Adolescent Idiopathic Scoliosis Minimum Data Set: Towards Standardization of Data Elements in History and Physical Examination.

INTRODUCTION: Nonoperative care represents a cornerstone of adolescent idiopathic scoliosis (AIS) management, although no consensus exists for a minimal data set. We aimed to determine a consensus in critical data points to obtain during clinical AIS visits. METHODS: A REDCap-based survey was distributed to Pediatric Orthopedic Society of America (POSNA), Pediatric Spine Study Group (PSSG), and International Society on Scoliosis Orthopedic and Rehabilitation Treatment (SOSORT). Respondents ranked the importance of data points in history, physical examination, and bracing during AIS visits.  Results: One hundred eighty-one responses were received (26% response rate), of which 86% were physicians and 14% were allied health professionals. About 80% of respondents worked at pediatric hospitals or pediatric spaces within adult hospitals, and 82% were academic, with the majority (57%) seeing 150+ unique AIS patients annually. Most respondents recommended six-month follow-up for patients under observation (60%) and bracing (54%). Most respondents (75%) considered family history and pain important (69%), with the majority (69%) asking about pain at every visit. Across all time points, Adam's forward bend test, shoulder level, sagittal contour, trunk shift, and curve stiffness were all considered critically important (>60%). At the first visit, scapular prominence, leg lengths, motor and neurological examination, gait, and iliac crest height were also viewed as critical. At the preoperative visit, motor strength and scapular prominence should also be documented. About 39% of respondents use heat sensors to monitor bracing compliance, and average brace wear since the prior visit was considered the most important (85%) compliance data point. CONCLUSIONS: This study establishes recommendations for a 19-item minimum data set for clinical AIS evaluation, including history, physical exam, and bracing, to allow for future multicenter registry-based studies.

Single-cell coating with biomimetic extracellular nanofiber matrices.

Cell therapies offer great promise in the treatment of diseases and tissue regeneration, but their clinical use has many challenges including survival, optimal performance in their intended function, or localization at sites where they are needed for effective outcomes. We report here on a method to coat a biodegradable matrix of biomimetic nanofibers on single cells that could have specific functions ranging from cell signaling to targeting and helping cells survive when used for therapies. The fibers are composed of peptide amphiphile (PA) molecules that self-assemble into supramolecular nanoscale filaments. The PA nanofibers were able to create a mesh-like coating for a wide range of cell lineages with nearly 100 % efficiency, without interrupting the natural cellular phenotype or functions. The targeting abilities of this system were assessed in vitro using human primary regulatory T (hTreg) cells coated with PAs displaying a vascular cell adhesion protein 1 (VCAM-1) targeting motif. This approach provides a biocompatible method for single-cell coating that does not negatively alter cellular phenotype, binding capacity, or immunosuppressive functionality, with potential utility across a broad spectrum of cell therapies. STATEMENT OF SIGNIFICANCE: Cell therapies hold great promise in the treatment of diseases and tissue regeneration, but their clinical use has been limited by cell survival, targeting, and function. We report here a method to coat single cells with a biodegradable matrix of biomimetic nanofibers composed of peptide amphiphile (PA) molecules. The nanofibers were able to coat cells, such as human primary regulatory T cells, with nearly 100 % efficiency, without interrupting the natural cellular phenotype or functions. The approach provides a biocompatible method for single-cell coating that does not negatively alter cellular phenotype, binding capacity, or immunosuppressive functionality, with potential utility across a broad spectrum of cell therapies.

Should I stay or should I go: an assessment of criteria for safe day of surgery discharge of displaced supracondylar humerus fractures.

Immobilization type and in-hospital observation following surgical management of displaced supracondylar fractures are subject to surgeon preference and training. Our goal was to determine criteria for immediate discharge and optimal type of immobilization. Medical records of 661 patients with type III, IV or flexion-type displaced supracondylar humerus fractures treated at a level 1 pediatric trauma center from January 2013 to September 2019 were reviewed. Patients were separated into 'admission appropriate' (AA = 113) and 'discharge appropriate' (DA = 548) sub-cohorts. Neurovascular deficit at presentation (P < 0.001), post-operative physical exam deterioration (P < 0.001), age (P < 0.001) and post-operative immobilization modality (P = 0.02) were significantly different between AA and DA groups. When comparing patients who presented with neurologic deficit to those neurovascularly intact, there was a significant difference in whether circumferential immobilization was used post-operatively (P < 0.001), IV medication need (P < 0.001), discharge or admission (P < 0.001), neurologic decline (P < 0.001), return to ED (P = 0.008) and vascular compromise (P = 0.05). Twenty-four of the 56 (43%) patients who were AA and had no neurovascular finding on presentation had their immobilization adjusted (bivalved or loosened) to accommodate for swelling overnight. Only 1 was initially maintained in a splint or bivalved cast; the other 23 were initially maintained post-operatively in circumferential immobilization (P = 0.01). Our findings suggest that patients with intact neurovascular exams at presentation are candidates for early discharge, and splinting or bivalved casting may be preferable, especially in patients who are discharged.

Rotation and Asymmetry of the Axial Plane Pelvis in Cerebral Palsy: A CT-Based Study.

Spinopelvic malignment is commonly seen with non-ambulatory cerebral palsy (CP). Axial plane deformation is not well described in the literature. The purpose of this study was to describe and quantify the axial plane deformity in CP using CT scans and compare it to normal controls. We retrospectively collected data using CT scans of the abdomen and pelvis of 40 patients with GMFCS IV/V CP and neuromuscular scoliosis (CPP) and normal controls (NP) matched by age and sex. Pre-operative Cobb angle was recorded for the CP patients. Pelvic anatomy was evaluated at the supra-acetabular region of bone using two angles-iliac wing angle and sacral ala angle, measured for each hemipelvis. The larger of each hemipelvis angle was considered externally rotated while the smaller angle was considered internally rotated, termed as follows-iliac wing external (IWE) and internal (IWI); sacral ala external (SAE), and internal (SAI). Differences were noted using an independent t-test while correlations with Cobb angle were performed using Pearson's correlation. Iliac wing measurements showed the externally rotated hemipelvis showed a significantly greater magnitude compared with normal controls at 47.3 ± 18.1 degrees vs. 26.4 ± 3.7 degrees in NP (p < 0.001) while no internal rotation was observed (p > 0.05). Sacral ala measurements showed greater magnitude in both external and internal rotation. SAE was 119.5 ± 9.5 degrees in CPP vs. 111.2 ± 7.7 degrees in NP (p < 0.001) while SAI was 114.1 ± 8.5 degrees in CPP vs. 107.9 ± 7.5 degrees in NP (p = 0.001). In the CP cohort, the mean Cobb angle was 61.54 degrees (n = 37/40). Cobb angle correlated with the degree of external iliac wing rotation-IWE (r = 0.457, p = 0.004) and degree of absolute difference in the rotation of the iliac wing (r = 0.506, p = 0.001). The pelvis in a patient with CP scoliosis is asymmetrically oriented exhibiting a greater external rotation of one hemipelvis relative to normal controls. The severity of neuromuscular scoliosis is related to the pelvic axial rotation in CP patients. Axial plane deformity exists in the CP pelvis and this deformity warrants consideration when considering spinopelvic instrumentation strategies and outcomes of supra-pelvic and infra-pelvic pathologies.

Pediatric Floating Elbows What Is All the Fuss About? A Multicenter Perspective.

BACKGROUND: Classic orthopaedic teaching states a high risk of pediatric acute compartment syndrome (PACS) and other adverse outcomes to be associated with pediatric floating elbow injuries. However, more recent data suggest otherwise. This study aims to evaluate treatment approaches and outcomes of pediatric floating elbow injuries and accurately determine the rate of associated PACS. METHODS: A multicenter retrospective database was created to review patients below 18 years old who presented between 2014 and 2019 with floating elbow injuries. Patient demographics, injury characteristics, treatment course, and outcomes were evaluated. A severity classification (Children's Orthopaedic Trauma and Infection Consortium for Evidence-Based Studies) was established: class 1 injuries included Gartland 1 supracondylar fracture, class 2 included Gartland 2 supracondylar fracture, and class 3 included Gartland 3 or 4 supracondylar or t-condylar fracture. Subclasses A and B were based on displacement of the distal fracture. RESULTS: Four hundred fifty four patients were evaluated across 15 institutions. The cohort was 51% male and a median of 6.8 years old at injury. Thirteen patients (2.9%) presented without a palpable or dopplerable pulse, all having class 3 injuries. Ninety patients (20.0%) presented with nerve injuries, which were more common in class 3 injuries ( P <0.001). Only 14 (3.1%) had persistent nerve injuries at the final follow-up. Displacement largely dictated whether the distal injury was treated with fixation ( P <0.001) or immobilization only. Open reduction rate of the proximal fracture was 7.7% overall. There was 1 case (0.2%) of PACS involving displaced proximal and distal fractures. The median length of follow-up was 2.5 months. Modified Flynn outcomes at the last clinical visit were excellent/good in 315 patients (70%). More severe injuries had less good/excellent outcomes than less severe injuries ( P =0.030). CONCLUSIONS: This multicenter study of a large cohort of pediatric floating elbow injuries identified a low rate of PACS (0.2%). Closed treatment of the distal fracture was more frequently performed for nondisplaced fractures. Nerve and vascular injury rates were consistent with those of isolated component fractures and were associated with fracture displacement. The Children's Orthopaedic Trauma and Infection Consortium for Evidence-based Studies classification was an effective predictor of outcomes. LEVEL OF EVIDENCE: Level IV.

Salactin, a dynamically unstable actin homolog in Haloarchaea.

IMPORTANCE: Protein filaments play important roles in many biological processes. We discovered an actin homolog in halophilic archaea, which we call Salactin. Just like the filaments that segregate DNA in eukaryotes, Salactin grows out of the cell poles towards the middle, and then quickly depolymerizes, a behavior known as dynamic instability. Furthermore, we see that Salactin affects the distribution of DNA in daughter cells when cells are grown in low-phosphate media, suggesting Salactin filaments might be involved in segregating DNA when the cell has only a few copies of the chromosome.

CD4+CD25+FOXP3+ regulatory T cells: a potential "armor" to shield "transplanted allografts" in the war against ischemia reperfusion injury.

Despite the advances in therapeutic interventions, solid organ transplantation (SOT) remains the "gold standard" treatment for patients with end-stage organ failure. Recently, vascularized composite allotransplantation (VCA) has reemerged as a feasible treatment option for patients with complex composite tissue defects. In both SOT and VCA, ischemia reperfusion injury (IRI) is inevitable and is a predominant factor that can adversely affect transplant outcome by potentiating early graft dysfunction and/or graft rejection. Restoration of oxygenated blood supply to an organ which was previously hypoxic or ischemic for a period of time triggers cellular oxidative stress, production of both, pro-inflammatory cytokines and chemokines, infiltration of innate immune cells and amplifies adaptive alloimmune responses in the affected allograft. Currently, Food and Drug Administration (FDA) approved drugs for the treatment of IRI are unavailable, therefore an efficacious therapeutic modality to prevent, reduce and/or alleviate allograft damages caused by IRI induced inflammation is warranted to achieve the best-possible transplant outcome among recipients. The tolerogenic capacity of CD4+CD25+FOXP3+ regulatory T cells (Tregs), have been extensively studied in the context of transplant rejection, autoimmunity, and cancer. It was not until recently that Tregs have been recognized as a potential cell therapeutic candidate to be exploited for the prevention and/or treatment of IRI, owing to their immunomodulatory potential. Tregs can mitigate cellular oxidative stress, produce anti-inflammatory cytokines, promote wound healing, and tissue repair and prevent the infiltration of pro-inflammatory immune cells in injured tissues. By using strategic approaches to increase the number of Tregs and to promote targeted delivery, the outcome of SOT and VCA can be improved. This review focuses on two sections: (a) the therapeutic potential of Tregs in preventing and mitigating IRI in the context of SOT and VCA and (b) novel strategies on how Tregs could be utilized for the prevention and/or treatment of IRI.

Modulating microbiome-immune axis in the deployment-related chronic diseases of Veterans: report of an expert meeting.

The present report summarizes the United States Department of Veterans Affairs (VA) field-based meeting titled "Modulating microbiome-immune axis in the deployment-related chronic diseases of Veterans." Our Veteran patient population experiences a high incidence of service-related chronic physical and mental health problems, such as infection, irritable bowel syndrome (IBS), inflammatory bowel disease (IBD), various forms of hematological and non-hematological malignancies, neurologic conditions, end-stage organ failure, requiring transplantation, and posttraumatic stress disorder (PTSD). We report the views of a group of scientists who focus on the current state of scientific knowledge elucidating the mechanisms underlying the aforementioned disorders, novel therapeutic targets, and development of new approaches for clinical intervention. In conclusion, we dovetailed on four research areas of interest: 1) microbiome interaction with immune cells after hematopoietic cell and/or solid organ transplantation, graft-versus-host disease (GVHD) and graft rejection, 2) intestinal inflammation and its modification in IBD and cancer, 3) microbiome-neuron-immunity interplay in mental and physical health, and 4) microbiome-micronutrient-immune interactions during homeostasis and infectious diseases. At this VA field-based meeting, we proposed to explore a multi-disciplinary, multi-institutional, collaborative strategy to initiate a roadmap, specifically focusing on host microbiome-immune interactions among those with service-related chronic diseases to potentially identify novel and translatable therapeutic targets.

Clubfoot and the Ponseti Method: A Bibliometric Analysis.

Background: The aim of the present study was to perform a bibliometric analysis of research articles published on clubfoot to provide a quantitative description of the literature and to gather information on the institutions, journals, researchers, and countries publishing on this topic. Methods: This bibliometric analysis consisted of 2 Web of Science searches. The first identified all articles published prior to April 25, 2022, with "clubfoot" in the title, abstract, or keywords, and the second identified all articles with "Ponseti." Studies were exported in BibTeX format and uploaded into Biblioshiny software in RStudio. Descriptive statistics are reported for variables related to the article, author, and country in which the research was conducted. Results: A total of 2,177 articles identified using the term "clubfoot" were included. The first article was published in 1902, and there was a 3% annual growth rate. A total of 762 articles identified using the term "Ponseti" were included, with the first published in 1992 and a 13.9% annual growth rate. The Journal of Pediatric Orthopaedics accounted for almost one-quarter of all published reports. Conclusions: The literature on clubfoot has expanded in the past decades, and the percentage of studies concerning the Ponseti method has increased dramatically in the years following adoption in the U.S. and, more recently, globally. While a number of studies involved collaboration between authors in high-income and low- and middle-income countries, further collaboration will be essential to evaluate outcomes and help improve service delivery as adoption of this method increases globally. Clinical Relevance: This paper explores how the orthopaedic and scientific communities have increasingly contributed to literature on Ponseti casting and clubfoot, and discusses how contributions to the literature are becoming increasingly widespread.

Beyond UPR: cell-specific roles of ER stress sensor IRE1α in kidney ischemic injury and transplant rejection.

Kidney damage due to ischemia or rejection results in the accumulation of unfolded and misfolded proteins in the endoplasmic reticulum (ER) lumen, a condition known as "ER stress." Inositol-requiring enzyme 1α (IRE1α), the first ER stress sensor found, is a type I transmembrane protein with kinase and endoribonuclease activity. On activation, IRE1α nonconventionally splices an intron from unspliced X-box-binding protein 1 (XBP1) mRNA to produce XBP1s mRNA that encodes the transcription factor, XBP1s, for the expression of genes encoding proteins that mediate the unfolded protein response. The unfolded protein response promotes the functional fidelity of ER and is required for secretory cells to sustain protein folding and secretory capability. Prolonged ER stress can lead to apoptosis, which may result in detrimental repercussions to organ health and has been implicated in the pathogenesis and progression of kidney diseases. The IRE1α-XBP1 signaling acts as a major arm of unfolded protein response and is involved in regulating autophagy, cell differentiation, and cell death. IRE1α also interacts with activator protein-1 and nuclear factor-κB pathways to regulate inflammatory responses. Studies using transgenic mouse models highlight that the roles of IRE1α differ depending on cell type and disease setting. This review covers these cell-specific roles of IRE1α signaling and the potential for therapeutic targeting of this pathway in the context of ischemia and rejection affecting the kidneys.

First-in-human, phase 1 study of PF-06753512, a vaccine-based immunotherapy regimen (VBIR), in non-metastatic hormone-sensitive biochemical recurrence and metastatic castration-resistant prostate cancer (mCRPC).

BACKGROUND: This phase 1 study evaluated PF-06753512, a vaccine-based immunotherapy regimen (PrCa VBIR), in two clinical states of prostate cancer (PC), metastatic castration-resistant PC (mCRPC) and biochemical recurrence (BCR). METHODS: For dose escalation, patients with mCRPC received intramuscular PrCa VBIR (adenovirus vector and plasmid DNA expressing prostate-specific membrane antigen (PSMA), prostate-specific antigen (PSA), and prostate stem cell antigen (PSCA)) with or without immune checkpoint inhibitors (ICIs, tremelimumab 40 or 80 mg with or without sasanlimab 130 or 300 mg, both subcutaneous). For dose expansion, patients with mCRPC received recommended phase 2 dose (RP2D) of PrCa VBIR plus tremelimumab 80 mg and sasanlimab 300 mg; patients with BCR received PrCa VBIR plus tremelimumab 80 mg (Cohort 1B-BCR) or tremelimumab 80 mg plus sasanlimab 130 mg (Cohort 5B-BCR) without androgen deprivation therapy (ADT). The primary endpoint was safety. RESULTS: Ninety-one patients were treated in dose escalation (mCRPC=38) and expansion (BCR=35, mCRPC=18). Overall, treatment-related and immune-related adverse events occurred in 64 (70.3%) and 39 (42.9%) patients, with fatigue (40.7%), influenza-like illness (30.8%), diarrhea (23.1%), and immune-related thyroid dysfunction (19.8%) and rash (15.4%), as the most common. In patients with mCRPC, the objective response rate (ORR, 95% CI) was 5.6% (1.2% to 15.4%) and the median radiographic progression-free survival (rPFS) was 5.6 (3.5 to not estimable) months for all; the ORR was 16.7% (3.6% to 41.4%) and 6-month rPFS rate was 45.5% (24.9% to 64.1%) for those who received RP2D with measurable disease (n=18). 7.4% of patients with mCRPC achieved a ≥50% decline in baseline PSA (PSA-50), with a median duration of 4.6 (1.2-45.2) months. In patients with BCR, 9 (25.7%) achieved PSA-50; the median duration of PSA response was 3.9 (1.9-4.2) and 10.1 (6.9-28.8) months for Cohorts 5B-BCR and 1B-BCR. Overall, antigen specific T-cell response was 88.0% to PSMA, 84.0% to PSA, and 80.0% to PSCA. CONCLUSIONS: PrCa VBIR overall demonstrated safety signals similar to other ICI combination trials; significant side effects were seen in some patients with BCR. It stimulated antigen-specific immunity across all cohorts and resulted in modest antitumor activity in patients with BCR without using ADT. TRIAL REGISTRATION NUMBER: NCT02616185.

Current trends in surgical magnitude of neuromuscular scoliosis curves: a study of 489 operative patients with non-ambulatory cerebral palsy.

PURPOSE: A curve magnitude at which posterior spinal fusion (PSF) is indicated for children with cerebral palsy (CP) scoliosis is not defined. We sought to evaluate whether agreement exists for a curve magnitude at which PSF is undertaken for CP scoliosis and to evaluate outcomes by quartile of curve magnitude and flexibility at time of fusion. METHODS: A prospective multicenter pediatric spine database was queried for patients with a Gross Motor Function Classification Scale (GMFCS) IV or V who underwent PSF for CP scoliosis. Demographics, surgical indications, and correlations between curve magnitude, postoperative radiographic outcomes, and Caregiver's Priorities and Child Health Index of Life and Disabilities (CPCHILD) scores were evaluated for patients with at least 2 years of follow-up. RESULTS: 489 patients from 15 sites were analyzed. Median major Cobb angle at time of PSF was 87° and significantly varied by site (p < 0.001). Median Cobb angle on flexibility studies was 55° and median percent correction on flexibility studies was 36.3%. Severity of the curve at surgery correlated significantly with lower overall quality of life and CPCHILD score (p < 0.05). Larger residual curves correlated with larger operative curves (p < 0.001) and decreased flexibility on preoperative flexibility studies (p < 0.001), although postoperative CPCHILD scores did not differ by curve size or flexibility at time of fusion or by size of residual curve (p > 0.05). CONCLUSION: The median curve magnitude is large and there is substantial variability in curve size of CP scoliosis at time of fusion, although clinical outcomes are not negatively influenced by larger operative magnitudes. Further study should aim to narrow surgical indications by defining unacceptable radiographic outcomes. LEVEL OF EVIDENCE: Level III.

Different Undercut Depths Influence on Fatigue Behavior and Retentive Force of Removable Partial Denture Clasp Materials: A Systematic Review.

PURPOSE: To perform a systematic review that provides an overview of the current literature on fatigue behavior of removable partial denture (RPD) clasp materials based on different retentive areas. MATERIALS AND METHODS: The review followed the Preferred Reporting Items for Systematic Review and Meta-Analyses (PRISMA) guidelines. Electronic searches were done via PubMed, Scopus, and OVID for studies reporting on RPD clasps and the fatigue failure of clasp materials. Inclusion criteria were English language with full text and in vitro studies only. Exclusion criteria were studies that did not assess the fatigue of RPD clasp materials. A quality assessment and selection of full-text articles were performed according to Consolidated Standards of Reporting Trials criteria. RESULTS: A total of 182 articles were initially identified and screened. After applying inclusion and exclusion criteria, 15 articles were selected for the final analysis. Seven of the included studies utilized a vertical insertion/removal testing approach. Ten studies used the constant deflection test. Three studies used untapered specimens, and 12 studies used tapered specimens. Ten studies performed post-test analysis. CONCLUSIONS: Cobalt-chromium (CoCr) is the strongest material in terms of fatigue in relation to the undercut depth and the modern, digitally manufactured RPD clasp materials also exhibit comparable fatigue behavior. Recent RPD clasp materials such as polyetheretherketone (PEEK) or laser sintered CoCr, however, require further study in terms of their fatigue behavior. In order to improve the quality of future studies, a standardized and calibrated fatigue testing method is needed with standardized specimen size and shape, which will reduce the risk of bias and enable meta-analysis for bulk comparison between studies.

Fatigue behavior of removable partial denture cast and laser-sintered cobalt-chromium (CoCr) and polyetheretherketone (PEEK) clasp materials.

OBJECTIVE: To investigate the fatigue behavior of cast and laser-sintered cobalt-chromium (CoCr) and polyetheretherketone (PEEK) material for a removable partial denture (RPD) clasps. METHODS: Dumbbell-shaped specimens were digitally designed with the center part of the dumbbell being a half-round shape at the cross-sectional dimension of 1.25 mm to simulate a typical clasp design and dimensions. A fatigue machine with an offset axis rotation system simulated a typical undercut depth of 0.25, 0.50, and 0.75 mm. Each group was subjected to 30,000 fatigue cycles (simulating 21 years) or till specimen failure. Before testing, the stress value at each undercut depth for each specimen was established in a universal testing machine and SN curves were plotted for each group. Data were statistically analyzed using Kruskal-Wallis and post hoc tests. The fractured surfaces were analyzed using SEM. RESULTS: The average fatigue cycles with 0.25, 0.50, and 0.75 mm undercuts were 27,155 ± 6277, 9298 ± 4033, 5642 ± 8785 for cast CoCr and 26,765 ± 6150, 11,318 ± 7931, 2861 ± 4803, for laser-sintered CoCr, respectively. Apart from three specimens, the PEEK groups did not fail during the simulation period. Clasps with 0.25 mm deflection showed significantly higher fatigue resistance than other groups (p < .001). There was no significant difference in fatigue behavior between the cast and laser-sintered CoCr. Microporosities at the fractured site along with irregular crack propagation were observed for cast and laser-sintered CoCr specimens. Fatigue-induced broken polymer crosslinking chains were observed in PEEK specimens. CONCLUSION: PEEK material exhibited the highest fatigue resistance and significantly lower deflection resistance. Cast and laser-sintered CoCr showed similar fatigue resistance and behavior.

Universal catastrophe time distributions of dynamically unstable polymers.

Dynamic instability-the growth, catastrophe, and shrinkage of quasi-one-dimensional filaments-has been observed in multiple biopolymers. Scientists have long understood the catastrophic cessation of growth and subsequent depolymerization as arising from the interplay of hydrolysis and polymerization at the tip of the polymer. Here we show that for a broad class of catastrophe models, the expected catastrophe time distribution is exponential. We show that the distribution shape is insensitive to noise, but that depletion of monomers from a finite pool can dramatically change the distribution shape by reducing the polymerization rate. We derive a form for this finite-pool catastrophe time distribution and show that finite-pool effects can be important even when the depletion of monomers does not greatly alter the polymerization rate.

A transient, closed-loop network of wireless, body-integrated devices for autonomous electrotherapy.

Temporary postoperative cardiac pacing requires devices with percutaneous leads and external wired power and control systems. This hardware introduces risks for infection, limitations on patient mobility, and requirements for surgical extraction procedures. Bioresorbable pacemakers mitigate some of these disadvantages, but they demand pairing with external, wired systems and secondary mechanisms for control. We present a transient closed-loop system that combines a time-synchronized, wireless network of skin-integrated devices with an advanced bioresorbable pacemaker to control cardiac rhythms, track cardiopulmonary status, provide multihaptic feedback, and enable transient operation with minimal patient burden. The result provides a range of autonomous, rate-adaptive cardiac pacing capabilities, as demonstrated in rat, canine, and human heart studies. This work establishes an engineering framework for closed-loop temporary electrotherapy using wirelessly linked, body-integrated bioelectronic devices.

Pre-transplant infusion of donor leukocytes treated with extracorporeal photochemotherapy induces immune hypo-responsiveness and long-term allograft survival in murine models.

Recipients of solid organ transplantation (SOT) rely on life-long immunosuppression (IS), which is associated with significant side effects. Extracorporeal photochemotherapy (ECP) is a safe, existing cellular therapy used to treat transplant rejection by modulating the recipient's own blood cells. We sought to induce donor-specific hypo-responsiveness of SOT recipients by infusing ECP-treated donor leukocytes prior to transplant. To this end, we utilized major histocompatibility complex mismatched rodent models of allogeneic cardiac, liver, and kidney transplantation to test this novel strategy. Leukocytes isolated from donor-matched spleens for ECP treatment (ECP-DL) were infused into transplant recipients seven days prior to SOT. Pre-transplant infusion of ECP-DL without additional IS was associated with prolonged graft survival in all models. This innovative approach promoted the production of tolerogenic dendritic cells and regulatory T-cells with subsequent inhibition of T-cell priming and differentiation, along with a significant reduction of donor-specific T-cells in the spleen and grafts of treated animals. This new application of donor-type ECP-treated leukocytes provides insight into the mechanisms behind ECP-induced immunoregulation and holds significant promise in the prevention of graft rejection and reduction in need of global immune suppressive therapy in patients following SOT.

"TRASH" Transolecranon Fracture-Dislocation with Occult Osteochondral Coronoid Fracture: A Case Report.

CASE: A 7-year-old girl sustained a radiographic appearance seemed harmless (TRASH) elbow lesion after falling from play equipment. Initial radiographs demonstrated a transolecranon fracture-dislocation. Additional injury was suspected, given valgus instability after reduction. Subsequent magnetic resonance imaging (MRI) revealed a large osteochondral coronoid fragment only partially visible on initial radiographs and computed tomography (CT). Successful outcomes were achieved by ulnar nerve decompression, open reduction, and fixation. CONCLUSION: TRASH lesions, including this osteochondral coronoid injury, may be overlooked in younger children because of an abundance of unossified cartilage. A high index of suspicion and early MRI can lead to successful diagnosis and treatment.

Model-Based Characterization of the Bidirectional Interaction Between Pharmacokinetics and Tumor Growth Dynamics in Patients with Metastatic Merkel Cell Carcinoma Treated with Avelumab.

PURPOSE: Empirical time-varying clearance models have been reported for several immune checkpoint inhibitors, including avelumab (anti-programmed death ligand 1). To investigate the exposure-response relationship for avelumab, we explored semimechanistic pharmacokinetic (PK)-tumor growth dynamics (TGD) models. PATIENTS AND METHODS: Plasma PK data were pooled from three phase I and II trials (JAVELIN Merkel 200, JAVELIN Solid Tumor, and JAVELIN Solid Tumor JPN); tumor size (TS) data were collected from patients with metastatic Merkel cell carcinoma (mMCC) enrolled in JAVELIN Merkel 200. A PK model was developed first, followed by TGD modeling to investigate interactions between avelumab exposure and TGD. A PK-TGD feedback loop was evaluated with simultaneous fitting of the PK and TGD models. RESULTS: In total, 1,835 PK observations and 338 TS observations were collected from 147 patients. In the final PK-TGD model, which included the bidirectional relationship between PK and TGD, avelumab PK was described by a two-compartment model with a positive association between clearance and longitudinal TS, with no additional empirical time-varying clearance identified. TGD was described by first-order tumor growth/shrinkage rates, with the tumor shrinkage rate decreasing exponentially over time; the exponential time-decay constant decreased with increasing drug concentration, representing the treatment effect through tumor shrinkage inhibition. CONCLUSIONS: We developed a TGD model that mechanistically captures the prevention of loss of antitumor immunity (i.e., T-cell suppression in the tumor microenvironment) by avelumab, and a bidirectional interaction between PK and TGD in patients with mMCC treated with avelumab, thus mechanistically describing previously reported time variance of avelumab elimination.