Expedited Surgical Care of Appendicitis is Associated With Improved Resource Utilization.

INTRODUCTION: Appendectomy for acute appendicitis is the most common pediatric intra-abdominal operation. Current literature supports the notion that modest in-hospital, preoperative delays are not associated with greater patient morbidity. However, there is less certainty regarding the role that hour-of-presentation plays in determining the timing of surgery. Thus, we aimed to evaluate how after-hours presentation may relate to the timing of surgery and to assess the outcomes and resource utilization associated with expedited appendectomy compared to nonexpedited. METHODS: Patient records for children who underwent an appendectomy at a freestanding pediatric hospital from 2015 to 2019 were reviewed. Business hour presentations were defined as arrival at the emergency department from 7 AM to 6 PM. Primary outcomes were hospital length of stay (LOS), cost derived from the Pediatric Health Information System database, perforation, surgical complications, and 30-day readmissions. RESULTS: Nine hundred forty-two patients underwent appendectomy over the study period. The median time to OR was 2.0 h in the expedited cohort and 9.8 h in the nonexpedited group. Presentation during business hours was associated with 4.4 higher odds (P < 0.001) of expedited workflow. Expedited appendectomies were associated with shorter hospital LOS (11.5 h, P < 0.001), less costly admissions ($1,155, P < 0.001); LOS measured in midnights, perforation and readmission rates were similar between groups. CONCLUSIONS: We found reduced resource utilization associated with expedited appendectomy. Additionally, the demonstrated association between the time of presentation to the emergency department (ED) and the timing of surgery may be utilized to inform staffing and resource deployment decisions. Further research regarding the generalizability and sustainability of an expedited presurgical workflow in pediatric appendectomy is certainly indicated.

Prolonged In-hospital Time to Appendectomy is Associated With Increased Complicated Appendicitis in Children.

OBJECTIVE: To examine the association between prolonged in-hospital time to appendectomy (TTA) and the risk of complicated appendicitis. SUMMARY BACKGROUND DATA: Historically, acute appendicitis was treated with emergency appendectomy. More recently, practice patterns have shifted to urgent appendectomy, with acceptable in-hospital delays of up to 24 hours. However, the consequences of prolonged TTA remain poorly understood. Herein, we present the largest individual analysis to date of outcomes associated with prolonged in-hospital delay before appendectomy in children. METHODS: Data from patients who underwent appendectomy within 24 hours of hospital presentation were obtained from the American College of Surgeons Pediatric National Surgical Quality Improvement Program Procedure Targeted Appendectomy database from 2016 to 2018. Appendectomy within 16 hours of presentation was considered early, whereas those between 16 to 24 hours were defined as late. The primary outcome was operative findings of complicated appendicitis. Secondary outcomes included 30-day complications and resource utilization. RESULTS: This study consisted of 18,927 patients, with 20.6% undergoing late appendectomy. The rate of complicated appendicitis was significantly higher in the late group (Early: 26.3%, Late: 30.3%, P < 0.05). Additionally, the late group had longer operative times, increased need for postoperative percutaneous drainage, antibiotics at discharge, parenteral nutrition, and an extended hospital length of stay (P < 0.05). On multivariate analysis, late appendectomy remained a predictor of complicated disease (odds ratio 1.17 [95% confidence interval, 1.08-1.27]). CONCLUSIONS: A significant proportion of pediatric patients with acute appendicitis experience prolonged in-hospital delays before appendectomy, which are associated with modestly increased rates of complicated appendicitis. Although this does not indicate appendectomy needs to be done emergently, prolonged in-hospital TTA should be avoided whenever possible.

Association of Operative Volume and Odds of Surgical Complication for Patients Undergoing Repair of Pectus Excavatum at Children's Hospitals.

OBJECTIVE: To determine whether procedure-specific provider volume is associated with outcomes for patients undergoing repair of pectus excavatum at tertiary care children's hospitals. STUDY DESIGN: We performed a cohort study of patients undergoing repair of pectus excavatum between January 1, 2013 and December 31, 2019, at children's hospitals using the Pediatric Health Information System database. The main exposures were the pectus excavatum repair volume quartile of the patient's hospital and the pectus excavatum repair volume category of their surgeon. Our primary outcome was surgical complication, identified using International Classification of Diseases, Ninth Revision, Clinical Modification, and International Classification of Diseases, Tenth Revision, Clinical Modification codes from Pediatric Health Information System. Secondary outcomes included high-cost admission and extended length of stay. RESULTS: In total, 7183 patients with an average age of 15.2 years (SD 2.0), 83% male, 74% non-Hispanic White, 68% no comorbidities, 72% private insurance, and 82% from metro areas were analyzed. Compared with the lowest-volume (≤10 cases/year) quartile of hospitals, patients undergoing repair of pectus excavatum at hospitals in the second (>10-18 cases/year), third (>18-26 cases/year), and fourth (>26 cases/year) volume quartiles had decreased odds of complication of OR 0.52 (CI 0.34-0.82), 0.51 (CI 0.33-0.78), and 0.41 (CI 0.27-0.62), respectively. Patients with pectus excavatum who underwent repair by surgeons in the second (>1-5 cases/year), third (>5-10 cases/year), and fourth (>10 cases/year) volume categories had decreased odds of complication of OR 0.91 (CI 0.68-1.20), OR 0.73 (CI 0.51-1.04), and OR 0.55 (CI 0.39-0.76), respectively, compared with the lowest-volume (≤1 case/year) category of surgeons. CONCLUSIONS: Procedure-specific case volume is an important factor when considering providers for elective surgery, even among specialized centers providing comprehensive patient care.

An Analysis of Factors Associated with Burn Injury Outcomes in Low- and Middle-Income Countries.

BACKGROUND: Burn injuries are a major cause of morbidity and mortality within low- and middle-income countries (LMICs). The World Health Organization developed the Global Burn Registry to centralize data collection for the guidance of burn prevention programs. This study analyzed the epidemiologic and hospital-specific factors associated with burn injury outcomes in LMICs and high-income countries (HICs). METHODS: A retrospective review was performed using the Global Burn Registry over 3 y. Patients were stratified by income region. Bivariate analyses and stepwise regressions were performed to evaluate patient and hospital demographics and variables associated with injury patterns and outcomes. Outcomes of interest included mortality and length of stay. RESULTS: Over the study period, data were collected on 1995 patients from 10 LMICs (20 hospitals) and four HICs (four hospitals). Significantly higher mortality was seen in LMICs compared with HICs (17% versus 9%; P < 0.001). There was no significant difference between income regions for injury patterns (P = 0.062) or total body surface area of the burn injury (P = 0.077). Of the LMIC hospitals in this data set, 11% did not have reliable access to an operating theater. CONCLUSIONS: HICs had a lower overall mortality even with higher rates of concurrent injuries, as well as longer length of stay. LMIC hospitals had fewer resources available, which could explain increased mortality, given similar total body surface area. This study highlights how investing in health care infrastructure could lead to improved outcomes for patients in low-resource settings.

Trends in gastrostomy tube placement with concomitant Nissen fundoplication for infants and young children at Pediatric Tertiary Centers.

PURPOSE: In infants and toddlers, gastrostomy tube placement (GT) is typically accompanied by consideration of concomitant Nissen fundoplication (NF). Historically, rates of NF have varied across providers and institutions. This study examines practice variation and longitudinal trends in NF at pediatric tertiary centers. METHODS: Patients ≤ 2 years who underwent GT between 2008 and 2018 were identified in the Pediatric Health Information System database. Patient demographics and rates of NF were examined. Descriptive statistics were used to evaluate the variation in the proportion of GT with NF at each hospital, by volume and over time. RESULTS: 40,348 patients were identified across 40 hospitals. Most patients were male (53.8%), non-Hispanic white (49.5%) and publicly-insured (60.4%). Rates of NF by hospital varied significantly from 4.2 to 75.2% (p < 0.001), though were not associated with geographic region (p = 0.088). Rates of NF decreased from 42.8% in 2008 to 14.2% in 2018, with a mean annual rate of change of - 3.07% (95% CI - 3.53, - 2.61). This trend remained when stratifying hospitals into volume quartiles. CONCLUSION: There is significant practice variation in performing NF. Regardless of volume, the rate of NF is also decreasing. Objective NF outcome measurements are needed to standardize the management of long-term enteral access in this population.

Echocardiography Reveals Heart Abnormalities in Pediatric Pectus Carinatum.

BACKGROUND: Symptoms including chest pain and palpitations are commonly described by pediatric patients with pectus deformity. Cardiac anomalies are thought to be less common in patients with pectus carinatum (PC) than those in patients with pectus excavatum; however, no literature supports this presumption. Echocardiogram (echo) assesses heart structure and function. We hypothesized that a screening echo would 1) determine the relationship between symptoms and echo findings and 2) define the incidence of cardiac defects in patients with PC. MATERIALS AND METHODS: This is an institutional review board-approved retrospective review of all patients with PC who received an echo from 2015 to 2019 at a tertiary care children's hospital. Echo findings and patient-reported symptoms were collected from electronic health records. Descriptive statistics were used to assess correlation between findings. RESULTS: We identified 155 patients with PC who received an echo with complete data available for analysis. Of these, 44 (28.4%) reported chest pain and 13 (8.4%) reported palpitations. Echo results showed that five patients (3.2%) had mitral valve prolapse and 11 (7.1%) had aortic root dilation. Patient-reported symptoms were not significantly associated with abnormal echo findings. CONCLUSIONS: Chest pain and palpitations frequently occur in the PC population but may not be related to abnormal echo findings. We recommend screening echo in patients with PC regardless of symptoms.

Conversion From Venovenous to Venoarterial Extracorporeal Membrane Oxygenation Is Associated With Increased Mortality in Children.

BACKGROUND: There is an increasing national trend toward initial venovenous (VV) extracorporeal membrane oxygenation (ECMO) for infants and children with respiratory disease; however, some proportion of patients initiated on VV ECMO will ultimately require conversion to venoarterial (VA) support for circulatory augmentation. The purpose of this work is to describe patients who required conversion from VV to VA ECMO and to highlight the increased mortality in this population. MATERIALS AND METHODS: Demographic and disease-specific data on children who underwent VV-to-VA ECMO conversion were extracted from the Extracorporeal Life Support Organization registry. Survival comparisons to age-matched patients undergoing unconverted ECMO runs were made using the 2016 Extracorporeal Life Support Organization International Summary report. The relative risk (RR) of death associated with VV-to-VA conversion was calculated, and statistical analysis of survival was performed using a chi-squared test with P < 0.05 for significance. RESULTS: This study cohort consisted of 1382 patients who required VV-to-VA conversion. The overall hospital survival rate for neonates requiring conversion was 60%, compared with 83% for unconverted VV runs and 64% for unconverted VA runs (RR 1.23; 95% confidence interval, 1.14-1.34). Similarly, the survival of older children requiring conversion was 46% compared with 66% and 51%, respectively (RR 1.16; 95% confidence interval, 1.06-1.27). CONCLUSIONS: VV-to-VA conversion does occur and is associated with increased mortality. The need for conversion from VV to VA ECMO may represent an early failure to recognize physiologic parameters or disease severity that would be better managed with initial VA support. Further research is needed to pinpoint the cause of increased mortality and to identify predictors of VV failure to optimize initial mode selection.

Tetrahydrocurcumin ameliorates homocysteine-mediated mitochondrial remodeling in brain endothelial cells.

Homocysteine (Hcy) causes endothelial dysfunction by inducing oxidative stress in most neurodegenerative disorders. This dysfunction is highly correlated with mitochondrial dynamics such as fusion and fission. However, there are no strategies to prevent Hcy-induced mitochondrial remodeling. Tetrahydrocurcumin (THC) is an anti-inflammatory and anti-oxidant compound. We hypothesized that THC may ameliorates Hcy-induced mitochondria remodeling in mouse brain endothelial cells (bEnd3) cells. bEnd3 cells were exposed to Hcy treatment in the presence or absence of THC. Cell viability and autophagic cell death were measured with MTT and MDC staining assay. Reactive oxygen species (ROS) production was determined using DCFH-DA staining by confocal microscopy. Autophagy flux was assessed using a conventional GFP-microtubule-associated protein 1 light chain 3 (LC3) dot assay. Interaction of phagophore marker LC-3 with mitochondrial receptor NIX was observed by confocal imaging. Mitochondrial fusion and fission were evaluated by western blot and RT-PCR. Our results demonstrated that Hcy resulted in cell toxicity in a dose-dependent manner and supplementation of THC prevented the detrimental effects of Hcy on cell survival. Furthermore, Hcy also upregulated fission marker (DRP-1), fusion marker (Mfn2), and autophagy marker (LC-3). Finally, we observed that Hcy activated mitochondrial specific phagophore marker (LC-3) and co-localized with the mitochondrial receptor NIX, as viewed by confocal microscopy. Pretreatment of bEnd3 with THC (15 µM) ameliorated Hcy-induced oxidative damage, mitochondrial fission/fusion, and mitophagy. Our studies strongly suggest that THC has beneficial effects on mitochondrial remodeling and could be developed as a potential therapeutic agent against hyperhomocysteinemia (HHcy) induced mitochondrial dysfunction.

Inhibition of MMP-9 attenuates hypertensive cerebrovascular dysfunction in Dahl salt-sensitive rats.

Hypertensive cerebropathy is a pathological condition associated with cerebral edema and disruption of the blood-brain barrier. However, the molecular pathways leading to this condition remains obscure. We hypothesize that MMP-9 inhibition can help reducing blood pressure and endothelial disruption associated with hypertensive cerebropathy. Dahl salt-sensitive (Dahl/SS) and Lewis rats were fed with high-salt diet for 6 weeks and then treated without and with GM6001 (MMP inhibitor). Treatment of GM6001 (1.2 mg/kg body weight) was administered through intraperitoneal injections on alternate days for 4 weeks. GM6001 non-administered groups were given vehicle (0.9% NaCl in water) treatment as control. Blood pressure was measured by tail-cuff method. The brain tissues were analyzed for oxidative/nitrosative stress, vascular MMP-9 expression, and tight junction proteins (TJPs). GM6001 treatment significantly reduced mean blood pressure in Dahl/SS rats which was significantly higher in vehicle-treated Dahl/SS rats. MMP-9 expression and activity was also considerably reduced in GM6001-treated Dahl/SS rats, which was otherwise notably increased in vehicle-treated Dahl/SS rats. Similarly MMP-9 expression in cerebral vessels of GM6001-treated Dahl/SS rats was also alleviated, as devised by immunohistochemistry analysis. Oxidative/nitrosative stress was significantly higher in vehicle-treated Dahl/SS rats as determined by biochemical estimations of malondialdehyde, nitrite, reactive oxygen species, and glutathione levels. RT-PCR and immunohistochemistry analysis further confirmed considerable alterations of TJPs in hypertensive rats. Interestingly, GM6001 treatment significantly ameliorated oxidative/nitrosative stress and TJPs, which suggest restoration of vascular integrity in Dahl/SS rats. These findings determined that pharmacological inhibition of MMP-9 in hypertensive Dahl-SS rats attenuate high blood pressure and hypertension-associated cerebrovascular pathology.

Applications for ultrasound in pediatric surgery.

Ultrasound (US) use within pediatric surgery is expanding rapidly. While US guidance for central line placement has been common practice for many years now, advances in the quality of images, portability of US machines, and a lack of radiation associated with imaging has led to broader application in many other aspects of surgery, ranging from diagnostics to performing operations under the direction of point-of-care ultrasound (POCUS). The relatively short learning curve for providers along with excellent image quality in children due to their small size provides an easy, effective imaging modality with diverse applications. Discussed here is a broad overview of the spectrum of US use within current pediatric surgical practices.

Association of Rural Residence With Surgical Outcomes Among Infants at US Children's Hospitals.

OBJECTIVES: Disparities in pediatric health outcomes are widespread. It is unclear whether rurality negatively impacts outcomes of infants with surgical congenital diseases. This study compared outcomes of rural versus urban infants requiring complex surgical care at children's hospitals in the United States. METHODS: Rural and urban infants (aged <1 year) receiving surgical care at children's hospitals from 2016 to 2019 for esophageal atresia, gastroschisis, Hirschsprung's disease, anorectal malformation, and congenital diaphragmatic hernia were compared over a 1-year postoperative period using the Pediatric Health Information System. Generalized linear mixed effects models compared outcomes of rural and urban infants. RESULTS: Among 5732 infants, 20.2% lived in rural areas. Rural infants were more frequently white, lived farther from the hospital, and lived in areas with lower median household income compared with urban infants (all P < .001). Rural infants with anorectal malformation and gastroschisis had lower adjusted hospital days over 1 year; rural infants with esophageal atresia had higher adjusted odds of 30-day hospital readmission. Adjusted mortality, hospital days, and readmissions were otherwise similar between the 2 groups. Outcomes remained similar when comparing urban infants to rural infant subgroups with the longest hospital travel distance (≥60 miles) and lowest median household income (<$35 000). CONCLUSIONS: Despite longer travel distances and lower financial resources, rural infants with congenital anomalies have similar postoperative outcomes to urban infants when treated at children's hospitals. Future work is needed to examine outcomes for infants treated outside children's hospitals and to determine whether efforts are necessary to increase access to children's hospitals.

Impact of the Affordable Care Act's Medicaid expansion on tertiary pediatric surgical care.

BACKGROUND: Many children gained insurance with the 2014 Affordable Care Act's (ACA) Medicaid Expansion (ME), yet its impact on access to pediatric tertiary surgical care remains unknown. We examined the effect of ME on rates of elective, ambulatory surgery (EAS), especially among publicly-insured and ethnoracial-minority patients. METHODS: Surgical patients ≤18 years between 2012 and 2018 were identified using the Pediatric Health Information System. Interrupted time series analyses were conducted to predict the monthly proportion of publicly-insured patients and EAS rates in ME and nonexpansion states. RESULTS: 3,270,842 patients were included. Nonexpansion states demonstrated a 1.10% (p<0.05) increase in the proportion of publicly-insured patients at ACA implementation, which then plateaued. No immediate change was observed in ME states, but there was an annual 1.08% (p<0.01) decrease in subsequent years. Publicly-insured EAS rates decreased by 1.09% (p<0.01) in nonexpansion states; no change was observed in ME states. A 3.36% (p<0.01) increase in EAS rates was observed in nonexpansion and ME states. The gap in EAS rates increased between private and publicly-insured patients in nonexpansion, but not ME states. CONCLUSIONS: Increased coverage for children in ME states was not associated with more access to tertiary pediatric surgical care; however, while nonexpansion states saw an increase in insurance-based disparities, ME states did not. Though insurance coverage is critical to access, other factors may be contributing to persistent disparities in access to pediatric surgical care.

Antibiotic resistance is common in the cultures of intraabdominal abscess drainage after appendectomy.

INTRODUCTION: Intraabdominal abscesses (IAA) are a common complication following appendectomy. Empiric antibiotic regimens may fail to prevent IAA due to changes in bacterial resistance. We aim to describe the bacteriology of pediatric patients requiring drainage of an IAA after an appendectomy for appendicitis. METHODS: We performed a retrospective study of patients ≤18 years who underwent percutaneous drainage of an IAA following appendectomy a single U.S. children's hospital between 2015 and 2018. Patient demographics, appendicitis characteristics, antibiotic regimens, and culture data were collected. RESULTS: In total, 71 patients required drainage of an IAA of which 48 (67%) were male, the average age was 9.81 (SD 3.31) years and 68 (95.7%) having complicated appendicitis. Ceftriaxone/metronidazole was the most common empiric regimen prior to IAA drainage occurring in 64 (90.1%) patients. IAA cultures isolated organisms in 34 (47.9%) patients. Of those with positive cultures, 17 (50%) cases demonstrated an antimicrobial resistant organism. Most notably, 20% of Escherichia coli was resistant to the empiric regimen. Empiric antimicrobial regimens did not appropriately cover 92.3% of Pseudomonas aeruginosa cultures or 100% of Enterococcus species cultures. Antimicrobial regimens were changed following IAA drainage in 30 (42.2%) instances with 23 (32.4%) instances due to resistance in culture results or lack of appropriate empiric antimicrobial coverage. CONCLUSIONS: IAA culture data following appendectomy for appendicitis frequently demonstrates resistance to or lack of appropriate coverage by empiric antimicrobial regimens. These data support close review of IAA culture results to identify prevalent resistant pathogens along with local changes in resistance. LEVEL OF EVIDENCE: Level III.

Controversy in the classification of appendicitis and utilization of postoperative antibiotics.

BACKGROUND: There is wide variability and considerable controversy regarding the classification of appendicitis and the need for postoperative antibiotics. This study aimed to assess interrater agreement with respect to the classification of appendicitis and its influence on the use of postoperative antibiotics amongst surgeons and surgical trainees. METHODS: A survey comprising 15 intraoperative images captured during appendectomy was distributed to surgeons and surgical trainees. Participants were asked to classify severity of disease (normal, inflamed, purulent, gangrenous, perforated) and whether they would prescribe postoperative antibiotics. Statistical analysis included percent agreement, Krippendorff's alpha for interrater agreement, and logistic regression. RESULTS: In total, 562 respondents completed the survey: 206 surgical trainees, 217 adult surgeons, and 139 pediatric surgeons. For classification of appendicitis, the statistical interrater agreement was highest for categorization as gangrenous/perforated versus nongangrenous/nonperforated (Krippendorff's alpha = 0.73) and lowest for perforated versus nonperforated (Krippendorff's alpha = 0.45). Fourteen percent of survey respondents would administer postoperative antibiotics for an inflamed appendix, 44% for suppurative, 75% for gangrenous, and 97% for perforated appendicitis. Interrater agreement of postoperative antibiotic use was low (Krippendorff's alpha = 0.28). The only significant factor associated with postoperative antibiotic utilization was 16 or more years in practice. CONCLUSIONS: Surgeon agreement is poor with respect to both subjective appendicitis classification and objective utilization of postoperative antibiotics. This survey demonstrates that a large proportion (59%) of surgeons prescribe antibiotics after nongangrenous or nonperforated appendectomy, despite a lack of evidence basis for this practice. These findings highlight the need for further consensus to enable standardized research and avoid overtreatment with unnecessary antibiotics.

The costs and benefits of emergent surgical workflow for acute appendicitis in children.

BACKGROUND: Controversy exists regarding how operative timing affects patient safety and resource utilization for acute appendicitis. Over 3 years, our institution trialed efforts to optimize appendectomy workflow. Our aim is to describe the ramifications of expediting appendectomy and implementing standardized protocols relative to historic controls. METHODS: Patient records at a freestanding children's hospital were reviewed from synchronized 6-month periods from 2019 to 2021. During Year 1 (historic), no standardized workflows existed. In Year 2 (expedited), appendicitis management was protocoled using a clinical quality improvement bundle, which included performing appendectomies within two hours of diagnosis. In Year 3 (QI), operative timing was relaxed to the same calendar day while all prior QI initiatives continued. Descriptive statistics were performed, using hospital length of stay (LOS) as the primary outcome. RESULTS: 298 patients underwent appendectomy for acute appendicitis. The median expedited workflow LOS was 15.3 hours shorter (p = 0.003) than historic controls; however, this was sustained despite relaxation of surgical urgency in the QI workflow. No differences in perforation rates were observed. During the expedited workflow, OR overtime staffing expense increased by $90,000 with no significant change in hospital costs. In multivariate regression, perforation was the only variable associated with LOS. CONCLUSION: Hospital LOS can be shortened by expediting appendectomy. However, in our institution this did not decrease hospital costs and was furthermore balanced by higher personnel expenses. A sustained decrease in LOS after relaxing operative urgency standards implies that concurrent QI initiatives represent a more effective and cost-efficient strategy to decrease hospital resource utilization. LEVEL OF EVIDENCE: Level III.

Electrical stimulation of cardiomyocytes activates mitochondrial matrix metalloproteinase causing electrical remodeling.

Cardiac arrhythmias, instigated by mechanical and electrical remodeling, are associated with activation of extracellular matrix metalloproteinases (MMPs). However, the connection between intracellular MMPs activation and arrhythmogenesis is not well established. Previously, we determined localization of MMP in the mitochondria using confocal microscopy. We tested the hypothesis that electrical pacing induces the activation of mitochondrial MMP (mtMMP) and is associated with myocyte mechanical dysfunction. Myocytes were isolated and field stimulated at 1 and 4 Hz. Myocyte mechanics and calcium transient was studied using Ion-Optix system. Mitochondrial MMP-9 activation was evaluated using zymography. There was a 25% increase in 1 Hz and 40% increase in 4 Hz stimulation. We observed an increase in mtMMP activation with increase in electrical pacing compared to 0 Hz with a significant increase (p<0.05, n=3). Field stimulation at 4 Hz decreased cell re-lengthening. The levels of calcium transient were reduced with increase in contraction frequency. We conclude that electrical stimulation activates mtMMP-9 that is associated with myocyte mechanical dysfunction.

Timeliness of pediatric surgical appendicitis care is associated with time of hospital admission.

BACKGROUND: Despite the frequency of acute appendicitis in children, there is no evidence-based consensus surrounding the urgency of the operation if a diagnosis is made after regular business hours. Although a modest delay in time to operation does not increase disease severity, postponing cases to the next calendar day may be associated with higher resource utilization. We aimed to evaluate the trend of delaying appendectomies to the next calendar day and its associated outcomes. METHODS: We queried the Pediatric Health Information System to analyze appendectomy patients younger than 18 y of age from 2010 to 2018. Same-day appendectomy and next-day appendectomy cohorts were created using admission hour and operative day. Healthcare cost, length of stay, surgical complications, and 30-day readmission rates were collected. Bivariate analyses and multivariable regressions were used to evaluate groups stratified by time of presentation. RESULTS: During the study period, 113,662 appendectomies were performed, comprising 88,715 (78.1%) same-day appendectomies and 24,947 (21.9%) next-day appendectomies. A higher proportion of same-day appendectomies (80.5%) were performed during hours 12:00am to 5:00pm and 19.5% were performed during hours 6:00pm to 11:00pm. The trend of next-day appendectomies increased during the study period from 13.9% to 20.2%. This was primarily evident in the 6:00pm to 11:00pm period. The 5:00pm cutoff was most predictive of a next-day appendectomy. Next-day appendectomies had similar rates of surgical complications; however, they were associated with higher costs, longer lengths of stay, and higher readmission rates. CONCLUSION: As the understanding of appendicitis urgency has changed, a more tempered approach of delivering surgical care has trended. Although short delays appear safe, postponement to the next calendar day is associated with higher resource utilization.

Cardiac specific deletion of N-methyl-d-aspartate receptor 1 ameliorates mtMMP-9 mediated autophagy/mitophagy in hyperhomocysteinemia.

Autophagy is an important process in the pathogenesis of cardiovascular diseases; however, the proximal triggers for mitochondrial autophagy were unknown. The N-methyl-d-aspartate receptor 1 (NMDA-R1) is a receptor for homocysteine (Hcy) and plays a key role in cardiac dysfunction. Cardiac-specific deletion of NMDA-R1 has been shown to ameliorate Hcy-induced myocyte contractility. Hcy activates mitochondrial matrix metalloproteinase-9 (mtMMP-9) and induces translocation of connexin-43 (Cxn-43) to the mitochondria (mtCxn-43). We sought to show cardiac-specific deletion of NMDA-R1 mitigates Hcy-induced mtCxn-43 translocation, mtMMP-9-mediated mtCxn-43 degradation, leading to mitophagy, in part, by decreasing mitochondrial permeability (MPT). Cardiac-specific knockout (KO) of NAMDA-R1 was generated using the cre/lox approach. The myocyte mitochondria were isolated from wild type (WT), WT + Hcy (1.8 g of DL-Hcy/L in the drinking water for 6 weeks), NMDA-R1 KO + Hcy, and NR1(fl/fl)/Cre (NR1(fl/fl)) genetic control mice. Mitochondrial respiratory capacity and MPT were measured by fluorescence-dye methods. The mitochondrial superoxide and peroxinitrite levels were detected by confocal microscopy using Mito-SOX and dihydrorhodamine-123. The mtMMP-9 activity and expression were detected by zymography and RT-PCR analyses. The mtCxn-43 translocation was detected by confocal microscopy. The degradation of mtCxn-43 and LC3-I/II (a marker of autophagy) were detected by Western blot. These results suggested that Hcy enhanced intramitochondrial nitrosative stress in myocytes. There was a robust increase in mtMMP-9 activity. An increase in translocation and degradation of mtCxn-43 was also noted. These increases led to mitophagy. The effects were ameliorated by cardiac-specific deletion of NMDA-R1. We concluded that HHcy increased mitochondrial nitrosative stress, thereby activating mtMMP-9 and inciting the degradation of mtCxn-43. This led to mitophagy, in part, by activating NMDA-R1. The findings of this study will lead to therapeutic ramifications for mitigating cardiovascular diseases by inhibiting the mitochondrial mitophagy and NMDA-R1 receptor.

Hydrogen sulfide protects against vascular remodeling from endothelial damage.

Remodeling by its very nature implied synthesis and degradation of extracellular matrix (ECM) proteins. Although oxidative stress, matrix metalloproteinase (MMP) and tissue inhibitor of metalloproteinase (TIMP) have been implicated in vascular remodeling, the differential role of MMPs versus TIMPs and oxidative stress in vascular remodeling was unclear. TIMP-3 induced vascular cell apoptosis, therefore, we hypothesized that during vascular injury TIMP-3, MMP-9 and -12 (elastin-degrading MMP) were increased, whereas MMP-2 (constitutive MMP) and TIMP-4 (cardioprotective TIMP) decreased. Because of the potent anti-oxidant, vasorelaxing, anti-hypertensive agent, hydrogen sulfide (H2S) was used to mitigate the vascular remodeling due to the differential expression of MMP and TIMP. Carotid artery injury was created by inserting a PE-10 catheter and rotating several times before pulling out. The insertion hole was sealed. Mice were grouped: wild type (WT), wild-type damaged artery (WTD), WT+NaHS (sodium hydrogen sulfide, precursor of H2S) treatment (30 µmol/L in drinking water/6 weeks) and WTD+NaHS treatment. Carotid arteries were analyzed for oxidative stress and remodeling, by measuring super oxide dismutase-1 (SOD1), p47 (NADPH oxidase subunit), nitrotyrosine, MMPs and TIMPs by in situ immunolabeling and by Western blot analyses. The results suggested robust increase in p47, nitrotyrosine, MMP-9, MMP-12, TIMP-3 and decrease in SOD1 and MMP-2 levels in the injured arteries. The treatment with H2S ameliorated these effects. We concluded that p47, TIMP-3, MMP-9 and -12 were increased where as SOD-1, MMP-2 and TIMP-4 were decreased in the injured arteries. The treatment with H2S mitigated the vascular remodeling by normalizing the levels of redox stress, MMPs and TIMPs.