Medical College of Wisconsin

Background: Diagnosing interstitial lung disease (ILD) remains challenging. Guidelines recommend utilizing a multidisciplinary discussion (MDD) to review clinical and radiographic data and if diagnostic uncertainty persists, then to obtain histopathology. Surgical lung biopsy and transbronchial lung cryobiopsy (TBLC) are acceptable methods, but risks of complications may be prohibitive. The Envisia genomic classifier (EGC) represents another option to determine a molecular usual interstitial pneumonia (UIP) signature to facilitate an ILD diagnosis at MDD with high sensitivity and specificity. We evaluated the concordance between TBLC and EGC at MDD and the safety of this procedure. Methods: Demographic data, pulmonary function values, chest imaging pattern, procedural information, and MDD diagnosis were recorded. Concordance was defined as agreement between the molecular EGC results and histopathology from TBLC in the context of the patient's High Resolution CT pattern. Results: 49 patients were enrolled. Imaging demonstrated a probable (n = 14) or indeterminate (n = 7) UIP pattern in 43% and an alternative pattern in 57% (n = 28). EGC results were positive for UIP in 37% (n = 18) and negative in 63% (n = 31). MDD diagnosis was obtained in 94% (n = 46) with fibrotic hypersensitivity pneumonitis (n = 17, 35%) and IPF (n = 13, 27%) most common. The concordance between EGC and TBLC at MDD was 76% (37/49) with discordant results seen in 24% (12/49) of patients. Conclusions: There appears to be reasonable concordance between EGC and TBLC results at MDD. Efforts clarifying the contributions of these tools to an ILD diagnosis may help identify specific patient populations that may benefit from a tailored diagnostic approach.

We have studied six cases in which focal consolidative pulmonary opacities observed on imaging studies led to surgical resection due to the suspicion of malignancy and showed on histopathologic examination a benign process characterized by an expansile tumor-like nodular accumulation of elastotic material. The patients were five women and one man aged 46 to 67 years (mean: 61 years). All lesions were found incidentally on imaging studies done for a variety of reasons, including surveillance for metastatic carcinoma in four patients. The lesions presented as solid nodules within lung parenchyma with irregular borders and spiculated margins and measured between 0.6 and 4.6 cm in diameter. Histological examination showed dense deposits of elastic tissue without evidence of malignancy, similar to those seen in pulmonary apical caps. Clinical follow-up between 5 and 16 years (mean: 10 years) showed that all patients were alive and well without evidence of disease. Pulmonary nodular elastosis is a localized intraparenchymatous process that may be confused clinically and radiographically for a malignant neoplasm and needs to be distinguished from other nodular lesions of the lung. To the best of our knowledge, tumor-forming lesions within lung parenchyma that are predominantly or almost exclusively composed of accumulation of elastic fibers have not been previously described.

Study objective: To evaluate the association between delirium and subsequent short-term mortality in geriatric patients presenting to the emergency department (ED). Methods: This was an observational cohort study of adults age ≥75 years who presented to an academic ED and were screened for delirium during their ED visit. The Delirium Triage Screen followed by the Brief Confusion Assessment Method were used to ascertain the presence of delirium. In-hospital, 7-day, and 30-day mortality were compared between patients with and without ED delirium. Odds ratios with 95% confidence intervals (CIs) were calculated through logistic regression after adjusting for confounders including age, sex, history of dementia, ED disposition, and acuity. Results: A total of 967 ED visits were included for analysis among which delirium was detected in 107 (11.1%). The median age of the cohort was 83 years (IQR 79, 88), 526 (54.4%) were female, 285 (29.5%) had documented dementia, and 171 (17.7%) had a high acuity Emergency Severity Index triage level 1 or 2. During the hospitalization, 5/107 (4.7%) of those with delirium and 4/860 (0.5%) of those without delirium died. Within 7 days of ED departure, 6/107 (5.6%) of those with delirium and 6/860 (0.7%) of those without delirium died (unadjusted OR 8.46, 95% CI 2.68-26.71). Within 30 days, 18/107 (16.8%) of those with delirium and 37/860 (4.3%) of those without delirium died (unadjusted OR 4.50, 95% CI 2.46-8.23). ED delirium remained associated with higher 7-day (adjusted OR 5.23, 95% CI 1.44-19.05, p = 0.008) and 30-day mortality (adjusted OR 2.82, 95% CI 1.45-5.46, p = 0.002). Conclusion: Delirium is an important prognostic factor that ED clinicians and nurses must be aware of to optimize delirium prevention, management, disposition, and communication with patients and families.

Changes in surface glycan determinants, specifically sialic acid loss, determine platelet life span. The gradual loss of stored platelet quality is a complex process that fundamentally involves carbohydrate structures. Here, we applied lipophilic extraction and glycan release protocols to sequentially profile N- and O-linked glycans in freshly isolated and seven-day room temperature stored platelet concentrates. Analytical methods including matrix assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS), tandem mass spectrometry (MSn), and liquid chromatography (LC) were used to obtain structural details of selected glycans and terminal epitopes. The fresh platelet repertoire of surface structures revealed diverse N-glycans, including high mannose structures, complex glycans with polylactosamine repeats, and glycans presenting blood group epitopes. The O-glycan repertoire was largely comprised of sialylated and fucosylated core-1 and core-2 structures. For both N- and O-linked glycans, we observed a loss in sialylated epitopes with a reciprocal increase in neutral structures as well as increased neuraminidase activity following platelet storage at room temperature. The data indicate that loss of sialylated glycans is associated with diminished platelet quality and untimely removal of platelets following storage.

The National Heart, Lung, and Blood Institute National MDS Natural History Study (NCT02775383) is a prospective cohort study enrolling cytopenic patients with suspected myelodysplastic syndromes (MDS) to evaluate factors associated with disease. Here, we sequenced 53 genes in bone marrow samples harvested from 1,298 patients diagnosed with myeloid malignancy, including MDS and non-MDS myeloid malignancy, or alternative marrow conditions with cytopenia based on concordance between independent histopathologic reviews (local, centralized, and tertiary to adjudicate disagreements when needed). We developed a novel two-stage diagnostic classifier based on mutational profiles in 18 of 53 sequenced genes that were sufficient to best (1) predict a diagnosis of myeloid malignancy and (2) within those with a predicted myeloid malignancy, predict whether they had MDS. The classifier achieved a PPV of 0.84 and NPV of 0.8 with an AUROC of 0.85 when classifying patients as myeloid vs. no myeloid malignancy based on VAFs in 17 genes and a PPV of 0.71 and NPV of 0.64 with an AUROC of 0.73 when classifying patients as MDS vs. non-MDS malignancy based on VAFs in 10 genes. We next assessed how this approach could complement histopathology to improve diagnostic accuracy. For 99 of 139 (71%) patients (PPV of 0.83 and NPV of 0.65) with local and centralized histopathologic disagreement in myeloid vs. no myeloid malignancy, the classifier-predicted diagnosis agreed with the tertiary pathology review (considered the internal gold standard). An online version of the classifier that can be used with either VAFs or binary mutation profiles is available at https://thenationalmdsstudy.net.

Chronic or recurrent episodes of acute inflammation cause attrition of normal hematopoietic stem cells (HSCs) that can lead to hematopoietic failure, but they drive progression in myeloid malignancies and their precursor clonal hematopoiesis (CH). Mechanistic parallels exist between hematopoiesis in chronic inflammation and the continuously increased proliferation of myeloid malignancies, particularly myeloproliferative neoplasms (MPNs). The ability to enter dormancy, a state of deep quiescence characterized by low oxidative phosphorylation, low glycolysis, reduced protein synthesis, and increased autophagy is central to the preservation of long term HSCs and likely MPN SCs. The metabolic features of dormancy resemble those of diapause, a state of arrested embryonic development triggered by adverse environmental conditions. To outcompete their normal counterparts in the inflammatory MPN environment, MPN SCs co-opt mechanisms used by HSCs to avoid exhaustion, including signal attenuation by negative regulators, insulation from activating cytokine signals, anti-inflammatory signaling, and epigenetic reprogramming. We propose that new therapeutic strategies may be derived from conceptualizing myeloid malignancies as an ecosystem out of balance, where residual normal and malignant hematopoietic cells interact in multiple ways, only few of which have been characterized in detail. Disrupting MPN SC insulation to overcome dormancy, interfering with aberrant cytokines circuits that favor MPN cells and directly boosting residual normal HSCs are potential strategies to tip the balance in favor of normal hematopoiesis. While eradicating the malignant cell clones remains the goal of therapy, this may be a more attainable objective in the short term.

Importance: Firearm violence is a public health crisis placing significant burden on individuals, communities, and health care systems. After firearm injury, there is increased risk of poor health, disability, and psychopathology. The newest 2022 guidelines from the American College of Surgeons Committee on Trauma require that all trauma centers screen for risk of psychopathology and provide referral to intervention. Yet, implementing these guidelines in ways that are responsive to the unique needs of communities and specific patient populations, such as after firearm violence, is challenging. Observations: The current review highlights important considerations and presents a model for trauma centers to provide comprehensive care to survivors of firearm injury. This model highlights the need to enhance standard practice to provide patient-centered, trauma-informed care, as well as integrate inpatient and outpatient psychological services to address psychosocial needs. Further, incorporation of violence prevention programming better addresses firearm injury as a public health concern. Conclusions and relevance: Using research to guide a framework for trauma centers in comprehensive care after firearm violence, we can prevent complications to physical and psychological recovery for this population. Health systems must acknowledge the socioecological context of firearm violence and provide more comprehensive care in the hospital and after discharge, to improve long-term recovery and serve as a means of tertiary prevention of firearm violence.

Background: Patients hospitalized with COVID-19 have an increased incidence of thromboembolism. The role of extended thromboprophylaxis after hospital discharge is unclear. Objective: To determine whether anticoagulation is superior to placebo in reducing death and thromboembolic complications among patients discharged after COVID-19 hospitalization. Design: Prospective, randomized, double-blind, placebo-controlled clinical trial. (ClinicalTrials.gov: NCT04650087). Setting: Done during 2021 to 2022 among 127 U.S. hospitals. Participants: Adults aged 18 years or older hospitalized with COVID-19 for 48 hours or more and ready for discharge, excluding those with a requirement for, or contraindication to, anticoagulation. Intervention: 2.5 mg of apixaban versus placebo twice daily for 30 days. Measurements: The primary efficacy end point was a 30-day composite of death, arterial thromboembolism, and venous thromboembolism. The primary safety end points were 30-day major bleeding and clinically relevant nonmajor bleeding. Results: Enrollment was terminated early, after 1217 participants were randomly assigned, because of a lower than anticipated event rate and a declining rate of COVID-19 hospitalizations. Median age was 54 years, 50.4% were women, 26.5% were Black, and 16.7% were Hispanic; 30.7% had a World Health Organization severity score of 5 or greater, and 11.0% had an International Medical Prevention Registry on Venous Thromboembolism risk prediction score of greater than 4. Incidence of the primary end point was 2.13% (95% CI, 1.14 to 3.62) in the apixaban group and 2.31% (CI, 1.27 to 3.84) in the placebo group. Major bleeding occurred in 2 (0.4%) and 1 (0.2%) and clinically relevant nonmajor bleeding occurred in 3 (0.6%) and 6 (1.1%) apixaban-treated and placebo-treated participants, respectively. By day 30, thirty-six (3.0%) participants were lost to follow-up, and 8.5% of apixaban and 11.9% of placebo participants permanently discontinued the study drug treatment. Limitations: The introduction of SARS-CoV-2 vaccines decreased the risk for hospitalization and death. Study enrollment spanned the peaks of the Delta and Omicron variants in the United States, which influenced illness severity. Conclusion: The incidence of death or thromboembolism was low in this cohort of patients discharged after hospitalization with COVID-19. Because of early enrollment termination, the results were imprecise and the study was inconclusive. Primary funding source: National Institutes of Health.

Background: A mental health crisis can create challenges for individuals, families, and communities. This multifaceted issue often involves different professionals from law enforcement and health care systems, which may lead to siloed and suboptimal care. The virtual crisis care (VCC) program was developed to provide rural law enforcement with access to behavioral health professionals and facilitated collaborative care via telehealth technology. Objective: This study was designed to evaluate the implementation and use of a VCC program from a telehealth hub for law enforcement in rural areas. Methods: This study used a mixed methods approach. The quantitative data came from the telehealth hub's electronic record system. The qualitative data came from in-depth interviews with law enforcement in the 18 counties that adopted the VCC program. Results: Across the 181 VCC encounters, the telehealth hub's recommended disposition and the actual disposition were similar for remaining in place (n=141, 77.9%, and n=137, 75.7%, respectively), voluntary admission (n=9, 5.0%, and n=10, 5.5%, respectively), and involuntary committal (IVC; n=27, 14.9%, and n=19, 10.5%, respectively). Qualitative insights related to the VCC program's implementation, use, benefits, and challenges were identified, providing a comprehensive view of the virtual partnership between rural law enforcement and behavioral health professionals. Conclusions: Use of a VCC program likely averts unnecessary IVCs. Law enforcement interviews affirmed the positive impact of VCC due to its ease of use and the benefits it provides to the individuals in need, the first responders involved, law enforcement resources, and the community.

Introduction: Screening and treatment initiation for perinatal psychiatric conditions is a recommended competency in OB/GYN practitioners, yet perinatal psychiatry is rapidly evolving. Practitioner-to-psychiatrist consultation programs have the potential to improve the management of psychiatric conditions in perinatal women. This study describes utilization of a statewide perinatal psychiatric consultation service by OB/GYN practitioners through examination of the volume, responsivity, content and outcomes of clinical inquiries, and satisfaction. Methods: This quality improvement study describes the 460 telephone or e-mail consultations requested by OB/GYN practitioners over 2 years and housed within a REDCap database. Data include the characteristics of consult users, month-over-month and total utilization, the patient's perinatal status, the reason for contact, current symptoms and medications, and the consulting psychiatrist recommendations. Practitioner satisfaction with consultation is also described. Results: After completion of triage, the psychiatrist returned the practitioner's call ≤5 min in 59% of consultations. The most common inquiries were for pregnant (64%) women for depressive (51%) or anxiety (46%) symptoms with 47% of inquiries reporting the patient was currently taking a psychiatric medication. Had consultation not been available, referral to mental health (41%) or starting a medication (15%) were most often reported. Conclusions: This perinatal psychiatric consultation service rapidly and effectively met the needs of practitioners practicing in OB/GYN settings across a state having a critical psychiatry shortage and varying urban and rural geography. Future recommendations include the assessment of direct patient outcomes, practitioner skill attainment, and long-term cost savings of this perinatal psychiatric consultation model.

Host-derived cellular pathways can provide an unfavorable environment for virus replication. These pathways have been a subject of interest for herpesviruses, including the betaherpesvirus human cytomegalovirus (HCMV). Here, we demonstrate that a compound, ARP101, induces the noncanonical sequestosome 1 (SQSTM1)/p62-Keap1-Nrf2 pathway for HCMV suppression. ARP101 increased the levels of both LC3 II and SQSTM1/p62 and induced phosphorylation of p62 at the C-terminal domain, resulting in its increased affinity for Keap1. ARP101 treatment resulted in Nrf2 stabilization and translocation into the nucleus, binding to specific promoter sites and transcription of antioxidant enzymes under the antioxidant response element (ARE), and HCMV suppression. Knockdown of Nrf2 recovered HCMV replication following ARP101 treatment, indicating the role of the Keap1-Nrf2 axis in HCMV inhibition by ARP101. SQSTM1/p62 phosphorylation was not modulated by the mTOR kinase or casein kinase 1 or 2, indicating ARP101 engages other kinases. Together, the data uncover a novel antiviral strategy for SQSTM1/p62 through the noncanonical Keap1-Nrf2 axis. This pathway could be further exploited, including the identification of the responsible kinases, to define the biological events during HCMV replication. IMPORTANCE Antiviral treatment for human cytomegalovirus (HCMV) is limited and suffers from the selection of drug-resistant viruses. Several cellular pathways have been shown to modulate HCMV replication. The autophagy receptor sequestosome 1 (SQSTM1)/p62 has been reported to interact with several HCMV proteins, particularly with components of HCMV capsid, suggesting it plays a role in viral replication. Here, we report on a new and unexpected role for SQSTM1/p62, in HCMV suppression. Using a small-molecule probe, ARP101, we show SQSTM1/p62 phosphorylation at its C terminus domain initiates the noncanonical Keap1-Nrf2 axis, leading to transcription of genes under the antioxidant response element, resulting in HCMV inhibition in vitro. Our study highlights the dynamic nature of SQSTM1/p62 during HCMV infection and how its phosphorylation activates a new pathway that can be exploited for antiviral intervention.

Background: Longitudinal rates, risk factors, and costs of superficial and deep incisional surgical site infection (SSI) were evaluated six months after primary total hip arthroplasty (pTHA) and revision total hip replacement (rTHA). Patients and Methods: Patients who had pTHA or rTHA between January 1, 2016 and March 31, 2018 were identified using the IBM® MarketScan® administrative claims databases. Kaplan-Meier survival curves evaluated time to SSI over six months. Cox proportional hazard models evaluated SSI risk factors. Generalized linear models estimated SSI costs up to 12 months. Results: The total cohort included 17,514 pTHA patients (mean [standard deviation] age 59.6 [10.1] years, 50.2% female; 66.4% commercial insurance), and 2,954 rTHA patients (61.2 [12.0] years, 52.0% female; 48.6% commercial insurance). Deep and superficial post-operative SSI at six months affected 0.30% (95% confidence interval [CI], 0.22%-0.39%) and 0.67% (95% CI, 0.55%-0.79% of patients in the pTHA, and 8.9% (95%CI: 7.8%-10.0%) and 4.8% (95% CI, 4.0%-5.6%) of patients in the rTHA cohorts. Hazards for SSI were related to patient comorbidities that included diabetes mellitus, obesity, renal failure, pulmonary or circulatory disorders, and depression. The adjusted average all-cause incremental commercial costs associated with post-operative infection ranged from $21,434 to $42,879 for superficial incisional SSI and $53,884 to $76,472 for deep incisional SSI, over a 12-month post-operative assessment period. Conclusions: The SSI rate after revision total hip arthroplasty (rTHA) was nearly 9% compared with 1.0% after pTHA. The risk of infection was influenced by several comorbid risk factors. The incremental cost associated with SSIs was substantial.

Background/purpose: This 8-year retrospective study of the National Trauma Data Bank describes temporal trends of traumatic injury by mechanism of injury (MOI) by demographic characteristics from 2012 to 2019 for adult patients 18 years and older. Methods: Overall, 5 630 461 records were included after excluding those with missing demographic information and International Classification of Disease codes. MOIs were calculated as proportions of total injury by year. Temporal trends of MOI were evaluated using two-sided non-parametric Mann-Kendall trend tests for (1) all patients and (2) within racial and ethnic groups (ie, Asian, 2% of total patient sample; Black, 14%; Hispanic or Latino, 10%; Multiracial, 3%; Native American, <1%; Pacific Islander, <1%; White, 69%) and stratified by age and sex. Results/outcomes: For all patients, falls increased over time (p=0.001), whereas burn (p<0.01), cut/pierce (p<0.01), cyclist (p=0.01), machinery (p<0.001), motor vehicle transport (MVT) motorcyclist (p<0.001), MVT occupant (p<0.001) and other blunt trauma (p=0.03) injuries decreased over time. The proportion of falls increased across all racial and ethnic groups and significantly for those aged 65 and older. There were further differences in decreasing trends of MOI by racial and ethnic categories and by age groups. Conclusions: These results suggest that falls are an important injury prevention target with an ageing US population across all racial and ethnic groups. Differing injury profiles by racial and ethnic identity indicate that injury prevention efforts be designed accordingly and targeted specifically to individuals most at risk for specific MOIs. Study type: Level I, prognostic/epidemiological.

Introduction: Intensive care unit (ICU) patient and provider attributes may prompt specialty consultation. We sought to determine practice patterns of surgical critical care (SCC) physicians for ICU consultation. Methods: We surveyed American Association for the Surgery of Trauma members. Various diagnoses were listed under each of nine related specialties. Respondents were asked for which conditions they would consult a specialist. Conditions were cross-referenced with the SCC fellowship curriculum. Other perspectives on practice and consultation were queried. Results: 314 physicians (18.6%) responded (68% male; 79% White; 96.2% surgical intensivist); 284 (16.8%) completed all questions. Percentage of clinical time practicing SCC was 26-50% in 57% and >50% in 14.5%. ICUs were closed (39%), open (25%), or hybrid (36%). Highest average confidence ratings (1 = least, 5 = most) for managing select conditions were ventilator, 4.64; palliative care, 4.51; infections, 4.44; organ donation, hemodynamics (tie), 4.31; lowest rating was myocardial ischemia, 3.85. Consults were more frequent for Cardiology, Hematology, and Neurology; less frequent for nephrology, palliative care, gastroenterology, infectious disease, and pulmonary; and low for curriculum topics (<25%) except for infectious diseases and palliative care. Attending staffing 24 h/day was associated with a lower mean number of topics for consultation (mean 24.03 versus 26.31, P = 0.015). Conclusions: ICU consultation practices vary based on consultant specialty and patient diagnosis. Consultation is most common for specialty-specific diseases and specialist interventions, but uncommon for topics found in the SCC curriculum, suggesting that respondents' scope of practice closely matched their training.

Purpose Improved life expectancy has increased the likelihood for long-term complications from chemotherapy among cancer survivors. One burdensome complication is chemotherapy-induced peripheral neuropathy (CIPN). We evaluated rates of CIPN outcomes in the Detroit Research on Cancer Survivorship (ROCS) cohort. Methods The population included 1,034 African American (AA) survivors who received chemotherapy for breast, colorectal, lung or prostate cancer. CIPN prevalence was based on initial occurrence of worsening of self-reported pain, numbness or tingling after chemotherapy. Current CIPN included symptoms still present at the time of the survey, and persistent CIPN symptoms were present 12 or more months post-chemotherapy. CIPN severity was ranked as mild, moderate or severe. Logistic regression was utilized to evaluate sociodemographic and clinical factors associated with the various categories of CIPN. Results CIPN prevalence was 68%, with 53% current and 52% persistent. The symptom severity distribution based on prevalent CIPN included 32.2% mild, 30.8% moderate, and 36.9% severe. Factors associated with prevalent CIPN (odds ratio, 95% confidence interval) included primary cancer site (breast: 3.88, 2.02–7.46); and (colorectal: 5.37, 2.69–10.73), lower risk for older age at diagnosis (0.66, 0.53–0.83) and divorced/separated marital status (2.13, 1.42–3.21). Current CIPN was in addition, associated with more advanced stage disease trend (1.34, 1.08–1.66) and greater number of co-morbid medical conditions trend (1.23, 1.09–1.40), as was persistent CIPN. Severity of prevalent CIPN was associated with history of arthritis (1.55, 1.06–2.26) and severity of persistent CIPN with higher BMI (1.58, 1.07–2.35). Conclusions CIPN is a common and persistent complication in AA cancer survivors. Further research is needed to improve our understanding of CIPN predictors in all groups of cancer survivors.

Background: Approximately 1 in 4 athletes returning to sports will sustain a second anterior cruciate ligament (ACL) injury. Psychological factors related to kinesiophobia, confidence, and psychological readiness are associated with second ACL injury; however, the evidence is conflicting. Hypothesis: Athletes who sustain a second ACL injury (ie, graft rupture or contralateral ACL rupture) within 2 years of ACL reconstruction (ACLR) would have greater kinesiophobia, less confidence, and lower psychological readiness prior to return to sport (RTS) compared with athletes who do not sustain a second ACL injury. Study design: Secondary analysis of a prospective randomized trial. Level of evidence: Level 3. Methods: A total of 39 female Level I/II athletes completed the following measures after postoperative rehabilitation and a 10-session RTS and second ACL injury prevention program: ACL Return to Sport after Injury (ACL-RSI) scale, the 11-item Tampa Scale of Kinesiophobia (TSK-11), and question 3 on the Knee injury and Osteoarthritis Outcome Score (KOOS) quality of life (QoL) subscale. Athletes were dichotomized based on whether they sustained a second ACL injury within 2 years of ACLR or not. Independent t tests determined group differences in TSK-11, KOOS-QoL, ACL-RSI, and the 3 individual components of the ACL-RSI (ie, emotions, confidence, risk appraisal). Results: Nine athletes sustained a second ACL injury (4 graft ruptures and 5 contralateral ACL ruptures). The group that sustained a second ACL injury had higher scores on the ACL-RSI (P = 0.03), higher on the risk appraisal questions of the ACL-RSI (P < 0.01), and met RTS criteria sooner than athletes who did not (P = 0.04). All second ACL injuries occurred in athletes who underwent primary ACLR with hamstring tendon autografts. Conclusion: Athletes who sustained a second ACL within 2 years of ACLR had a more positive psychological outlook, higher scores on the specific questions related to the risk appraisal construct of the ACL-RSI, and met RTS criteria sooner than athletes who did not sustain a second ACL injury. Clinical relevance: Counseling athletes about delaying RTS to reduce the risk of second ACL injury may be especially important in athletes who display high psychological readiness and meet RTS criteria sooner.

Many popular survival models rely on restrictive parametric, or semi-parametric, assumptions that could provide erroneous predictions when the effects of covariates are complex. Modern advances in computational hardware have led to an increasing interest in flexible Bayesian nonparametric methods for time-to-event data such as Bayesian additive regression trees (BART). We propose a novel approach that we call nonparametric failure time (NFT) BART in order to increase the flexibility beyond accelerated failure time (AFT) and proportional hazard models. NFT BART has three key features: 1) a BART prior for the mean function of the event time logarithm; 2) a heteroskedastic BART prior to deduce a covariate-dependent variance function; and 3) a flexible nonparametric error distribution using Dirichlet process mixtures (DPM). Our proposed approach widens the scope of hazard shapes including non-proportional hazards, can be scaled up to large sample sizes, naturally provides estimates of uncertainty via the posterior and can be seamlessly employed for variable selection. We provide convenient, user-friendly, computer software that is freely available as a reference implementation. Simulations demonstrate that NFT BART maintains excellent performance for survival prediction especially when AFT assumptions are violated by heteroskedasticity. We illustrate the proposed approach on a study examining predictors for mortality risk in patients undergoing hematopoietic stem cell transplant (HSCT) for blood-borne cancer, where heteroskedasticity and non-proportional hazards are likely present. This article is protected by copyright. All rights reserved.