Deep Learning to Estimate Cardiovascular Risk From Chest Radiographs: A Risk Prediction Study: Annals of Internal Medicine: Vol 177, No 4

Background: Guidelines for primary prevention of atherosclerotic cardiovascular disease (ASCVD) recommend a risk calculator (ASCVD risk score) to estimate 10-year risk for major adverse cardiovascular events (MACE). Because the necessary inputs are often missing, complementary approaches for opportunistic risk assessment are desirable. Objective: To develop and test a deep-learning model (CXR CVD-Risk) that estimates 10-year risk for MACE from a routine chest radiograph (CXR) and compare its performance with that of the traditional ASCVD risk score for implications for statin eligibility. Design: Risk prediction study. Setting: Outpatients potentially eligible for primary cardiovascular prevention. Participants: The CXR CVD-Risk model was developed using data from a cancer screening trial. It was externally validated in 8869 outpatients with unknown ASCVD risk because of missing inputs to calculate the ASCVD risk score and in 2132 outpatients with known risk whose ASCVD risk score could be calculated. Measurements: 10-year MACE predicted by CXR CVD-Risk versus the ASCVD risk score. Results: Among 8869 outpatients with unknown ASCVD risk, those with a risk of 7.5% or higher as predicted by CXR CVD-Risk had higher 10-year risk for MACE after adjustment for risk factors (adjusted hazard ratio [HR], 1.73 [95% CI, 1.47 to 2.03]). In the additional 2132 outpatients with known ASCVD risk, CXR CVD-Risk predicted MACE beyond the traditional ASCVD risk score (adjusted HR, 1.88 [CI, 1.24 to 2.85]). Limitation: Retrospective study design using electronic medical records. Conclusion: On the basis of a single CXR, CXR CVD-Risk predicts 10-year MACE beyond the clinical standard and may help identify individuals at high risk whose ASCVD risk score cannot be calculated because of missing data. Primary Funding Source: None.

Understanding the Varying Biological Behaviors of Breast and Other Types of Cancer to Avoid Overdiagnosis

SARS-CoV-2 Virologic Rebound With Nirmatrelvir–Ritonavir Therapy: An Observational Study: Annals of Internal Medicine: Vol 176, No 12

Background: Data are conflicting regarding an association between treatment of acute COVID-19 with nirmatrelvir−ritonavir (N-R) and virologic rebound (VR). Objective: To compare the frequency of VR in patients with and without N-R treatment for acute COVID-19. Design: Observational cohort study. Setting: Multicenter health care system in Boston, Massachusetts. Participants: Ambulatory adults with acute COVID-19 with and without use of N-R. Intervention: Receipt of 5 days of N-R treatment versus no COVID-19 therapy. Measurements: The primary outcome was VR, defined as either a positive SARS-CoV-2 viral culture result after a prior negative result or 2 consecutive viral loads above 4.0 log10 copies/mL that were also at least 1.0 log10 copies/mL higher than a prior viral load below 4.0 log10 copies/mL. Results: Compared with untreated persons (n = 55), those taking N-R (n = 72) were older, received more COVID-19 vaccinations, and more commonly had immunosuppression. Fifteen participants (20.8%) taking N-R had VR versus 1 (1.8%) who was untreated (absolute difference, 19.0 percentage points [95% CI, 9.0 to 29.0 percentage points]; P = 0.001). All persons with VR had a positive viral culture result after a prior negative result. In multivariable models, only N-R use was associated with VR (adjusted odds ratio, 10.02 [CI, 1.13 to 88.74]; P = 0.038). Virologic rebound was more common among those who started therapy within 2 days of symptom onset (26.3%) than among those who started 2 or more days after symptom onset (0%) (P = 0.030). Among participants receiving N-R, those who had VR had prolonged shedding of replication-competent virus compared with those who did not have VR (median, 14 vs. 3 days). Eight of 16 participants (50% [CI, 25% to 75%]) with VR also reported symptom rebound; 2 were completely asymptomatic. No post-VR resistance mutations were detected. Limitations: Observational study design with differences between the treated and untreated groups; positive viral culture result was used as a surrogate marker for risk for ongoing viral transmission. Conclusion: Virologic rebound occurred in approximately 1 in 5 people taking N-R, often without symptom rebound, and was associated with shedding of replication-competent virus. Primary Funding Source: National Institutes of Health.

Real-World Effectiveness of BNT162b2 Against Infection and Severe Diseases in Children and Adolescents

Background: The efficacy of the BNT162b2 vaccine in pediatrics was assessed by randomized trials before the Omicron variant’s emergence. The long-term durability of vaccine protection in this population during the Omicron period remains limited. Objective: To assess the effectiveness of BNT162b2 in preventing infection and severe diseases with various strains of the SARS-CoV-2 virus in previously uninfected children and adolescents. Design: Comparative effectiveness research accounting for underreported vaccination in 3 study cohorts: adolescents (12 to 20 years) during the Delta phase and children (5 to 11 years) and adolescents (12 to 20 years) during the Omicron phase. Setting: A national collaboration of pediatric health systems (PEDSnet). Participants: 77 392 adolescents (45 007 vaccinated) during the Delta phase and 111 539 children (50 398 vaccinated) and 56 080 adolescents (21 180 vaccinated) during the Omicron phase. Intervention: First dose of the BNT162b2 vaccine versus no receipt of COVID-19 vaccine. Measurements: Outcomes of interest include documented infection, COVID-19 illness severity, admission to an intensive care unit (ICU), and cardiac complications. The effectiveness was reported as (1-relative risk)*100, with confounders balanced via propensity score stratification. Results: During the Delta period, the estimated effectiveness of the BNT162b2 vaccine was 98.4% (95% CI, 98.1% to 98.7%) against documented infection among adolescents, with no statistically significant waning after receipt of the first dose. An analysis of cardiac complications did not suggest a statistically significant difference between vaccinated and unvaccinated groups. During the Omicron period, the effectiveness against documented infection among children was estimated to be 74.3% (CI, 72.2% to 76.2%). Higher levels of effectiveness were seen against moderate or severe COVID-19 (75.5% [CI, 69.0% to 81.0%]) and ICU admission with COVID-19 (84.9% [CI, 64.8% to 93.5%]). Among adolescents, the effectiveness against documented Omicron infection was 85.5% (CI, 83.8% to 87.1%), with 84.8% (CI, 77.3% to 89.9%) against moderate or severe COVID-19, and 91.5% (CI, 69.5% to 97.6%) against ICU admission with COVID-19. The effectiveness of the BNT162b2 vaccine against the Omicron variant declined 4 months after the first dose and then stabilized. The analysis showed a lower risk for cardiac complications in the vaccinated group during the Omicron variant period. Limitation: Observational study design and potentially undocumented infection. Conclusion: This study suggests that BNT162b2 was effective for various COVID-19–related outcomes in children and adolescents during the Delta and Omicron periods, and there is some evidence of waning effectiveness over time. Primary Funding Source: National Institutes of Health.

Beautiful

Ethical Guidance for Physicians and Health Care Institutions on Grateful Patient Fundraising: A Position Paper From the American College of Physicians

Physician solicitation of charitable contributions from patients—also known among other things as grateful patient fundraising—raises significant ethical concerns. These include pressure on patients to donate and the effects of this on the patient–physician relationship, potential expectations of donor patients for treatment that is not indicated or preferential care, justice and fairness issues, disclosure and use of confidential patient information for nontreatment purposes, and conflicts of interest. The patient–physician relationship and knowledge of the patient’s medical history, clinical status, personal information, and financial circumstances are some of the reasons development and administrative officials might see physicians as strong potential fundraisers. But those are among the reasons grateful patient fundraising is ethically problematic. This American College of Physicians position paper explores these issues and offers guidance.

Changes in Induced Medical and Procedural Abortion Rates in a Commercially Insured Population, 2018 to 2022: An Interrupted Time-Series Analysis: Annals of Internal Medicine: Vol 176, No 11

Background: During the COVID-19 pandemic, access to in-person care was limited, and regulations requiring in-person dispensing of mifepristone for medical abortions were relaxed. The effect of the pandemic and accompanying regulatory changes on abortion use is unknown. Objective: To estimate changes in the incidence rate of induced medical and procedural abortions. Design: Serial cross-sectional study with interrupted time-series analyses. Setting: Commercially insured persons in the United States. Participants: Reproductive-aged women. Intervention: Onset of the COVID-19 pandemic in March 2020 and subsequent regulatory changes affecting the in-person dispensing requirement for mifepristone. Measurements: Monthly age-adjusted incidence rates of medical and procedural abortions were measured among women aged 15 to 44 years from January 2018 to June 2022. Medical abortions were classified as in-person or telehealth. Linear segmented time-series regression was used to calculate changes in abortion rates after March 2020. Results: In January 2018, the estimated age-adjusted monthly incidence rate of abortions was 151 per million women (95% CI, 142 to 161 per million women), with equal rates of medical and procedural abortions. After March 2020, there was an immediate 14% decrease in the monthly incidence rate of abortions (21 per million women [CI, 7 to 35 per million women]; P = 0.004), driven by a 31% decline in procedural abortions (22 per million women [CI, 16 to 28 per million women]; P < 0.001). Fewer than 4% of medical abortions each month were administered via telehealth. Limitation: Only abortions reimbursed by commercial insurance were measured. Conclusion: The incidence rate of procedural abortions declined during the COVID-19 pandemic, and this lower rate persisted after other elective procedures rebounded to prepandemic rates. Despite removal of the in-person dispensing requirement for mifepristone, the use of telehealth for insurance-covered medical abortions remained rare. Amid increasing state restrictions, commercial insurers have the opportunity to increase access to abortion care, particularly via telehealth. Primary Funding Source: Health Resources and Services Administration.

Adoption of Internal Medicine Milestone Ratings and Changes in Bias Against Black, Latino, and Asian Internal Medicine Residents

Background: The 2014 adoption of the Milestone ratings system may have affected evaluation bias against minoritized groups. Objective: To assess bias in internal medicine (IM) residency knowledge ratings against Black or Latino residents—who are underrepresented in medicine (URiM)—and Asian residents before versus after Milestone adoption in 2014. Design: Cross-sectional and interrupted time-series comparisons. Setting: U.S. IM residencies. Participants: 59 835 IM residents completing residencies during 2008 to 2013 and 2015 to 2020. Intervention: Adoption of the Milestone ratings system. Measurements: Pre-Milestone (2008 to 2013) and post-Milestone (2015 to 2020) bias was estimated as differences in standardized knowledge ratings between U.S.-born and non–U.S.-born minoritized groups versus non-Latino U.S.-born White (NLW) residents, with adjustment for performance on the American Board of Internal Medicine IM certification examination and other physician characteristics. Interrupted time-series analysis measured deviations from pre-Milestone linear bias trends. Results: During the pre-Milestone period, ratings biases against minoritized groups were large (−0.40 SDs [95% CI, −0.48 to −0.31 SDs; P < 0.001] for URiM residents, −0.24 SDs [CI, −0.30 to −0.18 SDs; P < 0.001] for U.S.-born Asian residents, and −0.36 SDs [CI, −0.45 to −0.27 SDs; P < 0.001] for non–U.S.-born Asian residents). These estimates decreased to less than −0.15 SDs after adoption of Milestone ratings for all groups except U.S.-born Black residents, among whom substantial (though lower) bias persisted (−0.26 SDs [CI, −0.36 to −0.17 SDs; P < 0.001]). Substantial deviations from pre-Milestone linear bias trends coincident with adoption of Milestone ratings were also observed. Limitations: Unobserved variables correlated with ratings bias and Milestone ratings adoption, changes in identification of race/ethnicity, and generalizability to Milestones 2.0. Conclusion: Knowledge ratings bias against URiM and Asian residents was ameliorated with the adoption of the Milestone ratings system. However, substantial ratings bias against U.S.-born Black residents persisted. Primary Funding Source: None.

Gene Therapy Versus Common Care for Eligible Individuals With Sickle Cell Disease in the United States: A Cost-Effectiveness Analysis: Annals of Internal Medicine: Vol 177, No 2

Background: Sickle cell disease (SCD) and its complications contribute to high rates of morbidity and early mortality and high cost in the United States and African heritage community. Objective: To evaluate the cost-effectiveness of gene therapy for SCD and its value-based prices (VBPs). Design: Comparative modeling analysis across 2 independently developed simulation models (University of Washington Model for Economic Analysis of Sickle Cell Cure [UW-MEASURE] and Fred Hutchinson Institute Sickle Cell Disease Outcomes Research and Economics Model [FH-HISCORE]) using the same databases. Data Sources: Centers for Medicare & Medicaid Services claims data, 2008 to 2016; published literature. Target Population: Persons eligible for gene therapy. Time Horizon: Lifetime. Perspective: U.S. health care sector and societal. Intervention: Gene therapy versus common care. Outcome Measures: Incremental cost-effectiveness ratios (ICERs), equity-informed VBPs, and price acceptability curves. Results of Base-Case Analysis: At an assumed $2 million price for gene therapy, UW-MEASURE and FH-HISCORE estimated ICERs of $193 000 per QALY and $427 000 per QALY, respectively, under the health care sector perspective. Corresponding estimates from the societal perspective were $126 000 per QALY and $281 000 per QALY. The difference in results between models stemmed primarily from considering a slightly different target population and incorporating the quality-of-life (QOL) effects of splenic sequestration, priapism, and acute chest syndrome in the UW model. From a societal perspective, acceptable (>90% confidence) VBPs ranged from $1 million to $2.5 million depending on the use of alternative effective metrics or equity-informed threshold values. Results of Sensitivity Analysis: Results were sensitive to the costs of myeloablative conditioning before gene therapy, effect on caregiver QOL, and effect of gene therapy on long-term survival. Limitation: The short-term effects of gene therapy on vaso-occlusive events were extrapolated from 1 study. Conclusion: Gene therapy for SCD below a $2 million price tag is likely to be cost-effective when applying a societal perspective at an equity-informed threshold for cost-effectiveness analysis. Primary Funding Source: National Heart, Lung, and Blood Institute.

Surgery, Needle Fasciotomy, or Collagenase Injection for Dupuytren Contracture: A Randomized Controlled Trial: Annals of Internal Medicine: Vol 177, No 3

Background: Surgery, needle fasciotomy, and collagenase injection are used to treat Dupuytren contracture. The treatment decision requires balancing initial morbidity and costs of surgery against its potential long-term benefits over needle fasciotomy and collagenase. Objective: To compare the effectiveness of surgery, needle fasciotomy, and collagenase injection at 3 months and 2 years (secondary time points of the trial). Design: A multicenter, randomized, outcome assessor–blinded, superiority trial. (ClinicalTrials.gov: NCT03192020) Setting: 6 public hospitals in Finland. Participants: 302 persons with treatment-naive Dupuytren contracture (contracture angle <135°). Intervention: Surgery (n = 101), needle fasciotomy (n = 101), or collagenase (n = 100). Measurements: The primary outcome was the success rate, defined as greater than 50% contracture release and patients reaching the patient acceptable symptom state. Secondary outcomes included hand function, pain, quality of life, patient satisfaction, residual contracture angle, finger flexion, risk for retreatment, and serious adverse events. Results: A total of 292 (97%) and 284 (94%) participants completed the 3-month and 2-year follow-ups. Success rates were similar at 3 months: 71% (95% CI, 62% to 80%) for surgery, 73% (CI, 64% to 82%) for needle fasciotomy, and 73% (CI, 64% to 82%) for collagenase. At 2 years, surgery had superior success rates compared with both needle fasciotomy (78% vs. 50%; adjusted risk difference [aRD], 0.30 [CI, 0.17 to 0.43]) and collagenase (78% vs. 65%; aRD, 0.13 [CI, 0.01 to 0.26]). Secondary analyses paralleled with the primary analysis. Limitation: Participants were not blinded. Conclusion: Initial outcomes are similar between the treatments, but at 2 years success rates were maintained in the surgery group but were lower with both needle fasciotomy and collagenase despite retreatments. Primary Funding Source: Research Council of Finland.