Targeted DNA-seq and RNA-seq of Reference Samples with Short-read and Long-read Sequencing.

Next-generation sequencing (NGS) has revolutionized genomic research by enabling high-throughput, cost-effective genome and transcriptome sequencing accelerating personalized medicine for complex diseases, including cancer. Whole genome/transcriptome sequencing (WGS/WTS) provides comprehensive insights, while targeted sequencing is more cost-effective and sensitive. In comparison to short-read sequencing, which still dominates the field due to high speed and cost-effectiveness, long-read sequencing can overcome alignment limitations and better discriminate similar sequences from alternative transcripts or repetitive regions. Hybrid sequencing combines the best strengths of different technologies for a more comprehensive view of genomic/transcriptomic variations. Understanding each technology's strengths and limitations is critical for translating cutting-edge technologies into clinical applications. In this study, we sequenced DNA and RNA libraries of reference samples using various targeted DNA and RNA panels and the whole transcriptome on both short-read and long-read platforms. This study design enables a comprehensive analysis of sequencing technologies, targeting protocols, and library preparation methods. Our expanded profiling landscape establishes a reference point for assessing current sequencing technologies, facilitating informed decision-making in genomic research and precision medicine.

Comparison of Outcomes with the Use of Different Heat-Activated Crimping Prostheses in Stapedotomy.

OBJECTIVE: To determine differences in failure rate and hearing outcomes of a completely encircling heat-activated crimping prosthesis (SMart 360°) compared to partially encircling prosthesis (SMart). STUDY DESIGN: Retrospective chart review. SETTING: Private neurotology tertiary referral center. PATIENTS: Patients who underwent stapedotomies performed by the senior authors from 2008 to 2019 using the SMart prosthesis and SMart 360° prothesis. INTERVENTIONS: Stapedotomy operations with placement of a SMart or SMart 360° prosthesis. MAIN OUTCOME MEASURES: Incidence of early failure requiring revision surgery. Differences in preoperative air-bone gap (ABG) compared to postoperative ABG at 3 months, 1 year, and 2 years after surgery. RESULTS: A total of 228 stapedotomies were performed (SMart n = 48 and SMart 360° n = 180). Mean preoperative ABG for SMart and SMart 360° were 26.15 and 29 dB, respectively. The mean difference in ABG for the SMart at 3 months, 1 year, and 2 years were 17, 18, and 11 dB, respectively. The mean difference in ABG for the SMart 360° at 3 months, 1 year, and 2 years were 20, 20, and 19 dB. ABG differences at 3 months (p = 0.10) and 1 year (p = 0.36) were not statistically different. The failure rate for the SMart prosthesis was 12.5% and for the SMart 360° 2.2% (p = 0.002). CONCLUSIONS: There were no statistically significant differences in ABG changes for SMart compared to SMart 360°. The Smart 360 corrects the problem with early failure seen with the Smart prosthesis. PROFESSIONAL PRACTICE GAP AND EDUCATIONAL NEED: Determination of most efficacious stapes prosthesis. LEARNING OBJECTIVE: Which stapes prosthesis produces better hearing results with fewer failures. DESIRED RESULT: To disseminate information necessary to choose the best stapes prosthesis for patients. LEVEL OF EVIDENCE: Level III. INDICATE IRB OR IACUC: 2022-029-agh.

Metabolism of 2,4-D in plants: comparative analysis of metabolic detoxification pathways in tolerant crops and resistant weeds.

The commercialization of 2,4-D (2,4-dichlorophenoxyacetic acid) latifolicide in 1945 marked the beginning of the selective herbicide market, with this active ingredient playing a pivotal role among commercial herbicides due to the natural tolerance of monocots compared with dicots. Due to its intricate mode of action, involving interactions within endogenous auxin signaling networks, 2,4-D was initially considered a low-risk herbicide to evolve weed resistance. However, the intensification of 2,4-D use has contributed to the emergence of 2,4-D-resistant broadleaf weeds, challenging earlier beliefs. This review explores 2,4-D tolerance in crops and evolved resistance in weeds, emphasizing an in-depth understanding of 2,4-D metabolic detoxification. Nine confirmed 2,4-D-resistant weed species, driven by rapid metabolism, highlight cytochrome P450 monooxygenases in Phase I and glycosyltransferases in Phase II as key enzymes. Resistance to 2,4-D may also involve impaired translocation associated with mutations in auxin/indole-3-acetic acid (Aux/IAA) co-receptor genes. Moreover, temperature variations affect 2,4-D efficacy, with high temperatures increasing herbicide metabolism rates and reducing weed control, while drought stress did not affect 2,4-D efficacy. Research on 2,4-D resistance has primarily focused on non-target-site resistance (NTSR) mechanisms, including 2,4-D metabolic detoxification, with limited exploration of the inheritance and genetic basis underlying these traits. Resistance to 2,4-D in weeds is typically governed by a single gene, either dominant or incompletely dominant, raising questions about gain-of-function or loss-of-function mutations that confer resistance. Future research should unravel the physiological and molecular-genetic basis of 2,4-D NTSR, exploring potential cross-resistance patterns and assessing fitness costs that may affect future evolution of auxin-resistant weeds. © 2024 Society of Chemical Industry.

Post-exercise metabolic response to kettlebell complexes vs. high intensity functional training.

PURPOSE: This study compared the magnitude of excess post-exercise oxygen consumption (EPOC) between kettlebell complexes (KC) and high-intensity functional training (HIFT) and identified predictors of the EPOC response. METHODS: Active men (n = 11) and women (n = 10) (age 25 ± 6 yr) initially completed testing of resting energy expenditure and maximal oxygen uptake (VO2max), followed by lower and upper-body muscle endurance testing. On two subsequent days separated by ≥ 48 h, participants completed KC requiring 6 sets of kettlebell exercises (pushups, deadlifts, goblet squats, rows, and swings) with 60 s recovery between sets, and HIFT requiring 6 sets of bodyweight exercises (mountain climbers, jump squats, pushups, and air squats) with 60 s recovery. During exercise, gas exchange data and blood lactate concentration (BLa) were acquired and post-exercise, EPOC was assessed for 60 min. RESULTS: Results showed no difference in EPOC (10.7 ± 4.5 vs. 11.6 ± 2.7 L, p = 0.37), and VO2 and ventilation (VE) were significantly elevated for 30 and 60 min post-exercise in response to KC and HIFT. For KC and HIFT, HRmean and post-exercise BLa (R2 = 0.37) and post-exercise BLa and VE (R2 = 0.52) explained the greatest shared variance of EPOC. CONCLUSION: KC and HIFT elicit similar EPOC and elevation in VO2 which is sustained for 30-60 min post-exercise, leading to 55 extra calories expended. Results show no association between aerobic fitness and EPOC, although significant associations were revealed for mean HR as well as post-exercise VE and BLa.

External validation of two clinical prediction models for pediatric pneumonia.

OBJECTIVE: To externally validate two prediction models for pediatric radiographic pneumonia. METHODS: We prospectively evaluated the performance of two prediction models (Pneumonia Risk Score [PRS] and CARPE DIEM models) from a prospective convenience sample of children 90 days - 18 years of age from a pediatric emergency department undergoing chest radiography for suspected pneumonia between January 1, 2022, to December 31st, 2023. We evaluated model performance using the original intercepts and coefficients and evaluated for performance changes when performing recalibration and re-estimation procedures. RESULTS: We included 202 patients (median age 3 years, IQR 1-6 years), of whom radiographic pneumonia was found in 92 (41.0%). The PRS model had an area under the receiver operator characteristic curve of 0.72 (95% confidence interval [CI] 0.64-0.79), which was higher than the CARPE DIEM (0.59; 95% CI 0.51-0.67) (P<0.01). Using optimal cutpoints, the PRS model showed higher sensitivity (65.2%, 95% CI 54.6-74.9) and specificity (72.7%, 95% CI 63.4-80.8) compared to the CARPE DIEM model (sensitivity 56.5 [95% CI 45.8-66.8]; specificity 60.9 [95% CI 50.2-69.2]). Recalibration and re-estimation of models improved performance, particularly for the CARPE DIEM model, with gains in sensitivity and specificity, and improved calibration. CONCLUSION: The PRS model demonstrated better performance than the CARPE DIEM model in predicting radiographic pneumonia. Among children with a high rate of pneumonia, these models did not reach a level of performance sufficient to be used independently of clinical judgement. These findings highlight the need for further validation and improvement of models to enhance their utility.

Adherence patterns 1 year after initiation of SGLT2 inhibitors: results of a national cohort study.

OBJECTIVES: Adherence to medications is important for the management of chronic diseases. Although the proportion of days covered (PDC) is a common metric for measuring adherence, it may be insufficient to distinguish relevant differences in medication-taking behavior. Group-based trajectory models (GBTMs) have been used to better represent adherence over time. This study aims to examine adherence patterns 1 year after initiation among users of sodium-glucose cotransporter 2 (SGLT2) inhibitors using GBTMs and evaluate the ability of baseline characteristics to predict adherence trajectory. STUDY DESIGN: SGLT2 inhibitor new-user cohort study from 2014 to 2018. METHODS: We calculated 12-month PDC and categorized patients with PDC of 80% or greater as adherent. We performed multivariable logistic regression on adherence status controlling for baseline covariates. GBTMs were fit to identify adherence patterns 12 months following SGLT2 inhibitor initiation. Five multinomial logistic regression models including different subsets of predictors were used to predict adherence trajectory group assignment. RESULTS: In a cohort of 228,363 SGLT2 inhibitor users, the mean PDC was 57%, with 36% of the cohort being adherent. Overall, women and patients with anxiety or depression were less likely to be adherent. Six patterns of SGLT2 inhibitor adherence were identified with GBTMs: 1 fill (PDC = 0.08), early discontinuation (PDC = 0.22), consistently low adherence (PDC = 0.35), moderate adherence (PDC = 0.48), high adherence (PDC = 0.79), and near-perfect adherence (PDC = 0.95). All prediction models showed poor predictive accuracy (0.35). CONCLUSIONS: We found wide variation in adherence patterns among SGLT2 inhibitor users in a national cohort. Predictors from a health care claims database were unable to accurately predict adherence trajectory.

Chronic Toxicity of Per- and Polyfluoroalkyl Substance-Free Firefighting Foams to Aquatic Organisms.

Amid global concern regarding the health and environmental impacts of per- and polyfluoroalkyl substances (PFAS), there is an urgent need to develop and implement alternative products without PFAS. Consequently, PFAS-free firefighting foams used for fire suppression have been developed for use in military and residential settings. To facilitate the selection of lower-risk PFAS-free foams, the present study focused on the chronic toxicity of seven PFAS-free and one PFAS-containing foam to six aquatic species. Target species included two cladocerans, Daphnia magna and Ceriodaphnia dubia; the chironomid Chironomus dilutus; the mysid Americamysis bahia; and two fish species, Pimephales promelas and Cyprinodon variegatus, with endpoints including growth, development, reproduction, and survival. To facilitate comparison and product toxicity rankings, effective concentrations (20%, 50%) and no- and lowest-observed-effect concentrations (NOECs and LOECs, respectively) were calculated. Effective concentrations, NOECs, and LOECs varied by over an order of magnitude among foams and species, with several of the PFAS-free formulations ranked as highly toxic based on US Environmental Protection Agency alternatives assessment hazard criteria. Overall, the PFAS-free foams were found to exhibit either similar or greater toxicity compared to the PFAS-containing reference foam across several species and endpoints. Nonmonotonic and hormetic dose responses were observed in D. magna for several of the tested foams, with increased reproduction and growth at intermediate exposures. Generally, tested foam toxicity rankings were consistent with a related acute toxicity study using the same species and formulations, and other research using soil invertebrates. Combined with related efforts for other taxa including mammals, birds, and plants, the present research will facilitate the selection of appropriate PFAS-free firefighting foams that minimize harm to the environment. Environ Toxicol Chem 2024;00:1-19. © 2024 SETAC.

Microscopic Particle Image Velocimetry Analysis of Multiphase Flow in a Porous Media Micromodel.

Pore-scale oil displacement behavior was investigated in a porous media micromodel using microscopic particle image velocimetry (µPIV). Porous media micromodels consisting of an ordered square array of cylindrical pillars with 50 and 70% porosities were fabricated with photolithography. The oil displacement was performed with the injection of water at flow rates of 37.5, 75, and 150 µL/h. These flow rates correspond to Reynolds number of 1.1 × 10-2, 2.2 × 10-2, and 4.4 × 10-2, respectively in the 50% porous channel, and 1.84 × 10-3, 3.69 × 10-3, and 7.38 × 10-3, respectively in the 70% porous channel. The capillary numbers for these flow rates are 2.18 × 10-5, 4.36 × 10-5, and 8.72 × 10-5, respectively in the 50% porous channel, and 1.56 × 10-5, 3.12 × 10-5, and 6.23 × 10-5, respectively in the 70% porous channel. The micromodel is initially saturated with oil, with the invading water phase following the path of least resistance as it displaces the oil. The µPIV data were used to construct probability density functions (PDFs) which show an initial, nonzero, peak in transverse velocity as the water enters the micromodel. The PDFs broaden with time, indicating that the water is spreading, before retracting to a peak velocity of 0 mm/s, indicating that the water displacement has achieved equilibrium. We developed a model based on conservation of mass to describe the efficiency of the displacement process. All flow conditions demonstrate peak displacement efficiency when the amount of oil phase displacement is ∼9 pore volumes in 50% porous channel and ∼4 pore volumes in 70% porous channel.

Association of Serum Biochemical Biomarker Profiles of Joint Tissue Inflammation and Cartilage Metabolism With Posttraumatic Osteoarthritis-Related Symptoms at 12 Months After ACLR.

BACKGROUND: Anterior cruciate ligament injury and anterior cruciate ligament reconstruction (ACLR) are risk factors for symptomatic posttraumatic osteoarthritis (PTOA). After ACLR, individuals demonstrate altered joint tissue metabolism indicative of increased inflammation and cartilage breakdown. Serum biomarker changes have been associated with tibiofemoral cartilage composition indicative of worse knee joint health but not with PTOA-related symptoms. PURPOSE/HYPOTHESIS: The purpose of this study was to determine associations between changes in serum biomarker profiles from the preoperative sample collection to 6 months after ACLR and clinically relevant knee PTOA symptoms at 12 months after ACLR. It was hypothesized that increases in biomarkers of inflammation, cartilage metabolism, and cartilage degradation would be associated with clinically relevant PTOA symptoms after ACLR. STUDY DESIGN: Case-control study; Level of evidence, 3. METHODS: Individuals undergoing primary ACLR were included (N = 30). Serum samples collected preoperatively and 6 months after ACLR were processed to measure markers indicative of changes in inflammation (ie, monocyte chemoattract protein 1 [MCP-1]) and cartilage breakdown (ie, cartilage oligomeric matrix protein [COMP], matrix metalloproteinase 3, ratio of type II collagen breakdown to type II collagen synthesis). Knee injury and Osteoarthritis Outcome Score surveys were completed at 12 months after ACLR and used to identify participants with and without clinically relevant PTOA-related symptoms. K-means cluster analyses were used to determine serum biomarker profiles. One-way analyses of variance and logistic regressions were used to assess differences in Knee injury and Osteoarthritis Outcome Score subscale scores and clinically relevant PTOA-related symptoms between biomarker profiles. RESULTS: Two profiles were identified and characterized based on decreases (profile 1: 67% female; age, 21.4 ± 5.1 years; body mass index, 24.4 ± 2.4) and increases (profile 2: 33% female; age, 21.3 ± 3.2 years; body mass index, 23.4 ± 2.6) in sMCP-1 and sCOMP preoperatively to 6 months after ACLR. Participants with profile 2 did not demonstrate differences in knee pain, symptoms, activities of daily living, sports function, or quality of life at 12 months after ACLR compared to those with profile 1 (P = .56-.81; η2 = 0.002-0.012). No statistically significant associations were noted between biomarker profiles and clinically relevant PTOA-related symptoms (odds ratio, 1.30; 95% CI, 0.23-6.33). CONCLUSION: Serum biomarker changes in MCP-1 and sCOMP within the first 6 months after ACLR were not associated with clinically relevant PTOA-related symptoms.

Lipid droplet-associated hydrolase mobilizes stores of liver X receptor sterol ligands and protects against atherosclerosis.

Foam cells in atheroma are engorged with lipid droplets (LDs) that contain esters of regulatory lipids whose metabolism remains poorly understood. LD-associated hydrolase (LDAH) has a lipase structure and high affinity for LDs of foam cells. Using knockout and transgenic mice of both sexes, here we show that LDAH inhibits atherosclerosis development and promotes stable lesion architectures. Broad and targeted lipidomic analyzes of primary macrophages and comparative lipid profiling of atheroma identified a broad impact of LDAH on esterified sterols, including natural liver X receptor (LXR) sterol ligands. Transcriptomic analyzes coupled with rescue experiments show that LDAH modulates the expression of prototypical LXR targets and leads macrophages to a less inflammatory phenotype with a profibrotic gene signature. These studies underscore the role of LDs as reservoirs and metabolic hubs of bioactive lipids, and suggest that LDAH favorably modulates macrophage activation and protects against atherosclerosis via lipolytic mobilization of regulatory sterols.

Headache-related disability as a function of migraine aura: A daily diary study.

OBJECTIVE: To examine the unique role of migraine aura in predicting day-to-day levels of headache-related disability. BACKGROUND: Migraine symptoms and psychological variables contribute to headache-related disability. Migraine aura may be associated with more severe symptom profiles and increased risk of psychiatric comorbidities, but the impact of aura on daily functioning is unknown. The present study sought to evaluate the role of migraine aura in predicting same-day and subsequent-day migraine-related disability while accounting for demographic, headache, and psychological variables. METHODS: This was an observational prospective cohort study among 554 adults with migraine. For each participant, data on migraine symptoms and psychological variables were collected daily for 90 days using the N-1 Headache™ digital app (N = 11,156 total migraine days). Analyses assessed whether the presence of aura predicted daily ratings of migraine-related disability independently of other headache and psychological variables. Given the number of predictors examined, statistical significance was set at p < 0.01. RESULTS: The mean (standard deviation, range) patient-level Migraine Disability Assessment questionnaire score across days of the migraine episode was 1.18 (1.03, 0-3). Aura was significantly associated with higher disability ratings on all days of the migraine episode (odds ratio [OR] 1.40, 99% confidence interval [CI] 1.13-1.74; p < 0.001). This relationship remained unchanged after adjusting for patient-level variables (OR 1.40, 99% CI 1.13-1.73; p < 0.001) and day-level psychological variables (OR 1.39, 99% CI 1.12-1.73; p < 0.001) but was fully negated after controlling for day-level headache variables (OR 1.19, 99% CI 0.95-1.49; p = 0.039). Aura on the first day of the episode was associated with increased odds of allodynia (OR 1.87, 99% CI 1.22-2.86; p < 0.001), phonophobia (OR 1.62, 99% CI 1.17-2.25; p < 0.001), photophobia (OR 1.89, 99% CI 1.37-2.59; p < 0.001), and nausea/vomiting (OR 1.54, 99% CI 1.17-2.02; p < 0.001) on all days of the episode, but not episode duration (p = 0.171), peak severity (p = 0.098), or any examined psychological variables (sleep duration [p = 0.733], sleep quality [p = 0.186], stress [p = 0.110], anxiety [p = 0.102], or sadness [p = 0.743]). CONCLUSION: The presence of aura is predictive of increased headache-related disability during migraine episodes, but this effect is attributable to associated non-pain symptoms of migraine.

Population-Based Estimates of the Prevalence of Children With Congenital Heart Disease and Associated Comorbidities in the United States.

BACKGROUND: Congenital heart defects (CHD) are the most common birth defects and previous estimates report the disease affects 1% of births annually in the United States. To date, CHD prevalence estimates are inconsistent due to varied definitions, data reliant on birth registries, and are geographically limited. These data sources may not be representative of the total prevalence of the CHD population. It is therefore important to derive high-quality, population-based estimates of the prevalence of CHD to help care for this vulnerable population. METHODS: We performed a descriptive, retrospective 8-year analysis using all-payer claims data from Colorado from 2012 to 2019. Children with CHD were identified by applying International Classification of Diseases-Ninth Revision (ICD-9) and International Classification of Diseases-Tenth Revision (ICD-10) diagnosis codes from the American Heart Association-American College of Cardiology harmonized cardiac codes. We included children with CHD <18 years of age who resided in Colorado, had a documented zip code, and had at least 1 health care claim. CHD type was categorized as simple, moderate, and severe disease. Association with comorbid conditions and genetic diagnoses were analyzed using χ2 test. We used direct standardization to calculate adjusted prevalence rates, controlling for age, sex, primary insurance provider, and urban-rural residence. RESULTS: We identified 1 566 328 children receiving care in Colorado from 2012 to 2019. Of those, 30 512 children had at least 1 CHD diagnosis, comprising 1.95% (95% CI, 1.93-1.97) of the pediatric population. Over half of the children with CHD also had at least 1 complex chronic condition. After direct standardization, the adjusted prevalence rates show a small increase in simple severity diagnoses across the study period (adjusted rate of 11.5 [2012]-14.4 [2019]; P<0.001). CONCLUSIONS: The current study is the first population-level analysis of pediatric CHD in the United States. Using administrative claims data, our study found a higher CHD prevalence and comorbidity burden compared with previous estimates.

Integrated drug resistance and leukemic stemness gene-expression scores predict outcomes in large cohort of over 3500 AML patients from 10 trials.

In this study, we leveraged machine-learning tools by evaluating expression of genes of pharmacological relevance to standard-AML chemotherapy (ara-C/daunorubicin/etoposide) in a discovery-cohort of pediatric AML patients (N = 163; NCT00136084 ) and defined a 5-gene-drug resistance score (ADE-RS5) that was predictive of outcome (high MRD1 positivity p = 0.013; lower EFS p < 0.0001 and OS p < 0.0001). ADE-RS5 was integrated with a previously defined leukemic-stemness signature (pLSC6) to classify patients into four groups. ADE-RS5, pLSC6 and integrated-score was evaluated for association with outcome in one of the largest assembly of ~3600 AML patients from 10 independent cohorts (1861 pediatric and 1773 adult AML). Patients with high ADE-RS5 had poor outcome in validation cohorts and the previously reported pLSC6 maintained strong significant association in all validation cohorts. For pLSC6/ADE-RS5-integrated-score analysis, using Group-1 (low-scores for ADE-RS5 and pLSC6) as reference, Group-4 (high-scores for ADE-RS5 and pLSC6) showed worst outcome (EFS: p < 0.0001 and OS: p < 0.0001). Groups-2/3 (one high and one low-score) showed intermediate outcome (p < 0.001). Integrated score groups remained an independent predictor of outcome in multivariable-analysis after adjusting for established prognostic factors (EFS: Group 2 vs. 1, HR = 4.68, p < 0.001, Group 3 vs. 1, HR = 3.22, p = 0.01, and Group 4 vs. 1, HR = 7.26, p < 0.001). These results highlight the significant prognostic value of transcriptomics-based scores capturing disease aggressiveness through pLSC6 and drug resistance via ADE-RS5. The pLSC6 stemness score is a significant predictor of outcome and associates with high-risk group features, the ADE-RS5 drug resistance score adds further value, reflecting the clinical utility of simultaneous testing of both for optimizing treatment strategies.

Peak vertical ground reaction force used to identify sub-groups of individuals with differing biomechanical gait profiles post-anterior cruciate ligament reconstruction.

Lesser peak vertical ground reaction force (vGRF) has been widely reported among individuals with anterior cruciate ligament reconstruction (ACLR). Peak vGRF remains less than uninjured controls and relatively stable during the first year following ACLR. However, it is unknown whether there are subgroups of individuals exhibiting consistently greater peak vGRF in the first 6-months following ACLR and if individuals with consistently greater peak vGRF exhibit kinematic and kinetic gait differences compared to individuals with low vGRF. The purpose of this study was to determine if distinct clusters exist based upon magnitude of peak vGRF 2- and 6-months post-ACLR. Subsequently, we explored between cluster differences in vGRF, knee flexion angle, and sagittal and frontal plane knee kinetics throughout stance between clusters. Forty-three individuals (58.1%female, 21.4 ± 4.4 years-old, 95.3% patellar-tendon autograft) completed five gait trials at their habitual walking speed 2- and 6-months post-ACLR. A single K-means cluster analysis was used to identify clusters of individuals based on peak vGRF at 2- and 6-months post-ACLR. Functional waveform analyses were used to compare gait outcomes between clusters with and without controlling for gait speed and age. We identified two clusters that included a subgroup with high vGRF (n = 16) and low vGRF (n = 27). The cluster with high vGRF demonstrated greater vGRFs, knee flexion angles, and knee extension moments during early stance as compared to the low vGRF cluster 2- and 6-months post-ACLR. Individuals with peak vGRF ≥1.02 times body-weight 2-months post-ACLR had 35.4 times greater odds of being assigned to the high vGRF cluster.

Climatic temperature and precipitation jointly influence body size in species of western rattlesnakes.

Both the metabolic theory of ecology and dynamic energy budget theory predict that climate influences body size through its effects on first-order determinants of energetics: reactive temperatures, carbon resources and oxygen availability. Although oxygen is seldom limiting in terrestrial systems, temperature and resources vary spatially. We used redundancy analyses and variation partitioning to evaluate the influence of climatic temperature, precipitation and their seasonalities on multivariate body size across the distributions of four species of the western rattlesnake group in North America (Crotalus pyrrhus, C. scutulatus, C. oreganus and C. viridis). Most species showed a pattern of increased body size in cooler, mesic climates and decreased body size in warmer, xeric climates. Exceptions to the pattern provided additional context through climatic idiosyncrasies in the distributions of each species. For example, the general pattern of a negative influence of temperature on body size was not apparent for C. oreganus, which ranges across the mildest climates overall among the four species. In contrast to previous studies, we found that seasonality had negligible effects on body size. We suggest that precipitation gradients correlate positively with resource availability in driving intraspecific body size and that temperature compounds this gradient by increasing baseline metabolic demands and restricting activity in particularly warm or otherwise extreme climates.

Grace periods and exposure misclassification in self-controlled case-series studies of drug-drug interactions.

The self-controlled case-series (SCCS) research design is increasingly used in pharmacoepidemiologic studies of drug-drug interactions (DDIs), with the target of inference being the incidence rate ratio (IRR) associated with concomitant exposure to the object plus precipitant drug versus the object drug alone. While day-level drug exposure can be inferred from dispensing claims, these inferences may be inaccurate, leading to biased IRRs. Grace periods (periods assuming continued treatment impact after days' supply exhaustion) are frequently used by researchers, but the impact of grace period decisions on bias from exposure misclassification remains unclear. Motivated by an SCCS study examining the potential DDI between clopidogrel (object) and warfarin (precipitant), we investigated bias due to precipitant or object exposure misclassification using simulations. We show that misclassified precipitant treatment always biases the estimated IRR toward the null, whereas misclassified object treatment may lead to bias in either direction or no bias, depending on the scenario. Further, including a grace period for each object dispensing may unintentionally increase the risk of misclassification bias. To minimize such bias, we recommend 1) avoiding the use of grace periods when specifying object drug exposure episodes; and 2) including a washout period following each precipitant exposed period.

Testosterone, cortisol, and psychopathy: Further evidence with the Levenson self-report psychopathy scale and the inventory of callous unemotional traits.

The current study explored associations between testosterone, cortisol, and both the Levenson Self-Report Psychopathy Scale (LSRPS) and the Inventory of Callous Unemotional (ICU) traits. Data were gathered from a relatively large sample of university students (n = 522) and analyses considered direct and interactive associations between hormones and psychopathic traits, as well as interactions between these associations and the time of day at which samples were gathered and the sex of participants. Baseline cortisol had a negative association with LSRPS primary psychopathy scores. In addition, baseline cortisol interacted with the time of day in association with LSRPS total scores. Simple slopes analyses indicated cortisol had a negative association with LSRPS total scores in the morning but not the afternoon. Interactions among hormone measures were not statistically significant. There was also no evidence for the moderation of associations between hormones and psychopathic traits by sex.