An Open Drug Discovery Competition: Experimental Validation of Predictive Models in a Series of Novel Antimalarials.

The Open Source Malaria (OSM) consortium is developing compounds that kill the human malaria parasite, Plasmodium falciparum, by targeting PfATP4, an essential ion pump on the parasite surface. The structure of PfATP4 has not been determined. Here, we describe a public competition created to develop a predictive model for the identification of PfATP4 inhibitors, thereby reducing project costs associated with the synthesis of inactive compounds. Competition participants could see all entries as they were submitted. In the final round, featuring private sector entrants specializing in machine learning methods, the best-performing models were used to predict novel inhibitors, of which several were synthesized and evaluated against the parasite. Half possessed biological activity, with one featuring a motif that the human chemists familiar with this series would have dismissed as "ill-advised". Since all data and participant interactions remain in the public domain, this research project "lives" and may be improved by others.

Differences in LC3B expression and prognostic implications in oropharyngeal and oral cavity squamous cell carcinoma patients.

BACKGROUND: This study examined the prognostic significance of microtubule-associated protein light chain 3B (LC3B) expression in oropharyngeal and oral cavity squamous cell carcinoma (SCC). The prognostic significance of LC3B expression in relation to human papillomavirus (HPV) status in oropharyngeal SCC was also examined. METHODS: Tissue microarrays (TMAs) were constructed from formalin-fixed, paraffin-embedded oropharyngeal (n = 47) and oral cavity (n = 95) SCC tissue blocks from patients with long-term recurrence and overall survival data (median = 47 months). LC3B expression on tumour was assessed by immunohistochemistry and evaluated for associations with clinicopathological variables. LC3B expression was stratified into high and low expression cohorts using ROC curves with Manhattan distance minimisation, followed by Kaplan-Meier and multivariable survival analyses. Interaction terms between HPV status and LC3B expression in oropharyngeal SCC patients were also examined by joint-effects and stratified analyses. RESULTS: Kaplan-Meier survival and univariate analyses revealed that high LC3B expression was correlated with poor overall survival in oropharyngeal SCC patients (p = 0.007 and HR = 3.18, 95% CI 1.31-7.71, p = 0.01 respectively). High LC3B expression was also an independent prognostic factor for poor overall survival in oropharyngeal SCC patients (HR = 4.02, 95% CI 1.38-11.47, p = 0.011). In contrast, in oral cavity SCC, only disease-free survival remained statistically significant after univariate analysis (HR = 2.36, 95% CI 1.19-4.67, p = 0.014), although Kaplan-Meier survival analysis showed that high LC3B expression correlated with poor overall and disease-free survival (p = 0.046 and 0.011 respectively). Furthermore, oropharyngeal SCC patients with HPV-negative/high LC3B expression were correlated with poor overall survival in both joint-effects and stratified presentations (p = 0.024 and 0.032 respectively). CONCLUSIONS: High LC3B expression correlates with poor prognosis in oropharyngeal and oral cavity SCC, which highlights the importance of autophagy in these malignancies. High LC3B expression appears to be an independent prognostic marker for oropharyngeal SCC but not for oral cavity SCC patients. The difference in the prognostic significance of LC3B between oropharyngeal and oral cavity SCCs further supports the biological differences between these malignancies. The possibility that oropharyngeal SCC patients with negative HPV status and high LC3B expression were at particular risk of a poor outcome warrants further investigation in prospective studies with larger numbers.

QSAR ligand dataset for modelling mutagenicity, genotoxicity, and rodent carcinogenicity.

Five datasets were constructed from ligand and bioassay result data from the literature. These datasets include bioassay results from the Ames mutagenicity assay, Greenscreen GADD-45a-GFP assay, Syrian Hamster Embryo (SHE) assay, and 2 year rat carcinogenicity assay results. These datasets provide information about chemical mutagenicity, genotoxicity and carcinogenicity.

Combining machine learning models of in vitro and in vivo bioassays improves rat carcinogenicity prediction.

In vitro genotoxicity bioassays are cost-efficient methods of assessing potential carcinogens. However, many genotoxicity bioassays are inappropriate for detecting chemicals eliciting non-genotoxic mechanisms, such as tumour promotion, this necessitates the use of in vivo rodent carcinogenicity (IVRC) assays. In silico IVRC modelling could potentially address the low throughput and high cost of this assay. We aimed to develop and combine computational QSAR models of novel bioassays for the prediction of IVRC results and compare with existing software. QSAR models were generated from existing Ames (n = 6512), Syrian Hamster Embryonic (SHE, n = 410), ISSCAN rodent carcinogenicity (ISC, n = 834) and GreenScreen GADD45a-GFP (n = 1415) chemical datasets. These models mapped the molecular descriptors of each compound to their respective assay result using machine learning algorithms (adaboost, k-Nearest Neighbours, C.45 Decision Tree, Multilayer Perceptron, Random Forest). The best performing models were combined with k-Nearest Neighbours to create a cascade model for IVRC prediction. High QSAR model performance was observed from ten time 10-fold cross-validation with above 80% accuracy and 0.85 AUC for each assay dataset. The cascade model predicted rat carcinogenicity with 69.3% accuracy and 0.700 AUC. This study demonstrates the novelty of a combined approach for IVRC prediction, with higher performance than existing software.

Differences in survival outcome between oropharyngeal and oral cavity squamous cell carcinoma in relation to HPV status.

BACKGROUND: This study examined the prognostic significance of human papillomavirus (HPV) in patients with oropharyngeal and oral cavity squamous cell carcinoma (SCC). METHODS: Tissue microarrays were constructed from oropharyngeal and oral cavity SCC (n = 143). The presence of functional HPV in tumour was determined by combined assessments of p16 immunohistochemistry and HPV in situ hybridisation. RESULTS: Oropharyngeal SCC patients presented with more advanced disease in comparison with oral cavity SCC patients (P = 0.001). HPV is present in 60% and 61% of oropharyngeal and oral cavity SCC patients, respectively. HPV-positive oropharyngeal SCC patients with advanced TNM stages displayed better overall and disease-free survival outcomes than HPV-negative patients (P = 0.022 and 0.046, respectively). Such survival differences were not observed in oral cavity SCC. CONCLUSIONS: HPV is common in both oropharyngeal and oral cavity SCC and is associated with better survival outcome in oropharyngeal SCC but not in oral cavity SCC patients.

Medicine information exchange networks among healthcare professionals and prescribing in geriatric medicine wards.

AIMS: Effective transfer of information is vital for rational drug therapy. This is particularly important for older patients, who have a high prevalence of polypharmacy and are managed by multidisciplinary teams. We aimed to assess medicine information exchange (MIE) networks in geriatric medicine wards and whether they are associated with prescribing patterns. METHODS: We conducted network analysis in acute geriatric medicine wards from four hospitals to characterize MIE networks among multidisciplinary team members. Corresponding patient data were collected to analyze high-risk prescribing in conjunction with network characteristics. RESULTS: We found that junior doctors, senior nurses and pharmacists were central to MIE across all four hospitals. Doctors were more likely than other professions to receive medicines information in three hospitals. Reciprocity and the tendency to communicate within one's own profession also influenced network formation. No difference was observed in prescribing practice between hospitals. CONCLUSIONS: Understanding MIE networks can identify gaps in multidisciplinary communication that can be addressed. Networks may identify targets for dissemination of interventions to improve prescribing.

Older peoples' attitudes regarding polypharmacy, statin use and willingness to have statins deprescribed in Australia.

BACKGROUND: Deprescribing is the process of medication withdrawal with the aims of reducing the harms of potentially inappropriate medication use and improving patient outcomes. Deprescribing of statins may be indicated for some older people, because the evidence for benefit in primary prevention of cardiovascular disease is limited and there is an increased risk of side effects in old age. OBJECTIVE: To determine older peoples' attitudes and beliefs regarding medication use and their willingness to have regular medications, particularly statins, deprescribed. Setting An Australian acute-care hospital. METHOD: A cross-sectional study of patients admitted to a teaching hospital in Sydney, Australia, aged ≥65 years and taking a statin was conducted. Attitudes and beliefs regarding medication use and willingness to have medications or statins deprescribed were captured using the validated Patients' Attitudes Towards Deprescribing questionnaire, supplemented with additional statin-specific questions. MAIN OUTCOME MEASURES: Older inpatients' attitudes and perspectives towards stopping medications, in particular statins. RESULTS: Overall, 180 participants were recruited, with a median age of 78 years, (interquartile range 71-85). Eighty-nine percent (95% CI 84.4-93.6) of participants reported that they would be willing to stop one or more of their regular medications if their doctor said it was possible. Ninety-five percent (95% CI 91.8-98.2) agreed that they would be willing to have a statin deprescribed. Moreover, 94% (95% CI 90.5-97.5) of participants expressed concern regarding the potential side effects of taking a statin. CONCLUSION: The majority of older inpatients using statins are willing to have one or more of their current medications, including statins, deprescribed. These findings can be used to inform clinical practice and interventional statin deprescribing studies to optimise medication use in older adults.

Ischemic heart disease, prescription of optimal medical therapy and geriatric syndromes in community-dwelling older men: A population-based study.

BACKGROUND: Guideline recommended management of ischemic heart disease (IHD) suggests the concomitant use of antiplatelet, beta-blocker, renin angiotensin system blocker and statin therapy. In older people exposure to multiple medications has been associated with adverse events and geriatric syndromes. The study aimed to investigate the use of medications for IHD in older men with and without geriatric syndromes, and whether adherence to medication guidelines impacts on adverse outcomes. METHODS: Community-dwelling men, aged ≥ 70 years and enrolled in the Concord Health and Ageing in Men Project were studied. Data on self-reported IHD, number of guideline recommended medications (use of four guideline medications considered optimal medical therapy) and geriatric syndromes (frailty, falls, cognitive impairment and urinary incontinence) were obtained. Cox regression was used to assess the relationship between optimal medical therapy and adverse outcomes (mortality and institutionalization), stratifying by geriatric syndromes. RESULTS: At baseline, 462 (27%) men self-reported a history of IHD and of these, 226 (49%) had at least one geriatric syndrome. Among men with IHD, no significant difference was observed in patterns of prescribing between those with and without geriatric syndromes. Compared to zero medications, optimal medical therapy among men with IHD was associated with lower mortality [hazard ratio, HR = 0.40 (95% CI: 0.21-0.95)] and institutionalization risk (HR=0.31; 95% CI: 0.09-0.81). The presence of geriatric syndromes did not modify the association of increasing use of guideline recommended medications and clinical outcomes. CONCLUSION: In older men with IHD, greater adherence to medication guidelines appears to be positively associated with better clinical outcomes, independent of geriatric syndromes.

The impact of frailty on pharmacokinetics in older people: using gentamicin population pharmacokinetic modeling to investigate changes in renal drug clearance by glomerular filtration.

PURPOSE: Frailty, a multifactorial biological syndrome characterized by a cumulative dysregulation of physiological processes, is associated with changes in pharmacokinetics and pharmacodynamics. The aim of this study was to quantify the effect of frailty on glomerular filtration of drugs, using the probe drug gentamicin. METHODS: Gentamicin concentrations and clinical data including the Reported Edmonton Frail Scale score were pooled from two prospective observational inpatient studies, one on prophylactic gentamicin for urologic surgery and one on therapeutic gentamicin for the empiric treatment of sepsis. Population pharmacokinetic modeling was performed using non-linear mixed effects modeling (NONMEM program) to determine the impact of frailty on gentamicin clearance. RESULTS: A one-compartment linear pharmacokinetic model best described the data and the addition of frailty to the model reduced the random variability in gentamicin clearance by 12 % after adjustment for renal function (estimated creatinine clearance using lean body weight) and lean body weight. Frail patients had an approximately 12 % lower (bootstrapping results: 14 % median) gentamicin clearance than non-frail patients (calculated as a fractional effect of frailty). CONCLUSIONS: Frailty may independently predict reduced clearance of gentamicin in older patients. Frailty could be considered in the development of dosing guidelines for drugs that undergo significant excretion through glomerular filtration.

Prevalence and impact of fall-risk-increasing drugs, polypharmacy, and drug-drug interactions in robust versus frail hospitalised falls patients: a prospective cohort study.

BACKGROUND: Several measures of medication exposure are associated with adverse outcomes in older people. Exposure to and the clinical outcomes of these measures in robust versus frail older inpatients are not known. OBJECTIVE: In older robust and frail patients admitted to hospital after a fall, we investigated the prevalence and clinical impact of fall-risk-increasing drugs (FRIDs), total number of medications, and drug-drug interactions (DDIs). METHODS: Patients ≥60 years of age admitted with a fall to a tertiary referral teaching hospital in Sydney were recruited and frailty was assessed. Data were collected at admission, discharge, and 2 months after admission. RESULTS: A total of 204 patients were recruited (mean age 80.5 ± 8.3 years), with 101 robust and 103 frail. On admission, compared with the robust, frail participants had significantly higher mean ± SD number of FRIDs (frail 3.4 ± 2.2 vs. robust 1.6 ± 1.5, P < 0.0001), total number of medications (9.8 ± 4.3 vs. 4.4 ± 3.3, P < 0.0001), and DDI exposure (35 vs. 5 %, P = 0.001). Number of FRIDs on discharge was significantly associated with recurrent falls [odds ratio (OR) 1.7 (95 % confidence interval [CI] 1.3-2.1)], which were most likely to occur with 1.5 FRIDs in the frail and 2.5 FRIDs in the robust. Number of medications on discharge was also associated with recurrent falls [OR 1.2 (1.0-1.3)], but DDIs were not. CONCLUSION: Exposure to FRIDs and other measures of high-risk medication exposures is common in older people admitted with falls, especially the frail. Number of FRIDs and to a lesser extent total number of medicines at discharge were associated with recurrent falls.

Diagnosis of oligodendroglioma: molecular and classical histological assessment in the twenty-first century.

Advances in molecular genetics are currently challenging the traditional morphological categorization of gliomas. Recurrent molecular and cytogenetic aberrations add prognostic and predictive information over and above that provided by standard histomorphological techniques and may influence decisions to re-operate or observe, to deliver radiation or not, or to administer chemotherapy to glioma patients. The importance of routine hematoxylin and eosin (H-E pathological stains cannot be underestimated, especially in resource-poor areas and developing countries where there is likely to be a significant economic opportunity cost for molecular diagnosis services. New research tools for image analyses of histological H-E slides, such as the precise measures of cell area, curvature and nuclear roundness, may provide an increased ability to provide an accurate classification for an inherently subjective process of histological assessment. We discuss the current trends, limitations and impact of molecular classification in this mini review.

Acute starvation in C57BL/6J mice increases myocardial UCP2 and UCP3 protein expression levels and decreases mitochondrial bio-energetic function.

Associations between uncoupling protein (UCP) expression and functional changes in myocardial mitochondrial bio-energetics have not been well studied during periods of starvation stress. Our aim was to study the effects of acute starvation, for 24 or 48 h, on combined cardiac mitochondrial function and UCP expression in mice. Isolated heart mitochondria from female mice starved for 48 h compared to that from mice fed revealed a significantly (p < 0.05) decreased adenosine diphosphate-to-oxygen ratio, a significantly increased proton leak and an increased GTP inhibition on palmitic acid-induced state 4 oxygen consumption (p < 0.05). These bio-energetic functional changes were associated with increases in mitochondrial UCP2 and UCP3 protein expression. In conclusion, our findings suggest that increased UCP2 and UCP3 levels may contribute to decreased myocardial mitochondrial bio-energetic function due to starvation.

Understanding decision and enabling factors influencing clinical trial participation in Australia: a view point.

Understanding patient decision making with respect to clinical trial participation has the potential to improve both the efficiency of recruitment for clinical trials and their management. In this mini-review we consider 3 key factors influencing clinical trial recruitment outcomes that include; 1) patient personal characteristics, 2) enabling factors that involve patient centered attitudes or circumstances, and 3) aversion. These factors are explored across both Australian rural and urban settings and contrasted to reported outcomes from research across other countries. Australia has the lowest number of publications on rural clinical trial participation when compared to rural research in America and Canada. Across Australian urban areas where all 3 factors have been studied, trends are similar to those reported in other developed countries. In conclusion we suggest that trial participation could be improved if participants are better informed about a trial as this is a valuable factor to enable recruitment.

Gastric banding for the treatment of type 2 diabetes mellitus in morbidly obese.

BACKGROUND: To assess the efficacy of the Swedish adjustable gastric band in the treatment of type 2 diabetes mellitus (T2DM), impaired glucose tolerance (IGT), and the metabolic syndrome (MS) in the morbidly obese. METHODS: We identified all patients with T2DM, IGT, or the MS at surgery from our database of 905 consecutive patients who had undergone placement of the Swedish adjustable gastric band between January 2001 and April 2007. The patients were followed up by our multidisciplinary team, and their T2DM was managed by their treating primary care physician and/or endocrinologist. RESULTS: A total of 682 patients had >6 months of follow-up. Of these, 78 patients had T2DM, 64 had IGT, and 100 had the MS. At a median follow-up of 12.5 months, patients with T2DM had a mean +/- SD excess weight loss of 38% +/- 15%. This was associated with hemoglobin A1c and fasting blood sugar levels decreasing from 8.0% +/- 1.7% to 6.1% +/- 1.0% (P <.0001) and from 9.6 +/- 3.4 mmol/L to 5.7 +/- 1.5 mmol/L (P <.0001), respectively. Remission and/or improvement in patients with T2DM was judged by the complete cessation and/or reduction in medication and normalization of laboratory values. This occurred in 81% of those taking oral hypoglycemic agents. Of the patients taking a combination of oral hypoglycemic agents and insulin, 43% ceased and/or reduced their oral hypoglycemic agents, and 93% ceased and/or reduced their insulin requirements. Of those on insulin only, 75% ceased and/or reduced their insulin. No patient with IGT developed diabetes or progressed to require medications. Remission and/or improvement in the MS occurred in 88% of patients. Remission of T2DM was dependent on both the magnitude of excess weight loss (P = .008) and the duration of the pre-existing T2DM. Using binary logistic regression analysis, a duration of T2DM of <5 years before surgery was 6.5 times more likely to lead to resolution of T2DM after the weight loss (P = .004). CONCLUSION: Weight loss after Swedish adjustable gastric band placement is an effective treatment of T2DM in morbidly obese patients, with early intervention offering the greatest chance of remission. It might even prevent the occurrence of T2DM in patients with IGT.