Identification of a BRCA2-specific modifier locus at 6p24 related to breast cancer risk.

Common genetic variants contribute to the observed variation in breast cancer risk for BRCA2 mutation carriers; those known to date have all been found through population-based genome-wide association studies (GWAS). To comprehensively identify breast cancer risk modifying loci for BRCA2 mutation carriers, we conducted a deep replication of an ongoing GWAS discovery study. Using the ranked P-values of the breast cancer associations with the imputed genotype of 1.4 M SNPs, 19,029 SNPs were selected and designed for inclusion on a custom Illumina array that included a total of 211,155 SNPs as part of a multi-consortial project. DNA samples from 3,881 breast cancer affected and 4,330 unaffected BRCA2 mutation carriers from 47 studies belonging to the Consortium of Investigators of Modifiers of BRCA1/2 were genotyped and available for analysis. We replicated previously reported breast cancer susceptibility alleles in these BRCA2 mutation carriers and for several regions (including FGFR2, MAP3K1, CDKN2A/B, and PTHLH) identified SNPs that have stronger evidence of association than those previously published. We also identified a novel susceptibility allele at 6p24 that was inversely associated with risk in BRCA2 mutation carriers (rs9348512; per allele HR = 0.85, 95% CI 0.80-0.90, P = 3.9 × 10(-8)). This SNP was not associated with breast cancer risk either in the general population or in BRCA1 mutation carriers. The locus lies within a region containing TFAP2A, which encodes a transcriptional activation protein that interacts with several tumor suppressor genes. This report identifies the first breast cancer risk locus specific to a BRCA2 mutation background. This comprehensive update of novel and previously reported breast cancer susceptibility loci contributes to the establishment of a panel of SNPs that modify breast cancer risk in BRCA2 mutation carriers. This panel may have clinical utility for women with BRCA2 mutations weighing options for medical prevention of breast cancer.

Perceptions, Policy, and Partnerships: How Pharmacists Can Be Leaders in Reducing Overprescribing.

Medication overload - or harmful polypharmacy - is a widespread and growing public health issue, impacting millions of older Americans each year. Pharmacists are uniquely positioned to help deprescribe (collaboratively reduce inappropriate medication use), but also face significant obstacles to doing so. This paper explores three ways to involve pharmacists more in deprescribing to mitigate medication overload: Widen public perceptions of pharmacists' role in medication management, change policies that hinder pharmacist involvement in deprescribing, and encourage partnerships between stakeholders across disciplines.

Assessment of Overuse of Medical Tests and Treatments at US Hospitals Using Medicare Claims.

Importance: Overuse of health care services exposes patients to unnecessary risk of harm and costs. Distinguishing patterns of overuse among hospitals requires hospital-level measures across multiple services. Objective: To describe characteristics of hospitals associated with overuse of health care services in the US. Design, Setting, and Participants: This retrospective cross-sectional analysis used Medicare fee-for-service claims data for beneficiaries older than 65 years from January 1, 2015, to December 31, 2017, with a lookback of 1 year. Inpatient and outpatient services were included, and services offered at specialty and federal hospitals were excluded. Patients were from hospitals with the capacity (based on a claims filter developed for this study) to perform at least 7 of 12 investigated services. Statistical analyses were performed from July 1, 2020, to December 20, 2020. Main Outcomes and Measures: Outcomes of interest were a composite overuse score ranging from 0 (no overuse of services) to 1 (relatively high overuse of services) and characteristics of hospitals clustered by overuse rates. Twelve published low-value service algorithms were applied to the data to find overuse rates for each hospital, normalized and aggregated to a composite score and then compared across 6 hospital characteristics using multivariable regression. A k-means cluster analysis was used on normalized overuse rates to identify hospital clusters. Results: The primary analysis was performed on 2415 cohort A hospitals (ie, hospitals with capacity for 7 or more services), which included 1 263 592 patients (mean [SD] age, 72.4 [14] years; 678 549 women [53.7%]; 101 017 191 White patients [80.5%]). Head imaging for syncope was the highest-volume low-value service (377 745 patients [29.9%]), followed by coronary artery stenting for stable coronary disease (199 579 [15.8%]). The mean (SD) composite overuse score was 0.40 (0.10) points. Southern hospitals had a higher mean score than midwestern (difference in means: 0.06 [95% CI, 0.05-0.07] points; P < .001), northeast (0.08 [95% CI, 0.06-0.09] points; P < .001), and western hospitals (0.08 [95% CI, 0.07-0.10] points; P < .001). Nonprofit hospitals had a lower adjusted mean score than for-profit hospitals (-0.03 [95% CI, -0.04 to -0.02] points; P < .001). Major teaching hospitals had significantly lower adjusted mean overuse scores vs minor teaching hospitals (difference in means, -0.07 [95% CI, -0.08 to -0.06] points; P < .001) and nonteaching hospitals (-0.10 [95% CI, -0.12 to -0.09] points; P < .001). Of the 4 clusters identified, 1 was characterized by its low counts of overuse in all services except for spinal fusion; the majority of major teaching hospitals were in this cluster (164 of 223 major teaching hospitals [73.5%]). Conclusions and Relevance: This cross-sectional study used a novel measurement of hospital-associated overuse; results showed that the highest scores in this Medicare population were associated with nonteaching and for-profit hospitals, particularly in the South.