202 resultados para regimen


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BACKGROUND Multiple scores have been proposed to stratify bleeding risk, but their value to guide dual antiplatelet therapy duration has never been appraised. We compared the performance of the CRUSADE (Can Rapid Risk Stratification of Unstable Angina Patients Suppress Adverse Outcomes With Early Implementation of the ACC/AHA Guidelines), ACUITY (Acute Catheterization and Urgent Intervention Triage Strategy), and HAS-BLED (Hypertension, Abnormal Renal/Liver Function, Stroke, Bleeding History or Predisposition, Labile INR, Elderly, Drugs/Alcohol Concomitantly) scores in 1946 patients recruited in the Prolonging Dual Antiplatelet Treatment After Grading Stent-Induced Intimal Hyperplasia Study (PRODIGY) and assessed hemorrhagic and ischemic events in the 24- and 6-month dual antiplatelet therapy groups. METHODS AND RESULTS Bleeding score performance was assessed with a Cox regression model and C statistics. Discriminative and reclassification power was assessed with net reclassification improvement and integrated discrimination improvement. The C statistic was similar between the CRUSADE score (area under the curve 0.71) and ACUITY (area under the curve 0.68), and higher than HAS-BLED (area under the curve 0.63). CRUSADE, but not ACUITY, improved reclassification (net reclassification index 0.39, P=0.005) and discrimination (integrated discrimination improvement index 0.0083, P=0.021) of major bleeding compared with HAS-BLED. Major bleeding and transfusions were higher in the 24- versus 6-month dual antiplatelet therapy groups in patients with a CRUSADE score >40 (hazard ratio for bleeding 2.69, P=0.035; hazard ratio for transfusions 4.65, P=0.009) but not in those with CRUSADE score ≤40 (hazard ratio for bleeding 1.50, P=0.25; hazard ratio for transfusions 1.37, P=0.44), with positive interaction (Pint=0.05 and Pint=0.01, respectively). The number of patients with high CRUSADE scores needed to treat for harm for major bleeding and transfusion were 17 and 15, respectively, with 24-month rather than 6-month dual antiplatelet therapy; corresponding figures in the overall population were 67 and 71, respectively. CONCLUSIONS Our analysis suggests that the CRUSADE score predicts major bleeding similarly to ACUITY and better than HAS BLED in an all-comer population with percutaneous coronary intervention and potentially identifies patients at higher risk of hemorrhagic complications when treated with a long-term dual antiplatelet therapy regimen. CLINICAL TRIAL REGISTRATION URL: http://clinicaltrials.gov. Unique identifier: NCT00611286.

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BACKGROUND Management of tuberculosis in patients with HIV in eastern Europe is complicated by the high prevalence of multidrug-resistant tuberculosis, low rates of drug susceptibility testing, and poor access to antiretroviral therapy (ART). We report 1 year mortality estimates from a multiregional (eastern Europe, western Europe, and Latin America) prospective cohort study: the TB:HIV study. METHODS Consecutive HIV-positive patients aged 16 years or older with a diagnosis of tuberculosis between Jan 1, 2011, and Dec 31, 2013, were enrolled from 62 HIV and tuberculosis clinics in 19 countries in eastern Europe, western Europe, and Latin America. The primary endpoint was death within 12 months after starting tuberculosis treatment; all deaths were classified according to whether or not they were tuberculosis related. Follow-up was either until death, the final visit, or 12 months after baseline, whichever occurred first. Risk factors for all-cause and tuberculosis-related deaths were assessed using Kaplan-Meier estimates and Cox models. FINDINGS Of 1406 patients (834 in eastern Europe, 317 in western Europe, and 255 in Latin America), 264 (19%) died within 12 months. 188 (71%) of these deaths were tuberculosis related. The probability of all-cause death was 29% (95% CI 26-32) in eastern Europe, 4% (3-7) in western Europe, and 11% (8-16) in Latin America (p<0·0001) and the corresponding probabilities of tuberculosis-related death were 23% (20-26), 1% (0-3), and 4% (2-8), respectively (p<0·0001). Patients receiving care outside eastern Europe had a 77% decreased risk of death: adjusted hazard ratio (aHR) 0·23 (95% CI 0·16-0·31). In eastern Europe, compared with patients who started a regimen with at least three active antituberculosis drugs, those who started fewer than three active antituberculosis drugs were at a higher risk of tuberculosis-related death (aHR 3·17; 95% CI 1·83-5·49) as were those who did not have baseline drug-susceptibility tests (2·24; 1·31-3·83). Other prognostic factors for increased tuberculosis-related mortality were disseminated tuberculosis and a low CD4 cell count. 18% of patients were receiving ART at tuberculosis diagnosis in eastern Europe compared with 44% in western Europe and 39% in Latin America (p<0·0001); 12 months later the proportions were 67% in eastern Europe, 92% in western Europe, and 85% in Latin America (p<0·0001). INTERPRETATION Patients with HIV and tuberculosis in eastern Europe have a risk of death nearly four-times higher than that in patients from western Europe and Latin America. This increased mortality rate is associated with modifiable risk factors such as lack of drug susceptibility testing and suboptimal initial antituberculosis treatment in settings with a high prevalence of drug resistance. Urgent action is needed to improve tuberculosis care for patients living with HIV in eastern Europe. FUNDING EU Seventh Framework Programme.

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INTRODUCTION: To describe the clinical outcomes of intravitreal ranibizumab treatment for subfoveal choroidal neovascularisation (CNV) associated with Stargardt disease. METHODS: Prospective, interventional, case series. All patients underwent intravitreal ranibizumab injections following a pro re nata regimen with monthly examination, over a 24-month follow-up. RESULTS: Three eyes were included in the study. Best corrected visual acuity changed from 0.47±0.06 (mean±SD) at baseline to 0.90±0.17 LogMAR at the end of the 24-month follow-up. Overall, a mean number of 11 ranibizumab injections were administered in 24 months. Significant atrophic growth was detected in all cases, with the mean atrophy area increasing from 2.34±2.60 mm(2) (mean±SD) at baseline to 4.23±3.31 mm(2) at the end of the follow-up. CONCLUSIONS: Ranibizumab treatment can stop the CNV progression, but cannot ensure a significant visual improvement. Macular atrophy tends to significantly enlarge under ranibizumab treatment over the follow-up. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

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This study investigated the effects of oral treatments of Echinococcus multilocularis-infected mice with the antimalarial drug mefloquine (MEF) and identified proteins that bind to MEF in parasite extracts and human cells by affinity chromatography. In a pilot experiment, MEF treatment was applied 5 days per week and was intensified by increasing the dosage stepwise from 12.5 mg/kg to 200 mg/kg during 4 weeks followed by treatments of 100 mg/kg during the last 7 weeks. This resulted in a highly significant reduction of parasite weight in MEF-treated mice compared with mock-treated mice, but the reduction was significantly less efficacious compared with the standard treatment regimen of albendazole (ABZ). In a second experiment, MEF was applied orally in three different treatment groups at dosages of 25, 50 or 100 mg/kg, but only twice a week, for a period of 12 weeks. Treatment at 100 mg/kg had a profound impact on the parasite, similar to ABZ treatment at 200 mg/kg/day (5 days/week for 12 weeks). No adverse side effects were noted. To identify proteins in E. multilocularis metacestodes that physically interact with MEF, affinity chromatography of metacestode extracts was performed on MEF coupled to epoxy-activated Sepharose(®), followed by SDS-PAGE and in-gel digestion LC-MS/MS. This resulted in the identification of E. multilocularis ferritin and cystatin as MEF-binding proteins. In contrast, when human cells were exposed to MEF affinity chromatography, nicotinamide phosphoribosyltransferase was identified as a MEF-binding protein. This indicates that MEF could potentially interact with different proteins in parasites and human cells.

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Pneumococcal meningitis (PM) causes neurological sequelae in up to half of surviving patients. Neuronal damage associated with poor outcome is largely mediated by the inflammatory host response. Dexamethasone (DXM) is used as an adjuvant therapy in adult PM, but its efficacy in the treatment of pneumococcal meningitis in children is controversially discussed. While DXM has previously been shown to enhance hippocampal apoptosis in experimental PM, its impact on hippocampal cell proliferation is not known. This study investigated the impact of DXM on hippocampal proliferation in infant rat PM. Eleven-day-old nursing Wistar rats (n = 90) were intracisternally infected with Streptococcus pneumoniae to induce experimental meningitis. Treatment with DXM or vehicle was started 18 h after infection, concomitantly with antibiotics (ceftriaxone 100 mg/kg of body weight twice a day [b.i.d.]). Clinical parameters were monitored, and the amount of cells with proliferating activity was assessed using in vivo incorporation of bromodeoxyuridine (BrdU) and an in vitro neurosphere culture system at 3 and 4 d postinfection. DXM significantly worsened weight loss and survival. Density of BrdU-positive cells, as an index of cells with proliferating activity, was significantly lower in DXM-treated animals compared to vehicle controls (P < 0.0001). In parallel, DXM reduced neurosphere formation as an index for stem/progenitor cell density compared to vehicle treatment (P = 0.01). Our findings provide clear evidence that DXM exerts an antiproliferative effect on the hippocampus in infant rat PM. We conclude that an impairment of regenerative hippocampal capacity should be taken into account when considering adjuvant DXM in the therapeutic regimen for PM in children.

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To compare intraoperative cerebral microembolic load between minimally invasive extracorporeal circulation (MiECC) and conventional extracorporeal circulation (CECC) during isolated surgical aortic valve replacement (SAVR), we conducted a randomized trial in patients undergoing primary elective SAVR at a tertiary referral hospital. The primary outcome was the procedural phase-related rate of high-intensity transient signals (HITS) on transcranial Doppler ultrasound. HITS rate was used as a surrogate of cerebral microembolism in pre-defined procedural phases in SAVR using MiECC or CECC with (+F) or without (-F) an oxygenator with integrated arterial filter. Forty-eight patients were randomized in a 1:1 ratio to MiECC or CECC. Due to intraprocedural Doppler signal loss (n = 3), 45 patients were included in final analysis. MiECC perfusion regimen showed a significantly increased HITS rate compared to CECC (by a factor of 1.75; 95% confidence interval, 1.19-2.56). This was due to different HITS rates in procedural phases from aortic cross-clamping until declamping [phase 4] (P = 0.01), and from aortic declamping until stop of extracorporeal perfusion [phase 5] (P = 0.05). Post hoc analysis revealed that MiECC-F generated a higher HITS rate than CECC+F (P = 0.005), CECC-F (P = 0.05) in phase 4, and CECC-F (P = 0.03) in phase 5, respectively. In open-heart surgery, MiECC is not superior to CECC with regard to gaseous cerebral microembolism. When using MiECC for SAVR, the use of oxygenators with integrated arterial line filter appears highly advisable. Only with this precaution, MiECC confers a cerebral microembolic load comparable to CECC during this type of open heart surgery.

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BACKGROUND The monoclonal antibody natalizumab (NAT) inhibits the migration of lymphocytes throughout the blood-brain barrier by blocking very late antigen (VLA)-4 interactions, thereby reducing inflammatory central nervous system (CNS) activity in patients with multiple sclerosis (MS). We evaluated the effects of different NAT treatment regimens. METHODS We developed and optimised a NAT assay to measure free NAT, cell-bound NAT and VLA-4 expression levels in blood and cerebrospinal fluid (CSF) of patients using standard and prolonged treatment intervals and after the cessation of therapy. RESULTS In paired CSF and blood samples of NAT-treated MS patients, NAT concentrations in CSF were approximately 100-fold lower than those in serum. Cell-bound NAT and mean VLA-4 expression levels in CSF were comparable with those in blood. After the cessation of therapy, the kinetics of free NAT, cell-bound NAT and VLA-4 expression levels differed. Prolonged intervals greater than 4 weeks between infusions caused a gradual reduction of free and cell-bound NAT concentrations. Sera from patients with and without NAT-neutralising antibodies could be identified in a blinded assessment. The NAT-neutralising antibodies removed NAT from the cell surface in vivo and in vitro. Intercellular NAT exchange was detected in vitro. CONCLUSIONS Incorporating assays to measure free and cell-bound NAT into clinical practice can help to determine the optimal individual NAT dosing regimen for patients with MS.