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 Shape of LITTLE THINGS Dwarf Galaxies DDO 46 and DDO 168: Understanding the stellar and gas kinematics

We present the stellar and gas kinematics of DDO 46 and DDO 168 from the LITTLE THINGS survey and determine their respective Vmax/sigma_z,0 values. We used the KPNO's 4-meter telescope with the Echelle spectrograph as a long-slit spectrograph. We acquired spectra of DDO 168 along four position angles by placing the slit over the morphological major and minor axes and two intermediate position angles. However, due to poor weather conditions during our observing run for DDO 46, we were able to extract only one useful data point from the morphological major axis. We determined a central stellar velocity dispersion perpendicular to the disk, sigma_z,0, of 13.5+/-8 km/s for DDO 46 and of 10.7+/-2.9 km/s for DDO 168. We then derived the maximum rotation speed in both galaxies using the LITTLE THINGS HI data. We separated bulk motions from non-circular motions using a double Gaussian decomposition technique and applied a tilted-ring model to the bulk velocity field. We corrected the observed HI rotation speeds for asymmetric drift and found a maximum velocity, Vmax, of 77.4 +/- 3.7 and 67.4 +/- 4.0 km/s for DDO 46 and DDO 168, respectively. Thus, we derived a kinematic measure, Vmax/sigma_z,0, of 5.7 +/- 0.6 for DDO 46 and 6.3 +/- 0.3 for DDO 168. Comparing these values to ones determined for spiral galaxies, we find that DDO 46 and DDO 168 have Vmax/sigma_z,0 values indicative of thin disks, which is in contrast to minor-to-major axis ratio studies

SuperNet in Neural Architecture Search: A Taxonomic Survey

Deep Neural Networks (DNN) have made significant progress in a wide range of visual recognition tasks such as image classification, object detection, and semantic segmentation. The evolution of convolutional architectures has led to better performance by incurring expensive computational costs. In addition, network design has become a difficult task, which is labor-intensive and requires a high level of domain knowledge. To mitigate such issues, there have been studies for a variety of neural architecture search methods that automatically search for optimal architectures, achieving models with impressive performance that outperform human-designed counterparts. This survey aims to provide an overview of existing works in this field of research and specifically focus on the supernet optimization that builds a neural network that assembles all the architectures as its sub models by using weight sharing. We aim to accomplish that by categorizing supernet optimization by proposing them as solutions to the common challenges found in the literature: data-side optimization, poor rank correlation alleviation, and transferable NAS for a number of deployment scenarios

Fine-Tuning the Retrieval Mechanism for Tabular Deep Learning

While interests in tabular deep learning has significantly grown, conventional tree-based models still outperform deep learning methods. To narrow this performance gap, we explore the innovative retrieval mechanism, a methodology that allows neural networks to refer to other data points while making predictions. Our experiments reveal that retrieval-based training, especially when fine-tuning the pretrained TabPFN model, notably surpasses existing methods. Moreover, the extensive pretraining plays a crucial role to enhance the performance of the model. These insights imply that blending the retrieval mechanism with pretraining and transfer learning schemes offers considerable potential for advancing the field of tabular deep learning.Comment: Table Representation Learning Workshop at NeurIPS 202

Prefrontal dysfunction in schizophrenia involves mixed-lineage leukemia 1-regulated histone methylation at GABAergic gene promoters

Alterations in GABAergic mRNA expression play a key role for prefrontal dysfunction in schizophrenia and other neurodevelopmental disease. Here, we show that histone H3-lysine 4 methylation, a chromatin mark associated with the transcriptional process, progressively increased at GAD1 and other GABAergic gene promoters (GAD2, NPY, SST) in human prefrontal cortex (PFC) from prenatal to peripubertal ages and throughout adulthood. Alterations in schizophrenia included decreased GAD1 expression and H3K4-trimethylation, predominantly in females and in conjunction with a risk haplotype at the 5\u27 end of GAD1. Heterozygosity for a truncated, lacZ knock-in allele of mixed-lineage leukemia 1 (Mll1), a histone methyltransferase expressed in GABAergic and other cortical neurons, resulted in decreased H3K4 methylation at GABAergic gene promoters. In contrast, Gad1 H3K4 (tri)methylation and Mll1 occupancy was increased in cerebral cortex of mice after treatment with the atypical antipsychotic, clozapine. These effects were not mimicked by haloperidol or genetic ablation of dopamine D2 and D3 receptors, suggesting that blockade of D2-like signaling is not sufficient for clozapine-induced histone methylation. Therefore, chromatin remodeling mechanisms at GABAergic gene promoters, including MLL1-mediated histone methylation, operate throughout an extended period of normal human PFC development and play a role in the neurobiology of schizophrenia

An Analysis of Bordeaux Wine Ratings, 1970-2005: Implications for the Existing Classification of the Médoc and Graves

The French châteaux producing Bordeaux wines were classified in 1855, creating a taxonomy that continues in force to the present day. An analysis of the ratings of vintages from 1970 to 2005 from three popular rating sources—Robert Parker, Stephen Tanzer, and Wine Spectator—provides a lens into the status of that 1855 Classification, as well as allows a comparison of those three raters. The analysis found considerable internal consistency in the three rating sources and a high degree of correlation between those experts’ ratings. However, the raters differ systematically in the scores they assign. This study is based on 339 combinations of château and vintage for the “classified growths” for which we were able to find ratings from all three sources. We identify the top-rated years and top-rated châteaux, and compare this information to the 1855 Classification. Given our findings we propose an update to the 1855 Classification that incorporates the ratings we examine. To begin with, several châteaux showed remarkable staying power over the intervening 150 years. However, some châteaux had advanced to in the rankings, while others have faded, at least based on this sample of vintages. Notable changes include Château Leoville-Las-Cases (Saint-Julien) moving from second to first growth, replacing Château Mouton-Rothschild (Pauillac), and two châteaux moving from the fifth growth to the second growth: Château Lynch-Bages (Pauillac) and Château Pontet-Canet (Pauillac). Market prices of the 2005 vintage tend to support our findings. For example, as of early May 2008, the price of the Château Leoville-Las-Cases (Saint-Julien) was about three times that of the other nominally second-growth wines. While we believe it is unlikely that the classification will be changed, we believe that our proposed classification update (and our rank-ordering of the châteaux) can help guide wine purchase decisions of consumers and the restaurant industry

Physiotherapy for primary frozen shoulder in secondary care: Developing and implementing stand-alone and post-operative protocols for UK FROST and inferences for wider practice

Abstract Objectives The United Kingdom Frozen Shoulder Trial (UK FROST) compares stand alone physiotherapy and two operative procedures, both with post-operative rehabilitation, for primary frozen shoulder in secondary care. We developed physiotherapy protocols for UK FROST, incorporating best evidence but recognizing uncertainty and allowing flexibility. Methods We screened a UK Department of Health systematic review and UK evidence based guidelines 1, 2 for recommendations, and previous surveys of UK physiotherapists 3, 4 for strong consensus. We conducted a two-stage, questionnaire-based, modified Delphi survey of shoulder specialist physiotherapists in the UK National Health Service. This required positive, negative or neutral ratings of possible interventions in four clinical contexts (stand-alone physiotherapy for, respectively, predominantly painful and predominantly stiff frozen shoulder; and post-operative physiotherapy for, respectively, predominantly painful and predominantly stiff frozen shoulder). We proposed respectively mandating or recommending interventions with 100% and 90% positive consensus, and respectively disallowing or discouraging interventions with 90% and 80% negative consensus. Other interventions would be optional. Results The systematic review and guideline recommended including steroid injection and manual mobilizations in non-operative care, and we mandated these for standalone physiotherapy. Consensus in the pre-existing surveys strongly favoured advice, education and home exercises, which we mandated across contexts. The Delphi survey led to recommendation of some supervised exercise modalities, plus the disallowing or discouragement—in various contexts—of immobilization and some ‘higher-tech’ electrotherapies and alternative therapies. Conclusions We developed physiotherapy protocols despite incomplete empirical evidence. Their clear structure enabled implementation in data-sheets designed to facilitate recording, monitoring of fidelity and reporting of interventions. Other trials involving physiotherapy may benefit from this approach