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Background: Pediatric trauma centers have had challenges meeting the American College of Surgeons criteria for screening and intervening for alcohol with adolescent trauma patients. The study objective was to conduct an implementation trial to evaluate the effectiveness of the Science to Service Laboratory (SSL) implementation strategy in improving alcohol and other drugs (AOD) screening, brief intervention, and referral to treatment (SBIRT) delivery at pediatric trauma centers., Methods: Using a stepped wedge cross-over cluster randomized design, 10 US pediatric trauma centers received the SSL implementation strategy to deliver SBIRT with admitted adolescent (12-17 years old) trauma patients. The strategy adapted three core SSL elements: didactic training, performance feedback, and facilitation. The main outcome measured was SBIRT reach. Data were collected from each center's electronic health record (EHR) during pre- and post-implementation wedges (2018-2022)., Results: EHR data from 8461 adolescent patients were extracted. Aggregated across all sites, the reach of screening with a validated AOD screening tool increased significantly from 25.2% (95% CI: 23.9, 26.5%) of adolescents during pre-implementation to 47.7% (95% CI: 46.3%, 49.2%) post-implementation. There was variability of change across centers. Brief interventions continued to be delivered at high levels to identified adolescents. Referral to primary care providers for further AOD discussion or referral to specialty service for adolescents with high risk use did not improve post-implementation and remained low., Conclusions: The SSL implementation strategy can be successfully utilized by pediatric trauma centers to improve AOD screening, but challenges exist in connecting adolescents for continuation of AOD discussions after discharge., Level of Evidence: Level II, Therapeutic., Competing Interests: Conflicts of interest None., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Introduction: Pediatric firearm injuries are a significant public health concern in the United States. This study examines risk factors for firearm reinjury in Maryland's pediatric population., Methods: Pediatric patients (age 0-19 y) who presented to any hospital in Maryland with a firearm injury between October 1, 2015, and December 31, 2019, were identified in the Maryland Health Services Cost Review Commission database and were followed for repeat firearm injuries through March 31, 2020. Logistic regression was used to analyze risk factors for reinjury. Geospatial analysis was used to identify communities with the highest prevalence of reinjury., Results: Of 1351 index presentations for firearm injuries, 102 (7.3%) were fatal. Among children with nonfatal injuries, 40 (3.1%) re-presented with a second firearm injury, 25% of which were fatal. The median interval to reinjury was 149 d [interquartile range: 73-617]. Reinjury was more common in children aged ≥15 y (90% versus 76%), males (100% versus 87%), of Black race (90% versus 69%) or publicly insured (90% versus 68%) (all P < 0.05). Most lived in highly deprived neighborhoods of Baltimore City. No single factor was significant in multivariable models., Conclusions: Pediatric firearm reinjury is rare but highly morbid in Maryland. While prior studies have shown Black race to be independently associated with firearm reinjury, we found the effect of race was entirely attenuated after controlling for neighborhood deprivation. These findings underscore the urgent need for targeted interventions in areas identified as high risk in addition to policies to reduce youth firearm access., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Objective: Predicting high-value care outcomes is crucial in managing pediatric traumatic brain injuries (TBIs), where timely and accurate prognostication can significantly influence treatment decisions and resource allocation. This study aimed to enhance understanding of how well scoring systems such as the Trauma and Injury Severity Score (TRISS) can forecast high-value care outcomes. Furthermore, the authors compared the predictive power of TRISS with the routinely used Injury Severity Score (ISS)., Methods: The authors performed a retrospective review of their institutional database from June 2016 to June 2023 to identify cases of TBI based on a modified Centers for Disease Control and Prevention framework. Prolonged length of stay (LOS) was defined as a hospital stay falling into the upper quartile of the overall cohort. Discharge to an inpatient rehabilitation facility, acute care hospital, or foster care or death was defined as a nonroutine discharge disposition. Emergency department (ED) transfer to the intensive care unit (ICU) or operating room (OR) was defined as a proxy for severity of injuries. Multivariate logistic regression models were used to explore the association between ISS, TRISS, and high-value care outcomes. The DeLong test was used to assess the differences between the areas under the receiver operating characteristic curve (AUROCs)., Results: This study included 2705 patients with a mean age ± SD of 7.28 ± 5.46 years (63% male). In the overall cohort, 28% experienced prolonged LOS, 7% had a nonroutine discharge disposition from the hospital, and 23% were transferred to the ICU/OR from the ED. In multivariate regression models, both TRISS and ISS were correlated with higher odds of prolonged LOS, nonroutine discharge disposition, and transfer to the ICU/OR from the ED (all p < 0.001). TRISS had a significantly greater AUROC than ISS for nonroutine discharge disposition (0.883 vs 0.849, p < 0.001) and transfer to the ICU/OR (0.898 vs 0.887, p = 0.045), but this result was not significant for prolonged LOS (0.873 vs 0.880, p = 0.140)., Conclusions: TRISS and ISS are effective tools for predicting high-value care outcomes in pediatric TBI. Utilizing these resources can assist healthcare providers in making informed, risk-adjusted predictions.

Background: Traumatic brain injury (TBI) leads to acute gastrointestinal dysfunction and mucosal damage, resulting in feeding intolerance. C-C motif chemokine receptor 2 (Ccr2 + ) monocytes are crucial immune cells that regulate the gut's inflammatory response via the brain-gut axis. Using Ccr2 ko mice, we investigated the intricate interplay between these cells to better elucidate the role of systemic inflammation after TBI., Methods: A murine-controlled cortical impact model was used, and results were analyzed on postinjury days 1 and 3. The experimental groups included (1) sham C57Bl/6 wild type (WT), (2) TBI WT, (3) sham Ccr2 ko , and (4) TBI Ccr2 ko . Mice were euthanized on postinjury days 1 and 3 to harvest the ileum and study intestinal dysfunction and serotonergic signaling using a combination of quantitative real-time polymerase chain reaction, immunohistochemistry, fluorescein isothiocyanate-dextran motility assays, and flow cytometry. Student's t test and one-way analysis of variance were used for statistical analysis, with significance achieved when p < 0.05., Results: Traumatic brain injury resulted in severe dysfunction and dysmotility of the small intestine in WT mice as established by significant upregulation of inflammatory cytokines iNOS , Lcn2 , TNFα , and IL1β and the innate immunity receptor toll-like receptor 4 ( Tlr4 ). This was accompanied by disruption of genes related to serotonin synthesis and degradation. Notably, Ccr2 ko mice subjected to TBI showed substantial improvements in intestinal pathology. Traumatic brain injury Ccr2 ko groups demonstrated reduced expression of inflammatory mediators ( iNOS , Lcn2 , IL1β , and Tlr4 ) and improvement in serotonin synthesis genes, including tryptophan hydroxylase 1 ( Tph1 ) and dopa decarboxylase ( Ddc )., Conclusion: Our study reveals a critical role for Ccr2 + monocytes in modulating intestinal homeostasis after TBI. Ccr2 + monocytes aggravate intestinal inflammation and alter gut-derived serotonergic signaling. Therefore, targeting Ccr2 + monocyte-dependent responses could provide a better understanding of TBI-induced gut inflammation. Further studies are required to elucidate the impact of these changes on brain neuroinflammation and cognitive outcomes., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Background: National estimates suggest pediatric trauma recidivism is uncommon but are limited by short follow up and narrow ascertainment. We aimed to quantify the long-term frequency of trauma recidivism in a statewide pediatric population and identify risk factors for re-injury., Methods: The Maryland Health Services Cost Review Commission Dataset was queried for 0-19-year-old patients with emergency department or inpatient encounters for traumatic injuries between 2013 and 2019. We measured trauma recidivism by identifying patients with any subsequent presentation for a new traumatic injury. Univariate and multivariable regressions were used to estimate associations of patient and injury characteristics with any recidivism and inpatient recidivism., Results: Of 574,472 patients with at least one injury encounter, 29.6% experienced trauma recidivism. Age ≤2 years, public insurance, and self-inflicted injuries were associated with recidivism regardless of index treatment setting. Of those with index emergency department presentations 0.06% represented with an injury requiring inpatient admission; unique risk factors for ED-to-inpatient recidivism were age >10 years (aOR 1.61), cyclist (aOR 1.31) or burn (aOR 1.39) mechanisms, child abuse (aOR 1.27), and assault (aOR 1.43). Among patients with at least one inpatient encounter, 6.3% experienced another inpatient trauma admission, 3.4% of which were fatal. Unique risk factors for inpatient-to-inpatient recidivism were firearm (aOR 2.48) and motor vehicle/transportation (aOR 1.62) mechanisms of injury (all p < 0.05)., Conclusions: Pediatric trauma recidivism is more common and morbid than previously estimated, and risk factors for repeat injury differ by treatment setting. Demographic and injury characteristics may help develop and target setting-specific interventions., Level of Evidence: III (Retrospective Comparative Study)., Competing Interests: Conflicts of interest No conflicts of interest., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Objective: Screening, brief intervention, and referral to treatment (SBIRT) for adolescent alcohol and drug (AOD) use is recommended to occur with adolescents admitted to pediatric trauma centers. Most metrics on SBIRT service delivery only reference medical record documentation. In this analysis we examined changes in adolescents' perception of SBIRT services and concordance of adolescent-report and medical record data, among a sample of adolescents admitted before and after institutional SBIRT implementation., Methods: We implemented SBIRT for adolescent AOD use using the Science to Service Laboratory implementation strategy and enrolled adolescents at 9 pediatric trauma centers. The recommended clinical workflow was for nursing to screen, social work to provide adolescents screening positive with brief intervention and referral to their PCP for continued AOD discussions with those. Adolescents screening as high-risk also referred to specialty services. Adolescents were enrolled and contacted 30 days after discharge and asked about their perception of any SBIRT services received. Data were also extracted from enrolled patient's medical record., Results: There were 430 adolescents enrolled, with 424 that were matched to their EHR data and 329 completed the 30-day survey. In this sample, EHR documented screening increased from pre-implementation to post-implementation (16.3%-65.7%) and brief interventions increased (27.1%-40.7%). Adolescents self-reported higher rates of being asked about alcohol or drug use than in EHR data both pre- and post-implementation (80.7%-81%). Both EHR data and adolescent self-reported data demonstrated low referral back to PCP for continued AOD discussions., Conclusions: Implementation of SBIRT at pediatric trauma centers was not associated with change in adolescent perceptions of SBIRT, despite improved documentation of delivery of AOD screening and interventions. Adolescents perceived being asked about AOD use more often than was documented. Referral to PCP or specialty care for continued AOD discussion remains an area of needed attention., Trial Registration: Clinicaltrials.gov NCT03297060., Competing Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2024.)

Firearm injuries are a common and major public health problem in Baltimore, Maryland. The city is also one of the first U.S. cities in which the 1930s discriminatory practice of redlining first emerged. This study examines the association between current day firearm injuries and residence in these historically redlined areas at a neighborhood level using zip codes. Firearm injury outcomes in patients who presented to a hospital in Maryland from 2015 to 2020 were measured from the Health Services Cost Review Commission (HSCRC) in conjunction with both geospatial data from Richmond's Digital Scholarship Lab's Mapping Inequality project and population data from the U.S. Census. A redlining score was calculated to represent the extent of redlining in each zip code. Negative binomial regression models were utilized to measure the association between neighborhood zip codes and rate of firearm injuries. Our adjusted regression model shows that for every one-unit increase of the Home Owners' Loan Corporation (HOLC) redlining score, there is a 2.24-fold increase in the rate of firearm injuries (RR 2.24; 95% CI: 0.31, 1.31, p < 0.001). These findings suggest a strongassociation between historically redlined areas and population risk of firearm injury today. Further research is needed to investigate the underlying mechanisms that may contribute to this relationship, such as access to firearms or social and economic factors. Overall, our study highlights the potential impact of historical redlining policies on contemporary health outcomes in Baltimore.

Objective: The PEDSPINE I and PEDSPINE II scores were developed to determine when patients require advanced imaging to rule out cervical spine injury (CSI) in children younger than 3 years of age with blunt trauma. This study aimed to evaluate these scores in an institutional cohort., Methods: The authors identified patients younger than 3 years with blunt trauma who received cervical spine MRI from their institution's prospective database from 2012 to 2015. Patient demographics, injury characteristics, and imaging were compared between patients with and without CSI using chi-square and Wilcoxon rank-sum tests., Results: Eighty-eight patients were identified, 8 (9%) of whom had CSI on MRI. The PEDSPINE I system had a higher sensitivity (50% vs 25%) and negative predictive value (93% vs 92%), whereas PEDSPINE II had a higher specificity (91% vs 65%) and positive predictive value (22% vs 13%). Patients with CSI missed by the scores had mild, radiologically significant ligamentous injuries detected on MRI. Both models would have recommended advanced imaging for the patient who required halo-vest fixation (risk profile: no CSI, 81.9%; ligamentous, 10.1%; osseous, 8.0%). PEDSPINE I would have prevented 52 (65%) of 80 uninjured patients from receiving advanced imaging, whereas PEDSPINE II would have prevented 73 (91%). Using PEDSPINE I, 10 uninjured patients (13%) could have avoided intubation for imaging. PEDSPINE II would not have spared any patients intubation., Conclusions: Current cervical spine clearance algorithms are not sensitive or specific enough to determine the need for advanced imaging in children. However, these scores can be used as a reference in conjunction with physicians' clinical impressions to reduce unnecessary imaging.

Traumatic brain injury (TBI) is a chronic and debilitating disease, associated with a high risk of psychiatric and neurodegenerative diseases. Despite significant advancements in improving outcomes, the lack of effective treatments underscore the urgent need for innovative therapeutic strategies. The brain-gut axis has emerged as a crucial bidirectional pathway connecting the brain and the gastrointestinal (GI) system through an intricate network of neuronal, hormonal, and immunological pathways. Four main pathways are primarily implicated in this crosstalk, including the systemic immune system, autonomic and enteric nervous systems, neuroendocrine system, and microbiome. TBI induces profound changes in the gut, initiating an unrestrained vicious cycle that exacerbates brain injury through the brain-gut axis. Alterations in the gut include mucosal damage associated with the malabsorption of nutrients/electrolytes, disintegration of the intestinal barrier, increased infiltration of systemic immune cells, dysmotility, dysbiosis, enteroendocrine cell (EEC) dysfunction and disruption in the enteric nervous system (ENS) and autonomic nervous system (ANS). Collectively, these changes further contribute to brain neuroinflammation and neurodegeneration via the gut-brain axis. In this review article, we elucidate the roles of various anti-inflammatory pharmacotherapies capable of attenuating the dysregulated inflammatory response along the brain-gut axis in TBI. These agents include hormones such as serotonin, ghrelin, and progesterone, ANS regulators such as beta-blockers, lipid-lowering drugs like statins, and intestinal flora modulators such as probiotics and antibiotics. They attenuate neuroinflammation by targeting distinct inflammatory pathways in both the brain and the gut post-TBI. These therapeutic agents exhibit promising potential in mitigating inflammation along the brain-gut axis and enhancing neurocognitive outcomes for TBI patients., (© 2024. The Author(s).)

Introduction: While intravenous fluid therapy is essential to re-establishing volume status in children who have experienced trauma, aggressive resuscitation can lead to various complications. There remains a lack of consensus on whether pediatric trauma patients will benefit from a liberal or restrictive crystalloid resuscitation approach and how to optimally identify and transition between fluid phases., Methods: A panel was comprised of physicians with expertise in pediatric trauma, critical care, and emergency medicine. A three-round Delphi process was conducted via an online survey, with each round being followed by a live video conference. Experts agreed or disagreed with each aspect of the proposed fluid management algorithm on a five-level Likert scale. The group opinion level defined an algorithm parameter's acceptance or rejection with greater than 75% agreement resulting in acceptance and greater than 50% disagreement resulting in rejection. The remaining were discussed and re-presented in the next round., Results: Fourteen experts from five Level 1 pediatric trauma centers representing three subspecialties were included. Responses were received from 13/14 participants (93%). In round 1, 64% of the parameters were accepted, while the remaining 36% were discussed and re-presented. In round 2, 90% of the parameters were accepted. Following round 3, there was 100% acceptance by all the experts on the revised and final version of the algorithm., Conclusions: We present a validated algorithm for intavenous fluid management in pediatric trauma patients that focuses on the de-escalation of fluids. Focusing on this time point of fluid therapy will help minimize iatrogenic complications of crystalloid fluids within this patient population., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: The exstrophy-epispadias complex is a spectrum of ventral wall malformations including classic bladder exstrophy (CBE) and cloacal exstrophy (CE). Patients undergo multiple soft-tissues procedures to achieve urinary continence. If unsuccessful bladder neck closure (BNC) is performed, muscle flaps may be used to reinforce BNC or afterwards for fistula reconstruction. In this study, patients reconstructed using a rectus abdominis or gracilis muscle flap were reviewed., Methods: A retrospective cohort study of exstrophy-epispadias complex patients who underwent BNC and had a muscle fap was performed. Indication for flap use, surgical technique, risks for BNC failure including mucosal violations (MVs) were reviewed. MVs were prior bladder mucosa manipulation for exstrophy closure, repeat closure(s) and bladder neck reconstruction. Success was defined as BNC without fistula development., Results: Thirty-four patients underwent reconstruction. Indications included during BNC (n=13), fistula closure after BNC (n=17), following BNC during open cystolithotomy (n=1) or fistula closure after open cystolithotomy (n=3). A vesicourethral fistula developed most frequently in CBE (88.9%) and vesicoperineal fistula in CE (87.5%). Thirty-three rectus flaps and 3 gracilis flap were used with success achieved in 97.1% and 66.7%, respectively. All 34 patients achieved success and 2 CE patients required a second flap., Conclusion: The rectus flap is preferred as it covers the antero-inferior bladder and pelvic floor to prevent urethral, cutaneous, and perineal fistula formation. The gracilis flap only reaches the pelvic floor to prevent urethral and perineal fistula development. Increased MVs, increase the risk of fistula formation and may influence the need for prophylactic flaps., Competing Interests: Conflicts of interest: The authors have no conflicts of interest., (Copyright © 2024 by the American Society of Plastic Surgeons.)

Background: Cloacal exstrophy (CE) is rare and challenging to reconstruct. In the majority of CE patients voided continence cannot be achieved and so patients often undergo bladder neck closure (BNC). Prior mucosal violations (MVs), a surgical event when the bladder mucosa was opened or closed, significantly predicted failed BNC in classic bladder exstrophy with an increased likelihood of failure after 3 or more MVs. The aim of this study was to assess predictors for failed BNC in CE., Methods: CE patients who underwent BNC were reviewed for risk factors for failure including osteotomy use, successful primary closure, and number of MVs. Chi-squared and Fisher's exact tests were used for comparing baseline characteristics and surgical details., Results: Thirty-five patients underwent BNC. Eleven patients (31.4%) failed BNC including a vesicoperineal fistula in nine, vesicourethral and vesicocutaneous fistula in one each. The fistula rate in patients with 2 or more MVs was 47.4% (p = 0.0252). Two patients subsequently developed a vesicocutaneous fistula after undergoing repeated cystolithotomies. A rectus abdominis or gracilis muscle flap were used to close the fistula in 11 and 2 patients, respectively., Conclusions: MVs have a greater impact in CE with an increased risk of failed BNC after 2 MVs. CE patients are most likely to develop a vesicoperineal fistula while a vesicocutaneous fistula is more likely after repeat cystolithotomy. A prophylactic muscle flap should be considered at time of BNC in patients with 2 or more MVs., Levels of Evidence: Prognosis Study, Level III., (Copyright © 2023. Published by Elsevier Inc.)

Purpose: Staged pelvic osteotomy has been shown in the past to be an effective tool in the closure of the extreme pubic diastasis of cloacal exstrophy. The authors sought to compare orthopedic complications between non-staged pelvic osteotomies and staged pelvic osteotomies in cloacal exstrophy., Methods: A prospectively maintained exstrophy-epispadias complex database of 1510 patients was reviewed for cloacal exstrophy bladder closure events performed with osteotomy at the authors' institution. Bladder closure failure was defined as any fascial dehiscence, bladder prolapse, or vesicocutaneous fistula within one year of closure. There was a total of 172 cloacal exstrophy and cloacal exstrophy variant patients within the database and only closures at the authors' institution were included., Results: 64 closure events fitting the inclusion criteria were identified in 61 unique patients. Staged osteotomy was performed in 42 closure events and non-staged in 22 closures. Complications occurred in 46/64 closure events, with 16 grade III/IV complications. There were no associations between staged osteotomy and overall complication or grade III/IV complications (p = 0.6344 and p = 0.1286, respectively). Of the 46 total complications, 12 were orthopedic complications with 6 complications being grade III/IV. Staged osteotomy closure events experienced 10/42 orthopedic complications while non-staged osteotomy closures experienced 2/22 orthopedic complications, however this did not reach significance (p = 0.1519). Of the 64 closure events, 57 resulted in successful closure with 6 failures and one closure with planned cystectomy., Conclusion: This study confirms, in a larger series, superior outcomes when using staged pelvic osteotomy in cloacal exstrophy bladder closure. Staged osteotomy was shown to be a safe alternative to non-staged osteotomy that can decrease the risk of closure failure in this group. Staged pelvic osteotomy should be considered in all patients undergoing cloacal exstrophy bladder closure., Type of Study: Treatment study., Level of Evidence: Level III., Competing Interests: Conflict of interest The authors have no financial or personal relationships with other people or organizations that could inappropriately influence their work., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: Astrocytes are critical neuroimmune cells that modulate the neuroinflammatory response following traumatic brain injury (TBI) because of their ability to acquire neurotoxic (A1) or neuroprotective (A2) phenotypes. Using C34, a novel pharmacologic Toll-like receptor (TLR) 4 inhibitor, we explored their respective polarization states after TBI., Methods: A murine controlled cortical impact model was used, and the results were analyzed on postinjury days (PIDs) 1, 7, and 28. The experimental groups are as follows: (1) sham, (2) sham + C34, (3) TBI, and (4) TBI + C34. Quantitative real-time polymerase chain reaction was used to quantify gene expression associated with proinflammatory (A1) and anti-inflammatory (A2) phenotypes. Morris water maze was used to assess neurocognitive outcomes. Fixed frozen cortical samples were sectioned, stained for myelin basic protein and 4',6-diamidino-2-phenylindole, and then imaged. Student t test and one-way analysis of variance were used for statistical analysis with significance achieved when p < 0.05., Results: On quantitative real-time polymerase chain reaction, C34-treated groups showed a significant decrease in the expression of A1 markers such as Gbp2 and a significant increase in the expression of A2 markers such as Emp1 when compared with untreated groups on PID 1. On PIDs 7 and 28, the expression of most A1 and A2 markers was also significantly decreased in the C34-treated groups. On immunohistochemistry, C34-treated groups demonstrated increased myelin basic protein staining into the lesion by PID 28. C34-treated groups showed more platform entries on Morris water maze when compared with untreated groups on PID 7 and PID 28., Conclusion: Following TBI, early TLR4 blockade modulates astrocytic function and shifts its polarization toward the anti-inflammatory A2-like phenotype. This is accompanied by an increase in myelin regeneration, providing better neuroprotection and improved neurocognitive outcomes. Targeting A1/A2 balance with TLR4 inhibition provides a potential therapeutic target to improve neurobehavioral outcomes in the setting of TBI., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Traumatic brain injury (TBI) is the leading cause of morbidity and mortality in the pediatric population. Microglia and infiltrating monocyte-derived macrophages are crucial immune cells that modulate the neuroinflammatory response following TBI. Using C34, a novel pharmacologic toll-like receptor 4 inhibitor, we investigated the intricate interactions between these cells in a murine TBI model., Methods: A murine controlled cortical impact model was used, and the results were analyzed on postinjury days 1, 7, 28, and 35. The experimental groups are as follows: (1) sham C57BL/6 wild-type (WT), (2) TBI WT, (3) sham WT + C34, and (4) TBI WT + C34. Quantitative real-time polymerase chain reaction was used to quantify gene expression associated with microglial activation, apoptotic pathways, and type 1 interferon pathway. Flow cytometry was used to isolate microglia and infiltrating monocytes. Brain lesion volumes were assessed using magnetic resonance imaging. Last, neurocognitive outcomes were evaluated using the Morris Water Maze test. Student's t test and one-way analysis of variance were used for statistical analysis with significance achieved when p < 0.05., Results: Toll-like receptor 4 inhibition leads to improved neurological sequela post-TBI, possibly because of an increase in infiltrating anti-inflammatory monocytes and a decrease in IFN regulatory factor 7 during acute inflammation, followed by a reduction in apoptosis and M2 microglial expression during chronic inflammation., Conclusion: Toll-like receptor 4 inhibition with C34 skews infiltrating monocytes toward an anti-inflammatory phenotype, leading to enhanced neurocognitive outcomes. Moreover, although M2 microglia have been consistently shown as inducers of neuroprotection, our results clearly demonstrate their detrimental role during the chronic phases of healing post-TBI., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Background: The type of osteotomy and pelvic fixation in the management of primary cloacal exstrophy (CE) closure is variable. The purpose of this study was to evaluate primary CE closure outcomes with osteotomy, immobilization, and multi-staging procedure trends over time., Methods: An institutional database was retrospectively reviewed for patients who underwent primary CE closure from 1960 to 2020. Demographics, osteotomy, fixation, and outcomes were noted. Subanalyses by location of primary closure (AH=author's hospital; OH=outside hospital)., Results: Out of 122 patients, multi-stage became more common than single-stage procedures (p = 0.019), with multi-stage associated with higher success rates (77.4% v 45.7%; p = 0.001). The use of any osteotomy increased over time (p = 0.007), with a posterior approach falling out of favor and increasing prevalence of a combined osteotomy (p<0.001). The use of any osteotomy compared to no osteotomy was associated with successful closure (77.6% v 41.7%; p = 0.007). The combined, posterior, and anterior approaches were associated with 90%, 76.2%, and 60.9% successful primary closure rates, respectively (p<0.001). Fixation modalities changed over time as Buck's traction (p<0.001) and external fixation (p<0.001) became more prevalent. Spica casting has become less common (p = 0.0002). Immobilization type was associated with success rates with Buck's (92.1%; p<0.001) and external fixation (86.0%; p<0.001) performing best., Conclusions: The use of osteotomy and fixation in the CE spectrum has changed markedly. In this cohort, a staged approach with combination osteotomy was associated with better outcomes when using a multidisciplinary team approach., Level of Evidence: This is a retrospective comparative study (Type of Study: Treatment; Evidence Level: III)., Competing Interests: Declaration of Competing Interest None., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: The optimal timing of operative management in children with primary spontaneous pneumothorax (PSP) remains controversial. This study sought to determine early risk factors for failure of chest tube nonoperative management during the initial hospitalization in adolescents with PSP., Methods: A retrospective review was conducted for children (aged ≤18 years) admitted to a single tertiary care referral center for their first presentation of a PSP managed with at least 48 h of chest tube decompression (CTD) alone. Patient outcomes and early risk factors for operative management were analyzed by multivariate regression., Results: Of the 39 patients who met inclusion criteria, 15 (38.5%) patients failed nonoperative treatment while 24 (61.5%) patients were managed with CTD therapy alone. Progression to thoracoscopic surgery was associated with longer CTD of 8 vs 3 days and hospital length of stay of 9 vs 4 days when compared to nonoperative management (p < 0.001, both). Air leak and increase in pneumothorax size at 24 h after CTD were independently associated with progression to surgery (p = 0.007, p = 0.002). Combined, these risk factors were associated with a significant increase in recurrence (OR 6.00, 95% CI 1.11-41.11, p = 0.048). There were no significant differences between PSP management strategies regarding cumulative radiation exposure or 2 year recurrence., Conclusions: Air leak or increasing pneumothorax size within 24 h of CTD are highly correlated with failed nonoperative management during the initial hospitalization in pediatric patients with PSP. This data may be useful in the development of pediatric-specific treatment algorithms to optimally manage these patients., Level of Evidence: Treatment study, Level III., Competing Interests: Declaration of Competing Interest The authors have nothing to declare., (Copyright © 2022. Published by Elsevier Inc.)

Introduction: The value of chest computed tomography (CT) in pediatric primary spontaneous pneumothorax (PSP) remains controversial. This study sought to evaluate the utility of CT scans in a contemporary cohort of children with PSP., Materials and Methods: An institutional review board approval was obtained for a retrospective review of all children (aged ≤18 y) who underwent video-assisted thoracoscopic surgery (VATS) for PSP between 2009 and 2019 at a university-affiliated pediatric hospital. Preoperative CT scans were evaluated for diagnostic accuracy of the CT of bleb disease., Results: Thirty nine patients underwent VATS procedures for PSP, 34 (87%) of the patients were noted to have blebs. Twenty eight (72%) patients received preoperative CT scans with a 5.5:1 male to female ratio. On CT, 17 (61%) were diagnosed with blebs and all had blebs intraoperatively. CT did not identify disease in 11 patients, but seven had blebs intraoperatively. The positive and negative predictive values of preoperative CT for detecting ipsilateral bleb disease were 100% and 36%, respectively, with a sensitivity of 71%. Eleven patients had a contralateral disease on CT (39%). Five received elective contralateral VATS and three developed spontaneous PSP, with intraoperative blebs in all eight patients. Three never developed contralateral PSP. Six (21%) patients with no contralateral disease on CT developed spontaneous PSP with intraoperative blebs., Conclusions: The decision to operate for PSP should be made based on clinical findings rather than on the presence or absence of blebs identified by CT., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Introduction In the past two decades, Enhanced Recovery After Surgery (ERAS) pathways for adults have improved efficiency of care and decreased length of stay (LOS) without increasing postoperative complications. The effects of enhanced recovery pathways for children are less well known. In this retrospective cohort study, we evaluated the effects of an enhanced recovery protocol (ERP) implementation in children undergoing colorectal surgery. Methods We introduced a colorectal ERP in 2017. Children and young adults (ages 2-22 years) were divided into pre-intervention (2014-2016) and post-intervention groups (2017-2019) for analysis. We abstracted data, including demographics, primary surgery, LOS, postoperative pain scores, and postoperative complications. Results A total of 432 patients were included. Of those,148 (34%) were pre-ERP implementation and 284 (66%) were post-ERP implementation. Post-ERP patients experienced significantly shorter LOS (5.7 vs. 8.3 days, p<0.01); required less intraoperative local anesthetic (9.5% vs. 38.5%, p<0.01) because 55% of patients received an epidural and 18% received an abdominal plane block; and used less postoperative opioid (62.5% vs. 98.7%, p<0.01) than did pre-ERAS patients. After protocol implementation, average pain scores were lower on postoperative day 1 (3.6 vs. 4.5, p<0.05) and across the hospitalization (3.0 vs. 4.0, p<0.01). Conclusion Enhanced recovery pathways decrease LOS, opioid use, and postoperative pain scores for children undergoing colorectal surgery and should be considered for this patient population., (Copyright © 2022. Published by Elsevier Inc.)

The Covid-19 pandemic resulted in unprecedented restrictions on many public, private, and workplace activities throughout the United States and elsewhere. When restrictions were imposed, we were conducting a type III hybrid effectiveness-implementation trial in 10 pediatric trauma centers. In response to several pandemic-based restrictions, we had to develop procedures for engaging with potential research participants while limiting nonclinical, in-person interactions. This manuscript describes the procedures and challenges of obtaining electronic informed consent and assent in a multisite trauma center-based research study. We developed, tested, and trained staff to implement three options for obtaining informed consent. Twenty-five participants were enrolled in the effectiveness-implementation multisite trial during the first six months of utilization of the consent options, with eleven of these individuals enrolled using hybrid or electronic consent procedures. The challenges we identified involving electronic consent procedures included confusion over who would complete the electronic consent process and difficulties reconnecting with families. Lessons learned can strengthen electronic consent and assent procedures for future studies. More research is needed to further strengthen this process and increase its utilization., (© 2022 by The Hastings Center. All rights reserved.)

Objective: To describe demographic, injury, and clinical characteristics of pediatric patients treated in the ED for mild traumatic brain injury (mTBI), and to evaluate characteristics associated with mTBI-related return emergency department (ED) visit within 1 month of initial presentation., Methods: Retrospective cohort study from April 1, 2012, to September 30, 2017, of children 19 years or younger presenting to any Maryland ED for mTBI identified in the Maryland Health Services Cost Review Commission database using ICD-9/10 codes. Demographic, injury, and clinical characteristics of individuals were collected. The primary outcome was mTBI-related return ED visit within 4 weeks. Multiple logistic regression tested the associated of individual demographic, injury, and clinical characteristics with mTBI-related return ED visit., Results: There were 25,582 individuals who had an ED visit for mTBI, of which 717 (2.8%) returned to the ED within 4 weeks and 468 (1.8%) within 1 week with a mTBI-related diagnosis. In multivariable logistic regression analyses, public insurance (adjusted odds ratio [aOR], 1.44; 95% confidence interval [CI], 1.21-1.72) and female sex (aOR, 1.34; 95% CI, 1.15-1.56) were associated with increased odds of return to the ED within 4 weeks. Age younger than 2 years (aOR, 0.39; 95% CI, 0.21-0.72) was associated with decreased odds of return visit. There was a trend toward decreased odds of return patients receiving computed tomography head imaging (aOR, 0.86; 95% CI, 0.74-1.01)., Conclusions: Although return to the ED for mTBI-related complaints is uncommon, girls, older children, and publicly insured individuals may be at increased risk. Future targeted study may identify areas to improve access to appropriate longitudinal care and justify ED programs to better coordinate follow-up for mTBI., Competing Interests: Disclosure: The authors declare no conflict of interest., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Background and Objectives: The Covid-19 pandemic has forced mass closures of childcare facilities and schools. While these measures are necessary to slow virus transmission, little is known regarding the secondary health consequences of social distancing. The purpose of this study is to assess the proportion of injuries secondary to physical child abuse (PCA) at a level I pediatric trauma center during the Covid-19 pandemic., Methods: A retrospective review of patients at our center was conducted to identify injuries caused by PCA in the month following the statewide closure of childcare facilities in Maryland. The proportion of PCA patients treated during the Covid-19 era were compared to the corresponding period in the preceding two years by Fisher's exact test. Demographics, injury profiles, and outcomes were described for each period., Results: Eight patients with PCA injuries were treated during the Covid-19 period (13 % of total trauma patients), compared to four in 2019 (4 %, p < 0.05) and three in 2018 (3 %, p < 0.05). The median age of patients in the Covid-19 period was 11.5 months (IQR 6.8-24.5). Most patients were black (75 %) with public health insurance (75 %). All injuries were caused by blunt trauma, resulting in scalp/face contusions (63 %), skull fractures (50 %), intracranial hemorrhage (38 %), and long bone fractures (25 %)., Conclusions: There was an increase in the proportion of traumatic injuries caused by physical child abuse at our center during the Covid-19 pandemic. Strategies to mitigate this secondary effect of social distancing should be thoughtfully implemented., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Background: Incidence of firearm mortality in the United States is increasing. Baltimore, MD saw a substantial increase in violence in April 2015. We analyzed the effect of this localized surge in violence on the pediatric population., Methods: Using the Maryland Health Services Cost Review Commission database, initial hospital encounters for gunshot wound (GSW) or stab wound (SW) were identified. Baltimore Police Department victim-based crime data and homicide data on GSW and SW assault were used to capture those not seen at hospitals. Changes in incidence rate ratios from before/after April 2015 were analyzed using Poisson regression., Results: No change in mortality was seen in hospital-evaluated GSW patients. The pediatric population showed decreased incidence of SW (P < 0.001) and increase in GSW (P < 0.001) but no change in total penetrating trauma (tPT). The young adult population had decreased SW incidence (P < 0.001) without change in GSW or tPT. The pediatric populations saw no difference in SW/GSW deaths or homicide rate. However, in young adults, there were increased homicides (P < 0.001) and GSW deaths (P < 0.001) with unchanged SW deaths., Conclusions: After a surge in violence, the shifted mechanism of penetrating trauma in the pediatric population did not increase mortality or tPT. By contrast, GSW incidence is increasing in young adults with more lethal injuries. Intervention could be aimed at gun control and targeted education/intervention in the at-risk younger age group., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: Anorectal malformations (ARMs) have a wide spectrum of presentation ranging from mild defects with perineal fistulas to more severe defects requiring complex management. A primary repair of ARMs with perineal or rectovestibular fistulas has been shown to have good outcomes. However, the timing of the reconstruction is still debated. The aim of this study is to investigate the safety of early versus delayed repair., Methods: This study was performed using data from the National Surgical Quality Improvement Program-Pediatric (NSQIP-P) from 2012 to 2017. Patients who underwent repair of anorectal malformation with perineal or vestibular fistula were included in the study. Patients with associated diagnosis for Hirschsprung disease, cloaca, rectal prolapse or stenosis, bladder exstrophy, and tracheoesophageal fistula were excluded. 30-day postoperative outcomes included wound and nonwound complications, readmissions, and reoperations. Outcomes were compared by early (≤7 days of age) versus delayed repair (6 weeks to 8 months)., Results: A total of 291 patients were included, with 66 in the early and 231 in the delayed group. Patients in the early group were more likely to be male (68.2% vs 31.8%; p < 0.01) and have cardiac risk factors (71.2% vs 49.4%, p < 0.01). The mean operative time was significantly shorter in the early group (90.1 vs 129.6 min; p < 0.01). 30-day complications were not statistically significant between the two groups (p = 0.76). After multivariate analysis, timing of repair did not affect 30-day complications (p = 0.15)., Conclusion: Our study shows that early repair of low anorectal malformations with a perineal or vestibular fistula appears to be associated with no increase in risk of postoperative complications as compared to delayed repair. At present, the decision remains dependent on the surgeon's experience and judgment., Level of Evidence: Level III. Retrospective comparative study., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: The American College of Surgeons Committee on Trauma recommends universal alcohol screening be part of the evaluation of admitted trauma patients. Yet, suboptimal screening rates have been reported for admitted adult and adolescent trauma patients. This lack of screening, in turn, has limited the ability of trauma services to provide patients with brief interventions during their hospital admission and subsequent referrals to treatment after discharge. The primary aim of this study was to examine current rates of alcohol and other drug screening with admitted injured adolescents across a national cohort of 10 pediatric trauma centers., Methods: This retrospective observational study was nested within a larger adolescent screening, brief intervention, and referral to treatment implementation study (Clinicaltrials.gov NCT03297060). Ten pediatric trauma centers participated in a retrospective chart review of a random sample of adolescent trauma patients presenting for care between March 1, 2018, and November 30, 2018., Results: Three hundred charts were abstracted across the 10 participating trauma centers (n = 30 per site). Screening rates varied substantially across centers from five (16.7%) to 28 (93.3%) of the 30 extracted charts. The most frequent screening type documented was blood alcohol concentration (BAC) (N = 80, 35.2% of all screens), followed by the CRAFFT (N = 79, 26.3%), and then the urine drug screen (UDS) (N = 77, 25.6%). The BAC test identified 11 patients as positive for recent alcohol use. The CRAFFT identified 11 positive patients., Conclusions: Alcohol and drug screening is underutilized for adolescents admitted to pediatric trauma centers. More research is warranted on how best to utilize the teachable moment of the pediatric trauma visit to ensure comprehensive screening of adolescent alcohol or other drug (AOD) use.

Purpose: Firearm injuries continue to be a common cause of injury for American children. This pilot study was developed to evaluate the feasibility of providing guidance about firearm safety to the parents of pediatric patients using a tablet-based module in the outpatient setting., Methods: A tablet-based questionnaire that included a firearm safety message based on current best practice was administered to parents of pediatric patients at nine centers in 2018. Parents were shown a firearm safety video and then asked a series of questions related to firearm safety., Results: The study was completed by 543 parents from 15 states. More than one-third (37%) of families kept guns in their home. The majority of parents (81%, n = 438) thought it was appropriate for physicians to provide firearm safety counseling. Two-thirds (63%) of gun owning parents who do not keep their guns locked said that the information provided in the module would change the way they stored firearms at home., Conclusion: Use of a tablet based firearm safety module in the outpatient setting is feasible, and the majority of parents are receptive to receiving anticipatory guidance on firearm safety. Further data is needed to evaluate whether the intervention will improve firearm safety practices in the home., Level of Evidence: Level III., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Case: A 9-year-old boy with a widely displaced Type-III supracondylar humerus fracture presented with a painful mass at the antecubital fossa after pin fixation. Exploration of the mass caused bleeding from a brachial artery pseudoaneurysm that necessitated repair with a saphenous vein graft. Six weeks later, the fracture had healed without complications., Conclusion: We describe an unusual presentation of a pediatric supracondylar humerus fracture that highlights the importance of including vascular injury in the differential diagnosis for similar presentations.

Objectives: To describe the disposition of infants and young children with isolated mild traumatic brain injury and neuroimaging findings evaluated at a level 1 pediatric trauma center, and identify factors associated with their need for ICU admission., Design: Retrospective cohort., Setting: Single center., Patients: Children less than or equal to 4 years old with mild traumatic brain injury (Glasgow Coma Scale 13-15) and neuroimaging findings evaluated between January 1, 2013, and December 31, 2015. Polytrauma victims and patients requiring intubation or vasoactive infusions preadmission were excluded., Interventions: None., Measurements and Main Results: Two-hundred ten children (median age/weight/Glasgow Coma Scale: 6 mo/7.5 kg/15) met inclusion criteria. Most neuroimaging showed skull fractures with extra-axial hemorrhage/no midline shift (30%), nondisplaced skull fractures (28%), and intracranial hemorrhage without fractures/midline shift (19%). Trauma bay disposition included ICU (48%), ward (38%), intermediate care unit and home (7% each). Overall, 1% required intubation, 4.3% seizure management, and 4.3% neurosurgical procedures; 15% were diagnosed with nonaccidental trauma. None of the ward/intermediate care unit patients were transferred to ICU. Median ICU/hospital length of stay was 2 days. Most patients (99%) were discharged home without neurologic deficits. The ICU subgroup included all patients with midline shift, 62% patients with intracranial hemorrhage, and 20% patients with skull fractures. Across these imaging subtypes, the only clinical predictor of ICU admission was trauma bay Glasgow Coma Scale less than 15 (p = 0.018 for intracranial hemorrhage; p < 0.001 for skull fractures). A minority of ICU patients (18/100) required neurocritical care and/or neurosurgical interventions; risk factors included neurologic deficit, loss of consciousness/seizures, and extra-axial hemorrhage (especially epidural hematoma)., Conclusions: Nearly half of our cohort was briefly monitored in the ICU (with disposition mostly explained by trauma bay imaging, rather than clinical findings); however, less than 10% required ICU-specific interventions. Although ICU could be used for close neuromonitoring to prevent further neurologic injury, additional research should explore if less conservative approaches may preserve patient safety while optimizing healthcare resource utilization.

Traumatic brain injury (TBI) is one of the leading causes of both acute and long-term morbidity in the pediatric population, leading to a substantial, long-term socioeconomic burden. Despite the increase in the amount of pre-clinical and clinical research, treatment options for TBI rely heavily on supportive care with very limited targeted interventions that improve the acute and chronic sequelae of TBI. Other than injury prevention, not much can be done to limit the primary injury, which consists of tissue damage and cellular destruction. Secondary injury is the result of the ongoing complex inflammatory pathways that further exacerbate tissue damage, resulting in the devastating chronic outcomes of TBI. On the other hand, some level of inflammation is essential for neuronal regeneration and tissue repair. In this review article we discuss the various stages of the neuroimmune response in the immature, pediatric brain in the context of normal maturation and development of the immune system. The developing brain has unique features that distinguish it from the adult brain, and the immune system plays an integral role in CNS development. Those features could potentially make the developing brain more susceptible to worse outcomes, both acutely and in the long-term. The neuroinflammatory reaction which is triggered by TBI can be described as a highly intricate interaction between the cells of the innate and the adaptive immune systems. The innate immune system is triggered by non-specific danger signals that are released from damaged cells and tissues, which in turn leads to neutrophil infiltration, activation of microglia and astrocytes, complement release, as well as histamine release by mast cells. The adaptive immune response is subsequently activated leading to the more chronic effects of neuroinflammation. We will also discuss current attempts at modulating the TBI-induced neuroinflammatory response. A better understanding of the role of the immune system in normal brain development and how immune function changes with age is crucial for designing therapies to appropriately target the immune responses following TBI in order to enhance repair and plasticity., (Copyright © 2019. Published by Elsevier Inc.)

Background: Discordant assessments of Glasgow Coma Score (GCS) following trauma can result in inappropriate triage. This study sought to determine the reliability of prehospital GCS compared to emergency department (ED) GCS., Methods: We conducted a retrospective review of traumas from 01/2000 to 12/2015 at a Level-1 pediatric trauma center. We evaluated reliability between field and ED GCS using Pearson's correlation. We ascertained the difference between prehospital and ED GCS (delta-GCS). Associations between patient characteristics and delta-GCS were modeled using Poisson and linear regression, adjusting for demographic and clinical covariates., Results: We identified 5306 patients. Pearson's correlation for GCS measurements was 0.57 for ages 0-3, and 0.67-0.77 for other age groups. Mean delta-GCS was highest for age<3years (0.95, SD=2.4). Poisson regression demonstrated that compared to children 0-3years, higher age was associated with lower delta-GCS (RR 0.65 95% CI 0.56-0.74). Linear regression showed that in those with a delta-GCS, more severe injury (higher ISS, worse ED disposition) and older age were associated with a negative change, signifying decline in score., Conclusions: GCS is generally unreliable in pediatric trauma patients aged 0-3years, particularly the verbal score component. This may impact accuracy of triage priority for pediatric trauma patients., Level of Evidence: III, Prognostic., (Copyright © 2018 Elsevier Inc. All rights reserved.)

The mechanisms of skin rejection in vascularized composite allotransplantation (VCA) remain incompletely understood. The formation of tertiary lymphoid organs (TLO) in hand transplantation has been recently described. We assess this phenomenon in experimental and clinical VCA rejection. Skin biopsies of human (n = 187), nonhuman primate (n = 11), and rat (n = 15) VCAs were analyzed for presence of TLO. A comprehensive immunohistochemical assessment (characterization of the cell infiltrate, expression of adhesion molecules) including staining for peripheral node addressin (PNAd) was performed and correlated with rejection and time post-transplantation. TLO were identified in human, nonhuman primate, and rat skin samples. Expression of PNAd was increased in the endothelium of vessels upon rejection in human skin (P = 0.003) and correlated with B- and T-lymphocyte numbers and LFA-1 expression. PNAd expression was observed at all time-points after transplantation and increased significantly after year 5. In nonhuman primate skin, PNAd expression was found during inflammatory conditions early and late after transplantation. In rat skin, PNAd expression was strongly associated with acute rejection and time post-transplantation. Lymphoid neogenesis and TLO formation can be uniformly found in experimental and human VCA. PNAd expression in vascular endothelium correlates with skin rejection and T- and B-cell infiltration., (© 2014 Steunstichting ESOT.)

Tertiary lymphoid tissues are lymph node-like cell aggregates that arise at sites of chronic inflammation. They have been observed in transplanted organs undergoing chronic rejection, but it is not known whether they contribute to the rejection process by supporting local activation of naïve lymphocytes. To answer this question, we established a murine transplantation model in which the donor skin contains tertiary lymphoid tissues due to transgenic expression of lymphotoxin-alpha(RIP-LT alpha), whereas the recipient lacks all secondary lymphoid organs and does not mount primary alloimmune responses. We demonstrate in this model that RIP-LT alpha allografts that harbor tertiary lymphoid tissues are rejected, while wild-type allografts that lack tertiary lymphoid tissues are accepted. Wild-type allografts transplanted at the same time as RIP-LT alpha skin or 60 days later were also rejected, suggesting that tertiary lymphoid tissues, similar to secondary lymphoid organs, generate both effector and memory immune responses. Consistent with this observation, naive T cells transferred to RIP-LT alpha skin allograft but not syngeneic graft recipients proliferated and differentiated into effector and memory T cells. These findings provide direct evidence that tertiary lymphoid structures perpetuate the rejection process by supporting naïve T-cell activation.

Prior experimental strategies to induce transplantation tolerance have focused largely on modifying adaptive immunity. However, less is known concerning the role of innate immune signaling in the induction of transplantation tolerance. Using a highly immunogenic murine skin transplant model that resists transplantation tolerance induction when innate immunity is preserved, we show that absence of MyD88, a key innate Toll like receptor signal adaptor, abrogates this resistance and facilitates inducible allograft acceptance. In our model, absence of MyD88 impairs inflammatory dendritic cell responses that reduce T cell activation. This effect increases T cell susceptibility to suppression mediated by CD4+ CD25+ regulatory T cells. Therefore, this study provides evidence that absence of MyD88 promotes inducible allograft acceptance and implies that inhibiting innate immunity may be a potential, clinically relevant strategy to facilitate transplantation tolerance.

Immune responses are suppressed in immunologically privileged sites, which may provide a unique opportunity to prolong allograft survival. However, it is unknown whether testicular immune privilege promotes transplantation tolerance. Mechanisms underlying immune privilege are also not well understood. Here we found that islet transplantation in the testis, an immunologically privileged site, generates much less memory CD8(+) T cells but induces more Ag-specific CD4(+)CD25(+) regulatory T cells than in a conventional site. These CD4(+)CD25(+) cells exhibited the suppression of alloimmune responses in vivo and in vitro. Despite the immune regulation, intratesticular islet allografts all were rejected within 42 days after transplantation although they survived longer than renal subcapsular islet allografts. However, blocking CD40/CD40L costimulation induced the tolerance of intratesticular, but not renal subcapsular, islet allografts. Tolerance to intratesticular islet allografts spread to skin allografts in the non-privileged sites. Either transfer of memory CD8(+) T cells or deletion of CD25(+) T cells in vivo broke islet allograft tolerance. Thus, transplantation tolerance requires both costimulatory blockade, which suppresses acute allograft rejection, and a favorable balance between memory and regulatory T cells that could favorably prevent late allograft failure. These findings reveal novel mechanisms of immune privilege and provide direct evidence that testicular immune privilege fosters the induction of transplantation tolerance to allografts in both immunologically privileged and non-privileged sites.

Lymphoid neogenesis is the process by which ectopic lymphoid accumulations that resemble lymph nodes arise in nonlymphoid tissues. Such lymphoid accumulations, known as tertiary lymphoid organs (TLO), are observed in chronic autoimmunity and they propagate immune pathology by setting up local antigen presenting sites. Whether lymphoid neogenesis occurs in transplanted organs and contributes to rejection is not well understood. To begin to address this question, we retrospectively analyzed 319 murine cardiac allografts for microscopic evidence of lymph-node-like structures. We found 78 allografts that had either classical TLO, characterized by discrete T- and B-cell zones and high endothelial venules (HEV) expressing peripheral node addressin (PNAd) (n = 34), or PNAd(+) HEV without organized lymphoid accumulations (n = 44). These changes were present in both short- and long-lived allografts and were invariably associated with rejection. Importantly, they occurred in 78% of allografts undergoing chronic rejection (n = 85) but in only 7% of allografts undergoing primarily acute rejection (n = 184). These findings indicate that, like autoimmunity, alloimmunity is associated with lymphoid neogenesis in the target organ and suggest a role for local T-cell activation in chronic allograft rejection.

Foreign Ags that enter immunologically privileged sites such as the eye, brain, and testis persist for an extended period of time, whereas the same Ags are rapidly eliminated at conventional sites. Immune privilege, therefore, provides unwanted refuge for pathogens and tumor cells but is beneficial for the survival of allogeneic grafts. In this study, we asked whether memory T cells can eliminate foreign Ags deposited at an immunologically privileged site by studying CD8 memory T cell-mediated rejection of pancreatic islet allografts placed either in the testis (a privileged organ) or under the kidney capsule (a nonprivileged site) of diabetic mice. We found that CD8 memory T cells reject intratesticular grafts at a significantly slower rate than the rejection of intrarenal grafts. Delayed graft rejection in the testis was not due to reduced homing or proliferation of memory T cells but due to their increased apoptosis at that site. Apoptosis was mediated by the combined actions of two TNFR family members that are up-regulated on activated memory T cells, Fas, and CD30. Therefore, memory T cells survey immunologically privileged tissues but are subject to the immunosuppressive mechanisms present at these sites.

1. Exposure to midrange ultraviolet radiation (UVB) is known to produce skin inflammation similar to sunburn. The aim of this study was to characterize the hyperalgesia and cytokine upregulation induced by UVB and their modulation by antiinflammatory cytokines. 2. Acute exposure of the dorsal skin of mice to UVB (200, 250 and 300 mJ cm(2)) resulted in a dose-dependent decrease in the latencies of the hot plate and tail flick tests, without evident signs of skin lesions. 3. The observed hyperalgesia displayed a biphasic temporal evolution with an acute phase (3 - 6 h) and a late (48 - 96 h) phase. 4. Exposure to UVB (300 mJ cm(2)) elicited significant upregulation of interleukin (IL)-1 beta, tumour necrosis factor (TNF)-alpha and nerve growth factor (NGF), determined by ELISA in the exposed skin. This upregulation was more important during the acute phase of hyperalgesia. 5. Daily treatment of mice, with i.p. injections of either IL-10 or IL-13 (1.5, 7.5 and 15 ng in 100 microl saline) produced a dose-dependent attenuation of the UVB-induced hyperalgesia. 6. Treatment with the highest doses of either IL-10 or IL-13, produced significant attenuation of the levels of the cytokines and NGF by UVB, with relatively more pronounced effects by IL-13. 7. Acute exposure to moderate amounts of UVB results in a systemic hyperalgesia related to the upregulation of cytokine and NGF levels, since both were prevented by treatment with antiinflammatory cytokines.