A systematic review of the role of bisphosphonates in metastatic disease

Objectives: To identify evidence for the role of bisphosphonates in malignancy for the treatment of hypercalcaemia, prevention of skeletal morbidity and use in the adjuvant setting. To perform an economic review of current literature and model the cost effectiveness of bisphosphonates in the treatment of hypercalcaemia and prevention of skeletal morbidity Data sources: Electronic databases (1966-June 2001). Cochrane register. Pharmaceutical companies. Experts in the field. Handsearching of abstracts and leading oncology journals (1999-2001). Review methods: Two independent reviewers assessed studies for inclusion, according to predetermined criteria, and extracted relevant data. Overall event rates were pooled in a meta-analysis, odds ratios ( OR) were given with 95% confidence intervals (CI). Where data could not be combined, studies were reported individually and proportions compared using chi- squared analysis. Cost and cost-effectiveness were assessed by a decision analytic model comparing different bisphosphonate regimens for the treatment of hypercalcaemia; Markov models were employed to evaluate the use of bisphosphonates to prevent skeletal-related events (SRE) in patients with breast cancer and multiple myeloma. Results: For acute hypercalcaemia of malignancy, bisphosphonates normalised serum calcium in >70% of patients within 2-6 days. Pamidronate was more effective than control, etidronate, mithramycin and low-dose clodronate, but equal to high dose clodronate, in achieving normocalcaemia. Pamidronate prolongs ( doubles) the median time to relapse compared with clodronate or etidronate. For prevention of skeletal morbidity, bisphosphonates compared with placebo, significantly reduced the OR for fractures (OR [95% CI], vertebral, 0.69 [0.57-0.84], non-vertebral, 0.65 [0.54-0.79], combined, 0.65 [0.55-0.78]) radiotherapy 0.67 [0.57-0.79] and hypercalcaemia 0.54 [0.36-0.81] but not orthopaedic surgery 0.70 [0.46-1.05] or spinal cord compression 0.71 [0.47-1.08]. However, reduction in orthopaedic surgery was significant in studies that lasted over a year 0.59 [0.39-0.88]. Bisphosphonates significantly increased the time to first SRE but did not affect survival. Subanalyses were performed for disease groups, drugs and route of administration. Most evidence supports the use of intravenous aminobisphosphonates. For adjuvant use of bisphosphonates, Clodronate, given to patients with primary operable breast cancer and no metastatic disease, significantly reduced the number of patients developing bone metastases. This benefit was not maintained once regular administration had been discontinued. Two trials reported significant survival advantages in the treated groups. Bisphosphonates reduce the number of bone metastases in patients with both early and advanced breast cancer. Bisphosphonates are well tolerated with a low incidence of side-effects. Economic modelling showed that for acute hypercalcaemia, drugs with the longest cumulative duration of normocalcaemia were most cost-effective. Zoledronate 4 mg was the most costly, but most cost-effective treatment. For skeletal morbidity, Markov models estimated that the overall cost of bisphosphonate therapy to prevent an SRE was pound250 and pound1500 per event for patients with breast cancer and multiple myeloma, respectively. Bisphosphonate treatment is sometimes cost-saving in breast cancer patients where fractures are prevented. Conclusions: High dose aminobisphosphonates are most effective for the treatment of acute hypercalcaemia and delay time to relapse. Bisphosphonates significantly reduce SREs and delay the time to first SRE in patients with bony metastatic disease but do not affect survival. Benefit is demonstrated after administration for at least 6-12 months. The greatest body of evidence supports the use of intravenous aminobisphosphonates. Further evidence is required to support use in the adjuvant setting

Climate change rapidly warms and acidifies Australian estuaries.

Climate change is impacting ecosystems worldwide. Estuaries are diverse and important aquatic ecosystems; and yet until now we have lacked information on the response of estuaries to climate change. Here we present data from a twelve-year monitoring program, involving 6200 observations of 166 estuaries along >1100 kilometres of the Australian coastline encompassing all estuary morphologies. Estuary temperatures increased by 2.16 °C on average over 12 years, at a rate of 0.2 °C year-1, with waters acidifying at a rate of 0.09 pH units and freshening at 0.086 PSU year-1. The response of estuaries to climate change is dependent on their morphology. Lagoons and rivers are warming and acidifying at the fastest rate because of shallow average depths and limited oceanic exchange. The changes measured are an order of magnitude faster than predicted by global ocean and atmospheric models, indicating that existing global models may not be useful to predict change in estuaries

Review of final-year medical students’ rural attachment at district hospitals in KwaZulu-Natal: student perspectives

Objectives: This study aimed to investigate the views of students involved in rural community-based medical attachments during their final year at medical school. The programme has been in existence for some time, but no formal evaluation thereof has yet taken place. This paper describes the first two phases of what is described as a quality improvement project:namely to describe the problem state and to discuss possible activities to improve the programme.Design, setting and subjects: The study adopted a mixture of quantitative and qualitative type research. Data were collected by means of a  self-administered questionnaire which students at Nelson R Mandela Medical School, University of KwaZulu-Natal, completed at the end of their Family Medicine rotation. Consent was obtained from the participants andethical approval granted by the University of KwaZulu-Natal Humanities and Social Science Ethics Committee.Results: Students were generally positive about their rural attachment experience. The majority (86%) believed that their skills adequately prepared them to enter the community. Allocation of a supervisor and rostering were found to be of great importance. Academic activities provided adequate learning opportunities. The majority (76%) of students who used hospital accommodation found it to be satisfactory, although it was an area that needed attention. Technological support was lacking. Fewer than 50% of students had access to such facilities.Conclusion: Students’ responses were generally positive about the rural attachment experience, but logistical and technological support issues, as well as that of accommodation, need to be addressed if the programme is to flourish. Community-based education in a rural district hospital can provide unique learning opportunities for students if the opportunities are identified and the programme is well managed

Biotic habitats as refugia under ocean acidification.

Habitat-forming organisms have an important role in ameliorating stressful conditions and may be of particular relevance under a changing climate. Increasing CO2 emissions are driving a range of environmental changes, and one of the key concerns is the rapid acceleration of ocean acidification and associated reduction in pH. Such changes in seawater chemistry are anticipated to have direct negative effects on calcifying organisms, which could, in turn, have negative ecological, economic and human health impacts. However, these calcifying organisms do not exist in isolation, but rather are part of complex ecosystems. Here, we use a qualitative narrative synthesis framework to explore (i) how habitat-forming organisms can act to restrict environmental stress, both now and in the future; (ii) the ways their capacity to do so is modified by local context; and (iii) their potential to buffer the effects of future change through physiological processes and how this can be influenced by management adopted. Specifically, we highlight examples that consider the ability of macroalgae and seagrasses to alter water carbonate chemistry, influence resident organisms under current conditions and their capacity to do so under future conditions, while also recognizing the potential role of other habitats such as adjacent mangroves and saltmarshes. Importantly, we note that the outcome of interactions between these functional groups will be context dependent, influenced by the local abiotic and biotic characteristics. This dependence provides local managers with opportunities to create conditions that enhance the likelihood of successful amelioration. Where individuals and populations are managed effectively, habitat formers could provide local refugia for resident organisms of ecological and economic importance under an acidifying ocean

Mixed effects of elevated pCO2 on fertilisation, larval and juvenile development and adult responses in the mobile subtidal scallop Mimachlamys asperrima (Lamarck, 1819).

Ocean acidification is predicted to have severe consequences for calcifying marine organisms especially molluscs. Recent studies, however, have found that molluscs in marine environments with naturally elevated or fluctuating CO2 or with an active, high metabolic rate lifestyle may have a capacity to acclimate and be resilient to exposures of elevated environmental pCO2. The aim of this study was to determine the effects of near future concentrations of elevated pCO2 on the larval and adult stages of the mobile doughboy scallop, Mimachlamys asperrima from a subtidal and stable physio-chemical environment. It was found that fertilisation and the shell length of early larval stages of M. asperrima decreased as pCO2 increased, however, there were less pronounced effects of elevated pCO2 on the shell length of later larval stages, with high pCO2 enhancing growth in some instances. Byssal attachment and condition index of adult M. asperrima decreased with elevated pCO2, while in contrast there was no effect on standard metabolic rate or pHe. The responses of larval and adult M. asperrima to elevated pCO2 measured in this study were more moderate than responses previously reported for intertidal oysters and mussels. Even this more moderate set of responses are still likely to reduce the abundance of M. asperrima and potentially other scallop species in the world's oceans at predicted future pCO2 levels

Can prior exposure to stress enhance resilience to ocean warming in two oyster species?

Securing economically and ecologically significant molluscs, as our oceans warm due to climate change, is a global priority. South eastern Australia receives warm water in a strengthening East Australia Current and so resident species are vulnerable to elevated temperature and marine heat waves. This study tested whether prior exposure to elevated temperature can enhance resilience of oysters to ocean warming. Two Australian species, the flat oyster, Ostrea angasi, and the Sydney rock oyster, Saccostrea glomerata, were obtained as adults and "heat shocked" by exposure to a dose of warm water in the laboratory. Oysters were then transferred to elevated seawater temperature conditions where the thermal outfall from power generation was used as a proxy to investigate the impacts of ocean warming. Shell growth, condition index, lipid content and survival of flat oysters and condition of Sydney rock oysters were all significantly reduced by elevated seawater temperature in the field. Flat oysters grew faster than Sydney rock oysters at ambient temperature, but their growth and survival was more sensitive to elevated temperature. "Stress inoculation" by heat shock did little to ameliorate the negative effects of increased temperature, although the survival of heat-shocked flat oysters was greater than non-heat shocked oysters. Further investigations are required to determine if early exposure to heat stress can enhance resilience of oysters to ocean warming

Microbiomes of an oyster are shaped by metabolism and environment.

Microbiomes can both influence and be influenced by metabolism, but this relationship remains unexplored for invertebrates. We examined the relationship between microbiome and metabolism in response to climate change using oysters as a model marine invertebrate. Oysters form economies and ecosystems across the globe, yet are vulnerable to climate change. Nine genetic lineages of the oyster Saccostrea glomerata were exposed to ambient and elevated temperature and PCO2 treatments. The metabolic rate (MR) and metabolic by-products of extracellular pH and CO2 were measured. The oyster-associated bacterial community in haemolymph was characterised using 16 s rRNA gene sequencing. We found a significant negative relationship between MR and bacterial richness. Bacterial community composition was also significantly influenced by MR, extracellular CO2 and extracellular pH. The effects of extracellular CO2 depended on genotype, and the effects of extracellular pH depended on CO2 and temperature treatments. Changes in MR aligned with a shift in the relative abundance of 152 Amplicon Sequencing Variants (ASVs), with 113 negatively correlated with MR. Some spirochaete ASVs showed positive relationships with MR. We have identified a clear relationship between host metabolism and the microbiome in oysters. Altering this relationship will likely have consequences for the 12 billion USD oyster economy

Life-Cycle Cost and Risk Analysis of Alternative Configurations for Shipping Low-Level Radioactive Waste to the Nevada Test Site

The Nevada Test Site (NTS) is a major receiver of low-level radioactive waste (LLW) for disposal. Currently, all LLW received at NTS is shipped by truck. The trucks use highway routes to NTS that pass through the Las Vegas Valley and over Hoover Dam, which is a concern of local stakeholder groups in the State of Nevada. Rail service offers the opportunity to reduce transportation risks and costs, according to the Waste Management Programmatic Environmental Impact Statement (WM-PEIS). However, NTS and some DOE LLW generator sites are not served with direct rail service so intermodal transport is under consideration. Intermodal transport involves transport via two modes, in this case truck and rail, from the generator sites to NTS. LLW shipping containers would be transferred between trucks and railcars at intermodal transfer points near the LLW generator sites, NTS, or both. An Environmental Assessment (EA)for Intermodal Transportation of Low-Level Radioactive Waste to the Nevada Test Site (referred to as the NTSIntermodal -M) has been prepared to determine whether there are environmental impacts to alterations to the current truck routing or use of intermodal facilities within the State of Nevada. However, an analysis of the potential impacts outside the State of Nevada are not addressed in the NTS Intermodal EA. This study examines the rest of the transportation network between LLW generator sites and the NTS and evaluates the costs, risks, and feasibility of integrating intermodal shipments into the LLW transportation system. This study evaluates alternative transportation system configurations for NTS approved and potential generators based on complex-wide LLW load information. Technical judgments relative to the availability of DOE LLW generators to ship from their sites by rail were developed. Public and worker risk and life-cycle cost components are quantified. The study identifies and evaluates alternative scenarios that increase the use of rail (intermodal where needed) to transport LLW from generator sites to NTS

Psychological interventions in asthma

Asthma is a multifactorial chronic respiratory disease characterised by recurrent episodes of airway obstruction. The current management of asthma focuses principally on pharmacological treatments, which have a strong evidence base underlying their use. However, in clinical practice, poor symptom control remains a common problem for patients with asthma. Living with asthma has been linked with psychological co-morbidity including anxiety, depression, panic attacks and behavioural factors such as poor adherence and suboptimal self-management. Psychological disorders have a higher-than-expected prevalence in patients with difficult-to-control asthma. As psychological considerations play an important role in the management of people with asthma, it is not surprising that many psychological therapies have been applied in the management of asthma. There are case reports which support their use as an adjunct to pharmacological therapy in selected individuals, and in some clinical trials, benefit is demonstrated, but the evidence is not consistent. When findings are quantitatively synthesised in meta-analyses, no firm conclusions are able to be drawn and no guidelines recommend psychological interventions. These inconsistencies in findings may in part be due to poor study design, the combining of results of studies using different interventions and the diversity of ways patient benefit is assessed. Despite this weak evidence base, the rationale for psychological therapies is plausible, and this therapeutic modality is appealing to both patients and their clinicians as an adjunct to conventional pharmacological treatments. What are urgently required are rigorous evaluations of psychological therapies in asthma, on a par to the quality of pharmaceutical trials. From this evidence base, we can then determine which interventions are beneficial for our patients with asthma management and more specifically which psychological therapy is best suited for each patient