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Telemedicine use within pediatric surgery fields has been growing, but research on the utility of remote evaluation in the perioperative period remains scarce. The objective of this study was to examine the utility of perioperative telemedicine care for the pediatric patient by evaluating the outcomes following completion of an outpatient appointment with a surgical provider.We performed a retrospective chart review of all patients who completed a telemedicine appointment with a provider across nine pediatric surgery divisions, without a limitation based on patient-specific characteristics or telemedicine platform. We examined the result of the initial telemedicine appointment and the outcome of any surgical procedure that was performed as a result.A total of 803 patients were evaluated by telemedicine during the study period. Of the 164 encounters (20.2%) that were followed by a surgery, nearly 70% were performed using a video. There was no discordance in the preoperative and postoperative diagnoses for more than 98% of patients. Nearly 25% of operations were followed by at least a 1-night hospital stay and 6.7% of patients developed a postoperative complication.Telemedicine is a safe tool for evaluating pediatric patients in the preoperative and postoperative phases of care and offers potential value for families seeking an alternative to the traditional in-person appointment. Ongoing support will require permanent legislative changes aimed at ensuring comparable compensation and the development of strategies to adapt the outpatient healthcare model to better accommodate the evolving requirements of remotely evaluating and treating pediatric patients.

Patients experiencing functional constipation (FC) can participate in structured bowel management programs (BMPs) to manage constipation or fecal incontinence when standard management fails. We sought to evaluate the efficacy of BMPs for children with FC with and without neurodevelopmental disorders.We performed a retrospective review of children with FC who participated in our BMP from 2014 to 2021. Stool/urinary continence, bowel regimen, surgical history, parent-reported outcomes measures (PROMs: Cleveland Clinic Constipation Score, Baylor Continence Scale, Vancouver Symptom Score for Dysfunctional Elimination), and Pediatric Quality of Life Inventory (PedsQL) were assessed pre- and at least 9 months post-BMP.The cohort included 156 patients with a median age of 9 years and follow-up of 627 days (IQR: 389-808 days). Two sub-cohorts included patients with FC only (69%) and FC plus a neurodevelopmental disorder (31%): 59% attention-deficit/hyperactivity disorder, 33% autism spectrum disorder, and 8% obsessive-compulsive disorder. Both groups had significantly improved follow-up bowel movement frequency and continence (39%-90% neurodevelopmental, 44%-82% FC only, P0.001) and urinary continence (65%-90% neurodevelopmental, 69%-91% FC only, P0.02). There was a significant improvement in most of the PROMs at follow-up. Both groups experienced a clinically meaningful improvement in overall PedsQL scores (pre- and postBMP difference of4.5).Patients with FC with and without a neurodevelopmental disorder had significant improvement in stool and urinary continence after undergoing a BMP. Further studies are needed to see if this improvement is durable over a longer period of time in this challenging cohort.

Bowel management programs are efficacious in pediatric patients with fecal incontinence or intractable constipation unresponsive to standard treatment. No studies have been done examining outcomes in adults. The objective of this study was to assess continence and quality of life outcomes in adults who have underwent bowel management program.A retrospective review of patients 16 or older at the time they underwent a bowel management program for fecal incontinence or constipation was performed. Data collected included intake and follow-up stool and urinary continence, patient-reported outcomes measures (Cleveland Clinic Constipation Score, Baylor Continence Scale, Vancouver Symptom Score for Dysfunctional Elimination), and an age-adjusted health-related quality of life measure.The cohort included 38 patients with a median age of 19 years (range: 16-55) when they underwent our program. 50% of patients were female and the majority (33, 87%) were White. The most common diagnosis was anorectal malformation (16, 42%) followed by functional constipation (10, 27%). Stool continence rates improved after undergoing the program (52.7% prior to 87.6% at follow-up, p0.01). There was significant improvement in the Baylor Continence Scale, Cleveland Clinic Constipation Score, and PedsQL (p0.05).Adult patients who underwent a bowel management program for severe fecal incontinence or constipation show significant improvement in stool continence rates, patient-reported outcomes measures, and quality of life. A bowel management program (in-person or via telemedicine) is a feasible treatment strategy for adult patients who fail standard management of fecal incontinence or constipation and should be offered when appropriate.III.

To assess outcomes of children with functional constipation after antegrade continence enemas (ACEs) and determine if pre operative anorectal manometry (AMAN) findings, including dyssynergic defecation, are associated with outcomes.A retrospective review of pediatric patients with functional constipation who received a Malone appendicostomy or cecostomy after failed medical management was conducted. Patients were included if they had AMAN data prior to their operation. Patients that underwent colonic resection were excluded. Demographics, clinical characteristics, manometry results, and post ACE outcomes were obtained. Descriptive statistics were performed.Thirty-nine patients were identified with median age at ACE of 8.9 years (IQR: 7.2-12.6) and median follow-up of 2.5 years (IQR: 1.8-3.2 years). Twenty patients (51%) were female and most (35, 92%) were White. All patients had severe constipation prior to ACE and 59% had fecal incontinence. Thirty-four patients (87%) received a Malone and 5 (13%) received a cecostomy. Post ACE, 35 (90%) were clean with daily flushes and 6 (15%) eventually successfully transitioned to laxatives only. Awake AMAN and balloon expulsion test were performed in 15 patients, with 14 (93%) displaying evidence of dyssynergic defecation. Twelve of 14 of patients (86%) with dyssynergia were clean with ACE at follow-up. because of the majority of patients being clean post ACE, there was limited power to detect predictors of poor outcomes.ACEs are successful treatment options for patients with severe constipation and fecal incontinence, including those with dyssynergic defecation. Larger studies are needed to identify factors predictive of poor outcomes.III.

Objective Wound dehiscence after posterior sagittal anorectoplasty (PSARP) or anorectal vaginal urethroplasty (PSARVUP) for anorectal malformation (ARM) is a morbid complication. We present a novel anoplasty technique employing para-U-stitches along the anterior and posterior portions of the anoplasty, which helps buttress the midline U-stitch and evert the rectal mucosa. We hypothesized that, in addition to standardized pre- and postoperative protocols, this technique would lower rates of wound dehiscence. Materials and Methods A retrospective review of patievnts who underwent primary PSARP or PSARVUP with the para-U-stitch technique from 2015 to 2021 was performed. Wound dehiscence was defined as wound disruption requiring operative intervention within 30 days of the index operation. Superficial wound separations were excluded. Descriptive statistics were calculated. The final cohort included 232 patients. Results Rectoperineal fistula (28.9%) was the most common ARM subtype. PSARP was performed in 75% and PSARVUP in 25%. The majority were reconstructed with a stoma in place (63.4%). Wound dehiscence requiring operative intervention occurred in four patients, for an overall dehiscence rate of 1.7%. The dehiscence rate was lower in PSARPs compared with PSARVUPs (0.6 vs. 5.2%) and lower for reconstruction without a stoma compared with a stoma (1.2 vs. 2.0%). There were additional six patients (2.6%) with superficial wound infections managed conservatively. Conclusion We present the para-U-stitch anoplasty technique, which is an adjunct to the standard anoplasty during PSARP and PSARVUP. In conjunction with standardized pre- and postoperative protocols, this technique can help decrease rates of wound dehiscence in this patient population.

Many patients with anorectal malformations (ARM) need a bowel management program (BMP) to manage lifelong problems of fecal incontinence or severe constipation. We aimed to evaluate the sustainability of the results in such a program.A single-institution retrospective review was performed in children with ARM who attended our BMP (2015-2019). Standardized definitions and validated tools were used to assess fecal continence (Baylor Continence Scale), constipation (Cleveland Constipation Scoring System), urinary symptoms (Vancouver Symptoms Score), and the Pediatric Quality of Life (PedsQL) and health-related quality of life (HRQOL) at the start of BMP and 1-year after completion of the program.222 patients with ARM at a median age of 6.7 (IQR, 4.9-10.1) years were identified. All (100%) soiled at intake with 149 (67.1%) patients being treated with rectal or antegrade enemas and 73 (32.9%) with oral laxatives. At 1 year 150 (70.4%) were clean, 72.7% were on enemas and 27.3% were on laxatives (p = 0.08). 109 out of 148 (73.6%) patients were clean on enemas. A further 41 out of 66 (62.1%) patients were continent on laxatives with voluntary bowel movements and clean. In the group that was clean, there was improvement in Baylor Continence Scale (25 vs. 13.0, p 0.000000002), Vancouver (11 vs. 6, p = 0.0110) scores, and clinically relevant improvement in the total PedsQL HRQL (78-85) and the PedsQL HRQL physical function (86-92) and psychosocial domain (77-82). There was no improvement in Cleveland (10 vs. 9, p = 0.31) score.An intensive BMP offers significant benefits in the treatment of fecal incontinence in ARM. It appears to also improve urinary incontinence and urinary voiding as well as the patient's quality of life. These changes are sustainable over at least one year.

Hirschsprung-associated enterocolitis (HAEC) is the most common cause of morbidity and mortality in patients with Hirschsprung disease (HD). The objective of this study was to examine the association of social determinants of health (SDOH) with HAEC.A review of patients who underwent primary pull through for HD at our institution from 2014 to 2021 was performed. Clinical, surgical, and SDOH data were collected. HAEC was defined by an international scoring system. Categorical variables were analyzed via Fisher's exact tests and continuous variables with Mood's median tests.One hundred patients were identified with 29 patients (29%) having at least one episode of HAEC during a median follow-up of 31 months (IQR: 11.7-55.7). Children who utilized public transportation for clinic visits, had one or more missed appointments, had any reported safety concerns, were involved with Child Protective Services, had parents/guardians who were not married, lived with people other than their immediate family, or had mothers who reported drug use or lack of prenatal care were found to have a higher likelihood of developing HAEC (p0.04 for all). Age at HD diagnosis, age at pull through, operative approach, length of aganglionic colon, and Trisomy 21 were not significant predictors of HAEC.In our series of 100 patients undergoing primary pull through, there was a significant correlation of HAEC with several social determinants of health elements while anatomical and clinical factors were not associated with HAEC. Attention to social determinants of health and identifying high-risk patients may serve to prevent morbidity and mortality from HAEC.III.

Purpose Due to the COVID-19 pandemic, we transitioned from an in-person bowel management program (BMP) to a telemedicine BMP. The telemedicine BMP consisted of video and/or phone call visits (remote) or a single initial in-person visit followed by remote visits (hybrid). We hypothesized that patient/family satisfaction of a telemedicine BMP would be comparable to an in-person BMP and that there would be improvement in quality of life and functional outcomes after the telemedicine BMP. Methods After IRB approval, demographic and outcomes data were obtained for patients who underwent the telemedicine BMP from May-October 2020. Outcomes included a parent/patient satisfaction survey, Pediatric Quality of Life Inventory (PedsQL), and parent/patient-reported outcome measures (Vancouver, Baylor, and Cleveland scores) at baseline, 1-, and 3-month follow-up. Variables were compared using Chi-square or Wilcoxon–Mann–Whitney tests and a generalized mixed model was used to evaluate outcomes scores at follow-up compared to baseline. Results Sixty-seven patients were included in our analysis with an average age of 8.6 years (SD: 3.9). Patients had the following diagnoses: anorectal malformation (52.2%), Hirschsprung's disease (20.9%), functional constipation (19.4%), myelomeningocele (6.0%), and spinal injury (1.5%). Forty-eight patients (72%) underwent the remote BMP and 19 (28%) underwent the hybrid BMP. Sixty-two percent of parents completed the satisfaction survey, with a median score of 5 (very satisfied) for all questions. Over 75% of parents said they would prefer a telemedicine program over an in-person program. There was significant improvement in the Baylor and Vancouver scores after the BMP (p0.05). There was a significant improvement in stool continence after the BMP (p

Background Cardiac reperfusion injury can have devastating consequences. Histone deacetylase (HDAC) inhibitors are potent cytoprotective agents, but their role in the prevention of cardiac injury remains ill-defined. Objective We sought to determine the therapeutic potential of HDAC inhibitors in an in vitro model of cardiomyocyte hypoxia-reoxygenation (H/R). Method H9c2 cardiomyocytes were subjected to H/R and treated with various classspecific and pan-HDAC inhibitors in equal concentrations (5µM). Biological activity of inhibitors was determined, as a proxy for concentration adequacy, by Western blot for acetylated histone H3 and α-tubulin. Cell viability and cytotoxicity were measured by methyl thiazolyl tetrazolium and lactate dehydrogenase assays, respectively. Mechanistic studies were performed to better define the effects of the most effective agent, Tubastatin-A (Tub-A), on the phosphoinositide 3-kinase (PI3K)/mammalian target of rapamycin (mTOR) pathway effectors, and on the degree of autophagy. Results All inhibitors acetylated well-known target proteins (histone H3 and α-tubulin), suggesting that concentrations were adequate to induce a biological effect. Improved cell viability and decreased cell cytotoxicity were noted in cardiomyocytes exposed to Tub-A, whereas the cytoprotective effects of other HDAC inhibitors were inconsistent. Pro-survival mediators in the PI3K/mTOR pathway were up-regulated and the degree of autophagy was significantly attenuated in cells that were treated with Tub-A. Conclusion HDAC inhibitors improve cell viability in a model of cardiomyocyte H/R, with Class IIb inhibition (Tub-A) demonstrating superior cellular-level potency and effectiveness. This effect is, at least in part, related to an increased expression of prosurvival mediators and a decreased degree of autophagy.

Background Prior to the COVID-19 pandemic, the use of telemedicine to evaluate pediatric surgery patients was uncommon. Due in part to restrictions imposed to mitigate the spread of the virus, the use of telemedicine within pediatric surgery has significantly expanded. Methods Prior to the use of telemedicine within surgery divisions at our institution, pediatric surgeons were surveyed to determine their perspectives on the use of telemedicine. Following the expanded use of telemedicine in response to the COVID-19 pandemic, a follow up survey was distributed to determine the impact of telemedicine and the perceived benefits and barriers of continuing its use going forward. Results The pre-COVID survey was completed by 37 surgeons and the post-COVID survey by 36 surgeons and advanced practice providers across 10 pediatric surgical divisions. General surgeons were the most represented division for both the pre- (25%) and post-COVID (33.3%) survey. Less than 25% of providers reported use of telemedicine at any point in their career prior to COVID-19; but following the expanded use of telemedicine 95% of respondents reported interest in continuing its use. After expansion, 25% of respondents were concerned with the possibility of inaccurate diagnoses when using telemedicine compared to nearly 50% prior to expanded use. Conclusion Following the expanded use of telemedicine within pediatric surgery, there was a decrease in the concern for inaccurate diagnoses and a near uniform desire to continue its use. Going forward, it will be imperative for pediatric surgeons to take an active role in creating a process for implementing telemedicine that best fits their needs and the needs of their patients and patients’ families.

Patients with Hirschsprung disease (HD) are at risk of Hirschsprung associated enterocolitis (HAEC) following pull-through. The purpose of this study was to determine if routine Botulinum toxin (BT) injected one-month post pull-through decreases the incidence of HAEC.We reviewed patients who underwent a primary (not redo) pull-through operation for HD between April 2014 to December 2019. Over the most recent 18 months, BT was administered routinely one-month post-pull-through procedure; these patients were compared to the prior group that did not receive routine BT. A HAEC episode was defined as one that required initiation of treatment for obstructive symptoms in the inpatient or outpatient setting with antibiotics and irrigations. Categorical variables were compared using the nonparametric chi-square test or Fisher's exact test. Continuous variables were compared using the two-tailed Student's t-test. P-value0.05 was determined to be statistically significant.A total of 70 patients underwent Swenson pull-through during the study period (52% male). There were no statistically significant differences in demographics in the BT vs. non-BT group. Routine post-pull-through BT was given in 28 patients and did not significantly change HAEC incidence compared to the non-BT group (12/28, 43% vs. 16/42, 38%. P = 0.691). Of note, the BT group patients developed HAEC significantly sooner than the patients in the non-BT group (37.5 days vs. 253 days, p = 0.029). More patients in the BT group (n = 18, 64%) required at least one subsequent BT injection compared to the patients in the non-BT group (n = 11, 26%. P = 0.001).We conclude that routine postoperative botulinum toxin injection given one month postoperatively from Swenson pull-through did not change the incidence of HAEC. A prospective controlled study is necessary to confirm these findings.

Background: Within pediatrics, the use of telemedicine has grown considerably within the past decade, mostnotably within primary care and behavioral health However, within pediatric surgery the increase in use hasbeen modest In response to COVID-19, many healthcare institutions implemented strategies to curb thespread of the virus, including restricting non-emergent clinic appointments and quickly rolling outtelemedicine options for patients The utility of telemedicine options beyond the COVID-19 restrictive periodhas not been studied The purpose of this study is to assess the state of interest in telemedicine for caregiverspresenting to a pediatric surgery clinic prior to COVID-19 and to evaluate the potential benets of continuingtelemedicine use within pediatric surgery based on the caregiver perspective Methods: Following IRBapproval, caregivers for all patients that presented to a general pediatric surgery clinic from January 1, 2020 toMarch 1, 2020, were considered for enrollment Subjects were asked to complete a voluntary and anonymous survey Survey responses were recorded directly into REDCap by participants Categorical variables wereevaluated using frequencies and reported as percentages Results: In total, 58 caregivers completed a survey The majority (51%) of respondents were between 31-40 years old, with 71% identifying as Caucasian and 22%as African American A fourth (25%) of respondents traveled at least 100 miles, with more than one-third (36%)spending a minimum of 2 hours in travel time To get to and from the clinic appointment, 69% reportedspending at least $10 in fuel, with 13% spending more than $50 Three-quarters (75%) of participants reportedworking outside of the home, and the majority (53%) had to miss work for the appointment, resulting inmissed wages for 41% of respondents All caregivers had a cellphone and 93% had access to a computer ortablet, with 87% reporting daily internet use and 71% reporting use of video chat at least once per week Only26% of respondents were familiar with telemedicine prior to taking the survey However, following a briefdescription, 66% responded that they would be interested in remote appointments, with 74% citing cost as areason and 69% stating that time spent traveling was an important factor For 91% of respondents the mostimportant factor related to the visit was getting the correct diagnosis Conclusion: The COVID-19 restrictiveperiod has led to increased use of telemedicine within pediatric surgery Prior to COVID-19 most caregiverspresenting to a pediatric surgery clinic were unfamiliar with telemedicine options, however, the majority wereinterested in the benets afforded by remote evaluation Future studies are needed to determine how best tocontinue the use of telemedicine for the treatment of pediatric surgery patients beyond the restrictive period

Highlights • Segmental Hirschsprung’s is a rare phenomenon. • Rare aganglionic segment involving only the small bowel. • Trans-anal only pull-through is ill advisable., Introduction and importance Hirschsprung’s disease is a congenital anomaly that results from an incomplete craniocaudal migration and maturation of intestinal ganglion progenitor cells leading to distal intestinal aganglionosis. Skip segment Hirschsprung’s disease is an extremely rare phenomenon. We report a case involving only the small bowel with confirmed colonic ganglionosis. Case presentation A case report of a 14-month-old with a skipped segment involving the distal 50 cm of the small bowel associated with colonic ganglionosis is presented. A current review of the literature is discussed. Clinical discussion Our patient had persistent obstructive symptoms despite undergoing a technically good, ganglionic pull-through operation at an outside institution. A laparoscopic-assisted pull-through might have documented a small bowel wall diameter discrepancy. Conclusion Although rare, skip segment Hirschsprung’s disease is a real phenomenon that paediatric surgeons should be aware of and could involve small and large bowels.

Background Prior to COVID-19, the use of telemedicine within pediatric surgery was uncommon. To curb the spread of the virus many institutions restricted non-emergent clinic appointments, resulting in an increase in telemedicine use. We examined the value of telemedicine for patients presenting to a pediatric surgery clinic before and after COVID-19 Methods Perspectives and the potential value of telemedicine were assessed by surveying patients or caregivers of patients being evaluated by a general pediatric surgeon in-person prior to COVID-19 and by patients or caregivers of patients who completed a telemedicine appointment with a pediatric surgical provider during the COVID-19 period. Results The pre-COVID survey was completed by 57 respondents and the post-COVID survey by 123. Most respondents were white and were caregivers 31–40 years of age. Prior to COVID-19, only 26% were familiar with telemedicine, 25% reported traveling more than 100 miles and >50% traveled more than 40 miles for their appointment. More than 25% estimated additional travel costs of at least $30 and in 43% of households, at least one adult had to miss time from work. Following a telemedicine appointment during the COVID-19 period, 76% reported the care received as excellent, 86% were very satisfied with their care, 87% reported the appointment was less stressful for their child than an in-person appointment, and 57% would choose a telemedicine appointment in the future. Conclusion For families seeking an alternative to the in-person encounter, telemedicine can provide added value over the traditional in-person encounter by reducing the burden of travel without compromising the quality of care. Telemedicine should be viewed as a viable option for pediatric surgery patients and future research directed toward optimizing the experience for patients and providers. Level of Evidence III.

Patients with anorectal malformations (ARM) commonly have associated urologic anomalies. Few large studies exist to accurately characterize the incidence or associations between severity of malformation and urologic diagnosis. The purpose of our study was to determine the incidence of urologic diagnoses in a large cohort of children with ARM and evaluate for any correlation between severity of ARM and the incidence and number of associated urologic diagnoses.A retrospective review was performed of patients with ARM treated at our pediatric colorectal center. All patients underwent protocolized urologic screening. ARM subtypes were ordered with increasing severity as follows in males: perineal, bulbar, prostatic and bladder neck fistulae. Females were similarly categorized as perineal, vestibular and vaginal fistulae followed by cloaca with3 cm common channel and cloaca with3 cm common channel. The following urologic diagnoses were assessed to determine whether a correlation existed with the severity of the ARM subtype: hydronephrosis, vesicoureteral reflux (VUR), solitary kidney, renal ascent anomalies (ectopic or pelvic), renal fusion anomalies (horseshoe or cross fused kidney), duplex kidney, hypospadias and undescended testicle. ARM subtypes were defined by distal rectal anatomy.A total of 712 patients were included in our study with a mean age of 4 years and of whom 45% were male. The overall rate of urologic anomalies was greater in males than females (65% vs 56% p0.026). In both sexes, the rate of urologic anomalies increased with increasing severity of ARM subtype (p0.00010) finding that males with bladder neck fistula and females with cloacal malformations, particularly with long common channels, being the highest incidence. In males and females, the rate of hydronephrosis increased as the complexity of ARM increased and this correlated significantly (p0.0001 vs p0.0003 respectively). Similarly, the incidence of VUR also increased as complexity of ARM increased in both males and females (p = 0.01 and p0.0001 respectively). The remaining urologic diagnoses were not significantly correlated with severity of ARM.Urologic anomalies occur at a high rate in children with ARM and appear to increase in frequency with increasing complexity of ARM subtype. These findings stress the importance of proper ARM screening and proactive collaboration with a clinician with expertise in pediatric urology early in the management of such children to improve early recognition of urologic diagnoses.Level III.

Combined traumatic brain injury (TBI) and hemorrhagic shock (HS) remains a leading cause of preventable death worldwide. Mesenchymal stem cell-derived exosomes have demonstrated promise in small animal models of neurologic injury. To investigate the effects of exosome treatment in a clinically realistic large animal model, Yorkshire swine underwent TBI and HS. Animals were maintained in shock for 2 h before resuscitation with normal saline (NS). Animals were then resuscitated either with NS (3 × volume of shed blood) or with the same volume of NS with delayed exosome administration (1 × 10

Background Microvascular hyperpermeability resulting from endothelial barrier dysfunction (EBD) is associated with worse clinical outcomes in trauma-induced hemorrhagic shock. We have previously shown that treatment with Tubastatin A (TubA), a histone deacetylase 6 inhibitor, improves outcomes in animal models of shock. In this study, we investigate whether TubA treatment may prevent trauma-related EBD. Methods Wistar-Kyoto rats subjected to 40% hemorrhage were treated with TubA or vehicle control. Acute lung injury (ALI) was assessed histologically from tissues harvested 6 hours posthemorrhage. In vitro, human umbilical vein endothelial cells (HUVECs) were cultured in EGM BulletKit medium. Medium was exchanged for glucose-free Dulbecco's Modified Eagle Medium (0.5% fetal bovine serum) with or without TubA, and cells were placed in an anoxic chamber (5% CO2, 95% N2, 20-48 hours). Expression of acetylated tubulin and hypoxia-inducible factor 1α was measured by Western blot. Soluble Intercellular Adhesion Molecule-1 concentration within the medium, a marker of endothelial integrity, was determined using enzyme-linked immunosorbent assay. Monolayers were assessed for permeability via transwell assays using fluorescein isothiocyanate-labeled albumin. Results Rats treated with TubA had significantly reduced ALI relative to vehicle control. In vitro, TubA significantly attenuated anoxia-induced hyperpermeability, hypoxia-inducible factor 1α expression, and glycocalyx shedding. Conclusions Our findings demonstrate that TubA prevents hemorrhage-induced ALI in rats. Additionally, we have shown that TubA prevents anoxia-induced EBD in vitro. Taken together, these results suggest that TubA could attenuate microvascular hyperpermeability related to hemorrhagic shock.

Trauma-induced coagulopathy is associated with adverse patient outcome. Animal models demonstrate that histone deacetylase inhibitors, such as valproic acid (VPA), improve survival following injury. While in-vivo data suggest that improved survival may in part be because of an attenuation of coagulopathy, it remains unknown whether this is a direct effect of the drug, or the establishment of an overall prosurvival phenotype. We thus conducted an ex-vivo experiment to determine if VPA has an effect on coagulation and platelet function. Ten swine were subjected to traumatic brain injury (TBI) and hemorrhagic shock (HS). Blood samples were drawn prior to TBI+HS insult (Healthy group) and 2 h following TBI+HS (Shock group). Samples were incubated with VPA or vehicle controls for 1 h. Platelet aggregation was analyzed via impedance aggregometry and coagulation was measured using thromboelastography. Addition of VPA to the healthy blood did not affect platelet aggregation or coagulation parameters. In shock blood, incubation with VPA significantly reduced collagen-(P = 0.050), arachidonic acid-(P = 0.005), and adenosine diphosphate-(P = 0.023) induced platelet aggregation. VPA also significantly increased the clot strength (P = 0.002) and clot formation rate (P = 0.011). This is the first study to investigate the effect of VPA on platelet function ex vivo. Our results suggest that VPA has no effect on normal blood, but it decreases platelet activation and improves clot dynamics (strength and rate of formation) in blood from shocked animals. This suggests that VPA is capable of exerting a selective platelet sparing effect while enhancing the clot integrity.

Penetrating trauma in children is on the rise in the United States, often leading to severe injuries. Destructive injuries to the inferior vena cava (IVC) are rare in children, and outcomes of ligation are not well-described. This is a retrospective chart review of the cases and outcomes of two young children who required IVC ligation following abdominal gunshot wounds. The children's ages ranged from 3 to 6 years old. They both had concomitant duodenal injuries and additional intestinal injuries. The first patient also had a spinal cord injury. Their course was complicated by profound shock, breakdown of intestinal repairs, renal failure, and a necrotizing groin soft tissue infection, but they ultimately made a near-complete recovery. The second patient had a smooth postoperative course. Neither patient developed significant lower extremity edema. Ligation of the IVC in pediatric penetrating trauma patients is a viable and life-saving option but can be associated with complications.

BACKGROUND Combined traumatic brain injury (TBI) and hemorrhagic shock (HS) is highly lethal. In previous models of combined TBI + HS, we showed that early resuscitation with fresh frozen plasma (FFP) improves neurologic outcomes. Delivering FFP, however, in austere environments is difficult. Lyophilized plasma (LP) is a logistically superior alternative to FFP, but data are limited regarding its efficacy for treatment of TBI. We conducted this study to determine the safety and long-term outcomes of early treatment with LP in a large animal model of TBI + HS. METHODS Adult anesthetized swine underwent TBI and volume-controlled hemorrhage (40% blood volume) concurrently. After 2 hours of shock, animals were randomized (n = 5 per /group) to FFP or LP (1× shed blood) treatment. Serial blood gases were drawn, and thromboelastography was performed on citrated, kaolin-activated whole-blood samples. Five hours after treatment, packed red blood cells were administered, and animals recovered. A 32-point Neurologic Severity Score was assessed daily for 30 days (0 = normal, 32 = most severe injury). Cognitive functions were tested by training animals to retrieve food from color-coded boxes. Brain lesion size was measured on serial magnetic resonance imaging, and an autopsy was performed at 30 days. RESULTS The severity of shock and the degree of resuscitation were similar in both groups. Administration of FFP and LP was well tolerated with no differences in reversal of shock or thromboelastography parameters. Animals in both groups displayed the worst Neurologic Severity Score on postoperative Day 1 with rapid recovery and return to baseline within 7 days of injury. Lesion size on Day 3 in FFP-treated animals was 645 ± 85 versus 219 ± 20 mm 3 in LP-treated animals (p < 0.05). There were no differences in cognitive functions or delayed treatment-related complications. CONCLUSIONS Early treatment with LP in TBI + HS is safe and provides neuroprotection that is comparable to FFP.

Combined traumatic brain injury (TBI) and hemorrhagic shock (HS) is highly lethal. In a nonsurvival model of TBI + HS, addition of high-dose valproic acid (VPA) (300 mg/kg) to hetastarch reduced brain lesion size and associated swelling 6 hours after injury; whether this would have translated into better neurologic outcomes remains unknown. It is also unclear whether lower doses of VPA would be neuroprotective. We hypothesized that addition of low-dose VPA to normal saline (NS) resuscitation would result in improved long-term neurologic recovery and decreased brain lesion size.TBI was created in anesthetized swine (40-43 kg) by controlled cortical impact, and volume-controlled hemorrhage (40% volume) was induced concurrently. After 2 hours of shock, animals were randomized (n = 5 per group) to NS (3× shed blood) or NS + VPA (150 mg/kg). Six hours after resuscitation, packed red blood cells were transfused, and animals were recovered. Peripheral blood mononuclear cells were analyzed for acetylated histone-H3 at lysine-9. A Neurological Severity Score (NSS) was assessed daily for 30 days. Brain magnetic resonance imaging was performed on Days 3 and 10. Cognitive performance was assessed by training animals to retrieve food from color-coded boxes.There was a significant increase in histone acetylation in the NS + VPA-treated animals compared with NS treatment. The NS + VPA group demonstrated significantly decreased neurologic impairment and faster speed of recovery as well as smaller brain lesion size compared with the NS group. Although the final cognitive function scores were similar between the groups, the VPA-treated animals reached the goal significantly faster than the NS controls.In this long-term survival model of TBI + HS, addition of low-dose VPA to saline resuscitation resulted in attenuated neurologic impairment, faster neurologic recovery, smaller brain lesion size, and a quicker normalization of cognitive functions.

Traumatic injuries and their sequelae represent a major source of mortality in the United States and globally. Initial treatment for shock, traumatic brain injury, and polytrauma is limited to resuscitation fluids to replace lost volume. To date, there are no treatments with inherent prosurvival properties. Our laboratory has investigated the use of histone deacetylase inhibitors (HDACIs) as pharmacological agents to improve survival. This class of drugs acts through posttranslational protein modifications and is a direct regulator of chromatin structure and function, as well as the function of numerous cytoplasmic proteins. In models of hemorrhagic shock and polytrauma, administration of HDACIs offers a significant survival advantage, even in the absence of fluid resuscitation. Positive results have also been shown in two-hit models of hemorrhage and sepsis and in hemorrhagic shock combined with traumatic brain injury. Accumulating data generated by our group and others continue to support the use of HDACIs for the creation of a prosurvival phenotype. With further research and clinical trials, HDACIs have the potential to be an integral tool in the treatment of trauma, especially in the prehospital phase.

We have previously shown that early treatment with fresh frozen plasma (FFP) is neuroprotective in a swine model of hemorrhagic shock (HS) and traumatic brain injury (TBI). However, it remains unknown whether this strategy would be beneficial in a more clinical polytrauma model. Yorkshire swine (42-50 kg) were instrumented to measure hemodynamic parameters, brain oxygenation, and intracranial pressure (ICP) and subjected to computer-controlled TBI and multi-system trauma (rib fracture, soft-tissue damage, and liver injury) as well as combined free and controlled hemorrhage (40% blood volume). After 2 h of shock (mean arterial pressure, 30-35 mm Hg), animals were resuscitated with normal saline (NS; 3×volume) or FFP (1×volume; n=6/group). Six hours postresuscitation, brains were harvested and lesion size and swelling were evaluated. Levels of endothelial-derived vasodilator endothelial nitric oxide synthase (eNOS) and vasoconstrictor endothelin-1 (ET-1) were also measured. FFP resuscitation was associated with reduced brain lesion size (1005.8 vs. 2081.9 mm(3); p=0.01) as well as swelling (11.5% vs. 19.4%; p=0.02). Further, FFP-resuscitated animals had higher brain oxygenation as well as cerebral perfusion pressures. Levels of cerebral eNOS were higher in the FFP-treated group (852.9 vs. 816.4 ng/mL; p=0.03), but no differences in brain levels of ET-1 were observed. Early administration of FFP is neuroprotective in a complex, large animal model of polytrauma, hemorrhage, and TBI. This is associated with a favorable brain oxygenation and cerebral perfusion pressure profile as well as higher levels of endothelial-derived vasodilator eNOS, compared to normal saline resuscitation.

Since 1950, the United States has been in the midst of a profound demographic change: the rapid aging of the population. The baby boom generation began turning 65 in 2011 and is now driving growth at the older ages of the population. This article highlights geriatric demographic changes and illustrates how these and future trends will have wide ranging implications for the US health care system.

Introduction Recently, two large prospective clinical trials developed and validated prediction rules for children at very low risk for clinically important traumatic brain injuries (ciTBI) or abdominal injury for whom CT is unnecessary. Specific criteria/guidelines were identified which if met would obviate the need for CT scanning. The purpose of this study was to assess compliance at a level one pediatric center with these guidelines as a tool for quality improvement. Methods Records of children admitted to our pediatric trauma center one year before and two years after publication of head (Kuppermann '09) and abdominal trauma (Holmes '13) CT imaging guidelines were reviewed. Data collected included demographics, Glasgow coma score, (GCS), injury severity score (ISS), mechanism of injury, and indication for imaging based on criteria/guidelines from the prediction rule including history, symptoms, and physical exam findings. Results There were 296 total patients identified. Demographic data, GCS, ISS, and mechanism of injury were similar between both groups before and after guideline publication. Prior to publication of head trauma imaging guidelines, 20.7% of head trauma patients had no indication for head CT prior compared with 19.5% after publication of imaging guideline (p=0.85). Prior to publication of abdominal trauma imaging guidelines, 28.9% of patients had no indication for abdominal CT compared with 31.5% after publication of imaging guidelines (0.76). The rate of ciTBI requiring intervention was 4.6% before and 1.1% after guideline publication (p=0.4). The rate of abdominal injury requiring intervention was 7.9% before and 1.8% post guideline publication (p=0.2). None of the children at very low risk for ciTBI or abdominal injury required surgical intervention. Conclusion At our institution compliance with evidence-based guidelines for CT of children with head and abdominal trauma is poor with a significant number of patients undergoing unnecessary imaging. This provides an opportunity for quality improvement with evidence based methods to reduce unnecessary imaging for trauma. Level of evidence III Type of study Clinical Research Paper

We have shown previously that fresh frozen plasma (FFP) and lyophilized plasma (LP) decrease brain lesion size and improve neurological recovery in a swine model of traumatic brain injury (TBI) and hemorrhagic shock (HS). In this study, we examine whether these findings can be validated in a clinically relevant model of severe TBI, HS, and polytrauma. Female Yorkshire swine were subjected to TBI (controlled cortical impact), hemorrhage (40% volume), grade III liver and splenic injuries, rib fracture, and rectus abdominis crush. The animals were maintained in a state of shock (mean arterial pressure 30-35 mm Hg) for 2 h, and then randomized to resuscitation with normal saline (NS), FFP, or LP (n = 5 swine/group). Animals were recovered and monitored for 30 d, during which time neurological recovery was assessed. Brain lesion sizes were measured via magnetic resonance imaging (MRI) on post-injury days (PID) three and 10. Animals were euthanized on PID 30. The severity of shock and response to resuscitation was similar in all groups. When compared with NS-treated animals, plasma-treated animals (FFP and LP) had significantly lower neurologic severity scores (PID 1-7) and a faster return to baseline neurological function. There was no significant difference in brain lesion sizes between groups. LP treatment was well tolerated and similar to FFP. In this clinically relevant large animal model of severe TBI, HS, and polytrauma, we have shown that plasma-based resuscitation strategies are safe and result in neurocognitive recovery that is faster than recovery after NS-based resuscitation.

We have recently demonstrated that inhibition of histone deacetylase (HDAC) Class I, II, and IV with nonspecific HDAC inhibitors improves survival in a mouse model of lethal cecal ligation and puncture (CLP). However, the consequence of HDAC Class III inhibition is unknown in this model. The aims of the present study were to explore the effect of EX-527, a selective Sirtuin 1 (SIRT1) inhibitor, on survival in the lethal model of CLP-sepsis and to assess the impact of the treatment on inflammatory cytokine production, coagulopathy, and bone marrow atrophy during severe sepsis.For Experiment I, C57BL/6J mice were subjected to CLP and, 1 hour later, intraperitoneally injected with either EX-527 dissolved in dimethyl sulfoxide (DMSO) or DMSO only. Survival was monitored for 10 days. For Experiment II, 1 hour after CLP animals were randomly treated with (1) DMSO vehicle and (2) EX-527. Peritoneal fluid and blood samples were collected for measurement of cytokines, and blood was also used to evaluate coagulation status using thrombelastography. In addition, long bones (femurs and tibias) were examined to determine morphologic changes in the marrow by hematoxylin and eosin staining. For Experiment III, normal primary splenocytes were cultured and treated with lipopolysaccharide in the presence or absence of EX-527 to assess cytokine production.EX-527 significantly improved survival (50% vs. 0% survival as compared to vehicle, p = 0.0007) and attenuated levels of cytokines tumor necrosis factor α and interleukin 6 in the blood and the peritoneal fluid compared with the vehicle control. It also decreased tumor necrosis factor α and interleukin 6 production by splenocytes in vitro. Selective inhibition of SIRT1 was associated with significant improvements in fibrin cross-linkage, platelet function, and clot rigidity but had no significant impact on the clot initiation parameters. Moreover, inhibition of SIRT1 was associated with a significant decrease in bone marrow atrophy.Selective inhibition of Class III HDAC SIRT1 significantly improves survival, attenuates cytokine levels and sepsis-associated coagulopathy, and decreases bone marrow atrophy in a lethal mouse septic model.

Background Traumatic brain injury (TBI) and hemorrhagic shock (HS) are the leading causes of trauma-related deaths. These insults disrupt coagulation and endothelial systems. This study investigated whether previously reported differences in lesion size and brain swelling during normal saline (NS), colloids (Hextend [HEX]), and fresh frozen plasma (FFP) resuscitation are associated with differential effects on coagulation and endothelial systems. Methods We subjected 15 Yorkshire swine to TBI and HS (40% blood volume), and kept in HS for 2 hours before resuscitation with NS, HEX, or FFP. Markers of endothelial activation (E-selectin, Intercellular adhesion molecule [ICAM]-1), coagulation activation (prothrombin fragment 1 + 2), and natural anticoagulation (activated protein C [aPC]) were determined in serum and brain whole cell lysates. Results Serum levels of aPC were greater in the NS group (203 ± 30 pg/mL) compared with HEX (77 ± 28 pg/mL; P = .02) and FFP (110 ± 28 pg/mL; P = .09), as was PF 1 + 2 in the brain when compared with FFP (PF 1 + 2, 89 ± 46 vs 37 ± 14 ng/mL; P = .035). Brain E-selectin was greater in the NS group compared with FFP (3.36 ± 0.02 vs 3.31 ± 0.01 ng/mL; P = .029). Circulating ICAM-1 levels were increased in the NS group (151 ± 9 ng/mL) compared with the HEX (100 ± 9 ng/mL; P Conclusion In this clinically realistic large animal model of TBI + HS, NS resuscitation was associated with an early activation of coagulation, natural anticoagulation, and endothelial systems, compared with HEX and FFP.

Background Sepsis has a profound impact on the inflammatory and hemostatic systems. In addition to systemic inflammation, it can produce disseminated intravascular coagulation, microvascular thrombosis, consumptive coagulopathy, and multiple organ failure. We have shown that treatment with suberoylanilide hydroxamic acid (SAHA), a histone deacetylase inhibitor (HDACI), improves survival in a lethal model of cecal ligation and puncture (CLP) in mice, but its effect on coagulation remains unknown. The goal of this study was to quantify the impact of SAHA treatment on coagulopathy in sepsis. Methods C57BL/6J mice were subjected to CLP, and 1 hour later given intraperitoneally either SAHA dissolved in dimethyl sulfoxide (DMSO) or DMSO only. Sham-operated animals were handled in similar manner without CLP. Blood samples were collected by cardiac puncture and evaluated using the TEG 5000 Thrombelastograph Hemostasis Analyzer System. Results Compared with the sham group, all animals in DMSO vehicle group died within 72 hours, and developed coagulopathy that manifested as prolonged initial fibrin formation and fibrin cross-linkage time, and decreased clot formation speed, platelet function, and clot rigidity. SAHA treatment significantly improved survival and was associated with improvement in fibrin cross-linkage and clot formation, as well as platelet function and clot rigidity, without a significant impact on the clot initiation parameters. Conclusion SAHA treatment enhances survival and attenuates sepsis-associated coagulopathy by improving fibrin cross-linkage, rate of clot formation, platelet function, and clot strength. HDACI may represent a novel therapeutic strategy for correcting sepsis-associated coagulopathy.

Hemorrhagic shock (HS) can initiate an exaggerated systemic inflammatory response and multiple organ failure, especially if followed by a subsequent inflammatory insult ("second hit"). We have recently shown that histone deacetylase inhibitors can improve survival in rodent models of HS or septic shock, individually. In the present study, we examined whether valproic acid (VPA), a histone deacetylase inhibitor, could prolong survival in a rodent "two-hit" model: HS followed by septic shock from cecal ligation and puncture (CLP).Male Sprague-Dawley rats (250-300 g) were subjected to sublethal HS (40% blood loss) and then randomly divided into two groups (n = 7/group): VPA and control. The VPA group was treated intraperitoneally with VPA (300 mg/kg in normal saline [NS], volume = 750 μL/kg). The control group was injected with 750 μL/kg NS. After 24 h, all rats received CLP followed immediately by injection of the same dose of VPA (VPA group) or NS (vehicle group). Survival was monitored for 10 days. In a parallel study, serum and peritoneal irrigation fluid from VPA- or vehicle-treated rats were collected 3, 6, and 24 h after CLP, and enzyme-linked immunosorbent assay was performed to analyze myeloperoxidase activity and determine tumor necrosis factor α and interleukin 6 concentrations. Hematoxylin-eosin staining of lungs at 24-h time point was performed to investigate the grade of acute lung injury.Rats treated with VPA (300 mg/kg) showed significantly higher survival rates (85.7%) compared with the control (14.3%). Moreover, VPA significantly suppressed myeloperoxidase activity (marker of neutrophil-mediated oxidative damage) and inhibited levels of proinflammatory cytokine tumor necrosis factor α and interleukin 6 in the serum and peritoneal cavity. Meanwhile, the severity of acute lung injury was significantly reduced in VPA-treated animals.We have demonstrated that VPA treatment improves survival and attenuates inflammation in a rodent two-hit model.

The use of VADs as a BTT in children with heart failure has increased due to enhanced device design and reliability, leading to improved survival, functional capacity, and quality of life. However, the use of VADs in patients with Fontan physiology as a BTT is rare with few case reports. Here, we describe a case of implantation of the Berlin VAD as a BTT for 179 days, one of the longest reported periods of mechanical support, in a child with failing single ventricle.

Background Valproic acid (VPA) has been shown to improve survival in animal models of hemorrhagic shock at a dose of 300 mg/kg. Our aim was to identify the ideal dose through dose-escalation, split-dosing, and dose de-escalation regimens. Materials and methods Rats were subjected to sublethal 40% hemorrhage and treated with vehicle or VPA (dose of 300, 400, or 450 mg/kg) after 30 min of shock. Acetylated histones and activated proteins from the PI3K–Akt–GSK-3β survival pathway at different time points were quantified by Western blot analysis. In a similar model, a VPA dose of 200 mg/kg followed 2 h later by another dose of 100 mg/kg was administered. Finally, animals were subjected to a lethal 50% hemorrhage and VPA was administered in a dose de-escalation manner (starting at dose of 300 mg/kg) until a significant drop in percent survival was observed. Results Larger doses of VPA resulted in greater acetylation of histone 3 and increased activation of PI3K pathway proteins. Dose-dependent differences were significant in histone acetylation but not in the activation of the survival pathway proteins. Split-dose administration of VPA resulted in similar results to a single full dose. Survival was as follows: 87.5% with 300 and 250 mg/kg of VPA, 50% with 200 mg/kg of VPA, and 14% with vehicle-treated animals. Conclusions Although higher doses of VPA result in greater histone acetylation and activation of prosurvival protein signaling, doses as low as 250 mg/kg of VPA confer the same survival advantage in lethal hemorrhagic shock. Also, VPA can be given in a split-dose fashion without a reduction in its cytoprotective effectiveness.

Hirschsprung-associated enterocolitis (HAEC) is a common and sometimes life-threatening complication of Hirschsprung disease (HD). Presenting either before or after definitive surgery for HD, HAEC may manifest clinically as abdominal distension and explosive diarrhea, along with emesis, fever, lethargy, and even shock. The pathogenesis of HAEC, the subject of ongoing research, likely involves a complex interplay between a dysfunctional enteric nervous system, abnormal mucin production, insufficient immunoglobulin secretion, and unbalanced intestinal microflora. Early recognition of HAEC and preventative practices, such as rectal washouts following a pull-through, can lead to improved outcomes. Treatment strategies for acute HAEC include timely resuscitation, colonic decompression, and antibiotics. Recurrent or persistent HAEC requires evaluation for mechanical obstruction or residual aganglionosis, and may require surgical treatment with posterior myotomy/myectomy or redo pull-through. This chapter describes the incidence, pathogenesis, treatment, and preventative strategies in management of HAEC.

BACKGROUND High doses of the histone deacetylase inhibitor valproic acid (VPA, 150-400 mg/kg) improve outcomes in animal models of lethal insults. We are conducting a US Food and Drug Administration-approved Phase I, double-blind, placebo-controlled trial to evaluate the safety and tolerability of ascending doses of VPA in human volunteers. We hypothesized that VPA would induce significant changes in the proteome of healthy humans when given at doses lower than those used in prior animal studies. METHODS Peripheral blood mononuclear cells were obtained from three healthy subjects randomized to receive VPA (120 mg/kg over 1 hour) at baseline and at 4 and 8 hours following infusion. Detailed proteomic analysis was performed using 1D gel electrophoresis, liquid chromatography, and mass spectrometry. Proteins with differential expression were chosen for functional annotation and pathway analysis using Ingenuity Pathway Analysis (Qiagen GmbH, Hilden, Germany) and Panther Gene Ontology. RESULTS A total of 3,074 unique proteins were identified. The average number of proteins identified per sample was 1,716 ± 459. There were a total of 140 unique differentially expressed proteins (p < 0.05). There was a minor and inconsistent increase in histone and nonhistone protein acetylation. Functional annotation showed significant enrichment of apoptosis (p = 3.5E-43), cell death (p = 9.9E-72), proliferation of cells (p = 1.6E-40), dementia (p = 9.6E-40), amyloidosis (p = 6.3E-38), fatty acid metabolism (p = 4.6E-76), quantity of steroid (p = 4.2E-75), and cell movement (p = 1.9E-64). CONCLUSIONS Valproic acid induces significant changes to the proteome of healthy humans when given at a dose of 120 mg/kg. It alters the expression of key proteins and pathways, including those related to cell survival, without significant modification of protein acetylation. In the next part of the ongoing Phase I trial, we will study the effects of VPA on trauma patients in hemorrhagic shock. LEVEL OF EVIDENCE Therapeutic study, level V.

BACKGROUND We recently discovered that Tubastatin-A, a histone deacetylase (HDAC6) inhibitor, can improve survival in a rodent model of hemorrhagic shock (HS), but mechanisms remain poorly defined. In this study, we investigated whether Tubastatin-A could protect intestinal tight junction (TJ) in HS. METHODS In an in-vivo study with Wistar-Kyoto rats, the rats underwent HS (40% blood loss) followed by Tubastatin-A (70 mg/kg) treatment, without fluid resuscitation. The experimental groups were (1) sham (no hemorrhage, no treatment), (2) control (hemorrhage, without treatment), and (3) treatment (hemorrhage with Tubastatin-A administration). Six hours after hemorrhage, ileum was harvested. Whole cell lysate were analyzed for acetylated α-tubulin (Ac-tubulin), total tubulin, acetylated histone 3 at lysine 9 (Ac-H3K9), β-actin, claudin-3 and zonula occludens 1 (ZO-1) proteins by Western blot. Histological effects of Tubastatin-A on small bowel were examined. In an in-vitro study, human intestinal epithelial cells (Caco-2) were divided into three groups: (1) sham (normoxia), (2) control (anoxia, no treatment), and (3) treatment (anoxia, treatment with Tubastatin-A). After 12 hours in an anoxia chamber, the cells were examined for Ac-tubulin and Ac-H3K9, cellular viability, cytotoxicity, claudin-3 and ZO-1 protein expression, and transwell permeability study. RESULTS Tubastatin-A treatment significantly attenuated HS-induced decreases of Ac-tubulin, Ac-H3K9, ZO-1 and claudin-3 proteins in small bowel in-vivo (p < 0.05). In cultured Caco-2 cells, anoxia significantly decreased cellular viability (p < 0.001) and increased cytotoxicity (p < 0.001) compared to the sham group, while Tubastatin-A treatment offered significant protection (p < 0.0001). Moreover, expression of claudin-3 was markedly decreased in vitro compared to the sham group, whereas this was significantly attenuated by Tubastatin-A (p < 0.05). Finally, anoxia markedly increased the permeability of Caco-2 monolayer cells (p < 0.05), while Tubastatin-A significantly attenuated the alteration (p < 0.05). CONCLUSION Inhibition of HDAC6 can induce Ac-tubulin and Ac-H3K9, promote cellular viability, and prevent the loss of intestinal tight junction proteins during HS and anoxia.

Optimal cancer care requires a multidisciplinary approach. The purpose of the current study was to evaluate the impact of a multidisciplinary tumor board on the treatment plans of children with solid tumors.The records of 158 consecutive patients discussed at a formal multidisciplinary pediatric tumor board between July 2012 and April 2014 were reviewed. Treatment plans were based on clinical practice guidelines and on current Children's Oncology Group protocols. Alterations in radiologic, pathologic, surgical, and medical interpretations were analyzed to determine the impact on changes in recommendations for clinical management.Overall, 55 of 158 children (35%) had alterations in radiologic, pathologic, medical, or surgical interpretation of clinical data following multidisciplinary discussion. Of these, 64% had changes to the initial recommendation for clinical management. Review of imaging studies resulted in interpretation changes in 30 of 158 patients studied (19%), with 12 clinical management changes. Six of 158 patients (3.9%) had changes in pathologic interpretation, with four patients (2.5%) requiring treatment changes. In eight patients (5%), a change in medical management was recommended, while in 11 patients (7%) there were changes in surgical management that were based solely on discussion and not on interpretation of imaging or pathology.Formal multidisciplinary review led to alterations in interpretation of clinical data in 35% of patients, and the majority led to changes in recommendations for treatment. Comprehensive multidisciplinary tumor board incorporated into the care of children with cancer provides additional perspectives for families and care providers when delineating optimal treatment plans.

Background Despite the prevalence of ventral hernias, there is little agreement as to the most appropriate technique or prosthetic to repair these defects. Our objective was to determine biologic mesh practice patterns of reconstructive surgeons with regard to indications, most appropriate technique, choice of prosthetic, and experience with complications.

Background Mesh related infections are a major challenge with few adequate prevention and treatment options. We evaluate the ability of a slow affinity based drug-releasing polymer to prevent a Staphylococcus aureus mesh infection using an in vivo animal model. Methods A surgical wound infection model was used to evaluate a vancomycin (VM) drug loaded polymer. Fifty animals underwent creation of a dorsal subcutaneous pocket, insertion of a standard piece of polyester mesh and an inoculum of a clinical strain of green fluorescent protein (GFP) labeled S. aureus (SA) (104 CFU/mL). Animals were then randomly allocated to different treatment groups [saline flush (n = 10), VM flush (n = 20), VM polymer coated mesh (n = 20)]. Local tissue and mesh were evaluated at 2 (n = 25) and 4 wk (n = 25) via standard culture studies. Results Median GFP SA growth from tissue-mesh homogenates were as follows: 2 wk: saline flush = 2.2 × 107 CFU/g; VM flush = 1.6 × 106 CFU/g; VM polymer = sterile cultures [P value 0.0001]; 4 wk: saline flush = 1.5 × 106 CFU/g; VM flush = 1.6 × 103 CFU/g; VM polymer = sterile cultures [P value 0.001]. Conclusion Mesh infections pose a significant challenge in hernia surgery with suboptimal treatment modalities and little innovation. Using an in vivo wound infection model our novel affinity based drug delivering polymer was able to effectively prevent a SA mesh infection with efficacy demonstrated at 2 and 4 wk.

Background Hemorrhage is the leading cause of preventable trauma-related deaths. We have previously shown that treatment with Tubastatin A (Tub A), a histone deacetylase 6 (HDAC6) inhibitor, can improve survival in a rodent model of septic shock. The aims of the present study were to determine whether selective inhibition of HDAC6 can promote survival in a model of hemorrhagic shock (HS). Methods In Experiment I (survival study), Wistar-Kyoto rats were subjected to HS (55% volume blood loss), followed by intraperitoneal injection of either Tub A (70 mg/kg) dissolved in dimethyl sulfoxide (DMSO) or DMSO only (vehicle group) (n = 8 per group). Survival was monitored for 24 hours. In Experiment II (physiologic study), rats were subjected to a sublethal HS (40% blood loss), followed by the same treatment with Tub A (treatment group) or DMSO only (vehicle group, n = 5 per group). All animals were sacrificed 6 hours after hemorrhage, and the heart and liver tissues were harvested. Sham animals were not subjected to hemorrhage and treatment (sham group, n = 5 per group). Cardiac mitochondria were isolated to study the pyruvate dehydrogenase (PDH, an essential enzyme for adenosine triphosphate production) activity. Liver tissue lysates were analyzed for markers of apoptosis (cytochrome c, cleaved caspase 3) and inflammation (high-mobility group box 1) by Western blotting. Results Severe HS (55% blood loss) was associated with 75% mortality, which was significantly improved by Tub A treatment (37.5% mortality in 24 hours, p = 0.048). Tub A also significantly enhanced the cardiac PDH activity compared with the vehicle group, while suppressing the hepatic high-mobility group box 1 expression, cytochrome c release, and caspase 3 activation. Conclusion Our study has demonstrated for the first time that selective inhibition of HDAC6 can improve survival in a rodent model of HS. The potential mechanisms include enhanced PDH activity, decreased inflammatory drive, and attenuated cellular apoptosis.

The vast majority of congenital diaphragmatic cases present with severe respiratory distress in the immediate neonatal period. Obstructive jaundice secondary to CDH is a rare presenting symptom, previously unreported with Morgagni type hernias which comprise 2% of all CDHs. Although the safety of minimally invasive repair for CDH has been shown previously, there has been little data on its safety for patients with complex congenital cardiac disease. In this case report, we present an 18-month old infant with Fontan circulation presenting with jaundice secondary to Morgagni hernia who ultimately underwent laparoscopic repair. A brief discussion of the safety of laparoscopic surgery in patients post-Fontan is included.

Takayasu arteritis is a chronic, idiopathic, granulomatous vasculitis involving the aorta, its major branches, and occasionally the pulmonary arteries. Although rare in children, it is the third most common vasculitis in the paediatric population. Although aneurysmal disease has been reported in adults with Takayasu arteritis, it is a rare entity in children. We present the case of a 10-year-old boy with a giant ascending and arch aneurysm that necessitated follow-up surgery for a new aneurysm and occlusive disease. This is also the first published case involving endovascular aortic graft placement for the management of vascular sequela of Takayasu arteritis in a child.

Centrifugal pumps are increasingly used for extracorporeal membrane oxygenation (ECMO) rather than roller pumps. However, shear forces induced by these types of continuousflow pumps are associated with acquired von Willebrand factor deficiency and bleeding complications. This study was undertaken to compare adverse bleeding complications with the use of centrifugal and roller pumps in patients on prolonged ECMO support. The records of all adult ECMO patients from June 2002 to 2013 were retrospectively reviewed using the University of Michigan Health System database and the Extracorporeal Life Support Organization registry, focusing on patients supported for at least 5 days. Ninety-five ECMO patients met criteria for inclusion (48 roller vs. 47 centrifugal pump). Indications included pulmonary (79%), cardiac (15%), and extracorporeal cardiopulmonary resuscitation (6%), without significant difference between the two groups. Despite lower heparin anticoagulation (10.9 vs. 13.7 IU/kg/hr) with centrifugal pumps, there was a higher incidence of nonsurgical bleeding (gastrointestinal, pulmonary, and neurological) in centrifugal pump patients (26.1 vs. 9.0 events/1,000 patient-days, p = 0.024). In conclusion, in our historical comparison, despite reduced anticoagulation, ECMO support using centrifugal pumps was associated with a higher incidence of nonsurgical bleeding. The mechanisms behind this are multifactorial and require further investigation.

Sepsis, a systemic inflammatory response syndrome caused by severe infection, is still a tremendous burden for health-care systems and results in more than 225,000 deaths annually in the United States1. No pharmacological agents have been shown to effectively change the outcomes2. Acetylation of histone is an important epigenetic mechanism that governs amplitude of the immune signaling by controlling the chromatin structure, accessibility of transcription factors to DNA, and gene transcription. Regulation of this process needs the opposing actions of two families of enzymes: histone acetyltransferases (HATs) and histone deacetylases (HDACs). It is found that dysregulated HDAC activity is linked to the pathogenesis of inflammatory and autoimmune diseases3. So far, 18 HDAC isoforms have been identified in humans and mice and grouped into four classes 4. Classical HDACs (class I, II and IV) are Zn2+ dependent hydrolases, while the class III sirtuins are NAD+-dependent. Class I HDACs (HDAC1, 2, 3 and 8) play a role in cell survival and proliferation. Class II HDACs, subdivided into class IIa (HDAC4, 5, 7 and 9) and IIb (HDAC6 and 10) based on domain organization 5, may have tissue-specific roles 6. Recently, HDAC6 has become an important target for anti-cancer drug development, and inhibition of HDAC6 was also shown to have therapeutic potential to ameliorate injury of central nervous system7. MS-275 is a HDAC class I inhibitor with selectivity for HDAC1, 2, and 3. Tubastatin A is a newly synthesized selective inhibitor of HDAC class IIb with high selectivity for HDAC6 8. Suberoylanilide hydroxamic acid (SAHA, vorinostat) is a broad-spectrum histone deacetylase inhibitor (HDACI) with a selectivity for HDAC1, 2, 3 and 6 9. Our laboratory has previously demonstrated that administration of SAHA improves survival in rodent models of lipopolysaccharided (LPS)-induced endotoxemia and cecal ligation and puncture (CLP)-induced septic shock 10, 11. However, this HDACI was also found to increase host susceptibility to bacterial infection due to cell apoptosis 12. We hypothesized that targeting different HDACs could have different effect on animal survival in a mouse model of cecal ligation and puncture (CLP)-induced sepsis. In the present study, we first determined that inhibitor of HDAC6 (Tubastatin A) rather than that of HDAC1, 2, and 3 significantly prolonged animal lives in the CLP model. We then assessed impact of HDAC6 inhibition on production of some key pro-inflammatory cytokines, organ (liver) injury, and immune cell apoptosis. Our findings suggested that selective inhibition of HDAC6 has a substantial advantage for sepsis treatment.