Relationship Among Body Fat Percentage, Body Mass Index, and All-Cause Mortality: A Cohort Study: Annals of Internal Medicine: Vol 164, No 8

Background: Prior mortality studies have concluded that elevated body mass index (BMI) may improve survival. These studies were limited because they did not measure adiposity directly. Objective: To examine associations of BMI and body fat percentage (separately and together) with mortality. Design: Observational study. Setting: Manitoba, Canada. Participants: Adults aged 40 years or older referred for bone mineral density (BMD) testing. Measurements: Participants had dual-energy x-ray absorptiometry (DXA), entered a clinical BMD registry, and were followed using linked administrative databases. Adjusted, sex-stratified Cox models were constructed. Body mass index and DXA-derived body fat percentage were divided into quintiles, with quintile 1 as the lowest, quintile 5 as the highest, and quintile 3 as the reference. Results: The final cohort included 49 476 women (mean age, 63.5 years; mean BMI, 27.0 kg/m2; mean body fat, 32.1%) and 4944 men (mean age, 65.5 years; mean BMI, 27.4 kg/m2; mean body fat, 29.5%). Death occurred in 4965 women over a median of 6.7 years and 984 men over a median of 4.5 years. In fully adjusted mortality models containing both BMI and body fat percentage, low BMI (hazard ratio [HR], 1.44 [95% CI, 1.30 to 1.59] for quintile 1 and 1.12 [CI, 1.02 to 1.23] for quintile 2) and high body fat percentage (HR, 1.19 [CI, 1.08 to 1.32] for quintile 5) were associated with higher mortality in women. In men, low BMI (HR, 1.45 [CI, 1.17 to 1.79] for quintile 1) and high body fat percentage (HR, 1.59 [CI, 1.28 to 1.96] for quintile 5) were associated with increased mortality. Limitations: All participants were referred for BMD testing, which may limit generalizability. Serial measures of BMD and weight were not used. Some measures, such as physical activity and smoking, were unavailable. Conclusion: Low BMI and high body fat percentage are independently associated with increased mortality. These findings may help explain the counterintuitive relationship between BMI and mortality. Primary Funding Source: None.

Factors Associated With Rates of False-Positive and False-Negative Results From Digital Mammography Screening: An Analysis of Registry Data

Background: Women screened with digital mammography may receive false-positive and false-negative results and subsequent imaging and biopsies. How these outcomes vary by age, time since the last screening, and individual risk factors is unclear. Objective: To determine factors associated with false-positive and false-negative digital mammography results, additional imaging, and biopsies among a general population of women screened for breast cancer. Design: Analysis of registry data. Setting: Participating facilities at 5 U.S. Breast Cancer Surveillance Consortium breast imaging registries with linkages to pathology databases and tumor registries. Patients: 405 191 women aged 40 to 89 years screened with digital mammography between 2003 and 2011. A total of 2963 were diagnosed with invasive cancer or ductal carcinoma in situ within 12 months of screening. Measurements: Rates of false-positive and false-negative results and recommendations for additional imaging and biopsies from a single screening round; comparisons by age, time since the last screening, and risk factors. Results: Rates of false-positive results (121.2 per 1000 women [95% CI, 105.6 to 138.7]) and recommendations for additional imaging (124.9 per 1000 women [CI, 109.3 to 142.3]) were highest among women aged 40 to 49 years and decreased with increasing age. Rates of false-negative results (1.0 to 1.5 per 1000 women) and recommendations for biopsy (15.6 to 17.5 per 1000 women) did not differ greatly by age. Results did not differ by time since the last screening. False-positive rates were higher for women with risk factors, particularly family history of breast cancer; previous benign breast biopsy result; high breast density; and, for younger women, low body mass index. Limitations: Confounding by variation in patient-level characteristics and outcomes across registries and regions may have been present. Some factors, such as numbers of first- and second-degree relatives with breast cancer and diagnoses associated with previous benign biopsy results, were not examined. Conclusion: False-positive mammography results and additional imaging are common, particularly for younger women and those with risk factors, whereas biopsies occur less often. Rates of false-negative results are low. Primary Funding Source: Agency for Healthcare Research and Quality and National Cancer Institute.

Variability in Pathologists' Interpretations of Individual Breast Biopsy Slides: A Population Perspective

Background: The effect of physician diagnostic variability on accuracy at a population level depends on the prevalence of diagnoses. Objective: To estimate how diagnostic variability affects accuracy from the perspective of a U.S. woman aged 50 to 59 years having a breast biopsy. Design: Applied probability using Bayes' theorem. Setting: B-Path (Breast Pathology) Study comparing pathologists' interpretations of a single biopsy slide versus a reference consensus interpretation from 3 experts. Participants: 115 practicing pathologists (6900 total interpretations from 240 distinct cases). Measurements: A single representative slide from each of the 240 cases was used to estimate the proportion of biopsies with a diagnosis that would be verified if the same slide were interpreted by a reference group of 3 expert pathologists. Probabilities of confirmation (predictive values) were estimated using B-Path Study results and prevalence of biopsy diagnoses for women aged 50 to 59 years in the Breast Cancer Surveillance Consortium. Results: Overall, if 1 representative slide were used per case, 92.3% (95% CI, 91.4% to 93.1%) of breast biopsy diagnoses would be verified by reference consensus diagnoses, with 4.6% (CI, 3.9% to 5.3%) overinterpreted and 3.2% (CI, 2.7% to 3.6%) underinterpreted. Verification of invasive breast cancer and benign without atypia diagnoses is highly probable; estimated predictive values were 97.7% (CI, 96.5% to 98.7%) and 97.1% (CI, 96.7% to 97.4%), respectively. Verification is less probable for atypia (53.6% overinterpreted and 8.6% underinterpreted) and ductal carcinoma in situ (DCIS) (18.5% overinterpreted and 11.8% underinterpreted). Limitations: Estimates are based on a testing situation with 1 slide used per case and without access to second opinions. Population-adjusted estimates may differ for women from other age groups, unscreened women, or women in different practice settings. Conclusion: This analysis, based on interpretation of a single breast biopsy slide per case, predicts a low likelihood that a diagnosis of atypia or DCIS would be verified by a reference consensus diagnosis. This diagnostic grey zone should be considered in clinical management decisions in patients with these diagnoses. Primary Funding Source: National Cancer Institute.

Mechanical Symptoms and Arthroscopic Partial Meniscectomy in Patients With Degenerative Meniscus Tear: A Secondary Analysis of a Randomized Trial: Annals of Internal Medicine: Vol 164, No 7

Background: Recent evidence shows that arthroscopic partial meniscectomy (APM) offers no benefit over conservative treatment of patients with a degenerative meniscus tear. However, patients who report mechanical symptoms (sensations of knee catching or locking) may benefit from APM. Objective: To assess whether APM improves mechanical symptoms better than sham surgery. Design: Randomized, patient- and outcome assessor–blinded, sham surgery–controlled, multicenter trial. (ClinicalTrials.gov: NCT00549172) Setting: 5 orthopedic clinics in Finland. Patients: Adults (aged 35 to 65 years) with a degenerative medial meniscus tear and no knee osteoarthritis. Intervention: APM or sham surgery. Measurements: Patients' self-report of mechanical symptoms before surgery and at 2, 6, and 12 months after surgery. Results: 70 patients were randomly assigned to APM, and 76 were assigned to sham surgery. Thirty-two patients (46%) in the APM group and 37 (49%) in the sham surgery group reported catching or locking before surgery; the corresponding numbers at any follow-up were 34 (49%) and 33 (43%), with a risk difference of 0.03 (95% CI, −0.06 to 0.12). In the subgroup of 69 patients with preoperative catching or locking, the risk difference was 0.07 (CI, −0.08 to 0.22). Limitation: Analyses were post hoc, and the results are only generalizable to knee catching and occasional locking because few patients reported other types of mechanical symptoms. Conclusion: Resection of a torn meniscus has no added benefit over sham surgery to relieve knee catching or occasional locking. These findings question whether mechanical symptoms are caused by a degenerative meniscus tear and prompt caution in using patients' self-report of these symptoms as an indication for APM. Primary Funding Source: Academy of Finland.

Disclosing Pleiotropic Effects During Genetic Risk Assessment for Alzheimer Disease: A Randomized Trial: Annals of Internal Medicine: Vol 164, No 3

Background: Increasing use of genetic testing raises questions about disclosing secondary findings, including pleiotropic information. Objective: To determine the safety and behavioral effect of disclosing modest associations between apolipoprotein E (APOE) genotype and coronary artery disease (CAD) risk during APOE-based genetic risk assessments for Alzheimer disease (AD). Design: Randomized, multicenter equivalence clinical trial. (ClinicalTrials.gov: NCT00462917) Setting: 4 teaching hospitals. Participants: 257 asymptomatic adults were enrolled, 69% of whom had 1 AD-affected first-degree relative. Intervention: Disclosure of genetic risk information about AD and CAD (AD+CAD) or AD only (AD-only). Measurements: Primary outcomes were Beck Anxiety Inventory (BAI) and Center for Epidemiologic Studies Depression Scale (CES-D) scores at 12 months. Secondary outcomes were all measures at 6 weeks and 6 months and test-related distress and health behavior changes at 12 months. Results: At 12 months, mean BAI scores were 3.5 in both the AD-only and AD+CAD groups (difference, 0.0 [95% CI, −1.0 to 1.0]), and mean CES-D scores were 6.4 and 7.1 in the AD-only and AD+CAD groups, respectively (difference, 0.7 [CI, −1.0 to 2.4]). Both confidence bounds fell within the equivalence margin of ±5 points. Among carriers of the APOE ε4 allele, distress was lower in the AD+CAD groups (difference, −4.8 [CI, −8.6 to −1.0]) (P = 0.031 for the interaction between group and APOE genotype). Participants in the AD+CAD groups also reported more health behavior changes, regardless of APOE genotype. Limitations: Outcomes were self-reported by volunteers without severe anxiety, severe depression, or cognitive problems. Analyses omitted 33 randomly assigned participants. Conclusion: Disclosure of pleiotropic information did not increase anxiety or depression and may have decreased distress among persons at increased risk for 2 conditions. Providing risk modification information about CAD improved health behaviors. Findings highlight the potential benefits of disclosure of secondary genetic findings when options exist for decreasing risk. Primary Funding Source: National Human Genome Research Institute.

Medical Assistant–Based Care Management for High-Risk Patients in Small Primary Care Practices: A Cluster Randomized Clinical Trial: Annals of Internal Medicine: Vol 164, No 5

Background: Patients with multiple chronic conditions are at high risk for potentially avoidable hospitalizations, which may be reduced by care coordination and self-management support. Medical assistants are an increasingly available resource for patient care in primary care practices. Objective: To determine whether protocol-based care management delivered by medical assistants improves care in patients at high risk for future hospitalization in primary care. Design: Two-year cluster randomized clinical trial. (Current Controlled Trials: ISRCTN56104508) Setting: 115 primary care practices in Germany. Patients: 2076 patients with type 2 diabetes, chronic obstructive pulmonary disease, or chronic heart failure and a likelihood of hospitalization in the upper quartile of the population, as predicted by an analysis of insurance data. Intervention: Protocol-based care management, including structured assessment, action planning, and monitoring delivered by medical assistants, compared with usual care. Measurements: All-cause hospitalizations at 12 months (primary outcome) and quality-of-life scores (12-Item Short Form Health Survey [SF-12] and EuroQol instrument [EQ-5D]). Results: Included patients had an average of 4 co-occurring chronic conditions. All-cause hospitalizations did not differ between groups at 12 months (risk ratio [RR], 1.01 [95% CI, 0.87 to 1.18]) and 24 months (RR, 0.98 [CI, 0.85 to 1.12]). Quality of life (differences, 1.16 [CI, 0.24 to 2.08] on SF-12 physical component and 1.68 [CI, 0.60 to 2.77] on SF-12 mental component) and general health (difference on EQ-5D, 0.03 [CI, 0.00 to 0.05]) improved significantly at 24 months. Intervention costs totaled $10 per patient per month. Limitation: Small number of primary care practices and low intensity of intervention. Conclusion: This low-intensity intervention did not reduce all-cause hospitalizations but showed positive effects on quality of life at reasonable costs in high-risk multimorbid patients. Primary Funding Source: AOK Baden-Württemberg and AOK Bundesverband.

Warning Symptoms Are Associated With Survival From Sudden Cardiac Arrest

Background: Survival after sudden cardiac arrest (SCA) remains low, and tools for improved prediction of patients at long-term risk for SCA are lacking. Alternative short-term approaches aimed at preemptive risk stratification and prevention are needed. Objective: To assess characteristics of symptoms in the 4 weeks before SCA and whether response to these symptoms is associated with better outcomes. Design: Ongoing prospective population-based study. Setting: Northwestern United States (2002 to 2012). Patients: Residents aged 35 to 65 years with SCA. Measurement: Assessment of symptoms in the 4 weeks preceding SCA and association with survival to hospital discharge. Results: Of 839 patients with SCA and comprehensive assessment of symptoms (mean age, 52.6 years [SD, 8]; 75% men), 430 (51%) had warning symptoms (50% of men vs. 53% of women; P  = 0.59), mainly chest pain and dyspnea. In most symptomatic patients (93%), symptoms recurred within the 24 hours preceding SCA. Only 81 patients (19%) called emergency medical services (911) to report symptoms before SCA; these persons were more likely to be patients with a history of heart disease (P < 0.001) or continuous chest pain (P < 0.001). Survival when 911 was called in response to symptoms was 32.1% (95% CI, 21.8% to 42.4%) compared with 6.0% (CI, 3.5% to 8.5%) in those who did not call (P < 0.001). Limitation: Potential for recall and response bias, symptom assessment not available in 24% of patients, and missing data for some patients and SCA characteristics. Conclusion: Warning symptoms frequently occur before SCA, but most are ignored. Emergent medical care was associated with survival in patients with symptoms, so new approaches are needed for short-term prevention of SCA. Primary Funding Source: National Heart, Lung, and Blood Institute.

Correction: SARS-CoV-2 Virologic Rebound With Nirmatrelvir–Ritonavir Therapy

Screening for Colorectal Cancer in Asymptomatic Average-Risk Adults

Estimated Effect of Parathyroidectomy on Long-Term Kidney Function in Adults With Primary Hyperparathyroidism