SARS-CoV-2–Positive Sputum and Feces After Conversion of Pharyngeal Samples in Patients With COVID-19

Delayed Denosumab Injections and Fracture Risk Among Patients With Osteoporosis: A Population-Based Cohort Study: Annals of Internal Medicine: Vol 173, No 7

Background: Denosumab is effective for osteoporosis, but discontinuation leads to rapid reversal of its therapeutic effect. Objective: To estimate the risk for fracture among users of denosumab who delayed subsequent doses compared with users who received doses on time. Design: Population-based cohort study. Setting: The Health Improvement Network U.K. primary care database, 2010 to 2019. Patients: Persons aged 45 years or older who initiated denosumab therapy for osteoporosis. Measurements: Observational data were used to emulate an analysis of a hypothetical trial with 3 dosing intervals: subsequent denosumab injection given within 4 weeks after the recommended date (“on time”), delay by 4 to 16 weeks (“short delay”), and delay by more than 16 weeks (“long delay”). The primary outcome was a composite of all fracture types at 6 months after the recommended date. Secondary outcomes were major osteoporotic fracture, vertebral fracture, hip fracture, and nonvertebral fracture. Results: Investigators identified 2594 patients initiating denosumab therapy. The risk for composite fracture over 6 months was 27.3 in 1000 for on-time dosing, 32.2 in 1000 for short delay, and 42.4 in 1000 for long delay. Compared with on-time injections, short delay had a hazard ratio (HR) for composite fracture of 1.03 (95% CI, 0.63 to 1.69) and long delay an HR of 1.44 (CI, 0.96 to 2.17) (P for trend = 0.093). For vertebral fractures, short delay had an HR of 1.48 (CI, 0.58 to 3.79) and long delay an HR of 3.91 (CI, 1.62 to 9.45). Limitation: Dosing schedules were not randomly assigned. Conclusion: Although delayed administration of subsequent denosumab doses by more than 16 weeks is associated with increased risk for vertebral fracture compared with on-time dosing, evidence is insufficient to conclude that fracture risk is increased at other anatomical sites with long delay. Primary Funding Source: National Clinical Research Center for Orthopedics, Sports Medicine & Rehabilitation.

Effects of Interleukin-1β Inhibition on Incident Hip and Knee Replacement: Exploratory Analyses From a Randomized, Double-Blind, Placebo-Controlled Trial: Annals of Internal Medicine: Vol 173, No 7

Background: Osteoarthritis is a common inflammatory disorder with no disease-modifying therapies. Whether inhibition of interleukin-1β (IL-1β) can reduce the consequences of large joint osteoarthritis is unclear. Objective: To determine whether IL-1β inhibition with canakinumab reduces incident total hip or knee replacement (THR/TKR). Design: Exploratory analysis of a randomized trial. (ClinicalTrials.gov: NCT01327846) Setting: 1091 clinical sites in 39 countries. Participants: 10 061 CANTOS (Canakinumab Anti-inflammatory Thrombosis Outcomes Study) participants. Intervention: Random allocation to placebo or canakinumab (50, 150, or 300 mg) subcutaneously once every 3 months. Measurements: The primary and secondary outcomes were time to first incident THR/TKR and time to first occurrence of an osteoarthritis-related adverse event (AE). Data were obtained through blinded ascertainment of trial clinical and safety databases. Results: Median follow-up was 3.7 years. For the individual canakinumab dose groups, compared with placebo, hazard ratios (HRs) for incident THR/TKR during follow-up were 0.60 (95% CI, 0.38 to 0.95) for the 50-mg group, 0.53 (CI, 0.33 to 0.84) for the 150-mg group, and 0.60 (CI, 0.38 to 0.93) for the 300-mg group. Thus, in the pooled canakinumab groups, compared with the placebo group, incidence rates for THR/TKR were 0.31 and 0.54 events per 100 person-years (HR, 0.58 [CI, 0.42 to 0.80]; P = 0.001), respectively. The HR for the secondary end point of osteoarthritis-related AEs was 0.73 (CI, 0.61 to 0.87). Similar findings were observed in analyses restricted to participants with a history of osteoarthritis. Limitation: Because the parent trial was not designed to examine the efficacy of IL-1β inhibitors in osteoarthritis, information on structural joint outcomes was not collected. Conclusion: Findings from this exploratory analysis of a randomized controlled trial support further investigation of IL-1β inhibition for treatment of large joint osteoarthritis. Primary Funding Source: Novartis Pharmaceuticals.

Addressing Patient Bias Toward Health Care Workers: Recommendations for Medical Centers

Some patients engage in behavior or use language that demeans clinicians on the basis of their social identity traits, such as race, ethnicity, sex, disability, gender presentation, and sexual orientation, and some patients even request reassignment of involved clinicians. Despite the importance and prevalence of this problem, many medical centers lack an organizational approach for addressing patient conduct. Policy development can be daunting because organizations may encounter various barriers, including reluctance of staff to have difficult conversations about race or other identity traits; uncertainty about what constitutes an appropriate response to the spectrum of demeaning behaviors and who should make this determination; what, if any, support should be offered to targeted clinicians; whether these incidents should be reported and to whom; and whether the medical center's response should differ depending on whether nurses, trainees, or other clinicians are involved. These determinations have important implications for patients' informed consent rights, clinicians' employment rights, and medical centers' obligations to protect patients' health while adhering to workplace antidiscrimination laws and institutional commitments to diversity, equality, and inclusion. This article addresses these considerations and offers guidance to organizations on devising effective policies that meet the needs of medical centers, patients, and health care workers across services and roles, including physicians, nurses, and trainees.

Medication for Opioid Use Disorder: A National Survey of Primary Care Physicians

Utility, Appropriateness, and Content of Electronic Consultations Across Medical Subspecialties: A Cohort Study: Annals of Internal Medicine: Vol 172, No 10

Background: Electronic consultations (e-consults) can facilitate patient access to specialists, minimize travel, and reduce unnecessary in-person visits. However, metrics to enable study of e-consults and their effect on processes and patient care are lacking. Objective: To assess novel metrics of e-consult appropriateness and utility. Design: Retrospective cohort study. Setting: Primary and specialty care practices at 2 large academic and 2 community hospitals of an integrated health system. Participants: Patients with e-consult requests to 5 specialties—hematology, infectious disease, dermatology, rheumatology, and psychiatry—between October 2017 and November 2018. Measurements: The appropriateness of e-consult inquiries was assessed by review of medical records and defined as meeting the following 4 criteria: not answerable by reviewing evidence-based summary sources (“point-of-care resource test”), not merely requesting logistic information, having appropriate clinical urgency, and having appropriate patient complexity. Interrater agreement in assessments of e-consult appropriateness was assessed by the κ statistic. Utility of e-consults was assessed by the rate of avoided visits (AVs), defined by the absence of an in-person visit to the same specialty within 120 days. Results: Overall, 6512 eligible e-consults were made by 1096 referring providers to 121 specialist consultants. Inquiries were characterized as diagnostic, therapeutic, for provider education, or at the request of the patient. Most consultations were answered within 1 day, with variation across specialties (73.1% for psychiatry to 87.8% for infectious disease). Overall, 70.2% of e-consults met all 4 criteria for appropriateness; the frequency of unmet criteria varied among specialties. Raters agreed on the appropriateness of 94% of e-consults (κ = 0.57 [95% CI, 0.36 to 0.79]), indicating moderate agreement. The overall rate of AVs across the 5 specialties was 81.2%; the highest rate was in psychiatry (92.6%) and the lowest in dermatology (61.9%). Limitation: Generalizability is unknown outside a single integrated health system, where requesting and consulting providers share a common electronic health record. Conclusion: Novel metrics to assess the appropriateness and utility of e-consults provide meaningful insight into practice, provide a rubric for comparison in future studies in additional settings, and suggest areas to improve resource use and patient care. Primary Funding Source: None.

Annals Clinical Decision Making: Avoiding Cognitive Errors in Clinical Decision Making

Clinical Benefits, Harms, and Cost-Effectiveness of Breast Cancer Screening for Survivors of Childhood Cancer Treated With Chest Radiation: A Comparative Modeling Study: Annals of Internal Medicine: Vol 173, No 5

Background: Surveillance with annual mammography and breast magnetic resonance imaging (MRI) is recommended for female survivors of childhood cancer treated with chest radiation, yet benefits, harms, and costs are uncertain. Objective: To compare the benefits, harms, and cost-effectiveness of breast cancer screening strategies in childhood cancer survivors. Design: Collaborative simulation modeling using 2 Cancer Intervention and Surveillance Modeling Network breast cancer models. Data Sources: Childhood Cancer Survivor Study and published data. Target Population: Women aged 20 years with a history of chest radiotherapy. Time Horizon: Lifetime. Perspective: Payer. Intervention: Annual MRI with or without mammography, starting at age 25, 30, or 35 years. Outcome Measures: Breast cancer deaths averted, false-positive screening results, benign biopsy results, and incremental cost-effectiveness ratios (ICERs). Results of Base-Case Analysis: Lifetime breast cancer mortality risk without screening was 10% to 11% across models. Compared with no screening, starting at age 25 years, annual mammography with MRI averted the most deaths (56% to 71%) and annual MRI (without mammography) averted 56% to 62%. Both strategies had the most screening tests, false-positive screening results, and benign biopsy results. For an ICER threshold of less than $100 000 per quality-adjusted life-year gained, screening beginning at age 30 years was preferred. Results of Sensitivity Analysis: Assuming lower screening performance, the benefit of adding mammography to MRI increased in both models, although the conclusions about preferred starting age remained unchanged. Limitation: Elevated breast cancer risk was based on survivors diagnosed with childhood cancer between 1970 and 1986. Conclusion: Early initiation (at ages 25 to 30 years) of annual breast cancer screening with MRI, with or without mammography, might reduce breast cancer mortality by half or more in survivors of childhood cancer. Primary Funding Source: American Cancer Society and National Institutes of Health.

Uses and Limitations of the Restricted Mean Survival Time: Illustrative Examples From Cardiovascular Outcomes and Mortality Trials in Type 2 Diabetes

The restricted mean survival time (RMST) has been advocated as an alternative or a supplement to the hazard ratio for reporting the effect of an intervention in a randomized clinical trial. The RMST difference allows quantification of the postponement of an outcome during a specified (restricted) interval and corresponds to the difference between the areas under the 2 survival curves for the intervention and control groups. This article presents examples of the use of the RMST in a research and a clinical context. First, the authors demonstrate how the RMST difference can answer research questions about the efficacy of different treatments. Estimates are presented for the effects of pharmacologic or strategy-driven glucose-lowering interventions for adults with type 2 diabetes from 36 trials and 9 follow-up studies reporting cardiovascular outcomes and mortality. The authors show how these measures may be used to mitigate uncertainty about the efficacy of intensive glucose control. Second, the authors demonstrate how the RMST difference may be used in the setting of a clinical consultation to guide the decision to start or discontinue a treatment. They then discuss the advantages of the RMST over the absolute risk difference, the number needed to treat, and the median survival time difference. They argue that the RMST difference is both easy to interpret and flexible in its application to different settings. Finally, they highlight the major limitations of the RMST, including difficulties in comparing studies of heterogeneous designs and in inferring the long-term effects of treatments using trials of short duration, and summarize the available statistical software for calculating the RMST.

Achieving Health Equity in Preventive Services: A Systematic Review for a National Institutes of Health Pathways to Prevention Workshop

Background: Disadvantaged populations in the United States experience disparities in the use of preventive health services. Purpose: To examine effects of barriers that create health disparities in 10 recommended preventive services for adults, and to evaluate the effectiveness of interventions to reduce them. Data Sources: English-language searches of Ovid MEDLINE, PsycINFO, SocINDEX, and the Veterans Affairs Health Services database (1 January 1996 to 5 July 2019); reference lists. Study Selection: Trials, observational studies with comparison groups, and systematic reviews of populations adversely affected by disparities that reported effects of barriers on use of any of the 10 selected preventive services or that reported the effectiveness of interventions to reduce disparities in use of a preventive service by improving intermediate or clinical outcomes. Data Extraction: Dual extraction and assessment of study quality, strength of evidence, and evidence applicability. Data Synthesis: No studies reported effects of provider-specific barriers on preventive service use. Eighteen studies reporting effects of patient barriers, such as insurance coverage or lack of a regular provider, on preventive service use had mixed and inconclusive findings. Studies of patient–provider interventions (n = 12), health information technologies (n = 11), and health system interventions (n = 88) indicated higher cancer screening rates with patient navigation; telephone calls, prompts, and other outreach methods; reminders involving lay health workers; patient education; risk assessment, counseling, and decision aids; screening checklists; community engagement; and provider training. Single studies showed that clinician-delivered and technology-assisted interventions improved rates of smoking cessation and weight loss, respectively. Limitation: Insufficient or low strength of evidence and applicability for most interventions except patient navigation, telephone calls and prompts, and reminders involving lay health workers. Conclusion: In populations adversely affected by disparities, patient navigation, telephone calls and prompts, and reminders involving lay health workers increase cancer screening. Primary Funding Source: National Institutes of Health Office of Disease Prevention through an interagency agreement with the Agency for Healthcare Research and Quality. (PROSPERO: CRD42018109263)