The Student-Generated Reasoning Tool (SGRT): Linking medical knowledge and clinical reasoning in preclinical education.

INTRODUCTION: The simultaneous integration of knowledge acquisition and development of clinical reasoning in preclinical medical education remains a challenge. To help address this challenge, the authors developed and implemented the Student-Generated Reasoning Tool (SGRT)-a tool asking students to propose and justify pathophysiological hypotheses, generate findings, and critically appraise information. METHODS: In 2019, students in a first-year preclinical course (n = 171; SGRT group) were assigned to one of 20 teams. Students used the SGRT individually, then in teams, and faculty provided feedback. The control group (n = 168) consisted of students from 2018 who did not use SGRT. Outcomes included academic performance, effectiveness of collaborative environments using the SGRT, and student feedback. RESULTS: Students were five times more likely to get questions correct if they were in the SGRT group versus control group. Accuracy of pathophysiological hypotheses was significantly lower for individuals than teams. Qualitative analysis indicated students benefited from generating their own data, justifying their reasoning, and working individually as well as in teams. CONCLUSIONS: This study introduces the SGRT as a potentially engaging, case-based, and collaborative learning method that may help preclinical medical students become aware of their knowledge gaps and integrate their knowledge in basic and clinical sciences in the context of clinical reasoning.

Neonatal-Onset Chronic Diarrhea Caused by Homozygous Nonsense WNT2B Mutations.

Homozygous nonsense mutations in WNT2B were identified in three individuals from two unrelated families with severe, neonatal-onset osmotic diarrhea after whole-exome sequencing was performed on trios from the two families. Intestinal biopsy samples from affected individuals were used for histology and immunofluorescence and to generate enteroids ex vivo. Histopathologic evaluation demonstrated chronic inflammatory changes in the stomach, duodenum, and colon. Immunofluorescence demonstrated diminished staining for OLFM4, a marker for intestinal stem cells (ISCs). The enteroids generated from WNT2B-deficient intestinal epithelium could not be expanded and did not survive passage. Addition of CHIR-99021 (a GSK3A and GSK3B inhibitor and activator of canonical WNT/ß-CATENIN signaling) could not rescue WNT2B-deficient enteroids. Addition of supplemental recombinant murine WNT2B was able to perpetuate small enteroids for multiple passages but failed to expand their number. Enteroids showed a 10-fold increase in the expression of LEF1 mRNA and a 100-fold reduction in TLR4 expression, compared with controls by quantitative RT-PCR, indicating alterations in canonical WNT and microbial pattern-recognition signaling. In summary, individuals with homozygous nonsense mutations in WNT2B demonstrate severe intestinal dysregulation associated with decreased ISC number and function, likely explaining their diarrheal phenotype. WNT2B deficiency should be considered for individuals with neonatal-onset diarrhea.

Advances in Evaluation of Chronic Diarrhea in Infants.

Diarrhea is common in infants (children less than 2 years of age), usually acute, and, if chronic, commonly caused by allergies and occasionally by infectious agents. Congenital diarrheas and enteropathies (CODEs) are rare causes of devastating chronic diarrhea in infants. Evaluation of CODEs is a lengthy process and infrequently leads to a clear diagnosis. However, genomic analyses and the development of model systems have increased our understanding of CODE pathogenesis. With these advances, a new diagnostic approach is needed. We propose a revised approach to determine causes of diarrhea in infants, including CODEs, based on stool analysis, histologic features, responses to dietary modifications, and genetic tests. After exclusion of common causes of diarrhea in infants, the evaluation proceeds through analyses of stool characteristics (watery, fatty, or bloody) and histologic features, such as the villus to crypt ratio in intestinal biopsies. Infants with CODEs resulting from defects in digestion, absorption, transport of nutrients and electrolytes, or enteroendocrine cell development or function have normal villi to crypt ratios; defects in enterocyte structure or immune-mediated conditions result in an abnormal villus to crypt ratios and morphology. Whole-exome and genome sequencing in the early stages of evaluation can reduce the time required for a definitive diagnosis of CODEs, or lead to identification of new variants associated with these enteropathies. The functional effects of gene mutations can be analyzed in model systems such as enteroids or induced pluripotent stem cells and are facilitated by recent advances in gene editing procedures. Characterization and investigation of new CODE disorders will improve management of patients and advance our understanding of epithelial cells and other cells in the intestinal mucosa.

Identification and characterization of a novel DGAT1 missense mutation associated with congenital diarrhea.

Acyl-CoA:diacylglycerol acyltransferase (DGAT)1 and DGAT2 catalyze triglyceride (TG) biosynthesis in humans. Biallelic loss-of-function mutations in human DGAT1 result in severe congenital diarrhea and protein-losing enteropathy. Additionally, pharmacologic inhibition of DGAT1 led to dose-related diarrhea in human clinical trials. Here we identify a previously unknown DGAT1 mutation in identical twins of South Asian descent. These male patients developed watery diarrhea shortly after birth, with protein-losing enteropathy and failure to thrive. Exome sequencing revealed a homozygous recessive mutation in DGAT1, c.314T>C, p.L105P. We show here that the p.L105P DGAT1 enzyme produced from the mutant allele is less abundant, resulting in partial loss of TG synthesis activity and decreased formation of lipid droplets in patient-derived primary dermal fibroblasts. Thus, in contrast with complete loss-of-function alleles of DGAT1, the p.L105P missense allele partially reduces TG synthesis activity and causes a less severe clinical phenotype. Our findings add to the growing recognition of DGAT1 deficiency as a cause of congenital diarrhea with protein-losing enteropathy and indicate that DGAT1 mutations result in a spectrum of diseases.

Implementing Entrustable Professional Activities in Pediatric Fellowships: Facilitating the Process.

BACKGROUND AND OBJECTIVES: Entrustable professional activities (EPAs) will be used for initial certification by the American Board of Pediatrics by 2028. Less than half of pediatric fellowships currently use EPAs for assessment, yet all will need to adopt them. Our objectives were to identify facilitators and barriers to the implementation of EPAs to assess pediatric fellows and to determine fellowship program directors' (FPD) perceptions of EPAs and Milestones. METHODS: We conducted a survey of FPDs from 15 pediatric subspecialties. EPA users were asked about their implementation of EPAs, barriers encountered, and perceptions of EPAs. Nonusers were queried about deterrents to using EPAs. Both groups were asked about potential facilitators of implementation and their perceptions of Milestones. RESULTS: The response rate was 65% (575/883). Of these, 344 (59.8%) were EPA users and 231 (40.2%) were nonusers. Both groups indicated work burden as a barrier to implementation. Nonusers reported more barriers than users (mean [SD]: 7 [3.8] vs 5.8 [3.4], P < .001). Both groups identified training materials and premade assessment forms as facilitators to implementation. Users felt that EPAs were easier to understand than Milestones (89%) and better reflected what it meant to be a practicing subspecialty physician (90%). In contrast, nonusers felt that Milestones were easy to understand (57%) and reflected what it meant to be a practicing subspecialist (58%). CONCLUSIONS: Implementing EPA-based assessment will require a substantial investment by FPDs, facilitated by guidance and easily accessible resources provided by multiple organizations. Perceived barriers to be addressed include FPD time constraints, a need for additional assessment tools, and outcomes data.

A Case of Red Retching?

This piece features a 14-year-old young man who presented with epigastric pain and bright red emesis. His father brought both a photo and sample of the vomitus, which guided initial management in one direction, and then on closer inspection, diverted his diagnostic trajectory. Through a traditional case report and accompanied image and prose, we explore how we process and reinterpret visual data to help guide our management of hematemesis.

Pediatric Gastrointestinal Histopathology in Patients With Tetratricopeptide Repeat Domain 7A (TTC7A) Germline Mutations: A Rare Condition Leading to Multiple Intestinal Atresias, Severe Combined Immunodeficiency, and Congenital Enteropathy.

Mutations in the tetratricopeptide repeat domain 7A (TTC7A) gene are a rare cause of congenital enteropathy that can result in significant morbidity. TTC7A deficiency leads to disruption of the intestinal epithelium. The histopathology of this condition has been partly described in case reports and clinical studies. This manuscript describes an in-depth investigation of the pediatric gastrointestinal pathology of the largest histologically examined cohort with confirmed TTC7A mutations reported to date and, for the first time, compared the findings to age-matched and sex-matched control patients with intestinal atresia not thought to be associated with TTC7A mutations. Hematoxylin and eosin-stained slides of endoscopically obtained mucosal biopsies and surgical resection specimens from 7 patients with known TTC7A mutations were examined retrospectively. The microscopic findings were found to be on a spectrum from atresia-predominant to those with predominantly epithelial abnormalities. Several unique histopathologic characteristics were observed when compared with controls. These included neutrophilic colitis and prominent lamina propria eosinophilia throughout the gastrointestinal tract. Striking architectural abnormalities of the epithelium were observed in 4 of the 7 patients. The 5 patients with intestinal atresia demonstrated hypertrophy and disorganization of the colonic muscularis mucosae accompanied by bland spindle cell nodules within the intestinal wall. The components of the latter were further elucidated using immunohistochemistry, and we subsequently hypothesize that they represent obliterated mucosa with remnants of the muscularis mucosae. Finally, atrophic gastritis was noted in 4 patients. In conclusion, the unique histopathologic characteristics of TTC7A mutation-associated enteropathy described herein more fully describe this novel disease entity in infants who present with congenital enteropathy or enterocolitis.

Cisapride improves enteral tolerance in pediatric short-bowel syndrome with dysmotility.

BACKGROUND AND OBJECTIVES: Gastrointestinal dysmotility is common in pediatric short-bowel syndrome, leading to prolonged parenteral nutrition dependence. There is limited literature regarding the safety and efficacy of cisapride for this indication. The aim of the study was to describe the safety and efficacy of cisapride for enteral intolerance in pediatric short-bowel syndrome. METHODS: Open-labeled pilot study in a limited access program for cisapride. Indications were short-bowel syndrome with underlying dysmotility and difficulty advancing enteral feeds despite standard therapies and without evidence of anatomic obstruction. Patients received cisapride 0.1 to 0.2 mg/kg per dose for 3 to 4 doses per day. We collected electrocardiogram, nutrition, and anthropometric data prospectively at study visits. RESULTS: Ten patients with mean (SD) age of 30.3 (30.5) months were enrolled in our multidisciplinary pediatric intestinal rehabilitation program. Median (interquartile range [IQR]) duration of follow-up was 8.7 (3.1-14.3) months. Median (IQR) residual bowel length was 102 (85-130) cm. Median (IQR) citrulline level was 14.5 (10.5-31.3) µmol/L. Diagnoses included isolated gastroschisis (n = 3), gastroschisis with intestinal atresia (n = 4), necrotizing enterocolitis (n = 2), and long-segment Hirschsprung disease (n = 1). Six subjects had at least 1 prior bowel-lengthening procedure. Median (IQR) change in percentage enteral energy intake was 19.9% (15.4%-29.8%) during follow-up (P = 0.01). Seven patients improved in enteral tolerance during treatment and 2 were weaned completely from parenteral nutrition. Complications during therapy were prolonged corrected QT interval (n = 2), gastrointestinal bleeding (n = 2), D-lactic acidosis (n = 1), and death due to presumed sepsis (n = 1). Longitudinal analysis (general estimating equation model) showed a strong positive association between cisapride duration and improved enteral tolerance. Mean percentage of enteral intake increased by 2.9% for every month of cisapride treatment (P < 0.0001). CONCLUSIONS: Cisapride is a potentially useful therapy in patients with pediatric short-bowel syndrome with gastrointestinal dysmotility. We observed modest improvement in feeding tolerance where prior treatments failed; however, patients treated with cisapride require careful cardiac monitoring because corrected QT prolongation occurred in 20% of our cohort.

Understanding and Optimizing Group Dynamics in Case-Based Collaborative Learning.

Teamwork skills are recognized as a core competency of physicians. To more effectively prepare trainees for the demands of their future work, medical educators are increasingly turning to group-based instructional formats. We employ case-based collaborative learning (CBCL) - a format which requires daily in-class discussion and collaboration in assigned small groups. While students overwhelmingly embraced CBCL as stimulating and thought-provoking, some students reported that social dynamics among group members adversely impacted their experience. Using mixed methods, we demonstrate that a short intervention that asked students to discuss how they can best learn together improved small group dynamics, and promoted psychological safety among peers. Importantly, no specific instruction in team work was required, students overall had a clear understanding how they could improve, but they did not know how to start this conversation with each other. To promote team learning, we propose that educators emphasize students' accountability to their peers' learning in addition to their own, and devote some time in class for teams to reflect and discuss how to improve learning with each other. Our observations are of interest to anyone frequently relying on group work without peer assessment or formal feedback on group performance.

Variable management strategies for NEC totalis: a national survey.

BACKGROUND/OBJECTIVES: Necrotizing enterocolitis (NEC) is a serious disease linked to prematurity. A variant, NEC totalis, is associated with nearly 100% mortality. There is wide variation in counseling practices for NEC totalis. Our objectives are to determine what treatment options, if any, are offered to families, and which factors influence these decisions. METHODS: An anonymous survey was distributed to members of the AAP Sections on Neonatal-Perinatal Medicine and Pediatric Surgery. Data were analyzed utilizing chi-square tests and Spearman correlations, where applicable. RESULTS: In the setting of NEC totalis, 90% of the 378 respondents viewed offering life-sustaining interventions (LSI) as ethically permissible and 87% felt that transfer to another center willing to provide LSI should be considered; however, only 43% reported offering LSI to families. CONCLUSIONS: Management of NEC totalis remains challenging and significant practice variability persists. Most respondents do not offer ongoing medical/surgical management, despite believing it is an ethically permissible option.

Vitamin D status in gastrointestinal and liver disease.

PURPOSE OF REVIEW: The purpose of this review is to report on the vitamin D status and its relationship with bone health in individuals with gastrointestinal and liver disorders. In addition, recommendations regarding replacement and maintenance of optimal vitamin D stores, as well as the state of knowledge regarding its effect on the disease through its actions on the immune system, will be reviewed. RECENT FINDINGS: The scientific community has revised upward the serum levels of vitamin D considered optimal, and doses of vitamin D much larger than those currently recommended may be needed to maintain these levels, especially in individuals with gastrointestinal and liver disorders. The relationship between vitamin D and bone health in this population is controversial. The role of vitamin D in the regulation of the immune system continues to be elucidated. SUMMARY: Hypovitaminosis D is prevalent among individuals with gastrointestinal and liver disease. Although replacement and supplementation guidelines have not been well defined, practitioners should aim for a serum 25-hydroxyvitamin D level of at least 32 ng/ml. The contribution of vitamin D to the bone health of these individuals and its role in altering disease course through its actions on the immune system remain to be elucidated.

Overview of pediatric short bowel syndrome.

Short bowel syndrome (SBS) is a malabsorptive state occuring as a result of surgical resection or congenital disease of a significant portion of the small intestine . The amount of resection or remaining bowel generally dictates the degree of malabsorption and consequentely the need for specialized enteral nutrition or parenteral nutrition (PN). Intestinal failure in the context of SBS is defined as a dependence on PN to maintain minimal energy and fluid requirement for growth in children. Common causes of SBS in infants and children include necrotizing enterocolitis, midgut volvulus, intestinal atresia, and gastroschisis. Early identification of patients at risk for long-term PN dependency is the first step toward avoiding severe complications. Close monitoring of nutritional status, steady and early introduction of enteral nutrition, and aggressive prevention, diagnosis, and treatment of infections such as central venous catheter sepsis and bacterial overgrowth can significantly improve the prognosis. Intestinal transplantation is an emerging treatment that may be considered when intestinal failure is irreversible and children are experiencing serious complications related to TPN administration.

First report of the international serial transverse enteroplasty data registry: indications, efficacy, and complications.

BACKGROUND: Serial transverse enteroplasty (STEP) is a novel surgical therapy for short bowel syndrome and is being used with increasing frequency worldwide. Because no single center is likely to obtain sufficient experience for meaningful analysis, we created the International STEP Data Registry to allow for larger, multicenter patient accrual and followup. This report describes patient characteristics, operative parameters, and early results of STEP in the first 38 patients enrolled in the International STEP Data Registry. STUDY DESIGN: After IRB approval, data were entered online through password-protected enrollment and followup forms. Patient and procedural characteristics were analyzed. Pre- and postoperative small bowel length and enteral feeding tolerance were compared with the paired t-test. RESULTS: Between September 1, 2004, and April 30, 2006, 19 centers from 3 countries enrolled 38 patients. Median followup from STEP procedure to analysis was 12.6 months (range 0 to 66.9 months). Indications for STEP were short bowel syndrome (SBS, n=29), bacterial overgrowth (n=6), and neonatal atresia (n=3). Mean small intestine length was substantially increased in all groups (68+/-44 cm versus 115+/-87 cm, p < 0.0001, n=27). Notable complications included intraoperative staple line leak (n=2), bowel obstruction (n=2), and fluid collection or abscess (n=3). Late outcomes included progression to transplantation (n=3) and mortality (n=3). For the short bowel syndrome cohort, enteral tolerance was notably increased from 31%+/-31% to 67%+/-37% of calories (p < 0.01, n=21). CONCLUSIONS: STEP has been performed at multiple centers with minimal complications and encouraging outcomes. Indications for the procedure have broadened beyond short bowel syndrome to include bacterial overgrowth and neonatal intestinal obstruction with dilated proximal intestine. Continued accrual and followup of patients in the International STEP Data Registry will elucidate the longterm safety and efficacy of the procedure, with the goal of improved patient selection and operative timing.

Unpasteurized Shared Human Milk Use in Pediatric Inpatients: Health and Ethical Implications.

Growing evidence supporting the health benefits of human milk, particularly in the preterm population, has led to rising demand for donor human milk in NICUs and pediatric hospitals. There are no previous reports describing the use of unpasteurized shared human milk (USHM) in the hospital setting, but the use of USHM solicited from community donors through social networks appears to be common. Many pediatric hospitals permit inpatients to receive breast milk that has been screened and pasteurized by a human milk banking organization and will provide pasteurized donor human milk (PDHM) only to infants who are preterm or have specific medical conditions. These policies are designed to minimize potential adverse effects from improperly handled or screened donor milk and to target patients who would experience the greatest benefit in health outcomes with donor milk use. We explore the ethical and health implications of 2 cases of medically complex infants who did not meet criteria in our tertiary care hospital for the use of PDHM from a regulated human milk bank and were incidentally found to be using USHM. These cases raise questions about how best to balance the ethical principles of beneficence, nonmaleficence, justice, and patient autonomy in the provision of PDHM, a limited resource. Health care staff should ask about USHM use to provide adequate counseling about the risks and benefits of various feeding options in the context of an infant's medical condition.

The Case-Based Collaborative Learning Peer Observation Worksheet and Compendium: An Evaluation Tool for Flipped Classroom Facilitators.

INTRODUCTION: In a flipped classroom, students learn basic concepts before class, allowing them time during class to apply newly gained knowledge to problem sets and cases. Harvard Medical School (HMS) has introduced a form of flipped classroom, called case-based collaborative learning (CBCL), during preclinical curricula. Finding few published resources, the HMS Academy's Peer Observation of Teaching Interest Group developed a guide for observations and feedback to CBCL facilitators. METHODS: After conducting an extensive literature search, speaking to flipped classroom methodology experts, and observing 14 facilitators using CBCL methods, the interest group identified specific teaching behaviors that optimize student interaction and knowledge application. The group next engaged in several rounds of the modified Delphi method to develop the CBCL peer observation worksheet and compendium and then tested these materials' effectiveness in capturing CBCL teaching behaviors and providing feedback to CBCL faculty facilitators. RESULTS: Seventy-three percent of faculty rated the worksheet and compendium as extremely helpful or helpful in identifying new teaching techniques. Moreover, 90% found the CBCL peer observation and debriefing to be extremely helpful or helpful, and 90% were extremely likely or likely to incorporate peer suggestions in future teaching sessions. DISCUSSION: Medical schools have begun to embrace flipped classroom methods to eliminate passive, lecture-style instruction during the preclinical years of the MD curriculum. This tool identifies specific in-classroom approaches that engage students in active learning, guides peer observers in offering targeted feedback to faculty on teaching strategies, and presents consensus-based resources for use during CBCL faculty development and training.

Resistin levels in human immunodeficiency virus-infected patients with lipoatrophy decrease in response to rosiglitazone.

Resistin is a recently recognized adipocytokine thought to contribute to insulin resistance. We determined resistin levels and metabolic parameters in 24 HIV-infected men and women with lipoatrophy and hyperinsulinemia and studied the effect of 12 wk of the peroxisome proliferator-activated receptor-gamma agonist rosiglitazone (4-8 mg/d) on resistin in these subjects. Participants completed metabolic testing before and after rosiglitazone including fasting determination of resistin, adiponectin, and leptin levels, serum inflammatory markers, and hyperinsulinemic euglycemic clamp testing. Resistin concentration decreased significantly after rosiglitazone (12.17 +/- 1.15 ng/ml to 10.23 +/- 1.05 ng/ml; P = 0.02), in conjunction with significant increases in adiponectin- (P < 0.001) and insulin- stimulated glucose disposal (P = 0.004). Leptin levels, as well as TNF-alpha, did not change with rosiglitazone. In summary, among HIV-infected subjects with insulin resistance and lipoatrophy, resistin levels decreased significantly after rosiglitazone. Further investigation into the physiological role of this peroxisome proliferator-activated receptor-gamma-responsive adipocytokine in the metabolic abnormalities associated with HIV is warranted.