Biological and Procedural Predictors of Outcome in the Stroke Preclinical Assessment Network (SPAN) Trial.

BACKGROUND: The SPAN trial (Stroke Preclinical Assessment Network) is the largest preclinical study testing acute stroke interventions in experimental focal cerebral ischemia using endovascular filament middle cerebral artery occlusion (MCAo). Besides testing interventions against controls, the prospective design captured numerous biological and procedural variables, highlighting the enormous heterogeneity introduced by the multicenter structure that might influence stroke outcomes. Here, we leveraged the unprecedented sample size achieved by the SPAN trial and the prospective design to identify the biological and procedural variables that affect experimental stroke outcomes in transient endovascular filament MCAo. METHODS: The study cohort included all mice enrolled and randomized in the SPAN trial (N=1789). Mice were subjected to 60-minute MCAo and followed for a month. Thirteen biological and procedural independent variables and 4 functional (weight loss and 4-point neuroscore on days 1 and 2, corner test on days 7 and 28, and mortality) and 3 tissue (day 2, magnetic resonance imaging infarct volumes and swelling; day 30, magnetic resonance imaging tissue loss) outcome variables were prospectively captured. Multivariable regression with stepwise elimination was used to identify the predictors and their effect sizes. RESULTS: Older age, active circadian stage at MCAo, and thinner and longer filament silicone tips predicted higher mortality. Older age, larger body weight, longer anesthesia duration, and longer filament tips predicted worse neuroscores, while high-fat diet and blood flow monitoring predicted milder neuroscores. Older age and a high-fat diet predicted worse corner test performance. While shorter filament tips predicted more ipsiversive turning, longer filament tips appeared to predict contraversive turning. Age, sex, and weight interacted when predicting the infarct volume. Older age was associated with smaller infarcts on day 2 magnetic resonance imaging, especially in animals with larger body weights; this association was most conspicuous in females. High-fat diet also predicted smaller infarcts. In contrast, the use of cerebral blood flow monitoring and more severe cerebral blood flow drop during MCAo, longer anesthesia, and longer filament tips all predicted larger infarcts. Bivariate analyses among the dependent variables highlighted a disconnect between tissue and functional outcomes. CONCLUSIONS: Our analyses identified variables affecting endovascular filament MCAo outcome, an experimental stroke model used worldwide. Multiple regression refuted some commonly reported predictors and revealed previously unrecognized associations. Given the multicenter prospective design that represents a sampling of real-world conditions, the degree of heterogeneity mimicking clinical trials, the large number of predictors adjusted for in the multivariable model, and the large sample size, we think this is the most definitive analysis of the predictors of preclinical stroke outcome to date. Future multicenter experimental stroke trials should standardize or at least ensure a balanced representation of the biological and procedural variables identified herein as potential confounders.

Constitutional MLH1 Methylation Is a Major Contributor to Mismatch Repair-Deficient, MLH1-Methylated Colorectal Cancer in Patients Aged 55 Years and Younger.

BACKGROUND: Most mismatch repair-deficient (MMRd) colorectal cancer (CRC) cases arise sporadically, associated with somatic MLH1 methylation, whereas approximately 20% have germline mismatch repair pathogenic variants causing Lynch syndrome (LS). Universal screening of incident CRC uses presence of MLH1 methylation in MMRd tumors to exclude sporadic cases from germline testing for LS. However, this overlooks rare cases with constitutional MLH1 methylation (epimutation), a poorly recognized mechanism for LS. We aimed to assess the frequency and age distribution of constitutional MLH1 methylation among incident CRC cases with MMRd, MLH1-methylated tumors. METHODS: In retrospective population-based studies, we selected all CRC cases with MMRd, MLH1-methylated tumors, regardless of age, prior cancer, family history, or BRAF V600E status, from the Columbus-area HNPCC study (Columbus) and Ohio Colorectal Cancer Prevention Initiative (OCCPI) cohorts. Blood DNA was tested for constitutional MLH1 methylation by pyrosequencing and real-time methylation-specific PCR, then confirmed with bisulfite-sequencing. RESULTS: Results were achieved for 95 of 98 Columbus cases and all 281 OCCPI cases. Constitutional MLH1 methylation was identified in 4 of 95 (4%) Columbus cases, ages 34, 38, 52, and 74 years, and 4 of 281 (1.4%) OCCPI cases, ages 20, 34, 50, and 55 years, with 3 showing low-level mosaic methylation. Mosaicism in blood and normal colon, plus tumor loss of heterozygosity of the unmethylated allele, demonstrated causality in 1 case with sample availability. Age stratification showed high rates of constitutional MLH1 methylation among younger patients. In the Columbus and OCCPI cohorts, respectively, these rates were 67% (2 of 3) and 25% (2 of 8) of patients aged <50 years but with half of the cases missed, and 75% (3 of 4) and 23.5% (4 of 17) of patients aged ≤55 years with most cases detected. CONCLUSIONS: Although rare overall, a significant proportion of younger patients with MLH1-methylated CRC had underlying constitutional MLH1 methylation. Routine testing for this high-risk mechanism is warranted in patients aged ≤55 years for a timely and accurate molecular diagnosis that will significantly alter their clinical management while minimizing additional testing.

Simulation study comparing analytical methods for single-item longitudinal patient-reported outcomes data.

PURPOSE: Efficient analytical methods are necessary to make reproducible inferences on single-item longitudinal ordinal patient-reported outcome (PRO) data. A thorough simulation study was performed to compare the performance of the semiparametric probabilistic index models (PIM) with a longitudinal analysis using parametric cumulative logit mixed models (CLMM). METHODS: In the setting of a control and intervention arm, we compared the power of the PIM and CLMM to detect differences in PRO adverse event (AE) between these groups using several existing and novel summary scores of PROs. For each scenario, PRO data were simulated using copula multinomial models. Comparisons were also exemplified using clinical trial data. RESULTS: On average, CLMM provided substantially greater power than the PIM to detect differences in PRO-AEs between the groups when the baseline-adjusted method was used, and a small advantage in power when using the baseline symptom as a covariate. CONCLUSION: Although the CLMM showed the best performance among analytical methods, it relies on assumptions difficult to verify and that might not be fulfilled in the real world, therefore our recommendation is the use of PIM models with baseline symptom as a covariate.

Improved inference for MCP-Mod approach using time-to-event endpoints with small sample sizes.

The Multiple Comparison Procedures with Modeling Techniques (MCP-Mod) framework has been recently approved by the U.S. Food, Administration, and European Medicines Agency as fit-for-purpose for phase II studies. Nonetheless, this approach relies on the asymptotic properties of Maximum Likelihood (ML) estimators, which might not be reasonable for small sample sizes. In this paper, we derived improved ML estimators and correction for their covariance matrices in the censored Weibull regression model based on the corrective and preventive approaches. We performed two simulation studies to evaluate ML and improved ML estimators with their covariance matrices in (i) a regression framework (ii) the Multiple Comparison Procedures with Modeling Techniques framework. We have shown that improved ML estimators are less biased than ML estimators yielding Wald-type statistics that controls type I error without loss of power in both frameworks. Therefore, we recommend the use of improved ML estimators in the MCP-Mod approach to control type I error at nominal value for sample sizes ranging from 5 to 25 subjects per dose.

The Stroke Preclinical Assessment Network: Rationale, Design, Feasibility, and Stage 1 Results.

Cerebral ischemia and reperfusion initiate cellular events in brain that lead to neurological disability. Investigating these cellular events provides ample targets for developing new treatments. Despite considerable work, no such therapy has translated into successful stroke treatment. Among other issues-such as incomplete mechanistic knowledge and faulty clinical trial design-a key contributor to prior translational failures may be insufficient scientific rigor during preclinical assessment: nonblinded outcome assessment; missing randomization; inappropriate sample sizes; and preclinical assessments in young male animals that ignore relevant biological variables, such as age, sex, and relevant comorbid diseases. Promising results are rarely replicated in multiple laboratories. We sought to address some of these issues with rigorous assessment of candidate treatments across 6 independent research laboratories. The Stroke Preclinical Assessment Network (SPAN) implements state-of-the-art experimental design to test the hypothesis that rigorous preclinical assessment can successfully reduce or eliminate common sources of bias in choosing treatments for evaluation in clinical studies. SPAN is a randomized, placebo-controlled, blinded, multilaboratory trial using a multi-arm multi-stage protocol to select one or more putative stroke treatments with an implied high likelihood of success in human clinical stroke trials. The first stage of SPAN implemented procedural standardization and experimental rigor. All participating research laboratories performed middle cerebral artery occlusion surgery adhering to a common protocol and rapidly enrolled 913 mice in the first of 4 planned stages with excellent protocol adherence, remarkable data completion and low rates of subject loss. SPAN stage 1 successfully implemented treatment masking, randomization, prerandomization inclusion/exclusion criteria, and blinded assessment to exclude bias. Our data suggest that a large, multilaboratory, preclinical assessment effort to reduce known sources of bias is feasible and practical. Subsequent SPAN stages will evaluate candidate treatments for potential success in future stroke clinical trials using aged animals and animals with comorbid conditions.

Incorporating personal-device-based point-of-care ultrasound into obstetric care: a validation study.

BACKGROUND: Personal-device-based point-of-care-ultrasound (P-POCUS) probes plug directly into a cell phone or tablet to function as its display, creating the potential to increase access to obstetric ultrasonography in complex healthcare settings (COVID units, low resource settings); however, new technology must be proven to be reliable in the obstetric setting before integrating into practice. OBJECTIVE: To evaluate the intraclass correlation (reliability) of personal-device-based-point-of-care-ultrasound devices as compared with standard ultrasound machines in obstetrics. STUDY DESIGN: This was a prospective, observational study of patients between 19-39 weeks gestation in an urban, prenatal ultrasound diagnosis center. Each patient underwent assessment by an expert sonographer using standard ultrasound machines and personal-device-based-point-of-care-ultrasound devices to determine estimated fetal weight. The statistical reliability and agreement between the estimated fetal weights was assessed through intraclass correlation coefficients, Bland-Altman plots, and Pearson correlation coefficients. RESULTS: 100 paired sets of scans were performed from October 2020 to December 2020. For the estimated fetal weights, there was near-perfect agreement, with an intraclass correlation coefficient of 0.99 (P<.0001). Bland-Altman analysis showed an average difference of 53 grams, with 95% limit of agreement between -178 grams and 283 grams. Pearson correlation showed near-perfect correlation between the measurements (r=0.99, P<.0001). CONCLUSION: personal-device-based point-of-care-ultrasound devices are reliable tools for performing basic obstetrical ultrasound and have the potential to increase access to obstetrical ultrasound worldwide.

On the properties of the toxicity index and its statistical efficiency.

Cancer clinical trials typically generate detailed patient toxicity data. The most common measure used to summarize patient toxicity is the maximum grade among all toxicities and it does not fully represent the toxicity burden experienced by patients. In this article, we study the mathematical and statistical properties of the toxicity index (TI), in an effort to address this deficiency. We introduce a total ordering, (T-rank), that allows us to fully rank the patients according to how frequently they exhibit toxicities, and show that TI is the only measure that preserves the T-rank among its competitors. Moreover, we propose a Poisson-Limit model for sparse toxicity data. Under this model, we develop a general two-sample test, which can be applied to any summary measure for detecting differences among two population of toxicity data. We derive the asymptotic power function of this class as well as the asymptotic relative efficiency (ARE) of the members of the class. We evaluate the ARE formula empirically and show that if the data are drawn from a random Poisson-Limit model, the TI is more efficient, with high probability, than the maximum and the average summary measures. Finally, we evaluate our method on clinical trial toxicity data and show that TI has a higher power in detecting the differences in toxicity profile among treatments. The results of this article can be applied beyond toxicity modeling, to any problem where one observes a sparse array of scores on subjects and a ranking based on extreme scores is desirable.

Visualizing adverse events in clinical trials using correspondence analysis with R-package visae.

BACKGROUND: Graphical displays and data visualization are essential components of statistical analysis that can lead to improved understanding of clinical trial adverse event (AE) data. Correspondence analysis (CA) has been introduced decades ago as a multivariate technique that can communicate AE contingency tables using two-dimensional plots, while quantifying the loss of information as other dimension reduction techniques such as principal components and factor analysis. METHODS: We propose the application of stacked CA using contribution biplots as a tool to explore differences in AE data among treatments in clinical trials. We defined five levels of refinement for the analysis based on data derived from the Common Terminology Criteria for Adverse Events (CTCAE) grades, domains, terms and their combinations. In addition, we developed a Shiny app built in an R-package, visae, publicly available on Comprehensive R Archive Network (CRAN), to interactively investigate CA configurations based on the contribution to the explained variance and relative frequency of AEs. Data from two randomized controlled trials (RCT) were used to illustrate the proposed methods: NSABP R-04, a neoadjuvant rectal 2 × 2 factorial trial comparing radiation therapy with either capecitabine (Cape) or 5-fluorouracil (5-FU) alone with or without oxaliplatin (Oxa), and NSABP B-35, a double-blind RCT comparing tamoxifen to anastrozole in postmenopausal women with hormone-positive ductal carcinoma in situ. RESULTS: In the R04 trial (n = 1308), CA biplots displayed the discrepancies between single agent treatments and their combinations with Oxa at all levels of AE classes, such that these discrepancies were responsible for the largest portion of the explained variability among treatments. In addition, an interaction effect when adding Oxa to Cape/5-FU was identified when the distance between Cape+Oxa and 5-FU + Oxa was observed to be larger than the distance between 5-FU and Cape, with Cape+Oxa and 5-FU + Oxa in different quadrants of the CA biplots. In the B35 trial (n = 3009), CA biplots showed different patterns for non-adherent Anastrozole and Tamoxifen compared with their adherent counterparts. CONCLUSION: CA with contribution biplot is an effective tool that can be used to summarize AE data in a two-dimensional display while minimizing the loss of information and interpretation.

Impact of Brazilian expanded criteria for liver transplantation in patients with hepatocellular carcinoma: a multicenter study.

INTRODUCTION AND OBJECTIVES: Hepatocellular carcinoma (HCC) is one of the main indications for orthotopic liver transplantation (OLT). In Brazil, selection criteria for HCC is an expanded version of the Milan Criteria (MC), the so-called "Brazilian Milan Criteria" (BMC). Our aims were to evaluate post-OLT outcomes in patients with HCC and analyze the BMC performance. MATERIALS AND METHODS: We conducted a multicenter, retrospective cohort study, analyzing medical records of 1,059 liver transplant recipients with HCC. Tumor was staged according to MC and BMC and correlated with overall survival (OS) and disease-free survival (DFS). We compared the ability of MC and BMC to predict OS and DFS using Delta C-statistic. RESULTS: Post-OLT OS were 63% in five years and HCC recurrence was observed in 8% of patients. At diagnosis, 85% of patients were within MC. Patients within MC at diagnosis and in the explant showed a higher OS and DFS than patients outside MC and within BMC and patients outside both criteria (p < 0.001). Patients outside MC in the explant had an increased risk of tumor recurrence (HR: 3.78; p < 0.001) and poor survival (HR:1.77; p = 0.003). The BMC presented a lower performance than MC in properly classifying patients regarding recurrence risk. CONCLUSIONS: In a large Brazilian cohort of HCC patients submitted to liver transplantation, we observed satisfactory overall survival and recurrence rates. However, patients transplanted within the Brazilian expanded criteria had lower OS and DFS when compared to patients within MC, which may generate future discussions regarding the criteria currently used.

Prognosis in pathology: Are we "prognosticating" or only establishing correlations between independent variables and survival? A study with various analytics cautions about the overinterpretation of statistical results.

Survival data from 225 patients with resected pulmonary typical carcinoids were analyzed with Kaplan-Meier statistics (K-M) and "deep learning" methods to illustrate the difference between establishing "correlations" and "prognostications". Cases were stratified into G1 and G2 classes using a ≤5% Ki-67% cut-point. Overall survival, number of patients at risk and 95% confidence intervals (CI) were estimated for the two classes. Seven neural network models (NN) were developed with GMDH Shell 3.8.2 and Statgraphics Centurion 18.1 software, using variable prior probabilities and different numbers of training vs testing cases. The NNs used age, sex, and pTNM, G1 and G2 as input neurons and "alive" and "dead" as output neurons. Areas under the curve (AUC) and other performance measures were evaluated for all models. Log-rank test showed a significant difference in overall survival between G1 and G2 (p < 0.001). However, 95% CI estimates showed considerable variability in survival at different time intervals. Including the number of patients at risk at different time intervals showed that most G2 patients had been censored by 100 weeks. The NN models provided variable "prognostications", with AUC ranging from 0.5 to 1 and variability in the sensitivity, specificity, and other performance measures. The results illustrate the limitations of survival statistics and NNs in predicting the prognosis of individual patients. The need for pathologists not to overinterpret the finding of significant correlations as "prognostic" or "predictive" for individual patients is discussed.

Cointegration and Unit Root Tests: A Fully Bayesian Approach.

To perform statistical inference for time series, one should be able to assess if they present deterministic or stochastic trends. For univariate analysis, one way to detect stochastic trends is to test if the series has unit roots, and for multivariate studies it is often relevant to search for stationary linear relationships between the series, or if they cointegrate. The main goal of this article is to briefly review the shortcomings of unit root and cointegration tests proposed by the Bayesian approach of statistical inference and to show how they can be overcome by the Full Bayesian Significance Test (FBST), a procedure designed to test sharp or precise hypothesis. We will compare its performance with the most used frequentist alternatives, namely, the Augmented Dickey-Fuller for unit roots and the maximum eigenvalue test for cointegration.

Polyfunctional anti-human epidermal growth factor receptor 3 (anti-HER3) antibodies induced by HER3 vaccines have multiple mechanisms of antitumor activity against therapy resistant and triple negative breast cancers.

BACKGROUND: Upregulation of human epidermal growth factor receptor 3 (HER3) is a major mechanism of acquired resistance to therapies targeting its heterodimerization partners epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 2 (HER2), but also exposes HER3 as a target for immune attack. We generated an adenovirus encoding full length human HER3 (Ad-HER3) to serve as a cancer vaccine. Previously we reported the anti-tumor efficacy and function of the T cell response to this vaccine. We now provide a detailed assessment of the antitumor efficacy and functional mechanisms of the HER3 vaccine-induced antibodies (HER3-VIAs) in serum from mice immunized with Ad-HER3. METHODS: Serum containing HER3-VIA was tested in complement-dependent cytotoxicity (CDC) and antibody-dependent cellular cytotoxicity (ADCC) assays and for its effect on HER3 internalization and degradation, downstream signaling of HER3 heterodimers and growth of metastatic HER2+ (BT474M1), HER2 therapy-resistant (rBT474), and triple negative (MDA-MB-468) breast cancers. RESULTS: HER3-VIAs mediated CDC and ADCC, HER3 internalization, interruption of HER3 heterodimer-driven tumor signaling pathways, and anti-proliferative effects against HER2+ tumor cells in vitro and significant antitumor effects against metastatic HER2+ BT474M1, treatment refractory HER2+ rBT474 and triple negative MDA-MB-468 in vivo. CONCLUSIONS: In addition to the T cell anti-tumor response induced by Ad-HER3, the HER3-VIAs provide additional functions to eliminate tumors in which HER3 signaling mediates aggressive behavior or acquired resistance to HER2-targeted therapy. These data support clinical studies of vaccination against HER3 prior to or concomitantly with other therapies to prevent outgrowth of therapy-resistant HER2+ and triple negative clones.

3D whole-brain vessel wall cardiovascular magnetic resonance imaging: a study on the reliability in the quantification of intracranial vessel dimensions.

BACKGROUND: One of the potentially important applications of three-dimensional (3D) intracranial vessel wall (IVW) cardiovascular magnetic resonance (CMR) is to monitor disease progression and regression via quantitative measurement of IVW morphology during medical management or drug development. However, a prerequisite for this application is to validate that IVW morphologic measurements based on the modality are reliable. In this study we performed comprehensive reliability analysis for the recently proposed whole-brain IVW CMR technique. METHODS: Thirty-four healthy subjects and 10 patients with known intracranial atherosclerotic disease underwent repeat whole-brain IVW CMR scans. In 19 of the 34 subjects, two-dimensional (2D) turbo spin-echo (TSE) scan was performed to serve as a reference for the assessment of vessel dimensions. Lumen and wall volume, normalized wall index, mean and maximum wall thickness were measured in both 3D and 2D IVW CMR images. Scan-rescan, intra-observer, and inter-observer reproducibility of 3D IVW CMR in the quantification of IVW or plaque dimensions were respectively assessed in volunteers and patients as well as for different healthy subjectsub-groups (i.e. < 50 and ≥ 50 years). The agreement in vessel wall and lumen measurements between the 3D technique and the 2D TSE method was also investigated. In addition, the sample size required for future longitudinal clinical studies was calculated. RESULTS: The intra-class correlation coefficient (ICC) and Bland-Altman plots indicated excellent reproducibility and inter-method agreement for all morphologic measurements (All ICCs > 0.75). In addition, all ICCs of patients were equal to or higher than that of healthy subjects except maximum wall thickness. In volunteers, all ICCs of the age group of ≥50 years were equal to or higher than that of the age group of < 50 years. Normalized wall index and mean and maximum wall thickness were significantly larger in the age group of ≥50 years. To detect 5% - 20% difference between placebo and treatment groups, normalized wall index requires the smallest sample size while lumen volume requires the highest sample size. CONCLUSIONS: Whole-brain 3D IVW CMR is a reliable imaging method for the quantification of intracranial vessel dimensions and could potentially be useful for monitoring plaque progression and regression.

Overview of the 37th MaxEnt.

The 37th edition of MaxEnt was held in Brazil, hosting several distinguished researchers and students. The workshop offered four tutorials, nine invited talks, twenty four oral presentations and twenty seven poster presentations. All submissions received their first choice between oral and poster presentations. The event held a celebration to Julio Stern's 60th anniversary and awarded two prizes to young researchers. As customary, the workshop had one free afternoon, in which participants visited the city's surroundings and experienced Brazilian food and traditions.

m-RECIST at 1 month and Child A are survival predictors after percutaneous ethanol injection of hepatocellular carcinoma.

BACKGROUND AND AIMS: Percutaneous ethanol injection (PEI) is a well-established therapeutic option in patients with cirrhosis and hepatocellular carcinoma (HCC). The modified-Response Evaluation Criteria in Solid Tumors (m-RECIST) are an important tool for the assessment of HCC response to therapy. The aim was to evaluate whether HCC response according to the m-RECIST criteria could be an effective predictor of long-term survival in Barcelona Clinic Liver Cancer (BCLC) stage 0 and A HCC patients undergoing PEI. MATERIAL AND METHODS: 79 patients were followed-up for median time of 26.8 months. HCC diagnosis was based on the current guidelines of the American Association for Study of the Liver Diseases (AASLD) and European Association for Study of the Liver (EASL). Patient survival was calculated from the first PEI session to the end of the follow-up. RESULTS: The 1-, 3-, and 5-year overall survival rates were 79, 48 and 37%, respectively. In the multivariate analysis, Child-Pugh-Turcotte (CPT) (p = 0.022) and the response to m-RECIST criteria (p = 0.016) were associated with patient survival. CPT A patients who achieved Complete Response (CR) 1 month after PEI presented a 5-year survival rate of 55%. By contrast, the worst scenario, the group with CPT B but without CR had a 5-year survival rate of 9%, while the group with either CPT A or CR as a survival predictor had a 5-year survival rate of 31%. In conclusion, in BCLC stage 0 and A HCC-patients, m-RECIST at 1 month and Child A may predict survival rates after PEI.

Sex differences in brain-behavior relationships in the first two years of life.

Background: Evidence for sex differences in cognition in childhood is established, but less is known about the underlying neural mechanisms for these differences. Recent findings suggest the existence of brain-behavior relationship heterogeneities during infancy; however, it remains unclear whether sex underlies these heterogeneities during this critical period when sex-related behavioral differences arise. Methods: A sample of 316 infants was included with resting-state functional magnetic resonance imaging scans at neonate (3 weeks), 1, and 2 years of age. We used multiple linear regression to test interactions between sex and resting-state functional connectivity on behavioral scores of working memory, inhibitory self-control, intelligence, and anxiety collected at 4 years of age. Results: We found six age-specific, intra-hemispheric connections showing significant and robust sex differences in functional connectivity-behavior relationships. All connections are either with the prefrontal cortex or the temporal pole, which has direct anatomical pathways to the prefrontal cortex. Sex differences in functional connectivity only emerge when associated with behavior, and not in functional connectivity alone. Furthermore, at neonate and 2 years of age, these age-specific connections displayed greater connectivity in males and lower connectivity in females in association with better behavioral scores. Conclusions: Taken together, we critically capture robust and conserved brain mechanisms that are distinct to sex and are defined by their relationship to behavioral outcomes. Our results establish brain-behavior mechanisms as an important feature in the search for sex differences during development.

Comparative Effectiveness of Psychotherapy vs Antidepressants for Depression in Heart Failure: A Randomized Clinical Trial.

Importance: Heart failure (HF) affects more than 6 million adults in the US and more than 64 million adults worldwide, with 50% prevalence of depression. Patients and clinicians lack information on which interventions are more effective for depression in HF. Objective: To compare the effectiveness of behavioral activation psychotherapy (BA) vs antidepressant medication management (MEDS) on patient-centered outcomes inpatients with HF and depression. Design, Setting, and Participants: This pragmatic randomized comparative effectiveness trial was conducted from 2018 to 2022, including 1-year follow-up, at a not-for-profit academic health system serving more than 2 million people from diverse demographic, socioeconomic, cultural, and geographic backgrounds. Participant included inpatients and outpatients diagnosed with HF and depression, and data were analyzed as intention-to-treat. Data were analyzed from 2022 to 2023. Interventions: BA is an evidence-based manualized treatment for depression, promoting engagement in personalized pleasurable activities selected by patients. MEDS involves the use of an evidence-based collaborative care model with care managers providing coordination with patients, psychiatrists, and primary care physicians to only administer medications. Main Outcomes and Measures: The primary outcome was depressive symptom severity at 6 months, measured using the Patient Health Questionnaire 9-Item (PHQ-9). Secondary outcomes included physical and mental health-related quality of life (HRQOL), measured using the Short-Form 12-Item version 2 (SF-12); heart failure-specific HRQOL, measured using the Kansas City Cardiomyopathy Questionnaire; caregiver burden, measured with the Caregiver Burden Questionnaire for Heart Failure; emergency department visits; readmissions; days hospitalized; and mortality at 3, 6, and 12 months. Results: A total of 416 patients (mean [SD] age, 60.71 [15.61] years; 243 [58.41%] male) were enrolled, with 208 patients randomized to BA and 208 patients randomized to MEDS. At baseline, mean (SD) PHQ-9 scores were 14.54 (3.45) in the BA group and 14.31 (3.60) in the MEDS group; both BA and MEDS recipients experienced nearly 50% reduction in depressive symptoms at 3, 6, and 12 months (eg, mean [SD] score at 12 months: BA, 7.62 (5.73); P < .001; MEDS, 7.98 (6.06); P < .001; between-group P = .55). There was no statistically significant difference between BA and MEDS in the primary outcome of PHQ-9 at 6 months (mean [SD] score, 7.53 [5.74] vs 8.09 [6.06]; P = .88). BA recipients, compared with MEDS recipients, experienced small improvement in physical HRQOL at 6 months (mean [SD] SF-12 physical score: 38.82 [11.09] vs 37.12 [10.99]; P = .04), had fewer ED visits (3 months: 38% [95% CI, 14%-55%] reduction; P = .005; 6 months: 30% [95% CI, 14%-40%] reduction; P = .008; 12 months: 27% [95% CI, 15%-38%] reduction; P = .001), and spent fewer days hospitalized (3 months: 17% [95% CI, 8%-25%] reduction; P = .002; 6 months: 19% [95% CI, 13%-25%] reduction; P = .005; 12 months: 36% [95% CI, 32%-40%] reduction; P = .001). Conclusions and Relevance: In this comparative effectiveness trial of BA and MEDS in patients with HF experiencing depression, both treatments significantly reduced depressive symptoms by nearly 50% with no statistically significant differences between treatments. BA recipients experienced better physical HRQOL, fewer ED visits, and fewer days hospitalized. The study findings suggested that patients with HF could be given the choice between BA or MEDS to ameliorate depression. Trial Registration: ClinicalTrials.gov Identifier: NCT03688100.

Microvascular Aging and Eicosanoids-Women's Evaluation of Systemic Aging Tenacity ("You are never too old to become younger!") Specialized Center of Research Excellence on Sex Differences Career Enhancement Core: Building the Future.

The objective of the National Institutes of Health Office of Research in Women's Health (NIH/ORWH) Specialized Center of Research and Career Enhancement (SCORE) program is to expedite the development and application of new knowledge that affect women, to learn more about the etiology of these diseases, and to foster improved approaches to treatment and/or prevention. Each SCORE has a Career Enhancement Core (CEC) that serves to meet the career enhancement needs of translational science in the study of sex differences. The Microvascular Aging and Eicosanoids-Women's Evaluation of Systemic aging Tenacity (MAE-WEST) ("You are never too old to become younger!") Specialized Center of Research Excellence (SCORE) on Sex Differences will study pro- and anti-inflammatory responses and small vessel aging traits. As part of our SCORE CEC, we have advanced several initiatives to embed consideration of sex as a biological variable (SABV) into the infrastructure of our two CEC institutions. Unlike other professions, ongoing physician education through continuing medical education (CME) activities is required and embedded in the practice of medicine. The MAE-WEST SCORE in collaboration with the CSMC Clinical Scholars Program, the Center for Research in Women's Health and Sex-differences and the CSMC CME Office requires SABV and as Diversity, Equity, and Inclusion components in all CSMC CME programs. Clinical practice is also increasingly guided by evidence-based guidelines, with Class I recommendations resulting from clinical trials rather than expert consensus. It is essential that women be included in clinical trials proportionate to the prevalence and burden of disease. The MAE-WEST SCORE has developed our own unique CEC for providing novel educational, networking, funding opportunities, and translation to practice support. The developed best practices have found novel ways to enhance studies of women's health and SABV. We welcome visitors on-site and virtual to share with the broader academic and practicing community.

Sex differences in resting state functional connectivity across the first two years of life.

Sex differences in behavior have been reported from infancy through adulthood, but little is known about sex effects on functional circuitry in early infancy. Moreover, the relationship between early sex effects on the functional architecture of the brain and later behavioral performance remains to be elucidated. In this study, we used resting-state fMRI and a novel heatmap analysis to examine sex differences in functional connectivity with cross-sectional and longitudinal mixed models in a large cohort of infants (n = 319 neonates, 1-, and 2-year-olds). An adult dataset (n = 92) was also included for comparison. We investigated the relationship between sex differences in functional circuitry and later measures of language (collected in 1- and 2-year-olds) as well as indices of anxiety, executive function, and intelligence (collected in 4-year-olds). Brain areas showing the most significant sex differences were age-specific across infancy, with two temporal regions demonstrating consistent differences. Measures of functional connectivity showing sex differences in infancy were significantly associated with subsequent behavioral scores of language, executive function, and intelligence. Our findings provide insights into the effects of sex on dynamic neurodevelopmental trajectories during infancy and lay an important foundation for understanding the mechanisms underlying sex differences in health and disease.

The 24-Hour Movement Paradigm: An integrated approach to the measurement and promotion of daily activity in cancer clinical trials.

Increased physical activity (PA), improved sleep, and decreased sedentary behavior (SB) are essential components of supportive care for cancer survivors. However, researchers and health care professionals have achieved limited success in improving these behaviors among cancer survivors. One potential reasoning is that, over the past two decades, guidelines for promoting and measuring PA, sleep, and SB have been largely siloed. With greater understanding of these three behaviors, health behavior researchers have recently developed a new paradigm: the 24-Hour movement approach. This approach considers PA, SB, and sleep as movement behaviors along a continuum that represent low through vigorous intensity activity. Together these three behaviors form the sum of an individual's movement across a 24-hour day. While this paradigm has been studied in the general population, its usage is still limited in cancer populations. Here, we seek to highlight (a) the potential benefits of this new paradigm for clinical trial design in oncology; (b) how this approach can allow for greater integration of wearable technology as a means of assessing and monitoring patient health outside the clinical setting, improving patient autonomy through self-monitoring of movement behavior. Ultimately, implementation of the 24-Hour movement paradigm will allow health behavior research in oncology to better promote and assess critical health behaviors to support the long-term well-being for cancer patients and survivors.