A novel kinetic model to demonstrate the independent effects of ATP and ADP/Pi concentrations on sarcomere function.

Understanding muscle contraction mechanisms is a standing challenge, and one of the approaches has been to create models of the sarcomere-the basic contractile unit of striated muscle. While these models have been successful in elucidating many aspects of muscle contraction, they fall short in explaining the energetics of functional phenomena, such as rigor, and in particular, their dependence on the concentrations of the biomolecules involved in the cross-bridge cycle. Our hypothesis posits that the stochastic time delay between ATP adsorption and ADP/Pi release in the cross-bridge cycle necessitates a modeling approach where the rates of these two reaction steps are controlled by two independent parts of the total free energy change of the hydrolysis reaction. To test this hypothesis, we built a two-filament, stochastic-mechanical half-sarcomere model that separates the energetic roles of ATP and ADP/Pi in the cross-bridge cycle's free energy landscape. Our results clearly demonstrate that there is a nontrivial dependence of the cross-bridge cycle's kinetics on the independent concentrations of ATP, ADP, and Pi. The simplicity of the proposed model allows for analytical solutions of the more basic systems, which provide novel insight into the dominant mechanisms driving some of the experimentally observed contractile phenomena.

Interaction between the gut microbiota and colonic enteroendocrine cells regulates host metabolism.

Nutrient handling is an essential function of the gastrointestinal tract. Hormonal responses of small intestinal enteroendocrine cells (EECs) have been extensively studied but much less is known about the role of colonic EECs in metabolic regulation. To address this core question, we investigated a mouse model deficient in colonic EECs. Here we show that colonic EEC deficiency leads to hyperphagia and obesity. Furthermore, colonic EEC deficiency results in altered microbiota composition and metabolism, which we found through antibiotic treatment, germ-free rederivation and transfer to germ-free recipients, to be both necessary and sufficient for the development of obesity. Moreover, studying stool and blood metabolomes, we show that differential glutamate production by intestinal microbiota corresponds to increased appetite and that colonic glutamate administration can directly increase food intake. These observations shed light on an unanticipated host-microbiota axis in the colon, part of a larger gut-brain axis, that regulates host metabolism and body weight.

Early Versus Delayed Definitive Fixation Relative to Fasciotomy Closure in High-Energy Tibial Plateau Fractures With Compartment Syndrome.

OBJECTIVES: To evaluate the timing of definitive fixation of tibial plateau fractures relative to fasciotomy closure with regard to alignment and articular reduction. DESIGN: Retrospective case series. SETTING: Four Level I trauma centers. PATIENT SELECTION CRITERIA: Patients with tibial plateau fractures (TPF) with ipsilateral compartment syndrome treated with fasciotomy between 2006 and 2018 met inclusion criteria. Open fractures, patients younger than 18 years, patients with missed or delayed treatment of compartment syndrome, patients with a diagnosis of compartment syndrome after surgical fixation, and patients whose plateau fracture was not treated with open reduction and internal fixation were excluded. Patients were divided into 2 groups depending on the relative timing of fixation to fasciotomy closure: early fixation (EF) was defined as fixation before or at the time of fasciotomy closure, and delayed fixation (DF) was defined as fixation after fasciotomy closure. OUTCOME MEASURES AND COMPARISONS: Radiographic limb alignment (categorized as anatomic alignment (no varus/valgus), ≤5 degrees varus/valgus, or >5 degrees varus/valgus) and articular reduction (categorized as anatomic alignment with no residual gap or step-off, <2 mm, 2-5 mm, and >5 mm of articular surface step-off) were compared between early and delayed fixation groups. In addition, superficial and deep infection rates were compared between those in the EF and DF cohorts. Subgroup analysis within the EF cohort was performed to compare baseline characteristics and outcomes between those that received fixation before closure and those that underwent concurrent fixation and closure within one operative episode. RESULTS: A total of 131 patients met inclusion criteria for this study. Sixty-four patients (48.9%) were stratified into the delayed fixation group, and 67 patients (51.1%) were stratified into the early fixation group. In the EF cohort, 57 (85.1%) were male patients with an average age of 45.3 ± 13.6 years and an average body mass index of 31.0 ± 5.9. The DF cohort comprised primarily male patients (44, 68.8%), with an average age of 46.6 ± 13.9 years and an average body mass index of 28.4 ± 7.9. Fracture pattern distribution did not differ significantly between the early and delayed fixation cohorts ( P = 0.754 for Schatzker classification and P = 0.569 for OTA/AO classification). The relative risk of infection for the DF cohort was 2.17 (95% confidence interval, 1.04-4.54) compared with the EF cohort. Patients in the early fixation cohort were significantly more likely to have anatomic articular reduction compared with their delayed fixation counterparts (37.5% vs. 52.2%; P < 0.001). CONCLUSIONS: This study demonstrated higher rates of anatomic articular reduction in patients who underwent fixation of tibial plateau fractures before or at the time of fasciotomy closure for acute compartment syndrome compared with their counterparts who underwent definitive fixation for tibial plateau fracture after fasciotomy closure. The relative risk of overall infection for those who underwent fasciotomy closure after definitive fixation for tibial plateau fracture was 2.17 compared with the cohort that underwent closure before or concomitantly with definitive fixation. LEVEL OF EVIDENCE: Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence.

Wilderness Medical Society Clinical Practice Guidelines for the Treatment and Prevention of Drowning: 2024 Update.

The Wilderness Medical Society convened a panel to review available evidence supporting practices for acute management of drowning in out-of-hospital and emergency care settings. Literature about definitions and terminology, epidemiology, rescue, resuscitation, acute clinical management, disposition, and drowning prevention was reviewed. The panel graded available evidence supporting practices according to the American College of Chest Physicians criteria and then made recommendations based on that evidence. Recommendations were based on the panel's collective clinical experience and judgment when published evidence was lacking. This is the second update to the original practice guidelines published in 2016 and updated in 2019.

Aquatic Feasibility of Limbs Application of Tourniquets (AFLAT) during a Lifeguard Water Rescue: A Simulation Pilot Study.

INTRODUCTION: Control of massive hemorrhage (MH) is a life-saving intervention. The use of tourniquets has been studied in prehospital and battlefield settings but not in aquatic environments. OBJECTIVE: The aim of this research is to assess the control of MH in an aquatic environment by analyzing the usability of two tourniquet models with different adjustment mechanisms: windlass rod versus ratchet. METHODOLOGY: A pilot simulation study was conducted using a randomized crossover design to assess the control of MH resulting from an upper extremity arterial perforation in an aquatic setting. A sample of 24 trained lifeguards performed two randomized tests: one using a windlass-based Combat Application Tourniquet 7 Gen (T-CAT) and the other using a ratchet-based OMNA Marine Tourniquet (T-OMNA) specifically designed for aquatic use on a training arm for hemorrhage control. The tests were conducted after swimming an approximate distance of 100 meters and the tourniquets were applied while in the water. The following parameters were recorded: time of rescue (rescue phases and tourniquet application), perceived fatigue, and technical actions related to tourniquet skills. RESULTS: With the T-OMNA, 46% of the lifeguards successfully stopped the MH compared to 21% with the T-CAT (P = .015). The approach swim time was 135 seconds with the T-OMNA and 131 seconds with the T-CAT (P = .42). The total time (swim time plus tourniquet placement) was 174 seconds with the T-OMNA and 177 seconds with the T-CAT (P = .55). The adjustment time (from securing the Velcro to completing the manipulation of the windlass or ratchet) for the T-OMNA was faster than with the T-CAT (six seconds versus 19 seconds; P < .001; effect size [ES] = 0.83). The perceived fatigue was high, with a score of seven out of ten in both tests (P = .46). CONCLUSIONS: Lifeguards in this study demonstrated the ability to use both tourniquets during aquatic rescues under conditions of fatigue. The tourniquet with the ratcheting-fixation system controlled hemorrhage in less time than the windlass rod-based tourniquet, although achieving complete bleeding control had a low success rate.

Aqueous-phase product treatment and monetization options of wet waste hydrothermal liquefaction: Comprehensive techno-economic and life-cycle GHG emission assessment unveiling research opportunities.

While wet waste hydrothermal liquefaction technology has a high biofuel yield, a significant amount of the carbon and nitrogen in the feedstock reports to the aqueous-phase product. Pretreatment of this stream before sending to a conventional wastewater plant is essential or at the very least, advisable. In this work, techno-economic and life-cycle assessments were conducted for the state-of-technology baseline and four aqueous-phase product treatment and monetization options based on experimental data. These options can cut minimum fuel selling prices by up to 13 % and life-cycle greenhouse gas emissions by up to 39 % compared to the baseline. These findings highlight the substantial influence of aqueous produce treatment strategies on the entire wet waste hydrothermal liquefaction process, demonstrating the potential for optimizing economic viability and environmental impact through further research and development of milder treatment methods and diversified by-product valorization pathways.

The Role of Revision Total Joint Arthroplasty for Periprosthetic Fractures With Unstable Implants.

The management of periprosthetic fractures with unstable prosthetic implants is a challenging and commonly encountered problem. It is important to address the many current issues and controversies regarding the treatment of periprosthetic fractures with revision total joint arthroplasty. Key strategies to optimize surgical decision making around the use of arthroplasty and management of complications following these complex injuries will be addressed.

Reducing the Burden of Disease Associated With Periprosthetic Fractures: Prevention and the Need for Improved Perioperative Care.

The management of periprosthetic fractures remains challenging and controversial. There continues to be a significant burden of disease and substantial resource implications associated with fractures following total joint arthroplasty. Achieving consensus opinions regarding the prevention and treatment of this problem has important implications given the profound effect on patient outcomes. Multidisciplinary care in the preoperative and postoperative settings is critical, with a specific focus on bone health.

Fixation Strategies for Periprosthetic Fractures With Stable Implants.

The fixation of periprosthetic fractures remains challenging and controversial. It is important to achieve consensus opinions regarding the management of stable periprosthetic fractures with internal fixation. Key strategies to optimize surgical decision making and fixation and manage complications following these difficult injuries are addressed.

Advanced MRI Approaches for Evaluating Common Lower Extremity Injuries in Basketball Players: Current and Emerging Techniques.

Magnetic resonance imaging (MRI) can provide accurate and non-invasive diagnoses of lower extremity injuries in athletes. Sport-related injuries commonly occur in and around the knee and can affect the articular cartilage, patellar tendon, hamstring muscles, and bone. Sports medicine physicians utilize MRI to evaluate and diagnose injury, track recovery, estimate return to sport timelines, and assess the risk of recurrent injury. This article reviews the current literature and describes novel developments of quantitative MRI tools that can further advance our understanding of sports injury diagnosis, prevention, and treatment while minimizing injury risk and rehabilitation time. Innovative approaches for enhancing the early diagnosis and treatment of musculoskeletal injuries in basketball players span a spectrum of techniques. These encompass the utilization of T2 , T1ρ , and T2 * quantitative MRI, along with dGEMRIC and Na-MRI to assess articular cartilage injuries, 3D-Ultrashort echo time MRI for patellar tendon injuries, diffusion tensor imaging for acute myotendinous injuries, and sagittal short tau inversion recovery and axial long-axis T1 -weighted, and 3D Cube sequences for bone stress imaging. Future studies should further refine and validate these MR-based quantitative techniques while exploring the lifelong cumulative impact of basketball on players' knees. LEVEL OF EVIDENCE: 5 TECHNICAL EFFICACY: Stage 2.

A systematic review of interventions for resuscitation following drowning.

Objectives: The International Liaison Committee on Resuscitation, in collaboration with drowning researchers from around the world, aimed to review the evidence addressing seven key resuscitation interventions: 1) immediate versus delayed resuscitation; (2) compression first versus ventilation first strategy; (3) compression-only CPR versus standard CPR (compressions and ventilations); (4) ventilation with and without equipment; (5) oxygen administration prior to hospital arrival; (6) automated external defibrillation first versus cardiopulmonary resuscitation first strategy; (7) public access defibrillation programmes. Methods: The review included studies relating to adults and children who had sustained a cardiac arrest following drowning with control groups and reported patient outcomes. Searches were run from database inception through to April 2023. The following databases were searched Ovid MEDLINE, Pre-Medline, Embase, Cochrane Central Register of Controlled Trials. Risk of bias was assessed using the ROBINS-I tool and the certainty of evidence was assessed using Grading of Recommendations Assessment, Development and Evaluation. The findings are reported as a narrative synthesis. Results: Three studies were included for two of the seven interventions (2,451 patients). No randomised controlled trials were identified. A retrospective observational study reported in-water resuscitation with rescue breaths improved patient outcomes compared to delayed resuscitation on land (n = 46 patients, very low certainty of evidence). The two observational studies (n = 2,405 patients), comparing compression-only with standard resuscitation, reported no difference for most outcomes. A statistically higher rate of survival to hospital discharge was reported for the standard resuscitation group in one of these studies (29.7% versus 18.1%, adjusted odds ratio 1.54 (95% confidence interval 1.01-2.36) (very low certainty of evidence). Conclusion: The key finding of this systematic review is the paucity of evidence, with control groups, to inform treatment guidelines for resuscitation in drowning.

Postfasciotomy Classification System for Acute Compartment Syndrome of the Leg.

OBJECTIVE: Acute compartment syndrome (ACS) is a true emergency. Even with urgent fasciotomy, there is often muscle damage and need for further surgery. Although ACS is not uncommon, no validated classification system exists to aid in efficient and clear communication. The aim of this study was to establish and validate a classification system for the consequences of ACS treated with fasciotomy. METHODS: Using a modified Delphi method, an international panel of ACS experts was assembled to establish a grading scheme for the disease and then validate the classification system. The goal was to articulate discrete grades of ACS related to fasciotomy findings and associated costs. A pilot analysis was used to determine questions that were clear to the respondents. Discussion of this analysis resulted in another round of cases used for 24 other raters. The 24 individuals implemented the classification system 2 separate times to compare outcomes for 32 clinical cases. The accuracy and reproducibility of the classification system were subsequently calculated based on the providers' responses. RESULTS: The Fleiss Kappa of all raters was at 0.711, showing a strong agreement between the 24 raters. Secondary validation was performed for paired 276 raters and correlation was tested using the Kendall coefficient. The median correlation coefficient was 0.855. All 276 pairs had statistically significant correlation. Correlation coefficient between the first and second rating sessions was strong with the median pair scoring at 0.867. All surgeons had statistically significant internal consistency. CONCLUSION: This new ACS classification system may be applied to better understand the impact of ACS on patient outcomes and economic costs for leg ACS.

[Formula: see text] Field inhomogeneity correction for qDESS [Formula: see text] mapping: application to rapid bilateral knee imaging.

PURPOSE: [Formula: see text] mapping is a powerful tool for studying osteoarthritis (OA) changes and bilateral imaging may be useful in investigating the role of between-knee asymmetry in OA onset and progression. The quantitative double-echo in steady-state (qDESS) can provide fast simultaneous bilateral knee [Formula: see text] and high-resolution morphometry for cartilage and meniscus. The qDESS uses an analytical signal model to compute [Formula: see text] relaxometry maps, which require knowledge of the flip angle (FA). In the presence of [Formula: see text] inhomogeneities, inconsistencies between the nominal and actual FA can affect the accuracy of [Formula: see text] measurements. We propose a pixel-wise [Formula: see text] correction method for qDESS [Formula: see text] mapping exploiting an auxiliary [Formula: see text] map to compute the actual FA used in the model. METHODS: The technique was validated in a phantom and in vivo with simultaneous bilateral knee imaging. [Formula: see text] measurements of femoral cartilage (FC) of both knees of six healthy participants were repeated longitudinally to investigate the association between [Formula: see text] variation and [Formula: see text]. RESULTS: The results showed that applying the [Formula: see text] correction mitigated [Formula: see text] variations that were driven by [Formula: see text] inhomogeneities. Specifically, [Formula: see text] left-right symmetry increased following the [Formula: see text] correction ([Formula: see text] = 0.74 > [Formula: see text] = 0.69). Without the [Formula: see text] correction, [Formula: see text] values showed a linear dependence with [Formula: see text]. The linear coefficient decreased using the [Formula: see text] correction (from 24.3 ± 1.6 ms to 4.1 ± 1.8) and the correlation was not statistically significant after the application of the Bonferroni correction (p value > 0.01). CONCLUSION: The study showed that [Formula: see text] correction could mitigate variations driven by the sensitivity of the qDESS [Formula: see text] mapping method to [Formula: see text], therefore, increasing the sensitivity to detect real biological changes. The proposed method may improve the robustness of bilateral qDESS [Formula: see text] mapping, allowing for an accurate and more efficient evaluation of OA pathways and pathophysiology through longitudinal and cross-sectional studies.

Drowning in the United States: Patient and scene characteristics using the novel CARES drowning variables.

INTRODUCTION: Drowning results in more than 360,000 deaths annually, making it the 3rd leading cause of unintentional injury death worldwide. Prior studies examining drowning internationally have reviewed factors surrounding drowning however in the U.S. limited data exists. This study evaluated the novel drowning elements collected in the Cardiac Arrest Registry to Enhance Survival (CARES) during the first 2 years of data collection. METHODS: A retrospective analysis of the CARES database identified cases of drowning etiology for the two years 2020 and 2021. Demographics and incident characteristics were collected. Characteristics included items such as body of water, precipitating event, and who extracted patients. Survival to hospital discharge and neurological outcomes were compared between groups based on who initiated CPR using Pearson's Chi-Squared tests. RESULTS: Among 1,767 drowning cases, 69.7% were male, 47.1% white and 11.9% survived to hospital discharge. Body of water was often natural body (36.2%) or swimming pool (25.9%) and bystanders removed the patient in 42.7% of incidents. Swimming was the most common activity at time of submersion (18.6%) however in 50.2% of cases, activity was unknown or missing. When compared to EMS/First Responder initiating CPR, odds of neurologically favorable survival were significantly higher in the Bystander initiated CPR group (OR = 2.85, 95% confidence interval [CI] 2.02-4.01). CONCLUSION: In this national cohort of drowning patients in cardiac arrest, the novel CARES drowning elements provide additional detail of epidemiological factors. Bystander CPR was associated with improved neurological outcomes. Future studies utilizing the drowning elements can inform injury prevention strategies.

Breakthrough SARS-CoV-2 infections among patients with cancer following two and three doses of COVID-19 mRNA vaccines: a retrospective observational study from the COVID-19 and Cancer Consortium.

Background: Breakthrough SARS-CoV-2 infections following vaccination against COVID-19 are of international concern. Patients with cancer have been observed to have worse outcomes associated with COVID-19 during the pandemic. We sought to evaluate the clinical characteristics and outcomes of patients with cancer who developed breakthrough SARS-CoV-2 infections after 2 or 3 doses of mRNA vaccines. Methods: We evaluated the clinical characteristics of patients with cancer who developed breakthrough infections using data from the multi-institutional COVID-19 and Cancer Consortium (CCC19; NCT04354701). Analysis was restricted to patients with laboratory-confirmed SARS-CoV-2 diagnosed in 2021 or 2022, to allow for a contemporary unvaccinated control population; potential differences were evaluated using a multivariable logistic regression model after inverse probability of treatment weighting to adjust for potential baseline confounding variables. Adjusted odds ratios (aOR) and 95% confidence intervals (CI) are reported. The primary endpoint was 30-day mortality, with key secondary endpoints of hospitalization and ICU and/or mechanical ventilation (ICU/MV). Findings: The analysis included 2486 patients, of which 564 and 385 had received 2 or 3 doses of an mRNA vaccine prior to infection, respectively. Hematologic malignancies and recent receipt of systemic anti-neoplastic therapy were more frequent among vaccinated patients. Vaccination was associated with improved outcomes: in the primary analysis, 2 doses (aOR: 0.62, 95% CI: 0.44-0.88) and 3 doses (aOR: 0.20, 95% CI: 0.11-0.36) were associated with decreased 30-day mortality. There were similar findings for the key secondary endpoints of ICU/MV (aOR: 0.60, 95% CI: 0.45-0.82 and 0.37, 95% CI: 0.24-0.58) and hospitalization (aOR: 0.60, 95% CI: 0.48-0.75 and 0.35, 95% CI: 0.26-0.46) for 2 and 3 doses, respectively. Importantly, Black patients had higher rates of hospitalization (aOR: 1.47, 95% CI: 1.12-1.92), and Hispanic patients presented with higher rates of ICU/MV (aOR: 1.61, 95% CI: 1.06-2.44). Interpretation: Vaccination against COVID-19, especially with additional doses, is a fundamental strategy in the prevention of adverse outcomes including death, among patients with cancer. Funding: This study was partly supported by grants from the National Cancer Institute grant number P30 CA068485 to C-YH, YS, SM, JLW; T32-CA236621 and P30-CA046592 to C.R.F; CTSA 2UL1TR001425-05A1 to TMW-D; ACS/FHI Real-World Data Impact Award, P50 MD017341-01, R21 CA242044-01A1, Susan G. Komen Leadership Grant Hunt to MKA. REDCap is developed and supported by Vanderbilt Institute for Clinical and Translational Research grant support (UL1 TR000445 from NCATS/NIH).

Improving Data-Efficiency and Robustness of Medical Imaging Segmentation Using Inpainting-Based Self-Supervised Learning.

We systematically evaluate the training methodology and efficacy of two inpainting-based pretext tasks of context prediction and context restoration for medical image segmentation using self-supervised learning (SSL). Multiple versions of self-supervised U-Net models were trained to segment MRI and CT datasets, each using a different combination of design choices and pretext tasks to determine the effect of these design choices on segmentation performance. The optimal design choices were used to train SSL models that were then compared with baseline supervised models for computing clinically-relevant metrics in label-limited scenarios. We observed that SSL pretraining with context restoration using 32 × 32 patches and Poission-disc sampling, transferring only the pretrained encoder weights, and fine-tuning immediately with an initial learning rate of 1 × 10-3 provided the most benefit over supervised learning for MRI and CT tissue segmentation accuracy (p < 0.001). For both datasets and most label-limited scenarios, scaling the size of unlabeled pretraining data resulted in improved segmentation performance. SSL models pretrained with this amount of data outperformed baseline supervised models in the computation of clinically-relevant metrics, especially when the performance of supervised learning was low. Our results demonstrate that SSL pretraining using inpainting-based pretext tasks can help increase the robustness of models in label-limited scenarios and reduce worst-case errors that occur with supervised learning.

Locked Plating versus Nailing for Proximal Tibia Fractures: A Multicenter RCT.

OBJECTIVES: The main 2 forms of treatment for extraarticular proximal tibial fractures are intramedullary nailing (IMN) and locked lateral plating (LLP). The goal of this multicenter, randomized controlled trial was to determine whether there are significant differences in outcomes between these forms of treatment. DESIGN: Multicenter, randomized controlled trial. SETTING: 16 academic trauma centers. PATIENTS/PARTICIPANTS: 108 patients were enrolled. 99 patients were followed for 12 months. 52 patients were randomized to IMN, and 47 patients were randomized to LLP. INTERVENTION: IMN or lateral locked plating. MAIN OUTCOME MEASUREMENTS: Functional scoring including Short Musculoskeletal Functional Assessment, Bother Index, EQ-5Dindex and EQ-5DVAS. Secondary measures included alignment, operative time, range of motion, union rate, pain, walking ability, ability to manage stairs, need for ambulatory aid and number, and complications. RESULTS: Functional testing demonstrated no difference between the groups, but both groups were still significantly affected 12 months postinjury. Similarly, there was no difference in time of surgery, alignment, nonunion, pain, walking ability, ability to manage stairs, need for ambulatory support, or complications. CONCLUSIONS: Both IMN and LLP provide for similar outcomes after these fractures. Patients continue to improve over the course of the year after injury but remain impaired even 1 year later. LEVEL OF EVIDENCE: Therapeutic Level II. See Instructions for Authors for a complete description of levels of evidence.

Application of Bayesian Methods to Help Interpret the VANCO Trial Results.

OBJECTIVE: To determine whether a Bayesian analysis changes the results of the VANCO trial. DESIGN: A secondary analysis of a randomized clinical trial using Bayesian methods. SETTING: Thirty-six US trauma centers. PATIENTS: Patients ages 18-80 years with a tibial plateau or pilon fracture deemed high risk of infection and definitively treated with plate and screw fixation. INTERVENTION: Patients were randomly allocated to receive 1000 mg of intrawound vancomycin powder at their definitive fixation or to a control group that received no topical antibiotics. MAIN OUTCOME MEASUREMENTS: A deep surgical site infection requiring operative treatment within 6 months of definitive fixation. Secondary outcomes included gram-positive and gram-negative-only deep surgical site infections. RESULTS: Of the 980 patients randomized, 874 (89%) had at least 140 days of follow-up and were included in this Bayesian analysis. The estimated probability that intrawound vancomycin powder reduces the risk of a deep surgical site infection is >98% [relative risk (RR), 0.66; 95% credible interval (CrI), 0.46-0.98]. There is a >99% chance intrawound vancomycin powder reduces gram-positive infections and an 80% chance the magnitude of this risk reduction exceeds 35% (RR, 0.52; 95% CrI, 0.33-0.84) exists. It is unlikely (44%) that intrawound vancomycin powder prevents gram-negative surgical site infections (RR, 1.06; 95% CrI, 0.48-2.45). CONCLUSIONS: There is a high probability (>98%) that intrawound vancomycin powder reduces deep surgical site infections in patients with tibial plateau or pilon fractures at high risk of infection and even more likely it reduces deep infections with gram-positive pathogens (>99%). LEVEL OF EVIDENCE: Therapeutic Level I. See Instructions for Authors for a complete description of levels of evidence.

CABOSEQ: The Effectiveness of Cabozantinib in Patients With Treatment Refractory Advanced Renal Cell Carcinoma: Results From the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC).

BACKGROUND: There are limited data evaluating the activity of cabozantinib (CABO) as second line (2L) therapy post standard of care ipilimumab-nivolumab (IPI-NIVO) or immuno-oncology(IO)/vascular endothelial growth factor inhibitor (VEGFi) combinations (IOVE). MATERIALS AND METHODS: Using the IMDC database, we sought to identify the objective response rate, time to treatment failure (TTF) and overall survival (OS) of 2L CABO after IPI-NIVO, IOVE combinations, pazopanib or sunitinib (PAZ/SUN) or other first line (1L) therapies. Multivariable Cox regression, adjusted for underlying differences in IMDC groups, was used to compare differences in OS for 2L CABO based on preceding therapy. RESULTS: Three hundred and forty-six patients received 2L CABO (78 post IPI NIVO, 46 post IOVE, 161 post PAZ/SUN, 61 post Other). Of the entire cohort, 12.6%, 62.6%, and 24.8% were IMDC favourable, intermediate, and poor risk, respectively. Patients that received 1L IPI-NIVO had a median OS of 21.4 (95% CI, 12.1 - NE [Not evaluable]) months compared to 15.7 (95% CI, 9.3 - NE) months in 1L IOVE and 20.7 (95% CI, 15.6 - 35.6) months in 1L PAZ/SUN, P = .28. Median TTF from the initiation of 2L CABO in the overall population was 7.6 (95% CI, 6.6 - 9.0) months. We were unable to detect a significant difference in 2L CABO OS based on type of 1L therapy received: 1L IPI-NIVO (reference group) vs. 1L IOVE HR 1.73 (95% CI, 0.83 - 3.62 P = .14), 1L PAZ/SUN 1.16 (95% CI, 0.67 - 2.00 P = .60), however given the retrospective observational nature of this work a lack of sufficient power may contribute to this. CONCLUSION: In a large real world dataset, we identified clinically meaningful activity of 2L CABO after all evaluated contemporary 1L therapies, irrespective of whether the 1L regimen included a VEGFi. These are real world benchmarks with which to counsel our patients.

Generalizability of Deep Learning Segmentation Algorithms for Automated Assessment of Cartilage Morphology and MRI Relaxometry.

BACKGROUND: Deep learning (DL)-based automatic segmentation models can expedite manual segmentation yet require resource-intensive fine-tuning before deployment on new datasets. The generalizability of DL methods to new datasets without fine-tuning is not well characterized. PURPOSE: Evaluate the generalizability of DL-based models by deploying pretrained models on independent datasets varying by MR scanner, acquisition parameters, and subject population. STUDY TYPE: Retrospective based on prospectively acquired data. POPULATION: Overall test dataset: 59 subjects (26 females); Study 1: 5 healthy subjects (zero females), Study 2: 8 healthy subjects (eight females), Study 3: 10 subjects with osteoarthritis (eight females), Study 4: 36 subjects with various knee pathology (10 females). FIELD STRENGTH/SEQUENCE: A 3-T, quantitative double-echo steady state (qDESS). ASSESSMENT: Four annotators manually segmented knee cartilage. Each reader segmented one of four qDESS datasets in the test dataset. Two DL models, one trained on qDESS data and another on Osteoarthritis Initiative (OAI)-DESS data, were assessed. Manual and automatic segmentations were compared by quantifying variations in segmentation accuracy, volume, and T2 relaxation times for superficial and deep cartilage. STATISTICAL TESTS: Dice similarity coefficient (DSC) for segmentation accuracy. Lin's concordance correlation coefficient (CCC), Wilcoxon rank-sum tests, root-mean-squared error-coefficient-of-variation to quantify manual vs. automatic T2 and volume variations. Bland-Altman plots for manual vs. automatic T2 agreement. A P value < 0.05 was considered statistically significant. RESULTS: DSCs for the qDESS-trained model, 0.79-0.93, were higher than those for the OAI-DESS-trained model, 0.59-0.79. T2 and volume CCCs for the qDESS-trained model, 0.75-0.98 and 0.47-0.95, were higher than respective CCCs for the OAI-DESS-trained model, 0.35-0.90 and 0.13-0.84. Bland-Altman 95% limits of agreement for superficial and deep cartilage T2 were lower for the qDESS-trained model, ±2.4 msec and ±4.0 msec, than the OAI-DESS-trained model, ±4.4 msec and ±5.2 msec. DATA CONCLUSION: The qDESS-trained model may generalize well to independent qDESS datasets regardless of MR scanner, acquisition parameters, and subject population. EVIDENCE LEVEL: 1 TECHNICAL EFFICACY: Stage 1.