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Segel R.,Medical Genetics Institute | Ben-Pazi H.,Neuropediatric Unit | Zeligson S.,Medical Genetics Institute | Fatal-Valevski A.,Dana Childrens Hospital | And 9 more authors.
Neurology | Year: 2015

Objective: To determine the prevalence and characteristics of copy number variations (CNVs) in children with cerebral palsy (CP) of unknown etiology, comprising approximately 20% of the CP population. Methods: Fifty-two participants (age 10.5 ± 7.8 years; Gross Motor Function Classification System scale 2.8 ± 1.3) with nonprogressive pyramidal and/or extrapyramidal signs since infancy and no identified etiology were enrolled. Individuals with evidence of acquired causes were excluded. Participants underwent neurologic and clinical genetic examinations before the genomic testing. Chromosomal microarray analysis to detect CNVs was performed using the Affymetrix platform. CNVs identified were classified as pathogenic, likely pathogenic, likely benign, or benign. Only pathogenic and likely pathogenic CNVs were defined as clinically significant. Results: Thirty-nine CNVs were found in 25 of 52 participants (48%). Sixteen participants (31%) had clinically significant CNVs: 10 pathogenic and 6 likely pathogenic, of which 7 were not previously associated with motor disability. Nine participants had likely benign CNVs. Clinically significant CNVs were more frequently de novo (12/16; p < 0.001) including in 5 of 8 individuals who had a first- or second-degree relative with a major neurologic disorder. Dysmorphic features and nonmotor comorbidities were more prevalent in individuals with clinically significant CNVs (p < 0.05 for both). Conclusion: CNVs, most frequently de novo, are common in individuals with cryptogenic CP. We recommend CNV testing in individuals with CP of unknown etiology. © 2015 American Academy of Neurology.


Levkovitz Y.,Tel Aviv University | Isserles M.,Hebrew University of Jerusalem | Padberg F.,Ludwig Maximilians University of Munich | Lisanby S.H.,Duke University | And 21 more authors.
World Psychiatry | Year: 2015

Major depressive disorder (MDD) is a prevalent and disabling condition, and many patients do not respond to available treatments. Deep transcranial magnetic stimulation (dTMS) is a new technology allowing non-surgical stimulation of relatively deep brain areas. This is the first double-blind randomized controlled multicenter study evaluating the efficacy and safety of dTMS in MDD. We recruited 212 MDD outpatients, aged 22-68 years, who had either failed one to four antidepressant trials or not tolerated at least two antidepressant treatments during the current episode. They were randomly assigned to monotherapy with active or sham dTMS. Twenty sessions of dTMS (18 Hz over the prefrontal cortex) were applied during 4 weeks acutely, and then biweekly for 12 weeks. Primary and secondary efficacy endpoints were the change in the Hamilton Depression Rating Scale (HDRS-21) score and response/remission rates at week 5, respectively. dTMS induced a 6.39 point improvement in HDRS-21 scores, while a 3.28 point improvement was observed in the sham group (p=0.008), resulting in a 0.76 effect size. Response and remission rates were higher in the dTMS than in the sham group (response: 38.4 vs. 21.4%, p=0.013; remission: 32.6 vs. 14.6%, p=0.005). These differences between active and sham treatment were stable during the 12-week maintenance phase. dTMS was associated with few and minor side effects apart from one seizure in a patient where a protocol violation occurred. These results suggest that dTMS constitutes a novel intervention in MDD, which is efficacious and safe in patients not responding to antidepressant medications, and whose effect remains stable over 3 months of maintenance treatment. © 2015 World Psychiatric Association.


Smith S.W.,Hennepin County Medical Center | Smith S.W.,University of Minnesota | Dodd K.W.,Hennepin County Medical Center | Henry T.D.,Abbott Laboratories | And 2 more authors.
Annals of Emergency Medicine | Year: 2012

Study objective: Sgarbossa's rule, proposed for the diagnosis of acute myocardial infarction in the presence of left bundle branch block, has had suboptimal diagnostic utility. We hypothesize that a revised rule, in which the third Sgarbossa component (excessively discordant ST-segment elevation as defined by <5 mm of ST-segment elevation in the setting of a negative QRS) is replaced by one defined proportionally by ST-segment elevation to S-wave depth (ST/S ratio), will have better diagnostic utility for ST-segment elevation myocardial infarction (STEMI) equivalent, using documented coronary occlusion on angiography as reference standard. Methods: We collected admission ECGs for all patients with an acutely occluded coronary artery and left bundle branch block at 3 institutions. The ECGs of emergency department patients with chest pain or dyspnea and left bundle branch block, but without coronary occlusion, were used as controls. The R or S wave, whichever was most prominent, and ST segments, relative to the PR segment, were measured to the nearest 0.5 mm. The ST/S ratio was calculated for each lead that has both discordant ST deviation of greater than or equal to 1 mm and an R or S wave of opposite polarity; others were set to 0. The cut point for the most negative ST/S ratio with at least 90% specificity was determined. The revised rule is unweighted, requiring just 1 of 3 criteria. Diagnostic utilities of the original and revised Sgarbossa rules were computed and compared. McNemar's test was used to compare sensitivities and specificities. Results: The study and control groups included 33 and 129 ECGs, respectively. The cut point selected for relative discordant ST-segment elevation was -0.25. Excessive absolute discordant ST-segment elevation of 5 mm was present in at least one lead in 30% of ECGs in patients with confirmed coronary occlusion versus 9% of the control group, whereas excessive relative discordant ST-segment elevation less than -0.25 was present in 58% versus 8%. Sensitivity of the revised rule in which ST-segment elevation with an ST/S ratio less than or equal to -0.25 replaces ST-segment elevation greater than or equal to 5 mm was significantly greater than either the weighted (P<.001) or unweighted (P=.008) Sgarbossa rule: 91% (95% confidence interval [CI] 76% to 98%) versus 52% (95% CI 34% to 69%) versus 67% (95% CI 48% to 82%). Specificity of the revised rule was lower than that of the weighted rule (P=.002) and similar to that of the unweighted rule (P=1.0): 90% (95% CI 83% to 95%) versus 98% (95% CI 93% to 100%) versus 90% (95% CI 83% to 95%). Positive and negative likelihood ratios for the revised rule were 9.0 (95% CI 8.0 to 10) and 0.1 (95% CI 0.03 to 0.3). The revised rule was significantly more accurate than both the weighted (16% difference; 95% CI 5% to 27%) and unweighted (12% difference; 95% CI 2% to 22%) Sgarbossa rules. Conclusion: Replacement of the absolute ST-elevation measurement of greater than or equal to 5 mm in the third component of the Sgarbossa rule with an ST/S ratio less than -0.25 greatly improves diagnostic utility of the rule for STEMI. An unweighted rule using this criterion resulted in excellent prediction for acute coronary occlusion. Copyright © 2012 by the American College of Emergency Physicians.


Kapusta L.,Radboud University Nijmegen | Kapusta L.,Pediatric Cardiology Unit | Mainzer G.,Rambam Medical Center | Weiner Z.,Rambam Medical Center | And 4 more authors.
Journal of the American Society of Echocardiography | Year: 2013

Background The aim of this study was to detect normal changes in fetal two-dimensional speckle-tracking echocardiography-derived values for global and regional longitudinal left and right ventricular strain, strain rate, and time to peak (T2P) global strain during pregnancy. Methods Forty-four healthy fetuses were examined prospectively during the second-trimester and third-trimester ultrasound examinations (20-24 and 30-34 weeks, respectively). Clips with high frame rates (mean, 120 frames/sec) of two-dimensional (B-mode) grayscale images of apical or basal four-chamber views of both ventricles were used for offline analyses of global and regional walls and segments (basal, mid, and apical) of myocardial strain and strain rate as well as T2P global strain in the longitudinal direction. Results There were statistically significant decreases in global and regional strain of the right ventricle between the second and third trimesters. No statistically significant changes were observed in global and regional strain of the left ventricle. Global and regional strain rates of both ventricles decreased in a similar way during pregnancy. The mean T2P longitudinal left ventricular global strain (adjusted for heart rate) increased mildly during fetal life. Whereas T2P longitudinal strain of the left ventricle at 20 to 24 weeks was statistically significantly shorter than that of the right ventricle, no difference in T2P longitudinal strain was found at 30 to 34 weeks of gestation between both ventricles. Conclusions The establishment of these changes between the second-trimester and third-trimester two-dimensional speckle-tracking echocardiography-derived reference values is a mandatory prerequisite for its use in evaluating (pathologic) changes in both ventricular functions during pregnancy. © 2013 by the American Society of Echocardiography.


Kapusta L.,Radboud University Nijmegen | Kapusta L.,Pediatric Cardiology Unit | Mainzer G.,Rambam Medical Center | Weiner Z.,Rambam Medical Center | And 4 more authors.
Journal of the American Society of Echocardiography | Year: 2012

Background: Data on myocardial deformation during the internationally widely used second-trimester screening are scarce and confusing. Reference values of time to peak strain are missing. The aims of this study were to assess reference values derived from two-dimensional speckle-tracking echocardiography for global and regional longitudinal right ventricular (RV) and left ventricular (LV) strain, strain rate, and time to peak global strain and to determine the influence of heart rate and gender on these strain parameters. Methods: Seventy-five healthy fetuses were enrolled during second-trimester ultrasound (20-24 weeks). Clips with high frame rates (mean, 132 frames/sec) and two-dimensional (B-mode) grayscale images of apical or basal four-chamber views of both ventricles were used for offline analyses. Results: There were no statistically significant differences in global strain and strain rate between both ventricles (P =.679 and P =.734, respectively) or among the RV, septal, and LV free walls. Regional measurements, modeled also as an interaction of wall and segment (basal mid and apical), showed only a small, statistically significant difference between the basal RV and LV free walls. Strain and strain rate values were independent of heart rate. The mean time to peak LV global strain adjusted for heart rate was statistically significantly shorter than the RV value (P <.0001]). Strain, strain rate, and time to peak global strain were not found to be associated with gender. Conclusions: The establishment of second-trimester two-dimensional speckle-tracking echocardiographic reference values for global and regional strain, strain rate, and time to peak global strain in a healthy fetal cohort is a mandatory prerequisite for its use in evaluating (pathologic) changes in both ventricular functions during pregnancy. Copyright 2012 by the American Society of Echocardiography.


Weiniger C.F.,Hebrew University of Jerusalem | Einav S.,Shaare Zedek Medical Center | Deutsch L.,Biostatistical Consulting | Ginosar Y.,Hebrew University of Jerusalem | And 2 more authors.
International Journal of Obstetric Anesthesia | Year: 2013

Background Accurate diagnosis of placenta accreta is tentative before surgery. This study developed a predictive score for antenatal diagnosis of placenta accreta through mathematical modeling using clinical signs. Methods Antenatal cases of suspected placenta accreta were collected prospectively in a single-site tertiary delivery center. Women with clinical signs of placenta accreta (placenta previa, number of previous cesarean deliveries and/or ultrasound suspicion of placenta accreta) were included. The diagnosis of accreta was confirmed surgically. The primary endpoint was the proportion of surgically-diagnosed placenta accreta among all suspected cases. Logistic regression modeling was performed to assess preoperative risk factors for placenta accreta. The risk score was tested on a receiver operator characteristic curve to identify subjects with placenta accreta and the optimum cut-point was chosen. Results Over nine years, 92 suspected accreta cases were identified from 46 623 deliveries (0.2%). The diagnosis was confirmed at surgery in 52/92 cases (56%) and there were no maternal deaths. Blood transfusion requirements were greater in patients with placenta accreta versus patients without placenta accreta (median 7 [range 0-25, interquartile range 3-10] versus 0 [0-6, 0-2] units of blood, P <0.0001). Area under the curve of the receiver operator characteristic curve was 0.846, with contribution from three variables (placenta previa, number of previous cesarean deliveries and ultrasound suspicion), each with a P value <0.05. From the ROC curve a cut-point with 100% sensitivity and specificity 25% (95% CI 12.69%-41.20%) was achieved, compared with 86.6% sensitivity (95% CI 74.21%-94.41%) and 60.0% specificity (95% CI 43.33%-75.14%) using ultrasound alone. Conclusions Combining diagnostic features associated with placenta accreta through mathematical modeling has better positive predictive value than ultrasound alone. © 2013 Elsevier Ltd. All rights reserved.


Apple F.S.,University of Minnesota | Smith S.W.,University of Minnesota | Pearce L.A.,Biostatistical Consulting | Murakami M.M.,University of Minnesota
Clinical Biochemistry | Year: 2012

Objectives: We determined diagnostic accuracy and risk stratification using delta changes for the cardiac troponin I (cTnI) Centaur Ultra assay for ruling out acute myocardial infarction (AMI) and for risk prediction of adverse events in patients with symptoms of acute coronary syndrome. Design and methods: cTnI was measured on admission and 6-24. h in 371 patients. Optimal deltas (percent change, absolute value of percent change, change, absolute value of change) were determined from ROC curve analysis. Risk stratification was performed for cardiac events and death within 60. days. Results: AMI during hospitalization occurred in 49 patients and endpoints in 11 patients. Diagnostic accuracy by ROC curve was optimal (0.96) using the absolute value of change delta. Diagnostic specificities utilizing the 99th percentile (40. ng/L) for admission and follow-up samples were 84% and 81%, compared to: [90% percent change delta] 89.7%; [66.7% absolute value of percent change delta] 85.5%, [217. ng/L change delta] 99.0% and [55. ng/L absolute value of change delta] 93.7%. All four delta values showed substantially greater risk when the initial cTn value was normal. Conclusions: Utilizing delta cTnI values improves clinical specificity, diagnostic accuracy and risk assessment in patients presenting with symptoms of ACS. © 2012 The Canadian Society of Clinical Chemists.


Apple F.S.,University of Minnesota | Apple F.S.,Hennepin County Medical Center | Steffen L.M.,University of Minnesota | Pearce L.A.,Biostatistical Consulting | And 2 more authors.
Clinical Chemistry | Year: 2012

BACKGROUND: We examined several novel biomarkers of different pathophysiologic pathways as predictors of cardiovascular mortality in participants enrolled in the Minnesota Heart Survey (MHS), a population-based study of cardiovascular disease (CVD) risk factors. METHODS: In a nested case-control study within MHS, 7 biomarkers were assayed in serum samples from 211 patients identified after 8-15 years of follow-up who died of cardiovascular causes (cardiovascular heart disease, stroke, congestive heart failure) and 253 controls matched on age, sex, and study year. Logistic regression analysis, adjusted for age, race, sex, education, study year, smoking, abdominal obesity, diabetes, serum total cholesterol, systolic blood pressure, previous hospitalization for a CVD event, and other significant biomarkers, was used to evaluate the relations of biomarkers relative to the odds of CVD mortality. RESULTS: Cases survived a median of 7.2 years after enrollment. Increased N-Terminal pro-B type natriuretic peptide (NT-proBNP) (19% vs 4.3%), increased highsensitivity C-reactive protein (hs-CRP) (71% vs 51%), and increased high-sensitivity cardiac troponin I (hscTnI) (8.7% vs 1.0%) were more common among cases than among controls (all P<0.001 in unadjusted analyses). The adjusted odds of death were greater among cases compared to controls for increased NT-proBNP [odds ratio (OR) 5.67, 95% CI 2.17-15], hs-CRP (OR 1.73, 95% CI 1.03-2.89), and hs-cTnI (OR 8.53, 95% CI 1.68-43), and decreased ST2 (OR 1.92, 95% CI 1.05-3.48). CONCLUSIONS: When measured by an hs-cTnI assay, cTnI is a key biomarker associated with increased cardiovascular death in a community sample when evaluated in a multiple biomarker analysis. © 2012 American Association for Clinical Chemistry.


Apple F.S.,University of Minnesota | Smith S.W.,University of Minnesota | Pearce L.A.,Biostatistical Consulting | Schulz K.M.,University of Minnesota | And 2 more authors.
Clinical Chemistry | Year: 2011

BACKGROUND: We assessed the ability of myeloperoxidase (MPO) to identify the risk for major adverse cardiac events (MACE) in patients who present with ischemic symptoms suggestive of acute coronary syndrome and have a normal cardiac troponin I (cTnI) value. METHODS: We used Siemens (n = 400) and Abbott (n = 350) assays to measure MPO and cTnI in plasma samples from 400 patients. Event rates (myocardial infarction, cardiac death, percutaneous coronary intervention, coronary artery bypass grafting) were estimated by the Kaplan-Meier method and compared with the log-rank statistic. RESULTS: At the 30-day follow-up, the adjusted hazard ratios for MACE were 3.9 (P < 0.001) for increased cTnI and 2.7 (P = 0.006) for increased MPO for the Siemens assays and were 5.5 (P < 0.001) for increased cTnI and 2.9 (P = 0.001) for increased MPO for the Abbott assays. Similar findings were observed with 6 months of follow-up. Patients who initially had a normal cTnI value and an increased Siemens MPO value demonstrated a higher rate of MACE at 30 days than those in whom both values were normal (16.1% vs 3.6%, P = 0.002) and 6 months (18.1% vs 5.0%, P = 0.002). Similarly, patients who had an increased Abbott MPO result demonstrated a higher MACE rate at 30 days (12.3% vs 3.9%, P = 0.03) and at 6 months (16.2% vs 5.1%, P = 0.01) than those with normal values. CONCLUSIONS: A combination of MPO and cTnI allowed the identification of a greater proportion of patients at risk for MACE than the use of cTnI alone. Increased MPO values remained predictive of future cardiac events even when the cTnI value was normal. © 2011 American Association for Clinical Chemistry.


Rabany L.,Tel Aviv University | Rabany L.,Emotion Cognition Research Center | Deutsch L.,Biostatistical Consulting | Levkovitz Y.,Emotion Cognition Research Center
Journal of Psychopharmacology | Year: 2014

Negative symptoms and cognitive deficits are considered core symptoms of schizophrenia, yet treatment for them remains inadequate. Deep-transcranial magnetic stimulation (TMS) is a novel technology that enables non-invasive stimulation of deep layers of the prefrontal cortex. Preliminary evidence suggests that deep-TMS could be effective in the treatment of negative symptoms and cognitive deficits. The current study is the first double-blind, randomized sham-controlled study to examine the feasibility of deep-TMS add-on treatment for negative symptoms and cognitive deficits in schizophrenia. Twenty daily H1 deep-TMS treatments (20Hz, 120% MT) were delivered, in a double-blind, randomized sham-controlled design (n=30). Extensive clinical and cognitive assessments were carried out throughout the study and for an additional one month follow-up period. The results indicate that at the end of the treatment period, negative symptoms (as indicated by the Scale for the Assessment of Negative Symptoms (SANS)) significantly reduced in the TMS group (-7.7), but not in the sham group (-1.9). Differences between the groups were not statistically significant. © The Author(s) 2014.

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