortes , Disfunción Cognitiva/epidemiología , Disfunción Cognitiva/psicología , Envejecimiento/psicología

RESUMEN

BACKGROUND AND OBJECTIVES: Past studies on poststroke cognitive function have focused on the average performance or change over time, but few have investigated patterns of cognitive trajectories after stroke. This project used latent class growth analysis (LCGA) to identify clusters of patients with similar patterns of cognition scores over the first-year poststroke and the extent to which long-term cognitive outcome is predicted by the clusters ("trajectory groups"). METHODS: Data were sought from the Stroke and Cognition consortium. LCGA was used to identify clusters of trajectories based on standardized global cognition scores at baseline (T1) and at the 1-year follow-up (T2). One-step individual participant data meta-analysis was used to examine risk factors for trajectory groups and association of trajectory groups with cognition at the long-term follow-up (T3). RESULTS: Nine hospital-based stroke cohorts with 1,149 patients (63% male; mean age 66.4 years [SD 11.0]) were included. The median time assessed at T1 was 3.6 months poststroke, 1.0 year at T2, and 3.2 years at T3. LCGA identified 3 trajectory groups, which were characterized by different mean levels of cognition scores at T1 (low-performance, -3.27 SD [0.94], 17%; medium-performance, -1.23 SD [0.68], 48%; and high-performance, 0.71 SD [0.77], 35%). There was significant improvement in cognition for the high-performance group (0.22 SD per year, 95% CI 0.07-0.36), but changes for the low-performance and medium-performance groups were not significant (-0.10 SD per year, 95% CI -0.33 to 0.13; 0.11 SD per year, 95% CI -0.08 to 0.24, respectively). Factors associated with the low- (vs high-) performance group include age (relative risk ratio [RRR] 1.18, 95% CI 1.14-1.23), years of education (RRR 0.61, 95% CI 0.56-0.67), diabetes (RRR 3.78, 95% CI 2.08-6.88), large artery vs small vessel strokes (RRR 2.77, 95% CI 1.32-5.83), and moderate/severe strokes (RRR 3.17, 95% CI 1.42-7.08). Trajectory groups were predictive of global cognition at T3, but its predictive power was comparable with scores at T1. DISCUSSION: The trajectory of cognitive function over the first-year poststroke is heterogenous. Baseline cognitive function ∼3.6 months poststroke is a good predictor of long-term cognitive outcome. Older age, lower levels of education, diabetes, large artery strokes, and greater stroke severity are risk factors for lower cognitive performance over the first year.

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Trastornos del Conocimiento , Disfunción Cognitiva , Accidente Cerebrovascular , Humanos , Masculino , Anciano , Femenino , Cognición , Trastornos del Conocimiento/complicaciones , Factores de Riesgo , Disfunción Cognitiva/psicología

RESUMEN

Objective: To investigate the distribution of blood pressure and analyze the associated factors of blood pressure of the elderly with type 2 diabetes in Jiangsu Province. Methods: The elderly over 60 years old participants with type 2 diabetes in the communities of Huai'an City and Changshu City, Jiangsu Province were selected in this study. They were divided into two groups: taking antihypertensive drugs and not taking antihypertensive drugs. The demographic characteristics, such as age and sex, and relevant factors were collected by questionnaire. The systolic blood pressure (SBP) and diastolic blood pressure (DBP) were measured by physical examination. The percentile of SBP and DBP in each age group of men and women were described. The kernel density estimation curve was used to show the blood pressure distribution. The trend of blood pressure with age was fitted by locally weighted regression. The logistic regression model was used to analyze relevant factors of blood pressure. Results: A total of 12 949 participants were included in this study, including 7 775 patients in the antihypertensive drug group and 5 174 patients in the group without antihypertensive drugs. The SBP of participants was concentrated at 140-160 mmHg, and their DBP was concentrated at 75-85 mmHg. There were significant differences in the distribution of blood pressure among the subgroups of body mass index (BMI) and rural areas whether taking antihypertensive drugs and not. For participants aged under 80 years old, the SBP showed an increasing trend with age and the DBP showed a decreasing trend with age. Age, BMI ≥24 kg/m2, fasting blood glucose ≥7.0 mmol/L, living in rural areas and no smoking were influencing factors of the elevated SBP; BMI ≥24 kg/m2, male, living in rural areas, no smoking, drinking alcohol and not receiving drug hypoglycemic treatment were influencing factors of the elevated DBP. Conclusion: The SBP of older diabetic adults in Jiangsu Province is at a high level, and the distribution of blood pressure is significantly different between men and women in taking antihypertensive drugs group. The SBP presents a rising trend and the DBP is decreasing at the age of 60-80 years. The blood pressure level of this population are mainly affected by age, BMI, urban and rural areas, smoking.

Asunto(s)

Adulto , Anciano , Humanos , Masculino , Femenino , Persona de Mediana Edad , Anciano de 80 o más Años , Presión Sanguínea/fisiología , Diabetes Mellitus Tipo 2/epidemiología , Antihipertensivos/uso terapéutico , Fumar , Índice de Masa Corporal , Hipertensión/epidemiología

RESUMEN

Our knowledge of the role of the gut microbiome in acute coronavirus disease 2019 (COVID-19) and post-acute COVID-19 is rapidly increasing, whereas little is known regarding the contribution of multi-kingdom microbiota and host-microbial interactions to COVID-19 severity and consequences. Herein, we perform an integrated analysis using 296 fecal metagenomes, 79 fecal metabolomics, viral load in 1378 respiratory tract samples, and clinical features of 133 COVID-19 patients prospectively followed for up to 6 months. Metagenomic-based clustering identifies two robust ecological clusters (hereafter referred to as Clusters 1 and 2), of which Cluster 1 is significantly associated with severe COVID-19 and the development of post-acute COVID-19 syndrome. Significant differences between clusters could be explained by both multi-kingdom ecological drivers (bacteria, fungi, and viruses) and host factors with a good predictive value and an area under the curve (AUC) of 0.98. A model combining host and microbial factors could predict the duration of respiratory viral shedding with 82.1% accuracy (error ± 3 days). These results highlight the potential utility of host phenotype and multi-kingdom microbiota profiling as a prognostic tool for patients with COVID-19.

Asunto(s)

COVID-19 , Microbioma Gastrointestinal , Humanos , Microbioma Gastrointestinal/genética , Metagenómica/métodos , Heces/microbiología , Síndrome Post Agudo de COVID-19

RESUMEN

Systemic characterisation of the human faecal microbiome provides the opportunity to develop non-invasive approaches in the diagnosis of a major human disease. However, shared microbial signatures across different diseases make accurate diagnosis challenging in single-disease models. Herein, we present a machine-learning multi-class model using faecal metagenomic dataset of 2,320 individuals with nine well-characterised phenotypes, including colorectal cancer, colorectal adenomas, Crohn's disease, ulcerative colitis, irritable bowel syndrome, obesity, cardiovascular disease, post-acute COVID-19 syndrome and healthy individuals. Our processed data covers 325 microbial species derived from 14.3 terabytes of sequence. The trained model achieves an area under the receiver operating characteristic curve (AUROC) of 0.90 to 0.99 (Interquartile range, IQR, 0.91-0.94) in predicting different diseases in the independent test set, with a sensitivity of 0.81 to 0.95 (IQR, 0.87-0.93) at a specificity of 0.76 to 0.98 (IQR 0.83-0.95). Metagenomic analysis from public datasets of 1,597 samples across different populations observes comparable predictions with AUROC of 0.69 to 0.91 (IQR 0.79-0.87). Correlation of the top 50 microbial species with disease phenotypes identifies 363 significant associations (FDR < 0.05). This microbiome-based multi-disease model has potential clinical application in disease diagnostics and treatment response monitoring and warrants further exploration.

Asunto(s)

COVID-19 , Microbiota , Humanos , COVID-19/diagnóstico , Heces , Aprendizaje Automático , Síndrome Post Agudo de COVID-19

RESUMEN

BACKGROUND: Poor social connections (eg, small networks, infrequent interactions, and loneliness) are modifiable risk factors for cognitive decline. Existing meta-analyses are limited by reporting aggregate responses, a focus on global cognition, and combining social measures into single constructs. We aimed to investigate the association between social connection markers and the rate of annual change in cognition (ie, global and domain-specific), as well as sex differences, using an individual participant data meta-analysis. METHODS: We harmonised data from 13 longitudinal cohort studies of ageing in North America, South America, Europe, Africa, Asia, and Australia. Studies were eligible for inclusion if they had baseline data for social connection markers and at least two waves of cognitive scores. Follow-up periods ranged from 0 years to 15 years across cohorts. We included participants with cognitive data for at least two waves and social connection data for at least one wave. We then identified and excluded people with dementia at baseline. Primary outcomes were annual rates of change in global cognition and cognitive domain scores over time until final follow-up within each cohort study analysed by use of an individual participant data meta-analysis. Linear mixed models within cohorts used baseline social connection markers as predictors of the primary outcomes. Effects were pooled in two stages using random-effects meta-analyses. We assessed the primary outcomes in the main (partially adjusted) and fully adjusted models. Partially adjusted models controlled for age, sex, and education; fully adjusted models additionally controlled for diabetes, hypertension, smoking, cardiovascular risk, and depression. FINDINGS: Of the 40 006 participants in the 13 cohort studies, we excluded 1392 people with dementia at baseline. 38 614 individual participants were included in our analyses. For the main models, being in a relationship or married predicted slower global cognitive decline (b=0·010, 95% CI 0·000-0·019) than did being single or never married; living with others predicted slower global cognitive (b=0·007, 0·002-0·012), memory (b=0·017, 0·006-0·028), and language (b=0·008, 0·000-0·015) decline than did living alone; and weekly interactions with family and friends (b=0·016, 0·006-0·026) and weekly community group engagement (b=0·030, 0·007-0·052) predicted slower memory decline than did no interactions and no engagement. Never feeling lonely predicted slower global cognitive (b=0·047, 95% CI 0·018-0·075) and executive function (b=0·047, 0·017-0·077) decline than did often feeling lonely. Degree of social support, having a confidante, and relationship satisfaction did not predict cognitive decline across global cognition or cognitive domains. Heterogeneity was low (I2=0·00-15·11%) for all but two of the significant findings (association between slower memory decline and living with others [I2=58·33%] and community group engagement, I2=37·54-72·19%), suggesting robust results across studies. INTERPRETATION: Good social connections (ie, living with others, weekly community group engagement, interacting weekly with family and friends, and never feeling lonely) are associated with slower cognitive decline. FUNDING: EU Joint Programme-Neurodegenerative Disease Research grant, funded by the National Health and Medical Research Council Australia, and the US National Institute on Aging of the US National Institutes of Health.

Asunto(s)

Demencia , Enfermedades Neurodegenerativas , Estados Unidos , Humanos , Femenino , Masculino , Estudios Longitudinales , Estudios de Cohortes , Cognición , Trastornos de la Memoria

RESUMEN

Understanding the role of fecal microbiota transplantation (FMT) in the decolonization of multidrug-resistant organisms (MDRO) is critical. Specifically, little is known about virome changes in MDRO-infected subjects treated with FMT. Using shotgun metagenomic sequencing, we characterized longitudinal dynamics of the gut virome and bacteriome in three recipients who successfully decolonized carbapenem-resistant Enterobacteriaceae (CRE), including Klebsiella spp. and Escherichia coli, after FMT. We observed large shifts of the fecal bacterial microbiota resembling a donor-like community after transfer of a fecal microbiota dominated by the genus Ruminococcus. We found a substantial expansion of Klebsiella phages after FMT with a concordant decrease of Klebsiella spp. and striking increase of Escherichia phages in CRE E. coli carriers after FMT. We also observed the CRE elimination and similar evolution of Klebsiella phage in mice, which may play a role in the collapse of the Klebsiella population after FMT. In summary, our pilot study documented bacteriome and virome alterations after FMT which mediate many of the effects of FMT on the gut microbiome community. IMPORTANCE Fecal microbiota transplantation (FMT) is an effective treatment for multidrug-resistant organisms; however, introducing a complex mixture of microbes also has unknown consequences for landscape features of gut microbiome. We sought to understand bacteriome and virome alterations in patients undergoing FMT to treat infection with carbapenem-resistant Enterobacteriaceae. This finding indicates that transkingdom interactions between the virome and bacteriome communities may have evolved in part to support efficient FMT for treating CRE.

Asunto(s)

Bacteriófagos , Enterobacteriaceae Resistentes a los Carbapenémicos , Animales , Ratones , Trasplante de Microbiota Fecal , Viroma , Escherichia coli , Proyectos Piloto