Correction For Multiple Testing Research Articles

P336 Exploring Extracellular Matrix Markers in Ulcerative Colitis: Degradation and Formation Insights

Abstract Background The gold standard for assessing disease activity in ulcerative colitis (UC) is endoscopy, which is uncomfortable for the patient, and only evaluates the superficial layers of the colon. Intestinal extracellular matrix (ECM) remodeling is highly dynamic during disease activity and blood spillover of ECM components might reflect transmural disease burden. The aim of this study was to evaluate baseline serum markers of ECM formation (PRO-C11, PRO-C22, and PRO-C7) and degradation (C7M) to assess disease activity and treatment response in UC. Methods Forty-nine UC patients with active disease and 50 healthy controls (HC) were included. All underwent endoscopy and blood sampling at inclusion. UC patients additionally had fecal calprotectin (FCP) measured at baseline and had treatment adjusted at the discretion of the attending physician. Subsequent follow up of UC patients included clinical activity score, FCP, and blood samples at 3 and 6 months as well as an endoscopy at 6 months. Ulcerative Colitis Endoscopic Index of Severity (UCEIS), total Mayo score (TMS), and disease extent (E1-E3) was registered. Response was defined as a reduction from severe to moderate or mild disease based on TMS. If no follow-up endoscopy was performed (n=9), partial Mayo was used. Spearman’s correlation and one-way-ANOVA with Turkey correlation and correction for multiple testing were applied for statistical analysis. Results All markers of ECM degradation and formation were elevated in patients with severely active UC measured by both UCEIS and TMS compared to HC (adjusted p<0.0001 for each marker). CM7 and PRO-C22 differentiated moderate from severe UC by TMS (p<0.0001) and UCEIS (p<0.05) (Figure 1A-B). Baseline C7M, PRO-C7, and PRO-C11 correlated with CRP (Spearman’s: r=0.82, p<0.0001; r=-0.45, p=0.0012; and r=-0.33, p=0.032, respectively). None of the markers correlated with FCP. Elevated C7M, PRO-C7, and PRO-C11 levels for E3 could differentiate E3 from E1 (Difference ng/ml: 3.89 (SE of diff: 1.47), 13.15 (4.55), 10.08 (4.09), respectively, all p<0.05) (Figure 1C-E). Remission was achieved in 18/49 patients at 6 months. Both C7M and PRO-22 exhibited acceptable discriminative capabilities at baseline for 6-month TMS between remission and non-remission (AUC 0.72 (95% CI 0.58-0.87) p=0.01 and AUC 0.68 (95% CI 0.53-0.83) p=0.04, respectively) (Figure 1F-G). Conclusion This study demonstrates that ECM markers correlate with disease activity, disease extent, and predict future disease outcome in UC. ECM markers hold great promise as they provide a 'window' into transmural tissue remodeling and inflammatory and fibrotic burden, warranting further investigation.

P923 Haematological abnormalities during treatment with Janus kinase inhibitors in patients with Ulcerative Colitis: a post hoc analysis

Abstract Background Janus kinase inhibitors (JAKi) are used for Ulcerative Colitis treatment and could lead to haematological abnormalities, such as anaemia. In this post hoc analysis, we evaluated whether treatment with tofacitinib or filgotinib is associated with anaemia and other haematological laboratory abnormalities. Methods Data from randomized clinical trials [OCATVE 1 (NCT01465763), OCTAVE 2 (NCT01458951), OCTAVE Sustain (NCT01458574), and summary-level data from SELECTION (NCT02914522)] evaluating the efficacy of filgotinib and tofacitinib were used in this post hoc analysis. Adult patients with moderate-to-severe Ulcerative Colitis received induction therapy with filgotinib, tofacitinib, or placebo. After induction, patients in remission were re-randomized to receive either filgotinib 100 mg QD, filgotinib 200 mg QD, tofacitinib 5 mg BID, tofacitinib 10 mg BID, or placebo. We evaluated and compared the proportions of patients with anaemia, leukopenia, neutropenia, lymphopenia, and thrombocytopenia at baseline, after induction therapy (i.e., 8–10 weeks), and after 52–58 weeks of maintenance therapy in these treatment groups. Results At least a third of patients across all treatment groups had anaemia at baseline, the proportion of those who recovered from anaemia after induction did not differ (Table 1): 29.9% in the tofacitinib 10 mg group, 25.6% in the filgotinib 200 mg, and 30.7% in the filgotinib 100 mg group (P = 0.571). The proportion of patients who developed anaemia after the induction phase also did not differ: 16.7% in the tofacitinib 10 mg group, 17.3% in the filgotinib 200 mg, and 12.1% in the filgotinib 100 mg group (P = 0.880), as presented in Table 1. In contrast, 3.1–5.6% of patients in the tofacitinib groups vs. 7.1–14.5% in the filgotinib groups developed anaemia after 52–58 weeks of treatment (P = 0.036); however, the difference was not statistically significant after correction for multiple testing. Other haematological laboratory abnormalities, except lymphopenia, either did not occur or occurred infrequently across all treatment groups. Data regarding lymphopenia was available only from the OCTAVE trials; after 52 weeks of maintenance therapy, approximately 22% of patients in the tofacitinib groups had lymphopenia compared with 3.8% in the placebo group (P = 0.008). Conclusion Heterogeneous data limited this post hoc analysis. Haematological laboratory abnormalities, except for anaemia and lymphopenia, were infrequent. Therapy with JAKi was not associated with an increased occurrence of anaemia. However, since lymphopenia occurred more frequently in patients under treatment with tofacitinib, close monitoring is advisable to manage the risk of infection in these patients.

Association between psychiatric disorders and glioma risk: evidence from Mendelian randomization analysis

BackgroundObservational studies have explored the association of psychiatric disorders and the risk of brain cancers. However, the causal effect of specific mental illness on glioma remains elusive due to the lack of solid evidence.MethodsWe performed a two-sample bidirectional Mendelian randomization (MR) analysis to explore the causal relationships between 5 common psychiatric disorders (schizophrenia, major depressive disorder, bipolar disorder, autism spectrum disorder, and panic disorder) and glioma. Summary statistics for psychiatric disorders and glioma were extracted from Psychiatric Genomics Consortium (PGC) and 8 genome-wide association study (GWAS) datasets respectively. We calculated the MR estimates for odds ratio of glioma associated with each psychiatric disorder by using inverse-variance weighting (IVW) method. Sensitivity analyses such as weighted median estimator, MR-Egger and MR-PRESSO were leveraged to assess the strength of causal inference.ResultsA total of 30,657 participants of European ancestry were included in this study. After correction for multiple testing, we found that genetically predicted schizophrenia was associated with a statistically significant increase in odds of non-glioblastoma multiforme (non-GBM) (OR = 1.13, 95% CI: 1.03–1.23, P = 0.0096). There is little evidence for the causal relationships between the other 4 psychiatric disorders with the risk of glioma.ConclusionsIn this MR analysis, we revealed an increased risk of non-GBM glioma in individuals with schizophrenia, which gives an insight into the etiology of glioma.

Common infections and neuroimaging markers of dementia in three UK cohort studies.

We aimed to investigate associations between common infections and neuroimaging markers of dementia risk (brain volume, hippocampal volume, white matter lesions) across three population-based studies. We tested associations between serology measures (pathogen serostatus, cumulative burden, continuous antibody responses) and outcomes using linear regression, including adjustments for total intracranial volume and scanner/clinic information (basic model), age, sex, ethnicity, education, socioeconomic position, alcohol, body mass index, and smoking (fully adjusted model). Interactions between serology measures and apolipoprotein E (APOE) genotype were tested. Findings were meta-analyzed across cohorts (Nmain =2632; NAPOE-interaction =1810). Seropositivity to John Cunningham virus associated with smaller brain volumes in basic models (β=-3.89mL [-5.81, -1.97], Padjusted <0.05); these were largely attenuated in fully adjusted models (β=-1.59mL [-3.55, 0.36], P=0.11). No other relationships were robust to multiple testing corrections and sensitivity analyses, but several suggestive associations were observed. We did not find clear evidence for relationships between common infections and markers of dementia risk. Some suggestive findings warrant testing for replication.

Comparison of colorectal cancer (CRC) characteristics across genetic ancestries: Implications for early cancer detection (ECD).

164 Background: Blood-based ECD has the potential to reduce mortality rates by improving strategies for, adoption of, and adherence to screening. A deeper understanding of the cancer genomic landscape across genetic ancestries will aid comparable detection performance across a broad population. We evaluated the mutational landscape in patients with CRC across genetic ancestries. Methods: 16,080 de-identified patients with stage I-IV CRC who had personalized, tumor-informed commercial ctDNA testing (Signatera) based on whole exome sequencing (WES) were included. Genetic ancestry determined via supervised local ancestry inference (pmid36042219) included African (AFR), East Asian (EAS), European (EUR), Latino (LAT), and South Asian (SAS). Patients assigned to a single ancestry were included (except SAS due to small cohort size). Somatic single nucleotide variants called from WES were used for mutational signature inference. EUR was the reference group for standard statistical tests with corrections for multiple hypothesis testing. Results: A single genomic ancestry was assigned for 16,257 (99.2%) patients (AFR n=1697, 10%; EAS n=2247, 14%; EUR n=10,526, 64%; LAT n=1291, 1%; SAS n=184, 1%). Across AFR, EAS, EUR, and LAT, approximately half of patients were male (range, 47-54%) and most were aged &gt;50 years. Microsatellite instability (MSI) rates were significantly higher in EUR (14.5%) v AFR (11%, p&lt;0.001), EAS (8%, p&lt;0.001), and LAT (11%, p=0.002). Compared to EUR (range 0.027-875.1 mut/Mb), the distribution of TMB was significantly higher in EAS (0.304-906.2 mut/Mb, p&lt;0.001) and lower in LAT (0.053-476.7 mut/Mb, p&lt;0.001). The POLE hyper-mutator signature was seen in 1.2% of all patients and in 7.6% of all hyper-mutated cases. Patients with the POLE signature were less common in EUR (1.1%) v AFR (2%, p=0.001). There were significant differences in the frequency of driver mutations in APC, BRAF, KRAS, TP53, and PIK3CA between EUR and the other ancestry groups in both MSI and MSS tumors (Table). Median exposure levels to alkylation were higher in EAS v EUR. Conclusions: These data confirm previous results in AFR populations, and reveal novel differences in the EAS and LAT populations. Findings from this study may provide information for developing risk stratification and prevention strategies for the early detection of cancer and provide rationale for precision treatment based on ancestry. [Table: see text]

Interplay between polygenic risk for mood disorders and stressful life events in bipolar disorder

BackgroundAlthough genetic and environmental factors are involved in the aetiology of bipolar disorder [BD], studies focused on their interplay are lacking. The current investigation examines interactions and correlations between polygenic risk scores [PRS] for BD and major depressive disorder [MDD] with stressful life events [SLEs] in liability for BD. MethodsThis study used data from 1715 participants (862 bipolar cases and 853 controls) taken from UK and Canadian samples. The List of Threatening Experiences Questionnaire recorded SLEs that occurred 6 months before interview for controls and 6 months prior to the first (Canadian sample) and worst (UK sample) depressive and manic episodes for bipolar cases. PRS-BD and PRS-MDD were calculated from the Psychiatric Genomics Consortium. ResultsFor the worst depressive episode, the PRS-MDD was significantly correlated with total number of SLEs (β = 0.13, 95 % CI:0.04–0.22, p = 0.003) and dependent SLEs (β = 0.09, 95 % CI:0.02–0.16, p = 0.007). After correction for multiple testing nominally significant correlations were detected for PRS-BD with total number of SLEs (β = 0.11, 95 % CI:0.02–0.20, p = 0.015) and dependent SLEs (β = 0.08, 95 % CI:0.01–0.15, p = 0.019). Among bipolar cases, these associations were slightly stronger but were only of nominal significance for total number of SLEs (PRS-MDD: β = 0.19, 95 % CI:0.04–0.35, p = 0.015; PRS-BD: β = 0.16, 95 % CI:0.01–0.32, p = 0.042) and dependent SLEs (PRS-MDD: β = 0.14, 95 % CI:0.03–0.26, p = 0.015; PRS-BD: β = 0.12, 95 % CI:0.004–0.24, p = 0.043). No other significant gene-environment correlations or interactions were found. LimitationsUse of a larger sample size would be beneficial. ConclusionsThe relationship between SLEs and genetic risk for mood disorders may be best explained through correlations rather than interactions.

Causal relationship between COVID-19 and chronic pain: A mendelian randomization study.

COVID-19 is a highly transmissible disease that can result in long-term symptoms, including chronic pain. However, the mechanisms behind the persistence of long-COVID pain are not yet fully elucidated, highlighting the need for further research to establish causality. Mendelian randomization (MR), a statistical technique for determining a causal relationship between exposure and outcome, has been employed in this study to investigate the association between COVID-19 and chronic pain. The IVW, MR Egger, and weighted median methods were employed. Heterogeneity was evaluated using Cochran's Q statistic. MR Egger intercept and MR-PRESSO tests were performed to detect pleiotropy. The Bonferroni method was employed for the correction of multiple testing. R software was used for all statistical analyses. Based on the IVW method, hospitalized COVID-19 patients exhibit a higher risk of experiencing lower leg joint pain compared to the normal population. Meanwhile, the associations between COVID-19 hospitalization and back pain, headache, and pain all over the body were suggestive. Additionally, COVID-19 patients requiring hospitalization were found to have a suggestive higher risk of experiencing neck or shoulder pain and pain all over the body compared to those who did not require hospitalization. Patients with severe respiratory-confirmed COVID-19 showed a suggestive increased risk of experiencing pain all over the body compared to the normal population. Our study highlights the link between COVID-19 severity and pain in different body regions, with implications for targeted interventions to reduce COVID-19 induced chronic pain burden.

Thyroid function and epilepsy: a two-sample Mendelian randomization study.

Thyroid hormones (THs) play a crucial role in regulating various biological processes, particularly the normal development and functioning of the central nervous system (CNS). Epilepsy is a prevalent neurological disorder with multiple etiologies. Further in-depth research on the role of thyroid hormones in epilepsy is warranted. Genome-wide association study (GWAS) data for thyroid function and epilepsy were obtained from the ThyroidOmics Consortium and the International League Against Epilepsy (ILAE) Consortium cohort, respectively. A total of five indicators of thyroid function and ten types of epilepsy were included in the analysis. Two-sample Mendelian randomization (MR) analyses were conducted to investigate potential causal relations between thyroid functions and various epilepsies. Multiple testing correction was performed using Bonferroni correction. Heterogeneity was calculated with the Cochran's Q statistic test. Horizontal pleiotropy was evaluated by the MR-Egger regression intercept. The sensitivity was also examined by leave-one-out strategy. The findings indicated the absence of any causal relationship between abnormalities in thyroid hormone and various types of epilepsy. The study analyzed the odds ratio (OR) between thyroid hormones and various types of epilepsy in five scenarios, including free thyroxine (FT4) on focal epilepsy with hippocampal sclerosis (IVW, OR = 0.9838, p = 0.02223), hyperthyroidism on juvenile absence epilepsy (IVW, OR = 0.9952, p = 0.03777), hypothyroidism on focal epilepsy with hippocampal sclerosis (IVW, OR = 1.0075, p = 0.01951), autoimmune thyroid diseases (AITDs) on generalized epilepsy in all documented cases (weighted mode, OR = 1.0846, p = 0.0346) and on childhood absence epilepsy (IVW, OR = 1.0050, p = 0.04555). After Bonferroni correction, none of the above results showed statistically significant differences. This study indicates that there is no causal relationship between thyroid-related disorders and various types of epilepsy. Future research should aim to avoid potential confounding factors that might impact the study.

Genome-wide versus transcriptome-wide association studies: Prospects and limitations

Genome-wide Association Studies (GWAS) and Transcriptome-wide Association Studies (TWAS) are pivotal tools in genetics research. GWAS, with its comprehensive genome coverage, reveals insights into complex trait variations among different populations. It finds applications beyond gene identification, including historical population studies and linkage disequilibrium pattern assessments. However, GWAS faces challenges like multiple testing corrections and difficulties in pinpointing causal variants. Conversely, TWAS offers higher gene resolution and the potential for deeper insights into genetic mechanisms. Yet, TWAS prediction accuracy is contingent on gene heritability, and its complexity lies in navigating gene regulatory networks and epigenetic factors. Understanding the strengths and limitations of both GWAS and TWAS is crucial for harnessing their full potential in genetic research endeavours.

Medical and genetic correlates of long-term buprenorphine treatment in the electronic health records

Despite the benefits associated with longer buprenorphine treatment duration (i.e., >180 days) (BTD) for opioid use disorder (OUD), retention remains poor. Research on the impact of co-occurring psychiatric issues on BTD has yielded mixed results. It is also unknown whether the genetic risk in the form of polygenic scores (PGS) for OUD and other comorbid conditions, including problematic alcohol use (PAU) are associated with BTD. We tested the association between somatic and psychiatric comorbidities and long BTD and determined whether PGS for OUD-related conditions was associated with BTD. The study included 6686 individuals with a buprenorphine prescription that lasted for less than 6 months (short-BTD) and 1282 individuals with a buprenorphine prescription that lasted for at least 6 months (long-BTD). Recorded diagnosis of substance addiction and disorders (Odds Ratio (95% CI) = 22.14 (21.88–22.41), P = 2.8 × 10−116), tobacco use disorder (OR (95% CI) = 23.4 (23.13–23.68), P = 4.5 × 10−111), and bipolar disorder (OR(95% CI) = 9.70 (9.48–9.92), P = 1.3 × 10−91), among others, were associated with longer BTD. The PGS of OUD and several OUD co-morbid conditions were associated with any buprenorphine prescription. A higher PGS for OUD (OR per SD increase in PGS (95%CI) = 1.43(1.16–1.77), P = 0.0009), loneliness (OR(95% CI) = 1.39(1.13–1.72), P = 0.002), problematic alcohol use (OR(95%CI) = 1.47(1.19–1.83), P = 0.0004), and externalizing disorders (OR(95%CI) = 1.52(1.23 to 1.89), P = 0.0001) was significantly associated with long-BTD. Associations between BTD and the PGS of depression, chronic pain, nicotine dependence, cannabis use disorder, and bipolar disorder did not survive correction for multiple testing. Longer BTD is associated with diagnoses of psychiatric and somatic conditions in the EHR, as is the genetic score for OUD, loneliness, problematic alcohol use, and externalizing disorders.

Effects of endocrine disrupting chemicals and their interactions with genetic risk scores on cardiometabolic traits

Ubiquitous non-persistent endocrine disrupting chemicals (EDCs) have inconsistent associations with cardiometabolic traits. Additionally, large-scale genome-wide association studies (GWASs) have yielded many genetic risk variants for cardiometabolic traits and diseases. This study aimed to investigate the associations between a wide range of EDC exposures (parabens, bisphenols, and phthalates) and 14 cardiometabolic traits and whether these are moderated by their respective genetic risk scores (GRSs). Data were from 1074 participants aged 18 years or older of the Lifelines Cohort Study, a large population-based biobank. GRSs for 14 cardiometabolic traits were calculated based on genome-wide significant common variants from recent GWASs. The concentrations of 15 EDCs in 24-hour urine were measured by isotope dilution liquid chromatography tandem mass spectrometry technology. The main effects of trait-specific GRSs and each of the EDC exposures and their interaction effects on the 14 cardiometabolic traits were examined in multiple linear regression. The present study confirmed significant main effects for all GRSs on their corresponding cardiometabolic trait. Regarding the main effects of EDC exposures, 26 out of 280 EDC-trait tests were significant with explained variances ranging from 0.43 % (MMP- estimated glomerular filtration rate (eGFR)) to 2.37 % (PrP-waist-hip ratio adjusted body mass index (WHRadjBMI)). We confirmed the association of MiBP and MBzP with WHRadjBMI and body mass index (BMI), and showed that parabens, bisphenol F, and many other phthalate metabolites significantly contributed to the variance of WHRadjBMI, BMI, high-density lipoprotein (HDL), eGFR, fasting glucose (FG), and diastolic blood pressure (DBP). Only one association between BMI and bisphenol F was nominally significantly moderated by the GRS explaining 0.36 % of the variance. However, it did not survive multiple testing correction. We showed that non-persistent EDC exposures exerted effects on BMI, WHRadjBMI, HDL, eGFR, FG, and DBP. However no evidence for a modulating role of GRSs was found.

Associations of fatty acids with the risk of biliary tract calculus and inflammation: a Mendelian randomization study

BackgroundThe presence of gallstones in both the gallbladder and bile ducts is referred to as cholelithiasis. The prevalence of cholecystolithiasis and bile duct stones differs. Observational and Mendelian randomization (MR) studies have elucidated the significant contributing role of numerous fatty acids (FAs) in the development of cholelithiasis. Despite numerous studies about cholelithiasis, evidence on the relationship between serum FA levels and cholecystolithiasis, as well as bile duct stones with or without inflammation, remains insufficient.MethodsA two-sample MR study was designed to clarify the impact of serum FA levels on various bile duct inflammatory diseases. The summary statistics of single nucleotide polymorphisms (SNPs) associated with fatty acids were obtained from the UK Biobank (UKB) and included data from 114,999 participants. The researchers obtained GWAS summary statistics for cholecystolithiasis and bile duct stones in 463,010 and 361,194 European participants, including cases with and without inflammation. No sample overlap between the exposure and outcome was verified through the “mr-lap” package. The SNPs were screened to identify instrumental variables (IVs). Cochran’s Q test was applied for heterogeneity assessment. Inverse variance weighting (IVW) (fixed effects or random effects), MR-Egger regression and weighted median methods were used for MR. Multivariable MR was applied to determine the direct effect of each exposure on the outcome. A false discovery rate (FDR) was applied to adjust for multiple testing correction based on the Benjamini-Hochberg method. Finally, the FinnGen Consortium was used to validate some results.ResultsThe overall concentration of polyunsaturated fatty acids (PUFAs) in the serum was negatively associated with the risk of calculus of the gallbladder with acute cholecystitis (IVW, OR = 0.996, P = 0.038, CI 0.992–0.999; weighted median, OR = 0.995, P = 0.025, CI 0.991–0.999). The percentage of PUFAs to total monounsaturated fatty acids(MUFAs) (IVW, OR = 0.998, P = 0.045, CI 0.997–0.999) and the percentage of PUFAs to total FAs (IVW, OR = 0.997, P = 0.025, CI 0.995–0.999) had a protective role against cholecystitis. The percentage of PUFAs to total FAs had a protective role against calculus of the gallbladder without cholecystitis (IVW, OR = 0.995, P = 0.026, CI 0.990–0.999; MR Egger, OR = 0.99, P = 0.03, CI 0.982–0.998; weighted median, OR = 0.991, P = 5.41e-06, CI 0.988–0.995). Conversely, the percentage of MUFAs to total FAs increased the risk for cholecystitis (IVW, OR = 1.001, P = 0.034, CI 1.0001–1.002). However, there were no causal effects of the above exposures on the outcomes through multivariable MR and multiple testing correction. Finally, the causal effects of the above exposures on cholecystitis were validated in the FinnGen Consortium, which suggested that the percentage of PUFAs to total FAs (IVW, OR = 0.744, P = 0.021, CI 0.579–0.957) had a protective role against cholecystitis.ConclusionThese Mendelian randomization findings suggested that more attention should be focused on people who have low serum PUFA levels, which may have a potential role in the occurrence of calculus of the gallbladder or cholecystitis rather than calculus of the bile duct without cholangitis or cholecystitis.

In Vitro Handling Characteristics of a Particulate Bone Substitute for Ridge Preservation Procedures.

While particulate bone substitute materials are applied in a variety of augmentation procedures, standardized defects are being used for preclinical testing. This in vitro study evaluated the density and homogeneity of a particulate bone substitute in ridge preservation procedures. Premolars and molars were extracted in ten semimandibles of minipig cadavers. Light body impression material was used for determining the volume of the extraction sites followed by augmentation with particulate material, thereby weighing the graft material needed. Microradiographs and histologic sections were obtained for evaluating the homogeneity and density of the augmentation material. Statistical analyses were based on Shapiro-Wilk tests, Spearman's rho and one sample Wilcoxon test followed by Bonferroni-Holm correction for multiple testing (α = 0.05). Based on 103 single alveoli evaluated, the mean volume determined was 0.120 cm3 requiring a mean amount of graft material of 0.155 g. With only three exceptions, all parameters (volume, mass of augmentation material, density and homogeneity) correlated significantly (p < 0.020). The apical parts of the alveoli showed reduced density as compared to the middle parts (p < 0.001) and the homogeneity of the augmentation material was also lower as compared to the middle (p < 0.001) and cervical parts (p </= 0.040). The packing of augmentation material is critical when non-standardized defects are treated.

Reading the mind in the eyes in patients with idiopathic REM sleep behavior disorder.

Idiopathic rapid eye movement (REM) sleep behavior disorder (iRBD) is characterized by vocalizations, jerks, and motor behaviors during REM sleep, often associated with REM-related dream content, which is considered a prodromal stage of α-synucleinopathy. The results of the Reading the Mind in the Eyes (RME) reflecting affective Theory of Mind (ToM) are inconsistent in α-synucleinopathy. The present study tried to investigate the RME in patients with iRBD. A total of 35 patients with iRBD and 26 healthy controls were included in the study. All participants were administered the RME and the cognitive assessments according to a standard procedure. The patients with iRBD were further divided into two groups (high or low RME) according to the scores of the RME (> 21, or ≤ 20). The patients with iRBD had worse scores on cognitive tests compared with healthy controls involving global cognitive screening, memory, and visuospatial abilities (p < 0.05), but the scores of the RME were similar between the two groups (20.83 ± 3.38, 20.58 ± 3.43) (p ˃ 0.05). Patients with low RME had more obvious cognitive impairments than healthy controls. After applying Bonferroni correction for multiple tests, the low REM group only performed worse on the Sum of trials 1 to 5 and delayed recall of the RAVLT compared with the healthy control group (p < 0.001, = 0.002). The RME correlated with the scores of cognitive tests involving executive function, attention, memory, and visuospatial function. The changes in RME had a relationship with cognitive impairments, especially memory, in patients with iRBD.

Sexual dimorphism in medullary thyroid cancer aggressiveness.

Thyroid cancer is the only nonreproductive cancer with striking female predominance, although men with thyroid cancer develop more aggressive disease. This study aimed to quantify sex-specific differences in medullary thyroid cancer (MTC) spread after controlling for primary thyroid tumor size. Included in this retrospective analysis were all patients with unilateral solitary MTC who underwent initial neck surgery at a tertiary referral center. A total of 565 patients, 255 men and 310 women, were identified, of whom 467 had sporadic and 98 hereditary MTC. When stratified by sex, and after correction for multiple testing, men had higher preoperative basal calcitonin levels (medians of 655 vs 181 pg/mL; P < 0.001), more frequent extrathyroid extension (25 vs 9%; P < 0.001) and node metastasis (53 vs 27%; P < 0.001) with more involved nodes (medians of 2 vs 0 nodes; P < 0.001) than women but achieved less often biochemical cure (53 vs 74%; P < 0.001). Although absent in patients with very small (≤5 mm) thyroid tumors, sex disparities were immediately apparent in patients with 5.1-40 mm (node metastasis and biochemical cure) and 10.1-40 mm (extrathyroid extension) large thyroid tumors but were lost in patients with thyroid tumors >40 mm as women caught up. Sex disparities were strongest for node metastasis with a 27-41% (overall 24.0%) point difference, followed by biochemical cure with a -15-35% (overall -20.3%) point difference and extrathyroid extension with a 17-24% (14.2% overall) point difference. These findings indicate that the male predominance in MTC aggressiveness is largely biologically driven, warranting further research.

Genetic proxies for antihypertensive drugs and mental disorders: Mendelian randomization study in European and East Asian populations.

Mental disorders are among the top causes of disease burden worldwide. Existing evidence regarding the repurposing of antihypertensives for mental disorders treatment is conflicting and cannot establish causation. We used Mendelian randomization to assess the effects of angiotensin-converting-enzyme inhibitors (ACEIs), beta blockers (BBs), and calcium channel blockers (CCBs) on risk of bipolar disorder (BD), major depression disorder (MDD), and schizophrenia (SCZ). We used published genetic variants which are in antihypertensive drugs target genes and correspond to systolic blood pressure (SBP) in Europeans and East Asians, and applied them to summary statistics of BD (cases = 41,917; controls = 371,549 in Europeans), MDD (cases = 170,756; controls = 329,443 in Europeans and cases = 15,771; controls = 178,777 in East Asians), and SCZ (cases = 53,386; controls = 77,258 in Europeans and cases = 22,778; controls = 35,362 in East Asians) from the Psychiatric Genomics Consortium. We used inverse variance weighting with MR-Egger, weighted median, weighted mode, and Mendelian Randomization Pleiotropy RESidual Sum and Outlier. We performed gene-specific analysis and utilized various methods to address potential pleiotropy. After multipletesting correction, genetically proxied ACEIs were associated with an increased risk of SCZ in Europeans (odds ratio (OR) per 5mmHg lower in SBP 2.10, 95% CI 1.54 to 2.87) and East Asians (OR per 5mmHg lower in SBP 2.51, 95% CI 1.38 to 4.58). Genetically proxied BBs were not associated with any mental disorders in both populations. Genetically proxied CCBs showed no benefits on mental disorders. Antihypertensive drugs have no protection for mental disorders but potential harm. Their long-term use among hypertensive patients with, or with high susceptibility to, psychiatric illness needs careful evaluation.

Influence of study characteristics, methodological rigour and publication bias on efficacy of pharmacotherapy in obsessive-compulsive disorder: a systematic review and meta-analysis of randomised, placebo-controlled trials

QuestionWe examined the effect of study characteristics, risk of bias and publication bias on the efficacy of pharmacotherapy in randomised controlled trials (RCTs) for obsessive-compulsive disorder (OCD).Study selection and analysisWe...

Risk factors and cognitive correlates of white matter hyperintensities in ethnically diverse populations without dementia: The COSMIC consortium.

White matter hyperintensities (WMHs) are an important imaging marker for cerebral small vessel diseases, but their risk factors and cognitive associations have not been well documented in populations of different ethnicities and/or from different geographical regions. We investigated how WMHs were associated with vascular risk factors and cognition in both Whites and Asians, using data from five population-based cohorts of non-demented older individuals from Australia, Singapore, South Korea, and Sweden (N=1946). WMH volumes (whole brain, periventricular, and deep) were quantified with UBO Detector and harmonized using the ComBat model. We also harmonized various vascular risk factors and scores for global cognition and individual cognitive domains. Factors associated with larger whole brain WMH volumes included diabetes, hypertension, stroke, current smoking, body mass index, higher alcohol intake, and insufficient physical activity. Hypertension and stroke had stronger associations with WMH volumes in Whites than in Asians. No associations between WMH volumes and cognitive performance were found after correction for multiple testing. The current study highlights ethnic differences in the contributions of vascular risk factors to WMHs.

Osteoporosis in Relation to a Bone-Related Aging Biomarker Derived from the Urinary Proteomic Profile: A Population Study.

Screening for and prevention of osteoporosis and osteoporotic fractures is imperative, given the high burden on individuals and society. This study constructed and validated an aging-related biomarker derived from the urinary proteomic profile (UPP) indicative of osteoporosis (UPPost-age). In a prospective population study done in northern Belgium (1985-2019), participants were invited for a follow-up examination in 2005-2010 and participants in the 2005-2010 examination again invited in 2009-2013. Participants in both the 2005-2010 and 2009-2013 examinations (n = 519) constituted the derivation (2005-2016 data) and time-shifted validation (2009-2013 data) datasets; 187 participants with only 2005-2010 data formed the synchronous validation dataset. The UPP was assessed by capillary electrophoresis coupled with mass spectrometry. Analyses focused on 2372 sequenced urinary peptides (101 proteins) with key roles in maintaining the integrity of bone tissue. In multivariable analyses with correction for multiple testing, chronological age was associated with 99 urinary peptides (16 proteins). Peptides derived from IGF2 and MGP were upregulated in women compared to men, whereas COL1A2, COL3A1, COL5A2, COL10A1 and COL18A1 were downregulated. Via application of a 1000-fold bootstrapped elastic regression procedure, finally, 29 peptides (10 proteins) constituted the UPPost-age biomarker, replicated across datasets. In cross-sectional analyses of 2009-2013 data (n = 706), the body-height-to-arm-span ratio, an osteoporosis marker, was negatively associated with UPPost-age (p&;lt0.0001). Over 4.89 years (median), the 10-year risk of osteoporosis associated with chronological age and UPPost-age (53 cases including 37 fractures in 706 individuals) increased by 21% and 36% (p ≤ 0.044). Among 357 women, the corresponding estimates were 55% and 60% for incident osteoporosis (37 cases; p ≤ 0.0003) and 42% and 44% for osteoporotic fractures (25 cases; p ≤ 0.017). In conclusion, an aging-related UPP signature with focus on peptide fragments derived from bone-related proteins is associated with osteoporosis risk and available for clinical and trial research.

Distinct and Overlapping Metabolites Associated with Visual Impairment and Cognitive Impairment.

Previous studies found that visual impairment (VI) is associated with higher risk of cognitive impairment, but the molecular basis of these conditions is unknown. We aim to compare the metabolite associations of VI and cognitive impairment. The study population with comprehensive measurements was derived from the UK Biobank study. Visual acuity worse than 0.3 logMAR units were defined as VI. Failure in one or more of the four cognitive tests was defined as cognitive impairment. A panel of 249 metabolites was measured using a nuclear magnetic resonance metabolites profiling platform. Logistic regression models were applied to compare metabolite associations with VI and cognitive impairment. 23,775 participants with complete data on visual acuity, cognitive tests and metabolomics, and without a history of neurological disorders at baseline were included. After adjusting for confounding factors, VI was significantly associated with cognitive impairment (odds ratio[OR] = 1.49, 95% confidence interval [CI]: 1.27-1.74, p < 0.001). After multiple testing correction (p < 9×10-4), five metabolites including the ratio of omega-6 to omega-3 fatty acids (FAs) (OR = 1.18[1.10-1.27]), ratio of omega-3 to total FAs (OR = 0.84[0.77-0.91]), ratio of docosahexaenoic acid (DHA) to total FAs (OR = 0.86[0.80-0.94]), DHA (OR = 0.85[0.78-0.92]), and omega-3 FAs (OR = 0.84[0.77-0.91]) were uniquely associated with VI. Glycoprotein acetyls (OR = 1.06[1.03-1.10]) and alanine (OR = 0.95[0.92-0.98]) were exclusively associated with cognitive impairment. Albumin was identified as the common metabolite shared by the two phenotypes (OR = 0.90[0.85-0.95] for VI, and 0.95[0.92-0.98]) for cognitive impairment). We identified distinct and overlapping metabolites associated with VI and cognitive impairment, unveiling their distinct metabolic profiles and potential common pathophysiology.