Self-regulatory processes in goal striving during excellent distance-running performances: A qualitative study.

OBJECTIVE: Goal setting can improve endurance performance, yet how endurance performers maintain goal striving and bring it to a successful close has received limited attention. In this study, we investigated the self-regulatory processes employed by long-distance runners during goal striving in excellent competitive performances. METHOD: Through in-depth, event-focused interviews, we explored 21 long-distance runners' experiences of goal striving in excellent competitive performances (M = 77.43 h post-race). Furthermore, we recruited 10 additional participants with relevant experiences (runner n = 7, coach n = 2; sport psychologist n = 1) for external member-reflection interviews. FINDINGS: Through our matrix analysis, we interpreted that by contrasting their current and future goal status periodically throughout their excellent performances, using a process called mental contrasting with implementation intentions (MCII), this helped the runners to make decisions about whether to persist with a goal, or disengage from a goal and reengage with an alternative. Furthermore, our findings depict how these goal decisions unfolded when runners perceived they were behind, equalling, or exceeding their goal(s). We also illustrate how goal revision was used as an adaptive process to maximise performance, and to avert or manage action crises. CONCLUSIONS: Our findings extend theoretical understandings of goal striving and the self-regulatory processes endurance performers employ to attain and/or adapt their goals. Psychological support provided for athletes should go beyond simply setting goals, but also include training on mental frameworks such as MCII to manage goal-striving challenges and decisional conflict encountered during performances.

Assigning trend-based conservation status despite high uncertainty.

Estimates of temporal trends in species' occupancy are essential for conservation policy and planning, but limitations to the data and models often result in very high trend uncertainty. A critical source of uncertainty that degrades scientific credibility is that caused by disagreement among studies or models. Modelers are aware of this uncertainty but usually only partially estimate it and communicate it to decision makers. At the same time, there is growing awareness that full disclosure of uncertainty is critical for effective translation of science into policies and plans. But what are the most effective approaches to estimating uncertainty and communicating uncertainty to decision makers? We explored how alternative approaches to estimating and communicating uncertainty of species trends could affect decisions concerning conservation status of freshwater fishes. We used ensemble models to propagate trend uncertainty within and among models and communicated this uncertainty with categorical distributions of trend direction and magnitude. All approaches were designed to fit an established decision-making system used to assign species conservation status by the New Zealand government. Our results showed how approaches that failed to fully disclose uncertainty, while simplifying the information presented, could hamper species conservation or lead to ineffective decisions. We recommend an approach that was recently used effectively to communicate trend uncertainty to a panel responsible for setting the conservation status of New Zealand's freshwater fishes.

Designación del estado de conservación basada en tendencias a pesar de gran incertidumbre Resumen Las estimaciones de las tendencias temporales de la presencia de especies son esenciales para la planeación de la conservación y sus políticas, pero las limitaciones de los datos y los modelos suelen derivar en una incertidumbre muy elevada en cuanto a las tendencias. Los desacuerdos entre los estudios y los modelos son una fuente importante de incertidumbre que contribuye a la degradación de la credibilidad científica. Los modeladores están conscientes de esta incertidumbre, pero casi nunca la estiman o comunican por completo a los responsables de las decisiones. Al mismo tiempo, cada vez hay mayor conciencia de que divulgar esta incertidumbre es importante para que la ciencia se traduzca efectivamente en políticas y planes. ¿Pero cuáles son las estrategias más efectivas para estimar la incertidumbre y comunicarla a los responsables de las decisiones? Exploramos cómo las estrategias alternativas para estimar y comunicar la incertidumbre que rodea a las tendencias de las especies podría afectar las decisiones con respecto al estado de conservación de los peces de agua dulce. Usamos modelos de conjuntos para propagar la incertidumbre dentro y entre modelos y comunicamos esta incertidumbre con distribuciones categóricas de la dirección y magnitud de la tendencia. Diseñamos todas las estrategias para que se ajustaran a un sistema establecido de toma de decisiones que usa el gobierno de Nueva Zelanda para designar el estado de conservación de las especies. Nuestros resultados mostraron cómo las estrategias que no divulgaron por completo la incertidumbre, mientras simplificaban la información presentada, podrían dificultar la conservación de las especies o llevar a decisiones poco efectivas. Recomendamos una estrategia que se usó recientemente para comunicar eficientemente la incertidumbre de las tendencias a un panel responsable de establecer el estado de conservación de los peces de agua dulce de Nueva Zelanda.

Land-use Suitability is Not an Intrinsic Property of a Land Parcel.

Agricultural production has economic, environmental, social and cultural consequences beyond farm boundaries, but information about these impacts is not readily available to decision makers. This study applied the land use suitability concept by carrying out an assessment of a region that has the potential for intensification of agricultural production, but where eutrophication of river and estuary receiving environments due to nitrogen enrichment is a significant issue. The assessment evaluated three indicators for each farmable land parcel in the region: productive potential (the inherent productive and economic potential of the parcel), relative contribution (the potential for the parcel to contribute nitrogen to receiving environments compared to other land parcels), and pressure (the load of nitrogen delivered to receiving environments compared to the loads that ensure environmental objectives are achieved). The assessment indicated that land with high suitability for land-use intensification in Southland is limited because areas with high productive potential and low relative contribution rarely coincide with receiving environments with low pressure. Existing data, methods and models can be used to calculate the indicators under different choices for regional land-use intensity and receiving environment objectives. However, the spatial resolution and accuracy that is achievable may preclude using assessment outputs to make land use decisions at small spatial scales such as individual farms. The study highlighted that land use suitability is not an intrinsic property of a land parcel because it is dependent on choices about land use elsewhere in the landscape and the environmental objectives, and that land use suitability is inherently subjective because of decisions that concern how indicators are combined and weighted.

Quantifying the relative contributions of habitat modification and mammalian predators on landscape-scale declines of a threatened river specialist duck.

Habitat modification and introduced mammalian predators are linked to global species extinctions and declines, but their relative influences can be uncertain, often making conservation management difficult. Using landscape-scale models, we quantified the relative impacts of habitat modification and mammalian predation on the range contraction of a threatened New Zealand riverine duck. We combined 38 years of whio (Hymenolaimus malacorhynchos) observations with national-scale environmental data to predict relative likelihood of occurrence (RLO) under two scenarios using bootstrapped boosted regression trees (BRT). Our models used training data from contemporary environments to predict the potential contemporary whio distribution across New Zealand riverscapes in the absence of introduced mammalian predators. Then, using estimates of environments prior to human arrival, we used the same models to hindcast potential pre-human whio distribution prior to widespread land clearance. Comparing RLO differences between potential pre-human, potential contemporary and observed contemporary distributions allowed us to assess the relative impacts of the two main drivers of decline; habitat modification and mammalian predation. Whio have undergone widespread catastrophic declines most likely linked to mammalian predation, with smaller declines due to habitat modification (range contractions of 95% and 37%, respectively). We also identified areas of potential contemporary habitat outside their current range that would be suitable for whio conservation if mammalian predator control could be implemented. Our approach presents a practical technique for estimating the relative importance of global change drivers in species declines and extinctions, as well as providing valuable information to improve conservation planning.

Overall Survival Update for Patients with Metastatic Castration-resistant Prostate Cancer Treated with Capivasertib and Docetaxel in the Phase 2 ProCAID Clinical Trial.

The PI3K/AKT/PTEN pathway is frequently deregulated in metastatic castration-resistant prostate cancer (mCRPC). ProCAID was a phase 2 trial assessing addition of the AKT1/2/3 inhibitor capivasertib to docetaxel for patients with mCRPC. We previously reported that capivasertib did not extend a composite progression-free survival primary endpoint but did significantly improve the secondary endpoint of overall survival (OS). Here we present OS data after 66% of events had occurred in the intent-to-treat population (n = 150). Median OS was 25.3 mo for capivasertib plus docetaxel versus 20.3 mo for placebo plus docetaxel (hazard ratio [HR] 0.70, 95% confidence interval [CI] 0.47-1.05; nominal p = 0.09). Receipt of subsequent life-extending treatments was balanced between the treatment arms. The OS benefit associated with capivasertib was maintained in a subset of patients previously treated with abiraterone and/or enzalutamide (median OS 25.0 vs 17.6 mo; HR 0.57, 95% CI 0.36-0.91; nominal p = 0.02) but not in abiraterone/enzalutamide-naïve patients (median OS 31.1 mo vs not reached; HR 1.43, 95% CI 0.63-3.23). We conclude that OS may be extended by addition of capivasertib to docetaxel. Exploratory analysis revealed that the OS benefit was maintained in a subset of patients previously exposed to androgen receptor-targeted agents, which should be evaluated in prospective trials. PATIENT SUMMARY: The ProCAID study examined whether adding the AKT inhibitor drug capivasertib to docetaxel chemotherapy improves outcomes for patients with advanced prostate cancer. Initial analysis of the ProCAID results suggested that capivasertib improved overall survival benefit. This follow-up analysis suggests that capivasertib addition may be particularly beneficial for patients whose cancer was previously treated with drugs that target the androgen receptor.

The Effect of Think Aloud on Performance and Brain Oxygenation During Cycling - An Exploratory Study.

In this study, we aimed to investigate the effect of Think Aloud (TA) on performance in trained and untrained participants, using functional Near Infrared Spectroscopy, during incrementally paced cycling. A mixed design was implemented with cycling expertise (10 untrained vs. 9 trained) as the between groups variable and trial stage (5 stages of increasing effort), and condition (silent vs. TA) as within groups independent variables (IVs). Dependent measures were changes in cortical oxygenation (O2Hb) in 12 areas of the prefrontal cortex (PFC) and physiological indicators of percentage heart rate maximum (%HRmax), average power output (APO), peak power output (PPO), rate of perceived exertion (RPE) and blood lactate ([La]b) over time. Trained cyclists had higher APO and significantly higher PPO from stages 2-5, in addition to a greater increase in PPO over the duration of the test (range 168W-480 W vs. 133W-313 W). There were significant main effects of stage on %HRmax, Bla and RPE (p < .001), with effect sizes (ήp2) ranging from .31 to .97. On average, HRmax%, [La]b and RPE were significantly lower after stage 2 onwards within the TA trial than the silent trial, even though similar power outputs were obtained. Thus, the TA trial elicited a better pacing strategy. There was no main effect of group on changes in O2Hb, though O2Hb did change as a function of stage in four areas of the PFC, and as a function of condition in one area. In this first study to assess the effects of TA on performance during self-paced cycling, TA did not disrupt performance outcomes at low through to high levels of physical exertion for either untrained or trained participants.

Aspirin to target arterial events in chronic kidney disease (ATTACK): study protocol for a multicentre, prospective, randomised, open-label, blinded endpoint, parallel group trial of low-dose aspirin vs. standard care for the primary prevention of cardiovascular disease in people with chronic kidney disease.

BACKGROUND: Chronic kidney disease (CKD) is a very common long-term condition and powerful risk factor for cardiovascular disease (CVD). Low-dose aspirin is of proven benefit in the secondary prevention of myocardial infarction (MI) and stroke in people with pre-existing CVD. However, in people without CVD, the rates of MI and stroke are much lower, and the benefits of aspirin in the primary prevention of CVD are largely balanced by an increased risk of bleeding. People with CKD are at greatly increased risk of CVD and so the absolute benefits of aspirin are likely to be greater than in lower-risk groups, even if the relative benefits are the same. Post hoc evidence suggests the relative benefits may be greater in the CKD population but the risk of bleeding may also be higher. A definitive study of aspirin for primary prevention in this high-risk group, recommended by the National Institute for Health and Care Excellence (NICE) in 2014, has never been conducted. The question has global significance given the rising burden of CKD worldwide and the low cost of aspirin. METHODS: ATTACK is a pragmatic multicentre, prospective, randomised, open-label, blinded endpoint adjudication superiority trial of aspirin 75 mg daily vs. standard care for the primary prevention of CVD in 25,210 people aged 18 years and over with CKD recruited from UK Primary Care. Participants aged 18 years and over with CKD (GFR category G1-G4) will be identified in Primary Care and followed up using routinely collected data and annual questionnaires for an average of 5 years. The primary outcome is the time to first major vascular event (composite of non-fatal MI, non-fatal stroke and cardiovascular death [excluding confirmed intracranial haemorrhage and other fatal cardiovascular haemorrhage]). Deaths from other causes (including fatal bleeding) will be treated as competing events. The study will continue until 1827 major vascular events have occurred. The principal safety outcome is major intracranial and extracranial bleeding; this is hypothesised to be increased in those randomised to take aspirin. The key consideration is then whether and to what extent the benefits of aspirin from the expected reduction in CVD events exceed the risks of major bleeding. DISCUSSION: This will be the first definitive trial of aspirin for primary CVD prevention in CKD patients. The research will be of great interest to clinicians, guideline groups and policy-makers, in the UK and globally, particularly given the high and rising prevalence of CKD that is driven by population ageing and epidemics of obesity and diabetes. The low cost of aspirin means that a positive result would be of relevance to low- and middle-income countries and the impact in the developed world less diluted by any inequalities in health care access. TRIAL REGISTRATION: ISRCTN: ISRCTN40920200 . EudraCT: 2018-000644-26 . CLINICALTRIALS: gov: NCT03796156.

Rapid Transition to Telemedicine During the COVID-19 Pandemic: Medical Genetics Experience.

BACKGROUND: The coronavirus SARS-CoV-2 (COVID-19) pandemic interrupted delivery of outpatient health care to minimize risk of exposure. This pandemic threatened to increase longstanding national concerns about access to both initial and follow-up genetics clinics services. The Medical Genetics Clinic at the University of Wisconsin-Madison Waisman Center (WCMGC) rapidly transitioned to offering appointments using telemedicine in March 2020 when the public health emergency for COVID-19 pandemic was declared. METHODS: Datasets were reviewed for the periods April - July 2019 (pre-COVID baseline) and April - July 2020 (COVID project data). Patient schedules were accessed to determine the number of appointments kept, no-shows, and late cancellations. A telephone survey was utilized to assess patient satisfaction with telemedicine. RESULTS: Fewer appointments were missed and providers completed more clinic visits after transitioning to telemedicine. Patients and their families were equally satisfied with care received and were amenable to telemedicine use in the future. Telemedicine allowed WCMGC to continue serving patients during a period of restricted on-site services, suggesting its continuation would improve access to genetic services.

The Optimising Cardiac Surgery ouTcOmes in People with diabeteS (OCTOPuS) randomised controlled trial to evaluate an outpatient pre-cardiac surgery diabetes management intervention: a study protocol.

INTRODUCTION: Cardiothoracic surgical outcomes are poorer in people with diabetes compared with those without diabetes. There are two important uncertainties in the management of people with diabetes undergoing major surgery: (1) how to improve diabetes management in the weeks leading up to an elective procedure and (2) whether that improved management leads to better postoperative outcomes. We previously demonstrated the feasibility of delivering the Optimising Cardiac Surgery ouTcOmes in People with diabeteS (OCTOPuS) intervention, an outpatient intervention delivered by diabetes healthcare professionals for people with suboptimally managed diabetes over 8-12 weeks before elective cardiac surgery. The present study will assess the clinical and cost-effectiveness of the intervention in cardiothoracic centres across the UK. METHODS AND ANALYSIS: A multicentre, parallel group, single-blinded 1:1 individually randomised trial comparing time from surgery until clinically fit for discharge in adults with suboptimally managed type 1 diabetes or type 2 diabetes undergoing elective surgery between the OCTOPuS intervention and usual care (primary endpoint). Secondary endpoints will include actual time from surgery to discharge from hospital; days alive and either out of hospital or judged as clinically fit for discharge; mortality; time on intensive therapy unit (ITU)/ventilator; infections; acute myocardial infarction; change in weight; effect on postoperative renal function and incidence of acute kidney injury; change in HbA1c; frequency and severity of self-reported hypoglycaemia; operations permanently cancelled for suboptimal glycaemic levels; cost-effectiveness; psychosocial questionnaires. The target sample size will be 426 recruited across approximately 15 sites. The primary analysis will be conducted on an intention-to-treat population. A two-sided p value of 0.05 or less will be used to declare statistical significance for all analyses and results will be presented with 95% CIs. ETHICS AND DISSEMINATION: The trial was approved by the South Central-Hampshire A Research Ethics Committee (20/SC/0271). Results will be disseminated through conferences, scientific journals, newsletters, magazines and social media. TRIAL REGISTRATION NUMBER: ISRCTN10170306.

Pelargonium sidoides root extract for the treatment of acute cough due to lower respiratory tract infection in adults: a feasibility double-blind, placebo-controlled randomised trial.

BACKGROUND: Pelargonium sidoides DC (Geraniaceae) root extract, EPs®7630 or "Kaloba®", is a widely used herbal remedy for respiratory infections, with some evidence of effectiveness for acute bronchitis. However, it is not yet widely recommended by medical professionals in the UK. There is a need to undertake appropriately designed randomised trials to test its use as an alternative to antibiotics. The aim was to assess the feasibility of conducting a double-blind randomised controlled trial of Pelargonium sidoides root extract for treatment of acute bronchitis in UK primary care, investigating intervention compliance, patient preference for dosage form and acceptability of patient diaries. STUDY DESIGN: Feasibility double-blind randomised placebo-controlled clinical trial. METHODS: We aimed to recruit 160 patients with cough (≤ 21 days) caused by acute bronchitis from UK general practices. Practices were cluster-randomised to liquid or tablet preparations and patients were individually randomised to Kaloba® or placebo. We followed participants up for 28 days through self-reported patient diaries with telephone support and reviewed medical records at one month. Outcomes included recruitment, withdrawal, safety, reconsultation and symptom diary completion rates. We also assessed treatment adherence, antibiotic prescribing and consumption, mean symptom severity (at days 2-4 after randomisation) and time to symptom resolution. We interviewed 29 patients and 11 health professionals to identify barriers and facilitators to running such a randomised trial. RESULTS: Of 543 patients screened, 261 were eligible, of whom 134 (51%) were recruited and 103 (77%) returned a completed diary. Overall, 41% (41/100) of patients took antibiotics (Kaloba® liquid group: 48% [15/31]; placebo liquid group: 23% [6/26]; Kaloba® tablet group: 48% [9/21]; placebo tablet group: 50% [11/22]). Most patients adhered to the study medication (median 19 out of 21 doses taken in week 1, IQR 18-21 - all arms combined). There were no serious adverse events relating to treatment. Most patients interviewed found study recruitment to be straightforward, but some found the diary too complex. CONCLUSIONS: It was feasible and acceptable to recruit patients from UK primary care to a double-blind placebo-controlled trial of herbal medicine (Kaloba®) for the treatment of acute bronchitis, with good retention and low data attrition. TRIAL REGISTRATION: HATRIC was registered on the ISRCTN registry ( ISRCTN17672884 ) on 16 August 2018, retrospectively registered. The record can be found at http://www.isrctn.com/ISRCTN17672884 .

Phase I Trial of DNA Methyltransferase Inhibitor Guadecitabine Combined with Cisplatin and Gemcitabine for Solid Malignancies Including Urothelial Carcinoma (SPIRE).

PURPOSE: Preclinical data indicate that DNA methyltransferase inhibition will circumvent cisplatin resistance in various cancers. PATIENT AND METHODS: SPIRE comprised a dose-escalation phase for incurable metastatic solid cancers, followed by a randomized dose expansion phase for neoadjuvant treatment of T2-4a N0 M0 bladder urothelial carcinoma. The primary objective was a recommended phase II dose (RP2D) for guadecitabine combined with gemcitabine and cisplatin. Treatment comprised 21-day gemcitabine and cisplatin cycles (cisplatin 70 mg/m2, i.v., day 8 and gemcitabine 1,000 mg/m2, i.v., days 8 + 15). Guadecitabine was injected subcutaneously on days 1-5, within escalation phase cohorts, and to half of 20 patients in the expansion phase. Registration ID: ISRCTN 16332228. RESULTS: Within the escalation phase, dose-limiting toxicities related predominantly to myelosuppression requiring G-CSF prophylaxis from cohort 2 (guadecitabine 20 mg/m2, days 1-5). The most common grade ≥3 adverse events in 17 patients in the dose-escalation phase were neutropenia (76.5%), thrombocytopenia (64.7%), leukopenia (29.4%), and anemia (29.4%). Addition of guadecitabine to gemcitabine and cisplatin in the expansion phase resulted in similar rates of severe hematologic adverse events, similar cisplatin dose intensity, but modestly reduced gemcitabine dose intensity. Radical treatment options after chemotherapy were not compromised. Pharmacodynamics evaluations indicated guadecitabine maximal target effect at the point of cisplatin administration. Pharmacokinetics were consistent with prior data. No treatment-related deaths occurred. CONCLUSIONS: The guadecitabine RP2D was 20 mg/m2, days 1-5, in combination with gemcitabine and cisplatin and required GCSF prophylaxis. Gene promoter methylation pharmacodynamics are optimal with this schedule. Addition of guadecitabine to gemcitabine and cisplatin was tolerable, despite some additional myelosuppression, and warrants further investigation to assess efficacy.

Pan-AKT Inhibitor Capivasertib With Docetaxel and Prednisolone in Metastatic Castration-Resistant Prostate Cancer: A Randomized, Placebo-Controlled Phase II Trial (ProCAID).

PURPOSE: Capivasertib is a pan-AKT inhibitor. Preclinical data indicate activity in metastatic castration-resistant prostate cancer (mCRPC) and synergism with docetaxel. PATIENTS AND METHODS: ProCAID was a placebo controlled randomized phase II trial in mCRPC. Patients received up to ten 21-day cycles of docetaxel (75 mg/m2 intravenous, day 1) and prednisolone (5 mg twice daily, oral, day 1-21) and were randomly assigned (1:1) to oral capivasertib (320 mg twice daily, 4 days on/3 days off, from day 2 each cycle), or placebo, until disease progression. Treatment allocation used minimization factors: bone metastases; visceral metastases; investigational site; and prior abiraterone or enzalutamide. The primary objective, by intention to treat, determined if the addition of capivasertib prolonged a composite progression-free survival (cPFS) end point that included prostate-specific antigen progression events. cPFS and overall survival (OS) were also assessed by composite biomarker subgroup for PI3K/AKT/PTEN pathway activation status. RESULTS: One hundred and fifty patients were enrolled. Median cPFS was 7.03 (95% CI, 6.28 to 8.25) and 6.70 months (95% CI, 5.52 to 7.36) with capivasertib and placebo respectively (hazard ratio [HR], 0.92; 80% CI, 0.73 to 1.16; one-sided P = .32). Median OS was 31.15 (95% CI, 20.07 to not reached) and 20.27 months (95% CI, 17.51 to 24.18), respectively (HR, 0.54; 95% CI, 0.34 to 0.88; two-sided P = .01). cPFS and OS results were consistent irrespective of PI3K/AKT/PTEN pathway activation status. Grade III-IV adverse events were equivalent between arms (62.2%). The most common adverse events of any grade deemed related to capivasertib were diarrhea, fatigue, nausea, and rash. CONCLUSION: The addition of capivasertib to chemotherapy did not extend cPFS in mCRPC irrespective of PI3K/AKT/PTEN pathway activation status. The observed OS result (a secondary end point) will require prospective validation in future studies to address potential for bias.

Thinking Aloud: Stress and Coping in Junior Cricket Batsmen During Challenge and Threat States.

The present study examined stress and coping of cricket batsmen during challenge and threat states using the Think-Aloud method. Ten male elite-level junior cricket batsmen took part in the study. A repeated measures design was implemented, with participants verbalizing while both in (a) a threat state and (b) a challenge state. Participants were required to score 36 runs in 30 balls during the threat and challenge conditions. Verbalizations were subsequently transcribed verbatim and analyzed for stressors, coping strategies, and any other reoccurring themes. A paired-samples t-test was conducted to examine differences in the number of verbalizations made for each theme between conditions. Ten secondary themes were grouped into four primary themes; these included (a) stressors, (b) problem-focused coping, (c) emotion-focused coping, and (d) gathering information. There were significant differences( p⩽0.05) between stressor verbalizations, with significantly more verbalizations made by participants during a threat state. No significant differences were found between any other themes. Thus, during a threat state, participants reported significantly more stressor verbalizations compared to a challenge state, while there were no significant differences in coping strategies reported (p>0.05). This finding offers a potential explanation for why athletic performance diminishes when in a threat state, as athletes then experience a greater number of stressors but do not report engaging in more coping strategies.

Measuring impacts on species with models and metrics of varying ecological and computational complexity.

Approaches to assess the impacts of landscape disturbance scenarios on species range from metrics based on patterns of occurrence or habitat to comprehensive models that explicitly include ecological processes. The choice of metrics and models affects how impacts are interpreted and conservation decisions. We explored the impacts of 3 realistic disturbance scenarios on 4 species with different ecological and taxonomic traits. We used progressively more complex models and metrics to evaluate relative impact and rank of scenarios on the species. Models ranged from species distribution models that relied on implicit assumptions about environmental factors and species presence to highly parameterized spatially explicit population models that explicitly included ecological processes and stochasticity. Metrics performed consistently in ranking different scenarios in order of severity primarily when variation in impact was driven by habitat amount. However, they differed in rank for cases where dispersal dynamics were critical in influencing metapopulation persistence. Impacts of scenarios on species with low dispersal ability were better characterized using models that explicitly captured these processes. Metapopulation capacity provided rank orders that most consistently correlated with those from highly parameterized and data-rich models and incorporated information about dispersal with little additional computational and data cost. Our results highlight the importance of explicitly considering species' ecology, spatial configuration of habitat, and disturbance when choosing indicators of species persistence. We suggest using hybrid approaches that are a mixture of simple and complex models to improve multispecies assessments.

Medición de los Impactos sobre las Especies con Modelos y Medidas de Complejidad Ecológica y Computacional Variante Resumen Las estrategias para evaluar el impacto de los escenarios de perturbación de paisaje sobre la distribución de las especies van desde las medidas basadas en patrones de presencia o hábitat hasta los modelos integrales que incluyen explícitamente a los procesos ecológicos. La elección de medidas y modelos afecta la interpretación de los impactos y las decisiones de conservación. Exploramos los impactos de tres escenarios realistas de perturbación sobre cuatro especies con características ecológicas y taxonómicas diferentes. Usamos progresivamente modelos y medidas más complejas para evaluar el impacto relativo y la clasificación de los escenarios sobre las especies. Los modelos variaron desde aquellos de distribución de especies que dependen de las suposiciones implícitas acerca de los factores ambientales y la presencia de la especie hasta aquellos modelos poblacionales explícitos con una alta parametrización espacial que incluyen los procesos ecológicos y la estocasticidad. Las medidas tuvieron un desempeño uniforme en la clasificación de los diferentes escenarios de acuerdo a la gravedad, principalmente cuando la variación en el impacto fue causada por la cantidad de hábitat presente. Sin embargo, las medidas difirieron en la clasificación para los casos en los que las dinámicas de dispersión fueron significativas en la influencia de la persistencia metapoblacional. Los impactos de los escenarios sobre las especies con una habilidad reducida de dispersión estuvieron mejor caracterizados con el uso de modelos que capturaron explícitamente estos procesos. La capacidad metapoblacional proporcionó categorías de clasificación con la correlación más consistente a aquellas provenientes de los modelos ricos en datos y con una alta parametrización e incorporó información sobre la dispersión con un reducido costo adicional de cómputo y de datos. Nuestros resultados resaltan la importancia de la consideración explícita de la ecología de las especies, la configuración espacial del hábitat y la perturbación cuando se eligen los indicadores de la persistencia de una especie. Sugerimos que se usen estrategias híbridas que mezclen modelos simples y complejos para mejorar las evaluaciones realizadas a múltiples especies.

Systemic chemotherapy with or without cetuximab in patients with resectable colorectal liver metastasis (New EPOC): long-term results of a multicentre, randomised, controlled, phase 3 trial.

BACKGROUND: The interim analysis of the multicentre New EPOC trial in patients with resectable colorectal liver metastasis showed a significant reduction in progression-free survival in patients allocated to cetuximab plus chemotherapy compared with those given chemotherapy alone. The focus of the present analysis was to assess the effect on overall survival. METHODS: New EPOC was a multicentre, open-label, randomised, controlled, phase 3 trial. Adult patients (aged ≥18 years) with KRAS wild-type (codons 12, 13, and 61) resectable or suboptimally resectable colorectal liver metastases and a WHO performance status of 0-2 were randomly assigned (1:1) to receive chemotherapy with or without cetuximab before and after liver resection. Randomisation was done centrally with minimisation factors of surgical centre, poor prognosis cancer, and previous adjuvant treatment with oxaliplatin. Chemotherapy consisted of oxaliplatin 85 mg/m2 administered intravenously over 2 h, l-folinic acid (175 mg flat dose administered intravenously over 2 h) or d,l-folinic acid (350 mg flat dose administered intravenously over 2 h), and fluorouracil bolus 400 mg/m2 administered intravenously over 5 min, followed by a 46 h infusion of fluorouracil 2400 mg/m2 repeated every 2 weeks (regimen one), or oxaliplatin 130 mg/m2 administered intravenously over 2 h and oral capecitabine 1000 mg/m2 twice daily on days 1-14 repeated every 3 weeks (regimen two). Patients who had received adjuvant oxaliplatin could receive irinotecan 180 mg/m2 intravenously over 30 min with fluorouracil instead of oxaliplatin (regimen three). Cetuximab was given intravenously, 500 mg/m2 every 2 weeks with regimen one and three or a loading dose of 400 mg/m2 followed by a weekly infusion of 250 mg/m2 with regimen two. The primary endpoint of progression-free survival was published previously. Secondary endpoints were overall survival, preoperative response, pathological resection status, and safety. Trial recruitment was halted prematurely on the advice of the Trial Steering Committee on Nov 1, 2012. All analyses (except safety) were done on the intention-to-treat population. Safety analyses included all randomly assigned patients. This trial is registered with ISRCTN, number 22944367. FINDINGS: Between Feb 26, 2007, and Oct 12, 2012, 257 eligible patients were randomly assigned to chemotherapy with cetuximab (n=129) or without cetuximab (n=128). This analysis was carried out 5 years after the last patient was recruited, as defined in the protocol, at a median follow-up of 66·7 months (IQR 58·0-77·5). Median progression-free survival was 22·2 months (95% CI 18·3-26·8) in the chemotherapy alone group and 15·5 months (13·8-19·0) in the chemotherapy plus cetuximab group (hazard ratio [HR] 1·17, 95% CI 0·87-1·56; p=0·304). Median overall survival was 81·0 months (59·6 to not reached) in the chemotherapy alone group and 55·4 months (43·5-71·5) in the chemotherapy plus cetuximab group (HR 1·45, 1·02-2·05; p=0·036). There was no significant difference in the secondary outcomes of preoperative response or pathological resection status between groups. Five deaths might have been treatment-related (one in the chemotherapy alone group and four in the chemotherapy plus cetuximab group). The most common grade 3-4 adverse events reported were: neutrophil count decreased (26 [19%] of 134 in the chemotherapy alone group vs 21 [15%] of 137 in the chemotherapy plus cetuximab group), diarrhoea (13 [10%] vs 14 [10%]), skin rash (one [1%] vs 22 [16%]), thromboembolic events (ten [7%] vs 11 [8%]), lethargy (ten [7%] vs nine [7%]), oral mucositis (three [2%] vs 14 [10%]), vomiting (seven [5%] vs seven [5%]), peripheral neuropathy (eight [6%] vs five [4%]), and pain (six [4%] vs six [4%]). INTERPRETATION: Although the addition of cetuximab to chemotherapy improves the overall survival in some studies in patients with advanced, inoperable metastatic disease, its use in the perioperative setting in patients with operable disease confers a significant disadvantage in terms of overall survival. Cetuximab should not be used in this setting. FUNDING: Cancer Research UK.

A Heuristic Method for Determining Changes of Source Loads to Comply with Water Quality Limits in Catchments.

A common land and water management task is to determine where and by how much source loadings need to change to meet water quality limits in receiving environments. This paper addresses the problem of quantifying changes in loading when limits are specified in many locations in a large and spatially heterogeneous catchment, accounting for cumulative downstream impacts. Current approaches to this problem tend to use either scenario analysis or optimization, which suffer from difficulties of generating scenarios that meet the limits, or high complexity of optimization approaches. In contrast, we present a novel method in which simple catchment models, load limits, upstream/downstream spatial relationships and spatial allocation rules are combined to arrive at source load changes. The process iteratively establishes the critical location (river segment or lake) where the limits are most constraining, and then adjusts sources upstream of the critical location to meet the limit at that location. The method is demonstrated with application to New Zealand (268,000 km2) for nutrients and the microbial indicator E. coli, which was conducted to support policy development regarding water quality limits. The model provided useful insights, such as a source load excess (the need for source load reduction) even after mitigation measures are introduced in order to comply with E. coli limits. On the other hand, there was headroom (ability to increase source loading) for nutrients. The method enables assessment of the necessary source load reductions to achieve water quality limits over broad areas such as large catchments or whole regions.

Investigating the Comparative Suitability of Traditional and Task-Specific Think Aloud Training.

The think aloud (TA) protocol is used to capture conscious cognition for wide ranging applications. However, the methods used to train the TA technique have been inconsistent, involving a mixture of both traditional guidelines and task-specific examples. This study aimed to examine how best to train the TA process. We recruited 20 competitive golfers as research participants, and we randomly assigned them to equal sized groups of traditional TA training as described by Ericsson and Simon and task-specific training in which participants were familiarized with TA via task-specific examples. Following training, all participants performed a golf task and were asked to TA. We transcribed audiotapes of their verbatim TA content and analyzed them using a deductive framework. We also collected various social validation self-report measures to assess participant perceptions of TA training. Overall, we found no significant differences in the frequency or type of TA verbalizations when comparing traditional and task-specific TA training groups. However, participants in the task-specific training group reported more favorable perceptions of training and found training significantly clearer than did participants in the traditional training group. We suggest that these findings support traditional TA training following Ericsson and Simon's training guidelines, but adding task-specific examples seems to increase the familiarity of TA use and facilitate more reliable and accurate cognition data for research use.

HATRIC: a study of Pelargonium sidoides root extract EPs®7630 (Kaloba®) for the treatment of acute cough due to lower respiratory tract infection in adults-study protocol for a double blind, placebo-controlled randomised feasibility trial.

BACKGROUND: Acute lower respiratory tract infection is a common acute infection managed in primary care. The current dominant management strategy in the UK is antibiotics, despite widespread publicity regarding antimicrobial resistance and evidence that the small benefits of antibiotics do not outweigh the harms. There is a need to address the rising problem of antibiotic resistance by providing credible alternative strategies, which reduce symptom burden. There is sufficient evidence to recommend the use of Pelargonium sidoides root extract in order to warrant undertaking an independent clinical trial.We propose a feasibility study to demonstrate our ability to recruit and retain patients and conduct a placebo-controlled trial of Pelargonium sidoides extract EPs®7630 in lower respiratory tract infection where pneumonia is not suspected. Both the tablet and liquid formulations will be included. METHODS: The HATRIC trial is a double-blind randomised placebo-controlled feasibility study aiming to determine the potential to conduct a fully powered trial of Pelargonium sidoides root extract as an alternative to the inappropriate use of antibiotics for acute bronchitis in UK primary care.Primary care sites will be equally randomised to one of two formulation groups (tablet or liquid preparation). Additionally, within each site, patients will be evenly randomised to active or placebo treatment. Antibiotic consumption will be monitored during the trial, but the use of a delayed prescription strategy is encouraged. The target sample size for this study is 160 patients overall or 40 per arm, recruited from approximately 20 primary care sites. The analysis will be descriptive focusing on estimation with no formal comparison of groups taking place. DISCUSSION: If this trial demonstrates the feasibility of recruitment and delivery, we will seek funding for a fully powered placebo-controlled trial of Pelargonium sidoides root extract for the treatment of lower respiratory tract infections in primary care. TRIAL REGISTRATION: HATRIC was registered on the ISRCTN registry (ISRCTN17672884) on 16 August 2018.

Global synthesis of conservation studies reveals the importance of small habitat patches for biodiversity.

Island biogeography theory posits that species richness increases with island size and decreases with isolation. This logic underpins much conservation policy and regulation, with preference given to conserving large, highly connected areas, and relative ambivalence shown toward protecting small, isolated habitat patches. We undertook a global synthesis of the relationship between the conservation value of habitat patches and their size and isolation, based on 31 systematic conservation planning studies across four continents. We found that small, isolated patches are inordinately important for biodiversity conservation. Our results provide a powerful argument for redressing the neglect of small, isolated habitat patches, for urgently prioritizing their restoration, and for avoiding simplistic application of island biogeography theory in conservation decisions.

SPIRE - combining SGI-110 with cisplatin and gemcitabine chemotherapy for solid malignancies including bladder cancer: study protocol for a phase Ib/randomised IIa open label clinical trial.

BACKGROUND: Urothelial bladder cancer (UBC) accounts for 10,000 new diagnoses and 5000 deaths annually in the UK (Cancer Research UK, http://www.cancerresearchuk.org/health-professional/cancer-statistics/statistics-by-cancer-type/bladder-cancer , Cancer Research UK, Accessed 26 Mar 2018). Cisplatin-based chemotherapy is standard of care therapy for UBC for both palliative first-line treatment of advanced/metastatic disease and radical neoadjuvant treatment of localised muscle invasive bladder cancer. However, cisplatin resistance remains a critical cause of treatment failure and a barrier to therapeutic advance in UBC. Based on supportive pre-clinical data, we hypothesised that DNA methyltransferase inhibition would circumvent cisplatin resistance in UBC and potentially other cancers. METHODS: The addition of SGI-110 (guadecitabine, a DNA methyltransferase inhibitor) to conventional doublet therapy of gemcitabine and cisplatin (GC) is being tested within the phase Ib/IIa SPIRE clinical trial. SPIRE incorporates an initial, modified rolling six-dose escalation phase Ib design of up to 36 patients with advanced solid tumours followed by a 20-patient open-label randomised controlled dose expansion phase IIa component as neoadjuvant treatment for UBC. Patients are being recruited from UK secondary care sites. The dose escalation phase will determine a recommended phase II dose (RP2D, primary endpoint) of SGI-110, by subcutaneous injection, on days 1-5 for combination with GC at conventional doses (cisplatin 70 mg/m2, IV infusion, day 8; gemcitabine 1000 mg/m2, IV infusion, days 8 and 15) in every 21-day cycle. In the dose expansion phase, patients will be randomised 1:1 to GC with or without SGI-110 at the proposed RP2D. Secondary endpoints will include toxicity profiles, SGI-110 pharmacokinetics and pharmacodynamic biomarkers, and pathological complete response rates in the dose expansion phase. Analyses will not be powered for formal statistical comparisons and descriptive statistics will be used to describe rates of toxicity, efficacy and translational endpoints by treatment arm. DISCUSSION: SPIRE will provide evidence for whether SGI-110 in combination with GC chemotherapy is safe and biologically effective prior to future phase II/III trials as a neoadjuvant therapy for UBC and potentially in other cancers treated with GC. TRIAL REGISTRATION: EudraCT Number: 2015-004062-29 (entered Dec 7, 2015) ISRCTN registry number: 16332228 (registered on Feb 3, 2016).