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Background: Despite the urgency of mental health surveillance and treatment in humanitarian emergencies, there has been little evaluation of instruments that keep response burden to a minimum. We aimed to evaluate a sequential screening process for the detection of major depressive disorder that improves the efficiency of screening-confirmation procedures using the two-item and eight-item Patient Health Questionnaires (PHQ-2 and PHQ-8, respectively) in a refugee population. Methods: We analysed data from a cross-sectional survey completed by Syrian refugees in a camp in Greece between January and February, 2017. All survey items were translated to and back-translated from Arabic. Face-to-face interviews took place in an area with audio privacy. We used logistic regression to measure the correlation between the PHQ-2 classification and the summed score of the remaining six items of the PHQ-8, and used empirical data to simulate the sequential screening process for major depressive disorder. The sequential process replicates the diagnoses captured if the PHQ-2 were used to narrow the population who would complete the full PHQ-8 assessment. First, respondents complete the PHQ-2; next, only respondents who score above a threshold are considered at risk for depression and complete the remaining six items. We compared the positive and negative percent agreement of the PHQ-2 and sequential screening process. Response burden was assessed through item and instrument completion. Findings: We included data from 135 respondents, representing 40% of the adult population in the refugee camp at the time of the survey. Mean age was 30 years (range 18–61 years); 41% of respondents were women. The PHQ-2 and PHQ-8 instruments were completed by 123 (91%) and 113 (84%) respondents, respectively (p=0·014). The scores of the PHQ-2 and remaining six items of the PHQ-8 were significantly correlated (p

Introduction: Pediatric firearm injury prevention research in younger age groups is limited. This study evaluated a large multicenter cohort of younger children with firearm injuries, focusing on injury patterns and surgical resource utilization., Methods: Children ≤15 y old sustaining firearm injuries between 2016 and 2021 and treated at 10 pediatric trauma centers in Florida were included. Individual cases were reviewed for demographics, shooting details, injury patterns, resource utilization, and outcomes. Patients were grouped by age into preschool (0-5 y), elementary school (6-10 y), middle school (11-13 y), and early high school (14-15 y). Multivariable logistic regression was used to identify predictors of death and critical resource utilization., Results: A total of 489 children (80 preschool, 76 elementary school, 92 middle school, and 241 early high school) met inclusion criteria. Demographics, injury patterns, and resource utilization were similar across age groups. Assault and self-harm increased with age. Self-harm was implicated in 5% of cases but accounted for 18% of deaths. Hand surgery (i.e., below-elbow) procedures were common at 8%. Overall mortality was 10%, but markedly higher for self-harm injuries (47%). On multivariable regression, age and demographics were not predictive of death or critical resource utilization, but self-harm intent was a strong independent risk factor for both., Conclusions: This study suggests that given the age distribution and disproportionately high impact of self-harm injuries, behavioral health resources should be available to children at the middle school level or earlier. Hand surgery may represent an overlooked but frequently utilized resource to mitigate injury impact and optimize long-term function., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Abstract: Postsepsis early mortality is being replaced by survivors who experience either a rapid recovery and favorable hospital discharge or the development of chronic critical illness with suboptimal outcomes. The underlying immunological response that determines these clinical trajectories remains poorly defined at the transcriptomic level. As classical and nonclassical monocytes are key leukocytes in both the innate and adaptive immune systems, we sought to delineate the transcriptomic response of these cell types. Using single-cell RNA sequencing and pathway analyses, we identified gene expression patterns between these two groups that are consistent with differences in TNF-α production based on clinical outcome. This may provide therapeutic targets for those at risk for chronic critical illness in order to improve their phenotype/endotype, morbidity, and long-term mortality., Competing Interests: The authors report no conflicts of interest., (Copyright © 2024 by the Shock Society.)

Purpose: Infantile hypertrophic pyloric stenosis (IHPS) is suspected to have worse outcomes when length of illness prior to presentation is prolonged. Our objective was to evaluate how social determinants of health influence medical care and outcomes for babies with IHPS., Methods: A retrospective review was performed over 10 years. Census data were used as proxy for socioeconomic status via Geo-Identification codes and correlated with food access and social vulnerability variables. The cohort was subdivided to understand the impact of Medicaid Managed Care (MMC)., Results: The cohort (279 cases) was divided into two groups; early group from 2011 to 2015 and late from 2016 to 2021. Cases in the late group were older at the time of presentation (41.5 vs. 36.5 days; p = 0.022) and presented later in the disease course (12.8 vs. 8.9 days; p = 0.021). There was no difference in race (p = 0.282), gender (p = 0.874), or length of stay., Conclusions: Patients who presented with IHPS after implementation of phased MMC were older, had a longer symptomatic course, and shorter pylorus measurements. Patients with public insurance after the implementation of MMC were more likely to follow-up with an outpatient pediatrician within a month of hospitalization. These results suggest that MMC may have improved access to care for infants with IHPS., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Golf carts (GCs) and all-terrain vehicles (ATVs) are popular forms of personal transport. Although ATVs are considered adventurous and dangerous, GCs are perceived to be safer. Anecdotal experience suggests increasing numbers of both GC and ATV injuries, as well as high severity of GC injuries in children. This multicenter study examined GC and ATV injuries and compared their injury patterns, resource utilization, and outcomes., Methods: Pediatric trauma centers in Florida submitted trauma registry patients age <16 years from January 2016 to June 2021. Patients with GC or ATV mechanisms were identified. Temporal trends were evaluated. Injury patterns, resource utilization, and outcomes for GCs and ATVs were compared. Intensive care unit admission and immediate surgery needs were compared using multivariable logistic regression., Results: We identified 179 GC and 496 ATV injuries from 10 trauma centers. GC and ATV injuries both increased during the study period (R 2 0.4286, 0.5946, respectively). GC patients were younger (median 11 vs 12 years, p=0.003) and had more intracranial injuries (34% vs 19%, p<0.0001). Overall Injury Severity Score (5 vs 5, p=0.27), intensive care unit (ICU) admission (20% vs 16%, p=0.24), immediate surgery (11% vs 11%, p=0.96), and mortality (1.7% vs 1.4%, p=0.72) were similar for GCs and ATVs, respectively. The risk of ICU admission (OR 1.19, 95% CI 0.74 to 1.93, p=0.47) and immediate surgery (OR 1.04, 95% CI 0.58 to 1.84, p=0.90) remained similar on multivariable logistic regression., Conclusions: During the study period, GC and ATV injuries increased. Despite their innocuous perception, GCs had a similar injury burden to ATVs. Heightened safety measures for GCs should be considered., Level of Evidence: III, prognostic/epidemiological., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Introduction: Sepsis engenders distinct host immunologic changes that include the expansion of myeloid-derived suppressor cells (MDSCs). These cells play a physiologic role in tempering acute inflammatory responses but can persist in patients who develop chronic critical illness., Methods: Cellular Indexing of Transcriptomes and Epitopes by Sequencing and transcriptomic analysis are used to describe MDSC subpopulations based on differential gene expression, RNA velocities, and biologic process clustering., Results: We identify a unique lineage and differentiation pathway for MDSCs after sepsis and describe a novel MDSC subpopulation. Additionally, we report that the heterogeneous response of the myeloid compartment of blood to sepsis is dependent on clinical outcome., Discussion: The origins and lineage of these MDSC subpopulations were previously assumed to be discrete and unidirectional; however, these cells exhibit a dynamic phenotype with considerable plasticity., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Barrios, Leary, Darden, Rincon, Willis, Polcz, Gillies, Munley, Dirain, Ungaro, Nacionales, Gauthier, Larson, Morel, Loftus, Mohr, Maile, Kladde, Mathews, Brusko, Brusko, Moldawer, Bacher and Efron.)

Background: Relationships between social determinants of health and pediatric trauma mechanisms and outcomes are unclear in context of COVID-19., Methods: Children <16 years old injured between 2016 and 2021 from ten pediatric trauma centers in Florida were included. Patients were stratified by high vs. low Social Vulnerability Index (SVI). Injury mechanisms studied were child abuse, ATV/golf carts, and firearms. Mechanism incidence trends and mortality were evaluated by interrupted time series and multivariable logistic regression., Results: Of 19,319 children, 68% and 32% had high and low SVI, respectively. Child abuse increased across SVI strata and did not change with COVID. ATV/golf cart injuries increased after COVID among children with low SVI. Firearm injuries increased after COVID among children with high SVI. Mortality was predicted by injury mechanism, but was not independently associated with SVI, race, or COVID., Conclusion: Social vulnerability influences pediatric trauma mechanisms and COVID effects. Child abuse and firearm injuries should be targeted for prevention., Competing Interests: Declaration of competing interest There are no conflicts of interest to disclose., (Copyright © 2023. Published by Elsevier Inc.)

Introduction: Although SARS-CoV-2 infection can lead to severe COVID-19 in children, the role of biomarkers for assessing the risk of progression to severe disease is not well established in the pediatric population. Given the differences in monocyte signatures associated with worsening COVID-19 in adults, we aimed to determine whether monocyte anisocytosis early in the infectious course would correspond with increasing severity of COVID-19 in children., Methods: We performed a multicenter retrospective study of 215 children with SARS-CoV-2 infection, Multisystem Inflammatory Syndrome in Children (MIS-C), convalescent COVID-19, and healthy age-matched controls to determine whether monocyte anisocytosis, quantified by monocyte distribution width (MDW) on complete blood count, was associated with increasing severity of COVID-19. We performed exploratory analyses to identify other hematologic parameters in the inflammatory signature of pediatric SARS-CoV-2 infection and determine the most effective combination of markers for assessing COVID-19 severity in children., Results: Monocyte anisocytosis increases with COVID-19 severity and need for hospitalization. Although other inflammatory markers such as lymphocyte count, neutrophil/lymphocyte ratio, C-reactive protein, and cytokines correlate with disease severity, these parameters were not as sensitive as MDW for identifying severe disease in children. An MDW threshold of 23 offers a sensitive marker for severe pediatric COVID-19, with improved accuracy when assessed in combination with other hematologic parameters., Conclusion: Monocyte anisocytosis corresponds with shifting hematologic profiles and inflammatory markers in children with COVID-19, and MDW serves as a clinically accessible biomarker for severe COVID-19 in children., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2023 Kane, Boribong, Loiselle, Chitnis, Chavez, Moldawer, Larson, Badaki-Makun, Irimia and Yonker.)

Introduction: Limited English proficiency (LEP) is linked to lower health care access and worse clinical outcomes. This study aims to explore the potential role of LEP on clinical outcomes of pediatric burn patients., Methods: We conducted a single-institution retrospective study of burn patients presenting at a tertiary pediatric burn referral program between January 2016 and December 2020. Patient demographics, burn mechanism, severity, interventions, and primary patient language were abstracted from the electronic health record. Clinical outcomes (length of stay [LOS], clinic follow-up, and 30-day readmission) of patients with LEP were compared to patients with English as primary language (EPL)., Results: Thirty-five (4.2%) patients with LEP were identified of 840 total patients. On univariate analysis, there was no difference in mean total body surface area (6.5% versus 6.1%), report of physical abuse (2.9% versus 8.9%), or need for grafting (14.3% versus 15.0%) comparing patients with LEP to those with EPL. Patients with LEP were more likely to have a scald burn (68.6% versus 48.9%, P = 0.025) and less likely to have a flame/fire burn (20.0% versus 37.6%, P = 0.047). On multivariate analysis, there was no difference between patients with LEP compared to patients with EPL for LOS (2.9 versus 3.5 d), 30-day readmissions (5.6% versus 5.7%), or clinic follow-up (80.6% versus 75.0%). In patients with >10% total body surface area, patients with LEP had a longer emergency department LOS (277 min versus 145 min, P = 0.06) but no difference in outcome measures., Conclusions: Pediatric patients with LEP were not found to have worse burn outcomes compared to EPL patients in our patient sample. However, a true association is difficult to determine given the small sample size of LEP patients and the potential underestimation of language discordancy as recorded in the electronic medical record. Further research is needed to better explore the role of primary language and health communication as a social determinant of health in pediatric burn patients., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Abstract: Sepsis, a dysregulated host immune response to infection, is one of the leading causes of neonatal mortality worldwide. Improved understanding of the perinatal immune system is critical to improve therapies to both term and preterm neonates at increased risk of sepsis. Our narrative outlines the known and unknown aspects of the human immune system through both the immune tolerant in utero period and the rapidly changing antigen-rich period after birth. We will highlight the key differences in innate and adaptive immunity noted through these developmental stages and how the unique immune phenotype in early life contributes to the elevated risk of overwhelming infection and dysregulated immune responses to infection upon exposure to external antigens shortly after birth. Given an initial dependence on neonatal innate immune host responses, we will discuss the concept of innate immune memory, or "trained immunity," and describe several potential immune modulators, which show promise in altering the dysregulated immune response in newborns and improving resilience to sepsis., (Copyright © 2022 by the Shock Society.)

Abstract: Burn injury is a significant source of morbidity and mortality in the pediatric population. Although 40,000 pediatric patients in the United States are admitted to the hospital with burn wounds annually, significant differences exist in the management and treatment of these patients, even among highly specialized burn centers. Some aspects of pediatric burn research, such as metabolic changes and nutritional support after burn injury, have been studied extensively; however, in many aspects of burn care, pediatric research lags behind the study of adult populations. This review compares and contrasts a wide array of physiologic and immune responses between children and adults after burn injury. Such a review elucidates where robust research has been conducted, where adult research is applicable to pediatric patients, and where additional pediatric burn research needs to be conducted., (Copyright © 2022 by the Shock Society.)

Purpose: Child physical abuse (CPA) is closely linked to social factors like insurance status with limited evaluation at a structural population-level. This study evaluates the role of social determinants of health within the built environment on CPA., Methods: A single-institution retrospective review of pediatric trauma patients was conducted between January 2016 and December 2020. Patient address was geocoded to the census-tract level. Socioeconomic metrics, including poverty rate, supermarket access and Social Vulnerability Index (SVI) were estimated from the Food Access Research Atlas. Univariate and multivariable regression analyses were conducted to compare demographics and outcomes., Results: Of 3,540 patients, 317 (9.0%) had concern for physical abuse reported in the registry. CPA patients were younger (7.5 vs 9.6 years, p<0.0001) and more often Black (37.0%, N = 117 vs 23.5%, N = 753; p<0.0001). CPA had higher injury severity scores (ISS) (7.9 vs 5.8, p<0.0001) and longer length of stay (5.3 vs 2.9 days, p<0.0001). CPA had higher Medicaid (73.0%, N = 232 vs 53.8%, N = 1748, p<0.0001) and SVI (0.65 vs 0.59, p<0.0001) with lower median income ($52,100 vs $56,100, p<0.0001) and more low-food access tracts (59.6% vs 53.6%, p = 0.06). Combined low-income and low-food access populations showed widened disparities (40.0% vs 28.9%, p = 0.0002). On multivariate analysis, CPA was associated with poverty (OR 2.3, 95% CI [0.979, 3.60], p = 0.0006), low-access Black share (OR 3.3, 95% CI [1.18, 5.47], p = 0.002) and urban designation (OR 1.5, 95% CI [1.13, 1.87], p = 0.004)., Conclusion: The built-environment and population-level social determinants of health are related to child physical abuse and should influence advocacy and prevention., Level of Evidence: Level III., Type of Study: Retrospective., Competing Interests: Conflict of Interest None to disclose., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: Burn injury risk, severity, and outcomes have been associated with socioeconomic status. Limited data exist to evaluate health access-related influences at a structural population level. This study evaluated factors at the Census-tract level, specifically evaluating food access and social vulnerability in pediatric scald burns., Methods: A single-institution retrospective review using the trauma registry and electronic medical record was conducted of pediatric burns between 2016 and 2020. Home address was coded to the Census-tract level and bulk analyzed. Socioeconomic metrics of the home environment were evaluated from publicly available databases, the United States Food and Drug Administration Food Access Research Atlas, and the Centers for Disease Control's Social Vulnerability Index., Results: There were 840 patients that met inclusion criteria (49.8% scald, N = 418). The mean total body surface area for scalds was 6.6% with an age of 10.2 years; 76% (n = 317) of scalds had Medicaid, and 15% (n = 63) were due to hot noodles. Scalds occurred more in females (45.7%, N = 191 vs 28.0%, N = 118; P &lt; .0001), non-White race (62.7%, N = 262 vs 29.1%, N = 123; P &lt; .0001), and low-income and low-food access populations (39.8%, N = 147 vs 30.4%, N = 116; P = .007). Low-food access Black populations showed increased scald injury (18% [interquartile range 6-35] vs 10% [interquartile range 4-25]), whereas all other populations showed no association. The patients with scalds had a higher overall social vulnerability index (0.67 vs 0.62, P = .008)., Conclusion: Often related to poverty, health access, and health equity, population-level social determinants of health like social vulnerability and food access have significant impact on health care and should influence health outreach and systems improvement., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background and Objectives: Multisystem Inflammatory Syndrome in Children (MIS-C) is an emerging complication of COVID-19 which lacks a definitive diagnostic test and evidence-based guidelines for workup. We sought to assess practitioners' preferences when initiating a workup for pediatric patients presenting with symptoms concerning for MIS-C., Methods: In a cross-sectional vignette-based survey, providers were presented with clinical vignettes of a patient presenting with 24 h of fever from a community with high rates of COVID-19. Respondents were asked about their general practices in pursuing a workup for potential MIS-C including testing obtained, criteria for diagnosis, and timing to confirm or rule out the diagnosis., Results: Most of the 174 respondents were physicians from the United States at academic medical centers. The majority of providers would not initiate MIS-C workup for fever and non-specific symptoms unless the fever lasted more than 72 h. Skin rash, abdominal pain, and shortness of breath were symptoms that raised greatest concern for MIS-C. Most providers would obtain COVID-19 PCR or antigen testing, plus blood work, in the initial workup. The list of laboratory studies providers would obtain is extensive. Providers primarily rely on cardiac involvement to confirm a MIS-C diagnosis, and establishing a diagnosis takes 24-48 h., Conclusions: Significant heterogeneity exists amongst providers as to when to initiate the MIS-C workup, the order and content of the workup, and how to definitively diagnose MIS-C. A diagnostic test with high sensitivity and specificity for MIS-C and refined evidence-based guidelines are needed to expedite diagnosis and treatment., (© 2022. The Author(s).)

Background: Multisystem inflammatory syndrome in children (MIS-C) is a life-threatening complication that can develop weeks to months after an initial SARS-CoV-2 infection. A complex, time-consuming laboratory evaluation is currently required to distinguish MIS-C from other illnesses. New assays are urgently needed early in the evaluation process to expedite MIS-C workup and initiate treatment when appropriate. This study aimed to measure the performance of a monocyte anisocytosis index, obtained on routine complete blood count (CBC), to rapidly identify subjects with MIS-C at risk for cardiac complications., Methods: We measured monocyte anisocytosis, quantified by monocyte distribution width (MDW), in blood samples collected from children who sought medical care in a single medical center from April 2020 to October 2020 (discovery cohort). After identifying an effective MDW threshold associated with MIS-C, we tested the utility of MDW as a tier 1 assay for MIS-C at multiple institutions from October 2020 to October 2021 (validation cohort). The main outcome was the early screening of MIS-C, with a focus on children with MIS-C who displayed cardiac complications. The screening accuracy of MDW was compared to tier 1 routine laboratory tests recommended for evaluating a child for MIS-C., Results: We enrolled 765 children and collected 846 blood samples for analysis. In the discovery cohort, monocyte anisocytosis, quantified as an MDW threshold of 24.0, had 100% sensitivity (95% CI 78-100%) and 80% specificity (95% CI 69-88%) for identifying MIS-C. In the validation cohort, an initial MDW greater than 24.0 maintained a 100% sensitivity (95% CI 80-100%) and monocyte anisocytosis displayed a diagnostic accuracy greater that other clinically available hematologic parameters. Monocyte anisocytosis decreased with disease resolution to values equivalent to those of healthy controls., Conclusions: Monocyte anisocytosis detected by CBC early in the clinical workup improves the identification of children with MIS-C with cardiac complications, thereby creating opportunities for improving current practice guidelines., (© 2022. The Author(s).)

Background: While many factors influence medical student career choice, interactions with attending and resident physicians during clinical rotations are particularly important. To evaluate the influence of attending and resident physicians on medical students' career choices, particularly for those pursuing surgical careers, we quantified their respective influence in the context of other known influences., Methods: Rising fourth-year medical students and new graduates were given an IRB-exempt, 14-item online survey. Descriptive statistics were performed on the demographic information. Chi-square analysis was used, as were Kruskal-Wallis and Mann-Whitney analyses on the Likert responses (α = 0.05)., Results: Survey response was 24%. Students pursuing general surgery rated residents greater than or equal to attendings on 7 of 8 key mentoring characteristics. Of students choosing a different specialty than the one they intended to pursue upon entering medical school, the influence of residents was cited by 100% of the students pursuing general surgery, compared to 59% of the entire cohort. Identification of a role model and perceived personality fit were significantly more important than other factors (P < 0.0001). Students pursuing general surgery rated the importance of identifying a role model and perceived personality fit greater than their peers., Conclusions: Residents have greater influences on medical students' career choice compared to attendings. Students pursuing a surgical specialty, particularly general surgery, considered the influence of role models and perceived personality fit to be the most important factors in their specialty decision. These findings provide valuable insights to improve student experiences and career recruitment in surgical specialties, particularly general surgery., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Purpose: Trauma team activation is essential to provide rapid assessment of injured patients, however excessive utilization can overburden systems. We aimed to identify predictors of over triage and evaluate impact of prehospital personal discretion trauma activations on the over triage rate., Methods: Retrospective comparative study of pediatric trauma patients (<18 years) evaluated after activation of the trauma team to those evaluated as a trauma consult treated between 2010 and 2013. Cohort matching of trauma activated and consult patients was done on the basis of patients' age and ISS., Results: 1363 patients including 359 trauma team activations were evaluated. Median age was 6 years, Injury Severity Score (ISS) 4, 116 (8.5%) required operative intervention and 20 (1.4%) died. Matched analysis using age and ISS showed trauma activated patients were more likely to have penetrating MOI (4.7% vs.1.7%; p = 0.03) and need ICU admission(32.9% vs.16.7%; p = 0.0001). State of Florida discrete criteria based trauma activated patients when compared to paramedic discretion activations had a higher ISS (9 vs.5; p = 0.014), need for ICU admission (36.5% vs.20.4%; p = 0.004), ICU LOS(2 vs.0 days; p = 0.02), hospital LOS(2 vs.2 days; p = 0.014) and higher likelihood of death(4.9% vs.0%;p = 0.0001). Moreover, paramedic discretion trauma activated patients were similar to trauma consult patients in terms of ISS score(p = 0.86), need for ICU admission(p = 0.86), operative intervention(p = 0.86), death(p = 0.86) and hospital LOS(p = 0.86), with a considerably higher cost of care(p = 0.0002)., Conclusion: Discrete criteria-based trauma team activations appear to more reliably identify patients likely to benefit from initial multidisciplinary management., Competing Interests: Declaration of Competing Interest No external funding was secured for this study. The authors have no financial relationships or any other conflicts of interest to disclose., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Purpose: Numerous definitive surgical techniques exist for the treatment of pilonidal disease with varied recurrence rates and wound complications. Due to the wide array of techniques and lack of consensus on the best approach, we proposed to study our experience treating pilonidal disease in adolescents and young adults. Methods: A retrospective analysis was conducted of patients 10-24 years old treated at a tertiary medical center from 2011 to 2016. Data including demographics, management, and outcomes were collected and analyzed. Primary outcome was recurrence of disease. Results: One hundred and thirty three patients with pilonidal disease underwent operative management. Fifty one percent underwent primary closure and 49% healed by secondary intention with no significant difference in recurrence rates (primary 18%, secondary 11%; p = 0.3245). Secondary healing patients had significantly lower wound complication rates (primary 51%, secondary 23%; p = 0.0012). After accounting for sex, race, weight, and operative technique, age was predictive of disease recurrence with an adjusted odds ratio (OR) of 0.706 (0.560-0.888; p = 0.003). Age and sex were both predictive of wound complications. Older patients had decreased risk of wound complication (adjusted OR 0.806, 95% CI 0.684-0.951; p = 0.0105), and male patients had increased risk of wound complication (adjusted OR 2.902, 95% CI 1.001-8.409; p = 0.0497). Conclusion: In summary, there is no significant difference in the recurrence rates between operative techniques for pilonidal disease. Older patients have decreased risk of recurrence following intervention. Wound complication rates are lower in patients undergoing secondary healing, though this may be better explained by differences in age and sex. Additional research investigating newer, minimally-invasive techniques needs to be pursued., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Abraham, Raymond, Hawkins, Iqbal, Larson, Mustafa, Taylor and Islam.)

Improved management of severe sepsis has been one of the major health care accomplishments of the last two decades. Due to enhanced recognition and improved management of severe sepsis, in-hospital mortality has been reduced by up to 40%. With that good news, a new syndrome has unfortunately replaced in-hospital multi-organ failure and death. This syndrome of chronic critical illness (CCI) includes sepsis patients who survive the early "cytokine or genomic storm," but fail to fully recover, and progress into a persistent state of manageable organ injury requiring prolonged intensive care. These patients are commonly discharged to long-term care facilities where sepsis recidivism is high. As many as 33% of sepsis survivors develop CCI. CCI is the result, at least in part, of a maladaptive host response to chronic pattern-recognition receptor (PRR)-mediated processes. This maladaptive response results in dysregulated myelopoiesis, chronic inflammation, T-cell atrophy, T-cell exhaustion, and the expansion of suppressor cell functions. We have defined this panoply of host responses as a persistent inflammatory, immune suppressive and protein catabolic syndrome (PICS). Why is this important? We propose that PICS in survivors of critical illness is its own common, unique immunological endotype driven by the constant release of organ injury-associated, endogenous alarmins, and microbial products from secondary infections. While this syndrome can develop as a result of a diverse set of pathologies, it represents a shared outcome with a unique underlying pathobiological mechanism. Despite being a common outcome, there are no therapeutic interventions other than supportive therapies for this common disorder. Only through an improved understanding of the immunological endotype of PICS can rational therapeutic interventions be designed., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Fenner, Darden, Kelly, Rincon, Brakenridge, Larson, Moore, Efron and Moldawer.)

Abstract: Neonatal sepsis leads to significant morbidity and mortality with the highest risk of death occurring in preterm (<37 weeks) and low birth weight (<2,500 g) infants. The neonatal immune system is developmentally immature with well-described defects in innate and adaptive immune responses. Immune adjuvants used to enhance the vaccine response have emerged as potential therapeutic options, stimulating non-specific immunity and preventing sepsis mortality. Aluminum salts ("alum") have been used as immune adjuvants for over a century, but their mechanism of action remains poorly understood. This study aims to identify potential mechanisms by which pretreatment with alum induces host protective immunity to polymicrobial sepsis in neonatal mice. Utilizing genetic and cell-depletion studies, we demonstrate here that the prophylactic administration of aluminum adjuvants in neonatal mice improves sepsis survival via activation of the nucleotide oligomerization domain-like receptor family, pyrin-domain-containing 3 inflammasome and dendritic cell activation. Furthermore, this beneficial effect is dependent on myeloid, non-granulocytic Gr1-positive cells, and MyD88-signaling pathway activation. These findings suggest a promising therapeutic role for aluminum-based vaccine adjuvants to prevent development of neonatal sepsis and improve mortality in this highly vulnerable population., Competing Interests: The authors report no conflicts of interest., (Copyright © 2020 by the Shock Society.)

Studying the pathophysiology of sepsis still requires animal models, and the mouse remains the most commonly used species. Here we discuss the "cecal slurry" (CS) model of polymicrobial, peritoneal sepsis and compare and contrast it to other commonly used methods. Among the different murine models of sepsis, cecal ligation and puncture (CLP), and not the CS, is often considered the "gold standard" to induce polymicrobial sepsis in laboratory animals. CLP is a well-described model involving a simple surgical procedure that closely mimics the clinical course of intra-abdominal sepsis. However, CLP may not be an option for experiments involving newborn pups, where the cecum is indistinguishable from small bowel, where differences in microbiome content may affect the experiment, or where surgical procedures/anesthesia exposure needs to be limited. An important alternative method is the CS model, involving the intraperitoneal injection of cecal contents from a donor animal into the peritoneal cavity of a recipient animal to induce polymicrobial sepsis. Furthermore, CS is an effective alternative model of intraperitoneal polymicrobial sepsis in adult mice and can now be considered the "gold standard" for experiments in neonatal mice.

Background: Trauma is the leading cause of death in pediatric patients over 1 y of age. Controversy exists regarding prehospital airway management for these patients, with some studies suggesting that endotracheal intubation in the field or at a referring hospital is associated with increased mortality and complication rate. These studies were largely performed at urban centers, and it is unclear whether the results apply to suburban/rural networks with longer transport times and more stops at referring hospitals. The purpose of this study is to evaluate differential outcomes in pediatric trauma patients who underwent endotracheal intubation at the scene of injury, referring hospital, or pediatric trauma center in a predominantly rural/suburban setting., Materials and Methods: A retrospective review was performed evaluating trauma patients age 18 y or younger at a single institution over 10 y (2004-2014). Patients were selected who underwent endotracheal intubation and were classified based on location of intubation (scene, referring hospital, or trauma center). Fischer's exact test and t-tests were performed for comparison. Univariate and multivariate regression analyses were performed., Results: 288 patients were identified. 155 (53.8%) were intubated at the scene of injury, 55 (19.1%) at a referring hospital, and 72 (25%) at the trauma center. Overall mortality was 21.9%, which was highest in the scene intubation group (29.7%) compared with the referring hospital (20%) and trauma center (5.6%) groups (P < 0.01). Patients intubated at the scene had higher Injury Severity Scores and lower Glasgow Coma Scale scores (P < 0.01). Duration of intubation was lowest in the trauma center group (P < 0.01). Complication rate was highest in the referring hospital group (P < 0.05). Multivariate analysis revealed that age, injury severity, and neurologic status were the key drivers of mortality rather than location of intubation., Conclusions: Mortality and duration of intubation were lowest in trauma patients intubated at a pediatric trauma center. However, location of intubation was not a significant independent predictor of mortality or complications on multivariate analysis, suggesting that age, injury severity, and neurologic status are the main indicators of prognosis in severe pediatric trauma., (Copyright © 2019 Elsevier Inc. All rights reserved.)

This review will briefly examine the clinical presentation and important immunology of viral pneumonia with a focus on severe acute respiratory syndrome coronavirus 2 (coronavirus disease 2019)., Data Sources Study Selection Data Extraction and Data Synthesis: The most relevant, original and review literature were assessed for inclusion in this review. Sources included the Centers for Disease Control and Prevention, World Health Organization, and PubMed., Conclusions: Pneumonia is a leading cause of hospitalization and death worldwide, with viral etiologies being very common. Given the rapidly emerging pandemic associated with the novel severe acute respiratory syndrome coronavirus 2 causing coronavirus disease 2019, it is important to review the clinical presentation and immunologic changes associated with viral pneumonia. Symptoms of viral pneumonia include common respiratory tract infection symptoms of cough, fever, and shortness of breath. Immunologic changes include up-regulation of airway pro-inflammatory cytokines and pathogen- and damage-associated molecular patterns contributing to cytokine and genomic changes. Coronavirus disease 2019 clinical presentation is typical of viral pneumonia with an increased prevalence of early pulmonary infiltrates and lymphopenia. Principles of early coronavirus disease 2019 management and isolation as well as potential therapeutic approaches to the emerging pandemic are discussed., Competing Interests: The authors have disclosed that they do not have any potential conflicts of interest., (Copyright © 2020 The Authors. Published by Wolters Kluwer Health, Inc. on behalf of the Society of Critical Care Medicine.)

Purpose: Keloids occur as a result of abnormal wound healing and as many as 70% of keloids and hypertrophic scars affect the pediatric population. Earlobe keloids, similar to lesions elsewhere in the body, remain a challenging problem given the high rates of recurrence and lack of consensus regarding treatment strategy. This study aims to evaluate the outcomes and patterns of recurrences following treatment of earlobe keloids in a large cohort of pediatric patients to facilitate identification of the optimal treatment strategy., Methods: All pediatric patients who underwent surgical therapy for earlobe keloids over a 10-year period (2004-2015) were identified and demographic, clinical and outcomes data were collected. A follow-up phone survey was administered to assess rates of long-term recurrence and overall satisfaction with the treatment strategy. Data analysis was performed using Student's t-test and Fisher's exact as appropriate., Results: A total of 94 patients with 135 keloids were identified. Mean age was 14 years with slight preponderance of females (52%) and a majority (75%) of the patients were African American (AA). Mean keloid size was 2.4 cm (0.25-11 cm) with ear piercing being the most common inciting etiology. Excision with steroid injection (59%) was the most frequent treatment approach followed by excision alone (25%). During a median follow up of 2 years, keloid recurrence occurred in 27 (28.7%) patients, 19 (70.4%) underwent additional therapy with 10 (52.6%) re-recurrences noted. Median time to recurrence was 23 months, with a slightly higher recurrence rate in AA patients (32%; p = 0.26) and in those age < 10 years (50%; p = 0.11)., Conclusion: This represents the largest series of earlobe keloids treatment in children. Our data suggest that recurrence rates are unaffected by the age at excision and race of the patient. Moreover, adjuncts to excisional therapy such as steroid injection, compression therapy and radiation also did not appear to influence recurrence. Given the pattern of recurrences studies with longer term follow-up are needed to assess the efficacy of treatment strategies., Type of Study: Case series., Level of Evidence: IV., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Computational models are powerful tools for exploring the properties of complex biological systems. In neuroscience, data-driven models of neural circuits that span multiple scales are increasingly being used to understand brain function in health and disease. But their adoption and reuse has been limited by the specialist knowledge required to evaluate and use them. To address this, we have developed Open Source Brain, a platform for sharing, viewing, analyzing, and simulating standardized models from different brain regions and species. Model structure and parameters can be automatically visualized and their dynamical properties explored through browser-based simulations. Infrastructure and tools for collaborative interaction, development, and testing are also provided. We demonstrate how existing components can be reused by constructing new models of inhibition-stabilized cortical networks that match recent experimental results. These features of Open Source Brain improve the accessibility, transparency, and reproducibility of models and facilitate their reuse by the wider community., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

Purpose: Severe constipation and encopresis are significant problems in the pediatric population. Medical management succeeds in 50-70%; however, surgical considerations are necessary for the remainder such as the antegrade continence enema (ACE). The purpose of this study is to assess the long-term outcomes following the ACE procedure., Methods: All patients undergoing an ACE over a 14-year period were included. Data on clinical conditions, treatments, and outcomes were collected. A successful outcome was defined as remaining clean with ≤ 1 accident per week. Comparative data were analyzed using the Fisher's exact test, Mann-Whitney U test, or Student's t test., Results: There were 42 ACE patients, and overall, 79% had improvement in their bowel regimens. Encopresis rates decreased from 79 to 5% (P < 0.001). Admissions for cleanouts decreased from 52 to 19% (P = 0.003). All cases of Hirschsprung's, functional constipation and spina bifida were successful. Rates of success varied for other diseases such as slow-transit constipation (60%) and cerebral palsy (33%). A majority (85%) required a change in the enema composition for improvement., Conclusion: In our study, ACE reduced soiling, constipation, and need for fecal disimpaction. Higher volume saline flushes used once a day was the optimal solution and most preferred option., Level of Evidence: Level 4 (retrospective case series or cohort).

Thromboelastography (TEG) is a viscoelastic test that allows rapid evaluation of clot formation and fibrinolysis from a sample of whole blood. TEG is increasingly utilized to guide blood product resuscitation in surgical patients and transfusions for liver transplant patients. Patients with severe liver failure have significant derangement of their clotting function due to impaired production of procoagulant and anticoagulant factors. Traditional coagulation studies are limited by the short time needed for the result and provide little information about the dynamics and strength of clot formation. In addition, traditional coagulation studies do not correlate well with bleeding episodes and may lead to over-transfusion of various blood products. Evidence is less robust regarding the use of TEG for transfusion management decisions in severe liver failure patients awaiting, undergoing, or immediately after liver transplant surgery. However, the available evidence suggests that systematic implementation of TEG rather than traditional coagulation studies results in the administration of fewer blood products without increased mortality or complications. The purpose of this study is to review the literature regarding the use of TEG in liver failure patients prior to liver transplant, intraoperatively, and postoperatively. Additional high-quality randomized controlled studies should be performed to evaluate the use of TEG to guide transfusion decisions, particularly in the postoperative period following liver transplantation., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Purpose: Inguinal hernias have been reported in as many as 10-30% premature neonates, making inguinal herniorrhaphy (IHR) one of the most commonly performed surgical procedures. The timing of surgery remains controversial. The purpose of this report is to compare outcomes of IHR while in the NICU (inpatient) versus repair following discharge (outpatient) to determine optimal timing., Methods: Premature neonates having undergone IHR over a 5-year period were identified and a retrospective case cohort analysis was performed., Results: 263 patients underwent IHR during the 5-year study period with 115 (43.7%) having surgical repair inpatient (IP; prior to discharge) and 148 having outpatient herniorrhaphy (OP). Patients with IHR performed IP had significantly lower birth weight (p < 0.001), gestational age (p < 0.001), longer duration of surgery (p = 0.01) and were more likely to have post-operative ventilator dependence following repair; however, there were no differences in the rate of recurrence (p = 0.44) and incarceration (p = 0.45)., Conclusion: Our study demonstrated no significant differences in the rates of incarceration or recurrence, following in- or out-patient IHR. These findings suggest that IHR can potentially be offered as an outpatient procedure following hospital discharge in appropriate patients. The optimal timing of IHR in premature infants remains elusive and will likely require additional multicenter investigation.

Sepsis is a common and deadly complication among trauma and surgical patients. Neutrophils must mobilize to the site of infection to initiate an immediate immune response. To quantify the velocity of spontaneous migrating blood neutrophils, we utilized novel microfluidic approaches on whole blood samples from septic and healthy individuals. A prospective study at a level 1 trauma and tertiary care center was performed with peripheral blood samples collected at <12 hours, 4 days, and/or 14 days relative to study initiation. Blood samples were also collected from healthy subjects. Ex vivo spontaneous neutrophil migration was measured on 2 μl of whole blood using microfluidic devices and time-lapse imaging. For each sample, individual neutrophils were tracked to calculate mean instantaneous velocity. Forty blood samples were collected from 33 patients with sepsis, and 15 blood samples were collected from age- and gender-matched healthy, control subjects. Average age was 61 years for septic patients with a male predominance (67%). Overall, average spontaneous neutrophil migration velocity in septic samples was 16.9 μm/min, significantly lower than controls samples at 21.1 μm/min (p = 0.0135). Neutrophil velocity was reduced the greatest at <12 hours after sepsis (14.5 μm/min). Regression analysis demonstrated a significant, positive correlation between neutrophil velocity and days after sepsis (p = 0.0059). There was no significant association between neutrophil velocity and age, gender, APACHE II score, SOFA score, sepsis severity, total white blood cell count, or percentage of neutrophils. Circulating levels of the cytokines IL-6, IL-8, IL-10, MCP-1, IP-10, and TNF were additionally measured using bead-based multiplex assay and found to peak at <12 hours and be significantly increased in patients with sepsis at all three time points (<12 hours, 4 days, and 14 days after sepsis) compared to healthy subjects. In conclusion, these findings may demonstrate an impaired ability of neutrophils to respond to sites of infection during the proinflammatory phase of sepsis., Competing Interests: The authors have declared that no competing interests exist.

Purpose: The management of primary spontaneous pneumothorax (PSP) in the pediatric population is not standardized. The purpose of this study was to understand the management options for a first episode of PSP in children and adolescents, and their associated outcomes., Methods: A retrospective study was conducted for patients 5-20 years old with a diagnosis of PSP at a large academic children's hospital between 2002 and 2014. Patient data were reviewed for each case. Management and outcomes were analyzed and compared between groups., Results: Eighty patients met all inclusion criteria. Overall recurrence rate was 40% with 86% occurring within 12 months of the initial PSP. Patients with recurrent PSP were significantly taller. Size of pneumothorax based on initial chest x-ray was comparable between recurrent and nonrecurrent groups. A negative CT scan for subpleural blebs did not predict recurrence. Patients undergoing thoracoscopic blebectomy and mechanical pleurodesis at initial presentation had significantly lower recurrence rate compared to patients who underwent nonoperative management (operative group 14%, nonoperative group 45%; p=0.0373)., Conclusions: Recurrence following nonoperative management was high with the majority occurring within a year and requiring readmission. These findings support offering surgery to families as a potential initial management option., Level of Evidence: 3b/4 - retrospective series or case control study, single institution, very limited population., (Copyright © 2018 Elsevier Inc. All rights reserved.)

To better understand how a nervous system controls the movements of an organism, we have created a three-dimensional computational biomechanical model of the Caenorhabditis elegans body based on real anatomical structure. The body model is created with a particle system-based simulation engine known as Sibernetic, which implements the smoothed particle-hydrodynamics algorithm. The model includes an elastic body-wall cuticle subject to hydrostatic pressure. This cuticle is then driven by body-wall muscle cells that contract and relax, whose positions and shape are mapped from C. elegans anatomy, and determined from light microscopy and electron micrograph data. We show that by using different muscle activation patterns, this model is capable of producing C. elegans -like behaviours, including crawling and swimming locomotion in environments with different viscosities, while fitting multiple additional known biomechanical properties of the animal. This article is part of a discussion meeting issue 'Connectome to behaviour: modelling C. elegans at cellular resolution'., (© 2018 The Author(s).)

The OpenWorm project has the ambitious goal of producing a highly detailed in silico model of the nematode Caenorhabditis elegans A crucial part of this work will be a model of the nervous system encompassing all known cell types and connections. The appropriate level of biophysical detail required in the neuronal model to reproduce observed high-level behaviours in the worm has yet to be determined. For this reason, we have developed a framework, c302, that allows different instances of neuronal networks to be generated incorporating varying levels of anatomical and physiological detail, which can be investigated and refined independently or linked to other tools developed in the OpenWorm modelling toolchain.This article is part of a discussion meeting issue 'Connectome to behaviour: modelling C. elegans at cellular resolution'., (© 2018 The Authors.)

It has been 30 years since the 'mind of the worm' was published in Philosophical Transactions B (White et al 1986 Phil. Trans. R. Soc. Lond. B 314 , 1-340). Predicting Caenorhabditis elegans ' behaviour from its wiring diagram has been an enduring challenge since then. This special theme issue of Philosophical Transactions B combines research from neuroscientists, physicists, mathematicians and engineers to discuss advances in neural activity imaging, behaviour quantification and multiscale simulations, and how they are bringing the goal of whole-animal modelling at cellular resolution within reach.This article is part of a discussion meeting issue 'Connectome to behaviour: modelling C. elegans at cellular resolution'., (© 2018 The Author(s).)

The adoption of powerful software tools and computational methods from the software industry by the scientific research community has resulted in a renewed interest in integrative, large-scale biological simulations. These typically involve the development of computational platforms to combine diverse, process-specific models into a coherent whole. The OpenWorm Foundation is an independent research organization working towards an integrative simulation of the nematode Caenorhabditis elegans , with the aim of providing a powerful new tool to understand how the organism's behaviour arises from its fundamental biology. In this perspective, we give an overview of the history and philosophy of OpenWorm, descriptions of the constituent sub-projects and corresponding open-science management practices, and discuss current achievements of the project and future directions.This article is part of a discussion meeting issue 'Connectome to behaviour: modelling C. elegans at cellular resolution'., (© 2018 The Author(s).)

Neonates rely on their innate immune system, and neutrophils in particular, to recognize and combat life-threatening bacterial infections. Pretreatment with lipopolysaccharide (LPS), a toll-like receptor (TLR) 4 agonist, improves survival to polymicrobial sepsis in neonatal mice by enhancing neutrophil recruitment. To understand the response of human neonatal neutrophils to TLR4 stimulation, ex vivo spontaneous neutrophil migration, neutrophil transcriptomics, and cytokine production in the presence and absence of LPS were measured directly from whole blood of adults, term neonates, and preterm neonates. Spontaneous neutrophil migration was measured on novel microfluidic devices with time-lapse imaging for 10 h. Genome-wide neutrophil transcriptomics and plasma cytokine concentrations were also determined. Preterm neonates had significantly fewer spontaneously migrating neutrophils at baseline, and both term and preterm neonates had decreased neutrophil velocity, compared to adults. In the presence of LPS stimulation, the number of spontaneously migrating neutrophils was reduced in preterm neonates compared to term neonates and adults. Neutrophil velocity was not significantly different among groups with LPS stimulation. Preterm neonates upregulated expression of genes associated with the recruitment and response of neutrophils following LPS stimulation, but failed to upregulate the expression of genes associated with antimicrobial and antiviral responses. Plasma levels of IL-1β, IL-6, IL-8, MIP-1α, and TNF-α increased in response to LPS stimulation in all groups, but IL-10 was increased only in term and preterm neonates. In conclusion, age-specific changes in spontaneous neutrophil migration counts are not affected by LPS despite changes in gene expression and cytokine production., Key Messages: Preterm neonates have reduced spontaneous neutrophil migration compared to term neonates and adults in the absence and presence of TLR4 stimulation. Preterm and term neonates have reduced neutrophil velocities compared to adults in the absence of TLR4 stimulation but no difference in the presence of TLR4 stimulation. Unique transcriptomic response to TLR4 stimulation is observed in neutrophils from preterm neonates, term neonates, and adults. TLR4 stimulation produces an age-specific cytokine response.

Burns are a leading cause of injury in children. Management principles vary widely, with no consensus about the best treatment. The purpose of this study was to compare outcomes of three different dressings for pediatric partial-thickness scald burns. A retrospective, single-center study was conducted for patients 0-16 years old with a diagnosis of acute partial-thickness scald burn between July 2007 and December 2012. Data regarding prehospital, inpatient, and outpatient course were collected. Cohort was stratified into topical antimicrobial (TA) ointment, silver sulfadiazine (SS), and biosynthetic dressing (BD) groups for analysis. The primary outcome of interest was time to full healing. One hundred and seventy-seven patients met all study criteria. Overall, mean total body surface area burned was 8.3 per cent. TA was used in 24 per cent cases, SS in 32 per cent, and BD in 44 per cent. The groups were comparable in terms of presenting burn characteristics and hospital course with the exception of the BD group being associated with greater extent of injury. Patients treated with SS had a significantly longer time to full healing and increased requirement of compression garments for scar therapy. Based on these data, the authors have amended their practice and presently use BD or TA dressings to improve healing.

Clinical and technological advances promoting early hemorrhage control and physiologic resuscitation as well as early diagnosis and optimal treatment of sepsis have significantly decreased in-hospital mortality for many critically ill patient populations. However, a substantial proportion of severe trauma and sepsis survivors will develop protracted organ dysfunction termed chronic critical illness (CCI), defined as ≥14 days requiring intensive care unit (ICU) resources with ongoing organ dysfunction. A subset of CCI patients will develop the persistent inflammation, immunosuppression, and catabolism syndrome (PICS), and these individuals are predisposed to a poor quality of life and indolent death. We propose that CCI and PICS after trauma or sepsis are the result of an inappropriate bone marrow response characterized by the generation of dysfunctional myeloid populations at the expense of lympho- and erythropoiesis. This review describes similarities among CCI/PICS phenotypes in sepsis, cancer, and aging and reviews the role of aberrant myelopoiesis in the pathophysiology of CCI and PICS. In addition, we characterize pathogen recognition, the interface between innate and adaptive immune systems, and therapeutic approaches including immune modulators, gut microbiota support, and nutritional and exercise therapy. Finally, we discuss the future of diagnostic and prognostic approaches guided by machine and deep-learning models trained and validated on big data to identify patients for whom these approaches will yield the greatest benefits. A deeper understanding of the pathophysiology of CCI and PICS and continued investigation into novel therapies harbor the potential to improve the current dismal long-term outcomes for critically ill post-injury and post-infection patients.

The high mortality in neonatal sepsis has been related to both quantitative and qualitative differences in host protective immunity. Pretreatment strategies to prevent sepsis have received inadequate consideration, especially in the premature neonate, where outcomes from sepsis are so dismal. Aluminium salts-based adjuvants (alum) are used currently in many paediatric vaccines, but their use as an innate immune stimulant alone has not been well studied. We asked whether pretreatment with alum adjuvant alone could improve outcome and host innate immunity in neonatal mice given polymicrobial sepsis. Subcutaneous alum pretreatment improves survival to polymicrobial sepsis in both wild-type and T and B cell-deficient neonatal mice, but not in caspase-1/11 null mice. Moreover, alum increases peritoneal macrophage and neutrophil phagocytosis, and decreases bacterial colonization in the peritoneum. Bone marrow-derived neutrophils from alum-pretreated neonates produce more neutrophil extracellular traps (NETs) and exhibit increased expression of neutrophil elastase (NE) after in-vitro stimulation with phorbol esters. In addition, alum pretreatment increases bone marrow and splenic haematopoietic stem cell expansion following sepsis. Pretreatment of neonatal mice with an alum-based adjuvant can stimulate multiple innate immune cell functions and improve survival. These novel findings suggest a therapeutic pathway for the use of existing alum-based adjuvants for preventing sepsis in premature infants., (© 2017 British Society for Immunology.)

Neutrophils play a crucial role in combating life-threatening bacterial infections in neonates. Previous studies investigating neonatal cell function have been limited because of restricted volume sampling. Here, using novel microfluidic approaches, we provide the first description of neutrophil chemotaxis and transcriptomics from whole blood of human term and preterm neonates, as well as young adults. Ex vivo percent cell migration, neutrophil velocity, and directionality to N-formylmethionyl-leucyl-phenylalanine were measured from whole blood using time-lapse imaging of microfluidic chemotaxis. Genome-wide expression was also evaluated in CD66b + cells using microfluidic capture devices. Neutrophils from preterm neonates migrated in fewer numbers compared to term neonates (preterm 12.3%, term 30.5%, P = 0.008) and at a reduced velocity compared to young adults (preterm 10.1 μm/min, adult 12.7 μm/min, P = 0.003). Despite fewer neutrophils migrating at slower velocities, neutrophil directionality from preterm neonates was comparable to adults and term neonates. 3607 genes were differentially expressed among the 3 groups (P < 0.001). Differences in gene expression between neutrophils from preterm and term neonates were consistent with reduced pathogen recognition and antimicrobial activity but not neutrophil migration, by preterm neonates. In summary, preterm neonates have significant disturbances in neutrophil chemotaxis compared to term neonates and adults, and these differences in phenotype appear at the transcriptional level to target inflammatory pathways in general, rather than in neutrophil migration and chemotaxis., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Early host recognition of microbial invasion or damaged host tissues provides an effective warning system by which protective immune and inflammatory processes are initiated. Host tissues responsible for continuous sampling of their local environment employ cell surface and cytosolic pattern recognition receptors (PRRs) that provide redundant and overlapping identification of both microbial and host alarmins. Microbial products containing pathogen-associated molecular patterns (PAMPs), as well as damage-associated molecular patterns (DAMPs) serve as principle ligands for recognition by these PRRs. It is this interaction which plays both an essential survival role in response to infection and injury, as well as the pathologic role in tissue and organ injury associated with severe sepsis and trauma. Elucidating the interaction between ligands and their respective PRRs can provide both a better understanding of the host response, as well as a rational basis for therapeutic intervention. This article is part of a Special Issue entitled: Immune and Metabolic Alterations in Trauma and Sepsis edited by Dr. Raghavan Raju., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Sepsis is a major cause of morbidity and mortality, especially at the extremes of age. To understand the human age-specific transcriptomic response to sepsis, a multi-cohort, pooled analysis was conducted on adults, children, infants, and neonates with and without sepsis. Nine public whole-blood gene expression datasets (636 patients) were employed. Age impacted the transcriptomic host response to sepsis. Gene expression from septic neonates and adults was more dissimilar whereas infants and children were more similar. Neonates showed reductions in inflammatory recognition and signaling pathways compared to all other age groups. Likewise, adults demonstrated decreased pathogen sensing, inflammation, and myeloid cell function, as compared to children. This may help to explain the increased incidence of sepsis-related organ failure and death in adults. The number of dysregulated genes in septic patients was proportional to age and significantly differed among septic adults, children, infants, and neonates. Overall, children manifested a greater transcriptomic intensity to sepsis as compared to the other age groups. The transcriptomic magnitude for adults and neonates was dramatically reduced as compared to children and infants. These findings suggest that the transcriptomic response to sepsis is age-dependent, and diagnostic and therapeutic efforts to identify and treat sepsis will have to consider age as an important variable.

Essentially, all neonates are exposed to infections, antibiotics, or vaccines early in their lives. This is especially true for those neonates born underweight or premature. In contrast to septic adults and children who are at an increased risk for subsequent infections, exposure to infection during the neonatal period is not associated with an increased risk of subsequent infection and may be paradoxically associated with reductions in late-onset sepsis (LOS) in the most premature infants. Perinatal inflammation is also associated with a decreased incidence of asthma and atopy later in life. Conversely, septic neonates are at increased risk of impaired long-term neurodevelopment. While the positive effects of antibiotics in the setting of infection are irrefutable, prolonged administration of broad-spectrum, empiric antibiotics in neonates without documented infection is associated with increased risk of LOS, necrotizing enterocolitis, or death. Vaccines provide a unique opportunity to prevent infection-associated disease; unfortunately, vaccinations have been largely unsuccessful when administered in the first month of life with the exception of vaccines against hepatitis B and tuberculosis. Future vaccines will require the use of novel adjuvants to overcome this challenge. This review describes the influence of infections, antibiotics, and vaccines during the first days of life, as well as the influence on future health and disease. We will also discuss potential immunomodulating therapies, which may serve to train the preterm immune system and reduce subsequent infectious burden without subjecting neonates to the risks accompanied by virulent pathogens.

Background: The neonatal innate immune system differs to microbial infection both quantitatively and qualitatively when compared with adults. Here, we provide the first genome-wide ex-vivo expression profile of umbilical cord blood (UCB) neutrophils from full-term infants prior to and in response to whole-blood lipopolysaccharide (LPS) stimulation. Additionally, we provide cytokine expression prior to and following LPS stimulation. The genomic expression and cytokine profile are compared with LPS-stimulated whole blood from healthy adult subjects (HC)., Methods: Whole blood from UCB (n = 6) and HC (n = 6) was studied at baseline or was stimulated for 24 h with 100 ngs/mL of LPS. CD66b neutrophils were subsequently isolated with microfluidic techniques and genome-wide expression analyses were performed. Ingenuity Pathway Analysis (IPA) software was utilized to predict downstream functional effects. Additionally, cytokine concentrations in whole blood prior to and after 24 h of LPS incubation were determined., Results: LPS stimulated whole blood from UCB demonstrated significant differences in both ex-vivo cytokine production and PMN gene expression. Mixed-effect modeling identified 1,153 genes whose expression changed significantly in UCB and HC after exposure to LPS (P < 0.001 with a minimum 1.5-fold change). IPA downstream predictions suggest that PMNs from UCB fail to effectively upregulate genes associated with activation, phagocytosis, and chemotaxis in response to LPS stimulation. Furthermore, whole blood from UCB showed increased interleukin (IL)-10 production to LPS, but failed to significantly increase several pro-inflammatory cytokines., Conclusions: LPS-stimulated whole blood from UCB exhibited a markedly suppressed inflammatory cytokine production and PMN innate immune genome response. These differences in gene expression and cytokine production may be an adaptive response to a prior fetal environment, but may also explain their increased susceptibility to infections. Characterization of these deficits is the first step toward developing prophylactic and therapeutic interventions.

Despite advances in critical care medicine, neonatal sepsis remains a major cause of morbidity and mortality worldwide, with the greatest risk affecting very low birth weight, preterm neonates. The presentation of neonatal sepsis varies markedly from its presentation in adults, and there is no clear consensus definition of neonatal sepsis. Previous work has demonstrated that when neonates become septic, death can occur rapidly over a matter of hours or days and is generally associated with inflammation, organ injury, and respiratory failure. Studies of the transcriptomic response by neonates to infection and sepsis have led to unique insights into the early proinflammatory and host protective responses to sepsis. Paradoxically, this early inflammatory response in neonates, although lethal, is clearly less robust relative to children and adults. Similarly, the expression of genes involved in host protective immunity, particularly neutrophil function, is also markedly deficient. As a result, neonates have both a diminished inflammatory and protective immune response to infection which may explain their increased risk to infection, and their reduced ability to clear infections. Such studies imply that novel approaches unique to the neonate will be required for the development of both diagnostics and therapeutics in this high at-risk population.