Quantitative Ultrasound and Tibial Dysplasia in Neurofibromatosis Type 1.

Neurofibromatosis type 1 (NF1) is a common autosomal dominant disorder associated with unilateral anterolateral bowing with subsequent fracture and nonunion. In infancy, physiologic bowing of the lower leg can be confused with pathologic tibial dysplasia in NF1. Little is known about the bone physiology of the tibiae prior to fracture or predictors of fracture. The aim of this study was to characterize bone quality of bowed tibiae prior to fracture in NF1 using quantitative ultrasound (QUS). Bone quality was assessed on both tibiae (the non-bowed and bowed tibiae) using QUS to measure speed of sound (SOS) at the mid-shaft in 23 individuals with NF1. SOS (m/s) was determined and Z-scores generated using cross-sectional reference data of the same sex and age. The mean difference in SOS Z-scores when comparing the bowed tibia vs the individual's contralateral unaffected tibia was statistically significant with lower mean Z-scores in the bowed tibia (p = 0.001). Radiographs of all individuals with a clinical diagnosis of anterolateral bowing were reviewed, and in 2 individuals the radiographs showed minimal bowing with absence of characteristic cortical thickening and medullary canal narrowing in NF1-related tibial dysplasia, suggesting physiologic bowing. In both individuals, the Z-scores of the bowed leg were not lower than the unaffected leg supporting the suggestion of physiologic bowing rather than pathologic tibial dysplasia. These data show that dysplastic tibiae in NF1 prior to fracture and nonunion have abnormal bone quality with significant decreases in SOS even though radiographically the tibiae show a thickened cortex. These data also suggest that QUS can help distinguish dysplastic bowing vs physiologic bowing in infancy in NF1. QUS is an effective quantitative outcome measure for trials aimed at improving tibial bowing to prevent fracture, and it is a potential aid in diagnosis and clinical management in NF1.

Fractures in children with neurofibromatosis type 1 from two NF clinics.

Neurofibromatosis type 1 (NF1) is an autosomal dominant genetic disorder with osseous abnormalities occurring in up to one-third of patients. Several studies have documented osteopenia in both children and adults with NF1; however, the significance of lower bone mineral density (BMD) in relationship to fracture incidence is not well elucidated in NF1, particularly in children. We undertook a retrospective study to determine prevalence and location of fractures in children and adolescents with NF1, ages 5-20 years, using a standardized questionnaire. We surveyed 256 individuals with NF1 from two multidisciplinary NF centers and 178 controls without NF1 of similar ages and sex. Participants with known long bone dysplasia (LBD) were analyzed separately. Data collected included numbers and location of fractures, dietary calcium intake, and physical activity levels. There was no difference in prevalence of ever having a fracture between the NF1 group without LBD (22%) and the control group (25%); median number of fractures also did not differ. There were significant differences in fracture location with a higher frequency of fractures of the lower extremities in NF1 individuals without LBD compared to controls. Both NF1 cohorts had lower rates of physical activity than controls (P < 0.0001). Our data demonstrate that the likelihood of having had a fracture is not higher in young NF1 individuals without LBD in comparison to healthy controls. The lower physical activity level may have a "protective effect" for those with NF1, thus keeping their fracture incidence lower than expected for their relative degree of osteopenia.

Peripheral muscle weakness in RASopathies.

INTRODUCTION: RASopathies are a group of genetic conditions due to alterations of the Ras/MAPK pathway. Neurocutaneous findings are hallmark features of the RASopathies, but musculoskeletal abnormalities are also frequent. The objective was to evaluate handgrip strength in the RASopathies. METHODS: Individuals with RASopathies (e.g., Noonan syndrome, Costello syndrome, cardio-facio-cutaneous [CFC] syndrome, and neurofibromatosis type 1 [NF1]) and healthy controls were evaluated. Two methods of handgrip strength were tested: GRIP-D Takei Hand Grip Dynamometer and the Martin vigorimeter. A general linear model was fitted to compare average strength among the groups, controlling for confounders such as age, gender, height, and weight. RESULTS: Takei dynamometer: handgrip strength was decreased in each of the syndromes compared with controls. Decreased handgrip strength compared with sibling controls was also seen with the Martin vigorimeter (P < 0.0001). CONCLUSIONS: Handgrip strength is decreased in the RASopathies. The etiology of the reduced muscle force is unknown, but likely multifactorial.

Growth hormone receptor antagonism downregulates ATP-binding cassette transporters contributing to improved drug efficacy against melanoma and hepatocarcinoma in vivo.

Knockdown of GH receptor (GHR) in melanoma cells in vitro downregulates ATP-binding cassette-containing (ABC) transporters and sensitizes them to anti-cancer drug treatments. Here we aimed to determine whether a GHR antagonist (GHRA) could control cancer growth by sensitizing tumors to therapy through downregulation of ABC transporters in vivo. We intradermally inoculated Fluc-B16-F10 mouse melanoma cells into GHA mice, transgenic for a GHR antagonist (GHRA), and observed a marked reduction in tumor size, mass and tumoral GH signaling. Moreover, constitutive GHRA production in the transgenic mice significantly improved the response to cisplatin treatment by suppressing expression of multiple ABC transporters and sensitizing the tumors to the drug. We confirmed that presence of a GHRA and not a mere absence of GH is essential for this chemo-sensitizing effect using Fluc-B16-F10 allografts in GH knockout (GHKO) mice, where tumor growth was reduced relative to that in GH-sufficient controls but did not sensitize the tumor to cisplatin. We extended our investigation to hepatocellular carcinoma (HCC) using human HCC cells in vitro and a syngeneic mouse model of HCC with Hepa1-6 allografts in GHA mice. Gene expression analyses and drug-efflux assays confirm that blocking GH significantly suppresses the levels of ABC transporters and improves the efficacy of sorafenib towards almost complete tumor clearance. Human patient data for melanoma and HCC show that GHR RNA levels correlate with ABC transporter expression. Collectively, our results validate in vivo that combination of a GHRA with currently available anti-cancer therapies can be effective in attacking cancer drug resistance.

Characterization of an intestine-specific GH receptor knockout (IntGHRKO) mouse.

OBJECTIVE: Growth hormone (GH) has been reported to enhance the intestinal barrier; as such, recombinant GH has been administered for several intestinal diseases. However, excess GH action has been implicated in increasing the risk of intestinal dysfunction. The goal of this study was to examine the direct effects of GH on the small and large intestines to clarify the role GH plays in intestinal function through the use of a mouse model. DESIGN: An intestinal epithelial-specific GH receptor (GHR) knockout (IntGHRKO) mouse line was generated using Cre-lox with the villin promoter driving Cre expression. The generated mice were characterized with respect to growth and intestinal phenotypes. RESULTS: IntGHRKO mice showed no significant changes in body length, weight, or composition compared to floxed controls. Male IntGHRKO mice had significantly shorter large intestines at 4 and 12 months of age. Intestinal barrier function was assessed by measuring the expression of tight junction related genes, as well as levels of serum endotoxin and fecal albumin. Results showed sex differences as males had an increase in occludin levels but normal serum endotoxin and fecal albumin; while, females had changes in fecal albumin levels with normal occludin and serum endotoxin. Evaluation of glucose tolerance and fat absorption also showed sex differences as females were glucose intolerant, while males had impaired fat absorption. Histopathology revealed a trend towards decreased villus height in males, which could explain the sex difference in glucose homeostasis. CONCLUSIONS: Overall, the data demonstrate that disruption of GH on the intestinal epithelial cells modestly affects the intestinal gross anatomy, morphology, and function in a sex-specific manner.

Longitudinal analysis of hospital charges following injury in a level 1 pediatric trauma system.

BACKGROUND: The treatment of injured children contributes substantially to the financial burden of a health care system. The purpose of this study was to characterize these charges at a level-1 pediatric trauma center. METHODS: Financial data for children (<14 years) admitted for traumatic injury from 1/2009 to 12/2014 were analyzed. The charges of the index admission and first two years following discharge were evaluated. RESULTS: 5853 trauma patients were included with average annual charges of $11,128,730. The most common mechanisms of injury were fall (44%), sports (12%), and bike (9%). The median ISS was 6 (IQR 4-10) with a mortality rate of 1.8% and Z-score of 13.04 (p<0.001). The overall total charges per patient during the index admission were $9513. Spinal cord and major abdominal injuries had the greatest charges per patient ($55,560 and $23,618 respectively) primarily owing to hospital LOS. During the first year after discharge, the total charges per patient were $1733, of which spinal cord injury resulted in highest overall ($19,426), owing to inpatient rehabilitation. For all other injury patterns, mean total charges per patient were $2376 (range $791-$3573). CONCLUSIONS: The value proposition in health care requires us to define outcomes relative to costs. Injury severity, major injury location, and hospital length of stay are the highest contributors for the financial burden of pediatric traumatic injury, while inpatient readmissions and inpatient rehabilitation drove higher charges in the years following discharge. TYPE OF STUDY: Clinical Research Paper. LEVEL OF EVIDENCE: II - Cohort Study.

Clearance of tunneled central venous catheter associated blood stream infections in children.

BACKGROUND: The optimal time to reinsert central venous catheters (tCVC) after a documented central line associated blood stream infection (CLABSI) is unclear. The goal of this study is to identify risk factors for children who develop persistent bacteremia after tCVC removal due to CLABSI. METHODS: We performed a retrospective cohort study from a tertiary children's hospital. Children who underwent removal of a tCVC due to CLABSI were included in our analysis. Our primary outcome was persistent bacteremia after tCVC removal defined by a persistently positive blood culture. Salient patient demographic and clinical factors were extracted from the medical record. RESULTS: A total of 140 patients met inclusion criteria and 27 (19%) had a persistent CLABSI after removal of the tCVC. There were no significant differences between the patients who cleared their bacteremia and those who develop persistent bacteremia. The median (IQR) time to positive blood culture after tCVC removal was 2.7 days (1.7- 4.0). CONCLUSIONS: We did not identify any patient risk factors distinguishing between a child who will clear a CLABSI versus develop a persistent CLABSI after tCVC removal. Blood stream infection clearance was rapid after tCVC removal, supporting a brief line holiday prior to tCVC reinsertion. LEVEL OF EVIDENCE: Level III Retrospective Case-Control Study.

The utility of a "trauma 1 OP" activation at a level 1 pediatric trauma center.

PURPOSE: To expedite flow of injured children suspected to require operative intervention, a "trauma 1 OP" (T1OP) activation classification was created. The purpose of this study was to review this strategy at a level 1 pediatric trauma center. METHODS: A retrospective review of T1OP activations between 2003 and 2015 was performed. Children suspected of requiring neurosurgical intervention were classified as trauma 1 OP neuro (T1OP(N)). Comparisons were made to trauma 1 (T1) patients who required emergent operative intervention, excluding orthopedic injuries. RESULTS: Overall, 461 T1OP activations occurred (72% T1OP(N)) compared to 129 T1 activations requiring emergent surgery. Demographics were not significantly different between groups, although T1OP patients were slightly younger and more often experienced falls or were victims of abuse. Compared to T1 activations, T1OP activations had a significantly higher mortality rate (21% vs. 7%, p<0.001). Repeat head imaging was more common in the T1OP(N) group compared to imaged children in the T1 group (20% vs. 37%, p=0.05). T1OP(N) patients more often went directly to the OR (45% vs. 33%, p=0.02) and did so in a significantly faster period of time (32min vs. 53min, p<0.001). CONCLUSIONS: Use of the T1OP activations appropriately triaged surgical patients, resulting in significantly faster transport times to the OR. LEVEL OF EVIDENCE: II, prognosis study.

The use of angiography in pediatric blunt abdominal trauma patients.

BACKGROUND: Angiography is a common treatment used in adults with blunt abdominal trauma and/or severe pelvic fractures. The Committee on Trauma of the American College of Surgeons has recently advocated for this resource to be urgently available at pediatric trauma centers; however, its usefulness in the pediatric setting is unclear. The purpose of this study was to determine the incidence of angiography in the treatment of blunt abdominal trauma among injured children. METHODS: An analysis was performed using an established public use data set of children (younger than 18 years) treated at 20 participating trauma centers for blunt torso trauma through the Pediatric Emergency Care Applied Research Network. Patients who underwent angiography of the abdomen or pelvis were identified and analyzed. RESULTS: Of the 12,044 children evaluated for blunt abdominal trauma included within the data set, 973 sustained abdominopelvic injuries. Of these, only 26 (3%) underwent angiography. The median age was 14 years, 65% were males, with a mortality rate of 19%. Overall, 29 angiographic procedures were performed: 21 abdominal, 8 pelvic, with 3 patients undergoing both abdominal and pelvic. Eleven patients underwent embolization of a bleeding vessel, all of which were related to the spleen. No hepatic, renal, or pelvic vessels required embolization. The median time to angiography from emergency department evaluation was 7.3 hours. In addition to angiography, 50% also required surgical intervention, of which 31% underwent a laparotomy. Thirty-five percent of these patients required blood product transfusion, and 42% were admitted to the intensive care unit. CONCLUSION: The emergent use of angiography with embolization is uncommon in pediatric patients with blunt abdominal injuries. The requirement that pediatric trauma centers have access to interventional radiology within 30 minutes may be unnecessary. LEVEL OF EVIDENCE: Epidemiologic study, level III; therapeutic study, level IV.

Preventable pediatric intensive care unit admissions over a 13-year period at a level 1 pediatric trauma center.

BACKGROUND: No formal criteria exist to determine the need for admission of injured children to the pediatric intensive care unit. Our objective was to analyze trauma patient admissions to the PICU at a level 1 pediatric trauma center. METHODS: The trauma registry was analyzed between 2002 and 2015. A preventable PICU admission was defined as a child discharged home or transferred out of the PICU within 30h without surgical intervention, blood transfusion, or ventilator support. RESULTS: Of 16,209 children, 19% were admitted to the PICU: mean age 7.3years, median ISS 17, and overall mortality 7%. Per our definition, 36% were preventable PICU admissions of which 83% suffered a head injury. The preventable admissions were younger (6.9 vs. 7.6years, p<0.001) with a lower median ISS (16 vs. 21, p<0.001), shorter median PICU LOS (17 vs. 41h, p<0.001) and shorter median hospital LOS (51 vs. 121h, p<0.001). These admissions resulted in total facility charges of $9,981,454.76 with 54% produced by children with an isolated head injury. CONCLUSIONS: A significant number of children admitted to our PICU were classified as preventable. They carry a substantial economic burden to the health care system with an overutilization of resources. Methods to limit such admissions should be actively pursued.

Enterocolitis and bowel function in children with Hirschsprung disease and trisomy 21.

BACKGROUND/PURPOSE: The purpose of this study was to study the effect of trisomy 21 (T21) on enterocolitis rates and bowel function among children with Hirschsprung disease (HD). METHODS: A retrospective cohort study of patients with HD treated at our tertiary children's hospital (2000-2015) and a cohort of patients with HD treated in our pediatric colorectal center (CRC) (2011-2015) were performed. RESULTS: 26/207 (13%) patients with HD had T21. 70 (41%) with HD alone were diagnosed with enterocolitis episodes compared to 9 (38%) with HD+T21 (p=0.71). 55/207 patients were managed in the CRC. 11/55 patients (20%) had HD+T21. 25 (58%) with HD had one or more enterocolitis episodes compared to 4 (36%) with HD+T21 (p=0.20). Number of hospitalizations for enterocolitis was similar between all groups. Toilet training was assessed in 32 CRC patients (25 HD, 7 HD+T21). One child with HD+T21 was toilet trained by age 4years versus 12 with HD (p=0.20). Laxative or enema therapy was required for constipation management in 57% HD versus 64% HD+T21. CONCLUSION: Enterocolitis rates in children with HD+T21 did not differ from rates in children with HD alone. The majority of patients with CRC follow-up had constipation requiring laxative or enema therapy, which demonstrates the need for consistent postoperative follow-up. LEVEL OF EVIDENCE: Retrospective Study - Level II.

Preventable transfers in pediatric trauma: A 10-year experience at a level I pediatric trauma center.

BACKGROUND: Injured children are often treated at one facility then transferred to another that specializes in pediatric trauma care. The purpose of this study was to identify and characterize potentially preventable transfers (PT) to a freestanding level-I pediatric trauma center. METHODS: Children with traumatic injuries transferred between 2003 and 2013 were retrospectively analyzed. A PT was defined as a child who was discharged within 36hours of arrival without surgical intervention or advanced imaging studies. RESULTS: During this period, 6380 children were transferred, with head injury being the most common injury. 61% had CT imaging performed before transfer. The mean age was 6.9years, mean injury severity score (ISS) 10.4, and median transfer distance 37miles. 27% of these transfers were classified as PT. Air transport was used in 15% at mean charge of $18,574. 29% were discharged from the emergency department. When compared, PTs were younger (6.0 vs. 7.2years, p<0.001), with lower median ISS (5 vs. 9, p<0.001), shorter median LOS (15 vs. 43.6hours, p<0.001), and less PICU admissions (6% vs. 34%, p<0.001). CONCLUSION: A significant number of pediatric trauma transfers can be classified as preventable. Reducing preventable transfers could offer opportunities for improving value in a trauma care system.