Clinical and biochemical footprints of inherited metabolic diseases. VIII. Neoplasias.

Cancer, caused by multiple cumulative pathogenic variants in tumor suppressor genes and proto-oncogenes, is a leading cause of mortality worldwide. The uncontrolled and rapid cell growth of the tumors requires a reprogramming of the complex cellular metabolic network to favor anabolism. Adequate management and treatment of certain inherited metabolic diseases might prevent the development of certain neoplasias, such as hepatocellular carcinoma in tyrosinemia type 1 or hepatocellular adenomas in glycogen storage disorder type 1a. We reviewed and updated the list of known metabolic etiologies associated with various types of benign and malignant neoplasias, finding 64 relevant inborn errors of metabolism. This is the eighth article of the series attempting to create a comprehensive list of clinical and metabolic differential diagnosis by system involvement.

Genetic screening for hypertrophic cardiomyopathy in large, asymptomatic military cohorts.

Sudden cardiac death (SCD) is one of the leading causes of mortality in the U.S. military and competitive athletes. In this study, we simulate how genetic screening may be implemented in the military to prevent an SCD endpoint resulting from hypertrophic cardiomyopathy (HCM). We created a logistic regression model to predict variant pathogenicity in the most common HCM associated genes MYH7 and MYBPC3. Model predictions were used in conjunction with the gnomAD database to identify frequencies of pathogenic variants. Extrapolating these variants to a military population, lives saved and cost benefit analyses were conducted for screening for HCM related to pathogenic variants in MYH7 and MYBPC3. Genetic screening for HCM followed by echocardiography in individuals with pathogenic variants is predicted to save an average of 2.9 lives per accession cohort, based on historical cohort sizes, and result in a break-even cost of ~$7 per test. The false positives, defined as disqualified individuals for military service who do not have HCM, are predicted to be 0 individuals per accession cohort. This study suggests that the main barriers for the implementation of genetic screening for the U.S. military are the low detection rate and variant interpretation.

The genetic workup for structural congenital heart disease.

Congenital heart disease (CHD) is the most prevalent birth defect and is the result of multiple etiologies including genetic and environmental causes. This article reviews the genetic workup for structural CHD in the clinical setting, beginning with CHD epidemiology and etiology and then moving to genetic testing, clinical evaluation, and genetic counseling. An algorithm is presented as a guide to genetic test selection, and available tests are explained with their respective advantages and limitations. Finally, future advances are discussed. As this review focuses on structural heart disease, isolated cardiomyopathies, inherited primary arrhythmia syndromes and aortopathies are not discussed.

Five-year review of an international clinical research-training program.

The exponential increase in clinical research has profoundly changed medical sciences. Evidence that has accumulated in the past three decades from clinical trials has led to the proposal that clinical care should not be based solely on clinical expertise and patient values, and should integrate robust data from systematic research. As a consequence, clinical research has become more complex and methods have become more rigorous, and evidence is usually not easily translated into clinical practice. Therefore, the instruction of clinical research methods for scientists and clinicians must adapt to this new reality. To address this challenge, a global distance-learning clinical research-training program was developed, based on collaborative learning, the pedagogical goal of which was to develop critical thinking skills in clinical research. We describe and analyze the challenges and possible solutions of this course after 5 years of experience (2008-2012) with this program. Through evaluation by students and faculty, we identified and reviewed the following challenges of our program: 1) student engagement and motivation, 2) impact of heterogeneous audience on learning, 3) learning in large groups, 4) enhancing group learning, 5) enhancing social presence, 6) dropouts, 7) quality control, and 8) course management. We discuss these issues and potential alternatives with regard to our research and background.

[Utility of routine gastric biopsies and staining with methylene blue in the diagnosis of intestinal metaplasia in patients over 40 years]. / Utilidad de las biopsias gástricas rutinarias y de la tinción con azul de metileno en el diagnóstico de la metaplasia intestinal en mayores de 40 años.

OBJECTIVE: To evaluate the diagnostic utility of routine gastric biopsies taken at random versus targeted biopsies with methylene blue staining for the diagnosis of intestinal metaplasia. MATERIAL AND METHODS: We performed a validation study in 376 patients. We performed 2 antral biopsies, 2 gastric body biopsies, 1 biopsy for urease test and additional biopsies if demanded. One hundred and one patients underwent 2 biopsies after methylene blue staining. A total of 1,486 biopsies were analyzed. Frequencies of histological and endoscopic diagnosis and the validation of endoscopic diagnosis of intestinal metaplasia with and without staining against histology, which followed updated Sydney and Vienna criteria, were determined RESULTS: Metaplasia was found in 37.23% ofcases and in 6.38% was incomplete in antrum and body, moderate or severe. The endoscopic diagnosis had: sensitivity 46%, specificity 91%, positive predictive value (PPV) 75% and negative predictive value (NPV) 74%. The low sensitivity indicates the need for gastric biopsies. Staining had: sensitivity 95%, specificity 67%, PPV 84% and NPV 89%, with significant difference for staining (P < 0.05). The typical endoscopic appearance of intestinal metaplasia always coincided with staining and histology. Dysplasia was found in 0.53% ofcases, gastric cancer in 1.8% and Helicobacter pylori in 56%. CONCLUSION: Directed biopsy staining is superior to those taken at random for diagnosing metaplasia. Metaplasia was not found when endoscopy was normal and typical endoscopic appearance of metaplasia agreed with staining and histology.

Utilidad de las biopsias gástricas rutinarias y de la tinción con azul de metileno en el diagnóstico de la metaplasia intestinal en mayores de 40 años / [Utility of routine gastric biopsies and staining with methylene blue in the diagnosis of intestinal metaplasia in patients over 40 years].

OBJECTIVE: To evaluate the diagnostic utility of routine gastric biopsies taken at random versus targeted biopsies with methylene blue staining for the diagnosis of intestinal metaplasia. MATERIAL AND METHODS: We performed a validation study in 376 patients. We performed 2 antral biopsies, 2 gastric body biopsies, 1 biopsy for urease test and additional biopsies if demanded. One hundred and one patients underwent 2 biopsies after methylene blue staining. A total of 1,486 biopsies were analyzed. Frequencies of histological and endoscopic diagnosis and the validation of endoscopic diagnosis of intestinal metaplasia with and without staining against histology, which followed updated Sydney and Vienna criteria, were determined RESULTS: Metaplasia was found in 37.23

ofcases and in 6.38

was incomplete in antrum and body, moderate or severe. The endoscopic diagnosis had: sensitivity 46

. The low sensitivity indicates the need for gastric biopsies. Staining had: sensitivity 95

, with significant difference for staining (P < 0.05). The typical endoscopic appearance of intestinal metaplasia always coincided with staining and histology. Dysplasia was found in 0.53

ofcases, gastric cancer in 1.8

and Helicobacter pylori in 56

. CONCLUSION: Directed biopsy staining is superior to those taken at random for diagnosing metaplasia. Metaplasia was not found when endoscopy was normal and typical endoscopic appearance of metaplasia agreed with staining and histology.

Utilidad de las biopsias gástricas rutinarias y de la tinción con azul de metileno en el diagnóstico de la metaplasia intestinal en mayores de 40 años. / [Utility of routine gastric biopsies and staining with methylene blue in the diagnosis of intestinal metaplasia in patients over 40 years].

OBJECTIVE: To evaluate the diagnostic utility of routine gastric biopsies taken at random versus targeted biopsies with methylene blue staining for the diagnosis of intestinal metaplasia. MATERIAL AND METHODS: We performed a validation study in 376 patients. We performed 2 antral biopsies, 2 gastric body biopsies, 1 biopsy for urease test and additional biopsies if demanded. One hundred and one patients underwent 2 biopsies after methylene blue staining. A total of 1,486 biopsies were analyzed. Frequencies of histological and endoscopic diagnosis and the validation of endoscopic diagnosis of intestinal metaplasia with and without staining against histology, which followed updated Sydney and Vienna criteria, were determined RESULTS: Metaplasia was found in 37.23

ofcases and in 6.38

was incomplete in antrum and body, moderate or severe. The endoscopic diagnosis had: sensitivity 46

, specificity 91

, positive predictive value (PPV) 75

and negative predictive value (NPV) 74

. The low sensitivity indicates the need for gastric biopsies. Staining had: sensitivity 95

, specificity 67

, PPV 84

and NPV 89

, with significant difference for staining (P < 0.05). The typical endoscopic appearance of intestinal metaplasia always coincided with staining and histology. Dysplasia was found in 0.53

ofcases, gastric cancer in 1.8

and Helicobacter pylori in 56

. CONCLUSION: Directed biopsy staining is superior to those taken at random for diagnosing metaplasia. Metaplasia was not found when endoscopy was normal and typical endoscopic appearance of metaplasia agreed with staining and histology.