Immune Responses in Checkpoint Myocarditis Across Heart, Blood, and Tumor.

Immune checkpoint inhibitors (ICIs) are widely used anti-cancer therapies that can cause morbid and potentially fatal immune-related adverse events (irAEs). ICI-related myocarditis (irMyocarditis) is uncommon but has the highest mortality of any irAE. The pathogenesis of irMyocarditis and its relationship to anti-tumor immunity remain poorly understood. We sought to define immune responses in heart, tumor, and blood during irMyocarditis and identify biomarkers of clinical severity by leveraging single-cell (sc)RNA-seq coupled with T cell receptor (TCR) sequencing, microscopy, and proteomics analysis of 28 irMyocarditis patients and 23 controls. Our analysis of 284,360 cells from heart and blood specimens identified cytotoxic T cells, inflammatory macrophages, conventional dendritic cells (cDCs), and fibroblasts enriched in irMyocarditis heart tissue. Additionally, potentially targetable, pro-inflammatory transcriptional programs were upregulated across multiple cell types. TCR clones enriched in heart and paired tumor tissue were largely non-overlapping, suggesting distinct T cell responses within these tissues. We also identify the presence of cardiac-expanded TCRs in a circulating, cycling CD8 T cell population as a novel peripheral biomarker of fatality. Collectively, these findings highlight critical biology driving irMyocarditis and putative biomarkers for therapeutic intervention.

Radiation therapy as a bridging and salvage strategy in patients with relapsed or refractory multiple myeloma undergoing BCMA-targeted CAR T-cell therapy.

Radiation therapy (RT) may play an important role prior to and following BCMA-targeted CAR T-cell therapy in multiple myeloma (MM). We report a series of 13 patients: 5 patients received bridging RT pre-CAR T, 4 patients received salvage RT post-CAR T failure, and 4 patients received both. There was no worsening of CAR-T- or RT-related toxicities. The RT in-field local control rate was 100%, with a median follow-up after each RT course of 7.3 months. RT as a bridging and salvage strategy is safe, feasible, and offers excellent local control in MM patients treated with CAR T-cell therapy.

Young adult male LEW.1WR1 rats have reduced beta cell area and develop glucose intolerance.

Prediabetes affects 1 in 3 American adults and is characterized by insulin resistance, insulin hypersecretion, and impaired glucose tolerance. Weanling LEW.1WR1 (1WR1) rats have increased blood insulin concentrations, so we hypothesized that young adult 1WR1 rats would develop impaired glucose tolerance due to the poor regulation of insulin. We monitored glucose tolerance, insulin tolerance, and weight gain for 10 weeks to assess if there was a decline in glucose processing over time. 1WR1 rats were significantly more glucose intolerant after 8 weeks. 1WR1 rats had increased body mass, yet abdominal fat mass was not significantly increased. Although the 1WR1 rats had increased circulating insulin and glucagon protein levels, 1WR1 rat beta cell area was significantly reduced. There may be underlying insulin resistance as evidenced by dysfunctional insulin regulation during fasting. Understanding the metabolic phenotype of this rat model can provide insight into the human pathophysiological changes that increase susceptibility to glucose intolerance and prediabetes.

A model to evaluate Pauwels type III femoral neck fractures.

While many femoral neck fractures can be reliably treated with surgical intervention, Pauwels III femoral neck fractures in the young adult population continue to be a challenging injury, and there is no consensus on optimal treatment. As such, there are past and ongoing biomechanical studies to evaluate the fixation provided by different constructs for this inherently unstable fracture. While many investigations rely on cadavers to evaluate the biomechanical performance of a construct, significant inter-subject variability can confound the analysis. Biomechanical femur analogs are being used more frequently due to more consistent mechanical properties; however, they have not been stringently evaluated for morphology or suitability for instrumentation. This study sought to determine the variability among composite femoral analogs as well as consistently create a Pauwels III injury and instrument the analogs without the need for fluoroscopic guidance. In total, 24 fourth-generation composite femoral analogs were evaluated for femoral height, neck-shaft angle, anteversion, and cortical thickness. A method was developed to simulate a Pauwels III fracture and to prepare three different constructs: an inverted triangle of cannulated screws, a sliding hip screw, and a hybrid inverted triangle with cannulated screws and a sliding hip screw. Radiographs were utilized to evaluate the variation in implant position. All but one of the morphological parameters varied by <1%. The tip-to-apex distance for all sliding hip screw hardware was 18.8 ± 3.3 mm, and all relevant cannulated screw distances were within 5 mm of the adjacent cortex. All screws were parallel, on average, within 1.5° on anterior-posterior and lateral films. Fourth-generation composite femora were found to be morphologically consistent, and it is possible to consistently instrument the analogs without the use of fluoroscopy. This analog and hardware implantation model could serve as a screening model for new fracture repair constructs without the need for cadaveric tissues or radiologic technology.

Effect of Intraoperative Dexamethasone on Pain Scores and Narcotic Consumption in Patients Undergoing Total Knee Arthroplasty.

OBJECTIVE: To examine whether the addition of intravenous dexamethasone during total knee arthroplasty (TKA) would be effective at reducing postoperative pain scores and postoperative opioid consumption. METHODS: A total of 102 patients undergoing TKA were placed into two groups: 55 subjects received intraoperative dexamethasone 8 mg intravenously (treatment group) and 47 did not receive dexamethasone at any time during the perioperative period. Comparison was made using the 0-10 numeric pain rating scale and the amount of opioids used in each group. RESULTS: Patients who received dexamethasone required significantly less oral opioids compared to the control group. Pain scores at 24 h post-surgery were significantly less for the dexamethasone group compared to the control group. There was no difference between groups in regards to patient-controlled analgesic dose or pain scores in the post-anesthesia care unit, at 12 or 48 h post-surgery. CONCLUSION: A single dose of dexamethasone given intraoperatively significantly decreased oral narcotic consumption and decreased pain scores 24 h postoperatively. Dexamethasone appears to be a safe modality to use to control pain in patients undergoing TKA.

Mycobacterium bovis infection of total hip arthroplasty after intravesicular bacille Calmette-Guérin therapy.

Bacille Calmette-Guérin (BCG) is a live, attenuated strain of Mycobacterium bovis. Intravesicular BCG therapy is the most effective treatment for superficial bladder cancer. The most common complication of this treatment is cystitis; there is a wide range of other complications. The English-language literature includes reports of 3 total hip arthroplasty infections and 1 total knee arthroplasty infection with M bovis after BCG therapy. These secondary infections may present either acutely during the therapy, months, or even years later. In this article, we report the case of a patient who presented with a painful right hip 6 years after successful total hip arthroplasty and 3 years after treatment for bladder cancer. Left total hip arthroplasty was performed 2 years after right hip arthroplasty. Surgeons examining a painful joint arthroplasty should be particularly suspicious of infection if the patient has a history of BCG therapy.

Do shoulder vibration signals vary among asymptomatic volunteers?

Numerous studies document vibrations emanating from joints during active or passive motion. It has been proposed these vibrations, termed vibroarthrographic signals, are associated with changes in the shape or quality of tissues in and around the joint. Vibroarthrographic signals in articular joints have been tested to correlate a particular signal with a particular feature of a joint such as a specific lesion. Because of the limited morphologic changes noted in dominant and nondominant articular joints, we hypothesized shoulder vibroarthrographic signals would be similar between subjects. We determined vibroarthrographic signals in young, adult, asymptomatic volunteers evaluated by 21 different active physician-assisted physical examination tests. Comparisons of data from both shoulders with a two-sample statistical test and a neural network demonstrated difficulty distinguishing the dominant and nondominant shoulder. Four percent of the comparisons were different, and the sensitivity of the neural network averaged 50% for most physical examination tests when classifying shoulder signals as dominant or non-dominant. Our findings suggest future studies investigating vibroarthrographic signals from symptomatic shoulders can be compared with asymptomatic shoulders from young patients with little regard to limb dominance for most physical examination tests.

Volume and surface area study of tobramycin-polymethylmethacrylate beads.

Polymethylmethacrylate bone cement beads impregnated with antibiotic are a common treatment for patients with persistent articular joint infections or osteomyelitis. They also are used as a prophylaxis for infection in patients with large soft tissue wounds. The current study was designed to evaluate the relationship between bead geometry and elution of the antibiotic tobramycin by methodically varying the shape of the beads for a given set of volumes. Beads of five shapes (spherical to ovoid) and two volumes were prepared and studied. Only 0.9% to 3.3% of the total amount of tobramycin present actually eluted from the beads in a 96-hour period and of this amount, approximately 1/3 eluted within the first 4 hours. The elution mass data indicate the benefit of numerous, small and elliptically shaped beads for maximal antibiotic availability. Additionally, a mathematical model is presented that describes these findings and can be used to predict tobramycin delivery rates from bone cement beads. This model assumes that the antibiotic is delivered through two mechanisms: fast dissolution of tobramycin initially adhering to the bead surface and slow release by diffusion through the polymer. The results generate diffusion coefficients for tobramycin in polymethylmethacrylate bone cement on the order of 2 x 10 cm/s.

An under-hand steering wheel grasp produces significant injury risk to the upper extremity during airbag deployment.

Recent laboratory investigations suggest that a deploying airbag may fracture the forearm. These studies positioned the arm in an overhand grasp placing the forearm over the airbag module. However, there is little published data on how drivers grip the steering wheel and the general proximity of the upper extremity to the airbag module. The objective of the current study was to identify 'real world' upper extremity positions and to correlate these with accident and experimental data. A survey of the National Automotive Sampling System (NASS) for the years 1995-99 revealed an increase in the number of forearm fractures due to driver-airbag interaction. As NASS does not provide the position of the forearm, common upper extremity positions were identified in a volunteer driving population. These positions were simulated using a specially instrumented 50(th) percentile male dummy to determine the relative injury risk for the different positions. Analysis showed that an under hand grasp of the wheel turned 90 degrees yielded the highest magnitude impact event. This single position was then simulated in 9 cadaver experiments. Dual stage airbag deployments produced forearm fractures in 2 arms. Experiments using the contralateral arms from the fractured subjects with a single stage airbag deployment produced no fractures. Analysis of forearm kinematics suggests that increasing forearm velocity and thus, acceleration exposure, is associated with forearm injury. Further, the data suggests that reductions in acceleration exposure via reduced airbag inflation decreased the apparent risk of forearm fracture.

Elongation behavior of calcaneofibular and cervical ligaments in a closed kinetic chain: pathomechanics of lateral hindfoot instability.

Numerous reconstructive procedures are performed to correct both ankle and subtalar instability after trauma although the precise pathology which results in this chronic instability and pain is not yet known. This study examined the role of the calcaneofibular (CLFL) and cervical ligaments (CRVL) during physiologic loading and demonstrated the effect of CLFL deficiency on the CRVL. Talar and subtalar tilt as well as inversion range of motion before and after CLFL sectioning were studied. Eleven osteoligamentous fresh frozen cadaver legs were used in which each foot was taken through six positions: neutral, 35 degrees plantarflexion, dorsiflexion, inversion, plantarflexion-inversion, and dorsiflexion-inversion. The CLFL and CRVL stretched the greatest in dorsiflexion-inversion. The most interesting finding was that the CRVL was elongated relative to neutral in all other test positions of the foot. However, the CLFL was shortened relative to neutral in plantarflexion and plantarflexion-inversion. In the CLFL deficient state, CRVL ratios demonstrated significant increases in length of the CRVL. Talar tilt increased on average more than 9 degrees with CLFL deficiency (p < 0.008) while subtalar tilt did not change significantly. The maximum tibiocalcaneal angle, recorded for dorsiflexion-inversion, increased more than 5 degrees after sectioning the CLFL (p < 0.05).