The impact of non- and anthracycline-based chemotherapy on fatigue in breast cancer survivors: results from WF-97415.

PURPOSE: To examine the differential effect of non- and anthracycline-based chemotherapy on fatigue over 12 months post-diagnosis among breast cancer survivors. METHODS: This study is based on a prospective Wake Forest NCI Community Oncology Research Program (NCORP) multicenter cohort study (WF-97415) of women with stage I to III breast cancer and non-cancer controls. Analyses compared those: 1) receiving, or 2) not receiving anthracycline chemotherapy, 3) receiving aromatase inhibitors (AIs) without chemotherapy, with 4) a comparator group without a history of cancer. In-person clinic assessments were conducted at: baseline (prior to chemotherapy or start of AI therapy), and 3 and 12 months after baseline. The Functional Assessment of Chronic Illness Therapy-Fatigue scale was the primary outcome. Estimated least squares means by group using mixed models with a random subject effect, fixed effects of time and group, and the interaction between time and group was used to compare groups across time, controlling for age, comorbidities, and treatment variables. RESULTS: Among 284 women (mean age = 53.4 years, sd 11.9 years), there was a significant (p < 0.0001) group by time interaction, with a sharp increase in fatigue at 3 months in the two chemotherapy groups in comparison to the non-chemotherapy and non-cancer controls. The two chemotherapy groups did not significantly differ in fatigue at any time point. CONCLUSION: Women with breast cancer who receive non- or anthracycline-based chemotherapy experience similar trends in and levels of fatigue within the first year of treatment and greater fatigue than women receiving AIs alone or women without breast cancer.

The relationship between body composition and left ventricular performance in women with breast, lymphoma, or sarcoma cancer.

BACKGROUND: To understand how body composition in those with elevated body mass index impacts left ventricular function decline during cancer treatment, we determined the association between baseline body mass index (BMI), intra-abdominal adipose tissue (IAT) and subcutaneous adipose tissue (SAT) with baseline to 3-month left ventricular ejection fraction (LVEF) change among women receiving potentially cardiotoxic chemotherapy for breast cancer, lymphoma, or sarcoma. METHODS: Women underwent potentially cardiotoxic chemotherapy, such as doxorubicin, cyclophosphamide, paclitaxel, and trastuzumab, for treatment of breast cancer, lymphoma, or sarcoma. We obtained magnetic resonance images (MRIs) of body composition and cardiac function prior to treatment, and then a repeat MRI for cardiac function assessment at three months into treatment. Analyses and assessment of abdominal adipose tissue volumes and LVEF outcomes were conducted by independent reviewers blinded to all patient identifiers. A general linear model was created to examine associations between adipose tissue depots, BMI, and 3-month LVEF change. RESULTS: Women (n = 210) aged 56 ± 11 years with breast cancer, lymphoma, and sarcoma were enrolled (n = 195, 14, 1 respectively). Baseline BMI, IAT, and SAT fat were independently associated with 3-month LVEF declines (p = 0.001 to 0.025 for all). After adjusting for baseline cardiovascular disease risk factors, BMI, IAT, and SAT, BMI remained the only variable associated with 3-month LVEF decline (p = 0.047). CONCLUSIONS: These results suggest that factors other than abdominal adipose tissue or traditional cardiovascular risk factors may contribute to 3-month declines in LVEF among women with elevated BMI receiving potentially cardiotoxic chemotherapy. Further investigation should be conducted on psychosocial stress, physical activity, sleep, or diet. TRIAL REGISTRATION: DETECTIV_NCT01719562, WF99112, & WF97415-NCT02791581.

PLX038A, a long-acting SN-38, penetrates the blood-tumor-brain-barrier, accumulates and releases SN-38 in brain tumors to increase survival of tumor bearing mice.

Central nervous system tumors have resisted effective chemotherapy because most therapeutics do not penetrate the blood-tumor-brain-barrier. Nanomedicines between ~ 10 and 100 nm accumulate in many solid tumors by the enhanced permeability and retention effect, but it is controversial whether the effect can be exploited for treatment of brain tumors. PLX038A is a long-acting prodrug of the topoisomerase 1 inhibitor SN-38. It is composed of a 15 nm 4-arm 40 kDa PEG tethered to four SN-38 moieties by linkers that slowly cleave to release the SN-38. The prodrug was remarkably effective at suppressing growth of intracranial breast cancer and glioblastoma (GBM), significantly increasing the life span of mice harboring them. We addressed the important issue of whether the prodrug releases SN-38 systemically and then penetrates the brain to exert anti-tumor effects, or whether it directly penetrates the blood-tumor-brain-barrier and releases the SN-38 cargo within the tumor. We argue that the amount of SN-38 formed systemically is insufficient to inhibit the tumors, and show by PET imaging that a close surrogate of the 40 kDa PEG carrier in PLX038A accumulates and is retained in the GBM. We conclude that the prodrug penetrates the blood-tumor-brain-barrier, accumulates in the tumor microenvironment and releases its SN-38 cargo from within. Based on our results, we pose the provocative question as to whether the 40 kDa nanomolecule PEG carrier might serve as a "Trojan horse" to carry other drugs past the blood-tumor-brain-barrier and release them into brain tumors.

Transcendent thinking counteracts longitudinal effects of mid-adolescent exposure to community violence in the anterior cingulate cortex.

Adolescence involves extensive brain maturation, characterized by social sensitivity and emotional lability, that co-occurs with increased independence. Mid-adolescence is also a hallmark developmental stage when youths become motivated to reflect on the broader personal, ethical, and systems-level implications of happenings, a process we term transcendent thinking. Here, we examine the confluence of these developmental processes to ask, from a transdisciplinary perspective, how might community violence exposure (CVE) impact brain development during mid-adolescence, and how might youths' dispositions for transcendent thinking be protective? Fifty-five low-SES urban youth with no history of delinquency (32 female; 27 Latinx, 28 East Asian) reported their CVE and underwent structural MRI first at age 14-18, and again 2 years later. At the study's start, participants also discussed their feelings about 40 minidocumentaries featuring other teens' compelling situations in a 2-h private interview that was transcribed and coded for transcendent thinking. Controlling for CVE and brain structure at the start: (1) New CVE during the 2-year inter-scan interval was associated with greater gray matter volume (GMV) reduction over that interval in the anterior cingulate cortex (ACC), a central network hub whose reduced volume has been associated with posttraumatic stress disorder, and across multiple additional cortical and subcortical regions; (2) participants' transcendent thinking in the interview independently predicted greater GMV increase during the 2-year inter-scan interval in the ACC. Findings highlight the continued vulnerability of mid-adolescents to community violence and the importance of supporting teens' dispositions to reflect on the complex personal and systems-level implications and affordances of their civic landscape.

Examining State Licensing Requirements for Select Master's-Level Behavioral Health Providers for Children.

OBJECTIVE: The authors examined licensing requirements for select children's behavioral health care providers. METHODS: Statutes and regulations as of October 2021 were reviewed for licensed clinical social workers, licensed professional counselors, and licensed marriage and family therapists for all 50 U.S. states and the District of Columbia. RESULTS: All jurisdictions had laws regarding postgraduate training and license portability. No jurisdiction included language about specialized postgraduate training related to serving children and families or cultural competence. Other policies that related to the structure, composition, and authority of licensing boards varied across states and licensure types. CONCLUSIONS: In their efforts to address barriers to licensure, expand the workforce, and ensure that children have access to high-quality and culturally responsive care, states could consider their statutes and regulations.

Diverse adolescents' transcendent thinking predicts young adult psychosocial outcomes via brain network development.

Developmental scientists have long described mid-adolescents' emerging capacities to make deep meaning about the social world and self, here called transcendent thinking, as a hallmark developmental stage. In this 5-years longitudinal study, sixty-five 14-18 years-old youths' proclivities to grapple psychologically with the ethical, systems-level and personal implications of social stories, predicted future increases in the coordination of two key brain networks: the default-mode network, involved in reflective, autobiographical and free-form thinking, and the executive control network, involved in effortful, focused thinking; findings were independent of IQ, ethnicity, and socioeconomic background. This neural development predicted late-adolescent identity development, which predicted young-adult self-liking and relationship satisfaction, in a developmental cascade. The findings reveal a novel predictor of mid-adolescents' neural development, and suggest the importance of attending to adolescents' proclivities to engage agentically with complex perspectives and emotions on the social and personal relevance of issues, such as through civically minded educational approaches.

Lack of TGFß signaling competency predicts immune poor cancer conversion to immune rich and response to checkpoint blockade.

Background: Transforming growth factor beta (TGFß) is well-recognized as an immunosuppressive player in the tumor microenvironment but also has a significant impact on cancer cell phenotypes. Loss of TGFß signaling impairs DNA repair competency, which is described by a transcriptomic score, ßAlt. Cancers with high ßAlt have more genomic damage and are more responsive to genotoxic therapy. The growing appreciation that cancer DNA repair deficits are important determinants of immune response prompted us to investigate the association of ßAlt with response to immune checkpoint blockade (ICB). We predicted that high ßAlt tumors would be infiltrated with lymphocytes because of DNA damage burden and hence responsive to ICB. Methods: We analyzed public transcriptomic data from clinical trials and preclinical models using transcriptomic signatures of TGFß targets, DNA repair genes, tumor educated immune cells and interferon. A high ßAlt, immune poor mammary tumor derived transplant model resistant to programmed death ligand 1 (PD-L1) antibodies was studied using multispectral flow cytometry to interrogate the immune system. Results: Metastatic bladder patients in IMvigor 210 who responded to ICB had significantly increased ßAlt scores and experienced significantly longer overall survival compared to those with low ßAlt scores (hazard ratio 0.62, P=0.011) . Unexpectedly, 75% of high ßAlt cancers were immune poor as defined by low expression of tumor educated immune cell and interferon signatures. The association of high ßAlt with immune poor cancer was also evident in TCGA and preclinical cancer models. We used a high ßAlt, immune poor cancer to test therapeutic strategies to overcome its inherent anti-PD-L1 resistance. Combination treatment with radiation and TGFß inhibition were necessary for lymphocytic infiltration and activated NK cells were required for ICB response. Bioinformatic analysis identified high ßAlt, immune poor B16 and CT26 preclinical models and paired biopsies of cancer patients that also demonstrated NK cell activation upon response to ICB. Conclusions: Our studies support ßAlt as a biomarker that predicts response to ICB albeit in immune poor cancers, which has implications for the development of therapeutic strategies to increase the number of cancer patients who will benefit from immunotherapy.

Thrombolytic Treatment in Wake-Up Stroke: A Propensity Score-Matched Analysis of Treatment Effectiveness in the Norwegian Stroke Registry.

BACKGROUND: Previous clinical trials found improved outcome of thrombolytic treatment in patients with ischemic wake-up stroke (WUS) selected by advanced imaging techniques. The authors assessed the effectiveness of thrombolytic treatment in patients with WUS in a nationwide stroke registry. METHODS AND RESULTS: Using propensity score matching, the authors assessed the effectiveness and safety of thrombolytic treatment versus no thrombolytic treatment in 726 patients (363 matched pairs) with WUS in the Norwegian Stroke Registry in 2014 to 2019. Thrombolytic treatment in WUS versus known-onset stroke was compared in 730 patients (365 matched pairs). Functional outcomes were assessed by the modified Rankin Scale (mRS) at 3 months. A significant benefit of thrombolytic treatment in WUS was seen in ordinal analysis (odds ratio [OR], 1.48 [95% CI, 1.15-1.91]; P=0.003) and for mRS 0 to 2 (OR, 1.81 [95% CI, 1.29-2.52]; P=0.001) but not for mRS 0 or 1 (OR, 1.32 [95% CI, 1.00-1.74]; P=0.050). The proportion of patients with mRS 0 or 1 was lower in patients with WUS who underwent thrombolysis versus those with known-onset stroke (50.4% versus 59.5%; OR, 0.69 [95% CI, 0.52-0.93]; P=0.013), while outcomes were similar between groups for mRS 0 to 2 and ordinal analysis. Symptomatic intracranial hemorrhage after thrombolytic treatment occurred in 4.4% of patients with WUS and 3.9% of patients with known-onset stroke (OR, 1.14 [95% CI, 0.54-2.41]; P=0.726). CONCLUSIONS: Thrombolytic treatment in patients with WUS was associated with improved functional outcome compared with patients with no thrombolytic treatment and was not associated with increased rates of symptomatic intracranial hemorrhage compared with known-onset stroke. The results indicate that thrombolytic treatment is effective and safe in WUS in a real-life setting.

Disaster Preparedness in a Resettled Refugee Community: Qualitative Findings.

INTRODUCTION: Under-resourced communities face disaster preparedness challenges. Research is limited for resettled refugee communities, which have unique preparedness needs. STUDY OBJECTIVE: This study aims to assess disaster preparedness among the refugee community in Clarkston, GA. METHODS: Twenty-five semi-structured interviews were completed with community stakeholders. Convenience sampling using the snowball method was utilized until thematic saturation was reached. Thematic analysis of interviews was conducted through an inductive, iterative approach by a multidisciplinary team using manual coding and MAXQDA. RESULTS: Three themes were identified: First, prioritization of routine daily needs took precedence for families over disaster preparedness. Second, communication impacts preparedness. Community members speak different languages and often do not have proficiency in English. Access to resources in native languages and creative communication tactics are important tools. Finally, the study revealed a unique interplay between government, community-based organizations, and the refugee community. A web of formal and informal responses is vital to helping this community in times of need. CONCLUSION: The refugee community in Clarkston, GA faces challenges, and disaster preparedness may not be top of mind for them. However, clear communication, disaster preparedness planning, and collaboration between government, community-based organizations, and the community are possible areas to focus on to bolster readiness.

"God was with me": A qualitative study of Christian meaning-making among refugees.

In this consensual qualitative research study, we investigated the role of refugees' Christian faith in meaning-making coping. High percentages of religiosity in refugee populations support the need to understand the role of religion in their coping processes. Interviews with 20 Christian refugees from 10 African and Asian countries revealed that participants drew heavily from their faith resources to cope with their experiences. Specifically, refugees reported coping practices that included trust in God, prayer, intimacy with God, spiritual surrender, lament, worship, and social support. Although many participants described spiritual struggles, including doubting God, feeling distant from God, and questioning God, most found meaning amid refugee-related suffering and reported perspective shifts, a deepening of faith, seeing suffering as part of God's plan, experiencing a deepened sense of purpose, and growing in the likeness of Christ. Refugees also reported growth through suffering in the form of gratitude, altruism, testimony, and humility. Clinical implications include encouraging the use of religious resources for meaning-making and supporting the resolution of spiritual struggles.

Cardiovascular impact of near complete estrogen deprivation in premenopausal women with breast cancer: The CROWN study.

Survival with operable breast cancer has improved markedly in recent decades, however, treatment-related cardiovascular toxicities threaten to offset these gains. Ovarian function suppression paired with aromatase inhibition, for premenopausal women with hormone receptor (HR)-positive breast cancer, is a newer widely adopted therapy with the potential for significant long-term cardiovascular toxicity. Abrupt estrogen deprivation for non-cancer reasons is associated with accelerated coronary artery disease. Women with breast cancer treated with aromatase inhibition in addition to ovarian function suppression experience a dual hit with regards to estrogen exposure. The CaRdiac Outcomes With Near-complete estrogen deprivation (CROWN) study seeks to understand the early, subclinical natural history of cardiovascular compromise in young women undergoing near-complete estrogen deprivation (NCED) therapy. It is critical to understand the early subclinical development of cardiovascular disease to identify a window for therapeutic intervention before overt cardiovascular events occur. This three-site regional study (Atrium Health Wake Forest, Duke, and Virginia Commonwealth University) uses serial stress cardiac magnetic resonance (CMR) imaging and cardiac computed tomography angiography (CCTA) obtained during the initial two years of NCED therapy to study myocardial prefusion reserve (MPR), large cardiovascular vessel changes, left ventricular function, and other cardiovascular parameters. The CROWN cohort will consist of 90 premenopausal women with breast cancer, 67 with HR-positive disease receiving NCED and 23 comparators with HR-negative disease. Participants will undergo three annual CMR scans and 2 CCTA scans during the 2-year study period. After initial activation hurdles, accrual has been brisk, and the study is expected to complete accrual in December 2024. Efforts are in place to encourage participant retention with the study primary outcome, change in MPR between the two groups, to be reported in 2026 to 2027. The results of this study will enable premenopausal women with breast cancer to balance the health burdens of cancer at a young age and treatment-related cardiovascular morbidity. Finally, the tools developed here can be utilized to study cardiovascular risk across a range of cancer types and cancer therapies with the ultimate goals of both developing generalizable risk stratification tools as well as validating interventions which prevent overt cardiovascular compromise.

Psychological and Structural Burdens and Nursing Home Administrator Turnover Intentions During the COVID-19 Pandemic.

The COVID-19 pandemic created challenges for U. S. nursing home administrators (NHA) and staff. This study explored organizational and psychological factors associated with NHA stress, dissatisfaction, and turnover intent (TI) during the third year of the pandemic. Results from a nationwide, cross-sectional survey of 1139 NHAs were merged with Centers for Medicare and Medicaid Services nursing home survey deficiency, staffing, complaint, and other operations data. A hierarchical, generalized estimating equations model with ordered logit link found that NHAs with higher COVID stress (AOR = 1.65, 95% CI = 1.22, 2.23), higher use of agency/contract staff (AOR = 1.50, 95% CI = 1.08.2.09) and higher role conflict were more likely to indicate TI. NHAs with higher job satisfaction in workload, work content, and rewards were less likely to hold TI. Industry leaders should create strategies to reduce NHA's job stress and role conflicts and provide opportunities for improving staff recruitment and retention, reducing reliance on agency staffing.

Mental Well-being InSciEd Out: Health Partnerships with the Boys & Girls Clubs of Puerto Rico.

BACKGROUND: Mental health care is a top clinical concern for modern Puerto Rico, especially given a dramatically changing economic landscape paired with recurrent natural disasters. Youth are particularly at-risk due to long-term impacts of toxic stress and adverse childhood experiences on health and development. OBJECTIVES: Here we present a novel clinician-community-educator-scientist partnership to address Puerto Rican youth mental well-being and wellness. We deployed pilot health workshops within the Boys & Girls Clubs of Puerto Rico to build youth mental health conceptual understanding and competencies in stress recognition and management. The work in progress herein evaluates acceptability and feasibility of our curricular model. METHODS: Dialogue with community stakeholders guided curricular design of workshops for youth ages 6 to 13 and older. Prior to implementation, educators and volunteers attended a 1-day training on educational strategies. Workshop success was evaluated using qualitative approaches (i.e., narrative feedback, educator and volunteer reflections, youth Talking Drawings) to assess youth engagement, youth conceptual health understanding, and educator/volunteer impressions of feasibility and impact. RESULTS: Initial findings indicate high acceptability and feasibility of our curricular model. Youth engagement and enthusiasm were noted in educator feedback and continue to be sustained post-workshop. Preliminary analysis shows accompanying increases in youth conceptual mental health understanding, particularly for 6- to 12-year-olds in recognition of stress and healthy coping mechanisms. Reciprocal gains were observed for volunteers. CONCLUSIONS: Activities have evolved into a formal partnership called Semilla, which features expanded analysis of mental well-being and wellness outcomes. Our collaborative model continues to engage Puerto Rican youth in the science of their well-being.

Fast multiple-trait genome-wide association analysis for correlated longitudinal measurements.

Large-scale longitudinal biobank data can be leveraged to identify genetic variation contributing to human diseases progression and traits trajectories. While methods for genome-wide association studies (GWAS) of multiple correlated traits have been proposed, an efficient multiple-trait approach to model longitudinal phenotypes is not currently available. We developed GAMUT, a genome-wide association approach for multiple longitudinal traits. GAMUT employs a mixed-effects model to fit longitudinal outcomes where a fast algorithm for inversion by recursive partitioning of the random effects submatrix is introduced. To evaluate performance of the algorithms introduced and assess their statistical power and type I error, stochastic simulation was conducted. Consistent with our expectation, power was greater for cross-sectional (CS) than longitudinal (LT) effects, particularly with a diminishing LT/CS ratio. With a minimum minor allele count of 3 within genotype by time categories, observed type I error was roughly equal to theoretical genome-wide significance. Additionally, 28 blood-based biomarkers measured at 2 time points on participants of the UK Biobank were used to compare GAMUT against single-trait standard and longitudinal GWAS (including rate of change). Across all biomarkers, we observed 539 (CS) and 248 (LT) significant independent variants for the GAMUT method, and 513 (CS) and 30 (LT) for single-trait longitudinal GWAS, respectively. Only 37 variants were identified by modeling rates of change using standard GWAS.

Physical Activity During Breast Cancer Therapy Associates With Preserved Exercise Capacity and Cardiac Function (WF97415).

Background: Cancer treatment increases cardiovascular disease risk, but physical activity (PA) may prevent cardiovascular disease. Objectives: This study examined whether greater PA was associated with better submaximal exercise capacity and cardiac function during cancer therapy. Methods: Participants included 223 women with stage I to III breast cancer (BC) before and 3 months after undergoing treatment and 126 control participants. Leisure-time PA (LTPA) was reported using the Godin-Shephard LTPA questionnaire. Cardiac function was assessed by cardiac magnetic resonance. Submaximal exercise capacity was determined by 6-minute walk distance. Results: BC participants reported similar baseline LTPA scores (24.7; 95% CI: 21.7-28.0) as control participants (29.4; 95% CI: 25.0-34.2). The BC group declined to 16.9 (95% CI: 14.4-19.6) at 3 months relative to 30.8 (95% CI: 26.2-35.8) in control participants. Among BC participants, more LTPA was related to better exercise capacity (ß ± SE: 7.1 ± 1.6; 95% CI: 4.0-10.1) and left ventricular (LV) circumferential strain (-0.16 ± 0.07; 95% CI: -0.29 to -0.02). Increased LTPA over the 3 months was associated with decreased likelihood of treatment-induced cardiac dysfunction according to LV circumferential strain classifications (OR: 0.98; 95% CI: 0.97-0.998). BC participants reporting insufficient LTPA according to PA guidelines exhibited deteriorations in exercise capacity (adjusted mean difference ± SE: -29 ± 10 m; P = 0.029), LV end-systolic volume (5.8 ± 1.3 mL; P < 0.001), LV ejection fraction (-3.2% ± 0.8%; P = 0.002), and LV circumferential strain (2.5% ± 0.5%; P < 0.001), but BC participants meeting LTPA guidelines did not exhibit these adverse changes. Conclusions: PA declined during BC therapy; however, PA participation was associated with attenuated declines in exercise capacity and cardiac function that are often observed in this population. (Understanding and Predicting Breast Cancer Events After Treatment [WF97415 UPBEAT]; NCT02791581).

Plasma proteomic associations with genetics and health in the UK Biobank.

The Pharma Proteomics Project is a precompetitive biopharmaceutical consortium characterizing the plasma proteomic profiles of 54,219 UK Biobank participants. Here we provide a detailed summary of this initiative, including technical and biological validations, insights into proteomic disease signatures, and prediction modelling for various demographic and health indicators. We present comprehensive protein quantitative trait locus (pQTL) mapping of 2,923 proteins that identifies 14,287 primary genetic associations, of which 81% are previously undescribed, alongside ancestry-specific pQTL mapping in non-European individuals. The study provides an updated characterization of the genetic architecture of the plasma proteome, contextualized with projected pQTL discovery rates as sample sizes and proteomic assay coverages increase over time. We offer extensive insights into trans pQTLs across multiple biological domains, highlight genetic influences on ligand-receptor interactions and pathway perturbations across a diverse collection of cytokines and complement networks, and illustrate long-range epistatic effects of ABO blood group and FUT2 secretor status on proteins with gastrointestinal tissue-enriched expression. We demonstrate the utility of these data for drug discovery by extending the genetic proxied effects of protein targets, such as PCSK9, on additional endpoints, and disentangle specific genes and proteins perturbed at loci associated with COVID-19 susceptibility. This public-private partnership provides the scientific community with an open-access proteomics resource of considerable breadth and depth to help to elucidate the biological mechanisms underlying proteo-genomic discoveries and accelerate the development of biomarkers, predictive models and therapeutics1.