A Call for Universal Genetic Screening for Breast Cancer
Pioneering researcher Mary-Claire King, PhD, who discovered the BRCA1 and BRCA2 genes that put women at significant risk for breast and ovarian cancer, has called for population-based screening for BRCA1 and BRCA2, based on a study she recently conducted along with Israeli scientists (Proc Natl Acad Sci U S A 2014; doi:10.1073/pnas.1415979111).
The investigators sought to determine disease risk in the general population rather than through those identified based on personal or family history. King and her colleagues conducted the study among Ashkenazi Jewish participants in Israel because just three mutations account for most of the inherited BRCA1/BRCA2 cancer risk in this population, which made the study feasible before next-generation sequencing technologies had been implemented.
The study involved 8,222 male index subjects who were screened for BRCA1/BRCA2 status. In all, 175 participants were found to be carriers, representing 2.17% of the testing population. Both the carriers and a subset of non-carriers matched to the carriers were asked to provide new DNA samples to confirm their status, to undergo genetic counseling, and to refer their female relatives to the study.
The investigators found that BRCA1 mutation status conferred high risk of breast or ovarian cancer for women, rising from 60% at age 60 to about 83% by age 80. Risk for BRCA2 mutation carriers ranged from 33% at age 60 to 76% by age 80. As other studies have noted, the authors found age-specific cancer risks, with women born after 1958 at 3.8-fold higher risk in comparison to those born prior to 1958. Of note, the analysis revealed that “51% of families harboring BRCA1 or BRCA2 mutations had little or no history of relevant cancer,” generally because they tended to be small and had few females who had reached the ages of higher cancer risk. The women in these families typically would not have been tested for BRCA1 or BRCA2 status based on the current practice of doing so based on personal or family history.
These findings resolve an issue that has prevented groups like the U.S. Preventive Services Task Force from endorsing population-based screening, namely insufficient data on risks for mutation carriers determined from the general population, rather than based on family or personal history of cancer, King contended in an opinion article published in the Journal of the American Medical Association (2014; doi:10.1001/jama.2014.1248). She and her co-investigators wrote “it is now possible to identify, in one test and at reasonable cost, all actionable mutations in BRCA1 and BRCA2, as well as in all other known breast and ovarian cancer genes …We suggest that the time has come to apply our knowledge of these genes to consideration of a general screening program, with the aim of reducing the burden of breast and ovarian cancer.
Redundant Antimicrobial Therapy Raises Hospital Costs $163 Million Annually
Redundant antimicrobial therapy is “pervasive” in U.S. hospitals and raises hospital costs an estimated $163 million per year, according to investigators at the Premier Safety Institute and the Centers for Disease Control and Prevention (Infect Control Hosp Epidemiol 2014;35:1229–35). The authors reached these conclusions by analyzing inpatient administrative data from 505 hospitals for patients discharged during a 4-year period.
The investigators defined redundant antimicrobial usage as “administration of two agents that provide coverage for the same organism(s) for at least 2 consecutive days during the hospitalization.” They concentrated on 23 antibiotic combinations representing three categories, including antianaerobics, anti-methicillin-resistant Staphylococcus aureus agents, and dual-lactams. In all, 78% of the hospitals had evidence of one or more of the 23 combinations.
Just three combinations of antianaerobics, each involving metronidazole and another agent, accounted for more than 70% of potential redundant use. Among the studied hospitals, the cost of additional treatment exceeded $9 million. The researchers projected that these facilities would save $12.9 million in drug costs by reducing to monotherapy the 17 most frequent redundant antimicrobial combinations. Extrapolating this figure to hospitals nationwide, they estimated a $163 million annual savings.
Reflex Culture Needed After Negative Group A Rapid Antigen Detection Results
Study findings by University of Washington School of Medicine researchers call “into serious question” certain clinical guidelines that do not recommend reflexive culture following negative rapid antigen detection test (RADT) results for group A streptococcal (GAS) pharyngitis in adults (Clin Infect Dis 2014;59:643–50). In contrast, this analysis supports requirements of the College of American Pathologists (CAP), Joint Commission, and Food and Drug Administration (FDA) to confirm with another method negative RADT with sensitivity <80%, according to the authors.
The investigators conducted a retrospective analysis of patients at least age 13 who had negative RADT results but positive GAS culture results. The researchers identified test results through the laboratory information system, then reviewed relevant medical records to extract clinical data and score patients for GAS using a modified Centor score.
Of 726 patients, 55% had modified Centor scores ≥2, and of these, 77% had moderate or heavy bacterial burden. The researchers found the RADT used in this study had 76.3% sensitivity, below the 80% threshold required by CAP, Joint Commission, and FDA. RADTs also failed to detect some patients who had serious complications of GAS pharyngitis, including peritonsillar abscesses and acute rheumatic fever. The authors concluded that confirming negative RADT results with throat culture increases detection of true GAS infections and identifies patients with negative RADTs who would benefit from antibiotics.
Admission HbA1c in Hospital Discharge Algorithm Helps Tailor Type 2 Diabetic Treatment Regimens
A hospital discharge algorithm based on admission HbA1c helps assess glycemic control and tailor treatment regimens at the time type 2 diabetics are discharged (Diabetes Care 2014; doi:10.2337/dc14-0479). The researchers conducted the study because recent guidelines recommending intensification of glucose therapy in hospitalized patients with suboptimal glucose control and HbA1c were based on expert consensus. This prompted them to conduct a prospective, multicenter open-label study to test the safety and efficacy of a discharge algorithm.
Participants were from the Basal Plus trial involving hospitalized patients with type 2 diabetes. The researchers grouped patients according to their admission Hba1c level and modified their discharge regimens of oral agents or insulin therapy depending on whether their admission HbA1c levels were <7%, 7–9%, or >9%.
The mean admission HbA1c for the entire cohort of 224 patients was 8.7 ± 2.5%, and decreased to 7.9 ± 1.7% at 4 weeks and to 7.3 ± 1.5% at 12 weeks post-discharge. Reported hypoglycemia ranged from 22% for those discharged on oral agents only to 44% for patients treated with basal bolus, but was similar in patients with admission HbA1c ≤7%. These findings support recommendations that propose use of insulin during hospitalization for most patients with diabetes, but that many patients will not need this intensive therapy after discharge.
Sex Hormone Levels Linked to Sudden Cardiac Arrest
A case-control study conducted as part of the Oregon Sudden Unexpected Death Study (SUDS) found significantly different levels of sex hormones in patients who experienced sudden cardiac arrest (SCA) compared with matched controls (Heart Rhythm 2014; doi:10.1016/j.hrthm.2014.08.031). The findings warrant further exploration about the role of sex hormones in the genesis of fatal ventricular arrhythmias, according to the authors.
The role of sex hormones in the pathophysiology of SCA has not been studied extensively, but prior research has implicated age-related declining androgen levels as a risk factor for cardiac disease in men.
The study involved 149 SCA cases and 149 matched controls with coronary artery disease from SUDS, a prospective community based study of SCA in Portland, Oregon. The researchers measured testosterone and estradiol levels using an Access 2 Immunoassay system. In multivariate analysis, they found higher testosterone levels to be associated with lower SCA odds in male subjects, with an odds ratio of 0.75, while higher estradiol levels were associated with higher SCA odds in both male and female subjects, with odds ratios of 2.0 and 3.5, respectively. A higher testosterone:estrogen ratio was associated with lower SCA odds in men.