E-Cadherin Expression Is Regulated by miR-192/215 by a Mechanism That Is Independent of the Profibrotic Effects of Transforming Growth Factor-β

OBJECTIVE--Increased deposition of extracellular matrix (ECM) within the kidney is driven by profibrotic mediators including transforming growth factor-[beta] (TGF-[beta]) and connective tissue growth factor (CTGF). We investigated whether some of their effects may be mediated through changes in expression of certain microRNAs (miRNAs). RESEARCH DESIGN AND METHODS--Proximal tubular cells, primary rat mesangial cells, and human podocytes were analyzed for changes in the expression of key genes, ECM proteins, and miRNA after exposure to TGF-[beta] (1-10 ng/[micro]l). Tubular cells were also infected with CTGF-adenovirus. Kidneys from diabetic apoE mice were also analyzed for changes in gene expression and miRNA levels. RESULTS--TGF-[beta] treatment was associated with morphologic and phenotypic changes typical of epithelial-mesenchymal transition (EMT) including increased fibrogenesis in all renal cell types and decreased E-cadherin expression in tubular cells. TGF-[beta] treatment also modulated the expression of certain miRNAs, including decreased expression of miR-192/215 in tubular cells, mesangial cells, which are also decreased in diabetic kidney. Ectopic expression of miR-192/215 increased E-cadherin levels via repressed translation of ZEB2 mRNA, in the presence and absence of TGF-[beta], as demonstrated by a ZEB2 3'-untranslated region luciferase reporter assay. However, ectopic expression of miR-192/215 did not affect the expression of matrix proteins or their induction by TGF-[beta]. In contrast, CTGF increased miR-192/215 levels, causing a decrease in ZEB2, and consequently increased E-cadherin mRNA. CONCLUSIONS--These data demonstrate the linking role of miRNA-192/215 and ZEB2 in TGF-[beta]/CTGF-mediated changes in E-cadherin expression. These changes appear to occur independently of augmentation of matrix protein synthesis, suggesting that a multistep EMT program is not necessary for fibrogenesis to occur.Bo Wang, Michal Herman-Edelstein, Philip Koh, Wendy Burns, Karin Jandeleit-Dahm, Anna Watson, Moin Saleem, Gregory J. Goodall, Stephen M. Twigg, Mark E. Cooper and Phillip Kantharidi

Early versus Delayed Decompression for Traumatic Cervical Spinal Cord Injury: Results of the Surgical Timing in Acute Spinal Cord Injury Study (STASCIS)

BACKGROUND:There is convincing preclinical evidence that early decompression in the setting of spinal cord injury (SCI) improves neurologic outcomes. However, the effect of early surgical decompression in patients with acute SCI remains uncertain. Our objective was to evaluate the relative effectiveness of early (<24 hours after injury) versus late (≥ 24 hours after injury) decompressive surgery after traumatic cervical SCI. METHODS:We performed a multicenter, international, prospective cohort study (Surgical Timing In Acute Spinal Cord Injury Study: STASCIS) in adults aged 16-80 with cervical SCI. Enrolment occurred between 2002 and 2009 at 6 North American centers. The primary outcome was ordinal change in ASIA Impairment Scale (AIS) grade at 6 months follow-up. Secondary outcomes included assessments of complications rates and mortality. FINDINGS:A total of 313 patients with acute cervical SCI were enrolled. Of these, 182 underwent early surgery, at a mean of 14.2(± 5.4) hours, with the remaining 131 having late surgery, at a mean of 48.3(± 29.3) hours. Of the 222 patients with follow-up available at 6 months post injury, 19.8% of patients undergoing early surgery showed a ≥ 2 grade improvement in AIS compared to 8.8% in the late decompression group (OR = 2.57, 95% CI:1.11,5.97). In the multivariate analysis, adjusted for preoperative neurological status and steroid administration, the odds of at least a 2 grade AIS improvement were 2.8 times higher amongst those who underwent early surgery as compared to those who underwent late surgery (OR = 2.83, 95% CI:1.10,7.28). During the 30 day post injury period, there was 1 mortality in both of the surgical groups. Complications occurred in 24.2% of early surgery patients and 30.5% of late surgery patients (p = 0.21). CONCLUSION:Decompression prior to 24 hours after SCI can be performed safely and is associated with improved neurologic outcome, defined as at least a 2 grade AIS improvement at 6 months follow-up

Immunoglobulin, glucocorticoid, or combination therapy for multisystem inflammatory syndrome in children: a propensity-weighted cohort study

Background: Multisystem inflammatory syndrome in children (MIS-C), a hyperinflammatory condition associated with SARS-CoV-2 infection, has emerged as a serious illness in children worldwide. Immunoglobulin or glucocorticoids, or both, are currently recommended treatments. Methods: The Best Available Treatment Study evaluated immunomodulatory treatments for MIS-C in an international observational cohort. Analysis of the first 614 patients was previously reported. In this propensity-weighted cohort study, clinical and outcome data from children with suspected or proven MIS-C were collected onto a web-based Research Electronic Data Capture database. After excluding neonates and incomplete or duplicate records, inverse probability weighting was used to compare primary treatments with intravenous immunoglobulin, intravenous immunoglobulin plus glucocorticoids, or glucocorticoids alone, using intravenous immunoglobulin as the reference treatment. Primary outcomes were a composite of inotropic or ventilator support from the second day after treatment initiation, or death, and time to improvement on an ordinal clinical severity scale. Secondary outcomes included treatment escalation, clinical deterioration, fever, and coronary artery aneurysm occurrence and resolution. This study is registered with the ISRCTN registry, ISRCTN69546370. Findings: We enrolled 2101 children (aged 0 months to 19 years) with clinically diagnosed MIS-C from 39 countries between June 14, 2020, and April 25, 2022, and, following exclusions, 2009 patients were included for analysis (median age 8·0 years [IQR 4·2–11·4], 1191 [59·3%] male and 818 [40·7%] female, and 825 [41·1%] White). 680 (33·8%) patients received primary treatment with intravenous immunoglobulin, 698 (34·7%) with intravenous immunoglobulin plus glucocorticoids, 487 (24·2%) with glucocorticoids alone; 59 (2·9%) patients received other combinations, including biologicals, and 85 (4·2%) patients received no immunomodulators. There were no significant differences between treatments for primary outcomes for the 1586 patients with complete baseline and outcome data that were considered for primary analysis. Adjusted odds ratios for ventilation, inotropic support, or death were 1·09 (95% CI 0·75–1·58; corrected p value=1·00) for intravenous immunoglobulin plus glucocorticoids and 0·93 (0·58–1·47; corrected p value=1·00) for glucocorticoids alone, versus intravenous immunoglobulin alone. Adjusted average hazard ratios for time to improvement were 1·04 (95% CI 0·91–1·20; corrected p value=1·00) for intravenous immunoglobulin plus glucocorticoids, and 0·84 (0·70–1·00; corrected p value=0·22) for glucocorticoids alone, versus intravenous immunoglobulin alone. Treatment escalation was less frequent for intravenous immunoglobulin plus glucocorticoids (OR 0·15 [95% CI 0·11–0·20]; p<0·0001) and glucocorticoids alone (0·68 [0·50–0·93]; p=0·014) versus intravenous immunoglobulin alone. Persistent fever (from day 2 onward) was less common with intravenous immunoglobulin plus glucocorticoids compared with either intravenous immunoglobulin alone (OR 0·50 [95% CI 0·38–0·67]; p<0·0001) or glucocorticoids alone (0·63 [0·45–0·88]; p=0·0058). Coronary artery aneurysm occurrence and resolution did not differ significantly between treatment groups. Interpretation: Recovery rates, including occurrence and resolution of coronary artery aneurysms, were similar for primary treatment with intravenous immunoglobulin when compared to glucocorticoids or intravenous immunoglobulin plus glucocorticoids. Initial treatment with glucocorticoids appears to be a safe alternative to immunoglobulin or combined therapy, and might be advantageous in view of the cost and limited availability of intravenous immunoglobulin in many countries. Funding: Imperial College London, the European Union's Horizon 2020, Wellcome Trust, the Medical Research Foundation, UK National Institute for Health and Care Research, and National Institutes of Health

Immunoglobulin, glucocorticoid, or combination therapy for multisystem inflammatory syndrome in children: a propensity-weighted cohort study

Background Multisystem inflammatory syndrome in children (MIS-C), a hyperinflammatory condition associated with SARS-CoV-2 infection, has emerged as a serious illness in children worldwide. Immunoglobulin or glucocorticoids, or both, are currently recommended treatments. Methods The Best Available Treatment Study evaluated immunomodulatory treatments for MIS-C in an international observational cohort. Analysis of the first 614 patients was previously reported. In this propensity-weighted cohort study, clinical and outcome data from children with suspected or proven MIS-C were collected onto a web-based Research Electronic Data Capture database. After excluding neonates and incomplete or duplicate records, inverse probability weighting was used to compare primary treatments with intravenous immunoglobulin, intravenous immunoglobulin plus glucocorticoids, or glucocorticoids alone, using intravenous immunoglobulin as the reference treatment. Primary outcomes were a composite of inotropic or ventilator support from the second day after treatment initiation, or death, and time to improvement on an ordinal clinical severity scale. Secondary outcomes included treatment escalation, clinical deterioration, fever, and coronary artery aneurysm occurrence and resolution. This study is registered with the ISRCTN registry, ISRCTN69546370. Findings We enrolled 2101 children (aged 0 months to 19 years) with clinically diagnosed MIS-C from 39 countries between June 14, 2020, and April 25, 2022, and, following exclusions, 2009 patients were included for analysis (median age 8·0 years [IQR 4·2–11·4], 1191 [59·3%] male and 818 [40·7%] female, and 825 [41·1%] White). 680 (33·8%) patients received primary treatment with intravenous immunoglobulin, 698 (34·7%) with intravenous immunoglobulin plus glucocorticoids, 487 (24·2%) with glucocorticoids alone; 59 (2·9%) patients received other combinations, including biologicals, and 85 (4·2%) patients received no immunomodulators. There were no significant differences between treatments for primary outcomes for the 1586 patients with complete baseline and outcome data that were considered for primary analysis. Adjusted odds ratios for ventilation, inotropic support, or death were 1·09 (95% CI 0·75–1·58; corrected p value=1·00) for intravenous immunoglobulin plus glucocorticoids and 0·93 (0·58–1·47; corrected p value=1·00) for glucocorticoids alone, versus intravenous immunoglobulin alone. Adjusted average hazard ratios for time to improvement were 1·04 (95% CI 0·91–1·20; corrected p value=1·00) for intravenous immunoglobulin plus glucocorticoids, and 0·84 (0·70–1·00; corrected p value=0·22) for glucocorticoids alone, versus intravenous immunoglobulin alone. Treatment escalation was less frequent for intravenous immunoglobulin plus glucocorticoids (OR 0·15 [95% CI 0·11–0·20]; p<0·0001) and glucocorticoids alone (0·68 [0·50–0·93]; p=0·014) versus intravenous immunoglobulin alone. Persistent fever (from day 2 onward) was less common with intravenous immunoglobulin plus glucocorticoids compared with either intravenous immunoglobulin alone (OR 0·50 [95% CI 0·38–0·67]; p<0·0001) or glucocorticoids alone (0·63 [0·45–0·88]; p=0·0058). Coronary artery aneurysm occurrence and resolution did not differ significantly between treatment groups. Interpretation Recovery rates, including occurrence and resolution of coronary artery aneurysms, were similar for primary treatment with intravenous immunoglobulin when compared to glucocorticoids or intravenous immunoglobulin plus glucocorticoids. Initial treatment with glucocorticoids appears to be a safe alternative to immunoglobulin or combined therapy, and might be advantageous in view of the cost and limited availability of intravenous immunoglobulin in many countries. Funding Imperial College London, the European Union's Horizon 2020, Wellcome Trust, the Medical Research Foundation, UK National Institute for Health and Care Research, and National Institutes of Health

Two Cases of Respiratory Insufficiency Secondary to Pre-procedural Nerve Blocks for Upper Extremity Injuries

Interscalene nerve blocks are common procedures performed before upper extremity surgeries in order to provide post-op pain relief and improve recovery time. Here we present two cases of patients who underwent a unilateral supraclavicular and bilateral interscalene nerve block, respectively. The first patient had no risk factors but the second presented with a body mass index of 45.5 and a history of symptoms consistent with obstructive sleep apnea but never diagnosed. Both patients experienced some form of respiratory distress diagnosed via changes in chest x-ray and clinical presentation. The mechanism of injury that occurs in these procedures is typically from inadvertent damage to the phrenic nerve. Mild adverse effects in interscalene nerve block are relatively common. However, there is minimal data in regards to performing bilateral interscalene nerve blocks. The purpose of this study is to highlight that severe complication in both high and low-risk patients can occur but may be reduced with a safer approach and more effective communication among multidisciplinary team members

Patient Outcome from Nontraditional Motorized Vehicle Accidents

INTRODUCTION There have been little literature between the effect of patient’s ages and health outcome from nontraditional motor vehicle accidents (NMVA). These accidents are known as not car or motorcycle or truck accidents on the highways. This study examined the effect of NMVA and age on outcome of adult patients treated at the Johnson City Medical Center for over 7 years. MATERIALS AND METHODS This study was approved by the office for the protection of human research projects of East Tennessee State University. A total of 468 patients aged \u3e18 years involved in motorized vehicle accidents other than traditional cars, trucks or motorcycles from 2011 to 2017 were analyzed. Electronic health data of trauma patients was obtained from the Johnson City Medical Center trauma department registry. Patients were selected if primary reason for admission was injury due to nontraditional motorized vehicle (snow mobiles, lawn mowers, all-terrain vehicles (ATV’s), machinery- industrial or agricultural, and any other nontraditional motorized vehicle that was not a car or truck or motorcycle. The study design was observational (cross sectional survey). The International Classification of Diseases, Ninth Edition (ICD-9) and Tenth Edition (ICD-10) were used to obtain parameters for the study. The study parameters include Age Length of stay (LOS) Total length of stay in the ICU Total ventilator days Injury severity score (ISS) Mechanism of injury The health data and medical information were kept private, secured and safeguarded. The patients were split into three groups, ages 18 – 60 (study group 1), ages 61-89 (study group 2), and ages 90+ (study group 3).Descriptive statistics and Logistic regression were used to compare means and analyze each study parameters between the study groups. Finally, a comparison was done between study groups 1 and 2 of patients involved in ATV accidents using the same categories. Other NMVA such as lawn mower, machinery were not analyzed based on few fatalities. The analysis was done using SPSS, SAS v9.4. RESULTS There were a total of 468 observed patients, 18 died and 450 survived. Out of the 18 patients that died, 12 were in study group one while 6 were study group two. Of the 450 that survived, 5 were discharged to an acute care facility, 363 home or self-care (routine discharge), 40 in a rehabilitation facility (inpatient), 38 in skilled nursing facility. Overall the tests show that there was no difference between the groups observed except when comparing the total length of stay and total ICU days among patients in the study group 1 that were involved in all accidents. (Total ICU days P= 0.0028, total length of stay P= 0.003). The patients who survived on average spent 3 days longer in the hospital and 1 day longer in the Intensive care unit. CONCLUSION The patient outcome from nontraditional accident differs only by length of hospital stay and total ICU days among patients between ages 18 -60. Further longitudinal studies will help to identify other reasons for prolong stay in the hospital

The Effect of Single Accreditation on Medical Student Match Rates in Surgical Specialties

Introduction The year 2020 marked the first year in which a match under single accreditation took place. Both osteopathic (DO) and allopathic (MD) students would participate in the first match cycle without a dedicated DO match system. Our primary objective was to investigate how single accreditation has impacted the DO applicants attempting to match into surgical specialties. Our secondary objective was to investigate the impact of single accreditation at the program director (PD) level and whether or not this process would see a change in DO PD distribution in previously American Osteopathic Association (AOA)-approved programs. Method Information on number of applicants and post-match positions was gathered from AOA and National Residency Match Program (NRMP) websites. Credentials of PDs were obtained from the Accreditation Council on Graduate Medical Education website. Based on the available data, the following surgical specialties were compared for the years 2020, 2018, and 2016: General Surgery, Neurological Surgery (NSGY), Orthopedic Surgery, Otolaryngology/ENT (ENT), Plastic Surgery, and Thoracic Surgery. Data from 2016 were not included in the results as the AOA match results analysis was insufficient and unable to be directly compared to the NRMP data. Results of matched DO and MD applicants were compared using bivariate analysis. A p-value of \u3c0.05 was considered significant. Results From the year 2018 to 2020, the DO applicants saw a decrease of 3% in the total number of matched postgraduate year 1 spots in surgical specialties. NRMP results from 2020 saw that 51.7% of DO applicants matched and 67.7% (p \u3c 0.001) of MD applicants matched for the specialties examined. Percent of matched:applied for DO applicants was lower than MD applicants in the fields of NSGY (p \u3c 0.001), ENT (p \u3c 0.001), Plastic Surgery (p \u3c 0.001), General Surgery (p \u3c 0.001), and Thoracic Surgery (p = 0.011). After evaluating 60 former AOA General Surgery programs, 56% were found to have MD as PD. Another 26 former AOA surgical programs were investigated, and 58% were found to have MD PD. Conclusion Single accreditation has impacted the match process now that a large number of both MD and DO applicants are using the NRMP match system for postgraduate placement. Based on the available data, our results indicate that in the examined surgical specialties, there is a statistically significant difference in the number of MD and DO residents

An Old Idea is a Novel Concept for Supplemental Funding of Surgical Residency Programs

Background In July 2014, the Institute of Medicine released a review of the governance of Graduate Medical Education (GME), concluding that changes to GME financing were needed to reward desired performance and to reshape the workforce to meet the nation\u27s needs. In light of the rapid emergence of alternative payment systems, we evaluated the financial value of resident participation in operative surgical care. Methods The Department of Surgery provided Current Procedural Terminology (CPT) codes for procedures performed by the general surgical service at our institution for the 2011 academic year. For each code, the charge and total instances were provided. CPTs allowing an assistant fee were identified using the Searchable Medicare Physician Fee Schedule. This approach enabled calculation of the potential resident contribution to GME funding. Results A total of 515 unique CPTs were potentially billable for a total of 6,578 procedures, of which 2,552 (39%) were reimbursable. These CPTs would have generated $1,882,854 in assistant charges. The top 50 most frequent CPTs resulted in 4,247 procedures. Within the top 50, 1362 procedures (32$963,227 (51%) occurred in the top 50 most frequent CPTs. Conclusions Credit for resident participation in operative care as co-surgeon would average $67,244 per resident, compared to our current funding of$142,635 per resident. This type of alternative funding could provide 47% of current educational support. The skew in distribution of procedures also suggests that such a system could provide guidance to a more balanced operative experience. Such performance-based credentialing could be used to ensure appropriate housestaff for a given case; these reimbursements could also be adjusted based on quality metrics to provide for transformational change in patient outcomes