Maintenance of a fruit colour polymorphism along an elevational gradient in the Southern Alps of New Zealand.

Many plants produce colour-polymorphic fruits. However, the processes responsible for the evolution and maintenance of fruit colour polymorphisms are poorly understood. We investigated the fruit colour polymorphism in Gaultheria depressa var. novae-zealandiae (Ericaceae), a predominantly bird-dispersed, alpine shrub from New Zealand, by testing whether colour morph frequencies vary geographically to maximise fruit-foliage colour contrasts. We also conducted a seed germination experiment to test whether fruit colour morphs vary in their susceptibility to UV damage. Results showed that 'red' fruits were more abundant at lower elevations, while 'white' fruits were predominant at higher elevations. Leaf colours shifted from 'green' in appearance at lower elevations to 'red' at higher elevations. Analyses of fruit-foliage colour contrasts showed that 'red' fruits were more conspicuous at lower elevations, and 'white' fruits were more conspicuous at higher elevations, which was consistent with the hypothesis that colour morph frequencies vary geographically to maximise their conspicuousness to dispersers. However, 'red' fruits were generally more conspicuous than 'white' fruits, regardless of elevation, indicating that the maintenance of the polymorphism could not be attributed to fruit-foliage colour contrasts alone. The seed germination experiment showed that 'white' fruits were more resistant to UV damage, suggesting the preponderance of 'white' fruited individuals in the landscape results from a greater degree of protection from UV damage. The fruit colour polymorphism in Gaultheria depressa var. novae-zealandiae therefore appears to be maintained by trade-offs between conspicuousness to dispersers and tolerance to UV damage, advocating a pluralistic approach to the problem in the future.

Social inequities impact infant mortality due to congenital heart disease.

OBJECTIVES: To evaluate how educational, economic, and racial residential segregation may impact congenital heart disease infant mortality (CHD-IM). STUDY DESIGN: This is a population-based US ecological study. METHODS: This study evaluated linked live birth-infant death files from the National Center for Health Statistics for live births from 2006 to 2018 with cause of death attributed to CHD. Maternal race and education data were obtained from the live birth-infant death files, and income data were obtained from the American Community Survey. A spatial social polarization measure termed the Index of Concentration at the Extremes (ICE) was calculated and split by quintiles for maternal education, household income, and race for all US counties (n = 3142). The lowest quintile represents counties with highest concentration of disadvantaged groups (income < $25K, non-Hispanic Black, no high school degree). Proximity to a pediatric cardiac center (PCC) was also analyzed in a categorical manner based on whether each county was in a metropolitan area with a US News and World Report top 50 ranked PCC, a lower ranked PCC, or not proximal to any PCC. RESULTS: Between 2006 and 2018, 17,489 infant deaths were due to CHD, an unadjusted CHD-IM of 0.33 deaths per 1000 live births. The risk of CHD-IM was 1.5 times greater among those in the lowest ICE-education quintile (0.41 [0.39-0.44] vs 0.28 deaths/1000 live births [0.27-0.29], P < 0.0001) and the lowest ICE-income quintile (0.44 [0.41-0.47] vs 0.29 [0.28-0.30], P < 0.0001) in comparison to those in the highest quintiles. CHD-IM increases with higher ICE-race value (counties with a higher concentration of non-Hispanic White mothers). However, after adjusting for proximity to a US News and World Report top 50 ranked PCC in the multivariable models, CHD-IM decreases with higher ICE-race value. CONCLUSIONS: Counties with the highest concentration of lower-educated mothers and the highest concentration of low-income households were associated with higher rates of CHD-IM. Mortality as a function of race is more complicated and requires further investigation.

Plants obey (and disobey) the island rule.

The island rule predicts that small animals evolve to become larger on islands, while large animals evolve to become smaller. It has been studied for over half a century, and its validity is fiercely debated. Here, we provide a perspective on the debate by conducting a test of the island rule in plants. Results from an extensive dataset on islands in the southwest Pacific illustrate that plant stature and leaf area obey the island rule, but seed size does not. Our results indicate that the island rule may be more pervasive than previously thought and that support for its predictions varies among functional traits.

A framework for mapping and monitoring human-ocean interactions in near real-time during COVID-19 and beyond.

The human response to the COVID-19 pandemic set in motion an unprecedented shift in human activity with unknown long-term effects. The impacts in marine systems are expected to be highly dynamic at local and global scales. However, in comparison to terrestrial ecosystems, we are not well-prepared to document these changes in marine and coastal environments. The problems are two-fold: 1) manual and siloed data collection and processing, and 2) reliance on marine professionals for observation and analysis. These problems are relevant beyond the pandemic and are a barrier to understanding rapidly evolving blue economies, the impacts of climate change, and the many other changes our modern-day oceans are undergoing. The "Our Ocean in COVID-19″ project, which aims to track human-ocean interactions throughout the pandemic, uses the new eOceans platform (eOceans.app) to overcome these barriers. Working at local scales, a global network of ocean scientists and citizen scientists are collaborating to monitor the ocean in near real-time. The purpose of this paper is to bring this project to the attention of the marine conservation community, researchers, and the public wanting to track changes in their area. As our team continues to grow, this project will provide important baselines and temporal patterns for ocean conservation, policy, and innovation as society transitions towards a new normal. It may also provide a proof-of-concept for real-time, collaborative ocean monitoring that breaks down silos between academia, government, and at-sea stakeholders to create a stronger and more democratic blue economy with communities more resilient to ocean and global change.

National Guidelines on the Provision of Outpatient Parenteral Antimicrobial Therapy (OPAT).

Aim Outpatient parenteral antimicrobial therapy (OPAT) is an option in patients who require parenteral antimicrobial administration and are clinically well enough for hospital discharge. This is an update of the Irish National OPAT guidelines which were last reviewed in 2011. Methods The guideline was devised through a collaborative process with the national OPAT Working Group and a review of the literature. It is intended for clinicians who prescribe any intravenous (IV) antimicrobials outside of the inpatient setting in the Republic of Ireland. Results Patient care while on OPAT should be provided by a designated OPAT service, with clear managerial and clinical governance lines of responsibility. It should be conducted using a team approach with a clinical lead on each site either as an infection specialist, or a general medical physician with infection specialist input and an OPAT nurse. An antimicrobial pharmacist is also desirable. Several factors must be considered when assessing patient's suitability for OPAT including exclusion criteria, infection-specific factors, and patient specific factors such as physical, social and logistic criteria. Conclusion This updated guideline advocates a more individualised OPAT approach, with the recognition that specific antimicrobials and/or specific delivery models may be more appropriate for certain patient groups. Full guidelines are available through www.opat.ie.

Prognostic value of circulating tumour cells in limited-stage small-cell lung cancer: analysis of the concurrent once-daily versus twice-daily radiotherapy (CONVERT) randomised controlled trial.

BACKGROUND: The clinical significance of circulating tumour cells (CTCs) in limited-stage small-cell lung cancer (LS-SCLC) is not well defined. We report a planned exploratory analysis of the prevalence and prognostic value of CTCs in LS-SCLC patients enrolled within the phase III randomised CONVERT (concurrent once-daily versus twice-daily chemoradiotherapy) trial. PATIENTS AND METHODS: Baseline blood samples were enumerated for CTCs using CellSearch in 75 patients with LS-SCLC who were enrolled in the CONVERT trial and randomised between twice- and once-daily concurrent chemoradiation. Standard statistical methods were used for correlations of CTCs with clinical factors. Log-rank test and Cox regression analyses were applied to establish the associations of 2, 15 and 50 CTC thresholds with progression-free survival (PFS) and overall survival (OS). An optimal CTC count threshold for LS-SCLC was established. RESULTS: CTCs were detected in 60% (45/75) of patients (range 0-3750). CTC count thresholds of 2, 15 and 50 CTCs all significantly correlate with PFS and OS. An optimal CTC count threshold in LS-SCLC was established at 15 CTCs, defining 'favourable' and 'unfavourable' prognostic risk groups. The median OS in <15 versus ≥15 CTCs was 26.7 versus 5.9 m (P = 0.001). The presence of ≥15 CTCs at baseline independently predicted ≤1 year survival in 70% and ≤2 years survival in 100% of patients. CONCLUSION: We report the prognostic value of baseline CTC count in an exclusive LS-SCLC population at thresholds of 2, 15 and 50 CTCs. Specific to LS-SCLC, ≥15 CTCs was associated with worse PFS and OS independent of all other factors and predicted ≤2 years survival. These results may improve disease stratification in future clinical trial designs and aid clinical decision making. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT00433563.

Two phase I, pharmacokinetic, and pharmacodynamic studies of DFP-10917, a novel nucleoside analog with 14-day and 7-day continuous infusion schedules.

Purpose DFP-10917 is a novel deoxycytidine analog with a unique mechanism of action. Brief exposure to high concentrations of DFP-10917 inhibits DNA polymerase resulting in S-phase arrest, while prolonged exposure to DFP-10917 at low concentration causes DNA fragmentation, G2/M-phase arrest, and apoptosis. DFP-10917 demonstrated activity in tumor xenografts resistant to other deoxycytidine analogs. Experimental design Two phase I studies assessed the safety, pharmacokinetic, pharmacodynamic and preliminary efficacy of DFP-10917. Patients with refractory solid tumors received DFP-10917 continuous infusion 14-day on/7-day off and 7-day on/7-day off. Enrollment required age > 18 years, ECOG Performance Status 0-2 and adequate organ function. Results 29 patients were dosed in both studies. In 14-day infusion, dose-limiting toxicities (DLT) consisting of febrile neutropenia and thrombocytopenia occurred at 4.0 mg/m2/day. At 3.0 mg/m2/day, 3 patients experienced neutropenia in cycle 2. The dose of 2.0 mg/m2/day was well tolerated in 6 patients. In 7-day infusion, grade 4 neutropenia was DLT at 4.0 mg/m2/day. The maximum tolerated dose was 3 mg/m2/day. Other toxicities included nausea, vomiting, diarrhea, neutropenia, and alopecia. Eight patients had stable disease for >12 weeks. Paired comet assays performed for 7 patients showed an increase in DNA strand breaks at day 8. Pharmacokinetic data showed dose-proportionality for steady-state concentration and AUC of DFP-10917 and its primary metabolite. Conclusion Continuous infusion of DFP-10917 is feasible and well tolerated with myelosuppression as main DLT. The recommended doses are 2.0 mg/m2/day and 3.0 mg/m2/day on the 14-day and 7-day continuous infusion schedules, respectively. Preliminary activity was suggested. Pharmacodynamic data demonstrate biological activity at the tested doses.

The importance of both CYP2C19 and CYP2B6 germline variations in cyclophosphamide pharmacokinetics and clinical outcomes.

Cyclophosphamide is an alkylating agent used in the treatment of solid and haematological malignancies and as an immunosuppressive agent. As a prodrug, it is dependent on bioactivation to the active phosphoramide mustard metabolite to elicit its therapeutic effect. This focused review will highlight the evidence for the role of germline pharmacogenetic variation in both plasma pharmacokinetics and clinical outcomes. There is a substantial indication from 13 pharmacokinetic and 17 therapeutic outcome studies, in contexts as diverse as haematological malignancy, breast cancer, systemic lupus erythematosus and myeloablation, that pharmacogenetic variation in both CYP2C19 and CYP2B6 influence the bioactivation of cyclophosphamide. An additional role for pharmacogenetic variation in ALDH1A1 has also been reported. Future studies should comprehensively assess these 3 pharmacogenes and undertake appropriate statistical analysis of gene-gene interactions to confirm these findings and may allow personalised treatment regimens.

A time-driven, activity-based costing methodology for determining the costs of red blood cell transfusion in patients with beta thalassaemia major.

OBJECTIVES: To describe the methodology to estimate the total cost of administration of a single unit of red blood cells (RBC) in adults with beta thalassaemia major in an Australian specialist haemoglobinopathy centre. BACKGROUND: Beta thalassaemia major is a genetic disorder of haemoglobin associated with multiple end-organ complications and typically requiring lifelong RBC transfusion therapy. New therapeutic agents are becoming available based on advances in understanding of the disorder and its consequences. Assessment of the true total cost of transfusion, incorporating both product and activity costs, is required in order to evaluate the benefits and costs of these new therapies. METHODS: We describe the bottom-up, time-driven, activity-based costing methodology used to develop process maps to provide a step-by-step outline of the entire transfusion pathway. Detailed flowcharts for each process are described. Direct observations and timing of the process maps document all activities, resources, staff, equipment and consumables in detail. The analysis will include costs associated with performing these processes, including resources and consumables. Sensitivity analyses will be performed to determine the impact of different staffing levels, timings and probabilities associated with performing different tasks. RESULTS: Thirty-one process maps have been developed, with over 600 individual activities requiring multiple timings. These will be used for future detailed cost analyses. CONCLUSIONS: Detailed process maps using bottom-up, time-driven, activity-based costing for determining the cost of RBC transfusion in thalassaemia major have been developed. These could be adapted for wider use to understand and compare the costs and complexities of transfusion in other settings.

An alternative water transport system in land plants.

The evolution of vascular tissue is a key innovation enabling plants to inhabit terrestrial environments. Here, we demonstrate extra-vascular water transport in a giant, prop-rooted monocot from Lord Howe Island. Pandanus forsteri (Pandanaceae) produces gutter-like leaves that capture rainwater, which is then couriered along a network of channels to the tips of aerial roots, where it is stored by absorptive tissue. This passive mechanism of water acquisition, transport and storage is critical to the growth of aerial prop roots that cannot yet attain water via vascular conduction. This species therefore sheds light on the elaborate means by which plants have evolved to attain water.

Antimicrobial prescribing and infections in long-term care facilities (LTCF): a multilevel analysis of the HALT 2016 study, Ireland, 2017.

BackgroundThe 2016 point prevalence survey (PPS) of healthcare-associated infections (HAI) and antimicrobial use (AMU) in Irish long-term care facilities (LTCF) (HALT) showed a 9.8% AMU and 4.4% HAI prevalence, based on aggregated data analysis.AimOur aim was to identify institutional and resident risk factors of AMU and HAI.MethodsHALT 2016 gathered information using institutional and resident questionnaires, for residents who met the surveillance definition of active HAI and/or AMU, limiting analysis to the aggregated institutional level. In January 2017, we requested additional data on age, sex, urinary catheter use and disorientation of current residents from HALT 2016 LTCF and matched to 2016 HALT data.ResultsOf 224 HALT 2016 LTCF, 80 provided additional information on 3,816 residents; prevalence of AMU was 10.6% and HAI was 4.7%. Presence of a coordinating physician (Odds ratio (OR): 0.3; 95% confidence interval (CI): 0.2-0.6), antimicrobial stewardship committee (OR: 0.2; 95%; CI: 0.1-0.6), healthcare assistants (OR: 0.9; 95% CI: 0.9-1.0), antimicrobial consumption feedback (OR: 0.3; 95% CI: 0.1-0.6) and medical care by personal general practitioner (OR: 0.6; 95% CI: 0.7-1.0) were associated with less AMU and feedback on surveillance of infection prevention and control (IPC) practices (OR: 0.6; 95% CI: 0.3-1.0) with less HAI. AMU and HAI varied significantly between LTCF.ConclusionsMultilevel modelling identified significant inter-facility variation, as well as institutional factors associated with AMU and HAI. An antimicrobial stewardship committee linked with feedback on IPC and prescribing was associated with reduced AMU and HAI.

Protocol adherence for continuously titrated interventions in randomized trials: an overview of the current methodology and case study.

BACKGROUND: The standard definition for protocol adherence is the proportion of all scheduled doses that are delivered. In clinical research, this definition has several limitations when evaluating protocol adherence in trials that study interventions requiring continuous titration. DISCUSSION: Building upon a specific case study, we analyzed a recent trial of a continuously titrated intervention to assess the impact of different definitions of protocol deviations on the interpretation of protocol adherence. The OVATION pilot trial was an open-label randomized controlled trial of higher (75-80 mmHg) versus lower (60-65 mmHg) mean arterial pressure (MAP) targets for vasopressor therapy in shock. In this trial, potential protocol deviations were defined as MAP values outside the targeted range for >4 consecutive hours during vasopressor therapy without synchronous and consistent adjustments of vasopressor doses. An adjudication committee reviewed each potential deviation to determine if it was clinically-justified or not. There are four reasons for this contextual measurement and reporting of protocol adherence. First, between-arm separation is a robust measure of adherence to complex protocols. Second, adherence assessed by protocol deviations varies in function of the definition of deviations and the frequency of measurements. Third, distinguishing clinically-justified vs. not clinically-justified protocol deviations acknowledges clinically sensible bedside decision-making and offers a clear terminology before the trial begins. Finally, multiple metrics exist to report protocol deviations, which provides different information but complementary information on protocol adherence. CONCLUSIONS: In trials of interventions requiring continuous titration, metrics used for defining protocol deviations have a considerable impact on the interpretation of protocol adherence. Definitions for protocol deviations should be prespecified and correlated with between-arm separation, if it can be measured.

Participation in a randomised controlled feasibility study of a complex intervention for the management of the Respiratory Symptom Distress Cluster in lung cancer: patient, carer and research staff views.

This paper reports finding from a nested qualitative study designed to elicit the views and perceptions of those who participated in a randomised controlled feasibility trial testing a non-pharmacological intervention, Respiratory Distress Symptom Intervention (RDSI), for the management of the breathlessness-cough-fatigue symptom cluster in lung cancer. Semi-structured interviews were conducted with 11 lung cancer patients, three caregivers and seven researchers involved in recruitment, consent, RDSI training and delivery and participant follow-up. Thematic analysis identified key considerations including: the importance of informed consent emphasising commitment to completion of paperwork and raising awareness of potential sensitivities relating to content of questionnaires; ensuring screening for the presence of symptoms reflects the language used by patients; appreciation of the commitment required from participants to learn intervention techniques and embed them as part of everyday life; conduct of interviews with patients who decline to participate; and conduct of serial interviews with those receiving RDSI to further inform its routine implementation into clinical practice. This study will inform the development of a fully powered follow-on trial testing the hypothesis that RDSI plus usual care is superior to usual care alone in the effective management of this symptom cluster in lung cancer.

The Montara Oil Spill: A 2009 Well Blowout in the Timor Sea.

A well on the Montara platform on the Australian continental shelf blew out in August 2009 and spilled oil into the Timor Sea for 74 days. The oil, estimated at as much as 23.5 million L in total volume, spread over a large area of the shelf and eventually into Indonesian waters. This paper documents, through published literature, reports of both Australian and Indonesian governments and observations of coastal residents and fishermen the spread of the oil and attempts to estimate its impact. The lack of observers on the ocean and baseline, pre-spill data on populations of marine organisms, and delays in deploying scientific surveys after the spill severely limited efforts by the Australian government to determine damage in its territorial waters. Biological survey work was not done in Indonesian waters, but coastal residents attested to relatively severe impacts to algal farms. In addition fish landings declined in one port in southwest Timor Island.

Native-exotic richness relationships: a biogeographic approach using turnover in island plant populations.

Spatial variation in exotic species richness is often correlated with native species richness, for reasons that are poorly understood. To better understand the mechanisms underpinning native-exotic richness relationships, I quantified the colonization and extinction of 18 exotic and 16 native plant species on 39 small islands located off the coast of New Zealand for 8 consecutive yr. Results revealed a positive native-exotic richness relationship, which could be explained by similar demographic responses of native and exotic species to island area. However, native and exotic species showed subtle differences in their response to other island attributes. Turnover in native species declined with island isolation, whereas turnover in exotic species increased with the exposure of islands to ocean-borne disturbances. Overall results illustrate how long-term observations of species turnover can be used to better understand the mechanisms underpinning native-exotic richness relationships, and demonstrate that large, exposed islands can be especially susceptible to invasions by exotic species.

Correlates of psychological outcomes in people with diabetes: results from the second Diabetes Attitudes, Wishes and Needs (DAWN2(™) ) study.

AIMS: To assess country- and individual-level correlates of psychological outcomes, and differences among countries in the associations of individual characteristics with psychological outcomes among adults with diabetes. METHODS: The second Diabetes Attitudes, Wishes and Needs (DAWN2(™) ) study assessed self-reported characteristics of people with diabetes in 17 countries, including 1368 adults with Type 1 diabetes and 7228 with Type 2 diabetes. In each country, a sample of 500 adults, stratified by diabetes type and treatment, completed a questionnaire incorporating the validated WHO-5 wellbeing index, the WHOQOL-BREF, and the five-item Problem Areas in Diabetes Scale, as well as the newly developed Diabetes Impact on Life Dimensions that assessed impact ranging from very positive to very negative, with no impact as the midpoint. Multilevel regression analyses identified significant (P < 0.05) independent correlates of psychological outcomes. RESULTS: There were significant variations in all outcomes across countries before adjustment for individual-level factors; adjustment reduced between-country disparities. Worse psychological outcomes were associated with more complications, incidence of hypoglycaemia, hypoglycaemic medication, perceived burden of diabetes, family conflict and experience of discrimination. Better psychological outcomes were associated with higher self-rated health, greater access to diabetes education and healthcare, and more psychosocial support from others. The associations of many factors with the outcomes were mediated by modifiable factors. The association of all factors with the outcomes varied across (interacted with) countries, highlighting the need for country-specific analyses. CONCLUSIONS: Improvements in modifiable risk factors (reductions in burden and increases in support) may lead to better psychological outcomes in adults with diabetes.

Correlates of psychological care strategies for people with diabetes in the second Diabetes Attitudes, Wishes and Needs (DAWN2(™) ) study.

AIMS: To assess the ways in which healthcare professionals address psychological problems of adults with diabetes in the second Diabetes Attitudes, Wishes and Needs (DAWN2(™) ) study. METHODS: Approximately 120 primary care physicians, 80 diabetes specialists and 80 nurses and dietitians providing diabetes care participated in each of 17 countries (N=4785). Multiple regression analyses were used to evaluate independent statistically significant associations of respondent attributes concerning psychological care strategies, including assessment of diabetes impact on the patient's life, assessment of depression, provision of psychological assessment and support, and coordination with mental health professionals. RESULTS: Psychological care strategies were positively associated with each other but differed by healthcare practice site and discipline; nurses and dietitians were less likely to assess depression than other healthcare professionals, while primary care physicians were less likely to coordinate with mental health specialists or ask patients how diabetes affects their lives. Psychological care was positively associated with healthcare professionals' beliefs that patients need help dealing with emotional issues and that clinical success depends on doing so, and also with level of psychological care training, multidisciplinary team membership and availability of resources for psychological care. There were significant between-country variations in psychological care strategies, before and after adjustment for individual-level factors, and significant country-by-covariate interactions for almost all individual-level factors investigated. CONCLUSIONS: Improvements in training and resources, recognition and assessment of psychological problems, and increased belief in the efficacy of psychological support may enhance healthcare professionals' efforts to address psychological problems in adults with diabetes.

Correlates of psychological outcomes among family members of people with diabetes in the second Diabetes Attitudes, Wishes and Needs (DAWN2(™) ) study.

AIMS: To conduct a second Diabetes Attitudes, Wishes and Needs (DAWN2(™) ) study, examining the experiences of family members caring for adults with diabetes in order to identify correlates of family member psychological outcomes (generic psychological well-being, perceived quality of life, and diabetes-related burden, impact and distress). METHODS: A total of 2057 family members living with a person with diabetes and involved in their care participated in an online, telephone or in-person survey. Samples of 120 respondents were recruited in each of 17 countries. Significant (P < 0.05) correlates of psychological outcomes were identified by multi-level multiple regression. RESULTS: Outcomes were worse for family members not working because of diabetes or those who had other competing obligations. Outcomes were worse if the person with diabetes was not a partner or parent, used injected diabetes medication, or had more frequent hypoglycaemia. Outcomes were worse for family members who believed that diabetes was more severe, were more involved in diabetes care, had more conflict over diabetes care or were frustrated about not knowing how to help the person with diabetes. Outcomes were better for those who had greater support from others and felt they found good ways to help the person with diabetes. There were significant differences in outcomes among countries before and after adjustment for individual characteristics, and correlates of outcomes varied by country. CONCLUSIONS: Several modifiable risk and protective factors for family member psychological outcomes were identified in this study. Diabetes education and social support were associated with improved outcomes, especially if they were helpful in supporting people with diabetes.