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1.
Med Teach ; 44(2): 158-166, 2022 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-34459337

RESUMO

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.


Assuntos
Educação Médica , Estudantes de Medicina , Competência Clínica , Raciocínio Clínico , Humanos , Resolução de Problemas
2.
Am J Hum Genet ; 103(1): 131-137, 2018 07 05.
Artigo em Inglês | MEDLINE | ID: mdl-29909964

RESUMO

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.


Assuntos
Códon sem Sentido/genética , Diarreia/genética , Glicoproteínas/genética , Proteínas Wnt/genética , Criança , Pré-Escolar , Feminino , Homozigoto , Humanos , Lactente , Intestinos/patologia , Masculino , RNA Mensageiro/genética , Transdução de Sinais/genética , Células-Tronco/patologia
3.
Gastroenterology ; 154(8): 2045-2059.e6, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29654747

RESUMO

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.


Assuntos
Diarreia Infantil/diagnóstico , Enterócitos/patologia , Células Enteroendócrinas/patologia , Enteropatias/diagnóstico , Biópsia , Doença Crônica , Procedimentos Clínicos , Diarreia Infantil/classificação , Diarreia Infantil/etiologia , Diarreia Infantil/patologia , Endoscopia do Sistema Digestório , Enterócitos/metabolismo , Células Enteroendócrinas/metabolismo , Testes Genéticos/métodos , Humanos , Lactente , Recém-Nascido , Enteropatias/classificação , Enteropatias/etiologia , Enteropatias/patologia , Mutação , Sequenciamento Completo do Genoma
4.
J Lipid Res ; 58(6): 1230-1237, 2017 06.
Artigo em Inglês | MEDLINE | ID: mdl-28373485

RESUMO

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.


Assuntos
Diacilglicerol O-Aciltransferase/genética , Diarreia/congênito , Diarreia/genética , Mutação de Sentido Incorreto , Alelos , Linhagem Celular Tumoral , Pré-Escolar , Diarreia/enzimologia , Feminino , Homozigoto , Humanos , Mutação com Perda de Função , Masculino , Gravidez
6.
Pediatrics ; 153(6)2024 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-38757175

RESUMO

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.


Assuntos
Bolsas de Estudo , Pediatria , Pediatria/educação , Humanos , Competência Clínica , Estados Unidos , Certificação , Inquéritos e Questionários , Masculino , Feminino
7.
J Pediatr Gastroenterol Nutr ; 52(5): 590-4, 2011 May.
Artigo em Inglês | MEDLINE | ID: mdl-21502831

RESUMO

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.


Assuntos
Cisaprida/uso terapêutico , Ingestão de Energia , Nutrição Enteral/métodos , Fármacos Gastrointestinais/uso terapêutico , Motilidade Gastrointestinal , Síndrome do Intestino Curto/terapia , Criança , Pré-Escolar , Citrulina/sangue , Nutrição Enteral/efeitos adversos , Enterocolite Necrosante/terapia , Feminino , Seguimentos , Gastrosquise/terapia , Doença de Hirschsprung/terapia , Humanos , Lactente , Atresia Intestinal/terapia , Intestino Delgado/patologia , Masculino , Nutrição Parenteral , Projetos Piloto , Síndrome do Intestino Curto/tratamento farmacológico , Síndrome do Intestino Curto/fisiopatologia , Resultado do Tratamento
9.
J Perinatol ; 39(11): 1521-1527, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31371831

RESUMO

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.


Assuntos
Enterocolite Necrosante/diagnóstico , Enterocolite Necrosante/terapia , Doenças do Prematuro/diagnóstico , Doenças do Prematuro/terapia , Distribuição de Qui-Quadrado , Terapia Combinada , Estudos Transversais , Pesquisas sobre Atenção à Saúde , Humanos , Recém-Nascido , Recém-Nascido Prematuro , Laparotomia/estatística & dados numéricos , Neonatologistas , Padrões de Prática Médica/estatística & dados numéricos , Fatores de Risco , Cirurgiões , Ultrassonografia , Estados Unidos
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