Potential Effect Modifiers Research Articles

Association between ambient air pollution a week prior to delivery and preterm birth using a nationwide study in Sweden

BackgroundAir pollution exposure has been linked with increased risk of preterm birth, which is one of the leading causes of infant mortality. Limited studies have attempted to explore these associations in low-polluted areas. In this study, we aimed to assess the association between short-term exposure to ambient air pollution and preterm birth in Sweden. MethodIn this population-based study we included preterm births between 2014 and 2019 from the Swedish Pregnancy Register. We applied a spatiotemporal model to estimate daily levels of particulate matter <2.5 μm (PM2.5), PM < 10 μm (PM10), nitrogen dioxide (NO2), and ozone (O3) at the residential address of each participant. We applied a time-stratified case-crossover design with conditional logistic regression analysis to estimate odds ratios (OR) of preterm birth per 10 μg/m3 (PM10, NO2, O3) and 5 μg/m3 (PM2.5) increase in air pollution exposure at 0–6-day lag. Two-pollutant models were applied to evaluate the independent association of each exposure on preterm birth. We also stratified by maternal characteristics to identify potential effect modifiers. Results28,216 (4.5%) preterm births were included. An increase in O3 exposure was associated with increased odds of preterm birth [OR = 1.06 per 10 μg/m3 (95% CI, 1.02; 1.10]. PM2.5 and PM10 were not significantly associated with preterm birth, and NO2 displayed a negative nonlinear association with preterm birth. We did not observe any notable effect modification, but we found suggestive larger associations between O3 and preterm birth when stratifying by male sex, spontaneous delivery, and spring season. ConclusionsIncreased O3 exposure one week before delivery was associated with an increased risk of preterm birth in Sweden, a country with levels of air pollution below the current World Health Organization air quality guidelines. Increases in O3 levels with climate change make these findings especially concerning.

Insulin resistance and periodontitis: Mediation by blood pressure.

This study investigated the association between the triglyceride-glucose (TyG) index, a surrogate marker of insulin resistance, and moderate/severe periodontitis and the role of blood pressure as a mediator in this association. A second aim was to assess the role of cardiometabolic conditions such as obesity, hypertension, and dyslipidemia as potential effect modifiers. Data from 5733 US adults aged 30-64 years and with complete periodontal examination were analyzed (NHANES 2011-2014). Participants were classified as having moderate/severe periodontitis or mild/no periodontitis according to the CDC/AAP criteria as the outcome. The exposure was the TyG index, while both systolic (SBP), and diastolic (DBP) blood pressure were tested as mediators using parametric g-formula. Analyses were adjusted for relevant confounders, namely, age, sex, ethnicity, poverty-income ratio, and smoking, using inverse probability treatment weighting. Obesity status (based on a body mass index ≥30 kg/m2), self-report of hypertension and dyslipidemia (calculated based on the thresholds provided by National Cholesterol Education Program-Adult Treatment Panel-III) were tested as effect modifiers. The findings showed the TyG index to be associated with increased odds of moderate/severe periodontitis [odds ratio (OR), 95% confidence interval (CI) = 1.17 (1.11-1.23)], with 50% of the total effect mediated by SBP. Stratified analysis showed a stronger association in individuals with obesity, hypertension, and dyslipidemia compared to those without these conditions. However, in those taking anti-hypertensive medications, the association was partially mitigated. Sensitivity analysis using imputed data showed consistent results. The TyG index was associated with increased odds of moderate/severe periodontitis, especially in individuals with obesity, hypertension, and dyslipidemia. SBP levels partially mediated this association.

Air pollutants, genetic susceptibility and the risk of schizophrenia: large prospective study.

Evidence linking air pollutants and the risk of schizophrenia remains limited and inconsistent, and no studies have investigated the joint effect of air pollutant exposure and genetic factors on schizophrenia risk. To investigate how exposure to air pollution affects schizophrenia risk and the potential effect modification of genetic susceptibility. Our study was conducted using data on 485 288 participants from the UK Biobank. Cox proportional hazards models were used to estimate the schizophrenia risk as a function of long-term air pollution exposure presented as a time-varying variable. We also derived the schizophrenia polygenic risk score (PRS) utilising data provided by the UK Biobank, and investigated the modification effect of genetic susceptibility. During a median follow-up period of 11.9 years, 417 individuals developed schizophrenia (mean age 55.57 years, s.d. = 8.68; 45.6% female). Significant correlations were observed between long-term exposure to four air pollutants (PM2.5; PM10; nitrogen oxides, NOx; nitrogen dioxide, NO2) and the schizophrenia risk in each genetic risk group. Interactions between genetic factors and the pollutants NO2 and NOx had an effect on schizophrenia events. Compared with those with low PRS and low air pollution, participants with high PRS and high air pollution had the highest risk of incident schizophrenia (PM2.5: hazard ratio = 6.25 (95% CI 5.03-7.76); PM10: hazard ratio = 7.38 (95% CI 5.86-9.29); NO2: hazard ratio = 6.31 (95% CI 5.02-7.93); NOx: hazard ratio = 6.62 (95% CI 5.24-8.37)). Long-term exposure to air pollutants was positively related to the schizophrenia risk. Furthermore, high genetic susceptibility could increase the effect of NO2 and NOx on schizophrenia risk.

Racial disparities in prosthesis abandonment and mobility outcomes after lower limb amputation from a dysvascular etiology in a veteran population.

Non-Hispanic Black (NHB) individuals have higher rates of amputation and increased risk of a transfemoral amputation due to dysvascular disease than non-Hispanic White (NHW) individuals. However, it is unclear if NHB individuals have differences in prosthesis use or functional outcomes following an amputation. To determine if there are racial disparities in prosthesis abandonment and mobility outcomes in veterans who have undergone their first major unilateral lower extremity amputation (LEA) due to diabetes and/or peripheral artery disease. National cohort study that identified individuals retrospectively through the Veterans Affairs (VA) Corporate Data Warehouse (CDW) from March 1, 2018, to November 30, 2020, then prospectively collected their self-reported prosthesis abandonment and mobility. Multiple logistic regression was used to control for potential confounders and identify potential effect modifiers. The VA CDW, participant mailings and phone calls. Three hundred fifty-seven individuals who underwent an incident transtibial or transfemoral amputation due to diabetes and/or peripheral arterial disease. Not applicable. (1) Self-reported prosthesis abandonment. (2) Level of mobility assessed using the Locomotor Capabilities Index. Rurally located NHB individuals without a major depressive disorder (MDD) had increased odds of abandoning their prosthesis (adjusted odds ratios [aOR] = 5.3; 95% confidence interval [CI]: [1.3-21.1]). This disparity was nearly three times as large for rurally located NHB individuals with MDD diagnosis, compared with other races from rural areas and with MDD (aOR = 15.8; 95% CI, 2.5-97.6). NHB individuals living in an urban area were significantly less likely to achieve advanced mobility, both with MDD (aOR=0.16; 95% CI: [0.04-7.0]) and without MDD (aOR = 0.26; 95% CI: [0.09-0.73]). This study demonstrated that health care disparities persist for NHB veterans following a dysvascular LEA, with increased prosthesis abandonment and worse mobility outcomes.

Negative Association of GNRI with All-Cause Mortality in Chinese Atrial Fibrillation Patients: A Multicenter Retrospective Cohort Study

Introduction: Malnutrition is common in older atrial fibrillation (AF) patients and results in poor clinical outcomes. The Geriatric Nutritional Risk Index (GNRI) is a straightforward method for evaluating nutritional health. However, its prognostic value in AF patients is unclear. This research focused on examining the correlation between GNRI and overall mortality in Chinese individuals with AF. Methods: We performed a multicenter retrospective study at four Chinese hospitals involving patients diagnosed with AF between January 2019 and August 2023. Using GNRI, nutritional status was evaluated, classifying patients into three categories. Multivariable logistic regression and restricted cubic spline analysis assess the relationship between GNRI and mortality, with exploratory subgroup analyses investigating potential effect modifiers. Results: The study included 4,878 AF patients with a median follow-up of 19 months. The mean age was 71 (63–78), and the mean GNRI was 102 (95–108). Malnutrition was identified in 1,776 patients (36.41%). During the study, 419 (8.59%) deaths occurred. After controlling for confounders, moderate to severe malnutrition was linked to an increased risk of all-cause mortality compared to no malnutrition (odds ratio 1.50; 95% CI, 1.17–1.94). The relationship between GNRI and mortality risk was approximately linear, with consistent associations across subgroups. Conclusion: Malnutrition, as assessed by GNRI, is prevalent among Chinese AF patients and is independently linked to higher all-cause mortality risk.

The Association of Dietary Inflammatory Index with the Risk of Type 2 Diabetes: A Case-Control Study

Background: The prevalence rate of type 2 diabetes (T2DM) is increasing worldwide, and the role of diet in its etiology has been established. The Dietary inflammatory index (DII) has attracted significant attention in evaluating associations between diet and diseases due to the role of chronic inflammation as an underlying cause of numerous disease processes. Therefore, the relationship between DII score and the risk of T2DM is evaluated in the Iranian population for the first time. Methods: 113 newly diagnosed T2DM patients and 226 apparently disease-free control cases aged 23-59 participated in this case-control study. A valid semi-quantitative food frequency questionnaire was used to assess dietary intake. Then, energy-adjusted DII (E-DII) scores were computed and categorized into quartiles based on values in the population study. A logistic regression model was used to estimate the association between DII and the risk of T2DM after controlling for important potential confounders and effect modifiers. Results: A significant association was observed between E-DII score and T2DM in the crude model (P-trend&lt;0.001), model I (adjusted for physical activity, gender, education level, and family history of T2DM, P-trend&lt;0.001), model II (adjusted for model I + body mass index, P-trend=0.005) (ORquartile4vs1 =2.98 (95% CI: 1.18, 9.12; P= 0.005). Conclusions: A direct association was observed between DII score and the risk of T2D, implying that consuming a more anti-inflammatory diet would help to prevent T2DM. Future longitudinal studies should be conducted to further explore this association.

Variations in the use of oxytocin for augmentation of labour in Sweden: a population-based cohort study

National Swedish data shows substantial variation in the use of oxytocin for augmentation of spontaneous labour between obstetric units. This study aimed to investigate if variations in the use of oxytocin augmentation are associated with maternal and infant characteristics or clinical factors. We used a cohort design including women allocated to Robson group 1 (nulliparous women, gestational week ≥ 37 + 0, with singleton births in cephalic presentation and spontaneous onset of labour) and 3 (parous women, gestational week ≥ 37 + 0, with singleton births in cephalic presentation, spontaneous onset of labour, and no previous caesarean birth). Crude and adjusted logistic regression models with marginal standardisation were used to estimate risk ratios (RR) and risk differences (RD) with 95% confidence intervals (CI) for oxytocin use by obstetric unit. An interaction analysis was performed to investigate the potential modifying effect of epidural. The use of oxytocin varied between 47 and 73% in Robson group 1, and 10% and 33% in Robson group 3. Compared to the remainder of Sweden, the risk of oxytocin augmentation ranged from 13% lower (RD − 13.0, 95% CI − 15.5 to − 10.6) to 14% higher (RD 14.0, 95% CI 12.3–15.8) in Robson group 1, and from 6% lower (RD − 5.6, 95% CI − 6.8 to − 4.5) to 18% higher (RD 17.9, 95% CI 16.5–19.4) in Robson group 3. The most notable differences in risk estimates were observed among women in Robson group 3 with epidural. In conclusion, variations in oxytocin use remained despite adjusting for risk factors. This indicates unjustified differences in use of oxytocin in clinical practice.

Relationship between cognitive function and sleep quality in middle-aged and older adults for minimizing disparities and achieving equity in health: Evidence from multiple nationwide cohorts

BackgroundCognitive decline, a heavy burden on middle-aged and older adults as global aging is aggravated, was found to be associated with sleep quality. However, the country-between heterogeneity of the association prevented us from quantifying underlying relationship and identifying potential effect modifiers for vulnerable populations and targeted interventions. MethodsWe collected data from 79,922 eligible adults in five nationwide cohorts, examined the respective relationships between cognitive function and sleep quality, synthesized underlying average relationships by meta-analysis, and explored effect modifiers by meta-regressions. Additionally, we conducted subgroup and interaction analyses to identify vulnerable populations and to determine their disparities in vulnerability. ResultsAlthough country-between disparities exist, cognitive function is robustly associated with sleep quality in middle-aged and older adults worldwide, with an effect (β) of 0.015 [0.003, 0.027]. Executive function is the subdomain most relevant to sleep quality. Disparities in the effects of sleep quality on subdomains exist in populations with different sexes (orientation: βfemale/βmale = 1.615, P = 0.020), marital statuses (orientation: βunmarried/βmarried = 2.074, P < 0.001), education levels (orientation:βuneducated/βeducated = 2.074, P < 0.001) and chronic disease statuses (memory: βunhealthy/βhealthy = 1.560, P = 0.005). ConclusionsCognitive function decreases with worsening sleep quality in middle-aged and older adults. Vulnerability to poor sleep generally persists in singles, females, the uneducated and people with chronic diseases. To minimize disparities and achieve health equity, we advocate for targeted interventions, i.e., encouraging socialization in singles, confirming effectiveness of hormone replacement therapy in females, employing compulsory education in middle-aged and older adults.

The effectiveness of Hope Groups, a mental health, parenting support, and violence prevention program for families affected by the war in Ukraine: Findings from a pre-post study

BackgroundNearly one in six children lived in war zones in 2023. Evidence-based psychosocial and parenting support has potential to mitigate negative impacts for parents and children co-exposed to war and displacement, especially in relation to mental health and harsh parenting reactions. In the current war in Ukraine, local mental health experts co-created and evaluated, with global experts, the effectiveness of psychosocial and parenting support groups, called ‘Hope Groups’ on improvements in mental health, positive parenting, and violence against children. This paper aimed to assess the effectiveness of psychosocial and parenting support groups, called 'Hope Groups,' on improvements in caregiver mental health, positive parenting, and prevention of violence against children, for families affected by the war in Ukraine, using a pre/post study design. MethodsParticipants (n = 577) included Ukrainian caregivers, 66% (381) of whom were parents and co-residing caregivers of children ages 0–17, while the remaining 34% were non-resident informal caregivers. Internally displaced, externally displaced, and those living at-home in war-torn regions were invited to groups by trained Ukrainian peer facilitators. Using a pre-post design, we compared individual level frequency measures at three time-points – baseline, midline, and endline, to assess changes in 4 mental health, and 9 parenting and child health outcomes. We analyzed these outcomes using paired t-tests to compare outcomes at baseline-to-midline (after 4-sessions) and baseline-to-endline (after 10-sessions), which estimated the mean changes in days per week and associated percent change, during the respective periods; we quantified uncertainties using bias-corrected and accelerated (BCa) bootstrapping with 95% uncertainty ranges for baseline-midline and baseline-endline estimates. We used this same approach for stratified analyses to assess potential effect modification by displacement status and facilitator type. We further used linear models to adjust for age and sex. FindingsCompared to baseline, every mental health, parenting, and child health outcome improved significantly at midline and endline. Mental health ratings showed endline reductions in depressive symptoms of 56.8% (95% CI: -59.0,-54.3; -1.8 days/week), and increases in hopefulness, coping with grief, and self-care, ranging from 62.0% (95% CI: 53.6,71.3; 2.2 days/week) to 77.0% (95% CI: 66.3,88.3; 2.2 days/week). Significant improvements in parenting and child health outcomes included monitoring children, reinforcing positive behavior, supporting child development, protecting child, nonviolent discipline, and child verbalizing emotions. By endline, emotional violence, physical violence, and child despondency had dropped by 57.7% (95% CI: -63.0%,-51.9; -1.3 days/week), 64.0% (95% CI: -79.0,-39.5; -0.22 days/week), and 51.9% (95% CI: -45.1,-57.9; -1.2 days/week), respectively. Outcomes stratified by displacement status remained significant across all groups, as did those according to facilitator type (lay versus professional). InterpretationThis study demonstrates preliminary evidence, using a brief survey and pre-post design as is appropriate for acute and early protracted emergency settings, of the feasibility and effectiveness of Hope Groups for war-affected Ukrainian caregivers, on improved mental health, positive parenting, and reduced violence against children.

Neonatal BCG Vaccination for Prevention of Allergy in Infants: The MIS BAIR Randomised Controlled Trial.

The beneficial off-target effects of Bacille Calmette-Guérin (BCG) vaccination potentially include protection against allergy. In the MIS BAIR trial, we aimed to determine whether neonatal BCG vaccination reduces atopic sensitisation and clinical food allergy in infants. In this randomised controlled trial, 1272 neonates were allocated to BCG-Denmark vaccine (0.05 mL intradermal dose) or no BCG at birth. Randomisation was stratified by recruitment site, mode of delivery and plurality of birth. The primary outcome was the incidence of atopic sensitisation determined by skin prick test at 1 year of age. Food allergy was determined by 3-monthly online questionnaires and oral food challenges. Data were analysed by intention-to-treat using binary regression. gov (NCT01906853). Atopic sensitisation during the first year of life was 22.9% among infants in the BCG group and 18.9% in the control group (adjusted risk difference (aRD) 3.8% (95% CI -1.5 to 9.1) after multiple imputation). Clinical food allergy was similar between infants in the BCG and control groups (9.8% vs. 9.6%; aRD 0.2, 95% CI -3.4 to 3.8). An interaction was observed between the primary outcome and maternal history of BCG vaccination. No interaction was observed for the additional prespecified potential effect modifiers tested (sex, delivery mode, family history of any allergy, season of birth, hepatitis B vaccination at randomisation, BCG scar and age at BCG administration). Neonatal BCG-Denmark vaccination does not protect against atopic sensitisation or clinical food allergy in the first year of life.

The Impact of Obesity as a Peripheral Disruptor of Brain Inhibitory Mechanisms in Fibromyalgia: A Cross-Sectional Study.

Background/Objective: Obesity, characterized by chronic inflammation, may serve as a surrogate marker for more dysfunctional peripheral inflammation, potentially exacerbating FM symptomatology. Given this premise, this study aimed to investigate the effects of obesity as an effect modifier on neural and clinical variables, specifically those indexing pain-compensatory mechanisms in FM symptoms. Methods: A cross-sectional study was conducted with 108 participants who underwent a standardized TMS protocol assessment to measure resting motor threshold (MT), intracortical facilitation (ICF), and intracortical inhibition (ICI). Clinical data were collected using Beck's Depression Index (BDI), PROMIS, the Brief Pain Inventory (BPI), and conditioned pain modulation (CPM). Linear regression models were used to explore the relationship between these variables while examining Body Mass Index (BMI) as a potential effect modifier. If it was found to be a modifier, we stratified the sample into two groups with a BMI cutoff of 30 and performed another regression model within the subgroups. Results: BMI was identified as an effect modifier in the relationships between ICI and BDI, PROMIS fatigue, and CPM and in MT versus CPM. After stratification, non-obese fibromyalgia subjects demonstrated significant correlations between clinical symptoms and CPM and ICI activity. However, these correlations were absent in the obese group, suggesting obesity disrupts pain mechanisms and their compensatory effects. Higher MT values were associated with weaker endogenous pain control, particularly evident in the obese group. Conclusions: Obesity appears to be a significant effect modifier and delineates two patient groups across multiple clinical and neural assessments of fibromyalgia. Additionally, it suggests a role for obesity in exacerbating fibromyalgia symptoms and disrupting physiological pain-inhibitory mechanisms.

Modifiers of the Effects of Vitamin D Supplementation on Cardiometabolic Risk Factors: A Systematic Review and Meta-Analysis

The inconsistent findings concerning the effects of vitamin D supplementation on cardiometabolic risk factors and the large heterogeneity in the published literature call for further research to identify sources of heterogeneity and potential effect modifiers. We performed a meta-analysis of randomized controlled trials (RCTs) published until March 2024 that reported estimates for the effects of vitamin D supplementation on cardiometabolic factors and relevant baseline covariates of RCT participants. A total of 17 656 participants from 99 RCTs were analyzed, and weighted mean differences (95% confidence intervals (CI)) for the intervention status were derived using random-effects modeling. Overall, compared with the placebo, vitamin D supplementation (median dose: 3320 international unit (IU)·day−1; range 40–120 000 IU·day−1) had favorable effects on systolic blood pressure (SBP; −2.04(−3.50, −0.59) mmHg; 1 mmHg = 0.133 kPa), diastolic blood pressure (DBP; −3.00(−3.61, −2.39) mmHg), total cholesterol (TC; −0.12(−0.21, −0.03) mmol·L−1), fasting blood glucose (FBG; −0.13(−0.20, −0.05) mmol·L−1), hemoglobin A1C (A1C; −0.09% (−0.13%, −0.05%)), and fasting blood insulin (FBI: −7.61 (−11.93, −3.30) pmol·L−1). The benefits of vitamin D were most evident in trials performed in non-Westerners, participants with baseline 25-hydroxyvitamin D (25[OH]D) lower than 15.0 ng·mL−1, non-obese (body mass index (BMI) < 30 kg·m−2), and older (age ≥ 50 years). The findings of this study underscore the need for personalized vitamin D intervention strategies that comprehensively account for individual patient characteristics (such as ethnocultural background, age, BMI, and circulating 25[OH]D level), intervention dosage, and intervention duration to optimize cardiometabolic health outcomes.

Association between grit and depressive symptoms among medical students, moderated by academic performance

ABSTRACT Depression amongst medical students is a crucial matter. Grit, which is a potentially modifiable psychological factor, has been inversely linked to depressive symptoms. However, it remains unclear how grit is associated with depression. This study aims to examine the relationship between grit and depressive symptoms and to further investigate the potential effect modification by academic performance on the association between grit and depression among medical students. We focus on the total grit score and its subscales, namely perseverance of effort and consistency of interest. A cross-sectional study was conducted using data from second-year medical students at Tokyo Medical and Dental University in Japan from 2020 to 2023. The participants responded to questionnaire surveys comprising the Center for Epidemiologic Studies Depression Scale and the Short Grit Scale. Linear regression analysis was performed to assess the association between grit and depressive symptoms. We also tested for effect modification by first-year Grade Point Average (GPA) on the association between grit and depression. The total grit score and its subscales, perseverance of effort and consistency of interest, were all inversely associated with depressive symptoms (b = −4.7 [95%CI − 6.7 to − 2.6], b = −3.7 [95%CI − 5.3 to − 2.1], b = −1.8 [95%CI − 3.5 to − 0.2], respectively). While the interaction term for the total grit score and GPA was not significant, the interaction term for perseverance of effort and GPA was significant, indicating that the association between perseverance of effort and depression was stronger among the higher-achieving students. The interaction term for consistency of interest and GPA was also significant, indicating that the association was stronger among the lower-achieving students. We reveal a novel aspect of the association between grit and depressive symptoms in light of academic performance. The findings will contribute to future research on depression amongst medical students.

Potential relationship between cytomegalovirus and immunosenescence: Evidence from observational studies.

Immunosenescence (IS) occurs as a natural outcome of ageing and may be described as a decline in immune system flexibility and adaptability to sufficiently respond to new, foreign antigens. Potential factors that may precipitate IS include persistent herpesvirus infections, such as cytomegalovirus (CMV). Here, we conducted a review of the literature evaluating the potential association between CMV and IS. Twenty-seven epidemiologic studies that included direct comparisons between CMV-seropositive and CMV-seronegative immunocompetent individuals were analysed. The majority of these studies (n=20) were conducted in European populations. The strength of evidence supporting a relationship between CMV, and various IS-associated immunologic endpoints was assessed. T-cell population restructuring was the most prominently studied endpoint, described in 21 studies, most of which reported a relationship between CMV and reduced CD4:CD8 T-cell ratio or modified CD8+ T-cell levels. Telomere length (n=4) and inflammageing (n=3) were less frequently described in the primary literature, and the association of these endpoints with CMV and IS was less pronounced. An emergent trend from our review is the potential effect modification of the CMV-IS relationship with both sex and age, indicating the importance of considering various effector variables when evaluating associations between CMV and IS. Our analysis revealed plausible mechanisms that may underlie the larger epidemiologic trends seen in the literature that support the indirect effect of CMV on IS. Future studies are needed to clarify CMV-associated and IS-associated immunologic endpoints, as well as in more diverse global and immunocompromised populations.

Effect of concomitant medications on treatment response and survival in non-metastatic castrate resistant prostate cancer: Exploratory analysis of the SPARTAN trial

BackgroundWe performed an exploratory analysis of the SPARTAN trial to determine whether concomitant exposure to several classes of commonly prescribed medications influenced the effect of apalutamide on overall survival (OS) and metastasis-free survival (MFS) in patients with non-metastatic castration-resistant prostate cancer (nmCRPC). Patients and methodsSPARTAN was a phase III randomized controlled trial in which nmCRPC patients were randomly assigned in a 2:1 ratio to receive androgen deprivation therapy with or without apalutamide. We focused on 5 commonly prescribed classes of medications: metformin, statins, angiotensin converting enzyme inhibitors (ACEI), acetylsalicylic acid (ASA), and proton pump inhibitors (PPI) based on a plausible biological and clinical rationale. To determine the potential effect modification, we applied multivariable Cox regression models for OS and MFS separately with additional interaction terms. To determine the independent association of concomitant medications with OS and MFS, we used IPTW-based log-rank test. A 2-sided p < 0.01 was considered statistically significant. ResultsWe did not find statistically significant differences in effect from apalutamide on OS across subgroups stratified by concomitant exposure to any of the medication classes. While there was some difference in the treatment effect from apalutamide on MFS between patients with concomitant statins (adjusted hazard ratio [aHR]: 0.20; 95 % CI: 0.15–0.28) versus without concomitant statins (aHR: 0.31 [0.24–0.39]), this did not reach the pre-specified threshold of statistical significance (p = 0.011). On IPTW-based analysis, patients treated concomitantly with metformin (median: not reached versus 31 months; p = 0.002), or ACEI (median: 37 versus 29 months, p = 0.006) had significantly improved MFS. ConclusionsIn this post-hoc exploratory analysis of SPARTAN, effects of apalutamide on MFS and OS were consistent across subgroups stratified by exposure to concomitant medications. Exposure to concomitant metformin and ACEI was independently associated with a significant improvement in MFS.

Associations between urine glyphosate levels and metabolic health risks: insights from a large cross-sectional population-based study

BackgroundThe prevalence of metabolic syndrome (MetS) in American adults increased from 37.6% in the 2011–12 period to 41.8% in 2017–2018. Environmental exposure, particularly to common compounds such as glyphosate, has drawn increasing attention as a potential risk factor.MethodsWe employed three cycles of data (2013–2018) from the National Health and Nutrition Examination Survey (NHANES) in a cross-sectional study to examine potential associations between urine glyphosate measurements and MetS incidence. We first created a MetS score using exploratory factor analysis (EFA) of the International Diabetes Federation (IDF) criteria for MetS, with data drawn from the 2013–2018 NHANES cycles, and validated this score independently on an additional associated metric, the albumin-to-creatinine (ACR) ratio. The score was validated via a machine learning approach in predicting the ACR score via binary classification and then used in multivariable regression to test the association between quartile-categorized glyphosate exposure and the MetS score.ResultsIn adjusted multivariable regressions, regressions between quartile-categorized glyphosate exposure and MetS score showed a significant inverted U-shaped or saturating dose‒response profile, often with the largest effect for exposures in quartile 3. Exploration of potential effect modification by sex, race, and age category revealed significant differences by race and age, with older people (aged > 65 years) and non-Hispanic African American participants showing larger effect sizes for all exposure quartiles.ConclusionsWe found that urinary glyphosate concentration is significantly associated with a statistical score designed to predict MetS status and that dose–response coefficient is nonlinear, with advanced age and non-Hispanic African American, Mexican American and other Hispanic participants exhibiting greater effect sizes.

The effects of music-based interventions on behavioural and psychological symptoms of people living with dementia: a systematic review and network meta-analysis protocol

Objectives People living with dementia often experience behavioural and psychological symptoms of dementia (BPSD), which severely affect their well-being during the course of the disease. Particularly for BPSD outcomes, there is a high demand for increasing the evidence-based knowledge of non-pharmacological approaches, such as music-based interventions. Although previous reviews emphasize the potential effects of music-based interventions in people with dementia, they cover a wide range of different interventions and outcomes. Method Therefore, this systematic review (SR) and network meta-analysis (NMA) aims to not only investigate the efficacy of music-based interventions on BPSD, but also to compare the impact of different types of music-based interventions on outcomes. Preferred reporting items for SR and meta-analysis protocols (PRISMA-P) and the PRISMA NMA extension were followed. Several databases will be searched from inception to the date the search will be performed, for relevant randomized or non-randomized controlled trials comparing a music-based intervention with treatment as usual, active controls, or another music-based intervention. Multivariate pairwise meta-analyses will be conducted for each outcome. NMA based on a frequentist random-effects model will be used to estimate the comparative effects of each type of music-based intervention and related components across outcomes. Heterogeneity will be investigated by meta-regression models. Conclusion Based on our knowledge, this may be the first SR and NMA study to compare the efficacy of different types of music-based interventions. In addition, combined with our multivariate analysis approach, it will allow us to identify potential effect modifiers in music-based intervention for treating BPSD.

Lower in vivo locus coeruleus integrity is associated with lower cortical thickness in older individuals with elevated Alzheimer’s pathology: a cohort study

BackgroundAutopsy work indicates that the widely-projecting noradrenergic pontine locus coeruleus (LC) is among the earliest regions to accumulate hyperphosphorylated tau, a neuropathological Alzheimer’s disease (AD) hallmark. This early tau deposition is accompanied by a reduced density of LC projections and a reduction of norepinephrine’s neuroprotective effects, potentially compromising the neuronal integrity of LC’s cortical targets. Previous studies suggest that lower magnetic resonance imaging (MRI)-derived LC integrity may signal cortical tissue degeneration in cognitively healthy, older individuals. However, whether these observations are driven by underlying AD pathology remains unknown. To that end, we examined potential effect modifications by cortical beta-amyloid and tau pathology on the association between in vivo LC integrity, as quantified by LC MRI signal intensity, and cortical neurodegeneration, as indexed by cortical thickness.MethodsA total of 165 older individuals (74.24 ± 9.72 years, ~ 60% female, 10% cognitively impaired) underwent whole-brain and dedicated LC 3T-MRI, Pittsburgh Compound-B (PiB, beta-amyloid) and Flortaucipir (FTP, tau) positron emission tomography. Linear regression analyses with bootstrapped standard errors (n = 2000) assessed associations between bilateral cortical thickness and i) LC MRI signal intensity and, ii) LC MRI signal intensity interacted with cortical FTP or PiB (i.e., EC FTP, IT FTP, neocortical PiB) in the entire sample and a low beta-amyloid subsample.ResultsAcross the entire sample, we found a direct effect, where lower LC MRI signal intensity was associated with lower mediolateral temporal cortical thickness. Evaluation of potential effect modifications by FTP or PiB revealed that lower LC MRI signal intensity was related to lower cortical thickness, particularly in individuals with elevated (EC, IT) FTP or (neocortical) PiB. The latter result was present starting from subthreshold PiB values. In low PiB individuals, lower LC MRI signal intensity was related to lower EC cortical thickness in the context of elevated EC FTP.ConclusionsOur findings suggest that LC-related cortical neurodegeneration patterns in older individuals correspond to regions representing early Braak stages and may reflect a combination of LC projection density loss and emergence of cortical AD pathology. This provides a novel understanding that LC-related cortical neurodegeneration may signal downstream consequences of AD-related pathology, rather than being exclusively a result of aging.

Mode of Onset Modifies the Effect of Time to Endovascular Reperfusion on Clinical Outcomes after Acute Ischemic Stroke: An Analysis of the DAWN Trial.

We aimed to assess the impact of time to endovascular thrombectomy (EVT) on clinical outcomes in the DAWN trial, while also exploring the potential effect modification of mode of stroke onset on this relationship. The association between every 1-h treatment delay with 90-day functional independence (modified Rankin Scale [mRS] score 0-2), symptomatic intracranial hemorrhage, and 90-day mortality was explored in the overall population and in three modes of onset subgroups (wake-up vs. witnessed vs. unwitnessed). Out of the 205 patients, 98 (47.8%) and 107 (52.2%) presented in the 6 to 12 hours and 12 to 24 hours time window, respectively. Considering all three modes of onset together, there was no statistically significant association between time last seen well to randomization with either functional independence or mortality at 90 days in either the endovascular thrombectomy (mRS 0-2 1-hour delay OR 1.07; 95% CI 0.93-1.24; mRS 6 OR 0.84; 95% CI 0.65-1.03) or medical management (mRS 0-2 1-hour delay OR 0.98; 95% CI 0.80-1.14; mRS 6 1-hour delay OR 0.94; 95% CI 0.79-1.09) groups. Moreover, there was no significant interaction between treatment effect and time (p = 0.439 and p = 0.421 for mRS 0-2 and 6, respectively). However, within the thrombectomy group, the models that tested the association between time last seen well to successful reperfusion (modified Treatment in Cerebral Infarction ≥2b) and 90-day functional independence showed a significant interaction with mode of presentation (p = 0.013). This appeared to be driven by a nominally positive slope for both witnessed and unwitnessed strokes versus a significantly (p = 0.018) negative slope in wake-up patients. There was no association between treatment times and symptomatic intracranial hemorrhage. Mode of onset modifies the effect of time to reperfusion on thrombectomy outcomes, and should be considered when exploring different treatment paradigms in the extended window. ANN NEUROL 2024;96:356-364.

Short-term associations of PM10 attributed to biomass burning with respiratory and cardiovascular hospital admissions in Peninsular Malaysia.

Biomass burning (BB) is a major source of air pollution and particulate matter (PM) in Southeast Asia. However, the health effects of PM smaller than 10 µm (PM10) originating from BB may differ from those of other sources. This study aimed to estimate the short-term association of PM10 from BB with respiratory and cardiovascular hospital admissions in Peninsular Malaysia, a region often exposed to BB events. We obtained and analyzed daily data on hospital admissions, PM10 levels and BB days from five districts from 2005 to 2015. We identified BB days by evaluating the BB hotspots and backward wind trajectories. We estimated PM10 attributable to BB from the excess of the moving average of PM10 during days without BB hotspots. We fitted time-series quasi-Poisson regression models for each district and pooled them using meta-analyses. We adjusted for potential confounders and examined the lagged effects up to 3 days, and potential effect modification by age and sex. We analyzed 210960 respiratory and 178952 cardiovascular admissions. Almost 50% of days were identified as BB days, with a mean PM10 level of 53.1 µg/m3 during BB days and 40.1 µg/m3 during normal days. A 10 µg/m3 increment in PM10 from BB was associated with a 0.44% (95% CI: 0.06, 0.82%) increase in respiratory admissions at lag 0-1, with a stronger association in adults aged 15-64 years and females. We did not see any significant associations for cardiovascular admissions. Our findings suggest that short-term exposure to PM10 from BB increased the risk of respiratory hospitalizations in Peninsular Malaysia.