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Background: Although mental ill-health is more prevalent among people from lower socioeconomic groups, digital mental well-being innovations are often developed for people from higher socioeconomic groups, who already have resources to maintain good mental and physical health. To decrease health inequalities and ensure that available solutions are appealing and accessible to people with fewer resources, new approaches should be explored. We developed the app Wakey!, which focused on creating engaging mental health content that is accessible, particularly among lower socioeconomic groups in the United Kingdom., Objective: The aim of this study is to assess engagement with the app, investigate initial effectiveness data for 6 well-being outcomes, and explore participants' subjective experiences of using Wakey!, Methods: The app Wakey! was publicly launched on January 20, 2020, and was free to download from Apple Store and Google Play. The app provided its users with entertaining and educational content related to mental well-being. Concurrently, a single-arm mixed methods feasibility trial was carried out from January to April 2020 among people who had downloaded the app and created an account. The primary outcome was engagement, which was collected passively from data logs. Secondary outcome measures were 6 well-being outcomes collected from self-report questionnaires. Individual interviews with 19 app users were carried out in April 2020., Results: In total, 5413 people fit the inclusion criteria and were included in the final sample-65.62% (3520/5364) women, 61.07% (3286/5381) aged between 25 and 44 years, 61.61% (2902/4710) in employment, 8.92% (420/4710) belonging to the lower socioeconomic group, and 8.09% (438/5413) were engaged users. There was no evidence of a difference in engagement regarding sociodemographic and socioeconomic characteristics. There was evidence that users with a higher average daily sleep score, who joined the study more recently, who had higher baseline self-report of sleep quality, and who found episodes more entertaining were more likely to be engaged users. Among 230 users who provided follow-up data, there was evidence of improvements on four of the six well-being outcomes: life satisfaction (P<.001), feeling that life is worthwhile (P=.01), ease of getting up in the morning (P<.001), and self-efficacy (P=.04). The app and its content were well received by those who were interviewed, and several people perceived a positive change in their mental well-being., Conclusions: This study shows that the app Wakey! could potentially be engaging across different socioeconomic groups, and there is an indication that it could positively impact the mental well-being of those engaged with the app. However, this study was a pragmatic trial with a limited sample, and the selection bias was present in the qualitative and quantitative study. Further work is needed to make any generalizable conclusions., Trial Registration: ClinicalTrials.gov NCT04287296; https://clinicaltrials.gov/ct2/show/NCT04287296., (©Mariliis Öeren, Iain Jordan, Deborah Coughlin, Sophie Turnbull. Originally published in JMIR Formative Research (https://formative.jmir.org), 23.03.2022.)

Background: Atrial fibrillation (AF) is common in older people and increases the risk of stroke. The feasibility and effectiveness of the implementation of a patient-led AF screening program for older people are unknown., Objective: This study aims to examine the feasibility and effectiveness of an AF screening program comprising patient-led monitoring of single-lead electrocardiograms (ECGs) with clinician-coordinated central monitoring to diagnose AF among community-dwelling people aged ≥75 years in Australia., Methods: This is a nationwide randomized controlled implementation trial conducted via the internet and remotely among 200 community-dwelling adults aged ≥75 years with no known AF. Randomization will be performed in a 1:1 allocation ratio for the intervention versus control. Intervention group participants will be enrolled in the monitoring program at randomization. They will receive a handheld single-lead ECG device and training on the self-recording of ECGs on weekdays and submit their ECGs via their smartphones. The control group participants will receive usual care from their general practitioners for the initial 6 months and then commence the 6-month monitoring program. The ECGs will be reviewed centrally by trained personnel. Participants and their general practitioners will be notified of AF and other clinically significant ECG abnormalities., Results: This study will establish the feasibility and effectiveness of implementing the intervention in this patient population. The primary clinical outcome is the AF detection rate, and the primary feasibility outcome is the patient satisfaction score. Other outcomes include appropriate use of anticoagulant therapy, participant recruitment rate, program engagement (eg, frequency of ECG transmission), agreement in ECG interpretation between the device automatic algorithm and clinicians, the proportion of participants who complete the trial and number of dropouts, and the impact of frailty on feasibility and outcomes. We will conduct a qualitative evaluation to examine the barriers to and acceptability and enablers of implementation. Ethics approval was obtained from the human research ethics committee at the University of Sydney (project number 2020/680). The results will be disseminated via conventional scientific forums, including peer-reviewed publications and presentations at national and international conferences., Conclusions: By incorporating an integrated health care approach involving patient empowerment, centralized clinician-coordinated ECG monitoring, and facilitation of primary care and specialist services, it is possible to diagnose and treat AF early to reduce stroke risk. This study will provide new information on how to implement AF screening using digital health technology practicably and feasibly for older and frail populations residing in the community., Trial Registration: Australian New Zealand Clinical Trials Registry ACTRN12621000184875; https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=380877., International Registered Report Identifier (irrid): DERR1-10.2196/34778., (©Kam Cheong Wong, Tu N Nguyen, Simone Marschner, Samual Turnbull, Mason Jenner Burns, Jia Yi Anna Ne, Vishal Gopal, Anupama Balasuriya Indrawansa, Steven A Trankle, Tim Usherwood, Saurabh Kumar, Richard I Lindley, Clara K Chow. Originally published in JMIR Research Protocols (https://www.researchprotocols.org), 01.02.2022.)

Background: Patients with idiopathic nonischemic cardiomyopathy (NICM) and near-normal left ventricular ejection fraction (LVEF) may develop ventricular tachycardia (VT)., Objective: The purpose of this study was to describe procedural characteristics and outcomes in patients requiring ablation for NICM-related VT with near-normal LVEF compared to impaired LVEF., Methods: Over 8 years, 77 consecutive patients with NICM-related VT underwent catheter ablation. Of these patients, 47 had idiopathic NICM (20 near-normal LVEF, 27 impaired LVEF). Procedural characteristics and outcomes were compared., Results: Mean age was 64 ± 12years, mean LVEF was 40% ± 14%, and 75% were male. In the near-normal LVEF group compared to the impaired LVEF group, LVEF was higher (54% ± 5% vs 30 ± 8%; P <.001), scar was predominantly located in the perivalvular left ventricle (LV) and basal septum (15/20 [75%]), was smaller in size [bipolar: 9.7 (6.2-32.4) cm 2 vs 30.4 (21.1-37.6) cm 2 , P = .03; unipolar: 23.3 (6.6-39.9) cm 2 vs 57.2 (42.2-74.9) cm 2 , P = .009], and required smaller areas of ablation [7.0 (5.9-14.2) cm 2 vs 11.4 (8.5-16.7) cm 2 , P = .06]. Both groups experienced comparable procedure times, fluoroscopy doses, ablation times, VT cycle lengths, and acute success rates. After final ablation, VA-free survival was comparable between both groups (65% vs 63%; P = .63) at 12 months., Conclusion: Idiopathic NICM-related VT with near-normal LVEF was associated with discrete areas of arrhythmogenic, predominantly intramural, scar in the perivalvular LV and basal septum. Despite smaller scar, patients required similar ablation amounts and experienced comparable long-term outcomes compared to patients with idiopathic NICM-related VT and impaired LVEF. These findings underscore the "three-dimensionality" of substrate, whereby the intramural basal septum forms the third dimension and impacts ablation outcomes., (Crown Copyright © 2021. Published by Elsevier Inc. All rights reserved.)

Background: The emergence and re-emergence of infectious diseases presents a significant challenge to public health and broader society. This study utilises novel nationwide data to calculate the transmission risk and potential inequity of infectious disease outbreaks through use of network analysis., Methods: Nationwide employment and education microdata (∼4.7 million individuals in Aotearoa New Zealand) were used to develop the Aotearoa Co-incidence Network (ACN). The ACN considers connections generated when individuals are employed at the same workplaces or enrolled at the same schools. Through forms of network analysis, connections between geospatial areas can be established and provide proxy measures of infectious disease transmission risk. The ACN was also overlayed with nationwide population vulnerability data based on the number of older adults (>65 years) and individuals with long-term health conditions., Findings: We identify areas that have both high potential transmission risk (i.e., highly connected) and high vulnerability to infectious diseases. Community detection identified geographic boundaries that can be relevant to the application of regional restrictions for limiting infectious disease transmission., Interpretation: Integrating novel network science and geospatial analytics provides a simple way to study infectious disease transmission risk and population vulnerability to outbreaks. Our replicable method has utility for researchers globally with access to such data. It can help inform equitable preparation for, and responses to infectious disease outbreaks., Funding: This project was funded by the Health Research Council of New Zealand (20/1442) and from the NZ Government via Ministry for Business Innovation and Employment and Department of Prime Minister and Cabinet., Competing Interests: This project was funded by the Health Research Council of New Zealand (20/1442) and from the New Zealand Government via Ministry for Business Innovation and Employment and Department of Prime Minister and Cabinet contracts for modelling advice on responding to COVID-19 in Aotearoa New Zealand. The authors have no conflict of interests to declare., (© 2021 The Author(s).)

Objectives: This study hypothesized that catheter ablation in healthy ovine ventricular myocardium using low ionic 0.45% saline (half-normal saline [HNS]) and nonionic 5% dextrose in water (D5W) would result in larger lesions compared with use of 0.9% saline (normal saline [NS])., Background: Limited data exist regarding the safety and efficacy of catheter ablation using low and nonionic irrigants., Methods: Open irrigated ablation was performed on 14 beating ovine hearts (NS, n = 5; HNS, n = 4; D5W, n = 5). Ablation was delivered by using identical parameters (ie, 30 W in power control mode, 60-second duration, contact force of 10-20 g in the endocardial ventricles and 5-10 g in the epicardium). Catheter orientation and tissue contact were optimized by using intracardiac echocardiography. Lesion width, depth, and volume and number of steam pops were compared., Results: Overall, 196 lesions were analyzed (mean duration: 56.7 ± 8.3 seconds; mean contact force: 15.3 ± 6.1 g; and mean impedance drop: 31 ± 19.1 Ω). Compared with NS, HNS and D5W resulted in larger lesion volumes (NS 349.2 ± 245.1 mm 3 vs HNS 645.7 ± 386.4 mm 3 vs D5W 633.2 ± 387.1 mm 3 ; HNS vs NS; P < 0.001; D5W vs NS; P < 0.001; D5W vs HNS; P = 0.87). However, D5W was associated with higher steam pop occurrence (NS 5% vs HNS 11% vs D5W 35%; HNS vs NS; P = 0.22; D5W vs NS; P < 0.001; D5W vs HNS; P = 0.002)., Conclusions: Catheter ablation with HNS and D5W resulted in larger ablation lesions compared with NS but similar lesion dimensions between HNS and D5W. The increase in lesion size with HNS and D5W was associated with a higher incidence of steam pops, especially with D5W, compared with NS., Competing Interests: Funding Support and Author Disclosures Dr Kumar is supported by the NSW Early-mid Career Fellowship. Mr Campbell is a former employee of Biosense Webster, Inc; and has received speaker honoraria from Biosense Webster, Inc in the last 12 months. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2021 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Objectives: This study describes the clinical and electrophysiological characteristics of basal-septal ventricular tachycardias (VTs) in patients with structural heart disease (SHD)., Background: The basal septum is a common source of VT in patients with SHD., Methods: Data from 312 consecutive patients with SHD undergoing catheter ablation of ventricular arrhythmias were reviewed., Results: Thirty-three basal-septal VTs in 31 patients (mean age 67.4 ± 14.2 years, mean left ventricular ejection fraction [LVEF] 42% ± 15%) were identified. Patients with VTs with left ventricular basal-septal breakthrough were more likely to have ischemic cardiomyopathy and lower LVEF; patients with right ventricular basal-septal VT were more likely to have sarcoidosis or right ventricular cardiomyopathy of unknown significance, with higher LVEF. Atrioventricular block was present in 45% of patients and intraventricular block including persistent biventricular pacing in 77%. Unipolar scar was larger than bipolar scar (area 18.8% ± 19.4% vs 12.7% ± 14.6%; P < 0.001). VTs with right bundle branch block configuration and S wave in lead V 6 with positive V 3 /V 4 polarity consistently indicated left ventricular basal-septal breakthrough. Inferior limb-lead discordance with right bundle branch block configuration and "reverse pattern break in lead V 2 " were identified in left ventricular basal inferior-septal origin in 3 patients. VT noninducibility was achieved in 55%, and VT recurred in 42% of patients after a single procedure, but VT burden was significantly reduced after ablation (59 episodes before vs 2 episodes after ablation; P = 0.02)., Conclusions: Basal-septal VTs in patients with SHD have a distinct clinical, electrocardiographic, and electrophysiological profile depending on the breakthrough site, accompanied by a deep intramural septal substrate that limits procedural success after catheter ablation., Competing Interests: Funding Support and Author Disclosures This work was supported in part by the New South Wales Early-Mid Career Fellowship. Dr Kumar has received research grants from Abbott Medical and Biotronik; and has received honoraria from Biosense Webster, Abbott Medical, Biotronik, and Sanofi. Mr Campbell has received speaker honoraria from Biosense Webster. Dr Kotake is the recipient of a Nihon Koden/Abbott Arrhythmia Fellowship from the Japan Heart Rhythm Society. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Crown Copyright © 2021. Published by Elsevier Inc. All rights reserved.)

Background: There are limited data comparing ablation outcomes in patients with low intraprocedural burden of ventricular arrhythmias (VA) undergoing a pace mapping (PM)-guided strategy vs those with high burden guided by standard activation mapping strategy (non-PM)., Objective: We sought to determine if catheter ablation-guided by PM of low-intraprocedural-burden idiopathic outflow tract VA would be noninferior compared to non-PM-guided ablation., Methods: Outcomes of catheter ablation of idiopathic outflow tract VA in 22 patients with a low burden of intraprocedural VA using PM-guided ablation were compared to 44 patients with a high burden of intraprocedural VA undergoing ablation using standard techniques., Results: Sixty-six patients were included (age 46.5 ± 14.8 years; 68% female, left ventricular ejection fraction 59% ± 5%). Within the PM group, 24-hour preprocedure premature ventricular complex (PVC) burden was 9.5% (interquartile range [IQR] 4%-13.8%), number of pace maps 33.6 ± 18.5, surface area of ≥95% pace map correlation 1.9 ± 1.2 cm 2 , with best pace map correlation 96% (IQR 92%-97%). Within the non-PM group, 24-hour preprocedure PVC burden was 13.5% (IQR 6.6%-30%), earliest activation time -33.7 ± 9.9 ms. Procedural duration, general anesthesia administration, fluoroscopy dose, and complications were all comparable. Following final procedure, 24-hour VA burden (PM 0% [IQR 0-2.4%] vs non-PM 0% [IQR 0-4.2%], P = .98), along with VA-free survival at 6-month follow-up (PM 77% vs non-PM 71%, P  = .77), were both comparable., Conclusion: In patients with low intraprocedural burden of outflow tract VA, PM-guided catheter ablation can accurately identify the VA site of origin, leading to outcomes comparable to those achieved with standard ablation techniques., (© 2021 Heart Rhythm Society. Published by Elsevier Inc.)

Background: Rapid access cardiology services have been proposed for assessment of acute cardiac conditions via an outpatient model-of-care that potentially could reduce hospitalisations. We describe a new Rapid Access Arrhythmia Clinic (RAAC) and compare major safety endpoints to usual care., Methods: We matched 312 adult patients with suspected arrhythmia in RAAC to historical age and sex-matched controls discharged from hospital within Western Sydney Local Health District with suspected arrhythmia. The primary endpoint was a composite of time to first unplanned cardiovascular hospitalisation or cardiac death over 12 months., Results: The average age of RAAC patients was 52.2±18.8 years and 51.6±18.8 years for controls, and 48.4% were female in both groups. Mean time from referral to first attended RAAC appointment was 10.5 days. Most were referred from emergency (177, 56.7%) and cardiologists at time of discharge (65, 20.8%). The most common reason for referral was palpitations (180, 57.7%). In total, 155 (49.7%) had a documented arrhythmia, with the most common being atrial fibrillation/flutter (88, 28.2%). The primary endpoint occurred in 35 (11.2%) patients in the RAAC pathway (97.1[95% CI 70-131.3] per 1,000 person-years), compared to 72 (23.1%) patients for usual care controls (229.5[95% CI 180.2-288.1] per 1,000 person-years). Using a propensity score analysis, RAAC pathway significantly reduced the primary endpoint by 59% compared to usual care (HR 0.41, 95% CI 0.27-0.62; p<0.001)., Conclusions: RAACs for the early investigation and management of suspected arrhythmia is superior to usual care in terms of reduction in unplanned cardiovascular hospitalisation and death., (Copyright © 2020 Australian and New Zealand Society of Cardiac and Thoracic Surgeons (ANZSCTS) and the Cardiac Society of Australia and New Zealand (CSANZ). All rights reserved.)

Background and Objectives: There is little emphasis on the efficacy of catheter ablation for ventricular arrhythmia (VA) when using VA burden reduction as a marker for success. We examined the efficacy of catheter ablation using VA burden, rather than VA recurrence as a marker of success, following catheter ablation of structural heart disease (SHD) related VA., Methods: Catheter ablation of SHD related VA was performed at a single centre over 4-years. VA episodes and implantable cardioverter defibrillator (ICD) therapies were recorded over the 6-months before and after final ablation. Outcomes were reported in terms of burden reduction and compared to singular VA recurrence., Results: Overall, 108 patients were included in the study. Mean age 64.2±13.9 years, 86% male, mean left ventricular ejection fraction (LVEF) 42±16%. Median VA episodes and ICD therapy were significantly reduced after ablation (VA before: 10 [interquartile range, IQR: 2-38] vs. VA after: 0 [IQR: 0-2], p<0.001; anti-tachycardia pacing [ATP] before: 16 (IQR: 1.5-57) vs. ATP after: 0 [IQR: 0-2], p<0.001; shocks before: 1 [IQR: 0-5] vs. shocks after: 0 [IQR: 0-0], p<0.001). Procedural success at 6-months was significantly higher when considering ≥75% reduction in VA burden, rather than a singular VA-free survival (83% vs. 67%, p=0.001)., Conclusions: The vast majority (>80%) of patients achieve reduction in VA burden (≥75% reduction) after catheter ablation for VA. This data suggests that catheter ablation is highly therapeutic when procedure success is defined as reduction in VA, rather than using a single VA recurrence as a metric for failure., Competing Interests: Dr Saurabh Kumar is supported by the NSW Early-mid Career Fellowship, and Timothy Campbell is a former employee of Biosense Webster, Inc. and has received speakers' honoraria for Biosense Webster, Inc. in the last 12 months. We report no conflicts of interest., (Copyright © 2021. The Korean Society of Cardiology.)

Background: Veno-arterial extracorporeal membrane oxygenation (VA-ECMO) can provide circulatory support in high-risk patients undergoing drug refractory ventricular tachycardia (VT) ablation procedures. We report experience using VA-ECMO in a pre-emptive approach for high-risk patients with VT storm and previously ineffective ablation procedures., Methods and Results: Four (4) patients with drug refractory ventricular tachycardia (mean age 61±3 years; left ventricular ejection fraction 21±5%) presenting for VT ablation had pre-emptive VA-ECMO. All patients during current admission had VT storm. Pre-ablation, 22 total monomorphic VTs (cycle length 402±69 ms) were induced or spontaneously observed (median of 4, IQR 25-75% 1-6). At the end of the procedure, 86% of all inducible VTs were rendered non-inducible. Median hospitalisation following VA-ECMO supported ablation was 5 days (IQR 25-75% 3-12). During follow-up (median 138 days [IQR 25-75% 57-277]), VT recurred in one patient as an isolated episode reverted by anti-tachycardia pacing. There was a 99% reduction in VT burden post ablation. One (1) patient died of cardiogenic shock within 24 hours whilst still on VA-ECMO, all other patients were successfully weaned off support and discharged. Two (2) patients underwent cardiac transplantation at 199 and 512 days post ablation following implantation of ventricular assist devices for worsening heart failure., Conclusions: The pre-emptive use of VA-ECMO for high-risk patients undergoing catheter ablation for VT storm was found to be effective in maintaining haemodynamic status, and allowing successful mapping and catheter ablation for VT., (Crown Copyright © 2020. Published by Elsevier B.V. All rights reserved.)

Background: Type 2 Diabetes (T2D) is a common chronic disease, with socially patterned incidence and severity. Digital self-care interventions have the potential to reduce health disparities, by providing personalised low-cost reusable resources that can increase access to health interventions. However, if under-served groups are unable to access or use digital technologies, Digital Health Technologies (DHTs) might make no difference, or worse, exacerbate health inequity., Study Aims: To gain insights into how and why people with T2D access and use DHTs and how experiences vary between individuals and social groups., Methods: A purposive sample of people with experience of using a DHT to help them self-care for T2D were recruited through diabetes and community groups. Semi-structured interviews were conducted in person and over the phone. Data were analysed thematically., Results: A diverse sample of 21 participants were interviewed. Health care practitioners were not viewed as a good source of information about DHTs that could support T2D. Instead participants relied on their digital skills and social networks to learn about what DHTs are available and helpful. The main barriers to accessing and using DHT described by the participants were availability of DHTs from the NHS, cost and technical proficiency. However, some participants described how they were able to draw on social resources such as their social networks and social status to overcome these barriers. Participants were motivated to use DHTs because they provided self-care support, a feeling of control over T2D, and personalised advice or feedback. The selection of technology was also guided by participants' preferences and what they valued in relation to DHTs and self-care support, and these in turn were influenced by age and gender., Conclusion: This research indicates that low levels of digital skills and high cost of digital health interventions can create barriers to the access and use of DHTs to support the self-care of T2D. However, social networks and social status can be leveraged to overcome some of these challenges. If digital interventions are to decrease rather than exacerbate health inequalities, these barriers and facilitators to access and use must be considered when DHTs are developed and implemented.

Introduction: Testing for inducible ventricular tachycardia (VT) pre- and postablation forms the cornerstone of contemporary scar-related VT ablation procedures. There is significant heterogeneity in reported VT induction protocols. We examined the utility of an extensive induction protocol (up to 4 extra-stimuli [ES] ± burst ventricular pacing) compared to the current guideline-recommended protocol (up to 3ES, defined as limited induction protocol) in patients with scar-related VT., Methods and Results: Sixty-two patients (age: 64 ± 14 years; left ventricular ejection fraction: 37 ± 13%, ischemic cardiomyopathy: 31, nonischemic cardiomyopathy: 31) with at least one inducible VT were included. An extensive testing protocol induced 11%-17% more VTs, compared to the limited induction protocol before, and after the final ablation. VT recurred in 48% of patients during a mean follow up of 566 ± 428 days. Patients who were noninducible for any VT using the limited induction protocol had worse ventricular arrhythmia (VA)-free survival (12 months, 43% vs. 82%; p = .03) and worse survival free of VA, transplantation and mortality (12 months 46% vs. 82%; p = .02), compared to patients who were noninducible for any VT using the extensive induction protocol., Conclusions: Between 11% and 17% of inducible VTs may be missed if 4ES and burst pacing are not performed in induction protocols before and after ablation. Noninducibility for any VT after an extensive induction protocol after the final ablation portends more favorable prognostic outcomes when compared with the current guideline-recommended induction protocol of up to 3ES. This data suggests that the adoption of an extensive induction protocol is of prognostic benefit after VT ablation., (© 2020 Wiley Periodicals LLC.)

Melatonin is a neurohormone that has been shown to be protective in Alzheimer's diseases against amyloid-β (Aβ) toxicity, which involves interaction of Aβ with neuronal membrane. Non-specific interactions of melatonin with cell membrane may play a physiological role in this process by preserving membrane fluidity. In the brain, melatonin is derived from the amino acid tryptophan through a pathway that includes serotonin and N-acetylserotonin (NAS). How these molecules affect the membrane properties is not understood. In this work, we studied interactions of melatonin and its metabolic precursors tryptophan, serotonin and NAS with dipalmitoylphosphatidylcholine (DPPC) monolayers at the air-water interface using Langmuir monolayer technique. Analysis of compression isotherms, phase transitions and compressibility moduli indicate that all four molecules alter the DPPC monolayer properties in a structure and concentration dependent manner. This effect was most pronounced for melatonin followed by NAS. Melatonin and NAS both decreased the compressibility modulus and shifted the LE/LC phase transition suggesting an increase in the membrane fluidity. Tryptophan and serotonin caused less pronounced effects on the DPPC isotherm. These differences suggest different interaction mechanisms and may be attributed to the interplay between electrostatic and hydrophobic interactions of these molecules with the zwitterionic DPPC headgroups which correlate with water solubility and oil partition coefficients (LogS and LogP) of each the four molecules. The results here demonstrate how the physiochemical properties of indoles can affect lipid membranes which may shed light on the functional significance of these important neurochemicals and the neuroprotective mechanisms of melatonin., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier B.V. All rights reserved.)

A growing body of literature links claimant interactions with the UK social security system and negative psychological consequences. Psychologists for social change developed a framework to outline proposed mechanisms of psychological impact from austerity. This codesigned study aimed to make an informed comment on areas of dis(agreement) between the Austerity Ailments framework and how people claiming for mental health problems describe their own experiences. In line with the participatory social welfare design of the study, qualitative analysis was performed by both claimants and academics. The overall findings indicate that existing framework mostly captured claimant experiences. However, some aspects of the claimant experience (particularly social aspects) were not well captured. Claimants were keen to utilise this study as an opportunity to gather claimant ideas on how to improve the system. Therefore, we report their suggestions that may be useful for those designing and improving social welfare systems., (© 2019 Wiley Periodicals, Inc.)

Introduction: Minimal data exist on the Advisor HD Grid (HDG) catheter and the Precision electroanatomic mapping (EAM) system for ventricular arrhythmia (VA) procedures. Using the HDG catheter, the EAM uses the high-density (HD) wave mapping and best duplicate software to compare the maximum peak-to-peak bipolar voltages within a small zone independent of wavefront direction and catheter orientation. This study aimed to summarize the procedural experience for VAs using the HDG catheter., Methods: Clinical and procedural characteristics of VA ablation procedures were retrospectively reviewed that used the HDG catheter and the Precision EAM over a 12-month period., Results: A total of 22 patients, 18 with sustained ventricular tachycardia and 4 with premature ventricular contractions were included. Clinically indicated left and/or right ventricular (LV, RV, respectively), and aortic maps were created. LV substrate maps (n = 13) used a median 1700 points (interquartile range [IQR] 25%-75% , 1427-2412) out of a median 18 573 (IQR 25%-75% , 15 713-41 067) total points collected. RV substrate maps (n = 11) used a median 1435 points (IQR 25%-75% , 1114-1871) out of a median 16 005 (IQR 25%-75% , 11 063-21 405) total points collected. Total point utilization, used vs collected, was 9%. Mean mapping time was 43 ± 17 minutes (substrate, 34 ± 18 minutes; activation/pace mapping, 9 ± 13 minutes). Acute success was achieved in 56 (86%) and short-term success achieved in 16 patients (73%) at a median follow-up of 145 days (IQR 25%-75% , 62-273 days). There were no procedural complications., Conclusion: HD wave mapping using the novel HDG catheter integrated with the Precision EAM is safe and feasible in VA procedures in the LV, RV, and aorta. Mapping times are consistent with other multielectrode mapping catheters., (© 2020 Wiley Periodicals, Inc.)

Interspecific hybridization is recognized as an important process in the evolutionary dynamics of both speciation and the reversal of speciation. However, our understanding of the spatial and temporal patterns of hybridization that erode versus promote species boundaries is incomplete. The endangered, endemic koloa maoli (or Hawaiian duck, Anas wyvilliana) is thought to be threatened with genetic extinction through ongoing hybridization with an introduced congener, the feral mallard (A. platyrhynchos). We investigated spatial and temporal variation in hybrid prevalence in populations throughout the main Hawaiian Islands, using genomic data to characterize population structure of koloa, quantify the extent of hybridization, and compare hybrid proportions over time. To accomplish this, we genotyped 3,308 double-digest restriction-site-associated DNA (ddRAD) loci in 425 putative koloa, mallards, and hybrids from populations across the main Hawaiian Islands. We found that despite a population decline in the last century, koloa genetic diversity is high. There were few hybrids on the island of Kaua'i, home to the largest population of koloa. By contrast, we report that sampled populations outside of Kaua'i can now be characterized as hybrid swarms, in that all individuals sampled were of mixed koloa × mallard ancestry. Further, there is some evidence that these swarms are stable over time. These findings demonstrate spatial variation in the extent and consequences of interspecific hybridization, and highlight how islands or island-like systems with small population sizes may be especially prone to genetic extinction when met with a congener that is not reproductively isolated., (© 2019 John Wiley & Sons Ltd.)

Reactive attachment disorder (RAD) is one of the least researched and most poorly understood psychiatric disorders. Very little is known about the prevalence and stability of RAD symptoms over time. Until recently it has been difficult to investigate RAD due to limited tools for informing a diagnosis. Utilising a newly developed observational tool along with the Disturbances of Attachment Interview. this short-term prospective longitudinal study explored RAD symptoms in maltreated young children in Scotland (n=100, age range =12-62 months) over 12 months. Children were recruited as part of The Best Services Trial (BeST ? ), in which all infants who came in to the care of the local authority in Glasgow due to child protection concerns were invited to participate. Prevalence of RAD was found to be 5.0% (n=5, 95% CI [0.7-9.3]) when children were first placed in to foster care. Following at least 1 year of improved care conditions, prevalence in the 76 children remaining in the study was 2.1% (n=2, 95% CI [below 0-4.7]). RAD was associated with some mental health and cognitive difficulties. While levels of carer-reported RAD symptoms decreased significantly over time, observed symptoms did not. Findings suggest that RAD resolved in a small majority of cases but further exploration in larger samples would be invaluable.

Background: Severity assessments of respiratory tract infection (RTI) in children are known to differ between parents and clinicians, but determinants of perceived severity are unknown., Aim: To investigate the (dis)agreement between, and compare the determinants of, parent and clinician severity scores., Design and Setting: Secondary analysis of data from a prospective cohort study of 8394 children presenting to primary care with acute (≤28 days) cough and RTI., Method: Data on sociodemographic factors, parent-reported symptoms, clinician-reported findings, and severity assessments were used. Kappa (κ)-statistics were used to investigate (dis) agreement, whereas multivariable logistic regression was used to identify the factors associated with illness severity., Results: Parents reported higher illness severity (mean 5.2 [standard deviation (SD) 1.8], median 5 [interquartile range (IQR) 4-7]), than clinicians (mean 3.1 [SD 1.7], median 3 [IQR 2-4], P <0.0001). There was low positive correlation between these scores (+0.43) and poor inter-rater agreement between parents and clinicians (κ 0.049). The number of clinical signs was highly correlated with clinician scores (+0.71). Parent-reported symptoms (in the previous 24 hours) that were independently associated with higher illness severity scores, in order of importance, were: severe fever, severe cough, rapid breathing, severe reduced eating, moderate-to-severe reduced fluid intake, severe disturbed sleep, and change in cry. Three of these symptoms (severe fever, rapid breathing, and change in cry) along with inter/subcostal recession, crackles/crepitations, nasal flaring, wheeze, and drowsiness/irritability were associated with higher clinician scores., Conclusion: Clinicians and parents use different factors and make different judgements about the severity of children's RTI. Improved understanding of the factors that concern parents could improve parent-clinician communication and consultation outcomes., (© British Journal of General Practice 2019.)

Background: Little is known about respiratory tract infection (RTI) severity in children following consultation., Objectives: To investigate post-consultation symptom trajectories in children with acute cough and RTI and whether baseline characteristics predict trajectory group., Methods: Prospective cohort study of 2296 children (3 months-16 years) whose parents were invited to report cough severity and duration using a 7-point Likert scale. Longitudinal latent class analysis (LLCA) was used to identify post-consultation symptom trajectories in the first 15 days, and multinomial models to predict class membership., Results: Complete data were available for 1408 children (61%). The best LLCA model identified five post-consultation symptom trajectory groups: 'very rapid recovery' (28.5%), 'rapid recovery' (37.7%), 'intermediate recovery' (18.2%), 'persistent symptoms' (9.5%) and 'initial deterioration with persistent symptoms' (6.0%). Compared with very rapid recovery, parent-reported severe cough in the 24 hours prior to consultation increased the likelihood of rapid recovery (OR 1.79 [95% CI 1.23, 2.60]), intermediate recovery (OR 2.13 [1.38, 3.30] and initial deterioration with persistent symptoms (OR 2.29 [1.26, 4.16]). Initial deterioration was also associated with 'severe barking cough' (OR 3.64 [1.50, 8.82]), 'severely reduced energy in the 24 hours prior to consultation' (OR 3.80 [1.62, 8.87] and higher parent-assessed illness severity at consultation (OR 2.21 [1.17, 4.18])., Conclusion: We identified five distinct symptom trajectory groups showing the majority of children improved post-consultation, with only one group experiencing illness deterioration. The few characteristics associated with group membership did not fall into a pattern that seemed clinically useful.

Healthcare has advanced significantly, bringing with it longer life expectancies and a growing population of elders who suffer from dementia, specifically Alzheimer's disease (AD). The amyloid beta (Aβ) peptide has been implicated in the cause of AD, where the peptides undergo a conformational change and form neurotoxic amyloid oligomers which cause neuronal cell death. While AD has no cure, preventative measures are being designed to either slow down or stop the progression of this neurodegenerative disease. One of these measures involves dietary supplements with polyunsaturated fatty acids such as docosahexaenoic acid (DHA). This omega-3 fatty acid is a key component of brain development and has been suggested to reduce the progression of cognitive decline. However, different studies have yielded different results as to whether DHA has positive, negative, or no effects on Aβ fibril formation. We believe that these discrepancies can be explained with varying concentrations of DHA. Here, we test the inhibitory effect of different concentrations of DHA on amyloid fibril formation using atomic force microscopy. Our results show that DHA has a strong inhibitory effect on Aβ 1⁻42 fibril formation at lower concentrations (50% reduction in fibril length) than higher concentrations above its critical micelle concentration (70% increase in fibril length and three times the length of those at lower concentrations). We provide evidence that various concentrations of DHA can play a role in the inhibitory effects of amyloid fibril formation in vitro and help explain the discrepancies observed in previous studies.

Background: Clinicians commonly prescribe antibiotics to prevent major adverse outcomes in children presenting in primary care with cough and respiratory symptoms, despite limited meaningful evidence of impact on these outcomes., Aim: To estimate the effect of children's antibiotic prescribing on adverse outcomes within 30 days of initial consultation., Design and Setting: Secondary analysis of 8320 children in a multicentre prospective cohort study, aged 3 months to <16 years, presenting in primary care across England with acute cough and other respiratory symptoms., Method: Baseline clinical characteristics and antibiotic prescribing data were collected, and generalised linear models were used to estimate the effect of antibiotic prescribing on adverse outcomes within 30 days (subsequent hospitalisations and reconsultation for deterioration), controlling for clustering and clinicians' propensity to prescribe antibiotics., Results: Sixty-five (0.8%) children were hospitalised and 350 (4%) reconsulted for deterioration. Clinicians prescribed immediate and delayed antibiotics to 2313 (28%) and 771 (9%), respectively. Compared with no antibiotics, there was no clear evidence that antibiotics reduced hospitalisations (immediate antibiotic risk ratio [RR] 0.83, 95% confidence interval [CI] = 0.47 to 1.45; delayed RR 0.70, 95% CI = 0.26 to 1.90, overall P = 0.44). There was evidence that delayed (rather than immediate) antibiotics reduced reconsultations for deterioration (immediate RR 0.82, 95% CI = 0.65 to 1.07; delayed RR 0.55, 95% CI = 0.34 to 0.88, overall P = 0.024)., Conclusion: Most children presenting with acute cough and respiratory symptoms in primary care are not at risk of hospitalisation, and antibiotics may not reduce the risk. If an antibiotic is considered, a delayed antibiotic prescription may be preferable as it is likely to reduce reconsultation for deterioration., (© British Journal of General Practice 2018.)

Background: The objectives were to identify 1) the clinician and child characteristics associated with; 2) clinical management decisions following from, and; 3) the prognostic value of; a clinician's 'gut feeling something is wrong' for children presenting to primary care with acute cough and respiratory tract infection (RTI)., Methods: Multicentre prospective cohort study where 518 primary care clinicians across 244 general practices in England assessed 8394 children aged ≥3 months and < 16 years for acute cough and RTI. The main outcome measures were: Self-reported clinician 'gut feeling'; clinician management decisions (antibiotic prescribing, referral for acute admission); and child's prognosis (reconsultation with evidence of illness deterioration, hospital admission in the 30 days following recruitment)., Results: Clinician years since qualification, parent reported symptoms (illness severity score ≥ 7/10, severe fever < 24 h, low energy, shortness of breath) and clinical examination findings (crackles/ crepitations on chest auscultation, recession, pallor, bronchial breathing, wheeze, temperature ≥ 37.8 °C, tachypnoea and inflamed pharynx) independently contributed towards a clinician 'gut feeling that something was wrong'. 'Gut feeling' was independently associated with increased antibiotic prescribing and referral for secondary care assessment. After adjustment for other associated factors, gut feeling was not associated with reconsultations or hospital admissions., Conclusions: Clinicians were more likely to report a gut feeling something is wrong, when they were more experienced or when children were more unwell. Gut feeling is independently and strongly associated with antibiotic prescribing and referral to secondary care, but not with two indicators of poor child health.

Objective: To investigate recruitment and retention, data collection methods and the acceptability of a 'within-consultation' complex intervention designed to reduce antibiotic prescribing., Design: Primary care feasibility cluster randomised controlled trial., Setting: 32 general practices in South West England recruiting children from October 2014 to April 2015., Participants: Children (aged 3 months to <12 years) with acute cough and respiratory tract infection (RTI)., Intervention: A web-based clinician-focussed clinical rule to predict risk of future hospitalisation and a printed leaflet with individualised child health information for carers, safety-netting advice and a treatment decision record., Controls: Usual practice, with clinicians recording data on symptoms, signs and treatment decisions., Results: Of 542 children invited, 501 (92.4%) consented to participate, a month ahead of schedule. Antibiotic prescribing data were collected for all children, follow-up data for 495 (98.8%) and the National Health Service resource use data for 494 (98.6%). The overall antibiotic prescribing rates for children's RTIs were 25% and 15.8% (p=0.018) in intervention and control groups, respectively. We found evidence of postrandomisation differential recruitment: the number of children recruited to the intervention arm was higher (292 vs 209); over half were recruited by prescribing nurses compared with less than a third in the control arm; children in the intervention arm were younger (median age 2 vs 3 years controls, p=0.03) and appeared to be more unwell than those in the control arm with higher respiratory rates (p<0.0001), wheeze prevalence (p=0.007) and global illness severity scores assessed by carers (p=0.045) and clinicians (p=0.01). Interviews with clinicians confirmed preferential recruitment of less unwell children to the trial, more so in the control arm., Conclusion: Differential recruitment may explain the paradoxical antibiotic prescribing rates. Future cluster level studies should consider designs which remove the need for individual consent postrandomisation and embed the intervention within electronic primary care records., Trial Registration Number: ISRCTN 23547970 UKCRN STUDY ID: 16891., Competing Interests: Competing interests: None declared., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Background To determine the recommended dose (RD) of a combination of PM01183 and gemcitabine in patients with advanced solid tumors. Methods Forty-five patients received escalating doses of PM01183/gemcitabine on Days 1 and 8 every 3 weeks (d1,8 q3wk) following a standard 3 + 3 design. Results PM01183 3.5 mg flat dose (FD)/gemcitabine 1000 mg/m 2 was the highest dose level tested. Dose-limiting toxicities (DLTs) were mostly hematological and resulted in the expansion of a lower dose level (PM01183 3.5 mg FD/gemcitabine 800 mg/m 2 ); 19 patients at this dose level were evaluable but >30% had DLT and >20% had febrile neutropenia. No DLT was observed in 11 patients treated at PM01183 3.0 mg FD/gemcitabine 800 mg/m 2 , which was defined as the RD. This regimen was feasible and tolerable with manageable toxicity; mainly grade 3/4 myelosuppression. Non-hematological toxicity comprised fatigue, nausea, vomiting, and transaminases increases. Fifteen (33%) patients received ≥6 cycles with no cumulative hematological toxicity. Pharmacokinetic analysis showed no evidence of drug-drug interaction. Nine of 38 patients had response as per RECIST (complete [3%] and partial [21%]), for an overall response rate (ORR) of 24% (95% Confidence Interval [CI] 12-40%). Eleven patients (29%) had disease stabilization ≥4 months. Responses were durable (median of 8.5 months): overall median progression-free survival (PFS) was 4.2 months (95% CI, 2.7-6.5 months). Conclusions The RD for this combination is PM01183 3.0 mg FD (or 1.6 mg/m 2 )/gemcitabine 800 mg/m 2 d1,8 q3wk. This schedule is well tolerated and has antitumor activity in several advanced solid tumor types.

Attachment disorders, specifically Reactive Attachment Disorder (RAD) and Disinhibited Social Engagement Disorder (DSED) are disorders associated with neglect and abuse in which people have significant difficulties relating to others. This study aims to explore Attachment Disorder symptoms and diagnoses in young offenders and factors that may be associated with them such as mental health problems. A cross-sectional design was used with 29 young people who were known to Intensive Services, aged 12-17 (M=16.2, SD=1.3), 29 carers and 20 teachers. They completed measures investigating symptoms of Attachment Disorders and psychopathology. Eighty-six percent of the young people had experienced some form of maltreatment and the rates of an actual or borderline Attachment Disorder was 52%. A positive correlation between Attachment Disorder symptoms and other mental health problems (as rated by carer-report Strengths and Difficulties Questionnaire Total Difficulties Score), accounting for 36% of the variance was found, with a large effect size (r s =0.60). Attachment Disorder symptoms were associated with hyperactivity and peer relationship problems., (Copyright © 2017. Published by Elsevier Ltd.)

Background: Antimicrobial resistance is a serious threat to public health, with most antibiotics prescribed in primary care. General practitioners (GPs) report defensive antibiotic prescribing to mitigate perceived risk of future hospital admission in children with respiratory tract infections. We developed a clinical rule aimed to reduce clinical uncertainty by stratifying risk of future hospital admission., Methods: 8394 children aged between 3 months and 16 years presenting with acute cough (for ≤28 days) and respiratory tract infection were recruited to a prognostic cohort study from 247 general practitioner practices in England. Exposure variables included demographic characteristics, parent-reported symptoms, and physical examination signs. The outcome was hospital admission for respiratory tract infection within 30 days, collected using a structured, blinded review of medical records., Findings: 8394 (100%) children were included in the analysis, with 78 (0·9%, 95% CI 0·7%-1·2%) admitted to hospital: 15 (19%) were admitted on the day of recruitment (day 1), 33 (42%) on days 2-7; and 30 (39%) on days 8-30. Seven characteristics were independently associated (p<0·01) with hospital admission: age <2 years, current asthma, illness duration of 3 days or less, parent-reported moderate or severe vomiting in the previous 24 h, parent-reported severe fever in the previous 24 h or a body temperature of 37·8°C or more at presentation, clinician-reported intercostal or subcostal recession, and clinician-reported wheeze on auscultation. The area under the receiver operating characteristic (AUROC) curve for the coefficient-based clinical rule was 0·82 (95% CI 0·77-0·87, bootstrap validated 0·81). Assigning one point per characteristic, a points-based clinical rule consisting of short illness, temperature, age, recession, wheeze, asthma, and vomiting (mnemonic STARWAVe; AUROC 0·81, 0·76-0·85) distinguished three hospital admission risk strata: very low (0·3%, 0·2-0·4%) with 1 point or less, normal (1·5%, 1·0-1·9%) with 2 or 3 points, and high (11·8%, 7·3-16·2%) with 4 points or more., Interpretation: Clinical characteristics can distinguish children at very low, normal, and high risk of future hospital admission for respiratory tract infection and could be used to reduce antibiotic prescriptions in primary care for children at very low risk., Funding: National Institute for Health Research (NIHR)., (Copyright © 2016 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY-NC-ND license. Published by Elsevier Ltd.. All rights reserved.)

The Association of Cancer Physicians in the United Kingdom has developed a strategy to improve outcomes for cancer patients and identified the goals and commitments of the Association and its members.

Unlabelled: : Metastatic melanoma continues to present a significant therapeutic challenge, with an incidence rate rising faster than that of any other cancer. The last 5 years have seen a revolution in the development of new treatments for advanced melanoma, with oncogene targeted agents and checkpoint inhibitor immunotherapies providing the first convincing evidence of a positive shift in overall survival. The role of oncolytic virotherapy in this rapidly evolving field has long been the subject of debate. However, it is with the development of Talimogene Laheparepvec (T-Vec), an intratumourally administered, genetically modified clinical herpes simplex virus-1 strain that has shown positive results in Phase III testing, that the potential for the use of OV may be realised., Areas Covered: This review will outline some of the recent advances in the treatment of advanced melanoma, with a detailed overview of evidence surrounding the development of T-Vec. A literature search was conducted using the databases ‘Medline’ and ‘Pubmed’, including a subsequent manual search of references to identify papers of further relevance., Expert Opinion: As the pivotal OPTiM trial concludes, we outline some of the potential new directions for T-Vec and OV therapy and evaluate the ever-increasing role these novel agents are likely to play in the future landscape of cancer immunotherapy.

Pulmonary rehabilitation (PR) is an effective treatment for people with chronic obstructive pulmonary disease (COPD). However, uptake and adherence to rehabilitation is poor and non-adherence is associated with poorer clinical outcomes. This study investigated the factors that might predict an individual completing his/her PR programme. Demographic, physiological and psychological data were collected from routine assessment information. Non-completers (N = 213) who dropped out after initial assessment were compared with completers (N = 438) who attended all 6 weeks of PR programme. Regression analysis indicated that smoking status was the strongest predictor for completing PR programme, that is, ex-smokers were 2.6 times (95% confidence interval (CI) = 1.7-3.9) and those who had never smoked were 2.5 times (95% confidence interval (CI) = 1.1-5.7) more likely to complete in comparison with those who were current smokers. Scoring better on psychological well-being measures (odds ratio = 1.6; 95% CI = 1.2-1.9) was also a strong predictor. The findings suggest the areas that could be addressed to enhance adherence to rehabilitation, for example, targeted interventions for clients who continue to smoke and for those who require support for psychological distress.

A fidelity measure was developed for use with Real Men Are Safe-Culturally Adapted (REMAS-CA), an HIV prevention intervention for ethnically diverse men in substance abuse treatment. The aims of this analysis were to: 1) assess the reliability of the Fidelity Rating and Skill Evaluation (FRASE); 2) measure improvement in therapist competence and adherence over time while delivering REMAS-CA; and 3) identify which modules of REMAS-CA were most difficult to deliver. Results showed that, 1) the FRASE was a reliable instrument; 2) therapists achieved adequate adherence and competence after training and demonstrated significant improvement over time in Global Empathy; and 3) Sessions 4 and 5 of REMAS-CA contained the most challenging modules for therapists to deliver. Recommendations for future REMAS-CA therapist trainings and fidelity monitoring are made., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Background: People with intellectual disability (ID) are more likely to have health problems than people without disability. Little previous research has investigated health from the perspective of the people with ID themselves. We aimed to focus on what people with ID understand being healthy to mean and what their experiences are of healthy lifestyles., Method: Semistructured interviews were conducted with 13 adults with ID to ask them about their health and healthy lifestyles. Data were analysed thematically., Results: Participants demonstrated understanding of what it means to be healthy, have a healthy diet, the dangers of substance misuse, and the benefits of exercise. Participants demonstrated some knowledge about rationales for engaging in healthy behaviours. The idea of moderation was raised, along with barriers and facilitators to engaging in a healthy lifestyle., Conclusions: Findings suggest that people with ID demonstrate some understanding of what constitutes being healthy and are aware of healthy lifestyles, the consequences of unhealthy behaviours, and of the need for moderation.

From exploring knowledge from wise members of the community to investigating the science of homeostasis, students learn healthy ways of living through a new hands-on curriculum, Diabetes Education in Tribal Schools: Health Is Life in Balance. The curriculum integrates science and Native American traditions to educate students about science, diabetes and its risk factors, and the importance of nutrition and physical activity in maintaining health and balance in life. Applying an inquiry-based approach to learning, the curriculum builds skills in observation, measurement, prediction, experimentation, and communication, and provides healthy lifestyle messages and innovative science activities for all students. The curriculum is now available to teachers and health educators at no cost through a federal grant.Health Is life in Balance incorporates interdisciplinary standards as well as storytelling to help children understand important messages. Implementation evaluation of the curriculum indicated improved knowledge and attitudes about science and health, positive teacher and student comments, and culturally relevant content. The lessons highlighted in this article give a glimpse into this hands-on curriculum which integrates science and Native American traditions, looking to our past and listening to the wisdom of our Elders, to gain powerful information for healthy, holistic living. The circle of balance is a theme in many indigenous belief systems and is woven into the lessons, providing enduring understandings of health behaviours that can prevent type 2 diabetes in the context of Native American cultural themes.

Phosphoinositide (PI) 3-kinases play an important role in regulating the adhesive function of a variety of cell types through affinity modulation of integrins. Two type I PI 3-kinase isoforms (p110 beta and p110 gamma) have been implicated in G(i)-dependent integrin alpha(IIb)beta(3) regulation in platelets, however, the mechanisms by which they coordinate their signaling function remains unknown. By employing isoform-selective PI 3-kinase inhibitors and knock-out mouse models we have identified a unique mechanism of PI 3-kinase signaling co-operativity in platelets. We demonstrate that p110 beta is primarily responsible for G(i)-dependent phosphatidylinositol 3,4-bisphosphate (PI(3,4)P(2)) production in ADP-stimulated platelets and is linked to the activation of Rap1b and AKT. In contrast, defective integrin alpha(IIb)beta(3) activation in p110 gamma(-/-) platelets was not associated with alterations in the levels of PI(3,4)P(2) or active Rap1b/AKT. Analysis of the effects of active site pharmacological inhibitors confirmed that p110 gamma principally regulated integrin alpha(IIb)beta(3) activation through a non-catalytic signaling mechanism. Inhibition of the kinase function of PI 3-kinases, combined with deletion of p110 gamma, led to a major reduction in integrin alpha(IIb)beta(3) activation, resulting in a profound defect in platelet aggregation, hemostatic plug formation, and arterial thrombosis. These studies demonstrate a kinase-independent signaling function for p110 gamma in platelets. Moreover, they demonstrate that the combined catalytic and non-catalytic signaling function of p110 beta and p110 gamma is critical for P2Y(12)/G(i)-dependent integrin alpha(IIb)beta(3) regulation. These findings have potentially important implications for the rationale design of novel antiplatelet therapies targeting PI 3-kinase signaling pathways.

Amyloid deposits derived from the amylin peptide accumulate within pancreatic islet beta-cells in most cases of type-2 diabetes mellitus (T2Dm). Human amylin 'oligomers' are toxic to these cells. Using two different experimental techniques, we found that H(2)O(2) was generated during the aggregation of human amylin into amyloid fibrils. This process was greatly stimulated by Cu(II) ions, and human amylin was retained on a copper affinity column. In contrast, rodent amylin, which is not toxic, failed to generate any H(2)O(2) and did not interact with copper. We conclude that the formation of H(2)O(2) from amylin could contribute to the progressive degeneration of islet cells in T2Dm.

There is clear evidence implicating oxidative stress in the pathology of many neurodegenerative diseases. Reactive oxygen species (ROS) are the primary mediators of oxidative stress, and hydrogen peroxide, a key ROS, is generated during aggregation of the amyloid proteins associated with some of these diseases. Hydrogen peroxide is catalytically converted to the aggressive hydroxyl radical in the presence of Fe(II) and Cu(I), which renders amyloidogenic proteins such as beta-amyloid and alpha-synuclein (implicated in Alzheimer's disease (AD) and Parkinson's disease (PD), respectively) vulnerable to self-inflicted hydroxyl radical attack. Here, we report some of the peptide-derived radicals, detected by electron spin resonance spectroscopy employing sodium 3,5-dibromo-4-nitrosobenzenesulfonate as a spin-trap, following hydroxyl radical attack on Abeta(1-40), alpha-synuclein and some other related peptides. Significantly, we found that sufficient hydrogen peroxide was self-generated during the early stages of aggregation of Abeta(1-40) to produce detectable peptidyl radicals, on addition of Fe(II). Our results support the hypothesis that oxidative damage to Abeta (and surrounding molecules) in the brain in AD could be due, at least in part, to the self-generation of ROS. A similar mechanism could operate in PD and some other "protein conformational" disorders.

Alzheimer disease and familial British dementia are neurodegenerative diseases that are characterized by the presence of numerous amyloid plaques in the brain. These lesions contain fibrillar deposits of the beta-amyloid peptide (Abeta) and the British dementia peptide (ABri), respectively. Both peptides are toxic to cells in culture, and there is increasing evidence that early "soluble oligomers" are the toxic entity rather than mature amyloid fibrils. The molecular mechanisms responsible for this toxicity are not clear, but in the case of Abeta, one prominent hypothesis is that the peptide can induce oxidative damage via the formation of hydrogen peroxide. We have developed a reliable method, employing electron spin resonance spectroscopy in conjunction with the spin-trapping technique, to detect any hydrogen peroxide generated during the incubation of Abeta and other amyloidogenic peptides. Here, we monitored levels of hydrogen peroxide accumulation during different stages of aggregation of Abeta-(1-40) and ABri and found that in both cases it was generated as a short "burst" early on in the aggregation process. Ultrastructural studies with both peptides revealed that structures resembling "soluble oligomers" or "protofibrils" were present during this early phase of hydrogen peroxide formation. Mature amyloid fibrils derived from Abeta-(1-40) did not generate hydrogen peroxide. We conclude that hydrogen peroxide formation during the early stages of protein aggregation may be a common mechanism of cell death in these (and possibly other) neurodegenerative diseases.

By means of an ESR spin-trapping method, we have shown that Abeta (amyloid beta), alpha-synuclein and various toxic forms of the prion protein all appear to generate H2O2 in vitro. A fundamental molecular mechanism underlying the pathogenesis of cell death in several different neurodegenerative diseases could be the direct production of H2O2 during the early stages of protein aggregation.

We observed 10 sea lampreys (Petromyzon marinus) parasitizing basking sharks (Cetorhinus maximus), the world's second largest fish, in the Bay of Fundy. Due to the high concentrations of urea in the blood and tissues of ureosmotic elasmobranchs, we hypothesized that sea lampreys would have mechanisms to eliminate co-ingested urea while feeding on basking sharks. Post-removal urea excretion rates (J(Urea)) in two lampreys, removed from separate sharks by divers, were initially 450 ( approximately 9000 micromol N kg-1 h-1) and 75 times ( approximately 1500 micromol N kg-1 h-1) greater than basal (non-feeding) rates ( approximately 20 micromol N kg-1 h-1). In contrast, J(Urea) increased by 15-fold after parasitic lampreys were removed from non-ureosmotic rainbow trout (Oncorhynchus mykiss). Since activities of the ornithine urea cycle (OUC) enzymes, carbamoyl phosphate synthetase III (CPSase III) and ornithine carbamoyl transferase (OCT) were relatively low in liver and below detection in intestine and muscle, it is unlikely that the excreted urea arose from de novo urea synthesis. Measurements of arginase activity suggested that hydrolysis of dietary arginine made a minor contribution to J(Urea.). Post-feeding ammonia excretion rates (J(Amm)) were 15- to 25-fold greater than basal rates in lampreys removed from both basking sharks and rainbow trout, suggesting that parasitic lampreys have a high capacity to deaminate amino acids. We conclude that the sea lamprey's ability to penetrate the dermal denticle armor of sharks, to rapidly excrete large volumes of urea and a high capacity to deaminate amino acids, represent adaptations that have contributed to the evolutionary success of these phylogenetically ancient vertebrates.

The underlying cause of Alzheimer's disease is thought to be the aggregation of monomeric beta-amyloid (Abeta), through a series of toxic oligomers, which forms the mature amyloid fibrils that accumulate at the center of senile plaques. It has been reported that L-(-)-nicotine prevents Abeta aggregation and toxicity, and inhibits senile plaque formation. Previous NMR studies have suggested that this could be due to the specific binding of L-(-)-nicotine to histidine residues (His6, His13, and His14) in the peptide. Here, we have looked at the effects of both of the L-(-) and D-(+) optical enantiomers of nicotine on the aggregation and cytotoxicity of Abeta(1-40). Surprisingly, both enantiomers inhibited aggregation of the peptide and reduced the toxic effects of the peptide on cells. In NMR studies with Abeta(1-40), both enantiomers of nicotine were seen to interact with the three histidine residues. Overall, our data indicate that nicotine can delay Abeta fibril formation and maintain a population of less toxic Abeta species. This effect cannot be due to a highly specific binding interaction between nicotine and Abeta, as previously thought, but could be due instead to weaker, relatively nonspecific binding, or to the antioxidant or metal chelating properties of nicotine. D-(+)-nicotine, being biologically much less active than L-(-)-nicotine, might be a useful therapeutic agent.

The accumulation of protein aggregates in the brain is a central feature of several different neurodegenerative diseases. We have recently shown that Abeta and alpha-synuclein, associated with Alzheimer's disease, Parkinson's disease and related disorders, can both induce the formation of hydroxyl radicals following incubation in solution, upon addition of Fe(II). PrP106-126, a model peptide for the study of prion protein-mediated cell death, shares the same property. In this study we show that quinacrine (an anti-malarial drug and inhibitor of prion replication) acts as an effective antioxidant, readily scavenging hydroxyl radicals formed from hydrogen peroxide via the Fenton reaction or generated during incubation of the PrP106-126 peptide. Furthermore, the toxicity of PrP106-126 to cultured cells was significantly inhibited by quinacrine.

The reference standards used to monitor human immunodeficiency virus (HIV) infection are flow cytometric analysis of T lymphocyte subsets to provide the CD4+ T cell count and molecular assays to quantify plasma HIV load. Few laboratories in resource-constrained countries can afford to perform these tests. A number of lower-cost assays requiring less expensive equipment may be well-suited to such countries. These include manual CD4 cell assays (Dynal, Coulter, BioRad) and ultrasensitive reverse transcriptase (Cavidi) and p24 (Perkin Elmer Life Sciences) assays to monitor virus load. Quality control and access to quality assurance programs are essential. The total lymphocyte count, although readily available and inexpensive, generally does not correlate as closely with CD4+ T cell counts. Other surrogate markers, such as beta2-microglobulin, are not suitable for routine monitoring of HIV infection. This review discusses the above assays and their role in addition to clinical monitoring in resource-constrained countries.

By means of electron spin resonance spectroscopy, in conjunction with the spin trapping technique, we have shown previously that Abeta and alpha-synuclein (aggregating proteins that accumulate in the brain in Alzheimer's disease, Parkinson's disease, and related disorders) both induce the formation of hydroxyl radicals following incubation in solution, upon addition of Fe(II). These hydroxyl radicals are apparently formed from hydrogen peroxide, via Fenton's reaction. An N-terminally truncated fragment of the mouse prion protein (termed PrP121-231) is toxic to cerebellar cells in culture, and certain human mutations, responsible for inherited prion disease, enhance this toxicity. Here we report that PrP121-231 containing three such mutations (E200K, D178N, and F198S) also generated hydroxyl radicals, upon addition of Fe(II). The formation of these radicals was blocked by catalase, or by metal chelators, each of which also reduced the toxicity of the PrP121-231 fragments to cultured normal mouse cerebellar cells. Wild-type PrP121-231, full-length cellular PrP, and its homologue doppel did not generate any detectable hydroxyl radicals. We conclude that the additional cytotoxic effects of the mutant forms of PrP121-231 could be due to their ability to generate hydrogen peroxide, by a metal-dependent mechanism. Thus, one effect of these (and possibly other) prion mutations could be production of a particularly toxic form of the prion protein, with an enhanced capacity to induce oxidative damage, neurodegeneration, and cell loss.

Oligomeric forms of many of the aggregating proteins associated with neurodegenerative diseases are toxic to cultured cells. We have shown recently that Abeta and alpha-synuclein can both induce the formation of hydroxyl radicals following incubation in solution, upon the addition of Fe(II). Thus, they appear to generate hydrogen peroxide, which is converted to hydroxyl radicals via the Fenton reaction. Here we show that the widely studied toxic peptide fragment of the prion protein, PrP106-126, has exactly the same property, but only in the presence of copper ions. Since the aggregation and toxicity of PrP106-126 have been reported to be critically dependent on copper binding, our data suggest that the published cytotoxic effects of this peptide could also be due to its ability to generate hydrogen peroxide.

The formation of extracellular or intracellular deposits of amyloid-like protein fibrils is a prominent pathological feature of many different neurodegenerative diseases, including Alzheimer's disease (AD) and Parkinson's disease (PD). In AD, the beta-amyloid peptide (A(beta)) accumulates mainly extracellularly at the center of senile plaques, whereas, in PD, the alpha-synuclein protein accumulates within neurons inside the Lewy bodies and Lewy neurites. We have shown recently that solutions of A(beta) 1-40, A(beta) 1-42, A(beta) 25-35, alpha-synuclein and non-A(beta) component (NAC; residues 61-95 of alpha-synuclein) all liberate hydroxyl radicals upon incubation in vitro followed by the addition of small amounts of Fe(II). These hydroxyl radicals were readily detected by means of electron spin resonance spectroscopy, employing 5,5-dimethyl-1-pyrroline N-oxide (DMPO) as a spin trapping agent. Hydroxyl radical formation was inhibited by the inclusion of catalase or metal-chelators during A(beta) or alpha-synuclein incubation. Our results suggest that hydrogen peroxide accumulates during the incubation of A(beta) or alpha-synuclein, by a metal-dependent mechanism, and that this is subsequently converted to hydroxyl radicals, on addition of Fe (II), by Fenton's reaction. Consequently, one of the fundamental molecular mechanisms underlying the pathogenesis of cell death in AD and PD, and possibly other neurodegenerative or amyloid diseases, could be the direct production of hydrogen peroxide during formation of the abnormal protein aggregates.