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Markers that predict treatment effect have the potential to improve patient outcomes. For example, the OncotypeDX® RecurrenceScore® has some ability to predict the benefit of adjuvant chemotherapy over and above hormone therapy for the treatment of estrogen‐receptor‐positive breast cancer, facilitating the provision of chemotherapy to women most likely to benefit from it. Given that the score was originally developed for predicting outcome given hormone therapy alone, it is of interest to develop alternative combinations of the genes comprising the score that are optimized for treatment selection. However, most methodology for combining markers is useful when predicting outcome under a single treatment. We propose a method for combining markers for treatment selection which requires modeling the treatment effect as a function of markers. Multiple models of treatment effect are fit iteratively by upweighting or “boosting” subjects potentially misclassified according to treatment benefit at the previous stage. The boosting approach is compared to existing methods in a simulation study based on the change in expected outcome under marker‐based treatment. The approach improves upon methods in some settings and has comparable performance in others. Our simulation study also provides insights as to the relative merits of the existing methods. Application of the boosting approach to the breast cancer data, using scaled versions of the original markers, produces marker combinations that may have improved performance for treatment selection.

Physical exercise may increase brain volume and cortical thickness in late adulthood. However, few studies have examined the possibility for exercise to influence brain morphology in women treated for breast cancer. We conducted a nested sub-study within a randomized clinical trial to examine whether 6 months of moderate-intensity aerobic exercise in postmenopausal women with early-stage breast cancer influences brain morphology. We included twenty-eight postmenopausal women newly diagnosed with Stage 0-IIIa breast cancer (M age = 62.96 ± 5.40) who were randomized to either 45-60 min of supervised aerobic exercise 3 days/week ( = 16) or usual care ( = 12). Before beginning aromatase inhibitor aromatase inhibitor therapy, and the exercise intervention, and again at 6-month follow-up, volumetric and cortical thickness measures were derived from magnetic resonance imaging scans. There were no significant intervention effects on brain volume and cortical thickness. However, greater average exercise intensity (%) during the intervention was associated with greater post-intervention cortical volume, mean cortical thickness, precentral gyrus thickness, and superior parietal thickness (all < 0.05). Finally, total supervised exercise time was associated with higher precentral gyrus thickness after the intervention ( = 0.042, = 0.263). The exercise intervention did not significantly affect brain volumes and cortical thickness compared to the control group. However, positive associations were found between exercise intensity and brain morphology changes after the 6-month intervention, indicating that exercise may reduce the vulnerability of the brain to the deleterious effects of breast cancer and its treatment.

Background Screening for gastrointestinal (GI) cancers, specifically colorectal cancer (CRC) and hepatocellular carcinoma (HCC), is often inadequately and inequitably implemented, leading to preventable morbidity and mortality. This protocol paper describes a study designed to compare the effectiveness of external facilitation with patient navigation across hospitals in the Veterans Health Administration (VA). Methods Two hybrid type 3, cluster-randomized trials will compare the effectiveness of patient navigation versus external facilitation for supporting HCC and CRC screening completion. Twenty-four sites will be included in the HCC trial and 32 in the CRC trial, cluster-randomizing Veterans by their site of primary care. The primary outcome of reach of cancer screening completion will be measured after intervention and during sustainment. Multi-level implementation determinants (i.e., barriers and facilitators), preconditions, and moderators will be evaluated pre- and post-intervention, using Consolidated Framework for Implementation Research (CFIR)-mapped surveys and interviews of Veteran participants and provider participants. Discussion Comparing findings in the two trials will allow researchers to understand how implementation barriers and strategies operate differently for a one-time screening in a relatively healthy population (CRC) vs. repeated screening in a more medically complex population (HCC). Trial registration This project was registered at ClinicalTrials.Gov (NCT06458998) on 6/13/24. 

Background While guidelines recommend twice-yearly liver cancer (hepatocellular carcinoma, HCC) surveillance for people with cirrhosis, adherence to these guidelines remains variable. We aimed to empirically identify and apply successful implementation strategies through Getting to Implementation (GTI), a manualized facilitation approach. Methods A hybrid type III, stepped-wedge, cluster-randomized trial was conducted at 12 underperforming Veterans Health Administration (VA) sites between October 2020 and October 2022. GTI included a stepwise approach to guide sites to detail their current state, set implementation goals, identify implementation barriers, select implementation strategies, make a work plan, conduct an evaluation, and sustain their work. Outcomes were defined using the Reach , Effectiveness , Adoption , Implementation , and Maintenance (RE-AIM) framework. Results Facilitators supported site teams with an average of 20±6 facilitation hours over a 12-month period. Ten of 12 sites (83%) adopted GTI and applied a median of five strategies (e.g., dashboard use, small tests of change, direct patient outreach). Reach , the primary outcome, increased from mean 29.1% to mean 38.8% at-risk Veterans receiving HCC surveillance from pre- to post-intervention, and further increasing to 41.3% in the sustainment period. In both unadjusted and adjusted models, the odds of HCC surveillance were significantly higher during intervention (adjusted odds ratio, aOR=1.67, 95% CI:1.59, 1.75) and during sustainment (aOR=1.69, 95% CI:1.60, 1.78) compared with baseline, and with difference between active and sustainment periods, indicating sustained improvement after active facilitation ended. Conclusions GTI sustainably improved HCC surveillance, suggesting that applying data-driven implementation strategies within a manualized facilitation approach can improve care. Clinical Trial Registration ClinicalTrials.gov , NCT04178096

BACKGROUND: The single nucleotide polymorphism (SNP) rs9939609 in the fat mass and obesity associated FTO gene has been linked with increased BMI in adults. Higher BMI has been associated with poor brain health and may exert deleterious effects on neurocognitive health through cerebral hypoperfusion. However, it is unclear whether there is a relationship between the FTO genotype and cerebral perfusion or whether FTO genotype moderates the effects of weight loss on cerebral perfusion. Using data from a randomized controlled behavioral weight loss trial in adults with overweight and obesity, we tested (1) whether carriers of the A allele for FTO rs9939609 demonstrate reduced resting cerebral blood flow (rCBF) as compared to T carriers, and (2) whether the FTO genotype moderates the effects of weight loss on rCBF. We hypothesized that carriers of the A allele would exhibit lower resting CBF in frontal brain areas compared to T/T homozygotes at baseline, and that intervention-induced weight loss may partially remediate these differences. METHODS AND RESULTS: One hundred and five adults (75.2% female, mean age 44.9 years) with overweight or obesity were included in the analyses. A resting pseudo-continuous arterial spin labeling scan was acquired to examine rCBF. Age, sex, and BMI were included as covariates. At baseline, A carriers had greater rCBF in a diffuse cluster extending into the brainstem, motor cortex, and occipital lobe, but lower perfusion in the temporal lobe. We found no evidence that FTO moderated the effect of the intervention group assignment on rCBF changes. CONCLUSIONS: Overall, these results indicate that (a) individual variation in rCBF within a sample with overweight and obesity may be attributed to a common FTO variant, but (b) a weight loss intervention is effective at increasing rCBF, regardless of FTO genotype.

Background Aerobic exercise remains one of the most promising approaches for enhancing cognitive function in late adulthood, yet its potential positive effects on episodic memory remain poorly understood and a matter of intense debate. Prior meta-analyses have reported minimal improvements in episodic memory following aerobic exercise but have been limited by restrictive inclusion criteria and infrequent examination of exercise parameters. Methods We conducted a meta-analysis of randomized controlled trials to determine if aerobic exercise influences episodic memory in late adulthood ( M  = 70.82 years) and examine possible moderators. Thirty-six studies met inclusion criteria, representing data from 2750 participants. Results Here we show that aerobic exercise interventions are effective at improving episodic memory (Hedges’ g  = 0.28; p  = 0.002). Subgroup analyses revealed a moderating effect of age ( p  = 0.027), with a significant effect for studies with a mean age between 55–68 but not 69–85. Mixed-effects analyses demonstrated a positive effect on episodic memory among studies with a high percentage of females (65–100%), participants with normal cognition, studies reporting intensity, studies with a no-contact or nonaerobic physical activity control group, and studies prescribing >3900 total minutes of activity (range 540–8190 min). Conclusions Aerobic exercise positively influences episodic memory among adults ≥55 years without dementia, with larger effects observed among various sample and intervention characteristics—the clearest moderator being age. These results could have far-reaching clinical and public health relevance, highlighting aerobic exercise as an accessible, non-pharmaceutical intervention to improve episodic memory in late adulthood. Plain Language Summary One of the earliest memory systems to decline with increasing age is episodic memory. Episodic memory is the remembrance of past personal events and experiences. Given a lack of pharmaceutical treatments to prevent or reverse this deterioration, it is important to investigate non-pharmaceutical methods for promoting the integrity of episodic memory. It remains unclear whether aerobic exercise induces changes in episodic memory. This study examined the effects of aerobic exercise randomized controlled trials on episodic memory in older adults without dementia and assessed whether the effects depend on the characteristics of the sample and intervention. We found that aerobic exercise positively influences episodic memory, with larger effects observed among various sample and intervention characteristics. These results highlight aerobic exercise as an accessible, non-pharmaceutical intervention to improve episodic memory in late adulthood. Aghjayan et al. conduct a systematic review and meta-analysis of randomised controlled trials on the effect of aerobic exercise on episodic memory in late adulthood. The results demonstrate that exercise interventions improve episodic memory, with age being one moderator of this effect.

Disruptions in estrogen exposure (i.e., surgically induced menopause) have been linked to poorer cognitive aging and dementia risk. Hormone therapy use (e.g., birth control, menopausal hormone therapy) has shown mixed associations with cognitive performance, possibly due to limited cognitive test batteries. To address previous inconsistencies, we investigated baseline data from Investigating Gains in Neurocognition in an Intervention Trial of Exercise (IGNITE). We hypothesized that (1) oophorectomy prior to natural menopause would be associated with poorer cognitive performance, (2) timing and duration of birth control and menopausal hormone therapy would influence associations with cognitive performance, and (3) carrier status would interact with oophorectomy and hormone therapy to influence cognitive performance. In 461 post-menopausal females (M age = 69.6) we assessed oophorectomy and hormone therapy use to examine associations with the Montreal Cognitive Assessment (MoCA) and factor-analytically derived composite scores for episodic memory, processing speed, working memory, executive function/attentional control, and visuospatial processing. Hypothesis (1) We did not observe associations between oophorectomy prior to natural menopause and poorer cognitive performance. However, hormone therapy use, started on average within 2 years of oophorectomy, was associated with better episodic memory (β = 0.106, = 0.02), working memory (β = 0.120, = 0.005), and visuospatial processing (β = 0.095, = 0.03). Hypothesis (2) Birth control use was associated with better performance on the MoCA (β = 0.093, = 0.04), working memory (β = 0.102, = 0.02), and executive function/attentional control (β = 0.103, = 0.02). However, duration and timing of birth control and menopausal hormone therapy were not associated with cognitive performance. Hypothesis (3) We did not observe significant interactions between status and oophorectomy or hormone therapy in their associations with cognitive performance. Our results suggest exposure to estrogen during adulthood, specifically birth control and hormone therapy among women undergoing pre-menopausal oophorectomy, benefits cognitive function in older adulthood. Our comprehensive cognitive battery allowed us to examine cognitive function with a high degree of granularity. Future work should evaluate causal mechanisms of associations between lifetime estrogen exposure and later life cognitive function.

Age-related hippocampal atrophy is associated with memory loss in older adults, and certain hippocampal subfields are more vulnerable to age-related atrophy than others. Cardiorespiratory fitness (CRF) may be an important protective factor for preserving hippocampal volume, but little is known about how CRF relates to the volume of specific hippocampal subfields, and whether associations between CRF and hippocampal subfield volumes are related to episodic memory performance. To address these gaps, the current study evaluates the associations among baseline CRF, hippocampal subfield volumes, and episodic memory performance in cognitively unimpaired older adults from the Investigating Gains in Neurocognition Trial of Exercise (IGNITE) (NCT02875301). Participants (  = 601, ages 65-80, 72% female) completed assessments including a graded exercise test measuring peak oxygen comsumption (VO ) to assess CRF, cognitive testing, and high-resolution magnetic resonance imaging of the hippocampus processed with Automated Segmentation of Hippocampal Subfields (ASHS). Separate linear regression models examined whether CRF was associated with hippocampal subfield volumes and whether those assocations were moderated by age or sex. Mediation models examined whether hippocampal volumes statistically mediated the relationship between CRF and episodic memory performance. Covariates included age, sex, years of education, body mass index, estimated intracranial volume, and study site. Higher CRF was significantly associated with greater total left (  = 5.82,  = 0.039) and total right (  = 7.64,  = 0.006) hippocampal volume, as well as greater left CA2 (  = 0.14,  = 0.022) and dentate gyrus (DG;  = 2.34,  = 0.031) volume, and greater right CA1 (  = 3.99,  = 0.011), CA2 (  = 0.15,  = 0.002), and subiculum (  = 1.56,  = 0.004) volume. Sex significantly moderated left DG volume (  = -4.26,  = 0.017), such that the association was positive and significant only for males. Total left hippocampal volume [indirect effect = 0.002, 95% CI (0.0002, 0.00),  = 0.027] and right subiculum volume [indirect effect = 0.002, 95% CI (0.0007, 0.01),  = 0.006] statistically mediated the relationship between CRF and episodic memory performance. While higher CRF was significantly associated with greater total hippocampal volume, CRF was not associated with all underlying subfield volumes. Our results further demonstrate the relevance of the associations between CRF and hippocampal volume for episodic memory performance. Finally, our results suggest that the regionally-specific effects of aging and Alzheimer's disease on hippocampal subfields could be mitigated by maintaining higher CRF in older adulthood.

IntroductionPhysical activity (PA) has beneficial effects on brain health and cardiovascular disease (CVD) risk. Yet, we know little about whether PA-induced changes to physiological mediators of CVD risk influence brain health and whether benefits to brain health may also explain PA-induced improvements to CVD risk. This study combines neurobiological and peripheral physiological methods in the context of a randomised clinical trial to better understand the links between exercise, brain health and CVD risk.Methods and analysisIn this 12-month trial, 130 healthy individuals between the ages of 26 and 58 will be randomly assigned to either: (1) moderate-intensity aerobic PA for 150 min/week or (2) a health information control group. Cardiovascular, neuroimaging and PA measurements will occur for both groups before and after the intervention. Primary outcomes include changes in (1) brain structural areas (ie, hippocampal volume); (2) systolic blood pressure (SBP) responses to functional MRI cognitive stressor tasks and (3) heart rate variability. The main secondary outcomes include changes in (1) brain activity, resting state connectivity, cortical thickness and cortical volume; (2) daily life SBP stress reactivity; (3) negative and positive affect; (4) baroreflex sensitivity; (5) pulse wave velocity; (6) endothelial function and (7) daily life positive and negative affect. Our results are expected to have both mechanistic and public health implications regarding brain–body interactions in the context of cardiovascular health.Ethics and disseminationEthical approval has been obtained from the University of Pittsburgh Institutional Review Board (IRB ID: 19020218). This study will comply with the NIH Data Sharing Policy and Policy on the Dissemination of NIH-Funded Clinical Trial Information and the Clinical Trials Registration and Results Information Submission rule.Trial registration numberNCT03841669.