The stroke transitional care intervention for older adults with stroke and multimorbidity: a multisite pragmatic randomized controlled trial.

BACKGROUND: This study aimed to test, in real-world clinical practice, the effectiveness of a Transitional Care Stroke Intervention (TCSI) compared to usual care on health outcomes, self-management, patient experience, and health and social service use costs in older adults (≥ 55 years) with stroke and multimorbidity (≥ 2 chronic conditions). METHODS: This pragmatic randomized controlled trial (RCT) included older adults discharged from hospital to community with stroke and multimorbidity using outpatient stroke rehabilitation services in two communities in Ontario, Canada. Participants were randomized 1:1 to usual care (control group) or usual care plus the 6-month TCSI (intervention group). The TCSI was delivered virtually by an interprofessional (IP) team, and included care coordination/system navigation support, phone/video visits, monthly IP team conferences, and an online resource to support system navigation. The primary outcome was risk of hospital readmission (all cause) after six-months. Secondary outcomes included physical and mental functioning, stroke self-management, patient experience, and health and social service use costs. The intention-to-treat principle was used to conduct the primary and secondary analyses. RESULTS: Ninety participants were enrolled (44 intervention, 46 control); 11 (12%) participants were lost to follow-up, leaving 79 (39 intervention, 40 control). No significant between-group differences were seen for baseline to six-month risk of hospital readmission. Differences favouring the intervention group were seen in the following secondary outcomes: physical functioning (SF-12 PCS mean difference: 5.10; 95% CI: 1.58-8.62, p = 0.005), stroke self-management (Southampton Stroke Self-Management Questionnaire mean difference: 6.00; 95% CI: 0.51-11.50, p = 0.03), and patient experience (Person-Centred Coordinated Care Experiences Questionnaire mean difference: 2.64, 95% CI: 0.81, 4.47, p = 0.005). No between-group differences were found in total healthcare costs or other secondary outcomes. CONCLUSIONS: Although participation in the TCSI did not impact hospital readmissions, there were improvements in physical functioning, stroke self-management and patient experience in older adults with stroke and multimorbidity without increasing total healthcare costs. Challenges associated with the COVID-19 pandemic, including the shift from in-person to virtual delivery, and re-deployment of interventionists could have influenced the results. A larger pragmatic RCT is needed to determine intervention effectiveness in diverse geographic settings and ethno-cultural populations and examine intervention scalability. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04278794 . Registered May 2, 2020.

On a handshake: business-to-business trust in the biosecurity behaviours of the UK live plant trade.

The movement of plants through the ornamental plant trade presents a major source of risk for the introduction and spread of plant pests and pathogens. To minimise the likelihood of infested or infected plants moving through the value chain, individual businesses can adopt a range of biosecurity practices to prevent introduction on site, as well as detecting and then containing or eradicating any plant pests or pathogens present. However, a major additional source of risk is the arrival of unhealthy plants sourced from a supplier. Using the example of bacterial plant pathogen Xylella fastidiosa which has a large host range and potentially devastating economic and environmental impacts, we highlight the importance of trust when businesses navigate the risks of sourcing plants. Through interviews and a survey with a range of plant businesses, we show (i) how two general types of risk-relational risk associated with suppliers acting in good faith, and performance risk associated with suppliers having the ability to perform as expected-can be applied to the challenge of sourcing healthy plants, (ii) how businesses respond to these risks through behaviours based on trust and control, and (iii) the potential outcomes of trust-based and control-based behaviours in the presence of a hard to detect pathogen such as Xylella fastidiosa. We conclude that trust is a significant component in decision-making in the live plant trade, and as such any behavioural interventions designed to encourage better biosecurity practices in the industry should capitalise on this understanding to strengthen responses and avoid undermining of effort.

Differentiating multichannel block on the guinea pig ECG: Use of Tpeak-Tend and J-Tpeak.

INTRODUCTION: The anaesthetised guinea pig is a well characterised assay for early assessment of drug effects on ventricular repolarisation and risk of Torsade de Pointes (TdP). We assessed whether a selective hERG blocker with known TdP risk could be differentiated from lower risk, balanced ion channel blockers in the guinea pig, using corrected QT (QTc) interval alongside novel electrocardiogram (ECG) biomarkers J-Tpeakc and Tpeak-Tend. Effects were compared with previous clinical investigations at similar plasma concentrations and with another index of TdP risk, the electromechanical window (EMW). METHODS: Twenty-two Dunkin Hartley guinea pigs anaesthetised with sodium pentobarbitone were instrumented for haemodynamic measurement and ECG recording. Three ascending doses of vehicle (n = 6), dofetilide (2, 6 or 20 µg/kg; n = 7), ranolazine (2, 6 or 20 mg/kg; n = 5) or verapamil (0.1, 0.3 or 1.0 mg/kg; n = 4) were administered intravenously. RESULTS: As reported in previous clinical studies, dofetilide induced dose-dependent increases in QTc interval, with increases in both J-TpeakC or Tpeak-Tend, while verapamil caused no significant increase in QTc interval, J-TpeakC or Tpeak-Tend. Ranolazine caused dose-dependent increases in QTc interval and corrected J-Tpeakc, but had no effect on Tpeak-Tend, which is in contrast to the effects reported in humans at similar concentrations. Only dofetilide caused a clear, dose-related decrease in the EMW. DISCUSSION: These findings suggest that measurements of J-Tpeakc and Tpeak-Tend in addition to QT interval, may help differentiate pure hERG channel blockers with high risk of TdP from lower risk, multichannel blockers.

Hamstring and gluteal activation during high-speed overground running: Impact of prior strain injury.

This study examined the spatial patterns of hamstring and gluteal muscle activation during high-speed overground running in limbs with and without aprior hamstring strain injury. Ten active males with arecent (<18 month) unilateral biceps femoris long head (BFLH) strain injury underwent functional magnetic resonance imaging before and immediately after arepeat-sprint running protocol. Transverse relaxation (T2) time, an index of muscle activation, of the BFLH and short head (BFSH), semitendinosus (ST), semimembranosus (SM), gluteus maximus (GMAX) and medius (GMED) was assessed pre-post exercise. No significant between-limb differences in running-induced mean T2 changes were observed (p = 0.949), however, decision tree induction revealed that previously injured limbs were characterised by highly variable intramuscular activation of the ST (SD5.3). T2 times increased more for GMAX than all other muscles (all p< 0.001, d= 0.5-2.5). Further, T2 changes were greater for ST than BFSH, SM, GMED, and BFLH (all p≤ 0.001, d= 0.5-2.9); and were greater for BFLH than BFSH, SM, and GMED (all p< 0.001, d= 1.2-1.6). Athletes display heterogenous patterns of posterior thigh activation when sprinting (GMAX>ST>BFLH>GMED>SM>BFSH) and may exhibit altered intramuscular hamstring activation after returning to sport from BFLH strain injury.

Eco-Epidemiological Uncertainties of Emerging Plant Diseases: The Challenge of Predicting Xylella fastidiosa Dynamics in Novel Environments.

In order to prevent and control the emergence of biosecurity threats such as vector-borne diseases of plants, it is vital to understand drivers of entry, establishment, and spatiotemporal spread, as well as the form, timing, and effectiveness of disease management strategies. An inherent challenge for policy in combatting emerging disease is the uncertainty associated with intervention planning in areas not yet affected, based on models and data from current outbreaks. Following the recent high-profile emergence of the bacterium Xylella fastidiosa in a number of European countries, we review the most pertinent epidemiological uncertainties concerning the dynamics of this bacterium in novel environments. To reduce the considerable ecological and socio-economic impacts of these outbreaks, eco-epidemiological research in a broader range of environmental conditions needs to be conducted and used to inform policy to enhance disease risk assessment, and support successful policy-making decisions. By characterizing infection pathways, we can highlight the uncertainties that surround our knowledge of this disease, drawing attention to how these are amplified when trying to predict and manage outbreaks in currently unaffected locations. To help guide future research and decision-making processes, we invited experts in different fields of plant pathology to identify data to prioritize when developing pest risk assessments. Our analysis revealed that epidemiological uncertainty is mainly driven by the large variety of hosts, vectors, and bacterial strains, leading to a range of different epidemiological characteristics further magnified by novel environmental conditions. These results offer new insights on how eco-epidemiological analyses can enhance understanding of plant disease spread and support management recommendations.[Formula: see text] Copyright © 2020 The Author(s). This is an open access article distributed under the CC BY 4.0 International license.

Games as Tools to Address Conservation Conflicts.

Conservation conflicts represent complex multilayered problems that are challenging to study. We explore the utility of theoretical, experimental, and constructivist approaches to games to help to understand and manage these challenges. We show how these approaches can help to develop theory, understand patterns in conflict, and highlight potentially effective management solutions. The choice of approach should be guided by the research question and by whether the focus is on testing hypotheses, predicting behaviour, or engaging stakeholders. Games provide an exciting opportunity to help to unravel the complexity in conflicts, while researchers need an awareness of the limitations and ethical constraints involved. Given the opportunities, this field will benefit from greater investment and development.

Wicked conflict: Using wicked problem thinking for holistic management of conservation conflict.

Conservation conflict is widespread, damaging, and has proved difficult to manage using conventional conservation approaches. Conflicts are often "wicked problems," lacking clear solutions due to divergent values of stakeholders, and being embedded within wickedly complex environments. Drawing on the concept of wicked environmental problems could lead to management strategies better suited to tackling conflict. However, it is unclear whether managers are embracing ideas from the wicked problems concept. There is currently a lack of guidance for applying strategies to tackle particular wicked problems, such as conservation conflict. We explored the suitability of wicked problems-inspired management, using eight contemporary conflict case studies. Conservation conflict was managed predominantly using conventional approaches suited to tackling single objectives in simple environments, rather than balancing competing objectives in complex environments. To deal with different characteristics of wickedness, we recommend that managers develop strategies combining distributed decision-making, diverse opinions, pattern-based predictions, trade-off-based objectives, and reporting of failures. Recent advances in conservation conflict research have focused on improving interactions among stakeholders. We believe that such stakeholder-focused approaches would dovetail with the whole-system focus of a wicked problems framework, allowing conservationists to move toward a holistic strategy for managing conservation conflict.

Drug-induced blood pressure increase - recommendations for assessment in clinical and non-clinical studies.

INTRODUCTION: Changes in blood pressure (BP) are now proactively examined throughout the drug development process as an integral aspect of safety monitoring. This is because hypertension is a very strong risk factor for cardiovascular events and drug-induced increases in BP have attracted increased regulatory attention. However, there is currently no guidance from regulatory agencies on the minimum BP data required for submissions, and there are no specific criteria for what constitutes a safety signal for increased BP in non clinical studies. Areas covered: Evaluation of BP increases through the drug discovery and development process. Expert opinion: Research into the effects of drugs should begin before clinical development is initiated and continue throughout the clinical trial program. Non clinical studies should inform a benefit-risk analysis that will aid decision-making of whether to enter the drug into Phase I development. The degree of acceptable risk will vary according to the therapy area, treatment indication and intended population for the new drug, and the approach to BP assessment and risk mitigation should be tailored accordingly. However, BP monitoring should always be included in clinical trials, and data collected from multiple studies, to convincingly prove or refute a suspicion of BP effects.

Preliminary studies of the ICD-11 classification of personality disorder in practice.

OBJECTIVE: This study aims to compare ICD-10 and putative ICD-11 classifications of personality disorder in different clinical populations. DESIGN: Prospective recording of ICD-10 and ICD-11 personality disorder classifications was carried out in (1) an anxious medical population, (2) an acute psychiatric in-patient population and (3) a retrospective recording of a mixed anxiety depression cohort in which all baseline data were scored from baseline information using the ICD-11 classification and compared with the original ICD-10 assessments. METHOD: Comparison of ICD-10 and ICD-11 prevalence of personality disorder in each population was carried out. RESULTS: Data from 722 patients were recorded. Using the ICD-10 criteria, the prevalence of generic personality disorder was 33.8% compared with 40.4% using the ICD-11 ones (χ2 = 6.7; P < 0.01), with 103 (14.3%) discordant assessments. Using the severity definitions in ICD-11, 34.3% of patients had personality difficulty. Severity level varied greatly by population; severe personality disorder was five times more common in the inpatient group. The four domain traits originally denoted as qualifying severity in ICD-11, negative affective, dissocial, anankastic and detached, were linked to anxious, borderline, dissocial, anankastic and schizoid personality disorders in ICD-10. Many patients had pathology in two or more domains. CONCLUSIONS: The ICD-11 classification of personality disorder yields somewhat higher levels of personality dysfunction than ICD-10, possibly because the age range for the onset of diagnosis is now flexible. The range of severity levels make the classification more useful than ICD-10 in clinical practice as it identifies the greater pathology necessary for intervention.

Prediction and modeling of effects on the QTc interval for clinical safety margin assessment, based on single-ascending-dose study data with AZD3839.

Corrected QT interval (QTc) prolongation in humans is usually predictable based on results from preclinical findings. This study confirms the signal from preclinical cardiac repolarization models (human ether-a-go-go-related gene, guinea pig monophasic action potential, and dog telemetry) on the clinical effects on the QTc interval. A thorough QT/QTc study is generally required for bioavailable pharmaceutical compounds to determine whether or not a drug shows a QTc effect above a threshold of regulatory interest. However, as demonstrated in this AZD3839 [(S)-1-(2-(difluoromethyl)pyridin-4-yl)-4-fluoro-1-(3-(pyrimidin-5-yl)phenyl)-1H-isoindol-3-amine hemifumarate] single-ascending-dose (SAD) study, high-resolution digital electrocardiogram data, in combination with adequate efficacy biomarker and pharmacokinetic data and nonlinear mixed effects modeling, can provide the basis to safely explore the margins to allow for robust modeling of clinical effect versus the electrophysiological risk marker. We also conclude that a carefully conducted SAD study may provide reliable data for effective early strategic decision making ahead of the thorough QT/QTc study.

Translational pharmacokinetic-pharmacodynamic modeling of QTc effects in dog and human.

INTRODUCTION: Preclinical assessment of the heart rate corrected QT interval (QTc) is an important component of the cardiovascular safety evaluation in drug discovery. Here we aimed to quantify the translational relationship between QTc prolongation and shortening in the conscious telemetered dog and humans by a retrospective pharmacokinetic-pharmacodynamic (PKPD) analysis. METHODS: QTc effects of 2 proprietary compounds and 2 reference drugs (moxifloxacin and dofetilide) were quantified in conscious dogs and healthy volunteers via a linear and Emax pharmacokinetic-pharmacodynamic models. The translational relationship was quantified by correlating the QTc response from dog and human at matching free drug concentrations. RESULTS: A consistent translational relationship was found at low delta-QTc intervals indicating that a QTc change of 2.5-8 ms in dog would correspond to a 10 ms change in human. DISCUSSION: The translational relationship developed here can be used to predict the QTc liability in human using preclinical dog data. It could therefore help protect the health of human volunteers, for example by appropriate clinical study design and dose selection, as well as improve future decision-making and help reduce compound attrition due to changes in QT interval.

Evaluation of growth, nutrient utilization and production of bioproducts by a wastewater-isolated microalga.

Treatment of wastewater while producing microalgal biomass is receiving ever-increasing attention, particularly in the biofuels arena. In this study, a wastewater chlorophyte isolate, Kirchneriella sp., was tested for its ability to be mass cultivated, utilize nutrients from defined media and wastewater, and produce bioproducts of commercial interest. Growth studies were carried out in various systems at scales up to 60L, with Kirchneriella sp. showing an excellent amenability to being cultured. Biomass concentrations of greater than 1gL(-1) were consistently achieved, nitrogen and phosphorus uptake was rapid, and stable medium-term cultures were maintained. Nitrogen limitation affected biomass yield, fatty acid methyl ester (FAME) yield, and cetane index. In contrast, a low phosphorus condition had no effect. Kirchneriella sp. showed an ability to produce several products of commercial value, including carbohydrate-rich biomass, FAME/biodiesel and the pigments ß,ß-carotene and lutein.

An introduction to QT interval prolongation and non-clinical approaches to assessing and reducing risk.

Owing to its association with Torsades de Pointes, drug-induced QT interval prolongation has been and remains a significant hurdle to the development of safe, effective medicines. Genetic and pharmacological evidence highlighting the pivotal role the human ether-a-go-go-related gene (hERG) channel was a critical step in understanding how to start addressing this issue. It led to the development of hERG assays with the rapid throughput needed for the short timescales required in early drug discovery. The resulting volume of hERG data has fostered in silico models to help chemists design compounds with reduced hERG potency. In early drug discovery, a pragmatic approach based on exceeding a given potency value has been required to decide when a compound is likely to carry a low QT risk, to support its progression to late-stage discovery. At this point, the in vivo efficacy and metabolism characteristics of the potential drug are generally defined, as well its safety profile, which includes usually a dog study to assess QT interval prolongation risk. The hERG and in vivo QT data, combined with the likely indication and the estimated free drug level for efficacy, are put together to assess the risk that the potential drug will prolong QT in man. Further data may be required to refine the risk assessment before making the major investment decisions for full development. The non-clinical data are essential to inform decisions about compound progression and to optimize the design of clinical QT studies.

Value of non-clinical cardiac repolarization assays in supporting the discovery and development of safer medicines.

Non-clinical QT-related assays aligned to the pharmaceutical drug discovery and development phases are used in several ways. During the early discovery phases, assays are used for hazard identification and wherever possible for hazard elimination. The data generated enable us to: (i) establish structure-activity relationships and thereby; (ii) influence the medicinal chemistry design and provide tools for effective decision making; and provide structure-activity data for in silico predictive databases; (iii) solve problems earlier; (iv) provide reassurance for compound or project to progress; and (v) refine strategies as scientific and technical knowledge grows. For compounds progressing into pre-clinical development, the 'core battery' QT-related data enable an integrated risk assessment to: (i) fulfil regulatory requirements; (ii) assess the safety and risk-benefit for compound progression to man; (iii) contribute to defining the starting dose during the phase I clinical trials; (iv) influence the design of the phase I clinical trials; (v) identify clinically relevant safety biomarkers; and (vi) contribute to the patient risk management plan. Once a compound progresses into clinical development, QT-related data can be applied in the context of risk management and risk mitigation. The data from 'follow-up' studies can be used to: (i) support regulatory approval; (ii) investigate discrepancies that may have emerged within and/or between non-clinical and clinical data; (iii) understand the mechanism of an undesirable pharmacodynamic effect; (iv) provide reassurance for progression into multiple dosing in humans and/or large-scale clinical trials; and (v) assess drug-drug interactions. Based on emerging data, the integrated risk assessment is then reviewed in this article, and the benefit-risk for compound progression was re-assessed. Project examples are provided to illustrate the impact of non-clinical data to support compound progression throughout the drug discovery and development phases, and regulatory approval.

Dog left ventricular midmyocardial myocytes for assessment of drug-induced delayed repolarization: short-term variability and proarrhythmic potential.

BACKGROUND AND PURPOSE: Evaluation of the potential for delayed ventricular repolarization and proarrhythmia by new drugs is essential. We investigated if dog left ventricular midmyocardial myocytes (LVMMs) that can be used as a preclinical model to assess drug effects on action potential duration (APD) and whether in these cells, short-term variability (STV) or triangulation could predict proarrhythmic potential. EXPERIMENTAL APPROACH: Beagle LVMMs and Purkinje fibres (PFs) were used to record APs. Effects of six reference drugs were assessed on APD at 50% (APD(50)) and 90% (APD(90)) of repolarization, STV(APD), triangulation (ratio APD(90)/APD(50)) and incidence of early afterdepolarizations (EADs) at 1 and 0.5 Hz. KEY RESULTS: LVMMs provided stable recordings of AP, which were not affected by four sequential additions of dimethyl sulphoxide. Effects of dofetilide, d-sotalol, cisapride, pinacidil and diltiazem, but not of terfenadine, on APD in LVMMs were found to be comparable with those recorded in PFs. LVMMs, but not PFs, exhibited a proarrhythmic response to I(Kr) blockers. Incidence of EADs was not related to differences in AP prolongation or triangulation, but corresponded to beat-to-beat variability of repolarization, here quantified as STV of APD. CONCLUSIONS AND IMPLICATIONS: LVMMs provide a suitable preclinical model to assess the effects of new drugs on APD and also yield additional information about putative indicators of proarrhythmia that add value to an integrated QT/TdP risk assessment. Our findings support the concept that increased STV(APD) may predict drug-induced proarrhythmia.

I(Ks) restricts excessive beat-to-beat variability of repolarization during beta-adrenergic receptor stimulation.

In vivo studies have suggested that increased beat-to-beat variability of ventricular repolarization duration (BVR) is a better predictor of drug-induced torsades de pointes than repolarization prolongation alone. Cellular BVR and its dynamics before proarrhythmic events are poorly understood. We investigated differential responses of BVR in single myocytes during I(Ks) blockade versus I(Kr) blockade and late-I(Na) augmentation, under the influence of beta-adrenergic receptor stimulation. Transmembrane action potentials were recorded from isolated canine left-ventricular midmyocytes at various pacing rates. I(Ks) was blocked by HMR1556, I(Kr) by dofetilide. Late I(Na) was augmented by sea anemone toxin-II. Isoproterenol was added for beta-adrenergic receptor stimulation. BAPTA-AM buffered intracellular Ca(2+). SEA0400 partially inhibited the Na(+)-Ca(2+) exchanger. BVR was quantified as variability of action-potential duration at 90% repolarization: Sigma(|APD90; i+1 minus APD90; i|)/[nbeatsx radical2] for 30 consecutive action potentials. Baseline BVR was significantly increased by I(Kr) blockade and late-I(Na) augmentation, especially at slow pacing rates. beta-adrenergic stimulation restabilized these BVR changes. In contrast, I(Ks) blockade caused very little change in repolarization when compared to baseline conditions, but predisposed the myocyte to increased BVR during beta-adrenergic stimulation, especially at fast rates. BAPTA-AM and SEA0400 reduced this excessive BVR and eliminated early afterdepolarizations. In conclusion, beta-adrenergic receptor stimulation exaggerates BVR during I(Ks) blockade, indicating a BVR-stabilizing role of beta-adrenergic-sensitive I(Ks). Loss of I(Ks) plus overriding of Ca(2+)-dependent membrane currents, including inward Na(+)-Ca(2)(+) exchange current, conspire to proarrhythmic BVR under these conditions.

A framework to assess the translation of safety pharmacology data to humans.

This article outlines a strategy for collecting accurate data for the determination of the sensitivity, specificity and predictive value of safety pharmacology models. This entails performing a retrospective analysis on commonly used safety pharmacology endpoints and an objective assessment of new non-clinical models. Such assessments require a systematic quantitative analysis of safety pharmacology parameters as well as clinical Phase I adverse events. Once the sensitivity, specificity and predictive capacity of models have been determined, they can be aligned within specific phases of the drug discovery and development pipeline for maximal impact, or removed from the screening cascade altogether. Furthermore, data will contribute to evidence-based decision-making based on the knowledge of the model sensitivity and specificity. This strategy should therefore contribute to the reduction of candidate drug attrition and a more appropriate use of animals. More data are needed to increase the power of analysis and enable more accurate comparisons of models e.g. pharmacokinetic/phamacodynamic (PK/PD) relationships as well as non-clinical and clinical outcomes for determining concordance. This task requires the collaboration and agreement of pharmaceutical companies to share data anonymously on proprietary and candidate drugs.

Validation of a voltage-sensitive dye (di-4-ANEPPS)-based method for assessing drug-induced delayed repolarisation in beagle dog left ventricular midmyocardial myocytes.

INTRODUCTION: Evaluation of drug candidates in in-vitro assays of action potential duration (APD) is one component of preclinical safety assessment. Current assays are limited by technically-demanding, time-consuming electrophysiological methods. This study aimed to assess whether a voltage-sensitive dye-based assay could be used instead. METHODS: Optical APs were recorded using di-4-ANEPPS in electrically field stimulated beagle left ventricular midmyocardial myocytes (LVMMs). Pharmacological properties of di-4-ANEPPS on the main cardiac ion channels that shape the ventricular AP were investigated using IonWorks and conventional electrophysiology. Effects of 9 reference drugs (dofetilide, E4031, D-sotalol, ATXII, cisapride, terfenadine, alfuzosin, diltiazem and pinacidil) with known APD-modulating effects were assessed on optically measured APD at 1 Hz. RESULTS: Under optimum conditions, 0.1 microM di-4-ANEPPS could be used to monitor APs paced at 1 Hz during nine, 5 s exposures without altering APD. di-4-ANEPPS had no effect on either hI(ERG), hI(Na), hI(Ks) and hI(to) currents in transfected CHO cells (up to 10 microM) or I(Ca,L) current in LVMMs (at 16 microM). di-4-ANEPPS had no effect on APs recorded with microelectrodes at 1 or 0.5 Hz over a period of 30 min di-4-ANEPPS displayed the sensitivity to record changes in optically measured APD in response to altered pacing frequencies and sequential vehicle additions did not affect the optically measured APD. APD data obtained with 9 reference drugs were as expected except (i) D-sotalol-induced increases in duration were smaller than those caused by other I(Kr) blockers and (ii) increases in APD were not detected using low concentrations of terfenadine. DISCUSSION: Early in drug discovery, the di-4-ANEPPS-based method can reliably be used to assess drug effects on APD as part of a cardiac risk assessment strategy.

A case of liver metastasis from an oncocytoma with a focal area of chromophobe renal cell carcinoma: a wolf in sheep's clothing.

In 2004, the World Health Organization classified the renal oncocytomas as benign neoplasms of the kidney. There are reports of subtypes of renal tumors, with similar histological morphology to oncocytoma, but with malignant potential, one of these tumors is the eosinophilic variant of chromophobe renal cell carcinoma. It is important to characterize the histological features and the subtype of tumor, as this predicts biological behavior and cancer-specific survival rate. A rare case of a liver metastasis from a focal area of eosinophilic variant of chromophobe renal cell carcinoma mixed in oncocytoma in a 69-year-old woman is reported. Although some renal tumors may contain oncocytoma and eosinophilic variant of chromophobe renal cell carcinoma histology, caution should be exercised while diagnosing oncocytomas in needle biopsies as there may be unsampled area of chromophobe carcinoma which has a potential for metastatic spread representing a wolf in sheep's clothing.

Early clinical development: evaluation of drug-induced torsades de pointes risk.

Drug-induced arrhythmias or QT interval prolongation is one of the two most common reasons for drugs to be denied regulatory approval or to have warnings imposed on their clinical labelling. The assessment of torsades de pointes (TdP) risk during clinical development of a new pharmaceutical compound has been an issue of debate since the original description of drug-induced proarrhythmia. TdP risk assessment is complicated by the very low incidence (e.g., <1/100,000 patient years of exposure) of clinical events for non-antiarrhythmic agents and thus the improbable likelihood of observing even one event during clinical development. Thus surrogate methods of determining risk are necessary. A clinical approach to the issue of TdP risk assessment during drug development has been developed and implemented internationally. These efforts have markedly reduced the likelihood that drugs with unknown TdP risks will be commercialized, have resulted in fostering extensive productive pre-clinical and clinical research, and subsequent improved understanding of drug-induced proarrhythmia. Current research efforts are directed to increasing the efficiency of clinical QT assessment and the impact of pre-clinical assessment on clinical development. This article describes the clinical evaluation of TdP risk during drug development and how pre-clinical assessment can impact the early clinical development TdP risk assessment.