Breast cancer incidence and mortality by metabolic syndrome and obesity: The Women's Health Initiative.

BACKGROUND: In the Women's Health Initiative (WHI) randomized trial, dietary intervention significantly reduced breast cancer mortality, especially in women with more metabolic syndrome (MetS) components. Therefore, this study investigated the associations of MetS and obesity with postmenopausal breast cancer after long-term follow-up in the WHI clinical trials. METHODS: A total of 68,132 postmenopausal women, without prior breast cancer and with normal mammogram, were entered into WHI randomized clinical trials; 63,330 women with an entry MetS score comprised the study population. At entry, body mass index (BMI) was determined; MetS score (0, 1-2, and 3-4) included the following: (1) high waist circumference (≥88 cm), (2) high blood pressure (systolic ≥130 mm Hg and/or diastolic ≥85 mm Hg, or hypertension history), (3) high-cholesterol history, and (4) diabetes history. Study outcomes included breast cancer incidence, breast cancer mortality, deaths after breast cancer, and results by hormone receptor status. RESULTS: After a >20-year mortality follow-up, a higher MetS score (3-4), adjusted for BMI, was significantly associated with more poor prognosis, estrogen receptor (ER)-positive, progesterone receptor (PR)-negative cancers (p = .03), 53% more deaths after breast cancer (p < .001), and 44% higher breast cancer mortality (p = .03). Obesity status, adjusted for MetS score, was significantly associated with more good prognosis, ER-positive, PR-positive cancers (p < .001), more total breast cancers (p < .001), and more deaths after breast cancer (p < .001), with higher breast cancer mortality only in women with severe obesity (BMI, ≥35 kg/m2; p < .001). CONCLUSIONS: MetS and obesity status have independent, but differential, adverse associations with breast cancer receptor subtypes and breast cancer mortality risk. Both represent separate targets for breast cancer prediction and prevention strategies.

Association of clonal hematopoiesis and mosaic chromosomal alterations with solid malignancy incidence and mortality.

BACKGROUND: Understanding the impact of clonal hematopoiesis of indeterminate potential (CHIP) and mosaic chromosomal alterations (mCAs) on solid tumor risk and mortality can shed light on novel cancer pathways. METHODS: The authors analyzed whole genome sequencing data from the Trans-Omics for Precision Medicine Women's Health Initiative study (n = 10,866). They investigated the presence of CHIP and mCA and their association with the development and mortality of breast, lung, and colorectal cancers. RESULTS: CHIP was associated with higher risk of breast (hazard ratio [HR], 1.30; 95% confidence interval [CI], 1.03-1.64; p = .02) but not colorectal (p = .77) or lung cancer (p = .32). CHIP carriers who developed colorectal cancer also had a greater risk for advanced-stage (p = .01), but this was not seen in breast or lung cancer. CHIP was associated with increased colorectal cancer mortality both with (HR, 3.99; 95% CI, 2.41-6.62; p < .001) and without adjustment (HR, 2.50; 95% CI, 1.32-4.72; p = .004) for advanced-stage and a borderline higher breast cancer mortality (HR, 1.53; 95% CI, 0.98-2.41; p = .06). Conversely, mCA (cell fraction [CF] >3%) did not correlate with cancer risk. With higher CFs (mCA >5%), autosomal mCA was associated with increased breast cancer risk (HR, 1.39; 95% CI, 1.06-1.83; p = .01). There was no association of mCA (>3%) with breast, colorectal, or lung mortality except higher colon cancer mortality (HR, 2.19; 95% CI, 1.11-4.3; p = .02) with mCA >5%. CONCLUSIONS: CHIP and mCA (CF >5%) were associated with higher breast cancer risk and colorectal cancer mortality individually. These data could inform on novel pathways that impact cancer risk and lead to better risk stratification.

Uptake of screening and risk-reducing recommendations among women with hereditary breast and ovarian cancer syndrome due to pathogenic BRCA1/2 variants evaluated at a large urban comprehensive cancer center.

PURPOSE: Carriers of pathogenic variants in BRCA1/2 have an elevated lifetime cancer risk warranting high-risk screening and risk-reducing procedures for early detection and prevention. We report on prevention practices among women with pathogenic BRCA variants in order to document follow through with NCCN recommendations and to identify barriers to guideline-recommended care. METHODS: Our cohort included women who had genetic testing through a cancer genetic clinic and completed a 54-item questionnaire to measure socio-demographics, medical history, rates of cancer screening and risk-reducing surgery, disclosure of test results, and cancer worry. Outcomes included rates of completion of risk-reducing salpingo-oophorectomy (RRSO), risk-reducing mastectomy (RRM), and NCCN risk-reducing and age-dependent screening guidelines (version 3.2019). Multivariable logistic regression analyses were used to evaluate potential predictors of these outcomes. RESULTS: Of 129 evaluable women with pathogenic BRCA1/2 variants, 95 (74%) underwent RRSO and 77 (60%) had RRM, respectively, and 107 (83%) were considered adherent to NCCN guidelines. Women with a history of breast or ovarian cancer were more likely to have RRM (OR = 4.38; 95% CI 1.80-11.51; p = 0.002). Increasing age was associated with an increased likelihood of RRSO (OR = 1.05; 95% CI 1.01-1.09; p = 0.019) and decreased likelihood for RRM (OR = 0.95; 95% CI 0.92-0.99; p = 0.013). Women who had RRM were 3 times more likely to undergo RRSO (OR = 2.81; 95% CI 1.10-7.44; p = 0.025). Women who had genetic testing after June 2013 were less likely to have RRM than those tested before June 2013 (OR = 0.42; 95% CI 0.18-0.95; p = 0.040. None of the other measured factors were associated with rates of RRSO, RRM or follow through with NCCN recommendations. There was near universal (127/129) reported disclosure of genetic test results to family members, resulting in the discovery of a median of 1 relative with a pathogenic variant (range = 0-8). CONCLUSION: An evaluation of follow up practice in a cohort of women with pathogenic variants in BRCA1/2 revealed high rates of reported completion of screening and surgical risk-reducing recommendations. Educational efforts should continue to reinforce the importance of follow-through with guideline recommended care among this high-risk group.

Ductal carcinoma in situ and cause-specific mortality among younger and older postmenopausal women: the Women's Health Initiative.

BACKGROUND: Whether DCIS is associated with higher breast cancer-specific and all-cause mortality is unclear with few studies in older women. Therefore, we examined DCIS and breast cancer-specific, cardiovascular (CVD)-specific, and all-cause mortality among Women's Health Initiative (WHI) Clinical Trial participants overall and by age (< 70 versus ≥ 70 years). METHODS: Of 68,132 WHI participants, included were 781 postmenopausal women with incident DCIS and 781 matched controls. Serial screening mammography was mandated with high adherence. DCIS cases were confirmed by central medical record review. Adjusted multivariable Cox proportional hazard regression models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CI). Kaplan Meier (KM) plots were used to assess 10-year and 20-year mortality rates. RESULTS: After 20.3 years total, and 13.2 years median post-diagnosis follow-up, compared to controls, DCIS was associated with higher breast cancer-specific mortality (HR 3.29; CI = 1.32-8.22, P = 0.01). The absolute difference in 20-year breast cancer mortality was 1.2% without DCIS and 3.4% after DCIS, log-rank P = 0.026. Findings were similar by age (< 70 versus ≥ 70 years) with no interaction (P interaction = 0.80). Incident DCIS was not associated with CVD-specific mortality (HR 0.77; CI-0.54-1.09, P = 0.14) or with all-cause mortality (HR 0.96; CI = 0.80-1.16, P = 0.68) with similar findings by age. CONCLUSIONS: In postmenopausal women, incident DCIS was associated with over three-fold higher breast cancer-specific mortality, with similar findings in younger and older postmenopausal women. These finding suggest caution in using age to adjust DCIS clinical management or research strategies.

Safety and efficacy of linaclotide in children aged 7-17 years with irritable bowel syndrome with constipation.

OBJECTIVES: Linaclotide, a guanylate cyclase-C agonist, was recently approved in the United States for the treatment of children 6-17 years old with functional constipation. This study evaluated the safety and efficacy of various linaclotide doses in children 7-17 years old with irritable bowel syndrome with constipation (IBS-C). METHODS: In this 4-week, randomized, double-blind, placebo-controlled, parallel-group, Phase 2 study, children with IBS-C were randomized to once-daily placebo or linaclotide (Dose A: 18 or 36 µg, B: 36 or 72 µg, and C: 72 µg or 145 µg, or 290 µg); those aged 7-11 years in a 1:1:1:1 allocation based on weight (18 to <35 kg:18 µg, 36 µg, or 72 µg; or ≥35 kg: 36 µg, 72 µg, or 145 µg), and those aged 12-17 years in a 1:1:1:1:1 allocation (the higher option of Doses A-C or 290 µg). The primary efficacy endpoint was a change from baseline in 4-week overall spontaneous bowel movement (SBM) frequency rate over the treatment period. Adverse events and clinical laboratory measures were also assessed. RESULTS: Efficacy, safety, and tolerability were assessed in 101 patients. In the intent-to-treat population, numerical improvement was observed in overall SBM frequency rate with increasing linaclotide doses (A: 1.62, B: 1.52, and C: 2.30, 290 µg: 3.26) compared with placebo. The most reported treatment-emergent adverse events were diarrhea and pain, with most cases being mild and none being severe. CONCLUSIONS: Linaclotide was tolerated well in this pediatric population, showing numerical improvement in SBM frequency compared with placebo.

Randomized controlled trial of linaclotide in children aged 6-17 years with functional constipation.

OBJECTIVES: Linaclotide, a guanylate cyclase-C agonist, was recently approved in the United States for treatment of children 6-17 years old with functional constipation (FC). This study evaluated the safety and efficacy of several linaclotide doses in children 6-17 years old with FC. METHODS: In this multicenter, randomized, double-blind, placebo-controlled phase 2 study, 173 children with FC (based on Rome III criteria) were randomized to once-daily linaclotide (A: 9 or 18 µg, B: 18 or 36 µg, or C: 36 or 72 µg) or placebo in a 1:1:1:1 ratio for 6- to 11-year-olds (dosage determined by weight: 18 to <35 or ≥35 kg) and linaclotide (18, 36, 72, or 145 µg) or placebo in a 1:1:1:1:1 ratio for 12- to 17-year-olds. The primary efficacy endpoint was change from baseline in weekly spontaneous bowel movement (SBM) frequency throughout the 4-week treatment period. Adverse events (AE), clinical laboratory values, and electrocardiograms were monitored. RESULTS: Efficacy and safety were assessed in 173 patients (52.0% aged 6-11 years; 48.0% aged 12-17 years); 162 (93.6%) completed the treatment period. A numerical improvement in mean SBM frequency was observed with increasing linaclotide doses (1.90 in 6- to 11-year-olds [36 or 72 µg] and 2.86 in 12- to 17-year-olds [72 µg]). The most reported treatment-emergent AE was diarrhea, with most cases being mild; none were severe. CONCLUSIONS: Linaclotide was well tolerated in this pediatric population, with a trend toward efficacy in the higher doses, warranting further evaluation.

Hospitalization- and death-related financial and employment effects in parents of children with life-limiting conditions: a fixed-effects analysis.

The purpose of this study is to investigate out-of-pocket non-medical expenses and employment-related outcomes in families of children with life-limiting conditions, specifically, to quantify the financial and employment implications of two events: a child's hospitalization and death. This cohort study used panel data collected prospectively for a larger study investigating the effectiveness of specialized pediatric palliative care. Participants were recruited by medical professionals between November 2019 and May 2022 at four Swiss children's hospitals. The care follow-up and bereavement follow-up assessments were 330 and 300 days, respectively. We measured out-of-pocket non-medical expenses, individual full-time equivalent units, and personal income, as well as sick leave and vacation days taken. Analyses included descriptive statistics and two-way linear fixed-effects regressions. The analysis included 110 parents (mothers n = 59, fathers n = 51) of 61 children. Children were hospitalized for a median of 7 days (interquartile range 0-21, range 0-227). The fixed-effects models found a positive association between hospitalization, i.e., length of stay, and travel and accommodation expenses (coefficient 4.18, 95% confidence interval 2.20-6.16). On average, for each week of hospitalization, parents spent an additional 29 Swiss francs on travel and accommodation. During the 300-day bereavement follow-up, six (26%) of 23 parents increased their work commitments, while one reported a decrease. CONCLUSIONS: Families incur higher travel and accommodation expenses during hospitalization than during non-hospitalized periods. Instrumental support, e.g., parking vouchers, can help families minimize these costs. Future studies should investigate whether early return to work during bereavement is driven by economic considerations or a desire for distraction. CLINICAL TRIAL REGISTRATION: Data analyzed in this study were collected as part of a clinical trial, registered on ClinicalTrials.gov, No. NCT04236180, 15 March 2019 What Is Known: • Families of children with life-limiting conditions are at risk of substantial financial burden from high out-of-pocket medical expenses. • It is also known that parents often have to incur out-of-pocket non-medical expenses and reduce their work commitments. Little is known about the economic consequences of losing a child to a life-limiting condition. WHAT IS NEW: • We provide new longitudinal evidence on the hospitalization- and death-related financial and employment implications for families of children with life-limiting conditions. • Child hospitalizations add to families' financial burden through increased travel and accommodation expenses. Work commitments rose during early bereavement.

Exploring pulmonary involvement in newly diagnosed rheumatoid arthritis, and psoriatic arthritis: a single center study.

OBJECTIVES: This cross-sectional study aimed to determine the prevalence, manifestation, and risk factors of pulmonary involvement in newly diagnosed, untreated rheumatoid arthritis (RA) and psoriatic arthritis (PsA) patients, and to evaluate the efficacy of various diagnostic tools in screening for pulmonary involvement. METHODS: Untreated, newly diagnosed patients with RA and PsA underwent an extensive multimodal diagnostic approach including clinical and laboratory assessment, pulmonary function tests, and chest radiography. RESULTS: We recruited 50 arthritis patients (26 RA, 24 PsA) and 26 control subjects. Respiratory symptoms were found in 36.0 % of arthritis patients and 11.5 % of controls (p = 0.031). Pathologically reduced breathing width (< 3.0 cm) was significantly more common in arthritis patients (64.0 %) than in controls (23.1 %) (p < 0.001). Pulmonary function test results did not differ significantly between groups. Chest radiography revealed pulmonary involvement in 37.0 % of arthritis patients, higher in RA (50.0 %) than in PsA (22.7 %). Notably, only 35.3 % of arthritis patients with radiographic pulmonary involvement were symptomatic, with 64.7 % being asymptomatic. Radiographic pulmonary involvement was associated with advanced age (p = 0.002) and increased rheumatoid factor levels (p = 0.024). CONCLUSION: Our research underscores the significant prevalence of largely asymptomatic pulmonary involvement in newly diagnosed RA and PsA patients. These findings highlight the importance of an early, multidisciplinary screening approach, particularly for high-risk individuals. Further large-scale studies are needed to develop comprehensive screening protocols to improve early detection and treatment of pulmonary involvement in arthritis.

How external and agency characteristics are related to coordination in homecare - findings of the national multicenter, cross-sectional SPOTnat study.

BACKGROUND: Homecare client services are often distributed across several interdependent healthcare providers, making proper care coordination essential. However, as studies exploring care coordination in the homecare setting are scarce, serious knowledge gaps exist regarding how various factors influence coordination in this care sector. To fill such gaps, this study's central aim was to explore how external factors (i.e., financial and regulatory mechanisms) and homecare agency characteristics (i.e., work environment, workforce, and client characteristics) are related to care coordination in homecare. METHODS: This analysis was part of a national multicentre, cross-sectional study in the Swiss homecare setting that included a stratified random sample of 88 Swiss homecare agencies. Data were collected between January and September 2021 through agency and employee questionnaires. Using our newly developed care coordination framework, COORA, we modelled our variables to assess the relevant components of care coordination on the structural, process, and outcome levels. We conducted both descriptive and multilevel regression analyses-with the latter adjusting for dependencies within agencies-to explore which key factors are associated with coordination. RESULTS: The final sample size consisted of 1450 employees of 71 homecare agencies. We found that one explicit coordination mechanism ("communication and information exchange" (beta = 0.10, p <.001)) and four implicit coordination mechanisms-"knowledge of the health system" (beta = -0.07, p <.01), "role clarity" (beta = 0.07, p <.001), "mutual respect and trust" (beta = 0.07, p <.001), and "accountability, predictability, common perspective" (beta = 0.19, p <.001)-were significantly positively associated with employee-perceived coordination. We also found that the effects of agency characteristics and external factors were mediated through coordination processes. CONCLUSION: Implicit coordination mechanisms, which enable and enhance team communication, require closer examination. While developing strategies to strengthen implicit mechanisms, the involvement of the entire care team is vital to create structures (i.e., explicit mechanisms) that enable communication and information exchange. Appropriate coordination processes seem to mitigate the association between staffing and coordination. This suggests that they support coordination even when workload and overtime are higher.

First insights of integrating the Bonn Internship Curriculum for Point-of-Care Ultrasound (BI-POCUS): progress and educational aspects.

BACKGROUND: Point-of-care ultrasound (POCUS) is rapidly gaining prominence in various clinical settings. As its use becomes more widespread, there is a growing need for comprehensive ultrasound training in medical education to ensure that future healthcare professionals are proficient in this essential diagnostic tool. OBJECTIVE: This study is the first attempt by the University of Bonn to seamlessly integrate ultrasound courses and the use of ultrasound devices into the regular activities of final year medical students and to evaluate the usage of these devices. METHODS: A total of forty students in their practical year were provided with a hendheld ultrasound device for a period of four months. During this time, they were invited to take part in eight optional ultrasound courses in which they acquired images and those images were rated using a specially developed rating system. At the end of the tertial, students were able to take part in a voluntary survey on the use of the equipment. RESULTS: Participation in the optional ultrasound courses was well received, with the Introduction and FAST module drawing the largest number of participants (29). Among the ultrasound images acquired by students, those of the lungs obtaining the highest rating, with 18.82 (SD ± 4.30) points out of 23 points, while the aorta and vena cava images scored lowest, with an average of 16.62 (SD ± 1.55) points. The overall mean score for all images was 17.47 (SD ± 2.74). Only 21 students responded to the survey. Of the participating students, 67% used the device independently four times or fewer during the tertial. CONCLUSION: The study aimed to enhance the BI-POCUS curriculum by improving students' ultrasound skills during their practical year. However, device usage was lower than expected, with most students using it only once a month or less. This raises concerns about the justification of the effort and resources. Future initiatives will focus on technical improvements, better login data provision, and closer monitoring of usage and progress, emphasizing the need for practical ultrasound training in medical education.

How regulatory frameworks drive differences in home-care agencies: Results from a national multicenter cross-sectional study in Switzerland.

INTRODUCTION: The sustainability and rising costs of the health-care system are of concern. Although health-care reforms impact various areas of care, there is only limited evidence on how regulations affect home-care agencies and health-care delivery. OBJECTIVES: The primary aim was to explore different financial and regulatory mechanisms and how they drive differences in the organizational structures, processes, and work environment of home-care agencies. DESIGN AND METHODS: We used data from a national multicenter cross-sectional study of Swiss home care that included a random sample of 88 home-care agencies with a total of 3223 employees. Data was collected in 2021 through agency and personnel questionnaires including geographic characteristics, financial and regulatory mechanisms, service provision, financing, work environment, resources and time allocation, and personnel recruitment. We first conducted a cluster analysis to build agency groups with similar financial and regulatory mechanisms. We then performed Fisher's exact, ANOVA, and Kruskal-Wallis tests to determine group differences in organizational structures, processes, and work environments. Finally, we performed a lasso regression to determine which variables were predictive for the groups. RESULTS: Four agency groups were built, differing in view of financial and regulatory mechanisms and we found differences in the range and amount of services provided, with regard to employment conditions and cost structures. DISCUSSION: The most prominent differences were found between agency groups with versus agency groups without a service obligation. Financial incentives must be well aligned with the goal of achieving and maintaining financially sustainable, accessible, and high-quality home care.

Periocular Asymmetry Index in Caucasian Populations Using Three-dimensional Photogrammetry Assessment.

OBJECTIVE: To quantitatively assess the periocular asymmetry and investigate its sex and age-related differences in a Caucasian population using three-dimensional (3D) stereophotogrammetry. METHOD: Standardized 3D photos of the periocular region of 301 Caucasians were taken using the VECTRA M3 3D Imaging System. Standardized landmarks were positioned, and data measurements in the periocular region were obtained from these images using VAM software and assessed using intraclass correlation coefficients (ICC) for reliability. Absolute differences and asymmetry index between the right and the left periocular region were calculated with a focus on gender and age-related differences. RESULT: Fissure height asymmetry was positively correlated with age (p < 0.01). Furthermore, reflex distance asymmetry was positively correlated with age in the elderly group (p < 0.05). Absolute differences of upper eyelid crease were 0.65 ± 0.79 mm for females and 0.90 ± 0.94 mm for males (p < 0.05). In the elderly group, the absolute differences of reflex distance were 0.664 ± 0.471 mm for males and 0.470 ± 0.408 mm for females (p < 0.05), while the absolute differences of fissure height were 0.619 ± 0.469 mm and 0.436 ± 0.372 mm, respectively (p < 0.05). All measurements had an inter-rater ICC and intra-rater ICC between 0.761 and 0.957. CONCLUSION: Periocular asymmetry is more prominent in older and male people. 3D photogrammetry is a reliable tool to detect periocular asymmetry and might provide an accurate and effective reference for periocular cosmetic, plastic, and reconstructive surgery in the clinical routine. LEVEL OF EVIDENCE I: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors. www.springer.com/00266 .

The Effect of Statins on Markers of Breast Cancer Proliferation and Apoptosis in Women with In Situ or Early-Stage Invasive Breast Cancer.

Statins, inhibitors of HMG-CoA reductase, have been shown to have potential anti-carcinogenic effects through the inhibition of the mevalonate pathway and their impact on Ras and RhoGTAases. Prior studies have demonstrated a reduction in breast tumor proliferation, as well as increased apoptosis, among women with early-stage breast cancer who received statins between the time of diagnosis and the time of surgery. The aim of this study was to evaluate the impact of short-term oral high-potency statin therapy on the expression of markers of breast tumor proliferation, apoptosis, and cell cycle arrest in a window-of-opportunity trial. This single-arm study enrolled 24 women with stage 0-II invasive breast cancer who were administered daily simvastatin (20 mg) for 2-4 weeks between diagnosis and surgical resection. Pre- and post-treatment tumor samples were analyzed for fold changes in Ki-67, cyclin D1, p27, and cleaved caspase-3 (CC3) expression. Out of 24 enrolled participants, 18 received statin treatment and 17 were evaluable for changes in marker expression. There was no significant change in Ki-67 expression (fold change = 1.4, p = 0.597). There were, however, significant increases in the expression of cyclin D1 (fold change = 2.8, p = 0.0003), p27 cytoplasmic (fold change = 3.2, p = 0.025), and CC3 (fold change = 2.1, p = 0.016). Statin treatment was well tolerated, with two reported grade-1 adverse events. These results align with previous window-of-opportunity studies suggesting a pro-apoptotic role of statins in breast cancer. The increased expression of markers of cell cycle arrest and apoptosis seen in this window-of-opportunity study supports further investigation into the anti-cancer properties of statins in larger-scale clinical trials.

Setting new priorities for nursing research: The updated Swiss Nursing Research Agenda-a systematic, participative approach.

AIM: To identify current key areas for nursing research in Switzerland, we revised the Swiss Research Agenda for Nursing (SRAN) initially published in 2008. BACKGROUND: By developing a research agenda, nursing researchers internationally prioritize and cluster relevant topics within the research community. The process should be collaborative and systematic to provide credible information for decisionmakers in health care research, policy, and practice. SOURCES OF EVIDENCE: After a participative, systematic, and critical evaluation within and outside of the Swiss Association for Nursing Science, the updated SRAN 2019-2029 defines four research priorities (new models of care, nursing care interventions, work and care environment, and quality of care and patient safety) and four transversal themes (organization of research, research methodologies, research in health care policy and public health perspectives). CONCLUSION: Adding to other national nursing research agendas, the categories are organized in a framework of key research priorities and transversal themes. They relate to the importance of global and local foci of research as well as challenges in health care services and policy systems. The agenda is an important prerequisite for enhancing the influence of nursing research in Switzerland and provides guidance for the next decade. IMPLICATIONS FOR NURSING PRACTICE: The revised agenda ensures that research projects target key knowledge gaps and the discipline's core questions in respective countries. IMPLICATIONS FOR HEALTH POLICY: Nursing research should inform and influence health policy on all institutional and political levels. Therefore, the integration of public health perspectives in research is one of the most important new aspects of SRAN 2019-2029.

Racial and ethnic variation in BRCA1 and BRCA2 genetic test results among individuals referred for genetic counseling at a large urban comprehensive cancer center.

PURPOSE: The prevalence of pathogenic variants in BRCA1 and BRCA2 in populations other than Ashkenazi Jewish (AJ) is not well defined. We describe the racial and ethnic-specific prevalence of BRCA1/2 pathogenic variants and variants of uncertain significance (VUS) among individuals referred for genetic testing in a large urban comprehensive cancer center over a 20-year period. METHODS: The population included 3,537 unrelated individuals who underwent genetic testing from January 1999 to October 2019 at the Karmanos Cancer Institute. We estimated the prevalence of pathogenic variants and VUS and evaluated associations with race and ethnicity for African American (AA), Arab, AJ and Hispanic individuals compared to Non-Hispanic Whites (NHW). We used multivariable models to adjust for other predictors of pathogenic variants. We also reported the most common pathogenic variants by racial and ethnic group. RESULTS: The racial and ethnic breakdown of our population was: NHW (68.9%), AA (20.3%), AJ (2.5%), Arab (2.2%), Hispanic (1.0%), Asian Pacific Islander, Native American/Alaskan Native (4.7%), and < 1% unknown. The overall prevalence of pathogenic variants in BRCA1/2 was 8.9% and the prevalence of VUS was 5.6%. Compared to NHW, there were no racial or ethnic differences in the rate of pathogenic variants. However, AA individuals were more likely to have VUS in BRCA1 (adjusted OR 2.43, 95% CI 1.38-4.28) and AJ were more likely to have VUS in BRCA2 (adjusted OR 3.50, 95% CI 1.61-6.58). CONCLUSION: These results suggest the continued need for genetic testing and variant reclassification for individuals of all racial and ethnic groups.

Chemotherapy-induced peripheral neuropathy in the detroit research on cancer survivors (ROCS) cohort.

PURPOSE: Improved life expectancy has increased the likelihood for long-term complications from chemotherapy among cancer survivors. One burdensome complication is chemotherapy-induced peripheral neuropathy (CIPN). We evaluated rates of CIPN outcomes in the Detroit Research on Cancer Survivorship (ROCS) cohort. METHODS: The population included 1,034 African American (AA) survivors who received chemotherapy for breast, colorectal, lung or prostate cancer. CIPN prevalence was based on initial occurrence of worsening of self-reported pain, numbness or tingling after chemotherapy. Current CIPN included symptoms still present at the time of the survey, and persistent CIPN symptoms were present 12 or more months post-chemotherapy. CIPN severity was ranked as mild, moderate or severe. Logistic regression was utilized to evaluate sociodemographic and clinical factors associated with the various categories of CIPN. RESULTS: CIPN prevalence was 68%, with 53% current and 52% persistent. The symptom severity distribution based on prevalent CIPN included 32.2% mild, 30.8% moderate, and 36.9% severe. Factors associated with prevalent CIPN (odds ratio, 95% confidence interval) included primary cancer site (breast: 3.88, 2.02-7.46); and (colorectal: 5.37, 2.69-10.73), lower risk for older age at diagnosis (0.66, 0.53-0.83) and divorced/separated marital status (2.13, 1.42-3.21). Current CIPN was in addition, associated with more advanced stage disease trend (1.34, 1.08-1.66) and greater number of co-morbid medical conditions trend (1.23, 1.09-1.40), as was persistent CIPN. Severity of prevalent CIPN was associated with history of arthritis (1.55, 1.06-2.26) and severity of persistent CIPN with higher BMI (1.58, 1.07-2.35). CONCLUSIONS: CIPN is a common and persistent complication in AA cancer survivors. Further research is needed to improve our understanding of CIPN predictors in all groups of cancer survivors.

Proton Pump Inhibitor Use and Obesity-Associated Cancer in the Women's Health Initiative.

Proton pump inhibitors (PPIs) have off-target activity on fatty acid synthase (FASN), a critical enzyme in energy balance and cancer growth. We evaluated risk of common obesity-related cancers: breast, colorectal (CRC), and endometrial, with use of PPI and histamine-2 receptor antagonists (H2RA) in 124,931 postmenopausal women enrolled in the Women's Health Initiative. Incident cancer cases were physician-adjudicated. Cox proportional hazards models were used to estimate multivariable hazard ratios (HR) and 95% confidence intervals (CI) for cancer incidence after year 3. There were 7956 PPI ever users and 9398 H2RA only users. Ever use of either PPI or H2RA was not associated with risk of breast cancer (n = 9186) nor risk of endometrial cancer (n = 1231). The risk of CRC (n = 2280) was significantly lower in PPI users (HR = 0.75, 95% CI = 0.61-0.92), but not in H2RA users (HR = 1.13, 95% CI = 0.97-1.31). The association of PPI use with CRC was apparent regardless of BMI or NSAID use, and was stronger with longer PPI duration (p = 0.006) and potency (p = 0.005). The findings that PPI use, but not H2RA use, demonstrate an inverse dose-response relationship with risk of CRC is consistent with preclinical data showing FASN inhibition prevents colon cancer progression and supports a role of PPI in CRC prevention.

Quadrivalent meningococcal tetanus toxoid-conjugate booster vaccination in adolescents and adults: phase III randomized study.

BACKGROUND: The immunogenicity and safety of a booster dose of tetanus toxoid-conjugate quadrivalent meningococcal vaccine (MenACYW-TT), alone or co-administered with MenB vaccine, were assessed in healthy 13-25-year olds who received MenACYW-TT or a CRM-conjugate vaccine (MCV4-CRM) 3-6 years earlier. METHODS: This phase IIIb open-label trial (NCT04084769) evaluated MenACYW-TT-primed participants, randomized to receive MenACYW-TT alone or with a MenB vaccine, and MCV4-CRM-primed participants who received MenACYW-TT alone. Functional antibodies against serogroups A, C, W and Y were measured using human complement serum bactericidal antibody assay (hSBA). The primary endpoint was vaccine seroresponse (post-vaccination titers ≥1:16 if pre-vaccination titers <1:8; or a ≥4-fold increase if pre-vaccination titers ≥1:8) 30 days post booster. Safety was evaluated throughout the study. RESULTS: The persistence of the immune response following primary vaccination with MenACYW-TT was demonstrated. Seroresponse after MenACYW-TT booster was high regardless of priming vaccine (serogroup A: 94.8% vs 93.2%; C: 97.1% vs 98.9%; W: 97.7% vs 98.9%; and Y; 98.9% vs 100% for MenACWY-TT-primed and MCV4-CRM-primed groups, respectively). Co-administration with MenB vaccines did not affect MenACWY-TT immunogenicity. No vaccine-related serious adverse events were reported. CONCLUSIONS: MenACYW-TT booster induced robust immunogenicity against all serogroups, regardless of the primary vaccine received, and had an acceptable safety profile. IMPACT: A booster dose of MenACYW-TT induces robust immune responses in children and adolescents primed with MenACYW-TT or another MCV4 (MCV4-DT or MCV4-CRM), respectively. Here, we demonstrate that MenACYW-TT booster 3-6 years after primary vaccination induced robust immunogenicity against all serogroups, regardless of the priming vaccine (MenACWY-TT or MCV4-CRM), and was well tolerated. Persistence of the immune response following previous primary vaccination with MenACYW-TT was demonstrated. MenACYW-TT booster with MenB vaccine co-administration did not affect MenACWY-TT immunogenicity and was well tolerated. These findings will facilitate the provision of broader protection against IMD particularly in higher-risk groups such as adolescents.

The unrecognized role of fidelity in effectiveness-implementation hybrid trials: simulation study and guidance for implementation researchers.

BACKGROUND: Effectiveness-implementation hybrid designs are a relatively new approach to evaluate efficacious interventions in real-world settings while concurrently gathering information on the implementation. Intervention fidelity can significantly influence the effectiveness of an intervention during implementation. However little guidance exists for applied researchers conducting effectiveness-implementation hybrid trials regarding the impact of fidelity on intervention effects and power. METHODS: We conducted a simulation study based on parameters from a clinical example study. For the simulation, we explored parallel and stepped-wedge cluster randomized trials (CRTs) and hypothetical patterns of fidelity increase during implementation: slow, linear, and fast. Based on fixed design parameters, i.e., the number of clusters (C = 6), time points (T = 7), and patients per cluster (n = 10) we used linear mixed models to estimate the intervention effect and calculated the power for different fidelity patterns. Further, we conducted a sensitivity analysis to compare outcomes based on different assumptions for the intracluster-correlation coefficient and the cluster size. RESULTS: Ensuring high fidelity from the beginning is central to achieve accurate intervention effect estimates in stepped-wedge and parallel CRTs. The importance of high fidelity in the earlier stages is more emphasized in stepped-wedge designs than in parallel CRTs. In contrast, if the increase of fidelity is too slow despite relatively high starting levels, the study will likely be underpowered and the intervention effect estimates will also be biased. This effect is more accentuated in parallel CRTs, here reaching 100% fidelity within the next measurement points is crucial. CONCLUSIONS: This study discusses the importance of intervention fidelity for the study`s power and highlights different recommendations to deal with low fidelity in parallel and stepped-wedge CRTs from a design perspective. Applied researchers should consider the detrimental effect of low fidelity in their evaluation design. Overall, there are fewer options to adjust the trial design after the fact in parallel CRT as compared to stepped-wedge CRTs. Particular emphasis should be placed on the selection of contextually relevant implementation strategies.

Administrative burden in Swiss nursing homes and its association with care workers' outcomes-a multicenter cross-sectional study.

BACKGROUND: Care workers in nursing homes often perform tasks that are rather related to organizational or management activities than 'direct patient care'. 'Indirect care activities', such as documentation or other administrative tasks are often considered by care workers as a burden, as they increase overall workload and keep them away from caring for residents. So far, there is little investigation into what kind of administrative tasks are being performed in nursing homes, by which type of care workers, and to which extent, nor how administrative burden is associated with care workers' outcomes. PURPOSE: The objective of this study was to describe care workers' administrative burden in Swiss nursing homes and to explore the association with four care worker outcomes (i.e., job dissatisfaction, emotional exhaustion, intention to leave the current job and the profession). METHODS: This multicenter cross-sectional study used survey data from the Swiss Nursing Homes Human Resources Project 2018. It included a convenience sample of 118 nursing homes and 2'207 care workers (i.e., registered nurses, licensed practical nurses) from Switzerland's German- and French-speaking regions. Care workers completed questionnaires assessing the administrative tasks and burden, staffing and resource adequacy, leadership ability, implicit rationing of nursing care and care worker characteristics and outcomes. For the analysis, we applied generalized linear mixed models, including individual-level nurse survey data and data on unit and facility characteristics. RESULTS: Overall, 73.9% (n = 1'561) of care workers felt strongly or rather strongly burdened, with one third (36.6%, n = 787) reporting to spend 2 h or more during a "normal" day performing administrative tasks. Ratings for administrative burden ranged from 42.6% (n = 884; ordering supplies and managing stocks) to 75.3% (n = 1'621; filling out the resident's health record). One out of four care workers (25.5%, n = 561) intended to leave the profession, whereby care workers reporting higher administrative task burden (OR = 1.24; 95%CI: 1.02-1.50) were more likely to intend to leave the profession. CONCLUSION: This study provides first insights on care workers' administrative burden in nursing homes. By limiting care workers' burdensome administrative tasks and/or shifting such tasks from higher to lower educated care workers or administrative personnel when appropriate, nursing home managers could reduce care workers' workload and improve their job satisfaction and retention in the profession.