Appropriateness of therapy for active Crohn's disease: results of a multidisciplinary international expert panel (EPACT II)

Introduction: The development of novel therapies and the increasing number of trials testing management strategies for luminal Crohn's disease (CD) have not filled all the gaps in our knowledge. Thus, in clinical practice, many decisions for CD patients need to be taken without high quality evidence. For this reason, a multidisciplinary European expert panel followed the RAND method to develop explicit criteria for the management of individual patients with active, steroid-dependent (ST-D) and steroid-refractory (ST-R) CD. Methods: Twelve international experts convened in Geneva, Switzerland in December 2007, to rate explicit clinical scenarios, corresponding to real daily practice, on a 9-point scale according to the literature evidence and their own expertise. Median ratings were stratified into three categories: appropriate (7-9), uncertain (4-6) and inappropriate (1-3). Results: Overall, panelists rated 296 indications pertaining to mild-to-moderate, severe, ST-D, and ST-R CD. In anti-TNF naïve patients, budesonide and prednisone were found appropriate for mildmoderate CD, and infliximab (IFX) when those had previously failed or had not been tolerated. In patients with prior success with IFX, this drug with or without co-administration of a thiopurine analog was favored. Other anti-TNFs were appropriate in case of intolerance or resistance to IFX. High doses steroids, IFX or adalimumab were appropriate in severe active CD. Among 105 indications for ST-D or ST-R disease, the panel considered appropriate the thiopurine analogs, methotrexate, IFX, adalimumab and surgery for limited resection, depending on the outcome of prior therapies. Anti-TNFs were generally considered appropriate in ST-R. Conclusion: Steroids, including budesonide for mild-to-moderate CD, remain first-line therapies in active luminal CD. Anti-TNFs, in particular IFX with respect to the amount of available evidence, remain second-line for most indications. Thiopurine analogs are preferred to anti-TNFs when steroids are not appropriate, except when anti-TNFs were previously successful. These recommendations are available online (www.epact.ch). A prospective evaluation of these criteria in a large database in Switzerland in underway to validate these criteria.

Appropriateness of therapy for active Crohn's disease: results of a multidisciplinary International Expert Panel (EPACT II)

Introduction: The development of novel therapies and the increasing number of trials testing management strategies for luminal Crohn's disease (CD) have not filled all the gaps in our knowledge. Thus, in clinical practice, many decisions for CD patients need to be taken without high quality evidence. For this reason, a multidisciplinary European expert panel followed the RAND method to develop explicit criteria for the management of individual patients with active, steroid-dependent (ST-D) and steroid-refractory (ST-R) CD. Methods: Twelve international experts convened in Geneva, Switzerland in December 2007, to rate explicit clinical scenarios, corresponding to real daily practice, on a 9-point scale according to the literature evidence and their own expertise. Median ratings were stratified into three categories: appropriate (7-9), uncertain (4-6) and inappropriate (1-3). Results: Overall, panelists rated 296 indications pertaining to mild-to-moderate, severe, ST-D, and ST-R CD. In anti-TNF naïve patients, budesonide and prednisone were found appropriate for mildmoderate CD, and infliximab (IFX) when those had previously failed or had not been tolerated. In patients with prior success with IFX, this drug with or without co-administration of a thiopurine analog was favored. Other anti-TNFs were appropriate in case of intolerance or resistance to IFX. High doses steroids, IFX or adalimumab were appropriate in severe active CD. Among 105 indications for ST-D or ST-R disease, the panel considered appropriate the thiopurine analogs, methotrexate, IFX, adalimumab and surgery for limited resection, depending on the outcome of prior therapies. Anti-TNFs were generally considered appropriate in ST-R. Conclusion: Steroids, including budesonide for mild-to-moderate CD, remain first-line therapies in active luminal CD. Anti-TNFs, in particular IFX with respect to the amount of available evidence, remain second-line for most indications. Thiopurine analogs are preferred to anti-TNFs when steroids are not appropriate, except when anti-TNFs were previously successful. These recommendations are available online (www.epact.ch). A prospective evaluation of these criteria in a large database in Switzerland in underway to validate these criteria.

What influence do anticoagulants have on oral implant therapy? A systematic review.

OBJECTIVES: This systematic review aims to assess the risks (both thromboembolic and bleeding) of an oral anticoagulation therapy (OAT) patient undergoing implant therapy and to provide a management protocol to patients under OAT undergoing implant therapy. MATERIAL AND METHODS: Medline, Cochrane Data Base of Systematic Reviews, the Cochrane Central Register of Controlled Trials and EMBASE (from 1980 to December 2008) were searched for English-language articles published between 1966 and 2008. This search was completed by a hand research accessing the references cited in all identified publications. RESULTS: Nineteen studies were identified reporting outcomes after oral surgery procedures (mostly dental extractions in patients on OAT following different management protocols and haemostatic therapies). Five studies were randomized-controlled trials (RCTs), 11 were controlled clinical trials (CCTs) and three were prospective case series. The OAT management strategies as well as the protocols during and after surgery were different. This heterogeneity prevented any possible data aggregation and synthesis. The results from these studies are very homogeneous, reporting minor bleeding in very few patients, without a significant difference between the OAT patients who continue with the vitamin K antagonists vs. the patients who stopped this medication before surgery. These post-operative bleeding events were controlled only with local haemostatic measures: tranexamic acid mouthwashes, gelatine sponges and cellulose gauzes's application were effective. Post-operative bleeding did not correlate with the international normalised ratio (INR) status. In none of the studies was a thromboembolic event reported. CONCLUSIONS: OAT patients (INR 2-4) who do not discontinue the AC medication do not have a significantly higher risk of post-operative bleeding than non-OAT patients and they also do not have a higher risk of post-operative bleeding than OAT patients who discontinue the medication. In patients with OAT (INR 2-4) without discontinuation, topical haemostatic agents were effective in preventing post-operative bleeding. OAT discontinuation is not recommended for minor oral surgery, such as single tooth extraction or implant placement, provided that this does not involve autogenous bone grafts, extensive flaps or osteotomy preparations extending outside the bony envelope. Evidence does not support that dental implant placement in patients on OAT is contraindicated.

Maladies vasculaires rares [Rare vascular diseases].

Scarce knowledge of vascular rare diseases, defined by prevalence lower than 1/2000, is accompanied by increased patients mis-management and impaired quality of life. Recent advances in clinical knowledge, molecular biology, and genetic evaluation of certain vascular rare diseases allows designing new management strategies. A tight coordinated collaboration between angiologists and other specialists is therefore necessary to optimize patient's care.

Emerging viral infections after hematopoietic cell transplantation.

This overview summarizes recent data on emerging viruses after hematopoietic cell transplantation (HCT), including adenovirus, BK virus, human metapneumovirus (hMPV), and human herpesvirus (HHV) 6. The increased recognition of these infections is due to improved molecular detection methods, increased surveillance and more profound immunosuppression in the host. Adenovirus can cause serious disease especially in T-cell depleted transplant recipients. Adenovirus viremia is an important risk factor for disease in this setting. BK virus has been associated with hemorrhagic cystitis in HCT recipients. BK viremia is significantly associated with hemorrhagic cystitis. hMPV shows a seasonal distribution and can cause fatal pneumonia in HCT recipients. hMPV may be the etiology of some cases previously categorized as idiopathic pneumonia syndrome. HHV-6 commonly leads to viremia in HCT recipients. HHV-6 has been strongly associated with encephalitis and delayed platelet engraftment. Prospective studies are needed to further examine epidemiology, disease associations, and management strategies for these viruses.

Appropriateness of therapy for active Crohn's disease: results of a multidisciplinary international expert panel-EPACT II

The increasing number of trials testing management strategies for luminal Crohn's disease (CD) has not fitted all the gaps in our knowledge and thus, in clinical. practice, many decisions for CD patients have to be taken without the benefit of high-quality evidence. Methods: A multidisciplinary European expert panel used the RAND Appropriateness Method to develop and rate explicit criteria for the management of individual patients with active, steroid-dependent (ST-D) and steroid-refractory (ST-R) CD. Results: Overall., 296 indications pertaining to mild-to-moderate, severe, ST-D, and ST-R CD were rated. In anti-TNF naive patients, budesonide and prednisone were found to be appropriate for mild-moderate CD, and infliximab (IFX) was appropriate when these had previously failed or had not been tolerated. In patients with a prior successful treatment by IFX, this drug, with or without co-administration of a thiopurine analog, was favoured. Other anti-TNFs were appropriate in the presence of intolerance or resistance to IFX. High-dose steroids, IFX or adlimumab were appropriate in severe active CD. For the 105 indications for ST-D or ST-R disease, the panel considered the thiopurine analogs, methotrexate, IFX, adalimumab, and surgery for limited resection, to be appropriate, depending on the outcome of prior therapies. Anti-TNFs were generally considered appropriate in ST-R. Conclusion: Steroids, including budesonide for mild-to-moderate CD, remain the first-line therapy for active luminal CD. Anti-TNFs, in particular IFX as shown by the amount of available evidence, remain the second-line therapy for most indications. Thiopurine analogs, methotrexate and anti-TNFs are favoured in ST-D patients and ST-R patients. (C) 2009 European Crohn's and Colitis Organisation. Published by Elsevier B.V. All rights reserved.

ASTRAL-R score predicts non-recanalisation after intravenous thrombolysis in acute ischaemic stroke.

Intravenous thrombolysis (IVT) as treatment in acute ischaemic strokes may be insufficient to achieve recanalisation in certain patients. Predicting probability of non-recanalisation after IVT may have the potential to influence patient selection to more aggressive management strategies. We aimed at deriving and internally validating a predictive score for post-thrombolytic non-recanalisation, using clinical and radiological variables. In thrombolysis registries from four Swiss academic stroke centres (Lausanne, Bern, Basel and Geneva), patients were selected with large arterial occlusion on acute imaging and with repeated arterial assessment at 24 hours. Based on a logistic regression analysis, an integer-based score for each covariate of the fitted multivariate model was generated. Performance of integer-based predictive model was assessed by bootstrapping available data and cross validation (delete-d method). In 599 thrombolysed strokes, five variables were identified as independent predictors of absence of recanalisation: Acute glucose > 7 mmol/l (A), significant extracranial vessel STenosis (ST), decreased Range of visual fields (R), large Arterial occlusion (A) and decreased Level of consciousness (L). All variables were weighted 1, except for (L) which obtained 2 points based on β-coefficients on the logistic scale. ASTRAL-R scores 0, 3 and 6 corresponded to non-recanalisation probabilities of 18, 44 and 74 % respectively. Predictive ability showed AUC of 0.66 (95 %CI, 0.61-0.70) when using bootstrap and 0.66 (0.63-0.68) when using delete-d cross validation. In conclusion, the 5-item ASTRAL-R score moderately predicts non-recanalisation at 24 hours in thrombolysed ischaemic strokes. If its performance can be confirmed by external validation and its clinical usefulness can be proven, the score may influence patient selection for more aggressive revascularisation strategies in routine clinical practice.

Historical trends of organochlorine pesticides in a sediment core from the Gulf of Batabanó, Cuba.

Sediments can be natural archives to reconstruct the history of pollutant inputs into coastal areas. This is important to improve management strategies and evaluate the success of pollution control measurements. In this work, the vertical distribution of organochlorine pesticides (DDTs, Lindane, HCB, Heptachlor, Aldrin and Mirex) was determined in a sediment core collected from the Gulf of Batabanó, Cuba, which was dated by using the (210)Pb dating method and validated with the (239,240)Pu fallout peak. Results showed significant changes in sediment accumulation during the last 40 years: recent mass accumulation rates (0.321 g cm(-2) yr(-1)) double those estimated before 1970 (0.15 g cm(-2) yr(-1)). This change matches closely land use change in the region (intense deforestation and regulation of the Colon River in the late 1970s). Among pesticides, only DDTs isomers, Lindane and HCB were detected, and ranged from 0.029 to 0.374 ng g(-1) dw for DDTs, from<0.006 to 0.05 ng g(-1) dw for Lindane and from<0.04 to 0.134 ng g(-1) dw for HCB. Heptachlor, Aldrin and Mirex were below the detection limits (∼0.003 ng g(-1)), indicating that these compounds had a limited application in the Coloma watershed. Pesticide contamination was evident since the 1970s. DDTs and HCB records showed that management strategies, namely the banning the use of organochlorine contaminants, led to a concentration decline. However, Lindane, which was restricted in 1990, can still be found in the watershed. According to NOAA guidelines, pesticides concentrations encountered in these sediments are low and probably not having an adverse effect on sediment dwelling organisms.

Treatment of Retinoblastoma in 2015: Agreement and Disagreement.

The management of intraocular retinoblastoma is rapidly changing, and even recent reviews on the subject are behind existing practices. The 4 authors of this report collectively represent their management strategies with an emphasis on areas of agreement and disagreement. Ophthalmic artery chemosurgery and intravitreous chemotherapy have completely replaced external beam radiotherapy, reduced the use of systemic chemotherapy, and diminished enucleations by 90% without evidence of compromising patient survival.

Why evolution matters for species conservation: perspectives from three case studies of plant metapopulations

We advocate the advantage of an evolutionary approach to conservation biology that considers evolutionary history at various levels of biological organization. We review work on three separate plant taxa, spanning from one to multiple decades, illustrating extremes in metapopulation functioning. We show how the rare endemics Centaurea corymbosa (Clape Massif, France) and Brassica insularis in Corsica (France) may be caught in an evolutionary trap: disruption of metapopulation functioning due to lack of colonization of new sites may have counterselected traits such as dispersal ability or self-compatibility, making these species particularly vulnerable to any disturbance. The third case study concerns the evolution of life history strategies in the highly diverse genus Leucadendron of the South African fynbos. There, fire disturbance and the recolonization phase after fires are so integral to the functioning of populations that recruitment of new individuals is conditioned by fire. We show how past adaptation to different fire regimes and climatic constraints make species with different life history syndromes more or less vulnerable to global changes. These different case studies suggest that management strategies should promote evolutionary potential and evolutionary processes to better protect extant biodiversity and biodiversification.

An interactive web-GIS tool for risk analysis: a case study in the Fella River basin, Italy

This paper presents a prototype of an interactive web-GIS tool for risk analysis of natural hazards, in particular for floods and landslides, based on open-source geospatial software and technologies. The aim of the presented tool is to assist the experts (risk managers) in analysing the impacts and consequences of a certain hazard event in a considered region, providing an essential input to the decision-making process in the selection of risk management strategies by responsible authorities and decision makers. This tool is based on the Boundless (OpenGeo Suite) framework and its client-side environment for prototype development, and it is one of the main modules of a web-based collaborative decision support platform in risk management. Within this platform, the users can import necessary maps and information to analyse areas at risk. Based on provided information and parameters, loss scenarios (amount of damages and number of fatalities) of a hazard event are generated on the fly and visualized interactively within the web-GIS interface of the platform. The annualized risk is calculated based on the combination of resultant loss scenarios with different return periods of the hazard event. The application of this developed prototype is demonstrated using a regional data set from one of the case study sites, Fella River of northeastern Italy, of the Marie Curie ITN CHANGES project.

Predicting the future effectiveness of protected areas for bird conservation in Mediterranean ecosystems under climate change and novel fire regime scenarios

AimGlobal environmental changes challenge traditional conservation approaches based on the selection of static protected areas due to their limited ability to deal with the dynamic nature of driving forces relevant to biodiversity. The Natura 2000 network (N2000) constitutes a major milestone in biodiversity conservation in Europe, but the degree to which this static network will be able to reach its long-term conservation objectives raises concern. We assessed the changes in the effectiveness of N2000 in a Mediterranean ecosystem between 2000 and 2050 under different combinations of climate and land cover change scenarios. LocationCatalonia, Spain. MethodsPotential distribution changes of several terrestrial bird species of conservation interest included in the European Union's Birds Directive were predicted within an ensemble-forecasting framework that hierarchically integrated climate change and land cover change scenarios. Land cover changes were simulated using a spatially explicit fire-succession model that integrates fire management strategies and vegetation encroachment after the abandonment of cultivated areas as the main drivers of landscape dynamics in Mediterranean ecosystems. ResultsOur results suggest that the amount of suitable habitats for the target species will strongly decrease both inside and outside N2000. However, the effectiveness of N2000 is expected to increase in the next decades because the amount of suitable habitats is predicted to decrease less inside than outside this network. Main conclusionsSuch predictions shed light on the key role that the current N2000may play in the near future and emphasize the need for an integrative conservation perspective wherein agricultural, forest and fire management policies should be considered to effectively preserve key habitats for threatened birds in fire-prone, highly dynamic Mediterranean ecosystems. Results also show the importance of considering landscape dynamics and the synergies between different driving forces when assessing the long-term effectiveness of protected areas for biodiversity conservation.

Application in the STRATHE trial of a score system to compare the efficacy and the tolerability of different therapeutic strategies in the management of hypertension

A score system integrating the evolution of efficacy and tolerability over time was applied to a subpopulation of the STRATHE trial, a trial performed according to a parallel group design, with a double-blind, random allocation to either a fixed-dose combination strategy (perindopril/indapamide 2 mg/0.625 mg, with the possibility to increase the dose to 3 mg/0.935 mg, and 4 mg/1.250 mg if needed, n = 118), a sequential monotherapy approach (atenolol 50 mg, followed by losartan 50 mg and amlodipine 5 mg if needed, n = 108), or a stepped-care strategy (valsartan 40 mg, followed by valsartan 80 mg and valsartan 80 mg+ hydrochlorothiazide 12.5 mg if needed, n = 103). The aim was to lower blood pressure below 140/90 mmHg within a 9-month period. The treatment could be adjusted after 3 and 6 months. Only patients in whom the study protocol was strictly applied were included in this analysis. At completion of the trial the total score averaged 13.1 +/- 70.5 (mean +/- SD) using the fixed-dose combination strategy, compared with -7.2 +/- 81.0 using the sequential monotherapy approach and -17.5 +/- 76.4 using the stepped-care strategy. In conclusion, the use of a score system allows the comparison of antihypertensive therapeutic strategies, taking into account at the same time efficacy and tolerability. In the STRATHE trial the best results were observed with the fixed-dose combination containing low doses of an angiotensin enzyme converting inhibitor (perindopril) and a diuretic (indapamide).

Stratégies thérapeutiques pour le traitement des gliomes [Therapeutic strategies for the management of gliomas]

The management of gliomas remains challenging and requires a multidisciplinary approach that involves neurosurgeons, radiation therapists and oncologists. For patients with glioblastomas, progress has been made in recent years with the introduction of a combined modality treatment associating radiation therapy and concomitant chemotherapy with the novel alkylating agent temozolomide. This combination resulted in a significant prolongation of survival and increase in the number of patients with survival well beyond two years. Since then, interest in developing new agents in this disease has dramatically increased. In parallel, molecular markers, such as methylation status of MGMT or identification of the translocation of 1p and 19q in oligodendrogliomas have allowed to identify distinct subtypes with exquisite response to treatment or different prognosis. These developments have implications for the development of clinical trials of new potential drug treatments. In this article, we provide a review of the current management of low- and high-grade gliomas, including astrocytomas, oligodendrogliomas and glioblastomas and provide an outlook into future potential therapies.

Targeting Toll-Like Receptors: Promising Therapeutic Strategies for the Management of Sepsis-Associated Pathology and Infectious Diseases.

Toll-like receptors (TLRs) are pattern recognition receptors playing a fundamental role in sensing microbial invasion and initiating innate and adaptive immune responses. TLRs are also triggered by danger signals released by injured or stressed cells during sepsis. Here we focus on studies developing TLR agonists and antagonists for the treatment of infectious diseases and sepsis. Positioned at the cell surface, TLR4 is essential for sensing lipopolysaccharide of Gram-negative bacteria, TLR2 is involved in the recognition of a large panel of microbial ligands, while TLR5 recognizes flagellin. Endosomal TLR3, TLR7, TLR8, TLR9 are specialized in the sensing of nucleic acids produced notably during viral infections. TLR4 and TLR2 are favorite targets for developing anti-sepsis drugs, and antagonistic compounds have shown efficient protection from septic shock in pre-clinical models. Results from clinical trials evaluating anti-TLR4 and anti-TLR2 approaches are presented, discussing the challenges of study design in sepsis and future exploitation of these agents in infectious diseases. We also report results from studies suggesting that the TLR5 agonist flagellin may protect from infections of the gastrointestinal tract and that agonists of endosomal TLRs are very promising for treating chronic viral infections. Altogether, TLR-targeted therapies have a strong potential for prevention and intervention in infectious diseases, notably sepsis.