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Diabetic vascular pathology is largely attributable to impairments in tissue recovery from hypoxia. Circulating progenitor cells have been postulated to play a role in ischemic recovery, and deficiencies in these cells have been well described in diabetic

Background: In this study, we compared outcomes between intracranial pressure monitoring (ICP) only versus ventriculostomy (VT) using a nationwide database of pediatric trauma patients., Methods: Pediatric patients (<18 years) with severe blunt TBI who underwent ICP monitoring with or without VT were identified from the 2017-2021 ACS Trauma Quality Programs. We excluded patients who experienced death or craniotomy/craniectomy within 48 h. The primary outcome was discharge disposition. Secondary outcomes were subsequent intracranial surgery, length of stay (LOS), and infectious complications. Competing risks survival analysis was used to evaluate the multivariable association between ICP vs. VT and outcomes., Results: Of 1719 eligible patients, 65.9% were male and 54.1% had VT. Between the ICP and VT groups, there were no differences in mean age (11.4 vs. 11.0 years, p = 0.145), injury severity score (30.9 vs. 30.9, p = 0.937), or median GCS (3 vs. 3, p = 0.120). Multivariable analysis showed a robust association between VT and discharge home (compared to rehabilitation center; sHR 0.85, 95% CI 0.74-0.97, p = 0.017). VT use was not associated with increased mortality compared to ICP (p = 0.342). Finally, VT patients had longer median LOS (20.5 vs. 18.0 days, p < 0.001) but there was no difference in subsequent craniotomy/craniectomy (8.6 vs. 6.5%, p = 0.096) or infectious complications (1.2 vs. 0.9%, p = 0.549)., Conclusion: VT was associated with greater discharge to home. Although VT patients had a greater LOS, the risk for other secondary outcomes did not vary, suggesting that VT may have benefits for the treatment of severe TBI with respect to discharge disposition., Level of Evidence: III., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Nonaccidental trauma (NAT), or child abuse, is a leading cause of childhood injury and death in the US. Studies demonstrate that military-affiliated individuals are at greater risk of mental health complication and family violence, including child maltreatment. There is limited information about the outcomes of military children who experience NAT. This study compares the outcomes between military-dependent and civilian children diagnosed with NAT., Study Design: A single-institution, retrospective review of children admitted with confirmed NAT at a Level I trauma center was performed. Data were collected from the institutional trauma registry and the Child Abuse Team's database. Military affiliation was identified using insurance status and parental or caregiver self-reported active-duty status. Demographic and clinical data including hospital length of stay (LOS), morbidity, specialty consult, and mortality were compared., Results: Among 535 patients, 11.8% (n = 63) were military-affiliated. The median age of military-associated patients, 3 months (interquartile range [IQR] 1 to 7), was significantly younger than civilian patients, 7 months (IQR 3 to 18, p < 0.001). Military-affilif:ated patients had a longer LOS of 4 days (IQR 2 to 11) vs 2 days (IQR 1 to 7, p = 0.041), increased morbidity or complication (3 vs 2 counts, p = 0.002), and a higher mortality rate (10% vs 4%, p = 0.048). No significant difference was observed in the number of consults or injuries, trauma activation, or need for surgery., Conclusions: Military-affiliated children diagnosed with NAT experience more adverse outcomes than civilian patients. Increased LOS, morbidity or complication, and mortality suggest military-affiliated patients experience more life-threatening NAT at a younger age. Larger studies are required to further examine this population and better support at-risk families., (Copyright © 2024 by the American College of Surgeons. Published by Wolters Kluwer Health, Inc. All rights reserved.)

Introduction: There is limited literature on the optimal approach to treat adhesive small bowel obstruction (ASBO) in children. We sought to compare rates and outcomes of laparoscopic (LAP) and open (OPEN) surgery for pediatric ASBO., Methods: A California statewide database was used to identify children (<18 years old) with an index ASBO from 2007 to 2020. The primary outcome was the type of operative management: LAP or OPEN. Secondary outcomes were hospital characteristics, patient demographics, and postoperative complications. We excluded patients treated non-operatively., Results: Our study group had 545 patients. 381 (70%) underwent OPEN and 164 (30%) LAP during the index admission. Over the study period, there was increasing use of laparoscopic surgery, with higher use in older children (p < 0.001). LAP was associated with fewer overall complications (65.2% vs. 81.6%, p < 0.001), with a decreasing trend in complications over time (p < 0.001). The LAP group had significantly lower rates of bowel resection (4.9% vs. 17.1%, p < 0.001), length of stay (LOS) (17 vs. 23 days, p < 0.001), and TPN use (12.2% vs. 29.1%, p < 0.001). Mortality rates were equivalent. Although the LAP group had lower readmission rates (22.6% vs. 37.3%, p < 0.001), the length of time between discharge and readmission was similar (171 vs. 165 days, p = 0.190)., Discussion: The use of laparoscopic surgery for index ASBO increased over the study period. However, it was less commonly utilized in younger children. LAP had fewer overall complications as well as shorter LOS, decreased TPN use, and fewer readmissions. The benefits and risks of each approach must be weighed., Level of Evidence: III., Competing Interests: Conflict of interest None of the authors have a financial or other conflict of interest. Dr. Ignacio is a voluntary Associate Editor for the Journal of Surgical Research. There is no financial support or additional aid provided by the Journal of Surgical Research for this position, and he was excluded from the entire peer-review and editorial process for this manuscript. The views in this paper are those of the authors and do not reflect the official policy or position of the Department of the Navy, the Department of Defense, or the United States Government., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Introduction: The purpose of our study is to assess neighborhood socioeconomic disadvantage (NSD) as a risk factor for window falls (WF) in children., Methods: A single institution retrospective review was performed of patients ≤18 years old with fall injuries treated at a Level I trauma center between 2018 and 2021. Demographic, injury, and NSD characteristics which were collected from a trauma registry were analyzed and compared between WF versus non-window falls. Area Deprivation Index (ADI) was used to measure NSD levels based on patients' home address 9-digit zip code, with greater NSD being defined as ADI quintiles 4 and 5. Property type was used to compare falls that took place at single-family homes versus apartment buildings., Results: Among 1545 pediatric fall injuries, 194 were WF, of which 60 % were male and 46 % were Hispanic. WF patients were younger than NWF patients (median age WF 3.2 vs. age 4.3, p<0.047). WF patients were more likely to have a depressed Glasgow Coma Scale (GCS score ≤12, WF 9 % vs. 3 %) and sustain greater head/neck injuries (median AIS 3vs. AIS 2, p<0.001) when compared to NWF. WF patients had longer hospital and ICU lengths of stay than NWF patients (p<0.001 and p<0.001, respectively). WF patients were more likely to live in areas of greater NSD than NWF patients (53 % vs. 35 %, p<0.001), and 73 % of all WF patients lived in apartments or condominiums., Conclusions: Window fall injuries were associated with lower GCS, greater severity of head/neck injuries, and longer hospital and ICU length of stay than non-window falls. ADI research can provide meaningful data for targeted injury prevention programs in areas where children are at higher risk of window falls., Study Type: Retrospective review., Level of Evidence: III., Competing Interests: Declaration of competing interest The authors declare no conflicts of interest., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Objective: Our objective was to determine the utility of enteral contrast-based protocols in the diagnosis and management of adhesive small bowel obstruction (ASBO) for children., Background: Enteral contrast-based protocols for adults with ASBO are associated with decreased need for surgery and shorter hospitalization. Pediatric-specific data are limited., Methods: We conducted a prospective observational study between October 2020 and December 2022 at nine children's hospitals who are members of the Western Pediatric Surgery Research Consortium. Inclusion criteria were children aged 1-20 years diagnosed with ASBO who underwent a trial of nonoperative management (NOM) at hospital admission. Comparisons were made between those children who received an enteral contrast challenge and those who did not. The primary outcome was need for surgery., Results: We enrolled 136 children (71% male; median age: 12 y); 84 (62%) received an enteral contrast challenge. There was no difference in rate of operative intervention between the no contrast (34.6%) and contrast groups (36.9%; P=0.93). Eighty-seven (64%) were successfully managed nonoperatively with no difference in median length of stay (P=0.10) or rate of unplanned readmission (P=0.14). Among the 49 children who required an operation, there was no significant difference in time from admission to surgery or rate of small bowel resection based on prior contrast administration., Conclusions: The addition of enteral contrast-based protocols for management of pediatric ASBO does not decrease the likelihood of surgery or shorten hospitalization. Larger randomized studies may be needed to further define the role of radiologic contrast in the management of ASBO in children., Competing Interests: The authors report no conflicts of interest., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Introduction: To examine practice patterns and surgical outcomes of nonoperative versus operative management (OPM) of children presenting with an index adhesive small bowel obstruction (ASBO)., Methods: A California statewide health discharge database was used to identify children (<18 y old) with an index ASBO from 2007 to 2020. The primary study outcome was evaluating initial management patterns (nonoperative versus OPM and early [≤3 d] versus late surgery [>3 d]) of ASBO. Secondary outcomes were hospital characteristics, patient demographics, and postoperative complications., Results: Of the 2297 patients identified, 1948 (85%) underwent OPM for ASBO during the index admission. Of these, 14.7% underwent early surgery within 3 d. Teaching hospitals had higher operative intervention than nonteaching centers (87.1% versus 83.7%, P = 0.034). OPM was the highest in 0-5-year-olds compared to other ages (89% versus 82%, P < 0.001). In comparison to early surgery, late surgery was associated with longer length of stay (early 7[interquartile range 5-10], late 9[interquartile range 6-17], P < 0.001), increased infectious complications (16.4% versus 9.8%, P = 0.004), and greater use of total parenteral nutrition (28.0% versus 14.3%, P = 0.001); there was no difference in bowel resection (21% versus 18%, P = 0.102) or mortality (P = 0.423)., Conclusions: Our pediatric study demonstrated a high rate of OPM for index ASBO, especially in newborns and toddlers. Although operative intervention, especially late surgery, was associated with increased length of stay, increased infectious complications, and increased total parenteral nutrition use, the rates of bowel resection and mortality did not differ by management strategy. These trends need to be further evaluated to optimize outcomes., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: The purpose of this study was to identify clinical and traffic factors that influence pediatric pedestrian versus automobile collisions (P-ACs) with an emphasis on health care disparities., Methods: A retrospective review was performed of pediatric (18 years or younger) P-ACs treated at a Level I pediatric trauma center from 2008 to 2018. Demographic, clinical, and traffic scene data were analyzed. Area deprivation index (ADI) was used to measure neighborhood socioeconomic disadvantage (NSD) based on home addresses. Traffic scene data from the California Statewide Integrated Traffic Records System were matched to clinical records. Traffic safety was assessed by the streetlight coverage, the proximity of the collision to home addresses, and sidewalk coverage. Descriptive statistics and univariate analysis for key variables and outcomes were calculated using Kruskal-Wallis, Wilcoxon, χ 2 , or Fisher's exact tests. Statistical significance was attributed to p values of <0.05., Results: Among 770 patients, the majority were male (65%) and Hispanic (54%), with a median age of 8 years (interquartile range, 4-12 years). Hispanic patients were more likely to live in more disadvantaged neighborhoods than non-Hispanic patients (67% vs. 45%, p < 0.01). There were no differences in clinical characteristics or outcomes across ADI quintiles. Using the Statewide Integrated Traffic Records System (n = 272), patients with more NSD were more likely injured during dark streetlight conditions (15% vs. 4% least disadvantaged; p = 0.04) and within 0.5 miles from home ( p < 0.01). Pedestrian violations were common (65%). During after-school hours, 25% were pedestrian violations, compared with 12% driver violations ( p = 0.02)., Conclusion: A larger proportion of Hispanic children injured in P-ACs lived in neighborhoods with more socioeconomic disadvantage. Hispanic ethnicity and NSD are each independently associated with P-ACs. Poor streetlight conditions and close proximity to home were associated with the most socioeconomically disadvantaged neighborhoods. This research may support targeted prevention programs to improve pedestrian safety in children., Level of Evidence: Prognostic/Epidemiological; Level IV., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Surgical care is an important, yet often neglected component of child health in low- and middle-income countries (LMICs). This study examines the potential impact of scaling up surgical care at first-level hospitals in LMICs within the first 20 years of life., Methods: Epidemiological data from the global burden of disease 2019 Study and a counterfactual method developed for the disease control priorities; 3rd Edition were used to estimate the number of treatable deaths in the under 20 year age group if surgical care could be scaled up at first-level hospitals. Our model included three digestive diseases, four maternal and neonatal conditions, and seven common traumatic injuries., Results: An estimated 314,609 (95% UI, 239,619-402,005) deaths per year in the under 20 year age group could be averted if surgical care were scaled up at first-level hospitals in LMICs. Most of the treatable deaths are in the under-5 year age group (80.9%) and relates to improved obstetrical care and its effect on reducing neonatal encephalopathy due to birth asphyxia and trauma. Injuries are the leading cause of treatable deaths after age 5 years. Sixty-one percent of the treatable deaths occur in lower middle-income countries. Overall, scaling up surgical care at first-level hospitals could avert 5·1% of the total deaths in children and adolescents under 20 years of age in LMICs per year., Conclusions: Improving the capacity of surgical services at first-level hospitals in LMICs has the potential to avert many deaths within the first 20 years of life., (© 2022. The Author(s).)

Background: Laparoscopic gastrostomy tube (GT) placement carries the risk of early tube dislodgement and is often modified with absorbable subcutaneously-tunneled transabdominal tacking sutures that can aid in tube replacement. However, these buried sutures may increase the risk of surgical site infection (SSI). This study sought to evaluate SSI rates associated with different types of transabdominal tacking sutures used in modified laparoscopic GT placement., Methods: A single-institution, retrospective review was performed of all patients ≤18 years-old undergoing modified laparoscopic GT placement between September 2016 and March 2020. Patients were stratified into three groups by suture type used, and the primary outcome was SSI within six weeks of surgery. Demographic and perioperative data were analyzed by chi-square or Fisher's exact test., Results: A total of 113 modified laparoscopic GT placements were performed at a median age of 9 months (interquartile range 3 months to 3 years). Prophylactic antibiotic use was similar between groups. Eleven patients (10%) developed an SSI, and all were treated with antibiotics alone. No SSIs were observed with the use of poliglecaprone suture (n = 46), and higher SSI rates were observed with use of polyglactin (n = 17) and polydioxanone (n = 51) suture (18% polyglactin vs. 16% polydioxanone vs. 0% poliglecaprone, p<0.05). No differences were observed in rates of early postoperative dislodgement, leakage, or granulation tissue., Conclusion: Absorbable braided and long-lasting monofilament transabdominal tacking sutures may increase risk of SSI following modified laparoscopic gastrostomy tube placement. In this cohort, the use of poliglecaprone (Monocryl) suture was associated with no SSIs and similar rates of postoperative dislodgement, leakage, and granulation tissue., Level of Evidence: Treatment Study, Level III., (Published by Elsevier Inc.)

Background: Resuscitative endovascular balloon occlusion of the aorta (REBOA) is a potential adjunct in pediatric trauma patients with noncompressible truncal and pelvic hemorrhage; however, there are little data evaluating the anatomic considerations of REBOA in children. We evaluated the vascular dimensions and anatomic limitations of using REBOA in children., Methods: Computed tomography scans of pediatric patients performed between February 2016 and October 2019 were retrospectively reviewed by two investigators. Vascular measurements included diameters of aorta zones I and III, common iliac arteries, external iliac arteries, and common femoral arteries (CFAs), and distances between access site (CFA) and aorta zones I and III. Measurements were grouped within Broselow categories, based upon patient height. Interrater reliability for measurements was determined using intraclass correlation coefficients. Vascular dimensions were correlated with the patient's height, weight, and body mass index using linear regression analysis., Results: A total of 557 computed tomography scans met the inclusion criteria and were reviewed. Measurements of vessel diameter and distance from the CFA to aorta zones I and III were determined and grouped by Broselow category. Patient age ranged from 0 to 18 years, with a male to female ratio of 1:1. Overall interrater reliability of vessel measurements was good (average intraclass correlation coefficient, 0.90). Vessel diameter had greatest correlation with height (R2 = 0.665, aorta zone I; R2 = 0.611, aorta zone III) and poorly correlated with body mass index (R2 = 0.318 and R2 = 0.290, respectively)., Conclusion: This study represents the largest compilation of REBOA-related pediatric vessel diameter measurements and the first to provide data on distance between access site and balloon deployment zones. Based on our findings, the 7-Fr REBOA catheter would be appropriate for the Black, Green, and Orange Broselow categories, and a 4-Fr REBOA catheter would be warranted for Yellow, White, and Blue Broselow categories., Level of Evidence: Prognostic and epidemiological, level III., (Copyright © 2022 American Association for the Surgery of Trauma.)

Background: Ventriculoperitoneal shunt (VPS) placement into the reoperative abdomen can be challenging due to intraperitoneal adhesions. Laparoscopic guidance may provide safe abdominal access and identify an area for optimal cerebrospinal fluid drainage. The study aim was to compare laparoscopic-assisted VPS placement to an "open" approach in patients with prior abdominal surgery., Materials and Methods: A retrospective review was performed of children undergoing VPS placement into a reoperative abdomen from 2009-2019. Clinical data were collected, and patients undergoing laparoscopy (LAP) were compared to those undergoing an open approach (OPEN)., Results: A total of 120 children underwent 169 VPS placements at a median age of 8 y (IQR 2-15 y), and a mean number of two prior abdominal operations (IQR 1-2). Laparoscopy was used in 24% of cases. Shunt-related complications within 30 d were lower in the LAP group (0% versus 19%, P = 0.001), as were VPS-related postoperative emergency department visits (0% versus 13%, P = 0.003) and readmissions (0% versus 13%, P = 0.013). Shunt malfunction rates were higher (42% OPEN versus 25% LAP, P = 0.03) and occurred sooner in the OPEN group (median 26 versus 78 wk, P = 0.01). The LAP group demonstrated shorter operative times (63 versus 100 min, P < 0.0001), and the only bowel injury. Time to feeds, length of stay, and mortality were similar between groups., Conclusions: Laparoscopic guidance during VPS placement into the reoperative abdomen is associated with a decrease in shunt-related complications, longer shunt patency, and shorter operative times. Prospective study may clarify the potential benefits of laparoscopy in this setting., (Published by Elsevier Inc.)

Background: Pediatric surgeons are often asked to treat clinical problems for which little high-quality data exist. For adults with adhesive small bowel obstruction (ASBO), water soluble contrast-based protocols are used to guide management. Little is known about their utility in children. We aimed to better understand key factors in clinical decision-making processes and integration of adult based data in pediatric surgeon's approach to ASBO., Methods: We administered a web-based survey to practicing pediatric surgeons at institutions comprising the Western Pediatric Surgery Research Consortium., Results: The response rate was 69% (78/113). Over half of respondents reported using contrast protocols to guide ASBO management either routinely or occasionally (n = 47, 60%). Common themes regarding the incorporation of adult-based data into clinical practice included the need to adapt protocols for pediatric patients, the dearth of pediatric specific data, and the quality of the published adult evidence., Conclusions: Our findings demonstrate that pediatric surgeons use contrast-based protocols for the management of ASBO despite the paucity of pediatric specific data. Furthermore, our survey data help us understand how pediatric surgeons incorporate adult based evidence into their practice., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: Older aged adults and those with pre-existing conditions are at highest risk for severe COVID-19 associated outcomes., Methods: Using a large dataset of genome-wide RNA-seq profiles derived from human dermal fibroblasts (GSE113957) we investigated whether age affects the expression of pattern recognition receptor (PRR) genes and ACE2, the receptor for SARS-CoV-2., Results: Extremes of age are associated with increased expression of selected PRR genes, ACE2 and four genes that encode proteins that have been shown to interact with SAR2-CoV-2 proteins., Conclusions: Assessment of PRR expression might provide a strategy for stratifying the risk of severe COVID-19 disease at both the individual and population levels.

Background/purpose: This study aimed to compare preoperative management strategies for patients undergoing trephination for pilonidal disease and evaluate risk factors for recurrence., Methods: A retrospective review was performed of children undergoing index surgical treatment with trephination for pilonidal disease between September 2017 and April 2019. Intraoperative and postoperative management were standardized. Demographic and perioperative data were collected and analyzed., Results: One-hundred twenty patients were identified with a median follow-up time of 7.5 months (interquartile range 4.1-13.2 months). Overall, 24 (20%) patients had a postoperative recurrence of pilonidal disease. Patients with multiple preoperative surgery clinic visits were less likely to have recurrent disease compared to those seen only once preoperatively (11% vs 26%, p = 0.040). Compared to patients without recurrence, those who recurred went to the operating room sooner from the time of initial surgical consultation (32 days vs 54 days, p < 0.001). Perioperative antibiotics, history of acute infection, and prior drainage procedures were not risk factors for recurrence., Conclusions: Multiple preoperative clinic visits are associated with a lower recurrence rate in children undergoing trephination for pilonidal disease. An increased duration of preoperative medical management may be responsible for this finding. Prospective study is needed to confirm these findings and identify additional factors that influence recurrence., Type of Study: Treatment Study., Level of Evidence: III (Retrospective Comparative)., (Published by Elsevier Inc.)

Introduction: Disease Control Priorities, 3rd Edition (DCP3) is an evidence-based, published resource that outlines essential procedures recommended for developing health care systems. These systems must consider various populations and the incidence of certain surgical conditions that require treatment. In relation to pediatric patients, the prevalence of certain surgical conditions encountered remains unclear in several low- and middle-income countries. Over the past 15 years, the USNS Mercy, one of the U.S. Navy's large hospital ships, has led the Pacific Partnership missions, which provide large-scale humanitarian aid throughout Southeast Asia. The data collected during these missions provide an opportunity to analyze the scope of pediatric operations performed in resource-limited countries. This analysis may assist in future planning for specific needs during military humanitarian missions., Materials and Methods: Surgical case data were prospectively collected during the six Pacific Partnership missions from 2006 to 2018. Demographic data were analyzed for all patients ≤8 years of age who underwent an operation. These data were retrospectively reviewed and all case logs were categorized by mission year, procedure-type, and host nation. Operations were classified based on 44 essential operations delineated in DCP3. Primary outcome was incidence of DCP3 essential operations. Secondary outcomes were perioperative complications. Standard statistical methods were performed for descriptive analysis., Results: A total of 3,209 major and minor operations were performed during 24 port visits in nine countries. Pediatric cases represented 1,117 (38%) of these procedures. Pediatric surgeons performed 291 (26%) of these cases. Based on DCP3 criteria, 789 pediatric operations (71%) were considered essential procedures. The most common DCP3-aligned procedures were cleft lip repair (432, 57%), hernia repair (207, 27%), and hydrocelectomy (60, 8%). Operative volume for pediatric surgery was highest during the 2008 mission (522 cases), when two pediatric surgeons were deployed, and lowest during the 2018 mission (five cases), when the mission focus was on education rather than surgical procedures and lack of pediatric cases referred by the host nation. Overall complication rate for pediatric cases was 1%., Conclusions: This study represents the largest known analysis of military humanitarian assistance. Pediatric operations represented over one-third of the surgical volume during Pacific Partnership missions from 2006 to 2018. The majority of cases were DCP3-aligned and associated with a low complication rate. Future humanitarian aid missions and host nations should allocate appropriate medical and educational resources to treat DCP3 pediatric surgical diseases in low- and middle-income countries to support long-term capacity building while maintaining optimal surgical outcomes., (© Association of Military Surgeons of the United States 2020. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: The study aim was to evaluate the readability of patient-oriented resources in pediatric surgery from children's hospitals in the US., Methods: The websites of 30 children's hospitals were evaluated for information on 10 common pediatric surgical procedures. Hospitals of varying characteristics including bed number, geographic location and ACS Children's Surgery Verification (CSV) were selected for the study. Readability scores were calculated using validated algorithms, and text was assigned an overall grade level., Results: Of 195 patient-oriented resources identified, only three (2%) were written at or below the recommended sixth grade level. Larger hospitals provided patient information at a higher grade level than medium and smaller sized centers (10.7 vs 9.3 vs 9.0 respectively, p < 0.001). Hospital size also correlated with availability of information, with large and medium sized hospitals having information more often. Hospitals with ACS CSV had information available more often, and written at a lower grade level, compared to nonverified centers (78% vs 62%, p = 0.023; 9.0 vs 10.0, p = 0.013)., Conclusion: Most hospital provided patient-oriented resources in pediatric surgery are written at a grade level well above the national guidelines. Centers with ACS CSV status have improved availability and readability of this material, while larger hospitals have improved availability, but decreased readability., Type of Study: Modeling study., Level of Evidence: III., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Objective: To characterize procedure-level burden of revisit-associated resource utilization in pediatric surgery with the goal of establishing a prioritization framework for prevention efforts., Summary of Background Data: Unplanned hospital revisits are costly to the health care system and associated with lost productivity on behalf of patients and their families. Limited objective data exist to guide the prioritization of prevention efforts within pediatric surgery., Methods: Using the Pediatric Health Information System (PHIS) database, 30-day unplanned revisits for the 30 most commonly performed pediatric surgical procedures were reviewed from 47 children's hospitals between January 1, 2012 and March 31, 2015. The relative contribution of each procedure to the cumulative burden of revisit-associated length of stay and cost from all procedures was calculated as an estimate of public health relevance if prevention efforts were successfully applied (higher relative contribution = greater potential public health relevance)., Results: 159,675 index encounters were analyzed with an aggregate 30-day revisit rate of 10.8%. Four procedures contributed more than half of the revisit-associated length of stay burden from all procedures, with the highest relative contributions attributable to complicated appendicitis (18.4%), gastrostomy (13.4%), uncomplicated appendicitis (13.0%), and fundoplication (9.4%). Four procedures contributed more than half of the revisit-associated cost burden from all procedures, with the highest relative contributions attributable to complicated appendicitis (18.8%), gastrostomy (14.6%), fundoplication (10.4%), and uncomplicated appendicitis (10.2%)., Conclusions and Relevance: A small number of procedures account for a disproportionate burden of revisit-associated resource utilization in pediatric surgery. Gastrostomy, fundoplication, and appendectomy should be considered high-priority targets for prevention efforts within pediatric surgery.

Objective: To estimate how many children and adolescent worldwide do not have access to surgical care., Methods: We estimated the number of children and adolescents younger than 19 years worldwide without access to safe, affordable and timely surgical care, by using population data for 2017 from the United Nations and international data on surgical access in 2015. We categorized countries by World Bank country income group and obtained the proportion of the population with no access to surgical care from a study by the Lancet Commission on Global Surgery., Findings: An estimated 1.7 billion (95% credible interval: 1.6-1.8) children and adolescents worldwide did not have access to surgical care in 2017. Lack of access occurred overwhelmingly in low- and middle-income countries where children and adolescents make up a disproportionately large fraction of the population. Moreover, 453 million children younger than 5 years did not have access to basic life-saving surgical care. According to Lancet Commission on Global Surgery criteria, less than 3% of the paediatric population in low-income countries and less than 8% in lower-middle-income countries had access to surgical care., Conclusion: There were substantial gaps in the availability of surgical services for children worldwide, particularly in low- and middle-income countries. Future research should focus on developing specific measures for assessing paediatric surgical access, delivery and outcomes and on clarifying how limited surgical access in the poorest parts of the world affects child health, especially mortality in children younger than 5 years.

Background/objectives: An incidental appendectomy is performed by some surgeons during operative treatment for intussusception to eliminate future appendicitis as a diagnostic consideration. However, an appendectomy can increase the risk of infection and other noninfectious complications making an incidental appendectomy controversial. We examined outcomes for surgical intervention for intussusception with appendectomy (SWA) compared to surgical reduction alone (SRA)., Methods: The Pediatric Health Information System database, 8/2008-9/2015, was retrospectively analyzed for patients under the age of five who required an operative intervention for intussusception without bowel resection. Demographic data and postoperative outcomes were analyzed. Available data included need for postoperative enema, subsequent small bowel obstruction, recurrent intussusception, length of stay (LOS), and adjusted total cost (ATC)., Results: Fifty-seven percent (748/1312) of patients had appendectomy performed during surgical reduction, 564 (43%) did not. ATC ($10,594 vs. $8939, p < 0.001) and LOS (3.0 vs. 2.48, p < 0.001) are higher in the SWA group. Rates of readmission are similar, but post-operative small bowel obstruction may be higher in the SWA group (1.3% vs. 0.35%, p = 0.06)., Conclusion: There is a higher mean LOS and ATC in the SWA group. This study suggests that appendectomy during surgery for uncomplicated intussusception should be reconsidered and requires further investigation., Type of Study: retrospective comparative study., Level of Evidence: III., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Purpose: Serum D-dimer has been proposed as a biomarker to aid in the diagnosis of pediatric traumatic brain injury (TBI). We investigated the accuracy of D-dimer in predicting the absence of TBI and evaluated the degree by which D-dimer could limit unnecessary computed tomography scans of the head (CTH)., Methods: Retrospective review of patients with suspected TBI from 2011 to 2013 who underwent evaluation with CTH and quantitative D-dimer. D-dimer levels were compared among patients with clinically-important TBI (ciTBI), TBI, isolated skull fracture and no injury., Results: Of the 663 patients evaluated for suspected TBI, ciTBI was identified in 116 (17.5%), TBI in 77 (11.6%), skull fracture in 61 (9.2%) and no head injury in 409 (61.7%). Patients with no head injury had significantly lower D-dimer values (1531±1791pg/μL) compared to those with skull fracture, TBI and ciTBI (2504±1769, 2870±1633 and 4059±1287pg/μL, respectively, p<0.005). Using a D-dimer value <750pg/μL as a negative screen, no ciTBIs would be missed and 209 CTHs avoided (39.7% of total)., Conclusion: Low plasma D-dimer predicts the absence of ciTBI for pediatric patient with suspected TBI. Incorporating D-dimer into current diagnostic algorithms may significantly limit the number of unnecessary CTHs performed in this population., Type of Study: Study of diagnostic test., Level of Evidence: I., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Introduction: Patients with congenital diaphragmatic hernia (CDH), gastroschisis, and omphalocele are prone to abnormalities of intestinal rotation and thus future midgut volvulus. Controversy exists whether routine preemptive Ladd procedure in this subgroup of asymptomatic patients is of value to reduce future volvulus., Methods: The Pediatric Health Information System (PHIS) database was queried for neonates with CDH, gastroschisis, and omphalocele between January 2009 and September 2015. Standard univariate and multivariate analysis was completed to compare risk of volvulus between patients treated with a preemptive Ladd versus no Ladd (p<0.05)., Results: Seven thousand seven hundred forty-nine neonates with CDH (40%), gastroschisis (38%), omphalocele (14%), and abdominal wall malformation (NOS) (9%) were identified. Overall, 3.6% (n=279) had a preemptive. Thirty-two patients had subsequent volvulus. Ladd procedure did not reduce volvulus readmissions for any diagnosis and was associated with a significantly increased risk of volvulus for omphalocele patients (9.1% vs 0.1%, p<0.001). Overall, a Ladd procedure during the index admission was associated with a higher risk for volvulus (1.4% vs. 0.4%, p=0.021) and was associated with a 3.28 increased odds ratio of future volvulus (95% CI 1.12-9.68)., Conclusion: Ladd procedure performed prophylactically in patients with CDH, gastroschisis, and omphalocele did not reduce subsequent volvulus., Level of Evidence: III, Retrospective Comparative Study., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Purpose: Outcomes associated with primary laparoscopic gastrojejunal (GJ) tube placement in the pediatric population were evaluated., Methods: A single-institution, retrospective review examined patients undergoing laparoscopic GJ tube placement between June 2011 and December 2014. Outcomes included gastric feeding tolerance, subsequent fundoplication, complications, and mortality., Results: Ninety laparoscopic GJ tubes were placed. Median follow-up was 342days (interquartile range [IQR]=141-561days). Median patient age was 5months (IQR=3-11months) and weight was 5.2kg (IQR=4-8.4kg). The most common indications for placement were gastroesophageal reflux (n=85, 94.4%) and/or aspiration (n=40, 44.4%). Most common comorbidities included cardiac (n=34, 37.8%) and respiratory (n=29, 32.2%) diseases. The complication rate was 17.8%, including one case of intestinal perforation. Thirty-four (37.7%) patients transitioned to gastric feeding within 1year; time to conversion was 156days (IQR=117-210days); of those, 18.9% patients transitioned to oral feedings. A fundoplication was later performed in 4 children for persistent reflux. Mortality was 23.3% with no procedural-related deaths., Conclusion: Primary laparoscopically placed GJ tubes are a reliable means of enteral access for pediatric patients with gastric feeding intolerance. Many of these children are successfully transitioned to gastric and/or oral feedings over time. Further studies are needed to characterize which patients are best served with a GJ tube versus alternatives such as fundoplication., Level of Evidence: III (treatment) TYPE OF STUDY: Retrospective., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Importance: Practice variation is believed to be a driver of excess health care spending, although few objective data exist to guide the prioritization of comparative effectiveness research (CER) in pediatric surgery., Objective: To identify high-priority general pediatric surgical procedures for CER on the basis of the following 2 complementary measures: the magnitude of interhospital cost variation as a surrogate for the need for and potential effect of CER at the patient level and the cumulative fiscal burden of this cost variation when considering the case volume from all hospitals as a surrogate for public health relevance., Design, Setting, and Participants: This was a cohort study of patients undergoing 1 of the 30 most costly pediatric surgical operations at 45 children's hospitals between January 1, 2014, and September 30, 2015. Cost data were extracted from the Pediatric Health Information System database and adjusted for differences in unit-based costing at the hospital level and for differences in case mix and disease severity at the patient level., Main Outcomes and Measures: First, the width of the interquartile range (WIQR) of the adjusted procedure-specific median cost across hospitals. Second, the procedure-specific cost variation burden, which was calculated as the aggregate sum of absolute cost differences between the overall adjusted median cost derived from all patients treated at all hospitals and the adjusted cost of each individual patient treated at all hospitals., Results: A total of 92 535 encounters were analyzed. The median number of encounters per hospital was 2011 (interquartile range [IQR], 1224-2619), and the median number of encounters per procedure was 610 (IQR, 442-2610). In the final cohort, 66.9% (n = 61 933) of the patients were male, and the median age was 7 years (IQR, 1.9-12.3 years). Cost variation at the hospital level was greatest for gastroschisis (WIQR, $48 471; median, $111 566 [IQR, $91 195-$139 936]), congenital diaphragmatic hernia (WIQR, $43 948; median, $154 730 [IQR, $129 764-$173 712]), tracheoesophageal fistula/esophageal atresia (WIQR, $39 206; median, $105 259 [IQR, $87 335-$126 541]), and total colectomy for ulcerative colitis (WIQR, $24 497; median, $34 910 [IQR, $28 815-$53 312]). The following 5 diagnoses accounted for 52.5% of the cumulative cost variation burden from all 30 conditions: uncomplicated appendicitis (18.0% [$66 205 117]), complicated appendicitis (14.1% [$51 702 402]), gastroschisis (9.5% [$34 940 331]), gastrostomy (5.8% [$21 227 436]), and small-intestinal atresia (5.1% [$18 840 546]). Neonatal cases contributed 3.6% of the case volume and accounted for 26.8% of the cumulative cost variation burden from all 30 conditions., Conclusions and Relevance: A small number of procedures account for most of the cost variation burden in pediatric surgery, with some demonstrating wide cost variation among hospitals. Gastroschisis and small-intestinal atresia may be particularly high-yield targets for multidisciplinary CER efforts, while the management of appendicitis and gastrostomy should be considered high-priority conditions among pediatric surgeons.

Diabetic vascular pathology is largely attributable to impairments in tissue recovery from hypoxia. Circulating progenitor cells have been postulated to play a role in ischemic recovery, and deficiencies in these cells have been well described in diabetic patients. Here, we examine bone marrow-derived mesenchymal progenitor cells (BM-MPCs) that have previously been shown to be important for new blood vessel formation and demonstrate significant deficits in the context of diabetes. Further, we determine that this dysfunction is attributable to intrinsic defects in diabetic BM-MPCs that are not correctable by restoring glucose homeostasis. We identify two transcriptionally distinct subpopulations that are selectively depleted by both type 1 and type 2 diabetes, and these subpopulations have provasculogenic expression profiles, suggesting that they are vascular progenitor cells. These results suggest that the clinically observed deficits in progenitor cells may be attributable to selective and irreversible depletion of progenitor cell subsets in patients with diabetes., (© 2014 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.)

Colonoscopy is a commonly performed medical procedure generally considered safe and effective. Rare complications include postpolypectomy bleeding and perforation. A far less common and more unusual complication is splenic injury. We present the case of a patient who developed this very outcome, presenting to the emergency department with abdominal pain several hours after the procedure. The mechanism of such injury is not known but has been hypothesized to be either traction on the splenocolic ligament or previously formed adhesions, direct blunt injury, or special maneuvers used to advance the colonoscope. Patients typically present with severe abdominal pain less than 24 hours after the procedure and may demonstrate Kehr's sign. Computed tomographic imaging is the diagnostic method of choice, and suspicion of splenic injury should necessitate careful observation with potential for operative intervention.

An incomplete understanding of the nature of heterogeneity within stem cell populations remains a major impediment to the development of clinically effective cell-based therapies. Transcriptional events within a single cell are inherently stochastic and can produce tremendous variability, even among genetically identical cells. It remains unclear how mammalian cellular systems overcome this intrinsic noisiness of gene expression to produce consequential variations in function, and what impact this has on the biologic and clinical relevance of highly 'purified' cell subgroups. To address these questions, we have developed a novel method combining microfluidic-based single cell analysis and information theory to characterize and predict transcriptional programs across hundreds of individual cells. Using this technique, we demonstrate that multiple subpopulations exist within a well-studied and putatively homogeneous stem cell population, murine long-term hematopoietic stem cells (LT-HSCs). These subgroups are defined by nonrandom patterns that are distinguishable from noise and are consistent with known functional properties of these cells. We anticipate that this analytic framework can also be applied to other cell types to elucidate the relationship between transcriptional and phenotypic variation.

Although numerous factors are implicated in skin fibrosis, the exact pathophysiology of hypertrophic scarring remains unknown. We recently demonstrated that mechanical force initiates hypertrophic scar formation in a murine model, potentially enhancing cellular survival through Akt. Here, we specifically examined Akt-mediated mechanotransduction in fibroblasts using both strain culture systems and our murine scar model. In vitro, static strain increased fibroblast motility, an effect blocked by wortmannin (a phosphoinositide-3-kinase/Akt inhibitor). We also demonstrated that high-frequency cyclic strain was more effective at inducing Akt phosphorylation than low frequency or static strain. In vivo, Akt phosphorylation was induced by mechanical loading of dermal fibroblasts in both unwounded and wounded murine skin. Mechanically loaded scars also exhibited strong expression of α-smooth muscle actin, a putative marker of pathologic scar formation. In vivo inhibition of Akt increased apoptosis but did not significantly abrogate hypertrophic scar development. These data suggest that although Akt signaling is activated in fibroblasts during mechanical loading of skin, this is not the critical pathway in hypertrophic scar formation. Future studies are needed to fully elucidate the critical mechanotransduction components and pathways which activate skin fibrosis., (© 2010 by the Wound Healing Society.)

Diabetic wounds are a significant public health burden, with slow or nonhealing diabetic foot ulcers representing the leading cause of non-traumatic lower limb amputation in developed countries. These wounds heal poorly as a result of compromised blood vessel formation in response to ischemia. We have recently shown that this impairment in neovascularization results from a high glucose-induced defect in transactivation of hypoxia-inducible factor-1alpha (HIF-1alpha), the transcription factor regulating vascular endothelial growth factor (VEGF) expression. HIF-1 dysfunction is the end result of reactive oxygen species-induced modification of its coactivator p300 by the glycolytic metabolite methylglyoxal. Use of the iron chelator-antioxidant deferoxamine (DFO) reversed these effects and normalized healing of humanized diabetic wounds in mice. Here, we present additional data demonstrating that HIF-1alpha activity, not stability, is impaired in the high glucose environment. We demonstrate that high glucose-induced impairments in HIF-1alpha transactivation persist even in the setting of constitutive HIF-1alpha protein overexpression. Further, we show that high glucose-induced hydroxylation of the C-terminal transactivation domain of HIF-1alpha (the primary pathway regulating HIF-1alpha/p300 binding) does not alter HIF-1alpha activity. We extend our study of DFO's therapeutic efficacy in the treatment of impaired wound healing by demonstrating improvements in tissue viability in diabetic mice with DFO-induced increases in VEGF expression and vascular proliferation. Since DFO has been in clinical use for decades, the potential of this drug to treat a variety of ischemic conditions in humans can be evaluated relatively quickly.

Diabetes is associated with poor outcomes following acute vascular occlusive events. This results in part from a failure to form adequate compensatory microvasculature in response to ischemia. Since vascular endothelial growth factor (VEGF) is an essential mediator of neovascularization, we examined whether hypoxic up-regulation of VEGF was impaired in diabetes. Both fibroblasts isolated from type 2 diabetic patients, and normal fibroblasts exposed chronically to high glucose, were defective in their capacity to up-regulate VEGF in response to hypoxia. In vivo, diabetic animals demonstrated an impaired ability to increase VEGF production in response to soft tissue ischemia. This resulted from a high glucose-induced decrease in transactivation by the transcription factor hypoxia-inducible factor-1alpha (HIF-1alpha), which mediates hypoxia-stimulated VEGF expression. Decreased HIF-1alpha functional activity was specifically caused by impaired HIF-1alpha binding to the coactivator p300. We identify covalent modification of p300 by the dicarbonyl metabolite methylglyoxal as being responsible for this decreased association. Administration of deferoxamine abrogated methylglyoxal conjugation, normalizing both HIF-1alpha/p300 interaction and transactivation by HIF-1alpha. In diabetic mice, deferoxamine promoted neovascularization and enhanced wound healing. These findings define molecular defects that underlie impaired VEGF production in diabetic tissues and offer a promising direction for therapeutic intervention.

Background: Cells from the bone marrow contribute to ischemic neovascularization, but the identity of these cells remains unclear. The authors identify mesenchymal stem cells as a bone marrow-derived progenitor population that is able to engraft into peripheral tissue in response to ischemia., Methods: A murine model of skin ischemia was used. Bone marrow, blood, and skin were harvested at different time points and subjected to flow cytometric analysis for mesenchymal and hematopoietic markers (n = 3 to 7 per time point). Using a parabiotic model pairing donor green fluorescent protein (GFP)-positive with recipient wild-type mice, progenitor cell engraftment was examined in ischemic tissue by fluorescence microscopy, and engrafted cells were analyzed by flow cytometry for endothelial and mesenchymal markers. In vitro, the ability of both bone marrow- and adipose-derived mesenchymal stem cells to adopt endothelial characteristics was examined by analyzing (1) the ability of mesenchymal stem cells to take up DiI-acetylated low-density lipoprotein and Alexa Fluor lectin, and (2) phenotypic changes of mesenchymal stem cells co-cultured with GFP-labeled endothelial cells or under hypoxic/vascular endothelial growth factor stimulation., Results: In vivo, the bone marrow mesenchymal stem cell population decreased significantly immediately after surgery, with subsequent engraftment of these cells in ischemic tissue. Engrafted cells lacked the panhematopoietic antigen CD45, consistent with a mesenchymal origin. In vitro, bone marrow- and adipose-derived mesenchymal stem cells took up DiI-acetylated low-density lipoprotein and Alexa Fluor lectin, and expressed endothelial markers under hypoxic conditions., Conclusions: The authors' data suggest that mesenchymal precursor cells can give rise to endothelial progenitors. Consequently, cell-based therapies augmenting the mesenchymal stem cell population could represent powerful alternatives to current therapies for ischemic vascular disease.

Background: Age-related impairments in wound healing are associated with decreased neovascularization, a process that is regulated by hypoxia-responsive cytokines, including stromal cell-derived factor (SDF)-1 alpha. Interleukin-1 beta is an important inflammatory cytokine involved in wound healing and is believed to regulate SDF-1 alpha expression independent of hypoxia signaling. Thus, the authors examined the relative importance of interleukin (IL)-1 beta and hypoxia-inducible factor (HIF)-1 alpha on SDF-1 alpha expression in aged wound healing., Methods: Young and aged mice (n = 4 per group) were examined for wound healing using a murine excisional wound model. Wounds were harvested at days 0, 1, 3, 5, and 7 for histologic analysis, immunohistochemistry, enzyme-linked immunosorbent assay, and Western blot. An engineered wild-type and mutated SDF luciferase reporter construct were used to determine HIF transactivation., Results: Aged mice demonstrated significantly impaired wound healing, reduced granulation tissue, and increased epithelial gap compared with young controls. Real-time polymerase chain reaction demonstrated reduced SDF-1 alpha levels in aged wounds that correlated with reduced CD31+ neovessels. Western blots revealed decreased HIF-1 alpha protein in aged wounds. However, both IL-1 beta and macrophage infiltrate were unchanged between young and aged animals. Using the wild-type and mutated SDF luciferase reporter construct in which the hypoxia response element was deleted, only young fibroblasts were able to respond to IL-1 beta stimulation, and this response was abrogated by mutating the HIF-binding sites. This suggests that HIF binding is essential for SDF-1 transactivation in response to both inflammatory and hypoxic stimuli., Conclusions: SDF-1 alpha deficiency observed during aged wound healing is attributable predominantly to decreased HIF-1 alpha levels rather than impaired IL-1 beta expression.

Evolving evidence suggests a possible role for adipose stromal cells (ASCs) in adult neovascularization, although the specific cues that stimulate their angiogenic behavior are poorly understood. We evaluated the effect of hypoxia, a central mediator of new blood vessel development within ischemic tissue, on proneovascular ASC functions. Murine ASCs were exposed to normoxia (21% oxygen) or hypoxia (5%, 1% oxygen) for varying lengths of time. Vascular endothelial growth factor (VEGF) secretion by ASCs increased as an inverse function of oxygen tension, with progressively higher VEGF expression at 21%, 5%, and 1% oxygen, respectively. Greater VEGF levels were also associated with longer periods in culture. ASCs were able to migrate towards stromal cell-derived factor (SDF)-1, a chemokine expressed by ischemic tissue, with hypoxia augmenting ASC expression of the SDF-1 receptor (CXCR4) and potentiating ASC migration. In vivo, ASCs demonstrated the capacity to proliferate in response to a hypoxic insult remote from their resident niche, and this was supported by in vitro studies showing increasing ASC proliferation with greater degrees of hypoxia. Hypoxia did not significantly alter the expression of endothelial surface markers by ASCs. However, these cells did assume an endothelial phenotype as evidenced by their ability to tubularize when seeded with differentiated endothelial cells on Matrigel. Taken together, these data suggest that ASCs upregulate their proneovascular activity in response to hypoxia, and may harbor the capacity to home to ischemic tissue and function cooperatively with existing vasculature to promote angiogenesis.

Hemangiomas are the most common tumor of infancy, and although the natural history of these lesions is well described, their etiology remains unknown. One current theory attributes the development of hemangiomas to placentally-derived cells; however, conclusive evidence to support a placental origin is lacking. While placental tissue and hemangiomas do share molecular similarities, it is possible that these parallels are the result of analogous responses of endothelial cells and vascular progenitors to similar environmental cues. Specifically, both tissue types consist of actively proliferating cells that exist within a low oxygen, high estrogen environment. The hypoxic environment leads to an upregulation of hypoxia inducible factor-1alpha (HIF-1alpha) responsive chemokines such as stromal cell derived factor-1alpha (SDF-1alpha) and vascular endothelial growth factor (VEGF), both of which are known to promote the recruitment and proliferation of endothelial progenitor cells. Increased hormone levels in the postpartum period further potentiate the growth of these lesions. In this model, increased stabilization of HIF-1 in concert with increased levels of estrogen create a milieu that promotes new blood vessel development, ultimately contributing to the pathogenesis of infantile hemangiomas.

Despite the fact that mucus and bicarbonate are important macroscopic components of the gastric mucosal barrier, severe acidic and peptic conditions surely exist at the apical membrane of gastric glandular cells, and these membranes must have highly specialized adaptations to oppose external insults. Parietal cells abundantly express the heterodimeric, acid-pumping H-K-ATPase in their apical membranes. Its beta-subunit (HKbeta), a glycoprotein with >70% of its mass and all its oligosaccharides on the extracellular side, may play a protective role. Here, we show that the extracellular domain of HKbeta is highly resistant to trypsin in the native state (much more than that of the structurally related Na-K-ATPase beta-subunit) and requires denaturation to expose tryptic sites. Native HKbeta also resists other proteases, such as chymotrypsin and V8 protease, which hydrolyze at hydrophobic and anionic amino acids, respectively. Removal of terminal alpha-anomeric-linked galactose does not appreciably alter tryptic sensitivity of HKbeta. However, full deglycosylation makes HKbeta much more susceptible to all proteases tested, including pepsin at pH <2.0. We propose that 1) intrinsic folding of HKbeta, 2) bonding forces between subunits, and 3) oligosaccharides on HKbeta provide a luminal protein domain that resists gastric lytic conditions. Protein folding that protects susceptible charged amino acids and is maintained by disulfide bonding and hydrophilic oligosaccharides would provide a stable structure in the face of large pH changes. The H-K-ATPase is an obvious model, but other gastric luminally exposed proteins are likely to possess analogous protective specializations.