Novel Linker Variants of Antileishmanial/Antitubercular 7-Substituted 2-Nitroimidazooxazines Offer Enhanced Solubility

Antitubercular 7-substituted 2-nitroimidazo[2,1-b][1,3]oxazines were previously shown to exhibit potent antileishmanial and antitrypanosomal activities, culminating in a new clinical investigational drug for visceral leishmaniasis (DNDI-0690). To offset development risks, we continued to seek further leads with divergent candidate profiles, especially analogues possessing greater aqueous solubility. Starting from an efficacious monoaryl derivative, replacement of the side chain ether linkage by novel amine, amide, and urea functionality was first explored; the former substitution was well-tolerated in vitro and in vivo but elicited marginal alterations to solubility (except through a less stable benzylamine), whereas the latter groups resulted in significant solubility improvements (up to 53-fold) but an antileishmanial potency reduction of at least 10-fold. Ultimately, we discovered that O-carbamate 66 offered a more optimal balance of increased solubility, suitable metabolic stability, excellent oral bioavailability (100%), and strong in vivo efficacy in a visceral leishmaniasis mouse model (97% parasite load reduction at 25 mg/kg).     

Prognostic capabilities and clinical utility of cell cycle progression testing,prostate imaging reporting and data system,version 2, and clinicopathologic data in management of localized prostate cancer

ObjectivesTo compare the prognostic capabilities and clinical utility of the cell cycle progression (CCP) gene expression classifier test, multiparametric magnetic resonance imaging (mpMRI) with Prostate Imaging Reporting and Data System (PI-RADS) scoring, and clinicopathologic data in select prostate cancer (PCa) medical management scenarios.Patients and methodsRetrospective, observational analysis of patients (N = 222) ascertained sequentially from a single urology practice from January 2015 to June 2018. Men were included if they had localized PCa, a CCP score, and an mpMRI PI-RADS v2 score. Cohort 1 (n = 156): men with newly diagnosed PCa, with or without a previous negative biopsy. Cohort 2 (n = 66): men who initiated active surveillance (AS) without CCP testing, but who received the test during AS. CCP was combined with the UCSF Cancer of the Prostate Risk Assessment (CAPRA) score to produce a clinical cell-cycle risk (CCR) score, which was reported in the context of a validated AS threshold. Spearman's rank correlation test was used to evaluate correlations between variables. Generalized linear models were used to predict binary Gleason score category and medical management selection (AS or curative therapy). Likelihood-ratio tests were used to determine predictor significance in both univariable and multivariable models.ResultsIn the combined cohorts, modest but significant correlations were observed between PI-RADS score and CCP (r_s = 0.22, P = 8.1 × 10^?4), CAPRA (r_s= 0.36, P = 4.8 × 10^?8), or CCR (r_s = 0.37, P = 2.0 × 10^?8), suggesting that much of the prognostic information captured by these measures is independent. When accounting for CAPRA and PI-RADS score, CCP was a significant predictor of higher-grade tumor after radical prostatectomy, with the resected tumor approximately 4 times more likely to harbor Gleason ≥4+3 per 1-unit increase in CCP in Cohort 1 (Odds Ratio [OR], 4.10 [95% confidence interval [CI], 1.46, 14.12], P = 0.006) and in the combined cohorts (OR, 3.72 [95% CI, 1.39, 11.88], P = 0.008). On multivariable analysis, PI-RADS score was not a significant predictor of post-radical prostatectomy Gleason score. Both CCP and CCR were significant and independent predictors of AS versus curative therapy in Cohort 1 on multivariable analysis, with each 1-unit increase in score corresponding to an approximately 2-fold greater likelihood of selecting curative therapy (CCP OR, 2.08 [95% CI, 1.16, 3.94], P = 0.014) (CCR OR, 2.33 [95% CI, 1.48, 3.87], P = 1.5 × 10^?4). CCR at or below the AS threshold significantly reduced the probability of selecting curative therapy over AS (OR, 0.28 [95% CI, 0.13, 0.57], P = 4.4 × 10^?4), further validating the clinical utility of the AS threshold.ConclusionCCP was a better predictor of both tumor grade and subsequent patient management than was PI-RADS. Even in the context of targeted biopsy, molecular information remains essential to ensure precise risk assessment for men with newly diagnosed PCa.     

Process and Outcome of Rehabilitation of Homeless Veterans and Their Relationship with Personality Style

Abstract

Treatment process and outcome data for 225 consecutive admissions to a rehabilitation program for the homeless were reviewed. The Northeast Program Evaluation Center's criteria were employed to evaluate participation and outcome (e.g., general, employment, and housing) for participants. Significant relationships were found between predominant personality features and degree of participation in program and living arrangements at discharge.     

Predicting prostate tumour location from multiparametric MRI using Gaussian kernel support vector machines: a preliminary study

The performance of a support vector machine (SVM) algorithm was investigated to predict prostate tumour location using multi-parametric MRI (mpMRI) data. The purpose was to obtain information of prostate tumour location for the implementation of bio-focused radiotherapy. In vivo mpMRI data were collected from 16 patients prior to radical prostatectomy. Sequences included T2-weighted imaging, diffusion-weighted imaging and dynamic contrast enhanced imaging. In vivo mpMRI was registered with ‘ground truth’ histology, using ex vivo MRI as an intermediate registration step to improve accuracy. Prostate contours were delineated by a radiation oncologist and tumours were annotated on histology by a pathologist. Five patients with minimal imaging artefacts were selected for this study. A Gaussian kernel SVM was trained and tested on different patient data subsets. Parameters were optimised using leave-oneout cross validation. Signal intensities of mpMRI were used as features and histology annotations as true labels. Prediction accuracy, as well as area under the curve (AUC) of the receiver operating characteristics (ROC) curve, were used to assess performance. Results demonstrated the prediction accuracy ranged from 70.4 to 87.1% and AUC of ROC ranged from 0.81 to 0.94. Additional investigations showed the apparent diffusion coefficient map from diffusion weighted imaging was the most important imaging modality for predicting tumour location. Future work will incorporate additional patient data into the framework to increase the sensitivity and specificity of the model, and will be extended to incorporate predictions of biological characteristics of the tumour which will be used in bio-focused radiotherapy optimisation.     

Limitations of the Rey Fifteen-Item test in the detection of malingering

Abstract

The capacity of Rey's (1964) Fifteen-Item Test (FIT) to detect feigned memory impairment in a group of clinical malingerers was investigated. Seven malingerers were identified by significantly below chance performance on a forced-choice memory measure, the Recognition Memory Test, and were given the FIT. A reference group of 7 patients with acute moderate and severe traumatic brain injuries was also given the FIT. The brain-injured subjects recalled significantly more items on the FIT than the malingering subjects. Using a cutoff score of 7, the FIT was able to detect only 57% of the malingerers but did not misclassify any brain-injured subjects. Although possessing good specificity, the FIT appears to lack adequate sensitivity to detect feigned impairment when used as a single measure. The FIT may be sensitive primarily to blatant deceptive strategies.     

Radiofrequency-induced thermotherapy (RFiTT) in a porcine liver model and ex vivo great saphenous vein

Aims: To investigate the thermal spread achieved in porcine liver when using an optimised radiofrequency ablation protocol and correlate findings with the effects seen in ex vivo great saphenous vein (GSV), in order to justify clinical use with the new treatment protocol.

Material and methods: Porcine liver and GSV sections were treated with radiofrequency-induced thermotherapy (RFiTT) using the following settings: 20 W at 1?s/cm (linear endovenous energy density; LEED 20 J/cm), 18 W at 1?s/cm (LEED 18 J/cm), 18 W at 3?s/cm (LEED 54 J/cm), 6 W interrupted pull-back 6?s stationary every 0.5?cm (LEED 72 J/cm). Thermal spread in the liver was measured via digital imaging. GSV sections were sent to an independent laboratory for histological analysis. Previous work suggests a thermal spread of?>0.65?mm in liver correlates with transmural thermoablation of a GSV.

Results: Parameters giving a LEED of 72 J/cm produced the best results, with a clear transmural effect in the GSV and maximal thermal spread of 1.65?mm, without excessive thermal damage or carbonisation in the ablation tract.

Conclusions: Our porcine liver model correlated well with histological findings and was representative of the thermoablative effects observed in the GSV wall treated with RFiTT. Clinical investigations are now being carried out to investigate the efficacy of this protocol in the clinical setting.     

Guidelines for collecting and maintaining archives for genetic monitoring

Rapid advances in molecular genetic techniques and the statistical analysis of genetic data have revolutionized the way that populations of animals, plants and microorganisms can be monitored. Genetic monitoring is the practice of using molecular genetic markers to track changes in the abundance, diversity or distribution of populations, species or ecosystems over time, and to follow adaptive and non-adaptive genetic responses to changing external conditions. In recent years, genetic monitoring has become a valuable tool in conservation management of biological diversity and ecological analysis, helping to illuminate and define cryptic and poorly understood species and populations. Many of the detected biodiversity declines, changes in distribution and hybridization events have helped to drive changes in policy and management. Because a time series of samples is necessary to detect trends of change in genetic diversity and species composition, archiving is a critical component of genetic monitoring. Here we discuss the collection, development, maintenance, and use of archives for genetic monitoring. This includes an overview of the genetic markers that facilitate effective monitoring, describes how tissue and DNA can be stored, and provides guidelines for proper practice.