Modulation of Spontaneous Action Potential Rate by Inositol Trisphosphate in Myocytes from the Rabbit Atrioventricular Node.

The atrioventricular node (AVN) is a key component of the cardiac conduction system and takes over pacemaking of the ventricles if the sinoatrial node fails. IP3 (inositol 1,4,5 trisphosphate) can modulate excitability of myocytes from other regions of the heart, but it is not known whether IP3 receptor (IP3-R) activation modulates AVN cell pacemaking. Consequently, this study investigated effects of IP3 on spontaneous action potentials (APs) from AVN cells isolated from rabbit hearts. Immunohistochemistry and confocal imaging demonstrated the presence of IP3-R2 in isolated AVN cells, with partial overlap with RyR2 ryanodine receptors seen in co-labelling experiments. In whole-cell recordings at physiological temperature, application of 10 µM membrane-permeant Bt3-(1,4,5)IP3-AM accelerated spontaneous AP rate and increased diastolic depolarization rate, without direct effects on ICa,L, IKr, If or INCX. By contrast, application via the patch pipette of 5 µM of the IP3-R inhibitor xestospongin C led to a slowing in spontaneous AP rate and prevented 10 µM Bt3-(1,4,5)IP3-AM application from increasing the AP rate. UV excitation of AVN cells loaded with caged-IP3 led to an acceleration in AP rate, the magnitude of which increased with the extent of UV excitation. 2-APB slowed spontaneous AP rate, consistent with a role for constitutive IP3-R activity; however, it was also found to inhibit ICa,L and IKr, confounding its use for studying IP3-R. Under AP voltage clamp, UV excitation of AVN cells loaded with caged IP3 activated an inward current during diastolic depolarization. Collectively, these results demonstrate that IP3 can modulate AVN cell pacemaking rate.

The impact of transition of Spina Bifida Care: A retrospective population-based cohort study comparing outcomes and health care costs longitudinally from adolescence into adulthood.

Introduction: Transition from multidisciplinary paediatric to adult care results in a significant change in the intensity of care provided to patients with spina bifida (SB). Objective: To compare planned and unplanned health care utilization and costs of care of transitioning SB patients. Study Design: Through a retrospective population-based cohort study, patients with SB born in Ontario between 1988 and 1999 were studied using routinely collected data analysed at ICES. Patients were followed longitudinally from age 16 to 22 years with comparisons made between the paediatric baseline year (age 16) to the first 3 years of adulthood (ages 19 to 21). A composite primary outcome of unplanned emergency room (ER) visits, hospitalizations and emergency surgical procedures, was compared before and after transition. Secondary outcomes included these variables individually and estimated health care costs. Results: In the 299 patients, no significant differences were identified in the composite primary outcome between periods (P = 0.09). Unplanned ER visits (P = 0.004) and emergency surgical procedures (P = 0.02) increased after transition. Despite this, the estimated individual total cost of care declined after transition (P = 0.03). Further, multivariable analysis identified rural residence (RR 1.78, confidence interval [CI] 1.30 to 2.44) and previous urologic surgery (RR 1.91, CI 1.41 to 2.57) as significant predictors of increased need for emergent care and health care costs, respectively. Conclusion: Patients with SB in Ontario have higher rates of ER usage and unplanned surgery after the transition to adult care. While this does not drive an increase in health care costs, improvements in the care of transitioned SB patients, particularly rural patients and those with prior urologic surgery, may decrease the requirement for acute care.

Current Diagnostic Measures for Lymphedema: A Comprehensive Review.

ABSTRACT: Lymphedema presents diagnostic challenges due to complex symptomatology and multifaceted onset. This literature review synthesizes diagnostic measures ranging from clinical assessments to advanced imaging techniques and emerging technologies. It explores the challenges in early detection and delves into the disparities in access to advanced diagnostic tools, which exacerbate health outcome differences across populations. This review not only provides insights into the effectiveness of current diagnostic modalities but also underscores the necessity for ongoing research and innovation. The goal is to enhance the accuracy, affordability, and accessibility of lymphedema diagnostics. This is crucial for guiding future research directions and for the development of standardized diagnostic protocols that could help mitigate the progression of lymphedema and enhance the quality of life for affected individuals.

In-Vivo MRI in Rodents: A Protocol for Optimal Animal Positioning.

ABSTRACT: Magnetic resonance imaging (MRI) is a potentially powerful novel peripheral nerve diagnosis technique. To determine its validity, in-vivo preclinical studies are necessary. However, when using a rodent model, positioning rats and achieving high-resolution images can be challenging. We present a short report that outlines an optimal protocol for positioning rats for in-vivo MRI acquisition. Female Sprague-Dawley rats with sciatic nerve injury were induced into anesthesia using 4% isoflurane in oxygen and maintained at 1.5%. Rats were placed into a plexiglass cradle in a right lateral recumbent position, and a surface coil was placed over the left leg. Respiration rate and body temperature were monitored throughout the scan. Our protocol was successful as rats were able to undergo MRI scanning safely and efficiently. There were no adverse reactions, and clear images of the left sciatic nerve were obtained. Animal positioning took 30 minutes, and 5 different acquisitions were obtained in 2 hours. The total time from anesthesia induction to recovery was under 3 hours. Given the increasing interest in MRI diagnostic techniques, we hope this report aids other researchers studying peripheral nerve injury imaging in rat models.

The Thuss Lectureship Series at Vanderbilt University.

BACKGROUND: The Thuss lectureship began in 1978 and is carried at both Vanderbilt University Medical Center and Stanford Medical Center. The 2-day event consists of a resident and fellow workshop and dinner with an invited keynote speaker, followed by a didactic session and research presentation the following morning. This lecture honors the career of Dr Charles J. Thuss, Sr, and acts as a memorial for Dr Thuss, Jr, and his son, Carter. Trainee presentations have been catalogued since 2019, and we sought to identify the presentations that resulted in publications. METHODS: Internal records from 2019 to 2022 were referenced to catalogue presenters and project titles. PubMed searches were conducted to identify projects from these presenters with direct links to their presentations at the lectureship series. RESULTS: The event has been held consecutively from 1978 to 2023 with 44 keynote lecturers. Between 2019 and 2023, 17 residents, fellows, and medical students from Vanderbilt University Medical Center or/and the Tennessee Society of Plastic Surgery gave 19 research presentations for the Thuss lectureship at Vanderbilt. Due to the pandemic, no resident or trainee presentations were given in 2020. Nine of 11 project presentations resulted in publications, with presenters being the resultant first author of 6 of these articles. CONCLUSION: The Thuss lectureship at Vanderbilt serves as an academic conduit to share research and build camaraderie among plastic surgeons across Tennessee. Additionally, it fosters a platform for trainees to contribute to the academic literature and see projects from inception to publication.

The Departmental Scholarly Index: A Metric of Research Productivity.

INTRODUCTION: While bibliometric ranking systems have been designed to use citations, funding, and alumni productivity, there is a need for a simple metric that objectively evaluates the work of a group or organization. The present study describes a bibliometric tool, the Departmental Scholarly Index (DSI), for this purpose. METHODS: Publications from academic plastic surgery programs in qualifying states of the Southeastern Society of Plastic and Reconstructive Surgeons released in 2022 were collected via PubMed affiliation search. Publications were recorded in a running list alongside the title and 2022 impact factor of their respective journals. The impact factors were averaged by summing the impact factors and dividing by the number of articles to obtain a raw average. Any publication in a journal with an impact factor greater than five multiples of the raw average was removed as an outlier. The remaining impact factors were then summed and give the final numerical value representing the DSI. RESULTS: A total of 464 articles published in 139 individual journals were returned from PubMed between January 1, 2022, and December 31, 2022, for the 22 constituent departments. Calculated Spearman's rank coefficients comparing the DSI ranking with both the Doximity and Persad-Paisley rankings yielded values of 0.66 (P < 0.01) and 0.62 (P < 0.01), respectively. Overall, the DSI rankings largely agree with either the Persad-Paisley or Doximity rankings with notable differences seen in the rankings of Mayo Florida and the University of Alabama. A clear academic ranking of Southeastern Society of Plastic and Reconstructive Surgeons programs was generated from these data. CONCLUSIONS: The DSI represents a novel and simple approach to applying objective value to research with the advantage of using data bound to the most recent publication productivity.

The Growth and Development of a Research Division in the Plastic Surgery Department of a Large Urban Academic Medical Center.

INTRODUCTION: Research is a critical component of academic medicine that may or may not be prioritized in centers with high clinical volumes. The benefits of research expansion go beyond notoriety and industry partnerships, expanding into resident training and preparation of the next generation of physician-scientists. Improving a division or department's research portfolio requires a commitment to reorganizing structure, personnel, resources, and a dedication to innovative funding models. To improve research productivity and quality, our group placed several initiatives into motion beginning in August 2017 that we have outlined and evaluated in the present study. Some of these initiatives included restructuring leadership, resourcing both bench and clinical outcomes research, providing initial funding directly from clinical profits and rewarding research fiscally. METHODS: Reviews of hiring records, publications, grant allocations, and interviews with key personnel were used to generate a road map of initiatives. Average impact factor was calculated by averaging journal impact factors for all publications from the department each year, excluding any publications with greater than 5 times the raw average, and creating a corrected average that more accurately represented the work. Student t tests were used to compare mean number of publications and impact factors from 2010 to 2017 to those from 2018 to 2022. RESULTS: Prior to restructuring (2010-2017), the department published an average of 9 articles annually, which increased to an average of 42 articles since that time (P < 0.01). Average impact increased from 0 in 2010 to 4.02 in 2022, with the number of publications in top 10 plastic surgery journals following a similar trajectory with 1 publication in 2010 and 31 in 2023. Following an initial $1 million investment to create an institutionally directed fund in 2018, the department leveraged its research to earn $3 million in endowments, $1.25 million in industry partnerships, $3.23 million in Department of Defense funding, and $1.65 million from a multi-institutional National Institutes of Health grant. CONCLUSION: Deliberate prioritization of research initiatives as noted above has led to remarkable growth in academic output.

Incidence of High Risk and Malignant Pathological Findings in Transgender and Gender Diverse Individuals Undergoing Gender-Affirming Mastectomy.

BACKGROUND: Concrete, data-driven guidelines for breast cancer screening among the transgender and gender diverse (TGD) population is lacking. The present study evaluates possible associations of gender-affirming hormone therapy (GAHT) on incidental breast pathology findings in trans-masculine patients to inform decision making about breast cancer screening. PATIENTS AND METHODS: This was a retrospective cohort study of patients who had gender-affirming mastectomy or breast reduction at a single center from July 2019 to February 2024. A total of 865 patients met the inclusion criteria. Gender-affirming testosterone therapy and length of exposure were evaluated to seek differences in post-operative pathology findings. RESULTS: The median age at the time of surgery was 27 years [interquartile range (IQR) 21-30]. Most participants identified as female to male (658, 75.6%). A significant portion of the participants (688, 79.2%) were undergoing testosterone therapy at the time of surgery, with the median duration of testosterone use prior to surgery being 14 months (IQR 4-29). High risk or malignant findings were noted in pathology results for 12 of 1730 breasts (0.7%). Ordered logistic regression found that duration of testosterone therapy was not associated with increasing severity of incidental breast pathology. Additionally, patients under 25 years of age were 70% less likely to have any incidental finding on pathological evaluation than older patients [odds ratio (OR) 0.3, p < 0.01, confidence interval (CI) 0.18-0.50]. CONCLUSIONS: The present study found that patients undergoing GAHT should not be screened for breast cancer with increased frequency compared with cis-gender women. Additionally, it may be appropriate for trans women under the age of 25 with normal breast cancer risk to forego pathological breast tissue examination.

The Value of Drawing Practice in Plastic Surgery Training.

ABSTRACT: No specialty has such close relationship with art as plastic surgery among medicine. Both are intensely creative processes that combine technology with utmost dexterity and now are undervalued in the medical education. Art is a reservoir that provides a surgeon with creativity and improved dexterity. It is beneficial for the surgeons to practice drawing, for it can bring passion and inspiration, enhance observation and imagination, improve dexterity and accuracy, and help keep a good relation with patients. In some way, plastic surgery is art and plastic surgeon is artist.

Understanding barriers, enablers and motivational factors for Australian healthcare educators teaching university students on clinical placement using the validated Physician Teaching Motivation Questionnaire.

BACKGROUND: In Australia, university clinical programs rely heavily on external healthcare professionals to provide a range of authentic clinical training and professional development opportunities for students. There is, however, a limited understanding of the factors that motivate these professionals to be educators and whether this varies across different healthcare disciplines within Australia. As the demand for clinical placements continues to increase, it is critical for the ongoing success of these programs that universities identify both the barriers associated with teaching and the benefits that enhance job satisfaction. METHODS: A two-part questionnaire was emailed to 849 external healthcare educators teaching predominantly in Medicine, Medical Imaging, and Optometry programs at Deakin University. Part-one surveyed the socio-demographics, perceived benefits, and barriers to teaching, plus the utilisation of entitlements offered by the university. Part-two was modelled on Dybowski and Harendza's validated Physician Teaching Motivation Questionnaire (PTMQ) and adapted to an Australian audience. RESULTS: Overall, 776 out of the 849 questionnaires were considered in the final participant pool. The response rate for part-one was 19.7% (n = 153/776) and 18.3% (n = 142/776) for part-two. Across all professions, altruism was the primary source of motivation for teaching in Deakin University's healthcare programs. Medical Imaging educators placed a higher value on career-related teaching aspects compared to those in Medicine and Optometry (p < 0.003). The resources and benefits associated with teaching were generally perceived to be of minimal importance. External healthcare educators most commonly reported that there were no barriers to teaching (41.3%, n = 78) however, increased workloads and time constraints were the next most likely factors to affect teaching participation (31.8%, n = 60). CONCLUSION: Our validated adaptation of the PTMQ successfully targeted healthcare professions not focussed on by Dybowski and Harendza. Altruistic motivation was the overarching theme for why Australian external healthcare educators contribute to teaching with some differences in career-driven motivation additionally acknowledged. Despite there being no key benefits or barriers to teaching participation, universities must remain cognisant of the factors that influence the recruitment and retention of external healthcare educators and how to optimise these for the ongoing success and sustainability of their teaching programs.

Formulation Development of a COVID-19 Recombinant Spike Protein-Based Vaccine.

The purpose of this study was to develop a formulation for a recombinant prefusion spike protein vaccine against SARS-CoV-2. It was found that the spike protein was susceptible to aggregation due to mechanical stress. Therefore, formulation studies were initiated focused on screening pharmaceutical excipients capable of preventing this. The screening of a panel of potential stabilizing conditions found that Tween 20 could inhibit mechanically induced aggregation. A concentration-dependent study indicated that a higher concentration of Tween 20 (0.2% v/v) was required to prevent conformational changes in the trimer. The conformational changes induced by mechanical stress were characterized by size exclusion chromatography (SEC) and hydrogen-deuterium exchange mass spectrometry (HDX-MS), indicating the formation of an extended trimeric conformation that was also unable to bind to antibodies directed to the S2 domain. Long-term stability modeling, using advanced kinetic analysis, indicated that the formulation containing 0.2% (v/v) Tween 20 at a neutral pH was predicted to be stable for at least two years at 2 °C to 8 °C. Additional stabilizer screening conducted by thermal shift assay indicated that sucrose and glycerol were able to significantly increase the spike protein melting temperature (Tm) and improve the overall thermostability of the spike protein in a short-term stability study. Thus, while 0.2% (v/v) Tween 20 was sufficient to prevent aggregation and to maintain spike protein stability under refrigeration, the addition of sucrose further improved vaccine thermostability. Altogether, our study provides a systematic approach to the formulation of protein-based COVID-19 vaccine and highlights the impact of mechanical stress on the conformation of the spike protein and the significance of surfactants and stabilizers in maintaining the structural and functional integrity of the spike protein.

Engineered species-selective ion-exchange in tuneable dual-phase zeolite composites.

Controllable sorption selectivity in zeolites is crucial for their application in catalysis, gas separation and ion-exchange. Whilst existing approaches to achieving sorption selectivity with natural zeolites typically rely on screening for specific geological deposits, here we develop partial interzeolite transformation as a straightforward and highly tuneable method to achieve sorption selectivity via forming dual-phase composites with simultaneous control of both phase-ratio and morphology. The dual-cation (strontium and caesium) exchange properties of a series of granular mordenite/zeolite P composites formed from a parent natural mordenite material are demonstrated in complex, industrially relevant multi-ion environments pertinent to nuclear waste management. The relative uptake of caesium and strontium is controlled via the extent of transformation: composites exhibit significantly increased ion-exchange affinity for strontium compared to both the parent mordenite and physical mixtures of mordenite/zeolite P phases with similar phase ratios. The composite with a 40 : 60 mordenite : zeolite P ratio composite achieves higher uptake rates than the natural clinoptilolite material currently used to decontaminate nuclear waste streams at the Sellafield site, UK. In situ X-ray image-guided diffraction experiments during caesium exchange demonstrate that the mordenite core retains rapid caesium uptake likely responsible for the unique ion-exchange chemistry achievable through the partial inter-zeolite transformation. These results offer a straightforward and controllable route to optimised zeolite functionality and a strategy to engineer composites from low-grade natural sources at low cost and with formulation advantages for industrial deployment.

Optimizing Outcomes in the Management of the Burned Hand.

Burns of the hand are prevalent and must be managed aggressively in the acute phase to prevent deformity and disability. Proper early wound management, achieving durable soft tissue coverage, and appropriate positioning in the acute period offer substantial benefits to patients long-term. When contractures occur, secondary procedures are often indicated, and they range from laser therapy to local/regional flap coverage; rarely free flaps are used. Boutonniere deformities are common, and unfortunately, at times finger amputation renders the hand more functional than further efforts at reconstruction.

A novel Nav1.5-dependent feedback mechanism driving glycolytic acidification in breast cancer metastasis.

Solid tumours have abnormally high intracellular [Na+]. The activity of various Na+ channels may underlie this Na+ accumulation. Voltage-gated Na+ channels (VGSCs) have been shown to be functionally active in cancer cell lines, where they promote invasion. However, the mechanisms involved, and clinical relevance, are incompletely understood. Here, we show that protein expression of the Nav1.5 VGSC subtype strongly correlates with increased metastasis and shortened cancer-specific survival in breast cancer patients. In addition, VGSCs are functionally active in patient-derived breast tumour cells, cell lines, and cancer-associated fibroblasts. Knockdown of Nav1.5 in a mouse model of breast cancer suppresses expression of invasion-regulating genes. Nav1.5 activity increases ATP demand and glycolysis in breast cancer cells, likely by upregulating activity of the Na+/K+ ATPase, thus promoting H+ production and extracellular acidification. The pH of murine xenograft tumours is lower at the periphery than in the core, in regions of higher proliferation and lower apoptosis. In turn, acidic extracellular pH elevates persistent Na+ influx through Nav1.5 into breast cancer cells. Together, these findings show positive feedback between extracellular acidification and the movement of Na+ into cancer cells which can facilitate invasion. These results highlight the clinical significance of Nav1.5 activity as a potentiator of breast cancer metastasis and provide further evidence supporting the use of VGSC inhibitors in cancer treatment.

Global insights into keloid formation: An international systematic review of regional genetic risk factors and commonalities.

Keloid disorder is a morbid and disfiguring benign fibroproliferative disease with a higher incidence in groups with darker skin pigmentation. Predicting keloidogenesis in patients is difficult with treatment primarily aimed at preventing further scar expansion and improving aesthetics without addressing their unknown underlying pathophysiology. We aimed to identify potential genetic predispositions to keloid scarring in the literature. A search was conducted on 21 August 2023, by the first and second authors independently from 1985 to August 2023 using PubMed, MEDLINE, Embase, Web of Science, Scopus and CINAHL. The following MeSH terms were used: 'Keloid', 'Risk' and 'Genetic'. Two researchers independently searched for studies based on titles and abstracts and screened filtered articles by reviewing full text. If no agreement could be reached, a third senior author designated whether the article should be included. We used the Preferred Reporting Items for Systematic Reviews and Meta-Analyses 2020 statement as the basis of our organisation. Human studies with genetic analysis to determine an association of a protein or gene to keloidogenesis were selected for inclusion. Studies in languages other than English, reviews, conference articles, and book chapters were excluded. Fifty studies met inclusion criteria. The human leukocyte antigen (HLA) system was broadly implicated, and the DRB1*15 allele was associated with an increased risk of keloid in three separate ethnic groups. Some HLA Class I alleles were associated with keloid in one population but not in others. Additionally, polymorphisms in the E3 ubiquitin-protein ligase (NEDD4) signal cascade and vitamin D receptor (VDR) have been implicated in diverse groups. No current genetic test can predict keloid risk. Our review identified candidate predisposing genes, including NEDD4, VDR and components of the HLA system. Further studies in heterogeneous populations are needed to identify reliable screening targets.

Upper Blepharoplasty through Infrabrow Skin Excision to Treat Dermatochalasis with Lateral Hooding and Medial Orbital Fat Loss in Selected Patients.

PURPOSE: Dermatochalasis with lateral hooding and medial orbital fat loss are common signs of aging in the upper eyelid. Removing the excess skin in this area through infrabrow skin excision can effectively lift the loose skin of the upper eyelid and minimizes visible scarring. Additionally, we have identified three compartments of orbital fat prolapse based on orbital anatomy. Transferring volume from the lateral compartment to the intermediate region can flatten the lateral upper eyelid and create medial fullness, which ultimately rejuvenates the upper eyelid. This study presents an operative method for correcting age-related changes in the upper eyelid using this technique. METHODS: A total of 34 eyelids from 17 patients underwent a surgical procedure involving infrabrow skin excision, along with repositioning and lifting of lateral orbital fat. The inclusion criteria consisted of patients with moderate to severe upper eyelid dermatochalasis, coupled with middle fat loss and lateral hooding. To correct lateral hooding and restore midfacial fullness, lateral orbital fat was repositioned to an intermediate position, and the orbicularis oculi muscle was fold-sutured to the corrugator supercilii muscle. RESULTS: The mean age of the patients was 55.59 ± 3.20 years, with a range of 48 to 61 years. The mean follow-up period was 9.94 ± 1.35 months, ranging from 8 to 12 months. Patients were evaluated at 1-month, 3-month, and 6-month intervals. The Strasser system was used to evaluate the surgical outcomes at 3 months. All patients achieved good surgical outcomes, expressed through satisfactory cosmetic improvements, and improved visual field. The procedure effectively corrected lateral hooding and loss of middle orbital fat through infrabrow skin excision. No complications, such as wound dehiscence, lagophthalmos, noticeable scarring, ocular dyskinesia, or sensory changes, were observed. CONCLUSIONS: The combination of infrabrow skin excision, repositioning of lateral orbital fat, and lifting of the orbicularis oculi muscle effectively addresses moderate to severe dermatochalasis, lateral hooding, medial fat loss, and improves elasticity of the anterior wall of the upper lid in our patients. This procedure can produce satisfactory and long-lasting aesthetic results with an inconspicuous scar beneath the brow.

Perioperative nivolumab versus observation in patients with renal cell carcinoma undergoing nephrectomy (PROSPER ECOG-ACRIN EA8143): an open-label, randomised, phase 3 study.

BACKGROUND: The standard of care for patients with intermediate-to-high risk renal cell carcinoma is partial or radical nephrectomy followed by surveillance. We aimed to investigate use of nivolumab before nephrectomy followed by adjuvant nivolumab in patients with high-risk renal cell carcinoma to determine recurrence-free survival compared with surgery only. METHODS: In this open-label, randomised, phase 3 trial (PROSPER EA8143), patients were recruited from 183 community and academic sites across the USA and Canada. Eligible patients were aged 18 years or older with an Eastern Cooperative Oncology Group performance status of 0-1, with previously untreated clinical stage T2 or greater or Tany N+ renal cell carcinoma of clear cell or non-clear cell histology planned for partial or radical nephrectomy. Selected patients with oligometastatic disease, who were disease free at other disease sites within 12 weeks of surgery, were eligible for inclusion. We randomly assigned (1:1) patients using permuted blocks (block size of 4) within stratum (clinical TNM stage) to either nivolumab plus surgery, or surgery only followed by surveillance. In the nivolumab group, nivolumab 480 mg was administered before surgery, followed by nine adjuvant doses. The primary endpoint was investigator-reviewed recurrence-free survival in patients with renal cell carcinoma assessed in all randomly assigned patients regardless of histology. Safety was assessed in all randomly assigned patients who started the assigned protocol treatment. This trial is registered with ClinicalTrials.gov, NCT03055013, and is closed to accrual. FINDINGS: Between Feb 2, 2017, and June 2, 2021, 819 patients were randomly assigned to nivolumab plus surgery (404 [49%]) or surgery only (415 [51%]). 366 (91%) of 404 patients assigned to nivolumab plus surgery and 387 (93%) of 415 patients assigned to surgery only group started treatment. Median age was 61 years (IQR 53-69), 248 (30%) of 819 patients were female, 571 (70%) were male, 672 (88%) were White, and 77 (10%) were Hispanic or Latino. The Data and Safety Monitoring Committee stopped the trial at a planned interim analysis (March 25, 2022) because of futility. Median follow-up was 30·4 months (IQR 21·5-42·4) in the nivolumab group and 30·1 months (21·9-41·8) in the surgery only group. 381 (94%) of 404 patients in the nivolumab plus surgery group and 399 (96%) of 415 in the surgery only group had renal cell carcinoma and were included in the recurrence-free survival analysis. As of data cutoff (May 24, 2023), recurrence-free survival was not significantly different between nivolumab (125 [33%] of 381 had recurrence-free survival events) versus surgery only (133 [33%] of 399; hazard ratio 0·94 [95% CI 0·74-1·21]; one-sided p=0·32). The most common treatment-related grade 3-4 adverse events were elevated lipase (17 [5%] of 366 patients in the nivolumab plus surgery group vs none in the surgery only group), anaemia (seven [2%] vs nine [2%]), increased alanine aminotransferase (ten [3%] vs one [<1%]), abdominal pain (four [1%] vs six [2%]), and increased serum amylase (nine [2%] vs none). 177 (48%) patients in the nivolumab plus surgery group and 93 (24%) in the surgery only group had grade 3-5 adverse events due to any cause, the most common of which were anaemia (23 [6%] vs 19 [5%]), hypertension (27 [7%] vs nine [2%]), and elevated lipase (18 [5%] vs six [2%]). 48 (12%) of 404 patients in the nivolumab group and 40 (10%) of 415 in the surgery only group died, of which eight (2%) and three (1%), respectively, were determined to be treatment-related. INTERPRETATION: Perioperative nivolumab before nephrectomy followed by adjuvant nivolumab did not improve recurrence-free survival versus surgery only followed by surveillance in patients with high-risk renal cell carcinoma. FUNDING: US National Institutes of Health National Cancer Institute and Bristol Myers Squibb.