Sore throat, fever, and pancytopenia during winter.

Care must be taken to mitigate the effect of cognitive bias in times of frequent common presentations. The etiology of bicytopenias and pancytopenias must always be carefully investigated. Blast cells in low count B ALL may not be seen on a peripheral smear and diagnosis often requires confirmational bone marrow aspirate with flow cytometry and molecular typing.

Accuracy of transcutaneous bilirubinometry in term infants after phototherapy: a prospective observational study.

OBJECTIVE: To test the accuracy of transcutaneous bilirubinometry (TcB) in neonates 12 h after discontinuing phototherapy. STUDY DESIGN: In a prospective study of 91 neonates at ≥35 weeks of gestation, paired measurements of total serum bilirubin (TSB) and TcB were obtained 12 h after discontinuation of phototherapy. TcB measurements were obtained on the uncovered skin of the sternum and the covered skin of the lower abdomen. Bland-Altman plots were used to evaluate agreement between TSB and TcB. RESULTS: TcB was found to systematically underestimate TSB on both covered and uncovered skin. The smallest but statistically significant difference between TSB and TcB was found on the covered lower abdomen (-1.03, p < .0001) compared with the uncovered skin of the sternum (-1.44, p < .0001). The correlation between TSB and TcB was excellent on both covered (r = 0.86, p < .001) and uncovered skin (r = 0.90, p < .001). Bland and Altman plots showed poor agreement between TcB and TSB. CONCLUSIONS: This study demonstrated excellent correlation between TcB and TSB 12 h after phototherapy but poor TcB-TSB agreement. TcB cannot be reliably used in neonates exposed to phototherapy.

Ocean connectivity and habitat characteristics predict population genetic structure of seagrass in an extreme tropical setting.

Understanding patterns of gene flow and processes driving genetic differentiation is important for a broad range of conservation practices. In marine organisms, genetic differentiation among populations is influenced by a range of spatial, oceanographic, and environmental factors that are attributed to the seascape. The relative influences of these factors may vary in different locations and can be measured using seascape genetic approaches. Here, we applied a seascape genetic approach to populations of the seagrass, Thalassia hemprichii, at a fine spatial scale (~80 km) in the Kimberley coast, western Australia, a complex seascape with strong, multidirectional currents greatly influenced by extreme tidal ranges (up to 11 m, the world's largest tropical tides). We incorporated genetic data from a panel of 16 microsatellite markers, overwater distance, oceanographic data derived from predicted passive dispersal on a 2 km-resolution hydrodynamic model, and habitat characteristics from each meadow sampled. We detected significant spatial genetic structure and asymmetric gene flow, in which meadows 12-14 km apart were less connected than ones 30-50 km apart. This pattern was explained by oceanographic connectivity and differences in habitat characteristics, suggesting a combined scenario of dispersal limitation and facilitation by ocean current with local adaptation. Our findings add to the growing evidence for the key role of seascape attributes in driving spatial patterns of gene flow. Despite the potential for long-distance dispersal, there was significant genetic structuring over small spatial scales implicating dispersal and recruitment bottlenecks and highlighting the importance of implementing local-scale conservation and management measures.

Increased extent of waterfowl grazing lengthens the recovery time of a colonizing seagrass (Halophila ovalis) with implications for seagrass resilience.

Herbivore distributions and abundance are shifting because of climate change, leading to intensified grazing pressure on foundation species such as seagrasses. This, combined with rapidly increasing magnitudes of change in estuarine ecosystems, may affect seagrass resilience. While the overall resilience of seagrasses is generally well-studied, the timeframes of recovery has received comparatively little attention, particularly in temperate estuaries. We investigated how the recovery time (RT) of seagrass is affected by simulated grazing in a southwestern Australian estuary. Whilst excluding swans, we simulated different grazing intensities (25, 50, 75, and 100% removal from 1 m2 plots) at four locations in the Swan-Canning Estuary, Western Australia during summer and tracked the recovery of seagrass over 3 months, using seagrass cover as the main measure of recovery. We found that seagrass recovered within 4-6 weeks from the lower grazing intensities (25 and 50%) and 7-19 weeks from the higher grazing intensities (75 and 100%) across the estuary. Increased grazing intensity led to not only longer recovery times (RTs), but also greater variability in the RT among experimental locations. The RT from the higher grazing intensities at one location in particular was more than double other locations. Seagrass recovery was through vegetative mechanisms and not through sexual reproduction. There was a significant grazing treatment effect on seagrass meadow characteristics, particularly belowground biomass which had not recovered 3 months following grazing. As the pressure of climate change on estuarine environments increases, these quantified RTs for seagrass provide a baseline for understanding grazing pressure as a singular disturbance. Future work can now examine how grazing and other potentially interacting pressures in our changing climate could impact seagrass recovery even further.

Guidelines for model adaptation: A study of the transferability of a general seagrass ecosystem Dynamic Bayesian Networks model.

In general, it is not feasible to collect enough empirical data to capture the entire range of processes that define a complex system, either intrinsically or when viewing the system from a different geographical or temporal perspective. In this context, an alternative approach is to consider model transferability, which is the act of translating a model built for one environment to another less well-known situation. Model transferability and adaptability may be extremely beneficial-approaches that aid in the reuse and adaption of models, particularly for sites with limited data, would benefit from widespread model uptake. Besides the reduced effort required to develop a model, data collection can be simplified when transferring a model to a different application context. The research presented in this paper focused on a case study to identify and implement guidelines for model adaptation. Our study adapted a general Dynamic Bayesian Networks (DBN) of a seagrass ecosystem to a new location where nodes were similar, but the conditional probability tables varied. We focused on two species of seagrass (Zostera noltei and Zostera marina) located in Arcachon Bay, France. Expert knowledge was used to complement peer-reviewed literature to identify which components needed adjustment including parameterization and quantification of the model and desired outcomes. We adopted both linguistic labels and scenario-based elicitation to elicit from experts the conditional probabilities used to quantify the DBN. Following the proposed guidelines, the model structure of the general DBN was retained, but the conditional probability tables were adapted for nodes that characterized the growth dynamics in Zostera spp. population located in Arcachon Bay, as well as the seasonal variation on their reproduction. Particular attention was paid to the light variable as it is a crucial driver of growth and physiology for seagrasses. Our guidelines provide a way to adapt a general DBN to specific ecosystems to maximize model reuse and minimize re-development effort. Especially important from a transferability perspective are guidelines for ecosystems with limited data, and how simulation and prior predictive approaches can be used in these contexts.

Climate change, social vulnerability and child nutrition in South Asia.

Despite recent advancements in global population well-being and food security, climate change threatens to undermine child nutritional health, particularly for marginalized populations in tropical low- and middle-income countries. South Asia is at particular risk for climate-driven undernutrition due to a combination of historical weather exposures, existing nutritional deficits, and a lack of sanitation access. Previous studies have established that precipitation extremes increase rates of undernutrition in this region, but the existing literature lacks adequate consideration of temperature anomalies, mediating social factors, and the developmentally-relevant timing of exposure. We combine high-resolution temperature and precipitation data with large-sample survey data on household demographics and child anthropometry, using an approach that incorporates three key developmental periods and a rigorous fixed effects design. We find that precipitation extremes in the first year of life significantly decrease children's height-for-age (HAZ) in South Asia. The detrimental effects of extreme precipitation are especially concentrated in under-resourced households, such as those lacking access to proper sanitation and education for women, while anomalous heat is particularly harmful for children in Pakistan, though it tends to benefit children in some demographic groups. These results indicate that nutritional status in South Asia is highly responsive to climate exposures, and that addressing sanitation infrastructure and other development priorities is a pathway towards reducing this vulnerability.

Clinical trial recruiters' experiences working with trial eligibility criteria: results of an exploratory, cross-sectional, online survey in the UK.

BACKGROUND: Eligibility criteria are a fundamental element of clinical trial design, defining who can and who should not participate in a trial. Problems with the design or application of criteria are known to occur and pose risks to participants' safety and trial integrity, sometimes also negatively impacting on trial recruitment and generalisability. We conducted a short, exploratory survey to gather evidence on UK recruiters' experiences interpreting and applying eligibility criteria and their views on how criteria are communicated and developed. METHODS: Our survey included topics informed by a wider programme of work at the Clinical Trials Research Unit, University of Leeds, on assuring eligibility criteria quality. Respondents were asked to answer based on all their trial experience, not only on experiences with our trials. The survey was disseminated to recruiters collaborating on trials run at our trials unit, and via other mailing lists and social media. The quantitative responses were descriptively analysed, with inductive analysis of free-text responses to identify themes. RESULTS: A total of 823 eligible respondents participated. In total, 79% of respondents reported finding problems with eligibility criteria in some trials, and 9% in most trials. The main themes in the types of problems experienced were criteria clarity (67% of comments), feasibility (34%), and suitability (14%). In total, 27% of those reporting some level of problem said these problems had led to patients being incorrectly included in trials; 40% said they had led to incorrect exclusions. Most respondents (56%) reported accessing eligibility criteria mainly in the trial protocol. Most respondents (74%) supported the idea of recruiter review of eligibility criteria earlier in the protocol development process. CONCLUSIONS: Our survey corroborates other evidence about the existence of suboptimal trial eligibility criteria. Problems with clarity were the most often reported, but the number of comments on feasibility and suitability suggest some recruiters feel eligibility criteria and associated assessments can hinder recruitment to trials. Our proposal for more recruiter involvement in protocol development has strong support and some potential benefits, but questions remain about how best to implement this. We invite other trialists to consider our other suggestions for how to assure quality in trial eligibility criteria.

The surface bacterial community of an Australian kelp shows cross-continental variation and relative stability within regions.

Epiphytic microbial communities often have a close relationship with their eukaryotic host, assisting with defence, health, disease prevention and nutrient transfer. Shifts in the structure of microbial communities could therefore have negative effects on the individual host and indirectly impact the surrounding ecosystem, particularly for major habitat-forming hosts, such as kelps in temperate rocky shores. Thus, an understanding of the structure and dynamics of host-associated microbial communities is essential for monitoring and assessing ecosystem changes. Here, samples were taken from the ecologically important kelp, Ecklonia radiata, over a 17-month period, from six different sites in two distinct geographic regions (East and West coasts of Australia), separated by ∼3,300 kms, to understand variation in the kelp bacterial community and its potential environmental drivers. Differences were observed between kelp bacterial communities between the largely disconnected geographical regions. In contrast, within each region and over time the bacterial communities were considerably more stable, despite substantial seasonal changes in environmental conditions.

Aeromedical retrievals for gastrointestinal disorders in rural and remote Australia: the need for improved access to specialist advice.

The Royal Flying Doctor Service (RFDS) provides medical care to populations without access to traditional health-care services. From 2014 to 2018 the RFDS conducted 6007 (≈1201/year) aeromedical retrievals for gastrointestinal (GI) disorders. More detailed research is needed to determine specific GI disorders that contributed to this caseload, and in particular inform whether the establishment of a GI specialist service is justified.

The health impacts of waste incineration: a systematic review.

INTRODUCTION: Waste incineration is increasingly used to reduce waste volume and produce electricity. Several incinerators have recently been proposed in Australia and community groups are concerned about health impacts. An overview of the evidence on health effects has been needed. METHOD: A systematic review of English language literature for waste incinerators and health using PRISMA methodology. RESULTS: A range of adverse health effects were identified, including significant associations with some neoplasia, congenital anomalies, infant deaths and miscarriage, but not for other diseases. Ingestion was the dominant exposure pathway for the public. Newer incinerator technologies may reduce exposure. DISCUSSION: Despite these findings, diverse chemicals, poor study methodologies and inconsistent reporting of incinerator technology specifications precludes firmer conclusions about safety. CONCLUSION: Older incinerator technology and infrequent maintenance schedules have been strongly linked with adverse health effects. More recent incinerators have fewer reported ill effects, perhaps because of inadequate time for adverse effects to emerge. A precautionary approach is required. Waste minimisation is essential. Implications for public health: Public health practitioners can offer clearer advice about adverse health effects from incinerators. We suggest improved research design and methods to make future studies more robust and comparable. We offer ideas for better policy and regulation.

Identification and validation of DOCK4 as a potential biomarker for risk of bone metastasis development in patients with early breast cancer.

Skeletal metastasis occurs in around 75% of advanced breast cancers, with the disease incurable once cancer cells disseminate to bone, but there remains an unmet need for biomarkers to identify patients at high risk of bone recurrence. This study aimed to identify such a biomarker and to assess its utility in predicting response to adjuvant zoledronic acid (zoledronate). We used quantitative proteomics (stable isotope labelling by amino acids in cell culture-mass spectrometry; SILAC-MS) to compare protein expression in a bone-homing variant (BM1) of the human breast cancer cell line MDA-MB-231 with parental non-bone-homing cells to identify novel biomarkers for risk of subsequent bone metastasis in early breast cancer. SILAC-MS showed that dedicator of cytokinesis protein 4 (DOCK4) was upregulated in bone-homing BM1 cells, confirmed by western blotting. BM1 cells also had enhanced invasive ability compared with parental cells, which could be reduced by DOCK4-shRNA. In a training tissue microarray (TMA) comprising 345 patients with early breast cancer, immunohistochemistry followed by Cox regression revealed that high DOCK4 expression correlated with histological grade (p = 0.004) but not oestrogen receptor status (p = 0.19) or lymph node involvement (p = 0.15). A clinical validation TMA used tissue samples and the clinical database from the large AZURE adjuvant study (n = 689). Adjusted Cox regression analyses showed that high DOCK4 expression in the control arm (no zoledronate) was significantly prognostic for first recurrence in bone (HR 2.13, 95%CI 1.06-4.30, p = 0.034). No corresponding association was found in patients who received zoledronate (HR 0.812, 95%CI 0.176-3.76, p = 0.790), suggesting that treatment with zoledronate may counteract the higher risk for bone relapse from high DOCK4-expressing tumours. High DOCK4 expression was not associated with metastasis to non-skeletal sites when these were assessed collectively. In conclusion, high DOCK4 in early breast cancer is significantly associated with aggressive disease and with future bone metastasis and is a potentially useful biomarker for subsequent bone metastasis risk. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Future warming and acidification result in multiple ecological impacts to a temperate coralline alga.

Coralline algae are a crucial component of reef systems, stabilising reef substrate, providing habitat and contributing to accretion. Coralline algae and their surface microbial biofilms are also important as settlement cues for marine invertebrates, yet few studies address the impact of future environmental conditions on interactions between coralline algae, reef microbes and settlement by larvae of marine invertebrates. We exposed the temperate coralline algal species Amphiroa gracilis to warming and/or acidification scenarios for 21 days. Algae became bleached but photosystem II function was not measurably impacted. Settlement by larvae of the sea urchin Heliocidaris erythrogramma was reduced and the structure of the prokaryotic community associated with A. gracilis was altered. Coralline algae in ambient conditions were dominated by Alphaproteobacteria from the Rhodobacteraceae including Loktonella; those under warming were dominated by Bacteroidetes and Verrucomicrobia; acidification resulted in less Loktonella and more Planctomycetes and a combination of warming and acidification caused increases in Bacteroidetes, Verrucomicrobia and the Alphaproteobacteria family Hyphomonadaceae. These experiments indicate that predicted future environmental change may reduce the ability of some temperate reef coralline algae and associated reef microbes to facilitate settlement of invertebrate larvae as well as having a direct impact to algae via bleaching.

Determining light stress responses for a tropical multi-species seagrass assemblage.

Existing mitigations to address deterioration in water clarity associated with human activities are based on responses from single seagrass species but may not be appropriate for diverse seagrass assemblages common to tropical waters. We present findings from a light experiment designed to determine the effects of magnitude and duration of low light on a mixed tropical seagrass assemblage. Mixed assemblages of three commonly co-occurring Indo-West Pacific seagrasses, Cymodocea serrulata, Halodule uninervis and Halophila ovalis were grown in climate-controlled tanks, where replicate pots were subjected to a gradient in light availability (0.9-21.6 mols PAR m-2 day-1) for 12 weeks. Increased shading resulted in declines in growth and changes in cellular and photosynthesis responses for all species, although time-scale and magnitude of response were species-specific. Applying management criteria (e.g. thresholds) relevant to one species may under- or over-estimate potential for impact on other species and the meadow as a whole.

Seagrass ecosystem trajectory depends on the relative timescales of resistance, recovery and disturbance.

Seagrass ecosystems are inherently dynamic, responding to environmental change across a range of scales. Habitat requirements of seagrass are well defined, but less is known about their ability to resist disturbance. Specific means of recovery after loss are particularly difficult to quantify. Here we assess the resistance and recovery capacity of 12 seagrass genera. We document four classic trajectories of degradation and recovery for seagrass ecosystems, illustrated with examples from around the world. Recovery can be rapid once conditions improve, but seagrass absence at landscape scales may persist for many decades, perpetuated by feedbacks and/or lack of seed or plant propagules to initiate recovery. It can be difficult to distinguish between slow recovery, recalcitrant degradation, and the need for a window of opportunity to trigger recovery. We propose a framework synthesizing how the spatial and temporal scales of both disturbance and seagrass response affect ecosystem trajectory and hence resilience.

Disturbance Is an Important Driver of Clonal Richness in Tropical Seagrasses.

Clonality is common in many aquatic plant species, including seagrasses, where populations are maintained through a combination of asexual and sexual reproduction. One common measure used to describe the clonal structure of populations is clonal richness. Clonal richness is strongly dependent on the biological characteristics of the species, and how these interact with the environment but can also reflect evolutionary scale processes especially at the edge of species ranges. However, little is known about the spatial patterns and drivers of clonal richness in tropical seagrasses. This study assessed the spatial patterns of clonal richness in meadows of three tropical seagrass species, Thalassia hemprichii, Halodule uninervis, and Halophila ovalis, spanning a range of life-history strategies and spatial scales (2.5-4,711 km) in Indonesia and NW Australia. We further investigated the drivers of clonal richness using general additive mixed models for two of the species, H. uninervis and H. ovalis, over 8° latitude. No significant patterns were observed in clonal richness with latitude, yet disturbance combined with sea surface temperature strongly predicted spatial patterns of clonal richness. Sites with a high probability of cyclone disturbance had low clonal richness, whereas an intermediate probability of cyclone disturbance and the presence of dugong grazing combined with higher sea surface temperatures resulted in higher levels of clonal richness. We propose potential mechanisms for these patterns related to the recruitment and mortality rates of individuals as well as reproductive effort. Under a changing climate, increased severity of tropical cyclones and the decline in populations of mega-grazers have the potential to reduce clonal richness leading to less genetically diverse populations.

Timing anthropogenic stressors to mitigate their impact on marine ecosystem resilience.

Better mitigation of anthropogenic stressors on marine ecosystems is urgently needed to address increasing biodiversity losses worldwide. We explore opportunities for stressor mitigation using whole-of-systems modelling of ecological resilience, accounting for complex interactions between stressors, their timing and duration, background environmental conditions and biological processes. We then search for ecological windows, times when stressors minimally impact ecological resilience, defined here as risk, recovery and resistance. We show for 28 globally distributed seagrass meadows that stressor scheduling that exploits ecological windows for dredging campaigns can achieve up to a fourfold reduction in recovery time and 35% reduction in extinction risk. Although the timing and length of windows vary among sites to some degree, global trends indicate favourable windows in autumn and winter. Our results demonstrate that resilience is dynamic with respect to space, time and stressors, varying most strongly with: (i) the life history of the seagrass genus and (ii) the duration and timing of the impacting stress.

Assessment of ibrutinib plus rituximab in front-line CLL (FLAIR trial): study protocol for a phase III randomised controlled trial.

BACKGROUND: Treatment of chronic lymphocytic leukaemia (CLL) has seen a substantial improvement over the last few years. Combination immunochemotherapy, such as fludarabine, cyclophosphamide and rituximab (FCR), is now standard first-line therapy. However, the majority of patients relapse and require further therapy, and so new, effective, targeted therapies that improve remission rates, reduce relapses, and have fewer side effects, are required. The FLAIR trial will assess whether ibrutinib plus rituximab (IR) is superior to FCR in terms of progression-free survival (PFS). METHODS/DESIGN: FLAIR is a phase III, multicentre, randomised, controlled, open, parallel-group trial in patients with previously untreated CLL. A total of 754 participants will be randomised on a 1:1 basis to receive standard therapy with FCR or IR. Participants randomised to FCR will receive a maximum of six 28-day treatment cycles. Participants randomised to IR will receive six 28-day cycles of rituximab, and ibrutinib taken daily for 6 years until minimal residual disease (MRD) negativity has been recorded for the same amount of time as it took to become MRD negative, or until disease progression. The primary endpoint is PFS according to the International Workshop on CLL (IWCLL) criteria. Secondary endpoints include: overall survival; proportion of participants with undetectable MRD; response to therapy by IWCLL criteria; safety and toxicity; health-related quality of life (QoL); and cost-effectiveness. DISCUSSION: The trial aims to provide evidence for the future first-line treatment of CLL patients by assessing whether IR is superior to FCR in terms of PFS, and whether toxicity rates are favourable. TRIAL REGISTRATION: ISRCTN01844152 . Registered on 8 August 2014, EudraCT number 2013-001944-76 . Registered on 26 April 2013.

Indigenous health program evaluation design and methods in Australia: a systematic review of the evidence.

OBJECTIVE: Indigenous Australians experience a disproportionately higher burden of disease compared to non-Indigenous Australians. High-quality evaluation of Indigenous health programs is required to inform health and health services improvement. We aimed to quantify methodological and other characteristics of Australian Indigenous health program evaluations published in the peer-reviewed literature. METHODS: Systematic review of peer-reviewed literature (November 2009-2014) on Indigenous health program evaluation. RESULTS: We identified 118 papers describing evaluations of 109 interventions; 72.0% were university/research institution-led. 82.2% of evaluations included a quantitative component; 49.2% utilised quantitative data only and 33.1% used both quantitative and qualitative data. The most common design was a before/after comparison (30.5%, n=36/118). 7.6% of studies (n=9/118) used an experimental design: six individual-level and three cluster-randomised controlled trials. 56.8% (67/118) reported on service delivery/process outcomes (versus health or health risk factor outcomes) only. CONCLUSIONS: Given the number of Indigenous health programs that are implemented, few evaluations overall are published in the peer-reviewed literature and, of these, few use optimal methodologies such as mixed methods and experimental design. Implications for public health: Multiple strategies are required to increase high-quality, accessible evaluation in Indigenous health, including supporting stronger research-policy-practice partnerships and capacity building for evaluation by health services and government.

GA101 (obinutuzumab) monocLonal Antibody as Consolidation Therapy In CLL (GALACTIC) trial: study protocol for a phase II/III randomised controlled trial.

BACKGROUND: Chronic lymphocytic leukaemia (CLL) is the most common adult leukaemia. Achieving minimal residual disease (MRD) negativity in CLL is an independent predictor of survival even with a variety of different treatment approaches and regardless of the line of therapy. METHODS/DESIGN: GA101 (obinutuzumab) monocLonal Antibody as Consolidation Therapy In CLL (GALACTIC) is a seamless phase II/III, multi-centre, randomised, controlled, open, parallel-group trial for patients with CLL who have recently responded to chemotherapy. Participants will be randomised to receive either obinutuzumab (GA-101) consolidation or no treatment (as is standard). The phase II trial will assess safety and short-term efficacy in order to advise on continuation to a phase III trial. The primary objective for phase III is to assess the effect of consolidation therapy on progression-free survival (PFS). One hundred eighty-eight participants are planned to be recruited from forty research centres in the United Kingdom. DISCUSSION: There is evidence that achieving MRD eradication with alemtuzumab consolidation is associated with improvements in survival and time to progression. This trial will assess whether obinutuzumab is safe in a consolidation setting and effective at eradicating MRD and improving PFS. TRIAL REGISTRATION: ISRCTN, 64035629 . Registered on 12 January 2015. EudraCT, 2014-000880-42 . Registered on 12 November 2014.