Novel Oridonin Analog CYD0682 Inhibits Hepatic Stellate Cell Activation via the Heat Shock Protein 90-Dependent STAT3 Pathway.

INTRODUCTION: Activated hepatic stellate cells (HSCs) are the primary effector cells in hepatic fibrosis, over depositing extracellular matrix (ECM) proteins. Our previous work found oridonin analog CYD0682 attenuates proliferation, Transforming Growth Factor ß (TGFß)-induced signaling, and ECM production in immortalized HSCs. The underlying mechanism behind these reductions is unclear. The Signal Transduction and Activator of Transcription 3 (STAT3) pathway plays a central role in HSC activation and has been found to be overexpressed in models of hepatic injury. In this study, we will examine the effect of CYD0682 on STAT3 signaling. METHODS: Immortalized human (LX-2) and rat (HSC-T6) HSC lines were treated with CYD0682 or Tanespimycin (17-AAG) with or without TGF-ß. Nuclear and cytosolic proteins were extracted. Protein expression was analyzed with Western blot. DNA binding activity was assessed with STAT3 DNA Binding ELISA. Cell viability was assessed with Alamar blue assay. RESULTS: CYD0682 treatment inhibited STAT3 phosphorylation at tyrosine 705 in a dose-dependent manner in LX-2 and HSC-T6 cells. STAT3 DNA binding activity and STAT3 regulated protein c-myc were significantly decreased by CYD0682. Notably, TGFß-induced STAT3 phosphorylation and ECM protein expression were inhibited by CYD0682. STAT3 is reported to be a Heat Shock Protein 90 (HSP90) client protein. Notably, CYD0682 attenuated the expression of endogenous STAT3 and other HSP90 client proteins FAK, IKKα, AKT and CDK9. HSP90 specific inhibitor 17-AAG suppressed endogenous and TGFß-induced STAT3 phosphorylation and ECM protein production. CONCLUSIONS: CYD0682 attenuates endogenous and TGFß-induced STAT3 activation and ECM production via an HSP90 dependent pathway in HSCs. Further study of this pathway may present new targets for therapeutic intervention in hepatic fibrosis.

Identifying Community Safety and Policy-Based Injury Prevention Opportunities to Reduce Golf Cart Injuries.

BACKGROUND: In small US communities, golf cart utilization has become increasingly more common. In the past 3 years, the incidence and severity of pediatric golf cart-related trauma evaluated at our trauma center has noticeably increased. Thus, the aim of this study was to analyze trends, identify risk and protective factors, and provide community-level recommendations to improve golf cart safety for children in a coastal community. METHODS: A retrospective cross-sectional study of our institutional trauma registry was performed. The registry was queried for golf cart injuries between 2012 -2022. Demographics, accident details, hospital course and outcomes were reviewed. Data analysis involved quantitative statistics. Incident locations were mapped, including additional data from the County emergency medical service. Additionally, customer education at four prominent golf rental shops was observed. RESULTS: Annual golf cart-related traumas doubled starting in 2020. Of 235 total patients, 105 (46%) were children. Median age was 11.5 years (range 2-17). 55% were female and 67% were non-Hispanic White. 80% were out-of-county residents. The most common injury location was extremity (56%). Median ISS was 4, and 3% died. Only 10% of children were restrained. 41% were ejected and most (84%) were front-facing passengers. Ejection was associated with more severe injury (OR 4.13, p = 0.01). Most injuries occurred during 5-10 pm (47%), weekends and summertime. Nighttime injuries were more severe than daytime (p = 0.04). A hotspot of crashes was identified in a zone where golf carts were restricted. Rental stores provided education on seat belt use, car seat use for infants, and off-limit zones. However, rules were not enforced. CONCLUSION: Our results inform the following golf cart injury prevention opportunities: raising awareness of injury risks to children in high-tourist areas, partnering with rental stores to enforce rules, improving signage, adding protected lanes, and adopting a no nighttime operation policy. LEVEL OF EVIDENCE: IV.

Serum amyloid A and mitochondrial DNA in extracellular vesicles are novel markers for detecting traumatic brain injury in a mouse model.

This study investigates the potential use of circulating extracellular vesicles' (EVs) DNA and protein content as biomarkers for traumatic brain injury (TBI) in a mouse model. Despite an overall decrease in EVs count during the acute phase, there was an increased presence of exosomes (CD63+ EVs) during acute and an increase in microvesicles derived from microglia/macrophages (CD11b+ EVs) and astrocytes (ACSA-2+ EVs) in post-acute TBI phases, respectively. Notably, mtDNA exhibited an immediate elevation post-injury. Neuronal (NFL) and microglial (Iba1) markers increased in the acute, while the astrocyte marker (GFAP) increased in post-acute TBI phases. Novel protein biomarkers (SAA, Hp, VWF, CFD, CBG) specific to different TBI phases were also identified. Biostatistical modeling and machine learning identified mtDNA and SAA as decisive markers for TBI detection. These findings emphasize the importance of profiling EVs' content and their dynamic release as an innovative diagnostic approach for TBI in liquid biopsies.

The Social Media Footprint of Pediatric Surgery Fellowship Programs: Where Do We Stand?

INTRODUCTION: Social media utilization is expanding within graduate medical education and academic surgery. This study aims to quantify the current social media footprint of pediatric surgery (PS) fellowship training programs. METHODS: United States PS fellowship programs from the American Pediatric Surgical Association website and social media accounts on three platforms (Facebook, Instagram, Twitter) were identified. Authors quantified subject matter within public program content and compared PS social media utilization to other surgical training programs. A public Twitter survey was disseminated to evaluate recent PS applicant Twitter use and perceptions about content posted by programs. RESULTS: Of 51 PS fellowship programs, 23 (45.1%) had active Twitter accounts, 2 (3.9%) had active Facebook accounts, and 1 (2.0%) had an active Instagram account. Cumulatively, 5162 organic posts were published across all 26 accounts (90.4% on Twitter). Most commonly posted content included research/conference presentations (31.3%) and faculty accolades (15.1%), while clinical/OR experience (3.6%), gender/ethnic diversity (2.4%) had the least content. Compared to other training programs, PS has lower utilization of Facebook (p < 0.001) and Instagram (p < 0.001), but similar Twitter utilization (p = 0.09). Twenty-four recent applicants responded to the public Twitter survey. Most (62.5%) used Twitter intentionally for recruitment and networking purposes when applying to fellowship. They expressed desire for increased content related to clinical/OR experiences, program ethnic/gender diversity and recruitment information. CONCLUSION: Amongst PS training programs, Twitter is the most commonly utilized platform. Expanding Twitter usage to more programs and posting more varied content may facilitate opportunities for diverse applicant recruitment and serve as a platform to share clinical knowledge, which will ultimately move the needle towards growth and equity. LEVEL OF EVIDENCE: IV.

Preoperative Optimization Before Ventral Hernia Repair: A Systematic Review and Meta-analysis.

BACKGROUND: Obesity is associated with an increased risk of ventral hernia development and recurrence rates after ventral hernia repair (VHR). The metabolic derangements caused by obesity can also lead to many postoperative complications. Therefore, it is a common practice to attempt weight loss before VHR. However, there is still no consensus on optimal preoperative management for obese patients with a ventral hernia. This study aims to perform a meta-analysis to evaluate the effect of preoperative weight optimization on VHR outcomes. METHODS: We performed a literature search of PubMed, Scopus, and Cochrane Library databases to identify studies comparing obese patients who underwent surgical or non-surgical weight loss interventions before undergoing hernia repair surgery to obese patients who underwent hernia repair surgery without prehabilitation. Postoperative outcomes were assessed by means of pooled analysis and meta-analysis. Statistical analysis was performed using RevMan 5.4. Heterogeneity was assessed with I 2 statistics. RESULTS: One thousand six hundred nine studies were screened and 13 were thoroughly reviewed. Five studies comprising 465 patients undergoing hernia repair surgery were included. No differences in hernia recurrence [odds ratio (OR) 0.66; 95% CI 0.23-1.89; P =0.44; I 2 =20%], seroma (OR 0.70; 95% CI 0.25-1.95; P =0.50; I 2 =5%), hematoma (OR 2.00; 95% CI 0.5-7.94; P =0.45; I 2 =0%), surgical site infection (OR 1.96; 95% CI 0.52-7.40; P =0.32; I 2 =0%), and overall complication (OR 0.80; 95% CI 0.37-1.74; P =0.58; I 2 =40%) rates were noted when comparing patients who underwent a preoperative weight loss intervention (prehabilitation or bariatric surgery) versus those who did not. In the subgroup analysis of patients who underwent bariatric surgery, we found no difference in hernia recurrence (OR 0.64; 95% CI 0.12-3.33; P = 0.59; I 2 =41%) or overall complications (OR 1.14; 95% CI 0.36-3.64; P =0.82; I 2 =64%). In the subgroup analysis of patients who lost weight versus patients who did not, there was no significant difference in overall complication rates (OR 0.86; 95% CI 0.34-2.21; P =0.76; I 2 =55%). CONCLUSIONS: We found similar hernia recurrence, seroma, hematoma, and surgical site infection rates in patients who underwent preoperative optimization. These findings underline the need for prospective studies to define the optimal role of preoperative optimization and weight loss in obese patients undergoing ventral hernia repair.

A Rare Case of Erosive Esophagitis Due to Sarcina Ventriculi Infection.

Sarcina ventriculi is a Gram-positive anaerobic coccus found in soil that is a rare cause of inflammatory infections of the GI tract. This bacterium has a propensity for causing gastritis in patients with delayed gastric emptying. Of the 66 reported cases in the literature, 10 involved the esophagus. Symptoms of an esophageal infection are non-specific and may be mistaken for long-standing gastroesophageal reflux. We present a case of a 67-year-old female with chronic dysphagia and reflux diagnosed with erosive esophagitis caused by Sarcina ventriculi. Treatment strategies documented in the literature are reviewed.

PARP1 Inhibition and Effect on Burn Injury-Induced Inflammatory Response and Cardiac Function.

BACKGROUND: Burn injury induces multiple signaling pathways leading to a significant inflammatory storm that adversely affects multiple organs, including the heart. Poly (ADP-ribose) polymerase inhibitor 1 (PARP1) inhibition, with specific agents such as N-(5,6-Dihydro-6-oxo-2-phenanthridinyl)-2-acetamide (PJ34), is effective in reducing oxidative stress and cytokine expression in the heart. We hypothesized that PARP1 inhibition would reduce inflammatory signaling and protect against burn injury-induced cardiac dysfunction. STUDY DESIGN: Male Sprague-Dawley rats (8 weeks old, 300 to 350 g) were randomly assigned to sham injury (Sham), 60% total body surface area burn (24 hours post burn), or 60% total body surface area burn with intraperitoneal administration of PJ34 (20 mg/kg, 24 hours post burn + PJ34) and sacrificed 24 hours after injury. Cardiac function was determined using Vevo 2100 echocardiography. Genetic expression of 84 specific toll-like receptor-mediated signal transduction and innate immunity genes were examined using microarray to evaluate cardiac tissue. Qiagen GeneGlobe Data Analysis Center was used to analyze expression, and genetic clustering was performed using TreeView V2.0.8 software. Real-time quantitative polymerase chain reaction was used to validate identified differentially expressed genes. RESULTS: Burn injury significantly altered multiple genes in the toll-like receptor signaling, interleukin-17 signaling, tumor necrosis factor signaling, and nuclear factor-κB signaling pathways and led to significant cardiac dysfunction. PARP1 inhibition with PJ34 normalized these signaling pathways to sham levels as well as improved cardiac function to sham levels. CONCLUSIONS: PARP1 inhibition normalizes multiple inflammatory pathways that are altered after burn injury and improves cardiac dysfunction. PARP1 pathway inhibition may provide a novel methodology to normalize multiple burn injury-induced inflammatory pathways in the heart.

Risk factors for opioid use disorder after severe burns in adults.

INTRODUCTION: Risk factors for opioid dependence amongst burn patients have not been well-explored compared to other surgical fields. METHODS: The TrinetX database was queried for patients diagnosed with opioid use disorder (OUD) after thermal or chemical burn. Propensity score matching was performed. Opioid and non-opioid analgesia use, ICU care, surgery, and comparative risks among common opiates were examined using descriptive and univariate regression models, including odds ratios. Subgroup analysis evaluated the impact of multimodal analgesia. RESULTS: Odds of receiving IV opioids for acute analgesia (p = <0.0001, OR = 1.80, CI = 1.45-2.25), undergoing surgery (p = <0.0001, OR = 1.58, CI = 1.26-1.98), and ICU care (p = <0.0001, OR = 3.60, CI = 2.00-3.83) after burn injury were higher in patients who developed OUD. Patients receiving multimodal therapy within 24 hours of admission had lower odds of developing OUD (OR = 0.74, CI = 2.76-4.68, p = 0.0001) and chronic pain (OR = 0.89, CI = 0.78-1.00, p = 0.05) regardless of TBSA. CONCLUSION: Patients who developed opioid use disorder following burn injury had higher odds of receiving opioid exclusive pain management, more frequent surgery, ICU care.

Primary Hepatic Mesothelial Cyst: A Rare Entity to Be Considered in the Differential Diagnosis of Neonatal Cystic Lesions.

We report two cases of primary hepatic mesothelial cysts in neonates previously identified during perinatal imaging. Both neonatal cases were reimaged in the postnatal period, demonstrating the persistence of these cystic hepatic lesions. In both instances, the decision was made to treat with surgical resection and both patients tolerated the surgery well with no significant postoperative complications. Histopathological examination of these lesions discovered a cuboidal lining that was calretinin and WT1 positive and CD31 negative, indicating the diagnosis of a mesothelial cyst of hepatic origin. These cases bring attention to the broad differential diagnosis of congenital primary hepatic cystic lesions, as well as the diagnostic pathway to confirm a primary hepatic mesothelial cyst.

Cytokine Pathways in Cardiac Dysfunction following Burn Injury and Changes in Genome Expression.

In 2016, an estimated 486,000 individuals sustained burn injuries requiring medical attention. Severe burn injuries lead to a persistent, hyperinflammatory response that may last up to 2 years. The persistent release of inflammatory mediators contributes to end-organ dysfunction and changes in genome expression. Burn-induced cardiac dysfunction may lead to heart failure and changes in cardiac remodeling. Cytokines promote the inflammatory cascade and promulgate mechanisms resulting in cardiac dysfunction. Here, we review the mechanisms by which TNFα, IL-1 beta, IL-6, and IL-10 cause cardiac dysfunction in post-burn injuries. We additionally review changes in the cytokine transcriptome caused by inflammation and burn injuries.

Pilomatrix carcinoma of the right postauricular region: A case report and literature review.

INTRODUCTION: Pilomatrix carcinoma is a rare aggressive tumor with a high rate of local recurrence after surgical excision. Diagnosis is made by histopathology and when discovered, wide local excision has been shown to have the best results. PRESENTATION OF CASE: We report a case of a 74-year-old male incidentally found to have a large right postauricular mass and regional lymphadenopathy. The mass was biopsied and proven to be a malignant pilomatrixoma. Wide local excision and level II and III neck dissection with reconstruction using a right supraclavicular flap was performed. DISCUSSION: Pilomatrix carcinoma is a lesion first described in 1880 by Malherbe and Chenantais. It is unknown if these tumors arise de novo or arise through malignant transformation of a benign pilomatrixoma. There are similarities between the benign lesion and its malignant counterpart in terms of activating mutations in signaling pathways. A well-defined gold standard for surgical management has not been established, but currently wide local excision with safe margins is recommended along with regional lymph node dissection when metastasis is suspected. Currently, no chemotherapy regimen has been shown to be effective in local control or in preventing metastatic spread. CONCLUSION: Pilomatrix carcinoma, given its aggressive nature, has a high propensity for recurrence after excision. It is important to perform wide local excision to avoid an incomplete resection and higher recurrence rates. Further studies will be needed to create a more defined standard of treatment and to evaluate the role of adjuvant chemotherapy and radiation therapy.