Multivariable Linear Mixed Models Research Articles

Quantitative measurement of antibiotic resistance in Mycobacterium tuberculosis reveals genetic determinants of resistance and susceptibility in a target gene approach

The World Health Organization has a goal of universal drug susceptibility testing for patients with tuberculosis. However, molecular diagnostics to date have focused largely on first-line drugs and predicting susceptibilities in a binary manner (classifying strains as either susceptible or resistant). Here, we used a multivariable linear mixed model alongside whole genome sequencing and a quantitative microtiter plate assay to relate genomic mutations to minimum inhibitory concentration (MIC) in 15,211 Mycobacterium tuberculosis clinical isolates from 23 countries across five continents. We identified 492 unique MIC-elevating variants across 13 drugs, as well as 91 mutations likely linked to hypersensitivity. Our results advance genetics-based diagnostics for tuberculosis and serve as a curated training/testing dataset for development of drug resistance prediction algorithms.

Differences in the Evolution of Clinical, Biochemical, and Hematological Indicators in Hospitalized Patients with COVID-19 According to Their Vaccination Scheme: A Cohort Study in One of the World's Highest Hospital Mortality Populations.

COVID-19 vaccines primarily prevent severe illnesses or hospitalization, but there is limited data on their impact during hospitalization for seriously ill patients. In a Mexican cohort with high COVID-19 mortality, a study assessed vaccination's effects. From 2021 to 2022, 462 patients with 4455 hospital days were analyzed. The generalized multivariate linear mixed model (GENLINMIXED) with binary logistic regression link, survival analysis and ROC curves were used to identify risk factors for death. The results showed that the vaccinated individuals were almost half as likely to die (adRR = 0.54, 95% CI = 0.30-0.97, p = 0.041). When stratifying by vaccine, the Pfizer group (BNT162b2) had a 2.4-times lower risk of death (adRR = 0.41, 95% CI = 0.2-0.8, p = 0.008), while the AstraZeneca group (ChAdOx1-S) group did not significantly differ from the non-vaccinated (adRR = 1.04, 95% CI = 0.5-2.3, p = 0.915). The Pfizer group exhibited a higher survival, the unvaccinated showed increasing mortality, and the AstraZeneca group remained intermediate (p = 0.003, multigroup log-rank test). Additionally, BNT162b2-vaccinated individuals had lower values for markers, such as ferritin and D-dimer. Biochemical and hematological indicators suggested a protective effect of both types of vaccines, possibly linked to higher lymphocyte counts and lower platelet-to-lymphocyte ratio (PLR). It is imperative to highlight that these results reinforce the efficacy of COVID-19 vaccines. However, further studies are warranted for a comprehensive understanding of these findings.

Associations of Lower Extremity Muscle Strength, Area, and Specific Force With Lower Urinary Tract Symptoms in Older Men: The Baltimore Longitudinal Study of Aging.

Lower urinary tract symptoms (LUTS) in older men are associated with an increased risk of mobility limitations. Lower extremity muscle quality may represent a novel shared mechanism of both LUTS and mobility limitations. We evaluated associations of thigh skeletal muscle measures (strength, area, and specific force) with total LUTS severity (American Urologic Association Symptom Index; AUASI) and voiding and storage subscores among 352 men aged ≥60 years enrolled in the Baltimore Longitudinal Study of Aging. Thigh muscle strength (Nm) was defined as maximum concentric 30°/s knee extensor torque, area (cm2), and specific force (Nm/cm2) defined as strength/area. Associations with AUASI score were estimated using multivariable linear regression and linear mixed models. Mean thigh muscle strength at baseline was 139.7Nm. In cross-sectional multivariable models, each 39Nm increment in thigh muscle strength and 0.28Nm/cm2 increment in specific force was associated with -1.17 point (95% CI: -1.93 to -.41) and -0.95 point (95% CI: -1.63 to -0.27) lower AUASI score, respectively. Similar associations were observed for voiding and storage subscores, although somewhat attenuated. In longitudinal analyses, baseline muscle measures were not associated with annual change in AUASI, and current changes in muscle measures and AUASI were unrelated. Cross-sectionally, higher thigh muscle strength and specific force were associated with decreased LUTS severity in older men. However, we did not observe concurrent worsening LUTS severity with declining thigh muscle strength, area, or specific force in longitudinal analyses.

Hematocrit Is Associated with Cancer-Related Fatigue in Colorectal Cancer Survivors: A Longitudinal Analysis.

Cancer-related fatigue (CRF) is a frequent symptom in colorectal cancer survivors. It is unknown to what extent anemia may contribute to CRF in colorectal cancer survivors. This study aimed to investigate the association between hematocrit, as marker for anemia, and CRF among colorectal cancer survivors from diagnosis until two years thereafter. The study population included 1,506 newly diagnosed colorectal cancer survivors at any stage of disease from a prospective cohort study. Hematocrit and CRF (EORTC QLQ-C30) were assessed at diagnosis, six months, and two years after diagnosis. Multivariable logistic regression or multivariable linear mixed models were used to assess the associations of hematocrit with CRF prevalence, or CRF severity over time, respectively. A low hematocrit (levels <40% men/<36% women) was present in a third of the survivors at diagnosis and six months thereafter, and among 16% two years after diagnosis. The prevalence of CRF was 15% at diagnosis, peaked at 27% at six months, and was 14% two years after diagnosis. Hematocrit was associated with the prevalence of CRF at diagnosis [OR, 0.92; confidence interval (CI), 0.88-0.95], 6 months (OR, 0.89; 95% CI, 0.86-0.92), and 2 years (OR, 0.91; CI, 0.87-0.96) after diagnosis. Lower hematocrit was associated with higher severity of CRF over time (beta-coefficient = 1.3; CI, 1.5-1.1). Lower hematocrit levels were longitudinally associated with a higher prevalence and severity of CRF in colorectal cancer. Our findings emphasize the importance of long-term anemia monitoring and a potential role of anemia in CRF among colorectal cancer survivors.

The effects of semaglutide, empagliflozin and their combination on the kidney sodium signal from magnetic resonance imaging: A prespecified, secondary analysis from a randomized, clinical trial

AimsTo evaluate the effect of treatment with semaglutide and empagliflozin on the cortico-medullary sodium gradient (MCR; medulla/cortex ratio), urine sodium/creatinine ratio (UNACR), and estimated plasma volume (ePV) and to compare the MCR between persons with and without type 2 diabetes. MethodsUsing the 23Na magnetic resonance imaging (23Na-MRI) technique, we investigated the effects of 32 weeks of treatment with semaglutide, empagliflozin or their combination on MCR in 65 participants with type 2 diabetes and high risk of cardiovascular disease. The participants were recruited from a randomized, controlled interventional trial and further characterized by UNACR and ePV. In addition, in a cross-sectional design, we compared MCR by 23Na-MRI in 12 persons with type 2 diabetes and 17 matched controls. Data from the interventional trial were analyzed using a single, multivariate linear mixed model strategy for repeated measurements. Data from the cross-sectional study were analyzed by fitting a linear regression model adjusted for age and sex. ResultsCompared to placebo, semaglutide, but not empagliflozin, significantly decreased the MCR (−9 %, 95%CI (−18, −0.06)%, p = 0.035 and −0.05 %, 95%CI(−0.15, 0.05)%, p = 0.319, respectively). The UNACR decreased in the semaglutide group(−35 %, 95 % CI(−52, −14) %, p = 0.003) but not in the empagliflozin group (7 %, 95 % CI(−21, 44)%, p = 0.657), whereas the ePV decreased in the combination group. The MCR was not different between persons with and without type 2 diabetes. Conclusion23Na magnetic resonance imaging can identify drug induced changes in the MCR in persons with type 2 diabetes, and 32 weeks of semaglutide decreases the MCR in such persons. There is no difference in the MCR between persons with and without type 2 diabetes. Trial number and registryEUDRACT 2019-000781-38, clinicaltrialsregister.eu.

Impacts of preweaning colostrum feeding practices and health measures on dairy cow production, while accounting for genetic potential.

Calf management and health are essential for setting up the foundation of a productive cow. The objectives of this study were to estimate the impact of preweaning practices on milk production parameters while accounting for an animal's genetic potential in New Brunswick, Canada. A retrospective cohort study was performed on 220 heifer calves from eight herds born in 2014-2015. Preweaning practices and health data were recorded by producers and reviewed by the herd veterinarian for each calf. The herd veterinarian also visited the farms to collect serum samples from calves and frozen colostrum samples. The production outcomes assessed were milk, protein and fat yields, standardized to 305 d for the first lactation (L1) and a combined group of lactations two and three (L2 + 3). The genomic potential was determined as genomic parent averages (GPA) for the associated production parameters. Analysis was performed with multivariable linear (L1) and linear mixed (L2 + 3) regression models. In L1, for every 1.0kg increase in weaning weight, milk, protein, and fat yield increased by 25.5, 0.82, and 1.01kg, respectively (P < 0.006). Colostrum feeding time (CFT) positively impacted L1 milk and protein production, with feeding between 1-2h of life producing the greatest estimates of 626kg of milk and 18.2kg of protein yield (P < 0.007), compared to earlier or later CFT. Fat yield production was decreased by 80.5kg (P < 0.006) in L1 when evaluating animals that developed a preweaning disease and were not treated with antibiotics compared to healthy untreated animals. Impacts on L2 + 3 were similar across all production outcomes, with a positive interaction effect of CFT and weaning weight. Compared to CFT < 1h, the later CFT groups of 1-2h and > 2h produced greater yield outcomes of 68.2 to 72.6kg for milk (P < 0.006), 2.06 to 2.15kg for protein (P < 0.005), and 1.8 to 1.9kg for fat (P < 0.045) for every 1kg increase of weaning weight, respectively. The fit of all models was significantly improved with the inclusion of GPA. These results indicate that colostrum management and preweaning health measures impacted production parameters as adults. The inclusion of GPA significantly improved the accuracy of the models, indicating that this can be an important parameter to include in future studies.

Genome-wide association study identifies multiple loci influencing duck serum biochemical indicators in the laying period

ABSTRACT 1. Laying performance is an important economic trait in poultry. The blood is essential in transporting nutrients to the yolk and albumen and is necessary for egg formation. 2. This study calculated the phenotypic relationships of duck egg quality, egg production efficiency and 22 serum parameters in the egg-laying stage. Using a variety of methodologies, a genome-wide association study (GWAS) was carried out to uncover the genetic foundations of the 22 serum biochemical markers of laying ducks. 3. Spearman correlation coefficients between the egg production (226–329 per day) and the serum parameters were all weak, being less than 0.3. This analysis was done on 22 serum parameters, with total protein (TP), total triglycerides (TG), calcium (Ca) and phosphorous (P) having the highest correlation coefficients (r = 0.56–0.88). The coefficients for blood markers, such as total cholesterol (CHOL), total bilirubin (TBIL), low-density lipoprotein cholesterol (LDL-C) and high-density lipoprotein cholesterol (HDL-C) varied from 0.70–0.94. 4. Based on single-marker single-trait genome-wide analyses by a mixed linear model program of EMMAX, nine candidate genes were associated with enzyme traits (AST/ALT aspartate transaminase/glutamic-pyruvic transaminase, creatine kinase) and 19 candidate genes were associated with metabolism and protein-related serum parameters (glucose, total bile acid, uric acid (UA), albumin (ALB). 5. The mvLMM (multivariate linear mixed model) of GEMMA software was used to carry out multiple trait integrated GWAS. Two candidate genes were found in the TP-TG-CA-P analysis and seven candidate genes in the CHOL_LDL-C_HDL-C_TBIL study. There was a high genetic correlation between the two groups.

Circulating Ketone Bodies, Pyruvate, and Citrate and Risk of Cognitive Decline, Structural Brain Abnormalities, and Dementia.

The relationship between key energy metabolites and brain health is not well understood. We investigated the association between circulating ketone bodies, pyruvate, and citrate with cognitive decline, structural brain characteristics, and risk of dementia. We measured ketone bodies (acetoacetate, β-hydroxybutyrate, and acetone), pyruvate, and citrate species using NMR in plasma samples from 1,850 older adults in the Cardiovascular Health Study collected in 1989-90 or 1992-93. Cognitive decline was assessed using the modified Mini-Mental State Examination and the Digit Symbol Substitution Test. Dementia was adjudicated by a committee of experts through comprehensive evaluations including cognitive tests, medical records, and interviews with the next of kin. Dementia-related mortality was confirmed by a committee using death certificates and other clinical data from hospitalization. Multivariable linear mixed models were used to assess 9-year cognitive decline, while multivariable Cox regression models evaluated 6-year dementia incidence and 22-year dementia-related mortality. White matter lesions and ventricular size were measured using MRI in 1992-94 and were analyzed using multivariable linear regression models. Higher plasma levels of ketones, particularly β-hydroxybutyrate, were associated with faster cognitive decline (β, -0.10; 95% CI, -0.15 to -0.05; Padj&;lt.001) and dementia-related mortality (HR per SD, 1.29; 95% CI, 1.07 to 1.56; Padj=0.023). Higher pyruvate concentrations were associated with slower cognitive decline, smaller ventricular size, lower dementia risk (HR per SD, 0.87; 95% CI, 0.77 to 0.97; P=0.013; Padj=0.073), and lower dementia mortality. Higher citrate levels were associated with less cognitive decline and lower dementia risk. In adults aged 65 years and older, circulating ketone bodies are associated with faster cognitive decline and higher dementia mortality, while pyruvate and citrate are associated with lower dementia risk.

Social and clinical vulnerability in stroke and STEMI management during the COVID-19 pandemic: a registry-based study

ObjectiveThis study aims to evaluate whether the first wave of the COVID-19 pandemic resulted in a deterioration in the quality of care for socially and/or clinically vulnerable stroke and ST-segment...

Choroid Plexus Volume, Amyloid Burden, and Cognition in the Alzheimer's Disease Continuum.

As a part of the glymphatic system, the choroid plexus (CP) is involved in the clearance of harmful metabolites from the brain. We investigated the association between CP volume (CPV), amyloid-β (Aβ) burden, and cognition in patients on the Alzheimer's disease (AD) continuum. We retrospectively reviewed the records of 203 patients on the AD continuum and 82 healthy controls who underwent brain magnetic resonance imaging and 18F-florbetaben positron emission tomography. Automatic segmentation was performed, and the CPV was calculated. Cognitive function was assessed using detailed neuropsychological tests, and patients on the AD continuum were categorized into the non-dementia and dementia groups. The relationships between CPV, Aβ burden, and cognitive function were assessed using multivariate linear regression and linear mixed model. CPV was greater in the AD group than in the healthy control group (1.50 vs. 1.30, P < 0.001), but was comparable between the AD non-dementia and dementia groups (1.50 vs. 1.48, P = 0.585). After adjusting for age and sex, a larger CPV was significantly associated with greater global Aβ deposition (β = 0.20, P = 0.002). Larger CPV was also associated with worse general cognitive function assessed using the sum of boxes of the clinical dementia rating scale (β = 0.85, P = 0.034) and lower composite scores for memory (β = -0.68, P = 0.002) and frontal/executive function domains (β = -0.65, P < 0.001). In addition, a larger CPV was associated with a more rapid decline in Mini-Mental State Examination scores in the AD dementia group (β = -0.58, P = 0.004). The present study demonstrated that CP enlargement was associated with increased Aβ deposition and impaired memory and frontal/executive function in patients on the AD continuum.

Respiratory Function, Physical Capacity, and Metabolic Syndrome Components in Combustible Cigarettes and Heated Tobacco Products Users: a Five-Year Follow-Up Cohort Study

Purpose: Chronic obstructive pulmonary disease (COPD) is one of the leading causes of death worldwide and is the fourth leading cause of death in Kazakhstan. Cigarette smoking is a prevalent risk factor for COPD. While quitting smoking is the preferred way to reduce COPD risk, literature suggests that heated tobacco products (HTP) might be a better option for people who cannot quit smoking. The aim of this paper was to analyze the long-term effects of shifting to HTP use in long- term smokers compared to continued combustible cigarettes (CC) use. Patients and methods: A cohort of 1200 participants (393 HTP and 807 CC) aged 40-59 years with a minimum of 10 pack-year smoking history were recruited and followed for five years. The functional outcomes compared between HTP, CC users and No-Smokers (NS, people who stopping smoking) included: (1) COPD Assessment Test (CAT); (2) post-bronchodilator lung function; (3) 6-minute walking distance (6MWD) test; and (4) metabolic syndrome components. Multivariable linear mixed models (MIXED) were used to compare functional outcomes between visits and to test associations between health outcomes and smoking type (HTP vs. CC vs. NS) over time. Results: Out of 1200 participants 830 (466 CC users, 248 HTP users and 116 No-Smokers) remained in the study by the fifth year of follow up. Linear mixed models showed HTP use was associated with better CAT scores and HDL cholesterol level compared to CC users. Lung function (FVC) decrease was significantly less in HTP users. FEV, 6MWD, waist circumference, fasting blood glucose, triglycerides and diastolic blood pressure significantly changes over time, but without between-group difference in dynamic. Conclusion: This study demonstrated that HTP users experienced it to a significantly lesser decrease in lung function by FVC compared to CC users over time (in time dependent model), while demonstrating better stable levels in other functional outcomes. The results of this study suggest that HTP might be a less deleterious alternative compared to CC in people with long history of CC use and who cannot quit smoking.

LONGITUDINAL CHANGES IN PROTEOMIC BIOMARKERS IN ALZHEIMER’S DISEASE AND CARDIOVASCULAR DISEASE

Abstract Alzheimer’s disease (AD) and cardiovascular diseases (CVDs) commonly co-occur in older adults. This correlation prompts an investigation into the potential shared risk factors linking AD and CVDs, and the potential direct causative role of cardiovascular risk factors in AD. The cohort comprised 566 older adults including 111 individuals with AD, 58 without AD, 383 with mild cognitive impairment (MCI), 410 with CVD and 156 without CVD from the Alzheimer’s Disease Neuroimaging Initiative (ADNI). The multivariable linear mixed model (LMM) was used to investigate the associations of AD and CVD on longitudinal changes of 146 proteomic biomarkers (measured at baseline and 12-month follow-up), while adjusted for age, gender, education, racial groups, and APOE-ε4 alleles. The LMM showed that AD and CVD were associated with longitudinal changes in 48 and 46 proteomic biomarkers, respectively (p&amp;lt; 0.05). Interestingly, both AD and CVD were associated with longitudinal changes in 14 proteomic biomarkers (A1Micro, ApoH, B2M, BNP, Complement C3, Cystatin C, KIM1, NGAL, PPP, TIM1, THP, TFF3, TM, and VEGF). Furthermore, the single biggest risk gene for sporadic AD, APOE-ε4 was associated with 22 proteomic biomarkers. Moreover, MCI and CVD were associated with 13 proteomic biomarkers (A1Micro, ApoD, AXL, BNP, Calcitonin, CD40, C-peptide, pM, PPP, THP, TNFR2, TTR, and VEGF), while MCI, CVD and APOE-ε4 were associated with four proteomic biomarkers (A1Micro, Calcitonin, THP, and TNFR2). This study provides valuable insights into the shared and distinct pathophysiological mechanisms at play, offering a stepping-stone towards a deeper comprehension of the interrelationship between AD and CVDs.

Maternal Pre-Pregnancy BMI, Breastfeeding, and Child BMI.

Breastfeeding practices may protect against offspring obesity, but this relationship is understudied among women with obesity. We describe the associations between breastfeeding practices and child BMI for age z-score (BMIz), stratified by maternal BMI. We analyzed 8134 dyads from 21 cohorts in the Environmental Influences on Child Health Outcomes Program. Dyads with data for maternal pre-pregnancy BMI, infant feeding practices, and ≥1 child BMI assessment between the ages of 2 and 6 years were included. The associations between breastfeeding practices and continuous child BMIz were assessed by using multivariable linear mixed models. Maternal pre-pregnancy BMI category prevalence was underweight: 2.5%, healthy weight: 45.8%, overweight: 26.0%, and obese: 25.6%. Median child ages at the cessation of any breastfeeding and exclusive breastfeeding across the 4 BMI categories were 19, 26, 24, and 17 weeks and 12, 20, 17, and 12 weeks, respectively. Results were in the hypothesized directions for BMI categories. Three months of any breastfeeding was associated with a lower BMIz among children whose mothers were a healthy weight (-0.02 [-0.04 to 0.001], P = .06), overweight (-0.04 [-0.07 to -0.004], P = .03), or obese (-0.04 [-0.07 to -0.006], P = .02). Three months of exclusive breastfeeding was associated with a lower BMIz among children whose mothers were a healthy weight (-0.06 [-0.10 to -0.02], P = .002), overweight (-0.05 [-0.10 to 0.005], P = .07), or obese (-0.08 [-0.12 to -0.03], P = .001). Human milk exposure, regardless of maternal BMI category, was associated with a lower child BMIz in the Environmental Influences on Child Health Outcomes cohorts, supporting breastfeeding recommendations as a potential strategy for decreasing the risk of offspring obesity.

A hydrogen isoscape for tracing the migration of herbivorous lepidopterans across the Afro-Palearctic range.

Many insect species undertake multigenerational migrations in the Afro-tropical and Palearctic ranges, and understanding their migratory connectivity remains challenging due to their small size, short life span and large population sizes. Hydrogen isotopes (δ2 H) can be used to reconstruct the movement of dispersing or migrating insects, but applying δ2 H for provenance requires a robust isotope baseline map (i.e. isoscape) for the Afro-Palearctic. We analyzed the δ2 H in the wings (δ2 Hwing ) of 142 resident butterflies from 56 sites across the Afro-Palearctic. The δ2 Hwing values were compared to the predicted local growing-season precipitation δ2 H values (δ2 HGSP ) using a linear regression model to develop an insect wing δ2 H isoscape. We used multivariate linear mixed models and high-resolution and time-specific remote sensing climate and environmental data to explore the controls of the residual δ2 Hwing variability. A strong linear relationship was found between δ2 Hwing and δ2 HGSP values (r2 = 0.53). The resulting isoscape showed strong patterns across the Palearctic but limited variation and high uncertainty for the Afro-tropics. Positive residuals of this relationship were correlated with dry conditions for the month preceding sampling whereas negative residuals were correlated with more wet days for the month preceding sampling. High intra-site δ2 Hwing variance was associated with lower relative humidity for the month preceding sampling and higher elevation. The δ2 Hwing isoscape is applicable for tracing herbivorous lepidopteran insects that migrate across the Afro-Palearctic range but has limited geolocation potential in the Afro-tropics. The spatial analysis of uncertainty using high-resolution climatic data demonstrated that many African regions with highly variable evaporation rates and relative humidity have δ2 Hwing values that are less related to δ2 HGSP values. Increasing geolocation precision will require new modeling approaches using more time-specific environmental data and/or independent geolocation tools.

Daily Physical Activity Measured by Wearable Smartwatch for Patients Undergoing Transcatheter Aortic Valve Replacement: Insights From the SMART TAVR Study.

This study aims to evaluate limited data about daily physical activity patterns, influential factors, and their association with 1-year mortality or rehospitalization after transcatheter aortic valve replacement (TAVR) through smartwatches. Consecutive severe aortic stenosis patients undergoing elective transfemoral TAVR in a Chinese tertiary hospital were enrolled from July 2021 to May 2022 and received a Huawei smartwatch at least 1 day before TAVR. The primary outcome was a composite of all-cause mortality or hospital readmission within 1 year. Linear mixed-effects models were applied to determine influential factors of daily step counts, and Cox proportional hazard regression models were to estimate the association between baseline step counts within 1 month since discharge and composite outcome from months 2 to 12. The dose-response association was assessed using restricted cubic spline curves. A total of 222 participants and 59 469 valid monitoring person-day records were included (mean age, 72.7 years; 61% women). Step counts increased rapidly within the first 2 months (P<0.001), followed by a slower increase for those without composite outcomes (P=0.029) and a gradual decrease for those who developed composite outcomes (P<0.001). In multivariate linear mixed models, a 1-m increase in baseline 6-minute walk test and a 1-month delay after discharge were associated with 4 (95% CI, 1-7) and 170 (95% CI, 145-194) additional step counts, respectively. In restricted cubic spline analysis, the hazard ratio declined progressively until ≈5000 steps per day, after which they leveled. Below 5000 steps, the adjusted hazard ratio of composite outcome associated with each 1000-step count increase was 0.67 (0.50-0.89; P=0.007). However, above 5000 steps, step counts were not significantly associated with the composite outcome (P=0.645), with a hazard ratio of 1.12 (0.70-1.79). Daily step counts rapidly increased within the first 2 months post-TAVR. Increased physical activity was associated with a lower risk of 1-year mortality or rehospitalization after TAVR for patients with daily step counts below 5000. URL: https://www.clinicaltrials.gov; Unique identifier: NCT04454177.

Indoor particulate matter concentrations and air cleaner intervention association with biomarkers in former smokers with COPD

BackgroundIndoor pollutants have been associated with worse clinical outcomes in chronic obstructive pulmonary disease (COPD). Elevated biomarkers are associated with ambient pollution exposure, however the association with indoor pollution remains unclear. MethodsFormer smokers with spirometry-confirmed COPD were randomized to portable air cleaner or placebo. Indoor particulate matter (PM2.5, PM10, and ultrafine particles [UFP; PM<0.1]) and biomarkers were measured longitudinally at pre-specified intervals and course PM fraction (PM10-2.5) was calculated. Biomarkers were categorized based on associations with biologic mechanisms: inflammation (white blood cell count, interleukin [IL]-6, IL-8, IL-1β, tumor necrosis factor-α, interferon-γ, serum amyloid A), platelet activation (P-selectin, CD40 ligand [CD40L], 11-dehdydro-thromboxane-B2 [11dTxB2]), endothelial dysfunction (Vascular Cell Adhesion Molecule [VCAM]-1, Intercellular Adhesion Molecule [ICAM]-1), and oxidative stress (thiobarbituric acid reactive substances [TBARS], 8-hydroxydeoxyguanosine, 8-isoprostane). Associations between PM concentrations and each biomarker were analyzed using multivariable linear mixed models. An intention-to-treat analysis was performed to evaluate the air cleaner intervention on the biomarker levels longitudinally. ResultsFifty-eight participants were randomized to each group. Finer PM was more strongly associated with higher IL-8 (mean difference per doubling: UFP 13.9% [p = 0.02], PM2.5 6.8% [p = 0.002], PM10-2.5 5.0% [p = 0.02]) while interferon-γ was associated with UFP and IL-1β with PM10-2.5. UFP and PM2.5 were associated with elevated levels of the oxidative stress biomarkers TBARS and 8-isoprostane respectively. For platelet activation markers, UFP was associated with higher 11dTxB2 while PM2.5 was associated with higher P-selectin and CD40L. Pollutants were not associated with biomarkers of endothelial dysfunction. In intention-to-treat analysis there was no association of the air cleaner intervention with any of the biomarkers. DiscussionAmong former smokers with COPD, elevated levels of indoor air pollutants, particularly ultrafine particles (PM<0.1), were associated with elevated biomarkers of inflammation, platelet activation, and oxidative stress. However, an air cleaner intervention that reduced PM did not significantly reduce biomarker levels.

Racial differences in the effect of APOE‐ε4 genotypes on trail making test B in Alzheimer's disease: A longitudinal study

AbstractObjectivesThe trail making test part B (TMT‐B) evaluates executive functions, memory, and sensorimotor functions. No previous study was found to examine the longitudinal effect of APOE‐ε4 genotypes on the TMT‐B scores in Alzheimer's disease (AD) across racial groups.MethodsThis study used the data from Alzheimer's Disease Neuroimaging Initiative (ADNI): 382 participants with AD, 503 with cognitive normal (CN), 1293 with mild cognitive impairment (MCI) at baseline and follow‐up of four years. The multivariable linear mixed model was used to investigate the effect of APOE‐ε4 genotypes on changes in TMT‐B scores.ResultsCompared with Whites, African Americans (AA) and Hispanics had higher TMT‐B scores (poor cognitive function). Furthermore, Whites subjects with 1 or 2 APOE‐ε4 alleles had significantly higher TMT‐B scores compared with individuals without APOE‐ε4 allele at baseline and four follow‐up visits; however, no differences in TMT‐B were found between APOE‐ε4 alleles in the Hispanic and AA groups. No APOE‐ε4 by visit interactions was found for 3 racial groups. Stratified by AD diagnosis, the APOE‐ε4 allele was associated with TMT‐B scores only in the MCI group, while there were significant interactions for visit by education, APOE‐ε4 allele, and the Mini Mental State Examination (MMSE) score in the MCI group. In addition, TMT‐B was significantly correlated with the MMSE, AD Assessment Scale‐cognitive subscale 13 (ADAS13), tTau, pTau, Aβ42, and hippocampus.ConclusionsAPOE‐ɛ4 allele is associated with TMT‐B scores in Whites subjects, but not in the Hispanic and AA groups. APOE‐ε4 showed interaction with visit in the MCI group.

Apathy and dysfunction in Lewy Body Disease

AbstractBackgroundStudies in Alzheimer’s disease and frontal temporal lobe dementia have shown high prevalence and persistence of apathy at different disease stages and its strong association with functional decline. Here we use well‐established methods to examine the relationship between apathy and function in a cohort of well‐characterized patients with Lewy Body Disease (LBD) who had regular assessments over time.MethodSample includes participants in the National Alzheimer’s Coordinating Center Uniform Data Set (NACC‐UDS, 9/2005‐12/2019) who had at baseline (1) cognitive status of mild cognitive impairment (MCI) or dementia, (2) presumed etiologic diagnosis of LBD, and (3) ≥1 follow‐up. Baseline diagnosis of Parkinson’s disease (PD) was assessed. Apathy was identified using clinician judgment. Participants’ function was measured using the Functional Assessment Questionnaire (FAQ). Multivariable linear mixed model (LMM) was used to estimate relationships between apathy, cognitive status (baseline MCI vs dementia), and function over time.ResultThe sample included 339 participants with MCI and 748 with dementia. Average age = 72.7±8.3, 74% male, 86% non‐Hispanic white, 15.4±3.4 years of education, baseline MMSE = 23.7±5.8, with 3.4±1.7 years of follow‐up. Proportion of participants who reported difficulty with function at baseline ranged according to task complexity from 48% (Heating water, making a cup of coffee, turning off stove after use) to 85% (Assembling tax records, business affairs, or papers); with total FAQ = 13.0±9.1. Presence of apathy increased from 52% at baseline to 60% at visit 4. Across all follow‐ups, 24% of the participants were never apathetic, 13.7% had apathy intermittently (&lt;50% of all visits), 28.3% persistently (≥50% of all visits), and 34.0% were apathetic at all visits. LMM estimation results showed that, compared to participants who were never apathetic, FAQ was 3.8±0.8 points higher, i.e., greater dysfunction, at baseline in participants who were always apathetic, and 3.3±0.7 points higher in those who had intermittent/persistent apathy (both p&lt;0.001). Rate of functional decline was 0.41±0.3 points faster each year in those always apathetic compared to never apathetic (p&lt;0.1).ConclusionApathy is highly prevalent in individuals with LBD. Independent of cognitive status, more persistent apathy was strongly associated with worse function.

Association between severity of the cervical foraminal stenosis and paraspinal muscle parameters in patients undergoing anterior cervical discectomy and fusion.

The cervical multifidus and rotatores muscles are innervated by the posterior rami of the spinal nerves of the corresponding level, and it has been hypothesized that cervical foraminal stenosis (CFS) affecting the spinal nerves results in changes in these muscles. The purpose of this study was to evaluate the relationship between the severity of CFS and fat infiltration (FI) of the multifidus and rotatores muscles. Patients who received preoperative cervical MRI, underwent anterior cervical decompression and fusion between 2015 and 2018, and met inclusion and exclusion criteria were included. Multifidus and rotatores muscles were segmented bilaterally from C3 to C7, and the percent FI was measured using custom-written MATLAB software. The severity of the CFS was assessed by the Kim classification. Multivariable linear mixed models were conducted and adjusted for age, sex, BMI, and repeated measures. In total, 149 patients were included. Linear mixed modeling results showed that a more severe CFS at C3-4 was correlated with a greater FI of the multifidus and rotatores muscles at C4 (estimate 0.034, 95% CI 0.003-0.064; p = 0.031), a more severe CFS at C4-5 was correlated with a greater FI of the multifidus and rotatores muscles at C5 (estimate 0.037, 95% CI 0.015-0.057; p < 0.001), a more severe CFS at C5-6 was correlated with a greater FI of the multifidus and rotatores muscles at C6 (estimate 0.041, 95% CI 0.019-0.062; p < 0.001) and C7 (estimate 0.035, 95% CI 0.012-0.058; p = 0.003), and a more severe CFS at C6-7 was correlated with a greater FI of the multifidus and rotatores muscles at C7 (estimate 0.049, 95% CI 0.027-0.071; p < 0.001). These results demonstrated level- and side-specific correlations between the FI of the multifidus and rotatores muscles and severity of CFS. Given the segmental innervation of the multifidus and rotatores muscles, the authors hypothesize that the observed increased FI could be reflective of changes due to muscle denervation from CFS.

Sex differences in COVID-19 symptom severity and trajectories among ambulatory adults.

The ongoing COVID-19 pandemic has led to hundreds of millions of infections worldwide. Although differences in COVID-19 hospitalization rates between males and females have been described, many infections in the general population have been mild, and the severity of symptoms during the course of COVID-19 in non-hospitalized males and females is not well understood. We conducted a case-ascertained study to examine household transmission of SARS-CoV-2 infections in Nashville, Tennessee, between April 2020 and April 2021. Among enrolled ambulatory adult participants with laboratory-confirmed SARS-CoV-2 infections, we assessed the presence and severity of symptoms (total, systemic, and respiratory) daily using a symptoms severity questionnaire, from illness onset and throughout the 2-week follow-up period. We compared the mean daily symptom severity scores (0-3: none, mild, moderate, and severe) and change in symptoms between males and females using a multivariable linear mixed effects regression model. The analysis included 223 enrolled adults with SARS-CoV-2 infection (58% females, mostly white, non-Hispanic) from 146 households with 2917 total daily symptom reports. The overall mean severity of total symptoms reported over the illness period was 1.04 and 0.90 for females and males, respectively. Mean systemic and respiratory scores were higher for females than for males (p< 0.001). In multivariable analyses, females reported more severe total and systemic symptoms during the illness period compared with males. However, no significant differences in reported respiratory symptoms were observed. Our findings indicate that among ambulatory adults with SARS-CoV-2 infections, females reported slightly higher symptom severity during their illness compared with males.