Adjustment For Multiple Comparisons Research Articles

Is it more effective or efficient to coach teachers in pairs or individually? A comparison of teacher and student outcomes and coaching costs

A growing body of research documents the positive impacts of teacher coaching, but research contrasting the effectiveness of different coaching approaches is limited. This study contrasted paired coaching – delivered to two teachers simultaneously – with traditional coaching for individual in-service teachers. We examined the effects of these two approaches on observations of teachers' classroom management practices and student behavioral outcomes, relative to non-coached conditions, over the course of a single school year and at a 1-year follow-up. We also explored the relative time and cost efficiency of the two approaches. Two hundred fifty-two teachers from 18 elementary and middle schools participated in the randomized controlled trial. Hierarchical linear modeling was used to account for repeated measures nested within teachers and teachers within schools. Combined effects indicated improved global ratings by observers of teacher behavior management (∆ = 0.29) after a multiple comparison adjustment. Paired coaching was less effective than individual coaching at improving some observed student behaviors, although these did not remain significant after multiple comparison adjustments. Neither model demonstrated sustained effects after one year. Although the paired coaching was significantly more efficient for coach time, it represented just a modest overall cost savings per school. Results indicate a need for more research to identify feasible coaching approaches yielding sustainable effects.

Association of Congenital and Acquired Cardiovascular Conditions With COVID-19 Severity Among Pediatric Patients in the US

Identifying the associations between severe COVID-19 and individual cardiovascular conditions in pediatric patients may inform treatment. To assess the association between previous or preexisting cardiovascular conditions and severity of COVID-19 in pediatric patients. This retrospective cohort study used data from a large, multicenter, electronic health records database in the US. The cohort included patients aged 2 months to 17 years with a laboratory-confirmed diagnosis of COVID-19 or a diagnosis code indicating infection or exposure to SARS-CoV-2 at 85 health systems between March 1, 2020, and January 31, 2021. Diagnoses for 26 cardiovascular conditions between January 1, 2015, and December 31, 2019 (before infection with SARS-CoV-2). The main outcome was severe COVID-19, defined as need for supplemental oxygen or in-hospital death. Mixed-effects, random intercept logistic regression modeling assessed the significance and magnitude of associations between 26 cardiovascular conditions and COVID-19 severity. Multiple comparison adjustment was performed using the Benjamini-Hochberg false discovery rate procedure. The study comprised 171 416 pediatric patients; the median age was 8 years (IQR, 2-14 years), and 50.28% were male. Of these patients, 17 065 (9.96%) had severe COVID-19. The random intercept model showed that the following cardiovascular conditions were associated with severe COVID-19: cardiac arrest (odds ratio [OR], 9.92; 95% CI, 6.93-14.20), cardiogenic shock (OR, 3.07; 95% CI, 1.90-4.96), heart surgery (OR, 3.04; 95% CI, 2.26-4.08), cardiopulmonary disease (OR, 1.91; 95% CI, 1.56-2.34), heart failure (OR, 1.82; 95% CI, 1.46-2.26), hypotension (OR, 1.57; 95% CI, 1.38-1.79), nontraumatic cerebral hemorrhage (OR, 1.54; 95% CI, 1.24-1.91), pericarditis (OR, 1.50; 95% CI, 1.17-1.94), simple biventricular defects (OR, 1.45; 95% CI, 1.29-1.62), venous embolism and thrombosis (OR, 1.39; 95% CI, 1.11-1.73), other hypertensive disorders (OR, 1.34; 95% CI, 1.09-1.63), complex biventricular defects (OR, 1.33; 95% CI, 1.14-1.54), and essential primary hypertension (OR, 1.22; 95% CI, 1.08-1.38). Furthermore, 194 of 258 patients (75.19%) with a history of cardiac arrest were younger than 12 years. The findings suggest that some previous or preexisting cardiovascular conditions are associated with increased severity of COVID-19 among pediatric patients in the US and that morbidity may be increased among individuals children younger than 12 years with previous cardiac arrest.

TLR9 2848 G/A Gene Polymorphism in HCV+, HIV+, and HCV+/HIV+ Individuals.

Background: Host genetic factors play a major role with respect to susceptibility to infections. Many polymorphisms of the Toll-like receptors (TLRs), members of the innate immune response, are directly associated with the clinical outcomes following infection. The 2848 G/A variant (rs352140) of the TLR9 gene is associated with increased TLR9 expression. However, the impact of the genotypes of this SNP on HIV+, HCV+, and HCV+/HIV+ individuals is still debated. Materials and Methods: This study investigated the 2848 G/A polymorphism in HCV infection, HIV infection, and HCV/HIV co-infection in a large sample of Brazilians (n = 1,182). Groups were initially compared without considering stratification by ethnicity and subsequently stratifying individuals between whites and non-whites. Results: Considering non-white individuals, a significant difference between the HIV+/HCV+ group and controls was observed with the GG genotype serving as a protective factor (p = 0.023). Additionally, significant allelic differences were observed between the HCV+ group and controls (p = 0.042); between the HIV+/HCV+ group and controls (p = 0.011); and between the HIV+/HCV+ group and HIV+ individuals (p = 0.047). However, all significant results were lost following adjustment for multiple comparisons (p > 0.05). Conclusion: Although our initial results indicated a potential influence of the rs352140 genotype on host altered susceptibility to viral infections, following correction for multiple comparisions the standard (p < 0.05) for statistical association was lost. This may be due to insufficient sample size as we were examining many different associations. Thus, a larger study is warranted to further pursue this topic.

Marriage checkup in integrated primary care: A randomized controlled trial with active-duty military couples.

This study assessed the efficacy of the marriage checkup, as adapted to integrated primary care settings and active-duty military couples, for improving relationship health and depressive symptoms. Married couples (N = 244, Mage = 32.4, 67.6% Caucasian) in which at least one member was active-duty Air Force were recruited from bases across the U.S. via online advertisement, emails sent from medical clinics to enrolled beneficiaries, social media posts, and flyers, and randomly assigned to active treatment or waitlist control. Treatment and control couples were linked in pairs sequentially and pairs completed nine sets of questionnaires at baseline, 1-, and 6-month posttreatment. Outcome measures included the Couples Satisfaction Index, Intimate Safety Questionnaire, Responsive Attention Scale, Partner Compassion Scale, Communication Skills Test, and the Center for Epidemiologic Studies Depression Scale. A three-level multilevel model indicated, after adjustment for multiple comparisons, treatment couples experienced statistically significant small-to-moderate improvements compared to the control group (Cohen's d from 0.21 to 0.55) at 1 month that were sustained at 6 months for relationship satisfaction, responsive attention, compassion toward their partners, communication skills, intimate safety, and depressive symptoms. A longitudinal randomized control trial of the MC supports the hypothesis that the MC significantly improves relationship satisfaction, intimacy, communication, partner compassion, responsive attention, and depressive symptoms. Implications for theory, treatment, and dissemination are discussed. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Kidney-Metabolic Factors Associated with Cognitive Impairment in Chronic Kidney Disease: A Pilot Study

Introduction: The associations of kidney-metabolic biomarkers with cognitive impairment (CI) beyond the estimated glomerular filtration rate (eGFR, in mL/min/1.73 m²) and albuminuria levels are not well understood. In exploratory analysis, our objective was to determine the extent that three kidney-metabolic factors, previously proposed as mechanisms of CI and commonly abnormal in chronic kidney disease (CKD), were associated with prevalent CI in CKD participants, adjusted for kidney function measures. Methods: The study cohort included community-dwelling individuals aged ≥45 years with CKD (eGFR <60), not requiring dialysis, recruited from four health systems. We examined the serum biomarkers bicarbonate (CO₂), TNFαR1, and cholesterol as primary exposures. A structured neuropsychological battery conducted by trained staff measured global and domain-specific cognitive performance. Logistic regression analyses estimated the cross-sectional associations between kidney-metabolic measures and global and cognitive domain-specific moderate/severe (Mod/Sev) CI, adjusted for the eGFR, urinary albumin-creatinine ratio (UACR, mg/g), demographics, comorbid conditions, and other kidney-metabolic biomarkers commonly abnormal in CKD. Results: Among 436 CKD participants with mean age 70 years, 16% were Black, the mean eGFR was 34, and the median [IQR] UACR was 49 [0.0, 378] mg/g. In adjusted models, increased TNFαR1 was associated with global Mod/Sev CI (odds ratio [95% confidence interval] = 1.40 [1.02, 1.93]; p = 0.04); low bicarbonate (CO₂ <20 mEq/L) with Mod/Sev memory impairment (3.04 [1.09, 8.47]; p = 0.03), and each 10-mg/dL lower cholesterol was associated with Mod/Sev executive function/processing speed impairment (1.12 [1.02, 1.23]; p = 0.02). However, after adjustment for multiple comparisons, these associations were no longer significant nor were any other kidney-metabolic factors significant for any CI classification. Conclusion: In exploratory analyses in a CKD population, three kidney-metabolic factors were associated with CI, but after adjustment for multiple comparisons, were no longer significant. Future studies in larger CKD populations are needed to assess these potential risk factors for CI.

Novel cardiovascular biomarkers associated with peripheral arterial disease in men screened for abdominal aortic aneurysm.

Background: Peripheral arterial disease (PAD) is a common atherosclerotic disease with severity ranging from asymptomatic to chronic limb threatening ischemia. The aim of the present cross-sectional study was to identify novel biomarkers associated with PAD. Patients and methods: Levels of 91 cardiovascular specific proteins in plasma samples were measured by the Proseek Multiplex CVD III96x96 panel from a cohort consisting of 267 65-year-old men recruited from a screening program for abdominal aortic aneurysm (AAA) Levels of protein biomarkers were compared in men with and without PAD (defined as an ankle brachial index of <0.9) and their diagnostic potential was calculated by receiver-operating characteristic analysis. Results: The prevalence of PAD was 14.2% (38/267). After adjustment for multiple comparisons, levels of the following 11 biomarkers remained significantly higher (p<0.0001) in patients with PAD: secretoglobin family 3A member 2, osteoprotegerin, urokinase-type plasminogen activator surface receptor, serum macrophage chemokine ligand 16, matrix metalloproteinase 9, p-selectin, growth differentiation factor 15, elafin, cystatin B, trefoil factor 3, and fatty acid-binding protein 4. Multivariable logistic regression analysis (adjusted for smoking, use of antihypertensive and lipid-lowering medication, and metformin) showed that 11 biomarkers were significantly associated with higher risk of PAD with odds ratios ranging from 1.6 to 2.4. Area under curve calculated by receiver operating characteristic curve analysis (diagnostic value) for each protein biomarker ranged from 0.63 to 0.74. Conclusions: We have identified multiple proteins with a potential to be diagnostic biomarkers for PAD, and further research is warranted to clarify their potential predictive and prognostic value.

Identification of Key Modules and Genes Associated with Major Depressive Disorder in Adolescents.

Major depressive disorder (MDD) is a leading cause of disability worldwide. Adolescence is a crucial period for the occurrence and development of depression. There are essential distinctions between adolescent and adult depression patients, and the etiology of depressive disorder is unclear. The interactions of multiple genes in a co-expression network are likely to be involved in the physiopathology of MDD. In the present study, RNA-Seq data of mRNA were acquired from the peripheral blood of MDD in adolescents and healthy control (HC) subjects. Co-expression modules were constructed via weighted gene co-expression network analysis (WGCNA) to investigate the relationships between the underlying modules and MDD in adolescents. In the combined MDD and HC groups, the dynamic tree cutting method was utilized to assign genes to modules through hierarchical clustering. Moreover, functional enrichment analysis was conducted on those co-expression genes from interested modules. The results showed that eight modules were constructed by WGCNA. The blue module was significantly associated with MDD after multiple comparison adjustment. Several Gene Ontology (GO) terms and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways associated with stress and inflammation were identified in this module, including histone methylation, apoptosis, NF-kappa β signaling pathway, and TNF signaling pathway. Five genes related to inflammation, immunity, and the nervous system were identified as hub genes: CNTNAP3, IL1RAP, MEGF9, UBE2W, and UBE2D1. All of these findings supported that MDD was associated with stress, inflammation, and immune responses, helping us to obtain a better understanding of the internal molecular mechanism and to explore biomarkers for the diagnosis or treatment of depression in adolescents.

Abstract 022: Association Of Nutritionally-Rich Plant-Centered Diets With Gut Microbial Diversity And Composition Columbia Heart Failure-Microbiome Study

Introduction: A plant-centered diet is related to lower risk of cardiovascular disease. However, its association with the gut microbiome has not been well studied in populations with heart failure (HF), and mechanisms linking diet to improved outcomes among HF patients are poorly understood. Hypothesis: Consuming a more nutritionally-rich plant-centered diet is associated with increased microbial alpha diversity and with favorable taxonomic composition and features as compared to consuming less plant-centered diets. Methods: We conducted a cross-sectional analysis of 152 patients with NYHA class I-IV HF with reduced ejection fraction. Diet was assessed using a food frequency questionnaire. Plant-centered diet quality was evaluated using A Priori Diet Quality Score (APDQS) and the APDQS was classified into quintiles; high scores were characterized by higher consumption of nutritionally-rich plant foods with lower consumption of high-fat meats and unhealthy plant foods. Stool samples were analyzed using 16S rRNA gene sequencing. Associations of the APDQS with alpha (Shannon Index and Inverse Simpson) and beta diversity (defined via Bray-Curtis dissimilarity index) were evaluated by linear regression and permutational multivariate analysis of variance (PERMANOVA), respectively. Negative-binomial regressions using DESeq2 were used to study the association between the APDQS and the relative abundance of specific taxa at the phylum and genus levels. Adjustments for multiple comparisons were performed using the false discovery rate. Results: Mean Shannon Index and Inverse Simpson values were 6.28±0.5 and 407.7±183.37, respectively. Among patients aged &lt;61y, after multivariable adjustment, the APDQS (per 12 units) was associated with higher Shannon Index (0.13±0.05; P for slope=0.007) and Inverse Simpson (46.87±15.5; P for slope=0.004); no associations were observed among those aged ≥ 61y (P for interaction &lt;0.05 for each). APDQS quintiles were not associated with beta-diversity (PERMANOVA, P=0.54). At the genus level, the highest quintile of the ADPQS (vs the lowest quintile) was associated with higher abundance of Enterobacter and lower abundance of Catenibacterium. Conclusions: Consuming nutritionally-rich plant-centered diets was significantly associated with higher gut microbiota diversity in younger HF patients, as well as significantly higher or lower abundance of certain bacterial taxa at the genus level.

Clinical Imaging-Derived Metrics of Corticospinal Tract Structural Integrity Are Associated With Post-stroke Motor Outcomes: A Retrospective Study.

ObjectiveThe primary objective of this study was to retrospectively investigate associations between clinical magnetic resonance imaging-based (MRI) metrics of corticospinal tract (CST) status and paretic upper extremity (PUE) motor recovery in patients that completed acute inpatient rehabilitation (AR) post-stroke.MethodsWe conducted a longitudinal chart review of patients post-stroke who received care in the Emory University Hospital system during acute hospitalization, AR, and outpatient therapy. We extracted demographic information, stroke characteristics, and longitudinal documentation of post-stroke motor function from institutional electronic medical records. Serial assessments of paretic shoulder abduction and finger extension were estimated (E-SAFE) and an estimated Action Research Arm Test (E-ARAT) score was used to quantify 3-month PUE motor function outcome. Clinically-diagnostic MRI were used to create lesion masks that were spatially normalized and overlaid onto a white matter tract atlas delineating CST contributions emanating from six cortical seed regions to obtain the percentage of CST lesion overlap. Metric associations were investigated with correlation and cluster analyses, Kruskal-Wallis tests, classification and regression tree analysis.ResultsThirty-four patients met study eligibility criteria. All CST overlap percentages were correlated with E-ARAT however, ventral premotor tract (PMv) overlap was the only tract that remained significantly correlated after multiple comparisons adjustment. Lesion overlap percentage in CST contributions from all seed regions was significantly different between outcome categories. Using MRI metrics alone, dorsal premotor (PMd) and PMv tracts classified recovery outcome category with 79.4% accuracy. When clinical and MRI metrics were combined, AR E-SAFE, patient age, and overall CST lesion overlap classified patients with 88.2% accuracy.ConclusionsStudy findings revealed clinical MRI-derived CST lesion overlap was associated with PUE motor outcome post-stroke and that cortical projections within the CST, particularly those emanating from non-M1 cortical areas, prominently ventral premotor (PMv) and dorsal premotor (PMd) cortices, distinguished between PUE outcome groups. Exploratory predictive models using clinical MRI metrics, either alone or in combination with clinical measures, were able to accurately identify recovery outcome category for the study cohort during both the acute and early subacute phases of post-stroke recovery. Prospective studies are recommended to determine the predictive utility of including clinical imaging-based biomarkers of white matter tract structural integrity in predictive models of post-stroke recovery.

Abstract P4-10-02: Patient-reported outcomes in EA1131: A randomized phase III trial of platinum vs. capecitabine in patients with residual triple-negative breast cancer after neoadjuvant chemotherapy

Abstract Background: Understanding health-related quality of life (HRQOL), including side effects, is critical to guide supportive care during chemotherapy. The EA1131 trial demonstrated that Platinum (Plat) was unlikely to improve outcomes compared to capecitabine (Cape) in patients with stage II-III triple-negative breast cancer (TNBC) of basal subtype and ≥1 cm residual disease after neoadjuvant chemotherapy (NAC), supporting Cape as the continued standard of care. Patient-reported outcomes (PRO) were administered as a sub-study to understand HRQOL and symptoms from the patient’s perspective. Methods: EA1131 was amended in 9/2017 to add PRO endpoints and all patients enrolled after this amendment were eligible for the PRO sub-study. The Functional Assessment of Cancer Therapy-Breast Cancer Symptom Index (FBSI) and the Functional Assessment of Cancer Therapy/Gynecologic Oncology Group Neurotoxicity Subscale (NtxS; Plat arm only) were administered at baseline (BL), cycle 3 day 1 (C3D1), and following treatment at 6 and 15 months. Due to early trial termination, the PRO sub-study target accrual (n=362) was not reached. It was hypothesized that HRQOL, assessed by the FBSI-Treatment Side Effect (TSE) subscale (range 0-16, higher score = less side effects, better HRQOL), would indicate fewer post-treatment side effects at 6 and 15 months following Plat compared to Cape. The Wilcoxon rank sum test was used to compare FBSI-TSE subscale scores and total FBSI scores (range 0-64, higher score = better overall HRQOL) between arms at BL, C3D1, 6 months and 15 months. Two-sample t-tests were used to compare change in FBSI-TSE subscale scores and total FBSI scores from BL to C3D1 between arms. Change in NtxS scores (range 0-44, higher score = less neurotoxicity) from BL to C3D1 was evaluated with the paired t-test. Analyses were exploratory and p-values &amp;lt;0.05 considered significant without multiple comparisons adjustment. Results: Of 331 patients eligible for the PRO sub-study (156 Plat arm, 175 Cape arm), 296 (89.4%) completed ≥1 PRO. Mean FBSI-TSE subscale scores were better for Cape at BL (Cape 14.5, Plat 13.9, p-value 0.02), for Plat at C3D1 (Cape 13.5, Plat 14.0, p-value 0.04), and did not differ at 6 months (Cape 14.6, Plat 14.7, p-value 0.70) or 15 months (Cape 14.9, Plat 14.5, p-value 0.44). FBSI-TSE subscale scores worsened from BL to C3D1 for Cape but not for Plat (mean change Cape -0.72, mean change Plat 0.15, p-value 0.003). FBSI-TSE subscale change scores from BL to C3D1 exceeded the threshold for clinically meaningful worsening (&amp;gt; 1.5 points) in 27% of patients on Cape and 23% of patients on Plat (p-value 0.51). Mean total FBSI scores did not differ between arms at any time (BL: Cape 50.6, Plat 49.7; C3D1: Cape 48.1, Plat 48.0; 6 months: Cape 49.9, Plat 51.1; 15 months: Cape 53.3, Plat 50.3; all p &amp;gt; 0.05). Mean change in total FBSI scores from BL to C3D1 did not differ between arms (Cape -2.20, Plat -1.83, p = 0.75). Mean (standard deviation) NtxS scores for the Plat arm were 38 (6.3), 36.1 (7.8), 36 (7.1) and 34.5 (7.9) at BL, C3D1, 6 months and 15 months, respectively. Mean NtxS score decreased (indicating worsening neurotoxicity) from BL to C3D1 (p-value 0.006). Conclusions: Despite more frequent severe toxicity by CTCAE criteria for Plat than Cape, patient-reported side effects worsened during treatment with Cape but not Plat. Overall, changes in HRQOL were small for both arms and resolved after therapy. However approximately one-fourth of patients had clinically meaningful worsening side effects on both arms. PRO-assessed neurotoxicity increased in the Plat arm. This PRO sub-study demonstrates that PROs capture toxicities beyond CTCAE criteria and provides novel data about patients’ experience during adjuvant chemotherapy following NAC for TNBC. Citation Format: Karen L Smith, Fengmin Zhao, Ingrid A Mayer, Amye J Tevaarwerk, Sofia F Garcia, Carlos L Arteaga, William F Symmans, Ben H Park, Brian L Burnette, Della F Makower, Margaret Block, Kimberly A Morley, Chirag R Jani, Craig Mescher, Shabana J Dewani, Ursa Brown-Glaberman, Lisa E Flaum, Erica L Mayer, William M Sikov, Eve T Rodler, Angela M DeMichele, Joseph A Sparano, Antonio C Wolff, Kathy D Miller, Lynne I Wagner. Patient-reported outcomes in EA1131: A randomized phase III trial of platinum vs. capecitabine in patients with residual triple-negative breast cancer after neoadjuvant chemotherapy [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P4-10-02.

Relation Between Plasma Proteomics Analysis and Major Adverse Cardiovascular Events in Patients With Stable Coronary Artery Disease.

ObjectiveDespite the advances in the control of traditional risk factors, coronary artery disease (CAD) remains the greatest cause of morbidity and mortality. Our aim was to establish the relation between plasma proteomics analysis and the risk of cardiovascular events in patients with stable CAD.Materials and MethodsPatients with stable CAD and documented coronary atherosclerosis were screened for inclusion. Using proximity extension assays, 177 plasma proteins were simultaneously measured. The endpoint consisted of the first major adverse cardiovascular event (MACE) and was the composite of cardiovascular death, acute coronary syndrome, stroke, transient ischemic attack, or acute limb ischemia at 18 months follow-up. Cox proportional-hazards regression with adjustment for multiple comparisons was used to identify biomarkers for the outcomes of interest.ResultsThe cohort consisted of 229 patients. Six mediators were associated with MACE (p < 0.001). For these markers, the risk of MACE was calculated: tumor necrosis factor receptor superfamily member 13B (HR = 1.65; 95% CI: 1.30–2.10), C-C motif chemokine-3 (HR = 1.57; 95% CI: 1.23–1.98), decorin (HR = 1.65; 95% CI: 1.26–2.16), fibroblast growth factor-23 (HR = 1.56; 95% CI: 1.23–1.99), tumor necrosis factor-related apoptosis-inducing ligand-receptor 2 (TRAIL-R2) (HR = 1.61; 95% CI: 1.23–2.11), and tumor necrosis factor receptor superfamily member 10A (HR = 1.69; 95% CI: 1.25–2.29). Except for TRAIL-R2, the other proteins were associated with MACE independent of age, sex, diabetes mellitus, or estimated glomerular filtration rate.ConclusionsIn patients with stable CAD, five novel biomarkers were identified as independent risk factors for adverse outcomes. Novel biomarkers could represent pharmacological targets for the prevention of adverse cardiovascular events.

Diurnal Preference Contributes to Maximal UVB Sensitivity by the Hour of the Day in Human Skin In Vivo

Diurnal Preference Contributes to Maximal UVB Sensitivity by the Hour of the Day in Human Skin In Vivo

Predictors, Moderators, and Mediators Associated With Treatment Outcome in Randomized Clinical Trials Among Adolescents With Depression

The application of precision medicine principles for the treatment of depressive disorders in adolescents requires an examination of the variables associated with depression outcomes in randomized clinical trials (RCTs). To describe predictors, moderators, and mediators associated with outcomes in RCTs for the treatment of depressive disorders in adolescents. A scoping review of RCTs for the treatment of depression in adolescents was conducted. Databases searched included MEDLINE, Embase, APA PsycInfo, and CINAHL. Included publications tested predictors, moderators, and/or mediators associated with depression symptom outcomes (eg, symptom reduction, response, remission) in RCTs pertaining to the treatment of adolescents, ages 13 to 17 years. Predictors were defined as variables that were associated with depression outcomes, independent of treatment group. Moderators were defined as baseline variables that were associated with differential outcomes between treatment groups. Mediators were defined by a formal mediation analysis. In duplicate, variables were extracted and coded with respect to analysis type (univariable or multivariable), statistical significance, direction of effect size, reporting of a priori hypotheses, and adjustment for multiple comparisons. Aggregated results were summarized by variable domain and RCT sample. Eighty-one articles reporting on variables associated with outcomes across 33 RCTs were identified, including studies of biological (10 RCTs), psychosocial (18 RCTs), and combined (4 RCTs) treatments as well as a service delivery model (1 RCT). Fifty-three variable domains were tested as baseline predictors of depression outcome, 41 as moderators, 19 as postbaseline predictors, and 5 as mediators. Variable domains that were reported as significant in at least 3 RCTs included age, sex/gender, baseline depression severity, early response to treatment, sleep changes, parent-child conflict, overall psychopathology, suicidal ideation, hopelessness, functional impairment, attendance at therapy sessions, and history of trauma. Two publications reported a priori hypotheses and adjustment for multiple comparisons, both finding that baseline depression severity and family conflict were associated with poorer outcomes. This review identified commonly researched variables requiring more scrutiny as well as underresearched variables to inform future study designs. Further efforts to discover predictors, moderators, and mediators associated with treatment response have great potential to optimize care for adolescents with depression.

A multiple testing framework for diagnostic accuracy studies with co-primary endpoints.

Major advances have been made regarding the utilization of machine learning techniques for disease diagnosis and prognosis based on complex and high-dimensional data. Despite all justified enthusiasm, overoptimistic assessments of predictive performance are still common in this area. However, predictive models and medical devices based on such models should undergo a throughout evaluation before being implemented into clinical practice. In this work, we propose a multiple testing framework for (comparative) phase III diagnostic accuracy studies with sensitivity and specificity as co-primary endpoints. Our approach challenges the frequent recommendation to strictly separate model selection and evaluation, that is, to only assess a single diagnostic model in the evaluation study. We show that our parametric simultaneous test procedure asymptotically allows strong control of the family-wise error rate. A multiplicity correction is also available for point and interval estimates. Moreover, we demonstrate in an extensive simulation study that our multiple testing strategy on average leads to a better final diagnostic model and increased statistical power. To plan such studies, we propose a Bayesian approach to determine the optimal number of models to evaluate simultaneously. For this purpose, our algorithm optimizes the expected final model performance given previous (hold-out) data from the model development phase. We conclude that an assessment of multiple promising diagnostic models in the same evaluation study has several advantages when suitable adjustments for multiple comparisons are employed.

Association of a longitudinal, preclinical ultrasound curriculum with medical student performance

IntroductionPoint-of-care ultrasound (US) is used in clinical practice across many specialties. Ultrasound (US) curricula for medical students are increasingly common. Optimal timing, structure, and effect of ultrasound education during medical school remains poorly understood. This study aims to retrospectively determine the association between participation in a preclinical, longitudinal US curriculum and medical student academic performance.MethodsAll first-year medical students at a medical school in the Midwest region of the United States were offered a voluntary longitudinal US curriculum. Participants were selected by random lottery. The curriculum consisted of five three-hour hands on-sessions with matching asynchronous content covering anatomy and pathologic findings. Content was paired with organ system blocks in the standard first year curriculum at our medical school. Exam scores between the participating and non-participating students were compared to evaluate the objective impact of US education on performance in an existing curriculum. We hypothesized that there would be an association between participation in the curriculum and improved medical student performance. Secondary outcomes included shelf exam scores for the surgery, internal medicine, neurology clerkships and USMLE Step 1. A multivariable linear regression model was used to evaluate the association of US curriculum participation with student performance. Scores were adjusted for age, gender, MCAT percentile, and science or engineering degree.Results76 of 178 students applied to participate in the curriculum, of which 51 were accepted. US curriculum students were compared to non-participating students (n = 127) from the same class. The US curriculum students performed better in cardiovascular anatomy (mean score 92.1 vs. 88.7, p = 0.048 after adjustment for multiple comparisons). There were no significant differences in cumulative cardiovascular exam scores, or in anatomy and cumulative exam scores for the gastroenterology and neurology blocks. The effect of US curriculum participation on cardiovascular anatomy scores was estimated to be an improvement of 3.48 points (95% CI 0.78-6.18). No significant differences were observed for USMLE Step 1 or clerkship shelf exams. There were no significant differences in either preclinical, clerkship or Step 1 score for the 25 students who applied and were not accepted and the 102 who did not apply.ConclusionsParticipation in a preclinical longitudinal US curriculum was associated with improved exam performance in cardiovascular anatomy but not examination of other cardiovascular system concepts. Neither anatomy or comprehensive exam scores for neurology and gastrointestinal organ system blocks were improved.

Cerebral blood flow is lower in youth with type 2 diabetes compared to obese controls: A pilot study

The cerebral vasculature may be susceptible to the adverse effects of type 2 diabetes. In this pilot study, we compared cerebral blood flow (CBF) in youth with type 2 diabetes to obese, euglycemic controls, and explored the association between CBF and a non-invasive measure of atherosclerosis, carotid intima-medial thickness (IMT). Global and regional CBF were compared between youth with type 2 diabetes (mean age 16.7 ± 2.0 years, n=20) and age, race, and sex similar obese youth without diabetes (17.4 ± 1.9 years, n=19) using arterial spin labeling magnetic resonance imaging. Mean CBF values were compared between groups. Voxel-wise results were evaluated for statistical significance (p < 0.05) after adjustment for multiple comparisons. Carotid IMT in the type 2 diabetes group was correlated with CBF. Compared to obese controls, the type 2 diabetes group had significantly lower global CBF (49.7 ± 7.2 vs. 63.8 ± 11.5ml/gm/min, p < 0.001). Significantly lower CBF was observed in multiple brain regions for the type 2 diabetes group, while no regions with higher CBF were identified. In the type 2 diabetes group, carotid IMT was inversely correlated with CBF, both globally (r=-0.70, p=0.002) and in regional clusters. In this pilot study, lower CBF was seen in youth with type 2 diabetes compared to youth with obesity and IMT was inversely correlated with CBF. Cerebrovascular impairment may be present in youth with type 2 diabetes. These findings could represent a mechanistic link to explain previously reported brain volume and neurocognitive differences.

A double-blind, randomized, placebo-controlled trial of suvorexant for the treatment of vasomotor symptom-associated insomnia disorder in midlife women.

The neuropeptide orexin promotes wakefulness, modulates thermoregulation, increases after menopause, and is normalized in women receiving estrogen therapy, suggesting a role for orexin antagonism as a treatment for the vasomotor symptom (VMS)-associated insomnia disorder. We tested the efficacy of the dual orexin receptor antagonist suvorexant for chronic insomnia related to nighttime VMS. In a double-blind, placebo-controlled trial, 56 women with chronic insomnia associated with nighttime VMS, Insomnia Severity Index (ISI) scores ≥15, and >30 min of diary-rated wake after sleep-onset (WASO) were randomized to receive oral suvorexant 10-20 mg (n = 27) or placebo (n = 29) nightly for 4 weeks. Analysis of within-person change in ISI was adjusted for baseline ISI and race. Mean baseline ISI scores were 18.1 (95% CI, 16.8 to 19.4) and 18.3 (95% CI, 17.2 to 19.5) in the suvorexant and placebo groups, respectively (p = .81). The average 4-week ISI within-person decrease from baseline was greater on suvorexant (-8.1 [95% CI, -10.2 to -6.0]) compared to placebo (-5.6 [95% CI, -7.4 to -3.9], p = .04). Compared to placebo, nighttime diary-rated VMS frequency was significantly reduced with suvorexant (p < .01). While diary-rated WASO and total sleep time trended toward improvement on suvorexant, findings were not significant after adjustment for multiple comparisons. Daytime VMS and other sleep-related outcomes did not differ between groups. Suvorexant was well tolerated. These results suggest that suvorexant is likely a well-tolerated and efficacious treatment for VMS-associated insomnia disorder and reduces nighttime VMS. Antagonism of orexin receptors could provide a novel therapeutic option for midlife women with VMS-associated chronic insomnia. Efficacy of Suvorexant in the Treatment of Hot Flash-associated Insomnia, https://clinicaltrials.gov/ct2/show/NCT03034018, ClinicalTrials.gov Identifier: NCT03034018.

Prevalence of and Associations With Avascular Necrosis After Pediatric Sepsis: A Single-Center Retrospective Study.

Avascular necrosis (AVN) is a rare, but serious, complication after sepsis in adults. We sought to determine if sepsis is associated with postillness diagnosis of AVN, as well as potential-associated risk factors for AVN in children with sepsis. Retrospective observational study. Single academic children's hospital. Patients less than 18 years treated for sepsis or suspected bacterial infection from 2011 to 2017. Patients who developed AVN within 3 years after sepsis were compared with patients who developed AVN after suspected bacterial infection and with patients with sepsis who did not develop AVN. None. AVN was determined using International Classification of Diseases, 9th Edition/10th Edition codes and confirmed by chart review. The prevalence of AVN after sepsis was 0.73% (21/2,883) and after suspected bacterial infection was 0.43% (53/12,276; risk difference, 0.30; 95% CI, 0.0-0.63; p = 0.05). Compared with 43 sepsis controls without AVN, AVN in the 21 sepsis cases was associated with being older, having sickle cell disease and malignancy, higher body mass index, unknown source of infection, and low platelet count in the first 7 days of sepsis. Half of sepsis patients were treated with corticosteroids, and higher median cumulative dose of steroids was associated with AVN (23.2 vs 5.4 mg/kg; p < 0.01). Older age at infection (odds ratio [OR], 1.3; 95% CI, 1.1-1.4), malignancy (OR, 8.8; 95% CI, 2.6-32.9), unknown site of infection (OR, 12.7; 95% CI, 3.3-48.6), and minimal platelet count less than 100,000/µL in first 7 days of sepsis (OR, 5.0; 95% CI, 1.6-15.4) were identified as potential risk factors for AVN after sepsis following adjustment for multiple comparisons. Although rare, sepsis was associated with a higher risk of subsequent AVN than suspected bacterial infection in children. Older age, malignancy, unknown site of infection, and minimum platelet count were potential risk factors for AVN after sepsis.

Two-six Hours is the Optimal Timing of Intracytoplasmic Sperm Injection After Oocyte Pickup: Single-centre 10 Years Cohort Study.

Optimal incubation period for oocyte competence remains contentious despite intracytoplasmic sperm injection(ICSI) being in practice for 34 years. Dilemma exists as the current literature favors both early and delayed denudation with equivocal results. With ever-rising demand for the procedure this conundrum continues to plague the clinical outcomes. This study attempts to provide a consensus regarding optimal time duration required for incubating the oocytes after oocyte pickup(OPU) and time to perform ICSI. A retrospective study in a tertiary centre. A retrospective 10-year cohort study including 726 ICSI cycles was conducted in a single tertiary care infertility centre. All cycles comprised at least one metaphase-II oocyte injected with one good quality sperm followed by fresh embryo transfer. The cohort was broadly divided into two groups: (a) Group 1: OPU-ICSI <4 hours(n=466) and (b) Group 2: OPU-ICSI>4 hours(n=260). The fertilization(FR) and clinical pregnancy rates(CPR) were compared using the Pearson Chi-square test. The OPU-ICSI interval were subdivided into one-hourly intervals and CPR was compared after adjustment for multiple comparisons by holm method. The FR and CPR were similar between Group 1 and Group 2(p>0.05). Comparing CPR for each one-hourly OPU-ICSI interval revealed no significant clinical difference (p>0.05) amongst one another, however, the CPR was maximum for 2-3 hours as the OPU-ICSI interval. With no significant clinical difference amongst various temporal groups, this study advocates and reinstates 2-6 hours as the optimal timing for ICSI after the OPU. This will also translate into better time management for both embryologists and clinicians and help them prioritise the laboratory workflow.

Links between ceramides and cardiac function.

Total ceramide levels in cardiac tissue relate to cardiac dysfunction in animal models. However, emerging evidence suggests that the fatty acyl chain length of ceramides also impacts their relationship to cardiac function. This review explores evidence regarding the relationship between ceramides and left ventricular dysfunction and heart failure. It further explores possible mechanisms underlying these relationships. In large, community-based cohorts, a higher ratio of specific plasma ceramides, C16 : 0/C24 : 0, related to worse left ventricular dysfunction. Increased left ventricular mass correlated with plasma C16 : 0/C24 : 0, but this relationship became nonsignificant after adjustment for multiple comparisons. Decreased left atrial function and increased left atrial size also related to C16 : 0/C24 : 0. Furthermore, increased incident heart failure, overall cardiovascular disease (CVD) mortality and all-cause mortality were associated with higher C16 : 0/C24 : 0 (or lower C24 : 0/C16 : 0). Finally, a number of possible biological mechanisms are outlined supporting the link between C16 : 0/C24 : 0 ceramides, ceramide signalling and CVD. High cardiac levels of total ceramides are noted in heart failure. In the plasma, C16 : 0/C24 : 0 ceramides may be a valuable biomarker of preclinical left ventricular dysfunction, remodelling, heart failure and mortality. Continued exploration of the mechanisms underlying these profound relationships may help develop specific lipid modulators to combat cardiac dysfunction and heart failure.