Galunisertib Exerts Antifibrotic Effects on TGF-ß-Induced Fibroproliferative Dermal Fibroblasts.

Dermal fibroblasts in pathological scars secrete constitutively elevated levels of TGF-ß, signaling the transcription of fibrotic genes via activin-like kinase 5 (ALK5). In the present study, we examine the antifibrotic effects of galunisertib, a small-molecule inhibitor of ALK5, on fibroproliferative dermal fibroblasts in an in vitro model of wound healing. We induced fibrosis in human dermal fibroblasts with exogenous TGF-ß and performed cellular proliferation assays after treatment with varying concentrations of galunisertib. Dermal fibroblast proliferation was diminished to homeostatic levels without cytotoxicity at concentrations as high as 10 µM. An in vitro scratch assay revealed that galunisertib significantly enhanced cellular migration and in vitro wound closure beginning 24 h post-injury. A gene expression analysis demonstrated a significant attenuation of fibrotic gene expression, including collagen-1a, alpha-smooth muscle actin, fibronectin, and connective tissue growth factor, with increased expression of the antifibrotic genes MMP1 and decorin. Protein synthesis assays confirmed drug activity and corroborated the transcription findings. In summary, galunisertib simultaneously exerts antifibrotic effects on dermal fibroblasts while enhancing rates of in vitro wound closure. Galunisertib has already completed phase II clinical trials for cancer therapy with minimal adverse effects and is a promising candidate for the treatment and prevention of pathological cutaneous scars.

Risk of peritoneal dialysis catheter-associated peritonitis following kidney transplant.

OBJECTIVE: Peritoneal dialysis (PD) patients have equivalent or slightly better kidney transplant outcomes when compared to hemodialysis (HD) patients. However, given the risk for postoperative infection, we sought to determine the risk factors for PD catheter-associated infections for patients who do not have the PD catheter removed at the time of engraftment. METHODS: Demographic and outcomes data were collected from 313 sequential PD patients who underwent kidney transplant from 2000 to 2015. Risk factors for postoperative peritonitis were analyzed using logistical regression. RESULTS: Of 329 patients with PD catheters at transplant, 16 PD catheters were removed at engraftment. Of the remaining 313 patients, 8.9% suffered post-transplant peritonitis. On univariate analysis, patients with peritonitis were significantly more likely to have used the PD catheter or HD within 6 weeks after transplant. Multivariate analysis had similar findings, with increased risk for those using the PD catheter after transplant, with a trend for those who underwent HD only within 6 weeks of transplant. CONCLUSION: These results suggest that delayed graft function requiring any type of dialysis is associated with increased post-transplant peritonitis risk.

Uterine Angioleiomyoma: Clinical and Histopathologic Differentiation of an Underrecognized Mimicker of Uterine Leiomyoma.

Angioleiomyoma is an uncommon benign neoplasm of mesenchymal origin that arises from perivascular smooth muscle cells. This soft tissue neoplasm usually occurs in the dermal or subcutaneous tissues of the extremities, head and neck, or trunk with fewer than 40 reported angioleiomyomas arising in the uterine corpus. Herein we report a uterine angioleiomyoma in a 44-year-old G5P4 Hispanic woman with a longstanding history of recurrent abdominal pain, pelvic organ prolapse, abnormal uterine bleeding, anemia, and hypertension. The patient underwent surgical treatment with total laparoscopic hysterectomy with bilateral salpingectomy and a uterosacral ligament suspension. Uterine angioleiomyoma was diagnosed post-operatively based on gross and microscopic features. The location of the uterine angioleiomyoma within the myometrium corresponded with contrast enhancement apparent on preoperative imaging. This and other uterine angioleiomyomas have characteristic imaging, macroscopic, and microscopic features which distinguish it from leiomyoma. Enhancing awareness of this underrecognized entity will facilitate precise diagnosis and thereby enable improved understanding of the clinicopathological characteristics of uterine angioleiomyoma.

A challenging case of eosinophilic myocarditis leading to heart failure and transplantation.

The large spectrum of etiologies, severities, and histologic appearances of eosinophilic myocarditis (EoM) poses challenges to its diagnosis and management. Endomyocardial biopsy is the current gold standard for diagnosis. However, cardiovascular magnetic resonance imaging is becoming more frequently used to diagnose acute myocarditis because of enhanced sensitivity when compared to histopathologic examination, and its less invasive nature. We report a complicated case of EoM in a male in his mid-thirties that led to fulminant cardiogenic shock that required immunosuppressive therapy on day 5 of admission and implantation of a left ventricular assist device (LVAD) on day 30. EoM was diagnosed on histopathologic examination of the resected fragment of the left ventricular myocardium. Nine months after the initial presentation, the patient ultimately required heart transplantation. The explanted heart showed minimal residual interstitial inflammation with evidence of mildly active intimal arteritis and patchy areas of interstitial fibrosis. In this report, we describe our patient's clinical features and correlate them with imaging and histopathologic findings to illustrate the difficulty in diagnosing EoM, particularly in this complicated patient that ultimately required heart transplantation. The diagnosis can be challenging due to the variable histopathologic features, clinical presentation, and utilization of therapeutic medications and devices.

Patterns of antibiotic administration in patients with burn injuries: A TriNetX study.

BACKGROUND: In the advent of increasing antibiotic resistance, several studies sought to determine antibiotic prescription trends; however, no pattern has been firmly identified particularly for the burned population. We performed a query of burned patients in a large established database to understand differences in antibiotic use related to patient-specific factors. METHODS: Burned patients with systemic antibiotics given within 7 days of injury were identified on the TriNetX database. The patient population was stratified by age, 1-year time intervals of antibiotic prescription from 2004 to 2019, time of antibiotic prescription in 1-day intervals after injury, and % TBSA burned in 10% intervals ranging from < 10% to > 90%. Data were analyzed using χ2 with p < 0.05 considered significant. Pearson coefficients (r2) values were used to correlate differences in antibiotic prescription between age groups and to changes over time. RESULTS: Stratification by age revealed higher use of antibiotics in older burned patients compared to younger patients. Surprisingly, 87.6% of burn patients of those who received antibiotic therapy was on the day of injury. Penicillins and beta-lactam antimicrobials were used most often at a frequency of 64%. No statistically significant differences in rates of antibiotic therapy were observed in burned patients when stratified by %TBSA burned. CONCLUSIONS: The study elucidates current patterns of antibiotic use in burn care in the United States, allowing for improved understanding of both past and present patterns of antibiotic prescription.

Liver Metastasis of Thymoma: Case Report and Review of the Literature.

The 2021 "World Health Organization (WHO) Classification of Thoracic Tumours" classifies epithelial tumors of the thymus (thymomas) based on cytomorphology. Thymomas with benign cytomorphology are classified as type A, AB, B1, B2, and B3, while those with malignant cytomorphology are classified as thymic carcinoma. Although all thymomas have malignant potential, extra-thoracic metastasis of thymomas is exceedingly rare and the exact incidence is not known. Literature review demonstrated 39 cases of thymoma with extra-thoracic metastases reported since the publication of the 1999 WHO Classification of Thoracic Tumours. Nine of these cases presented with metastasis to the liver in the setting of concurrent metastasis to other organs, while only three cases metastasized solely to the liver. We herein report a well-documented case of type B1 thymoma with relatively limited stage (IIb) with an isolated, single liver metastasis occurring seven years after primary resection in a patient with concomitant myasthenia gravis. The following report includes a review of the literature, a discussion of thymoma classification and its relevance to prognosis, and an overview of other extra-thoracic metastatic thymoma cases.

A Fatal Fungal Infection: Cryptococcus gattii (VGI) Meningitis in Texas.

Cryptococcus gattii is an underrecognized cause of meningitis, especially in nonendemic regions. This report details C gattii disease progression from admission to autopsy in an otherwise healthy 40-year-old male in Texas. It brings awareness to an often unsuspected organism that can cause severe infection requiring early recognition and treatment in immunocompetent individuals.

Detection of Infection and Sepsis in Burns.

Background: Infection is the most frequent complication after severe burns and has a propensity to progress into sepsis then septic shock and multiple organ dysfunction syndrome (MODS). Improving outcomes in acute burn care depends on early detection of infection to allow prompt interventions. Diagnosis of sepsis in severe burns is uniquely challenging because otherwise-typical clinical signs are masked by the hypermetabolic state and systemic inflammation induced by the burn itself. For this reason, burns have historically been excluded from high-impact studies on the diagnosis and treatment of sepsis. Methods: This article provides a comprehensive three-fold review of current findings and guidelines pertinent to the early detection of infection and sepsis in severe burns. Results: First, evidence-based detection of the most common infections encountered in the burn intensive care unit is reviewed. Second, we analyze the evolution of the diagnostic criteria for sepsis and the evidence regarding their utility in severe burns. Last, we examine the development of biomarkers, from procalcitonin to molecular genomics, for the detection of sepsis. Conclusions: Although gold standard methods of early detection of sepsis in burn patients have yet to be identified, improved understanding and appropriate application of the available diagnostic criteria and assays are paramount to providing effective care of patients with severe burns.

Nonsurvival Distributions in Pediatric Burn Patients: A Comparative Study of Two National Databases.

A contemporary, age-specific model for the distribution of burn mortality in children has not been developed for over a decade. Using data from TriNetX, a global federated health research network, and the American Burn Association's Nation Burn Repository (NBR), we investigated nonsurvival distributions for pediatric burns in the United States. Pediatric burn patients aged 0 to 20 between 2010 and 2020 were identified in TriNetX from 41 Healthcare Organizations using ICD-10 codes (T.20-T.30) and identified as lived/died. These were compared to the nonsurvival data from 90 certified burn centers in the NBR database between 2016 and 2018. The patient population was stratified by age into subgroups of 0 to 4, 5 to 9, 10 to 14, and 15 to 20 years. Overall, mortality rates for pediatric burn patients were found to be 0.62% in NBR and 0.52% in TrinetX. Boys had a higher incidence of mortality than girls in both databases (0.34% vs 0.28% NBR, P = .13; 0.31% vs 0.21% TriNetX, P < .001). Comparison of ethnic cohorts between 2010 to 2015 and 2016 to 2020 subgroups showed that nonsurvival rates of African American children increased relative to white children (TriNetX, P < .001); however, evidence was insufficient to conclude that African American children die more frequently than other ethnicities (NBR, P = .054). When analyzing subgroups in TriNetX, burned children aged 5 to 9 had significantly increased frequency of nonsurvival (P < .001). However, NBR data suggested that children aged 0 to 4 experience the highest frequency of mortality (P < .001). The nonsurvival distributions between these two large databases accurately reflect nonsurvival rates in burned children.

Vascularized Composite Allotransplantation in Burn Reconstruction: Systematic Review and Meta-analysis.

Vascularized composite allotransplantation has been successfully employed for burn reconstruction since 2003. However, its safety in this population has been questioned due to high levels of alloimmunization from burn care-related tissue exposures. To investigate this, a systematic review of vascularized composite allotransplantation employed for burn reconstruction was conducted, evaluating literature from January 2000 to September 2019. Articles containing vascularized composite allotransplantation, composite tissue allotransplantation, and burn reconstructive surgery were included; articles without published outcomes were excluded. Observational meta-analysis of pooled mortality and acute rejection episodes relative to allograft type (face vs extremity) and reconstruction type (burn vs non-burn) was performed. Twenty-four of the 63 identified articles met the criteria for inclusion, with 5 more articles added after secondary review. To date, 152 allotransplantations have been performed in 117 patients: 45 face transplants and 107 extremity transplants. Of these, 34 (22%) were performed for burn reconstruction in 25 patients (21%) with an overall higher 1-year mortality rate (12.0% vs 1.1%, P = .030). Of these deaths, 75% received three or more simultaneous allografts. Additionally, more episodes of acute rejection occurred compared to non-burn patients (4.4 vs 2.4, P = .035). Vascularized composite allotransplantation performed for burn reconstruction was found to be associated with a greater risk of 1-year mortality and nearly twice the number of episodes of acute rejection. Future studies should seek to identify unique risk factors of burn patients undergoing this operation and evaluate the relationship between antigenic burden and surgical outcomes.

Stiffness Matters: Part I-The Effects of Plate Stiffness on the Biomechanics of ACDF In Vitro.

STUDY DESIGN: In vitro biomechanical testing of human cadaveric cervical and goat cervical motion segments. OBJECTIVE: The aim of this study was to measure the effects of plate stiffness on load-sharing, instantaneous axis of rotation (IAR), and posterior element loading after anterior cervical discectomy and fusion (ACDF). SUMMARY OF BACKGROUND DATA: ACDF is intended to create an environment, which facilitates sufficient stability and biomechanical conditions to promote bone formation. The relationship between cervical plate stiffness, load-sharing, and the IAR is complex. The ideal cervical plate is sufficiently stiff to limit interbody motion but is compliant enough to facilitate load-sharing rather than stress-shielding. METHODS: Anterior cervical plates of distinct bending stiffnesses were applied to human and goat cervical motion segments following ACDF. A validated custom force-sensing interbody implant was placed in the disc space to measure load-sharing in the spine. Interbody loads, posterior element strain, and the IAR were measured during flexion/extension for each plate. RESULTS: Load-sharing in the interbody space, posterior element strain, and the location of the IAR were all significantly affected by plate stiffness. More compliant plates resulted in more load sharing, less posterior element strain, and a more dorsally located IAR relative to stiffer plates. CONCLUSION: A more compliant plate fosters more consistent load-sharing through the entire range of flexion/extension, which may promote faster bone formation and better fusion. A more compliant plate causes less posterior element strain, which may reduce facet joint loads and in turn reduce facet joint arthrosis. An ideal plate may be one that is stiff enough to minimize interbody motion and yet compliant enough to allow consistent load-sharing and minimal increase in posterior element strain. LEVEL OF EVIDENCE: N/A.

Stiffness Matters: Part II-The Effects of Plate Stiffness on Load-Sharing and the Progression of Fusion Following Anterior Cervical Discectomy and Fusion In Vivo.

STUDY DESIGN: Real time in vivo measurement of forces in the cervical spine of goats following anterior cervical discectomy and fusion (ACDF). OBJECTIVE: To measure interbody forces in the cervical spine during the time course of fusion following ACDF with plates of different stiffnesses. SUMMARY OF BACKGROUND DATA: Following ACDF, the biomechanics of the arthrodesis is largely dictated by the plate. The properties of the plate prescribe the extent of load-sharing through the disc space versus the extent of stress-shielding. Load-sharing promotes interbody bone formation and stress-shielding can inhibit maturation of bone. However, these principles have never been validated in vivo. Measuring in vivo biomechanics of the cervical spine is critical to understanding the complex relationships between implant design, interbody loading, load-sharing, and the progression of fusion. METHODS: Anterior cervical plates of distinct bending stiffnesses were placed surgically following ACDF in goats. A validated custom force-sensing interbody implant was placed in the disc space to measure load-sharing in the spine. Interbody loads were measured in vivo in real time during the course of fusion for each plate. RESULTS: Interbody forces during flexion/extension were highly dynamic. In animals that received high stiffness plates, maximum forces were in extension whereas in animals that received lower stiffness plates, maximum forces were in flexion. As fusion progressed, interbody load magnitude decreased. CONCLUSION: The magnitude of interbody forces in the cervical spine is dynamic and correlates to activity and posture of the head and neck. The magnitude and consistency of forces in the interbody space correlates to plate stiffness with more compliant plates resulting in more consistent load-sharing. The magnitude of interbody forces decreases as fusion matures suggesting that smart interbody implants may be used as a diagnostic tool to indicate the progression of interbody fusion. LEVEL OF EVIDENCE: N/A.

Graph theoretical model of a sensorimotor connectome in zebrafish.

Mapping the detailed connectivity patterns (connectomes) of neural circuits is a central goal of neuroscience. The best quantitative approach to analyzing connectome data is still unclear but graph theory has been used with success. We present a graph theoretical model of the posterior lateral line sensorimotor pathway in zebrafish. The model includes 2,616 neurons and 167,114 synaptic connections. Model neurons represent known cell types in zebrafish larvae, and connections were set stochastically following rules based on biological literature. Thus, our model is a uniquely detailed computational representation of a vertebrate connectome. The connectome has low overall connection density, with 2.45% of all possible connections, a value within the physiological range. We used graph theoretical tools to compare the zebrafish connectome graph to small-world, random and structured random graphs of the same size. For each type of graph, 100 randomly generated instantiations were considered. Degree distribution (the number of connections per neuron) varied more in the zebrafish graph than in same size graphs with less biological detail. There was high local clustering and a short average path length between nodes, implying a small-world structure similar to other neural connectomes and complex networks. The graph was found not to be scale-free, in agreement with some other neural connectomes. An experimental lesion was performed that targeted three model brain neurons, including the Mauthner neuron, known to control fast escape turns. The lesion decreased the number of short paths between sensory and motor neurons analogous to the behavioral effects of the same lesion in zebrafish. This model is expandable and can be used to organize and interpret a growing database of information on the zebrafish connectome.