Reduced Likelihood of Hospitalization with the JN.1 or HV.1 SARS-CoV-2 Variants Compared to the EG.5 Variant.

Within a multi-state viral genomic surveillance program, we evaluated whether proportions of SARS-CoV-2 infections attributed to the JN.1 variant and to XBB-lineage variants (including HV.1 and EG.5) differed between inpatient and outpatient care settings during periods of cocirculation. Both JN.1 and HV.1 were less likely than EG.5 to account for infections among inpatients versus outpatients (aOR=0.60 [95% CI: 0.43-0.84; p=0.003] and aOR=0.35 [95% CI: 0.21-0.58; p<0.001], respectively). JN.1 and HV.1 variants may be associated with a lower risk of severe illness. The severity of COVID-19 may have attenuated as predominant circulating SARS-CoV-2 lineages shifted from EG.5 to HV.1 to JN.1.

A power-based sliding window approach to evaluate the clinical impact of rare genetic variants in the nucleotide sequence or the spatial position of the folded protein.

Systematic determination of novel variant pathogenicity remains a major challenge, even when there is an established association between a gene and phenotype. Here we present Power Window (PW), a sliding window technique that identifies the impactful regions of a gene using population-scale clinico-genomic datasets. By sizing analysis windows on the number of variant carriers, rather than the number of variants or nucleotides, statistical power is held constant, enabling the localization of clinical phenotypes and removal of unassociated gene regions. The windows can be built by sliding across either the nucleotide sequence of the gene (through 1D space) or the positions of the amino acids in the folded protein (through 3D space). Using a training set of 350k exomes from the UK Biobank (UKB), we developed PW models for well-established gene-disease associations and tested their accuracy in two independent cohorts (117k UKB exomes and 65k exomes sequenced at Helix in the Healthy Nevada Project, myGenetics, or In Our DNA SC studies). The significant models retained a median of 49% of the qualifying variant carriers in each gene (range 2%-98%), with quantitative traits showing a median effect size improvement of 66% compared with aggregating variants across the entire gene, and binary traits' odds ratios improving by a median of 2.2-fold. PW showcases that electronic health record-based statistical analyses can accurately distinguish between novel coding variants in established genes that will have high phenotypic penetrance and those that will not, unlocking new potential for human genomics research, drug development, variant interpretation, and precision medicine.

SARS-CoV-2 Antiviral Prescribing Gaps Among Nonhospitalized High-Risk Adults.

Within a multistate clinical cohort, SARS-CoV-2 antiviral prescribing patterns were evaluated from April 2022-June 2023 among nonhospitalized patients with SARS-CoV-2 with risk factors for severe COVID-19. Among 3247 adults, only 31.9% were prescribed an antiviral agent (87.6% nirmatrelvir/ritonavir, 11.9% molnupiravir, 0.5% remdesivir), highlighting the need to identify and address treatment barriers.

Racial/ethnic differences in anorexia and bulimia diagnoses among U.S. college students.

This study examined the prevalence of anorexia nervosa (AN) and bulimia nervosa (BN) diagnoses among college students from different racial/ethnic backgrounds. Utilizing archival data from the American College Health Association - National College Health Assessment II-C (ACHA-NCHA II-C), information from 426,425 college students collected between 2015 and 2019 was examined. Binary logistic regression analyses were conducted to determine the prevalence of AN and BN diagnoses among various racial and ethnic groups. The highest odds of AN diagnosis were observed among American Indian, Alaska Native, or Native Hawaiian (AI/AN/NH) students, with odds ranging from 2.143 (compared to White students) to 3.744 (compared to Black students). White students had higher odds of AN than Black (OR = 1.748), Hispanic/Latino (OR = 1.706), and Asian (OR = 1.531) students. Biracial/Multiracial students had significantly higher odds of AN than Black (OR = 1.653), Hispanic/Latino (OR = 1.616), and Asian (OR = 1.449) students. In terms of BN diagnoses, AI/AN/NH students had the highest odds compared to all other groups, ranging from 2.149 (compared to White students) to 2.899 (compared to Hispanic/Latino students). White students had higher odds of BN than Black (OR = 1.271) and Hispanic/Latino (OR = 1.350) students. Biracial/Multiracial students also had significantly higher odds of BN than Black (OR = 1.388) and Hispanic/Latino (OR = 1.474) students. Asian students had higher odds of BN than Black (OR = 1.252) and Hispanic/Latino (OR = 1.329) students. These findings demonstrate complex patterns of AN and BN diagnoses among different racial/ethnic groups. These results highlight the need for culturally sensitive prevention and treatment plans on college campuses.

The Autonomy Toolbox: A Multicenter Collaborative to Promote Resident Autonomy.

OBJECTIVES: Autonomy is necessary for resident professional development and well-being. A recent focus on patient safety has increased supervision and decreased trainee autonomy. Few validated interventions exist to improve resident autonomy. We aimed to use quality improvement methods to increase our autonomy metric, the Resident Autonomy Score (RAS), by 25% within 1 year and sustain for 6 months. METHODS: We developed a bundled-intervention approach to improve senior resident (SR) perception of autonomy on Pediatric Hospital Medicine (PHM) services at 5 academic children's hospitals. We surveyed SR and PHM faculty perceptions of autonomy and targeted interventions toward areas with the highest discordance. Interventions included SR and faculty development, expectation-setting huddles, and SR independent rounding. We developed a Resident Autonomy Score (RAS) index to track SR perceptions over time. RESULTS: Forty-six percent of SRs and 59% of PHM faculty completed the needs assessment survey querying how often SRs were afforded opportunities to provide autonomous medical care. Faculty and SR ratings were discordant in these domains: SR input in medical decisions, SR autonomous decision-making in straightforward cases, follow-through on SR plans, faculty feedback, SR as team leader, and level of attending oversight. The RAS increased by 19% (3.67 to 4.36) 1 month after SR and faculty professional development and before expectation-setting and independent rounding. This increase was sustained throughout the 18-month study period. CONCLUSIONS: SRs and faculty perceive discordant levels of SR autonomy. We created an adaptable autonomy toolbox that led to sustained improvement in perception of SR autonomy.

Racial and Ethnic Disparities in Weight Loss Behaviors Among US College Students.

Purpose: Weight loss behaviors are prevalent among college students and are associated with adverse physical and psychological outcomes, such as an elevated risk of developing an eating disorder. While cross-ethnic differences have been reported, no consistent pattern has emerged. The purpose of this study was to examine racial and ethnic differences in weight loss behaviors among female and male college students. Patients and Methods: The American College Health Association-National College Health Assessment (ACHA-NCHA) II-C survey data from the collection periods from 2015 to 2019 was used. A total of 426,425 students participated in the survey. Most participants were White (60%) and female (68.5%). Information on students' age, body mass index (BMI), and self-rated health was also collected. Logistic regression analyses were performed to determine cross-ethnic differences in weight loss methods among female and male students. Results: Students' weight loss behaviors were assessed and included dieting, exercising, vomiting or taking laxatives, and the use of diet pills in the past 30 days. More than half of the participants attempted to lose weight through exercise (53.5%), and 40.3% of students dieted to lose weight in the past month. Purging and the use of diet pills were endorsed by 2.9% and 2.8% of the participants, respectively. With few exceptions, male students from racial and ethnic minority backgrounds were more likely to engage in extreme weight control practices (ie, vomiting or taking laxatives, taking diet pills) than White male students, while female students from racial and ethnic minority backgrounds were less likely to use diet and exercise as weight loss methods than White female students. For all outcomes, Biracial/Multiracial and Hispanic/Latino male students were more likely to attempt weight loss than White male students. Biracial/Multiracial female students more frequently endorsed extreme weight control behaviors than White female students. Conclusion: The results of the present study add to the growing body of literature on the relationship between race and ethnicity and weight loss behaviors. The findings indicate the need for tailored educational and intervention programs on college campuses.

Cardiomyopathy prevalence exceeds 30% in individuals with TTN variants and early atrial fibrillation.

PURPOSE: TTN truncating variants (TTNtvs) represent the largest known genetic cause of dilated cardiomyopathies (DCMs), however their penetrance for DCM in general populations is low. More broadly, patients with cardiomyopathies (CMs) often exhibit other cardiac conditions, such as atrial fibrillation (Afib), which has also been linked to TTNtvs. This retrospective analysis aims to characterize the relationship between different cardiac conditions in those with TTNtvs and identify individuals with the highest risk of DCM. METHODS: In this work we leverage longitudinal electronic health record and exome sequencing data from approximately 450,000 individuals in 2 health systems to statistically confirm and pinpoint the genetic footprint of TTNtv-related diagnoses aside from CM, such as Afib, and determine whether vetting additional significantly associated phenotypes better stratifies CM risk across those with TTNtvs. We focused on TTNtvs in exons with a percentage spliced in >90% (hiPSI TTNtvs), a representation of constitutive cardiac expression. RESULTS: When controlling for CM and Afib, other cardiac conditions retained only nominal association with TTNtvs. A sliding window analysis of TTNtvs across the locus confirms that the association is specific to hiPSI exons for both CM and Afib, with no meaningful associations in percent spliced in ≤90% exons (loPSI TTNtvs). The combination of hiPSI TTNtv status and early Afib diagnosis (before age 60) found a subset of TTNtv individuals at high risk for CM. The prevalence of CM in this subset was 33%, a rate that was 3.5 fold higher than that in individuals with hiPSI TTNtvs (9% prevalence), 5-fold higher than that in individuals without TTNtvs with early Afib (6% prevalence), and 80-fold higher than that in the general population. CONCLUSION: Our retrospective analyses revealed that those with hiPSI TTNtvs and early Afib (∼1/2900) have a high prevalence of CM (33%), far exceeding that in other individuals with TTNtvs and in those without TTNtvs with an early Afib diagnosis. These results show that combining phenotypic information along with genomic population screening can identify patients at higher risk for progressing to symptomatic heart failure.

Evidence for SARS-CoV-2 Delta and Omicron co-infections and recombination.

BACKGROUND: Between November 2021 and February 2022, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Delta and Omicron variants co-circulated in the United States, allowing for co-infections and possible recombination events. METHODS: We sequenced 29,719 positive samples during this period and analyzed the presence and fraction of reads supporting mutations specific to either the Delta or Omicron variant. FINDINGS: We identified 18 co-infections, one of which displayed evidence of a low Delta-Omicron recombinant viral population. We also identified two independent cases of infection by a Delta-Omicron recombinant virus, where 100% of the viral RNA came from one clonal recombinant. In the three cases, the 5' end of the viral genome was from the Delta genome and the 3' end from Omicron, including the majority of the spike protein gene, though the breakpoints were different. CONCLUSIONS: Delta-Omicron recombinant viruses were rare, and there is currently no evidence that Delta-Omicron recombinant viruses are more transmissible between hosts compared with the circulating Omicron lineages. FUNDING: This research was supported by the NIH RADx initiative and by the Centers for Disease Control Contract 75D30121C12730 (Helix).

SARS-CoV-2 variant Delta rapidly displaced variant Alpha in the United States and led to higher viral loads.

We report on the sequencing of 74,348 SARS-CoV-2 positive samples collected across the United States and show that the Delta variant, first detected in the United States in March 2021, made up the majority of SARS-CoV-2 infections by July 1, 2021 and accounted for >99.9% of the infections by September 2021. Not only did Delta displace variant Alpha, which was the dominant variant at the time, it also displaced the Gamma, Iota, and Mu variants. Through an analysis of quantification cycle (Cq) values, we demonstrate that Delta infections tend to have a 1.7× higher viral load compared to Alpha infections (a decrease of 0.8 Cq) on average. Our results are consistent with the hypothesis that the increased transmissibility of the Delta variant could be due to the ability of the Delta variant to establish a higher viral load earlier in the infection as compared to the Alpha variant.

The Clinical Variant Analysis Tool: Analyzing the evidence supporting reported genomic variation in clinical practice.

PURPOSE: Genomic test results, regardless of laboratory variant classification, require clinical practitioners to judge the applicability of a variant for medical decisions. Teaching and standardizing clinical interpretation of genomic variation calls for a methodology or tool. METHODS: To generate such a tool, we distilled the Clinical Genome Resource framework of causality and the American College of Medical Genetics/Association of Molecular Pathology and Quest Diagnostic Laboratory scoring of variant deleteriousness into the Clinical Variant Analysis Tool (CVAT). Applying this to 289 clinical exome reports, we compared the performance of junior practitioners with that of experienced medical geneticists and assessed the utility of reported variants. RESULTS: CVAT enabled performance comparable to that of experienced medical geneticists. In total, 124 of 289 (42.9%) exome reports and 146 of 382 (38.2%) reported variants supported a diagnosis. Overall, 10.5% (1 pathogenic [P] or likely pathogenic [LP] variant and 39 variants of uncertain significance [VUS]) of variants were reported in genes without established disease association; 20.2% (23 P/LP and 54 VUS) were in genes without sufficient phenotypic concordance; 7.3% (15 P/LP and 13 VUS) conflicted with the known molecular disease mechanism; and 24% (91 VUS) had insufficient evidence for deleteriousness. CONCLUSION: Implementation of CVAT standardized clinical interpretation of genomic variation and emphasized the need for collaborative and transparent reporting of genomic variation.

HLA-A∗03:01 is associated with increased risk of fever, chills, and stronger side effects from Pfizer-BioNTech COVID-19 vaccination.

COVID-19 vaccines are safe and highly effective, but some individuals experience unpleasant reactions to vaccination. As the majority of adults in the United States have received a COVID-19 vaccine this year, there is an unprecedented opportunity to study the genetics of reactions to vaccination via surveys of individuals who are already part of genetic research studies. Here, we have queried 17,440 participants in the Helix DNA Discovery Project and Healthy Nevada Project about their reactions to COVID-19 vaccination. Our genome-wide association study identifies an association between severe difficulties with daily routine after vaccination and HLA-A∗03:01. This association was statistically significant only for those who received the Pfizer-BioNTech vaccine (BNT162b2; n = 3,694; p = 4.70E-11; OR = 2.07 [95% CI 1.67-2.56]), and showed a smaller effect size in those who received the Moderna vaccine (mRNA-1273; n = 3,610; p = 0.005; OR = 1.32 [95% CI 1.09-1.59]). In Pfizer-BioNTech recipients, HLA-A∗03:01 was associated with a 2-fold increase in risk of self-reported severe difficulties with daily routine following vaccination. The effect was consistent across ages, sexes, and whether the person had previously had a COVID-19 infection. The reactions experienced by HLA-A∗03:01 carriers were driven by associations with chills, fever, fatigue, and generally feeling unwell.

Using symptom-based case predictions to identify host genetic factors that contribute to COVID-19 susceptibility.

Epidemiological and genetic studies on COVID-19 are currently hindered by inconsistent and limited testing policies to confirm SARS-CoV-2 infection. Recently, it was shown that it is possible to predict COVID-19 cases using cross-sectional self-reported disease-related symptoms. Here, we demonstrate that this COVID-19 prediction model has reasonable and consistent performance across multiple independent cohorts and that our attempt to improve upon this model did not result in improved predictions. Using the existing COVID-19 prediction model, we then conducted a GWAS on the predicted phenotype using a total of 1,865 predicted cases and 29,174 controls. While we did not find any common, large-effect variants that reached genome-wide significance, we do observe suggestive genetic associations at two SNPs (rs11844522, p = 1.9x10-7; rs5798227, p = 2.2x10-7). Explorative analyses furthermore suggest that genetic variants associated with other viral infectious diseases do not overlap with COVID-19 susceptibility and that severity of COVID-19 may have a different genetic architecture compared to COVID-19 susceptibility. This study represents a first effort that uses a symptom-based predicted phenotype as a proxy for COVID-19 in our pursuit of understanding the genetic susceptibility of the disease. We conclude that the inclusion of symptom-based predicted cases could be a useful strategy in a scenario of limited testing, either during the current COVID-19 pandemic or any future viral outbreak.

Positive predictive value highlights four novel candidates for actionable genetic screening from analysis of 220,000 clinicogenomic records.

PURPOSE: To identify conditions that are candidates for population genetic screening based on population prevalence, penetrance of rare variants, and actionability. METHODS: We analyzed exome and medical record data from >220,000 participants across two large population health cohorts with different demographics. We performed a gene-based collapsing analysis of rare variants to identify genes significantly associated with disease status. RESULTS: We identify 74 statistically significant gene-disease associations across 27 genes. Seven of these conditions have a positive predictive value (PPV) of at least 30% in both cohorts. Three are already used in population screening programs (BRCA1, BRCA2, LDLR), and we also identify four new candidates for population screening: GCK with diabetes mellitus, HBB with ß-thalassemia minor and intermedia, PKD1 with cystic kidney disease, and MIP with cataracts. Importantly, the associations are actionable in that early genetic screening of each of these conditions is expected to improve outcomes. CONCLUSION: We identify seven genetic conditions where rare variation appears appropriate to assess in population screening, four of which are not yet used in screening programs. The addition of GCK, HBB, PKD1, and MIP rare variants into genetic screening programs would reach an additional 0.21% of participants with actionable disease risk, depending on the population.

Enhancing Residents' Warmth in Greeting Caregivers: An Inpatient Intervention to Improve Family-Centered Communication.

ABSTRACT: Hospitals are increasingly motivated to improve the patient and family experience and increase patient satisfaction scores. The manner by which a provider greets patients and their families sets the tone for the hospital stay. This study aimed to improve residents' greetings of caregivers in the inpatient pediatric setting to improve family-centered communication. The study was conducted from October 2017 to April 2018 at a single, urban children's hospital on a unit with patients primarily <5 years old. The intervention consisted of posting a prominent board outside of patients' rooms that (1) listed caregivers' preferred names (e.g., Mom/Dad, first names), (2) instructed residents to greet caregivers warmly by their preferred names, and (3) identified residents for families by name and photograph. During implementation, we conducted 5 Plan-Do-Study-Act cycles and surveyed 114 caregivers. Improvement was assessed using run charts. The primary outcome was the percentage of caregivers who rated residents' warmth of greetings as "excellent." This measure increased from a baseline median of 62.5%-84.4% with ≥6 consecutive postintervention points above the baseline median. The intervention improved caregiver-perceived quality of residents' greetings and could serve as a model for other hospitals to enhance provider-family rapport and improve communication.

Emergence and rapid transmission of SARS-CoV-2 B.1.1.7 in the United States.

The highly transmissible B.1.1.7 variant of SARS-CoV-2, first identified in the United Kingdom, has gained a foothold across the world. Using S gene target failure (SGTF) and SARS-CoV-2 genomic sequencing, we investigated the prevalence and dynamics of this variant in the United States (US), tracking it back to its early emergence. We found that, while the fraction of B.1.1.7 varied by state, the variant increased at a logistic rate with a roughly weekly doubling rate and an increased transmission of 40%-50%. We revealed several independent introductions of B.1.1.7 into the US as early as late November 2020, with community transmission spreading it to most states within months. We show that the US is on a similar trajectory as other countries where B.1.1.7 became dominant, requiring immediate and decisive action to minimize COVID-19 morbidity and mortality.

Comprehensive Allele Genotyping in Critical Pharmacogenes Reduces Residual Clinical Risk in Diverse Populations.

Genomic-guided pharmaceutical prescribing is increasingly recognized as an important clinical application of genetics. Accurate genotyping of pharmacogenomic (PGx) genes can be difficult, owing to their complex genetic architecture involving combinations of single-nucleotide polymorphisms and structural variation. Here, we introduce the Helix PGx database, an open-source star allele, genotype, and resulting metabolic phenotype frequency database for CYP2C9, CYP2C19, CYP2D6, and CYP4F2, based on short-read sequencing of >86,000 unrelated individuals enrolled in the Helix DNA Discovery Project. The database is annotated using a pipeline that is clinically validated against a broad range of alleles and designed to call CYP2D6 structural variants with high (98%) accuracy. We find that CYP2D6 has greater allelic diversity than the other genes, manifest in both a long tail of low-frequency star alleles, as well as a disproportionate fraction (36%) of all novel predicted loss-of-function variants identified. Across genes, we observe that many rare alleles (<0.1% frequency) in the overall cohort have 10 times higher frequency in one or more subgroups with non-European genetic ancestry. Extending these PGx genotypes to predicted metabolic phenotypes, we demonstrate that >90% of the cohort harbors a high-risk variant in one of the four pharmacogenes. Based on the recorded prescriptions for >30,000 individuals in the Healthy Nevada Project, combined with predicted PGx metabolic phenotypes, we anticipate that standard-of-care screening of these 4 pharmacogenes could impact nearly half of the general population.

Genome-Wide Identification of Rare and Common Variants Driving Triglyceride Levels in a Nevada Population.

Clinical conditions correlated with elevated triglyceride levels are well-known: coronary heart disease, hypertension, and diabetes. Underlying genetic and phenotypic mechanisms are not fully understood, partially due to lack of coordinated genotypic-phenotypic data. Here we use a subset of the Healthy Nevada Project, a population of 9,183 sequenced participants with longitudinal electronic health records to examine consequences of altered triglyceride levels. Specifically, Healthy Nevada Project participants sequenced by the Helix Exome+ platform were cross-referenced to their electronic medical records to identify: (1) rare and common single-variant genome-wide associations; (2) gene-based associations using a Sequence Kernel Association Test; (3) phenome-wide associations with triglyceride levels; and (4) pleiotropic variants linked to triglyceride levels. The study identified 549 significant single-variant associations (p < 8.75 × 10-9), many in chromosome 11's triglyceride hotspot: ZPR1, BUD13, APOC3, APOA5. A well-known protective loss-of-function variant in APOC3 (R19X) was associated with a 51% decrease in triglyceride levels in the cohort. Sixteen gene-based triglyceride associations were identified; six of these genes surprisingly did not include a single variant with significant associations. Results at the variant and gene level were validated with the UK Biobank. The combination of a single-variant genome-wide association, a gene-based association method, and phenome wide-association studies identified rare and common variants, genes, and phenotypes associated with elevated triglyceride levels, some of which may have been overlooked with standard approaches.

Genomic epidemiology identifies emergence and rapid transmission of SARS-CoV-2 B.1.1.7 in the United States.

As of January of 2021, the highly transmissible B.1.1.7 variant of SARS-CoV-2, which was first identified in the United Kingdom (U.K.), has gained a strong foothold across the world. Because of the sudden and rapid rise of B.1.1.7, we investigated the prevalence and growth dynamics of this variant in the United States (U.S.), tracking it back to its early emergence and onward local transmission. We found that the RT-qPCR testing anomaly of S gene target failure (SGTF), first observed in the U.K., was a reliable proxy for B.1.1.7 detection. We sequenced 212 B.1.1.7 SARS-CoV-2 genomes collected from testing facilities in the U.S. from December 2020 to January 2021. We found that while the fraction of B.1.1.7 among SGTF samples varied by state, detection of the variant increased at a logistic rate similar to those observed elsewhere, with a doubling rate of a little over a week and an increased transmission rate of 35-45%. By performing time-aware Bayesian phylodynamic analyses, we revealed several independent introductions of B.1.1.7 into the U.S. as early as late November 2020, with onward community transmission enabling the variant to spread to at least 30 states as of January 2021. Our study shows that the U.S. is on a similar trajectory as other countries where B.1.1.7 rapidly became the dominant SARS-CoV-2 variant, requiring immediate and decisive action to minimize COVID-19 morbidity and mortality.

Pediatric Residents' Sense of Meaning in Their Work: Is This Value Related to Higher Specialty Satisfaction and Reduced Burnout?

OBJECTIVE: Physician wellness is frequently measured as the absence of burnout, rather than the perception of meaningful work. This study of pediatric residents aimed to test the hypothesis that their sense of meaning at work is associated positively with specialty satisfaction and negatively with burnout. METHODS: In June 2018, we surveyed residents at a large urban pediatrics program, using the Work and Meaning Inventory (WAMI), the Global Specialty Satisfaction measure, and a single-item burnout measure. Residents were surveyed at the end of their intern, second or third/fourth year. We compared resident responses to outcome measures by year, gender, race, and type of program (pediatrics and medicine-pediatrics). We assessed the associations between WAMI scores and specialty satisfaction using linear regression and between WAMI scores and burnout using logistic regression, both adjusted for residency year and characteristics. RESULTS: The survey was completed by 119/154 (77.3%) residents. Mean WAMI score was 40.6 ± 5.6 (standard deviation), mean specialty satisfaction score was 11.9 ± 2.4, and 48.7% (58/119) of residents reported burnout with no significant differences in scores by residency year, gender, race, or type of program (all P > .05). Residents' WAMI scores were positively associated with specialty satisfaction (r = +0.57, P < .001) and negatively associated with burnout (adjusted odds ratio  = 0.80, 95% confidence interval 0.73-0.89). CONCLUSIONS: Pediatric residents' sense of meaning at work was significantly positively associated with specialty satisfaction and negatively associated with burnout. We recommend that efforts to improve resident wellness focus on interventions to foster meaning in work, such as supporting team cohesion and autonomy in job design.