Four intestinal ultrasound scores and bowel wall thickness alone correlated well with pediatric ulcerative colitis disease activity.

OBJECTIVES: Intestinal ultrasound (IUS) is a noninvasive tool in ulcerative colitis (UC), but scoring systems have mostly been developed for adults, Crohn's disease, and flaring UC. Our aim was to evaluate the performance of bowel wall thickness (BWT) and four IUS scores in pediatric patients with newly diagnosed UC. METHODS: Patients <18 years old with suspected UC were prospectively enrolled. Baseline IUS was done, and ulcerative colitis intestinal ultrasound score (UC-IUS), Milan criteria, simple pediatric activity ultrasound score (SPAUSS), and Civatelli Index were calculated. Mayo endoscopic segment subscore, pediatric ulcerative colitis activity index (PUCAI), and biomarkers were correlated with IUS using nonparametric and receiver operating characteristic analyses. RESULTS: Fifty-two patients (56% male, median age 13.9 years, interquartile range [IQR] 11.2-16.3) with 206 colon segments were included. Patients who needed hospitalization (n = 27/52) had significantly worse IUS (BWT and all scores) compared to those not hospitalized. For all patients, IUS scores and BWT significantly correlated with baseline endoscopic, clinical, and biochemical disease activity (p = 0.32-0.67, p < 0.05). BWT (τb = 0.53), UC-IUS (τb = 0.55), and Milan (τb = 0.52) had the strongest endoscopic correlations. For differentiating between endoscopic disease severity, BWT, UC-IUS, and Milan, had the highest areas under the curve (0.89-0.93). Using BWT alone, a thinner cut-off had improved sensitivity while maintaining high specificity: ≥2.5 mm for moderate/severe endoscopic inflammation (sensitivity 66%; specificity 94%) and ≥3.5 mm for severe endoscopic inflammation (sensitivity 92%; specificity 86%). CONCLUSIONS: BWT and all four IUS scores correlated well with endoscopic, clinical, and biochemical disease activity, and was another useful marker of severity in identifying patients needing hospitalization. Pediatric patients needed a thinner BWT cut-off, which should be accounted for when developing pediatric-specific scores. BWT alone may be just as clinically useful as composite US scores.

Pediatric inflammatory bowel disease: What's new and what has changed?

The incidence and prevalence of inflammatory bowel disease (IBD) is on the rise in North America and worldwide, with young children being the fastest growing patient population. It is therefore essential for pediatricians and pediatric sub-specialists to be able to recognize signs and symptoms suspicious for a new diagnosis of IBD, as well as potential complications associated with IBD or its treatment. This article reviews the most recent literature regarding clinical presentation, helpful diagnostic clues, newer monitoring tools being used by pediatric gastroenterologists, and emerging new biologic and small molecule treatments.

Characterizing the human intestinal chondroitin sulfate glycosaminoglycan sulfation signature in inflammatory bowel disease.

The intestinal extracellular matrix (ECM) helps maintain appropriate tissue barrier function and regulate host-microbial interactions. Chondroitin sulfate- and dermatan sulfate-glycosaminoglycans (CS/DS-GAGs) are integral components of the intestinal ECM, and alterations in CS/DS-GAGs have been shown to significantly influence biological functions. Although pathologic ECM remodeling is implicated in inflammatory bowel disease (IBD), it is unknown whether changes in the intestinal CS/DS-GAG composition are also linked to IBD in humans. Our aim was to characterize changes in the intestinal ECM CS/DS-GAG composition in intestinal biopsy samples from patients with IBD using mass spectrometry. We characterized intestinal CS/DS-GAGs in 69 pediatric and young adult patients (n = 13 control, n = 32 active IBD, n = 24 IBD in remission) and 6 adult patients. Here, we report that patients with active IBD exhibit a significant decrease in the relative abundance of CS/DS isomers associated with matrix stability (CS-A and DS) compared to controls, while isomers implicated in matrix instability and inflammation (CS-C and CS-E) were significantly increased. This imbalance of intestinal CS/DS isomers was restored among patients in clinical remission. Moreover, the abundance of pro-stabilizing CS/DS isomers negatively correlated with clinical disease activity scores, whereas both pro-inflammatory CS-C and CS-E content positively correlated with disease activity scores. Thus, pediatric patients with active IBD exhibited increased pro-inflammatory and decreased pro-stabilizing CS/DS isomer composition, and future studies are needed to determine whether changes in the CS/DS-GAG composition play a pathogenic role in IBD.

Imaging and endoscopic tools in pediatric inflammatory bowel disease: What's new?

Pediatric inflammatory bowel disease (IBD) is a chronic inflammatory disorder, with increasing incidence and prevalence worldwide. There have been recent advances in imaging and endoscopic technology for disease diagnosis, treatment, and monitoring. Intestinal ultrasound, including transabdominal, transperineal, and endoscopic, has been emerging for the assessment of transmural bowel inflammation and disease complications (e.g., fistula, abscess). Aside from surgery, IBD-related intestinal strictures now have endoscopic treatment options including through-the-scope balloon dilatation, injection, and needle knife stricturotomy and new evaluation tools such as endoscopic functional lumen imaging probe. Unsedated transnasal endoscopy may have a role in patients with upper gastrointestinal Crohn's disease or those with IBD with new upper gastrointestinal symptoms. Improvements to dysplasia screening in pediatric patients with longstanding colonic disease or primary sclerosing cholangitis hold promise with the addition of virtual chromoendoscopy and ongoing research in the field of artificial intelligence-assisted endoscopic detection. Artificial intelligence and machine learning is a rapidly evolving field, with goals of further personalizing IBD diagnosis and treatment selection as well as prognostication. This review summarized these advancements, focusing on pediatric patients with IBD.

Using existing pediatric cancer data from the Gabriella Miller Kids First Data Resource Program.

Childhood cancer and birth defects are leading causes of childhood mortality, and studies suggest that birth defects increase pediatric cancer risk. The Gabriella Miller Kids First Pediatric Research Program (Kids First) seeks to alleviate these conditions by building an expansive resource of genetic and clinical data from patients with pediatric cancer and birth defects and their families. This article describes the data and support provided by the Kids First Data Resource Center and the Kids First Data Resource Center Data Resource Portal, which enables the public to review Kids First studies and request access to individual data. The Kids First Portal contains data from more than 34 000 participants and connects with CAVATICA (Seven Bridges Genomics, Inc, now part of Velsera), a cloud-based analysis and sharing platform. Researchers have used Kids First data to investigate a variety of cancers and further funding opportunities are available. The Kids First Portal is a unique resource that unites pediatric cancer and birth defects to uncover their genetic etiology and improve patients' lives.

Intestinal Failure-Associated Liver Disease and Growth Pre- and Post-Transition to a Composite Lipid Emulsion.

OBJECTIVES: Infants with intestinal failure have an increased risk of intestinal failure-associated liver disease (IFALD). Composite intravenous lipid emulsion (ILE) may reduce the risk of cholestasis. The primary outcome was to compare IFALD rates in infants with intestinal failure, between those receiving a composite ILE versus soybean oil ILE. The secondary outcome compared growth between these 2 groups. METHODS: At our 2 tertiary neonatal/pediatric hospitals, we identified all patients (≤1 year old) who received ≥6 weeks parenteral nutrition (PN) from 2010 to 2018. Data included liver and growth parameters. IFALD was defined as serum conjugated bilirubin (CB) >33 µmol/L (≥2 mg/dL). Nonparametric tests were used for all comparisons. RESULTS: Fifty infants (35 composite ILE, 15 soybean oil ILE) were included. Those on composite ILE received PN for longer (10.1 vs 7.6 weeks; P = 0.001) and had higher baseline CB (29 vs 6.5 µmol/L; P = 0.001). No differences were found by 6 weeks (14.5 vs 5 µmol/L; P = 0.54) and by PN cessation (4 vs 4 µmol/L; P = 0.33). The proportion of patients with IFALD decreased from 54% to 20% for composite ILE, while stable given soybean oil ILE (7%). There were no differences in weight, length, or head circumference z scores ( P > 0.05). CONCLUSIONS: In our institutions, over 8 years, chronic intestinal failure was rare. Composite ILE was the predominant lipid choice for infants who needed longer courses of PN or had developed cholestasis. Despite longer PN duration, and higher baseline CB, overall rates of IFALD decreased with composite ILE. Regardless of parenteral lipid used, there were no differences in growth.

Pediatric Patient and Caregiver Satisfaction With the Use of Transabdominal Bowel Ultrasound in the Assessment of Inflammatory Bowel Diseases.

OBJECTIVES: Transabdominal bowel ultrasound (TABUS) is emerging as an attractive, noninvasive tool in inflammatory bowel disease (IBD). Patient and caregiver experience with TABUS is not well described. We aimed to determine pediatric patient and caregiver satisfaction with TABUS and the impact of IBD severity, gender, age, and a history of anxiety on satisfaction. METHODS: Pediatric patients (0-18 years old) with suspected IBD prospectively underwent baseline TABUS, magnetic resonance enterography (MRE), blood work, stool studies, and endoscopy. Patients and their caregiver each completed a cross-sectional satisfaction questionnaire (5-point Likert scale) after the baseline investigations. RESULTS: There were 54 patients included (67% male). The majority were completely satisfied and strongly agree TABUS was better tolerated than other investigations, regardless of disease severity ( P > 0.05). Patients with higher Simple Endoscopic Score for Crohn Disease (SES-CD) scores felt that TABUS increased their understanding of their IBD ( P < 0.05) and disease location ( P < 0.05). Patients with Crohn disease had similar responses to those with ulcerative colitis, but more strongly agreed that TABUS was better than MRE and endoscopy ( P < 0.05). Those with anxiety did not have an increased level of worry about potential ultrasound findings ( P > 0.05). CONCLUSIONS: Pediatric patients and their caregivers were highly satisfied with TABUS, preferring it to other modalities. It did not lead to increased worry, and was particularly important in those with severe IBD. These findings support wider implementation of this well tolerated and preferred monitoring tool in pediatrics.

Conditional Deletion of KOR (Oprk1) in Kisspeptin Cells Does Not Alter LH Pulses, Puberty, or Fertility in Mice.

Classic pharmacological studies suggested that endogenous dynorphin-KOR signaling is important for reproductive neuroendocrine regulation. With the seminal discovery of an interconnected network of hypothalamic arcuate neurons co-expressing kisspeptin, neurokinin B, and dynorphin (KNDy neurons), the KNDy hypothesis was developed to explain how gonadotropin-releasing hormone (GnRH) and luteinizing hormone (LH) pulses are generated. Key to this hypothesis is dynorphin released from KNDy neurons acting in a paracrine manner on other KNDy neurons via kappa opioid receptor (KOR) signaling to terminate neural "pulse" events. While in vitro evidence supports this aspect of the KNDy hypothesis, a direct in vivo test of the necessity of KOR signaling in kisspeptin neurons for proper LH secretion has been lacking. We therefore conditionally knocked out KOR selectively from kisspeptin neurons of male and female mice and tested numerous reproductive measures, including in vivo LH pulse secretion. Surprisingly, despite validating successful knockout of KOR in kisspeptin neurons, we found no significant effect of kisspeptin cell-specific deletion of KOR on any measure of puberty, LH pulse parameters, LH surges, follicle-stimulating hormone (FSH) levels, estrous cycles, or fertility. These outcomes suggest that the KNDy hypothesis, while sufficient normally, may not be the only neural mechanism for sculpting GnRH and LH pulses, supported by recent findings in humans and mice. Thus, besides normally acting via KOR in KNDy neurons, endogenous dynorphin and other opioids may, under some conditions, regulate LH and FSH secretion via KOR in non-kisspeptin cells or perhaps via non-KOR pathways. The current models for GnRH and LH pulse generation should be expanded to consider such alternate mechanisms.

Safety and Benefits of Intraoperative Enteral Nutrition in Critically Ill Pediatric Burn Patients: A Systematic Review and Pooled Analysis.

Burn injuries significantly increase a patient's metabolic demand. Adequate nutrition is essential as an adjunct to recovery and reducing morbidity and mortality. In contrast to adults, this is especially important for pediatric patients who have limited reserves and are in a period of growth. Burn patients often require multiple anesthetic procedures that are accompanied by standard perioperative fasting periods that result in substantial nutritional interruptions. Continuous intraoperative feeding has been proposed as a solution, but there is no current consensus on its role and safety, particularly in the pediatric population. Thus, the goal of this study was to examine the safety and benefits of intraoperative nutrition in critically ill pediatric burn injured patients. A systematic review of MEDLINE, PubMed, Scopus, and Web of Science was conducted using the following terms: feeding or enteral or nutrition or fasting and adolescent or youth or pediatric or child or teen and burn or thermal injury or fire. The primary outcome was incidence of aspiration. Secondary outcomes included patient nutritional status (caloric deficit and weight), wound healing, days spent in the intensive care unit, ventilator days, pneumonia, number of surgeries, length of hospital stay, and mortality. Pooled analyses of binary outcomes were computed. Four studies consisting of 496 patients, met inclusion criteria. All studies were level IV evidence, but had high methodological quality. The median burn TBSA was 43.8% (interquartile range 33.4%-58.8%), with a median of 30% of patients having an inhalational injury. Patients underwent a median of 4.2 surgeries (interquartile range 1.8-7.4). Intraoperative feeding was conducted through nasoduodenal tubes. There were no aspiration events. Pooled analysis demonstrated that there were no differences in rates of aspiration, pneumonia, or wound infection (P > .05) between patients who were intraoperatively fed and those who were not. Those fed intraoperatively had significantly more surgeries, ventilator days, longer hospital stays, but lower mortality (P < .05). There was large heterogeneity in nutritional assessment methods. Intraoperatively fed patients had an average gain of 144.4 kcal/kg, 1.7 days of exclusive enteral nutrition (vs loss of -119.1 kcal/kg and -1.4 days), and a cumulative positive caloric balance of +2673 kcal ± 2147 (vs loss of -7899 kcal ± 3123) compared to those with interrupted feeding. Continuous intraoperative duodenal feeding during burn surgery appears to be safe in the pediatric burn population, with no reported episodes of aspiration. Uninterrupted feeding was also associated with weight maintenance and reduced caloric deficit. It may also have a survival benefit, as continuously fed patients needed more surgeries and intensive/hospital care, but had decreased mortality.

Metabolic actions of kisspeptin signaling: Effects on body weight, energy expenditure, and feeding.

Kisspeptin (encoded by the Kiss1 gene) and its receptor, KISS1R (encoded by the Kiss1r gene), have well-established roles in stimulating reproduction via central actions on reproductive neural circuits, but recent evidence suggests that kisspeptin signaling also influences metabolism and energy balance. Indeed, both Kiss1 and Kiss1r are expressed in many metabolically-relevant peripheral tissues, including both white and brown adipose tissue, the liver, and the pancreas, suggesting possible actions on these tissues or involvement in their physiology. In addition, there may be central actions of kisspeptin signaling, or factors co-released from kisspeptin neurons, that modulate metabolic, feeding, or thermoregulatory processes. Accumulating data from animal models suggests that kisspeptin signaling regulates a wide variety of metabolic parameters, including body weight and energy expenditure, adiposity and adipose tissue function, food intake, glucose metabolism, respiratory rates, locomotor activity, and thermoregulation. Herein, the current evidence for the involvement of kisspeptin signaling in each of these physiological parameters is reviewed, gaps in knowledge identified, and future avenues of important research highlighted. Collectively, the discussed findings highlight emerging non-reproductive actions of kisspeptin signaling in metabolism and energy balance, in addition to previously documented roles in reproductive control, but also emphasize the need for more research to resolve current controversies and uncover underlying molecular and physiological mechanisms.

Dual Biologic Therapy in a Patient With Niemann-Pick Type C and Crohn Disease: A Case Report and Literature Review.

Dual biologic therapy has become a new area of interest in inflammatory bowel disease (IBD). Monogenic/polygenic IBD and the role of genetics in IBD is an evolving field, with many of these patients having difficult treatment courses. We present a case of a teenage patient with Niemann-Pick disease type C and Crohn colitis, who sustained clinical remission only after escalating to dual biologic therapy (anti-tumor necrosis factor alpha [infliximab] and anti-interleukin-12/anti-interleukin-23 [ustekinumab]). A literature review of dual biologic therapy in pediatric IBD revealed 8 case series and 1 cohort study. In pediatric patients with genetic disorders and IBD who are not responding adequately to biologic therapy, adding a second biologic medication with a different mechanism of action may be efficacious. Targeting both anti-tumor necrosis factor alpha (which induces pro-inflammatory cytokines) and the pro-inflammatory cytokines themselves (interleukin-12/interleukin-23) may be important in impaired macrophage function and increased cytokine response. Our case adds to the sparse literature on the utility of combining ustekinumab and infliximab in pediatric IBD and is the first to describe its use for treating ongoing active luminal disease.

Nicotine preference and affective behavior of Cd81 knockout mice.

RATIONALE: Cd81 -/- (knockout) mice have previously been reported to have reduced cocaine preference and increased striatal dopamine content and dopamine turnover, but normal learning and memory in the Morris water maze. The effects of Cd81 on other behaviors and drugs of abuse have not been investigated. OBJECTIVES AND METHODS: We measured the effects of Cd81 -/- in a modified two-bottle choice test for nicotine, as well as in somatic signs of nicotine withdrawal, four tests of affective behavior, and tyrosine hydroxylase gene expression assays. RESULTS: We found that Cd81 loss-of-function significantly increased voluntary nicotine consumption and somatic signs of nicotine withdrawal. Nicotine consumption of Cd81 -/- female mice increased for 3 weeks and then remained relatively stable for the next 5 weeks, suggesting that their nicotine consumption continued to be limited by aversion to higher nicotine doses. Cd81 -/- also produced a dramatic and significant increase in struggling in the forced swim test and a significant increase in the time spent in the light chamber of the light/dark box. The elevated plus maze and the tail suspension test did not show a main effect of genotype. Therefore, we conclude that Cd81 did not have an overall effect on anxiety- or depression-like behavior. Tyrosine hydroxylase mRNA levels were unchanged. CONCLUSIONS: Cd81 knockouts have a strongly increased nicotine preference, plus a proactive response to specific stressful situations. Together with reports of increased striatal dopamine content and anecdotal reports of increased aggressiveness, these provide intriguing parallels to some aspects of post-traumatic stress disorder.

Reduction Mammaplasty for Macromastia in Adolescents: A Systematic Review and Pooled Analysis.

BACKGROUND: Reduction mammaplasty for macromastia is one of the most common operations performed by plastic surgeons. There remains hesitancy in operating on adolescents, as there is ongoing debate about breast regrowth and potential impact on breastfeeding. The goal of this study was to analyze these concerns by reviewing the current literature. METHODS: A systematic review of MEDLINE, Scopus, and Google Scholar was conducted using the following terms: "breast reduction" or "mammaplasty" or "breast reconstruction" and "adolescent" or "youth" or "pediatric" or "child" or "teen." Primary outcomes were success of breastfeeding after the procedure and procedure-related complications. RESULTS: Twenty-three studies (87 percent retrospective), consisting of 2926 patients with preoperative cup sizes of C to KK (mean, DDD), met inclusion criteria. Mean age at the time of surgery ranged from 16 to 21 years, with the youngest patient being 12 years old. The overall complication rate was 27.3 percent (95 percent CI, 14.4 to 42.5 percent). Minor complications (22.8 percent; 95 percent CI, 10.2 to 38.5 percent) were more common than major (4.2 percent; 95 percent CI, 1.6 to 7.9 percent). Eighteen percent of patients (95 percent CI, 2.2 to 43.8 percent) reported regrowth of their breast tissue postoperatively, with 2.7 percent (95 percent CI, 0.9 to 5.5 percent) undergoing a second revision mammaplasty. Fifty-three percent of patients (95 percent CI, 36.0 to 69.3 percent) did not attempt breastfeeding. Of those who attempted, 55.1 percent (95 percent CI, 34.4 to 74.9 percent) were successful. CONCLUSIONS: Prospective data are lacking. Patient counseling should focus on encouraging a trial of breastfeeding, despite surgical history. One-fifth of adolescent patients may notice breast regrowth postoperatively; however, the amount of regrowth is likely small and unlikely to reexacerbate symptoms, as the rate of revision surgery is small.

New Feeding Assessment Scale for individuals with genetic syndromes: Validity and reliability in the CHARGE syndrome population.

AIM: To develop a feeding scale for parents/care givers of individuals of all ages with genetic syndromes experiencing extensive feeding and swallowing problems. Second, to assess its validity and reliability in CHARGE syndrome. METHODS: The new Feeding Assessment Scale (FAS) was adapted from a scale for children who need prolonged tube feeding (Paediatric Assessment Scale for Severe Feeding Problems, PASSFP). Ten parents piloted the new scale before it was sent out with the PASSFP and feeding history questions. A subset completed the new scale again 4-8 weeks later. RESULTS: One hundred parents of individuals with CHARGE syndrome participated from around the world. The new scale had good construct validity, with a significant effect for an increased number of feeding risk factors having higher scale scores (P < 0.001). Face validity was high, as scores significantly differed between individuals whose parents identified their feeding difficulties as very mild, mild, moderate, severe and very severe (P < 0.001). Test-retest reliability (r = 0.94, P < 0.001) and internal consistency (Cronbach's alpha 0.91) were both high. There was significant convergent validity between the new scale and the PASSFP (r = -0.79, P < 0.001). CONCLUSIONS: This new tool is reliable and valid for parents/care givers of individuals with CHARGE syndrome. It can be used to assess the current severity of feeding difficulties and to track progress before and after treatment. It expands upon previous existing tools in that it can be used in both individuals who are not tube fed, as well as in those who are, as well as across the life-span.

Canadian medical schools' preclerkship paediatric clinical skills curricula: How can we improve?

BACKGROUND: Little is known about how Canadian medical schools teach paediatric clinical skills (history and physical exam) to preclerkship students, or its cost to the institutions. METHODS: Clinical skills program directors from all 17 Canadian medical schools were contacted to complete a questionnaire focused on teaching methods, and barriers/strengths of their Preclerkship Paediatric Clinical Skills program. RESULTS: Seventeen schools (100% response rate) participated. Seven schools (41%) do not introduce paediatric clinical skills until the second year of medicine. Half of the schools (53%) dedicate <10 total hours to preclerkship paediatric clinical skills. Fifty-nine per cent have ≤6 total hours of hands-on paediatric patient interaction (real or simulated). Medical students were least likely to be exposed to the infant age group (age 1 to 24 months). Twelve schools (71%) used simulated parent/child dyads. The most significant barriers identified by programs were limited time for sessions and patient availability. We describe one sample medical school's simulated parent/paediatric patient program where every student has hands-on learning with paediatric patients of all ages (program cost $938/student). DISCUSSION: This study is the first to summarize Canadian preclerkship paediatric clinical skills programs, among which there is great variability and commonly experienced barriers. Many students are not being exposed to all age groups of paediatric patients before their clerkship years. Medical schools can use this information to strengthen this important and challenging aspect of the curriculum, while being mindful of its fiscal implications.