A history of lameness and low body condition score is associated with reduced digital cushion volume, measured by magnetic resonance imaging, in dairy cattle.

Claw horn lesions (CHL) are the result of a failing of the functional anatomy of the hoof in dairy cows. The digital cushion is understood to be a vital structure in the prevention of CHL. Claw horn lesions have previously been shown to lead to pathological change to the pedal bone; however, their effects on the digital cushion are unknown. The primary aim of this study was to examine associations between the history of CHL through an animal's life and the structure of the digital cushion at slaughter using magnetic resonance imaging. The retrospective cohort study resulted in the scanning of 102 pairs of hindfeet, collected from adult Holstein dairy cows culled from a research herd, using a 3-Tesla research-grade magnetic resonance imaging scanner. Volume and fat measurements were calculated for each digital cushion within each claw from a modified Dixon Quant sequence. Animal-level variables were constructed around the animals' lactating lifetime, with lameness scores and body condition score collected at least every 2 wk. The combined volume of digital cushion in the lateral claws was used as the outcome variable in multivariable linear models. The volume of the digital cushion was negatively associated with the number of lameness events or CHL recorded. Furthermore, animals with body condition score >3, culled later in lactation, or of a greater body weight were more likely to have a higher volume of digital cushion in the lateral claws. We propose that the observations made in the current study are the effects of a range of factors broadly associated with genetic, developmental, and disease-related inputs. Our understanding of how we can select for genetically more robust animals and how we can precondition the hoof before first calving needs to be improved to reduce the risk of future CHL in adult dairy cattle. Furthermore, understanding optimal treatment regimens and their effect on hoof anatomy may reduce the recurrence of CHL in the current lactation and future lactations.

One-year outcomes after successful chronic total occlusion percutaneous coronary intervention: The impact of dissection re-entry techniques.

We aimed to determine clinical outcomes 1 year after successful chronic total occlusion (CTO) PCI and, in particular, whether use of dissection and re-entry strategies affects clinical outcomes. Hybrid approaches have increased the procedural success of CTO percutaneous coronary intervention (PCI) but longer-term outcomes are unknown, particularly in relation to dissection and re-entry techniques. Data were collected for consecutive CTO PCIs performed by hybrid-trained operators from 7 United Kingdom (UK) centres between 2012 and 2014. The primary endpoint (death, myocardial infarction, unplanned target vessel revascularization) was measured at 12 months along with angina status. One-year follow up data were available for 96% of successful cases (n = 805). In total, 85% of patients had a CCS angina class of 2-4 prior to CTO PCI. Final successful procedural strategy was antegrade wire escalation 48%; antegrade dissection and re-entry (ADR) 21%; retrograde wire escalation 5%; retrograde dissection and re-entry (RDR) 26%. Overall, 47% of CTOs were recanalized using dissection and re-entry strategies. During a mean follow up of 11.5 ± 3.8 months, the primary endpoint occurred in 8.6% (n = 69) of patients (10.3% (n = 39/375) in DART group and 7.0% (n = 30/430) in wire-based cases). The majority of patients (88%) had no or minimal angina (CCS class 0 or 1). ADR and RDR were used more frequently in more complex cases with greater disease burden, however, the only independent predictor of the primary endpoint was lesion length. CTO PCI in complex lesions using the hybrid approach is safe, effective and has a low one-year adverse event rate. The method used to recanalize arteries was not associated with adverse outcomes. © 2017 Wiley Periodicals, Inc.

Hybrid approach improves success of chronic total occlusion angioplasty.

OBJECTIVES: Treatment options for coronary chronic total occlusions (CTO) are limited, with low historical success rates from percutaneous coronary intervention (PCI). We report procedural outcomes of CTO PCI from 7 centres with dedicated CTO operators trained in hybrid approaches comprising antegrade/retrograde wire escalation (AWE/RWE) and dissection re-entry (ADR/RDR) techniques. METHODS: Clinical and procedural data were collected from consecutive unselected patients with CTO between 2012 and 2014. Lesion complexity was graded by the Multicentre CTO Registry of Japan (J-CTO) score, with ≥2 defined as complex. Success was defined as thrombolysis in myocardial infarction 3 flow with <30% residual stenosis, subclassified as at first attempt or overall. Inhospital complications and 30-day major adverse cardiovascular events (MACEs, death/myocardial infarction/unplanned target vessel revascularisation) were recorded. RESULTS: 1156 patients were included. Despite high complexity (mean J-CTO score 2.5±1.3), success rates were 79% (first attempt) and 90% (overall) with 30-day MACE of 1.6%. AWE was highly effective in less complex lesions (J-CTO ≤1 94% success vs 79% in J-CTO score ≥2). ADR/RDR was used more commonly in complex lesions (J-CTO≤1 15% vs J-CTO ≥2 56%). Need for multiple approaches during each attempt increased with lesion complexity (17% J-CTO ≤1 vs 48% J-CTO ≥2). Lesion modification ('investment procedures') at the end of unsuccessful first attempts increased the chance of subsequent success (96% vs 71%). CONCLUSIONS: Hybrid-trained operators can achieve overall success rates of 90% in real world practice with acceptable MACE. Use of dissection re-entry and investment procedures maintains high success rates in complex lesions. The hybrid approach represents a significant advance in CTO treatment.

Impact of proctoring on success rates for percutaneous revascularisation of coronary chronic total occlusions.

OBJECTIVE: To assess the impact of proctoring for chronic total occlusion (CTO) percutaneous coronary intervention (PCI) in six UK centres. METHODS: We retrospectively analysed 587 CTO procedures from six UK centres and compared success rates of operators who had received proctorship with success rates of the same operators before proctorship (pre-proctored) and operators in the same institutions who had not been proctored (non-proctored). There were 232 patients in the pre-proctored/non-proctored group and 355 patients in the post-proctored group. Complexity was assessed by calculating the Japanese CTO (JCTO) score for each case. RESULTS: CTO PCI success was greater in the post-proctored compared with the pre-proctored/non-proctored group (77.5% vs 62.1%, p<0.0001). In more complex cases where JCTO≥2, the difference in success was greater (70.7% vs 49.5%, p=0.0003). After proctoring, there was an increase in CTO PCI activity in centres from 2.5% to 3.5%, p<0.0001 (as a proportion of total PCI), and the proportion of very difficult cases with JCTO score ≥3 increased from 15.3% (35/229) to 29.7% (105/354), p<0.0001. CONCLUSIONS: Proctoring resulted in an increase in procedural success for CTO PCI, an increase in complex CTO PCI and an increase in total CTO PCI activity. Proctoring may be a valuable way to improve access to CTO PCI and the likelihood of procedural success.

Nitrous oxide emissions from cattle excreta applied to a Scottish grassland: effects of soil and climatic conditions and a nitrification inhibitor.

Dung and urine excreted onto grasslands are a major source of nitrous oxide (N2O). These N2O emissions stem from inefficient utilisation of nitrogen (N) ingested by ruminants, and the inability of pasture to utilise the deposited N. Predicted growth in dairy and meat consumption means that there is a requirement to quantify N2O emissions, and investigate emission reduction mechanisms. Three 12 month 'seasonal' experiments were undertaken at Crichton, SW Scotland, where N2O emissions were measured from applications of cattle urine, dung, artificial urine and urine+a nitrification inhibitor (NI), dicyandiamide (DCD). The three application timings were 'spring', 'summer' and 'autumn', representative of early-, mid- and late grazing seasons. N2O emissions were measured from static chambers for 12 months. The aim was to quantify emissions from cattle excreta, and determine their dependence on the season of application, and the respective contribution of dung and urine to total excreta emissions. Measurement from NI amended urine was made to assess DCD's potential as an emission mitigation tool. Emissions were compared to the IPCC's default emission factor (EF) of 2% for cattle excreted N. Mean annual cumulative emissions from urine were the highest when applied in summer (5034 g N2O-N ha(-1)), with lower emissions from spring (1903 g N2O-N ha(-1)) and autumn (2014 g N2O-N ha(-1)) application, most likely due to higher temperatures and soil moisture conducive to both nitrification and denitrification in the summer months. Calculated EFs were significantly greater from urine (1.1%) than dung (0.2%) when excreta was applied in summer, and EFs varied with season of application, but in all experiments were lower than the IPCC default of 2%. These results support both lowering and disaggregating this EF into individual EFs for dung and urine. Addition of DCD to urine caused no significant reduction in emissions, suggesting that more research is required into its use as a mitigation option.

The impact of dystocia on dairy calf health, welfare, performance and survival.

Up to one-third of dairy calves are born after dystocia and this is a major cause of calf mortality. This study investigated the neonatal physiology, survival, health and subsequent growth of dairy calves following dystocia and is the first longitudinal study to analyse multiple effects and to look beyond the perinatal period. A total of 455 live born Holstein calves (N: No assistance, n=360; FN: Farmer assistance but normally presented calf, n=82; FM: Farmer assistance of malpresented calf, n=13) were followed from birth to first service (heifers) or until leaving the farm (bulls). Compared to N calves, FN and FM animals had higher salivary cortisol concentrations at day 1 (P<0.001) and FN calves had lower passive immune transfer (P=0.03). Dystocia had no biologically significant impact on rectal temperature throughout the first 4 days (P>0.05). During the first 60 days, FM calves had a higher proportion of days with non-routine health treatments (P<0.05) and, by the time of weaning, mortality in FN and FM heifers was higher than in N calves (2.8×; P<0.01). However, in surviving calves, growth to first service was not affected by dystocia category (P>0.05). Calves which survive dystocia experience lower passive immunity transfer, higher mortality and higher indicators of physiological stress. Such calves have poorer welfare in the neonatal period and possibly beyond. Strategies need to be implemented to improve the subsequent health and welfare of such calves and to lower the incidence of dystocia.

Endothelial cell-specific ETB receptor knockout: autoradiographic and histological characterisation and crucial role in the clearance of endothelin-1.

Inactivation of endothelin B receptors (ETB), either through selective pharmacological antagonism or genetic mutation, increases the circulating concentration of endothelin-1 (ET-1), suggesting ETB plays an important role in clearance of this peptide. However, the cellular site of ETB-mediated clearance has not yet been determined. We have used a novel mouse model of endothelial cell-specific knockout (KO) of ETB (EC ETB(-/-)) to evaluate the relative contribution of EC-ETB to the clearance of ET-1. Phenotypic evidence of EC-specific ETB KO was confirmed by immunocytochemistry and autoradiography. Binding of the radiolabelled selective ETB ligand BQ3020 was significantly and selectively decreased in EC-rich tissues of EC ETB(-/-) mice, including the lung, liver, and kidney. By contrast, ETA binding was unaltered. RT-PCR confirmed equal expression of ET-1 in tissue from EC ETB(-/-) mice and controls, despite increased concentration of plasma ET-1 in EC ETB(-/-). Clearance of an intravenous bolus of [(125)I]ET-1 was impaired in EC ETB(-/-) mice. Pretreatment with the selective ETB antagonist A192621 impaired [(125)I]ET-1 clearance in control animals to a similar extent, but did not further impair clearance in EC ETB(-/-) mice. These studies suggest that EC-ETB are largely responsible for the clearance of ET-1 from the circulation.

Randomised controlled trials for policy interventions: a review of reviews and meta-regression.

OBJECTIVES: To determine whether randomised controlled trials (RCTs) lead to the same effect size and variance as non-randomised studies (NRSs) of similar policy interventions, and whether these findings can be explained by other factors associated with the interventions or their evaluation. DATA SOURCES: Two RCTs were resampled to compare randomised and non-randomised arms. Comparable field trials were identified from a series of health promotion systematic reviews and a systematic review of transition for youths with disabilities. Previous methodological studies were sought from 14 electronic bibliographic databases (Applied Social Sciences Index and Abstracts, Australian Education Index, British Education Index, CareData, Dissertation Abstracts, EconLIT, Educational Resources Information Centre, International Bibliography of the Sociological Sciences, ISI Proceedings: Social Sciences and Humanities, PAIS International, PsycINFO, SIGLE, Social Science Citation Index, Sociological Abstracts) in June and July 2004. These were supplemented by citation searching for key authors, contacting review authors and searching key internet sites. REVIEW METHODS: Analyses of previous resampling studies, replication studies, comparable field studies and meta-epidemiology investigated the relationship between randomisation and effect size of policy interventions. New resampling studies and new analyses of comparable field studies and meta-epidemiology were strengthened by testing pre-specified associations supported by carefully argued hypotheses. RESULTS: Resampling studies offer no evidence that the absence of randomisation directly influences the effect size of policy interventions in a systematic way. Prior methodological reviews and meta-analyses of existing reviews comparing effects from RCTs and non-randomised controlled trials (nRCTs) suggested that effect sizes from RCTs and nRCTs may indeed differ in some circumstances and that these differences may well be associated with factors confounded with design. No consistent explanations were found for randomisation being associated with changes in effect sizes of policy interventions in field trials. CONCLUSIONS: From the resampling studies we have no evidence that the absence of randomisation directly influences the effect size of policy interventions in a systematic way. At the level of individual studies, non-randomised trials may lead to different effect sizes, but this is unpredictable. Many of the examples reviewed and the new analyses in the current study reveal that randomisation is indeed associated with changes in effect sizes of policy interventions in field trials. Despite extensive analysis, we have identified no consistent explanations for these differences. Researchers mounting new evaluations need to avoid, wherever possible, allocation bias. New policy evaluations should adopt randomised designs wherever possible.

Endothelial ET(B) limits vascular remodelling and development of pulmonary hypertension during hypoxia.

BACKGROUND: We hypothesised that the potential protective effects of endothelial ET(B) are important in limiting pulmonary vascular muscularisation, vasoconstriction and the development of pulmonary arterial hypertension in response to hypoxia. METHODS: EC-specific ET(B) knockout mice (EC ET(B)(-/-)) and control mice (ET(B)(f/f)) were subjected to hypobaric hypoxic (10% FiO2) or normoxic conditions for 14 days before assessment of right ventricular pressure and pulmonary vascular morphology and function. RESULTS: During normoxia, no difference in right ventricular pressure was detected between EC ET(B)(-/-) (23.7 +/- 1.7 mm Hg) and ET(B)(f/f) mice (20.2 +/- 1.5 mm Hg). Hypoxia induced an exaggerated increase in right ventricular pressure in EC ET(B)(-/-) mice (34.4 +/- 1.2 mm Hg vs. 24.6 +/- 1.4 mm Hg), accompanied by an increase in right ventricular mass. No effect was observed in ET(B)(f/f) mice. Endothelin-1 constricted pulmonary arteries from both groups, although maximum response was similar irrespective of inspired oxygen or genotype. Hypoxia increased the percentage of muscularised vessels in both groups of mice, but the percentage increase was significantly greater in EC ET(B)(-/-) mice. CONCLUSIONS: The potential protective effects of endothelial ET(B) are important in limiting pulmonary vascular muscularisation and the development of pulmonary arterial hypertension in response to hypoxia.

Spinal fixation surgery for acute traumatic spinal cord injury.

BACKGROUND: If the spine is unstable following traumatic spinal cord injury (SCI), surgical fusion and bracing may be necessary to obtain vertical stability and prevent re-injury of the spinal cord from repeated movement of the unstable bony elements. It has been suggested that this spinal fixation surgery may promote early rehabilitation and mobilisation. OBJECTIVES: To answer the question: is there a difference in functional outcome and other commonly measured outcomes between people who have a spinal cord injury and have had spinal fixation surgery and those who have not? SEARCH STRATEGY: The following databases were searched: AMED, CCTR, CINAHL, DARE, EMBASE, HEED, HMIC, MEDLINE, NRR, NHS EED. Searches were updated in May 2003 and MEDLINE was searched again in May 2007. The reference lists of retrieved articles were checked. SELECTION CRITERIA: Randomised controlled trials and controlled trials that compared surgical spinal fixation, with or without decompression, to any other treatment, in patients with a traumatic SCI. DATA COLLECTION AND ANALYSIS: Two reviewers independently selected studies. One reviewer assessed the quality of the studies and extracted data. MAIN RESULTS: No randomised controlled trials or controlled trials were identified that compared surgical spinal fixation surgery to other treatments in patients with a traumatic SCI. All of the studies identified were retrospective observational studies and of poor quality. AUTHORS' CONCLUSIONS: The current evidence does not enable conclusions to be drawn about the benefits or harms of spinal fixation surgery in patients with traumatic SCI. Well-designed, prospective experimental studies with appropriately matched controls are needed.

Risk factors for chronic fatigue syndrome/myalgic encephalomyelitis: a systematic scoping review of multiple predictor studies.

BACKGROUND: The aetiology of chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME) is still unknown. The identification of risk factors for CFS/ME is of great importance to practitioners. METHOD: A systematic scoping review was conducted to locate studies that analysed risk factors for CFS/ME using multiple predictors. We searched for published and unpublished literature in 11 electronic databases, reference lists of retrieved articles and guideline stakeholder submissions in conjunction with the development of a forthcoming national UK guideline. Risk factors and findings were extracted in a concise tabular overview and studies synthesized narratively. RESULTS: Eleven studies were identified that met inclusion criteria: two case-control studies, four cohort studies, three studies combining a cohort with a case-control study design, one case-control and twin study and one cross-sectional survey. The studies looked at a variety of demographic, medical, psychological, social and environmental factors to predict the development of CFS/ME. The existing body of evidence is characterized by factors that were analysed in several studies but without replication of a significant association in more than two studies, and by studies demonstrating significant associations of specific factors that were not assessed in other studies. None of the identified factors appear suitable for the timely identification of patients at risk of developing CFS/ME within clinical practice. CONCLUSIONS: Various potential risk factors for the development of CFS/ME have been assessed but definitive evidence that appears meaningful for clinicians is lacking.

The endothelin system as a therapeutic target in cardiovascular disease: great expectations or bleak house?

There is considerable evidence that the potent vasoconstrictor endothelin-1 (ET-1) contributes to the pathogenesis of a variety of cardiovascular diseases. As such, pharmacological manipulation of the ET system might represent a promising therapeutic goal. Many clinical trials have assessed the potential of ET receptor antagonists in cardiovascular disease, the most positive of which have resulted in the licensing of the mixed ET receptor antagonist bosentan, and the selective ET(A) receptor antagonists, sitaxsentan and ambrisentan, for the treatment of pulmonary arterial hypertension (PAH). In contrast, despite encouraging data from in vitro and animal studies, outcomes in human heart failure have been disappointing, perhaps illustrating the risk of extrapolating preclinical work to man. Many further potential applications of these compounds, including resistant hypertension, chronic kidney disease, connective tissue disease and sub-arachnoid haemorrhage are currently being investigated in the clinic. Furthermore, experience from previous studies should enable improved trial design and scope remains for development of improved compounds and alternative therapeutic strategies. Although ET-converting enzyme inhibitors may represent one such alternative, there have been relatively few suitable compounds developed, and consequently, clinical experience with these agents remains extremely limited. Recent advances, together with an increased understanding of the biology of the ET system provided by improved experimental tools (including cell-specific transgenic deletion of ET receptors), should allow further targeting of clinical trials to diseases in which ET is involved and allow the therapeutic potential for targeting the ET system in cardiovascular disease to be fully realized.

Loxapine for schizophrenia.

BACKGROUND: Some authors have suggested that loxapine is more effective than typical antipsychotics in reducing the negative symptoms of schizophrenia, that extrapyramidal adverse effects are not usually seen at clinically effective antipsychotic doses and that it should therefore be classed as atypical. OBJECTIVES: To determine the effects of loxapine compared with placebo, typical and other atypical antipsychotic drugs for schizophrenia and related psychoses. SEARCH STRATEGY: For this 2007 update, we searched the Cochrane Schizophrenia Group's Register (January 2007). SELECTION CRITERIA: We included all randomised controlled clinical trials relevant to the care of schizophrenia that compared loxapine to other treatments. DATA COLLECTION AND ANALYSIS: We independently inspected abstracts ordered papers, re-inspected and quality assessed these. For dichotomous data we calculated relative risks (RR) and their 95% confidence intervals (CI) on an intention-to-treat basis based on a fixed effects model. We calculated numbers needed to treat/harm (NNT/NNH) where appropriate. For continuous data, we calculated weighted mean differences (WMD) again based on a fixed effects model. MAIN RESULTS: We were able to include 41 studies in this review. Compared with placebo, loxapine has an antipsychotic effect (Global effect - not improved at six weeks: n=78, 2 RCTs, RR 0.30 CI 0.1 to 0.6 NNT 3 CI 3 to 5). It is as effective as typical drugs in the short term (4 -12 weeks) (Global effect: n=580, 13 RCTs, RR 0.86 CI 0.7 to 1.1; mental state: n=915, 6 RCTs, RR 0.89 CI 0.8 to 1.1). Very limited heterogeneous data suggest that, given intramuscularly (IM), loxapine may be at least as sedating as IM haloperidol and thiothixene. Loxapine is also as effective as atypicals (risperidone, quetiapine) (n=468, 6 RCTs, RR mental state not improved 1.07 CI 0.8 to 1.5). Adverse effect profile is similar to typicals but loxapine may cause more extrapyramidal adverse effects when compared with atypicals (n=340, 4 RCTs, RR 2.18 CI 1.6 to 3.1). AUTHORS' CONCLUSIONS: Loxapine is an antipsychotic which is not clearly distinct from typical or atypical drugs in terms of its effects on global or mental state. Loxapines profile of adverse effects is similar to that of the older generation of antipsychotic drugs.

Molindone for schizophrenia and severe mental illness.

BACKGROUND: Antipsychotic therapy is the mainstay of treatment for people with schizophrenia. In recent years new or atypical antipsychotics have been introduced. These are less likely to produce movement disorders and raise serum prolactin. Researchers have suggested that molindone should be classified as an atypical antipsychotic. OBJECTIVES: To determine the effects of molindone compared with placebo, typical and other atypical antipsychotic drugs for schizophrenia and related psychoses. SEARCH STRATEGY: For the original search we searched the following databases: Biological Abstracts (1980-1999), The Cochrane Library CENTRAL (Issue 1, 1999), The Cochrane Schizophrenia Group's Register (January 1999), CINAHL (1982-1999), EMBASE (1980-1999), MEDLINE (1966-1999), LILACS (1982-1999), PSYNDEX (1977-1999), and PsycLIT (1974-1999). We also searched pharmaceutical databases on the Dialog Corporation Datastar and Dialog and the references of all identified studies for further trials. Finally, we contacted the manufacturer of molindone and the authors of any relevant trials. For the update of this review, we searched The Cochrane Schizophrenia Group's Trials Register (August 2005). SELECTION CRITERIA: We included all randomised controlled trials that compared molindone to other treatments for schizophrenia and schizophrenia-like psychoses. DATA COLLECTION AND ANALYSIS: We extracted data independently and analysed on an intention to treat basis calculating, for binary data, the fixed effect relative risk (RR), their 95% confidence intervals (CI), and the number needed to treat or harm (NNT or NNH). We excluded data if loss to follow up was greater than 50%. MAIN RESULTS: We included fourteen studies. Duration ranged from very short (10 days) studies of the intramuscular preparation, to trials lasting over three months. For measures of global assessment, available data do not justify any conclusions on the comparative efficacy of molindone and placebo. When compared to other typical antipsychotics we found no evidence of a difference in effectiveness (doctors' 4 RCTs n=150, RR 1.13, CI 0.69 to 1.86; nurses 4RCTs n=146, RR 1.23, CI 0.82 to 1.86). Molindone is no more or less likely than typical drugs to cause movement disorders, but it does cause significantly more weight loss (2RCTs n=60 RR 2.78, CI 1.10 to 6.99, NNH 5 CI 2 to 77). AUTHORS' CONCLUSIONS: The strength of the evidence relating to this compound is limited, owing to small sample size, poor study design, limited outcomes and incomplete reporting. Molindone may be an effective antipsychotic but its adverse effect profile does not differ significantly from that of typical antipsychotics (apart from the event of weight loss). Data from this review suggest, at present, there is no evidence to suggest that it may have an atypical profile.

Systematic review of effectiveness of different treatments for childhood retinoblastoma.

OBJECTIVES: To assess the clinical effectiveness of treatments for childhood retinoblastoma. DATA SOURCES: Electronic databases were searched from inception to April 2004. REVIEW METHODS: Studies of participants diagnosed with childhood retinoblastoma, any interventions and all clinical outcomes were eligible for inclusion. Randomised and non-randomised controlled trials and cohort studies with clear comparisons between treatment groups were included. Methodological quality was assessed. A narrative synthesis was conducted. Where possible, studies assessing common interventions were grouped together, with prospective and retrospective studies grouped separately. Emphasis was placed on prospective studies. RESULTS: Thirty-one individual studies, from 42 publications, were included in the review. Apart from one non-randomised controlled trial, only comparative studies of observational design were available for any of the treatments. Four of the included studies were prospective and the remaining 27 were retrospective. Most of the studies were of radiotherapy or chemotherapy, with few studies available on enucleation or focal treatments such as brachytherapy, photocoagulation, cryotherapy and thermotherapy. The methodological quality was generally poor, with a high risk of bias in all included studies. The main problems were in relation to how treatment was allocated and lack of consideration of potentially confounding factors, such as initial disease severity, in the study design and data analysis. The evidence base for effectiveness of treatments for childhood retinoblastoma is extremely limited. Owing to the considerable limitations of the evidence identified, it was not possible to make meaningful and robust conclusions about the relative effectiveness of different treatment approaches for childhood retinoblastoma. CONCLUSIONS: In the authors' opinion, the evidence base for the effectiveness of treatments for childhood retinoblastoma is not sufficiently robust to provide clear guidance for clinical practice. Ideally, good-quality randomised controlled trials (RCTs) assessing the effectiveness of different treatment options for childhood retinoblastoma are required. Research is required on all the treatments currently used for this condition. Where RCTs are not feasible, for ethical or practical reasons, only high-quality, prospective, non-randomised studies should be given consideration, owing to the generally higher risk of bias in retrospective studies. To reduce the risk of confounding due to allocation by clinical indication, studies should compare patients with similar disease severity rather than compare patients of mixed disease severities. Standardised outcomes should be agreed for use in studies assessing the effectiveness of treatment. These outcomes should encompass potential important adverse effects of treatment such as loss of visual acuity and cosmetic outcome, as well as beneficial effects.

Sertindole for schizophrenia.

BACKGROUND: Sertindole is an atypical antipsychotic, which is thought to give a lower incidence of extrapyramidal side effects at clinically effective doses than typical antipsychotic drugs. In December 1998, Lundbeck Ltd., the manufacturers of sertindole, voluntarily suspended the availability of the drug due to concerns about cardiac arrhythmia and sudden cardiac death associated with its use. However, based on the advice of an appointed expert group, the Committee for Proprietary Medicinal Products (CPMP) lifted the suspension of sertindole in October 2001, a decision that was ratified by the European Commission on the 26th of June 2002. Lundbeck have committed to the CPMP to carry out two post-marketing surveillance (PMS) studies (which were initiated in July 2002) to provide additional epidemiological data under conditions of normal drug usage. Initial marketing of the product will be restricted and Lundbeck is currently in discussions with the US health authorities (FDA) to investigate whether, and if so when, it would be possible to launch Serdolect in the US market. OBJECTIVES: To determine the effects of sertindole compared with placebo, typical and other atypical antipsychotic drugs for schizophrenia and related psychoses. SEARCH STRATEGY: Our Initial searches included electronic searches of Biological Abstracts (1980-1999), The Cochrane Library (Issue 1, 1999), The Cochrane Schizophrenia Group's Register (August 2000), EMBASE (1980-1999), LILACS (1982-1996), MEDLINE (1966-1999), PSYNDEX (1977-1995) and PsycLIT (1974-1999). In addition, we searched pharmaceutical databases on the Dialog Corporation Datastar and Dialog services. We searched references of all identified studies for further trials. We contacted the manufacturer of sertindole and authors of trials. We updated the literature search by searching the Cochrane Schizophrenia Group's Trials Register in April 2003. SELECTION CRITERIA: All randomised controlled trials that compared sertindole to placebo or other antipsychotic (atypical or typical) drug treatments for patients with schizophrenia or related psychosis . DATA COLLECTION AND ANALYSIS: We independently inspected citations and, where possible abstracts; ordered papers for re-inspection and quality assessment and independently extracted data. For homogeneous dichotomous data, we calculated the risk ratio (RR), 95% confidence interval (CI) and, where appropriate, the number needed to treat (NNT) or number needed to harm (NNH) on an intention-to-treat basis. For continuous data, we calculated weighted mean differences (WMD). We inspected all data for heterogeneity. MAIN RESULTS: Currently the review includes three studies with a total of 1,104 participants. One was a medium term (eight weeks) placebo controlled study that examined three different doses of sertindole (8, 12 and 20mg/day). The remaining two studies compared the use of sertindole with haloperidol (10mg/day). One was a short term study (six weeks) that looked at four different doses of sertindole (8, 16, 20, 24mg/day) and the other was a long term study (one year) that evaluated the use of sertindole 24mg/day in participants attending outpatients. We excluded two large important studies because they did not report any usable data. (Both had greater than 50% loss to follow-up and data on 'leaving the study early' was inadequately reported). SERTINDOLE VERSUS PLACEBO: Sertindole at 20mg/day was found to be more effective than placebo in terms of BPRS total scores (1 study, n=78, MD 6.2, CI -11.8 to -0.6) and CGI total end point scores (1 study, n=78, MD -0.9, CI -1.6 to -0.2). A marginally statistically significantly greater number of participants that were treated with 20 mg of sertindole were reported to have been 'very much improved' as compared to those taking placebo (1 study, n=102, RR 7.6, CI 1.0 to 57.9, NNT 7.9, CI 4.3 to 41.1). There was no statistically significant difference between sertindole at 8 or 12 mg/day and placebo for these three outcome measures. There were no statistically significant differences between sertindole (8, 12 or 20 mg) and placebo for the incidence of extrapyramidal symptoms, extrapyramidal related events or use of medication to avoid extrapyramidal symptoms. There were no statistically significant differences found between sertindole and placebo for the movement disorders akathisia, cogwheel rigidity, hypertonia and tremor or somnolence. At eight weeks a statistically significant difference between placebo and all sertindole groups (8, 12 and 20 mg) for mean change from baseline in the QT and QTc intervals were observed (p values and SD were not reported). There was a statistically significant greater mean weight gain among participants taking sertindole (20 mg, mean weight gain of 3.3 kg) as compared to placebo (mean weight gain of 0.8 kg; p<0.05). SERTINDOLE VERSUS HALOPERIDOL: At one year, a greater number of participants who were treated with haloperidol as compared to sertindole (24mg/day) were leaving the study early due to any reason (1 study, n=282, RR 0.6, CI 0.4 to 1.0, NNH 8.8, CI 4.7 to 74.0) or non-compliance (1 study, n=282, RR 0.2, CI 0.0 to 0.7, NNH 12.8, CI 7.7 to 37.8). However, at six weeks, there was no statistically significant difference between sertindole (at 8, 16, 20, or 24mg) and haloperidol for this latter outcome. The incidence of EPS was higher among those treated with haloperidol than sertindole at 8, 16, 20 or 24mg/day (8mg: 1 study, n=245, RR 0.1, CI 0.0 to 0.7, NNH 11.4, CI 7.1 to 29.8; 16mg: 1 study, n=252, RR 0.3, CI 0.1 to 1.0, NNH 15.5, CI 8.0 to 217.9; and 20mg: 1 study, n=253, RR 0.2, CI 0.1 to 0.8, NNH 13.7, CI 7.7 to 68.3; 24mg: 2 studies, n=524, RR 0.6, CI 0.4 to 0.8, NNH 8.7, CI 5.4 to 23.0). More participants treated with haloperidol experienced akathisia, tremor and hypertonia than those treated with sertindole (Akathisia - 8mg: 1 study, n=245, RR 0.2, CI 0.1 to 0.5, NNH 6.0, CI 4.1 to 11.2; 16mg: 1 study, n=252, RR 0.1, CI 0.0 to 0.3, NNH 5.4, CI 3.9 9.0; 20mg: 1 study, n=253, RR 0.3, CI 0.2 to 0.7, NNH 7.3, CI 4.6 to 17.9; 24mg: 2 studies, n=524, RR 0.5, CI 0.3 to 0.7, NNH 8.6, CI 5.6 to 18.3. Tremor - 8mg: 1 study, n=245, RR 0.3, CI 0.1 to 0.7, NNH 8.5, CI 5.2 to 24.0; 16mg: 1 study, n=252, RR 0.2, CI 0.1 to 0.5, NNH 7.3, 4.8 to 15.6; 20mg: 1 study, n=253, RR 0.2, CI 0.1 to 0.6, NNH 7.8, CI 4.9 to 18.1; 24mg: 2 studies, n=524, RR 0.4, CI 0.2 to 0.6, NNH 8.2, CI 5.6 to 15.3. For Hypertonic - 24mg: 2 studies, n=524, RR 0.5, CI 0.3 to 0.8, NNH 12.4, CI 7.5 to 35.0; for sertindole 8, 16 and 20mg there was no statistically significant differences between the treatment groups). One study reported that at six weeks, there was a statistically significant greater increase from baseline to final value in mean QTc interval in the sertindole 16, 20 and 24mg groups (20, 26, and 24msec, respectively) than in the haloperidol group (0msec; p value was not reported), but no SD or any other measure of variance for the effect sizes were reported. For one long term study only one participant from the sertindole group (24mg) had a QT interval that exceeded 500msec (1 study, n=282, RR 3.0 CI 0.1 to 73.0), but 11participants treated with Sertindole had QTc intervals of at least 500msec, compared to none in the haloperidol treated group (1 study, n=282, RR 23.0, CI 1.4 to 386.6, NNH 12.8, CI 8.2 to 29.6). At six weeks, fewer participants treated with sertindole at 8mg or 24mg were affected by somnolence than those treated with haloperidol (sertindole 8mg: 1 study, n=245, RR 0.1, CI 0.0 to 0.7, NNH 11.4, CI 7.1 to 29.8; 24mg: 2 studies, n=524, RR 0.6, CI 0.4 to 1.0, NNH 14.8, CI 7.7 to 205.2). The incidence of rhinitis was found to be statistically significantly higher among those taking sertindole at 16 or 24mg as compared to haloperidol (16mg: 1 study, n=252, RR 10.8, CI 1.4 to 82.6, NNH 12.7, CI 7.7 to 36.7; 24mg: 2 studies, n= 524, RR 2.1, CI 1.4 to 3.1, NNH 8.7, CI 5.6 to 18.6). At one year, 33 participants treated with sertindole (24mg) had experienced the sexual adverse event of decreased ejaculatory volume, compared with six participants treated with haloperidol. However the number of included male participants was not reported and therefore the RR could not be calculated. At one year, more participants taking sertindole (24mg/day) had put on weight compared to those taking haloperidol (1 study, n=282, RR 6.3, CI 1.9 to 20.9, NNH 8.8, CI 5.7 to 19.1). At six weeks, all of the sertindole groups showed an increase in body weight from baseline to final evaluation ranging from 1.3kg to 1.9kg, all of which represented a statistically significantly different weight change than that recorded for the haloperidol treatment group (-0.1Kg). However, the actual weight gain for each sertindole dosage group was not reported and no SD or any other measure of variance was given. AUTHORS' CONCLUSIONS: Sertindole at a dose of 20mg/day was found to be more antipsychotic than placebo. When used at 8, 12 or 20mg/day it appears to be as acceptable as placebo (in terms of various adverse events including movement disorders and somnolence), but seems to be associated with more cardiac problems (8, 12 or 20mg/day) and an increase in weight gain (20mg/day) than placebo. Sertindole at a dose of 24mg/day was better tolerated than haloperidol (in terms of participants leaving the study early). It was also found to be was associated with fewer movement disorders (at 8, 16, 20 or 24mg/day) and sedation (8 or 24mg/day) than haloperidol. However, it was shown to cause more cardiac anomalies (16, 20 or 24mg/day), weight gain (all doses combined), rhinitis (16 or 24mg/day), and problems with sexual functioning (24mg/day) than haloperidol. One short term study reported that sertindole 16mg/day was the most optimal dose.

Spinal injuries centres (SICs) for acute traumatic spinal cord injury.

BACKGROUND: The majority of complications in traumatic spinal cord injury (SCI) can occur in the first 24 hours and it has been suggested that spinal injury centres (SICs) may influence the pre-transfer care of people with SCI. The specialist SIC concept has been adopted in a number of high-income countries. However, even in such countries, a potentially significant number of people with SCI do not have the opportunity to access this system and are managed in a non-specialist environment. OBJECTIVES: To answer the question: does immediate referral to an SIC result in a better outcome than delayed referral? SEARCH STRATEGY: The following databases were searched: AMED, CCTR, CINAHL, DARE, EMBASE, HEED, HMIC, MEDLINE, NRR, NHS EED, and PsycLIT. Searches were updated in May 2003 and included the Cochrane Injuries Group Specialist Register. The reference lists of retrieved articles were checked. SELECTION CRITERIA: Randomised controlled trials and controlled trials that compared immediate referral to an SIC with delayed referral in patients with a traumatic SCI. DATA COLLECTION AND ANALYSIS: Two reviewers independently selected studies. One reviewer was to have assessed the quality of the studies and extracted data. MAIN RESULTS: No randomised controlled trials or controlled trials were identified that compared immediate referral to an SIC with delayed referral in patients with a traumatic SCI. All of the studies identified were retrospective observational studies and of poor quality. REVIEWERS' CONCLUSIONS: The current evidence does not enable conclusions to be drawn about the benefits or disadvantages of immediate referral versus late referral to SICs. Well-designed, prospective experimental studies with appropriately matched controls are needed.

A rapid and systematic review and economic evaluation of the clinical and cost-effectiveness of newer drugs for treatment of mania associated with bipolar affective disorder.

OBJECTIVES: To evaluate the clinical and cost-effectiveness of quetiapine, olanzapine and valproate semisodium in the treatment of mania associated with bipolar disorder. DATA SOURCES: Electronic databases; industry submissions made to the National Institute for Clinical Excellence. REVIEW METHODS: Randomised trials and economic evaluations that evaluated the effectiveness of quetiapine, olanzapine or valproate semisodium in the treatment of mania associated with bipolar disorder were selected for inclusion. Data were extracted by one reviewer into a Microsoft Access database and checked for quality and accuracy by a second. The quality of the cost-effectiveness studies was assessed using a checklist updated from that developed by Drummond and colleagues. Relative risk and mean difference data were presented as Forest plots but only pooled where this made sense clinically and statistically. Studies were grouped by drug and, within each drug, by comparator used. Chi-squared tests of heterogeneity were performed for the outcomes if pooling was indicated. A probabilistic model was developed to estimate costs from the perspective of the NHS, and health outcomes in terms of response rate, based on an improvement of at least 50% in a patient's baseline manic symptoms derived from an interview-based mania assessment scale. The model evaluated the cost-effectiveness of the alternative drugs when used as part of treatment for the acute manic episode only. RESULTS: Eighteen randomised trials met the inclusion criteria. Aspects of three of the quetiapine studies were commercial-in-confidence. The quality of the included trials was limited and overall, key methodological criteria were not met in most trials. Quetiapine, olanzapine and valproate semisodium appear superior to placebo in reducing manic symptoms, but may cause side-effects. There appears to be little difference between these treatments and lithium in terms of effectiveness, but quetiapine is associated with somnolence and weight gain, whereas lithium is associated with tremor. Olanzapine as adjunct therapy to mood stabilisers may be more effective than placebo in reducing mania and improving global health, but it is associated with more dry mouth, somnolence, weight gain, increased appetite, tremor and speech disorder. There was little difference between these treatments and haloperidol in reducing mania, but haloperidol was associated with more extrapyramidal side-effects and negative implications for health-related quality of life. Intramuscular olanzapine and lorazepam were equally effective and safe in one very short (24 hour) trial. Valproate semisodium and carbamazepine were equally effective and safe in one small trial in children. Olanzapine may be more effective than valproate semisodium in reducing mania, but was associated with more dry mouth, increased appetite, oedema, somnolence, speech disorder, Parkinson-like symptoms and weight gain. Valproate semisodium was associated with more nausea than olanzapine. The results from the base-case analysis demonstrate that choice of optimal strategy is dependent on the maximum that the health service is prepared to pay per additional responder. For a figure of less than 7179 British pounds per additional responder, haloperidol is the optimal decision; for a spend in excess of this, it would be olanzapine. Under the most favourable scenario in relation to the costs of responders and non-responders beyond the 3-week period considered in the base-case analysis, the incremental cost-effectiveness ratio of olanzapine is reduced to 1236 British pounds. CONCLUSIONS: In comparison with placebo, quetiapine, olanzapine and valproate semisodium appear superior in reducing manic symptoms, but all drugs are associated with adverse events. In comparison with lithium, no significant differences were found between the three drugs in terms of effectiveness, and all were associated with adverse events. Several limitations of the cost-effectiveness analysis exist, which inevitably means that the results should be treated with some caution. There remains a need for well-conducted, randomised, double-blind head-to-head comparisons of drugs used in the treatment of mania associated with bipolar disorder and their cost-effectiveness. Participant demographic, diagnostic characteristics, the treatment of mania in children, the use of adjunctive therapy and long-term safety issues in the elderly population, and acute and long-term treatment are also subjects for further study.

Effectiveness and cost-effectiveness of acute hospital-based spinal cord injuries services: systematic review.

OBJECTIVES: To examine four key areas: (1) the effectiveness and cost-effectiveness of spinal fixation surgery, (2) the consequences of immediate versus delayed referral to a spinal injuries unit (SIU), (3) the number of people with a new spinal cord injury (SCI) who are discharged from hospital without ever being transferred to an SIU, and (4) the effectiveness and cost-effectiveness of steroids for people with SCI. DATA SOURCES: Searches were carried out on several databases and also on the Internet. Specialist SCI and spinal injury related websites were searched, specifically the Spinal Injuries Association, the British Association of Spinal Cord Injury Specialists and the National Spinal Cord Injury Association. REVIEW METHODS: Three separate search strategies were devised to find studies relating to the four key areas. Two reviewers independently screened all study citations for inclusion. The lists of all retrieved studies were scanned for additional studies. Quality of studies was assessed and data were extracted by one reviewer then checked by the second. Data from included studies were summarised within each key area. For dichotomous data, relative risks were calculated with 95% confidence intervals. Pooled relative risks were calculated as appropriate. For continuous data, mean differences with 95% confidence intervals were calculated and, if data were pooled, weighted mean differences were calculated. Searches were carried out to identify economic evaluations, details of these together with a critical appraisal of quality are presented in structured tables. Quality was assessed using a checklist supplemented with additional comments on the adequacy of methodology where appropriate. RESULTS: For spinal fixation versus no fixation, 68 retrospective observational studies were found that suggested some benefits of fixation surgery. Only four studies were found on fixation surgery in SIUs compared with non-SIU hospitals and no significant differences were seen. All 28 studies concerning delayed referral to a SIU were retrospective observational studies. In most, study details were poorly reported and there was doubt over the comparability of groups at baseline and on confounding factors. Times of referral and transfer were not reported separately. Evidence suggested an effect in favour of the SIU group for neurological improvement. No relevant published studies of any design were found regarding how many people with a new SCI are discharged from hospital without ever being transferred to an SIU. Two systematic reviews were found that assessed the effectiveness of steroids. No studies were identified that considered both costs and the impact on patient outcomes of a given intervention. CONCLUSIONS: Although there was evidence to suggest some benefits of fixation surgery and also a benefit of immediate referral to SIUs compared with delayed or no referral, owing to the limitations of the data these should be interpreted with caution. Not enough data were found to assess whether surgery is more beneficial when carried out in SIUs and further research is required in this area. Well-designed prospective observational studies with appropriately matched controls are needed. High-dose methylprednisolone steroid therapy may be effective in promoting some degree of neurological recovery if given within 8 hours of injury. There is a need for more randomised controlled trials (RCTs) of pharmacological therapy for acute SCI. No published studies of any design were found to answer the question of how many people with acute SCI are discharged from hospital without ever being transferred to an SIU. Primary research involving audit of selected hospital records should be commissioned and published. The search strategy did not identify any full economic evaluations. Future research should include full economic evaluations, possibly alongside a large RCT, which fully consider the costs and consequences of implementing interventions.