Bonferroni-corrected Significance Level Research Articles

Sex-specific comparative outcomes between oral anticoagulants in patients with atrial fibrillation: a systematic review and meta-analysis

AimsWomen with atrial fibrillation (AF) are under-represented in randomised controlled trials (RCTs) of direct oral anticoagulants (DOACs). This systematic review and meta-analysis of RCTs and observational studies examined sex-specific outcomes...

Genome-wide association study identified candidate genes for egg production traits in the Longyan Shan-ma duck

Egg production is an important economic trait in layer ducks and understanding the genetics basis is important for their breeding. In this study, a genome-wide association study (GWAS) for egg production traits in 303 female Longyan Shan-ma ducks was performed based on a genotyping-by-sequencing strategy. Sixty-two single nucleotide polymorphisms (SNPs) associated with egg weight traits were identified (P < 9.48 × 10-5), including 8 SNPs at 5% linkage disequilibrium (LD)-based Bonferroni-corrected genome-wide significance level (P < 4.74 × 10-6). One hundred and nineteen SNPs were associated with egg number traits (P < 9.48 × 10-5), including 13 SNPs with 5% LD-based Bonferroni-corrected genome-wide significance (P < 4.74 × 10-6). These SNPs annotated 146 target genes which contained known candidate genes for egg production traits, such as prolactin and prolactin releasing hormone receptor. This study identified that these associated genes were significantly enriched in egg production-related pathways (P < 0.05), such as the oxytocin signaling, MAPK signaling, and calcium signaling pathways. It was notable that 18 genes were differentially expressed in ovarian tissues between higher and lower egg production in Shan-ma ducks. The identified potential candidate genes and pathways provide insight into the genetic basis underlying the egg production trait of layer ducks.

Alterations in neural activation in the ventral frontoparietal network during complex magnocellular stimuli in developmental dyslexia associated with READ1 deletion

BackgroundAn intronic deletion within intron 2 of the DCDC2 gene encompassing the entire READ1 (hereafter, READ1d) has been associated in both children with developmental dyslexia (DD) and typical readers (TRs), with interindividual variation in reading performance and motion perception as well as with structural and functional brain alterations. Visual motion perception -- specifically processed by the magnocellular (M) stream -- has been reported to be a solid and reliable endophenotype of DD. Hence, we predicted that READ1d should affect neural activations in brain regions sensitive to M stream demands as reading proficiency changes.MethodsWe investigated neural activations during two M-eliciting fMRI visual tasks (full-field sinusoidal gratings controlled for spatial and temporal frequencies and luminance contrast, and sensitivity to motion coherence at 6%, 15% and 40% dot coherence levels) in four subject groups: children with DD with/without READ1d, and TRs with/without READ1d.ResultsAt the Bonferroni-corrected level of significance, reading skills showed a significant effect in the right polar frontal cortex during the full-field sinusoidal gratings-M task. Regardless of the presence/absence of the READ1d, subjects with poor reading proficiency showed hyperactivation in this region of interest (ROI) compared to subjects with better reading scores. Moreover, a significant interaction was found between READ1d and reading performance in the left frontal opercular area 4 during the 15% coherent motion sensitivity task. Among subjects with poor reading performance, neural activation in this ROI during this specific task was higher for subjects without READ1d than for READ1d carriers. The difference vanished as reading skills increased.ConclusionsOur findings showed a READ1d-moderated genetic vulnerability to alterations in neural activation in the ventral attentive and salient networks during the processing of relevant stimuli in subjects with poor reading proficiency.

A multi-tissue, splicing-based joint transcriptome-wide association study identifies susceptibility genes for breast cancer

Splicing-based transcriptome-wide association studies (splicing-TWASs) of breast cancer have the potential to identify susceptibility genes. However, existing splicing-TWASs test the association of individual excised introns in breast tissue only and thus have limited power to detect susceptibility genes. In this study, we performed a multi-tissue joint splicing-TWAS that integrated splicing-TWAS signals of multiple excised introns in each gene across 11 tissues that are potentially relevant to breast cancer risk. We utilized summary statistics from a meta-analysis that combined genome-wide association study (GWAS) results of 424,650 women of European ancestry. Splicing-level prediction models were trained in GTEx (v.8) data. We identified 240 genes by the multi-tissue joint splicing-TWAS at the Bonferroni-corrected significance level; in the tissue-specific splicing-TWAS that combined TWAS signals of excised introns in genes in breast tissue only, we identified nine additional significant genes. Of these 249 genes, 88 genes in 62 loci have not been reported by previous TWASs, and 17 genes in seven loci are at least 1 Mb away from published GWAS index variants. By comparing the results of our splicing-TWASs with previous gene-expression-based TWASs that used the same summary statistics and expression prediction models trained in the same reference panel, we found that 110 genes in 70 loci that are identified only by the splicing-TWASs. Our results showed that for many genes, expression quantitative trait loci (eQTL) did not show a significant impact on breast cancer risk, whereas splicing quantitative trait loci (sQTL) showed a strong impact through intron excision events.

Trends in research grant applications and outcomes among medical students in the United Kingdom: a national self-reported cross-sectional survey.

Background: Research funding disparities contribute to clinical-academic workforce inequalities1-3. Hence, our study explores the association between student demographics and research grant application rates and outcomes among UK medical students. Methods: This is a national multicentre cross-sectional survey of UK medical students in the 2020-21 academic year. Multiple zero-inflated negative binomial regression and generalized linear model (binomial distribution; logit link) were utilized to investigate the association between student demographics, number of grant applications submitted, and successful grant applications (yes or no). P-values less than a Bonferroni-corrected significance level of 0.05/36 = 0.0014 were statistically significant. Results: 1528 students participated from 36 medical schools. 151 respondents (9.9%) had applied for research grants. Black students submitted applications 2.90 times more often than white students [Incident rate ratio (IRR): 2.90, 95% confidence interval (CI): 1.37-6.16], with no ethnic disparity in the odds of successful applications. Gender did not influence application rates significantly (P = .248), but women were 4.61 times more likely to secure a grant than men [odds ratio: 4.61, 95% CI: 2.04-10.4]. Being a PubMed-indexed author was associated with increased grant application submission rates [IRR: 3.61, 95% CI: 2.20- 5.92] while conducting more research was associated with greater odds of securing a grant [odds ratio: 1.42, 95% CI: 1.17- 1.73]. Conclusion: Although black students submitted more applications, ethnicity did not influence success rates. Gender did not influence application rates, but women were more successful. These findings underscore the need for strategies supporting women and underrepresented students for continued academic achievement after graduation. This abstract has been published as a paper4

Improving Automated Hemorrhage Detection at Sparse-View CT via U-Net-based Artifact Reduction.

Purpose To explore the potential benefits of deep learning-based artifact reduction in sparse-view cranial CT scans and its impact on automated hemorrhage detection. Materials and Methods In this retrospective study, a U-Net was trained for artifact reduction on simulated sparse-view cranial CT scans in 3000 patients, obtained from a public dataset and reconstructed with varying sparse-view levels. Additionally, EfficientNet-B2 was trained on full-view CT data from 17 545 patients for automated hemorrhage detection. Detection performance was evaluated using the area under the receiver operating characteristic curve (AUC), with differences assessed using the DeLong test, along with confusion matrices. A total variation (TV) postprocessing approach, commonly applied to sparse-view CT, served as the basis for comparison. A Bonferroni-corrected significance level of .001/6 = .00017 was used to accommodate for multiple hypotheses testing. Results Images with U-Net postprocessing were better than unprocessed and TV-processed images with respect to image quality and automated hemorrhage detection. With U-Net postprocessing, the number of views could be reduced from 4096 (AUC: 0.97 [95% CI: 0.97, 0.98]) to 512 (0.97 [95% CI: 0.97, 0.98], P < .00017) and to 256 views (0.97 [95% CI: 0.96, 0.97], P < .00017) with a minimal decrease in hemorrhage detection performance. This was accompanied by mean structural similarity index measure increases of 0.0210 (95% CI: 0.0210, 0.0211) and 0.0560 (95% CI: 0.0559, 0.0560) relative to unprocessed images. Conclusion U-Net-based artifact reduction substantially enhanced automated hemorrhage detection in sparse-view cranial CT scans. Keywords: CT, Head/Neck, Hemorrhage, Diagnosis, Supervised Learning Supplemental material is available for this article. © RSNA, 2024.

Improving the Efficiency of Single-Isocenter Multiple Metastases Stereotactic Radiosurgery Treatment

PurposeMultiple brain metastases can be treated efficiently with Stereotactic Radio Surgery (SRS) using a Single Isocenter Dynamic Conformal Arc (SIDCA) technique. Currently plans are manually optimized, which may lead to unnecessary table angles and arcs being used. This study aimed to evaluate an automatic 4π-optimization SIDCA algorithm for treatment efficiency and plan quality.Methods and MaterialsAutomatic 4π-optimized SIDCA plans were created and compared to the manually optimized clinical plans for 54 patients who received single-fraction SRS to 2-10 metastases. The number of table angles and arcs were compared with a paired t-test using a Bonferroni-corrected significance level of p<0.05/4=0.0125. The reduction in treatment time was estimated from the difference in the number of table angles and arcs. Plan quality was assessed through the volume-averaged inverse Paddick Conformity Index (CI) and Gradient Index (GI), and the volume of normal brain surrounding each metastasis receiving 12 Gy (local V12 Gy). For a five-patient subset the automatic plans were manually adjusted further. CI and GI were assessed for non-inferiority using a one-sided t-test with the non-inferiority limit equal to the 95% inter-observer reproducibility limit from a separate planning study (corrected significance level p<0.05/(4−1)=0.017).ResultsThe automatic plans significantly improved treatment efficiency with a mean reduction in the number of table angles and arcs of −0.5±0.1 and −1.3±0.2 respectively (± standard error, both p<0.001). Estimated treatment time saving was −2.7±0.5minutes, 14% of the total. The volume-averaged CI and GI were non-inferior to the clinical plans (both p<0.001), although there was a small systematic shift in CI of 0.07±0.01. The resulting difference in local V12 Gy, 0.25±0.04cm3, was not clinically significant. Minor manual adjustment of the automatic plans removed these slight differences whilst preserving the improved treatment efficiency.ConclusionsAutomatic 4π-optimization can generate SIDCA SRS plans with improved treatment efficiency and non-inferior plan quality.

Detecting Gene-Gene Interaction among DNA Repair Genes in Chinese non-Syndromic Cleft lip with or Without Palate Trios.

The objective of this study is to investigate the gene-gene interactions associated with NSCL/P among DNA repair genes. This study included 806 NSCL/P case-parent trios from China. Quality control process was conducted for genotyped single nucleotide polymorphisms (SNPs) located in six DNA repair genes (ATR, ERCC4, RFC1, TYMS, XRCC1 and XRCC3). We tested gene-gene interactions with Cordell's method using statistical package TRIO in R software. Bonferroni corrected significance level was set as P = 4.24 × 10-4. We also test the robustness of the interactions by permutation tests. Not applicable. A total of 806 NSCL/P case-parent trios (complete trios: 682, incomplete trios: 124) with Chinese ancestry. Not applicable. Not applicable. A total of 118 SNPs were extracted for the interaction tests. Fourteen pairs of significant interactions were identified after Bonferroni correction, which were confirmed in permutation tests. Twelve pairs were between ATR and ERCC4 or XRCC3. The most significant interaction occurred between rs2244500 in TYMS and rs3213403 in XRCC1(P = 8.16 × 10-15). The current study identified gene-gene interactions among DNA repair genes in 806 Chinese NSCL/P trios, providing additional evidence for the complicated genetic structure underlying NSCL/P. ATR, ERCC4, XRCC3, TYMS and RFC1 were suggested to be possible candidate genes for NSCL/P.

A Blended Intervention Targeting Emotion Dysregulation in Adults With Attention-Deficit/Hyperactivity Disorder: Development and Feasibility Study.

Many adults with attention-deficit/hyperactivity disorder (ADHD) experience difficulties related to emotion regulation. Such difficulties are known to substantially impact quality of life and overall functioning. Yet, there is a lack of treatment interventions specifically designed to address these challenges. This study aimed to describe the development and assess the feasibility, along with the initial clinical outcomes, of a novel blended intervention for adults with ADHD. The blended intervention combines both face-to-face and digital components and is specifically designed to address emotion dysregulation in ADHD. This intervention was an 8-week blended intervention combining weekly face-to-face group sessions with a supplementary digital companion app. The intervention is based on elements from dialectic behavioral therapy skills training and positive psychology. To evaluate its feasibility, we performed a 10-week feasibility study with an uncontrolled pre-post study design, including 16 adults with ADHD and co-occurring emotion dysregulation. The feasibility measures encompassed adherence, satisfaction, and perceived credibility of the intervention. Clinical outcomes were evaluated by self-reported symptoms of emotion dysregulation, inattention, hyperactivity-impulsivity, executive function, depression, anxiety, and a measure of quality of life. Paired sample 2-tailed t tests were used to analyze clinical outcomes with a Bonferroni-corrected significance level. Both treatment credibility and treatment satisfaction were rated favorably by the majority of the participants. In particular, the participants emphasized meeting others with ADHD as beneficial. In terms of adherence, 3 participants withdrew before initiating the intervention, while another 4 participants did not complete the intervention. On average, the participants who enrolled in the intervention attended 6.2 of the 8 group sessions and completed 6.7 of the 8 skills training modules in the companion app. In terms of clinical outcomes, there was a reduction in symptoms of emotion dysregulation from before to after the intervention (d=2.0). Significant improvements were also observed in measures of inattention (d=1.1) and hyperactivity-impulsivity (d=0.9). However, no significant improvements were found in the domains of depression, anxiety, quality of life, and executive functioning. The results are encouraging, both in terms of feasibility and the preliminary clinical results on emotion dysregulation. The blended format, combining digital and face-to-face elements, may also seem to offer some advantages: the group-based format was valued as it facilitated peer interaction, while a rather high completion of modules in the companion app highlights its potential to enhance skills training between the group sessions. Future randomized controlled trials are called for to further evaluate the clinical effectiveness of the intervention. ClinicalTrials.gov NCT05644028; https://clinicaltrials.gov/study/NCT05644028.

Standardized viscosity as a source of error in computational fluid dynamic simulations of cerebral aneurysms.

Computational fluid dynamics (CFD) simulations are a powerful tool for studying cerebral aneurysms, capable of evaluating hemodynamics in a way that is infeasible with imaging alone. However, the difficulty of incorporating patient-specific information and inherent obstacles of in vivo validation have limited the clinical usefulness of CFD of cerebral aneurysms. In this work we investigate the effect of using standardized blood viscosity values in CFD simulations of cerebral aneurysms when compared to simulations of the same aneurysms using patient-specific viscosity values derived from hematocrit measurements. The objective of this work is to determine the level of error, on average, that is, caused by using standardized values of viscosity in CFD simulations of cerebral aneurysms. By quantifying this error, we demonstrate the need for incorporating patient-specific viscosity in future CFD investigations of cerebral aneurysms. CFD simulations of forty-one cerebral aneurysms were conducted using patient-specific boundary conditions. For each aneurysm two simulations were conducted, one utilizing patient-specific blood viscosity derived from hematocrit measurements and another using a standardized value for blood viscosity. Hemodynamic parameters such as wall shear stress (WSS), wall shear stress gradient (WSSG), and the oscillatory shear index (OSI) were calculated for each of the simulations for each aneurysm. Paired t-tests for differences in the time-averaged maps of these hemodynamic parameters between standardized and patient-specific viscosity simulations were conducted for each aneurysm. Bland-Altman analysis was used to examine the cohort-wide changes in the hemodynamic parameters. Subjects were broken into two groups, those with higher than standard viscosity and those with lower than standard viscosity. An unpaired t-test was used to compare the percent change in WSS, WSSG, and OSI between patient-specific and standardized viscosity simulations for the two cohorts. The percent changes in hemodynamic parameters were correlated against the direction and magnitude of percent change in viscosity, aneurysm size, and aneurysm location. For all t-tests, a Bonferroni-corrected significance level of 0.0167 was used. 63.2%, 41.5%, and 48.7% of aneurysms showed statistically significant differences between patient-specific and standardized viscosity simulations for WSS, WSSG, and OSI respectively. No statistically significant difference was found in the percent changes in WSS, WSSG, and OSI between the group with higher than standard viscosity and those with lower than standard viscosity, indicating an increase in viscosity can cause either an increase or decrease in each of the hemodynamic parameters. On a study-wide level no significant bias was found in either direction for WSS, WSSG, or OSI between the simulation groups due to the bidirectional effect of changing viscosity. No correlation was found between percent change of viscosity and percent change of WSS, WSSG, or OSI, meaning an after-the-fact correction for patient-specific viscosity is not feasible. Standardizing viscosity values in CFD of cerebral aneurysms has a large and unpredictable impact on the calculated WSS, WSSG, and OSI when compared to CFD simulations of the same aneurysms using a patient-specific viscosity. We recommend implementing hematocrit-based patient-specific blood viscosity values for all CFD simulations of cerebral aneurysms.

Trends in research grant applications and outcomes among medical students in the United Kingdom: a national self-reported cross-sectional survey.

Research funding disparities contribute to clinical academic workforce inequalities. Hence, our study explores the association between student demographics and research grant application rates and outcomes among UK medical students. This is a national multicentre cross-sectional survey of UK medical students in the 2020-21 academic year. Multiple zero-inflated negative binomial regression and generalized linear model (binomial distribution; logit link) were utilized to investigate the association between student demographics, number of grant applications submitted, and successful grant applications (yes or no). P-values less than a Bonferroni-corrected significance level of 0.05/36 = 0.0014 were considered to be statistically significant. A total of 1528 students participated from 36 medical schools. One hundred fifty-one respondents (9.9%) had applied for research grants. Black students submitted applications 2.90 times more often than white students [Incident rate ratio (IRR): 2.90, 95% confidence interval (CI): 1.37-6.16], with no ethnic disparity in the odds of successful applications. Gender did not influence application rates significantly (P = .248), but women were 4.61 times more likely to secure a grant than men [odds ratio: 4.61, 95% CI: 2.04-10.4]. Being a PubMed-indexed author was associated with increased grant application submission rates [IRR: 3.61, 95% CI: 2.20- 5.92] while conducting more research was associated with greater odds of securing a grant [odds ratio: 1.42, 95% CI: 1.17- 1.73]. Although black students submitted more applications, ethnicity did not influence success rates. Gender did not influence application rates, but women were more successful. These findings underscore the need for strategies supporting women and underrepresented students for continued academic achievement after graduation. What is already known on this topic Research funding for post-PhD researchers is believed to be a major driver of gender and ethnic inequalities in the clinical academic workforce.Students who receive research grants are more likely to receive postgraduate research grants.What this study adds Black students applied for more research grants than white students, but there were no ethnic differences in the odds of securing a grant.There were no gender differences in the research grant application rates. However, female students had greater odds of securing research grants compared to male students.How this study might affect research, practice or policy Medical schools should incorporate grant writing skills into the undergraduate research curriculum. Also, to sustain women's academic success post medical school, the NIHR and affiliates should provide research award extensions and childcare support for women when required.

Impact of attenuation correction of radiotherapy hardware for positron emission tomography-magnetic resonance in ano-rectal radiotherapy patients.

Positron Emission Tomography-Magnetic Resonance (PET-MR) scanners could improve ano-rectal radiotherapy planning through improved Gross Tumour Volume (GTV) delineation and enabling dose painting strategies using metabolic measurements. This requires accurate quantitative PET images acquired in the radiotherapy treatmentposition. This study aimed to evaluate the impact on GTV delineation and metabolic parameter measurement of using novel Attenuation Correction (AC) maps that included the radiotherapy flat couch, coil bridge and anterior coil to see if they werenecessary. Seventeen ano-rectal radiotherapy patients received a -FluoroDeoxyGlucose PET-MR scan in the radiotherapy position. PET images were reconstructed without ( ) and with ( ) the radiotherapy hardware included. Both AC maps used the same Computed Tomography image for patient AC. Semi-manual and threshold GTVs were delineated on both PET images, the volumes compared and the Dice coefficient calculated. Metabolic parameters: Standardized Uptake Values , and Total Lesion Glycolysis (TLG) were compared using paired t-tests with a Bonferroni corrected significance level of . Differences in semi-manual GTV volumes between and were approaching statistical significance (difference , ), with larger differences in low FDG-avid tumours ( ). The and GTVs were concordant with Dice coefficients (manual) and (threshold). Metabolic parameters were significantly different, with , and TLG differences of ( ), ( ) and ( ) respectively. The TLG difference resulted in 1/8 rectal cancer patients changing prognosis group, based on literature TLG cut-offs, when using rather than . This study suggests that using AC maps with the radiotherapy hardware included is feasible for patient imaging. The impact on tumour delineation was mixed and needs to be evaluated in larger cohorts. However using AC of the radiotherapy hardware is important for situations where accurate metabolic measurements are required, such as dose painting and treatmentprognostication.

A metabolomic investigation of serum perfluorooctane sulfonate and perfluorooctanoate

BackgroundExposures to perfluorooctane sulfonate (PFOS) and perfluorooctanoate (PFOA), environmentally persistent chemicals detectable in the blood of most Americans, have been associated with several health outcomes. To offer insight into their possible biologic effects, we evaluated the metabolomic correlates of circulating PFOS and PFOA among 3,647 participants in eight nested case-control serum metabolomic profiling studies from the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial. MethodsMetabolomic profiling was conducted by Metabolon Inc., using ultra high-performance liquid chromatography/tandem accurate mass spectrometry. We conducted study-specific multivariable linear regression analyses estimating the associations of metabolite levels with levels of PFOS or PFOA. For metabolites measured in at least 3 of 8 nested case-control studies, random effects meta-analysis was used to summarize study-specific results (1,038 metabolites in PFOS analyses and 1,100 in PFOA analyses). ResultsThe meta-analysis identified 51 and 38 metabolites associated with PFOS and PFOA, respectively, at a Bonferroni-corrected significance level (4.8x10-5 and 4.6x10-5, respectively). For both PFOS and PFOA, the most common types of associated metabolites were lipids (sphingolipids, fatty acid metabolites) and xenobiotics (xanthine metabolites, chemicals). Positive associations were commonly observed with lipid metabolites sphingomyelin (d18:1/18:0) (P = 2.0x10-10 and 2.0x10-8, respectively), 3-carboxy-4-methyl-5-pentyl-2-furanpropionate (P = 2.7x10-15, 1.1x10-17), and lignoceroylcarnitine (C24) (P = 2.6x10-8, 6.2x10-6). The strongest positive associations were observed for chemicals 3,5-dichloro-2,6-dihydroxybenzoic acid (P = 3.0x10-112 and 6.8x10-13, respectively) and 3-bromo-5-chloro-2,6-dihydroxybenzoic acid (P = 1.6x10-14, 2.3x10-6). Other metabolites positively associated with PFOS included D-glucose (carbohydrate), carotene diol (vitamin A metabolism), and L-alpha-aminobutyric acid (glutathione metabolism), while uric acid (purine metabolite) was positively associated with PFOA. PFOS associations were consistent even after adjusting for PFOA as a covariate, while PFOA associations were greatly attenuated with PFOS adjustment. ConclusionsIn this large metabolomic study, we observed robust positive associations with PFOS for several molecules. Further investigation of these metabolites may offer insight into PFOS-related biologic effects.

Assessing the causal association of trauma with subsequent psychiatric disorders by a Mendelian randomization study trauma and common psychiatric disorders.

Trauma has been proposed as a risk factor for the development of psychiatric disorders. This study aimed to determine the causal role of trauma in six common psychiatric disorders. We obtained summary-level data for genetic variants associated with trauma and the corresponding association with psychiatric disorders from previous genome-wide association studies. Two-sample Mendelian randomization analyzes were performed to estimate the causal association between trauma and psychiatric disorders, with inverse variance weighted used as the main method. Genetically predisposed trauma was associated with an increased risk of psychiatric disorders [odds ratio (OR) =1.24, 95%, confidence interval (CI), 1.09-1.40], anxiety disorder (OR = 1.30, 95% CI, 1.10-1.52) and schizophrenia (OR = 1.48, 95% CI, 1.18-1.84). However, the associations between trauma and sleep disorder (OR = 1.17, 95% CI, 1.01-1.35), as well as depression (OR = 1.09, 95% CI, 1.02-1.16) did not reach a Bonferroni corrected significance level. Besides, no association was observed between trauma and risk of bipolar disorder (OR = 1.21, 95% CI, 0.98-1.48) and eating disorder (OR = 1.28, 95% CI, 0.88-1.86). Trauma might be causally associated with an increased risk of some common psychiatric disorders such as anxiety disorder and schizophrenia. However, little evidence supported an association between trauma and risk of depression, bipolar disorder, sleep disorder, and eating disorder. Our findings offered novel insights into the trauma-mediated development mechanism of psychiatric disorders, and psychological intervention to patients with trauma may be an effective prevention strategy for psychological diseases.

Causal Association Between Anemia and Cardiovascular Disease: A 2-Sample Bidirectional Mendelian Randomization Study.

Background Although previous observational studies have shown an association between anemia and cardiovascular disease (CVD), the underlying causal relationship between anemia and CVD remains uncertain. Methods and Results We conducted a 2-sample bidirectional Mendelian randomization (MR) study to assess the causal association between anemia and CVD. We extracted summary statistics data for anemia, heart failure (HF), coronary artery disease (CAD), atrial fibrillation, any stroke, and any ischemic stroke (AIS) from relevant published genome-wide association studies. After rigorous quality control steps, independent single-nucleotide polymorphisms for each disease were selected as instrumental variables. Inverse-variance weighting was used as the primary method to estimate the causal association between anemia and CVD in the 2-sample MR analysis. Simultaneously, we performed a series of multiple methods analyses (median weighting, maximum likelihood [MR robust adjusted profile score]), sensitivity analyses (Cochran's Q test and MR-Egger intercept, leave-one-out test [MR pleiotropy residual sum and outlier]), instrumental variable strength evaluations (F statistic), and statistic power estimates to verify the robustness and reliability of our results. Furthermore, the associations between anemia and CVD from different studies, including the UK Biobank and FinnGen studies, were combined by meta-analysis. The MR analysis showed that genetically predicted anemia was significantly associated with HF risk at the Bonferroni-corrected significance level (odds ratio [OR], 1.11 [95% CI, 1.04-1.18]; P=0.002) and was suggestively associated with CAD risk (OR, 1.11 [95% CI, 1.02-1.22]; P=0.020). However, the associations between anemia and atrial fibrillation, any stroke, or AIS were not statistically significant. In the reverse MR analysis, we found that genetic susceptibility to HF, CAD, and AIS was significantly associated with anemia risk. The ORs of HF, CAD, and AIS were 1.64 (95% CI, 1.39-1.94; P=7.60E-09), 1.16 (95% CI, 1.08-1.24; P=2.32E-05), and 1.30 (95% CI, 1.11-1.52; P=0.001), respectively. Genetically predicted atrial fibrillation was suggestively associated with anemia (OR, 1.06 [95% CI, 1.01-1.12]; P=0.015). Sensitivity analyses found weak evidence of horizontal pleiotropy and heterogeneity, which ensured the robustness and reliability of the results. Meta-analysis also showed the statistically significant association between anemia and HF risk. Conclusions Our study supports bidirectional causality between anemia and HF and significant associations between genetic predisposition to CAD and AIS with anemia, which contributes to the clinical management of both diseases.

Abstract 6474: Stress-related sick leave and subsequent cancer risk: A Swedish national register study of 516 678 cancer cases

Abstract Background: Despite previous studies investigating psychological stress in relation to cancer risk, no consensus has been reached as to whether stress is a modifiable risk factor for cancer. This study aims to investigate whether sick leave due to psychological stress can affect the risk of developing cancer. Method: This is a matched case-control study using Swedish nation-wide register data (study period 2005-2018). The main exposure is stress-related sick leave defined as registered sick leave due to psychological stress with the diagnosis codes of F43 (International Classification of Diseases codes: ICD) and its subclassifications and hereafter referred to as stress leave. For each primary cancer case (except non-melanoma skin cancer), up to five cancer-free controls were matched based on sex, age and county. Conditional logistic regression, conditioned on matching factors and adjusting for socioeconomic factors, was used to calculate odds ratios (ORs) with 95% confidence intervals (CIs). For subgroup analyses by specific tumor sites, Bonferroni-corrected significance level of 0.002 (alpha value divided by the number of tumor sites = 0.05/24) was also applied. Results: The study comprised 516 678 cancer cases and 2 357 433 matched controls. Stress leave of any duration, was associated with a modestly increased risk of cancer, with the highest risk observed for 1-30 days of leave, vs no leave during follow-up (adjusted OR 1.05, 95% CI 1.02-1.09). In subgroup analyses by tumor sites, stress leave was associated with an increased risk of prostate cancer (adjusted OR for &amp;gt;90 days vs no stress leave 1.10, 95% CI 1.01-1.20) and cervix cancer (adjusted OR&amp;gt;90 days vs no leave 1.11, 95% CI 1.05-1.17). For lung cancer, an inverse risk relationship was found (adjusted OR&amp;gt;90 days vs no leave 0.88, 95% CI 0.77-0.99). For other tumor sites, associations were generally null or had wide confidence intervals. After applying a Bonferroni-corrected significance level, the association was still significant for cervical cancer. Further examination by sex, specific types of psychological stress and cancer groups based on established etiology (tobacco use, obesity, alcohol consumption and gastric hyperacidity) showed a clear exposure-response trend in men and pronounced associations for exhaustion disorder (ICD code: F43.8A) and tobacco-related cancers. In a post-hoc analysis, the association for other HPV-related cancers was similar to that for cervical cancer but not statistically significant. Conclusion: In this register study covering the entire Swedish population, we found that stress-related sick leave was associated with modestly higher risk of cancer, particularly the risk of cervical cancer. Potential higher risk of prostate cancer and lower risk of lung cancer were observed, though these associations were not statistically significant after controlling for multiple testing. Citation Format: Sai San Moon Lu, Jenny Hadrévi, Lisbeth Slunga Järvholm, Florentin Späth, Richard Palmqvist, Tommy Olsson, Sophia Harlid, Bethany van Guelpen. Stress-related sick leave and subsequent cancer risk: A Swedish national register study of 516 678 cancer cases [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6474.

Potential protection of computer gaming against mental health issues: Evidence from a Mendelian randomization study

Computer gaming may negatively impact mental health. To mitigate the inherent defects of the existing observational studies, we employed the Mendelian randomization (MR) design to examine the role of computer gaming on mental health issues using large-scale genome-wide association study (GWAS) data. A computer gaming and four mental health issue datasets were obtained from UK-Biobank and FinnGen respectively. We evaluated the causal effects using inverse variance weighted (IVW), weighted median, and MR-Egger estimators, followed by a series of sensitivity analyses. We found no distinctive results under a Bonferroni-corrected significance level (p < 0.013). Nevertheless, we observed suggestive evidence in IVW estimations supporting the causal effects of computer gaming on depression medication consumption (OR = 0.579; 95%CI: 0.347–0.996; p = 0.036) and anxiety disorders (OR = 0.471; 95%CI: 0.246–0.903, p = 0.023). Our findings indicate a potential protective effect of computer gaming against mental health issues, which underscores the bright sides of computer gaming, and also offers insights into the health promotion strategies based on digital interventions. Given our limitations, we call for future research to re-examine our findings and explore underlying mechanisms.

Predictors of self-reported research self-efficacy and perception of research amongst medical students in the United Kingdom: a national cross-sectional survey.

There has been a decline in the number of academic clinicians in the UK, and there are ethnic/gender disparities in the academic workforce. Higher research self-efficacy (RSE) and a positive perception of research (PoR) amongst students are associated with a higher motivation to engage in academic medicine. Hence, this study aimed to determine the factors that influence RSE and PoR amongst UK medical students. This is a multicentre cross-sectional survey of medical students in 36 UK medical schools in the 2020/21 academic year. Multiple linear regression was used to investigate the association between students' demographics and RSE/PoR. P-values less than a Bonferroni-corrected significance level of .05/28=.0018 were considered statistically significant. In total, 1573 individuals participated from 36 medical schools. There were no ethnic differences in PoR or RSE scores. Although there were no gender differences in PoR, female students had lower RSE scores than male students (adjusted β=-1.75; 95% CI: -2.62, -0.89). Research experience before medical school (adjusted β=3.02; 95% CI: 2.11, 3.93), being in the clinical training phase (adjusted β=1.99; 95% CI: 1.09, 2.90), and completing a degree before medical school (adjusted β=3.66; 95% CI: 2.23, 5.09) were associated with higher RSE. There were no associations between the predictor variables and PoR. Female students had lower self-reported RSE scores. Future studies should investigate the role of targeted research mentorship in improving RSE amongst female medical students.

The prognostic implication of visual acuity at the time of uveal melanoma diagnosis

BackgroundVisual outcomes after primary tumour treatment of uveal melanoma (UM) have been investigated repeatedly. This study evaluates the correlation between best-corrected visual acuity (BCVA) before treatment with clinicopathological factors and patient survival.Subjects/MethodsPre-treatment BCVA was examined in relation to tumour dimensions and location, and survival in a retrospective cohort of 1809 patients who underwent plaque brachytherapy. BCVA was also correlated to tumour histological factors in a second cohort of 137 enucleated eyes.ResultsThe mean BCVA of the tumour eye prior to plaque brachytherapy was LogMAR 0.42 (SD 0.46). Patients with low BCVA (LogMAR ≥ 1.00) did not differ in age (p = 0.19) and had similar frequency of ciliary body involvement (p = 0.99) but had tumours with greater apical thickness (p < 0.0001), greater diameter (p < 0.0001) and shorter distance to the optic disc and fovea (p < 0.0001). There were no significant relations between low BCVA and any of 13 examined tumour histological factors at a Bonferroni-corrected significance level (p > 0.004). Patients with low BCVA had greater incidence of UM-related mortality in competing risk analysis (p = 0.0019) and shorter overall survival (p < 0.0001). Low BCVA was also associated with increased hazard ratio (HR) for UM-related mortality in univariate analysis (HR 1.5, 95% confidence interval 1.2 to 1.9), but not in multivariate analysis with tumour size and location as covariates.ConclusionsUM patients with low BCVA before primary tumour treatment have a worse prognosis, likely related to increased tumour dimensions. Future studies should examine the prognostic significance of BCVA in relation to macula-involving retinal detachment and genetic factors.

Eight pharmacokinetic genetic variants are not associated with the risk of bleeding from direct oral anticoagulants in non-valvular atrial fibrillation patients.

Background: Atrial fibrillation (AF) is the leading cause of ischemic stroke and treatment has focused on reducing this risk through anticoagulation. Direct Oral Anticoagulants (DOACs) are the first-line guideline-recommended therapy since they are as effective and overall safer than warfarin in preventing AF-related stroke. Although patients bleed less from DOACs compared to warfarin, bleeding remains the primary safety concern with this therapy. Hypothesis: Genetic variants known to modify the function of metabolic enzymes or transporters involved in the pharmacokinetics (PK) of DOACs could increase the risk of bleeding. Aim: To assess the association of eight, functional PK-related single nucleotide variants (SNVs) in five genes (ABCB1, ABCG2, CYP2J2, CYP3A4, CYP3A5) with the risk of bleeding from DOACs in non-valvular AF patients. Methods: A retrospective cohort study was carried out with 2,364 self-identified white non-valvular AF patients treated with either rivaroxaban or apixaban. Genotyping was performed with Illumina Infinium CoreExome v12.1 bead arrays by the Michigan Genomics Initiative biobank. The primary endpoint was a composite of major and clinically relevant non-major bleeding. Cox proportional hazards regression with time-varying analysis assessed the association of the eight PK-related SNVs with the risk of bleeding from DOACs in unadjusted and covariate-adjusted models. The pre-specified primary analysis was the covariate-adjusted, additive genetic models. Six tests were performed in the primary analysis as three SNVs are in the same haplotype, and thus p-values below the Bonferroni-corrected level of 8.33e-3 were considered statistically significant. Results: In the primary analysis, none of the SNVs met the Bonferroni-corrected level of statistical significance (all p > 0.1). In exploratory analyses with other genetic models, the ABCB1 (rs4148732) GG genotype tended to be associated with the risk of bleeding from rivaroxaban [HR: 1.391 (95%CI: 1.019-1.900); p = 0.038] but not from apixaban (p = 0.487). Conclusion: Eight functional PK-related genetic variants were not significantly associated with bleeding from either rivaroxaban or apixaban in more than 2,000 AF self-identified white outpatients.