The Jews of Spain and Portugal and the inquisition

by Frederic David Mocatta

Die Juden in Spanien u. Portugal und die Inquisition

von Frederic David Mocatta. Ins Deutsche übertr. von S. Kayserling

Manual Electrode Array Insertion Through a Robot-assisted Minimal Invasive Cochleostomy: Feasibility and Comparison of Two Different Electrode Array Subtypes.

HYPOTHESIS To evaluate the feasibility and the results of insertion of two types of electrode arrays in a robotically assisted surgical approach. BACKGROUND Recent publications demonstrated that robot-assisted surgery allows the implantation of free-fitting electrode arrays through a cochleostomy drilled via a narrow bony tunnel (DCA). We investigated if electrode arrays from different manufacturers could be used with this approach. METHODS Cone-beam CT imaging was performed on fivecadaveric heads after placement of fiducial screws. Relevant anatomical structures were segmented and the DCA trajectory, including the position of the cochleostomy, was defined to target the center of the scala tympani while reducing the risk of lesions to the facial nerve. Med-El Flex 28 and Cochlear CI422 electrodes were implanted on both sides, and their position was verified by cone-beam CT. Finally, temporal bones were dissected to assess the occurrence of damage to anatomical structures during DCA drilling. RESULTS The cochleostomy site was directed in the scala tympani in 9 of 10 cases. The insertion of electrode arrays was successful in 19 of 20 attempts. No facial nerve damage was observed. The average difference between the planned and the postoperative trajectory was 0.17 ± 0.19 mm at the level of the facial nerve. The average depth of insertion was 305.5 ± 55.2 and 243 ± 32.1 degrees with Med-El and Cochlear arrays, respectively. CONCLUSIONS Robot-assisted surgery is a reliable tool to allow cochlear implantation through a cochleostomy. Technical solutions must be developed to improve the electrode array insertion using this approach.

The Importance of Patency in Patients with Critical Limb Ischemia Undergoing Endovascular Revascularization for Infrapopliteal Arterial Disease.

Critical limb ischemia (CLI) represents the most severe form of peripheral arterial disease (PAD) and frequently occurs in medically frail patients. CLI patients frequently exhibit multi-segmental PAD commonly including the tibial arterial segment. Endovascular therapy has been established as first-line revascularization strategy for most CLI patients. Restenosis was reported to occur in up to more than two-thirds of CLI patients undergoing angioplasty of complex tibial arterial obstructions. Nevertheless, favorable clinical outcomes were observed for infrapopliteal angioplasty when compared with bypass surgery, despite higher patency rates for the latter. Based on these observations, infrapopliteal patency was considered to be only of secondary importance upon clinical outcomes in CLI patients. In contrast to these earlier observations, however, recent findings from two randomized clinical trials indicate that infrapopliteal patency does impact on clinical outcomes in CLI patients. The purpose of the present manuscript is to provide a critical reappraisal of the present literature on the clinical importance of tibial arterial patency in CLI patients undergoing endovascular revascularization and to discuss utility and limitations of currently available anti-restenosis technologies.

Association of lectin pathway proteins with intra-abdominal Candida infection in high-risk surgical intensive-care unit patients. A prospective cohort study within the fungal infection network of Switzerland

OBJECTIVES Human studies on the role of mannose-binding lectin (MBL) in patients with invasive candidiasis have yielded conflicting results. We investigated the influence of MBL and other lectin pathway proteins on Candida colonization and intra-abdominal candidiasis (IAC) in a cohort of high-risk patients. METHODS Prospective observational cohort study of 89 high-risk intensive-care unit (ICU) patients. Levels of lectin pathway proteins at study entry and six MBL2 single-nucleotide polymorphisms were analyzed by sandwich-type immunoassays and genotyping, respectively, and correlated with development of heavy Candida colonization (corrected colonization index (CCI) ≥0.4) and occurrence of IAC during a 4-week period. RESULTS Within 4 weeks after inclusion a CCI ≥0.4 and IAC was observed in 47% and 38% of patients respectively. Neither serum levels of MBL, ficolin-1, -2, -3, MASP-2 or collectin liver 1 nor MBL2 genotypes were associated with a CCI ≥0.4. Similarly, none of the analyzed proteins was found to be associated with IAC with the exception of lower MBL levels (HR 0.74, p = 0.02) at study entry. However, there was no association of MBL deficiency (<0.5 μg/ml), MBL2 haplo- or genotypes with IAC. CONCLUSION Lectin pathway protein levels and MBL2 genotype investigated in this study were not associated with heavy Candida colonization or IAC in a cohort of high-risk ICU patients.

Prognostic and diagnostic value of EEG signal coupling measures in coma.

OBJECTIVE Our aim was to assess the diagnostic and predictive value of several quantitative EEG (qEEG) analysis methods in comatose patients. METHODS In 79 patients, coupling between EEG signals on the left-right (inter-hemispheric) axis and on the anterior-posterior (intra-hemispheric) axis was measured with four synchronization measures: relative delta power asymmetry, cross-correlation, symbolic mutual information and transfer entropy directionality. Results were compared with etiology of coma and clinical outcome. Using cross-validation, the predictive value of measure combinations was assessed with a Bayes classifier with mixture of Gaussians. RESULTS Five of eight measures showed a statistically significant difference between patients grouped according to outcome; one measure revealed differences in patients grouped according to the etiology. Interestingly, a high level of synchrony between the left and right hemisphere was associated with mortality on intensive care unit, whereas higher synchrony between anterior and posterior brain regions was associated with survival. The combination with the best predictive value reached an area-under the curve of 0.875 (for patients with post anoxic encephalopathy: 0.946). CONCLUSIONS EEG synchronization measures can contribute to clinical assessment, and provide new approaches for understanding the pathophysiology of coma. SIGNIFICANCE Prognostication in coma remains a challenging task. qEEG could improve current multi-modal approaches.

Masked hypertension and cardiac remodeling in middle-aged endurance athletes

OBJECTIVES: Extensive endurance training and arterial hypertension are established risk factors for atrial fibrillation. We aimed to assess the proportion of masked hypertension in endurance athletes and the impact on cardiac remodeling, mechanics, and supraventricular tachycardias (SVT). METHODS: Male participants of a 10-mile race were recruited and included if office blood pressure was normal (<140/90 mmHg). Athletes were stratified into a masked hypertension and normotension group by ambulatory blood pressure. Primary endpoint was diastolic function, expressed as peak early diastolic mitral annulus velocity (E'). Left ventricular global strain, left ventricular mass/volume ratio, left atrial volume index, signal-averaged P-wave duration (SAPWD), and SVT during 24-h Holter monitoring were recorded. RESULTS: From 108 runners recruited, 87 were included in the final analysis. Thirty-three (38%) had masked hypertension. The mean age was 42 +/- 8 years. Groups did not differ with respect to age, body composition, cumulative training hours, and 10-mile race time. Athletes with masked hypertension had a lower E' and a higher left ventricular mass/volume ratio. Left ventricular global strain, left atrial volume index, SAPWD, and SVT showed no significant differences between the groups. In multiple linear regression analysis, masked hypertension was independently associated with E' (beta = -0.270, P = 0.004) and left ventricular mass/volume ratio (beta = 0.206, P = 0.049). Cumulative training hours was the only independent predictor for left atrial volume index (beta = 0.474, P < 0.001) and SAPWD (beta = 0.481, P < 0.001). CONCLUSION: In our study, a relevant proportion of middle-aged athletes had masked hypertension, associated with a lower diastolic function and a higher left ventricular mass/volume ratio, but unrelated to left ventricular systolic function, atrial remodeling, or SVT.

Length of the Mitral Isthmus But Not Anatomical Location of Ablation Line Predicts Bidirectional Mitral Isthmus Block in Patients Undergoing Catheter Ablation of Persistent Atrial Fibrillation: A Randomized Controlled Trial

INTRODUCTION Mitral isthmus (MI) ablation is an effective option in patients undergoing ablation for persistent atrial fibrillation (AF). Achieving bidirectional conduction block across the MI is challenging, and predictors of MI ablation success remain incompletely understood. We sought to determine the impact of anatomical location of the ablation line on the efficacy of MI ablation. METHODS AND RESULTS A total of 40 consecutive patients (87% male; 54 ± 10 years) undergoing stepwise AF ablation were included. MI ablation was performed in sinus rhythm. MI ablation was performed from the left inferior PV to either the posterior (group 1) or the anterolateral (group 2) mitral annulus depending on randomization. The length of the MI line (measured with the 3D mapping system) and the amplitude of the EGMs at 3 positions on the MI were measured in each patient. MI block was achieved in 14/19 (74%) patients in group 1 and 15/21 (71%) patients in group 2 (P = NS). Total MI radiofrequency time (18 ± 7 min vs. 17 ± 8 min; P = NS) was similar between groups. Patients with incomplete MI block had a longer MI length (34 ± 6 mm vs. 24 ± 5 mm; P < 0.001), a higher bipolar voltage along the MI (1.75 ± 0.74 mV vs. 1.05 ± 0.69 mV; P < 0.01), and a longer history of continuous AF (19 ± 17 months vs. 10 ± 10 months; P < 0.05). In multivariate analysis, decreased length of the MI was an independent predictor of successful MI block (OR 1.5; 95% CI 1.1-2.1; P < 0.05). CONCLUSIONS Increased length but not anatomical location of the MI predicts failure to achieve bidirectional MI block during ablation of persistent AF.

Definitions and outcome measures for mucous membrane pemphigoid: recommendations of an international panel of experts

Mucous membrane pemphigoid encompasses a group of autoimmune bullous diseases with a similar phenotype characterized by subepithelial blisters, erosions, and scarring of mucous membranes, skin, or both. Although knowledge about autoimmune bullous disease is increasing, there is often a lack of clear definitions of disease, outcome measures, and therapeutic end points. With clearer definitions and outcome measures, it is possible to directly compare the results and data from various studies using meta-analyses. This consensus statement provides accurate and reproducible definitions for disease extent, activity, outcome measures, end points, and therapeutic response for mucous membrane pemphigoid and proposes a disease extent score, the Mucous Membrane Pemphigoid Disease Area Index.

Promoting palliative care in the community: production of the primary palliative care toolkit by the European Association of Palliative Care Taskforce in primary palliative care

BACKGROUND A multidisciplinary European Association of Palliative Care Taskforce was established to scope the extent of and learn what facilitates and hinders the development of palliative care in the community across Europe. AIM To document the barriers and facilitators for palliative care in the community and to produce a resource toolkit that palliative care specialists, primary care health professionals or policymakers, service developers, educationalists and national groups more generally could use to facilitate the development of palliative care in their own country. DESIGN (1) A survey instrument was sent to general practitioners with knowledge of palliative care services in the community in a diverse sample of European countries. We also conducted an international systematic review of tools used to identify people for palliative care in the community. (2) A draft toolkit was then constructed suggesting how individual countries might best address these issues, and an online survey was then set up for general practitioners and specialists to make comments. Iterations of the toolkit were then presented at international palliative care and primary care conferences. RESULTS Being unable to identify appropriate patients for palliative care in the community was a major barrier internationally. The systematic review identified tools that might be used to help address this. Various facilitators such as national strategies were identified. A primary palliative care toolkit has been produced and refined, together with associated guidance. CONCLUSION Many barriers and facilitators were identified. The primary palliative care toolkit can help community-based palliative care services to be established nationally.

Ramucirumab versus placebo as second-line treatment in patients with advanced hepatocellular carcinoma following first-line therapy with sorafenib (REACH): a randomised, double-blind, multicentre, phase 3 trial

BACKGROUND VEGF and VEGF receptor-2-mediated angiogenesis contribute to hepatocellular carcinoma pathogenesis. Ramucirumab is a recombinant IgG1 monoclonal antibody and VEGF receptor-2 antagonist. We aimed to assess the safety and efficacy of ramucirumab in advanced hepatocellular carcinoma following first-line therapy with sorafenib. METHODS In this randomised, placebo-controlled, double-blind, multicentre, phase 3 trial (REACH), patients were enrolled from 154 centres in 27 countries. Eligible patients were aged 18 years or older, had hepatocellular carcinoma with Barcelona Clinic Liver Cancer stage C disease or stage B disease that was refractory or not amenable to locoregional therapy, had Child-Pugh A liver disease, an Eastern Cooperative Oncology Group performance status of 0 or 1, had previously received sorafenib (stopped because of progression or intolerance), and had adequate haematological and biochemical parameters. Patients were randomly assigned (1:1) to receive intravenous ramucirumab (8 mg/kg) or placebo every 2 weeks, plus best supportive care, until disease progression, unacceptable toxicity, or death. Randomisation was stratified by geographic region and cause of liver disease with a stratified permuted block method. Patients, medical staff, investigators, and the funder were masked to treatment assignment. The primary endpoint was overall survival in the intention-to-treat population. This study is registered with ClinicalTrials.gov, number NCT01140347. FINDINGS Between Nov 4, 2010, and April 18, 2013, 565 patients were enrolled, of whom 283 were assigned to ramucirumab and 282 were assigned to placebo. Median overall survival for the ramucirumab group was 9·2 months (95% CI 8·0-10·6) versus 7·6 months (6·0-9·3) for the placebo group (HR 0·87 [95% CI 0·72-1·05]; p=0·14). Grade 3 or greater adverse events occurring in 5% or more of patients in either treatment group were ascites (13 [5%] of 277 patients treated with ramucirumab vs 11 [4%] of 276 patients treated with placebo), hypertension (34 [12%] vs ten [4%]), asthenia (14 [5%] vs five [2%]), malignant neoplasm progression (18 [6%] vs 11 [4%]), increased aspartate aminotransferase concentration (15 [5%] vs 23 [8%]), thrombocytopenia (13 [5%] vs one [<1%]), hyperbilirubinaemia (three [1%] vs 13 [5%]), and increased blood bilirubin (five [2%] vs 14 [5%]). The most frequently reported (≥1%) treatment-emergent serious adverse event of any grade or grade 3 or more was malignant neoplasm progression. INTERPRETATION Second-line treatment with ramucirumab did not significantly improve survival over placebo in patients with advanced hepatocellular carcinoma. No new safety signals were noted in eligible patients and the safety profile is manageable. FUNDING Eli Lilly and Co.

Long-term data from the Swiss pulmonary hypertension registry.

BACKGROUND Registries are important for real-life epidemiology on different pulmonary hypertension (PH) groups. OBJECTIVE To provide long-term data of the Swiss PH registry of 1998-2012. METHODS PH patients have been classified into 5 groups and registered upon written informed consent at 5 university and 8 associated hospitals since 1998. New York Heart Association (NYHA) class, 6-min walk distance, hemodynamics and therapy were registered at baseline. Patients were regularly followed, and therapy and events (death, transplantation, endarterectomy or loss to follow-up) registered. The data were stratified according to the time of diagnosis into prevalent before 2000 and incident during 2000-2004, 2005-2008 and 2009-2012. RESULTS From 996 (53% female) PH patients, 549 had pulmonary arterial hypertension (PAH), 36 PH due to left heart disease, 127 due to lung disease, 249 to chronic thromboembolic PH (CTEPH) and 35 to miscellaneous PH. Age and BMI significantly increased over time, whereas hemodynamic severity decreased. Overall, event-free survival was 84, 72, 64 and 58% for the years 1-4 and similar for time periods since 2000, but better during the more recent periods for PAH and CTEPH. Of all PAH cases, 89% had target medical therapy and 43% combination therapy. Of CTEPH patients, 14 and 2% underwent pulmonary endarterectomy or transplantation, respectively; 87% were treated with PAH target therapy. CONCLUSION Since 2000, the incident Swiss PH patients registered were older, hemodynamically better and mostly treated with PAH target therapies. Survival has been better for PAH and CTEPH diagnosed since 2008 compared with earlier diagnosis or other classifications.

Biomarkers of the involvement of mast cells, basophils and eosinophils in asthma and allergic diseases.

Biomarkers of disease activity have come into wide use in the study of mechanisms of human disease and in clinical medicine to both diagnose and predict disease course; as well as to monitor response to therapeutic intervention. Here we review biomarkers of the involvement of mast cells, basophils, and eosinophils in human allergic inflammation. Included are surface markers of cell activation as well as specific products of these inflammatory cells that implicate specific cell types in the inflammatory process and are of possible value in clinical research as well as within decisions made in the practice of allergy-immunology.

VERIFICATION OF DNA PREDICTED PROTEIN SEQUENCES BY ENZYME HYDROLYSIS AND MASS SPECTROMETRIC ANALYSIS

The focus of this thesis lies in the development of a sensitive method for the analysis of protein primary structure which can be easily used to confirm the DNA sequence of a protein's gene and determine the modifications which are made after translation. This technique involves the use of dipeptidyl aminopeptidase (DAP) and dipeptidyl carboxypeptidase (DCP) to hydrolyze the protein and the mass spectrometric analysis of the dipeptide products.^ Dipeptidyl carboxypeptidase was purified from human lung tissue and characterized with respect to its proteolytic activity. The results showed that the enzyme has a relatively unrestricted specificity, making it useful for the analysis of the C-terminal of proteins. Most of the dipeptide products were identified using gas chromatography/mass spectrometry (GC/MS). In order to analyze the peptides not hydrolyzed by DCP and DAP, as well as the dipeptides not identified by GC/MS, a FAB ion source was installed on a quadrupole mass spectrometer and its performance evaluated with a variety of compounds.^ Using these techniques, the sequences of the N-terminal and C-terminal regions and seven fragments of bacteriophage P22 tail protein have been verified. All of the dipeptides identified in these analysis were in the same DNA reading frame, thus ruling out the possibility of a single base being inserted or deleted from the DNA sequence. The verification of small sequences throughout the protein sequence also indicates that no large portions of the protein have been removed after translation. ^

Minding the 3 R's: Response, Remediation and Restoration

Working with CT DEP, the NOAA Office of Damage Assessment, Remediation and Restoration uses funds recovered from polluters to conduct restoration projects. Here in Connecticut, projects include the Jordan Brook Fishway in Waterford, the Remington Gun Club site at Lordship Point in Stratford, and more.