Unraveling interindividual variation of trimethylamine N-oxide and its precursors at the population level.

Trimethylamine N-oxide (TMAO) is a circulating microbiome-derived metabolite implicated in the development of atherosclerosis and cardiovascular disease (CVD). We investigated whether plasma levels of TMAO, its precursors (betaine, carnitine, deoxycarnitine, choline), and TMAO-to-precursor ratios are associated with clinical outcomes, including CVD and mortality. This was followed by an in-depth analysis of their genetic, gut microbial, and dietary determinants. The analyses were conducted in five Dutch prospective cohort studies including 7834 individuals. To further investigate association results, Mendelian Randomization (MR) was also explored. We found only plasma choline levels (hazard ratio [HR] 1.17, [95% CI 1.07; 1.28]) and not TMAO to be associated with CVD risk. Our association analyses uncovered 10 genome-wide significant loci, including novel genomic regions for betaine (6p21.1, 6q25.3), choline (2q34, 5q31.1), and deoxycarnitine (10q21.2, 11p14.2) comprising several metabolic gene associations, for example, CPS1 or PEMT. Furthermore, our analyses uncovered 68 gut microbiota associations, mainly related to TMAO-to-precursors ratios and the Ruminococcaceae family, and 16 associations of food groups and metabolites including fish-TMAO, meat-carnitine, and plant-based food-betaine associations. No significant association was identified by the MR approach. Our analyses provide novel insights into the TMAO pathway, its determinants, and pathophysiological impact on the general population.

Predictors of 30-day recurrent emergency department visits for hyperglycemia in patients with types 1 and 2 diabetes: a population-based cohort study.

OBJECTIVES: This study's aims were to describe the outcomes of patients with diabetes presenting with their first ED visit for hyperglycemia, and to identify predictors of recurrent ED visits for hyperglycemia. METHODS: Using linked databases, we conducted a population-based cohort study of adult and pediatric patients with types 1 and 2 diabetes presenting with a first ED visit for hyperglycemia from April 2010 to March 2020 in Ontario, Canada. We determined the proportion of patients with a recurrent ED visit for hyperglycemia within 30 days of the index visit. Using multivariable regression analysis, we examined clinical and socioeconomic predictors for recurrent visits. RESULTS: There were 779,632 patients with a first ED visit for hyperglycemia. Mean (SD) age was 64.3 (15.2) years; 47.7% were female. 11.0% had a recurrent visit for hyperglycemia within 30 days. Statistically significant predictors of a recurrent visit included: male sex, type 1 diabetes, regions with fewer visible minority groups and with less education or employment, higher hemoglobin A1C, more family physician or internist visits within the past year, being rostered to a family physician, previous ED visits in the past year, ED or hospitalization within the previous 14 days, access to homecare services, and previous hyperglycemia encounters in the past 5 years. Alcoholism and depression or anxiety were positive predictors for the 18-65 age group. CONCLUSIONS: This population-level study identifies predictors of recurrent ED visits for hyperglycemia, including male sex, type 1 diabetes, regions with fewer visible minority groups and with less education or employment, higher hemoglobin A1C, higher previous healthcare system utilization (ED visits and hospitalization) for hyperglycemia, being rostered to a family physician, and access to homecare services. Knowledge of these predictors may be used to develop targeted interventions to improve patient outcomes and reduce healthcare system costs.

ABSTRAIT: OBJECTIFS: Les objectifs de cette étude étaient de décrire les résultats des patients diabétiques présentant leur première visite aux urgences pour hyperglycémie, et d'identifier les prédicteurs des visites récurrentes aux urgences pour hyperglycémie. MéTHODES: À l'aide de bases de données couplées, nous avons mené une étude de cohorte basée sur la population de patients adultes et pédiatriques atteints de diabète de type 1 et 2 présentant une première visite aux urgences pour l'hyperglycémie d'avril 2010 à mars 2020 en Ontario, au Canada. Nous avons déterminé la proportion de patients présentant une visite récurrente à l'urgence pour hyperglycémie dans les 30 jours suivant la visite d'index. À l'aide d'une analyse de régression multivariée, nous avons examiné les prédicteurs cliniques et socioéconomiques des visites récurrentes. RéSULTATS: Il y avait 779 632 patients avec une première visite à l'urgence pour hyperglycémie. L'âge moyen (ET) était de 64,3 (15,2) ans; 47,7% étaient des femmes. 11,0 % avaient une visite récurrente pour hyperglycémie dans les 30 jours. Les prédicteurs statistiquement significatifs d'une visite récurrente comprenaient le sexe masculin, le diabète de type 1, les régions comptant moins de groupes de minorités visibles et ayant moins d'études ou d'emploi, une hémoglobine A1C plus élevée, plus de visites chez un médecin de famille ou un interniste au cours de la dernière année, être inscrit auprès d'un médecin de famille, consulter le service d'urgence au cours de la dernière année, être hospitalisé au cours des 14 derniers jours, avoir accès à des services de soins à domicile et avoir été confronté à une hyperglycémie au cours des 5 dernières années. L'alcoolisme et la dépression ou l'anxiété étaient des prédicteurs positifs pour le groupe des 18-65 ans. CONCLUSIONS: Cette étude au niveau de la population identifie des prédicteurs de visites récurrentes aux urgences pour l'hyperglycémie, y compris le sexe masculin, le diabète de type 1, les régions avec moins de groupes de minorités visibles et avec moins d'études ou d'emploi, plus d'hémoglobine A1C, l'utilisation antérieure plus élevée du système de soins de santé (visites aux urgences et hospitalisation) pour l'hyperglycémie, le fait d'être inscrit auprès d'un médecin de famille et l'accès aux services de soins à domicile. La connaissance de ces prédicteurs peut être utilisée pour élaborer des interventions ciblées afin d'améliorer les résultats pour les patients et de réduire les coûts du système de santé.

Effect of Magnetic Resonance Image Quality on Structural and Functional Brain Connectivity: The Maastricht Study.

In population-based cohort studies, magnetic resonance imaging (MRI) is vital for examining brain structure and function. Advanced MRI techniques, such as diffusion-weighted MRI (dMRI) and resting-state functional MRI (rs-fMRI), provide insights into brain connectivity. However, biases in MRI data acquisition and processing can impact brain connectivity measures and their associations with demographic and clinical variables. This study, conducted with 5110 participants from The Maastricht Study, explored the relationship between brain connectivity and various image quality metrics (e.g., signal-to-noise ratio, head motion, and atlas-template mismatches) that were obtained from dMRI and rs-fMRI scans. Results revealed that in particular increased head motion (R2 up to 0.169, p < 0.001) and reduced signal-to-noise ratio (R2 up to 0.013, p < 0.001) negatively impacted structural and functional brain connectivity, respectively. These image quality metrics significantly affected associations of overall brain connectivity with age (up to -59%), sex (up to -25%), and body mass index (BMI) (up to +14%). Associations with diabetes status, educational level, history of cardiovascular disease, and white matter hyperintensities were generally less affected. This emphasizes the potential confounding effects of image quality in large population-based neuroimaging studies on brain connectivity and underscores the importance of accounting for it.

Associations of type 2 diabetes and the risk of migraine in Chinese populations.

AIM: We aimed to explore the relationship between type 2 diabetes mellitus (T2DM) and the incidence rate of migraine in a Chinese population, and analyze the clinical characteristics of migraine patients with T2DM. METHODS: Data on the study cohort of 9873 individuals were obtained from the China Health and Retirement Longitudinal Study (CHARLS). The incidence rate of migraine from 2015 to 2018 was assessed. The Cox proportional hazards model was used to estimate hazard ratios (HRs) and their 95% confidence intervals (CIs) for the relationship between T2DM and the incidence of migraine. In addition, a cross-sectional study including 168 migraine patients was conducted in Xiamen, China. Migraine patients were grouped according to their T2DM status. Multivariable linear regression models were used to estimate ßs and their 95% CIs for the relationship between migraine characteristics and T2DM. RESULTS: The cumulative incidence rate of migraine from 2015 to 2018 in the T2DM group and control group was 7.26% [6.04%.8.65%] and 8.91% [8.27%.9.58%], respectively. The risk of migraine in patients with T2DM was reduced by 21% (HR 0.79 [0.65;0.95]) compared to patients with no T2DM after adjustment for confounders. The cross-sectional study showed that the presence of T2DM significantly reduced migraine frequency and relieved migraine intensity. CONCLUSION: This was the first study to validate that T2DM reduced the risk of migraine in a Chinese population cohort. Patients with migraine and T2DM may experience significant relief from their headache symptoms. Carrying out relevant mechanistic research may help to identify new targets for migraine treatment and contribute to further understanding the impact of T2DM or related metabolic disorders on an individual's health.

How a "Something Else" Response Option for Sexual Identity Affects National Survey Estimates of Associations Between Sexual Identity, Reproductive Health, and Substance Use.

This randomized experiment tested whether the inclusion of a "something else" response option for a question about sexual identity in a national health survey would significantly moderate estimated differences between sexual identity subgroups in terms of various health outcomes, including substance use and reproductive health. We conducted secondary analyses of data from five consecutive years of the National Survey of Family Growth (NSFG; 2015-2019), where two large national half-samples were randomly assigned to receive one of two different versions of a question about sexual identity (a four-category version that included a "something else" response option or a three-category version omitting this option). We focused on national estimates of differences between subgroups defined by sexual identity. Multivariable models indicated that the estimated subgroup differences changed in a statistically significant fashion when using the four-category version of the sexual identity question for several measures, including 16% of male measures (household size, past-year cigarette use, and past-year illicit drug use) and 15% of female measures (wanting a/another child, ever had a sexually transmitted disease, and past-year marijuana use). The absence of a "something else" response option for questions about sexual identity in national health surveys may cause respondents to select options that do not accurately describe their identities, and this can have a significant effect on national estimates of differences between sexual identity subgroups in terms of selected health outcomes.

Elevated soluble LOX-1 predicts risk of first-time myocardial infarction.

BACKGROUND: There is an unmet clinical need for novel therapies addressing the residual risk in patients receiving guideline preventive therapy for coronary heart disease. Experimental studies have identified a pro-atherogenic role of the oxidized LDL receptor LOX-1. We investigated the association between circulating soluble LOX-1 (sLOX-1) and the risk for development of myocardial infarction. METHODS: The study subjects (n = 4658) were part of the Malmö Diet and Cancer study. The baseline investigation was carried out 1991-1994 and the incidence of cardiovascular events monitored through national registers during a of 19.5 ± 4.9 years follow-up. sLOX-1 and other biomarkers were analyzed by proximity extension assay and ELISA in baseline plasma. RESULTS: Subjects in the highest tertile of sLOX-1 had an increased risk of myocardial infarction (hazard ratio (95% CI) 1.76 (1.40-2.21) as compared with those in the lowest tertile. The presence of cardiovascular risk factors was related to elevated sLOX-1, but the association between sLOX-1 and risk of myocardial infarction remained significant when adjusting for risk factors. CONCLUSIONS: In this prospective population study we found an association between elevated sLOX-1, the presence of carotid disease and the risk for first-time myocardial infarction. Taken together with previous experimental findings of a pro-atherogenic role of LOX-1, this observation supports LOX-1 inhibition as a possible target for prevention of myocardial infarction.

Activation of the lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) represents a possible target for treatment of the residual inflammatory risk in cardiovascular patients on guideline therapy.Having high levels of soluble LOX-1, a marker of cellular LOX-1 activation, is associated with an increased risk for development of myocardial infarction and heart failure.sLOX-1 levels correlated with major cardiovascular risk factors and biomarkers reflecting LDL oxidation.

Burden and unmet need for specialist care in poorly controlled and severe childhood asthma in a Danish nationwide cohort.

BACKGROUND: Asthma is a common disease in childhood and adolescence with lifelong consequences particularly among those at risk of severe disease, poor control and/or frequent exacerbations. Specialist care is recommended for at-risk children and adolescents, yet access to specialist management in free-to-access healthcare settings remains poorly understood. METHODS: A Danish nationwide cohort of children and adolescents aged 2-17 years with persistent asthma, defined as repeated redemption of inhaled corticosteroids (ICS) during 2015, were followed for two years, to identify at-risk children and adolescents comprising those with severe asthma (classified according to GINA 2020 guidelines), poor control (defined as use of 400/600 (ages 2-11/12 +) annual doses of short-acting bronchodilators), or frequent exacerbations (defined as use of oral steroids or hospitalization), and access to specialist care. The population is chosen due to detailed medical records in the setting of universal health care. RESULTS: The cohort comprised of 29,851 children and adolescents (59% boys), with a median age of 9 years. While 17% of children were on high dose ICS, 22% were on daily ICS below GINA low dose cut-off. Prevalence of severe asthma (3.0-6.5%) was lower than poor asthma control (6.4-25%); both declined from childhood to adolescence. Exacerbations occurred in 7.1-9.0% of children, with median number of exacerbations being 1 (IQR 1-1). Despite being classified as having mild-to-moderate asthma, 15% had poor asthma control and 3.8% experienced exacerbation(s), respectively. While 61% of children with severe asthma and 58% with exacerbation-prone disease were in specialist care, only 24% with uncontrolled disease were receiving specialist care. Of children and adolescents using high-dose ICS, 71% were managed in primary care, while the use of additional controllers was more common in specialist care. CONCLUSIONS: Throughout childhood and adolescence, there was a high prevalence of severe asthma and poor control, although their prevalence declined with age. We demonstrate a large unmet need for specialist care among children with at-risk asthma, particularly among those with poorly controlled asthma, even in a system with free-to-access, tax-funded healthcare.

How to Ensure Inclusivity in Large-Scale General Population Cohort Studies? Lessons Learned with Regard to Including and Assessing Sex, Gender, and Sexual Orientation.

Despite recent advances in the measurement of sex, gender, and sexual orientation in large-scale cohort studies, the three concepts are still gaining relatively little attention, may be mistakenly equated, or non-informatively operationalized. The resulting imprecise or lacking information hereon in studies is problematic, as sex, gender, and sexual orientation are important health-related factors. Omission of these concepts from general population cohort studies might dismiss participants' identity and experiences and pushes research on sexual or gender minority populations toward purposive sampling, potentially introducing selection bias. It also reinforces the unintentional notion of irrelevance of these concepts to health research, ultimately disadvantaging sexual and gender minority populations. Similarly, a lack of uniform measures on sex, gender, and sexual orientation hampers multi-cohort studies in which data from multiple studies are combined, facilitating increased statistical power. This paper discusses the encountered pitfalls and lessons learned on including and assessing sex, gender, and sexual orientation in large-scale general population cohort studies, exemplified by the Dutch Lifelines Cohort Study. Additionally, we propose hands-on strategies on how to operationalize these concepts in an inclusive manner that is useful for large-scale general population cohort studies.

Characterization of pharmacogenomic variants in a Brazilian admixed cohort of elderly individuals based on whole-genome sequencing data.

Introduction: Research in the field of pharmacogenomics (PGx) aims to identify genetic variants that modulate response to drugs, through alterations in their pharmacokinetics (PK) or pharmacodynamics (PD). The distribution of PGx variants differs considerably among populations, and whole-genome sequencing (WGS) plays a major role as a comprehensive approach to detect both common and rare variants. This study evaluated the frequency of PGx markers in the context of the Brazilian population, using data from a population-based admixed cohort from Sao Paulo, Brazil, which includes variants from WGS of 1,171 unrelated, elderly individuals. Methods: The Stargazer tool was used to call star alleles and structural variants (SVs) from 38 pharmacogenes. Clinically relevant variants were investigated, and the predicted drug response phenotype was analyzed in combination with the medication record to assess individuals potentially at high-risk of gene-drug interaction. Results: In total, 352 unique star alleles or haplotypes were observed, of which 255 and 199 had a frequency < 0.05 and < 0.01, respectively. For star alleles with frequency > 5% (n = 97), decreased, loss-of-function and unknown function accounted for 13.4%, 8.2% and 27.8% of alleles or haplotypes, respectively. Structural variants (SVs) were identified in 35 genes for at least one individual, and occurred with frequencies >5% for CYP2D6, CYP2A6, GSTM1, and UGT2B17. Overall 98.0% of the individuals carried at least one high risk genotype-predicted phenotype in pharmacogenes with PharmGKB level of evidence 1A for drug interaction. The Electronic Health Record (EHR) Priority Result Notation and the cohort medication registry were combined to assess high-risk gene-drug interactions. In general, 42.0% of the cohort used at least one PharmGKB evidence level 1A drug, and 18.9% of individuals who used PharmGKB evidence level 1A drugs had a genotype-predicted phenotype of high-risk gene-drug interaction. Conclusion: This study described the applicability of next-generation sequencing (NGS) techniques for translating PGx variants into clinically relevant phenotypes on a large scale in the Brazilian population and explores the feasibility of systematic adoption of PGx testing in Brazil.

Associations between neonatal jaundice and autism spectrum disorder or attention deficit hyperactivity disorder: Nationwide population based cohort study.

BACKGROUND/PURPOSE: Neonatal jaundice might result brain insults. Both autistic spectrum disorder (ASD) and attention deficit hyperactivity disorder (ADHD) are developmental disorders, which might result from early brain injury at neonatal period. We aimed to explore the association between neonatal jaundice treated with phototherapy and the ASD or ADHD. METHODS: This retrospective nationwide population cohort study was based on a nationally representative database of Taiwan, and neonates born from 2004 to 2010 were enrolled. All eligible infants were divided into 4 groups, without jaundice, jaundice with no treatment, jaundice with simple phototherapy only and jaundice with intensive phototherapy or blood exchange transfusion (BET). Each infant was follow-up until the date of incident primary outcomes, death, or 7-year-old, whichever occurred first. Primary outcomes were ASD, ADHD. Using cox proportional hazard model to analyze their associations. RESULTS: In total, 118,222 infants with neonatal jaundice were enrolled, including diagnosed only (7260), simple phototherapy (82,990), intensive phototherapy or BET (27,972 infants). The cumulative incidences of ASD in each group was 0.57%, 0.81%, 0.77%, and 0.83%, respectively. The cumulative incidences of ADHD in each group was 2.83%, 4.04%, 3.52% and 3.48%, respectively. Jaundice groups were significantly associated with ASD, ADHD, or either one, even after all other extraneous maternal and neonatal variables were adjusted. After stratification, the associations were still existed in subgroup with birth weights ≥2500 grams and in male subgroup. CONCLUSION: Neonatal jaundice correlated with the ASD and ADHD. The associations were significant in infants of both sexes and with birth weights larger than 2500 grams.

Infant gut microbiome composition correlated with type 1 diabetes acquisition in the general population: the ABIS study.

AIMS/HYPOTHESIS: While autoantibodies are traditional markers for type 1 diabetes development, we identified gut microbial biomarkers in 1-year-old infants associated with future type 1 diabetes up to 20 years before diagnosis. METHODS: Infants enrolled in the longitudinal general population cohort All Babies In Southeast Sweden (ABIS) provided a stool sample at a mean age of 12.5 months. Samples (future type 1 diabetes, n=16; healthy controls, n=268) were subjected to 16S ribosomal RNA (rRNA) sequencing and quantitative PCR. Microbial differences at the taxonomic and core microbiome levels were assessed. PICRUSt was used to predict functional content from the 16S rRNA amplicons. Sixteen infants, with a future diagnosis of type 1 diabetes at a mean age of 13.3±5.4 years, and one hundred iterations of 32 matched control infants, who remained healthy up to 20 years of age, were analysed. RESULTS: Parasutterella and Eubacterium were more abundant in healthy control infants, while Porphyromonas was differentially more abundant in infants with future type 1 diabetes diagnosis. Ruminococcus was a strong determinant in differentiating both control infants and those with future type 1 diabetes using random forest analysis and had differing trends of abundance when comparing control infants and those with future type 1 diabetes. Flavonifractor and UBA1819 were the strongest factors for differentiating control infants, showing higher abundance in control infants compared with those with future type 1 diabetes. Alternatively, Alistipes (more abundant in control infants) and Fusicatenibacter (mixed abundance patterns when comparing case and control infants) were the strongest factors for differentiating future type 1 diabetes. Predicted gene content regarding butyrate production and pyruvate fermentation was differentially observed to be higher in healthy control infants. CONCLUSIONS/INTERPRETATION: This investigation suggests that microbial biomarkers for type 1 diabetes may be present as early as 1 year of age, as reflected in the taxonomic and functional differences of the microbial communities. The possibility of preventing disease onset by altering or promoting a 'healthy' gut microbiome is appealing. DATA AVAILABILITY: The forward and reverse 16S raw sequencing data generated in this study are available through the NCBI Sequence Read Archive under BioProject PRJNA875929. Associated sample metadata used for statistical comparison are available in the source data file. R codes used for statistical comparisons and figure generation are available at: https://github.com/PMilletich/T1D_Pipeline .

The impact of 22q11.2 copy-number variants on human traits in the general population.

While extensively studied in clinical cohorts, the phenotypic consequences of 22q11.2 copy-number variants (CNVs) in the general population remain understudied. To address this gap, we performed a phenome-wide association scan in 405,324 unrelated UK Biobank (UKBB) participants by using CNV calls from genotyping array. We mapped 236 Human Phenotype Ontology terms linked to any of the 90 genes encompassed by the region to 170 UKBB traits and assessed the association between these traits and the copy-number state of 504 genotyping array probes in the region. We found significant associations for eight continuous and nine binary traits associated under different models (duplication-only, deletion-only, U-shape, and mirror models). The causal effect of the expression level of 22q11.2 genes on associated traits was assessed through transcriptome-wide Mendelian randomization (TWMR), revealing that increased expression of ARVCF increased BMI. Similarly, increased DGCR6 expression causally reduced mean platelet volume, in line with the corresponding CNV effect. Furthermore, cross-trait multivariable Mendelian randomization (MVMR) suggested a predominant role of genuine (horizontal) pleiotropy in the CNV region. Our findings show that within the general population, 22q11.2 CNVs are associated with traits previously linked to genes in the region, and duplications and deletions act upon traits in different fashions. We also showed that gain or loss of distinct segments within 22q11.2 may impact a trait under different association models. Our results have provided new insights to help further the understanding of the complex 22q11.2 region.

Gestational age at birth, chronic conditions and school outcomes: a population-based data linkage study of children born in England.

INTRODUCTION: We aimed to generate evidence about child development measured through school attainment and provision of special educational needs (SEN) across the spectrum of gestational age, including for children born early term and >41 weeks of gestation, with and without chronic health conditions. METHODS: We used a national linked dataset of hospital and education records of children born in England between 1 September 2004 and 31 August 2005. We evaluated school attainment at Key Stage 1 (KS1; age 7) and Key Stage 2 (KS2; age 11) and any SEN by age 11. We stratified analyses by chronic health conditions up to age 2, and size-for-gestation, and calculated population attributable fractions (PAF). RESULTS: Of 306 717 children, 5.8% were born <37 weeks gestation and 7.0% had a chronic condition. The percentage of children not achieving the expected level at KS1 increased from 7.6% at 41 weeks, to 50.0% at 24 weeks of gestation. A similar pattern was seen at KS2. SEN ranged from 29.0% at 41 weeks to 82.6% at 24 weeks. Children born early term (37-38 weeks of gestation) had poorer outcomes than those born at 40 weeks; 3.2% of children with SEN were attributable to having a chronic condition compared with 2.0% attributable to preterm birth. CONCLUSIONS: Children born with early identified chronic conditions contribute more to the burden of poor school outcomes than preterm birth. Evaluation is needed of how early health characteristics can be used to improve preparation for education, before and at entry to school.

Methamphetamine use and psychotic symptoms: findings from a New Zealand longitudinal birth cohort.

BACKGROUND: This study examined the association between methamphetamine use and psychotic symptoms in a New Zealand general population birth cohort (n = 1265 at birth). METHODS: At age 18, 21, 25, 30, and 35, participants reported on their methamphetamine use and psychotic symptoms in the period since the previous interview. Generalized estimating equations modelled the association between methamphetamine use and psychotic symptoms (percentage reporting any symptom, and number of symptoms per participant). Confounding factors included childhood individual characteristics, family socioeconomic circumstances and family functioning. Long term effects of methamphetamine use on psychotic symptoms were assessed by comparing the incidence of psychotic symptoms at age 30-35 for those with and without a history of methamphetamine use prior to age 30. RESULTS: After adjusting for confounding factors and time-varying covariate factors including concurrent cannabis use, methamphetamine use was associated with a modest increase in psychosis risk over five waves of data (adjusted odds ratio (OR) 1.33, 95% confidence interval (CI) 1.03-1.72 for the percentage measure; and IRR 1.24, 95% CI 1.02-1.50 for the symptom count measure). The increased risk of psychotic symptoms was concentrated among participants who had used at least weekly at any point (adjusted OR 2.85, 95% CI 1.21-6.69). Use of methamphetamine less than weekly was not associated with increased psychosis risk. We found no evidence for a persistent vulnerability to psychosis in the absence of continuing methamphetamine use. CONCLUSION: Methamphetamine use is associated with increased risk of psychotic symptoms in the general population. Increased risk is chiefly confined to people who ever used regularly (at least weekly), and recently.

Childhood anxious/withdrawn behaviour and later anxiety disorder: a network outcome analysis of a population cohort.

BACKGROUND: Several previous studies have identified a continuity between childhood anxiety/withdrawal and anxiety disorder (AD) in later life. However, not all children with anxiety/withdrawal problems will experience an AD in later life. Previous studies have shown that the severity of childhood anxiety/withdrawal accounts for some of the variability in AD outcomes. However, no studies to date have investigated how variation in features of anxiety/withdrawal may relate to continuity prognoses. The present research addresses this gap. METHODS: Data were gathered as part of the Christchurch Health and Development Study, a 40-year population birth cohort of 1265 children born in Christchurch, New Zealand. Fifteen childhood anxiety/withdrawal items were measured at 7-9 years and AD outcomes were measured at various interviews from 15 to 40 years. Six network models were estimated. Two models estimated the network structure of childhood anxiety/withdrawal items independently for males and females. Four models estimated childhood anxiety/withdrawal items predicting adolescent AD (14-21 years) and adult AD (21-40 years) in both males and females. RESULTS: Approximately 40% of participants met the diagnostic criteria for an AD during both the adolescent (14-21 years) and adult (21-40 years) outcome periods. Outcome networks showed that items measuring social and emotional anxious/withdrawn behaviours most frequently predicted AD outcomes. Items measuring situation-based fears and authority figure-specific anxious/withdrawn behaviour did not consistently predict AD outcomes. This applied across both the male and female subsamples. CONCLUSIONS: Social and emotional anxious/withdrawn behaviours in middle childhood appear to carry increased risk for AD outcomes in both adolescence and adulthood.

Risk-Adapted Starting Age for Personalized Colorectal Cancer Screening: Validated Evidence From National Population-Based Studies.

BACKGROUND & AIMS: A one-size-fits-all approach to colorectal cancer (CRC) screening that does not account for CRC risk factors is not conducive to personalized screening. On the basis of the principle of equal management of equal risks, we aimed to tailor and validate risk-adapted starting ages of CRC screening for individuals with different CRC risk factors. METHODS: A multi-center community-based population cohort (N = 3,165,088) was used to evaluate the starting age of CRC screening with comprehensive consideration of risk factors. Age-specific 10-year cumulative risk curves were used to determine when individuals at greater risk for CRC reached the same risk level as the 50-year-old general population, which is currently the recommended starting age for CRC screening in China. RESULTS: During the study follow-up period (2013-2021), 4,840 incident CRCs were recorded. Family history of CRC, adverse lifestyle, and comorbidities demonstrated heterogeneous associations with CRC risk (hazard ratios, 1.05-1.55; P < .05). Men and women with CRC family history and at least 2 risk factors reached the standard benchmark risk (0.28%) for screening at the age of 40, 10 years earlier than their peers without risk factors in the general population. Proposed starting ages for CRC screening were validated in an independent community-based population cohort (N = 1,023,367). CONCLUSIONS: We determined a risk-adapted CRC screening starting age for individuals with various CRC risk factors. Earlier, personalized screening based on these findings could allow for scarce health resources to be dedicated to individuals who benefit most.

Midlife Intakes of the Isoflavone Genistein and Soy and the Risk of Late-life Cognitive Impairment: The JPHC Saku Mental Health Study.

BACKGROUND: The number of people with cognitive impairment, including dementia, in the world is steadily increasing. Although the consumption of isoflavones and soy is associated with a reduced risk of cardiovascular disease, it might also be associated with cognitive impairment. The low number of studies investigating the association between soy/isoflavone intake and cognitive function warrant additional research. METHODS: The Japan Public Health Center-based prospective (JPHC) Study is a large population-based cohort. Midlife dietary intake of soy and the isoflavone genistein was assessed on two occasions: in the years 1995 and 2000. In 2014-2015, 1,299 participants from Nagano prefecture completed a mental health screening. Of these, a total of 1,036 participants were included in analyses. Logistic regression was used to determine Odds Ratios (OR) and 95% Confidence Intervals (CI) for the association between midlife energy-adjusted genistein and soy food intake and cognitive impairment. RESULTS: There were 392 cases of cognitive impairment (346 cases of MCI and 46 cases of dementia). Compared to the lowest dietary quartile of energy-adjusted genistein intake, the highest quartile was significantly associated with cognitive impairment (OR = 1.51; 95% CI, 1.02-2.24; P for trend = 0.03) in the final multivariable analysis. CONCLUSION: High midlife intake of the isoflavone genistein is associated with late-life cognitive impairment.

Physical and financial impacts caused by the COVID-19 pandemic exacerbate knee pain: A longitudinal study of a large-scale general population.

OBJECTIVES: This study aimed to evaluate the changes in knee pain, a dominant cause of physical disability, following the coronavirus disease (COVID-19) pandemic, and to identify factors affecting the changes in knee pain. METHODS: We analysed the pre- and post-COVID-19 longitudinal data set of the Nagahama Study. Knee pain was assessed using the Knee Society Score (KSS). The estimated KSS from the age and sex using regression model in the pre- and post-COVID-19 data set was compared. Factors including the activity score, educational level, and various impacts of COVID-19 were analysed for correlation analyses with changes in KSS. RESULTS: Data collected from 6409 participants showed statistically significant differences in KSS, pre- (mean = 22.0; SD = 4.4) and post-COVID-19 (mean = 19.5; SD = 6.4). Low activity score (p = .008), low educational level (p < .001), and undesirable financial impact (p = .030) were independently associated with knee pain exacerbation. CONCLUSION: The harmful effects of the COVID-19 pandemic on knee pain were suggested. People should be encouraged to engage in physical activities, such as walking, despite the state of emergency. Furthermore, social support for economically disadvantaged groups may improve healthcare access, preventing the acute exacerbations of knee pain.

Associations Between Attention Deficit Hyperactivity Disorder Symptom Dimensions and Disordered Eating Symptoms in Adolescence: A Population-Based Twin Study.

Although bivariate associations between attention-deficit/hyperactivity disorder (ADHD) and eating disorders in adolescent girls and boys have been previously identified, the mechanistic link underlying the symptom-level associations remains unclear. We evaluated shared genetic and environmental influences on ADHD symptoms and disordered eating in 819 female and 756 male twins from the Swedish TCHAD cohort using bivariate models. Common additive genetic and unique environmental effects accounted for majority of ADHD and disordered eating associations in a differential manner. For girls, the strongest genetic correlation was observed for cognitive/inattention problems-bulimia (0.54), with genetic factors accounting for 67% of the phenotypic correlation. For boys, the strongest genetic correlations were observed for conduct problems-bulimia and hyperactivity-bulimia (~ 0.54), accounting for 83% and 95% of the phenotypic correlation, respectively. As per our findings, the risk of comorbidity and shared genetics highlights the need for preventative measures and specialized treatment for ADHD and disordered eating in both sexes.

Detrimental effect of high social risk on the cardiovascular health status of community-dwelling older adults living in rural settings. A population-based, longitudinal prospective study.

BACKGROUND: Information of the effect of social risk on the cardiovascular health (CVH) status among individuals living in rural settings is limited. We aim to assess this effect in participants of the Three Villages Study cohort. METHODS: Following a longitudinal prospective design, older adults living in rural Ecuador received baseline social risk determinations by means of social determinants of health components included in the Gijon's Social-Familial Evaluation Scale (SFES) together with clinical interviews and procedures to determine CVH status included in the Life's Simple 7 construct. Those who also received CVH assessment at the end of the study were included. Random-effects generalized least square and mixed logistic regression models were fitted to assess the longitudinal effect of social risk on CVH metrics, after adjusting for relevant covariates. RESULTS: The study included 443 community dwellers (mean age: 67 ± 7 years). The Gijon's SFES mean score was 9.8 ± 2.7 points. The mean number of ideal CVH metrics at baseline was 3.1 ± 1.3, which decreased to 2.6 ± 1.2 (ß: -0.467; 95% C.I.: -0.588 to -0.346), after a mean of 7.31 ± 3.26 years of follow-up. The total Gijon's SFES score was higher among individuals with a worsening CVH status compared to those who did not (10.4 ± 2.6 versus 9.3 ± 2.6; p < 0.001). The ideal CVH status declined 1.23 (95% C.I.: 1.13-1.34) times per point of change in the total Gijon's SFES score. CONCLUSION: Study results indicate a deleterious effect of high social risk on CVH status at follow-up in this underserved population.