Tomer Ziv-Baran

Oral, Capsulized, Frozen Fecal Microbiota Transplantation for Relapsing Clostridium difficile Infection

IMPORTANCE Fecal microbiota transplantation (FMT) has been shown to be effective in treating relapsing or refractory Clostridium difficile infection, but practical barriers and safety concerns have prevented its widespread use. OBJECTIVE To evaluate the safety and rate of resolution of diarrhea following administration of frozen FMT capsules from prescreened unrelated donors to patients with recurrent C. difficile infection. DESIGN, SETTING, AND PARTICIPANTS Open-label, single-group, preliminary feasibility study conducted from August 2013 through June 2014 at Massachusetts General Hospital, Boston. Twenty patients (median age, 64.5 years; range, 11-89 years) with at least 3 episodes of mild to moderate C. difficile infection and failure of a 6- to 8-week taper with vancomycin or at least 2 episodes of severe C. difficile infection requiring hospitalization were enrolled. INTERVENTIONS Healthy volunteers were screened as potential donors and FMT capsules were generated and stored at -80°C (-112°F). Patients received 15 capsules on 2 consecutive days and were followed up for symptom resolution and adverse events for up to 6 months. MAIN OUTCOMES AND MEASURES The primary end points were safety, assessed by adverse events of grade 2 or above, and clinical resolution of diarrhea with no relapse at 8 weeks. Secondary end points included improvement in subjective well-being per standardized questionnaires and daily number of bowel movements. RESULTS No serious adverse events attributed to FMT were observed. Resolution of diarrhea was achieved in 14 patients (70%; 95% CI, 47%-85%) after a single capsule-based FMT. All 6 nonresponders were re-treated; 4 had resolution of diarrhea, resulting in an overall 90% (95% CI, 68%-98%) rate of clinical resolution of diarrhea (18/20). Daily number of bowel movements decreased from a median of 5 (interquartile range [IQR], 3-6) the day prior to administration to 2 (IQR, 1-3) at day 3 (P = .001) and 1 (IQR, 1-2) at 8 weeks (P < .001). Self-ranked health scores improved significantly on a scale of 1 to 10 from a median of 5 (IQR, 5-7) for overall health and 4.5 (IQR, 3-7) for gastrointestinal-specific health on the day prior to FMT to 8 (IQR, 7-9) after FMT administration for both overall and gastrointestinal health (P = .001). Patients needing a second treatment to obtain resolution of diarrhea had lower pretreatment health scores (median, 6.5 [IQR, 5-7.3] vs 5 [IQR, 2.8-5]; P = .02). CONCLUSIONS AND RELEVANCE This preliminary study among patients with relapsing C. difficile infection provides data on adverse events and rates of resolution of diarrhea following administration of FMT using frozen encapsulated inoculum from unrelated donors. Larger studies are needed to confirm these results and to evaluate long-term safety and effectiveness. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT01914731.

The Burden of Cryptosporidium Diarrheal Disease among Children < 24 Months of Age in Moderate/High Mortality Regions of Sub-Saharan Africa and South Asia, Utilizing Data from the Global Enteric Multicenter Study (GEMS)

Background The importance of Cryptosporidium as a pediatric enteropathogen in developing countries is recognized. Methods Data from the Global Enteric Multicenter Study (GEMS), a 3-year, 7-site, case-control study of moderate-to-severe diarrhea (MSD) and GEMS-1A (1-year study of MSD and less-severe diarrhea [LSD]) were analyzed. Stools from 12,110 MSD and 3,174 LSD cases among children aged <60 months and from 21,527 randomly-selected controls matched by age, sex and community were immunoassay-tested for Cryptosporidium. Species of a subset of Cryptosporidium-positive specimens were identified by PCR; GP60 sequencing identified anthroponotic C. parvum. Combined annual Cryptosporidium-attributable diarrhea incidences among children aged <24 months for African and Asian GEMS sites were extrapolated to sub-Saharan Africa and South Asian regions to estimate region-wide MSD and LSD burdens. Attributable and excess mortality due to Cryptosporidium diarrhea were estimated. Findings Cryptosporidium was significantly associated with MSD and LSD below age 24 months. Among Cryptosporidium-positive MSD cases, C. hominis was detected in 77.8% (95% CI, 73.0%-81.9%) and C. parvum in 9.9% (95% CI, 7.1%-13.6%); 92% of C. parvum tested were anthroponotic genotypes. Annual Cryptosporidium-attributable MSD incidence was 3.48 (95% CI, 2.27–4.67) and 3.18 (95% CI, 1.85–4.52) per 100 child-years in African and Asian infants, respectively, and 1.41 (95% CI, 0.73–2.08) and 1.36 (95% CI, 0.66–2.05) per 100 child-years in toddlers. Corresponding Cryptosporidium-attributable LSD incidences per 100 child-years were 2.52 (95% CI, 0.33–5.01) and 4.88 (95% CI, 0.82–8.92) in infants and 4.04 (95% CI, 0.56–7.51) and 4.71 (95% CI, 0.24–9.18) in toddlers. We estimate 2.9 and 4.7 million Cryptosporidium-attributable cases annually in children aged <24 months in the sub-Saharan Africa and India/Pakistan/Bangladesh/Nepal/Afghanistan regions, respectively, and ~202,000 Cryptosporidium-attributable deaths (regions combined). ~59,000 excess deaths occurred among Cryptosporidium-attributable diarrhea cases over expected if cases had been Cryptosporidium-negative. Conclusions The enormous African/Asian Cryptosporidium disease burden warrants investments to develop vaccines, diagnostics and therapies.

CYP2D6 genotyping in paediatric patients with autism treated with risperidone: a preliminary cohort study

To evaluate the association between cytochrome P450 2D6 (CYP2D6) phenotypes in paediatric patients with autistic spectrum disorders (ASD) treated with risperidone, adverse drug reactions (ADRs), and drug efficacy.

Red blood cell distribution width (RDW) and long-term survival in patients with ST elevation myocardial infarction.

INTRODUCTION High RDW values are associated with adverse prognosis in many clinical conditions including short and medium term outcome of patients with ST Elevation Myocardial Infarction (STEMI). The aim of the present study was to evaluate the association between RDW and long term mortality in STEMI patients undergoing primary angioplasty (PPCI). MATERIAL AND METHODS A cohort of 535 STEMI patients undergoing PPCI were divided into two groups (RDW > 14%, RDW ≤ 14%) using CHAID and CART methods. The association between RDW and 5-year all-cause mortality was assessed using Coxs proportional hazards analysis. RESULTS A total of 37 patients died during follow up of 5 years (mean: 1059, median: 1013, range 2-2130 days). RDW > 14% was associated with increased risk of all-cause mortality (HR = 5, CI 95% 2.7- 9.9, p < 0.001). In multivariate analysis, RDW > 14 remained significantly associated with increased risk for all-cause mortality (HR = 3.8, CI 95% 1.8- 7.99, p < 0.001). Patients with RDW above 14% did not have lower ejection fraction, higher CPK or more conventional risk factors. CONCLUSION RDW value above 14 is independently associated with increased long term all-cause mortality in patients with STEMI undergoing PPCI.

Antibiotic Use in Children - A Cross-National Analysis of 6 Countries.

Objectives To describe the rates of pediatric antibiotic use across 6 countries on 3 continents. Study design Cross‐national analysis of 7 pediatric cohorts in 6 countries (Germany, Italy, South Korea, Norway, Spain, and the US) was performed for 2008‐2012. Antibiotic dispensings were identified and grouped into subclasses. We calculated the rates of antimicrobial prescriptions per person‐year specific to each age group, comparing the rates across different countries. Results A total of 74 744 302 person‐years from all participating centers were included in this analysis. Infants in South Korea had the highest rate of antimicrobial consumption, with 3.41 prescribed courses per child‐year during the first 2 years of life. This compares with 1.6 in Lazio, Italy; 1.4 in Pedianet, Italy; 1.5 in Spain; 1.1 in the US; 1.0 in Germany; and 0.5 courses per child‐year in Norway. Of antimicrobial prescriptions written in Norway, 64.8% were for first‐line penicillins, compared with 38.2% in Germany, 31.8% in the US, 27.7% in Spain, 25.1% in the Italian Pedianet population, 9.8% in South Korea, and 8% in the Italian Lazio population. Conclusions We found substantial differences of up to 7.5‐fold in pediatric antimicrobial use across several industrialized countries from Europe, Asia, and North America. These data reinforce the need to develop strategies to decrease the unnecessary use of antimicrobial agents.

Prediction of Mortality in Pulmonary Embolism Based on Left Atrial Volume Measured on CT Pulmonary Angiography

BACKGROUND Preliminary reports suggest that a small left atrium (LA) is associated with severe acute pulmonary embolism (PE). This study used data derived from volumetric analyses of computed tomographic pulmonary angiography (CTPA) to investigate whether a reduced LA volume can predict adverse outcome in a large series of patients with acute PE. METHODS We retrospectively analyzed 756 consecutive patients who received a diagnosis of acute PE by nongated CTPA between January 2007 and December 2010. Each CTPA was investigated with volumetric analysis software that automatically provides the volumes of the LA, right atrium, right ventricle, and left ventricle. A classification tree divided the cardiac chamber volumes and ratios into categories according to mortality. Cox regression assessed the association between these categories and 30-day mortality after adjustment for age, sex, and clinical background. RESULTS The final study group consisted of 636 patients who had successful volumetric segmentation and complete outcome data. Eighty-four patients (13.2%) died within 30 days of PE diagnosis. There was a higher mortality rate among patients with an LA volume ≤62 mL compared with those with an LA volume >62 mL (19.6% vs 8.9%, respectively; HR, 2.44; P < .001), a left ventricle volume ≤67 mL (16.4% vs 8.3%; HR, 1.8; P = .024) and a right atrium/LA volume ratio >1.2 (17% vs 9.4%; HR, 2.1; P = .002). A reduced LA volume was the best predictor of adverse outcome. CONCLUSIONS Decreased LA volume is associated with higher mortality and is the first among the various cardiac compartments to predict mortality in patients with acute PE.

Pulmonary Hypertension: A Nomogram Based on CT Pulmonary Angiographic Data for Prediction in Patients without Pulmonary Embolism

PURPOSE To use cardiovascular data from computerized tomographic (CT) pulmonary angiography for facilitating the identification of pulmonary hypertension (PH) in patients without acute pulmonary embolism. MATERIALS AND METHODS The institutional human research committee approved this retrospective study; informed consent was waived. Patients without pulmonary embolism who underwent CT pulmonary angiography and echocardiography within 24 hours of each other between December 2008 and October 2012 were retrospectively identified. The diameters of the pulmonary artery, aorta, and right and left ventricles and the severity of reflux of contrast material were assessed. The volumes of each cardiac compartment were calculated. Doppler echocardiography served as a reference standard for PH. A prediction model for PH was built by using backward logistic regression and was presented on a nomogram. The prediction model was evaluated with 10-fold cross-validation, and a test group of patients was studied between November 2012 and June 2014. RESULTS The final study group included 182 patients, of whom 98 (54%) were given a diagnosis of PH on the basis echocardiographic results. Age of 67 years or older (odds ratio [OR] = 4.46), reflux grade of 3 or higher (OR = 2.63), right atrial volume of greater than or equal to 106 cm(3) (OR = 3.59), pulmonary artery diameter greater than or equal to 28 mm (OR = 2.52) and pulmonary artery diameter to aorta diameter ratio of greater than or equal to 0.86 (OR = 2.17) were independently associated with PH. The logistic model showed good discrimination ability (area under the curve = 0.844, discrimination slope = 0.359). Tenfold cross-validation showed 85.7% sensitivity, 60.7% specificity, 71.3% positive predictive value, and 76.1% negative predictive value for identification of PH, while the test group showed similar results (84.1%, 60.5%, 71.2%, and 76.7%, respectively). CONCLUSION Cardiovascular data derived from CT pulmonary angiography are associated with PH, and a nomogram can be created that may facilitate identification of PH after exclusion of acute pulmonary embolism.

Change in incidence of clinic visits for all-cause and rotavirus gastroenteritis in young children following the introduction of universal rotavirus vaccination in Israel.

Both rotavirus vaccines RotaTeq and Rotarix were efficacious against severe rotavirus gastroenteritis in clinical trials; yet real-world data on the effect of rotavirus vaccines on mild to moderate disease are limited. We used a large computerised database of Maccabi Health Services Health Maintenance Organisation (HMO), the second largest HMO in Israel covering 25% of the Israeli population, to compare the incidence of acute gastroenteritis (AGE) clinic visits in community settings (n=302,445) before (2005-10) and after (2011-13) the introduction of universal rotavirus immunisation in Israel. We retrieved laboratory results of rotavirus antigen tests (n=18,133) and using a weighted analysis, we estimated the impact of rotavirus immunisation on the disease burden of rotavirus AGE clinic visits. Following the introduction of universal rotavirus immunisation, the typical winter peaks of rotavirus AGE were substantially lower and significant reductions of 14.8% (95% confidence interval (CI): 13.5-16.1) in all-cause AGE clinic visits and of 59.7% (95% CI: 59.8-62.6) in rotavirus AGE clinic visits were observed. The decrease was observed in all age groups, but it was greater in children aged 0 to 23 months than those aged 24 to 59 months. Continued rotavirus laboratory surveillance is warranted to monitor the sustainability of these changes.

Outcomes of different protocols of pelvic floor physical therapy and anti-cholinergics in women with wet over-active bladder: A 4-year follow-up.

We investigated the 4‐year outcomes of three protocols of pelvic floor physical therapy and anticholinergic drug in women with wet over‐active bladder (OAB).

Prognostic implications of fluid balance in ST elevation myocardial infarction complicated by cardiogenic shock

Background: Positive fluid balance has been associated with adverse outcomes in patients admitted to general intensive care units. We analysed the relationship between a positive fluid balance and its persistence over time in terms of in-hospital outcomes among ST elevation myocardial infarction (STEMI) patients complicated by cardiogenic shock. Methods: We retrospectively studied fluid intake and output for 96 hours following hospital admission in 48 consecutive adult patients with STEMI complicated by cardiogenic shock, all undergoing primary angioplasty. Daily and accumulated fluid balance was registered at up to 96 hours following admission. The cohort was stratified into two groups based on the presence or absence of positive fluid balance on day 4. Patients’ records were assessed for in-hospital adverse outcomes, as well as 30-day all-cause mortality. Results: A positive fluid balance was present in 19/48 patients (40%). Patients with positive fluid balance were older and more likely to be treated by intra-aortic balloon counter-pulsation and antibiotics. These patients were more likely to develop acute kidney injury and to need new intubation and were less likely to have renal function recovery as well as successful weaning from mechanical ventilation (p < 0.05 for all). Patients with positive fluid balance had higher 30-day mortality (68% vs. 10%; p < 0.001). In a multivariate Cox regression model, for every 1-L increase in positive fluid balance, the adjusted risk for 30-day mortality increased by 24% (hazard ratio: 1.24, 95% confidence interval: 1.07–1.42; p = 0.003). Conclusions: A positive fluid balance was strongly associated with higher 30-day mortality in STEMI complicated by cardiogenic shock.