Potential Effect Modifiers Research Articles

Prognostic Factors and Treatment Effect Modifiers for Physical Health, Opioid Prescription, and Health Care Utilization in Patients With Musculoskeletal Disorders in Primary Care: Exploratory Secondary Analysis of the STEMS Randomized Trial of Direct Access to Physical Therapist-Led Care.

The aims of the study were to identify prognostic factors associated with health care outcomes in patients with musculoskeletal (MSK) conditions in primary care and to determine whether characteristics associated with choice of care modify treatment effects of a direct-access physical therapist-led pathway in addition to general practitioner (GP)-led care compared to GP-led care alone. A secondary analysis of a 2-parallel-arm, cluster randomized controlled trial involving general practices in the United Kingdom was conducted. Practices were randomized to continue offering GP-led care or to also offer a direct-access physical therapist-led pathway. Data from adults with MSK conditions who completed the 6-month follow-up questionnaire were analyzed. Outcomes included physical health, opioid prescription, and self-reported health care utilization over 6months. Treatment effect modifiers were selected a priori from associations in observational studies. Multivariable regression models identified potential prognostic factors, and interaction analysis tested for potential treatment effect modifiers. Analysis of 767 participants indicated that baseline pain self-efficacy, pain severity, and having low back pain statistically predicted outcomes at 6months. Higher pain self-efficacy scores at baseline were associated with improved physical health scores, reduced opioid prescription, and less health care utilization. Higher bodily pain at baseline and having low back pain were associated with worse physical health scores and increased opioid prescription. Main interaction analyses did not reveal that patients' age, level of education, duration of symptoms, or MSK presentation influenced response to treatment, but visual trends suggested those in the older age group proceeded to fewer opioid prescriptions and utilized less health care when offered direct access to physical therapy. Patients with MSK conditions with lower levels of pain self-efficacy, higher pain severity, and presenting with low back pain have less favorable clinical and health care outcomes in primary care. Prespecified characteristics did not modify the treatment effect of the offer of a direct-access physical therapist-led pathway compared to GP-led care. Patients with MSK conditions receiving primary care in the form of direct-access physical therapist-led or GP-led care who have lower levels of self-efficacy, higher pain severity, and low back pain are likely to have a less favorable prognosis. Age and duration of symptoms should be explored as potential patient characteristics that modify the treatment response to a direct-access physical therapist-led model of care.

Association between coffee and caffeine intake and risk of COPD: Findings based on NHANES 2007–2012

BackgroundThe association between coffee and caffeine intake and the risk of COPD and lung function has not been thoroughly discussed in Americans, with subgroup and threshold effects remaining unclear. ObjectivesThis study investigated the association between coffee and caffeine consumption and the risk of chronic obstructive pulmonary disease (COPD) as well as lung function utilizing data from the NHANES 2007–2012. MethodsWe assessed the associations of coffee and caffeine consumption with the risk of COPD and lung function parameters, including FEV1 and FVC, adjusting for common demographic and disease characteristics in a cross-sectional analysis of NHANES data. ResultsA total of 9763 participants were included in the study, and 592 were diagnosed with COPD. Multivariate regression models revealed positive associations between coffee and caffeine consumption and the risk of COPD and lung function. Subgroup analyses stratified by sex, DM, hypertension status, and smoking habits identified potential effect modifiers as well as inflection points from threshold effect examinations. ConclusionsThe results of this cross-sectional study indicated significant positive correlations between coffee and caffeine consumption and the risk of COPD. Additionally, positive correlations between exposure variables and FEV1 and FVC were detected. Among the stratification factors, smoking status exhibited the most potential for modifying effects. Future practices and research are needed to validate the results and explore the underlying mechanisms

Investigating the causal association of generalized and abdominal obesity with microvascular complications in patients with type 2 diabetes: A community-based prospective study.

The paradoxical protective association between overweight/obesity and diabetic microvascular complications (DMC), a phenomenon well-known as the obesity paradox, has been considered a non-causal association based on methodological influences. We aimed to investigate the association of generalized and abdominal obesity, as measured by body mass index (BMI) and waist circumference (WC), respectively, with DMC in patients with type 2 diabetes (T2D), using a causal inference approach. We enrolled 1436 patients with clinically diagnosed T2D but not DMC at baseline in a community-based prospective cohort in China between 2017 and 2019 and followed them annually until 2022 with new-onset DMC recorded. Marginal structural Cox models with inverse probability weighting were constructed to determine the causal association. Subgroup analyses were performed to identify potential effect modifiers. We observed 360 incident DMC cases, including 109 cases of diabetic nephropathy (DN) and 277 cases of diabetic retinopathy (DR) during four follow-up visits. Multivariable-adjusted hazard ratios (95% confidence intervals) for overall DMC, DN and DR were 1.037 (1.005-1.071), 1.117 (1.062-1.175) and 1.018 (0.980-1.059) for 1 kg/m2 increase in BMI, and 1.005 (0.994-1.017), 1.034 (1.018-1.051) and 1.000 (0.987-1.014) for 1 cm increase in WC, respectively. Similar patterns were observed across the BMI and WC categories, while the positive association appeared to be more pronounced in women. Generalized but not abdominal obesity was associated with an increased risk for the overall DMC, whereas both obesities were causally related to DN, albeit not DR, in T2D. Routine weight management should not be neglected in diabetes care, particularly in women.

Treatment Effect Modifiers for Return-to-Work in Patients With Musculoskeletal Disorders

Investigating how individual characteristics modify treatment effects can improve understanding, interpretation, and translation of trial findings. The purpose of this secondary analysis was to identify treatment effect modifiers of the MI-NAV trial, a 3 arm, parallel randomized controlled trial which compared motivational interviewing and stratified vocational advice intervention in addition to usual case management (UC), to UC alone. This study included (n = 514) participants with musculoskeletal disorders on sick leave for at least 50% of their contracted work hours for at least 7 consecutive weeks with the Norwegian Labour and Welfare Administration. Sickness absence days was the primary outcome, measured from baseline assessment date until the 6-month follow-up. Potential treatment effect modifiers, identified a priori and informed by expert consultation and literature, were evaluated using linear regression models and statistical interaction tests. For motivational interviewing versus UC, age (mean difference [MD] −.7, 95% confidence interval [CI] −1.5 to .2; P = .13) and self-perceived health status (MD −.3, 95% CI −.7 to .1; P = .19) were identified as potential effect modifiers (P ≤ .2). For stratified vocational advice intervention versus UC, analgesic medication use (MD −26.2, 95% CI −45.7 to −6.7; P = .009) was identified as a treatment effect modifier (P ≤ .05). These findings may assist in more targeted treatment adaptation and translation as well as the planning of future clinical trials. PerspectiveThis secondary analysis of the MI-NAV trial found that analgesic medication use, age, and self-perceived health may modify the effect of 2 vocational interventions on reducing sickness absence in people with musculoskeletal disorders.

Water Fluoridation and Birth Outcomes in California.

There is a lack of research on the relationship between water fluoridation and pregnancy outcomes. We assessed whether hypothetical interventions to reduce fluoride levels would improve birth outcomes in California. We linked California birth records from 2000 to 2018 to annual average fluoride levels by community water system. Fluoride levels were collected from consumer confidence reports using publicly available data and public record requests. We estimated the effects of a hypothetical intervention reducing water fluoride levels to (the current level recommended by the US Department of Health and Human Services) and (below the current recommendation) on birth weight, birth-weight-for-gestational age z-scores, gestational age, preterm birth, small-for-gestational age, large-for-gestational age, and macrosomia using linear regression with natural cubic splines and G-computation. Inference was calculated using a clustered bootstrap with Wald-type confidence intervals. We evaluated race/ethnicity, health insurance type, fetal sex, and arsenic levels as potential effect modifiers. Fluoride levels ranged from 0 to , with a median of . There was a small negative association on birth weight with the hypothetical intervention to reduce fluoride levels to [; 95% confidence interval (CI): , 0.0] and to (; 95% CI: , ). There were small negative associations with birth-weight-for-gestational-age z-scores for both hypothetical interventions (: ; 95% CI: , 0.000 and : ; 95% CI: , 0.000). We also observed small negative associations for risk of large-for-gestational age for both the hypothetical interventions to [; 95% CI: , 0.000 and (; 95% CI: , 0.000)]. We did not observe any associations with preterm birth or with being small for gestational age for either hypothetical intervention. We did not observe any associations with risk of preterm birth or small-for-gestational age for either hypothetical intervention. We estimated that a reduction in water fluoride levels would modestly decrease birth weight and birth-weight-for-gestational-age z-scores in California. https://doi.org/10.1289/EHP13732.

Identification of individual-level clinical factors associated with increased risk of death during heatwaves: a time-stratified case-crossover study using national primary care records in England

BackgroundDespite an increase in heat-related deaths occurring in England in recent years, one of the key recommended actions of identifying individuals at risk and deploying targeted interventions is not routinely...

Prior COVID-19 vaccination and reduced risk of cerebrovascular diseases among COVID-19 survivors.

The effects of COVID-19 vaccination on short-term and long-term cerebrovascular risks among COVID-19 survivors remained unknown. We conducted a national multi-center retrospective cohort study with 151 597 vaccinated and 151 597 unvaccinated COVID-19 patients using the TriNetX database, from January 1, 2020 to December 31, 2023. Patients baseline characteristics were balanced with propensity score matching (PSM). The outcomes were incident cerebrovascular diseases occurred between 1st and 30th days (short-term) after COVID-19 diagnosis. Nine subgroup analyses were conducted to explore potential effect modifications. We performed six sensitivity analyses, including evaluation of outcomes between 1st to 180th days, accounting for competing risk, and incorporating different variant timeline to test the robustness of our results. Kaplan-Meier curves and Log-Rank tests were performed to evaluate survival difference. Cox proportional hazards regressions were adopted to estimate the PSM-adjusted hazard ratios (HR). The overall short-term cerebrovascular risks were lower in the vaccinated group compared to the unvaccinated group (HR: 0.66, 95% CI: 0.56-0.77), specifically cerebral infarction (HR: 0.62, 95% CI: 0.48-0.79), occlusion and stenosis of precerebral arteries (HR: 0.74, 95% CI: 0.53-0.98), other cerebrovascular diseases (HR: 0.57, 95% CI: 0.42-0.77), and sequelae of cerebrovascular disease (HR: 0.39, 95% CI:0.23-0.68). Similarly, the overall cerebrovascular risks were lower in those vaccinated among most subgroups. The long-term outcomes, though slightly attenuated, were consistent (HR: 0.80, 95% CI: 0.73-0.87). Full 2-dose vaccination was associated with a further reduced risk of cerebrovascular diseases (HR: 0.63, 95% CI: 0.50-0.80) compared to unvaccinated patients. Unvaccinated COVID-19 survivors have significantly higher cerebrovascular risks than their vaccinated counterparts. Thus, clinicians are recommended to monitor this population closely for stroke events during postinfection follow-up.

ASSOCIATION OF C-REACTIVE PROTEIN LEVEL WITH THE RISK OF TYPE 2 DIABETES: SYSTEMATIC REVIEW AND A DOSE-RESPONSE META-ANALYSIS

Objective: The relationship between C-reactive protein (CRP) levels and the risk of type 2 diabetes were positive; however, the non-linearity pattern was still unknown. We conducted a systematic review and a dose-response meta-analysis to examine the association between CRP levels and the risk of diabetes and the dose-response curve pattern. Design and method: A comprehensive search was conducted in PubMed and Embase databases from the inception to March 7, 2023. We treated CRP as both a continuous and a categorical variable to analyze the risk ratio of incident diabetes. In addition, we performed a dose-response meta-analysis to explore the pattern of the dose-response curve, and a meta-regression analysis for potential effect modifiers. Results: A total of 17 studies with high study quality were collected. The CRP level as a continuous variable was associated with a 12% increase in the risk of diabetes [95% confidence interval (CI), 1.06-1.17] per 1 mg/L increase. The high-low comparison showed a significantly higher risk of 71% (95% CI, 1.42-2.06). The dose-response analysis showed a saturation curve pattern, suggesting a high risk among CRP levels within 5 mg/L. In addition, we found that smoking played a modest effect modifier for the association between CRP and diabetes risk (p, 0.11). Conclusions: We validated that a high CRP level was associated with the risk of diabetes, and the pattern was likely to be a saturation shape.

Estimated pulse wave velocity as a predictor of all-cause and cardiovascular mortality in patients with hypertension in China: a prospective cohort study.

Whether the estimated pulse wave velocity (ePWV) in Chinese patients with hypertension can serve as an independent predictor of cardiovascular and all-cause mortality remains unknown. Therefore, this study investigated the associations between ePWV and cardiovascular and all-cause mortalities and explored potential effect modifiers influencing these relationships. Finally, we compared the ePWV with the brachial-ankle pulse wave velocity (baPWV) to determine which parameter better predicts mortality. The population of this longitudinal cohort study was selected from the China H-type Hypertension Registry Study. The exposure and outcome variables were ePWV and all-cause and cardiovascular mortalities, respectively. The Cox proportional hazard regression model was applied to assess the associations between ePWV and all-cause and cardiovascular mortalities. The performances of ePWV and baPWV in predicting death were compared using the receiver operating characteristic (ROC) curve area, net reclassification improvement index (NRI), and integrated discrimination improvement index (IDI). This prospective study enrolled 14,232 patients with hypertension. Following an average follow-up of 48 months, 806 individuals succumbed to all-cause mortality, with 397 cases specifically attributed to cardiovascular diseases. The Cox proportional regression analysis revealed a significant association between a 1 m/s increase in ePWV and a 37% higher risk of all-cause mortality (hazard ratio [HR]: 1.37, 95% confidence interval [CI]: 1.31-1.43) as well as a 52% higher risk of cardiovascular mortality (HR: 1.52, 95% CI: 1.43-1.62) in the fully adjusted model. The findings for ePWV according to quartile demonstrated hazard ratios for all-cause mortality for Q2 (10.25 < ePWV < 11.32), Q3 (11.32 < ePWV < 12.40), and Q4 (ePWV ≥ 12.40) of 1.50 (HR: 1.50, 95% CI: 1.07-2.10), 2.34 (HR: 2.34, 95% CI: 1.73-3.18), and 4.09 (HR: 4.09, 95% CI: 3.05-5.49), respectively, compared with Q1 (ePWV < 10.25). The risk of cardiovascular death also increased in proportion to the rise in ePWV. The results of the area under the ROC curve, NRI, and IDI all indicated that ePWV outperformed baPWV in predicting mortality. The results of the subgroup analysis demonstrated that body mass index (BMI) and hypoglycemic drug use modified the association between ePWV and mortality. The performance of ePWV in predicting all-cause and cardiovascular mortalities was superior to that of baPWV alone. Patients who were overweight or obese with higher ePWV values exhibited a significantly increased risk of all-cause death. The correlation between elevated ePWV and the risk of cardiovascular death was more pronounced in patients who had not received hypoglycemic drugs.

Antidepressant use and ovarian cancer risk: Evidence from nationwide studies with >14,000 cases from Denmark and Sweden

ObjectiveGiven that the evidence regarding the link between antidepressant use and ovarian cancer risk is equivocal, we investigated this research question by conducting two nationwide nested case-control studies among the Danish and Swedish populations. MethodsAltogether, 14,121 women with epithelial ovarian cancer (30–84 years old) (Denmark: 8976 diagnosed 2000–2019, Sweden: 5145 diagnosed 2010–2018) were randomly age-matched with 564,840 female controls (359,040 from Denmark, and 205,800 from Sweden) using risk set sampling. We used conditional logistic regression to estimate odds ratios (OR) with 95 % confidence intervals (CI) and combined the estimates based on the fixed-effect assumption. We also investigated potential effect modification by well-established risk factors for ovarian cancer. ResultsAntidepressant use was associated with an overall reduced risk of ovarian cancer (OR = 0.92, 95%CI: 0.88–0.96), and that reduction was more pronounced in postmenopausal women and long-term users. The effect was most pronounced for serous ovarian tumors (OR = 0.90, 95%CI: 0.86–0.95) but was also observed in other subtypes, although not statistically significant. Among different types of antidepressants, selective serotonin reuptake inhibitors in general and citalopram in particular exhibited a noteworthy reduction in ovarian cancer risk (OR = 0.89, 95%CI: 0.82–0.96). Additionally, use of oral contraceptives and hormone replacement therapy individually modified the association between antidepressant use and ovarian cancer risk. ConclusionsUse of an antidepressant was associated with a slight, but statistically significant, decrease in ovarian cancer risk. Given the morbidity and mortality associated with ovarian cancer, and increasing use of antidepressants, these findings may be of significance to cancer prevention and should be studied in more detail mechanistically.

Adherence to the low-fat diet pattern reduces the risk of lung cancer in American adults aged 55 years and above: a prospective cohort study

ObjectivesThere is little evidence on the association between low-fat dietary patterns and lung cancer risk among middle-aged and older adults. To fill this gap, we comprehensively investigated the association of adherence to a low-fat diet (LFD) and intake of different fat components including saturated, monounsaturated, and polyunsaturated fatty acids with incidence of lung cancer and its subtypes [non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC)] among adults aged 55 years and older. DesignA prospective cohort study with a mean follow-up time of 8.8 years. Setting and participantsThis study used data from the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial. The study population included 98,459 PLCO participants age 55 and over at baseline who completed food frequency questionnaires providing detailed dietary information and had no history of cancer. MethodsDietary intake was assessed using a validated food frequency questionnaire at baseline. A LFD score was calculated based on fat, protein, and carbohydrate intake as a percentage of total calories. Cox proportional hazards regression models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for the association between LFD score and intake of fat components (in quartiles) and incident lung cancer and its subtypes over follow-up. Restricted cubic spline analyses were conducted to examine possible nonlinear relationships. Subgroup analyses were performed to evaluate potential effect modifiers, and several sensitivity analyses were conducted to assess the stability of the findings. ResultsDuring a follow-up of 869,807.9 person-years, 1,642 cases of lung cancer were observed, consisting of 1,408 (85.75%) cases of NSCLC and 234 (14.25%) cases of SCLC. The highest versus the lowest quartiles of the LFD score were found to be associated with a reduced risk of lung cancer (HR, 0.76; 95% CI, 0.66−0.89), NSCLC (HR, 0.79; 95% CI, 0.67−0.93), and SCLC (HR, 0.59; 95% CI, 0.38−0.92). The restricted cubic spline plots demonstrated a linear dose-response relationship between the LFD score and the risk of lung cancer as well as its subtypes. This risk reduction association for overall lung cancer was more pronounced in smokers (HR, 0.71; 95% CI, 0.60−0.84; P for interaction = 0.003). For fat components, high consumption of saturated fatty acids was associated with an increased lung cancer risk (HR, 1.35; 95% CI, 1.10–1.66), especially for SCLC (HR, 2.05; 95% CI, 1.20–3.53). No significant association was found between consumption of monounsaturated or polyunsaturated fatty acids and incident lung cancer and its subtypes. ConclusionsOur findings suggest that adherence to LFD may reduce the lung cancer risk, particularly in smokers; while high saturated fatty acids consumption may increase lung cancer risk, especially for SCLC, among middle-aged and older adults in the US population.

Mandibular torus thickness associated with age: Postmortem computed tomographic analysis

Age estimation is an essential step in identifying human corpses. Several mandibular landmarks have been highlighted as skeletal sites for age estimation since aging causes morphological changes. Reports suggest that mandibular torus size may be associated with aging; however, thorough investigation has not been performed owing to the difficulty in measuring it. Therefore, this study aimed to determine the association between age and mandibular torus thickness using postmortem computed tomography data from Japanese corpses. This study included 2,792 corpses with mean (standard deviation) age of 58.0 (22.4) years (range, 0–101 years) and 67.6 % males. Further, 2,662 (95.3 %), 14 (0.5 %), 59 (2.1 %), and 57 (2.0 %) corpses were in the permanent, mixed, primary, and predental dentition periods, respectively. Multivariable analysis was performed to quantify the impact of age on mandibular torus thickness, adjusting for sex, height, weight, and occlusal contact status. The model also included an interaction term between age and occlusal status because of the potential effect modification by occlusion. Results of the multivariable regression analysis showed that mandibular torus thickness increased with age (the regression coefficients (95 % confidence interval) were 0.6 (0.2–1.0), 0.7 (0.3–1.0), 1.0 (0.6–1.4), 1.3 (0.9–1.7), 1.3 (0.8–1.8), and 1.1 (0.4–1.7) for age groups 30–39, 40–49, 50–59, 60–69, 70–79, and 80–89 years, respectively), especially in males with occlusal contact. A significant association between mandibular torus thickness and age, modified by occlusal status and sex, was identified. Therefore, data regarding the thickness of the mandibular torus and occlusal status may be useful for age estimation in human corpses.

Assessing treatment effect heterogeneity in the presence of missing effect modifier data in cluster-randomized trials.

Understanding whether and how treatment effects vary across subgroups is crucial to inform clinical practice and recommendations. Accordingly, the assessment of heterogeneous treatment effects based on pre-specified potential effect modifiers has become a common goal in modern randomized trials. However, when one or more potential effect modifiers are missing, complete-case analysis may lead to bias and under-coverage. While statistical methods for handling missing data have been proposed and compared for individually randomized trials with missing effect modifier data, few guidelines exist for the cluster-randomized setting, where intracluster correlations in the effect modifiers, outcomes, or even missingness mechanisms may introduce further threats to accurate assessment of heterogeneous treatment effect. In this article, the performance of several missing data methods are compared through a simulation study of cluster-randomized trials with continuous outcome and missing binary effect modifier data, and further illustrated using real data from the Work, Family, and Health Study. Our results suggest that multilevel multiple imputation and Bayesian multilevel multiple imputation have better performance than other available methods, and that Bayesian multilevel multiple imputation has lower bias and closer to nominal coverage than standard multilevel multiple imputation when there are model specification or compatibility issues.

25 Evaluating serum copper and kidney function in a cohort of bariatric surgery patients

OBJECTIVES/GOALS: High serum copper (Cu) levels have previously been described in bariatric patients. The kidneys are a target organ for Cu toxic insult but the role of Cu on kidney function (eGFR) is uncertain. This study examines the association between Cu and eGFR in a bariatric population in Southeast Louisiana. METHODS/STUDY POPULATION: Seven hundred fifty patients will be recruited from the Bariatric Center of the University Medical Center in New Orleans. Inclusion criteria include: age ≥ 18 years, clinic visit between June 1, 2018 – May 31st 2024, and having a serum Cu test result. Covariables such as inflammatory markers and hormonal contraception use will be assessed as potential confounders. Blood pressure will be assessed as a potential effect modifier. Data will be obtained from electronic medical records. Two cohorts will be assembled, a pre-surgery cross-sectional cohort and another followed post-surgery. Separate models will be developed stratified by race-ethnicity. RESULTS/ANTICIPATED RESULTS: In a pilot study of bariatric patients 26% had elevated (&gt;155 mcg/dl) serum Cu and pronounced racial differences were noted. Characteristics consisted of a mean BMI of approximately 50 kg/m2; 91% were female and 69% were Black. Black patients had approximately double the prevalence (OR 1.98; 95% CI: 1.15, 3.4) compared to white patients. Due to the dual nature of the kidneys’ involvement in metabolism via excretion and being the target organ for toxic insult, racial differences in exposure, coupled with the disproportionate rates of chronic kidney disease in Black adults, may be an explanation for the association between elevated Cu levels and eGFR in Black adults in this study. DISCUSSION/SIGNIFICANCE: Results from this study will provide insight into the prevalence of Cu and its association with kidney function in a bariatric population. Chronic kidney disease or other forms of renal impairment may result in the need for more conservative guidelines for dietary copper in bariatric medicine.

Evaluating the Correlation of SARS-CoV-2 Reverse-transcription Polymerase Chain Reaction Cycle Threshold Values at Diagnosis with Subsequent COVID-19 Disease Severity and Humoral Immune Responses in Children: A Prospective Observational Study

Abstract Background and Objective: Few studies in adults and none in children have analyzed simultaneously, the correlation of SARS-CoV-2 reverse-transcription polymerase chain reaction (RT-PCR) cycle threshold (Ct) value (inversely correlated to viral load) at diagnosis, with subsequent disease severity and antibody responses. A correlation could potentially inform treatment and vaccination decisions in advance. Materials and Methods: This prospective observational study was conducted from February 2021 to January 2022 in children below 16 years who tested RT-PCR test positive for SARS-CoV-2, including multisystem inflammatory syndrome in children. Disease severity was stratified as per standard definitions. Ct values were analyzed at diagnosis; IgG antibodies to S and N2 were quantified using a binding antibody test, 4–6 weeks after diagnosis. Multivariable analyses factored in potential effect modifiers such as age, gender, time from onset of symptoms to RT-PCR testing, time from RT-PCR to antibody testing, and immunocompromised state. Results: Of the 79 (47 male: 32 female) children who completed the study, 23 (29%) were asymptomatic, 47 (59%) had mild-to-moderate disease, 9 (11.4%) had severe disease; and 30/79 (38%) had comorbidities. The mean Ct/standard deviation (SD) value of the study population was 27.94 (±6.8); with mean Ct/SD values of 30.71 (±4.82), 26.25 (±6.82), and 29.69 (±8.5) in asymptomatic, mild-to–moderate, and severe disease, respectively. Although differences were observed between disease groups in mean Ct values and anti-N antibody titers using multiple-comparison correction, multivariable analyses showed no statistically significant correlation between Ct values, disease severity, and antibody titers. Conclusions: In children, SARS-CoV-2 Ct value at diagnosis independently predicts neither subsequent disease course/severity nor antibody response after 4–6 weeks.

First trimester plasma per- and Polyfluoroalkyl Substances (PFAS) and blood pressure trajectories across the second and third trimesters of pregnancy

BackgroundEvidence suggests that exposure to per- and polyfluoroalkyl substances (PFAS) increases risk of high blood pressure (BP) during pregnancy. Prior studies did not examine associations with BP trajectory parameters (i.e., overall magnitude and velocity) during pregnancy, which is linked to adverse pregnancy outcomes. ObjectivesTo estimate associations of multiple plasma PFAS in early pregnancy with BP trajectory parameters across the second and third trimesters. To assess potential effect modification by maternal age and parity. MethodsIn 1297 individuals, we quantified six PFAS in plasma collected during early pregnancy (median gestational age: 9.4 weeks). We abstracted from medical records systolic BP (SBP) and diastolic BP (DBP) measurements, recorded from 12 weeks gestation until delivery. BP trajectory parameters were estimated via Super Imposition by Translation and Rotation modeling. Subsequently, Bayesian Kernel Machine Regression (BKMR) was employed to estimate individual and joint associations of PFAS concentrations with trajectory parameters – adjusting for maternal age, race/ethnicity, pre-pregnancy body mass index, income, parity, smoking status, and seafood intake. We evaluated effect modification by age at enrollment and parity. ResultsWe collected a median of 13 BP measurements per participant. In BKMR, higher concentration of perfluorooctane sulfonate (PFOS) was independently associated with higher magnitude of overall SBP and DBP trajectories (i.e., upward shift of trajectories) and faster SBP trajectory velocity, holding all other PFAS at their medians. In stratified BKMR analyses, participants with ≥ 1 live birth had more pronounced positive associations between PFOS and SBP velocity, DBP magnitude, and DBP velocity – compared to nulliparous participants. We did not observe significant associations between concentrations of the overall PFAS mixture and either magnitude or velocity of the BP trajectories. ConclusionEarly pregnancy plasma PFOS concentrations were associated with altered BP trajectory in pregnancy, which may impact future cardiovascular health of the mother.

Exploring autism spectrum disorder (ASD) and attention deficit disorder (ADD/ADHD) in children exposed to polybrominated biphenyl.

Although the causes of attention-deficit/hyperactivity disorder (ADHD) and autism have not been identified, exposure to endocrine-disrupting chemicals, such as polybrominated biphenyl (PBB), during fetal development and early life has been suspected to impact neurological development. This study aims to investigate the association between prenatal and early life exposure to PBB and the development of ADHD and autism later in life. Data from the Michigan PBB Registry, a cohort of Michigan residents who had been exposed to PBB in a mass contamination event in 1973, was leveraged for this nested case-control analysis among two distinct samples: (1) Those who self-reported ADHD or autism diagnosis, and (2) mothers who reported their child's ADHD or autism diagnosis. PBB exposure was measured in participants of the PBB Registry, and the mother's PBB level was used in mother-reported analyses. Cases were matched with controls by sex and year of birth. Conditional logistic regression models were used to estimate the association between PBB level and case status. PBB levels were higher among those who were exposed in early life compared with those exposed in utero (geometric mean: 0.300 ng/ml vs. 0.016 ng/ml). Among women in this cohort, a higher than expected proportion of self-reported ADHD diagnosis (11.11%), compared with population estimates. PBB was not associated with ADHD or autism in either self-reported or mother-reported analyses. This study adds to the sparse literature about prenatal and early life exposure to PBB-153 and ADHD and autism. Future studies should examine potential effect modification by sex.

Dietary intake changes the associations between long-term exposure to fine particulate matter and the surrogate indicators of insulin resistance

The relationship of fine particulate matter (PM2.5) exposure and insulin resistance remains inclusive. Our study aimed to investigate this association in the project of Prediction for Atherosclerotic Cardiovascular Disease Risk in China (China-PAR). Specifically, we examined the associations between long-term PM2.5 exposure and three surrogate indicators of insulin resistance: the triglyceride-glucose index (TyG), TyG with waist circumference (TyG-WC) and metabolic score for insulin resistance (METS-IR). Additionally, we explored potential effect modification of dietary intake and components. Generalized estimating equations were used to evaluate the associations between PM2.5 and the indicators with an unbalanced repeated measurement design. Our analysis incorporated a total of 162,060 observations from 99,329 participants. Each 10 μg/m3 increment of PM2.5 was associated with an increase of 0.22 % [95 % confidence interval (CI): 0.20 %, 0.25 %], 1.60 % (95 % CI: 1.53 %, 1.67 %), and 2.05 % (95 % CI: 1.96 %, 2.14 %) in TyG, TyG-WC, and METS-IR, respectively. These associations were attenuated among participants with a healthy diet, particularly those with sufficient intake of fruit and vegetable, fish or tea (pinteraction < 0.0028). For instance, among participants with a healthy diet, TyG increased by 0.11 % (95 % CI: 0.08 %, 0.15 %) per 10 μg/m3 PM2.5 increment, significantly lower than the association observed in those with an unhealthy diet. The findings of this study emphasize the potential of a healthy diet to mitigate these associations, highlighting the urgency for improving air quality and implementing dietary interventions among susceptible populations in China.

Association Between Physical Activity and the Prevalence of Kidney Stones in American Adults: Results From a Multiyear National Survey

ObjectiveTo investigate the association between physical activity and the prevalence of kidney stones. MethodsA cross-section study was conducted using data from National Health and Nutrition Examination Survey 2007-2018. Physical activity was evaluated based on the Global Physical Activity Questionnaire. Multivariable logistic regression was performed to elucidate the association between physical activity (patterns, intensity, duration and frequency of moderate and vigorous physical activity) and the prevalence of kidney stones after adjusting for potential confounders. Stratified and interaction analyses were conducted to detect potential effect modifiers. In addition, physical activity was assessed using metabolic equivalent and physical volume, and followed the regression above. Water intake was obtained from the day 2 dietary recall and was included in the sensitivity analysis. ResultsA total of 34,390 participants were included in the analysis. The multivariable logistic regression revealed that individuals who engaged in moderate physical activity for 30-60 minutes per day had a significant inverse association with the prevalence of kidney stones in the fully-adjusted model (OR=0.804, 95%CI 0.700 to 0.923), while no more significant finding was observed for other physical activity parameters. Interaction and stratified analyses indicated no covariate modifying the association. The results above were robust in the sensitivity analysis. ConclusionThe duration of moderate physical activity (30-60 mins/day) is inversely associated with the prevalence of kidney stones, while no more significant association was observed between other physical activity parameters (including patterns, intensity, duration and frequency of vigorous physical activity, frequency of moderate physical activity) and kidney stones. Data availabilityData available in a publicly accessible repository that does not issue DOIs. Publicly available datasets were analyzed in this study. These data can be found here: https://www.cdc.gov/nchs/nhanes/index.htm.

Association between combined exposure to ambient air pollutants, genetic risk, and incident gout risk: A prospective cohort study in the UK Biobank

BackgroundLimited research has been conducted on the association between long-term exposure to air pollutants and the incidence of gout. ObjectivesThis study aims to assess the individual and combined effects of prolonged exposure to five air pollutants (NO2, NOx, PM10, PMcoarse and PM2.522NO2, nitrogen dioxide; NOx, nitrogen oxides; PM10, particulate matter with diameters ≤ 10 µm; PMcoarse, particulate matter with diameters between 2.5 and 10 µm;PM2.5, particulate matter with diameters ≤ 2.5 µm.) on the incidence of gout among 458,884 initially gout-free participants enrolled in the UK Biobank. MethodsEmploying a land use regression model, we utilized an estimation method to ascertain the annual concentrations of the five air pollutants. Subsequently, we devised a weighted air pollution score to facilitate a comprehensive evaluation of exposure. The Cox proportional hazards model was utilized to investigate the association between ambient air pollution and gout risk. Interaction and stratification analyses were conducted to evaluate age, sex, BMI, and genetic predisposition as potential effect modifiers in the air pollution-gout relationship. Furthermore, mediation analyses were conducted to explore the potential involvement of biomarkers in mediating the association between air pollution and gout. ResultsOver a median follow-up time of 12.0 years, 7,927 cases of gout were diagnosed. Significant associations were observed between the risk of gout and a per IQR increase in NO2 (HR33HR, hazard ratio.: 1.05, 95 % CI44CI, confidence interval.: 1.02–1.08, p = 0.003), NOx (HR: 1.04, 95 % CI: 1.01–1.06, p = 0.003), and PM2.5 (HR: 1.03, 95 % CI: 1.00–1.06, p = 0.030). Per IQR increase in the air pollution score was associated with an elevated risk of gout (p = 0.005). Stratified analysis revealed a significant correlation between the air pollution score and gout risk in participants ≥60 years (HR: 1.05, 95 % CI: 1.02–1.09, p = 0.005), but not in those <60 years (p = 0.793), indicating a significant interaction effect with age (p-interaction=0.009). Mediation analyses identified five serum biomarkers (SUA:15.87 %, VITD: 5.04 %, LDLD: 3.34 %, GGT: 1.90 %, AST: 1.56 %55UA, urate; HDL, high-density lipoprotein; VITD, vitamin D; LDLD, low density lipoprotein direct; GGT, gamma glutamyltransferase; AST, aspartate aminotransferase.) with potential mediation effects on this association. ConclusionsLong-term exposure to air pollutants, particularly among the elderly population, is associated with an increased risk of gout. The underlying mechanisms of these associations may involve the participation of five serum biomarkers.