Mapping the global endemicity and clinical burden of Plasmodium vivax, 2000-17: a spatial and temporal modelling study.

BACKGROUND: Plasmodium vivax exacts a significant toll on health worldwide, yet few efforts to date have quantified the extent and temporal trends of its global distribution. Given the challenges associated with the proper diagnosis and treatment of P vivax, national malaria programmes-particularly those pursuing malaria elimination strategies-require up to date assessments of P vivax endemicity and disease impact. This study presents the first global maps of P vivax clinical burden from 2000 to 2017. METHODS: In this spatial and temporal modelling study, we adjusted routine malariometric surveillance data for known biases and used socioeconomic indicators to generate time series of the clinical burden of P vivax. These data informed Bayesian geospatial models, which produced fine-scale predictions of P vivax clinical incidence and infection prevalence over time. Within sub-Saharan Africa, where routine surveillance for P vivax is not standard practice, we combined predicted surfaces of Plasmodium falciparum with country-specific ratios of P vivax to P falciparum. These results were combined with surveillance-based outputs outside of Africa to generate global maps. FINDINGS: We present the first high-resolution maps of P vivax burden. These results are combined with those for P falciparum (published separately) to form the malaria estimates for the Global Burden of Disease 2017 study. The burden of P vivax malaria decreased by 41·6%, from 24·5 million cases (95% uncertainty interval 22·5-27·0) in 2000 to 14·3 million cases (13·7-15·0) in 2017. The Americas had a reduction of 56·8% (47·6-67·0) in total cases since 2000, while South-East Asia recorded declines of 50·5% (50·3-50·6) and the Western Pacific regions recorded declines of 51·3% (48·0-55·4). Europe achieved zero P vivax cases during the study period. Nonetheless, rates of decline have stalled in the past five years for many countries, with particular increases noted in regions affected by political and economic instability. INTERPRETATION: Our study highlights important spatial and temporal patterns in the clinical burden and prevalence of P vivax. Amid substantial progress worldwide, plateauing gains and areas of increased burden signal the potential for challenges that are greater than expected on the road to malaria elimination. These results support global monitoring systems and can inform the optimisation of diagnosis and treatment where P vivax has most impact. FUNDING: Bill & Melinda Gates Foundation and the Wellcome Trust.

Mapping the global prevalence, incidence, and mortality of Plasmodium falciparum, 2000-17: a spatial and temporal modelling study.

BACKGROUND: Since 2000, the scale-up of malaria control interventions has substantially reduced morbidity and mortality caused by the disease globally, fuelling bold aims for disease elimination. In tandem with increased availability of geospatially resolved data, malaria control programmes increasingly use high-resolution maps to characterise spatially heterogeneous patterns of disease risk and thus efficiently target areas of high burden. METHODS: We updated and refined the Plasmodium falciparum parasite rate and clinical incidence models for sub-Saharan Africa, which rely on cross-sectional survey data for parasite rate and intervention coverage. For malaria endemic countries outside of sub-Saharan Africa, we produced estimates of parasite rate and incidence by applying an ecological downscaling approach to malaria incidence data acquired via routine surveillance. Mortality estimates were derived by linking incidence to systematically derived vital registration and verbal autopsy data. Informed by high-resolution covariate surfaces, we estimated P falciparum parasite rate, clinical incidence, and mortality at national, subnational, and 5 × 5 km pixel scales with corresponding uncertainty metrics. FINDINGS: We present the first global, high-resolution map of P falciparum malaria mortality and the first global prevalence and incidence maps since 2010. These results are combined with those for Plasmodium vivax (published separately) to form the malaria estimates for the Global Burden of Disease 2017 study. The P falciparum estimates span the period 2000-17, and illustrate the rapid decline in burden between 2005 and 2017, with incidence declining by 27·9% and mortality declining by 42·5%. Despite a growing population in endemic regions, P falciparum cases declined between 2005 and 2017, from 232·3 million (95% uncertainty interval 198·8-277·7) to 193·9 million (156·6-240·2) and deaths declined from 925 800 (596 900-1 341 100) to 618 700 (368 600-952 200). Despite the declines in burden, 90·1% of people within sub-Saharan Africa continue to reside in endemic areas, and this region accounted for 79·4% of cases and 87·6% of deaths in 2017. INTERPRETATION: High-resolution maps of P falciparum provide a contemporary resource for informing global policy and malaria control planning, programme implementation, and monitoring initiatives. Amid progress in reducing global malaria burden, areas where incidence trends have plateaued or increased in the past 5 years underscore the fragility of hard-won gains against malaria. Efforts towards elimination should be strengthened in such areas, and those where burden remained high throughout the study period. FUNDING: Bill & Melinda Gates Foundation.

Potential strategy for assessing QT/QTc interval for drugs that produce rapid changes in heart rate: Electrocardiographic assessment of the effects of intravenous remimazolam on cardiac repolarization.

AIMS: Remimazolam is a new, ultra-short-acting benzodiazepine developed for intravenous (IV) use during procedural sedation and in general anaesthesia. Two trials were conducted to characterize its effects on cardiac repolarization. METHODS: A thorough QT/QTc (TQT) study assessed electrocardiography effects of therapeutic and supratherapeutic doses of remimazolam and midazolam. To investigate whether RR-QT hysteresis effects due to rapid heart rate changes might have confounded the QTc assessments in the TQT trial, a second trial used continuous IV remimazolam infusion to achieve stable heart rates during periods of stable remimazolam plasma concentration. RESULTS: During the TQT, both compounds produced a 10-20-beats/min increase in heart rate within 30 seconds, persisting for 5-10 minutes. Within 30 seconds, the upper bound of the 2-sided 90% confidence interval for the placebo-corrected change from baseline for QTcI (ΔΔQTcI) exceeded 10 ms for both doses of remimazolam (ΔΔQTcI 7.2 [3.2, 11.2] ms for the 10 mg dose and 10.4 [6.5, 14.3] ms for the 20 mg dose) as well as for the 7.5-mg dose of midazolam (8.2 [4.4, 12.1] ms). At 2 minutes after IV bolus, the upper bound of the 2-sided 90% confidence interval for ΔΔQTcI exceeded 10 ms only for the remimazolam 20-mg dose (6.3 [2.3, 10.2] ms). During the second study, during periods of stable heart rate, remimazolam had no clinically significant effect on QTc (peak ΔΔQTcI 3.4 [-1.1, 7.6] ms). CONCLUSION: Remimazolam does not prolong cardiac repolarization (QTc). The methods reported here may allow assessment of the QTc effects of other drugs given by IV bolus.

Queensland Alcohol-related violence and Night Time Economy Monitoring project (QUANTEM): a study protocol.

BACKGROUND: Alcohol-related harm is a substantial burden on the community in Australia and internationally, particularly harm related to risky drinking practices of young people in the night-time economy. This protocol paper describes a study that will report on the changes in a wide range of health and justice outcome measures associated with major policy changes in the state of Queensland, Australia. A key element includes trading hours restrictions for licensed premises to 2 am for the state and 3 am in Safe Night Precincts (SNPs). Other measures introduced include drinks restrictions after midnight, increased patron banning measures for repeat offenders, mandatory ID scanning of patrons in late-night venues, and education campaigns. METHODS: The primary aim of the study is to evaluate change in the levels of harm due to these policy changes using administrative data (e.g., police, hospital, ambulance, and court data). Other study elements will investigate the impact of the Policy by measuring foot traffic volume in SNPs, using ID scanner data to quantify the volume of people entering venues and measure the effectiveness of banning notices, using patron interviews to quantify the levels of pre-drinking, intoxication and illicit drug use within night-time economy districts, and to explore the impacts of the Policy on business and live music, and costs to the community. DISCUSSION: The information gathered through this project aims to evaluate the effectiveness of the Policy and to draw on these findings to inform future prevention and enforcement approaches by policy makers, police, and venue staff.

A thorough QT study to evaluate the effects of therapeutic and supratherapeutic doses of delafloxacin on cardiac repolarization.

A randomized, double-blind, placebo-controlled, 4-period crossover study was conducted in 52 healthy adults to assess the effect of delafloxacin on the corrected QT (QTc) interval. The QT interval, corrected for heart rate using Fridericia's formula (QTcF), was determined predose and at 0.5, 1, 1.25, 1.5, 1.75, 2, 2.5, 3, 4, 5, 6, 12, 18, and 24 h after dosing with delafloxacin at 300 mg intravenously (i.v.; therapeutic), delafloxacin at 900 mg i.v. (supratherapeutic), moxifloxacin at 400 mg orally (p.o.; positive control), and placebo. The pharmacokinetic profile of delafloxacin was also evaluated. At each time point after delafloxacin administration, the upper limit of the 90% confidence interval (CI) for the placebo-corrected change from the predose baseline in QTcF (ΔΔQTcF) was less than 10 ms (maximum, 3.9 ms at 18 h after dosing), indicating an absence of a clinically meaningful increase in the QTc interval. The lower limit of the 90% CI of ΔΔQTcF for moxifloxacin versus placebo was longer than 5 ms at all 5 time points selected for assay sensitivity analysis, demonstrating that the study was adequately sensitive to assess QTc prolongation. There was no positive relationship between delafloxacin plasma concentrations and ΔΔQTcF. Treatment-emergent adverse events (AEs) were more frequent among subjects receiving a single supratherapeutic dose of 900 mg delafloxacin. There were no deaths, serious AEs, or AEs leading to study discontinuation and no clinically meaningful abnormalities in laboratory values or vital signs observed at any time point after any dose of the study drug.

Moxifloxacin-induced QTc interval prolongations in healthy male Japanese and Caucasian volunteers: a direct comparison in a thorough QT study.

AIM: We investigated whether moxifloxacin-induced QTc prolongations in Japanese and Caucasian healthy male volunteers were significantly different. METHODS: A two period, randomized, crossover, ICH-E14-compliant thorough QT (TQT) study compared placebo-corrected changes in QTc interval from baseline (ΔΔQTc F) and concentration-effect relationships following administration of placebo and 400 mg moxifloxacin to 40 healthy male volunteers from each ethnic population. The point estimates of ΔΔQTc F for each population, and the difference between the two, were calculated at a geometric mean Cmax of moxifloxacin using a linear mixed effects model. The concentration-effect slopes of the two populations were also compared. Equivalence was concluded if the two-sided 90% confidence interval of the difference in ΔΔQTc F was contained within -5 ms to +5 ms limits and the ratio of the slopes was between 0.5 and 2. RESULTS: There were no statistically significant differences between the two populations studied, Japanese vs. Caucasians, respectively, for moxifloxacin Cmax (3.27 ± 0.6 vs. 2.98 ± 0.7 µg ml(-1) ), ΔΔQTc F (9.63 ± 1.15 vs. 11.46 ± 1.19 ms at Cmax of 3.07 µg ml(-1) ) and concentration-response slopes (2.58 ± 0.62 vs. 2.34 ± 0.64 ms per µg ml(-1) ). The difference in the two ΔΔQTc F of -1.8 (90% CI -4.6, 0.9) and the ratio of the two slopes (1.1; 90% CI 0.63, 1.82) were within pre-specified equivalence limits. CONCLUSIONS: Moxifloxacin-induced QTc prolongations did not differ significantly between the Japanese and Caucasian subjects. However, before our findings are more widely generalized, further studies in other populations and with other QT-prolonging drugs are needed to clarify whether inter-ethnic differences in QT sensitivity exist and whether ethnicity of the study population may affect the outcome of a TQT study.

Pooled analysis of phase III clinical studies of palonosetron versus ondansetron, dolasetron, and granisetron in the prevention of chemotherapy-induced nausea and vomiting (CINV).

PURPOSE: Preventing chemotherapy-induced nausea and vomiting (CINV) is integral to treatment success in patients with cancer. This analysis was undertaken to assess the relative efficacy and safety of palonosetron versus older 5HT3 RAs in preventing CINV associated with moderately or highly emetogenic chemotherapy. METHODS: Patient-level data from four randomized, double-blind, phase III trials comparing palonosetron 0.25 or 0.75 mg with ondansetron 32 mg, dolasetron 100 mg, or granisetron 40 µg/kg were analyzed. Endpoints included complete response (CR: no emesis and no rescue antiemetics) in the acute (0-24 h), delayed (>24-120 h), and overall (0-120 h) postchemotherapy periods (primary), complete control (CC: no emesis, no rescue antiemetics, and no more than mild nausea), number of emetic episodes, and nausea severity. RESULTS: CR rates were significantly higher for palonosetron (n = 1,787) versus older 5HT3 RAs (n = 1,175) in the delayed (57 vs 45 %, P < 0.0001) and overall periods (51 vs 40 %, P < 0.0001); odds ratios (95 % CI) in the acute, delayed, and overall periods were 1.15 (0.98-1.34), 1.62 (1.40-1.88), and 1.56 (1.34-1.81), respectively. Significant differences in CC rates and nausea severity were observed for the delayed and overall periods and in emetic episodes for all three periods. The incidence of treatment-related adverse events was similar with palonosetron (0.25 mg, 20.0 %; 0.75 mg, 26.5 %) and older 5HT3 RAs (27.5 %). CONCLUSIONS: Palonosetron is more effective than older 5HT3 RAs for controlling CINV in the delayed and overall postchemotherapy periods.

Vilazodone lacks proarrhythmogenic potential in healthy participants: a thorough ECG study.

OBJECTIVE: Vilazodone is a potent serotonin reuptake inhibitor and 5-HT1A receptor partial agonist approved for the treatment of major depressive disorder (MDD) in adults. The effect of clinical and supratherapeutic doses of vilazodone on cardiac repolarization was determined in healthy volunteers. METHODS: In this Phase 1, randomized, doubleblind, placebo- and active-controlled, 3-arm, parallel, single-center study, healthy subjects received placebo; moxifloxacin 400 mg; or vilazodone (sequentially escalated every 3 days) 10, 20, 40, 60, and 80 mg/day. The primary endpoint was the time-matched change from baseline in the QT interval corrected for heart rate (QTc) using an individual correction method (QTcI). RESULTS: Placebo-corrected time-matched analysis of the QTcI duration for the vilazodone treatment effect indicated that no vilazodone dose had an upper bound that approached or exceeded 10 ms, demonstrating no signal for a significant vilazodone effect on cardiac repolarization. Vilazodone had no significant effect on heart rate, PR, or QRS interval duration. The pharmacokinetic/pharmacodynamic model showed that the QTcI slope for vilazodone was not different from 0.0 and that the predicted increase from baseline in the QTc at Cmax for the highest therapeutic dose (156 ng/ml after 40 mg/day) was < 1 ms. The incidence of adverse events (AEs) was higher in the vilazodone group (57.6%) than in the moxifloxacin (37.0%) and placebo (35.6%) groups, though AEs were generally mild to moderate in severity and resulted in few discontinuations. CONCLUSIONS: Vilazodone had no significant effect on cardiac repolarization, heart rate, PR or QRS interval duration, or ECG morphology in healthy adult participants.

Attitudinal factors associated with drink counting.

INTRODUCTION: 'Count your drinks' is a protective behavioural strategy (PBS) that has been found to be effective in reducing alcohol consumption. Previous research has shown that females, older people and low-risk drinkers are more likely to use this strategy, but little is known about the attitudinal factors associated with engaging in drink counting. This information is important for developing effective interventions to encourage use of this PBS. The aim of this paper was to assess whether the following attitudinal factors are associated with frequency of enactment of the 'Count your drinks' PBS: (i) perceived ease of use; (ii) perceived effectiveness; (iii) personal relevance; and (iv) believability. METHODS: A total of 683 Australian drinkers completed an online survey assessing demographic variables, alcohol consumption, frequency of drink counting and attitudes to the 'Count your drinks' PBS. A hierarchical regression analysis was used to determine whether the attitudinal factors were associated with frequency of enactment after controlling for demographic and alcohol-related factors. RESULTS: Attitudes to the 'Count your drinks' PBS accounted for 28% of the variance in reported frequency of drink counting. Perceptions of personal relevance, ease of use and effectiveness were found to be significantly associated with frequency of enactment. DISCUSSION AND CONCLUSIONS: Interventions designed to encourage drinkers to count their drinks should aim to increase the perceived personal relevance, ease of use and effectiveness of this strategy.

The effects of alcohol pricing policies on consumption, health, social and economic outcomes, and health inequality in Australia: a protocol of an epidemiological modelling study.

INTRODUCTION: Alcohol use and misuse are associated with substantial health and social issues in Australia and internationally. Pricing policy is considered as one of the most effective means to reduce risky drinking and related harms. This protocol paper describes a study that will model and estimate the effects, effectiveness and cost-benefit of alcohol pricing policy initiatives in reducing risky drinking, health and social harms, and health inequalities among subpopulations in Australia. METHODS AND ANALYSIS: The study is a modelling and epidemiological study using data from various resources, such as survey, previous literatures and response agencies. A number of statistical procedures will be undertaken to evaluate the impact of different alcohol pricing policy initiatives on various outcomes, including alcohol consumption in population subgroups, and health and social problems, and to measure health inequalities and cost-effectiveness of those proposed pricing policies, such as a 10% tax increase on all alcohol beverages or introduction of a minimum unit price. ETHICS AND DISSEMINATION: The ethics approval of this study was obtained from the College Human Ethics Sub-Committee of the La Trobe University on 9 November 2017 (Ref: S17-206). While examining the heterogeneous effects of price policy across population subgroups, this study will provide the first comprehensive estimates of the likely impacts of alcohol price changes on health inequalities. The study will also provide sophisticated economic analyses of the impact of price policy changes, which is critical information for policy makers and will assist policy makers in directing resources to a more efficient alcohol strategy. Results will be made available to communities and societies, health departments and other researchers.

Repeat prescribing safety survey.

INTRODUCTION Repeat prescribing is an accepted part of general practice activities in New Zealand and in many developed countries. However, there has been little research on how this service is used in New Zealand, or on clinicians' attitudes towards it. AIM To discover the opinions of vocationally registered general practitioners (GPs) and general practice registrars regarding repeat prescribing, availability of practice policy and mechanisms for issuing such prescriptions. METHODS A survey was developed by an expert group and shared through the Royal New Zealand College of General Practitioners' (the College) weekly newsletter, epulse, inviting members to participate in the survey. The survey was also emailed to registrars. RESULTS In total, 144 vocationally registered GPs and 115 registrars responded (n=259), giving a response rate of 3.2% for GPs and 12.7% for registrars. Patient convenience and time efficiency for the practice were the most commonly cited reasons for repeat prescribing. Registrars had low awareness of practice policy on repeat prescribing and only one-quarter of practices had an orientation pack that contained advice on repeat prescribing. DISCUSSION Better practice systems are likely to improve the safety profile of repeat prescribing and should be addressed. There is substantial unwanted variability currently in these practice systems.

Egg size and the adaptive capacity of early life history traits in Chinook salmon (Oncorhynchus tshawytscha).

Offspring traits are greatly influenced by maternal effects, and these maternal effects may provide an important pathway through which populations can adapt to changing thermal environments. We investigated the effect of egg size on the among- and within-population variation in early life history traits among introduced Great Lakes Chinook salmon (Oncorhynchus tshawytscha) populations under varying thermal conditions. We reared Chinook salmon from three populations in a common-garden hatchery study at 6.5, 9.4, and 15.2°C and measured a variety of fitness-related traits during development. We found that most of the among-population variation in early life history traits was explained by egg size. However, the contribution of egg size to the among-population variation decreased with an increase in temperature suggesting that other effects, such as genetic, contribute at high temperature. Within populations, egg size explained much of the dam variance and maternal effect for traits in every temperature, whereas egg size generally had little to no influence on the sire variance and heritability. Overall, our results demonstrate the significant contribution egg size makes to shaping early life history phenotypes among and within populations, and suggest that egg size is an important pathway through which offspring phenotypes can evolve on contemporary timescales.

The National Alcohol Strategy 2018-2026 has to become a set of commitments.

Alcohol consumption is behind only smoking and obesity among leading contributors to the burden of disease in Australia. For the first time in over a decade, Australian governments are developing a National Alcohol Strategy, and plan to finalise it in 2018. The draft contains evidence-based recommendations but lacks a framework for accountability, and the Commonwealth Minister of Health recently suggested that the alcohol industry help devise the final version. We recommend that the Government rely on advice from health experts for health policy, pre-specify outcome indicators, commit to modest activities initially, to develop momentum; and commission independent evaluation after 3 years.

Validation of the AAST EGS grading system for perforated peptic ulcer disease.

INTRODUCTION: Perforated peptic ulcer disease (PPUD) including both duodenl and gastric ulcers is a severe disease and outcomes are influenced by comorbidities and physiology. We validated the AAST EGS grading system at two diverse centers (Mayo Clinic, USA and Pietermaritzburg, South Africa). METHODS: Dual-center review of historic data (2010-2016) of adults with PPUD was performed. Preoperative, procedural, and postoperative data were abstracted. ASA, Boey, PULP and AAST EGS grades were generated. Comparative, multivariable, and pairwise analyses were performed. RESULTS: There were 306 patients, 42% female with a mean (±SD) age of 56 ±20 years. Overall, the patints were categorized into the following AAST EGS grades: I (30, 10%), II (38, 12%), III (104, 34%), IV (76, 2e%), V (58, 18.9%). Initial management included: midline laparotomy (51%, n=157), laparoscopy (18%, n=58), laparoscopy converted to laparotomy (1%, n=3), and endoscopy (30%, n=88). Duration of stay increased with AAST EGS grade. In United States cohort, factors predictive for 30-day mortality included AAST EGS grade and patient comorbidity status. The AAST EGS grade was comparable to other scoring systems (Boey, PULP, and ASA). CONCLUSIONS: Differences exist between centers for management of PPUD and their outcomes; however, the AAST EGS grade can be utilized to stratify thedisease severity of the patient and this demonstrates initial construct validity in a United States but not in a South African population.

Effects of buprenorphine on QT intervals in healthy subjects: results of 2 randomized positive- and placebo-controlled trials.

OBJECTIVES: To study the effect of transdermal buprenorphine on QTc prolongation at dose levels of 10, 40, and 80 mcg/h, (BTDS 10, BTDS 40, BTDS 80). METHODS: Two randomized, placebo- and positive-controlled, parallel-group, dose-escalating clinical studies evaluated healthy adult subjects randomized to BTDS, placebo, or moxifloxacin in the first study; and to BTDS only, BTDS plus naltrexone, naltrexone alone at the same dose, placebo, or moxifloxacin in the second study. QT intervals were corrected for heart rate using data from each individual subject (QTcI). RESULTS: In the first study (n = 44), the maximum upper bounds of the 90% confidence interval (CI) for mean placebo-corrected change from baseline in QTcI across 13 time points over 24 h were: 10.0 msec for BTDS 10 (Day 6) and 13.3 msec for BTDS 40 (Day 13); and 17.0 msec (Day 6) and 15.5 msec (Day 13) for moxifloxacin, respectively. Similarly, in the second study (n = 66), the upper bound of the 90% CI for mean placebo-corrected change from baseline for QTcI was under 10 msec at all time points for BTDS 10 (maximum upper bound, 5.63 msec), over 10 msec at 5 time points for BTDS 40 (maximum 11.81 msec) and over 10 msec at all 13 time points for BTDS 80 (maximum, 14.14 msec). Naltrexone administered with BTDS eliminated the QTcI prolongation seen with supratherapeutic BTDS doses (BTDS 40, BTDS 80) administered without naltrexone. CONCLUSIONS: At the therapeutic dose of 10 mcg/h, BTDS has no clinically significant effect on QTc. At supratherapeutic doses of 40 and 80 mcg/h, BTDS treatment produces prolongation of QTcI similar in magnitude to that produced by a 400 mg dose of moxifloxacin. Despite the modest, dose-dependent increase in QTcI noted in these studies, transdermal buprenorphine has not been associated with proarrhythmic effects.

Feasibility of Serial 6-min Walk Tests in Patients with Acute Heart Failure.

BACKGROUND: Functional status assessment is common in many cardiovascular diseases but it has undergone limited study in the setting of acute heart failure (AHF). Accordingly, we performed a pilot study of the feasibility of the six-minute walk test (6MWT) at the emergency department (ED) presentation and through the hospitalization in patients with AHF. METHODS AND RESULTS: From November 2014 to February 2015, we conducted a multicenter, observational study of ED patients, aged 18-85 years, whose primary ED admission diagnosis was AHF. Other criteria for enrollment included a left ventricular ejection fraction ≤40%, systolic blood pressure between 90 and 170 mmHg, and verbal confirmation that the patient was able to walk >30 m at the baseline, prior to ED presentation. Study teams were uniformly trained to administer a 6MWT. Patients underwent a baseline 6MWT within 24 h of ED presentation (Day 1) and follow-up 6MWTs at 24 (Day 2), 48 (Day 3), and 120 h (Day 5). A total of 46 patients (65.2% male, 73.9% African American) had a day one mean walk distance of 137.3 ± 78 m, day 2 of 170.9 ± 100 m, and day 3 of 180.8 ± 98 m. The 6MWT demonstrated good reproducibility, as the distance walked on the first 6MWT on Day 3 was similar to the distance on the repeated 6MWT the same day. CONCLUSIONS: Our pilot study demonstrates the feasibility of the 6MWT as a functional status endpoint in AHF patients. A larger study in a more demographically diverse cohort of patients is necessary to confirm its utility and association with 30-day heart failure (HF) events.

A randomized, multicenter study to determine the safety and efficacy of the immunoconjugate SGN-15 plus docetaxel for the treatment of non-small cell lung carcinoma.

PURPOSE: Chemotherapy prolongs survival and improves quality of life (QOL) for good performance status (PS) patients with advanced non-small cell lung cancer (NSCLC). Targeted therapies may improve chemotherapy effectiveness without worsening toxicity. SGN-15 is an antibody-drug conjugate (ADC), consisting of a chimeric murine monoclonal antibody recognizing the Lewis Y (Le(y)) antigen, conjugated to doxorubicin. Le(y) is an attractive target since it is expressed by most NSCLC. SGN-15 was active against Le(y)-positive tumors in early phase clinical trials and was synergistic with docetaxel in preclinical experiments. This Phase II, open-label study was conducted to confirm the activity of SGN-15 plus docetaxel in previously treated NSCLC patients. EXPERIMENTAL DESIGN: Sixty-two patients with recurrent or metastatic NSCLC expressing Le(y), one or two prior chemotherapy regimens, and PS< or =2 were randomized 2:1 to receive SGN-15 200 mg/m2/week with docetaxel 35 mg/m2/week (Arm A) or docetaxel 35 mg/m2/week alone (Arm B) for 6 of 8 weeks. Intrapatient dose-escalation of SGN-15 to 350 mg/m2 was permitted in the second half of the study. Endpoints were survival, safety, efficacy, and quality of life. RESULTS: Forty patients on Arm A and 19 on Arm B received at least one treatment. Patients on Arms A and B had median survivals of 31.4 and 25.3 weeks, 12-month survivals of 29% and 24%, and 18-month survivals of 18% and 8%, respectively. Toxicity was mild in both arms. QOL analyses favored Arm A. CONCLUSIONS: SGN-15 plus docetaxel is a well-tolerated and active second and third line treatment for NSCLC patients. Ongoing studies are exploring alternate schedules to maximize synergy between these agents.

Medical Students and informed consent: A consensus statement prepared by the Faculties of Medical and Health Science of the Universities of Auckland and Otago, Chief Medical Officers of District Health Boards, New Zealand Medical Students' Association and the Medical Council of New Zealand.

To develop a national consensus statement to promote a pragmatic, appropriate and unified approach to seeking consent for medical student involvement in patient care. A modified Delphi technique was used to develop the consensus statement involving stakeholders. Feedback from consultation and each stakeholder helped to shape the final consensus statement. The consensus statement is a nationally-agreed statement concerning medical student involvement in patient care, which will be useful for medical students, health care professionals and patients.