Maternal reproductive performance and fetal development of the Wistar Audiogenic Rat (WAR) strain

Wistar Audiogenic Rat (WAR) strain is an animal model for epilepsy studies, the chronic multifactorial disease that affects millions of people worldwide. The animals of this strain are genetically predisposed to sound-induced seizures, called audiogenic seizures, and have been used for many years in studies to understand the mechanisms involved in the epilepsies and their neuropsychiatric comorbidities, as well as the screening of potential anti-convulsant agents. Nevertheless, little is known about the reproductive characteristics of these animals. The main goal of this study was to characterize the female reproductive performance and the fetal growth of WARs in comparison to the Wistar rats, obtaining important information for physiology and behavioral studies, as well as for the preservation of the strain. The results indicated few differences between WAR and Wistar regarding the female reproductive performance. There was no significant difference in the number of pregnant females by mating, number of live births per female, number of cells per blastocyst, and several characteristics related to reproductive performance, such as pre- and post-implantation losses. However, significant differences were observed in birth weight and weight gain until weaning, with WAR animals presenting a body weight below Wistar at birth and reduced body weight gain during the lactation period. In addition, the WAR females showed lower body weight on the day 20 of pregnancy and a larger number of corpora lutea, when compared with those of Wistar animals. Thus, we conclude that although Wistar and WAR strains have few differences in their reproductive performance, which might impact future physiological life challenges or others experimentally induced procedures, it still is a very viable strain regarding reproduction.

Abbreviations: CONCEA: National Council for the Control of Animal Experimentation; GEPR: genetically epilepsy-prone rats; WAR: Wistar Audiogenic Rat.     

Ticagrelor Versus Clopidogrel in Patients With STEMI Treated With Fibrinolysis: TREAT Trial

BackgroundThe efficacy of ticagrelor in the long-term post–ST-segment elevation myocardial infarction (STEMI) treated with fibrinolytic therapy remains uncertain.ObjectivesThe purpose of this study was to evaluate the efficacy of ticagrelor when compared with clopidogrel in STEMI patients treated with fibrinolytic therapy.MethodsThis international, multicenter, randomized, open-label with blinded endpoint adjudication trial enrolled 3,799 patients (age <75 years) with STEMI receiving fibrinolytic therapy. Patients were randomized to ticagrelor (180-mg loading dose, 90 mg twice daily thereafter) or clopidogrel (300- to 600-mg loading dose, 75 mg daily thereafter). The key outcomes were cardiovascular mortality, myocardial infarction, or stroke, and the same composite outcome with the addition of severe recurrent ischemia, transient ischemic attack, or other arterial thrombotic events at 12 months.ResultsThe combined outcome of cardiovascular mortality, myocardial infarction, or stroke occurred in 129 of 1,913 patients (6.7%) receiving ticagrelor and in 137 of 1,886 patients (7.3%) receiving clopidogrel (hazard ratio: 0.93; 95% confidence interval: 0.73 to 1.18; p = 0.53). The composite of cardiovascular mortality, myocardial infarction, stroke, severe recurrent ischemia, transient ischemic attack, or other arterial thrombotic events occurred in 153 of 1,913 patients (8.0%) treated with ticagrelor and in 171 of 1,886 patients (9.1%) receiving clopidogrel (hazard ratio: 0.88; 95% confidence interval: 0.71 to 1.09; p = 0.25). The rates of major, fatal, and intracranial bleeding were similar between the ticagrelor and clopidogrel groups.ConclusionAmong patients age <75 years with STEMI, administration of ticagrelor after fibrinolytic therapy did not significantly reduce the frequency of cardiovascular events when compared with clopidogrel. (Ticagrelor in Patients With ST Elevation Myocardial Infarction Treated With Pharmacological Thrombolysis [TREAT]; NCT02298088)     

Dose optimization of moxifloxacin and linezolid against tuberculosis using mathematical modeling and simulation

Introduction

There is an urgent need for new anti-tuberculosis (TB) drugs and optimization of current TB treatment. Moxifloxacin and linezolid are valuable options for the treatment of drug-resistant TB; however, it is crucial to find a dose at which these drugs not only show high efficacy but also suppress the development of further drug resistance.

The Effect of Donor- and Recipient-Related Factors on Corneal Graft Survival in Penetrating Keratoplasty

Purpose: To investigate the impact of donor and recipient factors on graft survival in penetrating keratoplasty (PK).

Material and Methods: This retrospective study included 365 eyes that underwent PK using corneas from 231 donors between June 2010 and June 2015. Patients were divided into three groups (group 1: primary endothelial diseases; group 2: iatrogenic endothelial disorders; and group 3: other pathologies with a healthy endothelium) according to PK indications. The primary outcome measure was corneal graft survival at the last visit (clear or opaque). Graft clarity was assessed using Kaplan–Meier survival analysis.

Results: The most frequent PK indication was keratoconus (KC) (20.5%) followed by pseudophakic bullous keratopathy (PBK) (18.9%). Donor age had a negative impact on endothelial cell density (ECD) measured by an eye bank specular microscope (p < 0.001). Median best-corrected visual acuity in logarithm of the minimum angle of resolution units increased from 2.1 to 0.8 at 1 year after PK (p < 0.001). The clear graft rate was 96.7% at year 1, 88.8% at year 2, and 85.5% at year 3. Overall graft survival was 84.9% during a median of 39 months (range: 24–79 months) of follow-up. A higher graft survival rate (67.2%) was observed in KC compared to PBK during 6 years (p < 0.001). Recipients younger than 50 years of age showed a better graft survival rate than those older than 70 years of age (p = 0.037). Donor ECD, time between excision and death, and preservation time had no significant effect on graft survival. Frequent graft rejection episodes (GREs) and additional procedures during surgery had a negative impact on graft survival (p < 0.001 and p = 0.014, respectively). A worse graft survival was observed in group 2 compared to groups 1 and 3 (p = 0.042).

Conclusions: Young recipient age and KC were associated with a better graft survival. Graft endothelial density and preservation time had no impact on graft survival. PBK, low vision at baseline and year 1, frequent GREs, and additional interventions during surgery had a negative impact on graft survivals.     

Treatment Experiences,Information Needs,Pain and Quality of Life in Men with Metastatic Castrate-resistant Prostate Cancer: Results from the EXTREQOL Study

Aims

Delaying progression, ameliorating symptoms and maintaining quality of life (QoL) are primary aims of treatment for metastatic castrate-resistant prostate cancer (mCRPC). Real-world rather than clinical trial data about symptoms and side-effects are sparse. In EXTREQOL, patients' QoL, pain and information needs were recorded during treatment.

Prediction modelling using routine clinical parameters to stratify survival in Malignant Pleural Mesothelioma patients undergoing cytoreductive surgery

Introduction

Malignant pleural mesothelioma (MPM) is an uncommon cancer with a poor prognosis and heterogeneous survival. Surgery for MPM is offered in some specialist centers to highly selected patients. A previously described classification and regression tree (CART) model stratified survival in unselected MPM patients using routinely collected clinical data. This study aimed to examine the performance of this CART model on a highly selected surgical population.

locStra: Fast analysis of regional/global stratification in whole‐genome sequencing studies

locStra is an ‐package for the analysis of regional and global population stratification in whole‐genome sequencing (WGS) studies, where regional stratification refers to the substructure defined by the loci in a particular region on the genome. Population substructure can be assessed based on the genetic covariance matrix, the genomic relationship matrix, and the unweighted/weighted genetic Jaccard similarity matrix. Using a sliding window approach, the regional similarity matrices are compared with the global ones, based on user‐defined window sizes and metrics, for example, the correlation between regional and global eigenvectors. An algorithm for the specification of the window size is provided. As the implementation fully exploits sparse matrix algebra and is written in C++, the analysis is highly efficient. Even on single cores, for realistic study sizes (several thousand subjects, several million rare variants per subject), the runtime for the genome‐wide computation of all regional similarity matrices does typically not exceed one hour, enabling an unprecedented investigation of regional stratification across the entire genome. The package is applied to three WGS studies, illustrating the varying patterns of regional substructure across the genome and its beneficial effects on association testing.     

Standardizing Postoperative Complications—Validating the Clavien-Dindo Complications Classification in Cardiac Surgery

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A hotspot mutation in transcription factor IKZF3 drives B cell neoplasia via transcriptional dysregulation

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