Background and purpose: Current guidelines on cerebral venous thrombosis (CVT) diagnosis and management were issued by the European Federation of Neurological Societies in 2010. We aimed to update the previous European Federation of Neurological Societies guidelines using a clearer and evidencebased methodology. Method: We followed the Grading of Recommendations, Assessment, Development and Evaluation system, formulating relevant diagnostic and treatment questions, performing systematic reviews and writing recommendations based on the quality of available scientific evidence. Results: We suggest using magnetic resonance or computed tomographic angiography for confirming the diagnosis of CVT and not routinely screening patients with CVT for thrombophilia or cancer. We recommend parenteral anticoagulation in acute CVT and decompressive surgery to prevent death due to brain herniation. We suggest preferentially using low-molecular-weight heparin in the acute phase and not direct oral anticoagulants. We suggest not using steroids and acetazolamide to reduce death or dependency. We suggest using antiepileptics in patients with an early seizure and supratentorial lesions to prevent further early seizures. We could not make recommendations concerning duration of anticoagulation after the acute phase, thrombolysis and/or thrombectomy, therapeutic lumbar puncture, and prevention of remote seizures with antiepileptic drugs. We suggest that, in women who have suffered a previous CVT, contraceptives containing oestrogens should be avoided. We suggest that subsequent pregnancies are safe, but use of prophylactic lowmolecular-weight heparin should be considered throughout pregnancy and puerperium. Conclusions: Multicentre observational and experimental studies are needed to increase the level of evidence supporting recommendations on the diagnosis and management of CVT.

IMPORTANCE Little information is available on the long-term clinical outcome of patients with splanchnic vein thrombosis (SVT).OBJECTIVE To assess the incidence rates of bleeding, thrombotic events, and mortality in a large international cohort of patients with SVT. DESIGN, SETTING, AND PARTICIPANTSA prospective cohort study was conducted beginning May 2, 2008, and completed January 30, 2014, at hospital-based centers specialized in the management of thromboembolic disorders; a 2-year follow-up period was completed January 30, 2014, and data analysis was conducted from July 1, 2014, to February 28, 2015. Participants included 604 consecutive patients with objectively diagnosed SVT; there were no exclusion critieria. Information was gathered on baseline characteristics, risk factors, and antithrombotic treatment. Clinical outcomes during the follow-up period were documented and reviewed by a central adjudication committee. MAIN OUTCOMES AND MEASURESMajor bleeding, defined according to the International Society on Thrombosis and Hemostasis; bleeding requiring hospitalization; thrombotic events, including venous and arterial thrombosis; and all-cause mortality. RESULTSOf the 604 patients (median age, 54 years; 62.6% males), 21 (3.5%) did not complete follow-up. The most common risk factors for SVT were liver cirrhosis (167 of 600 patients [27.8%]) and solid cancer (136 of 600 [22.7%]); the most common sites of thrombosis were the portal vein (465 of 604 [77.0%]) and the mesenteric veins (266 of 604 [44.0%]). Anticoagulation was administered to 465 patients in the entire cohort (77.0%) with a mean duration of 13.9 months; 175 of the anticoagulant group (37.6%) received parenteral treatment only, and 290 patients (62.4%) were receiving vitamin K antagonists. The incidence rates (reported with 95% CIs) were 3.8 per 100 patient-years (2.7-5.2) for major bleeding, 7.3 per 100 patient-years (5.8-9.3) for thrombotic events, and 10.3 per 100 patient-years (8.5-12.5) for all-cause mortality. During anticoagulant treatment, these rates were 3.9 per 100 patient-years (2.6-6.0) for major bleeding and 5.6 per 100 patient-years (3.9-8.0) for thrombotic events. After treatment discontinuation, rates were 1.0 per 100 patient-years (0.3-4.2) and 10.5 per 100 patient-years (6.8-16.3), respectively. The highest rates of major bleeding and thrombotic events during the whole study period were observed in patients with cirrhosis (10.0 per 100 patient-years [6.6-15.1] and 11.3 per 100 patient-years [7.7-16.8], respectively); the lowest rates were in patients with SVT secondary to transient risk factors (0.5 per 100 patient-years [0.1-3.7] and 3.2 per 100 patient-years [1.4-7.0], respectively). CONCLUSIONS AND RELEVANCEMost patients with SVT have a substantial long-term risk of thrombotic events. In patients with cirrhosis, this risk must be balanced against a similarly high risk of major bleeding. Anticoagulant treatment appears to be safe and effective in most patients with SVT.

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Replacement of the congenitally deficient factor VIII or IX through plasma-derived or recombinant concentrates is the mainstay of treatment for hemophilia. Concentrate infusions when hemorrhages occur typically in joint and muscles (on-demand treatment) is able to resolve bleeding, but does not prevent the progressive joint deterioration leading to crippling hemophilic arthropathy. Therefore, primary prophylaxis, ie, regular infusion of concentrates started after the first joint bleed and/or before the age of two years, is now recognized as first-line treatment in children with severe hemophilia. Secondary prophylaxis, whenever started, aims to avoid (or delay) the progression of arthropathy and improve patient quality of life. Interestingly, recent data suggest a role for early prophylaxis also in preventing development of inhibitors, the most serious complication of treatment in hemophilia, in which multiple genetic and environmental factors may be involved. Treatment of bleeds in patients with inhibitors requires bypassing agents (activated prothrombin complex concentrates, recombinant factor VIIa). However, eradication of inhibitors by induction of immune tolerance should be the first choice for patients with recent onset inhibitors. The wide availability of safe factor concentrates and programs for comprehensive care has now resulted in highly satisfactory treatment of hemophilia patients in developed countries. Unfortunately, this is not true for more than two-thirds of persons with hemophilia, who live in developing countries.

ObjectivesTo evaluate prospectively the effect of weight loss on the achievement of minimal disease activity (MDA) in overweight/obese patients with psoriatic arthritis (PsA) starting treatment with tumour necrosis factor α (TNFα) blockers.MethodsAmong subjects with PsA starting treatment with TNFα blockers, 138 overweight/obese patients received a concomitant dietary intervention (69 a hypocaloric diet (HD) and 69 a free-managed diet (FD)). Changes in metabolic variables were measured and a complete clinical rheumatological evaluation was made in all patients at baseline and after a 6-month follow-up to define the achievement of MDA.Results126 subjects completed the study. MDA was more often achieved by HD than by FD subjects (HR=1.85, 95% CI 1.019 to 3.345, p=0.043). A diet was successful (≥5% weight loss) in 74 (58.7%) patients. Regardless of the type of diet, after 6 months of treatment with TNFα blockers, ≥5% of weight loss was a predictor of the achievement of MDA (OR=4.20, 95% CI 1.82 to 9.66, p<0.001). For increasing weight-loss categories (<5%, 5–10%, >10%), MDA was achieved by 23.1%, 44.8% and 59.5%, respectively. A higher rate of MDA achievement was found in subjects with 5–10% (OR=3.75, 95% CI 1.36 to 10.36, p=0.011) and in those with >10% (OR=6.67, 95% CI 2.41 to 18.41, p<0.001) weight loss in comparison with those with <5% weight loss.ConclusionsRegardless of the type of diet, a successful weight loss (≥5% from baseline values) is associated with a higher rate of achievement of MDA in overweight/obese patients with PsA who start treatment with TNFα blockers.

SummaryImmune tolerance induction (ITI) is the only strategy proven to eradicate persistent inhibitors in severe haemophilia A patients. Thirty years experience has shown high success rates (60-80%) with heterogeneous dose regimens and has led to the identification of clinical features that define the patients' prognostic profile. Children with recently diagnosed inhibitors are the best candidates for ITI and adequate management may further contribute to improve the shortand long-term ITI outcome. In these patients inhibitor eradication represents a cost-effective option because it enables the restoration of FVIII prophylaxis and consequently prevents arthropathy development. Adults with long-standing inhibitors often show bad predictors of ITI outcome, however, ITI may be considered as a suitable and costeffective approach in cases with frequent bleeds that are not satisfactorily controlled by by-passing treatment and/or when orthopaedic surgery is needed. Optimal ITI regimens should be established in these different settings and randomized trials are addressing these issues. This article reviews the available literature evidence and clinical implications with current recommendations on ITI management, and highlights the issues still unsolved.

The current proposal for cerebral venous thrombosis guideline followed the Grading of Recommendations, Assessment, Development, and Evaluation system, formulating relevant diagnostic and treatment questions, performing systematic reviews of all available evidence and writing recommendations and deciding on their strength on an explicit and transparent manner, based on the quality of available scientific evidence. The guideline addresses both diagnostic and therapeutic topics. We suggest using magnetic resonance or computed tomography angiography for confirming the diagnosis of cerebral venous thrombosis and not screening patients with cerebral venous thrombosis routinely for thrombophilia or cancer. We recommend parenteral anticoagulation in acute cerebral venous thrombosis and decompressive surgery to prevent death due to brain herniation. We suggest to use preferentially low-molecular weight heparin in the acute phase and not using direct oral anticoagulants. We suggest not using steroids and acetazolamide to reduce death or dependency. We suggest using antiepileptics in patients with an early seizure and supratentorial lesions to prevent further early seizures. We could not make recommendations due to very poor quality of evidence concerning duration of anticoagulation after the acute phase, thrombolysis and/or thrombectomy, therapeutic lumbar puncture, and prevention of remote seizures with antiepileptic drugs. We suggest that in women who suffered a previous cerebral venous thrombosis, contraceptives containing oestrogens should be avoided. We suggest that subsequent pregnancies are safe, but use of prophylactic low-molecular weight heparin should be considered throughout pregnancy and puerperium. Multicentre observational and experimental studies are needed to increase the level of evidence supporting recommendations on the diagnosis and management of cerebral venous thrombosis. KeywordsCerebral venous thrombosis, dural sinus thrombosis, Grading of Recommendations, Assessment, Development, and Evaluation, angiography, venography, D dimers, prothrombotic screening, cancer screening, anticoagulation, heparin, thrombolysis, thrombectomy, acetazolamide, steroids, decompressive surgery, hemicraniectomy, lumbar puncture, shunt, pregnancy, puerperium, contraception, antiepileptic drugs These guidelines followed the traditional methodology of combining review of scientific evidence with expert opinion and classifying evidence and recommendations in complex grading systems, using a matrix combining classes of recommendations with levels of evidence.Since 2010-2011 new information has accumulated on multiple aspects of the diagnosis and management of CVT. We aim to update previous EFNS guidelines using a clearer and evidence base methodology. To achieve that aim, the current proposal for CVT guidelines followed the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) system, 3 formulating relevant diagnostic and treatment questions, performing systematic reviews of all available eviden...

The classic view on the pathogenesis of drug-induced liver injury is that the so-called parent compounds are made hepatotoxic by metabolism (formation of neo-substances that react abnormally), mainly by cytochromes P-450 (CYP), with further pathways, such as mitochondrial dysfunction and apoptosis, also playing a role. Risk factors for drug-induced liver injury include concomitant hepatic diseases, age and genetic polymorphisms of CYP. However, some susceptibility can today be predicted before drug administration, working on the common substrate, by phenotyping and genotyping studies and by taking in consideration patients' health status. Physicians should always think of this adverse effect in the absence of other clear hepatic disease. Ethical and legal problems towards operators in the health care system are always matters to consider.