Notes

Checking out Hidden Troubles in the Use of Antipsychotic Polypharmacy in the Treatment of Schizophrenia.
Each participant's highest callus grade score on the treated foot either improved or remained the same following product use (compared to baseline). Mean callus grade scores were 1.75 at baseline, 1.55 immediately post use, 1.25 1-day post use, and 1.50 1-week post use.

Results from this pilot study suggest that callus softening products containing less than 10% potassium hydroxide are likely to be safe and effective products under intended use scenarios of 3-5 minute application times, as dictated by product label instructions.
Results from this pilot study suggest that callus softening products containing less than 10% potassium hydroxide are likely to be safe and effective products under intended use scenarios of 3-5 minute application times, as dictated by product label instructions.Sugar alcohols (polyols) have important roles as nutrients, anti-freezing agents and scavengers of free radicals in cold-adapted bacteria, but the characteristics of polyol dehydrogenases in cold-adapted bacteria remain largely unknown. In this study, based on the observation that a cold-adapted bacterium Pseudomonas mandelii JR-1 predominantly utilized d-sorbitol as its carbon source, among the four polyols examined (d-galactitol, d-mannitol, d-sorbitol and d-xylitol), we cloned and characterized a sorbitol dehydrogenase (SDH, EC 1.1.1.14) belonging to the short-chain dehydrogenase/reductase family from this bacterium (the SDH hereafter referred to as PmSDH). PmSDH contained Asn111, Ser140, Tyr153 and Lys157 as catalytic active site residues and existed as an ∼67-kDa dimer in size-exclusion chromatography. PmSDH converted d-sorbitol to d-fructose using nicotinamide adenine dinucleotide (NAD+) as a cofactor and, vice versa, d-fructose to d-sorbitol using nicotinamide adenine dinucleotide reduced (NADH) as a cofactor. PmSDH maintained its conformational flexibility, secondary and tertiary structures, and thermal stability at 4-25°C. These results indicate that PmSDH, which has a flexible structure and a high catalytic activity at colder temperatures, is well suited to sorbitol utilization in the cold-adapted bacterium P. mandelii JR-1.
Population-scale sequenced cohorts are foundational resources for genetic analyses, but processing raw reads into analysis-ready cohort-level variants remains challenging.

We introduce an open-source cohort-calling method that uses the highly-accurate caller DeepVariant and scalable merging tool GLnexus. Using callset quality metrics based on variant recall and precision in benchmark samples and Mendelian consistency in father-mother-child trios, we optimized the method across a range of cohort sizes, sequencing methods, and sequencing depths. The resulting callsets show consistent quality improvements over those generated using existing best practices with reduced cost. We further evaluate our pipeline in the deeply sequenced 1000 Genomes Project (1KGP) samples and show superior callset quality metrics and imputation reference panel performance compared to an independently-generated GATK Best Practices pipeline.

We publicly release the 1KGP individual-level variant calls and cohort callset (https//console.cloud.google.com/storage/browser/brain-genomics-public/research/cohort/1KGP) to foster additional development and evaluation of cohort merging methods as well as broad studies of genetic variation. Both DeepVariant (https//github.com/google/deepvariant) and GLnexus (https//github.com/dnanexus-rnd/GLnexus) are open-sourced, and the optimized GLnexus setup discovered in this study is also integrated into GLnexus public releases v1.2.2 and later.

Supplementary data are available at Bioinformatics online.
Supplementary data are available at Bioinformatics online.
Restricted mean survival time (RMST) is a useful summary measurement of the time-to-event data, and it has attracted great attention for its straightforward clinical interpretation. In this article, I propose a deep neural network model that directly relates the RMST to its baseline covariates for simultaneous prediction of RSMT at multiple times. Each subject's survival time is transformed into a series of jackknife pseudo observations and then used as quantitative response variables in a deep neural network model. By using the pseudo values, a complex survival analysis is reduced to a standard regression problem, which greatly simplifies the neural network construction. By jointly modelling RMST at multiple times, the neural network model gains prediction accuracy by information sharing across times. The proposed network model was evaluated by extensive simulation studies and was further illustrated on three real datasets. In real data analyses, I also used methods to open the blackbox by identifying subject-specific predictors and their importance in contributing to the risk prediction.

The source code is freely available at http//github.com/lilizhaoUM/DnnRMST.

Supplementary data are available at Bioinformatics online.
Supplementary data are available at Bioinformatics online.
Racemic ketoconazole (RK) is a steroidogenesis inhibitor used for treatment of Cushing's syndrome. Levoketoconazole (COR-003), the pure 2S,4R enantiomer, is potentially more potent and safe compared to RK. We compared in vitro effects of levoketoconazole and RK on adrenocortical and pituitary adenoma cells.

HAC15 cells and 15 primary human neoplastic adrenocortical cultures (+/- ACTH), and murine (AtT20) and human corticotroph adenoma cultures were incubated with levoketoconazole or RK (0.01-10 µM). Cortisol and ACTH were measured using a chemiluminescence immunoassay system, and steroid profiles by liquid chromatography-tandem mass spectrometry (LC-MS/MS).

In HAC15, levoketoconazole inhibited cortisol at lower concentrations (IC50 0.300 µM) compared to RK (0.611 µM; P < 0.0001). IC50 values of levoketoconazole for basal cortisol production in primary adrenocortical cultures varied over a 24-fold range (0.00578-0.140 µM), with 2 patients having a higher sensitivity for levoketoconazole vs RK (2.1- anoduction more potently compared to RK and might also inhibit ACTH secretion and growth of pituitary adenoma cells. check details Together with previously reported potential advantages, this indicates that levoketoconazole is a promising novel pharmacotherapy for Cushing's syndrome.
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