Putative Risk Factors Research Articles

Alzheimer Disease and Epilepsy: A Mendelian Randomization Study.

Observational studies suggested a bidirectional relationship between Alzheimer disease (AD) and epilepsies. However, it remains debated whether and in which direction a causal association exists. This study aims to explore the relationship between genetic predisposition to AD, CSF biomarkers of AD (β-amyloid [Aβ] 42 and phosphorylated tau [pTau]), and epilepsies with 2-sample, bidirectional Mendelian randomization (MR) method. Genetic instruments were obtained from large-scale genome-wide meta-analysis of AD (Ncase/proxy = 111,326, Ncontrol = 677,663), CSF biomarkers of AD (Aβ42 and pTau, N = 13,116), and epilepsy (Ncase = 15,212, Ncontrol = 29,677) of European ancestry. Epilepsy phenotypes included all epilepsy, generalized epilepsy, focal epilepsy, childhood absence epilepsy, juvenile absence epilepsy, juvenile myoclonic epilepsy, generalized epilepsy with tonic-clonic seizures, focal epilepsy with hippocampal sclerosis (focal HS), and lesion-negative focal epilepsy. Main analyses were performed using generalized summary data-based MR. Sensitivity analyses included inverse variance weighted, MR pleiotropy residual sum and outlier, MR-Egger, weighted mode, and weighted median. For forward analysis, genetic predisposition to AD was associated with an increased risk of generalized epilepsy (odds ratio [OR] 1.053, 95% CI 1.002-1.105, p = 0.038) and focal HS (OR 1.013, 95% CI 1.004-1.022, p = 0.004). These associations were consistent across sensitivity analyses and replicated using a separate set of genetic instruments from another AD genome-wide association study. For reverse analysis, there was a suggestive effect of focal HS on AD (OR 3.994, 95% CI 1.172-13.613, p = 0.027). In addition, genetically predicted lower CSF Aβ42 was associated with an increased risk of generalized epilepsy (β = 0.090, 95% CI 0.022-0.158, p = 0.010). This MR study supports a causal link between AD, amyloid pathology, and generalized epilepsy. This study also indicates a close association between AD and focal HS. More effort should be made to screen seizure in AD, unravel its clinical implications, and explore its role as a putative modifiable risk factor.

Unrecognized hypertension among a general adult Ghanaian population: An urban community-based cross-sectional study of prevalence and putative risk factors of lifestyle and obesity indices.

Hypertension (HTN) is the leading cause of cardiovascular diseases. Nevertheless, most individuals in developing countries are unaware of their blood pressure status. We determined the prevalence of unrecognized hypertension and its association with lifestyle factors and new obesity indices among the adult population. This community-based study was conducted among 1288 apparently healthy adults aged 18-80 years in the Ablekuma North Municipality, Ghana. Sociodemographic, lifestyle characteristics, blood pressure and anthropometric indices were obtained. The prevalence of unrecognized HTN was 18.4% (237 / 1288). The age groups 45-54 years [aOR = 2.29, 95% CI (1.33-3.95), p = 0.003] and 55-79 years [aOR = 3.25, 95% CI (1.61-6.54), p = 0.001], being divorced [aOR = 3.02 95% CI (1.33-6.90), p = 0.008], weekly [aOR = 4.10, 95% CI (1.77-9.51), p = 0.001] and daily alcohol intake [aOR = 5.62, 95% CI (1.26-12.236), p = 0.028] and no exercise or at most once a week [aOR = 2.25, 95% CI (1.56-3.66), p = 0.001] were independently associated with HTN. Among males, the fourth quartile (Q4) of both body roundness index (BRI) and waist to height ratio (WHtR) [aOR = 5.19, 95% CI (1.05-25.50), p = 0.043] were independent determinants of unrecognized HTN. Among females, the third quartile (Q3) [aOR = 7.96, 95% CI (1.51-42.52), p = 0.015] and Q4 [aOR = 9.87 95% CI (1.92-53.31), p = 0.007] of abdominal volume index (AVI), the Q3 of both BRI and WHtR [aOR = 6.07, 95% CI (1.05-34.94), p = 0.044] and Q4 of both BRI and WHtR [aOR = 9.76, 95% CI (1.74-54.96), p = 0.010] were independent risk factors of HTN. Overall, BRI (AUC = 0.724) and WHtR (AUC = 0.724) for males and AVI (AUC = 0.728), WHtR (AUC = 0.703) and BRI (AUC = 0.703) for females yielded a better discriminatory power for predicting unrecognized HTN. Unrecognized hypertension is common among the apparently healthy adults. Increased awareness of its risk factors, screening, and promoting lifestyle modification is needed to prevent the onset of hypertension.

Molecular identification, antimicrobial resistance and virulence gene profiling of Staphylococcus spp. associated with bovine sub-clinical mastitis in Bangladesh

This study was conducted to investigate the diversity and antimicrobial resistance profiling of Staphylococcus species causing sub-clinical mastitis (SCM) in dairy herds in Bangladesh as well as putative risk factors associated with the infections. Individual quarter milk samples were collected from a total of 284 lactating cows from 30 dairy farms were screened by means of California mastitis test; 178 (62.7%) of them had at least of quarter affected by SCM. After conventional microbiological isolation procedures, PCR tests were used for Staphylococcus species identification and detection of antimicrobial resistance and virulence genes. S. chromogenes (65.7%) was the most predominant species followed by, S. epidermidis (20.2%), S. haemolyticus (19.1%), S. aureus (15.7%), and S. sciuri (5.6%). High levels of antimicrobial resistance to ampicillin and amoxicillin/clavulanic acid were observed in S. aureus (82.1% and 75%) and S. sciuri (80% and 70%), while resistance to cefepime was markedly higher in S. chromogenes (95.7%), S. haemolyticus (94.1%), and S. epidermidis (97.2%). Multidrug resistance isolates were identified in all five species. The mecA gene was detected in S. aureus (32.1%) and S. chromogenes (5.98%). In addition, 20% S. sciuri and 17.7% S. haemolyticus carried the cytotoxin (pvl) gene, while 14.3% S. aureus harbored the toxic shock syndrome toxin (tst) gene. Multivariable logistic regression analysis identified “Old aged” (OR [CI]: 3.5 [1–12.4]); “Early stage of lactation” (OR [CI]: 3.4 [1.2–9.7]) and, “Firm udder condition” (OR [CI]: 4.2 [1.2–14.6]) as risk factors associated with SCM caused by S. aureus, S. chromogenes, and S. haemolyticus, respectively. Moreover, “Use of antimicrobials” (OR [CI]: 10.4 [3.4–32.1] and “History of previous clinical mastitis” (OR [CI]: 4.9 [1.2–19.7] for the carriage of methicillin-resistant Staphylococcus spp.

(292) Impact of Urinary Incontinence on Sexual Function in Patients Presenting for Lower Urinary Tract Symptoms

Abstract Introduction Patients with low urinary tract symptoms (LUTS) frequently complain some sexual dysfunction and sometimes even episodes of bothersome urinary incontinence (UI). Objective We aimed to assess the relationship between UI (as measured with the ICIQ-UI-SF), and sexual disfunction (as measured with the IIEF), in men presenting with LUTS at a tertiary-referral centre. Methods In this cross-sectional study, data were retrospectively retrieved from 938 consecutive patients aged >18 years seeking first medical help for self-reported LUTS (i.e., all patients had IPSS≥1). All patients had a complete clinical assessment and completed the IPSS, the ICIQ-UI-SF, the OAB-q and the IIEF questionnaires. Patients were stratified into “no UI” (ICIQ-UI-SF=0), “mild UI” (ICIQ-UI-SF=1-7), “moderate UI” (ICIQ-UI-SF=8-13) or “severe UI” (ICIQ-UI-SF=14-21). ANOVA test assessed differences in baseline characteristics among these groups. Spearman correlation test was applied to evaluate the correlation between ICIQ-UI-SF and IIEF domain scores. A linear regression analyses tested putative risk factors associated with increased ICIQ-UI-SF scores. Results Of 938, 589 (63%) patients had no UI, 237 (25%) had mild UI, 76 (8%) moderate UI and 36 (4%) severe UI. There were no substantial differences in total PSA levels and uroflowmetry parameters among UI groups, whereas prostate volume, IPSS and OAB-q scores were higher as UI symptoms increased (all p≤ 0.03). A negative correlation was found between IIEF-total, IIEF-Erectile Function, IIEF-Intercourse Satisfaction and IIEF-Overall Satisfaction scores and ICIQ-UI-SF scores (i.e., the worse UI symptoms, the worse the overall sexual function (rho= -0.12; p<0.001), IIEF-EF (rho= -0.15; p<0.001), IIEF-IS (rho = -0.1; p=0.004) and IIEF-OS (rho = -0.12; p<0.001). Sexual desire and orgasmic function domains were not correlated with ICIQ-UI-SF. Finally, higher BMI (Coeff 0.12; 95% CI 0.03-0.32; p=0.011), diabetes (Coeff 1.76; 0.35-3.18; p=0.015) and presence of comorbidities (Coeff: 0.9; 0.06-0.1.74; p=0.035) were associated with higher ICIQ-UI-SF scores. Main limitations of the study were that ICIQ-UI-SF does not discriminate between urge or stress UI. Conclusions In patients presenting with LUTS, the presence of urinary incontinence was associated with worsening of overall sexual function (i.e., erectile function, intercourse satisfaction and overall satisfaction). Disclosure No

Investigation of incidence and geographic distribution of gliomas in Canada from 1992 to 2010: a national population-based study highlighting the importance of exposure to airport operations.

Gliomas account for over two-thirds of all malignant brain tumors and have few established risk factors beyond family history and exposure to ionizing radiation. Importantly, recent studies highlighted the exposure to ultrafine particles (UFP) as a putative risk factor for malignant brain tumors. Clinical and geographic data encompassing all provinces and territories from 1992 to 2010 was obtained from the Canadian Cancer Registry and Le Registre Québécois du Cancer. Linear regression and joinpoint analyses were performed to assess incidence trends. Significantly higher and lower incidence postal codes were then interrogated using Standard Industrial Classification codes to detect significant industrial activity. In Canada, between 1992 and 2010, there were ~32,360 cases of glioma. Of these, 17,115 (52.9%) were glioblastoma. The overall crude incidence rates of 5.45 and 2.87 cases per 100,000 individuals per year for gliomas and glioblastomas, respectively, were identified. Our findings further revealed increasing crude incidence of gliomas/glioblastomas over time. A male predominance was observed. Provinces leading in glioma incidence included Quebec, Nova Scotia, and New Brunswick. Significantly lower crude incidence of glioma was found in Nunavut, Northwest Territories, Ontario, and Alberta. A putative regional clustering of gliomas was observed, with higher incidence rates in postal code areas correlating with industrial activity related to airport operations. This study describes the geographic distribution of the glioma disease burden and, potentially, identifies industrial activity related to airport operations as potentially being associated with higher incidence of this cancer.

Comorbidities in transplant recipients with acute myeloid leukemia receiving low-intensity conditioning regimens: an ALWP EBMT study.

Older age and a high burden of comorbidities often drive the selection of low-intensity conditioning regimens in allogeneic hematopoietic stem cell transplantation recipients. However, the impact of comorbidities in the low-intensity conditioning setting is unclear. We sought to determine the contribution of individual comorbidities and their cumulative burden on the risk of nonrelapse mortality (NRM) among patients receiving low-intensity regimens. In a retrospective analysis of adults (≥18 years) who underwent transplantation for acute myeloid leukemia in the first complete remission between 2008 and 2018, we studied recipients of low-intensity regimens as defined by the transplantation conditioning intensity (TCI) scale. Multivariable Cox models were constructed to study associations of comorbidities with NRM. Comorbidities identified as putative risk factors in the low-TCI setting were included in combined multivariable regression models assessed for overall survival, NRM, and relapse. A total of 1663 patients with a median age of 61 years received low-TCI regimens. Cardiac comorbidity (including arrhythmia/valvular disease) and psychiatric disease were associated with increased NRM risk (hazard ratio [HR], 1.54; 95% confidence interval [CI], 1.13-2.09 and HR, 1.69; 95%CI, 1.02-2.82, respectively). Moderate pulmonary dysfunction, though prevalent, was not associated with increased NRM. In a combined model, cardiac, psychiatric, renal, and inflammatory bowel diseases were independently associated with adverse transplantation outcomes. These findings may inform patient and regimen selection and reinforce the need for further investigation of cardioprotective transplantation approaches.

Modifiable pathways for longevity: A Mendelian randomization analysis

A variety of factors, including diet and lifestyle, obesity, physiology, metabolism, hormone levels, psychology, and inflammation, have been associated with longevity. The specific influences of these factors, however, are poorly understood. Here, possible causal relationships between putative modifiable risk factors and longevity are investigated. A random effects model was used to investigate the association between 25 putative risk factors and longevity. The study population comprised 11,262 long-lived subjects (≥90 years old, including 3484 individuals ≥99 years old) and 25,483 controls (≤60 years old), all of European ancestry. The data were obtained from the UK Biobank database. Genetic variations were used as instruments in two-sample Mendelian randomization to reduce bias. The odds ratios for genetically predicted SD unit increases were calculated for each putative risk factor. Egger regression was used to determine possible violations of the Mendelian randomization model. Thirteen potential risk factors showed significant associations with longevity (≥90th) after correction for multiple testing. These included smoking initiation (OR:1.606; CI: 1.112-2.319) and educational attainment (OR:2.538, CI: 1.685-3.823) in the diet and lifestyle category, systolic and diastolic blood pressure (OR per SD increase: 0.518; CI: 0.438-0.614 for SBP and 0.620; CI 0.514-0.748 for DBP) and venous thromboembolism (OR:0.002; CI: 0.000-0.047) in the physiology category, obesity (OR: 0.874; CI: 0.796-0.960), BMI (OR per 1-SD increase: 0.691; CI: 0.628-0.760), and body size at age 10 (OR per 1-SD increase:0.728; CI: 0.595-0.890) in the obesity category, type 2 diabetes (T2D) (OR:0.854; CI: 0.816-0.894), LDL cholesterol (OR per 1-SD increase: 0.743; CI: 0.668-0.826), HDL cholesterol (OR per 1-SD increase: 1.243; CI: 1.112-1.390), total cholesterol (TC) (OR per 1-SD increase: 0.786; CI: 0.702-0.881), and triglycerides (TG) (OR per 1-SD increase: 0.865; CI: 0.749-0.998) in the metabolism category. Both longevity (≥90th) and super-longevity (≥99th), smoking initiation, body size at age 10, BMI, obesity, DBP, SBP, T2D, HDL, LDL, and TC were consistently associated with outcomes. The examination of underlying pathways found that BMI indirectly affected longevity through three pathways, namely, SBP, plasma lipids (HDL/TC/LDL), and T2D (p<0.05). BMI was found to significantly affect longevity through SBP, plasma lipid (HDL/TC/LDL), and T2D. Future strategies should focus on modifying BMI to improve health and longevity.

Prevention of long COVID: progress and challenges

Prevention of long COVID: progress and challenges

Clinical Indicators of Hepatotoxicity in Newly Diagnosed Acute Promyelocytic Leukemia Patients Undergoing Arsenic Trioxide Treatment

Arsenic trioxide (ATO)-induced hepatotoxicity is often observed in acute promyelocytic leukemia (APL) patients and decreases therapeutic effect of ATO. Thus, concerns over hepatotoxicity have been raised. The aim of this study was to explore some noninvasive clinical indicators that can be used to guide the individualized application of ATO in the future. APL patients treated with ATO were identified retrospectively via electronic health records at our hospital from August 2014 through August 2019. APL patients without hepatotoxicity were selected as controls. The association between putative risk factors and ATO-induced hepatotoxicity was estimated with ORs and 95% CIs, which were calculated using the chi-square test. The subsequent multivariate analysis was performed using logistic regression analysis. In total, 58.04% of patients experienced ATO-induced hepatotoxicity during the first week. Elevated hemoglobin (OR 8.653, 95% CI, 1.339–55.921), administration of nonprophylactic hepatoprotective agents (OR 36.455, 95% CI, 7.409–179.364), non-single-agent ATO to combat leukocytosis (OR 20.108, 95% CI, 1.357–297.893) and decreased fibrinogen (OR 3.496, 95% CI, 1.127–10.846) were found to be statistically significant risk factors for ATO-induced hepatotoxicity. The area under the ROC curve values were 0.846 for “overall ATO-induced hepatotoxicity” and 0.819 for “early ATO-induced hepatotoxicity.” The results revealed that hemoglobin ≥ 80 g/L, nonprophylactic hepatoprotective agents, and non-single-agent ATO and fibrinogen < 1 g/L are risk factors for ATO-induced hepatotoxicity in newly diagnosed APL patients. These findings can enhance the clinical diagnosis of hepatotoxicity. Prospective studies should be performed in the future to validate these findings.

Circulating markers of microbial translocation and host response to bacteria with risk of colorectal cancer: a prospective, nested case-control study in men

Gut microbial dysbiosis contributes to colorectal cancer (CRC) pathogenesis, possibly mediated in part by increased intestinal permeability to endotoxin lipopolysaccharide (LPS), microbial translocation, and subsequent endotoxemia and inflammation. However, epidemiologic evidence linking circulating markers of microbial translocation with CRC risk is limited. We conducted a prospective, nested case-control study of 261 incident CRC cases and 261 controls (matched on age and time of blood draw) among 18,159 men with pre-diagnostic blood specimens in the Health Professionals Follow-Up Study (1993-2009). We examined three complementary markers of microbial translocation and host response to bacteria, including LPS-binding protein (LBP), soluble CD14 (sCD14), and endotoxincore antibody (EndoCAb) immunoglobulin M (IgM), with subsequent risk of CRC. Unconditional logistic regressions were used to estimate odds ratios (ORs) and 95% confidence intervals (CIs). Pre-diagnostic circulating levels of sCD14 were associated with a higher risk of incident CRC. Compared to men in the lowest quartile, the multivariable OR was 1.90 (95% CI, 1.13-3.22) for men in the highest quartile (OR per standard deviation [SD] increase, 1.28; 95%CI 1.06-1.53; Ptrend=0.01). This positive association remained similar after adjusting for C-reactive protein, interleukin-6, and soluble tumor necrosis factor receptor-2, and within strata of putative CRC risk factors. We also observed a suggestive inverse association between EndoCAb IgM and risk of CRC (OR per SD increase, 0.84; 95%CI 0.69-1.02; Ptrend=0.09). Microbial translocation and host response to bacteria, as reflected by sCD14, is associated with risk of incident CRC in men. US National Institutes of Health.

Metabolic syndrome as a late effect of childhood hematopoietic stem cell transplantation - A thorough statistical evaluation of putative risk factors.

Metabolic syndrome (MetS) is frequent among survivors of childhood hematopoietic stem-cell transplantation (HSCT), but assessment of risk factors is challenged by survivor and participation bias in long-term follow-up studies. A cohort of 395 pediatric patients transplanted between 1980 and 2018 was investigated. MetS was assessed at follow-up between December 2018 and March 2020. Two composite outcomes ((a) combining MetS and death, (b) combining MetS, death, and nonparticipation) were considered to address the risk of selection bias. Among 234 survivors invited to the follow-up, 96 individuals (median age 27 years) participated. MetS prevalence was 30% among participants. The only significant HSCT risk factor was a variable combining HSCT indication and conditioning with total-body irradiation (TBI) (p = .0011). Compared to acute leukemias (AL) treated with high-grade TBI (8-12 Gy), a lower MetS prevalence was seen for nonmalignant diseases treated with no/low-grade TBI (0-4.5 Gy) (OR = 0.04, 95% confidence interval (CI): 0.00-0.23). Analyses of the composite outcomes indicated overestimation of the effect of high-grade TBI due to selection bias. Scrutiny showed strong residual confounding between HSCT indication and high-grade TBI within AL-patients. The HSCT effect on MetS reflected HSCT effects on high-density-lipoprotein (HDL) and triglycerides. Compared to AL treated with high-grade TBI, nonmalignant diagnoses treated with no/low-grade TBI had higher HDL (+40%, 95% CI: +21% to +62%) and lower triglyceride (-59%, 95% CI: -71% to -42%). The TBI effect on MetS may be overestimated in follow-up studies due to selection bias and confounding. The TBI effect was confined to the potentially modifiable MetS criteria HDL and triglyceride.

Influence of Surgical Experience and Risk Factors for Surgical Failure in Primary Retinal Detachment Surgery

Introduction: The aim of this study was to report surgical outcomes and risk factors for primary surgical failure following rhegmatogenous retinal detachment (RRD) repair. Methods: In this retrospective cohort study, RRD patients who underwent primary surgery at a tertiary center between January 1, 2006, and December 31, 2020, were enrolled. Surgical failure was defined as reoperation within 60 days postoperatively due to retinal re-detachment and putative risk factors for surgical failure were analyzed. Results: Of 2,383 eyes (2,335 patients), 1,342 (56.3%) underwent vitrectomy and 1,041 (43.7%) underwent scleral buckling. The surgical failure rate was 9.1% overall, and 6.0% and 13.1% for the vitrectomy and scleral buckling groups, respectively. In the multivariate logistic regression analysis, surgical failure was associated with surgical experience (first-year fellow vs. senior professor) (odds ratio [OR]: 1.66; p = 0.018), scleral buckling (OR: 2.33; p < 0.001), and longer axial length (AL; ≥26.5 mm) (OR: 1.49; p = 0.017). In each surgical approach, age <40 years (OR: 2.11; p = 0.029) in the vitrectomy group and age >40 years (OR, 1.84; p = 0.004), male sex (OR: 1.65; p = 0.015), and first-year fellows compared to senior professors (OR: 1.95; p = 0.013) in the scleral buckling group were associated with surgical failure. Lens status were not associated with the surgical failure rate. Conclusion: In this large retrospective study using data from Korea, vitrectomy was superior to scleral buckling in terms of primary anatomical outcomes in the management of RRD. First-year fellows were a risk factor for surgical failure, especially for scleral buckling. Longer AL was a significant parameter for predicting the success rates.

A Case Control Study on Risk Factors and Drug Prescription Patterns in Glaucoma at a tertiary eye care center in a city of Western India

Introduction: Glaucoma is an idiopathic, progressive optic disc neuropathy complicating into irreversible blindness if untreated. Early diagnosis by screening cases from high-risk populations has a pivotal role in managing this major public health problem with high treatment expenditures. Objectives: To identify the various ocular and non ocular risk factors of glaucoma and to identify the drug prescription pattern among glaucoma patients. Method: This was an observational, case-control study including 165 adult Glaucoma patients on treatment as cases and 165 age and sex-matched healthy individuals as controls, all of which were randomly selected from the patients visiting a tertiary eye care center. Various risk factors, drug prescription pattern and symptoms of the patients were recorded and analyzed.Results: A total of 165 adult Glaucoma patients and age and gender matched 165 controls were enrolled. Majority of the patients (41.21%) complained of blurring of vision at the time of study. The Odds ratios for Family history, Hypertension, Diabetes Mellitus, Migraine, Sleep apnea and Smoking showed strong association as risk factors for Glaucoma and the differences between the two groups were statistically significant (p value &lt; 0.05). The mean number of drugs per prescription ± SD was 1.88 ± 0.79. Fixed drug formulations were prescribed in 42.4% patients. All the drugs were prescribed by their brand names and majority of them were in the form of eye drops. Conclusion: Primary Open Angle Glaucoma (POAG) was the most common subtype in the study. Age, Family history, Myopia, Hypertension, Diabetes Mellitus, Sleep Apnea, Migraine, Corticosteroid usage and Smoking emerged as putative risk factors. In consistence with present guidelines, Prostaglandin analogs were the most prescribed antiglaucoma drugs. The considerable proportion of asymptomatic cases (23%) suggests the need for periodic eye examinations to detect glaucomatous changes at an early stage.

Putative risk and resiliency factors among Royal Canadian Mounted Police cadets.

Mental health disorders are prevalent among active-duty Royal Canadian Mounted Police (RCMP) officers. The current study was designed to assess whether RCMP cadets commencing the Cadet Training Program are inherently at greater risk of developing mental health challenges by statistically comparing cadet putative risk and resiliency scores to scores from young adult populations. The study was also designed to assess for sociodemographic differences in putative risk and resiliency variables among RCMP cadets in order to facilitate future comparisons. Cadets (n = 772; 72.2% men) completed self-report measures of several putative risk variables (i.e., anxiety sensitivity, fear of negative evaluation, pain anxiety, illness and injury sensitivity, intolerance of uncertainty, and state anger) and resiliency. Scores were statistically compared to samples from Canadian, American, Australian, and European young adult populations. Cadets had statistically significantly lower scores on all putative risk variables and statistically significantly higher resiliency scores compared to the young adult populations. In the cadet sample, there were statistically significant differences in putative risk and resiliency variables across gender and sex. Cadets' significantly lower scores on putative risk variables and higher scores on resiliency suggest that they may be psychologically strong; as such, it may be that the nature of police work, as opposed to inherent individual differences in risk and resiliency, accounts for active-duty RCMP officers' comparatively higher prevalence of mental health disorders over time.Clinical Trial Registration: ClinicalTrials.gov, Identifier NCT05527509.

Longitudinal Relations Between Emotion Regulation and Internalizing Symptoms in Emerging Adults During the Covid-19 Pandemic.

Maladaptive and adaptive emotion regulation are putative risk and protective factors for depression and anxiety, but most prior research does not differentiate within-person effects from between-person individual differences. The current study does so during the early part of the Covid-19 pandemic when internalizing symptoms were high. A sample of emerging adult undergraduate students (N = 154) completed online questionnaires bi-weekly on depression, anxiety, and emotion regulation across eight weeks during the early days of the Covid-19 pandemic (April 2nd to June 27th, 2020). Depression demonstrated significantly positive between-person correlations with overall maladaptive emotion regulation, catastrophizing, and self-blame, and negative correlations with overall adaptive emotion regulation and reappraisal. Anxiety demonstrated significantly positive between-person correlations with overall maladaptive emotion regulation, rumination, and catastrophizing, and a negative correlation with reappraisal. After controlling for these between-person associations, however, there were generally no within-person associations between emotion regulation and internalizing symptoms. Emotion regulation and internalizing symptoms might be temporally stable individual differences that cooccur with one another as opposed to having a more dynamic relation. Alternatively, these dynamic mechanisms might operate over much shorter or longer periods compared to the two-week time lag in the current study. The online version contains supplementary material available at 10.1007/s10608-023-10366-9.

Reciprocal causation mixture model for robust Mendelian randomization analysis using genome-scale summary data

Mendelian randomization using GWAS summary statistics has become a popular method to infer causal relationships across complex diseases. However, the widespread pleiotropy observed in GWAS has made the selection of valid instrumental variables problematic, leading to possible violations of Mendelian randomization assumptions and thus potentially invalid inferences concerning causation. Furthermore, current MR methods can examine causation in only one direction, so that two separate analyses are required for bi-directional analysis. In this study, we propose a ststistical framework, MRCI (Mixture model Reciprocal Causation Inference), to estimate reciprocal causation between two phenotypes simultaneously using the genome-scale summary statistics of the two phenotypes and reference linkage disequilibrium information. Simulation studies, including strong correlated pleiotropy, showed that MRCI obtained nearly unbiased estimates of causation in both directions, and correct Type I error rates under the null hypothesis. In applications to real GWAS data, MRCI detected significant bi-directional and uni-directional causal influences between common diseases and putative risk factors.

Vascular Factors in Patients with Midlife Sensorineural Hearing Loss and the Progression to Mild Cognitive Impairment.

Background and Objectives: Midlife hearing loss (HL) has been considered as a major modifiable risk factor for a later-life progression to dementia. Our aim was to detect a link between precocious sensorineural hearing loss (SNHL) and mild cognitive impairment (MCI) and their association to putative risk factors for a common pathology. Materials and methods: In this study, a retrospective case-control study was carried out. A total of 112 patients were enrolled as following: 81 patients with bilateral SNHL and 31 subjects with normal hearing, whose ages ranged from 50 to 65 years. Both groups performed pure tone audiometry, a tinnitus handicap inventory (THI), Mini-Mental State examination (MMSE), and the Montreal Cognitive Assessment (MoCA), Hospital Anxiety and Depression Scale (HADS-A and HADS-D). Results: The mean age was 58 ± 5.2 in SNHL patients and 53.2 ± 4.8 in the control group. The mean pure tone average in the SNHL group was 40.2 ± 18.7 dB HL on the right side and 41.2 ± 17.2 dB HL on the left side, while in the control group it was 12.5 ± 2.8 dB HL on right side and 12.4 ± 3.1 dB HL on left side. About 64% of patients with SNHL exhibited comorbidities, and the most common condition was hypertension. Altered MoCA test scores were significantly related to the pure tone averages in patients with SNHL compared to the control group (p = 0.0004), while the differences in the HADS-A and HADS-D were not significant. Furthermore, a significant correlation was observed in SNHL patients between an altered MoCA test and hypercholesterolemia (p = 0.043). Conclusions: Hearing impairment and screening tests to detect MCI should be considered in the midlife in order to carry out strategies to prevent the progression to dementia. Hypertension and hypercholesterolemia are two risk factors in the development of endothelial dysfunction, oxidative stress, and vascular inflammation, and may represent the common pathology linking the inner ear and brain damage.

Asbestos exposure as an additional risk factor for small duct intrahepatic cholangiocarcinoma: a pilot study

Intrahepatic cholangiocarcinoma (iCCA) is a rare malignancy, recently classified in small duct and large duct morphological subtypes. Growing evidence suggests asbestos as a putative risk factor for iCCA, albeit no correlation between asbestos and iCCA morphology has been investigated so far. The aim of the present study was to assess the relationship between asbestos exposure and iCCA morphological subtype. Forty patients with surgically removed iCCA were prospectively enrolled: asbestos exposure was assessed according to the Italian National Mesothelioma Register questionnaire. From the surgical iCCA specimens the main histopathological variables were collected, including the small duct (sd-iCCA, 32 patients) and large duct subtypes (ld-iCCA, 8 patients). Five sd-iCCA cases had a definite/probable occupational exposure to asbestos, while no cases of ld-iCCA were classified as being occupationally exposed (definite/probable). Other kind of asbestos exposure (i.e. possible occupational, familial, environmental) were recorded in 16 sd-iCCA and 3 ld-iCCA. Cases with unlikely exposure to asbestos were 11 sd-iCCA (35.5%) and 5 ld-iCCA (62.5%). In conclusion, these findings seem to indicate that sd-iCCA might be more frequently associated to asbestos exposure rather than ld-iCCA, suggesting that asbestos fibres might represent a parenchymal, rather than a ductal risk factor for iCCA. This pilot study must be confirmed by further case–control studies or large independent cohorts.

Mendelian randomisation identifies priority groups for prophylactic EBV vaccination

BackgroundEpstein Barr virus (EBV) infects ~ 95% of the population worldwide and is known to cause adverse health outcomes such as Hodgkin’s, non-Hodgkin’s lymphomas, and multiple sclerosis. There is substantial interest and investment in developing infection-preventing vaccines for EBV. To effectively deploy such vaccines, it is vital that we understand the risk factors for infection. Why particular individuals do not become infected is currently unknown. The current literature, describes complex, often conflicting webs of intersecting factors—sociodemographic, clinical, genetic, environmental-, rendering causality difficult to decipher. We aimed to use Mendelian randomization (MR) to overcome the issues posed by confounding and reverse causality to determine the causal risk factors for the acquisition of EBV.MethodsWe mapped the complex evidence from the literature prior to this study factors associated with EBV serostatus (as a proxy for infection) into a causal diagram to determine putative risk factors for our study. Using data from the UK Biobank of 8422 individuals genomically deemed to be of white British ancestry between the ages of 40 and 69 at recruitment between the years 2006 and 2010, we performed a genome wide association study (GWAS) of EBV serostatus, followed by a Two Sample MR to determine which putative risk factors were causal.ResultsOur GWAS identified two novel loci associated with EBV serostatus. In MR analyses, we confirmed shorter time in education, an increase in number of sexual partners, and a lower age of smoking commencement, to be causal risk factors for EBV serostatus.ConclusionsGiven the current interest and likelihood of a future EBV vaccine, these factors can inform vaccine development and deployment strategies by completing the puzzle of causality. Knowing these risk factors allows identification of those most likely to acquire EBV, giving insight into what age to vaccinate and who to prioritise when a vaccine is introduced.

Single-molecule studies on co-transcriptional R-loop formation at DNA damage site.

R-loop, a non-canonical nucleic acid structure, is composed of an RNA-DNA hybrid and a single-stranded DNA(ssDNA). This abnormal structure can form through transcription. R-loop can play a role in some biological processes such as gene regulation, but R-loop has been considered a putative risk factor causing genome instability. Recent studies, however, suggest that R-loop formation is also required for certain DNA double-strand break (DSB) repair processes implying even positive aspects of R-loop in light of the maintenance of genome integrity. Here, we show that E. coli RNA polymerases have an unexpected ability to create R-loop when they encounter DSB during transcription. The efficiency of DSB induced R-loop formation under single-round transcription was quantitatively measured. We also observed the propagation of RNA-DNA hybrids from break sites to upstream. These extended RNA-DNA hybrids hindered the next round of transcription. Furthermore, we studied whether other types of genetic lesions and abnormal structures could induce co-transcriptional R-loop formation.