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.

Loss of humeral immunity in childhood cancer survivors not having undergone hematopoietic stem cell transplantation.

BACKGROUND: Data are limited and conflicting regarding loss of immunity in childhood cancer survivors who did not undergo hematopoietic stem cell transplantation. The purpose of this retrospective, single center study is to provide further data to help build unifying revaccination guidelines post-chemotherapy in childhood cancer survivors not having undergone hematopoietic stem cell transplantation. METHODS: This retrospective study included 28 childhood cancer survivors, 14 males and 14 females, whose treatment consisted of at least 3 months of chemotherapy and with confirmation of completing their primary vaccination series prior to therapy. The rate of vaccine titer seropositivity for cancer survivors was compared with the expected general population, based on long-term studies of anti-body persistence. RESULTS: Decreased seropositivity for measles, mumps, rubella, varicella, tetanus, and hepatitis B was found in patients across all categories of malignancy compared with the general population. However, tetanus was not statistically significant. Results were more pronounced for those with hematological malignancies. CONCLUSIONS: This study indicates that pediatric cancer survivors, especially those with hematological malignancies, may have greater loss of protective antibodies from primary vaccinations. Further studies are needed to provide guidelines for revaccination of both hematologic malignancies and solid tumor childhood cancer survivors who did not undergo hematopoietic stem cell transplantation.

Dynamic Risk Prediction of Treatment Discontinuation Using Patient-Reported Outcomes Data in the Phase III NSABP B-35 Trial.

Predicting an individual's risk of treatment discontinuation is critical for the implementation of precision chemoprevention. We developed partly conditional survival models to predict discontinuation of tamoxifen or anastrozole using patient-reported outcome (PRO) data from postmenopausal women with ductal carcinoma in situ enrolled in the NSABP B-35 clinical trial. In a secondary analysis of the NSABP B-35 clinical trial PRO data, we proposed two models for treatment discontinuation within each treatment arm (anastrozole or tamoxifen treated patients) using partly conditional Cox-type models with time-dependent covariates. A 70/30 split of the sample was used for the training and validation datasets. The predictive performance of the models was evaluated using calibration and discrimination measures based on the Brier score and AUC from time-dependent ROC curves. The predictive models stratified high-risk versus low-risk early discontinuation at a 6-month horizon. For anastrozole-treated patients, predictive factors included baseline body mass index (BMI) and longitudinal patient-reported symptoms such as insomnia, joint pain, hot flashes, headaches, gynecologic symptoms, and vaginal discharge, all collected up to 12 months [Brier score, 0.039; AUC, 0.76; 95% confidence interval (CI), 0.57-0.95]. As for tamoxifen-treated patients, predictive factors included baseline BMI, and time-dependent covariates: cognitive problems, feelings of happiness, calmness, weight problems, and pain (Brier score, 0.032; AUC, 0.78; 95% CI, 0.65-0.91). A real-time calculator based on these models was developed in Shiny to create a web-based application with a future goal to aid healthcare professionals in decision-making. PREVENTION RELEVANCE: The dynamic prediction provided by partly conditional models offers valuable insights into the treatment discontinuation risks using PRO data collected over time from clinical trial participants. This tool may benefit healthcare professionals in identifying patients at high risk of premature treatment discontinuation and support interventions to prevent potential discontinuation.

A multi-laboratory preclinical trial in rodents to assess treatment candidates for acute ischemic stroke.

Human diseases may be modeled in animals to allow preclinical assessment of putative new clinical interventions. Recent, highly publicized failures of large clinical trials called into question the rigor, design, and value of preclinical assessment. We established the Stroke Preclinical Assessment Network (SPAN) to design and implement a randomized, controlled, blinded, multi-laboratory trial for the rigorous assessment of candidate stroke treatments combined with intravascular thrombectomy. Efficacy and futility boundaries in a multi-arm multi-stage statistical design aimed to exclude from further study highly effective or futile interventions after each of four sequential stages. Six independent research laboratories performed a standard focal cerebral ischemic insult in five animal models that included equal numbers of males and females: young mice, young rats, aging mice, mice with diet-induced obesity, and spontaneously hypertensive rats. The laboratories adhered to a common protocol and efficiently enrolled 2615 animals with full data completion and comprehensive animal tracking. SPAN successfully implemented treatment masking, randomization, prerandomization inclusion and exclusion criteria, and blinded assessment of outcomes. The SPAN design and infrastructure provide an effective approach that could be used in similar preclinical, multi-laboratory studies in other disease areas and should help improve reproducibility in translational science.

Comparing the Safety Action Feedback and Engagement (SAFE) Loop with an established incident reporting system: Study protocol for a pragmatic cluster randomized controlled trial.

Background: Incident reporting is widely used in hospitals to improve patient safety, but current reporting systems do not function optimally. The utility of incident reports is limited because hospital staff may not know what to report, may fear retaliation, and may doubt whether administrators will review reports and respond effectively. Methods: This is a clustered randomized controlled trial of the Safety Action Feedback and Engagement (SAFE) Loop, an intervention designed to transform hospital incident reporting systems into effective tools for improving patient safety. The SAFE Loop has six key attributes: obtaining nurses' input about which safety problems to prioritize on their unit; focusing on learning about selected high-priority events; training nurses to write more informative event reports; prompting nurses to report high-priority events; integrating information about events from multiple sources; and providing feedback to nurses on findings and mitigation plans. The study will focus on medication errors and randomize 20 nursing units at a large academic/community hospital in Los Angeles. Outcomes include: (1) incident reporting practices (rates of high-priority reports, contributing factors described in reports), (2) nurses' attitudes toward incident reporting, and (3) rates of high-priority events. Quantitative analyses will compare changes in outcomes pre- and post-implementation between the intervention and control nursing units, and qualitative analyses will explore nurses' experiences with implementation. Conclusion: If effective, SAFE Loop will have several benefits: increasing nurses' engagement with reporting, producing more informative reports, enabling safety leaders to understand problems, designing system-based solutions more effectively, and lowering rates of high-priority patient safety events.

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.

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.

Benefits of nature-based walking for breast cancer survivors.

INTRODUCTION: Physical activity (PA) promotes significant physical and psychosocial benefits for breast cancer survivors. While evidence exists regarding recommendations for the frequency, duration and intensity of exercise that optimise PA benefits for cancer survivors, the role of the environment in achieving optimal outcomes has yet to be determined. This paper presents a protocol for a clinical trial to evaluate the feasibility of a 3-month nature-based walking programme for breast cancer survivors. Secondary outcomes assessed include the impact of the intervention on fitness, quality of life outcomes, and biomarkers of ageing and inflammation. METHODS AND ANALYSIS: The trial is a 12-week single-arm pilot study. Twenty female breast cancer survivors will engage in a supervised moderate intensity walking intervention in small groups in a nature reserve for 50 minutes three times per week. Data will be collected at baseline and end of study, and include assessment of inflammatory cytokines and anti-inflammatory myokines (TNF-α, IL-1ß, IL-6, CRP, TGF-ß, IL-10, IL-13), as well as ageing (DNA methylation, ageing genes) biomarkers; surveys (Patient-Reported Outcomes Measurement Information System-29, Functional Assessment of Cancer Therapy-General, Post-Traumatic Growth Inventory); and fitness assessments (6 min Walk Test, Grip-Strength, One Repetition-Maximum Leg Press). Participants will also complete weekly surveys assessing social support and participate in an exit interview. This is an important first step for future research on the influence of exercise environment on cancer survivor PA outcomes. ETHICS AND DISSEMINATION: This study was approved by the Cedars Sinai Medical Center Institutional Review Board (IIT2020-20). Findings will be disseminated through academic manuscripts, conferences, and community presentations. TRIAL REGISTRATION NUMBER: NCT04896580.

A 6-Week Program to Strengthen Resiliency Among Women With Metastatic Cancer: A Randomized Clinical Trial.

PURPOSE: The objective of this study was to evaluate the effect of an intervention (Growing Resilience And CouragE; GRACE) on spiritual well-being, quality of life, and general well-being in women with metastatic cancers reporting existential or spiritual distress. PATIENTS AND METHODS: Prospective, randomized, wait-list control clinical trial. Women with metastatic cancer experiencing existential or spiritual concerns were randomized to GRACE or waitlist control. Survey data were collected at baseline, end of program, and 1-month follow-up. Participants included English-speaking women, 18 or older, with metastatic cancer, existential or spiritual concerns, and reasonable medical stability. Eighty-one women were assessed for eligibility; 10 were excluded (not meeting exclusion criteria, refusal to participate, and death). The primary outcome was spiritual well-being measured pre- and post-program. Secondary measures assessed quality of life, anxiety, depression, hopelessness, and loneliness. RESULTS: Seventy-one women (aged 47-72) were enrolled (GRACE n = 37, waitlist control n = 34). GRACE participants demonstrated significant improvements in spiritual well-being compared to control at end of program (parameter estimate (PE), 16.67, 95% CI, 13.17, 20.16) and 1-month follow-up (PE, 10.31, 95% CI, 6.73, 13.89). Additionally, significant improvements were demonstrated in quality of life at the end of program (PE, 8.51, 95% CI, 4.26, 12.76) and 1-month follow-up (PE, 6.17, 95% CI, 1.75, 10.58). GRACE participants also demonstrated improved depression and hopelessness at follow-up, as well as improved anxiety. CONCLUSIONS: Findings suggest the value of evidence-based psychoeducational and experiential interventions for improving the well-being and quality of life of women with advanced cancer. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02707510.

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 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.

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.

Comparison of computed tomography response criteria after chemoembolization of hepatic carcinoma in dogs.

The objective of this study was to evaluate unidimensional (mm), bidimensional (mm2), or tridimensional (mL) computed tomography (CT) tumor measurements for ability to discriminate changes in lesion size and predict survival in dogs with nonresectable hepatic carcinoma treated with drug-eluting bead transarterial-chemoembolization (DEB-TACE) and to compare CT response via Response Evaluation Criteria in Solid Tumors 1.1 (mm), World Health Organization (mm2), ellipsoid and spherical volume (mL), and percent necrosis, for their ability to differentiate treatment responders. This was a prospective, single-arm clinical trial. DEB-TACE was performed to varying levels of blood flow stasis in 16 client-owned dogs with nonresectable hepatic carcinoma. Computed tomography imaging responses were assessed and compared to median survival time. Results revealed that initial, follow-up, or changes in unidimensional, bidimensional, or tridimensional tumor measurements were not associated with survival. Larger bidimensional and tridimensional tumor measurements/body weight on initial and follow-up CT were significantly associated with a shorter median survival time [bidimensional (P = 0.04, 0.016) and tridimensional (P = 0.025, 0.015), respectively]. A higher percent necrosis on initial CT was significantly associated with a shorter median survival time (P = 0.038). Ellipsoid volumetric criteria detected treatment response most frequently; however, response classification was not associated with median survival time. Computed tomography bidimensional and tridimensional tumor measurements/body weight before and after DEB-TACE may help to predict median survival time for dogs undergoing DEB-TACE for hepatic carcinoma.

L'objectif de cette étude était d'évaluer les mesures tumorales unidimensionnelles (mm), bidimensionnelles (mm2) ou tridimensionnelles (mL) par tomodensitométrie (CT) pour déterminer la capacité de discriminer les changements de taille des lésions et de prédire la survie chez les chiens atteints d'un carcinome hépatique non-résécable traité avec un médicament par chimioembolisation transartérielle par billes à élution (DEB-TACE) et pour comparer la réponse CT via les critères d'évaluation de la réponse dans les tumeurs solides 1,1 (mm), l'Organisation mondiale de la santé (mm2), le volume ellipsoïde et sphérique (mL) et le pourcentage de nécrose, pour leur capacité à différencier les répondeurs au traitement. Il s'agissait d'un essai clinique prospectif à un seul volet. Le DEB-TACE a été réalisé à différents niveaux de stase du flux sanguin chez 16 chiens appartenant à des clients atteints d'un carcinome hépatique non-résécable. Les réponses d'imagerie par tomodensitométrie ont été évaluées et comparées au temps de survie médian. Les résultats ont révélé que les mesures initiales, de suivi ou les modifications des mesures tumorales unidimensionnelles, bidimensionnelles ou tridimensionnelles n'étaient pas associées à la survie. Des mesures tumorales bidimensionnelles et tridimensionnelles plus grandes/poids corporel sur la CT initiale et de suivi étaient significativement associées à un temps de survie médian plus court [bidimensionnel (P = 0,04, 0,016) et tridimensionnel (P = 0,025, 0,015), respectivement]. Un pourcentage plus élevé de nécrose au scanner initial CT était significativement associé à une durée de survie médiane plus courte (P = 0,038). Les critères volumétriques ellipsoïdes ont détecté la réponse au traitement le plus fréquemment; cependant, la classification des réponses n'était pas associée à la durée médiane de survie. La tomodensitométrie bidimensionnelle et tridimensionnelle des mesures tumorales/poids corporel avant et après DEB-TACE peut aider à prédire la durée médiane de survie des chiens subissant DEB-TACE pour un carcinome hépatique.(Traduit par Docteur Serge Messier).

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.

Supplementing a widely available weight loss program with gamified inhibitory control training: A randomized pilot study.

Background: Increasing evidence suggests that targeting self-regulatory processes may improve obesity treatment outcomes. Incorporating gamification principles in inhibitory control training may promote sustained training adherence and resulting benefits. This pilot study evaluated the preliminary efficacy of supplementing an evidence-based weight management program (WW) with sustained gamified inhibitory control training (PolyRules!) on change in Body Mass Index (BMI) among adults with overweight/obesity. Methods: 30 adults with overweight/obesity (M age 49.9 ± 12.4, 86.7% female; 23.3% Hispanic, mean BMI 35.3 ± 6.3) were randomly assigned to receive WW with or without PolyRules! for 12 weeks. The primary outcome was change in BMI from baseline to post-intervention across study arms. Implementation and process indicators were captured to inform larger trials. Results: Average change in BMI was -0.9 in the WW arm and -1.2 in the WW + PolyRules! arm (Cohen's d = 0.26). In the WW + PolyRules! arm, increased training was associated with greater decreases in BMI (r = -0.506, p = 0.0454). WW + PolyRules! participants completed an average of 60.4% sessions and reported positive experiences. There was no difference in frequency of food (d = -0.02) and weight tracking (d = -0.19) between arms. Conclusions: Studies in larger samples should evaluate training-related effects on weight. Supplementing WW with gamified inhibitory training appears feasible, with no detrimental effect on engagement.

Toxicity Index, patient-reported outcomes, and persistence of breast cancer chemotherapy-associated side effects in NRG Oncology/NSABP B-30.

Adjuvant chemotherapy improves breast cancer survival but is associated with bothersome short- and long-term toxicity. Factors associated with toxicity, especially subacute toxicity up to 2 years following chemotherapy, have not been fully elucidated. The NRG Oncology/NSABP B-30 clinical trial compared 3 different doxorubicin-, cyclophosphamide-, and docetaxel-based chemotherapy regimens given over 3-6 months. Patients with hormone receptor-positive breast cancer received subsequent adjuvant endocrine therapy. From baseline through 24 months, 2156 patients completed questionnaires serially. We used multivariable probabilistic index models to identify factors associated with acute (>0-12 months) and subacute (>12-24 months) difficulties with pain, cognition, vasomotor symptoms, and vaginal symptoms. For all symptom domains, presence of symptoms prior to chemotherapy initiation were associated with symptoms in the subacute period (all p < 0.001). In addition, different combinations of patient factors and breast cancer treatments were associated with increased likelihood of pain, vasomotor, and vaginal symptoms in the subacute period. Consideration of pre-treatment symptoms and patient factors, as well as treatments for breast cancer, can facilitate identification of groups of patients that may experience symptoms following completion of chemotherapy. This information may be important for treatment-decision-making when alternative regimens are equivalent in benefit.

Salivary Biomarker Evaluation of Chronic Pancreatitis Patients Reveals Alterations in Human Proteins, Cytokines, Prostaglandin E2 Levels, and Bacterial Diversity.

OBJECTIVES: Chronic pancreatitis (CP) is a chronic fibroinflammatory condition of the pancreas difficult to diagnose in early stages. Novel biomarkers useful to facilitate early diagnosis or treatment responses may be found in biofluids. Although saliva can be easily and noninvasively collected from patients, useful salivary biomarkers from CP patients have not yet been identified. METHODS: Here, we analyzed the proteome by quantitative proteomics, cytokine/chemokine levels by Luminex analysis, prostaglandin E2 (PGE2) levels by a mass spectrometry-based assay, and bacterial species diversity by 16S ribosomal ribonucleic acid sequencing in saliva samples from confirmed CP patients and healthy controls. RESULTS: Our results indicate the presence of various differentially expressed proteins, cytokines/chemokines, and a loss of oral bacterial diversity in the saliva of CP patients. The PGE2 levels trend toward elevation in CP patients. Area under the receiver operating characteristic curve models for proteomic, cytokine, and PGE2 assays ranged from 0.59 to 0.90. CONCLUSIONS: Collectively, our studies identify a range of putative CP biomarkers and alterations in human saliva requiring further validation. The biomarker discovery approaches we used might lead to identification of biomarkers useful for CP diagnosis and monitoring.

Evaluating environmental and inhibitory control strategies to improve outcomes in a widely available weight loss program.

BACKGROUND: Although many people try to lose weight, a large proportion of individuals do not achieve clinically significant weight loss. Nonresponse and relapse rates in lifestyle interventions are largely explained by challenges in avoiding or resisting temptation in the context of omnipresent food access. Innovative enhancement strategies are needed to help individuals manage temptation in evidence-based lifestyle interventions. METHODS: This prospective, four-parallel-arm, randomized controlled trial tests the efficacy of two weight management enhancement strategies on weight and dietary outcomes among individuals with overweight or obesity: (1) an environmental control strategy combining modification of the home food environment and grocery delivery (AVOID) and (2) an impulse control strategy involving daily, gamified inhibitory control training (RESIST). Women and men (n = 500) with overweight or obesity (Body Mass Index between 25 and 40.0 kg/m2) will be enrolled in a 12-month commercial weight-loss program (WW, formerly Weight Watchers©) and randomly assigned to one of four conditions: (1) WW alone, (2) WW + AVOID, (3) WW + RESIST, or (4) WW + AVOID + RESIST. Anthropometric, dietary, cognitive, and household food environment assessments will be conducted in English or Spanish at enrollment and at 6- and 12-month follow-up. DISCUSSION: This research addresses the pragmatic question of how to best optimize behavior change: Should we modify the choice environment, strengthen individuals' self-regulation, or both, to maximize behavior change? This work can inform the development of enhancement strategies to promote adherence to lifestyle recommendations and other impulse control challenges.

Statistical methods for validation of predictive models.

Predictive models are widely used in clinical practice. Despite of the increasing number of published AI systems, recent systematic reviews have identified lack of statistical rigor in the development and validation of predictive models. This work reviewed the current literature for predictive performance measures and resampling methods. Furthermore, common pitfalls were discussed.