Differences between repeated lipid profile measurements in a tertiary hospital over a short time period.

BACKGROUND: Measurement of the plasma lipid profile, mainly low-density lipoprotein cholesterol (LDL-C), is widely used in the management of hospitalized patients as part of their cardiometabolic risk assessment. In common practice, LDL-C is calculated indirectly by the Friedewald equation. For many years, fasting of 8-14 h is needed to obtain an accurate lipid profile measurement, although recent guidelines do not necessitate it. The aim of this study was to find patients with two consecutive LDL-C measurements taken over a short time period on the same admission to see if a significant difference exists and to suggest reasons that may explain it. We also aim to define whether the difference between LDL-C calculated by the Friedewald equation is diminished while using the newer Martin/Hopkins, de Cordova or Sampson/NIH equations. METHODS: This was a retrospective cohort study performed in one medical center in Israel. In a five-year time period, 772 patients with two repeated LDL-C measurements taken on the same admission were found. The median time gap between tests was 2 days. Correlations between laboratory results and LDL-C measurements were determined. RESULTS: A total of 414 patients (53.6%) had a difference greater than the acceptable total error of 8.9% in LDL-C calculation using the Friedewald equation, with a mean 25.8% difference between the two tests. Newer LDL-C calculations showed less diversity. Non-HDL-C was found as the only variable with a major correlation with LDL-C results in all equations. A weaker correlation was found with HDL-C. Triglycerides showed an even weaker correlation, and glucose differences had no correlation with LDL-C differences. CONCLUSIONS: Repeated LDL-C measurements can vary widely, even during a short period of hospitalization. In this study, more than half of the patients had a significant difference between their consecutive LDL-C results. This wide difference between two consecutive tests was diminished using newer calculations, yet not well explained. The fasting state likely has no effect on LDL-C levels. The results of this study might emphasize that many factors influence LDL-C calculation, especially in the disease state. Further research is needed, especially in looking for a more accurate LDL-C calculation from existing formulas.

Hospital Care Efficiency - Measuring Lipid Profile During Hospitalization.

Background: Lipid profile measurement in order to identify patients with elevated low-density lipoprotein cholesterol (LDL-C) is clearly recommended for all age groups. However, the value of screening patients for elevated LDL-C during hospitalization has not been determined. The aim of this study was to investigate the value of lipid screening tests in patients admitted to internal medicine wards, and as part of our efforts to promote a more intelligent and efficient use of laboratory and imaging tests during hospital care. Methods: We conducted this retrospective, observational study, in which medical charts of patients for whom at least one lipid profile measurement was performed during hospitalization were reviewed. The patients were categorized into 5 groups according to admission diagnosis, and for each patient, we looked if the lipid profile was mentioned or referred to, based on guidelines, in the discharge summary. Results: Lipid profile taken during hospitalization was referred to in the discharge letter in only 38.7% of patients, and even in the case of a need to consider according to guidelines, only a 45.7% consideration rate was found. Conclusion: This study highlights the need for a more efficient and focused approach to the use of lipid profile measurement during hospitalization.

Immune reconstitution inflammatory syndrome (IRIS) in a patient with neuro pulmonary nocardiosis following hematopoietic cells transplantation (HCT).

Immune reconstitution inflammatory syndrome (IRIS) is increasingly reported in various HIV negative patients with immunosuppression, but the relationship with hematopoietic cell transplantation (HCT) is not well defined. We report a case of IRIS in a patient infected with pulmonary and CNS Nocardiosis following HCT due to primary myelofibrosis.

[TEACHING INTERNAL MEDICINE IN THE SHADOW OF THE COVID-19 OUTBREAK - THE EXPERIENCE OF THE TECHNION FACULTY OF MEDICINE].

INTRODUCTION: The clerkship of internal medicine is pursued in the 2nd semester of the 4th year at the Technion Medical School. Following the COVID-19 outbreak, frontal and bedside teaching was interrupted. Therefore, we decided to provide distant teaching until having the opportunity to resume clinical bedside teaching. A team of tutors composed a course of weekly units, each week assigned to a different subject in internal medicine. A total of 120 students were divided into 15 groups of 8 students, each group guided by a personal tutor. The format of each unit included online pretest, clinical virtual cases and two separate 2 hour ZOOM sessions with the tutor. The pretest was based on 1-3 chapters from Harrison's Internal Medicine textbook, 20th edition, and consisted of both clinical reasoning and knowledge questions. During ZOOM sessions with the tutor, the students practiced clinical problem solving. In addition, all the students were granted free access to the commercial "Aquifer" case-based virtual course for more practice. The students' feedback at the end of the learning period revealed that, although frustrated in being away from the clinics, the overall level of satisfaction from the course was good (rated 5 or 4/5 by 65% of responders) and the time was used efficiently. In conclusion, the students received a positive proactive learning experience of both theoretical aspects and clinical reasoning skills in internal medicine. There is no doubt that bedside teaching in medicine is invaluable and can't be replaced by any other means, however, given the circumstances, our format provided a reasonable temporary alternative.

Teaching During the COVID-19 Pandemic: The Experience of the Faculty of Medicine at the Technion-Israel Institute of Technology.

BACKGROUND: The coronavirus disease-2019 (COVID-19) pandemic forced drastic changes in all layers of life. Social distancing and lockdown drove the educational system to uncharted territories at an accelerated pace, leaving educators little time to adjust. OBJECTIVES: To describe changes in teaching during the first phase of the COVID-19 pandemic. METHODS: We described the steps implemented at the Technion-Israel Institute of Technology Faculty of Medicine during the initial 4 months of the COVID-19 pandemic to preserve teaching and the academic ecosystem. RESULTS: Several established methodologies, such as the flipped classroom and active learning, demonstrated effectiveness. In addition, we used creative methods to teach clinical medicine during the ban on bedside teaching and modified community engagement activities to meet COVID-19 induced community needs. CONCLUSIONS: The challenges and the lessons learned from teaching during the COVID-19 pandemic prompted us to adjust our teaching methods and curriculum using multiple online teaching methods and promoting self-learning. It also provided invaluable insights on our pedagogy and the teaching of medicine in the future with emphasis on students and faculty being part of the changes and adjustments in curriculum and teaching methods. However, personal interactions are essential to medical school education, as are laboratories, group simulations, and bedside teaching.

Relative fat mass is a better predictor of dyslipidemia and metabolic syndrome than body mass index.

Relative fat mass (RFM) had been recently developed. We aimed to examine RFM predictability to various cardiometabolic risk factors, compared to BMI. METHODS: Observational, cohort study, among patients who visited the Rambam Periodic Examinations Institute (RPEI). We compared the correlation of BMI and RFM to hypertension, impaired fasting glucose, high LDL, low HDL and metabolic syndrome, by gender. RESULTS: During study years, 20 167 patients visited the RPEI and included in the trial. Compared to BMI, RFM showed significantly better predictability (odds ratio [OR], [95% confidence interval (CI), P value]) of high LDL [1.618 (1.441-1.816, P < 0.001) vs. 0.732 (0.67-0.8, P < 0.001) in men; 1.572 (1.377-1.794, P < 0.001) vs. 0.938 (0.849-1.163, P = 0.94) in women], low HDL [2.944 (2.569-3.373, P < 0.001) vs. 2.177 (2-2.369, P < 0.001) in men, 2.947 (2.519-3.448, P < 0.001) vs. 1.9 (1.658-2.176, P < 0.001) in women], high triglycerides [4.019 (3.332-4.847, P < 0.001) vs. 1.994 (1.823-2.181, P < 0.001) in men, 3.93 (2.943-5.247, P < 0.001) vs. 2.24 (1.887-2.62, P < 0.001) in women] and metabolic syndrome [7.479, (4.876-11.47, P < 0.001) vs. 3.263 (2.944-3.616, P < 0.001) in men, 16.247 (8.348-31.619, P < 0.001) vs. 5.995 (5.099-7.048, P < 0.001) in women]. There was no significant difference in the predictability of BMI and RFM to hypertension and diabetes mellitus. CONCLUSION: RFM provides high predictability for dyslipidemias and metabolic syndrome.

Normal body mass index (BMI) can rule out metabolic syndrome: An Israeli cohort study.

The aim of the study was to assess whether body mass index (BMI) can be used as a simple and reliable survey test for metabolic syndrome.The study is an observational cohort study among patients who visited the Rambam Periodic Examinations Institute (RPEI). We analyzed the correlation between obesity indices and presence of metabolic syndrome. We identified the ideal value of BMI for identification of patients at risk for metabolic syndrome. We also described the correlation between different BMI values and its negative predictive value (NPV) for metabolic syndrome.During the study years, 23,993 patients visited the RPEI, and 12.5% of them fulfilled the criteria for metabolic syndrome. Women with metabolic syndrome had higher proportion of obesity, when compared with men (89.9% vs 52.6%; P < .0001). Normal BMI had very high NPV to rule out metabolic syndrome among men and women (98% and 96%, respectively). Using receiver-operating characteristic curve, we found BMI 27 to be the ideal value for identification of metabolic syndrome for the entire cohort (area under the curve [AUC] 0.767, 95% confidence interval [CI] 0.758-0.775, P < .0001), for men (AUC 0.726, 95% CI 0.715-0.738, P < .0001), and for women (AUC 0.843, 95% CI 0.831-0.855, P < .0001). BMI below 30 provided NPV of 91.1% to rule out metabolic syndrome.The BMI as single survey measurement of obesity offers high NPV for metabolic syndrome and can be used by physician and patients for this purpose.

Risk Factors for Low Bone Density in Inflammatory Bowel Disease: Use of Glucocorticoids, Low Body Mass Index, and Smoking.

BACKGROUND: Inflammatory bowel disease (IBD) patients are reported to have lower bone density compared to healthy controls. There is limited consensus regarding factors affecting bone density among these patients. Our aim, therefore, was to determine clinical and genetic variables that contribute to lower bone mineral density (BMD) in IBD patients. METHODS: A cross-sectional study of IBD patients treated in a tertiary referral center was performed. Epidemiological and clinical data were collected, and genetic testing for the common mutations in Nucleotide-binding Oligomerization Domain-containing protein (NOD)2 was performed. We examined correlations between the different variables and BMD in the total hip, femoral neck, and lumbar spine. RESULTS: Eighty-nine patients (49% males, 67 Crohn's disease [CD]) participated in the study. 42Forty-two (63%) of the CD and 13 (59%) of the ulcerative colitis patients met the criteria for osteoporosis/osteopenia. Factors associated with lower Z scores were low body mass index (BMI; r = -0.307, p = 0.005), use of glucocorticoids (likelihood ratio [LR] 5.1, p = 0.028), and a trend for male gender (LR = 3.4, p = 0.079). Among CD patients, low bone density showed borderline significance for association with gastrointestinal surgery (LR = 4.1, p = 0.07) and smoking (LR = 3.58, p = 0.06). Low levels of 25OHD were not associated with low BMD, nor were mutations in NOD2. No increased rate of fractures was seen among patients with osteopenia or osteoporosis. CONCLUSION: In addition to the generally accepted risk factors for osteoporosis (glucocorticoids, low BMI, smoking), male IBD patients had a trend toward lower BMD. Carrying a mutaticon in NOD2 did not confer a risk for bone loss.

NOD2/CARD15 Mutations among Bedouin Arabs with Inflammatory Bowel Disease: Frequency and Phenotype Correlation.

BACKGROUND: Inflammatory bowel disease (IBD) prevalence is increasing among Bedouin Arabs in Israel. This population is known to have a high rate of consanguinity. NOD2/CARD15 mutations are well-studied in IBD. OBJECTIVES: To investigate the frequency of NOD2/CARD15 mutations in IBD Bedouin patients and their relevance to disease phenotype. METHODS: The IBD-Arab cohort in southern Israel included 68 patients, of which 25 Crohn's disease (CD) patients and 25 ulcerative colitis (UC) patients consented to participate (72%). Blood samples were obtained from all participants who were genotyped for NOD2/CARD15 variants Arg702Trp, Gly908Arg, and Leu1007fsinsC. RESULTS: The NOD2/CARD15 mutation frequency was higher in Crohn's disease than in ulcerative colitis patients. Carrier frequency for the Gly908Arg mutation in CD and UC patients was 8/25 (32%) and 3/25 (12%), respectively (P = 0.08). Neither the Arg702Trp nor Leu1007fsinsC mutation was found in our cohort. No homozygous/compound heterozygote mutations were found. Genotype-phenotype analysis revealed that CD patients carrying the Gly908Arg mutation were younger at diagnosis, 22.8 ± 4.5 vs. 28.82 ± 9.1 years (P = 0.04). All carriers were males, compared with 41.2% in non-carriers (P = 0.005). NOD2/CARD15 mutation carriers with UC were older, 67.0 ± 24.5 years compared with 41.2 ± 12.3 years (P = 0.006). No other associations regarding disease localization or other clinical parameter were found. CONCLUSIONS: The frequency of NOD2/CARD15 gene mutations is high in CD and UC among Bedouin Arab IBD patients and is associated with younger age at onset in CD and male gender.

Pleural Fluid B-Type Natriuretic Peptide Level as an Additional Indicator for the Fluid's Etiology.

BACKGROUND: The identification of the etiology of a pleural effusion can be difficult. Measurement of serum B-type natriuretic peptide (BNP) levels is helpful in the diagnosis of congestive heart failure (CHF) as a cause of respiratory failure, but pleural fluid BNP measurement is still not part of the workup for pleural effusion. OBJECTIVES: To identify the correlation between pleural fluid BNP levels and clinical diagnosis. METHODS: In this cross-sectional study, data from 107 patients admitted to the department of internal medicine between November 2009 and January 2015 were obtained from medical records. Patients underwent a diagnostic thoracocentesis as part of their evaluation. They were grouped according to final diagnosis at discharge and clinical judgment of the attending physician. RESULTS: Serum BNP levels were significantly higher in the CHF patients compared to patients with non-cardiac causes of pleural effusion (1519.2 and 314.1 respectively, P < 0.0001). Mean pleural fluid BNP was also significantly higher in the CHF patients (1063.2 vs. 208.3, P < 0.0001). Optional cutoff points to distinguish between cardiac and non-cardiac etiology of pleural effusion were 273.4 pg/ml (sensitivity 83.3%, specificity 72.3%, accuracy 76.7%) or 400 pg/ml (sensitivity 78.6%, specificity 86.2%, accuracy 83.0%). A strong correlation was found between serum BNP and pleural fluid BNP levels. CONCLUSIONS: High levels of serum BNP in patients presenting with pleural effusion suggest CHF. In cases with doubt regarding the etiology of pleural effusion, high levels of pleural fluid BNP can support the diagnosis, but are not superior to serum BNP levels.

[THE NATIONAL FINAL INTERNAL MEDICINE EXAMINATION SCORE - IS IT PREDICTABLE?]

INTRODUCTION: There is no current medical licensing examination in Israel (2016). The only objective indicators which reflect students' medical knowledge and basic clinical reasoning skills are the national medical examination scores. The aim of the present study was to investigate the nature of the relationship between students' demography, gender and academic achievements during their pre-clinical studies and their final national internal medicine examination scores. METHODS: The study was based on data collected by the Technion information system. The study cohort consisted of medical students admitted to the Technion Faculty of Medicine over a decade from 2005-2014, via a standard admission procedure. Students accepted on the basis of former academic achievement were not part of this cohort. The cohort was divided into three, based on the level of success in the final national examination in internal medicine. CONCLUSIONS: Our main conclusions were: (1) the admission screening criteria (scores of matriculation and psychometric tests) are helpful markers for predicting success in the final examination in internal medicine; (2) students who performed the psychometric tests in the Arabic language have relatively lower-achieving grades in the final examination in internal medicine in comparison to students taking the same psychometric exam in the Hebrew language. Furthermore, (3) high achievements in core preclinical courses and especially in the "integrative course" in the first 2 trimesters of the fourth year of studies are relatively strong predictors for success in the final examination in internal medicine.

[REDUCTION OF ANTIBIOTIC CONSUMPTION IN RAMBAM HEALTH CARE CAMPUS - THE ROLE OF AN ANTIBIOTIC STEWARDSHIP PROGRAM].

INTRODUCTION: Antibiotic stewardship programs (ASP) are designed to optimize antibiotic use in hospitals. Antibiotic consumption is one of the measures assessing the effects of ASPs. AIMS: To evaluate the effect of an ASP on antibiotic consumption in our hospital and compare it to hospitals in Israel and worldwide. METHODS: Between October 2012 and March 2013 an ASP was implemented in Rambam Hospital. The program included educational activities, publication of local guidelines for empirical antibiotic treatment, structured infectious diseases consultations, pre-authorization antibiotic restrictions and stop orders. We compared antibacterial antibiotic consumption in defined daily doses (DDD)/100 hospital days (HD) between the periods before (1/2010-3/2013) and after (4/2013-9/2014) implementing the ASP. The study was conducted in the medical departments, hematology, the intensive care unit (ICU) and all pediatric wards. RESULTS: Total antibiotic consumption before implementing the ASP was 96±11.2 DDD/100 HD in medical departments, 186.4±42.8 in the ICU and 185.5±59 in hematology; all values were higher than the worldwide-reported averages for these departments. Following the ASP, total antibiotic consumption decreased by 12% (p=0.008) in the medical departments and by 26% (p=0.002) in hematology, mostly due to reductions in non-restricted antibiotics. No significant changes were observed overall in the ICU and in pediatric wards. There was a significant reduction in consumption of vancomycin and carbapenems in all settings, the latter was reduced to nearly half. Amikacin use quadrupled in the medical departments. CONCLUSIONS: Implementation of an ASP lead to a reduction in non-restricted and restricted antibiotic consumption, especially carbapenems.

Early histological findings may predict the clinical phenotype in Crohn's colitis.

BACKGROUND AND AIMS: Predicting the clinical course of Crohn's disease (CD) is relevant for treatment selection. Currently, such diagnostic tools are lacking. In a previous pilot study, morphometric tissue image analysis showed promise in predicting the clinical phenotype and need for surgery. In this study, we aimed to validate our previous results on a larger cohort. METHODS: Colonic biopsies from CD patients with colonic or ileocolonic disease and at least five years of post-biopsy clinical follow-up were analyzed. The results were used to predict post-biopsy clinical phenotypes and outcomes. Data analysis was performed using multivariate regression models, discriminant score (DS) computations and Neural Network (NNET). RESULTS: Multivariate analysis of morphometric variables differentiated between B1 and B2 phenotypes (sensitivity 81%, specificity 74%, accuracy on cross-validation 75%; area under the curve (AUC) of 0.74 (CI 0.6-0.84; NNET model sensitivity 87%, specificity 67% on the testing population)). Differentiation between B1 and B3 phenotypes was also possible (sensitivity 69%, specificity 76%, accuracy 70.5% on cross-validation; AUC 0.78 (CI 0.68-0.89); NNET model sensitivity 78%, specificity 77% on the testing population)). Differentiating between B2 and B3 phenotypes was not possible using morphometric variables. Multivariate analysis predicted surgery (sensitivity 67%, specificity 72.5%, accuracy 69%; AUC 0.72 (CI 0.61-0.82); NNET model sensitivity 80%, specificity 91% on the testing population)). CONCLUSIONS: This study validates previous results and suggests that morphometric image analysis of early biopsies from Crohn's colitis patients may contribute to the prediction of future outcomes such as clinical phenotype and surgery. Prospective validation on larger cohorts is still needed.

Diagnosis and Classification of 17 Diseases from 1404 Subjects via Pattern Analysis of Exhaled Molecules.

We report on an artificially intelligent nanoarray based on molecularly modified gold nanoparticles and a random network of single-walled carbon nanotubes for noninvasive diagnosis and classification of a number of diseases from exhaled breath. The performance of this artificially intelligent nanoarray was clinically assessed on breath samples collected from 1404 subjects having one of 17 different disease conditions included in the study or having no evidence of any disease (healthy controls). Blind experiments showed that 86% accuracy could be achieved with the artificially intelligent nanoarray, allowing both detection and discrimination between the different disease conditions examined. Analysis of the artificially intelligent nanoarray also showed that each disease has its own unique breathprint, and that the presence of one disease would not screen out others. Cluster analysis showed a reasonable classification power of diseases from the same categories. The effect of confounding clinical and environmental factors on the performance of the nanoarray did not significantly alter the obtained results. The diagnosis and classification power of the nanoarray was also validated by an independent analytical technique, i.e., gas chromatography linked with mass spectrometry. This analysis found that 13 exhaled chemical species, called volatile organic compounds, are associated with certain diseases, and the composition of this assembly of volatile organic compounds differs from one disease to another. Overall, these findings could contribute to one of the most important criteria for successful health intervention in the modern era, viz. easy-to-use, inexpensive (affordable), and miniaturized tools that could also be used for personalized screening, diagnosis, and follow-up of a number of diseases, which can clearly be extended by further development.

Guaiac faecal occult blood screening in individuals younger than 50 years of age.

To determine the effectiveness of guaiac faecal occult blood tests (gFOBT) in the early detection of colorectal cancer (CRC) within a population of asymptomatic individuals who attended general periodic examinations, and to suggest the recommended age for this screening tool, the electronic database of the periodic examination institute of Rambam Healthcare Campus for the years 2004-2013 was reviewed. Individuals with positive gFOBT results were interviewed for further workup. Proportions of individuals for whom a polyp or CRC was detected were evaluated according to sex and age. 18 858 individuals were examined during the study period, mean age 48 years. The overall gFOBT uptake was 40.8%. Uptake was significantly higher among men and increased with age. Positive gFOBT was detected in 105 individuals (1.4%). The proportion of positive gFOBT was significantly lower among individuals aged 30-50 years than those older than 50 years of age (1.1 and 1.7%, respectively, P=0.005). No positive gFOBT was detected among individuals younger than 30 years of age. Positive gFOBT was higher in men than in women: 1.8 and 0.9% respectively (P=0.002). CRC was detected in six individuals, including two younger than 50 years of age. Polyps were detected in 15 individuals; of these, four were younger than 50 years of age. In the gFOBT-positive group, proportions of polyps and CRC were the same for subgroups according to age. The findings support consideration of annual gFOBT screening from the age of 40 years.

The association of the MTHFR C677T polymorphism with inflammatory bowel diseases in the Israeli Jewish population: An example of genetic heterogeneity.

MTHFR C677T is a common gene polymorphism that has been shown to be associated with hyperhomocysteinemia. Studies on the role of MTHFR in inflammatory bowel diseases (IBD) have yielded conflicting results, perhaps due in part to genetic heterogeneity. The prevalence of the MTHFR C677T variant allele varies according to Jewish subpopulations: Ashkenazi vs non-Ashkenazi. The aim of this study was to examine the association between MTHFR C677T genotype and IBD in the different Jewish populations.DNA samples were assessed for the presence of the MTHFR C677T variant allele in 445 Jewish Israeli IBD patients: 338 with Crohn's disease [CD] (214 Ashkenazi and 124 non-Ashkenazi Jews) and 107 with ulcerative colitis [UC] (73 Ashkenazi and 34 non-Ashkenazi Jews), and in 347 healthy controls: 173 Ashkenazi and 174 Non-Ashkenazi Jews. Possible genotype-phenotype associations were investigated.We showed a significantly higher frequency of MTHFR 677T variant genotypes in non-Ashkenazi CD patients: Odds ratio of 1.86 for heterozygotes (CT) and 2.89 for homozygotes (TT) compared to non-Ashkenazi healthy controls. No significant association was found for UC in non-Ashkenazi patients or for CD or UC in Ashkenazi patients.Our findings suggest that the MTHFR 677T variant may contribute to the risk of CD in non-Ashkenazi but not Ashkenazi Jews. This may result from genetic heterogeneity and highlights the complexity of the genetic etiology of IBD.

Programmed Nanoparticles for Tailoring the Detection of Inflammatory Bowel Diseases and Irritable Bowel Syndrome Disease via Breathprint.

Chemical sensors based on programmable molecularly modified gold nanoparticles are tailored for the detection and discrimination between the breathprint of irritable bowel syndrome (IBS) and inflammatory bowel diseases (IBD). The sensors are examined in both lab- and real-world clinical conditions. The results reveal a discriminative power accuracy of 81% between IBD and IBS and 75% between Crohn's and Colitis states.

Age-Adjusted Cutoff D-Dimer Level to Rule Out Acute Pulmonary Embolism: A Validation Cohort Study.

BACKGROUND: The diagnosis of pulmonary embolism in the Emergency Room setting is challenging. Multiple patients have to undergo radiologic assessment with its inherent shortcomings. The D-dimer test with accepted cutoff level of 500 µg/L is associated with a high proportion of false-positive results. The present study aimed to validate the advantages of using an age-adjusted D-dimer cutoff level, compared with 500-µg/L value in the diagnosis of acute pulmonary embolism. METHODS: This study evaluated patients admitted to the Rambam Emergency Room between 2011 and 2014 with a suspected diagnosis of pulmonary embolism. Patient data, D-dimer plasma levels, and imaging results were collected. The study cohort was subdivided according to the D-dimer levels below and above 500 µg/L. The group with levels above 500 µg/L was further assessed using the newly suggested age-adjusted D-dimer cutoff level, defined as age multiplied by 10. RESULTS: Files of 1241 patients were reviewed; 654 patients with low or intermediate risk for pulmonary embolism had a D-dimer level above 500 µg/L. Two hundred eight (208) patients had a D-dimer level above 500 µg/L but below the age-adjusted cutoff value; one of them was diagnosed with pulmonary embolism (0.48% [95% confidence interval 0%-2.6%]). Four hundred forty-six (446) patients had a D-dimer level above the age-adjusted cutoff value, and 28 of them were diagnosed with pulmonary embolism (6.28% [95% confidence interval 4.2%-8.9%]), representing a negative predictive value of 99.5% for the age-adjusted cutoff level. CONCLUSIONS: An age-adjusted D-dimer cutoff level may be safely used to exclude pulmonary embolism in patients with a low or intermediate probability for acute pulmonary embolism, alleviating the need to perform unnecessary imaging evaluations.

Rac1 Polymorphisms and Thiopurine Efficacy in Children With Inflammatory Bowel Disease.

OBJECTIVES: Thiopurines are effective for maintenance of remission in inflammatory bowel disease (IBD) in only about half of patients. Predictors of response may assist in selecting the most appropriate patients for thiopurine therapy. Thiopurines inhibit Rac1, a GTPase that exerts an antiapoptotic effect on T-lymphocytes. A genetic association was recently demonstrated between a Rac1 single nucleotide polymorphism (SNP) and poorer response to thiopurines in adult patients with Crohn disease. We aimed to determine whether Rac1 SNPs are associated with response to thiopurines in children with IBD. METHODS: Children with IBD treated with thiopurines were prospectively followed for 1 year and were genotyped for 3 Rac1 SNPs previously found to be relevant to IBD: rs10951982, rs4720672, and rs34932801. The rate of sustained steroid-free remission (SSFR) without treatment escalation by 12 months was compared between wild types (WTs) and heterozygotes. RESULTS: A total of 59 patients were studied (63% boys, 80% having Crohn disease, mean age 13 ±â€Š4.1). Nineteen of the 41 WT (46%) and 9 of the 15 (60%) heterozygotes for rs10951982 were in SSFR (P = 0.55). Similarly, 21 of the 45 (47%) WT and 8 of the 12 (67%) heterozygotes for rs4720672 were in remission (P = 0.33). Finally, 21 of the 45 (47%) WT and 3 of the 5 (60%) heterozygotes for rs34932801 were in remission (P = 0.66). All of the 3 comparisons remained nonsignificant in a sensitivity analysis of only the patients with Crohn disease. CONCLUSIONS: We did not find an association between 3 Rac1 SNPs and thiopurine effectiveness by 12 months in a prospective study of children with IBD. Other predictors of response should be sought to optimize patient selection for thiopurine therapy.

HLA-DQA1-HLA-DRB1 variants confer susceptibility to pancreatitis induced by thiopurine immunosuppressants.

Pancreatitis occurs in approximately 4% of patients treated with the thiopurines azathioprine or mercaptopurine. Its development is unpredictable and almost always leads to drug withdrawal. We identified patients with inflammatory bowel disease (IBD) who had developed pancreatitis within 3 months of starting these drugs from 168 sites around the world. After detailed case adjudication, we performed a genome-wide association study on 172 cases and 2,035 controls with IBD. We identified strong evidence of association within the class II HLA region, with the most significant association identified at rs2647087 (odds ratio 2.59, 95% confidence interval 2.07-3.26, P = 2 × 10(-16)). We replicated these findings in an independent set of 78 cases and 472 controls with IBD matched for drug exposure. Fine mapping of the HLA region identified association with the HLA-DQA1*02:01-HLA-DRB1*07:01 haplotype. Patients heterozygous at rs2647087 have a 9% risk of developing pancreatitis after administration of a thiopurine, whereas homozygotes have a 17% risk.