Non-benzodiazepine Hypnotics and Police-Reported Motor Vehicle Crash Risk among Older Adults: A Sequential Target Trial Emulation.

Non-benzodiazepine hypnotics ( "Z-drugs") are prescribed for insomnia, but might increase risk of motor vehicle crash (MVC) among older adults through prolonged drowsiness and delayed reaction times. We estimated the effect of initiating Z-drug treatment on the 12-week risk of MVC in a sequential target trial emulation. After linking New Jersey driver licensing and police-reported MVC data to Medicare claims, we emulated a new target trial each week (July 1, 2007 - October 7, 2017) in which Medicare fee-for-service beneficiaries were classified as Z-drug-treated or untreated at baseline and followed for an MVC. We used inverse probability of treatment and censoring weighted pooled logistic regression models to estimate risk ratios (RR) and risk differences with 95% bootstrap confidence limits (CLs). There were 257,554 person-trials, of which 103,371 were Z-drug-treated and 154,183 untreated, giving rise to 976 and 1,249 MVCs, respectively. The intention-to-treat RR was 1.06 (95%CLs 0.95, 1.16). For the per-protocol estimand, there were 800 MVCs and 1,241 MVCs among treated and untreated person-trials, respectively, suggesting a reduced MVC risk (RR 0.83 [95%CLs 0.74, 0.92]) with sustained Z-drug treatment. Z-drugs should be prescribed to older patients judiciously but not withheld entirely over concerns about MVC risk.

Revision Rotator Cuff Repair Versus Primary Repair: An Assessment of Longitudinal Outcomes Outcomes in Revision Rotator Cuff Repair.

BACKGROUND: Information about outcomes after revision rotator cuff repair (RCR) is limited. A more thorough investigation of pain, range of motion (ROM), strength, and functional outcomes is needed. Comparing outcomes between primary and revision rotator cuff repair patients can help surgeons guide patient expectations of the revision procedure. The aim of this study was to compare the outcomes of a revision repair group to a control group of primary RCR patients. We expect revision RCR patients to have worse clinical outcomes than primary RCR patients. METHODS: A retrospective review of patients who underwent primary or revision RCR between 2012 to 2020 was performed. The case group included 104 revision patients, and the control group included 414 primary RCR patients. Patient visual analog score (VAS) for pain, ROM, strength, Simple Shoulder Test (SST), American Shoulder and Elbow Surgeons (ASES), and Constant-Murley scores were collected at baseline, 12 months, 24 months, and final follow-up. RESULTS: The average final follow-up was 43.9 months for primary patients and 63.8 months for revision patients. 352 primary patients and 55 revision patients had a final follow-up of 2 or more years. By final follow-up, primary patients had less pain than revision patients (Δ of 2.11, P < .0001), but both groups improved overall. Primary patients had significant improvements in forward flexion, external rotation, internal rotation, and abduction at 2 years that were lost by final follow-up, but revision patients did not experience any long-term improvement in ROM. These differences in ROM between groups were not significant. Supraspinatus strength in the revision group did not improve nor decline by final follow-up. By final follow-up, both primary and revision patients had improved SST and ASES scores from baseline. Primary patient ASES scores were 17.9 points higher (P < .0001) than revision patients by final follow-up, and there was no difference between groups in SST scores at this time. CONCLUSION: Revision RCR significantly improves patient pain, SST score, and ASES score at 4 years. Revision patients should not expect to see the improvements in range of motion that may occur after primary repair.

Hemospray® (hemostatic powder TC-325) as monotherapy for acute gastrointestinal bleeding: a multicenter prospective study.

Background: Hemostatic powders are used as second-line treatment in acute gastrointestinal (GI) bleeding (AGIB). Increasing evidence supports the use of TC-325 as monotherapy in specific scenarios. This prospective, multicenter study evaluated the performance of TC-325 as monotherapy for AGIB. Methods: Eighteen centers across Europe and USA contributed to a registry between 2016 and 2022. Adults with AGIB were eligible, unless TC-325 was part of combined hemostasis. The primary endpoint was immediate hemostasis. Secondary outcomes were rebleeding and mortality. Associations with risk factors were investigated (statistical significance at P≤0.05). Results: One hundred ninety patients were included (age 51-81 years, male: female 2:1), with peptic ulcer (n=48), upper GI malignancy (n=79), post-endoscopic treatment hemorrhage (n=37), and lower GI lesions (n=26). The primary outcome was recorded in 96.3% (95% confidence interval [CI]: 92.6-98.5) with rebleeding in 17.4% (95%CI 11.9-24.1); 9.9% (95%CI 5.8-15.6) died within 7 days, and 21.7% (95%CI 15.6-28.9) within 30 days. Regarding peptic ulcer, immediate hemostasis was achieved in 88% (95%CI 75-95), while 26% (95%CI 13-43) rebled. Higher ASA score was associated with mortality (OR 23.5, 95%CI 1.60-345; P=0.02). Immediate hemostasis was achieved in 100% of cases with malignancy and post-intervention bleeding, with rebleeding in 17% and 3.1%, respectively. Twenty-six patients received TC-325 for lower GI bleeding, and in all but one the primary outcome was achieved. Conclusions: TC-325 monotherapy is safe and effective, especially in malignancy or post-endoscopic intervention bleeding. In patients with peptic ulcer, it could be helpful when the primary treatment is unfeasible, as bridge to definite therapy.

Effects of bench press technique variations on musculoskeletal shoulder loads and potential injury risk.

While shoulder injuries resulting from the bench press exercise are commonly reported, no biomechanical evidence for lowering injury risk is currently available. Therefore, the aim of the present study was to compare musculoskeletal shoulder loads and potential injury risk during several bench press variations. Ten experienced strength athletes performed 21 technical variations of the barbell bench press, including variations in grip width of 1,1.5 and 2 bi-acromial widths (BAW), shoulder abduction angles of 45°, 70° and 90°, and scapula poses including neutral, retracted, and released conditions. Motions and forces were recorded by an opto-electronic measurement system and an instrumented barbell. An OpenSim musculoskeletal shoulder model was employed to estimate joint reaction forces in the glenohumeral and acromioclavicular joints. Time-series of joint reaction forces were compared between techniques by statistical non-parametric mapping. Results showed that narrower grip widths of < 1.5 BAW decreased acromioclavicular compression (p < 0.05), which may decrease the risk for distal clavicular osteolysis. Moreover, scapula retraction, as well as a grip width of < 1.5 BAW (p < 0.05), decreased glenohumeral posterior shear force components and rotator cuff activity and may decrease the risk for glenohumeral instability and rotator cuff injuries. Furthermore, results showed that mediolaterally exerted barbell force components varied considerably between athletes and largely affected shoulder reaction forces. It can be concluded that the grip width, scapula pose and mediolateral exerted barbell forces during the bench press influence musculoskeletal shoulder loads and the potential injury risk. Results of this study can contribute to safer bench press training guidelines.

Radiographic Findings Associated With Mild Hip Dysplasia in 3869 Patients Using a Deep Learning Measurement Tool.

Background: Hip dysplasia is considered one of the leading etiologies contributing to hip degeneration and the eventual need for total hip arthroplasty (THA). We validated a deep learning (DL) algorithm to measure angles relevant to hip dysplasia and applied this algorithm to determine the prevalence of dysplasia in a large population based on incremental radiographic cutoffs. Methods: Patients from the Osteoarthritis Initiative with anteroposterior pelvis radiographs and without previous THAs were included. A DL algorithm automated 3 angles associated with hip dysplasia: modified lateral center-edge angle (LCEA), Tönnis angle, and modified Sharp angle. The algorithm was validated against manual measurements, and all angles were measured in a cohort of 3869 patients (61.2 ± 9.2 years, 57.1% female). The percentile distributions and prevalence of dysplastic hips were analyzed using each angle. Results: The algorithm had no significant difference (P > .05) in measurements (paired difference: 0.3°-0.7°) against readers and had excellent agreement for dysplasia classification (kappa = 0.78-0.88). In 140 minutes, 23,214 measurements were automated for 3869 patients. LCEA and Sharp angles were higher and the Tönnis angle was lower (P < .01) in females. The dysplastic hip prevalence varied from 2.5% to 20% utilizing the following cutoffs: 17.3°-25.5° (LCEA), 9.4°-15.6° (Tönnis), and 41.3°-45.9° (Sharp). Conclusions: A DL algorithm was developed to measure and classify hips with mild hip dysplasia. The reported prevalence of dysplasia in a large patient cohort was dependent on both the measurement and threshold, with 12.4% of patients having dysplasia radiographic indices indicative of higher THA risk.

Sacral nerve stimulation leads to long-term improvement in fecal incontinence and quality of life for children with functional and organic defecation disorders.

BACKGROUND: Our objective was to evaluate long-term outcomes of sacral nerve stimulation (SNS) for children with functional and organic defecation disorders. METHODS: We performed a prospective study of children <21 years of age who started SNS treatment between 2012 and 2018. We recorded demographics, medical history, and diagnostic testing. We obtained measures of symptom severity and quality of life at baseline and follow up at 1, 6, 12, 24, 36, 48, and ≥60 months. Successful response was defined as bowel movements >2 times/week and fecal incontinence (FI) <1 time/week. Families were contacted to administer the Glasgow Children's Benefit Inventory and to evaluate patient satisfaction. KEY RESULTS: We included 65 patients (59% female, median age at SNS 14 years, range 9-21) with median follow-up of 32 months. Thirty patients had functional constipation (FC), 15 had non-retentive FI (NRFI), and 16 had an anorectal malformation (ARM). The percentage with FI <1 time/week improved from 30% at baseline to 64% at 1 year (p < 0.001) and 77% at most recent follow-up (p < 0.001). Patients with FC, NRFI, and ARM had sustained improvement in FI (p = 0.02, p < 0.001, p = 0.02). Patients also reported fewer hard stools (p = 0.001). Bowel movement frequency did not improve after SNS. At most recent follow-up, 77% of patients with a functional disorder and 50% with an organic disorder had responded (p = 0.03). Nearly all families reported benefit. CONCLUSIONS AND INFERENCES: SNS led to sustained improvement in FI regardless of underlying etiology, but children with functional disorders were more likely to respond than those with organic disorders.

Early intermediates in bacterial RNA polymerase promoter melting visualized by time-resolved cryo-electron microscopy.

During formation of the transcription-competent open complex (RPo) by bacterial RNA polymerases (RNAPs), transient intermediates pile up before overcoming a rate-limiting step. Structural descriptions of these interconversions in real time are unavailable. To address this gap, here we use time-resolved cryogenic electron microscopy (cryo-EM) to capture four intermediates populated 120 ms or 500 ms after mixing Escherichia coli σ70-RNAP and the λPR promoter. Cryo-EM snapshots revealed that the upstream edge of the transcription bubble unpairs rapidly, followed by stepwise insertion of two conserved nontemplate strand (nt-strand) bases into RNAP pockets. As the nt-strand 'read-out' extends, the RNAP clamp closes, expelling an inhibitory σ70 domain from the active-site cleft. The template strand is fully unpaired by 120 ms but remains dynamic, indicating that yet unknown conformational changes complete RPo formation in subsequent steps. Given that these events likely describe DNA opening at many bacterial promoters, this study provides insights into how DNA sequence regulates steps of RPo formation.

HumanIslets: An integrated platform for human islet data access and analysis.

Comprehensive molecular and cellular phenotyping of human islets can enable deep mechanistic insights for diabetes research. We established the Human Islet Data Analysis and Sharing (HI-DAS) consortium to advance goals in accessibility, usability, and integration of data from human islets isolated from donors with and without diabetes at the Alberta Diabetes Institute (ADI) IsletCore. Here we introduce HumanIslets.com, an open resource for the research community. This platform, which presently includes data on 547 human islet donors, allows users to access linked datasets describing molecular profiles, islet function and donor phenotypes, and to perform various statistical and functional analyses at the donor, islet and single-cell levels. As an example of the analytic capacity of this resource we show a dissociation between cell culture effects on transcript and protein expression, and an approach to correct for exocrine contamination found in hand-picked islets. Finally, we provide an example workflow and visualization that highlights links between type 2 diabetes status, SERCA3b Ca2+-ATPase levels at the transcript and protein level, insulin secretion and islet cell phenotypes. HumanIslets.com provides a growing and adaptable set of resources and tools to support the metabolism and diabetes research community.

Trajectories in Intensity of Medical Interventions at the End of Life: Clustering Analysis in a Pediatric, Single-Center Retrospective Cohort, 2013-2021.

OBJECTIVE: Pediatric deaths often occur within hospitals and involve balancing aggressive treatment with minimization of suffering. This study first investigated associations between clinical/demographic features and the level of intensity of various therapies these patients undergo at the end of life (EOL). Second, the work used these data to develop a new, broader spectrum for classifying pediatric EOL trajectories. DESIGN: Retrospective, single-center study, 2013-2021. SETTING: Four hundred sixty-one bed tertiary, stand-alone children's hospital with 112 ICU beds. PATIENTS: Patients of age 0-26 years old at the time of death. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Of 1111 included patients, 85.7% died in-hospital. Patients who died outside the hospital were older. Among the 952 in-hospital deaths, most occurred in ICUs (89.5%). Clustering analysis was used to distinguish EOL trajectories based on the presence of intensive therapies and/or an active resuscitation attempt at the EOL. We identified five simplified categories: 1) death during active resuscitation, 2) controlled withdrawal of life-sustaining technology, 3) natural progression to death despite maximal therapy, 4) discontinuation of nonsustaining therapies, and 5) withholding/noninitiation of future therapies. Patients with recent surgical procedures, a history of organ transplantation, or admission to the Cardiovascular ICU had more intense therapies at EOL than those who received palliative care consultations, had known genetic conditions, or were of older age. CONCLUSIONS: In this retrospective study of pediatric EOL trajectories based on the intensity of technology and/or resuscitation discontinued at the EOL, we have identified associations between these trajectories and patient characteristics. Further research is needed to investigate the impact of these trajectories on families, patients, and healthcare providers.

The Use of Clips to Prevent Post-Polypectomy Bleeding: A Clinical Review.

GOALS: The goal of this clinical review is to provide an overview of the current literature regarding the utility of prophylactic clips in reducing postpolypectomy bleeding and to provide an expert statement regarding their appropriateness in clinical practice. BACKGROUND: Colonoscopy enables the identification and removal of premalignant and malignant lesions through polypectomy, yet complications including postpolypectomy bleeding (PPB) can arise. While various studies have explored applying clips prophylactically to prevent PPB, their effectiveness remains uncertain. STUDY: A literature search conducted in PubMed and Embase identified 671 publications discussing clip use postpolypectomy; 67 were found to be relevant after screening, reporting outcomes related to PPB. Data related to clip utilization, polyp characteristics, and adverse events were extracted and discussed. RESULTS: The current literature suggests that prophylactic clipping is most beneficial for nonpedunculated polyps ≥20 mm, especially those in the proximal colon. The utility of clipping smaller polyps and those in the distal colon remains less clear. Antithrombotic medication usage, particularly anticoagulants, has been linked to an increased risk of bleeding, prompting consideration for clip placement in this patient subgroup. While cost-effectiveness analyses may indicate potential savings, the decision to clip should be tailored to individual patient factors and polyp characteristics. CONCLUSIONS: Current research suggests that the application of prophylactic clips can be particularly beneficial in preventing delayed bleeding after removal of large nonpedunculated polyps, especially for those in the proximal colon and in patients on antithrombotic medications. In addition, for large pedunculated polyps prophylactic clipping is most effective at controlling immediate bleeding.

CD39 delineates chimeric antigen receptor regulatory T cell subsets with distinct cytotoxic & regulatory functions against human islets.

Human regulatory T cells (Treg) suppress other immune cells. Their dysfunction contributes to the pathophysiology of autoimmune diseases, including type 1 diabetes (T1D). Infusion of Tregs is being clinically evaluated as a novel way to prevent or treat T1D. Genetic modification of Tregs, most notably through the introduction of a chimeric antigen receptor (CAR) targeting Tregs to pancreatic islets, may improve their efficacy. We evaluated CAR targeting of human Tregs to monocytes, a human ß cell line and human islet ß cells in vitro. Targeting of HLA-A2-CAR (A2-CAR) bulk Tregs to HLA-A2+ cells resulted in dichotomous cytotoxic killing of human monocytes and islet ß cells. In exploring subsets and mechanisms that may explain this pattern, we found that CD39 expression segregated CAR Treg cytotoxicity. CAR Tregs from individuals with more CD39low/- Tregs and from individuals with genetic polymorphism associated with lower CD39 expression (rs10748643) had more cytotoxicity. Isolated CD39- CAR Tregs had elevated granzyme B expression and cytotoxicity compared to the CD39+ CAR Treg subset. Genetic overexpression of CD39 in CD39low CAR Tregs reduced their cytotoxicity. Importantly, ß cells upregulated protein surface expression of PD-L1 and PD-L2 in response to A2-CAR Tregs. Blockade of PD-L1/PD-L2 increased ß cell death in A2-CAR Treg co-cultures suggesting that the PD-1/PD-L1 pathway is important in protecting islet ß cells in the setting of CAR immunotherapy. In summary, introduction of CAR can enhance biological differences in subsets of Tregs. CD39+ Tregs represent a safer choice for CAR Treg therapies targeting tissues for tolerance induction.

Neurorehabilitation in a Pediatric Stroke Patient Supported on a CentriMag.

Patients supported on ventricular assist devices (VADs) benefit from rehabilitation while awaiting heart transplantation to recover from surgery, prevent deconditioning, and, in most cases, optimize transplant candidacy. With bleeding and neurological dysfunction as the most common VAD complications, the importance of rehabilitation dramatically increases when a patient on a VAD also suffers from a neurological injury. The rehabilitation needs for cardiac conditioning and neurological reeducation are not the same. Patients with severe neurological deficits require intense rehabilitation that often includes base-of-support challenges, usage of bolsters and balls, partial weight-bearing treadmill training, and assumption of various body positions in prone, kneeling, or quadruped for neuromotor reeducation. However, some devices are more conducive to rehabilitation than others. For children supported by the CentriMag in particular, rehabilitation is challenged by short cannula tubing, an external motor, a large interface, and an intensive care unit (ICU) admission. We report a safe and successful physical therapy course of a pediatric stroke patient with a diagnosis of Ebstein's anomaly supported by a CentriMag right VAD (RVAD) while awaiting heart transplant in the ICU.

An Advanced Knee Simulator Model Can Reproducibly Be Used for Ligament Balancing Training during Total Knee Arthroplasty.

A critical and difficult aspect of total knee arthroplasty (TKA) is ligamentous balancing for which cadavers and models have played a large role in the education and training of new arthroplasty surgeons, although they both have several shortcomings including cost, scarcity, and dissimilarity to in vivo ligament properties. An advanced knee simulator (AKS) model based on computed tomography (CT) scans was developed in the setting of these challenges with cadavers and previous models. In this study, we compared the ligament balancing between AKS and human cadaveric knees to assess the validity of using the AKS for ligament balancing training during TKA. A CT scan of a TKA patient with varus deformity was used to design the AKS model with modular components, using three-dimensional printing. Three fellowship-trained arthroplasty surgeons used technology-assisted TKA procedure to plan and balance three cadaver knees and the AKS model. Medial and lateral laxity data were captured using manual varus and valgus stress assessments for cadavers and the model in an extension pose (10 degrees of flexion from terminal extension) and between 90 and 95 degrees for flexion. After preresection assessments, surgeons planned a balanced cruciate-retaining TKA. Following bony cuts and trialing, extension and flexion ligament laxity values were recorded in a similar manner. Descriptive statistics and Student's t-tests were performed to compare the cadavers and model with a p-value set at 0.05. Preresection medial/lateral laxity data for both extension and flexion were plotted and showed that the highest standard deviation (SD) for the cadavers was 0.67 mm, whereas the highest SD for the AKS was 1.25 mm. A similar plot for trialing demonstrated that the highest SD for the cadavers was 0.6 mm, whereas the highest SD for the AKS was 0.61 mm. The AKS trialing data were highly reproducible when compared with cadaveric data, demonstrating the value of the AKS model as a tool to teach ligament balancing for TKA and for future research endeavors.

Bomb radiocarbon evidence for strong global carbon uptake and turnover in terrestrial vegetation.

Vegetation and soils are taking up approximately 30% of anthropogenic carbon dioxide emissions because of small imbalances in large gross carbon exchanges from productivity and turnover that are poorly constrained. We combined a new budget of radiocarbon produced by nuclear bomb testing in the 1960s with model simulations to evaluate carbon cycling in terrestrial vegetation. We found that most state-of-the-art vegetation models used in the Coupled Model Intercomparison Project underestimated the radiocarbon accumulation in vegetation biomass. Our findings, combined with constraints on vegetation carbon stocks and productivity trends, imply that net primary productivity is likely at least 80 petagrams of carbon per year presently, compared with the 43 to 76 petagrams per year predicted by current models. Storage of anthropogenic carbon in terrestrial vegetation is likely more short-lived and vulnerable than previously predicted.

Effects of HMGCR deficiency on skeletal muscle development.

Pathogenic variants in HMGCR were recently linked to a limb-girdle muscular dystrophy (LGMD) phenotype. The protein product HMG CoA reductase (HMGCR) catalyzes a key component of the cholesterol synthesis pathway. The two other muscle diseases associated with HMGCR, statin-associated myopathy (SAM) and autoimmune anti-HMGCR myopathy, are not inherited in a Mendelian pattern. The mechanism linking pathogenic variants in HMGCR with skeletal muscle dysfunction is unclear. We knocked down Hmgcr in mouse skeletal myoblasts, knocked down hmgcr in Drosophila, and expressed three pathogenic HMGCR variants (c.1327C>T, p.Arg443Trp; c.1522_1524delTCT, p.Ser508del; and c.1621G>A, p.Ala541Thr) in Hmgcr knockdown mouse myoblasts. Hmgcr deficiency was associated with decreased proliferation, increased apoptosis, and impaired myotube fusion. Transcriptome sequencing of Hmgcr knockdown versus control myoblasts revealed differential expression involving mitochondrial function, with corresponding differences in cellular oxygen consumption rates. Both ubiquitous and muscle-specific knockdown of hmgcr in Drosophila led to lethality. Overexpression of reference HMGCR cDNA rescued myotube fusion in knockdown cells, whereas overexpression of the pathogenic variants of HMGCR cDNA did not. These results suggest that the three HMGCR-related muscle diseases share disease mechanisms related to skeletal muscle development.

The single-cell opioid responses in the context of HIV (SCORCH) consortium.

Substance use disorders (SUD) and drug addiction are major threats to public health, impacting not only the millions of individuals struggling with SUD, but also surrounding families and communities. One of the seminal challenges in treating and studying addiction in human populations is the high prevalence of co-morbid conditions, including an increased risk of contracting a human immunodeficiency virus (HIV) infection. Of the ~15 million people who inject drugs globally, 17% are persons with HIV. Conversely, HIV is a risk factor for SUD because chronic pain syndromes, often encountered in persons with HIV, can lead to an increased use of opioid pain medications that in turn can increase the risk for opioid addiction. We hypothesize that SUD and HIV exert shared effects on brain cell types, including adaptations related to neuroplasticity, neurodegeneration, and neuroinflammation. Basic research is needed to refine our understanding of these affected cell types and adaptations. Studying the effects of SUD in the context of HIV at the single-cell level represents a compelling strategy to understand the reciprocal interactions among both conditions, made feasible by the availability of large, extensively-phenotyped human brain tissue collections that have been amassed by the Neuro-HIV research community. In addition, sophisticated animal models that have been developed for both conditions provide a means to precisely evaluate specific exposures and stages of disease. We propose that single-cell genomics is a uniquely powerful technology to characterize the effects of SUD and HIV in the brain, integrating data from human cohorts and animal models. We have formed the Single-Cell Opioid Responses in the Context of HIV (SCORCH) consortium to carry out this strategy.

Corrigendum to "Androgen Deprivation and Radiotherapy with or Without Docetaxel for Localized High-risk Prostat Cancer: Long-term Follow-up from the Randomized NRG Oncology RTOG 0521 Trial" [Eur. Eurol. 84(2) (2023) 156-163].

BACKGROUND: Intensification of therapy may improve outcomes for patients with high-risk localized prostate cancer. OBJECTIVE: To provide long-term follow-up data from phase III RTOG 0521, which compared a combination of androgen deprivation therapy (ADT) + external beam radiation therapy (EBRT) + docetaxel with ADT + EBRT. DESIGN, SETTING, AND PARTICIPANTS: High-risk localized prostate cancer patients (>50% of patients had Gleason 9-10 disease) were prospectively randomized to 2 yr of ADT + EBRT or ADT + EBRT + six cycles of docetaxel. A total of 612 patients were accrued, and 563 were eligible and included in the modified intent-to-treat analysis. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The primary endpoint was overall survival (OS). Analyses with Cox proportional hazards were performed as prespecified in the protocol; however, there was evidence of nonproportional hazards. Thus, a post hoc analysis was performed using the restricted mean survival time (RMST). The secondary endpoints included biochemical failure, distant metastasis (DM) as detected by conventional imaging, and disease-free survival (DFS). RESULTS AND LIMITATIONS: After 10.4 yr of median follow-up among survivors, the hazard ratio (HR) for OS was 0.89 (90% confidence interval [CI] 0.70-1.14; one-sided log-rank p = 0.22). Survival at 10 yr was 64% for ADT + EBRT and 69% for ADT + EBRT + docetaxel. The RMST at 12 yr was 0.45 yr and not statistically significant (one-sided p = 0.053). No differences were detected in the incidence of DFS (HR = 0.92, 95% CI 0.73-1.14), DM (HR = 0.84, 95% CI 0.73-1.14), or prostate-specific antigen recurrence risk (HR = 0.97, 95% CI 0.74-1.29). Two patients had grade 5 toxicity in the chemotherapy arm and zero patients in the control arm. CONCLUSIONS: After a median follow-up of 10.4 yr among surviving patients, no significant differences are observed in clinical outcomes between the experimental and control arms. These data suggest that docetaxel should not be used for high-risk localized prostate cancer. Additional research may be warranted using novel predictive biomarkers. PATIENT SUMMARY: No significant differences in survival were noted after long-term follow-up for high-risk localized prostate cancer patients in a large prospective trial where patients were treated with androgen deprivation therapy + radiation to the prostate ± docetaxel.

A comprehensive, multifaceted strategy to increase pediatric donor heart utilization.

BACKGROUND: In 2016, we initiated a quality improvement endeavor to increase pediatric heart offer acceptance. This study assessed the effect of these interventions at our center. METHODS: We evaluted pre- and postimplementation cohorts (January 1, 2008-December 31, 2016 vs January 1, 2017-July 1, 2023) comparing donor heart utilization. Six interventions were iterated over time to increase offer acceptance ("extended criteria"): ABO-incompatible transplant, ex vivo perfusion for distanced donors, 3-dimensional total cardiac volume (TCV) assessment, acceptance of hepatitis-C or Severe Acute Respiratory Syndrome Coronavirus 2 infected donors, and institutional culture change favoring consideration of donors previously considered unacceptable. Outcomes studied included annual HT volume, median waitlist duration, sequence number at acceptance, and post-transplant clinical outcomes. RESULTS: During the study period, annual transplant volume increased from 16/year to 25/year pre- and postimplementation. Three hundred thirteen of 389 (80%) listed patients were transplanted. Waitlist duration shortened postimplementation (p = 0.01), as did the percentage of accepted heart offers utilizing at least 1 extended criterion (p < 0.001). Institutional culture change and TCV assessment had the largest impact on donor heart utilization (p = 0.04 and p < 0.001). There was no difference in post-HT intubation or intensive care unit days (p = 0.05-0.9), though post-transplant hospitalization duration (p < 0.001) increased. Post-transplant survival was unaffected by the use of extended criteria hearts (p = 0.3). CONCLUSIONS: We report a successful longitudinal, multifaceted effort to increase organ offer utilization, with institutional culture change and TCV assessments most impactful. The use of extended criteria hearts was not associated with inferior survival.