Embolization for pediatric trauma.

BACKGROUND: The management of pediatric trauma with trans-arterial embolization is uncommon, even in level 1 trauma centers; hence, there is a dearth of literature on this subject compared to the adult experience. OBJECTIVE: To describe a single-center, level 1 trauma center experience with arterial embolization for pediatric trauma. MATERIALS AND METHODS: A retrospective review was performed to identify demographics, transfusion requirements, pre-procedure imaging, procedural details, adverse events, and arterial embolization outcomes over a 19-year period. Twenty children (age 4.5 months to 17 years, median 13.5 years; weight 3.6 to 108 kg, median 53 kg) were included. Technical success was defined as angiographic resolution of the bleeding-related abnormality on post-embolization angiography or successful empiric embolization in the absence of an angiographic finding. Clinical success was defined as not requiring additional intervention after embolization. RESULTS: Seventy-five percent (n=15/20) of patients required red blood cell transfusions prior to embolization with a mean volume replacement 64 ml/kg (range 12-166 ml/kg) and the median time from injury to intervention was 3 days (range 0-16 days). Technical success was achieved in 100% (20/20) of children while clinical success was achieved in 80% (n=16/20). For the 4 children (20%) with continued bleeding following initial embolization, 2 underwent repeat embolization, 1 underwent surgery, and 1 underwent repeat embolization and surgery. Mortality prior to discharge was 15% (n=3). A post-embolization mild adverse event included one groin hematoma, while a severe adverse event included one common iliac artery pseudoaneurysm requiring open surgical ligation. CONCLUSIONS: In this single-center experience, arterial embolization for hemorrhage control in children after trauma is feasible but can be challenging and the clinical failure rate of 20% in this series reflects this complexity. Standardization of pre-embolization trauma assessment parameters and embolic techniques may improve outcomes.

Trends in Histrelin Implantation at a Pediatric Tertiary Care Center.

INTRODUCTION: Determine procedural outcomes and identify changing trends of utilization among patients undergoing histrelin implantation at a large pediatric tertiary care center over 15 y. METHODS: Retrospective review of all patients undergoing histrelin implantation between January 2008 and April 2022. RESULTS: A total of 746 patients underwent 1794 unique procedures (1364 placements/replacements, 430 removals). Procedures were performed in the clinic (1071, 60%), sedation unit (630, 35%), and operating room (93, 5%). A total of 14 (0.8%) complications were identified, including two patients that required early implant removal and one patient requiring antibiotics. Implants were placed for central precocious puberty (CPP, 579) or gender dysphoria (GD, 167). Cohort included 25.9% males and 74.1% females with mean age of implantation of 9.48 y (SD: 2.34, range: 1.05-17.34). The GD group is comprised of 52.4% males and 47.6% females, compared to 18.3% males and 81.7% females in the CPP. Significant difference was identified for mean age at placement by indication (CPP 8.65 y versus GD 12.34, P < 0.001). New patient referrals and implant procedures increased significantly over 14 y. Yearly frequency of patients receiving implants for CPP and GD increased significantly (P < 0.001), with proportion of GD patients increasing from 7% to 32%. CONCLUSIONS: Histrelin procedures have increased in frequency overall with the greater increase noted in the GD cohort. The development of a streamlined process and a dedicated team have enabled histrelin procedures to be safely performed in the clinic setting for most, with a very low complication rate.

A proposed clinical pathway for the patients with Borderline Personality Disorder presenting to Emergency Departments.

OBJECTIVE: Emergency Department (ED) care of repeated self-injury, intensive affective lability, and interpersonal dysfunction associated with borderline personality disorder (BPD) is challenging. We propose an evidence-based acute clinical pathway for people with BPD. CONCLUSION: Our standardised evidence-based short-term acute hospital treatment pathway includes structured ED assessment, structured short-term hospital admission when clinically indicated, and immediate short-term (4-sessions) clinical follow-up. This approach could be adopted nationally to reduce iatrogenic harm, acute service overdependence and negative healthcare system impacts of BPD.

Surgical insights and management in patients with the 22q11.2 deletion syndrome.

PURPOSE: 22q11.2 deletion syndrome (22q11.2DS) can present with a variety challenges to patients and their caregivers, many of which require surgical evaluation and intervention. Surgical needs can also extend long into adulthood, prompting evaluation and intervention throughout development and beyond. Here, we identify common concerns and patient needs associated with the 22q11.2DS from a general surgery perspective, their management, and typical management based on our institution's experience with 1263 patients. METHODS: 1263 patients evaluated and treated at the 22q And You Center at the Children's Hospital of Philadelphia were enrolled and included in the study, from January 1992 to May 2017 Co-morbidities, procedures, and imaging studies performed were quantified and assessed via descriptive analysis. RESULTS: Gastroesophageal reflux disease (GERD) and feeding difficulties were the most common surgical issues identified, while gastrostomy tube placement, anorectal procedures, and hernia repairs were the most common surgical interventions performed by general surgeons. CONCLUSIONS: General surgical procedures are commonly needed in this population and are part of the complex needs these patients and their surgeons may encounter in the setting of a 22q11.2DS diagnosis. These findings will help to inform a well-coordinated, multidisciplinary approach to care.

Settling the Score: Injury Severity Score Fails to Capture Nuances in Pediatric Trauma.

OBJECTIVES: Recent work has questioned the accuracy of the Injury Severity Score (ISS) and the Abbreviated Injury Scale (AIS) in the pediatric population. We sought to determine mortality rates in pediatric trauma patients at ISSs considered "severe" in adults and whether mortality would vary substantially between adults and children sustaining injuries with the same AIS. METHODS: Univariate logistic regression was used to generate mortality rates associated with ISS scores, for children (<16 years of age) and adults, using the 2016 National Trauma Data Bank. Mortality rates at an ISS of 15 were calculated in both groups. We similarly calculated ISS scores associated with mortality rates of 10%, 25%, and 50%. Receiver operating characteristic curves were constructed to compare the discriminative ability of ISS to predict mortality after blunt and penetrating injuries in adults and children. Mortality rates associated with 1 or more AIS 3 injuries per body region were defined. RESULTS: There were 855,454 cases, 86,414 (10.1%) of which were children. The ISS associated with 10%, 25%, and 50% mortality were 35, 44, and 53, respectively, in children; they were 27, 38, and 48 in adults. At an ISS of 15, pediatric mortality was 1.0%; in adults, it was 3.1%. A 3.1% mortality rate was not observed in children until an ISS of 25. On receiver operating characteristic analysis, the ISS performed better in children compared with adults (area under the curve, 0.965 vs 0.860 [P < 0.001]). Adults consistently suffered from higher mortality rates than did children with the same number of severe injuries to a body region, and mortality varied widely between specific selected AIS 3 injuries. CONCLUSIONS: Although the ISS predicts mortality well, children have lower mortality than do adults for the same ISS, and therefore, the accepted definition of severe injury is not equivalent between these 2 cohorts. Mortality risk is highly dependent on the specific nature of the injury, with large variability in outcomes despite identical AIS scores.

Audit of blood product utilization in the care of injured children.

BACKGROUND: Blood product utilization in injured children is poorly characterized; the decision to prepare products or transfuse patients can be difficult due to a lack of reliable evidence of transfusion needs across pediatric age-groups and injury types. We conducted an audit of transfusion practices in pediatric trauma based on age, injuries, and mechanism of injury. METHODS: We reviewed and cross-referenced blood product transfusion practice data from the trauma registry and the anesthesia transfusion record database at a level 1 pediatric trauma center over a 10-year period. Demographic data, injury severity scores, and survival statistics were obtained from the trauma registry. Transfusion rates are reported separately for hospital admission and for intraoperative transfusions for procedures performed during the first two hospital days. Descriptive statistical analysis was used to compare specific groups based on age, injury type, and mechanism of injury. RESULTS: We report 14 569 trauma admissions of 14 606 patients. The transfusion rate during the admission was 1.56% (227/14 569). 4591 (30.9%) admissions had surgical interventions in first two days of hospitalization with an intraoperative transfusion rate of 2.98%. Patients younger than one year had the highest transfusion rate during admission (2.8%), and the highest transfusion rate during surgical procedures performed in the first two days of the admission (18.87%). Admissions due to vascular injuries had the highest transfusion rates in infancy followed by hollow visceral injuries in adolescents (71.4% and 25%, respectively). Vascular injuries in most age-groups also had high transfusion rates ranging from 11% in 5- to 9-year age-group to 71% in infants. Mechanisms with the highest transfusion rates were firearm wounds in patients older than one year and vehicular accidents for patients younger than one year. CONCLUSIONS: The overall blood product needs in the pediatric trauma population are low (1.56%). Selected populations requiring higher rates of need include infants younger than one year, and children with thoracic and vascular injuries. Understanding transfusion patterns is important to optimize resource allocation.

Pediatric Firearm Injuries and Fatalities: Do Racial Disparities Exist?

OBJECTIVE: To evaluate racial disparities among White and Black pediatric firearm injury patients on a national level. BACKGROUND: Pediatric firearm-related morbidity and mortality are rising in the United States. There is a paucity of data examining racial disparities in those patients. METHODS: The Pediatric Trauma Quality Improvement Program (2017) was queried for pediatric (age ≤17 years) patients admitted with firearm injuries. Patients were stratified by race: White and Black. Injury characteristics were assessed. Outcomes were mortality, hospital length of stay, and discharge disposition. Hierarchical regression models were performed to determine predictors of mortality and longer hospital stays. RESULTS: A total of 3717 pediatric firearm injury patients were identified: Blacks (67.0%) and Whites (33.0%). The majority of patients were male (84.2%). The most common injury intent in both groups was assault (77.3% in Blacks vs in 45.4% Whites; P<0.001), followed by unintentional (21.1% vs 35.4%; P<0.001), and suicide (1.0% vs 14.0%; P<0.001). The highest fatality rate was in suicide injuries (62.6%). On univariate analysis, White children had higher mortality (17.5% vs 9.8%; P<0.001), longer hospital stay [3 (1-7) vs 2 (1-5) days; P = 0.021], and more psychiatric hospital admissions (1.3% vs 0.1%; P<0.001). On multivariate analysis, suicide intent was found to be an independent predictor of mortality (aOR 2.67; 95% CI 1.35-5.29) and longer hospital stay (ß + 4.13; P<0.001), while White race was not. CONCLUSION: Assault is the leading intent of injury in both Black and White children, but White children suffer more from suicide injuries that are associated with worse outcomes. LEVEL OF EVIDENCE: Level III Prognostic.

AAV9 Edits Muscle Stem Cells in Normal and Dystrophic Adult Mice.

CRISPR editing of muscle stem cells (MuSCs) with adeno-associated virus serotype-9 (AAV9) holds promise for sustained gene repair therapy for muscular dystrophies. However, conflicting evidence exists on whether AAV9 transduces MuSCs. To rigorously address this question, we used a muscle graft model. The grafted muscle underwent complete necrosis before regenerating from its MuSCs. We injected AAV9.Cre into Ai14 mice. These mice express tdTomato upon Cre-mediated removal of a floxed stop codon. About 28%-47% and 24%-89% of Pax7+ MuSCs expressed tdTomato in pre-grafts and regenerated grafts (p > 0.05), respectively, suggesting AAV9 efficiently transduced MuSCs, and AAV9-edited MuSCs renewed successfully. Robust MuSC transduction was further confirmed by delivering AAV9.Cre to Pax7-ZsGreen-Ai14 mice in which Pax7+ MuSCs are genetically labeled by ZsGreen. Next, we co-injected AAV9.Cas9 and AAV9.gRNA to dystrophic mdx mice to repair the mutated dystrophin gene. CRISPR-treated and untreated muscles were grafted to immune-deficient, dystrophin-null NSG.mdx4cv mice. Grafts regenerated from CRISPR-treated muscle contained the edited genome and yielded 2.7-fold more dystrophin+ cells (p = 0.015). Importantly, increased dystrophin expression was not due to enhanced formation of revertant fibers or de novo transduction by residual CRISPR vectors in the graft. We conclude that AAV9 effectively transduces MuSCs. AAV9 CRISPR editing of MuSCs may provide enduring therapy.

Eye Tracking as a Biomarker for Concussion in Children.

OBJECTIVE: Concussion is the most common type of brain injury in both pediatric and adult populations and can potentially result in persistent postconcussion symptoms. Objective assessment of physiologic "mild" traumatic brain injury in concussion patients remains challenging. This study evaluates an automated eye-tracking algorithm as a biomarker for concussion as defined by its symptoms and the clinical signs of convergence insufficiency and accommodation dysfunction in a pediatric population. DESIGN: Cross-sectional case-control study. SETTING: Primary care. PATIENTS: Concussed children (N = 56; mean age = 13 years), evaluated at a mean of 22-week post-injury, compared with 83 uninjured controls. INDEPENDENT VARIABLES: Metrics comparing velocity and conjugacy of eye movements over time were obtained and were compared with the correlation between Acute Concussion Evaluation (ACE) scores, convergence, and accommodation dysfunction. MAIN OUTCOME MEASURES: Subjects' eye movements recorded with an automated eye tracker while they watched a 220-second cartoon film clip played continuously while moving within an aperture. RESULTS: Twelve eye-tracking metrics were significantly different between concussed and nonconcussed children. A model to classify concussion as diagnosed by its symptoms assessed using the ACE achieved an area under the curve (AUC) = 0.854 (71.9% sensitivity, 84.4% specificity, a cross-validated AUC = 0.789). An eye-tracking model built to identify near point of convergence (NPC) disability achieved 95.8% specificity and 57.1% sensitivity for an AUC = 0.810. Reduced binocular amplitude of accommodation had a Spearman correlation of 0.752(P value <0.001) with NPC. CONCLUSION: Eye tracking correlated with concussion symptoms and detected convergence and accommodative abnormalities associated with concussion in the pediatric population. It demonstrates utility as a rapid, objective, noninvasive aid in the diagnosis of concussion.

Is Systemic Inflammatory Response Syndrome Relevant to Pulmonary Complications and Mortality in Multiply Injured Children?

BACKGROUND: Systemic inflammatory response syndrome (SIRS) is a well-recognized phenomenon in adult trauma populations. The "initial hit" of the traumatic event is often coupled with a systemic immune response characterized by changes in vital signs and laboratory indicators. A "second hit" from surgery during this time frame often results in acute lung injury, along with deterioration of the patient's clinical condition. We hypothesized that children and adolescents would experience SIRS physiology, but would not experience adult respiratory distress syndrome (ARDS) or "second hit" related death to the extent seen in the adult populations. METHODS: We queried the trauma database of our level 1 pediatric trauma center from January 2005 to December 2015 for patients with injury severity scores of >16. We used the electronic medical record to track SIRS criteria in patients days 1 to 4 posttrauma. Trends were examined in patients with an orthopaedic injury (OI) and with no orthopaedic injury. Patients were further subcategorized and analyzed by age group based on the convention for definition of pediatric SIRS. Patients in the orthopaedic cohort were further examined for pulmonary complications and death. Logistic regression was used to identify risk factors for SIRS physiology in the first 4 days of hospitalization. RESULTS: 81.4% (OI) and 69.1% no orthopaedic injury reached the threshold for SIRS within their first 4 days of hospitalization. Nine patients died in the hospital. Only 3 OI patients developed the criteria for ARDS, and only 3 patients with orthopaedic injuries died, 2 died within 24 hours of presentation and 1 within 48 hours, all had severe brain trauma. Increasing age groups showed increasing proportion of patients with SIRS. Increasing injury severity score and increasing age were independent predictors of SIRS during days 1 to 4. DISCUSSION: SIRS seems to be as common in children as the reported rates for adults, and the proportion of SIRS in children increases with increasing age and injury severity. The high mortality rate and rate of ARDS observed in adults was not observed in our cohort. The presence or absence of major orthopaedic injuries was not a significant predictor. The SIRS response in polytraumatized children is poorly understood. The clinical phenomenon of acute lung injury/ARDS is observed less often in children, but the exact mechanism by which this occurs is unknown. LEVEL OF EVIDENCE: Level III-case control.

Meconium aspiration syndrome requiring ECMO in newborns with gastroschisis: incidence and surgical outcomes.

AIM OF THE STUDY: To evaluate the incidence of respiratory failure requiring ECMO in newborns with gastroschisis (GC), compare it to the incidence in the general population, review the surgical outcomes of newborns with GC requiring ECMO and compare them to newborns with GC not requiring ECMO. METHODS: This is a retrospective review of all neonatal admissions for GC from December 2010 to September 2015. MAIN RESULTS: 110 newborns with GC were admitted to our NICU between 12/2010 and 9/2015; 36 were term. Four cases, all term, all prenatally diagnosed, all outborn, developed respiratory failure requiring ECMO secondary to meconium aspiration syndrome (MAS). This 11% (4/36 term GC) represents a 300-fold increase in the incidence of MAS-associated respiratory failure requiring ECMO compared to the general population of term newborns (0.037%). Median time on ECMO was 12 (9-20) days. The time to achieve full enteral feedings in the GC/ECMO group was twice the time of the 106 newborns in the GC/non-ECMO group [median: 70 (48-77) vs. 35 (16-270) days, respectively]. Time to hospital discharge was three times longer in the GC/ECMO group compared to the GC/non-ECMO group (median: 42 [20-282] versus 125 [69-223] days, respectively). All patients survived. CONCLUSION: The incidence of respiratory failure requiring ECMO is remarkably higher in patients with GC than in the general population and much higher in the subgroup of term GC. While infrequent, the possibility of this event supports the concept that fetuses with GC benefit from being delivered at tertiary centers with immediate pediatric surgery and ECMO capabilities.

A National Analysis of Pediatric Trauma Care Utilization and Outcomes in the United States.

OBJECTIVES: More childhood deaths are attributed to trauma than all other causes combined. Our objectives were to provide the first national description of the proportion of injured children treated at pediatric trauma centers (TCs), and to provide clarity to the presumed benefit of pediatric TC verification by comparing injury mortality across hospital types. METHODS: We performed a population-based cohort study using the 2006 Healthcare Cost and Utilization Project Kids Inpatient Database combined with national TC inventories. We included pediatric discharges (≤16 y) with the International Classification of Diseases, Ninth Revision code(s) for injury. Descriptive analyses were performed evaluating proportions of injured children cared for by TC level. Multivariable logistic regression models were used to estimate differences in in-hospital mortality by TC type (among level-1 TCs only). Analyses were survey-weighted using Healthcare Cost and Utilization Project sampling weights. RESULTS: Of 153,380 injured children, 22.3% were admitted to pediatric TCs, 45.2% to general TCs, and 32.6% to non-TCs. Overall mortality was 0.9%. Among level-1 TCs, raw mortality was 1.0% pediatric TC, 1.4% dual TC, and 2.1% general TC. In adjusted analyses, treatment at level-1 pediatric TCs was associated with a significant mortality decrease compared to level-1 general TCs (adjusted odds ratio, 0.6; 95% confidence intervals, 0.4-0.9). CONCLUSIONS: Our results provide the first national evidence that treatment at verified pediatric TCs may improve outcomes, supporting a survival benefit with pediatric trauma verification. Given lack of similar survival advantage found for level-1 dual TCs (both general/pediatric verified), we highlight the need for further investigation to understand factors responsible for the survival advantage at pediatric-only TCs, refine pediatric accreditation guidelines, and disseminate best practices.

The development and implementation of a discharge checklist for psychiatric inpatients: a pilot study.

OBJECTIVES: Readmission rates are a routinely used measure of patient and service outcomes, potentially improved by discharge planning. This pilot study aimed to develop a discharge checklist for psychiatric inpatients, exploring its feasibility, applicability, and impact on readmission rates. METHODS: The study used a quasi-experimental, pre-post intervention design. The checklist was designed from an evidence-based literature review, and introduced for a three-month period, comparing 28-day readmission rates with the previous three months using interrupted time series analysis. RESULTS: Checklists were completed for 80% of patients in the trial period, with 100% completion of checklist items. Demographic and clinical details for pre- and post-intervention groups were closely aligned. There was a small, but statistically non-significant, reduction in readmission rates. CONCLUSIONS: There was a high rate of checklist completion. The lack of significant reductions in readmission rates supports more development of the checklist application and design before a longer implementation period and re-evaluation.

Congenital diaphragmatic hernia in 22q11.2 deletion syndrome.

We report the important association of congenital diaphragmatic hernia (CDH) and 22q11.2 deletion syndrome (22q11.2DS). The prevalence of CDH in our cohort of patients with 22q11.2DS is 0.8% (10/1246), which is greater than in the general population (0.025%). This observation suggests that 22q11.2DS should be considered when a child or fetus presents with CDH, in particular when other clinical findings associated with the 22q11.2DS are present, such as congenital cardiac defects. Furthermore, this finding may lead to the identification of an additional locus for diaphragmatic hernia in the general population. © 2016 Wiley Periodicals, Inc.

Mapping Activity Patterns to Quantify Risk of Violent Assault in Urban Environments.

BACKGROUND: We collected detailed activity paths of urban youth to investigate the dynamic interplay between their lived experiences, time spent in different environments, and risk of violent assault. METHODS: We mapped activity paths of 10- to 24-year-olds, including 143 assault patients shot with a firearm, 206 assault patients injured with other types of weapons, and 283 community controls, creating a step-by-step mapped record of how, when, where, and with whom they spent time over a full day from waking up until going to bed or being assaulted. Case-control analyses compared cases with time-matched controls to identify risk factors for assault. Case-crossover analyses compared cases at the time of assault with themselves earlier in the day to investigate whether exposure increases acted to the trigger assault. RESULTS: Gunshot assault risks included being alone (odds ratio [OR] = 1.6, 95% confidence interval [CI] = 1.3, 1.9) and were lower in areas with high neighbor connectedness (OR = 0.7, 95% CI = 0.6, 0.8). Acquiring a gun (OR = 1.4, 95% CI = 1.1, 1.6) and entering areas with more vacancy, violence, and vandalism (OR = 1.7, 95% CI = 1.1, 2.7) appeared to trigger the risk of getting shot shortly thereafter. Nongunshot assault risks included being in areas with recreation centers (OR = 1.2, 95% CI = 1.1, 1.4). Entering an area with higher truancy (OR = 1.6, 95% CI = 1.1, 2.5) and more vacancy, violence, and vandalism appeared to trigger the risk of nongunshot assault. Risks varied by age group. CONCLUSIONS: We achieved a large-scale study of the activities of many boys, adolescents, and young men that systematically documented their experiences and empirically quantified risks for violence. Working at a temporal and spatial scale that is relevant to the dynamics of this phenomenon gave novel insights into triggers for violent assault.

Utility of neurocognitive testing of mild traumatic brain injury in children treated and released from the emergency department.

PRIMARY OBJECTIVE: To assess feasibility and utility of neurocognitive testing of children evaluated and discharged from the ED with mild traumatic brain injury (MTBI). METHODS: Paediatric blunt trauma patients (aged 11-18 years) evaluated in the ED for MTBI and control patients with isolated lower extremity injury were prospectively enrolled. All patients were administered a validated neurocognitive test (ImPACT(©)). Wilcoxon sign rank tests were used to compare reported symptoms and neurocognitive performance between subjects and controls, as well as to matched normative data. RESULTS: Thirty-nine subjects and 46 controls were enrolled. The MTBI patients had a mean age of 13.9 years (53.8% male). An abnormal symptom score was reported in 89.7% of MTBI subjects (mean score = 29.4, normal ≤ 8), differing significantly (p < 0.05) from controls, in whom 39.1% demonstrated an abnormal score (mean score = 8.7). In all neurocognitive test domains, visual motor speed and reaction time, MTBI patients demonstrated lower scores than normative data (p < 0.05). CONCLUSIONS: Patients with MTBI were more likely than control subjects to have scores on any or all neurocognitive domains below the 25th percentile and 10th percentile. In the ED setting, acute neurocognitive testing of MTBI in children is feasible. This highlights the importance of structured follow-up for this treated and released population.

Attenuated sarcomere lengthening of the aged murine left ventricle observed using two-photon fluorescence microscopy.

The Frank-Starling mechanism, whereby increased diastolic filling leads to increased cardiac output, depends on increasing the sarcomere length (Ls) of cardiomyocytes. Ventricular stiffness increases with advancing age, yet it remains unclear how such changes in compliance impact sarcomere dynamics in the intact heart. We developed an isolated murine heart preparation to monitor Ls as a function of left ventricular pressure and tested the hypothesis that sarcomere lengthening in response to ventricular filling is impaired with advanced age. Mouse hearts isolated from young (3-6 mo) and aged (24-28 mo) C57BL/6 mice were perfused via the aorta under Ca(2+)-free conditions with the left ventricle cannulated to control filling pressure. Two-photon imaging of 4-{2-[6-(dioctylamino)-2-naphthalenyl]ethenyl}1-(3-sulfopropyl)-pyridinium fluorescence was used to monitor t-tubule striations and obtain passive Ls between pressures of 0 and 40 mmHg. Ls values (in µm, aged vs. young, respectively) were 2.02 ± 0.04 versus 2.01 ± 0.02 at 0 mmHg, 2.13 ± 0.04 versus 2.23 ± 0.02 at 5 mmHg, 2.21 ± 0.03 versus 2.27 ± 0.03 at 10 mmHg, and 2.28 ± 0.02 versus 2.36 ± 0.01 at 40 mmHg, indicative of impaired sarcomere lengthening in aged hearts. Atomic force microscopy nanoindentation revealed that intact cardiomyocytes enzymatically isolated from aged hearts had increased stiffness compared with those of young hearts (elastic modulus: aged, 41.9 ± 5.8 kPa vs. young, 18.6 ± 3.3 kPa; P = 0.006). Impaired sarcomere lengthening during left ventricular filling may contribute to cardiac dysfunction with advancing age by attenuating the Frank-Starling mechanism and reducing stroke volume.

Peptide spectra in Wilms tumor that associate with adverse outcomes.

BACKGROUND: The 2013 Children's Oncology Group (COG) blueprint for renal tumor research challenges investigators to develop new, risk-specific biological therapies for unfavorable histology and higher-risk Wilms tumor (WT) in an effort to close a persistent survival gap and to reduce treatment toxicities. As an initial response to this call from the COG, we used imaging mass spectrometry to determine peptide profiles of WT associated with adverse outcomes. MATERIALS AND METHODS: We created a WT tissue microarray containing 2-mm punches of formalin-fixed, paraffin-embedded specimens archived from 48 sequentially treated WT patients at our institutions. Imaging mass spectrometry was performed to compare peptide spectra between three patient groups as follows: unfavorable versus favorable histology, treatment success versus failure, and COG higher- versus lower-risk disease. Statistically significant peptide peaks differentiating groups were identified and incorporated into a predictive model using a genetic algorithm. RESULTS: One hundred thirty-one peptide peaks were differentially expressed in unfavorable versus favorable histology WT (P < 0.05). Two hundred three peaks differentiated treatment failure from success (P < 0.05). Seventy-one peaks differentiated COG higher-risk disease from the very-low, low, and standard-risk groups (P < 0.05). These peaks were used to develop predictive models that could differentiate among patient groups 98.49%, 94.46%, and 98.55% of the time, respectively. Spectral patterns were internally cross-validated using a leave-20% out model. CONCLUSIONS: Peptide spectra can discriminate adverse behavior of WT. After future external validation and refinement, these models could be used to predict WT behavior and to stratify intensity of chemotherapy regimens. Furthermore, peptides discovered in the model could be sequenced to identify potential risk-specific drug targets.