An update of the Worldwide Integrated Assessment (WIA) on systemic insecticides. Part 2: impacts on organisms and ecosystems

New information on the lethal and sublethal effects of neonicotinoids and fipronil on organisms is presented in this review, complementing the previous WIA in 2015. The high toxicity of these systemic insecticides to invertebrates has been confirmed and expanded to include more species and compounds. Most of the recent research has focused on bees and the sublethal and ecological impacts these insecticides have on pollinators. Toxic effects on other invertebrate taxa also covered predatory and parasitoid natural enemies and aquatic arthropods. Little, while not much new information has been gathered on soil organisms. The impact on marine coastal ecosystems is still largely uncharted. The chronic lethality of neonicotinoids to insects and crustaceans, and the strengthened evidence that these chemicals also impair the immune system and reproduction, highlights the dangers of this particular insecticidal classneonicotinoids and fipronil. , withContinued large scale – mostly prophylactic – use of these persistent organochlorine pesticides has the potential to greatly decreasecompletely eliminate populations of arthropods in both terrestrial and aquatic environments. Sublethal effects on fish, reptiles, frogs, birds and mammals are also reported, showing a better understanding of the mechanisms of toxicity of these insecticides in vertebrates, and their deleterious impacts on growth, reproduction and neurobehaviour of most of the species tested. This review concludes with a summary of impacts on the ecosystem services and functioning, particularly on pollination, soil biota and aquatic invertebrate communities, thus reinforcing the previous WIA conclusions (van der Sluijs et al. 2015)

Signal transduction underlying the control of urinary bladder smooth muscle tone by muscarinic receptors and β-adrenoceptors

The normal physiological contraction of the urinary bladder, which is required for voiding, is predominantly mediated by muscarinic receptors, primarily the M3 subtype, with the M2 subtype providing a secondary backup role. Bladder relaxation, which is required for urine storage, is mediated by β-adrenoceptors, in most species involving a strong β3-component. An excessive stimulation of contraction or a reduced relaxation of the detrusor smooth muscle during the storage phase of the micturition cycle may contribute to bladder dysfunction known as the overactive bladder. Therefore, interference with the signal transduction of these receptors may be a viable approach to develop drugs for the treatment of overactive bladder. The prototypical signaling pathway of M3 receptors is activation of phospholipase C (PLC), and this pathway is also activated in the bladder. Nevertheless, PLC apparently contributes only in a very minor way to bladder contraction. Rather, muscarinic-receptor-mediated bladder contraction involves voltage-operated Ca2+ channels and Rho kinase. The prototypical signaling pathway of β-adrenoceptors is an activation of adenylyl cyclase with the subsequent formation of cAMP. Nevertheless, cAMP apparently contributes in a minor way only to β-adrenoceptor-mediated bladder relaxation. BKCa channels may play a greater role in β-adrenoceptor-mediated bladder relaxation. We conclude that apart from muscarinic receptor antagonists and β-adrenoceptor agonists, inhibitors of Rho kinase and activators of BKCa channels may have potential to treat an overactive bladder

Prognostic model to predict postoperative acute kidney injury in patients undergoing major gastrointestinal surgery based on a national prospective observational cohort study.

Background: Acute illness, existing co-morbidities and surgical stress response can all contribute to postoperative acute kidney injury (AKI) in patients undergoing major gastrointestinal surgery. The aim of this study was prospectively to develop a pragmatic prognostic model to stratify patients according to risk of developing AKI after major gastrointestinal surgery. Methods: This prospective multicentre cohort study included consecutive adults undergoing elective or emergency gastrointestinal resection, liver resection or stoma reversal in 2-week blocks over a continuous 3-month period. The primary outcome was the rate of AKI within 7 days of surgery. Bootstrap stability was used to select clinically plausible risk factors into the model. Internal model validation was carried out by bootstrap validation. Results: A total of 4544 patients were included across 173 centres in the UK and Ireland. The overall rate of AKI was 14·2 per cent (646 of 4544) and the 30-day mortality rate was 1·8 per cent (84 of 4544). Stage 1 AKI was significantly associated with 30-day mortality (unadjusted odds ratio 7·61, 95 per cent c.i. 4·49 to 12·90; P < 0·001), with increasing odds of death with each AKI stage. Six variables were selected for inclusion in the prognostic model: age, sex, ASA grade, preoperative estimated glomerular filtration rate, planned open surgery and preoperative use of either an angiotensin-converting enzyme inhibitor or an angiotensin receptor blocker. Internal validation demonstrated good model discrimination (c-statistic 0·65). Discussion: Following major gastrointestinal surgery, AKI occurred in one in seven patients. This preoperative prognostic model identified patients at high risk of postoperative AKI. Validation in an independent data set is required to ensure generalizability

Older People’s Adherence to Community-Based Group Exercise Programmes: A Multiple-Case Study

Physical inactivity is a global phenomenon, with estimates of one in four adults not being active enough to achieve health benefits, thus heightening the risk of developing non-communicable diseases. In order to realise the health and wellbeing gains associated with physical activity the behaviour must be sustained. Community-based group exercise programmes (CBGEP) utilising social support have been shown to be one means of not only increasing activity levels for older people, but sustaining physical activity. A mixed-methods systematic review revealed a gap in the literature around older people’s long-term adherence to real-life CBGEP within a UK context. This study therefore sought to address this gap by understanding older people’s ongoing adherence to CBGEP with a view to gaining further insight about which factors contribute to enabling people to sustain their physical activity levels. A multiple case study research design was employed to understand older people’s (≥ 60 years, n=27) adherence (≥ 69%, for ≥ 1 year) to three current CBGEP in the South- West of England. Qualitative data (participant observation, focus groups, documents, and interviews) were collected and analysed using inductive thematic analysis followed by the analytic technique of explanation building. In order to gain deeper insights into adherence, the humanisation framework was utilised in an a priori manner to further understand adherence from a humanising perspective. Quantitative data were analysed using descriptive statistics and used to set the context of the study. This study found that older people’s adherence to CBGEP was mediated through six factors: factors relating to the individual, the instructor, programme design, social features, participant perceived benefits, and a humanised exercise environment. These all served to explain older people’s adherence to CBGEP. The humanising qualities of these CBGEP must be considered if we wish to support older people in sustaining a physically active lifestyle as they age. These findings are of interest to practitioners and policy makers in how CBGEP serve to aid older people in maintaining a physically active lifestyle with a view to preventing non-communicable diseases and in maintaining social connectivity

Methadone and buprenorphine for the management of opioid dependence: A systematic review and economic evaluation

Objectives: To assess the clinical effectiveness and cost-effectiveness of buprenorphine maintenance therapy (BMT) and methadone maintenance therapy (MMT) for the management of opioid-dependent individuals. Data sources: Major electronic databases were searched from inception to August 2005. Industry submissions to the National Institute for Health and Clinical Excellence were accessed. Review methods: The assessment of clinical effectiveness was based on a review of existing reviews plus an updated search for randomised controlled trials (RCTs). A decision tree with Monte Carlo simulation model was developed to assess the cost-effectiveness of BMT and MMT. Retention in treatment and opiate abuse parameters were sourced from the meta-analysis of RCTs directly comparing flexible MMT with flexible dose BMT. Utilities were derived from a panel representing a societal perspective. Results: Most of the included systematic reviews and RCTs were of moderate to good quality, and focused on short-term (up to 1-year follow-up) outcomes of retention in treatment and the level of opiate use (self-report or urinalysis). Most studies employed a trial design that compared a fixed-close strategy (i.e. all individuals received a standard dose) of MMT or BMT and were conducted in predominantly young men who fulfilled criteria as opiate-dependent or heroin-dependent users, without significant co-morbidities. RCT meta-analyses have shown that a fixed dose of MMT or BMT has superior levels of retention in treatment and opiate use than placebo or no treatment, with higher fixed doses being more effective than lower fixed doses. There was evidence, primarily from non-randomised observational studies, that fixed-dose MMT reduces mortality, HIV risk behavior and levels of crime compared with no therapy and one small RCT has shown the level of mortality with fixed-dose BMT to be significantly less than with placebo. Flexible dosing (i.e. individualised doses) of MMT and BMT is more reflective of real-world practice. Retention in treatment was superior for flexible MMT than flexible BMT dosing but there was no significant difference in opiate use. Indirect comparison of data from population cross-sectional studies suggests that mortality with BMT may be lower than that with MMT. A pooled RCT analysis showed no significant difference in serious adverse events with MMT compared with BMT. Although treatment modifier evidence was limited, adjunct psychosocial and contingency interventions (e.g. financial incentives for opiate-free urine samples) appeared to enhance the effects of both, MMT and BMT. Also, MMT and BMT appear to be similarly effective whether delivered in a primary care or outpatient clinic setting. Although most of the included economic evaluations were considered to be of high quality, none used all of the appropriate parameters, effectiveness data, perspective and comparators required to make their results generalisable to the NHS context. One company (Schering-Plough) submitted cost-effectiveness evidence based on an economic model that had a 1-year time horizon and sourced data from a single RCT of flexible-dose MMT compared with flexible-dose BMT and utility values obtained from the literature; the results showed that for MMT vs no drug therapy, the incremental cost-effectiveness ratio (ICER) was £12,584/quality-adjusted life-year (QALY), for BMT versus no drug therapy, the ICER was £30,048/QALY and in a direct comparison, MMT was found to be slightly more effective and less costly than BMT. The assessment group model found for MMT versus no drug therapy that the ICER was £13,697/QALY, for BMT versus no drug therapy that the ICER was £26,429/QALY and, as with the industry model, in direct comparison, MMT was slightly more effective and less costly than BMT. When considering social costs, both MMT and BMT gave more health gain and were less costly than no drug treatment. These findings were robust to deterministic and probabilistic sensitivity analyses. Conclusions: Both flexible-dose MMT and BMT are more clinically effective and more cost-effective than no drug therapy in dependent opiate users. In direct comparison, a flexible dosing strategy with MMT was found be somewhat more effective in maintaining individuals in treatment than flexible-dose BMT and therefore associated with a slightly higher health gain and lower costs. However, this needs to be balanced by the more recent experience of clinicians in the use of buprenorphine, the possible risk of higher mortality of MMT and individual opiate-dependent users' preferences. Future research should be directed towards the safety and effectiveness of MMT and BMT; potential safety concerns regarding methadone and buprenorphine, specifically mortality and key drug interactions; efficacy of substitution medications (in particular patient subgroups, such as within the criminal justice system, or within young people); and uncertainties in cost-effectiveness identified by current economic models. © Queen's Printer and Controller of HMSO 2007. All rights reserved

Cost-effectiveness of adding-on new antiepileptic drugs to conventional regimens in controlling intractable seizures in children

<p>Abstract</p> <p>Background and purpose of the study</p> <p>Intractable seizures are a subgroup of epileptic disorders challenging the physicians’ skills to become controlled. Showing resistance towards common pharmacotherapy, they demand newer antiepileptic drugs acquired at higher costs. 0.06% of children around the world are estimated to suffer from epilepsy and its consequences. The aim of the present study has been to evaluate the cost-effectiveness of these drugs in the treatment of intractable seizures in children.</p> <p>Methods</p> <p>Clinical and cost data were collected from medical and cost records preserved at a neurologist office and a referral pharmacy respectively. Based on the new AED which are accessible in Iran, regimens were categorized into eight groups. The first group consisting of conventional AEDs was considered as comparator and the effectiveness of other groups was compared with it. Incremental Cost-effectiveness Ratio (ICER) of adding-on each new antiepileptic drug was calculated in terms of Rials per consequence (Rls/consq) and compared with each other. Furthermore ICER of the regimens was compared with the GDP per capita (Gross Domestic Product) of the year (2010).</p> <p>Results</p> <p>the ICER of the adding-on regimens range from negative values for Gabapentin, Levetiracetam and Zonisamide to low values for Lamotrigine (~ 6.4 million Rials/consequence [mil Rls/consq]) and Oxcarbazepine (~7.7 mil Rls/consq) and followed by high values for Topiramate (~21 mil Rls/consq) and Vigabatrin (~43.7 mil Rls/consq) considering the three months of remaining on regimen. By increasing the limit of remaining time to six months, the previously mentioned regimens persist on negative values. However Oxcarbazepine (~28.7 mil Rls/consq) and Lamotrigine (~13.8 mil Rls/consq) show a steep increase. Topiramate (~23.6 mil Rls/consq) displays a less change. Opposite to other regimens, the ICER value of Vigabatrin (~17.26 mil Rls/consq) has shown an important increase.</p> <p>Major conclusions</p> <p>Adding-on new antiepileptics to conventional regimens are cost-effective and justified considering the GDP per capita.</p