Tacrolimus Versus Cyclosporin as Primary Immunosuppression for Kidney Transplant Recipients

Background: Kidney transplantation is the treatment of choice for most patients with end-stage renal disease (ESRD). Standard protocols in use typically involve three drug groups each directed to a site in the T-cell activation or proliferation cascade which are central to the rejection process: calcineurin inhibitors (e.g. cyclosporin, tacrolimus), anti-proliferative agents (e.g. azathioprine, mycophenolate mofetil) and steroids (prednisolone). It remains unclear whether new regimens are more specific or simply more potent immunosuppressants. Objectives: To compare the effects of tacrolimus with cyclosporin as primary therapy for kidney transplant recipients. Search strategy: MEDLINE, EMBASE, the Cochrane Central Register of Controlled Trials, the Cochrane Renal Group's specialist register and conference proceedings were searched to identify relevant reports of randomised controlled trials (RCTs). Two reviewers assessed trials for eligibility, quality and extracted data independently. Selection criteria: All RCTs where tacrolimus was compared with cyclosporin for the initial treatment of kidney transplant recipients Data collection and analysis: Data were synthesised (random effects model) and results expressed as relative risk (RR), values <1 favouring tacrolimus, with 95% confidence intervals (CI). Subgroup analysis and meta-regression were used to examine potential effect modification by differences in trial design and immunosuppressive co-interventions. Main results: 123 reports from 30 trials (4102 patients) were included. At six months graft loss was significantly reduced in tacrolimus-treated recipients (RR 0.56, 95% CI 0.36 to 0.86), and this effect was persistent up to three years. Meta-regression showed that this benefit diminished as higher trough levels of tacrolimus were targeted (P = 0.04), after allowing for differences in cyclosporin formulation (P = 0.97) and cyclosporin target trough level (P = 0.38). At one year, tacrolimus patients suffered less acute rejection (RR 0.69, 95% CI 0.60 to 0.79), and less steroid-resistant rejection (RR 0.49, 95% CI 0.37 to 0.64), but more insulin-requiring diabetes mellitus (RR 1.86, 1.11 to 3.09), tremor, headache, diarrhoea, dyspepsia and vomiting. Cyclosporin-treated recipients experienced significantly more constipation and cosmetic side-effects. We demonstrated no differences in infection or malignancy. Authors' conclusions: Tacrolimus is superior to cyclosporin in improving graft survival and preventing acute rejection after kidney transplantation, but increases post-transplant diabetes, neurological and gastrointestinal side effects. Treating 100 recipients with tacrolimus instead of cyclosporin would avoid 12 suffering acute rejection, two losing their graft but cause an extra five to become insulin-requiring diabetics

"Flogging dead horses": evaluating when have clinical trials achieved sufficiency and stability? A case study in cardiac rehabilitation

<p>Abstract</p> <p>Background</p> <p>Most systematic reviews conclude that another clinical trial is needed. Measures of sufficiency and stability may indicate whether this is true.</p> <p>Objectives: To show how evidence accumulated on centre-based versus home-based cardiac rehabilitation, including estimates of sufficiency and stability</p> <p>Methods</p> <p>Systematic reviews of clinical trials of home versus centre-based cardiac rehabilitation were used to develop a cumulative meta-analysis over time. We calculated the standardised mean difference (SMD) in effect, confidence intervals and indicators of sufficiency and stability. Sufficiency refers to whether the meta-analytic database adequately demonstrates that an intervention works - is statistically superior to another. It does this by assessing the number of studies with null results that would be required to make the meta-analytic effect non-statistically significant. Stability refers to whether the direction and size of the effect is stable as new studies are added to the meta-analysis.</p> <p>Results</p> <p>The standardised mean effect difference reduced over fourteen comparisons from a non-significant difference favouring home-based cardiac rehabilitation to a very small difference favouring hospital (SMD -0.10, 95% CI -0.32 to 0.13). This difference did not reach the sufficiency threshold (failsafe ratio 0.039 < 1) but did achieve the criteria for stability (cumulative slope 0.003 < 0.005).</p> <p>Conclusions</p> <p>The evidence points to a relatively small effect difference which was stable but not sufficient in terms of the suggested thresholds. Sufficiency should arguably be based on substantive significance and decided by patients. Research on patient preferences should be the priority. Sufficiency and stability measures are useful tools that need to be tested in further case studies.</p

The community-based prevention of diabetes (ComPoD) study: A randomised, waiting list controlled trial of a voluntary sector-led diabetes prevention programme

© 2019 The Author(s). Objective: This two-site randomised trial compared the effectiveness of a voluntary sector-led, community-based diabetes prevention programme to a waiting-list control group at 6 months, and included an observational follow-up of the intervention arm to 12 months. Methods: Adults aged 18-75 years at increased risk of developing type 2 diabetes due to elevated blood glucose and being overweight were recruited from primary care practices at two UK sites, with data collected in participants' homes or community venues. Participants were randomised using an online central allocation service. The intervention, comprising the prototype "Living Well, Taking Control" (LWTC) programme, involved four weekly two-hour group sessions held in local community venues to promote changes in diet and physical activity, plus planned follow-up contacts at two, three, six, nine and 12 months alongside 5 hours of additional activities/classes. Waiting list controls received usual care for 6 months before accessing the programme. The primary outcome was weight loss at 6 months. Secondary outcomes included glycated haemoglobin (HbA1c), blood pressure, physical activity, diet, health status and well-being. Only researchers conducting analyses were blinded. Results: The target sample of 314 participants (157 each arm) was largely representative of local populations, including 44% men, 26% from ethnic minorities and 33% living in deprived areas. Primary outcome data were available for 285 (91%) participants (141 intervention, 144 control). Between baseline and 6 months, intervention participants on average lost more weight than controls (- 1.7 kg, 95% CI - 2.59 to - 0.85). Higher attendance was associated with greater weight loss (- 3.0 kg, 95% CI - 4.5 to - 1.5). The prototype LWTC programme more than doubled the proportion of participants losing > 5% of their body weight (21% intervention vs. 8% control, OR 2.83, 95% CI 1.36 to 5.90) and improved self-reported dietary behaviour and health status. There were no impacts on HbA1c, blood pressure, physical activity and well-being at 6 months and, amongst intervention participants, few further changes from six to 12-months (e.g. average weight re-gain 0.36 kg, 95% CI - 0.20 to 0.91). There were no serious adverse events but four exercise-related injuries were reported in the intervention arm. Conclusions: This voluntary sector-led diabetes prevention programme reached a broad spectrum of the population and had modest effects on weight-related outcomes, but limited impacts on other diabetes risk factors. Trial registration: Trial registration number: ISRCTN70221670, 5 September 2014 Funder (National Institute for Health Research School for Public Health Research) project reference number: SPHR-EXE-PES-COM

On the Origin and Spread of the Scab Disease of Apple: Out of Central Asia

Background Venturia inaequalis is an ascomycete fungus responsible for apple scab, a disease that has invaded almost all apple growing regions worldwide, with the corresponding adverse effects on apple production. Monitoring and predicting the effectiveness of intervention strategies require knowledge of the origin, introduction pathways, and population biology of pathogen populations. Analysis of the variation of genetic markers using the inferential framework of population genetics offers the potential to retrieve this information. Methodology/Principal Findings Here, we present a population genetic analysis of microsatellite variation in 1,273 strains of V. inaequalis representing 28 orchard samples from seven regions in five continents. Analysis of molecular variance revealed that most of the variation (88%) was distributed within localities, which is consistent with extensive historical migrations of the fungus among and within regions. Despite this shallow population structure, clustering analyses partitioned the data set into separate groups corresponding roughly to geography, indicating that each region hosts a distinct population of the fungus. Comparison of the levels of variability among populations, along with coalescent analyses of migration models and estimates of genetic distances, was consistent with a scenario in which the fungus emerged in Central Asia, where apple was domesticated, before its introduction into Europe and, more recently, into other continents with the expansion of apple growing. Across the novel range, levels of variability pointed to multiple introductions and all populations displayed signatures of significant post-introduction increases in population size. Most populations exhibited high genotypic diversity and random association of alleles across loci, indicating recombination both in native and introduced areas. Conclusions/Significance Venturia inaequalis is a model of invasive phytopathogenic fungus that has now reached the ultimate stage of the invasion process with a broad geographic distribution and well-established populations displaying high genetic variability, regular sexual reproduction, and demographic expansion.Contexte Venturia inaequalis est un champignon ascomycete responsable de la tavelure du pommier, une maladie qui a envahi presque toutes les régions du monde où le pommier est cultivé posant ainsi de graves problèmes en production. Prévenir et enrayer efficacement la réussite d’un tel succès invasif nécessite des connaissances approfondies sur l’origine, les voies d’introduction, la biologie et la génétique de ces populations invasives. En utilisant le potentiel d’inférence de la génétique des populations, l’analyse de la variation de marqueurs génétiques offre la possibilité d’accéder à ces informations. Méthodologie et Principaux résultats Ici nous présentons l’analyse de données microsatellites obtenues pour 1273 souches de V. inaequalis provenant de 28 vergers prélevées dans 7 régions sur les 5 continents. L’analyse de la variance moléculaire révèle que 88% de la variation se retrouve dans les vergers échantillonnés, ce qui est compatible avec d’importantes migrations historiques du champignon entre et à l’intérieur même des régions. Malgré cette très faible structuration des populations, les différentes analyses de clustering mettent en évidence un partage des populations en groupes séparés correspondant à leur origine géographique, montrant ainsi que chaque région héberge une population distincte du champignon. Ensemble, les résultats obtenus sur la comparaison du niveau de variabilité entre populations, les analyses de coalescence et les modèles de migration testés plaident en faveur d’un scénario dans lequel le champignon aurait émergé d’Asie Centrale, où le pommier a été domestiqué, avant d’être introduit en Europe puis plus récemment dans les autres continents suite à l’expansion de la culture du pommier. Les niveaux de variabilité indiquent que ces territoires ont subi des introductions multiples et que les populations portent toutes des signatures révélant de fortes expansions démographiques après leur introduction. Enfin, la forte diversité génotypique des populations et l’association aléatoire des allèles entre loci suggèrent que le champignon présente une reproduction sexuée régulière à la fois dans les régions où il a été introduit et dans sa région native. Conclusion et Portée. Venturia inaequalis est un modèle de champignons phytopathogène invasif qui a maintenant atteint le stade ultime du processus invasif, c’est à dire une très large distribution géographique par des populations bien établies montrant une grande diversité génétique, une reproduction sexuée régulière et une histoire d’expansion démographique

Balloon kyphoplasty in the management of vertebral compression fractures: an updated systematic review and meta-analysis

This systematic review updates the understanding of the evidence base for balloon kyphoplasty (BKP) in the management of vertebral compression fractures. Detailed searches of a number of electronic databases were performed from March to April 2006. Citation searches of included studies were undertaken and no language restrictions were applied. All controlled and uncontrolled studies were included with the exception of case reports. Prognostic factors responsible for pain relief and cement leakage were examined using meta-regression. Combined with previous evidence, a total of eight comparative studies (three against conventional medical therapy and five against vertebroplasty) and 35 case series were identified. The majority of studies were undertaken in older women with osteoporotic vertebral compression fractures with long-term pain that was refractory to medical treatment. In direct comparison to conventional medical management, patients undergoing BKP experienced superior improvements in pain, functionality, vertebral height and kyphotic angle at least up to 3-years postprocedure. Reductions in pain with BKP appeared to be greatest in patients with newer fractures. Uncontrolled studies suggest gains in health-related quality of life at 6 and 12-months following BKP. Although associated with a finite level of cement leakage, serious adverse events appear to be rare. Osteoporotic vertebral compression fractures appear to be associated with a higher level of cement leakage following BKP than non-osteoporotic vertebral compression fractures. In conclusion, there are now prospective studies of low bias, with follow-up of 12 months or more, which demonstrate balloon kyphoplasty to be more effective than medical management of osteoporotic vertebral compression fractures and as least as effective as vertebroplasty. Results from ongoing RCTs will provide further information in the near future

Exercise training for chronic heart failure (ExTraMATCH II): Protocol for an individual participant data meta-analysis

BACKGROUND: Patients with chronic heart failure (HF) experience a marked reduction in their exercise capacity, health-related quality of life, and life expectancy. Despite substantive evidence supporting exercise training in HF, uncertainties remain in the interpretation and understanding of this evidence base. Clinicians and healthcare providers seek definitive estimates of impact on mortality, hospitalisation and health-related quality of life, and which HF patient subgroups are likely to most benefit. The original Exercise Training Meta-Analysis for Chronic Heart Failure (ExTraMATCH) individual participant data (IPD) meta-analysis conducted in 2004 will be updated by the current collaboration (ExTraMATCH II), to investigate the effects of exercise training in HF. METHODS: Randomised controlled trials have been identified from the updated 2014 Cochrane systematic review and the original ExTraMATCH IPD meta-analysis with exercise training of 3 weeks' duration or more compared with a non-exercise control and a minimum follow-up of 6 months. Particular outcomes of interest are mortality, hospitalisation and health-related quality of life plus key baseline patient demographic and clinical data. Original IPD will be requested from the authors of all eligible trials; we will check original data and compile a master dataset. IPD meta-analyses will be conducted using a one-step approach where the IPD from all studies are modelled simultaneously whilst accounting for the clustering of participants with studies. DISCUSSION: The information from ExTraMATCH II will help inform future national and international clinical and policy decision-making on the use of exercise-based interventions in HF and improve the quality, design and reporting of future trials in this field