Clinical trials of potential cognitive-enhancing drugs in schizophrenia: what have we learned so far?

In light of the number of studies conducted to examine the treatment of cognitive impairment associated with schizophrenia (CIAS), we critically reviewed recent CIAS trials. Trials were identified through searches of the website "www.clinicaltrials.gov" using the terms "schizophrenia AND cognition," "schizophrenia AND neurocognition," "schizophrenia AND neurocognitive tests," "schizophrenia AND MATRICS," "schizophrenia AND MCCB," "schizophrenia AND BACS," "schizophrenia AND COGSTATE," and "schizophrenia AND CANTAB" and "first-episode schizophrenia AND cognition." The cutoff date was 20 April 2011. Included trials were conducted in people with schizophrenia, the effects on cognition were either a primary or secondary outcome, and the effect of a pharmacologically active substance was examined. Drug challenge, pharmacokinetic, pharmacodynamic, or prodrome of psychosis studies were excluded. We identified 118 trials, with 62% using an add-on parallel group design. The large majority of completed trials were underpowered to detect moderate effect sizes, had ≤8 weeks duration, and were performed in samples of participants with chronic stable schizophrenia. The ongoing add-on trials are longer, have larger sample sizes (with a number of them being adequately powered to detect moderate effect sizes), and are more likely to use a widely accepted standardized cognitive battery (eg, the MATRICS Consensus Cognitive Battery) and MATRICS guidelines. Ongoing studies performed in subjects with recent onset schizophrenia may help elucidate which subjects are most likely to show an effect in cognition. New insights into the demands of CIAS trial design and methodology may help increase the probability of identifying treatments with beneficial effect on cognitive impairment in schizophrenia

The 1st Balloon Valvuloplasty: An Historical Note

Balloon valvuloplasty (BV) is currently the treatment of choice for pulmonic stenosis in humans and dogs. Before permission was obtained to attempt the 1st BV in a child in 1982, the safety and efficacy of the procedure were tested in 1980 in an English Bulldog with spontaneous pulmonic stenosis. A fatal outcome would have caused indefinite postponement of BV in human patients, a procedure that currently benefits over 25,000 patients a year worldwide. This article describes the initial test procedure and its fortunate outcome in spite of unrecognized coronary anomalies in the bulldog. A small balloon was used in the test procedure, and fatal disruption of the anomalous left coronary artery (CA) did not occur as it has in several bulldogs since that time

Electronic Health Record-Based Surveillance for Community Transmitted COVID-19 in the Emergency Department

Introduction: SARS-CoV-2, a novel coronavirus, manifests as a respiratory syndrome (COVID-19) and is the cause of an ongoing pandemic. The response to COVID-19 in the United States has been hampered by an overall lack of diagnostic testing capacity. To address uncertainty about ongoing levels of SARS-CoV-2 community transmission early in the pandemic, we aimed to develop a surveillance tool using readily available emergency department (ED) operations data extracted from the electronic health record (EHR). This involved optimizing the identification of acute respiratory infection (ARI)-related encounters and then comparing metrics for these encounters before and after the confirmation of SARS-CoV-2 community transmission.Methods: We performed an observational study using operational EHR data from two Midwest EDs with a combined annual census of over 80,000. Data were collected three weeks before and after the first confirmed case of local SARS-CoV-2 community transmission. To optimize capture of ARI cases, we compared various metrics including chief complaint, discharge diagnoses, and ARI-related orders. Operational metrics for ARI cases, including volume, pathogen identification, and illness severity, were compared between the pre- and post-community transmission timeframes using chi-square tests of independence.Results: Compared to our combined definition of ARI, chief complaint, discharge diagnoses, and isolation orders individually identified less than half of the cases. Respiratory pathogen testing was the top performing individual ARI definition but still only identified 72.2% of cases. From the pre to post periods, we observed significant increases in ED volumes due to ARI and ARI cases without identified pathogen.Conclusion: Certain methods for identifying ARI cases in the ED may be inadequate and multiple criteria should be used to optimize capture. In the absence of widely available SARS-CoV-2 testing, operational metrics for ARI-related encounters, especially the proportion of cases involving negative pathogen testing, are useful indicators for active surveillance of potential COVID-19 related ED visits

Historical-institutionalist perspectives on the development of the EU budget system

The EU budget has only recently started to feature in theories of European integration. Studies typically adopt a historical-institutionalist framework, exploring notions such as path dependency. They have, however, generally been rather aggregated, or coarse-grained, in their approach. The EU budget has thus been treated as a single entity rather than a series of inter-linked institutions. This paper seeks to address these lacunae by adopting a fine-grained approach. This enables us to emphasize the connections that exist between EU budgetary institutions, in both time and space. We show that the initial set of budgetary institutions was unable, over time, to achieve consistently their treaty-based objectives. In response, rather than reform these institutions at potentially high political cost, additional institutions were layered on top of the extant structures. We thus demonstrate how some EU budgetary institutions have remained unchanged, whilst others have been added or changed over time

Geographic variation in the PRNP gene and its promoter, and their relationship to chronic wasting disease in North American deer

PRNP genotypes, number of octarepeats (PHGGGWGQ) and indels in the PRNP promoter can influence the progression of prion disease in mammals. We found no relationship between presence of promoter indels in white-tailed deer and mule deer from Nebraska and CWD presence. White-tailed deer with the 95 H allele and G20D mule deer were more likely to be CWD- free, but unlike other studies white-tailed deer with the 96S allele(s) were equally likely to be CWD-free. We provide the first information on PRNP genotypes and indels in the promoter for Key deer (all homozygous 96SS) and Coues deer (lacked 95 H and 96S alleles, but possessed a uniquely high frequency of 103 T). All deer surveyed were homozygous for three tandem octarepeats

Expanding a Supercomputer Facility Using Modular Data Center Technology

With the expansion of high-end computing resources needed to support NASA's increasing demands for physics-based simulations, the facility housing Pleiades-the agency's largest supercomputer-recently reached its power and cooling capacity. In response, the NASA Advanced Supercomputing Division at Ames Research Center undertook a prototype project that resulted in a new facility based on modular data center technology. The facility, a ~1000 square-foot module on a concrete pad with room for 16-18 compute racks, was completed in fall 2016 and an SGI computer system, named Electra, was deployed there in early 2017. Cooling is performed via an evaporative system built into the module, and preliminary experience shows a Power Usage Effectiveness (PUE) of ~1.03. Electra achieved over a petaflop on the LINPACK benchmark, sufficient to rank number 96 on the November 2016 TOP500 list. The system consists of 1,152 InfiniBand-connected Intel Xeon Broadwell-based nodes. Its users access their files on a facility wide file system shared by all compute assets via Mellanox MetroX InfiniBand extenders, which connect the Electra fabric to Lustre routers InfiniBand fabric over fiber-optic links about 300 meters long. The prototype has exceeded expectations and is serving as a blueprint for future expansions.

The characteristics of cognitive neuroscience tests in a schizophrenia cognition clinical trial: Psychometric properties and correlations with standard measures.

In comparison to batteries of standard neuropsychological tests, cognitive neuroscience tests may offer a more specific assessment of discrete neurobiological processes that may be aberrant in schizophrenia. However, more information regarding psychometric properties and correlations with standard neuropsychological tests and functional measures is warranted to establish their validity as treatment outcome measures. The N-back and AX-Continuous Performance Task (AX-CPT) are two promising cognitive neuroscience tests designed to measure specific components of working memory and contextual processing respectively. In the current study, we report the psychometric properties of multiple outcome measures from these two tests as well as their correlations with standard neuropsychological measures and functional capacity measures. The results suggest that while the AX-CPT and N-back display favorable psychometric properties, they do not exhibit greater sensitivity or specificity with functional measures than standard neurocognitive tests