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Sample records for randomized multicentre phase

  1. Imatinib mesylate in scleroderma-associated diffuse skin fibrosis: a phase II multicentre randomized double-blinded controlled trial.

    PubMed

    Prey, S; Ezzedine, K; Doussau, A; Grandoulier, A-S; Barcat, D; Chatelus, E; Diot, E; Durant, C; Hachulla, E; de Korwin-Krokowski, J-D; Kostrzewa, E; Quemeneur, T; Paul, C; Schaeverbeke, T; Seneschal, J; Solanilla, A; Sparsa, A; Bouchet, S; Lepreux, S; Mahon, F-X; Chene, G; Taïeb, A

    2012-11-01

    Imatinib mesylate is a potent inhibitor of platelet-derived growth factor and transforming growth factor-β signalling pathways which may play a role in systemic sclerosis (SSc)-associated skin changes. We aimed primarily at assessing the efficacy of imatinib mesylate in scleroderma skin fibrosis. We performed a phase II double-blinded trial on patients with scleroderma with either morphoea involving > 20% of body surface area or SSc with extensive skin involvement: modified Rodnan Skin Score (mRSS) ≥ 20/51. Each patient was randomized to receive either imatinib mesylate 400 mg or placebo daily for a total of 6 months, and then was followed up 6 months after therapy discontinuation. Skin fibrosis was assessed by mRSS and measurement of the dermal thickness using skin biopsies performed at inclusion and at 6 months of treatment. In addition, quality of life (Dermatology Life Quality Index and modified Health Assessment Questionnaire for Scleroderma) was recorded at each visit, and pulmonary function before and after intervention. Twenty-eight patients were included in the study with a mean age of 48·9 years (range 30-71): 25 had a diagnosis of a SSc and three of diffuse cutaneous scleroderma. Demographic data, frequency of organ involvement of SSc and mRSS were comparable between groups. At 6 months, the proportion of variation of mRSS from inclusion was not statistically significantly different between the two groups (median +0·10 in imatinib group vs. -0·16 in placebo group, P = 0·098). Similarly, changes in dermal thickness, quality of life and diffusion capacity for carbon monoxide were not significantly different between groups. This study failed to demonstrate the efficacy of imatinib 400 mg daily to improve skin fibrosis of diffuse scleroderma after 6 months of treatment based on validated outcome measurements. © 2012 The Authors. BJD © 2012 British Association of Dermatologists.

  2. Tretinoin Nanogel 0.025% Versus Conventional Gel 0.025% in Patients with Acne Vulgaris: A Randomized, Active Controlled, Multicentre, Parallel Group, Phase IV Clinical Trial

    PubMed Central

    Chandrashekhar, B S; Anitha, M.; Ruparelia, Mukesh; Vaidya, Pradyumna; Aamir, Riyaz; Shah, Sunil; Thilak, S; Aurangabadkar, Sanjeev; Pal, Sandeep; Saraswat, Abir

    2015-01-01

    Background: Conventional topical tretinoin formulation is often associated with local adverse events. Nanogel formulation of tretinoin has good physical stability and enables good penetration of tretinoin into the pilo-sebaceous glands. Aim: The present study was conducted to assess the efficacy and safety of a nanogel formulation of tretinoin as compared to its conventional gel formulation in the treatment of acne vulgaris of the face. Materials and Methods: This randomized, active controlled, multicentric, phase IV clinical trial evaluated the treatment of patients with acne vulgaris of the face by the two gel formulations locally applied once daily at night for 12 wk. Acne lesion counts (inflammatory, non-inflammatory & total) and severity grading were carried out on the monthly scheduled visits along with the tolerability assessments. Results: A total of 207 patients were randomized in the study. Reductions in the total (72.9% vs. 65.0%; p = 0.03) and inflammatory (78.1% vs. 66.9%; p = 0.02) acne lesions were reported to be significantly greater with the nanogel formulation as compared to the conventional gel formulation. Local adverse events were significantly less (p = 0.04) in the nanogel group (13.3%) as compared to the conventional gel group (24.7%). Dryness was the most common adverse event reported in both the treatment groups while peeling of skin, burning sensation and photosensitivity were reported in patients using the conventional gel only. Conclusion: In the treatment of acne vulgaris of the face, tretinoin nanogel formulation appears to be more effective and better tolerated than the conventional gel formulation. PMID:25738069

  3. Clindamycin 1% Nano-emulsion Gel Formulation for the Treatment of Acne Vulgaris: Results of a Randomized, Active Controlled, Multicentre, Phase IV Clinical Trial

    PubMed Central

    Bhavsar, Bhavik; Choksi, Bimal; Dogra, Alka; Haq, Rizwan; Mehta, Sudhanshu; Mukherjee, Santanu; Subramanian, V; Sheikh, Shafiq; Mittal, Ravindra

    2014-01-01

    Background: Acne vulgaris of the face is a common dermatological disease with a significant impact on the quality of life, psychosocial development as well as self-esteem of the patients. Nano emulsion gel formulations are said to have various advantages over the conventional formulations. Aim: The present study was conducted to assess the comparative efficacy and safety of a nano-emulsion gel formulation of clindamycin with its conventional formulation in the treatment of acne vulgaris of the face. Materials and Methods: This prospective, active controlled, multicentric, phase IV clinical trial evaluated the treatment of patients with acne vulgaris of the face by a nano emulsion gel formulation or conventional gel formulation of clindamycin (as phosphate) 1% locally applied twice daily for 12 weeks as per random allocation. Acne lesion counts (inflammatory, non-inflammatory and total) and severity grading were carried out on the monthly scheduled visits along with tolerability assessments. Results: A total of 200 patients (97 males) were included for Intention to Treat analysis in the trial with 100 patients in each group. Reductions in total (69.3 vs. 51.9%; p<0.001), inflammatory (73.4 vs. 60.6%; p<0.005) and non inflammatory (65.1 vs. 43.7%; p<0.001) acne lesions were reported to be significantly greater with the nano-emulsion gel formulation as compared to the conventional gel formulation. Significantly more reduction in the mean acne severity score was noticeable with the nano-emulsion gel formulation (-1.6 ± 0.9 vs. -1.0 ± 0.8; p<0.001) than the comparator. A trend towards better safety profile of the nano emulsion gel formulation was reported. Conclusion: In the treatment of acne vulgaris of the face, clindamycin nano emulsion gel formulation appears to be more effective than the conventional gel formulation and is also well tolerated. PMID:25302253

  4. Safety and immunogenicity of Bio Pox™, a live varicella vaccine (Oka strain) in Indian children: A comparative multicentric, randomized phase II/III clinical trial.

    PubMed

    Dubey, Anand Prakash; Faridi, Mohammad Moonis Akbar; Mitra, Monjori; Kaur, Iqbal Rajinder; Dabas, Aashima; Choudhury, Jaydeep; Mukherjee, Mallar; Mishra, Devendra

    2017-09-02

    Varicella or chickenpox is a highly contagious disease with a high secondary attack rate. Almost 30% of Indian adolescents lack protective antibodies against varicella, emphasizing the need of routine varicella immunization. The Oka VZV is a well-established, safe and efficacious vaccine strain that is highly immunogenic and produces lifelong protective immunity. The present multicentric, open label, randomized, controlled Phase II/III study, compared the Bio Pox™ (indigenous investigational vaccine) with a licensed vaccine, Varivax™ ([a])([a]) Please note that this article refers to the product named VARIVAX as manufactured by Changchun Keygen Biological Products Ltd., China and marketed in India by VHB Life Sciences Limited, Mumbai, and not the product VARIVAX® owned by Merck Sharp & Dohme Corp., Rahway, New Jersey, USA. Merck Sharp & Dohme Corp. have asked us to make clear that the product manufactured by Changchun Keygen Biological Products Ltd. is unrelated to and is not sponsored, endorsed or otherwise authorised by Merck Sharp & Dohme Corp. , for its safety and immunogenicity profile in 252 healthy subjects in the age group of 1-12 y (cohort I: 6-12 years, II:1-6 years) in 3 tertiary medical institutions. Antibodies were measured by VZV Glycoprotein Enzyme Linked Immunoassay (IgG ELISA) kit. Seroconversion percentage in children having pre-vaccination anti VZV IgG titer <10 mIU/mL (< 5 gp ELISA units/mL) were 80% for Bio Pox™ and 77% for Varivax™ (p = 0.692). The seroconversion rate in the group receiving Bio Pox™ was non-inferior to the group that received Varivax™. There were mild local reactions for both the vaccines; none of the patient had fever or required hospitalization or medication. The Bio Pox™ was found to be safe and immunogenic in children against VZV infection.

  5. The efficacy and safety of blonanserin compared with haloperidol in acute-phase schizophrenia: a randomized, double-blind, placebo-controlled, multicentre study.

    PubMed

    Garcia, Esther; Robert, Marta; Peris, Francesc; Nakamura, Hiroshi; Sato, Noriko; Terazawa, Yoshikatsu

    2009-01-01

    Blonanserin is a novel atypical antipsychotic agent with potent dopamine D(2) and serotonin 5-HT(2) antagonist properties. It may potentially have a lower incidence of adverse events than other antipsychotic agents. To determine the efficacy and safety of three doses of blonanserin compared with placebo and haloperidol in patients with acute-phase schizophrenia. This was a 6-week, randomized, double-blind, placebo- and haloperidol-controlled, international, multicentre study. Patients with an acute exacerbation of their schizophrenia, with a Positive and Negative Syndrome Scale (PANSS) score >/=70 and a Clinical Global Impression - Severity of Illness (CGI-S) score >/=4 ('moderately ill') [with no decrease >/=20% or >/=1 point, respectively, during the wash-out period] were randomized into one of five treatment groups (blonanserin 2.5, 5 or 10 mg, haloperidol 10 mg or placebo once daily). Patients were assessed weekly for clinical efficacy, adverse events, extrapyramidal symptoms (EPS) and drug compliance, and were assessed biweekly for other safety variables. All 307 randomized patients received at least one dose of study medication and 228 (74.3%) completed the study. The mean reduction in PANSS total score at week 6 was significantly greater with all active treatments compared with placebo (-12.58; p < 0.001); blonanserin 10 mg was significantly superior to blonanserin 2.5 mg (-30.18 vs -20.6; p < 0.001), but blonanserin 5 mg (-27.19) and haloperidol 10 mg (-28.16) were not. All active treatments showed greater efficacy against the positive symptoms of schizophrenia, and blonanserin (5 and 10 mg) was more effective against the negative symptoms than haloperidol. Blonanserin was well tolerated at all doses and there was no evidence of clinically important weight gain, orthostatic hypotension, corrected QT interval prolongation or clinically relevant changes in laboratory test results. Haloperidol caused persistent elevation in prolactin levels, but this was not

  6. Efficacy and safety of teneligliptin, a novel dipeptidyl peptidase-4 inhibitor, in Korean patients with type 2 diabetes mellitus: a 24-week multicentre, randomized, double-blind, placebo-controlled phase III trial.

    PubMed

    Hong, S; Park, C-Y; Han, K A; Chung, C H; Ku, B J; Jang, H C; Ahn, C W; Lee, M-K; Moon, M K; Son, H S; Lee, C B; Cho, Y-W; Park, S-W

    2016-05-01

    We assessed the 24-week efficacy and safety of teneligliptin, a novel dipeptidyl peptidase-4 inhibitor, in Korean patients with type 2 diabetes mellitus (T2DM) that was inadequately controlled with diet and exercise. The present study was designed as a multicentre, randomized, double-blind, placebo-controlled, parallel-group, phase III study. Patients (n = 142) were randomized 2 : 1 into two different treatment groups as follows: 99 received teneligliptin (20 mg) and 43 received placebo. The primary endpoint was change in glycated haemoglobin (HbA1c) level from baseline to week 24. Teneligliptin significantly reduced the HbA1c level from baseline compared with placebo after 24 weeks. At week 24, the differences between changes in HbA1c and fasting plasma glucose (FBG) in the teneligliptin and placebo groups were -0.94% [least-squares (LS) mean -1.22, -0.65] and -1.21 mmol/l (-1.72, -0.70), respectively (all p < 0.001). The incidence of hypoglycaemia and adverse events were not significantly different between the two groups. This phase III, randomized, placebo-controlled study provides evidence of the safety and efficacy of 24 weeks of treatment with teneligliptin as a monotherapy in Korean patients with T2DM.

  7. Efficacy and safety of teneligliptin, a novel dipeptidyl peptidase‐4 inhibitor, in Korean patients with type 2 diabetes mellitus: a 24‐week multicentre, randomized, double‐blind, placebo‐controlled phase III trial

    PubMed Central

    Hong, S.; Park, C.‐Y.; Han, K. A.; Chung, C. H.; Ku, B. J.; Jang, H. C.; Ahn, C. W.; Lee, M.‐K.; Moon, M. K.; Son, H. S.; Lee, C. B.; Cho, Y.‐W.

    2016-01-01

    We assessed the 24‐week efficacy and safety of teneligliptin, a novel dipeptidyl peptidase‐4 inhibitor, in Korean patients with type 2 diabetes mellitus (T2DM) that was inadequately controlled with diet and exercise. The present study was designed as a multicentre, randomized, double‐blind, placebo‐controlled, parallel‐group, phase III study. Patients (n = 142) were randomized 2 : 1 into two different treatment groups as follows: 99 received teneligliptin (20 mg) and 43 received placebo. The primary endpoint was change in glycated haemoglobin (HbA1c) level from baseline to week 24. Teneligliptin significantly reduced the HbA1c level from baseline compared with placebo after 24 weeks. At week 24, the differences between changes in HbA1c and fasting plasma glucose (FBG) in the teneligliptin and placebo groups were −0.94% [least‐squares (LS) mean −1.22, −0.65] and −1.21 mmol/l (−1.72, −0.70), respectively (all p < 0.001). The incidence of hypoglycaemia and adverse events were not significantly different between the two groups. This phase III, randomized, placebo‐controlled study provides evidence of the safety and efficacy of 24 weeks of treatment with teneligliptin as a monotherapy in Korean patients with T2DM. PMID:26749529

  8. FOCUS 1: a randomized, double-blinded, multicentre, Phase III trial of the efficacy and safety of ceftaroline fosamil versus ceftriaxone in community-acquired pneumonia.

    PubMed

    File, Thomas M; Low, Donald E; Eckburg, Paul B; Talbot, George H; Friedland, H David; Lee, Jon; Llorens, Lily; Critchley, Ian A; Thye, Dirk A

    2011-04-01

    Ceftaroline, the active form of the prodrug ceftaroline fosamil, is a novel cephalosporin with bactericidal activity against important pathogens associated with community-acquired pneumonia (CAP), including Streptococcus pneumoniae and common Gram-negative pathogens. FOCUS 1 is a randomized, double-blinded, Phase III study that was conducted to evaluate the efficacy and safety of ceftaroline fosamil in treating patients with CAP. The primary objective was to determine non-inferiority [lower limit of 95% confidence interval (CI) ≥ -10%] in clinical cure rates achieved with ceftaroline fosamil compared with those achieved with ceftriaxone in the clinically evaluable (CE) and modified intent-to-treat efficacy (MITTE) populations. Patients hospitalized in a non-intensive care unit setting with CAP of Pneumonia Outcomes Research Team (PORT) risk class III or IV requiring intravenous (iv) therapy were randomized (1:1) to receive 600 mg of ceftaroline fosamil iv every 12 h or 1 g of ceftriaxone iv every 24 h. Patients also received two 500 mg doses of oral clarithromycin every 12 h administered on day 1. Clinical cure, microbiological response, adverse events (AEs) and laboratory tests were assessed. FOCUS 1 registration number NCT00621504 (http://clinicaltrials.gov/ct2/show/NCT00621504). Of 613 enrolled patients, 298 received ceftaroline fosamil and 308 received ceftriaxone. Baseline characteristics between treatment groups were comparable. Clinical cure rates were as follows: CE population, 86.6% (194/224) for ceftaroline fosamil and 78.2% (183/234) for ceftriaxone [difference (95% CI), 8.4% (1.4, 15.4)]; and MITTE population, 83.8% (244/291) for ceftaroline fosamil and 77.7% (233/300) for ceftriaxone [difference (95% CI), 6.2% (-0.2, 12.6)]. Clinical cure rates for CAP caused by S. pneumoniae in the microbiological MITTE population were 88.9% (24/27) and 66.7% (20/30) for ceftaroline fosamil and ceftriaxone, respectively. Both agents were well tolerated, with similar

  9. Ketoprofen versus paracetamol (acetaminophen) or ibuprofen in the management of fever: results of two randomized, double-blind, double-dummy, parallel-group, repeated-dose, multicentre, phase III studies in children.

    PubMed

    Kokki, Hannu; Kokki, Merja

    2010-01-01

    Fever is a common symptom in children and one of the major concerns of parents of younger and preschool-age children. To compare the efficacy and safety of ketoprofen with that of paracetamol (acetaminophen) and ibuprofen in the treatment of febrile conditions in children. Two prospective, randomized, double-blind, double-dummy, repeated-dose, multicentre, phase III studies with two parallel groups in each study were conducted in primary-care outpatient clinics. Children aged 6 months to 6 years presenting with a febrile condition and an oral body temperature of > or =38.8 degrees C or rectal temperature of > or =39 degrees C were eligible for inclusion. Patients were randomized to receive either ketoprofen syrup 0.5 mg/kg, ibuprofen suspension 5 mg/kg or paracetamol suspension 15 mg/kg every 6 hours by the oral route. The primary outcome measure was the change in temperature at 3 hours (H3), compared with baseline (H0). All three treatments provided similar mean maximum decreases of 1.4-1.5 degrees C in body temperature at H3 compared with H0. Use of ketoprofen was not associated with any increased risk of adverse events compared with the two reference compounds. Ketoprofen 0.5 mg/kg appeared to be equivalent to the standard antipyretic doses of the reference products ibuprofen 5 mg/kg and paracetamol 15 mg/kg. Ketoprofen at the 0.5 mg/kg dose should be an effective and safe option for symptomatic management of fever in children.

  10. Ethnic sensitivity assessment of fluticasone furoate/vilanterol in East Asian asthma patients from randomized double-blind multicentre Phase IIb/III trials.

    PubMed

    Gross, Annette S; Goldfrad, Caroline; Hozawa, Soichiro; James, Mark H; Clifton, Christine S; Sugiyama, Yutaro; Jacques, Loretta

    2015-12-24

    Fluticasone furoate (FF)/vilanterol (VI) is a once daily (OD) inhaled corticosteroid/long-acting β2-agonist combination asthma therapy approved in Japan and the EU. FF/VI efficacy and safety data from asthma studies including patients in East Asia were evaluated to assess ethnic sensitivity. Randomized, double-blind, multicenter Phase IIb/III trials were assessed. Change from baseline relative to placebo or twice-daily fluticasone propionate 500 μg in trough FEV1 was compared between patients from Japan (N = 148) and Not-Japan (N = 3,066; three studies). Adverse events (AEs), laboratory results, and electrocardiograms were compared between patients from Japan + Korea (N = 188) and Not-Japan + Korea (N = 3,840; five studies). For trough FEV1, improvements from baseline (least-squares mean difference [95% confidence interval]) were reported for FF/VI 100/25 μg OD versus placebo at Week 12 (Japan: 0.323 L [0.104-0.542]; Not-Japan: 0.168 L [0.095-0.241]). Improvements from baseline (least-squares mean change [standard error]) were reported with FF/VI 200/25 μg OD at Week 24 (Japan: 0.355 L [0.1152]; Not-Japan: 0.396 L [0.0313]). A greater proportion of patients from Japan + Korea versus Not-Japan + Korea reported AEs in all treatment arms including placebo (FF/VI 100/25 μg: 79% versus 57%; FF/VI 200/25 μg: 64% versus 45%; placebo: 41% versus 23%). There were no notable differences in treatment-related or class-related AEs. No clinically significant changes in electrocardiogram assessments or statistically significant differences in 24 h urinary cortisol excretion were observed between the Japan + Korea and Not-Japan + Korea cohorts. Good efficacy and an acceptable safety profile were observed for FF/VI 100/25 μg and 200/25 μg OD in East Asian asthma patients; these globally recommended doses are appropriate for asthma patients in Japan. Clinicaltrials.gov registration numbers: NCT01165138 , NCT01134042 , NCT01086384 , NCT

  11. Heterogeneous FDG-guided dose-escalation for locally advanced NSCLC (the NARLAL2 trial): Design and early dosimetric results of a randomized, multi-centre phase-III study.

    PubMed

    Møller, Ditte Sloth; Nielsen, Tine Bjørn; Brink, Carsten; Hoffmann, Lone; Lutz, Christina Maria; Drøgemüller Lund, Mikkel; Hansen, Olfred; Schytte, Tine; Khalil, Azza Ahmed; Knap, Marianne Marquard; Nyhus, Christa Haugaard; Ottosson, Wiviann; Sibolt, Patrik; Borissova, Svetlana; Josipovic, Mirjana; Persson, Gitte; Appelt, Ane Lindegaard

    2017-08-01

    Local recurrence is frequent in locally advanced NSCLC and is primarily located in FDG-avid parts of tumour and lymph nodes. Aiming at improving local control without increasing toxicity, we designed a multi-centre phase-III trial delivering inhomogeneous dose-escalation driven by FDG-avid volumes, while respecting normal tissue constraints and requiring no increase in mean lung dose. Dose-escalation driven by FDG-avid volumes, delivering mean doses of 95Gy (tumour) and 74Gy (lymph nodes), was pursued and compared to standard 66Gy/33F plans. Dose plans for the first thirty patients enroled were analysed. Standard and escalated plans were created for all patients, blinded to randomization, and compared for each patient in terms of the ability to escalate while protecting normal tissue. The median dose-escalation in FDG-avid areas was 93.9Gy (tumour) and 73.0Gy (lymph nodes). Escalation drove the GTV and CTV to mean doses for the tumour of 87.5Gy (GTV-T) and 81.3Gy (CTV-T) in median. No significant differences in mean dose to lung and heart between standard and escalated were found, but small volumes of e.g. the bronchi received doses between 66 and 74Gy due to escalation. FDG-driven inhomogeneous dose-escalation achieves large increment in tumour and lymph node dose, while delivering similar doses to normal tissue as homogenous standard plans. Copyright © 2017. Published by Elsevier B.V.

  12. A phase 3, multicentre, randomized, double-blind, placebo-controlled, parallel-group study to evaluate the efficacy and safety of etelcalcetide (ONO-5163/AMG 416), a novel intravenous calcimimetic, for secondary hyperparathyroidism in Japanese haemodialysis patients.

    PubMed

    Fukagawa, Masafumi; Yokoyama, Keitaro; Shigematsu, Takashi; Akiba, Takashi; Fujii, Akifumi; Kuramoto, Takuto; Odani, Motoi; Akizawa, Tadao

    2017-10-01

    Secondary hyperparathyroidism (SHPT) is a major complication associated with chronic kidney disease. We evaluated the efficacy and safety of etelcalcetide (ONO-5163/AMG 416), a novel intravenous calcimimetic, in Japanese haemodialysis patients with SHPT. In this phase 3, multicentre, randomized, double-blind, placebo-controlled, parallel-group study, etelcalcetide was administered three times per week at an initial dose of 5 mg, and subsequently adjusted to doses between 2.5 and 15 mg at 4-week intervals for 12 weeks. A total of 155 SHPT patients with serum intact parathyroid hormone (iPTH) levels ≥300 pg/mL were assigned to receive etelcalcetide (n = 78) or placebo (n = 77). The primary endpoint was the proportion of patients with decreased serum iPTH to the target range proposed by the Japanese Society for Dialysis Therapy (60-240 pg/mL). The major secondary endpoint was the proportion of patients with ≥30% reductions in serum iPTH from baseline. The proportion of patients meeting the primary endpoint was significantly higher for etelcalcetide (59.0%) versus placebo (1.3%). Similarly, the proportion of patients meeting the major secondary endpoint was significantly higher for etelcalcetide (76.9%) versus placebo (5.2%). Serum albumin-corrected calcium, phosphorus and intact fibroblast growth factor-23 levels were decreased in the etelcalcetide group. Nausea, vomiting and symptomatic hypocalcaemia were mild with etelcalcetide. Serious adverse events related to etelcalcetide were not observed. This study demonstrated the efficacy and safety of etelcalcetide. As the only available intravenous calcium-sensing receptor agonist, etelcalcetide is likely to provide a new treatment option for SHPT in haemodialysis patients.

  13. Efficacy and safety of sucroferric oxyhydroxide compared with sevelamer hydrochloride in Japanese haemodialysis patients with hyperphosphataemia: A randomized, open‐label, multicentre, 12‐week phase III study

    PubMed Central

    Yokoyama, Keitaro; Fukagawa, Masafumi; Terao, Akira; Akizawa, Tadao

    2017-01-01

    Abstract Aim We aimed to investigate the non‐inferiority of PA21 (sucroferric oxyhydroxide) to sevelamer hydrochloride (sevelamer) in terms of efficacy and safety in Japanese haemodialysis patients with hyperphosphataemia. Methods In this Phase III, open‐label, multicentre study, 213 haemodialysis patients with hyperphosphataemia were randomized to PA21 or sevelamer treatment for 12 weeks. The primary outcome was adjusted serum phosphorus concentration at the end of treatment; the non‐inferiority of PA21 was confirmed if the upper limit of the two‐sided 95% confidence interval (CI) is ≤0.32 mmol/L. Secondary outcomes were corrected serum calcium and intact‐parathyroid hormone concentrations. Adverse events (AEs) and adverse drug reactions (ADRs) were evaluated. Results The adjusted mean serum phosphorus concentration at the end of treatment confirmed the non‐inferiority of PA21 for lowering serum phosphorus compared with sevelamer (1.62 vs 1.72 mmol/L; difference, −0.11 mmol/L; 95% CI, −0.20 to −0.02 mmol/L). The mean daily tablet intake was 5.6 ± 2.6 and 18.7 ± 7.1 tablets in the PA21 and sevelamer groups, respectively. The incidences of AEs and ADRs were not significantly different between the two groups. Conclusion The non‐inferiority of PA21 to sevelamer was confirmed for the treatment of Japanese haemodialysis patients with hyperphosphataemia. PA21 was effective, safe, and well tolerated, while having a considerably lower pill burden than sevelamer. PMID:27496336

  14. Clinical efficacy and safety of topiroxostat in Japanese male hyperuricemic patients with or without gout: an exploratory, phase 2a, multicentre, randomized, double-blind, placebo-controlled study.

    PubMed

    Hosoya, T; Sasaki, T; Hashimoto, H; Sakamoto, R; Ohashi, T

    2016-06-01

    In Japan, although topiroxostat, a selective xanthine oxidoreductase inhibitor, has been used for the treatment of patients with hyperuricemia including gout, no published randomized controlled studies evaluating the dose-dependent relationship with respect to the serum urate-lowering efficacy have been reported. The aim of this study was to evaluate the dose-dependent relationship with serum urate-lowering efficacy and safety of topiroxostat in Japanese hyperuricemic patients including gout. We conducted an exploratory, phase 2a, multicentre, randomized, double-blind, 8-week, placebo-controlled study in Japanese hyperuricemic patients with or without gout. The study arms were placebo and topiroxostat 40, 60, 80 or 120 mg/day. The primary efficacy endpoint was the per cent change in serum urate level from baseline to the final visit. One hundred and eighty-seven eligible patients were randomized and 186 received at least one dose of the study drug. The study results demonstrated a dose-dependent serum urate reduction effect ranging from 40 to 120 mg/day (P < 0·001, Jonckheere-Terpstra test). The mean per cent change in serum urate level from baseline at the final visit was -30·8% in the 120-mg group and 1·6% with placebo, with a between-group difference of -32·4% ([95% confidence interval, -38·9% to -25·9%]; P < 0·001). Incidences of overall adverse events (AEs) in the topiroxostat groups were comparable to those in the placebo group; however, the incidence of AEs in the 120-mg group was statistically lower than that in the placebo group. The incidences of gouty arthritis were not statistically but numerically higher in the topiroxostat 80- and 120-mg groups. A dose-dependent serum urate-lowering efficacy of topiroxostat was observed in Japanese hyperuricemic male patients with or without gout. Further clinical studies aimed at evaluating the long-term safety and clinical efficacy are warranted. © 2016 The Authors. Journal of Clinical Pharmacy and

  15. Comparison of topiroxostat and allopurinol in Japanese hyperuricemic patients with or without gout: a phase 3, multicentre, randomized, double-blind, double-dummy, active-controlled, parallel-group study.

    PubMed

    Hosoya, T; Ogawa, Y; Hashimoto, H; Ohashi, T; Sakamoto, R

    2016-06-01

    There are no clinical reports that have compared topiroxostat, a selective xanthine oxidase inhibitor, with allopurinol in serum urate-lowering efficacy. The aim of this study was to compare the efficacy and safety of topiroxostat and allopurinol in Japanese hyperuricemic patients with or without gout. A phase 3, multicentre, randomized, double-blind, double-dummy, active-controlled, parallel-group study conducted in Japan. Patients who had inadequate serum urate levels (a gout patient: serum urate level ≥416·4 μmol/L; an asymptomatic hyperuricemic patient with specific complications (urinary lithiasis, hypertension, hyperlipidemia and/or diabetes): serum urate level ≥475·8 μmol/L; and an asymptomatic hyperuricemic patient with no specific complications: serum urate level ≥535·3 μmol/L) were randomized to topiroxostat 120 mg/day or allopurinol 200 mg/day, with an equal allocation ratio, for 16 weeks. To prevent the onset of gouty arthritis by rapid serum urate reduction, these doses were increased in a stepwise manner. The primary efficacy endpoint was the per cent change in serum urate level from baseline to the final visit. Overall, 206 patients were randomly assigned to topiroxostat and allopurinol. Two hundred and three patients (allopurinol: n = 105, topiroxostat: n = 98) received at least one dose of the study drug and had their serum urate level assessed at least once. The baseline characteristics were comparable between groups. The mean age of patients was 53·0 ± 11·4 years and 99% of patients were male. The primary efficacy endpoint was -34·3 ± 11·1% in the allopurinol group (n = 105) and -36·3 ± 12·7% in the topiroxostat group (n = 98). Non-inferiority of the serum urate-lowering efficacy of topiroxostat to allopurinol was proved by the predefined non-inferiority margin (95% confidence interval, -5·3 to 1·3%). The overall incidences of adverse events and adverse drug reactions were similar between both groups. Topiroxostat 120 mg

  16. Fluvoxamine CR in the long-term treatment of social anxiety disorder: the 12- to 24-week extension phase of a multicentre, randomized, placebo-controlled trial.

    PubMed

    Stein, Dan J; Westenberg, Herman G M; Yang, Haichen; Li, David; Barbato, Luigi M

    2003-12-01

    Fluvoxamine CR has been reported effective in the short-term (12-wk) treatment of generalized social anxiety disorder (social phobia). Social anxiety disorder (SAD) is, however, a chronic disorder thought to require maintenance treatment. We report on data from the extension phase of a short-term study, in order to explore the efficacy and safety profile of fluvoxamine CR (100-300 mg/d) in the longer-term treatment of this disorder. Adult outpatients with generalized social anxiety disorder (GSAD) at 35 centres in Europe, South Africa, and USA were included in an acute phase study (12 wk). Subjects who demonstrated at least minimal improvement by endpoint (n=112), were offered participation in an extension phase, in which medication was continued for a further 12 wk under double-blind conditions. Efficacy was assessed using the Liebowitz Social Anxiety Disorder Scale (LSAS), the Clinical Global Impression Global Improvement score (CGI-I), the Clinical Global Impressions Severity of Illness score (CGI-S), and the Sheehan Disability Scale (SDS). Safety and tolerability assessments were also performed at regular intervals. Subjects treated with fluvoxamine CR had a numerically greater decrease in LSAS total scores than subjects treated with placebo at endpoint. Analysis of data from baseline (day 1) to endpoint (last observation carried forward) demonstrated that this difference tended towards significance, while severity of illness on the CGI-S and disability on the SDS were significantly lower in the fluvoxamine CR group than in the placebo group. The same trends were observed when only data from weeks 12-24 were included in the analysis; although the magnitude of changes was smaller in the extension phase than in the acute phase, fluvoxamine CR-treated subjects continued to show improvement compared to placebo-treated subjects. Most treatment-emergent signs and symptoms (TESS) were mild to moderate in severity. No unexpected abnormalities were reported on vital

  17. Diclofenac epolamine plus heparin plaster versus diclofenac epolamine plaster in mild to moderate ankle sprain: a randomized, double-blind, parallel-group, placebo-controlled, multicentre, phase III trial.

    PubMed

    Costantino, Cosimo; Kwarecki, Jacek; Samokhin, Anatoly V; Mautone, Giuseppe; Rovati, Stefano

    2011-01-01

    In general sports, ankle sprain is the most frequently reported ankle injury and can cause chronic lateral ankle pain and tenderness. Treatment with NSAIDs is preferred, and several topical NSAID formulations are now available, helping to avoid the systemic adverse events typically associated with oral preparations. To compare the efficacy and tolerability of a newly developed fixed-dose diclofenac epolamine (diclofenac hydroxyethylpyrrolidine, DHEP)/heparin plaster (Flectoparin® Tissugel) with that of a DHEP (Flector EP Tissugel®) or placebo plaster in the treatment of mild to moderate ankle sprain in adults. This was a randomized, double-blind, parallel-group, placebo-controlled, multicentre, phase III study conducted in the emergency medical centres of hospitals or private clinics in Europe. Outpatients aged 18-65 years who had suffered an acute ankle sprain (O'Donoghue grade I or II in severity, with external lateral ligament involvement) within the previous 48 hours and had peri-malleolar oedema were eligible for inclusion. A total of 430 patients were randomized to receive a DHEP/heparin 1.3%/5600 IU (n = 142), DHEP 1.3% (n = 146) or placebo (n = 142) plaster, applied once daily to the injured ankle for a total of 7 days. The primary endpoint was the mean change from baseline in pain on movement on day 3, as measured by a visual analogue scale (VAS). The DHEP/heparin plaster was associated with a significantly (p = 0.002) greater mean reduction from baseline in pain on movement after 3 days of treatment than the DHEP plaster (-24.2 vs -18.8 mm VAS), with each active treatment providing significantly (p ≤ 0.005) greater pain relief than placebo (-13.7 mm VAS). Both DHEP/heparin and DHEP were also effective in relieving other measures of pain, with DHEP/heparin recipients experiencing significantly less daily pain while leaning on the injured limb than DHEP recipients (p < 0.001). In addition, oedema was reduced to a

  18. Safety and efficacy of golimumab in Chinese patients with active ankylosing spondylitis: 1-year results of a multicentre, randomized, double-blind, placebo-controlled phase III trial.

    PubMed

    Bao, Chunde; Huang, Feng; Khan, Muhammad Asim; Fei, Kaiyin; Wu, Zhong; Han, Chenglong; Hsia, Elizabeth C

    2014-09-01

    The aim of this study was to assess the efficacy and safety of golimumab in Chinese patients with active AS. Two hundred and thirteen patients were randomized in a 1:1 ratio to receive either s.c. injections of placebo from weeks 0 to 20 followed by golimumab 50 mg from weeks 24 to 48 (group 1, n = 105) or golimumab 50 mg from weeks 0 to 48 (group 2, n = 108), both every 4 weeks. Placebo crossover occurred at week 24, while early escape was at week 16. The primary endpoint was an improvement of at least 20% in the Assessment of SpondyloArthritis international Society (ASAS20) criteria at week 14. Major secondary endpoints included week 24 ASAS20 response and week 14 change scores for BASFI and BASMI. Golimumab treatment elicited significantly better responses than placebo in week 14 ASAS20 response [49.1% (53/108) vs 24.8% (26/105), respectively, P < 0.001], week 24 ASAS20 response (50.0% vs 22.9%, P < 0.001) and mean improvements in BASFI (-1.26 vs 0.11, P < 0.001) and BASMI (-0.42 vs -0.19, P = 0.021) scores at week 14. Additionally, golimumab treatment led to significant improvements in the mental and physical components of health-related quality of life (HRQoL) and sleep problems at week 24, all of which were further improved through week 52. During the 16-week placebo-controlled study period, 31.4% and 30.6% of patients had adverse events (AEs) in groups 1 and 2, respectively; similar AE reporting rates were observed through week 24 (34.3% and 32.0%) and among the golimumab-treated patients through week 56 (41.2%). Golimumab significantly reduced clinical symptoms/signs and improved physical function, range of motion and HRQoL in Chinese patients with active AS without unexpected safety concerns. ClinicalTrials.gov, NCT01248793. © The Author 2014. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  19. Oral 5-aminolevulinic acid mediated photodynamic diagnosis using fluorescence cystoscopy for non-muscle-invasive bladder cancer: A randomized, double-blind, multicentre phase II/III study.

    PubMed

    Inoue, Keiji; Anai, Satoshi; Fujimoto, Kiyohide; Hirao, Yoshihiko; Furuse, Hiroshi; Kai, Fumitake; Ozono, Seiichiro; Hara, Takahiko; Matsuyama, Hideyasu; Oyama, Masafumi; Ueno, Munehisa; Fukuhara, Hideo; Narukawa, Mamoru; Shuin, Taro

    2015-06-01

    Photodynamic diagnosis (PDD) of non-muscle-invasive bladder cancer (NMIBC) following transurethral administration of a hexalated form of 5-aminolevulinic acid (5-ALA), 5-ALA hexyl ester, is widely performed in Western countries. In this study, effectiveness and safety of the oral administration of 5-ALA is assessed in a phase II/III study of PDD for NMIBC in comparison to those of conventional white-light endoscopic diagnosis. Patients with NMIBC were allocated to two groups that were orally administered 10 and 20 mg/kg of 5-ALA under the double-blind condition. Effectiveness was evaluated by setting the primary endpoint to sensitivity. Safety was also analyzed. Moreover, clinically recommended doses of 5-ALA was also investigated as an investigator-initiated multicenter cooperative clinical trial in which five medical institutions participated. All 62 enrolled patients completed the clinical trial. The sensitivities of PDD were higher (84.4 and 75.8% in the 10 and 20 m g/kg-groups, respectively) than those of conventional endoscopic diagnosis (67.5 and 47.6%, respectively) (p = 0.014 and p < 0.001, respectively). Five episodes of serious adverse events developed in four patients; whereas a causal relationship with the investigational agent was ruled out in all episodes. This investigator-initiated clinical trial confirmed the effectiveness and safety of PDD for NMIBC following oral administration of 5-ALA. Both doses of 5-ALA may be clinically applicable; however, the rate of detecting tumors only by PDD was higher in the 20 mg/kg-group suggesting that this dose would be more useful. Copyright © 2015 Elsevier B.V. All rights reserved.

  20. A multicentric, randomized clinical trial of Gaviscon in reflux esophagitis.

    PubMed

    McHardy, G

    1978-01-01

    Gaviscon tablets and the standard antacid proved equally effective in reducing the number of heartburn attacks. Chi-square tests revealed no significant difference between the two treatment groups at the end of weeks 1, 2, 3, or 4. Heartburn score was arrived at by multiplying heartburn incidence by heartburn severity. This heartburn score also indicated no significant difference between the two treatment groups at the end of the four weeks. Tabulation of the mean number of tablets consumed by patients in the two groups was made. There was no significant difference between the two groups in tablet consumption, indicating equal demand as well as equal compliance in the two groups. Esophagoscopy done before and after 28 days of treatment showed that Gaviscon and the standard antacid tablets were equally effective in each group. There was significant, and equal, decrease in the severity in the specific signs of esophagitis, friability, erosion, and ulceration in both treatment groups, as well as in such nonspecific signs as hyperemia, edema, and exudate. The validity and clinical acceptance of an alginic acid-containing agent, Gaviscon, which through a foaming action delivers a minimal dose of antacid directly at the site of acid irritation of the esophageal mucosa, has been confirmed in a multicentric, well-controlled randomized clinical trial.

  1. Evaluation of safety and immunogenicity of HNVAC, an MDCK-based H1N1 pandemic influenza vaccine, in Phase I single centre and Phase II/III multi-centre, double-blind, randomized, placebo-controlled, parallel assignment studies.

    PubMed

    Basavaraj, V H; Sampath, G; Hegde, Nagendra R; Mohan, V Krishna; Ella, Krishna M

    2014-07-31

    The clinical evaluation of the MDCK-based H1N1 pandemic influenza vaccine HNVAC in adults aged 18-65 years is reported. In the Phase I randomized, double-blind, placebo-controlled, single-centre study, 160 subjects were parallelly assigned 3:1 to vaccine:placebo groups (n=60:20) with both the aluminium hydroxide adjuvanted and non-adjuvanted vaccine formulations. A single dose of both the formulations containing 15 μg of haemagglutinin protein showed minimal adverse reactions, the most common of which were pain at injection site (11.67%) and fever (10.00%). Both formulations produced 74-81% seroprotection (SRP: titre of ≥40), 67-70% seroconversion (SRC: four-fold increase in titres between days 0 and 21), and a four-fold increase in geometric mean titres (GMT). Aluminium hydroxide did not have a significant effect either on immunogenicity or on reactogenicity. Nevertheless, based on its recognized positive effects on the stability and immunogenicity of many vaccines, and its marginal benefit in both pre-clinical and Phase I studies of HNVAC, alum adjuvanted HNVAC was further tested in a staggered Phase II/III randomized, double-blind, placebo-controlled, multi-centre study of 200 and 195 subjects, respectively, parallelly assigned 4:1 to adjuvanted vaccine and placebo groups. In these studies, the most common adverse reactions were pain at injection site (6.88% and 5.77% in Stage 1 and Stage 2, respectively) and fever (7.50% and 7.05%, respectively), and a single dose resulted in 87-90% SRP, 85-86% SRC, and a nearly six-fold increase in GMT, meeting or exceeding licensing criteria. It is concluded that HNVAC is safe and immunogenic to adults of 18-65 years.

  2. Efficacy and safety of a nano-emulsion gel formulation of adapalene 0.1% and clindamycin 1% combination in acne vulgaris: a randomized, open label, active-controlled, multicentric, phase IV clinical trial.

    PubMed

    Prasad, Siva; Mukhopadhyay, Amiya; Kubavat, Amit; Kelkar, Amit; Modi, Ajay; Swarnkar, Bhavesh; Bajaj, Bobby; Vedamurthy, Maya; Sheikh, Shafiq; Mittal, Ravindra

    2012-01-01

    Acne vulgaris is a very common skin disease with a significant detrimental effect on the quality of life of the patients. To assess the comparative efficacy and safety of a nano-emulsion gel formulation of adapalene and clindamycin combination with its conventional formulation in the treatment of acne vulgaris of the face. It was a prospective, randomized, open label, active-controlled, multicentric, clinical trial. Eligible patients suffering from acne vulgaris of the face were randomized to receive once-daily treatment with a nano-emulsion gel or conventional gel formulation of adapalene 0.1% and clindamycin (as phosphate) 1% combination for 12 weeks. Total, inflammatory and noninflammatory lesion counts, with grading of acne severity were carried out on a monthly basis. Safety assessments were done to determine the comparative local and systemic tolerability. Two-tailed significance testing was carried out with appropriate statistical tests, and P-values < 0.05 were considered as significant. 209/212 patients enrolled in the study were eligible for efficacy and safety assessments in both nano-emulsion gel (118/119 patients) and conventional gel (91/93 patients) groups. Significantly better reductions in total (79.7% vs. 62.7%), inflammatory (88.7% vs. 71.4%) and noninflammatory (74.9% vs. 58.4%) lesions were reported with the nano-emulsion gel as compared to the conventional gel (P < 0.001 for all). Mean acne severity score also reduced significantly more with the nano-emulsion formulation (1.9 ± 0.9 vs. 1.4 ± 1.0; P < 0.001) than the comparator. Significantly lower incidence and lesser intensity of adverse events like local irritation (4.2% vs. 19.8%; P < 0.05) and erythema (0.8% vs. 9.9%; P < 0.05) were recorded with the nano-emulsion gel. The nano-emulsion gel formulation of adapalene and clindamycin combination appears to be more efficacious and better tolerated than the conventional formulation for the treatment of acne vulgaris in Indian patients

  3. Relative efficiency of unequal cluster sizes for variance component estimation in cluster randomized and multicentre trials.

    PubMed

    van Breukelen, Gerard Jp; Candel, Math Jjm; Berger, Martijn Pf

    2008-08-01

    Cluster randomized and multicentre trials evaluate the effect of a treatment on persons nested within clusters, for instance patients within clinics or pupils within schools. Although equal sample sizes per cluster are generally optimal for parameter estimation, they are rarely feasible. This paper addresses the relative efficiency (RE) of unequal versus equal cluster sizes for estimating variance components in cluster randomized trials and in multicentre trials with person randomization within centres, assuming a quantitative outcome. Starting from maximum likelihood estimation, the RE is investigated numerically for a range of cluster size distributions. An approximate formula is presented for computing the RE as a function of the mean and variance of cluster sizes and the intraclass correlation. The accuracy of this approximation is checked and found to be good. It is concluded that the loss of efficiency for variance component estimation due to variation of cluster sizes rarely exceeds 20% and can be compensated by sampling 25% more clusters.

  4. Prospective randomized double-blind multicentre phase II study comparing gemcitabine and cisplatin plus sorafenib chemotherapy with gemcitabine and cisplatin plus placebo in locally advanced and/or metastasized urothelial cancer: SUSE (AUO-AB 31/05).

    PubMed

    Krege, Susanne; Rexer, Heidrun; vom Dorp, Frank; de Geeter, Patrick; Klotz, Theodor; Retz, Margitte; Heidenreich, Axel; Kühn, Michael; Kamradt, Joern; Feyerabend, Susan; Wülfing, Christian; Zastrow, Stefan; Albers, Peter; Hakenberg, Oliver; Roigas, Jan; Fenner, Martin; Heinzer, Hans; Schrader, Mark

    2014-03-01

    To evaluate the efficacy and safety of gemcitabine and cisplatin in combination with sorafenib, a tyrosine-kinase inhibitor, compared with chemotherapy alone as first-line treatment in advanced urothelial cancer. The study was a randomized phase II trial. Its primary aim was to show an improvement in progression-free survival (PFS) of 4.5 months by adding sorafenib to conventional chemotherapy. Secondary objectives were objective response rate (ORR), overall survival (OS) and toxicity. The patients included in the trial had histologically confirmed locally advanced and/or metastatic urothelial cancer of the bladder or upper urinary tract. Chemotherapy with gemcitabine (1250 mg/qm on days 1 and 8) and cisplatin (70 mg/qm on day 1) repeated every 21 days, was administered to all patients in a double-blind randomization of additional sorafenib (400 mg twice daily) vs placebo (two tablets twice daily) on days 3-21. Treatment continued until progression or unacceptable toxicity, the maximum number of cycles was limited to eight. The response assessment was repeated after every two cycles. Between October 2006 and October 2010, 98 of 132 planned patients were recruited. Nine patients were ineligible. The final analysis included 40 patients in the sorafenib and 49 patients in the placebo arm. There were no significant differences between the two arms concerning ORR (sorafenib: complete response [CR] 12.5%, partial response [PR] 40%; placebo: CR 12%, PR 35%), median PFS (sorafenib: 6.3 months, placebo: 6.1 months) or OS (sorafenib: 11.3 months, placebo: 10.6 months). Toxicity was moderately higher in the sorafenib arm. Diarrrhoea occurred significantly more often in the sorafenib arm and hand-foot syndrome occurred only in the sorafenib arm. The study was closed prematurely because of slow recruitment. Although the addition of sorafenib to standard chemotherapy showed acceptable toxicity, the trial failed to show a 4.5 months improvement in PFS. © 2013 The Authors

  5. Efficacy and safety of alogliptin in patients with type 2 diabetes mellitus: A multicentre randomized double-blind placebo-controlled Phase 3 study in mainland China, Taiwan, and Hong Kong.

    PubMed

    Pan, Changyu; Han, Ping; Ji, Qiuhe; Li, Chengjiang; Lu, Juming; Yang, Jinkui; Li, Wenhui; Zeng, Jiaoe; Hsieh, An-Tsz; Chan, Juliana

    2017-04-01

    This study determined the efficacy and safety of once-daily oral alogliptin in patients from mainland China, Taiwan, and Hong Kong with type 2 diabetes mellitus. In this Phase 3 multicenter double-blind placebo-controlled 16-week trial, 506 patients were randomized to receive once-daily alogliptin 25 mg or placebo: 185 in the monotherapy group, 197 in the add-on to metformin group, and 124 in the add-on to pioglitazone group. The primary efficacy variable was the change from baseline (CFB) in HbA1c at Week 16; other efficacy measures included CFB to Week 16 in fasting plasma glucose (FPG), incidence of marked hyperglycemia (FPG ≥11.1 mmol/L), and the incidence of clinical HbA1c ≤6.5 % (48 mmol/mol) and ≤7.0 % (53 mmol/mol) at Week 16. Safety was assessed throughout the trial. Alogliptin monotherapy provided a significantly greater decrease in HbA1c from baseline to Week 16 compared with placebo (-0.58 %; 95 % confidence interval [CI] -0.78 %, -0.37 %; P < 0.001). As an add-on to metformin or pioglitazone, alogliptin also significantly decreased HbA1c compared with placebo (-0.69 % [95 % CI -0.87 %, -0.51 %; P < 0.001] and -0.52 % [95 % CI -0.75 %, -0.28 %; P < 0.001], respectively). In any treatment group versus placebo, alogliptin led to greater decreases in FPG (P ≤ 0.004) and a higher percentage of patients who achieved an HbA1c target of ≤6.5 % and ≤7.0 % (P ≤ 0.003). No weight gain was observed in any treatment group. A similar percentage of patients experienced drug-related, treatment-emergent adverse events in the alogliptin and placebo arms. Four and two patients in the alogliptin and placebo arms, respectively, experienced mild or moderate hypoglycemia. Alogliptin 25 mg once daily reduced HbA1c and FPG and enhanced clinical response compared with placebo when used as monotherapy or as an add-on to metformin or pioglitazone. Therapy with alogliptin was well tolerated. © 2016 The Authors. Journal

  6. Advanced life support performance with manual and mechanical chest compressions in a randomized, multicentre manikin study.

    PubMed

    Tomte, Oystein; Sunde, Kjetil; Lorem, Tonje; Auestad, Bjorn; Souders, Chris; Jensen, Jeff; Wik, Lars

    2009-10-01

    Clinical mechanical chest compression studies report diverging outcomes. Confounding effects of variability in hands-off fraction (HOF) and timing of necessary tasks during advanced life support (ALS) may contribute to this divergence. Study site variability in these factors coupled to randomization of cardiopulmonary resuscitation (CPR) method was studied during simulated cardiac arrest prior to a multicentre clinical trial. Ambulance personnel from four sites were tested in randomized, simulated cardiac arrest scenarios with manual CPR or load-distributing band CPR (LDB-CPR) on manikins. Primary emphasis was on HOF and time spent before necessary predefined ALS task (ALS milestones). Results are presented as mean differences (confidence interval). At the site with lowest HOF during manual CPR, HOF deteriorated with LDB-CPR by 0.06 (0.005, 0.118, p=0.04), while it improved at the two sites with highest HOF during manual CPR by 0.07 (0.019, 0.112, p=0.007) and 0.08 (0.004, 0.165, p=0.042). Initial defibrillation was 29 (3, 55, p=0.032)s delayed for LDB-CPR vs. manual CPR. Other ALS milestones trended toward earlier completion with LDB-CPR; only significant for intravenous access, mean difference 70 (24, 115, p=0.003)s. In this manikin study, HOF for manual vs. mechanical chest compressions varied between sites. Study protocol implementation should be simulation tested before launching multicentre trials, to optimize performance and improve reliability and scientific interpretation.

  7. Lobeglitazone and pioglitazone as add-ons to metformin for patients with type 2 diabetes: a 24-week, multicentre, randomized, double-blind, parallel-group, active-controlled, phase III clinical trial with a 28-week extension.

    PubMed

    Jin, S-M; Park, C-Y; Cho, Y M; Ku, B J; Ahn, C W; Cha, B-S; Min, K W; Sung, Y A; Baik, S H; Lee, K W; Yoon, K-H; Lee, M-K; Park, S W

    2015-06-01

    We aimed to compare the efficacy and safety of lobeglitazone and pioglitazone as add-ons to metformin in patients with type 2 diabetes. Patients who were inadequately controlled by metformin were randomized and treated once daily with either lobeglitazone (0.5 mg, n = 128) or pioglitazone (15 mg, n = 125) for 24 weeks, with a 28-week extension trial of lobeglitazone treatment in patients who consented. The primary endpoint was the change in glycated haemoglobin (HbA1c) concentration from baseline to week 24. At week 24, the mean change from baseline in HbA1c was -0.74% for the lobeglitazone group and -0.74% for the pioglitazone group, with a mean difference of 0.01% [95% confidence interval (CI) of difference, -0.16 to 0.18]. The effects of lobeglitazone on lipid variables and the adverse events associated with lobeglitazone were similar to those observed with pioglitazone. Lobeglitazone was not inferior to pioglitazone as an add-on to metformin in terms of their efficacy and safety.

  8. A randomized, double-blind, phase III, multicentre study to evaluate the safety and efficacy of BF-200 ALA (Ameluz(®) ) vs. placebo in the field-directed treatment of mild-to-moderate actinic keratosis with photodynamic therapy (PDT) when using the BF-RhodoLED(®) lamp.

    PubMed

    Reinhold, U; Dirschka, T; Ostendorf, R; Aschoff, R; Berking, C; Philipp-Dormston, W G; Hahn, S; Lau, K; Jäger, A; Schmitz, B; Lübbert, H; Szeimies, R-M

    2016-10-01

    Multiple actinic keratosis (AK) lesions may arise from the cancerization of large, sun-damaged skin areas. Although photodynamic therapy (PDT) is considered the most effective therapeutic option, the efficacy and safety of field treatment of multiple AK lesions with PDT has never before been tested in a pivotal trial. To evaluate the efficacy, safety and cosmetic outcome of BF-200 ALA (a nanoemulsion formulation containing 10% aminolaevulinic acid hydrochloride) combined with the BF-RhodoLED(®) lamp for the field-directed treatment of mild-to-moderate AK with PDT. The study was performed as a randomized, multicentre, double-blind, placebo-controlled, parallel-group, phase III trial with BF-200 ALA and placebo in seven centres in Germany. A total of 94 patients were enrolled in this study; 87 were randomized (55 patients received BF-200 ALA, 32 received placebo). Patients received one PDT. If residual lesions remained at 3 months after treatment, PDT was repeated. Illumination was performed with the PDT lamp BF-RhodoLED (635 nm ± 9 nm) until a total light dose of 37 J cm(-2) was achieved. BF-200 ALA was superior to placebo with respect to patient complete clearance rate (91% vs. 22%, P < 0·0001) and lesion complete clearance rate (94·3% vs. 32·9%, P < 0·0001) after a maximum of two PDTs. The confirmatory analysis of all key secondary variables supported this superiority" should not be skipped since this is an important result. Treatment-emergent adverse events (TEAEs) were experienced by 100% of the BF-200 ALA group and 69% of the placebo group. The most commonly reported TEAEs were TEAEs of the application site. The cosmetic outcome was improved in the BF-200 ALA group compared with placebo. Field-directed therapy with BF-200 ALA and BF-RhodoLED lamp is highly effective and well tolerated for multiple mild-to-moderate AK lesions, providing greatly improved skin quality. © 2016 The Authors. British Journal of Dermatology published by John Wiley & Sons Ltd on

  9. Treatment Extension of Pegylated Interferon Alpha and Ribavirin Does Not Improve SVR in Patients with Genotypes 2/3 without Rapid Virological Response (OPTEX Trial): A Prospective, Randomized, Two-Arm, Multicentre Phase IV Clinical Trial

    PubMed Central

    Heidrich, Benjamin; Cordes, Hans-Jörg; Klinker, Hartwig; Möller, Bernd; Naumann, Uwe; Rössle, Martin; Kraus, Michael R.; Böker, Klaus H.; Roggel, Christoph; Schuchmann, Marcus; Stoehr, Albrecht; Trein, Andreas; Hardtke, Svenja; Gonnermann, Andrea; Koch, Armin; Wedemeyer, Heiner; Manns, Michael P.; Cornberg, Markus

    2015-01-01

    Although sofosbuvir has been approved for patients with genotypes 2/3 (G2/3), many parts of the world still consider pegylated Interferon alpha (P) and ribavirin (R) as standard of care for G2/3. Patients with rapid virological response (RVR) show response rates >80%. However, SVR (sustained virological response) in non-RVR patients is not satisfactory. Longer treatment duration may be required but evidence from prospective trials are lacking. A total of 1006 chronic HCV genotype 2/3 patients treated with P/R were recruited into a German HepNet multicenter screening registry. Of those, only 226 patients were still HCV RNA positive at week 4 (non-RVR). Non-RVR patients with ongoing response after 24 weeks P-2b/R qualified for OPTEX, a randomized trial investigating treatment extension of additional 24 weeks (total 48 weeks, Group A) or additional 12 weeks (total 36 weeks, group B) of 1.5 μg/kg P-2b and 800-1400 mg R. Due to the low number of patients without RVR, the number of 150 anticipated study patients was not met and only 99 non-RVR patients (n=50 Group A, n=49 Group B) could be enrolled into the OPTEX trial. Baseline factors did not differ between groups. Sixteen patients had G2 and 83 patients G3. Based on the ITT (intention-to-treat) analysis, 68% [55%; 81%] in Group A and 57% [43%; 71%] in Group B achieved SVR (p= 0.31). The primary endpoint of better SVR rates in Group A compared to a historical control group (SVR 70%) was not met. In conclusion, approximately 23% of G2/3 patients did not achieve RVR in a real world setting. However, subsequent recruitment in a treatment-extension study was difficult. Prolonged therapy beyond 24 weeks did not result in higher SVR compared to a historical control group. Trial Registration ClinicalTrials.gov NCT00803309 PMID:26057627

  10. Randomized phase II clinical trials.

    PubMed

    Jung, Sin-Ho; Sargent, Daniel J

    2014-01-01

    Traditionally, Phase II trials have been conducted as single-arm trials to compare the response probabilities between an experimental therapy and a historical control. Historical control data, however, often have a small sample size, are collected from a different patient population, or use a different response assessment method, so that a direct comparison between a historical control and an experimental therapy may be severely biased. Randomized Phase II trials entering patients prospectively to both experimental and control arms have been proposed to avoid any bias in such cases. The small sample sizes for typical Phase II clinical trials imply that the use of exact statistical methods for their design and analysis is appropriate. In this article, we propose two-stage randomized Phase II trials based on Fisher's exact test, which does not require specification of the response probability of the control arm for testing. Through numerical studies, we observe that the proposed method controls the type I error accurately and maintains a high power. If we specify the response probabilities of the two arms under the alternative hypothesis, we can identify good randomized Phase II trial designs by adopting the Simon's minimax and optimal design concepts that were developed for single-arm Phase II trials.

  11. Randomized multicentric Italian study on two treatment regimens for marrow relapse in childhood acute lymphoblastic leukemia.

    PubMed

    Rossi, M R; Masera, G; Zurlo, M G; Amadori, S; Mandelli, F; Bagnulo, S; Carli, M; Zanesco, L; Dini, G; Guazzelli, C

    1986-01-01

    This paper reports the results of a multicentric randomized clinical trial on the treatment of first hematological relapse in childhood ALL. Induction treatment consisted of vincristine, adriamycin, L-asparaginase, and prednisone. Patients achieving complete remission were randomized to two maintenance regimens (A and B). Regimen A consisted of five different drug associations including VM26 and IDMTX in a sequential schedule; Regimen B was essentially classical Spiers schedule for the first year, followed by a milder treatment. Eighty-four of 102 evaluable patients (82%) achieved second complete remission. The two maintenance regimens were similar as regards duration of second complete remission (median duration A, 32 weeks; B, 37 weeks) and toxicity. Better results were obtained in patients relapsing after 12 months from suspension of treatment in first complete remission than in those relapsing within the first year off therapy (82.8% vs. 31.4%). In group A fewer CNS relapses were reported. The two regimens produced results similar to those reported by other authors. The good prognosis in patients relapsing at least 1 year after treatment suspension in first complete remission must be emphasized.

  12. Tetrodotoxin alleviates acute heroin withdrawal syndrome: a multicentre, randomized, double-blind, placebo-controlled study.

    PubMed

    Song, Hui; Li, Jing; Lu, Chang-Li; Kang, Lin; Xie, Liang; Zhang, Yang-Yang; Zhou, Xiao-Bo; Zhong, Sheng

    2011-08-01

    1. Tetrodotoxin (TTX) is a powerful sodium channel blocker extracted from the puffer fish. The efficacy and safety of TTX as monotherapy for the treatment of acute heroin withdrawal syndrome were evaluated in the present study. This 7-day, multicentre, randomized, double-blind, placebo-controlled study was carried out between December 2008 and October 2009. In total, 216 patients who met the Diagnostic and Statistical Manual of Mental Disorders IV diagnosis of heroin addiction were recruited. After providing written informed consent, subjects were randomly assigned to double-blind treatment in one of the following groups: 5 μg TTX group (group 1), 10 μg TTX group (group 2) or the placebo group (group 3). 2. Evidence suggests that both 5 and 10 μg TTX significantly reduced withdrawal symptoms by day 3 compared with placebo, and there was no significant difference in the incidence of adverse events in the three groups. 3. In conclusion, this clinical trial shows that TTX (5 and 10 μg given t.i.d.) is effective in alleviating opiate withdrawal symptoms with few side-effects.

  13. Particle number and random phases

    SciTech Connect

    Kandrup, H.E.

    1988-09-15

    This paper focuses on the particle content of some scalar field as defined with respect to two sets of modes connected via a well-behaved (and unitarily implementable) Bogoliubov transformation. The principal conclusion impacts on the special role of ''random phase'' states, for which the relative phases associated with the projection of the quantum state into two different numbers eigenstates are treated as ''random'' and averaged over in a density matrix. Specifically, it is demonstrated that if, with respect to one set of modes, the field is in a ''random phase'' state, then any other mode decomposition related via a nontrivial Bogoliubov transformation will yield a larger expectation value for the total particle number. This special role of ''random phase'' states is also related to a recently discussed measure of entropy S/sub N/ which assesses the ''spread'' or ''uncertainty'' in particle number. One specific example of all this is the relative particle content in Minkowski space as defined with respect to the modes natural for inertial and uniformly accelerated observers. Another is the initial and final particle numbers detected by two observers in a ''statically bounded'' universe of the form examined by Parker and Zel'dovich.

  14. NASHA hyaluronic acid vs. methylprednisolone for knee osteoarthritis: a prospective, multi-centre, randomized, non-inferiority trial.

    PubMed

    Leighton, R; Akermark, C; Therrien, R; Richardson, J B; Andersson, M; Todman, M G; Arden, N K

    2014-01-01

    To compare NASHA hyaluronic acid gel as single-injection intra-articular (IA) treatment for knee osteoarthritis (OA) against methylprednisolone acetate (MPA). This was a prospective, multi-centre, randomized, active-controlled, double-blind, non-inferiority clinical trial. A unique, open-label extension phase (OLE) was undertaken to answer further important clinical questions. Subjects with painful unilateral knee OA were treated and followed for 26 weeks (blinded phase). All patients attending the clinic at 26 weeks were offered NASHA treatment, with a subsequent 26-week follow-up period (extension phase). The primary objective was to show non-inferiority of NASHA vs MPA in Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain responder rate (percentage of patients with ≥40% improvement from baseline in WOMAC pain score and an absolute improvement of ≥5 points) at 12 weeks. In total, 442 participants were enrolled. The primary objective was met, with NASHA producing a non-inferior response rate vs MPA at 12 weeks (NASHA: 44.6%; MPA: 46.2%; difference [95% CI]: 1.6% [-11.2%; +7.9%]). Effect size for WOMAC pain, physical function and stiffness scores favoured NASHA over MPA from 12 to 26 weeks. In response to NASHA treatment at 26 weeks, sustained improvements were seen in WOMAC outcomes irrespective of initial treatment. No serious device-related adverse events (AEs) were reported. This study shows that single-injection NASHA was well tolerated and non-inferior to MPA at 12 weeks. The benefit of NASHA was maintained to 26 weeks while that of MPA declined. An injection of NASHA at 26 weeks conferred long-term improvements without increased sensitivity or risk of complications. STUDY IDENTIFIER: NCT01209364 (www.clinicaltrials.gov). Copyright © 2013 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.

  15. Whole body vibration for older persons: an open randomized, multicentre, parallel, clinical trial

    PubMed Central

    2011-01-01

    Background Institutionalized older persons have a poor functional capacity. Including physical exercise in their routine activities decreases their frailty and improves their quality of life. Whole-body vibration (WBV) training is a type of exercise that seems beneficial in frail older persons to improve their functional mobility, but the evidence is inconclusive. This trial will compare the results of exercise with WBV and exercise without WBV in improving body balance, muscle performance and fall prevention in institutionalized older persons. Methods/Design An open, multicentre and parallel randomized clinical trial with blinded assessment. 160 nursing home residents aged over 65 years and of both sexes will be identified to participate in the study. Participants will be centrally randomised and allocated to interventions (vibration or exercise group) by telephone. The vibration group will perform static/dynamic exercises (balance and resistance training) on a vibratory platform (Frequency: 30-35 Hz; Amplitude: 2-4 mm) over a six-week training period (3 sessions/week). The exercise group will perform the same exercise protocol but without a vibration stimuli platform. The primary outcome measure is the static/dynamic body balance. Secondary outcomes are muscle strength and, number of new falls. Follow-up measurements will be collected at 6 weeks and at 6 months after randomization. Efficacy will be analysed on an intention-to-treat (ITT) basis and 'per protocol'. The effects of the intervention will be evaluated using the "t" test, Mann-Witney test, or Chi-square test, depending on the type of outcome. The final analysis will be performed 6 weeks and 6 months after randomization. Discussion This study will help to clarify whether WBV training improves body balance, gait mobility and muscle strength in frail older persons living in nursing homes. As far as we know, this will be the first study to evaluate the efficacy of WBV for the prevention of falls. Trial

  16. Efficacy and safety of foscarnet for recurrent orolabial herpes: a multicentre randomized double-blind study.

    PubMed Central

    Lawee, D; Rosenthal, D; Aoki, F Y; Portnoy, J

    1988-01-01

    Foscarnet sodium (trisodium phosphonoformate hexahydrate) has been shown to inhibit herpes simplex virus (HSV) in vitro and to be efficacious for topical treatment of experimental HSV infection in animals. To assess its clinical efficacy in the treatment of recurrent orolabial herpes a multicentre collaborative, double-blind, placebo-controlled trial was conducted. The study patients were randomly assigned to receive either 3% foscarnet cream (78 patients) or placebo (cream vehicle) (75 patients) and were asked to start treatment at the earliest indication of a recurrence. Efficacy was evaluated in 143 patients (74 in the foscarnet group and 69 in the placebo group). There was no significant difference in time to healing or duration of virus shedding between the two groups. However, in the subgroup of patients who started treatment before vesicles appeared, the duration of virus shedding was shorter in the foscarnet group than in the placebo group (p = 0.04), and the proportion of lesions that evolved to the vesicular stage was smaller (p = 0.03). No significant difference in the incidence of local or systemic adverse effects was noted between the two groups. We conclude that the beneficial effect of foscarnet was limited to a subgroup of patients who started treatment in the prevesicular stage. PMID:2962712

  17. L-Carnitine-supplementation in advanced pancreatic cancer (CARPAN) - a randomized multicentre trial

    PubMed Central

    2012-01-01

    Background Cachexia, a >10% loss of body-weight, is one factor determining the poor prognosis of pancreatic cancer. Deficiency of L-Carnitine has been proposed to cause cancer cachexia. Findings We screened 152 and enrolled 72 patients suffering from advanced pancreatic cancer in a prospective, multi-centre, placebo-controlled, randomized and double-blinded trial to receive oral L-Carnitine (4 g) or placebo for 12 weeks. At entry patients reported a mean weight loss of 12 ± 2,5 (SEM) kg. During treatment body-mass-index increased by 3,4 ± 1,4% under L-Carnitine and decreased (−1,5 ± 1,4%) in controls (p < 0,05). Moreover, nutritional status (body cell mass, body fat) and quality-of-life parameters improved under L-Carnitine. There was a trend towards an increased overall survival in the L-Carnitine group (median 519 ± 50 d versus 399 ± 43 d, not significant) and towards a reduced hospital-stay (36 ± 4d versus 41 ± 9d,n.s.). Conclusion While these data are preliminary and need confirmation they indicate that patients with pancreatic cancer may have a clinically relevant benefit from the inexpensive and well tolerated oral supplementation of L-Carnitine. PMID:22824168

  18. Adverse events associated with acupuncture: three multicentre randomized controlled trials of 1968 cases in China

    PubMed Central

    2011-01-01

    Background In order to evaluate the safety of acupuncture in China objectively, we investigated the adverse events associated with acupuncture based on three multicentre randomized controlled trials (RCTs) to assess the safety of acupuncture, identifying the common types of acupuncture adverse events, and analysing the related risk factors for their occurrence. Methods This observational study included patients who received acupuncture from three multicentre RCTs respectively for migraine, functional dyspepsia and Bell's palsy. The 1968 patients and their acupuncturists documented adverse events associated with acupuncture after treatment. We collected data about adverse events due to acupuncture treatment from their case report forms. We analysed the incidence and details of the adverse effects, and studied the risk factors for acupuncture adverse events with non-conditional logistic regression analysis. Results Among the 1968 patients, 74 patients (3.76%) suffered at least one adverse event throughout the treatment period. We did not observe the occurrence of serious adverse events. 73 patients with adverse events recovered within 2 weeks through effective treatment such as physiotherapy or self-treatment. A total of 3 patients withdrew because of adverse events. There were 9 types of adverse events related to acupuncture, including subcutaneous haematoma, bleeding, skin bruising and needle site pain. Subcutaneous haematoma and haemorrhage in the needling points were the most common adverse events. Age and gender were related to the occurrence of acupuncture adverse events. The older the patients were, the higher the risk of adverse events was. In addition, male patients had slightly higher risk of an adverse event than female patients. Conclusions Acupuncture is a safe therapy with low risk of adverse events in clinical practice. The risk factors for adverse events (AEs) were related to the patients' gender and age and the local anatomical structure of the

  19. Effects of acupuncture on patients with fibromyalgia: study protocol of a multicentre randomized controlled trial

    PubMed Central

    2011-01-01

    Background Fibromyalgia is a multidimensional disorder for which treatment as yet remains unsatisfactory. Studies of an acupuncture-based approach, despite its broad acceptance among patients and healthcare staff, have not produced sufficient evidence of its effectiveness in treating this syndrome. The present study aims to evaluate the effectiveness of individualized acupuncture for patients with fibromyalgia, with respect to reducing their pain and level of incapacity, and improving their quality of life. Methods/design Randomized controlled multicentre study, with 156 outpatients, aged over 17 years, diagnosed with fibromyalgia according to American College of Rheumatology criteria, either alone or associated with severe depression, according to the criteria of the Diagnostic and Statistical Manual for Mental Disorders. The participants will be randomly assigned to receive either "True acupuncture" or "Sham acupuncture". They will be evaluated using a specific measurement system, constituted of the Fibromyalgia Impact Questionnaire and the Hamilton rating scale for depression. Also taken into consideration will be the clinical and subjective pain intensity, the patient's family structure and relationships, psychological aspects, quality of life, the duration of previous temporary disability, the consumption of antidepressant, analgesic and anti-inflammatory medication, and the potential effect of factors considered to be predictors of a poor prognosis. All these aspects will be examined by questionnaires and other suitably-validated instruments. The results obtained will be analysed at 10 weeks, and 6 and 12 months from the start of treatment. Discussion This trial will utilize high quality trial methodologies in accordance with CONSORT guidelines. It may provide evidence for the effectiveness of acupuncture as a treatment for fibromyalgia either alone or associated with severe depression. Trial registration ISRCTN trial number ISRCTN60217348 (19 October 2010

  20. Participation in colorectal cancer screening with FOBT and colonoscopy: an Italian, multicentre, randomized population study.

    PubMed

    Lisi, Daniele; Hassan, Cesare; Hassan, C Cesare; Crespi, Massimo

    2010-05-01

    Data on the adherence rate to screening colonoscopy (OC) in the average-risk general population are limited and variable. Aim of this study was to compare the uptake of OC screening with that of fecal occult blood (FOBT). A nationwide, population-based, multicentre, randomized trial comparing attendance to OC with that to FOBT was performed. Sixty-four general practitioners (GPs), overall including in their lists 9889 average-risk subjects aged 55-64 years, were randomized between OC and FOBT screening programs. Eligible subjects were mailed a personal invitation letter co-signed by their GP and the coordinator of the area-reference GI centre. Attendance rate and detection rate for advanced neoplasia (colorectal cancer, adenoma >10mm or with villous histology or high-grade dysplasia) for each arm of the study were assessed. The overall attendance rate was 18.7% (1563/8378 eligible subjects). It was markedly lower in the OC than in the FOBT strategy (10% vs. 27.1%; OR 0.28, 95% CI: 0.25-0.32; P<0.0001). In particular, participation in OC screening arm was extremely low in South Italy (2.8%), whilst it was higher in North-Central Italy (12.4%; P<0.0001). Compliance to colonoscopy in those with a positive FOBT was only 58%. Advanced neoplasia was detected in 28 (6.8%) patients in the OC arm and in 6 (18%) in those with a positive FOBT submitted to OC. The results of our study underline the difficulties and barriers to implement a OC population screening in Italy, at least through primary care. Although attendance to FOBT was higher, it was disappointingly less than 30%. Significant actions to improve awareness amongst GPs and the population are a high priority. Copyright 2009 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.

  1. Spinal cord stimulation in patients with painful diabetic neuropathy: a multicentre randomized clinical trial.

    PubMed

    de Vos, Cecile C; Meier, Kaare; Zaalberg, Paul Brocades; Nijhuis, Harold J A; Duyvendak, Wim; Vesper, Jan; Enggaard, Thomas P; Lenders, Mathieu W P M

    2014-11-01

    Painful diabetic neuropathy (PDN) is a peripheral neuropathic pain condition that is often difficult to relieve. Spinal cord stimulation (SCS) is a proven effective therapy for various types of mixed neuropathic conditions, yet effectiveness of SCS treatment for PDN is not well established. To our knowledge, ours is the first multicentre randomized controlled trial investigating the effectiveness of SCS in patients with PDN. Sixty patients with PDN in the lower extremities refractory to conventional medical therapy were enrolled and followed for 6 months. They were randomized 2:1 to best conventional medical practice with (SCS group) or without (control group) additional SCS therapy, and both groups were assessed at regular intervals. At each follow-up visit, the EuroQoL 5D, the short form McGill Pain Questionnaire (SF-MPQ) and a visual analogue scale (VAS, ranging 0-100) to measure pain intensity were recorded. The average VAS score for pain intensity was 73 in the SCS group and 67 in the control group at baseline. After 6 months of treatment, the average VAS score was significantly reduced to 31 in the SCS group (P<.001) and remained 67 (P=.97) in the control group. The SF-MPQ and EuroQoL 5D questionnaires also showed that patients in the SCS group, unlike those in the control group, experienced reduced pain and improved health and quality of life after 6 months of treatment. In patients with refractory painful diabetic neuropathy, spinal cord stimulation therapy significantly reduced pain and improved quality of life.

  2. Effects of acupuncture on patients with fibromyalgia: study protocol of a multicentre randomized controlled trial.

    PubMed

    Vas, Jorge; Modesto, Manuela; Aguilar, Inmaculada; Santos-Rey, Koldo; Benítez-Parejo, Nicolás; Rivas-Ruiz, Francisco

    2011-02-28

    Fibromyalgia is a multidimensional disorder for which treatment as yet remains unsatisfactory. Studies of an acupuncture-based approach, despite its broad acceptance among patients and healthcare staff, have not produced sufficient evidence of its effectiveness in treating this syndrome. The present study aims to evaluate the effectiveness of individualized acupuncture for patients with fibromyalgia, with respect to reducing their pain and level of incapacity, and improving their quality of life. Randomized controlled multicentre study, with 156 outpatients, aged over 17 years, diagnosed with fibromyalgia according to American College of Rheumatology criteria, either alone or associated with severe depression, according to the criteria of the Diagnostic and Statistical Manual for Mental Disorders. The participants will be randomly assigned to receive either "True acupuncture" or "Sham acupuncture". They will be evaluated using a specific measurement system, constituted of the Fibromyalgia Impact Questionnaire and the Hamilton rating scale for depression. Also taken into consideration will be the clinical and subjective pain intensity, the patient's family structure and relationships, psychological aspects, quality of life, the duration of previous temporary disability, the consumption of antidepressant, analgesic and anti-inflammatory medication, and the potential effect of factors considered to be predictors of a poor prognosis. All these aspects will be examined by questionnaires and other suitably-validated instruments. The results obtained will be analysed at 10 weeks, and 6 and 12 months from the start of treatment. This trial will utilize high quality trial methodologies in accordance with CONSORT guidelines. It may provide evidence for the effectiveness of acupuncture as a treatment for fibromyalgia either alone or associated with severe depression. ISRCTN trial number ISRCTN60217348 (19 October 2010).

  3. Week 96 results of the randomized, multicentre Maraviroc Switch (MARCH) study.

    PubMed

    Pett, S L; Amin, J; Horban, A; Andrade-Villanueva, J; Losso, M; Porteiro, N; Madero, J S; Belloso, W; Tu, E; Silk, D; Kelleher, A; Harrigan, R; Clark, A; Sugiura, W; Wolff, M; Gill, J; Gatell, J; Clarke, A; Ruxrungtham, K; Prazuck, T; Kaiser, R; Woolley, I; Alberto Arnaiz, J; Cooper, D; Rockstroh, J K; Mallon, P; Emery, S

    2017-07-13

    The Maraviroc Switch (MARCH) study week 48 data demonstrated that maraviroc, a chemokine receptor-5 (CCR5) inhibitor, was a safe and effective switch for the ritonavir-boosted protease inhibitor (PI/r) component of a two nucleos(t)ide reverse transcriptase inhibitor [N(t)RTI] plus PI/r-based antiretroviral regimen in patients with R5-tropic virus. Here we report the durability of this finding. MARCH, an international, multicentre, randomized, 96-week open-label switch study, enrolled HIV-1-infected adults with R5-tropic virus who were stable (> 24 weeks) and virologically suppressed [plasma viral load (pVL) < 50 HIV-1 RNA copies/mL]. Participants were randomized to continue their current PI/r-based regimen (PI/r) or to switch to MVC plus two N(t)RTIs (MVC) (1:2 randomization). The primary endpoint was the difference in the proportion with pVL < 200 copies/mL at 96 weeks. The switch arm was defined as noninferior if the lower limit of the 95% confidence interval (CI) for the difference was < -12% in the intention-to-treat (ITT) population. Safety endpoints (the difference in the mean change from baseline or a comparison of proportions) were analysed as key secondary endpoints. Eighty-two (PI/r) and 156 (MVC) participants were randomized and included in the ITT analysis; 71 (87%) and 130 (83%) were in follow-up and on therapy at week 96. At week 96, 89.0% and 90.4% in the PI/r and MVC arms, respectively, had pVL < 50 copies/mL (95% CI -6.6, 10.2). Moreover, in those switching away from PI/r, there were significant reductions in mean total cholesterol (differences 0.31 mmol/L; P = 0.02) and triglycerides (difference 0.44 mmol/L; P < 0.001). Changes in CD4 T-cell count, renal function, and serious and nonserious adverse events were similar in the two arms. MVC as a switch for a PI/r is safe and effective at maintaining virological suppression while having significant lipid benefits over 96 weeks. © 2017 British HIV Association.

  4. Phase transitions in random surfaces

    NASA Astrophysics Data System (ADS)

    Baig, M.; Espriu, D.; Wheater, J. F.

    1989-03-01

    We investigate the statistical properties of triangulated random surfaces of fixed connectivity embedded in d-dimensional space and weighted with an action that contains the extrinsic curvature of the surface as well as the usual Nambu-Goto term. Numerically, we find no second-order phase transition for finite values of the rigidity coupling, in contrast to results obtained by Kantor and Nelson using a different action. Rather, there is a third order "crumpling" transition which, however, is not associated with an infinite correlation length between the normals to the surface. We compare the Monte Carlo results with several approximations, particularly with the mean field solution of the model. Our results indicate that there are no fixed points other than those already found in perturbation theory. We comment on several other aspects of random surfaces.

  5. Remifentanil patient controlled analgesia versus epidural analgesia in labour. A multicentre randomized controlled trial

    PubMed Central

    2012-01-01

    Background Pain relief during labour is a topic of major interest in the Netherlands. Epidural analgesia is considered to be the most effective method of pain relief and recommended as first choice. However its uptake by pregnant women is limited compared to other western countries, partly as a result of non-availability due to logistic problems. Remifentanil, a synthetic opioid, is very suitable for patient controlled analgesia. Recent studies show that epidural analgesia is superior to remifentanil patient controlled analgesia in terms of pain intensity score; however there was no difference in satisfaction with pain relief between both treatments. Methods/design The proposed study is a multicentre randomized controlled study that assesses the cost-effectiveness of remifentanil patient controlled analgesia compared to epidural analgesia. We hypothesize that remifentanil patient controlled analgesia is as effective in improving pain appreciation scores as epidural analgesia, with lower costs and easier achievement of 24 hours availability of pain relief for women in labour and efficient pain relief for those with a contraindication for epidural analgesia. Eligible women will be informed about the study and randomized before active labour has started. Women will be randomly allocated to a strategy based on epidural analgesia or on remifentanil patient controlled analgesia when they request pain relief during labour. Primary outcome is the pain appreciation score, i.e. satisfaction with pain relief. Secondary outcome parameters are costs, patient satisfaction, pain scores (pain-intensity), mode of delivery and maternal and neonatal side effects. The economic analysis will be performed from a short-term healthcare perspective. For both strategies the cost of perinatal care for mother and child, starting at the onset of labour and ending ten days after delivery, will be registered and compared. Discussion This study, considering cost effectiveness of remifentanil as

  6. An integrated approach to consumer representation and involvement in a multicentre randomized controlled trial.

    PubMed

    Langston, Anne L; McCallum, Marilyn; Campbell, Marion K; Robertson, Clare; Ralston, Stuart H

    2005-01-01

    Although, consumer involvement in individual studies is often limited, their involvement in guiding health research is generally considered to be beneficial. This paper outlines our experiences of an integrated relationship between the organisers of a clinical trial and a consumer organisation. The PRISM trial is a UK multicentre, randomized controlled trial comparing treatment strategies for Paget's disease of the bone. The National Association for the Relief of Paget's Disease (NARPD) is the only UK support group for sufferers of Paget's disease and has worked closely with the PRISM team from the outset. NARPD involvement is integral to the conduct of the trial and specific roles have included: peer-review; trial steering committee membership; provision of advice to participants, and promotion of the trial amongst Paget's disease patients. The integrated relationship has yielded benefits to both the trial and the consumer organisation. The benefits for the trial have included: recruitment of participants via NARPD contacts; well-informed participants; unsolicited patient advocacy of the trial; and interested and pro-active collaborators. For the NARPD and Paget's disease sufferers, benefits have included: increased awareness of Paget's disease; increased access to relevant health research; increased awareness of the NARPD services; and wider transfer of diagnosis and management knowledge to/from health care professionals. Our experience has shown that an integrated approach between a trial team and a consumer organisation is worthwhile. Adoption of such an approach in other trials may yield significant improvements in recruitment and quality of participant information flow. There are, however, resource implications for both parties.

  7. Octatropine methyl bromide and diazepam combination (Valpinax) in patients with irritable bowel syndrome: a multicentre, randomized, placebo-controlled trial.

    PubMed

    Pace, F; Maurano, A; Ciacci, C; Savarino, V; Attili, A; Iaquinto, G; Magni, E; Porro, G Bianchi

    2010-03-01

    To investigate the efficacy and tolerability of octatropine methyl bromide plus diazepam (Valpinax) in patients with irritable bowel syndrome (IBS). We conducted a randomized, double-blind, multicentre study in 186 patients aged 18-65 years with IBS diagnosed according to Rome II criteria. Following a 2-week washout period, patients received octatropine plus diazepam 40 mg/2.5 mg twice daily or placebo for 6 weeks. The primary efficacy endpoint was response to a weekly question: "did you have satisfactory relief of your abdominal pain and discomfort during the last week?" Other endpoints included abdominal swelling, abdominal pain and discomfort, symptom severity, and the number of bowel movements. A prespecified subgroup analysis was conducted in patients with an abdominal pain and discomfort score > or = 3. The primary efficacy endpoint showed a tendency towards a statistically significant benefit for octatropine plus diazepam over placebo among patients with a baseline abdominal pain and discomfort score of > or = 3 (3 vs. 0 patients; p = 0.059). Octatropine plus diazepam demonstrated significant improvements from baseline in all parameters assessed, but not compared with placebo. Adverse events were reported in 15.1% of patients receiving octatropine plus diazepam. Patients with IBS and an abdominal pain and discomfort score of > or = 3, who may be considered in the active phase of the disease, may derive some benefits from octatropine plus diazepam. This study highlights that Rome II criteria should be considered with particular care in the design of a clinical trial, since it does not consider disease activity level on admission.

  8. Substrate and Trigger Ablation for Reduction of Atrial Fibrillation (STAR AF): a randomized, multicentre, international trial.

    PubMed

    Verma, Atul; Mantovan, Roberto; Macle, Laurent; De Martino, Guiseppe; Chen, Jian; Morillo, Carlos A; Novak, Paul; Calzolari, Vittorio; Guerra, Peter G; Nair, Girish; Torrecilla, Esteban G; Khaykin, Yaariv

    2010-06-01

    This multicentre, randomized trial compared three strategies of AF ablation: ablation of complex fractionated electrograms (CFE) alone, pulmonary vein isolation (PVI) alone, and combined PVI + CFE ablation, using standardized automated mapping software. Patients with drug-refractory, high-burden paroxysmal (episodes >6 h, >4 in 6 months) or persistent atrial fibrillation (AF) were enrolled at eight centres. Patients (n = 100) were randomized to one of three arms. For CFE alone (n = 34), spontaneous/induced AF was mapped using validated, automated CFE software and all sites <120 ms were ablated until AF termination/non-inducibility. For PVI (n = 32), all four PV antra were isolated and confirmed using a circular catheter. For PVI + CFE (n = 34), all four PV antra were isolated, followed by AF induction and ablation of all CFE sites until AF termination/non-inducibility. Patients were followed at 3, 6, and 12 months with a visit, ECG, 48 h Holter. Atrial fibrillation symptoms were confirmed by loop recording. Repeat procedures were allowed within the first 6 months. The primary endpoint was freedom from AF >30 s at 1 year. Patients (age 57 +/- 10 years, LA size 42 +/- 6 mm) were 35% persistent AF. In CFE, ablation terminated AF in 68%. Only 0.4 PVs per patient were isolated as a result of CFE. In PVI, 94% had all four PVs successfully isolated. In PVI + CFE, 94% had all four PVs isolated, 76% had inducible AF with additional CFE ablation, with 73% termination of AF. There were significantly more repeat procedures in the CFE arm (47%) vs. PVI (31%) or PVI + CFE (15%) (P = 0.01). After one procedure, PVI + CFE had a significantly higher freedom from AF (74%) compared with PVI (48%) and CFE (29%) (P = 0.004). After two procedures, PVI + CFE still had the highest success (88%) compared with PVI (68%) and CFE (38%) (P = 0.001). Ninety-six percent of these patients were off anti-arrhythmics. Complications were two tamponades, no PV stenosis, and no mortality. In high

  9. Substrate and Trigger Ablation for Reduction of Atrial Fibrillation (STAR AF): a randomized, multicentre, international trial†

    PubMed Central

    Verma, Atul; Mantovan, Roberto; Macle, Laurent; De Martino, Guiseppe; Chen, Jian; Morillo, Carlos A.; Novak, Paul; Calzolari, Vittorio; Guerra, Peter G.; Nair, Girish; Torrecilla, Esteban G.; Khaykin, Yaariv

    2010-01-01

    Aims This multicentre, randomized trial compared three strategies of AF ablation: ablation of complex fractionated electrograms (CFE) alone, pulmonary vein isolation (PVI) alone, and combined PVI + CFE ablation, using standardized automated mapping software. Methods and results Patients with drug-refractory, high-burden paroxysmal (episodes >6 h, >4 in 6 months) or persistent atrial fibrillation (AF) were enrolled at eight centres. Patients (n = 100) were randomized to one of three arms. For CFE alone (n = 34), spontaneous/induced AF was mapped using validated, automated CFE software and all sites <120 ms were ablated until AF termination/non-inducibility. For PVI (n = 32), all four PV antra were isolated and confirmed using a circular catheter. For PVI + CFE (n = 34), all four PV antra were isolated, followed by AF induction and ablation of all CFE sites until AF termination/non-inducibility. Patients were followed at 3, 6, and 12 months with a visit, ECG, 48 h Holter. Atrial fibrillation symptoms were confirmed by loop recording. Repeat procedures were allowed within the first 6 months. The primary endpoint was freedom from AF >30 s at 1 year. Patients (age 57 ± 10 years, LA size 42 ± 6 mm) were 35% persistent AF. In CFE, ablation terminated AF in 68%. Only 0.4 PVs per patient were isolated as a result of CFE. In PVI, 94% had all four PVs successfully isolated. In PVI + CFE, 94% had all four PVs isolated, 76% had inducible AF with additional CFE ablation, with 73% termination of AF. There were significantly more repeat procedures in the CFE arm (47%) vs. PVI (31%) or PVI + CFE (15%) (P = 0.01). After one procedure, PVI + CFE had a significantly higher freedom from AF (74%) compared with PVI (48%) and CFE (29%) (P = 0.004). After two procedures, PVI + CFE still had the highest success (88%) compared with PVI (68%) and CFE (38%) (P = 0.001). Ninety-six percent of these patients were off anti-arrhythmics. Complications were two tamponades, no PV stenosis, and no

  10. A multicentre phase II study of cisplatin and gemcitabine for malignant mesothelioma

    PubMed Central

    Nowak, A K; Byrne, M J; Williamson, R; Ryan, G; Segal, A; Fielding, D; Mitchell, P; Musk, A W; Robinson, B W S

    2002-01-01

    Our previous phase II study of cisplatin and gemcitabine in malignant mesothelioma showed a 47.6% (95% CI 26.2–69.0%) response rate with symptom improvement in responding patients. Here we confirm these findings in a multicentre setting, and assess the effect of this treatment on quality of life and pulmonary function. Fifty-three patients with pleural malignant mesothelioma received cisplatin 100 mg m−2 i.v. day 1 and gemcitabine 1000 mg m−2 i.v. days 1, 8, and 15 of a 28 day cycle for a maximum of six cycles. Quality of life and pulmonary function were assessed at each cycle. The best response achieved in 52 assessable patients was: partial response, 17 (33%, 95% CI 20–46%); stable disease, 31 (60%); and progressive disease, four (8%). The median time to disease progression was 6.4 months, median survival from start of treatment 11.2 months, and median survival from diagnosis 17.3 months. Vital capacity and global quality of life remained stable in all patients and improved significantly in responding patients. Major toxicities were haematological, limiting the mean relative dose intensity of gemcitabine to 75%. This schedule of cisplatin and gemcitabine is active in malignant mesothelioma in a multicentre setting. Investigation of alternative scheduling is needed to decrease haematological toxicity and increase the relative dose intensity of gemcitabine whilst maintaining response rate and quality of life. British Journal of Cancer (2002) 87, 491–496. doi:10.1038/sj.bjc.6600505 www.bjcancer.com © 2002 Cancer Research UK PMID:12189542

  11. Random-Phase Approximation Methods

    NASA Astrophysics Data System (ADS)

    Chen, Guo P.; Voora, Vamsee K.; Agee, Matthew M.; Balasubramani, Sree Ganesh; Furche, Filipp

    2017-05-01

    Random-phase approximation (RPA) methods are rapidly emerging as cost-effective validation tools for semilocal density functional computations. We present the theoretical background of RPA in an intuitive rather than formal fashion, focusing on the physical picture of screening and simple diagrammatic analysis. A new decomposition of the RPA correlation energy into plasmonic modes leads to an appealing visualization of electron correlation in terms of charge density fluctuations. Recent developments in the areas of beyond-RPA methods, RPA correlation potentials, and efficient algorithms for RPA energy and property calculations are reviewed. The ability of RPA to approximately capture static correlation in molecules is quantified by an analysis of RPA natural occupation numbers. We illustrate the use of RPA methods in applications to small-gap systems such as open-shell d- and f-element compounds, radicals, and weakly bound complexes, where semilocal density functional results exhibit strong functional dependence.

  12. Taurolidine reduces the tumor stimulating cytokine interleukin-1beta in patients with resectable gastrointestinal cancer: a multicentre prospective randomized trial

    PubMed Central

    Braumann, Chris; Gutt, Carsten N; Scheele, Johannes; Menenakos, Charalambos; Willems, Wilhelm; Mueller, Joachim M; Jacobi, Christoph A

    2009-01-01

    Background The effect of additional treatment strategies with antineoplastic agents on intraperitoneal tumor stimulating interleukin levels are unclear. Taurolidine and Povidone-iodine have been mainly used for abdominal lavage in Germany and Europe. Methods In the settings of a multicentre (three University Hospitals) prospective randomized controlled trial 120 patients were randomly allocated to receive either 0.5% taurolidine/2,500 IU heparin (TRD) or 0.25% povidone-iodine (control) intraperitoneally for resectable colorectal, gastric or pancreatic cancers. Due to the fact that IL-1beta (produced by macrophages) is preoperatively indifferent in various gastrointestinal cancer types our major outcome criterion was the perioperative (overall) level of IL-1beta in peritoneal fluid. Results Cytokine values were significantly lower after TRD lavage for IL-1beta, IL-6, and IL-10. Perioperative complications did not differ. The median follow-up was 50.0 months. The overall mortality rate (28 vs. 25, p = 0.36), the cancer-related death rate (17 vs. 19, p = .2), the local recurrence rate (7 vs. 12, p = .16), the distant metastasis rate (13 vs. 18, p = 0.2) as well as the time to relapse were not statistically significant different. Conclusion Reduced cytokine levels might explain a short term antitumorigenic intraperitoneal effect of TRD. But, this study analyzed different types of cancer. Therefore, we set up a multicentre randomized trial in patients undergoing curative colorectal cancer resection. Trial registration ISRCTN66478538 PMID:19309495

  13. Randomized Grain Boundary Liquid Crystal Phase

    NASA Astrophysics Data System (ADS)

    Chen, D.; Wang, H.; Li, M.; Glaser, M.; Maclennan, J.; Clark, N.

    2012-02-01

    The formation of macroscopic, chiral domains, in the B4 and dark conglomerate phases, for example, is a feature of bent-core liquid crystals resulting from the interplay of chirality, molecular bend and molecular tilt. We report a new, chiral phase observed in a hockey stick-like liquid crystal molecule. This phase appears below a smectic A phase and cools to a crystal phase. TEM images of the free surface of the chiral phase show hundreds of randomly oriented smectic blocks several hundred nanometers in size, similar to those seen in the twist grain boundary (TGB) phase. However, in contrast to the TGB phase, these blocks are randomly oriented. The characteristic defects in this phase are revealed by freeze-fracture TEM images. We will show how these defects mediate the randomized orientation and discuss the intrinsic mechanism driving the formation of this phase. This work is supported by NSF MRSEC Grant DMR0820579 and NSF Grant DMR0606528.

  14. Intravenous autologous bone marrow mononuclear stem cell therapy for ischemic stroke: a multicentric, randomized trial.

    PubMed

    Prasad, Kameshwar; Sharma, Alka; Garg, Ajay; Mohanty, Sujata; Bhatnagar, Shinjini; Johri, Sharat; Singh, Kunwar Karni; Nair, Velu; Sarkar, Ravi Shankar; Gorthi, Sankar Prasad; Hassan, Kaukab Maqbool; Prabhakar, Sudesh; Marwaha, Neelam; Khandelwal, Niranjan; Misra, Usha Kant; Kalita, Jayantee; Nityanand, Soniya

    2014-12-01

    Pilot studies have suggested benefit from intravenous administration of bone marrow mononuclear stem cells (BMSCs) in stroke. We explored the efficacy and safety of autologous BMSCs in subacute ischemic stroke. This was a phase II, multicenter, parallel group, randomized trial with blinded outcome assessment that included 120 patients. Patients with subacute ischemic stroke were randomly assigned to the arm that received intravenous infusion of autologous BMSCs or to control arm. Coprimary clinical efficacy outcomes were Barthel Index score and modified Rankin scale at day 180. Secondary outcomes were change in infarct volume, National Institute of Health Stroke Scale (NIHSS) at day 90 and 180. Main safety outcomes were adverse events, any new area of (18)fluorodeoxyglucose positron emission tomography uptake in any body part over 365 days. Fifty-eight patients received a mean of 280.75 million BMSCs at median of 18.5 days after stroke onset. There was no significant difference between BMSCs arm and control arm in the Barthel Index score (63.1 versus 63.6; P=0.92), modified Rankin scale shift analysis (P=0.53) or score >3 (47.5% versus 49.2%; P=0.85), NIHSS score (6.3 versus 7.0; P=0.53), change in infarct volume (-11.1 versus -7.36; P=0.63) at day 180. Adverse events were also similar in the 2 arms, and no patient showed any new area of (18)fluorodeoxyglucose uptake. With the methods used, results of this hitherto first randomized controlled trial indicate that intravenous infusion of BMSCs is safe, but there is no beneficial effect of treatment on stroke outcome. URLs: http://ctri.nic.in/Clinicaltrials and http://www.clinicaltrials.gov. Unique identifiers: CTRI-ROVCTRI/2008/091/0004 and NCT0150177. © 2014 American Heart Association, Inc.

  15. Efficacy and safety of pioglitazone added to alogliptin in Japanese patients with type 2 diabetes mellitus: a multicentre, randomized, double-blind, parallel-group, comparative study.

    PubMed

    Kaku, K; Katou, M; Igeta, M; Ohira, T; Sano, H

    2015-12-01

    A phase IV, multicentre, randomized, double-blind, parallel-group, comparative study was conducted in Japanese subjects with type 2 diabetes mellitus (T2DM) who had inadequate glycaemic control, despite treatment with alogliptin in addition to diet and/or exercise therapy. Subjects with glycated haemoglobin (HbA1c) concentrations of 6.9-10.5% were randomized to receive 16 weeks' double-blind treatment with pioglitazone 15 mg, 30 mg once daily or placebo added to alogliptin 25 mg once daily. The primary endpoint was the change in HbA1c from baseline at the end of treatment period (week 16). Both pioglitazone 15 and 30 mg combination therapy resulted in a significantly greater reduction in HbA1c than alogliptin monotherapy [-0.80 and -0.90% vs 0.00% (the least squares mean using analysis of covariance model); p < 0.0001, respectively]. The overall incidence rates of treatment-emergent adverse events were similar among the treatment groups. Pioglitazone/alogliptin combination therapy was effective and generally well tolerated in Japanese subjects with T2DM and is considered to be useful in clinical settings. © 2015 John Wiley & Sons Ltd.

  16. Simvastatin in aneurysmal subarachnoid haemorrhage (STASH): a multicentre randomised phase 3 trial.

    PubMed

    Kirkpatrick, Peter J; Turner, Carole L; Smith, Christopher; Hutchinson, Peter J; Murray, Gordon D

    2014-07-01

    The benefit of statins in patients with acute aneurysmal subarachnoid haemorrhage is unclear. We aimed to determine whether simvastatin 40 mg could improve the long-term outcome in patients with this disorder. In this international, multicentre, randomised, double-blind trial, we enrolled patients aged 18-65 years with confirmatory evidence of an aneurysmal subarachnoid haemorrhage and presenting less than 96 h from ictus from 35 acute neurosurgical centres in nine countries. Patients were randomly allocated (1:1) to receive either simvastatin 40 mg or placebo once a day for up to 21 days. We used a computer-generated randomisation code to randomise patients in every centre by blocks of ten (five simvastatin, five placebo). Participants and investigators were masked to treatment assignment. The primary outcome was the distribution of modified Rankin Scale (mRS) score obtained by questionnaire at 6 months. Analyses were done on the intention-to-treat population. This trial has been completed and is registered with Current Controlled Trials, number ISRCTN75948817. Between Jan 6, 2007, and Feb 1, 2013, apart from the period between May 15, 2009, and Feb 8, 2011, when recruitment was on hold, 803 patients were randomly assigned to receive either simvastatin 40 mg (n=391) or placebo (n=412). All patients were included in the intention-to-treat population. 782 (97%) patients had outcome data recorded at 6 months, of whom 560 (72%) were classed as having a favourable outcome, mRS 0-2 (271 patients in the simvastatin group vs 289 in the placebo group). The primary ordinal analysis of the mRS, adjusted for age and World Federation of Neurological Surgeons grade on admission, gave a common odds ratio (OR) of 0·97, 95% CI 0·75-1·25; p=0·803. At 6 months, we recorded 37 (10%) deaths in the simvastatin group compared with 35 (9%) in the placebo group (log-rank p=0·592). 70 (18%) serious adverse events were reported in the simvastatin group compared with 74 (18%) in the

  17. Phase transitions on random lattices: how random is topological disorder?

    PubMed

    Barghathi, Hatem; Vojta, Thomas

    2014-09-19

    We study the effects of topological (connectivity) disorder on phase transitions. We identify a broad class of random lattices whose disorder fluctuations decay much faster with increasing length scale than those of generic random systems, yielding a wandering exponent of ω=(d-1)/(2d) in d dimensions. The stability of clean critical points is thus governed by the criterion (d+1)ν>2 rather than the usual Harris criterion dν>2, making topological disorder less relevant than generic randomness. The Imry-Ma criterion is also modified, allowing first-order transitions to survive in all dimensions d>1. These results explain a host of puzzling violations of the original criteria for equilibrium and nonequilibrium phase transitions on random lattices. We discuss applications, and we illustrate our theory by computer simulations of random Voronoi and other lattices.

  18. The effect of bright light therapy on sleep and circadian rhythms in renal transplant recipients: a pilot randomized, multicentre wait-list controlled trial.

    PubMed

    Burkhalter, Hanna; Wirz-Justice, Anna; Denhaerynck, Kris; Fehr, Thomas; Steiger, Jürg; Venzin, Reto Martin; Cajochen, Christian; Weaver, Terri Elisabeth; De Geest, Sabina

    2015-01-01

    This study assessed the effect and feasibility of morning bright light therapy (BLT) on sleep, circadian rhythms, subjective feelings, depressive symptomatology and cognition in renal transplant recipients (RTx) diagnosed with sleep-wake disturbances (SWD). This pilot randomized multicentre wait-list controlled trial included 30 home-dwelling RTx randomly assigned 1:1 to either 3 weeks of BLT or a wait-list control group. Morning BLT (10 000 lux) was individually scheduled for 30 min daily for 3 weeks. Wrist actimetry (measuring sleep and circadian rhythms), validated instruments (subjective feelings and cognition) and melatonin assay (circadian timing) were used. Data were analysed via a random-intercept regression model. Of 30 RTx recipients (aged 58 ± 15, transplanted 15 ± 6 years ago), 26 completed the study. While BLT had no significant effect on circadian and sleep measures, sleep timing improved significantly. The intervention group showed a significant get-up time phase advance from baseline to intervention (+24 min) [(standardized estimates (SE): -0.23 (-0.42; -0.03)] and a small (+14 min) but significant bedtime phase advance from intervention to follow-up (SE: -0.25 (-0.41; -0.09). Improvement in subjective feelings and depressive symptomatology was observed but was not statistically significant. Bright light therapy showed preliminary indications of a beneficial effect in RTx with sleep-wake disturbances. (ClinicalTrials.gov number: NCT01256983).

  19. Barrett's Oesophagus Surveillance versus endoscopy at need Study (BOSS): protocol and analysis plan for a multicentre randomized controlled trial.

    PubMed

    Old, Oliver; Moayyedi, Paul; Love, Sharon; Roberts, Corran; Hapeshi, Julie; Foy, Chris; Stokes, Clive; Briggs, Andrew; Jankowski, Janusz; Barr, Hugh

    2015-09-01

    The absolute annual risk of patients with Barrett's oesophagus (BO) developing oesophageal adenocarcinoma (OAC) is ≤ 0.5%. Screening BO patients for malignant progression using endoscopic surveillance is widely practised. To assess the efficacy and cost-effectiveness of this, we developed a protocol for a randomized controlled trial of surveillance versus 'at need' endoscopy. In a multicentre trial, 3400 BO patients randomized to either 2-yearly endoscopic surveillance or 'at need' endoscopy will be followed up for 10 years. Urgent endoscopy will be offered to all patients who develop symptoms of dysphagia, unexplained weight loss > 7lb (3.2 kg), iron deficiency anaemia, recurrent vomiting, or worsening upper gastrointestinal symptoms. Participants must have endoscopically and histologically confirmed BO, with circumferential BO ≥ 1 cm or maximal tongue/island length ≥ 2 cm. Candidates with existing oesophageal high-grade dysplasia or cancer, or previous upper gastrointestinal cancer will be excluded. Primary outcome will be overall survival. Secondary outcomes will be cost effectiveness (cost per life year saved and quality adjusted life years); cancer-specific survival; time to OAC diagnosis and stage at diagnosis; morbidity and mortality related to any interventions; and frequency of endoscopy. This randomized trial will provide data to evaluate the efficacy and cost-effectiveness of screening BO patients for OAC. © The Author(s) 2015.

  20. Efficacy of night-time compression for breast cancer related lymphedema (LYNC): protocol for a multi-centre, randomized controlled efficacy trial.

    PubMed

    McNeely, Margaret L; Campbell, Kristin L; Webster, Marc; Kuusk, Urve; Tracey, Karen; Mackey, John

    2016-08-04

    Lymphedema is a prevalent long-term effect of breast cancer treatment that is associated with reduced quality of life. More recent observational data suggest that the addition of night-time compression to day-time use of a compression garment results in better long-term control of arm lymphedema. The primary objectives of the randomized controlled phase of the trial are to determine the efficacy of night-time compression on arm lymphedema volume maintenance and quality of life in breast cancer survivors who have completed intensive reduction treatment for their lymphedema. The study will be a parallel 3-arm, multi-centre randomized fast-track trial. A total of 120 women with breast cancer related lymphedema will be recruited from 3 centres in Canada and randomized to group 1: Day-time compression garment alone or Group 2: Day-time compression garment + night-time compression bandaging or Group 3: Day-time compression garment + use of a night-time compression system garment. The duration of the primary intervention period will be 12 weeks. The follow-up period after the intervention (weeks 13 to 24) will follow a longitudinal observational design. The primary outcome variables: differences from baseline to week 12 in arm volume and quality of life (Lymphoedema Functioning, Disability and Health Questionnaire: Lymph-ICF). Secondary outcomes include bioimpedance analysis, sleep disturbance and self-efficacy. All measurements are standardized and will be performed prior to randomization, and at weeks 6, 12, 18 and 24. The use of night-time compression as a self-management strategy for chronic breast cancer related lymphedema is seen as an innovative approach to improve long-term control over the condition. This trial aims to advance the knowledge on self-management strategies for lymphedema. This trial was registered at clinicaltrials.gov on July 9(th), 2014 ( NCT02187289 ).

  1. Quantum walks with random phase shifts

    SciTech Connect

    Kosik, Jozef; Buzek, Vladimir; Hillery, Mark

    2006-08-15

    We investigate quantum walks in multiple dimensions with different quantum coins. We augment the model by assuming that at each step the amplitudes of the coin state are multiplied by random phases. This model enables us to study in detail the role of decoherence in quantum walks and to investigate the quantum-to-classical transition. We also provide classical analog of the quantum random walks studied. Interestingly enough, it turns out that the classical counterparts of some quantum random walks are classical random walks with a memory and biased coin. In addition random phase shifts 'simplify' the dynamics (the cross-interference terms of different paths vanish on average) and enable us to give a compact formula for the dispersion of such walks.

  2. Optimizing exposure-based CBT for anxiety disorders via enhanced extinction: Design and methods of a multicentre randomized clinical trial.

    PubMed

    Heinig, Ingmar; Pittig, Andre; Richter, Jan; Hummel, Katrin; Alt, Isabel; Dickhöver, Kristina; Gamer, Jennifer; Hollandt, Maike; Koelkebeck, Katja; Maenz, Anne; Tennie, Sophia; Totzeck, Christina; Yang, Yunbo; Arolt, Volker; Deckert, Jürgen; Domschke, Katharina; Fydrich, Thomas; Hamm, Alfons; Hoyer, Jürgen; Kircher, Tilo; Lueken, Ulrike; Margraf, Jürgen; Neudeck, Peter; Pauli, Paul; Rief, Winfried; Schneider, Silvia; Straube, Benjamin; Ströhle, Andreas; Wittchen, Hans-Ulrich

    2017-06-01

    Exposure-based psychological interventions currently represent the empirically best established first line form of cognitive-behavioural therapy for all types of anxiety disorders. Although shown to be highly effective in both randomized clinical and other studies, there are important deficits: (1) the core mechanisms of action are still under debate, (2) it is not known whether such treatments work equally well in all forms of anxiety disorders, including comorbid diagnoses like depression, (3) it is not known whether an intensified treatment with more frequent sessions in a shorter period of time provides better outcome than distributed sessions over longer time intervals. This paper reports the methods and design of a large-scale multicentre randomized clinical trial (RCT) involving up to 700 patients designed to answer these questions. Based on substantial advances in basic research we regard extinction as the putative core candidate model to explain the mechanism of action of exposure-based treatments. The RCT is flanked by four add-on projects that apply experimental neurophysiological and psychophysiological, (epi)genetic and ecological momentary assessment methods to examine extinction and its potential moderators. Beyond the focus on extinction we also involve stakeholders and routine psychotherapists in preparation for more effective dissemination into clinical practice. Copyright © 2017 John Wiley & Sons, Ltd.

  3. Are minimized perfusion circuits the better heart lung machines? Final results of a prospective randomized multicentre study.

    PubMed

    El-Essawi, A; Hajek, T; Skorpil, J; Böning, A; Sabol, F; Ostrovsky, Y; Hausmann, H; Harringer, W

    2011-11-01

    Minimized perfusion circuits (MPCs), although aiming at minimizing the adverse effects of cardiopulmonary bypass, have not yet gained popularity. This can be attributed to concerns regarding their safety, as well as lack of sufficient evidence of their benefit. Described is a randomized, multicentre study comparing the MPC - ROCsafeRX to standard cardiopulmonary bypass in patients undergoing elective coronary artery bypass grafting and/ or aortic valve replacement. Five hundred patients were included in the study (252 randomized to the ROCsafeRX group and 248 to standard cardiopulmonary bypass). Both groups were well matched for demographic characteristics and type of surgery. No operative mortality and no device-related complications were encountered. Transfusion requirement (333 ± 603 vs. 587 ± 1010 ml; p=0.001), incidence of atrial fibrillation (16.3% vs. 24.2%; p=0.03) and the incidence of major adverse events (9.1% vs. 16.5%; p=0.02) were all in favour of the MPC group. These results confirm both the safety and efficacy of the ROCsafeRX MPC for a large variety of cardiac patients. Minimized perfusion circuits should, therefore, play a greater role in daily practice so that as many patients as possible can benefit from their advantages.

  4. Alcohol screening and brief interventions for offenders in the probation setting (SIPS Trial): a pragmatic multicentre cluster randomized controlled trial.

    PubMed

    Newbury-Birch, Dorothy; Coulton, Simon; Bland, Martin; Cassidy, Paul; Dale, Veronica; Deluca, Paolo; Gilvarry, Eilish; Godfrey, Christine; Heather, Nick; Kaner, Eileen; McGovern, Ruth; Myles, Judy; Oyefeso, Adenekan; Parrott, Steve; Patton, Robert; Perryman, Katherine; Phillips, Tom; Shepherd, Jonathan; Drummond, Colin

    2014-01-01

    To evaluate the effectiveness of different brief intervention strategies at reducing hazardous or harmful drinking in the probation setting. Offender managers were randomized to three interventions, each of which built on the previous one: feedback on screening outcome and a client information leaflet control group, 5 min of structured brief advice and 20 min of brief lifestyle counselling. A pragmatic multicentre factorial cluster randomized controlled trial. The primary outcome was self-reported hazardous or harmful drinking status measured by Alcohol Use Disorders Identification Test (AUDIT) at 6 months (negative status was a score of <8). Secondary outcomes were AUDIT status at 12 months, experience of alcohol-related problems, health utility, service utilization, readiness to change and reduction in conviction rates. Follow-up rates were 68% at 6 months and 60% at 12 months. At both time points, there was no significant advantage of more intensive interventions compared with the control group in terms of AUDIT status. Those in the brief advice and brief lifestyle counselling intervention groups were statistically significantly less likely to reoffend (36 and 38%, respectively) than those in the client information leaflet group (50%) in the year following intervention. Brief advice or brief lifestyle counselling provided no additional benefit in reducing hazardous or harmful drinking compared with feedback on screening outcome and a client information leaflet. The impact of more intensive brief intervention on reoffending warrants further research. © The Author 2014. Medical Council on Alcohol and Oxford University Press. All rights reserved.

  5. A prospective, randomized, multicentre trial for the treatment of refractory status epilepticus; experiences from evaluating the effect of the novel drug candidate, NS1209.

    PubMed

    Sabers, Anne; Wolf, Peter; Møller, Arne; Rysgaard, Karen; Ben-Menachem, Elinor

    2013-09-01

    Refractory status epilepticus (RSE) is a life-threatening condition that requires immediate and aggressive treatment. Unfortunately, sometimes standard antiepileptic treatment is insufficient. Furthermore, alternative therapeutic options are limited by low evidence of efficacy. The primary objective of this study was to evaluate the effects of the novel drug candidate, NS1209 versus third-line standard treatment (phenytoin/valproate) for RSE. Having not reached the study end-points, the purpose of this paper is to discuss the challenges that are encountered in conducting a controlled study of RSE. This was a phase II, prospective, multicentre, single-blinded, randomized clinical trial and included patients to two separate protocols for convulsive and non-convulsive RSE (NS1209-006 and NS1209-007). In total, 28 patients were included and 14 patients were exposed to NS1209. At study conclusion, the study was insufficiently powered to detect any statistically significant difference between the two treatment groups. This was especially true for the convulsive RSE protocol. We conclude that high-quality studies in RSE are difficult to conduct owing to a number of ethical and practical problems associated with this critical illness. Challenges for further studies are discussed. Copyright © 2013 Elsevier B.V. All rights reserved.

  6. Daptomycin plus fosfomycin versus daptomycin monotherapy in treating MRSA: protocol of a multicentre, randomised, phase III trial

    PubMed Central

    Shaw, E; Miró, J M; Puig-Asensio, M; Pigrau, C; Barcenilla, F; Murillas, J; Garcia-Pardo, G; Espejo, E; Padilla, B; Garcia-Reyne, A; Pasquau, J; Rodriguez-Baño, J; López-Contreras, J; Montero, M; de la Calle, C; Pintado, V; Calbo, E; Gasch, O; Montejo, M; Salavert, M; Garcia-Pais, M J; Carratalà, J; Pujol, M

    2015-01-01

    Introduction Despite the availability of new antibiotics such as daptomycin, methicillin-resistant Staphylococcus aureus (MRSA) bacteraemia continues to be associated with high clinical failure rates. Combination therapy has been proposed as an alternative to improve outcomes but there is a lack of clinical studies. The study aims to demonstrate that combination of daptomycin plus fosfomycin achieves higher clinical success rates in the treatment of MRSA bacteraemia than daptomycin alone. Methods and analysis A multicentre open-label, randomised phase III study. Adult patients hospitalised with MRSA bacteraemia will be randomly assigned (1:1) to group 1: daptomycin 10 mg/kg/24 h intravenous; or group 2: daptomycin 10 mg/kg/24 h intravenous plus fosfomycin 2 gr/6 g intravenous. The main outcome will be treatment response at week 6 after stopping therapy (test-of-cure (TOC) visit). This is a composite variable with two values: Treatment success: resolution of clinical signs and symptoms (clinical success) and negative blood cultures (microbiological success) at the TOC visit. Treatment failure: if any of the following conditions apply: (1) lack of clinical improvement at 72 h or more after starting therapy; (2) persistent bacteraemia (positive blood cultures on day 7); (3) therapy is discontinued early due to adverse effects or for some other reason based on clinical judgement; (4) relapse of MRSA bacteraemia before the TOC visit; (5) death for any reason before the TOC visit. Assuming a 60% cure rate with daptomycin and a 20% difference in cure rates between the two groups, 103 patients will be needed for each group (α:0.05, ß: 0.2). Statistical analysis will be based on intention to treat, as well as per protocol and safety analysis. Ethics and dissemination The protocol was approved by the Spanish Medicines and Healthcare Products Regulatory Agency (AEMPS). The sponsor commits itself to publishing the data in first quartile peer-review journals

  7. Pioglitazone in early Parkinson's disease: a phase 2, multicentre, double-blind, randomised trial

    PubMed Central

    2015-01-01

    Summary Background A systematic assessment of potential disease-modifying compounds for Parkinson's disease concluded that pioglitazone could hold promise for the treatment of patients with this disease. We assessed the effect of pioglitazone on the progression of Parkinson's disease in a multicentre, double-blind, placebo-controlled, futility clinical trial. Methods Participants with the diagnosis of early Parkinson's disease on a stable regimen of 1 mg/day rasagiline or 10 mg/day selegiline were randomly assigned (1:1:1) to 15 mg/day pioglitazone, 45 mg/day pioglitazone, or placebo. Investigators were masked to the treatment assignment. Only the statistical centre and the central pharmacy knew the treatment name associated with the randomisation number. The primary outcome was the change in the total Unified Parkinson's Disease Rating Scale (UPDRS) score between the baseline and 44 weeks, analysed by intention to treat. The primary null hypothesis for each dose group was that the mean change in UPDRS was 3 points less than the mean change in the placebo group. The alternative hypothesis (of futility) was that pioglitazone is not meaningfully different from placebo. We rejected the null if there was significant evidence of futility at the one-sided alpha level of 0.10. The study is registered at ClinicalTrials.gov, number NCT01280123. Findings 210 patients from 35 sites in the USA were enrolled between May 10, 2011, and July 31, 2013. The primary analysis included 72 patients in the 15 mg group, 67 in the 45 mg group, and 71 in the placebo group. The mean total UPDRS change at 44 weeks was 4.42 (95% CI 2.55–6.28) for 15 mg pioglitazone, 5.13 (95% CI 3.17–7.08) for 45 mg pioglitazone, and 6.25 (95% CI 4.35–8.15) for placebo (higher change scores are worse). The mean difference between the 15 mg and placebo groups was −1.83 (80% CI −3.56 to −0.10) and the null hypothesis could not be rejected (p=0.19). The mean difference between the 45 mg and placebo

  8. Phase Transitions on Random Lattices: How Random is Topological Disorder?

    NASA Astrophysics Data System (ADS)

    Barghathi, Hatem; Vojta, Thomas

    2015-03-01

    We study the effects of topological (connectivity) disorder on phase transitions. We identify a broad class of random lattices whose disorder fluctuations decay much faster with increasing length scale than those of generic random systems, yielding a wandering exponent of ω = (d - 1) / (2 d) in d dimensions. The stability of clean critical points is thus governed by the criterion (d + 1) ν > 2 rather than the usual Harris criterion dν > 2 , making topological disorder less relevant than generic randomness. The Imry-Ma criterion is also modified, allowing first-order transitions to survive in all dimensions d > 1 . These results explain a host of puzzling violations of the original criteria for equilibrium and nonequilibrium phase transitions on random lattices. We discuss applications, and we illustrate our theory by computer simulations of random Voronoi and other lattices. This work was supported by the NSF under Grant Nos. DMR-1205803 and PHYS-1066293. We acknowledge the hospitality of the Aspen Center for Physics.

  9. [Multicentre randomized trial comparing triptorelin medical castration versus surgical castration in the treatment of locally advanced or metastatic prostate cancer].

    PubMed

    Botto, Henry; Rouprêt, Morgan; Mathieu, François; Richard, François

    2007-04-01

    To report the results of a trial comparing the efficacy of triptorelin and surgical castration in the treatment of locally advanced or metastatic prostate cancer. 80 patients with previously untreated locally advanced or metastatic prostate cancer prostate cancer were included in a one-year multicentre, randomized, prospective, open-label therapeutic trial. Patients either received a monthly injection of triptorelin (group 1; n = 40), or were treated by pulpectomy (group 2; n = 40). Patients were reviewed every 3 months, then every 6 months. The mean age of the patients was 71.22 +/- 8.25 years. At 1 month, 38 patients were castrated (plasma testosterone < 0.5 mg/ml) in the pulpectomy group versus 35 in the triptorelin group. The mean follow-up was 38.8 +/- 26 months in the triptorelin group and 36.3 +/- 25 months in the pulpectomy group. On multivariate analysis, age, impaired performance status and PAP level (> 3.2 ng/ml) were predictive factors of a poor outcome. The median survival was 37.5 +/- 9 months in the triptorelin group and 33 +/- 3 months in the pulpectomy group. At 3 years, no significant difference in specific survival was observed between the 2 groups. At 8 years of follow-up, 63 patients had died. This study demonstrates an equivalent specific survival between patients treated by triptorelin or surgical castration. Castration is rapidly obtained with triptorelin (< 2 months) and is maintained over time throughout the duration of treatment.

  10. Trospium chloride versus oxybutynin: a randomized, double-blind, multicentre trial in the treatment of detrusor hyper-reflexia.

    PubMed

    Madersbacher, H; Stöhrer, M; Richter, R; Burgdörfer, H; Hachen, H J; Mürtz, G

    1995-04-01

    To compare trospium chloride (TCl), a quaternary ammonium derivative with atropine-like effects and predominantly antispasmodic activity, with oxybutynin (Oxy) in terms of efficacy and adverse effects. In a randomized, double-blind, multicentre trial, 95 patients with spinal cord injuries and detrusor hyper-reflexia were studied. Treatment consisted of three doses per day over a 2 week period, with either Oxy (5 mg three times daily) or with TCl (20 mg twice daily) with an additional placebo at midday. The results were evaluated with regard to changes in objective (urodynamic) data and subjective symptoms as well as the incidence/severity of adverse effects. With both drugs there was a significant increase in maximum bladder capacity, a significant decrease in maximum voiding detrusor pressure and a significant increase in compliance and residual urine; there were no statistically significant differences between the treatment groups. The percentage of patients who reported severe dryness of the mouth was considerably lower (4%) in those receiving TCl 2 x 20 mg/day than in those receiving Oxy (23%) 3 x 5 mg/day. Withdrawal from treatment was also less frequent in those receiving TCl (6%) than in those receiving Oxy (16%). Trospium chloride and oxybutynin, judged in terms of objective urodynamic parameters, are of substantially equal value as parasympathetic antagonists. However, assessment of tolerance in terms of adverse drug effects showed that TCl had certain advantages.

  11. Emedastine difumarate versus loratadine in chronic idiopathic urticaria: a randomized, double-blind, controlled European multicentre clinical trial.

    PubMed

    Pons-Guiraud, Annik; Nekam, Kristof; Lahovsky, J; Costa, Angela; Piacentini, Andrea

    2006-01-01

    Emedastine difumarate (2 mg b.i.d.) was compared to loratadine (10 mg o.d.) in a randomized, double-blind, multicentre trial for 4 weeks in 192 patients with idiopathic chronic urticaria. After one week of treatment significant differences were recorded: body skin involvement diminished to 0-10% in 57.1% of emedastine patients vs. 38.2% of loratadine patients (p = 0.0019) and 83.3% had a total urticaria symptom score of 0-1 vs. 64.5% with loratadine (p = 0.0134). After 4 weeks of treatment the efficacy of the two drugs was similar in terms of mean change in total urticaria symptom score (- 5.57 +/- 3.15 with emedastine - 5.67 +/- 3.26 with loratadine), proportion of symptom-free patients (52.4% vs. 54.5%), intensity of erythema, number of hives, size of the largest hive, extent of skin area involved and overall assessment of urticaria symptoms.Twenty-three emedastine patients (23.9%) and 17 loratadine patients (17.7%) experienced an adverse event. Nineteen events in 15 emedastine patients and 9 in 9 loratadine patients were related to treatment (p = 0.0294). Only one event caused discontinuation in both treatment groups. The most common adverse event was sleepiness (7 patients with emedastine and 2 with loratadine). Emedastine is well tolerated, and as effective as loratadine in the short-term treatment of chronic idiopathic urticaria.

  12. Random-phase metasurfaces at optical wavelengths

    NASA Astrophysics Data System (ADS)

    Pors, Anders; Ding, Fei; Chen, Yiting; Radko, Ilya P.; Bozhevolnyi, Sergey I.

    2016-06-01

    Random-phase metasurfaces, in which the constituents scatter light with random phases, have the property that an incident plane wave will diffusely scatter, hereby leading to a complex far-field response that is most suitably described by statistical means. In this work, we present and exemplify the statistical description of the far-field response, particularly highlighting how the response for polarised and unpolarised light might be alike or different depending on the correlation of scattering phases for two orthogonal polarisations. By utilizing gap plasmon-based metasurfaces, consisting of an optically thick gold film overlaid by a subwavelength thin glass spacer and an array of gold nanobricks, we design and realize random-phase metasurfaces at a wavelength of 800 nm. Optical characterisation of the fabricated samples convincingly demonstrates the diffuse scattering of reflected light, with statistics obeying the theoretical predictions. We foresee the use of random-phase metasurfaces for camouflage applications and as high-quality reference structures in dark-field microscopy, while the control of the statistics for polarised and unpolarised light might find usage in security applications. Finally, by incorporating a certain correlation between scattering by neighbouring metasurface constituents new types of functionalities can be realised, such as a Lambertian reflector.

  13. Random-phase metasurfaces at optical wavelengths

    PubMed Central

    Pors, Anders; Ding, Fei; Chen, Yiting; Radko, Ilya P.; Bozhevolnyi, Sergey I.

    2016-01-01

    Random-phase metasurfaces, in which the constituents scatter light with random phases, have the property that an incident plane wave will diffusely scatter, hereby leading to a complex far-field response that is most suitably described by statistical means. In this work, we present and exemplify the statistical description of the far-field response, particularly highlighting how the response for polarised and unpolarised light might be alike or different depending on the correlation of scattering phases for two orthogonal polarisations. By utilizing gap plasmon-based metasurfaces, consisting of an optically thick gold film overlaid by a subwavelength thin glass spacer and an array of gold nanobricks, we design and realize random-phase metasurfaces at a wavelength of 800 nm. Optical characterisation of the fabricated samples convincingly demonstrates the diffuse scattering of reflected light, with statistics obeying the theoretical predictions. We foresee the use of random-phase metasurfaces for camouflage applications and as high-quality reference structures in dark-field microscopy, while the control of the statistics for polarised and unpolarised light might find usage in security applications. Finally, by incorporating a certain correlation between scattering by neighbouring metasurface constituents new types of functionalities can be realised, such as a Lambertian reflector. PMID:27328635

  14. Azithromycin for Indigenous children with bronchiectasis: study protocol for a multi-centre randomized controlled trial

    PubMed Central

    2012-01-01

    Background The prevalence of chronic suppurative lung disease (CSLD) and bronchiectasis unrelated to cystic fibrosis (CF) among Indigenous children in Australia, New Zealand and Alaska is very high. Antibiotics are a major component of treatment and are used both on a short or long-term basis. One aim of long-term or maintenance antibiotics is to reduce the frequency of acute pulmonary exacerbations and symptoms. However, there are few studies investigating the efficacy of long-term antibiotic use for CSLD and non-CF bronchiectasis among children. This study tests the hypothesis that azithromycin administered once a week as maintenance antibiotic treatment will reduce the rate of pulmonary exacerbations in Indigenous children with bronchiectasis. Methods/design We are conducting a multicentre, randomised, double-blind, placebo controlled clinical trial in Australia and New Zealand. Inclusion criteria are: Aboriginal, Torres Strait Islander, Maori or Pacific Island children aged 1 to 8 years, diagnosed with bronchiectasis (or probable bronchiectasis) with no underlying disease identified (such as CF or primary immunodeficiency), and having had at least one episode of pulmonary exacerbation in the last 12 months. After informed consent, children are randomised to receive either azithromycin (30 mg/kg once a week) or placebo (once a week) for 12–24 months from study entry. Primary outcomes are the rate of pulmonary exacerbations and time to pulmonary exacerbation determined by review of patient medical records. Secondary outcomes include length and severity of pulmonary exacerbation episodes, changes in growth, school loss, respiratory symptoms, forced expiratory volume in 1-second (FEV1; for children ≥6 years), and sputum characteristics. Safety endpoints include serious adverse events. Antibiotic resistance in respiratory bacterial pathogens colonising the nasopharynx is monitored. Data derived from medical records and clinical assessments every 3 to 4

  15. Immune plasma for the treatment of severe influenza: an open-label, multicentre, phase 2 randomised study.

    PubMed

    Beigel, John H; Tebas, Pablo; Elie-Turenne, Marie-Carmelle; Bajwa, Ednan; Bell, Todd E; Cairns, Charles B; Shoham, Shmuel; Deville, Jaime G; Feucht, Eric; Feinberg, Judith; Luke, Thomas; Raviprakash, Kanakatte; Danko, Janine; O'Neil, Dorothy; Metcalf, Julia A; King, Karen; Burgess, Timothy H; Aga, Evgenia; Lane, H Clifford; Hughes, Michael D; Davey, Richard T

    2017-06-01

    Influenza causes substantial morbidity and mortality despite available treatments. Anecdotal reports suggest that plasma with high antibody titres to influenza might be of benefit in the treatment of severe influenza. In this randomised, open-label, multicentre, phase 2 trial, 29 academic medical centres in the USA assessed the safety and efficacy of anti-influenza plasma with haemagglutination inhibition antibody titres of 1:80 or more to the infecting strain. Hospitalised children and adults (including pregnant women) with severe influenza A or B (defined as the presence of hypoxia or tachypnoea) were randomly assigned to receive either two units (or paediatric equivalent) of anti-influenza plasma plus standard care, versus standard care alone, and were followed up for 28 days. The primary endpoint was time to normalisation of patients' respiratory status (respiratory rate of ≤20 breaths per min for adults or age-defined thresholds of 20-38 breaths per min for children) and a room air oxygen saturation of 93% or more. This study is registered with ClinicalTrials.gov, number NCT01052480. Between Jan 13, 2011, and March 2, 2015, 113 participants were screened for eligibility and 98 were randomly assigned from 20 out of 29 participating sites. Of the participants with confirmed influenza (by PCR), 28 (67%) of 42 in the plasma plus standard care group normalised their respiratory status by day 28 compared with 24 (53%) of 45 participants on standard care alone (p=0·069). The hazard ratio (HR) comparing plasma plus standard care with standard care alone was 1·71 (95% CI 0·96-3·06). Six participants died, one (2%) from the plasma plus standard care group and five (10%) from the standard care group (HR 0·19 [95% CI 0·02-1·65], p=0·093). Participants in the plasma plus standard care group had non-significant reductions in days in hospital (median 6 days [IQR 4-16] vs 11 days [5-25], p=0·13) and days on mechanical ventilation (median 0 days [IQR 0-6] vs 3 days

  16. Random fields at a nonequilibrium phase transition.

    PubMed

    Barghathi, Hatem; Vojta, Thomas

    2012-10-26

    We study nonequilibrium phase transitions in the presence of disorder that locally breaks the symmetry between two equivalent macroscopic states. In low-dimensional equilibrium systems, such random-field disorder is known to have dramatic effects: it prevents spontaneous symmetry breaking and completely destroys the phase transition. In contrast, we show that the phase transition of the one-dimensional generalized contact process persists in the presence of random-field disorder. The ultraslow dynamics in the symmetry-broken phase is described by a Sinai walk of the domain walls between two different absorbing states. We discuss the generality and limitations of our theory, and we illustrate our results by large-scale Monte Carlo simulations.

  17. A comparison of topical application of penciclovir 1% cream with acyclovir 3% cream for treatment of genital herpes: a randomized, double-blind, multicentre trial.

    PubMed

    Chen, X S; Han, G Z; Guo, Z P; Lu, N Z; Chen, J; Wang, J B

    2000-09-01

    Genital herpes simplex virus (HSV) infection, a sexually transmitted disease (STD), is the commonest cause of ulcerative genital infections among the young and adult population. The significant association of genital ulceration and transmission of human immunodeficiency virus (HIV) has been shown in many studies. To explore the potential efficacy of topical treatment of genital herpes with penciclovir cream, a randomized, double-blind, multicentre, acyclovir-controlled Phase II clinical trial of penciclovir 1% cream 5 times daily up to 7 days for suppression of genital herpes was conducted in China. A total of 205 patients aged 20-59 years (mean age 36.0+/-8.8 years for acyclovir and 34.8+/-8.4 years for penciclovir) with a clinical diagnosis of genital herpes were randomly allocated to one of the 2 parallel treatment groups and used for analysis. Clinical assessment were made before treatment and followed up at every visit during the study. Our results show that there was an encouraging improvement simultaneously in the 2 groups although no significant differences in clinical efficacy with respect to clinical cure rate, and times to healing, resolution of all symptoms, absence of blisters, cessation of new blisters, crusting, and loss of crust between penciclovir and acyclovir groups in terms of primary, non-primary and total patients were found. However a significantly shorter time to crusting was found in primary penciclovir group when compared with primary acyclovir group. Adverse experience was generally infrequent and mild, and was comparable in the 2 treatment groups. Based on these preliminary clinical findings, further evaluation of penciclovir 3% cream for topical treatment of genital herpes is planned.

  18. Multicentric liposarcoma.

    PubMed

    Conesa, Xavier; Seijas, Roberto; Ares, Oscar; Huguet, Pere; Perez-Dominguez, Manuel

    2011-02-01

    Liposarcoma is one of the most common malignant soft tissue tumours. It usually presents as a single mass, and the prognosis varies according to the degree of histological differentiation. Multicentric liposarcoma is an unusual presentation of this tumour in which several independent lesions develop and generally display an aggressive pattern. It may be difficult to establish a precise diagnosis because of the problems differentiating between recurrence or metastasis of a single liposarcoma and multicentric primary lesions. A systematic review was undertaken, assessing articles on multicentric liposarcoma, with emphasis on the diagnostic criteria and treatment for this condition. Illustrative cases of multicentric liposarcoma from our Institution are presented.

  19. Effect of melatonin on incidence of delirium among patients with hip fracture: a multicentre, double-blind randomized controlled trial

    PubMed Central

    de Jonghe, Annemarieke; van Munster, Barbara C.; Goslings, J. Carel; Kloen, Peter; van Rees, Carolien; Wolvius, Reinder; van Velde, Romuald; Levi, Marcel; de Haan, Rob J.; de Rooij, Sophia E.

    2014-01-01

    Background: Disturbance of the sleep–wake cycle is a characteristic of delirium. In addition, changes in melatonin rhythm influence the circadian rhythm and are associated with delirium. We compared the effect of melatonin and placebo on the incidence and duration of delirium. Methods: We performed this multicentre, double-blind, randomized controlled trial between November 2008 and May 2012 in 1 academic and 2 nonacademic hospitals. Patients aged 65 years or older who were scheduled for acute hip surgery were eligible for inclusion. Patients received melatonin 3 mg or placebo in the evening for 5 consecutive days, starting within 24 hours after admission. The primary outcome was incidence of delirium within 8 days of admission. We also monitored the duration of delirium. Results: A total of 452 patients were randomly assigned to the 2 study groups. We subsequently excluded 74 patients for whom the primary end point could not be measured or who had delirium before the second day of the study. After these postrandomization exclusions, data for 378 patients were included in the main analysis. The overall mean age was 84 years, 238 (63.0%) of the patients lived at home before admission, and 210 (55.6%) had cognitive impairment. We observed no effect of melatonin on the incidence of delirium: 55/186 (29.6%) in the melatonin group v. 49/192 (25.5%) in the placebo group; difference 4.1 (95% confidence interval −0.05 to 13.1) percentage points. There were no between-group differences in mortality or in cognitive or functional outcomes at 3-month follow-up. Interpretation: In this older population with hip fracture, treatment with melatonin did not reduce the incidence of delirium. Trial registration: Netherlands Trial Registry, NTR1576: MAPLE (Melatonin Against PLacebo in Elderly patients) study; www.trialregister.nl/trialreg/admin/rctview.asp?TC=1576 PMID:25183726

  20. MRI in multiple sclerosis: an intra-individual, randomized and multicentric comparison of gadobutrol with gadoterate meglumine at 3 T.

    PubMed

    Saake, Marc; Langner, Soenke; Schwenke, Carsten; Weibart, Marina; Jansen, Olav; Hosten, Norbert; Doerfler, Arnd

    2016-03-01

    To compare contrast effects of gadobutrol with gadoterate meglumine for brain MRI in multiple sclerosis (MS) in a multicentre, randomized, prospective, intraindividual study at 3 T. Institutional review board approval was obtained. Patients with known or suspected active MS lesions were included. Two identical MRIs were performed using randomized contrast agent order. Four post-contrast T1 sequences were acquired (start time points 0, 3, 6 and 9 min). If no enhancing lesion was present in first MRI, second MRI was cancelled. Quantitative (number and signal intensity of enhancing lesions) and qualitative parameters (time points of first and all lesions enhancing; subjective preference regarding contrast enhancement and lesion delineation; global preference) were evaluated blinded. Seventy-four patients (male, 26; mean age, 35 years) were enrolled in three centres. In 45 patients enhancing lesions were found. Number of enhancing lesions increased over time for both contrast agents without significant difference (median 2 for both). Lesions signal intensity was significantly higher for gadobutrol (p < 0.05 at time points 3, 6 and 9 min). Subjective preference rating showed non-significant tendency in favour of gadobutrol. Both gadobutrol and gadoterate meglumine can be used for imaging of acute inflammatory MS lesions. However, gadobutrol generates higher lesion SI. Contrast-enhanced MRI plays a key role in the management of multiple sclerosis. Different gadolinium-based contrast agents are available. Number of visibly enhancing lesions increases over time after contrast injection. Gadobutrol and gadoterate meglumine do not differ in number of visible lesions. Gadobutrol generates higher signal intensity than gadoterate meglumine.

  1. Efficacy and safety of retapamulin ointment as treatment of impetigo: randomized double-blind multicentre placebo-controlled trial.

    PubMed

    Koning, S; van der Wouden, J C; Chosidow, O; Twynholm, M; Singh, K P; Scangarella, N; Oranje, A P

    2008-05-01

    Impetigo is a common skin infection, primarily caused by Staphylococcus aureus and mainly occurring in children. It is usually treated topically with antibiotics to achieve a quick cure and prevent spread of the infection. Worldwide, resistance rates of S. aureus against commonly used antibiotics are rising. Retapamulin belongs to a newly developed class of antibiotics for the treatment of uncomplicated skin infections. Our aim was to compare the efficacy and safety of topical application of retapamulin ointment with topical placebo ointment in the treatment of primary impetigo. In a randomized, double-blind, multicentre study, patients received either topical retapamulin ointment 1% twice daily for 5 days or topical placebo. Patients were enrolled into the study for 14 days and attended the clinic for three visits during which clinical and laboratory evaluations were performed. Two hundred and thirteen patients were randomized, with 139 evaluable patients in the retapamulin group and 71 in the placebo group. Based on the primary efficacy endpoint of clinical response after 7 days (intention to treat), retapamulin ointment was superior to placebo (success rate 85.6% vs. 52.1%; P<0.0001). Similar results were found in the per protocol analysis and in the subgroup of patients who had a pathogen isolated at baseline. The most common adverse effect, pruritus at the application site, was reported by 6% and 1% of patients in the retapamulin and placebo groups, respectively. This study shows that topical retapamulin is effective and safe in the treatment of primary impetigo, offering a new treatment option.

  2. Inhomogeneous random phase approximation: A solvable model

    SciTech Connect

    Lemm, J.C.

    1995-11-15

    A recently developed method to include particle-hole correlations into the time-independent mean field theory for scattering (TIMF) by an inhomogeneous random phase approximation (IRPA) is applied to a numerically solvable model. Having adapted the procedure according to numerical requirements, IRPA calculations turn out to be tractable. The obtained results improve TIMF results. 8 refs., 28 figs., 3 tabs.

  3. Video-based feedback of oral clinical presentations reduces the anxiety of ICU medical students: a multicentre, prospective, randomized study

    PubMed Central

    2014-01-01

    Background Oral presentations of clinical cases by medical students during medical rounds in hospital wards are a source of anxiety and little is known about how this anxiety can be alleviated. The objective of this study was to investigate whether video-based feedback of public oral presentations can reduce anxiety in 4th year medical students. Methods Multicentre randomized study conducted in six intensive care units (ICU) and emergency departments (ED) in France over a 9-month period in 2012. One hundred and forty two 4th year medical students were randomized to two groups: intervention and control. Students in the intervention group were recorded while making an oral presentation of a patient during morning ward rounds, followed by video-based feedback. Students in the control group conducted presented classical oral presentations without being filmed and with no formal feedback. Anxiety levels during a public oral presentation were assessed using the Spielberger State Anxiety Inventory (STAI-S). The primary outcome was the difference in STAI-S scores between groups at the beginning and at the end of a 3-month ICU or ED internship. Results Seventy four students were randomized to the ‘video-based feedback’ group and 68 were randomized to the control group. In both groups, STAI-S scores were significantly lower after 3 months of internship. However, the reduction in STAI-S scores was significantly greater in the “video-based feedback” group than in controls (-9.2 ± 9.3 vs. –4.6 ± 8.2, p = 0.024. Compared to the control group, significantly fewer students with high-level anxiety were observed in the “video-based feedback” group after 3 months of internship (68 vs. 28%, p <0.001). Conclusions Compared to “usual practice”, video-assisted oral feedback reduced anxiety and significantly decreased the proportion of students experiencing severe anxiety. PMID:24885005

  4. Ofatumumab maintenance versus observation in relapsed chronic lymphocytic leukaemia (PROLONG): an open-label, multicentre, randomised phase 3 study.

    PubMed

    van Oers, Marinus H J; Kuliczkowski, Kazimierz; Smolej, Lukáš; Petrini, Mario; Offner, Fritz; Grosicki, Sebastian; Levin, Mark-David; Gupta, Ira; Phillips, Jennifer; Williams, Vanessa; Manson, Stephanie; Lisby, Steen; Geisler, Christian

    2015-10-01

    Ofatumumab is a human anti-CD20 monoclonal antibody that has proven efficacy as monotherapy in refractory chronic lymphocytic leukaemia. We assessed the efficacy and safety of ofatumumab maintenance treatment versus observation for patients in remission after re-induction treatment for relapsed chronic lymphocytic leukaemia. This open-label, multicentre, randomised phase 3 study enrolled patients aged 18 years or older from 130 centres in 24 countries who had chronic lymphocytic leukaemia in complete or partial remission after second-line or third-line treatment. Eligible patients had a WHO performance status of 0-2, had a response assessment within the previous 3 months, did not have refractory disease, autoimmune haemolytic anaemia requiring treatment, chronic or active infection requiring treatment, and had not previously received maintenance treatment or autologous or allogeneic stem-cell transplant. Using a randomisation list generated by a central computerised system and an interactive voice recognition system, we randomly assigned (1:1) patients to receive ofatumumab (300 mg followed by 1000 mg 1 week later and every 8 weeks for up to 2 years) or undergo observation. Randomisation was stratified by number and type of previous treatment and remission status after induction treatment (block size of four). Treatment assignment was open label. The primary endpoint was investigator-assessed progression-free survival in the intention-to-treat population. We report the results of a prespecified interim analysis after two-thirds of the planned study events (disease progression or death) had happened. This trial is closed to accrual but follow-up is ongoing. This trial is registered with ClinicalTrials.gov, number NCT00802737. Between May 6, 2010, and June 19, 2014, we enrolled 474 patients: 238 patients were randomly assigned to receive ofatumumab maintenance treatment and 236 to undergo observation. One (<1%) patient in the ofatumumab group did not receive the

  5. The talent study: a multicentre randomized controlled trial assessing the impact of a 'tailored lifestyle self-management intervention' (talent) on weight reduction.

    PubMed

    Melchart, Dieter; Doerfler, Wolfgang; Eustachi, Axel; Wellenhofer-Li, Yanqing; Weidenhammer, Wolfgang

    2015-01-01

    Overweight is considered an important risk factor for diseases in the context of metabolic syndrome. Lifestyle modifications are the means of choice to reduce weight in persons with a Body Mass Index of 28 to 35. The study examines whether there are any differences between two intervention strategies regarding weight reduction in overweight persons. The study is a multicentre randomized controlled trial with observation duration of 12 months. Eight study centres are involved to include a minimal sample size of 150 participants. Randomization ratio is 2:1. Feasible persons are checked according to inclusion and exclusion criteria and after given informed consent are assigned randomly to one of two intervention programs: A) intervention group: comprehensive lifestyle modification program (Individual Health Management IHM) with 3 months reduction phase plus 9 months maintaining phase, B) control group: written information with advice for healthy food habits (Usual care UC). Participants of the IHM group have access to a web-based health portal and join 3 full-day and 10 two-hour training sessions during the first 3 months. During the remaining 9 months four refresh trainings will be performed. There are 3 different diet strategies (fasting, two-day diet, meal replacement) for free choice. Participants of the control group are provided with acknowledged rules for healthy food according to the German Nutrition Society (DGE). Examinations are conducted at baseline, after 3, 6, 9 and 12 months. They include body weight, waist circumference, blood pressure, laboratory findings and a bio-impedance analysis to measure body composition. Statistical analysis of the primary outcome 'change of body weight after 12 months' is based on ITT population including analysis of variance of the weight differences between month 0 and 12 with the factors 'group', 'baseline value' and 'study centre'. Secondary outcomes will be analyzed exploratively. The monitoring of the study will

  6. Double random phase encoding using phase reservation and compression

    NASA Astrophysics Data System (ADS)

    Chen, Wen; Chen, Xudong

    2014-02-01

    In recent years, various studies have been conducted to illustrate the vulnerability of double random phase encoding (DRPE). In this paper, we propose a novel method via phase reservation and compression to enhance DRPE security. Only a compressed phase distribution is available in the CCD plane, and the amplitude component is not available or requested for optical decryption. Since only noise-like distributions can be obtained by using the correct security keys during optical decryption, a nonlinear correlation algorithm is further applied for authenticating the decrypted image. It is demonstrated that valid conditions for attack algorithms are broken and high security can be achieved for the DRPE system.

  7. Neoadjuvant chemotherapy versus surgery first for resectable pancreatic cancer (Norwegian Pancreatic Cancer Trial - 1 (NorPACT-1)) - study protocol for a national multicentre randomized controlled trial.

    PubMed

    Labori, Knut Jørgen; Lassen, Kristoffer; Hoem, Dag; Grønbech, Jon Erik; Søreide, Jon Arne; Mortensen, Kim; Smaaland, Rune; Sorbye, Halfdan; Verbeke, Caroline; Dueland, Svein

    2017-08-25

    Pancreatic cancer is the fourth leading cause of cancer-related death. While surgical resection remains the foundation for potentially curative treatment, survival benefit is achieved with adjuvant oncological treatment. Thus, completion of multimodality treatment (surgical resection and (neo)adjuvant chemotherapy) to all patients and early treatment of micrometastatic disease is the ideal goal. NorPACT-1 aims to test the hypothesis that overall mortality at one year after allocation of treatment can be reduced with neoadjuvant chemotherapy in surgically treated patients with resectable pancreatic cancer. The NorPACT- 1 is a multicentre, randomized controlled phase III trial organized by the Norwegian Gastrointestinal Cancer Group for Hepato-Pancreato-Biliary cancer. Patients with resectable adenocarcinoma of the pancreatic head are randomized to receive either surgery first (Group 1: SF/control) or neoadjuvant chemotherapy (Group 2: NT/intervention) with four cycles FOLFIRINOX followed by resection. Both groups receive adjuvant chemotherapy with gemicitabine and capecitabine (six cycles in Group 1, four cycles in Group 2). In total 90 patients will be randomized in all the five Norwegian university hospitals performing pancreatic surgery. Primary endpoint is overall mortality at one year following commencement of treatment for those who ultimately undergo resection. Secondary endpoints are overall survival after date of randomization (intention to treat), overall survival after resection, disease-free survival, histopathological response, complication rates after surgery, feasibility of neoadjuvant and adjuvant chemotherapy, completion rates of all parts of multimodal treatment, and quality-of-life. Bolt-on to the study is a translational research program that aims at identifying factors that are predictive of response to NT, the risk of distant cancer spread, and patient outcome. NorPACT- 1 is designed to investigate the additional benefit of NT compared to

  8. Study protocol for multicentre randomized controlled trial of HeLP (Heat Loss Prevention) in the delivery room.

    PubMed

    Vohra, Sunita; Reilly, Maureen; Rac, Valeria E; Bhaloo, Zafira; Zayack, Denise; Wimmer, John; Vincer, Michael; Ferrelli, Karla; Kiss, Alex; Soll, Roger; Dunn, Michael

    2013-09-01

    Immediate postnatal hypothermia is an independent risk factor for death in premature newborns. Three randomized controlled trials (RCTs) and five historical controlled trials show statistically significant differences in admission temperature between infants wrapped in occlusive skin wrap and unwrapped infants. This paper presents a study protocol for The Vermont Oxford Network (VON) Heat Loss Prevention (HeLP) Trial, a multicentre RCT of two interventions (standard of care vs. occlusive wrap) that investigates the effect of polyethylene occlusive wrap applied immediately after birth on mortality in infants born 24 + 0/7 to 27 + 6/7 week gestation. Inclusion criteria include: infants 24 + 0/7 to 27 + 6/7 weeks gestational age and a firm decision prior to birth to provide full resuscitative measures. Exclusion criteria comprise infants born with blistering skin conditions or congenital anomalies that are not covered by skin. The primary outcome measure is all-cause mortality until discharge from the hospital or at six months corrected gestational age. The secondary outcome measures include baseline and post-stabilization axillary temperatures, acidosis, hypotension, hypoglycaemia, seizures in the first 12h, patent ductus arteriosus, and respiratory distress syndrome. Long-term follow-up at 18 to 24 months corrected age will be assessed with the combined risk of death and major neurosensory disability as the primary outcome. Key covariates and protocol deviations are addressed and steps to monitor these are described. Wrapping may prove an inexpensive and easy method to benefit premature newborns in level I and II nurseries, in both developed and developing countries, as well as large tertiary care centres. Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada-355-2003 University of Alberta, Edmonton, Alberta, Canada-Pro00003810 Vermont Oxford Network, Burlington, Vermont, USA-CHRMS: M04-295. Copyright © 2013 Elsevier Inc. All rights reserved.

  9. Short-course eflornithine in Gambian trypanosomiasis: a multicentre randomized controlled trial.

    PubMed Central

    Pépin, J.; Khonde, N.; Maiso, F.; Doua, F.; Jaffar, S.; Ngampo, S.; Mpia, B.; Mbulamberi, D.; Kuzoe, F.

    2000-01-01

    OBJECTIVE: A randomized controlled trial was conducted to determine whether 7 days of intravenous eflornithine (100 mg/kg every 6 h) was as effective as the standard 14-day regimen in the treatment of late-stage Trypanosoma brucei gambiense trypanosomiasis. METHODS: A total of 321 patients (274 new cases, 47 relapsing cases) were randomized at four participating centres in Congo, Côte d'Ivoire, the Democratic Republic of the Congo, and Uganda to one of these treatment regimens and followed up for 2 years. RESULTS: Six patients died during treatment, one of whom was on the 7-day regimen, whereas the other five had been on the 14-day regimen (P = 0.2). The response to eflornithine differed markedly between Uganda and other countries. Among new cases in Uganda, the 2-year probability of cure was 73% on the 14-day course compared with 62% on the 7-day regimen (hazard ratio (HR) for treatment failure, 7-day versus 14-day regimen: 1.45, 95% CI: 0.7, 3.1, P = 0.3). Among new cases in Côte d'Ivoire, Congo, and the Democratic Republic of the Congo combined, the 2-year probability of cure was 97% on the 14-day course compared with 86.5% on the 7-day regimen (HR for treatment failure, 7-day vs 14-day: 6.72, 95% confidence interval (CI): 1.5, 31.0, P = 0.003). Among relapsing cases in all four countries, the 2-year probability of cure was 94% with 7 days and 100% with 14 days of treatment. Factors associated with a higher risk of treatment failure were: a positive lymph node aspirate (HR 4.1; 95% CI: 1.8-9.4), a cerebrospinal fluid (CSF) white cell count > or = 100/mm3 (HR 3.5; 95% CI: 1.1-10.9), being treated in Uganda (HR 2.9; 95% CI: 1.4-5.9), and CSF trypanosomes (HR 1.9; 95% CI: 0.9-4.1). Being stuporous on admission was associated with a lower risk of treatment failure (HR 0.18; 95% CI: 0.02-1.4) as was increasing age (HR 0.977; 95% CI: 0.95-1.0, for each additional year of age). DISCUSSION: The 7-day course of eflornithine is an effective treatment of relapsing cases

  10. Efficacy of Propolis on the Denture Stomatitis Treatment in Older Adults: A Multicentric Randomized Trial

    PubMed Central

    Pina, Gisela de M. S.; Lia, Erica N.; Berretta, Andresa A.; Nascimento, Andresa P.; Torres, Elina C.; Buszinski, Andrei F. M.; de Campos, Tatiana A.; Martins, Vicente de P.

    2017-01-01

    Our hypothesis tested the efficacy and safety of a mucoadhesive oral gel formulation of Brazilian propolis extract compared to miconazole oral gel for the treatment of denture stomatitis due to Candida spp. infection in older adults. Forty patients were randomly allocated in a noninferiority clinical trial into two groups. The control group (MIC) received 20 mg/g miconazole oral gel and the study group (PROP) received mucoadhesive formulation containing standardized extract of 2% (20 mg/g) propolis (EPP-AF®) during 14 days. Patients were examined on days 1, 7, and 14. The Newton's score was used to classify the severity of denture stomatitis. The colony forming unity count (CFU/mL) was quantified and identified (CHROMagar Candida®) before and after the treatment. Baseline characteristics did not differ between groups. Both treatments reduced Newton's score (P < 0.0001), indicating a clinical improvement of the symptoms of candidiasis with a clinical cure rate of 70%. The microbiological cure with significant reduction in fungal burden on T14 was 70% in the miconazole group and 25% in the EPP-AF group. The EPP-AF appears to be noninferior to miconazole considering the clinical cure rate and could be recommended as an alternative treatment in older patients. PMID:28396692

  11. Comparison of tinzaparin and acenocoumarol for the secondary prevention of venous thromboembolism: a multicentre, randomized study.

    PubMed

    Pérez-de-Llano, Luis A; Leiro-Fernández, Virginia; Golpe, Rafael; Núñez-Delgado, Jose M; Palacios-Bartolomé, Ana; Méndez-Marote, Lidia; Colomé-Nafria, Esteve

    2010-12-01

    The objective of the present study was to evaluate the efficacy, safety and healthcare resource utilization of long-term treatment with tinzaparin in symptomatic patients with acute pulmonary embolism as compared to standard therapy. In this open-label trial, 102 patients with objectively confirmed pulmonary embolism were randomized to receive, after initial treatment with tinzaparin, either tinzaparin (175 IU/kg/day) or international normalized ratio-adjusted acenocoumarol for 6 months. Clinical endpoints were assessed during the 6 months of treatment. A pharmacoeconomic analysis was carried out to evaluate the cost of the long-term treatment with tinzaparin in comparison with the standard one. In an intention-to-treat analysis, one of 52 patients developed recurrent venous thromboembolism in the tinzaparin group compared with none of the 50 patients in the acenocoumarol group. One patient in each group had a major haemorrhagic complication. Six patients in the acenocoumarol group had minor bleeding compared with none in the tinzaparin group (P = 0.027). Median hospital length of stay was shorter in the tinzaparin group compared to the acenocoumarol group (7 versus 9 days; P = 0.014). When all the direct and indirect cost components were combined for the entire population, we found a slight, nonstatistically significant (mean difference €345; 95% CI 1382-2071; P = 0.69) reduction in total cost with tinzaparin. Symptomatic acute pulmonary embolism treatment with full therapeutic doses of tinzaparin for 6 months is a feasible alternative to conventional treatment with vitamin K antagonists.

  12. Long-term effects of high-efficiency on-line haemodiafiltration on uraemic toxicity. A multicentre prospective randomized study.

    PubMed

    Pedrini, Luciano A; De Cristofaro, Vincenzo; Comelli, Mario; Casino, Francesco G; Prencipe, Mario; Baroni, Adriana; Campolo, Gesualdo; Manzoni, Celestina; Colì, Luigi; Ruggiero, Pio; Acquistapace, Irene; Auriemma, Laura

    2011-08-01

    Haemodiafiltration (HDF) may improve survival of chronic dialysis patients. This prospective, multicentre randomized cross-over study evaluated the effects of long-term on-line HDF on the levels of solutes of different molecular weight markers or causative agents of the most common metabolic derangements in uraemia. Sixty-nine patients from eight Italian centres were randomly assigned to two 6-month treatment sequences: A-B and B-A [A, low-flux haemodialysis (HD) and B, on-line HDF]. Comparative evaluation of basal levels of small, medium-sized and protein-bound solutes at the end of the two treatment periods and analysis of parameters dependence during the interventions were performed. On-line HDF showed greater efficiency than low-flux HD in removing small solutes (eKt/Vurea 1.60 ± 0.31 versus 1.44 ± 0.26, P < 0.0001) and in reducing basal levels of beta2-microglobulin (22.2 ± 7.8 versus 33.5 ± 11.8 mg/L, P < 0.0001), total homocysteine (15.4 ± 5.0 versus 18.7 ± 8.2 μmol/L, P = 0 .003), phosphate (4.6 ± 1.3 versus 5.0 ± 1.4 mg/dL, P = 0.008) and, remarkably, of intact parathyroid hormone (202 ± 154 versus 228 ± 176 pg/mL, P = 0.03). Moreover, in on-line HDF, lower levels of C-reactive protein (5.5 ± 5.5 versus 6.7 ± 6.1 mg/L, P = 0.03) and triglycerides (148 ± 77 versus 167 ± 87 mg/dL, P = 0.008) and increased HDL cholesterol (49.2 ± 12.7 versus 44.7 ± 12.4 mg/dL, P = <0.0001) were observed. The asymmetric dimethylarginine level was not significantly affected (0.97 ± 0.4 versus 0.84 ± 0.37 μmol/L). Erythropoietin and phosphate binders' doses could be reduced. On-line high-efficiency HDF resulted in enhanced removal and lower basal levels of small, medium-sized and protein-bound solutes, which are markers or causative agents of uraemic pathologies, mainly inflammation, secondary hyperparathyroidism and dyslipidaemia. This may contribute to reducing uraemic complications and possibly to improving patient survival.

  13. [Acupuncture and moxibustion for peripheral facial palsy at different stages: multi-central large-sample randomized controlled trial].

    PubMed

    Li, Ying; Li, Yan; Liu, Li-an; Zhao, Ling; Hu, Ka-ming; Wu, Xi; Chen, Xiao-qin; Li, Gui-ping; Mang, Ling-ling; Qi, Qi-hua

    2011-04-01

    To explore the best intervention time of acupuncture and moxibustion for peripheral facial palsy (Bell's palsy) and the clinical advantage program of selective treatment with acupuncture and moxibustion. Multi-central large-sample randomized controlled trial was carried out. Nine hundreds cases of Bell's palsy were randomized into 5 treatment groups, named selective filiform needle group (group A), selective acupuncture + moxibustion group (group B), selective acupuncture + electroacupuncture (group C), selective acupuncture + line-up needling on muscle region of meridian group (group D) and non-selective filiform needle group (group E). Four sessions of treatment were required in each group. Separately, during the enrollment, after 4 sessions of treatment, in 1 month and 3 months of follow-up after treatment, House-Brackmann Scale, Facial Disability Index Scale and Degree of Facial Nerve Paralysis (NFNP) were adopted for efficacy assessment. And the efficacy systematic analysis was provided in view of the intervention time and nerve localization of disease separately. The curative rates of intervention in acute stage and resting stage were 50.1% (223/445) and 52.1% (162/311), which were superior to recovery stage (25.9%, 35/135) separately. There were no statistical significant differences in efficacy in comparison among 5 treatment programs at the same stage (all P > 0.05). The efficacy of intervention of group A and group E in acute stage was superior to that in recovery stage (both P < 0.01). The difference was significant statistically between the efficacy on the localization above chorda tympani nerve and that on the localization below the nerve in group D (P < 0.01). The efficacy on the localization below chorda tympani nerve was superior to the localization above the nerve. The best intervention time for the treatment of Bell's palsy is in acute stage and resting stage, meaning 1 to 3 weeks after occurrence. All of the 5 treatment programs are advantageous

  14. Mono- versus polyaxial locking plates in distal femur fractures: a prospective randomized multicentre clinical trial.

    PubMed

    Hanschen, Marc; Aschenbrenner, Ina M; Fehske, Kai; Kirchhoff, Sonja; Keil, Leonhard; Holzapfel, Boris M; Winkler, Sebastian; Fuechtmeier, Bernd; Neugebauer, Rainer; Luehrs, Sven; Liener, Ulrich; Biberthaler, Peter

    2014-04-01

    Treatment of complex fractures of the distal femur utilizing monoaxial locking plates (e.g. Less Invasive Stabilisation System, LISS®, Synthes) is considered to be superior to conventional plating systems. Due to the limitation that the thread forces the screw into pre-determined positions, modifications have been made to allow screw positioning within a range of 30° (Non Contact Bridging, NCB®-DF, Zimmer). For the first time, this multicenter prospective randomized clinical trial (RCT) investigates the outcome of LISS® vs. NCB®-DF treatment following complex fractures of the distal femur. Since June 2008, 27 patients with a fracture of the distal femur (AO ASIF 33-A-C and periprosthetic fractures) were enrolled in this study by four university trauma centres in southern Germany. Clinical (e.g. range of motion, Oxford knee score, Tegner score) and radiological (e.g. axis deviation, secondary loss of realignment) follow-ups were conducted one and six weeks, as well as three, six, and 12 months after the operation. This study comprises data of 27 patients (8 male, 19 female; 15 NCB®-DF, 12 LISS®). Polyaxial osteosynthesis using the NCB® system tended to result in better functional knee scores and a higher range of motion. Interestingly, fracture union tended to be more rapid using the polyaxial plating system. We present the analysis of a multicenter prospective RCT to compare the monoaxial LISS® vs. the polyaxial NCB®-DF treatment following complex fractures of the distal femur. NCB®-DF treatment tended to result in better functional and radiological outcomes than LISS® treatment. Level I.

  15. Relativistic Random Phase Approximation At Finite Temperature

    SciTech Connect

    Niu, Y. F.; Paar, N.; Vretenar, D.; Meng, J.

    2009-08-26

    The fully self-consistent finite temperature relativistic random phase approximation (FTRRPA) has been established in the single-nucleon basis of the temperature dependent Dirac-Hartree model (FTDH) based on effective Lagrangian with density dependent meson-nucleon couplings. Illustrative calculations in the FTRRPA framework show the evolution of multipole responses of {sup 132}Sn with temperature. With increased temperature, in both monopole and dipole strength distributions additional transitions appear in the low energy region due to the new opened particle-particle and hole-hole transition channels.

  16. Reduction of relapses of atopic dermatitis with methylprednisolone aceponate cream twice weekly in addition to maintenance treatment with emollient: a multicentre, randomized, double-blind, controlled study.

    PubMed

    Peserico, A; Städtler, G; Sebastian, M; Fernandez, R Suarez; Vick, K; Bieber, T

    2008-04-01

    The relapsing nature of atopic dermatitis (AD) presents a challenge for its long-term treatment. Efficacy and safety of corticosteroids have been proven in the acute treatment of active AD, but their long-term efficacy and potential to reduce or prevent relapses have only partially been addressed. To investigate long-term management (16 weeks) of AD with methylprednisolone aceponate (MPA) 0.1% cream twice weekly in addition to an emollient (Advabase((R))) after stabilization of an acute severe or very severe flare of AD with MPA cream. Patients > or = 12 years of age with a > or = 2-year history of moderate to severe AD were eligible for this multicentre, randomized, double-blind, controlled study if they presented with an acute flare of severe or very severe AD [Investigator's Global Assessment (IGA) score > or = 4]. After successful treatment of the flare in an acute phase (AP), patients received either MPA twice weekly plus emollient or emollient alone over a 16-week maintenance phase (MP). The primary study endpoint was time to relapse of AD. Secondary endpoints included relapse rate and disease status, the patient's assessment of intensity of itch, the Eczema Area and Severity Index, the IGA score, affected body surface area, Dermatology Life Quality Index (DLQI) and children's DLQI (CDLQI), patient's and investigator's global assessment of response and patient's assessment of quality of sleep. Two hundred and forty-nine patients entered the AP and 221 continued into the MP. Time to relapse was longer in the MPA group than in the emollient group. The probability of remaining free from relapse after 16 weeks was 87.1% in the MPA group compared with 65.8% for the emollient. Patients treated with MPA twice weekly had a 3.5-fold lower risk of experiencing a relapse than patients treated with emollient alone (hazard ratio 3.5, 95% confidence interval 1.9-6.4; P < 0.0001). MPA was also superior to emollient for all other efficacy endpoints. Therapy with both

  17. The influence of review pathology on study outcome of a randomized multicentre superficial bladder cancer trial. Members of the Dutch South East Cooperative Urological Group.

    PubMed

    Witjes, J A; Kiemeney, L A; Schaafsma, H E; Debruyn, F M

    1994-02-01

    To determine whether differences between local and review pathology in a multicentre study influence the results of treatment and results from prognostic factor analysis. A randomized multicentre study in superficial bladder cancer is reported, in which the influence of local and review pathology on the study outcome was investigated. The conformity between local and review pathology of the pT category was 79.3%, of the grade 70.2%, and the combination of both 59.7%. In local pathology, undergrading was more frequent than overgrading and overstaging more frequent than understaging. However, the risks of recurrent disease in the separate stage and grade groups remained the same after correcting the pathology result. A prognostic factor analysis with regard to the risk of recurrent disease was carried out. The Cox hazard ratios of tumour localization, multiplicity, patient age (significant factors), tumour grade, size, history and gender (not significant) remained almost the same after correction for review pathology. Only the prognostic relevance of tumour stage increased after pathology correction. We conclude that, although review pathology caused considerable changes in the pathology results, this did not change the results of treatment, and hardly altered the results of a prognostic factor analysis in this randomized study.

  18. Modulation of 5-fluorouracil as adjuvant systemic chemotherapy in colorectal cancer: the IGCS-COL multicentre, randomised, phase III study

    PubMed Central

    De Placido, S; Lopez, M; Carlomagno, C; Paoletti, G; Palazzo, S; Manzione, L; Iannace, C; Ianniello, G P; De Vita, F; Ficorella, C; Farris, A; Pistillucci, G; Gemini, M; Cortesi, E; Adamo, V; Gebbia, N; Palmeri, S; Gallo, C; Perrone, F; Persico, G; Bianco, A R

    2005-01-01

    The aims of this multicentre, randomised phase III trial were to evaluate: (1) the role of levamisol (LEV); and (2) the role of folinic acid (FA), added to 5-fluorouracil (5FU) in the adjuvant treatment of colorectal cancer. Patients with histologically proven, radically resected stage II or III colon or rectal cancer were eligible. The study had a 2 × 2 factorial design with four treatment arms: (a) 5FU alone, (b) 5FU+LEV, (c) 5FU+FA, (d) 5FU+LEV+FA, and two planned comparisons, testing the role of LEV and of FA, respectively. From March 1991, to September 1998, 1327 patients were randomised. None of the two comparisons resulted in a significant disease-free (DFS) or overall (OAS) survival advantage. The hazard ratio (HR) of relapse was 0.89 (95% confidence intervals (CI): 0.73–1.09) for patients receiving FA and 0.99 (95% CI 0.80–1.21) for those receiving LEV; corresponding HRs of death were 1.02 (95% CI: 0.80–1.30) and 0.94 (95% CI 0.73–1.20). Nonhaematological toxicity (all grade vomiting, diarrhoea, mucositis, congiuntivitis, skin, fever and fatigue) was significantly worse with FA, while all other toxicities were similar. In the present trial, there was no evidence that the addition of FA or LEV significantly prolongs DFS and OAS of radically resected colorectal cancer patients. PMID:16222322

  19. Multicentre phase II trial of trastuzumab and capecitabine in patients with HER2 overexpressing metastatic pancreatic cancer

    PubMed Central

    Harder, J; Ihorst, G; Heinemann, V; Hofheinz, R; Moehler, M; Buechler, P; Kloeppel, G; Röcken, C; Bitzer, M; Boeck, S; Endlicher, E; Reinacher-Schick, A; Schmoor, C; Geissler, M

    2012-01-01

    Background: New therapeutic options for metastatic pancreatic cancer are urgently needed. In pancreatic cancer, overexpression of the epidermal growth factor receptor 2 (HER2) has been reported in up to 45%. This multicentre phase II study investigated the efficacy and toxicity of the HER2 antibody trastuzumab combined with capecitabine in the patients with pancreatic cancer and HER2 overexpression. Methods: Primary endpoint was progression-free survival (PFS) after 12 weeks. A total of 212 patients were screened for HER2 expression. Results: Immunohistochemical (IHC) HER2 expression was: 83 (40%) grade 0, 71 (34%) grade 1, 31 (15%) grade 2, 22 (11%) grade 3. A total of 17 patients with IHC +3 HER2 expression or gene amplification could be assessed for the treatment response. Grade 3/4 treatment toxicities were: each 7% leucopenia, diarrhoea, nausea and hand-foot syndrome. Progression-free survival after 12 weeks was 23.5%, median overall survival (OS) 6.9 months. Conclusion: This study demonstrates +3 HER2 expression or gene amplification in 11% of patients. Contrary to breast and gastric cancer, only 7 out of 11 (64%) patients with IHC +3 HER2 expression showed gene amplification. Although the therapy was well tolerated, PFS and OS did not perform favourably compared with standard chemotherapy. Together, we do not recommend further evaluation of anti-HER2 treatment in patients with metastatic pancreatic cancer. PMID:22374460

  20. Guadecitabine (SGI-110) in treatment-naive patients with acute myeloid leukaemia: phase 2 results from a multicentre, randomised, phase 1/2 trial.

    PubMed

    Kantarjian, Hagop M; Roboz, Gail J; Kropf, Patricia L; Yee, Karen W L; O'Connell, Casey L; Tibes, Raoul; Walsh, Katherine J; Podoltsev, Nikolai A; Griffiths, Elizabeth A; Jabbour, Elias; Garcia-Manero, Guillermo; Rizzieri, David; Stock, Wendy; Savona, Michael R; Rosenblat, Todd L; Berdeja, Jesus G; Ravandi, Farhad; Rock, Edwin P; Hao, Yong; Azab, Mohammad; Issa, Jean-Pierre J

    2017-10-01

    The hypomethylating drugs azacitidine and decitabine have shown efficacy in myelodysplastic syndromes and acute myeloid leukaemia, but complete tumour responses are infrequent and of short duration, possibly because of the short half-lives and suboptimal bone marrow exposure of the drugs. Guadecitabine, a next-generation hypomethylating drug, has a longer half-life and exposure than its active metabolite decitabine. A phase 1 study established 60 mg/m(2) guadecitabine for 5 days as an effective treatment schedule. In this phase 2 study, we aimed to assess the safety and activity of two doses and schedules of guadecitabine in older (≥65 years) patients with treatment-naive acute myeloid leukaemia who were not candidates for intensive chemotherapy. We did a multicentre, randomised, open-label, phase 1/2 study of guadecitabine in cohorts of patients with treatment-naive acute myeloid leukaemia, relapsed or refractory acute myeloid leukaemia, and myelodysplastic syndromes; here we report the phase 2 results from the cohort of treatment-naive patients with acute myeloid leukaemia. We included patients aged at least 65 years from 14 US medical centres (hospitals and specialist cancer clinics) who were not candidates for intensive chemotherapy and randomly assigned them (1:1) using a computer algorithm (for dynamic randomisation) to guadecitabine 60 or 90 mg/m(2) on days 1-5 (5-day schedule) of a 28-day treatment cycle. Treatment allocation was not masked. We also assigned additional patients to guadecitabine 60 mg/m(2) in a 10-day schedule in a 28-day treatment cycle after a protocol amendment. The primary endpoint was composite complete response (complete response, complete response with incomplete platelet recovery, or complete response with incomplete neutrophil recovery regardless of platelets). Response was assessed in all patients (as-treated) who received at least one dose of guadecitabine. We present the final analysis, although at the time of the database lock

  1. Oral epigallocatechin-3-gallate for treatment of dystrophic epidermolysis bullosa: a multicentre, randomized, crossover, double-blind, placebo-controlled clinical trial.

    PubMed

    Chiaverini, Christine; Roger, Coralie; Fontas, Eric; Bourrat, Emmanuelle; Bourdon-Lanoy, Eva; Labrèze, Christine; Mazereeuw, Juliette; Vabres, Pierre; Bodemer, Christine; Lacour, Jean-Philippe

    2016-03-25

    Recessive dystrophic epidermolysis bullosa (RDEB) is a rare genodermatosis with severe blistering. No curative treatment is available. Scientific data indicated that epigallocatechin-3-gallate (EGCG), a green tea extract, might improve the phenotype of RDEB patients. In a multicentre, randomized, crossover, double-blind, placebo-controlled clinical trial, we evaluated a 4-month oral EGCG treatment regimen in 17 RDEB patients. We found that EGCG treatment was not more effective than placebo in modified intention to treat and per protocol analysis (n = 16; p = 0.78 and n = 10; p = 1 respectively). Tolerance was good. Specific organizational and technical difficulties of controlled randomized double-blind trials in EB patients are discussed. US National Institutes of Health Clinical Trial Register ( NCT00951964 ).

  2. Random bilayer phases of dilute surfactant solutions

    NASA Astrophysics Data System (ADS)

    Cates, M. E.; Roux, D.

    1990-12-01

    Surfactant molecules in dilute solution may aggregate reversibly into extended structures. For suitably chosen molecules, the preferred packing involves a locally flat bilayer which tends to wander entropically at large distances. At low temperatures (and/or high concentrations) the system forms a stack of flat sheets with one-dimensional quasi-long range order (a smectic liquid crystal), but at high temperatures or low concentrations, the stack can melt into a random surface structure that resembles a multiply connected labyrinth or 'sponge' of bilayer in a sea of solvent. Recent theoretical and experimental progress in understanding the properties of the sponge is reviewed. The authors argue that the sponge phase may provide a good system for the study of various liquid-state critical phenomena.

  3. Phase transitions in random quantum satisfiability

    NASA Astrophysics Data System (ADS)

    Laumann, Chris; Moessner, Roderich; Scardicchio, Antonello; Sondhi, Shivaji

    2009-03-01

    The potential power of quantum computers is a subject of great current interest and the raison d'etre for the intense effort and progress to build them. Naturally much theoretical interest has focused on algorithms that outperform their classical counterpart but recent developments in quantum complexity theory suggest that we already know problems, those shown to be QMA-complete, whose worst case instances would take a quantum computer exponentially long to solve. As in classical complexity theory the supposed difficulty of QMA complete problems follows from the existence of polynomial transformations relating any of the large class of QMA problems to instances of QMA-complete questions. This does not directly address the question of why this problem has hard instances and what features they posses. In this work we attempt to investigate the features of hard instances of a QMA complete problem introduced by S. Bravyi: quantum k-SAT. We use techniques of statistical physics of disordered systems in order to study a random ensemble of quantum k-SAT instances parametrized by clause density α in a program that is analogous to recent studies of classical random k-SAT. We establish a phase transition in satisfiability as a function of clause density and show that the problem almost always reduces to identifying a classical graph property.

  4. Coulomb glass in the random phase approximation

    NASA Astrophysics Data System (ADS)

    Basylko, S. A.; Onischouk, V. A.; Rosengren, A.

    2002-01-01

    A three-dimensional model of the electrons localized on randomly distributed donor sites of density n and with the acceptor charge uniformly smeared on these sites, -Ke on each, is considered in the random phase approximation (RPA). For the case K=1/2 the free energy, the density of the one-site energies (DOSE) ɛ, and the pair OSE correlators are found. In the high-temperature region (e2n1/3/T)<1 (T is the temperature) RPA energies and DOSE are in a good agreement with the corresponding data of Monte Carlo simulations. Thermodynamics of the model in this region is similar to the one of an electrolyte in the regime of Debye screening. In the vicinity of the Fermi level μ=0 the OSE correlations, depending on sgn(ɛ1.ɛ2) and with very slow decoupling law, have been found. The main result is that even in the temperature range where the energy of a Coulomb glass is determined by Debye screening effects, the correlations of the long-range nature between the OSE still exist.

  5. Clinical efficacy and mechanistic evaluation of aflibercept for proliferative diabetic retinopathy (acronym CLARITY): a multicentre phase IIb randomised active-controlled clinical trial.

    PubMed

    Sivaprasad, Sobha; Prevost, A Toby; Bainbridge, James; Edwards, Rhiannon Tudor; Hopkins, David; Kelly, Joanna; Luthert, Phil; Murphy, Caroline; Ramu, Jayashree; Sarafraz-Shekary, Negin; Vasconcelos, Joana; White-Alao, Beverley; Hykin, Philip

    2015-09-14

    Proliferative diabetic retinopathy (PDR) is the main cause of severe visual loss in people with diabetes mellitus. The standard treatment for this condition is panretinal photocoagulation (PRP). This laser treatment is inherently destructive, with predictable adverse effects on visual function, and a safer alternative is required. Intravitreal injection of vascular endothelial growth factor (VEGF) inhibitors can induce short-term regression of retinal neovascularisation. The aim of this randomised controlled trial is to determine the efficacy, safety and cost-effectiveness of intravitreal aflibercept, an inhibitor of VEGF-A, VEGF-B and placental growth factor (PLGF), in PDR, and to investigate the impact on local oxygenation. This is a phase IIb randomised controlled single-masked multicentre clinical trial to determine the impact of repeated intravitreal aflibercept injections in the treatment and prevention of PDR. 220 participants with treatment-naïve or treated but active retinal neovascularisation in at least one eye will be randomly allocated 1:1 to intravitreal aflibercept injections or PRP for a period of 52 weeks. The primary outcome is the change in best-corrected visual acuity in the study eye at 52 weeks. Secondary outcomes include changes from baseline in other visual functions, anatomical changes and cost-effectiveness. Ocular and non-ocular adverse events will also be reported over 52 weeks. The study has been approved by the National Research Ethics Service (NRES) committee with respect to scientific content and compliance with applicable research and human subjects' regulations. Findings will be reported through scientific publications and research conferences. The results of this study will provide clinical evidence for the feasibility, efficacy safety and cost-effectiveness of intravitreal aflibercept for PDR. ISRCTN 32207582. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence

  6. A pollen extract (Cernilton) in patients with inflammatory chronic prostatitis-chronic pelvic pain syndrome: a multicentre, randomised, prospective, double-blind, placebo-controlled phase 3 study.

    PubMed

    Wagenlehner, Florian M E; Schneider, Henning; Ludwig, Martin; Schnitker, Jörg; Brähler, Elmar; Weidner, Wolfgang

    2009-09-01

    National Institutes of Health (NIH) category III prostatitis/chronic pelvic pain syndrome (CP/CPPS) is a prevalent condition for which no standardised treatment exists. To assess the safety and efficacy of a standardised pollen extract in men with inflammatory CP/CPPS. We conducted a multicentre, prospective, randomised, double-blind, placebo-controlled phase 3 study comparing the pollen extract (Cernilton) to placebo in men with CP/CPPS (NIH IIIA) attending urologic centres. Participants were randomised to receive oral capsules of the pollen extract (two capsules q8h) or placebo for 12 wk. The primary endpoint of the study was symptomatic improvement in the pain domain of the NIH Chronic Prostatitis Symptom Index (NIH-CPSI). Participants were evaluated using the NIH-CPSI individual domains and total score, the number of leukocytes in post-prostatic massage urine (VB3), the International Prostate Symptom Score (IPSS), and the sexuality domain of a life satisfaction questionnaire at baseline and after 6 and 12 wk. In the intention-to-treat analysis, 139 men were randomly allocated to the pollen extract (n=70) or placebo (n=69). The individual domains pain (p=0.0086) and quality of life (QoL; p=0.0250) as well as the total NIH-CPSI score (p=0.0126) were significantly improved after 12 wk of treatment with pollen extract compared to placebo. Response, defined as a decrease of the NIH-CPSI total score by at least 25% or at least 6 points, was seen in the pollen extract versus placebo group in 70.6% and 50.0% (p=0.0141), respectively. Adverse events were minor in all patients studied. Compared to placebo, the pollen extract significantly improved total symptoms, pain, and QoL in patients with inflammatory CP/CPPS without severe side-effects.

  7. High versus low energy administration in the early phase of acute pancreatitis (GOULASH trial): protocol of a multicentre randomised double-blind clinical trial.

    PubMed

    Márta, Katalin; Szabó, Anikó N; Pécsi, Dániel; Varjú, Péter; Bajor, Judit; Gódi, Szilárd; Sarlós, Patrícia; Mikó, Alexandra; Szemes, Kata; Papp, Mária; Tornai, Tamás; Vincze, Áron; Márton, Zsolt; Vincze, Patrícia A; Lankó, Erzsébet; Szentesi, Andrea; Molnár, Tímea; Hágendorn, Roland; Faluhelyi, Nándor; Battyáni, István; Kelemen, Dezső; Papp, Róbert; Miseta, Attila; Verzár, Zsófia; Lerch, Markus M; Neoptolemos, John P; Sahin-Tóth, Miklós; Petersen, Ole H; Hegyi, Péter

    2017-09-14

    Acute pancreatitis (AP) is an inflammatory disease with no specific treatment. Mitochondrial injury followed by ATP depletion in both acinar and ductal cells is a recently discovered early event in its pathogenesis. Importantly, preclinical research has shown that intracellular ATP delivery restores the physiological function of the cells and protects from cell injury, suggesting that restoration of energy levels in the pancreas is therapeutically beneficial. Despite several high quality experimental observations in this area, no randomised trials have been conducted to date to address the requirements for energy intake in the early phase of AP. This is a randomised controlled two-arm double-blind multicentre trial. Patients with AP will be randomly assigned to groups A (30 kcal/kg/day energy administration starting within 24 hours of hospital admission) or B (low energy administration during the first 72 hours of hospital admission). Energy will be delivered by nasoenteric tube feeding with additional intravenous glucose supplementation or total parenteral nutrition if necessary. A combination of multiorgan failure for more than 48 hours and mortality is defined as the primary endpoint, whereas several secondary endpoints such as length of hospitalisation or pain will be determined to elucidate more detailed differences between the groups. The general feasibility, safety and quality checks required for high quality evidence will be adhered to. The study has been approved by the relevant organisation, the Scientific and Research Ethics Committee of the Hungarian Medical Research Council (55961-2/2016/EKU). This study will provide evidence as to whether early high energy nutritional support is beneficial in the clinical management of AP. The results of this trial will be published in an open access way and disseminated among medical doctors. The trial has been registered at the ISRCTN (ISRTCN 63827758). © Article author(s) (or their employer(s) unless

  8. Clinical efficacy and mechanistic evaluation of aflibercept for proliferative diabetic retinopathy (acronym CLARITY): a multicentre phase IIb randomised active-controlled clinical trial

    PubMed Central

    Sivaprasad, Sobha; Prevost, A Toby; Bainbridge, James; Edwards, Rhiannon Tudor; Hopkins, David; Kelly, Joanna; Luthert, Phil; Murphy, Caroline; Ramu, Jayashree; Sarafraz-Shekary, Negin; Vasconcelos, Joana; White-Alao, Beverley; Hykin, Philip

    2015-01-01

    Introduction Proliferative diabetic retinopathy (PDR) is the main cause of severe visual loss in people with diabetes mellitus. The standard treatment for this condition is panretinal photocoagulation (PRP). This laser treatment is inherently destructive, with predictable adverse effects on visual function, and a safer alternative is required. Intravitreal injection of vascular endothelial growth factor (VEGF) inhibitors can induce short-term regression of retinal neovascularisation. The aim of this randomised controlled trial is to determine the efficacy, safety and cost-effectiveness of intravitreal aflibercept, an inhibitor of VEGF-A, VEGF-B and placental growth factor (PLGF), in PDR, and to investigate the impact on local oxygenation. Methods and analysis This is a phase IIb randomised controlled single-masked multicentre clinical trial to determine the impact of repeated intravitreal aflibercept injections in the treatment and prevention of PDR. 220 participants with treatment-naïve or treated but active retinal neovascularisation in at least one eye will be randomly allocated 1:1 to intravitreal aflibercept injections or PRP for a period of 52 weeks. The primary outcome is the change in best-corrected visual acuity in the study eye at 52 weeks. Secondary outcomes include changes from baseline in other visual functions, anatomical changes and cost-effectiveness. Ocular and non-ocular adverse events will also be reported over 52 weeks. Ethics and dissemination The study has been approved by the National Research Ethics Service (NRES) committee with respect to scientific content and compliance with applicable research and human subjects’ regulations. Findings will be reported through scientific publications and research conferences. The results of this study will provide clinical evidence for the feasibility, efficacy safety and cost-effectiveness of intravitreal aflibercept for PDR. Trial registration number ISRCTN 32207582. PMID:26369798

  9. Early hormonal data from a multicentre phase II trial using transdermal oestrogen patches as first-line hormonal therapy in patients with locally advanced or metastatic prostate cancer

    PubMed Central

    Langley, Ruth E.; Godsland, Ian F.; Kynaston, Howard; Clarke, Noel W.; Rosen, Stuart D.; Morgan, Rachel C.; Pollock, Philip; Kockelbergh, Roger; Lalani, El-Nasir; Dearnaley, David; Parmar, Mahesh; Abel, Paul D.

    2008-01-01

    OBJECTIVE To assess the hormonal effects of Fem7® (Merck, KGaA, Darmstadt, Germany) 100 μg transdermal oestrogen patches on men undergoing first-line androgen-deprivation therapy for prostate cancer. PATIENTS AND METHODS PATCH is a multicentre, randomized, phase II trial for men with locally advanced or metastatic prostate cancer, comparing luteinizing hormone-releasing hormone agonist therapy with oestrogen patches. To assess the dosing schedule for the patches, as this was the first time that this brand of patch had been used in men, and to reassure patients and participating clinicians, the Independent Data Monitoring Committee agreed to early release of hormonal data from this study. RESULTS Oestradiol, testosterone and prostate-specific antigen (PSA) levels are presented for the first group of 14 patients who received the patches (with 1 withdrawal) and for whom there were ≥12 weeks of follow-up by March 2007. After 12 weeks, testosterone levels (nmol/L) in eight of the 13 patients were <1.7, two were 1.7–2 and three were >2. The median (range) serum oestradiol levels was 442 (52.1–1542) pmol/L and all patients had a PSA response, with eight having a PSA level of <4 ng/mL. CONCLUSION These results confirm that oestrogen patches produce castrate levels of testosterone and concomitant PSA responses. They also highlighted the potential differences between different brands of oestrogen patches, and the need to monitor hormonal response, toxicity and efficacy until more experience with oestrogen patches for this clinical indication is obtained. The number of patches recommended in the PATCH study has now been increased. PMID:18422771

  10. Near zerO fluoroscopic exPosure during catheter ablAtion of supRavenTricular arrhYthmias: the NO-PARTY multicentre randomized trial

    PubMed Central

    Casella, Michela; Dello Russo, Antonio; Pelargonio, Gemma; Del Greco, Maurizio; Zingarini, Gianluca; Piacenti, Marcello; Di Cori, Andrea; Casula, Victor; Marini, Massimiliano; Pizzamiglio, Francesca; Zucchetti, Martina; Riva, Stefania; Russo, Eleonora; Narducci, Maria Lucia; Soldati, Ezio; Panchetti, Luca; Startari, Umberto; Bencardino, Gianluigi; Perna, Francesco; Santangeli, Pasquale; Di Biase, Luigi; Cichocki, Fabrizio; Fattore, Giovanni; Bongiorni, Mariagrazia; Picano, Eugenio; Natale, Andrea; Tondo, Claudio

    2016-01-01

    Aims Aim of this study was to compare a minimally fluoroscopic radiofrequency catheter ablation with conventional fluoroscopy-guided ablation for supraventricular tachycardias (SVTs) in terms of ionizing radiation exposure for patient and operator and to estimate patients' lifetime attributable risks associated with such exposure. Methods and results We performed a prospective, multicentre, randomized controlled trial in six electrophysiology (EP) laboratories in Italy. A total of 262 patients undergoing EP studies for SVT were randomized to perform a minimally fluoroscopic approach (MFA) procedure with the EnSiteTMNavXTM navigation system or a conventional approach (ConvA) procedure. The MFA was associated with a significant reduction in patients' radiation dose (0 mSv, iqr 0–0.08 vs. 8.87 mSv, iqr 3.67–22.01; P < 0.00001), total fluoroscopy time (0 s, iqr 0–12 vs. 859 s, iqr 545–1346; P < 0.00001), and operator radiation dose (1.55 vs. 25.33 µS per procedure; P < 0.001). In the MFA group, X-ray was not used at all in 72% (96/134) of cases. The acute success and complication rates were not different between the two groups (P = ns). The reduction in patients' exposure shows a 96% reduction in the estimated risks of cancer incidence and mortality and an important reduction in estimated years of life lost and years of life affected. Based on economic considerations, the benefits of MFA for patients and professionals are likely to justify its additional costs. Conclusion This is the first multicentre randomized trial showing that a MFA in the ablation of SVTs dramatically reduces patients' exposure, risks of cancer incidence and mortality, and years of life affected and lost, keeping safety and efficacy. Trial registration clinicaltrials.gov Identifier: NCT01132274. PMID:26559916

  11. Targeted therapeutic mild hypercapnia after cardiac arrest: A phase II multi-centre randomised controlled trial (the CCC trial).

    PubMed

    Eastwood, Glenn M; Schneider, Antoine G; Suzuki, Satoshi; Peck, Leah; Young, Helen; Tanaka, Aiko; Mårtensson, Johan; Warrillow, Stephen; McGuinness, Shay; Parke, Rachael; Gilder, Eileen; Mccarthy, Lianne; Galt, Pauline; Taori, Gopal; Eliott, Suzanne; Lamac, Tammy; Bailey, Michael; Harley, Nerina; Barge, Deborah; Hodgson, Carol L; Morganti-Kossmann, Maria Cristina; Pébay, Alice; Conquest, Alison; Archer, John S; Bernard, Stephen; Stub, Dion; Hart, Graeme K; Bellomo, Rinaldo

    2016-07-01

    In intensive care observational studies, hypercapnia after cardiac arrest (CA) is independently associated with improved neurological outcome. However, the safety and feasibility of delivering targeted therapeutic mild hypercapnia (TTMH) for such patients is untested. In a phase II safety and feasibility multi-centre, randomised controlled trial, we allocated ICU patients after CA to 24h of targeted normocapnia (TN) (PaCO2 35-45mmHg) or TTMH (PaCO2 50-55mmHg). The primary outcome was serum neuron specific enolase (NSE) and S100b protein concentrations over the first 72h assessed in the first 50 patients surviving to day three. Secondary end-points included global measure of function assessment at six months and mortality for all patients. We enrolled 86 patients. Their median age was 61 years (58, 64 years) and 66 (79%) were male. Of these, 50 patients (58%) survived to day three for full biomarker assessment. NSE concentrations increased in the TTMH group (p=0.02) and TN group (p=0.005) over time, with the increase being significantly more pronounced in the TN group (p(interaction)=0.04). S100b concentrations decreased over time in the TTMH group (p<0.001) but not in the TN group (p=0.68). However, the S100b change over time did not differ between the groups (p(interaction)=0.23). At six months, 23 (59%) TTMH patients had good functional recovery compared with 18 (46%) TN patients. Hospital mortality occurred in 11 (26%) TTMH patients and 15 (37%) TN patients (p=0.31). In CA patients admitted to the ICU, TTMH was feasible, appeared safe and attenuated the release of NSE compared with TN. These findings justify further investigation of this novel treatment. Copyright © 2016. Published by Elsevier Ireland Ltd.

  12. Noninvasive diagnosis of hypolactasia with 4-Galactosylxylose (Gaxilose): a multicentre, open-label, phase IIB-III nonrandomized trial.

    PubMed

    Aragón, Juan J; Hermida, Carmen; Martínez-Costa, Oscar H; Sánchez, Valentina; Martín, Igor; Sánchez, José J; Codoceo, Rosa; Cano, José M; Cano, Ana; Crespo, Laura; Torres, Yolanda; García, Francisco J; Fernández-Mayoralas, Alfonso; Solera, Jesús; Martínez, Pilar

    2014-01-01

    Hypolactasia affects over half of the world population. Diagnosis remains problematic as currently available tests, such as the hydrogen breath test, have low reliability and lactose intolerance symptoms are unspecific. We evaluated the diagnostic performance and safety of a new noninvasive diagnostic test based on urine or serum measurement of D-xylose after lactase cleavage of orally administered 4-galactosylxylose (gaxilose). In a multicentre, open-label, nonrandomized, phase IIb-III study, consecutive patients with symptoms suggestive of lactose intolerance sequentially underwent intestinal biopsy for direct measurement of lactase activity (reference standard), hydrogen breath test, and blood glucose test after lactose challenge, 4- and 5-hour urine-based gaxilose test, and blood-based gaxilose test. For the gaxilose tests, 0 to 4 and 4 to 5 hours urine samples were taken after a 0.45 g gaxilose dose, whereas serum samples were taken 90 minutes after a 2.7 g dose for D-xylose determination. Genetic testing of hypolactasia was also assessed. Of the 222 patients enrolled, 203 completed all diagnostic tests; 108 were hypolactasic according to biopsy. The sensitivities and specificities and positive and negative predictive values of the gaxilose tests were all >90% versus 69% to 85% for the hydrogen breath test and the blood glucose test. The area under the ROC curve was significantly higher for the gaxilose tests (>0.9, P≤0.007). These tests also had higher sensitivity than genetic testing for hypolactasia and were well tolerated. The diagnostic performance of the gaxilose tests is excellent and can substantially improve the diagnosis of hypolactasia.

  13. Chemoimmunotherapy with bleomycin, vincristine, lomustine, dacarbazine (BOLD) plus interferon alpha for metastatic melanoma: a multicentre phase II study.

    PubMed Central

    Punt, C. J.; van Herpen, C. M.; Jansen, R. L.; Vreugdenhil, G.; Muller, E. W.; de Mulder, P. H.

    1997-01-01

    High response rates in patients with metastatic melanoma have been achieved with combination chemoimmunotherapy. A response rate of 62% in 45 patients has been reported for treatment with dacarbazine, bleomycin, vincristine, lomustine (BOLD) plus interferon alpha (IFN-alpha). We conducted a multicentre phase II study to confirm these results. Melanoma patients with distant metastases were treated as outpatients with dacarbazine 200 mg m(-2) on days 1-5, vincristine 1 mg m(-2) on days 1 and 4, bleomycin 15 mg on days 2 and 5 i.v. and lomustine 80 mg orally on day 1, repeated every 4 weeks. IFN-alpha-2b was initiated s.c. on day 8 at 3 MU daily for 6 weeks, and 6 MU t.i.w. thereafter. Forty-three patients entered the study. The median number of metastatic sites was three (range 1-5), and 81% of patients had visceral metastases. Nine patients had brain metastases, and seven patients were systemically pretreated. Among the 41 patients that were evaluable for response, the response rate was 27% (95% CI 14-3%), with one complete and ten partial remissions. The response rate in 25 previously untreated patients without brain metastases was 40% (95% CI 21-61%). Median duration of response was 6 (range 2-14+) months; median overall survival was 5 (1-26) months. The main toxicity was malaise/fatigue. We confirm that BOLD plus IFN-alpha has activity in metastatic melanoma. The lower response rate in our study compared with the previous report is probably related to patient selection, as in the previous study 46% of patients had stage III disease, whereas all our patients had stage IV disease, which is associated with a worse prognosis. PMID:9231931

  14. Efficacy of a standardized herbal preparation (Roidosanal®) in the treatment of hemorrhoids: A randomized, controlled, open-label multicentre study

    PubMed Central

    Aggrawal, Kapil; Satija, Naveen; Dasgupta, Gita; Dasgupta, Partha; Nain, Parul; Sahu, Aditya R.

    2014-01-01

    Background: Catechins and epicatechins are monomers of naturally occurring proanthocyanidins, which have been reported with free radical scavenging, antioxidant, antiinflammatory, antiallergic, and vasodilatory properties. Plant parts rich in proanthocyanidins have been used for years in treatment of various ano-rectal diseases. This study compares the efficacy of two herbal preparations, Daflon® 500 mg and Roidosanal®, in ameliorating the signs and symptoms associated with hemorrhoids. Objective: To evaluate the safety and to compare the efficacy of a herbal preparation, Roidosanal® versus Daflon® 500 mg, on signs and symptoms of hemorrhoidal disease. Materials and Methods: In this pilot, active controlled, open-labeled multicentre study, 73 patients with proctoscopy proven hemorrhoids (Grade I to III) were randomly assigned to receive either Roidosanal® (Gr R; n = 37) or Daflon® 500 mg (Gr D; n = 36), for 15 days, at three centers in India. Assessment of hemorrhoidal symptoms was carried out in all patients at different time points. Intent-to-treat analysis was performed for both primary and secondary endpoints. Results: Baseline characteristics were comparable between the two groups. Both products were found to be equally effective in improving the ano-rectal conditions in Grade I and Grade II hemorrhoids; however, Roidosanal® demonstrated better efficacy in patients with Grade III hemorrhoids. Hemorrhoids associated symptoms like bleeding, pain, etc., improved in both groups, although intergroup comparisons were comparable. Conclusion: Both Roidosanal® and Daflon® 500 mg were equally effective in resolving signs and symptoms of hemorrhoids. Roidosanal® can be tried as a safe and effective treatment option for treatment of hemorrhoids. Further randomized, double-blind and large multicentre studies are recommended. PMID:24948863

  15. Four-phase rhinomanometry: a multicentric retrospective analysis of 36,563 clinical measurements.

    PubMed

    Vogt, Klaus; Wernecke, Klaus-Dieter; Behrbohm, Hans; Gubisch, Wolfgang; Argale, Mara

    2016-05-01

    Rhinomanometry can still be considered as the standard technique for the objective assessment of the ventilatory function of the nose. Reliable technical requirements are given by fast digital sensors and modern information technology. However, the xyimaging of the pressure-flow relation typically shows loops as a sign of hysteresis, with the need for resolution of the breath in four phases. The three pillars of 4-phase rhinomanometry (4PR) are the replacement of estimations by measurements, the introduction of parameters related to the subjective sensing of obstruction, and the graphical information regarding the disturbed function of the nasal valve. In a meta-analysis of 36,563 clinical measurements, we analyze the errors of the "classic" parameters (flow in 150 Pa) and reject the further use of these parameters as obsolete, because they correspond to an inaccurate estimation rather than proper measurement. In a pre-study of 1580 measurements, the logarithmic effective resistance (Reff) was found to have the highest correlation with values obtained from a visual analog scale. Next, we classify the inspiratory effective resistance in 20,069 measurements without treatment and 16,494 measurements after decongestion with xylometazoline 0.1 % spray in 20 % percentiles. The gradation of obstruction delivers not only "normal" values but also indications for the severity of the obstruction in adult Caucasian noses. Adoption of the distribution for the growing nose and analysis of the total nasal resistance is addressed, and typical findings of nasal valve phenomena are outlined.

  16. Erythropoietin in amyotrophic lateral sclerosis: a multicentre, randomised, double blind, placebo controlled, phase III study

    PubMed Central

    Lauria, Giuseppe; Dalla Bella, Eleonora; Antonini, Giovanni; Borghero, Giuseppe; Capasso, Margherita; Caponnetto, Claudia; Chiò, Adriano; Corbo, Massimo; Eleopra, Roberto; Fazio, Raffaella; Filosto, Massimiliano; Giannini, Fabio; Granieri, Enrico; La Bella, Vincenzo; Logroscino, Giancarlo; Mandrioli, Jessica; Mazzini, Letizia; Monsurrò, Maria Rosaria; Mora, Gabriele; Pietrini, Vladimiro; Quatrale, Rocco; Rizzi, Romana; Salvi, Fabrizio; Siciliano, Gabriele; Sorarù, Gianni; Volanti, Paolo; Tramacere, Irene; Filippini, Graziella

    2015-01-01

    Objective To assess the efficacy of recombinant human erythropoietin (rhEPO) in amyotrophic lateral sclerosis (ALS). Methods Patients with probable laboratory-supported, probable or definite ALS were enrolled by 25 Italian centres and randomly assigned (1:1) to receive intravenous rhEPO 40 000 IU or placebo fortnightly as add-on treatment to riluzole 100 mg daily for 12 months. The primary composite outcome was survival, tracheotomy or >23 h non-invasive ventilation (NIV). Secondary outcomes were ALSFRS-R, slow vital capacity (sVC) and quality of life (ALSAQ-40) decline. Tolerability was evaluated analysing adverse events (AEs) causing withdrawal. The randomisation sequence was computer-generated by blocks, stratified by centre, disease severity (ALSFRS-R cut-off score of 33) and onset (spinal or bulbar). The main outcome analysis was performed in all randomised patients and by intention-to-treat for the entire population and patients stratified by severity and onset. The study is registered, EudraCT 2009-016066-91. Results We randomly assigned 208 patients, of whom 5 (1 rhEPO and 4 placebo) withdrew consent and 3 (placebo) became ineligible (retinal thrombosis, respiratory insufficiency, SOD1 mutation) before receiving treatment; 103 receiving rhEPO and 97 placebo were eligible for analysis. At 12 months, the annualised rate of death (rhEPO 0.11, 95% CI 0.06 to 0.20; placebo: 0.08, CI 0.04 to 0.17), tracheotomy or >23 h NIV (rhEPO 0.16, CI 0.10 to 0.27; placebo 0.18, CI 0.11 to 0.30) did not differ between groups, also after stratification by onset and ALSFRS-R at baseline. Withdrawal due to AE was 16.5% in rhEPO and 8.3% in placebo. No differences were found for secondary outcomes. Conclusions RhEPO 40 000 IU fortnightly did not change the course of ALS. PMID:25595151

  17. Liraglutide efficacy and action in non-alcoholic steatohepatitis (LEAN): study protocol for a phase II multicentre, double-blinded, randomised, controlled trial.

    PubMed

    Armstrong, Matthew J; Barton, Darren; Gaunt, Piers; Hull, Diana; Guo, Kathy; Stocken, Deborah; Gough, Stephen C L; Tomlinson, Jeremy W; Brown, Rachel M; Hübscher, Stefan G; Newsome, Philip N

    2013-11-04

    Non-alcoholic steatohepatitis (NASH) is now the commonest cause of chronic liver disease. Despite this, there are no universally accepted pharmacological therapies for NASH. Liraglutide (Victoza), a human glucagon-like peptide-1 (GLP-1) analogue, has been shown to improve weight loss, glycaemic control and liver enzymes in type 2 diabetes. There is currently a lack of prospective-controlled studies investigating the efficacy of GLP-1 analogues in patients with NASH. Liraglutide efficacy and action in NASH (LEAN) is a phase II, multicentre, double-blinded, placebo-controlled, randomised clinical trial designed to investigate whether a 48-week treatment with 1.8 mg liraglutide will result in improvements in liver histology in patients with NASH. Adult, overweight (body mass index ≥25 kg/m(2)) patients with biopsy-confirmed NASH were assessed for eligibility at five recruitment centres in the UK. Patients who satisfied the eligibility criteria were randomly assigned (1:1) to receive once-daily subcutaneous injections of either 1.8 mg liraglutide or liraglutide-placebo (control). Using A'Hern's single stage phase II methodology (significance level 0.05; power 0.90) and accounting for an estimated 20% withdrawal rate, a minimum of 25 patients were randomised to each treatment group. The primary outcome measure will be centrally assessed using an intention-to-treat analysis of the proportion of evaluable patients achieving an improvement in liver histology between liver biopsies at baseline and after 48 weeks of treatment. Histological improvement will be defined as a combination of the disappearance of active NASH and no worsening in fibrosis. The protocol was approved by the National Research Ethics Service (East Midlands-Northampton committee; 10/H0402/32) and the Medicines and Healthcare products Regulatory Agency. Recruitment into the LEAN started in August 2010 and ended in May 2013, with 52 patients randomised. The treatment follow-up of LEAN participants is

  18. Liraglutide efficacy and action in non-alcoholic steatohepatitis (LEAN): study protocol for a phase II multicentre, double-blinded, randomised, controlled trial

    PubMed Central

    Armstrong, Matthew J; Barton, Darren; Gaunt, Piers; Hull, Diana; Guo, Kathy; Stocken, Deborah; Gough, Stephen C L; Tomlinson, Jeremy W; Brown, Rachel M; Hübscher, Stefan G; Newsome, Philip N

    2013-01-01

    Introduction Non-alcoholic steatohepatitis (NASH) is now the commonest cause of chronic liver disease. Despite this, there are no universally accepted pharmacological therapies for NASH. Liraglutide (Victoza), a human glucagon-like peptide-1 (GLP-1) analogue, has been shown to improve weight loss, glycaemic control and liver enzymes in type 2 diabetes. There is currently a lack of prospective-controlled studies investigating the efficacy of GLP-1 analogues in patients with NASH. Methods and analysis Liraglutide efficacy and action in NASH (LEAN) is a phase II, multicentre, double-blinded, placebo-controlled, randomised clinical trial designed to investigate whether a 48-week treatment with 1.8 mg liraglutide will result in improvements in liver histology in patients with NASH. Adult, overweight (body mass index ≥25 kg/m2) patients with biopsy-confirmed NASH were assessed for eligibility at five recruitment centres in the UK. Patients who satisfied the eligibility criteria were randomly assigned (1:1) to receive once-daily subcutaneous injections of either 1.8 mg liraglutide or liraglutide-placebo (control). Using A'Hern's single stage phase II methodology (significance level 0.05; power 0.90) and accounting for an estimated 20% withdrawal rate, a minimum of 25 patients were randomised to each treatment group. The primary outcome measure will be centrally assessed using an intention-to-treat analysis of the proportion of evaluable patients achieving an improvement in liver histology between liver biopsies at baseline and after 48 weeks of treatment. Histological improvement will be defined as a combination of the disappearance of active NASH and no worsening in fibrosis. Ethics and dissemination The protocol was approved by the National Research Ethics Service (East Midlands—Northampton committee; 10/H0402/32) and the Medicines and Healthcare products Regulatory Agency. Recruitment into the LEAN started in August 2010 and ended in May 2013, with 52

  19. Alemtuzumab consolidation in chronic lymphocytic leukaemia: a phase I/II multicentre trial.

    PubMed

    Al-Sawaf, Othman; Fischer, Kirsten; Herling, Carmen D; Ritgen, Matthias; Böttcher, Sebastian; Bahlo, Jasmin; Elter, Thomas; Stilgenbauer, Stephan; Eichhorst, Barbara F; Busch, Raymonde; Elberskirch, Ute; Abenhardt, Wolfgang; Kneba, Michael; Hallek, Michael; Wendtner, Clemens-Martin

    2017-03-01

    Despite high rates of long-lasting remissions in patients with chronic lymphocytic leukaemia (CLL) treated with chemoimmunotherapy, none of the current therapeutic approaches is curative with the exception of allogeneic transplantation. One strategy to extend progression-free survival and long-term survival might be the establishment of consolidation therapies. In this trial, patients with complete or partial second remission after fludarabine-based treatment received consolidation therapy with alemtuzumab. The aim of this phase I/II trial was to determine the maximal tolerable dose (MTD) of alemtuzumab consolidation and to evaluate safety and efficacy in patients who responded to second-line fludarabine-based treatment. Thirteen patients in complete (CR) or partial remission (PR) received alemtuzumab dose escalation starting with 10 mg intravenously (iv) once weekly for 8 wk and increasing in 10-mg intervals per dose level. The main dose-limiting toxicities (DLTs) were infectious complications, and the MTD was determined at 10 mg. After alemtuzumab consolidation, seven of 13 patients (53%) were in CR, and four of these patients (30.7%) achieved minimal residual disease (MRD) negativity (<1 × 10E-4). At a median follow-up of 71.5 months, four patients were progression-free, with a median progression-free survival (PFS) of 28.5 months after the end of second-line treatment. The results provide a safe and efficient schedule with weekly intravenous application of 10 mg of alemtuzumab as a consolidation regime in patients with CLL. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  20. Implementation phase of a multicentre prehospital telemedicine system to support paramedics: feasibility and possible limitations

    PubMed Central

    2013-01-01

    Background Legal regulations often limit the medical care that paramedics can provide. Telemedical solutions could overcome these limitations by remotely providing expert support. Therefore, a mobile telemedicine system to support paramedics was developed. During the implementation phase of this system in four German emergency medical services (EMS), the feasibility and possible limitations of this system were evaluated. Methods After obtaining ethical approval and providing a structured training program for all medical professionals, the system was implemented on three paramedic-staffed ambulances on August 1st, 2012. Two more ambulances were included subsequently during this month. The paramedics could initiate a consultation with EMS physicians at a teleconsultation centre. Telemedical functionalities included audio communication, real-time vital data transmission, 12-lead electrocardiogram, picture transmission on demand, and video streaming from a camera embedded into the ceiling of each ambulance. After each consultation, telephone-based debriefings were conducted. Data were retrieved from the documentation protocols of the teleconsultation centre and the EMS. Results During a one month period, teleconsultations were conducted during 35 (11.8%) of 296 emergency missions with a mean duration of 24.9 min (SD 12.5). Trauma, acute coronary syndromes, and circulatory emergencies represented 20 (57%) of the consultation cases. Diagnostic support was provided in 34 (97%) cases, and the administration of 50 individual medications, including opioids, was delegated by the teleconsultation centre to the paramedics in 21 (60%) missions (range: 1–7 per mission). No medical complications or negative interpersonal effects were reported. All applications functioned as expected except in one case in which the connection failed due to the lack of a viable mobile network. Conclusion The feasibility of the telemedical approach was demonstrated. Teleconsultation enabled early

  1. Implementation phase of a multicentre prehospital telemedicine system to support paramedics: feasibility and possible limitations.

    PubMed

    Bergrath, Sebastian; Czaplik, Michael; Rossaint, Rolf; Hirsch, Frederik; Beckers, Stefan Kurt; Valentin, Bernd; Wielpütz, Daniel; Schneiders, Marie-Thérèse; Brokmann, Jörg Christian

    2013-07-11

    Legal regulations often limit the medical care that paramedics can provide. Telemedical solutions could overcome these limitations by remotely providing expert support. Therefore, a mobile telemedicine system to support paramedics was developed. During the implementation phase of this system in four German emergency medical services (EMS), the feasibility and possible limitations of this system were evaluated. After obtaining ethical approval and providing a structured training program for all medical professionals, the system was implemented on three paramedic-staffed ambulances on August 1st, 2012. Two more ambulances were included subsequently during this month. The paramedics could initiate a consultation with EMS physicians at a teleconsultation centre. Telemedical functionalities included audio communication, real-time vital data transmission, 12-lead electrocardiogram, picture transmission on demand, and video streaming from a camera embedded into the ceiling of each ambulance. After each consultation, telephone-based debriefings were conducted. Data were retrieved from the documentation protocols of the teleconsultation centre and the EMS. During a one month period, teleconsultations were conducted during 35 (11.8%) of 296 emergency missions with a mean duration of 24.9 min (SD 12.5). Trauma, acute coronary syndromes, and circulatory emergencies represented 20 (57%) of the consultation cases. Diagnostic support was provided in 34 (97%) cases, and the administration of 50 individual medications, including opioids, was delegated by the teleconsultation centre to the paramedics in 21 (60%) missions (range: 1-7 per mission). No medical complications or negative interpersonal effects were reported. All applications functioned as expected except in one case in which the connection failed due to the lack of a viable mobile network. The feasibility of the telemedical approach was demonstrated. Teleconsultation enabled early initiation of treatments by paramedics

  2. Random phase approximation in a deformed Hartree-Fock basis

    SciTech Connect

    Gering, M.Z.I.; Heiss, W.D.

    1984-03-01

    The validity of the random phase approximation in a deformed Hartree-Fock basis is investigated in a soluble model. There is strong evidence that the random phase approximation reproduces well the vibrational excitations of the system. Within the framework of the Green's function technique, the significance of the deformed single particle basis is established.

  3. Pembrolizumab versus ipilimumab for advanced melanoma: final overall survival results of a multicentre, randomised, open-label phase 3 study (KEYNOTE-006).

    PubMed

    Schachter, Jacob; Ribas, Antoni; Long, Georgina V; Arance, Ana; Grob, Jean-Jacques; Mortier, Laurent; Daud, Adil; Carlino, Matteo S; McNeil, Catriona; Lotem, Michal; Larkin, James; Lorigan, Paul; Neyns, Bart; Blank, Christian; Petrella, Teresa M; Hamid, Omid; Zhou, Honghong; Ebbinghaus, Scot; Ibrahim, Nageatte; Robert, Caroline

    2017-08-16

    Interim analyses of the phase 3 KEYNOTE-006 study showed superior overall and progression-free survival of pembrolizumab versus ipilimumab in patients with advanced melanoma. We present the final protocol-specified survival analysis. In this multicentre, open-label, randomised, phase 3 trial, we recruited patients from 87 academic institutions, hospitals, and cancer centres in 16 countries (Australia, Austria, Belgium, Canada, Chile, Colombia, France, Germany, Israel, Netherlands, New Zealand, Norway, Spain, Sweden, UK, and USA). We randomly assigned participants (1:1:1) to one of two dose regimens of pembrolizumab, or one regimen of ipilimumab, using a centralised, computer-generated allocation schedule. Treatment assignments used blocked randomisation within strata. Eligible patients were at least 18 years old, with an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, at least one measurable lesion per Response Evaluation Criteria In Solid Tumors version 1.1 (RECIST v1.1), unresectable stage III or IV melanoma (excluding ocular melanoma), and up to one previous systemic therapy (excluding anti-CTLA-4, PD-1, or PD-L1 agents). Secondary eligibility criteria are described later. Patients were excluded if they had active brain metastases or active autoimmune disease requiring systemic steroids. The primary outcome was overall survival (defined as the time from randomisation to death from any cause). Response was assessed per RECIST v1.1 by independent central review at week 12, then every 6 weeks up to week 48, and then every 12 weeks thereafter. Survival was assessed every 12 weeks, and final analysis occurred after all patients were followed up for at least 21 months. Primary analysis was done on the intention-to-treat population (all randomly assigned patients) and safety analyses were done in the treated population (all randomly assigned patients who received at least one dose of study treatment). Data cutoff date for this analysis was Dec 3

  4. Cixutumumab for patients with recurrent or refractory advanced thymic epithelial tumours: a multicentre, open-label, phase 2 trial.

    PubMed

    Rajan, Arun; Carter, Corey A; Berman, Arlene; Cao, Liang; Kelly, Ronan J; Thomas, Anish; Khozin, Sean; Chavez, Ariel Lopez; Bergagnini, Isabella; Scepura, Barbara; Szabo, Eva; Lee, Min-Jung; Trepel, Jane B; Browne, Sarah K; Rosen, Lindsey B; Yu, Yunkai; Steinberg, Seth M; Chen, Helen X; Riely, Gregory J; Giaccone, Giuseppe

    2014-02-01

    No standard treatment exists for refractory or relapsed advanced thymic epithelial tumours. We investigated the efficacy of cixutumumab, a fully human IgG1 monoclonal antibody targeting the insulin-like growth factor 1 receptor in thymic epithelial tumours after failure of previous chemotherapy. Between Aug 25, 2009, and March 27, 2012, we did a multicentre, open-label, phase 2 trial in patients aged 18 years or older with histologically confirmed recurrent or refractory thymic epithelial tumours. We enrolled individuals who had progressed after at least one previous regimen of platinum-containing chemotherapy, had an Eastern Cooperative Oncology Group performance status of 0 or 1, and had measurable disease and adequate organ function. Eligible patients received intravenous cixutumumab (20 mg/kg) every 3 weeks until disease progression or development of intolerable toxic effects. The primary endpoint was the frequency of response, analysed on an intention-to-treat basis. We also did pharmacodynamic studies. This trial is registered with ClinicalTrials.gov, number NCT00965250. 49 patients were enrolled (37 with thymomas and 12 with thymic carcinomas) who received a median of eight cycles of cixutumumab (range 1-46). At the final actuarial analysis when follow-up data were updated (Nov 30, 2012), median potential follow-up (from on-study date to most current follow-up date) was 24·0 months (IQR 17·3-36·9). In the thymoma cohort, five (14%) of 37 patients (95% CI 5-29) achieved a partial response, 28 had stable disease, and four had progressive disease. In the thymic carcinoma cohort, none of 12 patients (95% CI 0-26) had a partial response, five had stable disease, and seven had progressive disease. The most common grade 3-4 adverse events in both cohorts combined were hyperglycaemia (five [10%]), lipase elevation (three [6%]), and weight loss, tumour pain, and hyperuricaemia (two each [4%]). Nine (24%) of 37 patients with thymoma developed autoimmune conditions

  5. A multi-centre randomized controlled trial comparing electrothermal arthroscopic capsulorrhaphy versus open inferior capsular shift for patients with shoulder instability: Protocol implementation and interim performance: Lessons learned from conducting a multi-centre RCT [ISRCTN68224911; NCT00251160

    PubMed Central

    Mohtadi, NG; Hollinshead, RM; Ceponis, PJ; Chan, DS; Fick, GH

    2006-01-01

    Background The shoulder is the most frequently dislocated joint in the body. Multiple causes and pathologies account for the various types of shoulder instability. Multi-directional instability (MDI) and multi-directional laxity with antero-inferior instability (MDL-AII) are similar in pathology, less common and more difficult to treat. These instabilities are caused by ligamentous capsular redundancy. When non-operative management fails for these patients, quality of life is significantly impaired and surgical treatment is required to tighten the ligaments and joint capsule. The current reference (gold) standard treatment for MDI/MDL-AII is an open inferior capsular shift (ICS) surgical procedure. An alternative treatment involves arthroscopic thermal shrinkage of redundant capsular tissue to tighten the joint. However, there is a lack of scientific evidence to support the use of this technique called, electrothermal arthroscopic capsulorrhaphy (ETAC). This trial will compare the effectiveness of ETAC to open ICS in patients with MDI and MDL-AII, using patient-based quality of life outcome assessments. Methods This study is a multi-centre randomized clinical trial with a calculated sample size of 58 patients (p = 0.05, 80% power). Eligible patients are clinically diagnosed with MDI or MDL-AII and have failed standardized non-operative management. A diagnostic shoulder arthroscopy is performed to confirm eligibility, followed by intra-operative randomization to the ETAC or ICS surgical procedure. The primary outcome is the disease-specific quality of life questionnaire (Western Ontario Shoulder Instability Index), measured at baseline, 3, 6, 12 and 24 months. Secondary outcomes include shoulder-specific measures (American Shoulder and Elbow Surgeons Score and Constant Score). Other outcomes include recurrent instability, complications and operative time. The outcome measurements will be compared on an intention-to-treat basis, using two-sample independent t

  6. The addition of sirolimus to the graft-versus-host disease prophylaxis regimen in reduced intensity allogeneic stem cell transplantation for lymphoma: a multicentre randomized trial.

    PubMed

    Armand, Philippe; Kim, Haesook T; Sainvil, Marie-Michele; Lange, Paulina B; Giardino, Angela A; Bachanova, Veronika; Devine, Steven M; Waller, Edmund K; Jagirdar, Neera; Herrera, Alex F; Cutler, Corey; Ho, Vincent T; Koreth, John; Alyea, Edwin P; McAfee, Steven L; Soiffer, Robert J; Chen, Yi-Bin; Antin, Joseph H

    2016-04-01

    Inhibition of the mechanistic target of rapamycin (mTOR) pathway has clinical activity in lymphoma. The mTOR inhibitor sirolimus has been used in the prevention and treatment of graft-versus-host disease (GVHD) after allogeneic haematopoietic stem cell transplantation (HSCT). A retrospective study suggested that patients with lymphoma undergoing reduced intensity conditioning (RIC) HSCT who received sirolimus as part of their GVHD prophylaxis regimen had a lower rate of relapse. We therefore performed a multicentre randomized trial comparing tacrolimus, sirolimus and methotrexate to standard regimens in adult patients undergoing RIC HSCT for lymphoma in order to assess the possible benefit of sirolimus on HSCT outcome. 139 patients were randomized. There was no difference overall in 2-year overall survival, progression-free survival, relapse, non-relapse mortality or chronic GVHD. However, the sirolimus-containing arm had a significantly lower incidence of grade II-IV acute GVHD (9% vs. 25%, P = 0·015), which was more marked for unrelated donor grafts. In conclusion, the addition of sirolimus for GVHD prophylaxis in RIC HSCT is associated with no increased overall toxicity and a lower risk of acute GVHD, although it does not improve survival; this regimen is an acceptable option for GVHD prevention in RIC HSCT. This trial is registered at clinicaltrials.gov (NCT00928018).

  7. Effect of lansoprazole on the epigastric symptoms of functional dyspepsia (ELF study): A multicentre, prospective, randomized, double-blind, placebo-controlled clinical trial

    PubMed Central

    Kusunoki, Hiroaki; Kamiya, Takeshi; Futagami, Seiji; Yamaguchi, Yasuharu; Nishizawa, Toshihiro; Iwasaki, Eisuke; Matsuzaki, Juntaro; Takahashi, Shinichi; Sakamoto, Choitsu; Haruma, Ken; Joh, Takashi; Asakura, Keiko; Hibi, Toshifumi

    2013-01-01

    Background: Since the publication of the Rome III criteria for functional dyspepsia (FD), the evidence about the efficacy of half-dose of proton pump inhibitors for dyspepsia symptoms have been limited. Objective: To examine the efficacy of lansoprazole for functional dyspepsia (FD) diagnosed with the Rome III criteria by the multicentre, double-blind, randomized, placebo-controlled study in Japan. Methods: A total of 54 FD participants were randomized to lansoprazole 15 mg once daily or placebo for a 4-week double-blind treatment period. The primary efficacy endpoint was an overall dyspeptic symptom relief rate evaluated by 5-point Likert scale scores. The alteration of dyspeptic symptom scores during the study period was also assessed. Results: At week 4, the overall dyspeptic symptom relief rates were higher in the lansoprazole group (30.4%) than in the placebo group (6.7%) (p = 0.045). The scores for epigastric pain (p = 0.045) and epigastric burning (p = 0.03) were significantly improved in the lansoprazole group compared to the placebo group, whereas the improvement of the scores for postprandial fullness (p = 0.81) and early satiation (p = 0.33) was not different between lansoprazole and placebo groups. Conclusions: Lansoprazole 15 mg ameliorates dyspeptic symptoms, particularly the epigastric pain syndrome-related symptoms of FD. PMID:24917996

  8. [Multicentric reticulohistiocytosis].

    PubMed

    Sokolović, Sekib; Kasumagić, Sida

    2009-01-01

    A very rare inflammatory systemic rheumatic disorder--Multicentric reticulohistiocytosis--was described as a case report in this paper. A 22 year old female patient was presented with a destructive polyarthritis and prominent multiple skin nodules that pointed to possible presence of this rare disease. The final diagnosis was made based on the biopsy finding. Application of the cytotoxic drug Metotrexate in the therapy, besides non-steroidal anti-inflammatory drugs and corticosteroids, leaded to full remission with disappearance of skin changes.

  9. Ordering and phase transitions in random-field Ising systems

    NASA Technical Reports Server (NTRS)

    Maritan, Amos; Swift, Michael R.; Cieplak, Marek; Chan, Moses H. W.; Cole, Milton W.; Banavar, Jayanth R.

    1991-01-01

    An exact analysis of the Ising model with infinite-range interactions in a random field and a local mean-field theory in three dimensions is carried out leading to a phase diagram with several coexistence surfaces and lines of critical points. The results show that the phase diagram depends crucially on whether the distribution of random fields is symmetric or not. Thus, Ising-like phase transitions in a porous medium (the asymmetric case) are in a different universality class from the conventional random-field model (symmetric case).

  10. Boson expansions based on the random phase approximation representation

    SciTech Connect

    Pedrocchi, V.G.; Tamura, T.

    1984-04-01

    A new boson expansion theory based on the random phase approximation is presented. The boson expansions are derived here directly in the random phase approximation representation with the help of a technique that combines the use of the Usui operator with that of a new bosonization procedure, called the term-by-term bosonization method. The present boson expansion theory is constructed by retaining a single collective quadrupole random phase approximation component, a truncation that allows for a perturbative treatment of the whole problem. Both Hermitian, as well as non-Hermitian boson expansions, valid for even nuclei, are obtained.

  11. Safety and tolerability of guadecitabine (SGI-110) in patients with myelodysplastic syndrome and acute myeloid leukaemia: a multicentre, randomised, dose-escalation phase 1 study.

    PubMed

    Issa, Jean-Pierre J; Roboz, Gail; Rizzieri, David; Jabbour, Elias; Stock, Wendy; O'Connell, Casey; Yee, Karen; Tibes, Raoul; Griffiths, Elizabeth A; Walsh, Katherine; Daver, Naval; Chung, Woonbok; Naim, Sue; Taverna, Pietro; Oganesian, Aram; Hao, Yong; Lowder, James N; Azab, Mohammad; Kantarjian, Hagop

    2015-09-01

    Hypomethylating agents are used to treat cancers driven by aberrant DNA methylation, but their short half-life might limit their activity, particularly in patients with less proliferative diseases. Guadecitabine (SGI-110) is a novel hypomethylating dinucleotide of decitabine and deoxyguanosine resistant to degradation by cytidine deaminase. We aimed to assess the safety and clinical activity of subcutaneously given guadecitabine in patients with acute myeloid leukaemia or myelodysplastic syndrome. In this multicentre, open-label, phase 1 study, patients from nine North American medical centres with myelodysplastic syndrome or acute myeloid leukaemia that was refractory to or had relapsed after standard treatment were randomly assigned (1:1) to receive subcutaneous guadecitabine, either once-daily for 5 consecutive days (daily × 5), or once-weekly for 3 weeks, in a 28-day treatment cycle. Patients were stratified by disease. A 3 + 3 dose-escalation design was used in which we treated patients with guadecitabine doses of 3-125 mg/m(2) in separate dose-escalation cohorts. A twice-weekly treatment schedule was added to the study after a protocol amendment. The primary objective was to assess safety and tolerability of guadecitabine, determine the maximum tolerated and biologically effective dose, and identify the recommended phase 2 dose of guadecitabine. Safety analyses included all patients who received at least one dose of guadecitabine. Pharmacokinetic and pharmacodynamic analyses to determine the biologically effective dose included all patients for whom samples were available. This study is registered with ClinicalTrials.gov, number NCT01261312. Between Jan 4, 2011, and April 11, 2014, we enrolled and treated 93 patients: 35 patients with acute myeloid leukaemia and nine patients with myelodysplastic syndrome in the daily × 5 dose-escalation cohorts, 28 patients with acute myeloid leukaemia and six patients with myelodysplastic syndrome in the once-weekly dose

  12. Implementing and evaluating the German adaptation of the "Strengthening Families Program 10 - 14"- a randomized-controlled multicentre study.

    PubMed

    Bröning, Sonja; Sack, Peter-Michael; Thomsen, Monika; Stolle, Martin; Wendell, Astrid; Stappenbeck, Julian; Thomasius, Rainer

    2014-01-27

    Substance use problems in childhood and adolescence can severely impact youth's physical and mental well-being. When substance use is initiated early, the risk for moving from hazardous substance use to substance use disorders (SUD) is particularly high to developmentally induced biological and psychological vulnerability towards chronic trajectories in youth. Thus, risk factors for developing SUD should be addressed early in life by adequate preventive measures reaching out to children, adolescents, and their families. The study described in this protocol will test the effectiveness of the German adaptation of the Strengthening Families Program for Parents and Youth 10-14 (SFP 10-14) aimed at ten to 14 year old adolescents and their caregivers. The study is conducted in four large German cities by counselling centres in the areas of youth welfare, social work and addiction aid. The effectiveness of the manualised group programme "Familien Stärken" consisting of seven sessions and four booster-sessions is tested among N = 288 children and participating parents in a multicentre randomised controlled trial with standardised assessment instruments. The control condition receives a minimal 2-hour intervention on parenting delivered in a school setting. Data are collected shortly before and after as well as six and 18 months after the intervention. We expect to replicate the favourable effects of the SFP 10-14 programme in the United States in the area of substance use initiation, family functioning and individual psychosocial adjustment. The trial is expected to contribute to the growing literature on family-based preventive interventions, their effectiveness and feasibility. It is in line with several other current European efforts aimed at strengthening families against the detrimental effects of substance abuse in youth. The results of these trials will expand our knowledge on adapting evidence-based interventions and delivering them in diverse cultures and

  13. Randomized multicentre pilot study of sacubitril/valsartan versus irbesartan in patients with chronic kidney disease: United Kingdom Heart and Renal Protection (HARP)- III-rationale, trial design and baseline data.

    PubMed

    2016-09-19

    Patients with chronic kidney disease (CKD) are at risk of progression to end-stage renal disease and cardiovascular disease. Data from other populations and animal experiments suggest that neprilysin inhibition (which augments the natriuretic peptide system) may reduce these risks, but clinical trials among patients with CKD are required to test this hypothesis. UK Heart and Renal Protection III (HARP-III) is a multicentre, double-blind, randomized controlled trial comparing sacubitril/valsartan 97/103 mg two times daily (an angiotensin receptor-neprilysin inhibitor) with irbesartan 300 mg one time daily among 414 patients with CKD. Patients ≥18 years of age with an estimated glomerular filtration rate (eGFR) of ≥45 but <60 mL/min/1.73 m(2) and urine albumin:creatinine ratio (uACR) >20 mg/mmol or eGFR ≥20 but <45 mL/min/1.73 m(2) (regardless of uACR) were invited to be screened. Following a 4- to 7-week pre-randomization single-blind placebo run-in phase (during which any current renin-angiotensin system inhibitors were stopped), willing and eligible participants were randomly assigned either sacubitril/valsartan or irbesartan and followed-up for 12 months. The primary aim was to compare the effects of sacubitril/valsartan and irbesartan on measured GFR after 12 months of therapy. Important secondary outcomes include effects on albuminuria, change in eGFR over time and the safety and tolerability of sacubitril/valsartan in CKD. Between November 2014 and January 2016, 620 patients attended a screening visit and 566 (91%) entered the pre-randomization run-in phase. Of these, 414 (73%) participants were randomized (mean age 63 years; 72% male). The mean eGFR was 34.0 mL/min/1.73 m(2) and the median uACR was 58.5 mg/mmol. UK HARP-III will provide important information on the short-term effects of sacubitril/valsartan on renal function, tolerability and safety among patients with CKD. © The Author 2016. Published by Oxford University Press on behalf of ERA-EDTA.

  14. Carfilzomib and dexamethasone versus bortezomib and dexamethasone for patients with relapsed or refractory multiple myeloma (ENDEAVOR): a randomised, phase 3, open-label, multicentre study.

    PubMed

    Dimopoulos, Meletios A; Moreau, Philippe; Palumbo, Antonio; Joshua, Douglas; Pour, Ludek; Hájek, Roman; Facon, Thierry; Ludwig, Heinz; Oriol, Albert; Goldschmidt, Hartmut; Rosiñol, Laura; Straub, Jan; Suvorov, Aleksandr; Araujo, Carla; Rimashevskaya, Elena; Pika, Tomas; Gaidano, Gianluca; Weisel, Katja; Goranova-Marinova, Vesselina; Schwarer, Anthony; Minuk, Leonard; Masszi, Tamás; Karamanesht, Ievgenii; Offidani, Massimo; Hungria, Vania; Spencer, Andrew; Orlowski, Robert Z; Gillenwater, Heidi H; Mohamed, Nehal; Feng, Shibao; Chng, Wee-Joo

    2016-01-01

    Bortezomib with dexamethasone is a standard treatment option for relapsed or refractory multiple myeloma. Carfilzomib with dexamethasone has shown promising activity in patients in this disease setting. The aim of this study was to compare the combination of carfilzomib and dexamethasone with bortezomib and dexamethasone in patients with relapsed or refractory multiple myeloma. In this randomised, phase 3, open-label, multicentre study, patients with relapsed or refractory multiple myeloma who had one to three previous treatments were randomly assigned (1:1) using a blocked randomisation scheme (block size of four) to receive carfilzomib with dexamethasone (carfilzomib group) or bortezomib with dexamethasone (bortezomib group). Randomisation was stratified by previous proteasome inhibitor therapy, previous lines of treatment, International Staging System stage, and planned route of bortezomib administration if randomly assigned to bortezomib with dexamethasone. Patients received treatment until progression with carfilzomib (20 mg/m(2) on days 1 and 2 of cycle 1; 56 mg/m(2) thereafter; 30 min intravenous infusion) and dexamethasone (20 mg oral or intravenous infusion) or bortezomib (1·3 mg/m(2); intravenous bolus or subcutaneous injection) and dexamethasone (20 mg oral or intravenous infusion). The primary endpoint was progression-free survival in the intention-to-treat population. All participants who received at least one dose of study drug were included in the safety analyses. The study is ongoing but not enrolling participants; results for the interim analysis of the primary endpoint are presented. The trial is registered at ClinicalTrials.gov, number NCT01568866. Between June 20, 2012, and June 30, 2014, 929 patients were randomly assigned (464 to the carfilzomib group; 465 to the bortezomib group). Median follow-up was 11·9 months (IQR 9·3-16·1) in the carfilzomib group and 11·1 months (8·2-14·3) in the bortezomib group. Median progression-free survival

  15. Venetoclax in relapsed or refractory chronic lymphocytic leukaemia with 17p deletion: a multicentre, open-label, phase 2 study.

    PubMed

    Stilgenbauer, Stephan; Eichhorst, Barbara; Schetelig, Johannes; Coutre, Steven; Seymour, John F; Munir, Talha; Puvvada, Soham D; Wendtner, Clemens-Martin; Roberts, Andrew W; Jurczak, Wojciech; Mulligan, Stephen P; Böttcher, Sebastian; Mobasher, Mehrdad; Zhu, Ming; Desai, Monali; Chyla, Brenda; Verdugo, Maria; Enschede, Sari Heitner; Cerri, Elisa; Humerickhouse, Rod; Gordon, Gary; Hallek, Michael; Wierda, William G

    2016-06-01

    Deletion of chromosome 17p (del[17p]) in patients with chronic lymphocytic leukaemia confers very poor prognosis when treated with standard chemo-immunotherapy. Venetoclax is an oral small-molecule BCL2 inhibitor that induces chronic lymphocytic leukaemia cell apoptosis. In a previous first-in-human study of venetoclax, 77% of patients with relapsed or refractory chronic lymphocytic leukaemia achieved an overall response. Here we aimed to assess the activity and safety of venetoclax monotherapy in patients with relapsed or refractory del(17p) chronic lymphocytic leukaemia. In this phase 2, single-arm, multicentre study, we recruited patients aged 18 years and older with del(17p) relapsed or refractory chronic lymphocytic leukaemia (as defined by 2008 Modified International Workshop on Chronic Lymphocytic Leukemia guidelines) from 31 centres in the USA, Canada, UK, Germany, Poland, and Australia. Patients started once daily venetoclax with a weekly dose ramp-up schedule (20, 50, 100, 200, 400 mg) over 4-5 weeks. Patients were then given daily 400 mg continuous dosing until disease progression or discontinuation for another reason. The primary endpoint was the proportion of patients achieving an overall response, assessed by an independent review committee. Activity and safety analyses included all patients who received at least one dose of study drug (per protocol). This study is registered with ClinicalTrials.gov, number NCT01889186. Follow-up is ongoing, and patients are still receiving treatment. Between May 27, 2013, and June 27, 2014, 107 patients were enrolled into the study. At a median follow-up of 12·1 months (IQR 10·1-14·2), an overall response by independent review was achieved in 85 (79·4%; 95% CI 70·5-86·6) of 107 patients. The most common grade 3-4 adverse events were neutropenia (43 [40%]), infection (21 [20%]), anaemia (19 [18%]), and thrombocytopenia (16 [15%]). Serious adverse events occurred in 59 (55%) patients, irrespective of their

  16. Cixutumumab and temsirolimus for patients with bone and soft-tissue sarcoma: a multicentre, open-label, phase 2 trial

    PubMed Central

    Schwartz, Gary K; Tap, William D; Qin, Li-Xuan; Livingston, Michael B; Undevia, Samir D; Chmielowski, Bartosz; Agulnik, Mark; Schuetze, Scott M; Reed, Damon R; Okuno, Scott H; Ludwig, Joseph A; Keedy, Vicki; Rietschel, Petra; Kraft, Andrew S; Adkins, Douglas; Van Tine, Brian A; Brockstein, Bruce; Yim, Vincent; Bitas, Christiana; Abdullah, Abdul; Antonescu, Cristina R; Condy, Mercedes; Dickson, Mark A; Vasudeva, Shyamprasad Deraje; Ho, Alan L; Doyle, L Austin; Chen, Helen X; Maki, Robert G

    2013-01-01

    Summary Background Preclinical studies have shown synergistic antitumour activity by inhibition of insulin-like growth factor-1 receptor (IGF-1R) and mTOR. The expression of IGF-1R seems to be crucial for this effect. We investigated the safety and efficacy of the combination of the IGF-1R antibody cixutumumab and the mTOR inhibitor temsirolimus in patients with chemotherapy-refractory bone and soft-tissue sarcomas according to IGF-1R expression by immunohistochemistry. Methods We undertook a multicentre, open-label, phase 2 study in 19 cancer centres in the USA. Patients aged at least 16 years with a histologically confirmed diagnosis of bone or soft-tissue sarcoma were allocated on the basis of IGF-1R expression by immunohistochemistry to one of three treatment groups: IGF-1R-positive soft-tissue sarcoma (group A), IGF-1R-positive bone sarcomas (group B), or IGF-1R-negative bone and soft-tissue sarcoma (group C). Patients received weekly treatment with cixutumumab (6 mg/kg, intravenous) and temsirolimus (25 mg, intravenous flat dose) in 6-week cycles. A Simon optimal two-stage design was used for every arm. The primary endpoint was progression-free survival (PFS) at 12 weeks by intention-to-treat analysis in the first 54 patients assigned to every treatment arm. Although patients still remain on treatment, this trial has completed enrolment and this represents the final analysis. This study is registered with ClinicalTrials.gov, number NCT01016015. Findings Between Nov 18, 2009, and April 11, 2012, 388 patients were screened for IGF-1R expression and 54 were assigned to each arm. 17 of 54 patients in the IGF-1R-positive soft-tissue sarcoma group (31%; one-sided 95% CI lower bound 21%; two-sided 90% CI 21–43), 19 of 54 in IGF-1R-positive bone sarcoma group (35%; one-sided 95% CI lower bound 24%; two-sided 90% CI 24–47), and 21 of 54 in the IGF-1R-negative group (39%, one-sided 95% CI lower bound 28%; two-sided 90% CI 28–51) were progression free at 12 weeks

  17. Decryption of a random-phase multiplexing recording system

    NASA Astrophysics Data System (ADS)

    Chang, Chi-Ching; Liu, Jung-Ping; Lee, Hsiao-Yi; Lin, Ching-Yang; Chang, Tsung-Chien; Yau, Hon-Fai

    2006-03-01

    In practice, decrypting a random-phase encrypted volume holographic data storage system is impossible unless the original random-phase plate for the encryption is available. However, this study demonstrates that under certain conditions, ways are available that can decrypt an encrypted photorefractive LiNbO3 crystal holographic storage system. In addition to presenting experimental results that show the efficacy of this decryption approach, problems and difficulties in the experiments are discussed.

  18. Interval iud insertion in parous women: a randomized multicentre comparative trial of the Lippes Loop D, TCu220c and the Copper 7.

    PubMed

    1982-07-01

    A multicentre randomized clinical trial of the TCu220C, Lippes Loop D and Copper 7 was undertaken in nine WHO Collaborating centres for Clinical Research in Human Reproduction. A total of 984, 992 and 994 devices, respectively, were inserted between 1976 and 1978. The subjects were followed for two years. At this time 18,743, 17,013 and 17,927 woman-months experience had been accumulated with each device, respectively. The Lippes Loop consistently failed to perform as well as the TCu220C regardless of age or parity. The TCu220C had statistically significantly lower pregnancy rates at one and two years of use than either of the other two devices as well as lower expulsion rates. The TCu220C had lower removal rates at one and two years than the Lippes Loop and Copper 7. At one and two years the TCu220C had significantly higher continuation rates than the other two devices. It is concluded that the TCu220C is the device of choice amongst the three devices studied.

  19. Impact of rapid antigen detection testing on antibiotic prescription in acute pharyngitis in adults. FARINGOCAT STUDY: a multicentric randomized controlled trial.

    PubMed

    Madurell, Jordi; Balagué, Montse; Gómez, Mónica; Cots, Josep M; Llor, Carl

    2010-03-23

    Acute pharyngitis is one of the most frequent consultations to the general practitioner and in most of the cases an antibiotic is prescribed in primary care in Spain. Bacterial etiology, mainly by group A beta-hemolytic streptococcus (GABHS), accounts for 10-20% of all these infections in adults. The purpose of this study is to assess the impact of rapid antigen detection testing (RADT) to identify GABHS in acute pharyngitis on the utilization of antibiotics in primary care. Multicentric randomized controlled trial in which antibiotic prescription between two groups of patients with acute pharyngitis will be compared. The trial will include two arms, a control and an intervention group in which RADT will be performed. The primary outcome measure will be the proportion of inappropriate antibiotic prescription in each group. Two hundred seventy-six patients are required to detect a reduction in antibiotic prescription from 85% in the control group to 75% in the intervention group with a power of 90% and a level of significance of 5%. Secondary outcome measures will be specific antibiotic treatment, antibiotic resistance rates, secondary effects, days without working, medical visits during the first month and patient satisfaction. The implementation of RADT would allow a more rational use of antibiotics and would prevent adverse effects of antibiotics, emergence of antibiotic resistance and the growth of inefficient health expenses.

  20. Single-exposure phase-shifting digital holography using a random-phase reference wave.

    PubMed

    Nomura, Takanori; Imbe, Masatoshi

    2010-07-01

    We propose a single-exposure phase-shifting digital holography based on a wave-splitting method using a random-phase reference wave. A random-phase reference wave gives random-phase distribution on the digital hologram. Using the amplitude and the phase distributions of the reference wave, the fully complex amplitude of the object wave is obtained. The proposed method requires not devised optical systems but ordinary imaging devices, such as CCD cameras. A preliminary experimental result is given to confirm the proposed method.

  1. Ferroquine and artesunate in African adults and children with Plasmodium falciparum malaria: a phase 2, multicentre, randomised, double-blind, dose-ranging, non-inferiority study.

    PubMed

    Held, Jana; Supan, Christian; Salazar, Carmen L O; Tinto, Halidou; Bonkian, Léa N; Nahum, Alain; Moulero, Bancole; Sié, Ali; Coulibaly, Boubacar; Sirima, Sodiomon B; Siribie, Mohamadou; Otsyula, Nekoye; Otieno, Lucas; Abdallah, Ahmed M; Kimutai, Robert; Bouyou-Akotet, Marielle; Kombila, Maryvonne; Koiwai, Kimiko; Cantalloube, Cathy; Din-Bell, Chantal; Djeriou, Elhadj; Waitumbi, John; Mordmüller, Benjamin; Ter-Minassian, Daniel; Lell, Bertrand; Kremsner, Peter G

    2015-12-01

    Artemisinin-based combination therapies (ACTs) are the recommended first-line treatment for uncomplicated Plasmodium falciparum malaria. Ferroquine is a new combination partner for fast-acting ACTs such as artesunate. We aimed to assess different doses of ferroquine in combination with artesunate against uncomplicated P falciparum malaria in a heterogeneous population in Africa. We did a phase 2, multicentre, parallel-group, double-blind, randomised, dose-ranging non-inferiority trial at eight African hospitals (two in Gabon, three in Burkina Faso, one in Benin, and two in Kenya). We recruited patients presenting with acute P falciparum monoinfection (1000-200,000 parasites per μL), and a central body temperature of at least 37·5°C or history of fever in the past 24 h. We assessed patients in two sequential cohorts: cohort 1 contained adults (bodyweight >50 kg) and adolescents (aged ≥14 years, >30 kg), and cohort 2 contained children (aged 2-13 years, 15-30 kg). We randomly assigned patients (1:1:1:1) to receive artesunate 4 mg/kg per day plus ferroquine 2 mg/kg, 4 mg/kg, or 6 mg/kg, given double-blind once per day for 3 days, or ferroquine monotherapy 4 mg/kg per day given single-blind (ie, allocation was only masked from the patient) once per day for 3 days. We did 14 patient visits (screening, 3 treatment days and 48 h post-treatment surveillance, a visit on day 7, then one follow-up visit per week until day 63). The primary endpoint was non-inferiority of treatment in terms of PCR-corrected cure rate against a reference value of 90%, with a 10% non-inferiority margin, assessed in patients treated without major protocol deviations for parasitologically confirmed malaria. We assessed safety in all treated patients. This study is registered with ClinicalTrials.gov, number NCT00988507, and is closed. Between Oct 16, 2009, and Sept 22, 2010, we randomly assigned 326 eligible patients to treatment groups, with last follow-up visit on Dec 1, 2010. 284 patients

  2. Gemcitabine plus cisplatin versus fluorouracil plus cisplatin in recurrent or metastatic nasopharyngeal carcinoma: a multicentre, randomised, open-label, phase 3 trial.

    PubMed

    Zhang, Li; Huang, Yan; Hong, Shaodong; Yang, Yunpeng; Yu, Gengsheng; Jia, Jun; Peng, Peijian; Wu, Xuan; Lin, Qing; Xi, Xuping; Peng, Jiewen; Xu, Mingjun; Chen, Dongping; Lu, Xiaojun; Wang, Rensheng; Cao, Xiaolong; Chen, Xiaozhong; Lin, Zhixiong; Xiong, Jianping; Lin, Qin; Xie, Conghua; Li, Zhihua; Pan, Jianji; Li, Jingao; Wu, Shixiu; Lian, Yingni; Yang, Quanlie; Zhao, Chong

    2016-10-15

    Outcomes are poor for patients with recurrent or metastatic nasopharyngeal carcinoma and no well established first-line chemotherapy is available for the disease. We compared the efficacy and safety of gemcitabine plus cisplatin versus fluorouracil plus cisplatin in patients with recurrent or metastatic nasopharyngeal carcinoma. In this multicentre, randomised, open-label, phase 3 trial, patients with recurrent or metastatic nasopharyngeal carcinoma were recruited from 22 hospitals in China. Key inclusion criteria were Eastern Cooperative Oncology Group performance status of 0 or 1, adequate organ function, and measurable lesions according to Response Evaluation Criteria in Solid Tumors version 1.1. Patients were randomly assigned in a 1:1 ratio to receive either gemcitabine (1 g/m(2) intravenously on days 1 and 8) and cisplatin (80 mg/m(2) intravenously on day 1), or fluorouracil (4 g/m(2) in continuous intravenous infusion over 96 h) and cisplatin (80 mg/m(2) on day 1 given intravenously) once every 3 weeks for a maximum of six cycles. The randomisation was done centrally via an interactive phone response system using block randomisation with a size of six. The primary endpoint was progression-free survival assessed by the independent image committee in the intention-to-treat population. Safety analyses were done in patients who received at least one cycle of study drug. This study is ongoing and is registered with ClinicalTrials.gov, number NCT01528618. Between Feb 20, 2012, and Oct 30, 2015, 362 patients were randomly assigned to a group (181 to the gemcitabine [plus cisplatin] group and 181 to the fluorouracil [plus cisplatin] group). Median follow-up time for progression-free survival was 19·4 months (IQR 12·1-35·6). The median progression-free survival was 7·0 months (4·4-10·9) in the gemcitabine group and 5·6 months (3·0-7·0) in the fluorouracil group (hazard ratio [HR] 0·55 [95% CI 0·44-0·68]; p<0·0001). A total of 180 patients in the

  3. Brentuximab vedotin or physician's choice in CD30-positive cutaneous T-cell lymphoma (ALCANZA): an international, open-label, randomised, phase 3, multicentre trial.

    PubMed

    Prince, H Miles; Kim, Youn H; Horwitz, Steven M; Dummer, Reinhard; Scarisbrick, Julia; Quaglino, Pietro; Zinzani, Pier Luigi; Wolter, Pascal; Sanches, Jose A; Ortiz-Romero, Pablo L; Akilov, Oleg E; Geskin, Larisa; Trotman, Judith; Taylor, Kerry; Dalle, Stephane; Weichenthal, Michael; Walewski, Jan; Fisher, David; Dréno, Brigitte; Stadler, Rudolf; Feldman, Tatyana; Kuzel, Timothy M; Wang, Yinghui; Palanca-Wessels, Maria Corinna; Zagadailov, Erin; Trepicchio, William L; Zhang, Wenwen; Lin, Hui-Min; Liu, Yi; Huebner, Dirk; Little, Meredith; Whittaker, Sean; Duvic, Madeleine

    2017-08-05

    Cutaneous T-cell lymphomas are rare, generally incurable, and associated with reduced quality of life. Present systemic therapies rarely provide reliable and durable responses. We aimed to assess efficacy and safety of brentuximab vedotin versus conventional therapy for previously treated patients with CD30-positive cutaneous T-cell lymphomas. In this international, open-label, randomised, phase 3, multicentre trial, we enrolled adult patients with CD30-positive mycosis fungoides or primary cutaneous anaplastic large-cell lymphoma who had been previously treated. Patients were enrolled across 52 centres in 13 countries. Patients were randomly assigned (1:1) centrally by an interactive voice and web response system to receive intravenous brentuximab vedotin 1·8 mg/kg once every 3 weeks, for up to 16 3-week cycles, or physician's choice (oral methotrexate 5-50 mg once per week or oral bexarotene 300 mg/m(2) once per day) for up to 48 weeks. The primary endpoint was the proportion of patients in the intention-to-treat population achieving an objective global response lasting at least 4 months per independent review facility. Safety analyses were done in all patients who received at least one dose of study drug. This trial was registered with ClinicalTrials.gov, number NCT01578499. Between Aug 13, 2012, and July 31, 2015, 131 patients were enrolled and randomly assigned to a group (66 to brentuximab vedotin and 65 to physician's choice), with 128 analysed in the intention-to-treat population (64 in each group). At a median follow-up of 22·9 months (95% CI 18·4-26·1), the proportion of patients achieving an objective global response lasting at least 4 months was 56·3% (36 of 64 patients) with brentuximab vedotin versus 12·5% (eight of 64) with physician's choice, resulting in a between-group difference of 43·8% (95% CI 29·1-58·4; p<0·0001). Grade 3-4 adverse events were reported in 27 (41%) of 66 patients in the brentuximab vedotin group and 29 (47%) of 62

  4. A multicentre, prospective, randomized, controlled trial comparing EVARREST™ fibrin sealant patch to standard of care in controlling bleeding following elective hepatectomy: anatomic versus non-anatomic resection

    PubMed Central

    Koea, Jonathan B.; Batiller, Jonathan; Aguirre, Nicolas; Shen, Jessica; Kocharian, Richard; Bochicchio, Grant; Garden, O. James

    2016-01-01

    Background This multicentre, randomized clinical trial assessed the safety and effectiveness of the EVARREST™ Fibrin Sealant Patch (FP) in treating parenchymal bleeding following anatomic and non-anatomic liver resections. Methods One hundred and two patients were stratified according to the type of hepatic resection (anatomic/non-anatomic), and randomized (1:1) after identification of an appropriate bleeding site, to FP vs Standard of Care (SoC, manual compression ± topical haemostat). The primary endpoint was haemostasis at 4 min from bleeding site identification with no re-bleeding requiring re-treatment. Results The FP was superior in achieving haemostasis at 4 min (96%, 48/50) to SoC (46%, 24/52; p < 0.001). Stratification for resection type showed treatment differences for primary endpoint for anatomic (24/25 FP vs 13/23 SoC; p = 0.001) and non-anatomic liver resections (24/25FP vs 11/29 SoC; p < 0.001). Adverse events related to the study procedure were reported in 40/50 patients (80%) in the FP group and 43/52 patients (83%) in the SoC group. One (2%) adverse event (infected intra-abdominal fluid collection) was possibly related to study treatment. Conclusion This clinical trial confirms that the FP is safe and highly effective in controlling parenchymal bleeding following hepatectomy regardless of the type of resection. ClinicalTrials.gov NCT01993888. PMID:27017161

  5. [Effect of "Jin three-needle therapy" on cognitive function and activity of daily living in patients of hemiplegia after stroke: a multi-central randomized controlled study].

    PubMed

    Xu, Shi-fen; Zhuang, Li-xing; Jia, Chao; Chen, Xing-hua; Wu, Si-ping; Jiang, Gui-mei; Zhu, Bo-chang; Xu, Di-jing; Pan, Chao-an

    2009-09-01

    To provide reliable evidence of "J in three-needle therapy" for treatment of stroke. Multi-central randomized controlled trials were adopted, 180 hemiplegia patients of ischemic stroke were randomly divided into a fin three-needle group (90 cases) and a routine acupuncture group (90 cases). Two groups were both treated with basic neurology therapies, and J in three-needle group was treated with J in three-needle therapy, three acupoints of tempora, hand and foot etc. were selected; the routine acupuncture group was treated with traditional acupuncture, Quchi (LI 11), Huantiao (GB 30), Futu (ST 32) etc. were selected. Both groups were treated with acupuncture for 5 weeks. The cognitive function score of functional comprehensive assessment scale (FCA), the scores of mini-mental state examination scale (MMSE) and modified Barthel index (BI) were compared before and after treatment between two groups. Results After treatment, the scores of FCA, MMSE and BI in both groups were significantly improved compared to those before treatment (P < 0.01, P < 0.05); the improvement of FCA score, MMSE score and BI score in the J in three-needle group were superior to those of the routine acupuncture group after treatment (P < 0.01, P < 0.05). The total effective rate of 85.4% in the J in three-needle group was superior to tohat of 70.0% in the routine acupuncture group (P < 0.05). J in three-needle acupuncture treatment can obviously improve the cognitive function and activity ability of daily life of hemiplegia patients after stroke, and the therapeutic effect of J in three-needle therapy is superior to that of traditional acupuncture treatment.

  6. Recombinant streptokinase suppositories in the treatment of acute haemorrhoidal disease. Multicentre randomized double-blind placebo-controlled trial (THERESA-2).

    PubMed

    Hernández-Bernal, F; Valenzuela-Silva, C M; Quintero-Tabío, L; Castellanos-Sierra, G; Monterrey-Cao, D; Aguilera-Barreto, A; López-Saura, P

    2013-11-01

    A four-arm multicentre randomized double-blind placebo-controlled trial was undertaken to assess the effect and safety of suppositories containing recombinant streptokinase (rSK) at two dose levels (100,000 IU and 200,000 IU) with sodium salicylate (SS) compared with placebo and SS for the treatment of acute haemorrhoidal disease. Patients with acute symptoms of haemorrhoids were randomized to four treatment groups: (I) placebo, (II) SS, (III) SS + rSK 100,000 IU and (IV) SS + rSK 200,000 IU per suppository. Inpatient treatment was by four suppositories given every 6 h to discharge at 24 h. Evaluations were made at the time of discharge (24 h) and at 3, 5 and 20 days later. The main end-point was the degree of relief of pain, oedema and reduction in the size of the lesion by 90% on day 5. Adverse events and the occurrence of anti-SK antibodies were also determined. Eighty patients were included. Respective response rates in the four groups were 16%, 30%, 25% and 52%. In the last group there was a significant difference (36.8%) compared with control (95% CI 7.0-58.4%). The time to response was significantly shorter (median 5 days) in the 200,000 IU rSK group with respect to the others. There were no adverse events attributable to the treatment. No increase in anti-SK antibodies was detected 20 days after treatment. Suppositories with 200,000 IU rSK showed a significant improvement in symptoms of acute haemorrhoids, with an adequate safety profile. Colorectal Disease © 2013 The Association of Coloproctology of Great Britain and Ireland.

  7. Multicentre, randomized, open-label study of on-demand treatment with two prophylaxis regimens of recombinant coagulation factor IX in haemophilia B subjects.

    PubMed

    Valentino, L A; Rusen, L; Elezovic, I; Smith, L M; Korth-Bradley, J M; Rendo, P

    2014-05-01

    Few randomized studies have reported on the use of factor IX (FIX) for secondary prophylaxis in haemophilia B patients. This study aimed to evaluate the efficacy and safety of two secondary prophylaxis regimens of recombinant coagulation FIX, nonacog alfa, compared with on-demand therapy. Male subjects aged 6-65 years with severe or moderately severe haemophilia B (FIX:C ≤ 2, n = 50) and ≥12 bleeding episodes (including ≥6 haemarthroses episodes) within 12 months of study participation were enrolled in this multicentre, randomized, open-label, four-period crossover trial. The primary measure was the annualized bleeding rate (ABR) of two prophylactic regimens vs. on-demand therapy. In the intent-to-treat group, mean ABR values were 35.1, 2.6 and 4.6 for the first on-demand period, the 50 IU kg(-1) twice-weekly period, and the 100 IU kg(-1) once-weekly period respectively. Differences in ABR between the first on-demand period and both prophylaxis regimens were significant (P < 0.0001); no significant differences were observed between prophylaxis regimens (P = 0.22). Seven serious adverse events occurred in five subjects, none related to study drug. Results demonstrated that secondary prophylaxis therapy with nonacog alfa 50 IU kg(-1) twice weekly or 100 IU kg(-1) once weekly reduced ABR by 89.4% relative to on-demand treatment. Both prophylaxis regimens demonstrated favourable safety profiles in subjects with haemophilia B.

  8. Impairment-oriented training or Bobath therapy for severe arm paresis after stroke: a single-blind, multicentre randomized controlled trial.

    PubMed

    Platz, T; Eickhof, C; van Kaick, S; Engel, U; Pinkowski, C; Kalok, S; Pause, M

    2005-10-01

    To study the effects of augmented exercise therapy time for arm rehabilitation as either Bobath therapy or the impairment-oriented training (Arm BASIS training) in stroke patients with arm severe paresis. Single blind, multicentre randomized control trial. Three inpatient neurorehabilitation centres. Sixty-two anterior circulation ischaemic stroke patients. Random assignment to three group: (A) no augmented exercise therapy time, (B) augmented exercise therapy time as Bobath therapy and (C) augmented exercise therapy time as Arm BASIS training. Fugl-Meyer arm motor score. Secondary measure: Action Research Arm Test (ARA). Ancillary measures: Fugl-Meyer arm sensation and joint motion/pain scores and the Ashworth Scale (elbow flexors). An overall effect of augmented exercise therapy time on Fugl-Meyer scores after four weeks was not corroborated (mean and 95% confidence interval (CI) of change scores: no augmented exercise therapy time (n=20) 8.8, 5.2-12.3; augmented exercise therapy time (n=40) 9.9, 6.8-13.9; p = 0.2657). The group who received the augmented exercise therapy time as Arm BASIS training (n=20) had, however, higher gains than the group receiving the augmented exercise therapy time as Bobath therapy (n=20) (mean and 95% CI of change scores: Bobath 7.2, 2.6-11.8; BASIS 12.6, 8.4-16.8; p = 0.0432). Passive joint motion/pain deteriorated less in the group who received BASIS training (mean and 95% CI of change scores: Bobath -3.2, -5.2 to -1.1; BASIS 0.1, -1.8-2.0; p = 0.0090). ARA, Fugl-Meyer arm sensation, and Ashworth Scale scores were not differentially affected. The augmented exercise therapy time as Arm BASIS training enhanced selective motor control. Type of training was more relevant for recovery of motor control than therapeutic time spent.

  9. Automatic environmental disinfection with hydrogen peroxide and silver ions versus manual environmental disinfection with sodium hypochlorite: a multicentre randomized before-and-after trial.

    PubMed

    Mosci, D; Marmo, G W; Sciolino, L; Zaccaro, C; Antonellini, R; Accogli, L; Lazzarotto, T; Mongardi, M; Landini, M P

    2017-10-01

    New technologies for automated disinfection have been developed, including the use of hydrogen peroxide atomized by specific equipment, with associated silver compounds. To compare the effectiveness of an automated disinfection system with hydrogen peroxide <8% and silver ion versus a manual method with 0.5% sodium hypochlorite solution when evaluating the reduction of microbial mesophilic contamination and Clostridium difficile presence; and to evaluate the time required for both of these processes. This was a randomized multicentre trial performed in different hospital wards that had been occupied previously by patients with Clostridium difficile infection. When patients were discharged their rooms were randomized to one of two decontamination arms. The surfaces where sampled using swabs, before and after disinfection. Swab samples were cultured for quantitative detection of microbial mesophilic contamination and qualitative detection of C. difficile. Before disinfection, 13% of surfaces decontaminated with hydrogen peroxide and silver ions and 20% of surfaces decontaminated with sodium hypochlorite showed presence of C. difficile spores. After disinfection, the samples containing C. difficile were 0% (P < 0.001) in the group decontaminated with hydrogen peroxide and silver ions, and were 3% (P < 0.001) in the group decontaminated with sodium hypochlorite. This difference was not statistically significant; nor was the difference in the reduction of the microbial mesophilic contamination. The differences between the groups were not statistically significant; however, the disinfection with hydrogen peroxide and silver ions is preferable due to less dependence on operators. Copyright © 2017 The Healthcare Infection Society. Published by Elsevier Ltd. All rights reserved.

  10. Effects of Blockiness on the phase behavior of random copolymers

    NASA Astrophysics Data System (ADS)

    Vanderwoude, Gordon; Shi, An-Chang

    Theoretical study of random block copolymers remains a challenging topic due in part to the sheer enormity of their phase space. In this study we use the self-consistent field theory to investigate the phase behaviour of linear (AB)n-type and (AB)n-C-type multiblock copolymers with randomly distributed A and B blocks. In particular, we examine the effect of ``blockiness'' of the random copolymers on the formation of ordered phases. The blockiness can be quantified by the average length of individual A or B blocks, which can be taken as a measure of the heterogeneity of the random copolymers. We observed that the critical value of the χ parameter, at which the order-disorder transition occurs, decreases with increasing blockiness in the (AB)n copolymers. We also observed that the phase behaviour of the (AB)n-C copolymers depends strongly on the blockiness of the random chain. In particular, the blockiness governs whether or not the A/B blocks can phase separate within the A/B domains, thus dictating whether the (AB)n-C behaves as A/B-C diblock copolymers or as ABC terpolymers. The theoretical phase diagrams will be compared with available experiments.

  11. Phase transition in random adaptive walks on correlated fitness landscapes

    NASA Astrophysics Data System (ADS)

    Park, Su-Chan; Szendro, Ivan G.; Neidhart, Johannes; Krug, Joachim

    2015-04-01

    We study biological evolution on a random fitness landscape where correlations are introduced through a linear fitness gradient of strength c . When selection is strong and mutations rare the dynamics is a directed uphill walk that terminates at a local fitness maximum. We analytically calculate the dependence of the walk length on the genome size L . When the distribution of the random fitness component has an exponential tail, we find a phase transition of the walk length D between a phase at small c , where walks are short (D ˜lnL ) , and a phase at large c , where walks are long (D ˜L ) . For all other distributions only a single phase exists for any c >0 . The considered process is equivalent to a zero temperature Metropolis dynamics for the random energy model in an external magnetic field, thus also providing insight into the aging dynamics of spin glasses.

  12. A multicentre, randomized, controlled study of the efficacy, safety and cost-effectiveness of a combination therapy with amorolfine nail lacquer and oral terbinafine compared with oral terbinafine alone for the treatment of onychomycosis with matrix involvement.

    PubMed

    Baran, R; Sigurgeirsson, B; de Berker, D; Kaufmann, R; Lecha, M; Faergemann, J; Kerrouche, N; Sidou, F

    2007-07-01

    Onychomycosis is common, accounting for up to 50% of all nail disorders. Toenail onychomycosis can cause nail deformity, embarrassment, pain and walking difficulties. Some populations, such as individuals with diabetes, are at higher risk for developing secondary complications such as infections. Treatment takes many months and therapeutic choices can increase clinical effectiveness, lower toxicity and minimize healthcare costs. Based on the results of a previous pilot study, the objective of the present study was to show, in a larger population, the enhanced efficacy of a combination of amorolfine nail lacquer and oral terbinafine in the treatment of onychomycosis with matrix involvement. In addition, a cost-effectiveness analysis was performed. In this multicentre, randomized, open-label, parallel group study, patients were randomized to receive either a combination of amorolfine hydrochloride 5% nail lacquer once weekly for 12 months plus terbinafine 250 mg once daily for 3 months (AT group) or terbinafine alone once daily for 3 months (T group). The study duration was 18 months including a 6-month treatment-free phase following the 12-month active treatment phase for the AT group and a 15-month treatment-free phase following the 3-month active treatment phase for the T group. The primary efficacy criterion was overall response, dichotomized into success or failure, success being the combination of clinical cure and negative mycology at month 18. This criterion was used as the effectiveness measure in the pharmacoeconomic analysis, conducted from a payer perspective. In total, 249 patients were included into the study: 120 in the AT group and 129 in the T group. A significantly higher success rate was observed for patients in the AT group relative to those in the T group at 18 months (59.2% vs. 45.0%; P = 0.03). Both treatment regimens were safe and well tolerated. Treatment cost per cured patient was lower for the combination than for terbinafine alone in all

  13. SCOPE1: a randomised phase II/III multicentre clinical trial of definitive chemoradiation, with or without cetuximab, in carcinoma of the oesophagus

    PubMed Central

    2011-01-01

    Background Chemoradiotherapy is the standard of care for patients with oesophageal cancer unsuitable for surgery due to the presence of co-morbidity or extent of disease, and is a standard treatment option for patients with squamous cell carcinoma of the oesophagus. Modern regimens of chemoradiotherapy can lead to significant long-term survival. However the majority of patients will die of their disease, most commonly with local progression/recurrence of their tumours. Cetuximab may overcome one of the principal mechanisms of tumour radio-resistance, namely tumour repopulation, in patients treated with chemoradiotherapy. The purpose of this research is first to determine whether the addition of cetuximab to definitive chemoradiotherapy for treatment of patients with non-metastatic carcinoma of the oesophagus is active (in terms of failure-free rate), safe, and feasible within the context of a multi-centre randomised controlled trial in the UK. If the first stage is successful then the trial will continue to accrue sufficient patients to establish whether the addition of cetuximab to the standard treatment improves overall survival. Methods/Design SCOPE1 is a two arm, open, randomised multicentre Phase II/III trial. Eligible patients will have histologically confirmed carcinoma of the oesophagus and have been chosen to receive definitive chemoradiotherapy by an accredited multidisciplinary team including a specialist Upper GI surgeon. 420 patients will be randomised to receive definitive chemoradiotherapy with or without cetuximab using a 1:1 allocation ratio. During Phase II of the study, the trial will assess safety (toxicity), activity (failure-free rate) and feasibility (recruitment rate and protocol dose modifications/delays) in 90 patients in the experimental arm. If the experimental arm is found to be active, safe, and feasible by the Independent Data Monitoring Committee then recruitment will continue into Phase III. This second stage will recruit a further

  14. The Condensation Phase Transition in Random Graph Coloring

    NASA Astrophysics Data System (ADS)

    Bapst, Victor; Coja-Oghlan, Amin; Hetterich, Samuel; Raßmann, Felicia; Vilenchik, Dan

    2016-01-01

    Based on a non-rigorous formalism called the "cavity method", physicists have put forward intriguing predictions on phase transitions in diluted mean-field models, in which the geometry of interactions is induced by a sparse random graph or hypergraph. One example of such a model is the graph coloring problem on the Erdős-Renyi random graph G( n, d/ n), which can be viewed as the zero temperature case of the Potts antiferromagnet. The cavity method predicts that in addition to the k-colorability phase transition studied intensively in combinatorics, there exists a second phase transition called the condensation phase transition (Krzakala et al. in Proc Natl Acad Sci 104:10318-10323, 2007). In fact, there is a conjecture as to the precise location of this phase transition in terms of a certain distributional fixed point problem. In this paper we prove this conjecture for k exceeding a certain constant k 0.

  15. Catheter ablation vs. antiarrhythmic drug treatment of persistent atrial fibrillation: a multicentre, randomized, controlled trial (SARA study).

    PubMed

    Mont, Lluís; Bisbal, Felipe; Hernández-Madrid, Antonio; Pérez-Castellano, Nicasio; Viñolas, Xavier; Arenal, Angel; Arribas, Fernando; Fernández-Lozano, Ignacio; Bodegas, Andrés; Cobos, Albert; Matía, Roberto; Pérez-Villacastín, Julián; Guerra, José M; Ávila, Pablo; López-Gil, María; Castro, Victor; Arana, José Ignacio; Brugada, Josep

    2014-02-01

    Catheter ablation (CA) is a highly effective therapy for the treatment of paroxysmal atrial fibrillation (AF) when compared with antiarrhythmic drug therapy (ADT). No randomized studies have compared the two strategies in persistent AF. The present randomized trial aimed to compare the effectiveness of CA vs. ADT in treating persistent AF. Patients with persistent AF were randomly assigned to CA or ADT (excluding patients with long-standing persistent AF). Primary endpoint at 12-month follow-up was defined as any episode of AF or atrial flutter lasting >24 h that occurred after a 3-month blanking period. Secondary endpoints were any atrial tachyarrhythmia lasting >30 s, hospitalization, and electrical cardioversion. In total, 146 patients were included (aged 55 ± 9 years, 77% male). The ADT group received class Ic (43.8%) or class III drugs (56.3%). In an intention-to-treat analysis, 69 of 98 patients (70.4%) in the CA group and 21 of 48 patients (43.7%) in the ADT group were free of the primary endpoint (P = 0.002), implying an absolute risk difference of 26.6% (95% CI 10.0-43.3) in favour of CA. The proportion of patients free of any recurrence (>30 s) was higher in the CA group than in the ADT group (60.2 vs. 29.2%; P < 0.001) and cardioversion was less frequent (34.7 vs. 50%, respectively; P = 0.018). Catheter ablation is superior to medical therapy for the maintenance of sinus rhythm in patients with persistent AF at 12-month follow-up. NCT00863213 (http://clinicaltrials.gov/ct2/show/NCT00863213).

  16. Catheter ablation vs. antiarrhythmic drug treatment of persistent atrial fibrillation: a multicentre, randomized, controlled trial (SARA study)

    PubMed Central

    Mont, Lluís; Bisbal, Felipe; Hernández-Madrid, Antonio; Pérez-Castellano, Nicasio; Viñolas, Xavier; Arenal, Angel; Arribas, Fernando; Fernández-Lozano, Ignacio; Bodegas, Andrés; Cobos, Albert; Matía, Roberto; Pérez-Villacastín, Julián; Guerra, José M.; Ávila, Pablo; López-Gil, María; Castro, Victor; Arana, José Ignacio; Brugada, Josep

    2014-01-01

    Background Catheter ablation (CA) is a highly effective therapy for the treatment of paroxysmal atrial fibrillation (AF) when compared with antiarrhythmic drug therapy (ADT). No randomized studies have compared the two strategies in persistent AF. The present randomized trial aimed to compare the effectiveness of CA vs. ADT in treating persistent AF. Methods and results Patients with persistent AF were randomly assigned to CA or ADT (excluding patients with long-standing persistent AF). Primary endpoint at 12-month follow-up was defined as any episode of AF or atrial flutter lasting >24 h that occurred after a 3-month blanking period. Secondary endpoints were any atrial tachyarrhythmia lasting >30 s, hospitalization, and electrical cardioversion. In total, 146 patients were included (aged 55 ± 9 years, 77% male). The ADT group received class Ic (43.8%) or class III drugs (56.3%). In an intention-to-treat analysis, 69 of 98 patients (70.4%) in the CA group and 21 of 48 patients (43.7%) in the ADT group were free of the primary endpoint (P = 0.002), implying an absolute risk difference of 26.6% (95% CI 10.0–43.3) in favour of CA. The proportion of patients free of any recurrence (>30 s) was higher in the CA group than in the ADT group (60.2 vs. 29.2%; P < 0.001) and cardioversion was less frequent (34.7 vs. 50%, respectively; P = 0.018). Conclusion Catheter ablation is superior to medical therapy for the maintenance of sinus rhythm in patients with persistent AF at 12-month follow-up. Clinical Trial Registration Information NCT00863213 (http://clinicaltrials.gov/ct2/show/NCT00863213). PMID:24135832

  17. Cognitive behaviour therapy for non-cardiac pain in the chest (COPIC): a multicentre randomized controlled trial with economic evaluation.

    PubMed

    Tyrer, Peter; Tyrer, Helen; Cooper, Sylvia; Barrett, Barbara; Kings, Stephanie; Lazarevic, Valentina; Bransby-Adams, Kate; Whittamore, Katherine; Walker, Gemma; McNulty, Antoinette; Donaldson, Emma; Midgley, Luke; McCoy, Shani; Evered, Rachel; Yang, Min; Guo, Boliang; Lisseman-Stones, Yvonne; Doukani, Asmae; Mulder, Roger; Morriss, Richard; Crawford, Mike

    2015-11-24

    Most patients with chest pain have nothing wrong with their cardiac function. Psychological forms of treatment for this condition are more likely to be successful than others. A two-arm parallel controlled randomized trial of standard care versus a modified form of cognitive behaviour therapy for chest pain (CBT-CP) in patients who have attended emergency hospital services. Inclusion criteria include (i) emergency attendance more than once in the previous year with chest pain when no physical pathology has been found, (ii) aged between 16 and 75, (iii) signed consent to take part in the study. Exclusion criteria are (i) under current psychiatric care, (ii) those who have had new psychotropic drugs prescribed within the last two months, (iii) are receiving or about to receive a formal psychological treatment. Those satisfying these criteria will be randomized to 4-10 sessions of CBT-CP or to continue with standard care. Participants are randomized using a remote web-based system using permuted stacked blocks stratified by study centre. Assessment is carried out at baseline by researchers subsequently masked to allocation and at 6 months and 1 year after randomization. The primary outcome is the Health Anxiety Inventory score at 6 months, and secondary outcomes are generalised anxiety and depressive symptoms, the Lucock Health Anxiety Questionnaire adapted for chest pain, visual analogue scales for chest pain and discomfort (Inskip Scale), the Schedule for Evaluating Persistent Symptoms (SEPS), health related quality of life, social functioning and medical resource usage. Intention to treat analyses will be carried out with clinical and functioning data, and a cost-utility analysis will compare differences in total costs and differences in quality of life using QALYs derived from the EQ-5D. The data will also be linked to another parallel study in New Zealand where 126 patients with the same inclusion criteria have been treated in a similar trial; the form of

  18. Nonequilibrium phase transition on a randomly diluted lattice.

    PubMed

    Vojta, Thomas; Lee, Man Young

    2006-01-27

    We show that the interplay between geometric criticality and dynamical fluctuations leads to a novel universality class of the contact process on a randomly diluted lattice. The nonequilibrium phase transition across the percolation threshold of the lattice is characterized by unconventional activated (exponential) dynamical scaling and strong Griffiths effects. We calculate the critical behavior in two and three space dimensions, and we also relate our results to the recently found infinite-randomness fixed point in the disordered one-dimensional contact process.

  19. Day hospital Mentalization-based treatment versus intensive outpatient Mentalization-based treatment for patients with severe borderline personality disorder: protocol of a multicentre randomized clinical trial.

    PubMed

    Laurenssen, Elisabeth M P; Smits, Maaike L; Bales, Dawn L; Feenstra, Dine J; Eeren, Hester V; Noom, Marc J; Köster, Maartje A; Lucas, Zwaan; Timman, Reinier; Dekker, Jack J M; Luyten, Patrick; Busschbach, Jan J V; Verheul, Roel

    2014-11-18

    Borderline personality disorder (BPD) is associated with a high socioeconomic burden. Although a number of evidence-based treatments for BPD are currently available, they are not widely disseminated; furthermore, there is a need for more research concerning their efficacy and cost-effectiveness. Such knowledge promises to lead to more efficient use of resources, which will facilitate the effective dissemination of these costly treatments. This study focuses on the efficacy and cost-effectiveness of Mentalization-Based Treatment (MBT), a manualized treatment for patients with BPD. Studies to date have either investigated MBT in a day hospitalization setting (MBT-DH) or MBT offered in an intensive outpatient setting (MBT-IOP). No trial has compared the efficacy and cost-effectiveness of these MBT programmes. As both interventions differ considerably in terms of intensity of treatment, and thus potentially in terms of efficacy and cost-effectiveness, there is a need for comparative trials. This study therefore sets out to investigate the efficacy and cost-effectiveness of MBT-DH versus MBT-IOP in patients with BPD. A secondary aim is to investigate the association between baseline measures and outcome, which might improve treatment selection and thus optimize efficacy and cost-effectiveness. A multicentre randomized controlled trial comparing MBT-DH versus MBT-IOP in severe BPD patients. Patients are screened for BPD using the Structured Clinical Interview for DSM-IV Axis II Personality Disorders, and are assessed before randomization, at the start of treatment and 6, 12, 18, 24, 30 and 36 months after the start of treatment. Patients who refuse to participate will be offered care as usual in the same treatment centre. The primary outcome measure is symptom severity as measured by the Brief Symptom Inventory. Secondary outcome measures include parasuicidal behaviour, depression, substance use, social, interpersonal, and personality functioning, attachment, mentalizing

  20. Multicolumn spinal cord stimulation for significant low back pain in failed back surgery syndrome: design of a national, multicentre, randomized, controlled health economics trial (ESTIMET Study).

    PubMed

    Roulaud, M; Durand-Zaleski, I; Ingrand, P; Serrie, A; Diallo, B; Peruzzi, P; Hieu, P D; Voirin, J; Raoul, S; Page, P; Fontaine, D; Lantéri-Minet, M; Blond, S; Buisset, N; Cuny, E; Cadenne, M; Caire, F; Ranoux, D; Mertens, P; Naous, H; Simon, E; Emery, E; Gadan, B; Regis, J; Sol, J-C; Béraud, G; Debiais, F; Durand, G; Guetarni Ging, F; Prévost, A; Brandet, C; Monlezun, O; Delmotte, A; d'Houtaud, S; Bataille, B; Rigoard, P

    2015-03-01

    Many studies have demonstrated the efficacy of spinal cord stimulation (SCS) for chronic neuropathic radicular pain over recent decades, but despite global favourable outcomes in failed back surgery syndrome (FBSS) with leg pain, the back pain component remains poorly controlled by neurostimulation. Technological and scientific progress has led to the development of new SCS leads, comprising a multicolumn design and a greater number of contacts. The efficacy of multicolumn SCS lead configurations for the treatment of the back pain component of FBSS has recently been suggested by pilot studies. However, a randomized controlled trial must be conducted to confirm the efficacy of new generation multicolumn SCS. Évaluation médico-économique de la STImulation MEdullaire mulTi-colonnes (ESTIMET) is a multicentre, randomized study designed to compare the clinical efficacy and health economics aspects of mono- vs. multicolumn SCS lead programming in FBSS patients with radicular pain and significant back pain. FBSS patients with a radicular pain VAS score≥50mm, associated with a significant back pain component were recruited in 14 centres in France and implanted with multicolumn SCS. Before the lead implantation procedure, they were 1:1 randomized to monocolumn SCS (group 1) or multicolumn SCS (group 2). Programming was performed using only one column for group 1 and full use of the 3 columns for group 2. Outcome assessment was performed at baseline (pre-implantation), and 1, 3, 6 and 12months post-implantation. The primary outcome measure was a reduction of the severity of low back pain (bVAS reduction≥50%) at the 6-month visit. Additional outcome measures were changes in global pain, leg pain, paraesthesia coverage mapping, functional capacities, quality of life, neuropsychological aspects, patient satisfaction and healthcare resource consumption. Trial recruitment started in May 2012. As of September 2013, all 14 study centres have been initiated and 112

  1. Randomized multi-centre trial of the effects of a catheter coated with hydrogel and silver salts on the incidence of hospital-acquired urinary tract infections.

    PubMed

    Thibon, P; Le Coutour, X; Leroyer, R; Fabry, J

    2000-06-01

    Catheters coated with hydrogel and silver salts have been proposed to prevent hospital-acquired urinary tract infections (UTI). We carried out a randomized, prospective, double-blind multi-centre trial to compare those catheters with classical urinary tract catheters. We included in the study 199 patients requiring urethral catheterization for more than three days: 109 in group 1 (classical catheter) and 90 in group 2 (catheter coated with hydrogel and silver salts). Urine from the patients was tested for 10 days after the insertion of the catheter (reactive dipsticks each day and diagnostic urinalysis every two days). The UTI associated with catheterization was defined on the basis of bacterial and cytological criteria (>10(5)cfu bacteria per mL and >10 leucocytes per mm(3)). Twenty-two UTIs were recorded: 13 in group 1 and nine in group 2. The cumulative incidence of UTI associated with catheterization was 11.1% overall, 11.9% for group 1 and 10% for group 2; the odds ratio was 0.82 (95% confidence interval: 0.30 to 2. 20); the cumulative incidence for UTI, calculated by the Kaplan-Meier method was 36.3 overall, 35.2 in group 1 and 36.0 in group 2; the overall incidence density was 19 per thousand days of catheterization, 21 in group 1 and 18 in group 2. The differences between the two groups were not significant. Overall, we feel that there is not enough evidence to conclude that catheters coated with silver salts and hydrogel give greater protection than classical catheters and to recommend widespread use.

  2. A topical microemulsion for the prevention of allergic rhinitis symptoms: results of a randomized, controlled, double-blind, parallel group, multicentre, multinational clinical trial (Nares study)

    PubMed Central

    2013-01-01

    Background Since barrier protection measures to avoid contact with allergens are being increasingly developed, we assessed the clinical efficacy and tolerability of a topical nasal microemulsion made of glycerol esters in patients with allergic rhinitis. Methods Randomized, controlled, double-blind, parallel group, multicentre, multinational clinical trial in which adult patients with allergic rhinitis or rhinoconjunctivitis due to sensitization to birch, grass or olive tree pollens received treatment with topical microemulsion or placebo during the pollen seasons. Efficacy variables included scores in the mini-RQLQ questionnaire, number and severity of nasal, ocular and lung signs and symptoms, need for symptomatic medications and patients’ satisfaction with treatment. Adverse events were also recorded. Results Demographic characteristics were homogeneous between groups and mini-RQLQ scores did not differ significantly at baseline (visit 1). From symptoms recorded in the diary cards, the ME group showed statistically significant better scores for nasal congestion (0.72 vs. 1.01; p = 0.017) and mean total nasal symptoms (0.7 vs. 0.9; p = 0.045). At visit 2 (pollen season), lower values were observed in the mini-RQLQ in the ME group, although there were no statistically significant differences between groups in both full analysis set (FAS) and patients completing treatment (PPS) populations. The results obtained in the nasal symptoms domain of the mini-RQLQ at visit 2 showed the highest difference (−0.43; 95% CI: -0.88 to 0.02) for the ME group in the FAS population. The topical microemulsion was safe and well tolerated and no major discomforts were observed. Satisfaction rating with the treatment was similar between the groups. Conclusions The topical application of the microemulsion is a feasible and safe therapy in the prevention of allergic symptoms, particularly nasal congestion. Trial registration ClinicalTrials.gov Identifier: NCT01478425 PMID

  3. A randomized, double-blind, placebo-controlled, multicentre study to assess haemodynamic effects of serelaxin in patients with acute heart failure

    PubMed Central

    Ponikowski, Piotr; Mitrovic, Veselin; Ruda, Mikhail; Fernandez, Alberto; Voors, Adriaan A.; Vishnevsky, Alexander; Cotter, Gad; Milo, Olga; Laessing, Ute; Zhang, Yiming; Dahlke, Marion; Zymlinski, Robert; Metra, Marco

    2014-01-01

    Aims The aim of this study was to evaluate the haemodynamic effects of serelaxin (30 µg/kg/day 20-h infusion and 4-h post-infusion period) in patients with acute heart failure (AHF). Methods and results This double-blind, multicentre study randomized 71 AHF patients with pulmonary capillary wedge pressure (PCWP) ≥18 mmHg, systolic blood pressure (BP) ≥115 mmHg, and estimated glomerular filtration rate ≥30 mL/min/1.73 m2 to serelaxin (n = 34) or placebo (n = 37) within 48 h of hospitalization. Co-primary endpoints were peak change from baseline in PCWP and cardiac index (CI) during the first 8 h of infusion. Among 63 patients eligible for haemodynamic analysis (serelaxin, n = 32; placebo, n = 31), those treated with serelaxin had a significantly higher decrease in peak PCWP during the first 8 h of infusion (difference vs. placebo: −2.44 mmHg, P = 0.004). Serelaxin showed no significant effect on the peak change in CI vs. placebo. Among secondary haemodynamic endpoints, a highly significant reduction in pulmonary artery pressure (PAP) was observed throughout the serelaxin infusion (largest difference in mean PAP vs. placebo: −5.17 mmHg at 4 h, P < 0.0001). Right atrial pressure, systemic/pulmonary vascular resistance, and systolic/diastolic BP decreased from baseline with serelaxin vs. placebo and treatment differences reached statistical significance at some time points. Serelaxin administration improved renal function and decreased N-terminal pro-brain natriuretic peptide levels vs. placebo. Treatment with serelaxin was well tolerated with no apparent safety concerns. Conclusion The haemodynamic effects of serelaxin observed in the present study provide plausible mechanistic support for improvement in signs and symptoms of congestion observed with this agent in AHF patients. ClinicalTrials.gov identifier NCT01543854. PMID:24255129

  4. Comparison of the effects of imidapril and enalapril in a prospective, multicentric randomized trial in dogs with naturally acquired heart failure.

    PubMed

    Amberger, Chris; Chetboul, Valérie; Bomassi, Eric; Rougier, Sandrine; Woehrlé, Frédérique; Thoulon, Fabrice

    2004-11-01

    To compare the efficacy and tolerability of the long-term administration of two different angiotensin-converting enzyme inhibitors, imidapril and enalapril, in a multicentric, prospective, randomized parallel-group scheme clinical trial in dogs with naturally acquired heart disease. One hundred twenty eight dogs with clinical signs of heart failure (stage II (64-50%) - III (45-35%) - IV (19-15%) New York Heart Association) caused by chronic valvular disease or dilated cardiomyopathy were selected. Imidapril (minimum dosage 0.25 mg/kg) or enalapril (median dosage 0.5 mg/kg) was administered orally once daily for 12 months, either alone or as an add-on therapy to diuretics and/or digoxin. The primary outcome measure was the quality of life score after 3 months of therapy. Sixty-one percent of the dogs in the imidapril group (36/59) and 52 % in the enalapril group (30/58) were considered responders. After 12 months, a clear improvement compared to baseline was maintained in each treatment group for most parameters reflecting the quality of life such as fatigue, exercise tolerance, dyspnea, cough and general condition. Quality of life scores and survival times were similar in both groups after 12 months. Both drugs were well tolerated over the one-year follow-up. Imidapril proved to be as effective as the reference drug enalapril in the treatment of dogs with NYHA class II-IV heart failure. As with enalapril, imidapril was well tolerated during the long-term treatment period of one year in the dose range used in the study.

  5. A multicentre cluster-randomized controlled study to evaluate a train-the-trainer programme for implementing internal and external participation in medical rehabilitation.

    PubMed

    Koerner, Mirjam; Wirtz, Markus; Michaelis, Martina; Ehrhardt, Heike; Steger, Anne-Kathrin; Zerpies, Eva; Bengel, Jürgen

    2014-01-01

    Evaluation of the effect of the train-the-trainer programme 'Fit for Shared Decision-Making' on internal (team) and external (patient) participation in medical rehabilitation from a patient and staff perspective. A multicentre, cluster-randomized controlled study. Eleven medical rehabilitation clinics, divided into intervention and control groups. A staff and a patient survey were conducted pre- and post-intervention, plus a further patient survey six months later. Train-the-trainer programme 'Fit for Shared Decision-Making' for interprofessional settings. Each survey measured internal participation with a self-compiled six-item scale (Internal Participation Scale, IPS), and external participation by means of a nine-item Shared Decision-Making Questionnaire (SDM-Q-9) for the patients and for healthcare professionals. Patient samples numbered 402 for the pre-, 463 for the post-intervention data collection period and 461 six months after the intervention. Patients' appraisal of external participation (Fperiod x group (2) = 0.256, p=0.774, η(2)=0.000) showed no change, whereas internal participation (Fperiod x group (2) = 3.785, p=0.023, η(2)=0.007) showed a significant increase. A total of 195 healthcare professionals participated in the pre- and 168 in the post-intervention staff survey. Here external participation was significantly enhanced in the intervention group (F(period x group) (1) = 4.893, p=0.028, η(2)=0.014). The train-the-trainer approach can be recommended for implementing internal and external participation in interprofessional settings such as medical rehabilitation clinics. However, there is a need for more intensive staff training for internal participation and an additional intervention for patients to achieve success in all aspects.

  6. Optimization of ventilator setting by flow and pressure waveforms analysis during noninvasive ventilation for acute exacerbations of COPD: a multicentric randomized controlled trial

    PubMed Central

    2011-01-01

    Introduction The analysis of flow and pressure waveforms generated by ventilators can be useful in the optimization of patient-ventilator interactions, notably in chronic obstructive pulmonary disease (COPD) patients. To date, however, a real clinical benefit of this approach has not been proven. Methods The aim of the present randomized, multi-centric, controlled study was to compare optimized ventilation, driven by the analysis of flow and pressure waveforms, to standard ventilation (same physician, same initial ventilator setting, same time spent at the bedside while the ventilator screen was obscured with numerical data always available). The primary aim was the rate of pH normalization at two hours, while secondary aims were changes in PaCO2, respiratory rate and the patient's tolerance to ventilation (all parameters evaluated at baseline, 30, 120, 360 minutes and 24 hours after the beginning of ventilation). Seventy patients (35 for each group) with acute exacerbation of COPD were enrolled. Results Optimized ventilation led to a more rapid normalization of pH at two hours (51 vs. 26% of patients), to a significant improvement of the patient's tolerance to ventilation at two hours, and to a higher decrease of PaCO2 at two and six hours. Optimized ventilation induced physicians to use higher levels of external positive end-expiratory pressure, more sensitive inspiratory triggers and a faster speed of pressurization. Conclusions The analysis of the waveforms generated by ventilators has a significant positive effect on physiological and patient-centered outcomes during acute exacerbation of COPD. The acquisition of specific skills in this field should be encouraged. Trial registration ClinicalTrials.gov NCT01291303. PMID:22115190

  7. Recombinant human C1 esterase inhibitor for prophylaxis of hereditary angio-oedema: a phase 2, multicentre, randomised, double-blind, placebo-controlled crossover trial.

    PubMed

    Riedl, Marc A; Grivcheva-Panovska, Vesna; Moldovan, Dumitru; Baker, James; Yang, William H; Giannetti, Bruno M; Reshef, Avner; Andrejevic, Sladjana; Lockey, Richard F; Hakl, Roman; Kivity, Shmuel; Harper, Joseph R; Relan, Anurag; Cicardi, Marco

    2017-09-30

    Hereditary angio-oedema is a recurrent, oedematous disorder caused by deficiency of functional C1 inhibitor. Infusions of plasma-derived C1 esterase inhibitor deter attacks of hereditary angio-oedema, but the prophylactic effect of recombinant human C1 esterase inhibitor has not been rigorously studied. We aimed to assess the efficacy of recombinant human C1 esterase inhibitor for prophylaxis of hereditary angio-oedema. We conducted this phase 2, multicentre, randomised, double-blind, placebo-controlled crossover trial at ten centres in Canada, the Czech Republic, Israel, Italy, Macedonia, Romania, Serbia, and the USA. We enrolled patients aged 13 years or older with functional C1-inhibitor concentrations of less than 50% of normal and a history of four or more attacks of hereditary angio-oedema per month for at least 3 months before study initiation. Patients were randomly assigned centrally (1:1:1:1:1:1), via an interactive response technology system with fixed allocation, to receive one of six treatment sequences. During each sequence, patients received intravenous recombinant human C1 esterase inhibitor (50 IU/kg; maximum 4200 IU) twice weekly, recombinant human C1 esterase inhibitor once weekly and placebo once weekly, and placebo twice weekly, each for 4 weeks with a 1 week washout period between crossover. All patients, investigators, and study personnel who participated in patient care were masked to group allocation during the study. The primary efficacy endpoint was the number of attacks of hereditary angio-oedema observed in each 4 week treatment period. Attack symptoms were recorded daily. The primary efficacy analysis was done in the intention-to-treat population. Safety was assessed in all patients who received at least one injection of study medication. This study is registered with ClinicalTrials.gov, number NCT02247739. Between Dec 29, 2014, and May 3, 2016, we enrolled 35 patients, of whom 32 (91%) underwent randomisation (intention

  8. Custirsen in combination with docetaxel and prednisone for patients with metastatic castration-resistant prostate cancer (SYNERGY trial): a phase 3, multicentre, open-label, randomised trial.

    PubMed

    Chi, Kim N; Higano, Celestia S; Blumenstein, Brent; Ferrero, Jean-Marc; Reeves, James; Feyerabend, Susan; Gravis, Gwenaelle; Merseburger, Axel S; Stenzl, Arnulf; Bergman, Andries M; Mukherjee, Som D; Zalewski, Pawel; Saad, Fred; Jacobs, Cindy; Gleave, Martin; de Bono, Johann S

    2017-04-01

    Clusterin is a chaperone protein associated with treatment resistance and upregulated by apoptotic stressors such as chemotherapy. Custirsen is a second-generation antisense oligonucleotide that inhibits clusterin production. The aim of the SYNERGY trial was to investigate the effect of custirsen in combination with docetaxel and prednisone on overall survival in patients with metastatic castration-resistant prostate cancer. SYNERGY was a phase 3, multicentre, open-label, randomised trial set at 134 study centres in 12 countries. Patients were eligible for participation if they had: metastatic castration-resistant prostate cancer and had received no previous chemotherapy; prostate-specific antigen greater than 5 ng/mL; and a Karnofsky performance score of 70% or higher. Patients were randomly assigned 1:1 centrally to either the docetaxel, prednisone, and custirsen combination or docetaxel and prednisone alone. Patients were not masked to treatment allocation. Randomisation was stratified by opioid use for cancer-related pain and radiographic evidence of progression. All patients received docetaxel 75 mg/m(2) intravenously with 5 mg of prednisone orally twice daily. Patients assigned docetaxel, prednisone, and custirsen received weekly doses of custirsen 640 mg intravenously after three loading doses of 640 mg. The primary endpoint was overall survival analysed in the intention-to-treat population. Patients who received at least one study dose were included in the safety analysis set. This trial is registered with ClinicalTrials.gov, number NCT01188187. The trial is completed and final analyses are reported here. Between Dec 10, 2010, and Nov 7, 2012, 1022 patients were enrolled to the trial, of whom 510 were assigned docetaxel, prednisone, and custirsen and 512 were allocated docetaxel and prednisone. No difference in overall survival was recorded between the two groups (median survival 23·4 months [95% CI 20·9-24·8] with docetaxel, prednisone, and custirsen vs

  9. Lenvatinib, everolimus, and the combination in patients with metastatic renal cell carcinoma: a randomised, phase 2, open-label, multicentre trial.

    PubMed

    Motzer, Robert J; Hutson, Thomas E; Glen, Hilary; Michaelson, M Dror; Molina, Ana; Eisen, Timothy; Jassem, Jacek; Zolnierek, Jakub; Maroto, Jose Pablo; Mellado, Begoña; Melichar, Bohuslav; Tomasek, Jiri; Kremer, Alton; Kim, Han-Joo; Wood, Karen; Dutcus, Corina; Larkin, James

    2015-11-01

    Currently, metastatic renal cell carcinoma is treated with sequential single agents targeting VEGF or mTOR. Here, we aimed to assess lenvatinib, everolimus, or their combination as second-line treatment in patients with metastatic renal cell carcinoma. We did a randomised, phase 2, open-label, multicentre trial at 37 centres in five countries and enrolled patients with advanced or metastatic, clear-cell, renal cell carcinoma. We included patients who had received treatment with a VEGF-targeted therapy and progressed on or within 9 months of stopping that agent. Patients were randomised via an interactive voice response system in a 1:1:1 ratio to either lenvatinib (24 mg/day), everolimus (10 mg/day), or lenvatinib plus everolimus (18 mg/day and 5 mg/day, respectively) administered orally in continuous 28-day cycles until disease progression or unacceptable toxic effects. The randomisation procedure dynamically minimised imbalances between treatment groups for the stratification factors haemoglobin and corrected serum calcium. The primary objective was progression-free survival in the intention-to-treat population. This study is closed to enrolment but patients' treatment and follow-up is ongoing. This study is registered with ClinicalTrials.gov, number NCT01136733. Between March 16, 2012, and June 19, 2013, 153 patients were randomly allocated to receive either the combination of lenvatinib plus everolimus (n=51), single-agent lenvatinib (n=52), or single-agent everolimus (n=50). Lenvatinib plus everolimus significantly prolonged progression-free survival compared with everolimus alone (median 14·6 months [95% CI 5·9-20·1] vs 5·5 months [3·5-7·1]; hazard ratio [HR] 0·40, 95% CI 0·24-0·68; p=0·0005), but not compared with lenvatinib alone (7·4 months [95% CI 5·6-10·2]; HR 0·66, 95% CI 0·30-1·10; p=0·12). Single-agent lenvatinib significantly prolonged progression-free survival compared with everolimus alone (HR 0·61, 95% CI 0·38-0·98; p=0·048

  10. Platform switch versus platform match in the posterior mandible – 1-year results of a multicentre randomized clinical trial.

    PubMed

    Guerra, Fernando; Wagner, Wilfried; Wiltfang, Jörg; Rocha, Salomão; Moergel, Maximilian; Behrens, Eleonore; Nicolau, Pedro

    2014-05-01

    The purpose of this ongoing randomized study was to assess differences in bone level changes and success rates using implants supporting single crowns in the posterior mandible either with platform matched or platform switched abutments. Patients aged 18 and above, missing at least two teeth in the posterior mandible and with a natural tooth mesial to the most proximal implant site were enrolled. Randomization followed implant placement. Definitive restorations were placed after a minimum transgingival healing period of 8 weeks. Changes in crestal bone level from surgery and loading (baseline) to 12-month post-loading were radiographically measured. Implant survival and success were determined. Sixty-eight patients received 74 implants in the platform switching group and 72 in the other one. The difference of mean marginal bone level change from surgery to 12 months was significant between groups (p < 0.004). Radiographical mean bone gain or no bone loss from loading was noted for 67.1% of the platform switching and 49.2% of the platform matching implants. Implant success rates were 97.3% and 100%, respectively. Within the same implant system the platform switching concept showed a positive effect on marginal bone levels when compared with restorations with platform matching.

  11. [Randomized controlled multi-central study on acupuncture at Tanzhong (CV 17) for treatment of postpartum hypolactation].

    PubMed

    He, Jun-Qin; Chen, Bao-Ying; Huang, Tao; Li, Ning; Bai, Jian; Gu, Mei; Yu, Mei; He, Xiang-Ping; Wang, Hua-Ying

    2008-05-01

    To study on clinical role of acupuncture at Tanzhong (CV 17) for treatment of postpartum hypolactation and to provide clinical basis for indications of acupoints. This was a single blind randomized controlled multi-center study by Beijing obstetrical and gynecological hospital, Beijing Mother and Child health institute and Haidian Mother and Child health institute, 276 cases of postpartum hypolactation were randomly divided into an acupuncture group and a Chinese drug group. The acupuncture group were treated with acupuncture at Tanzhong (CV 17) and the Chinese drug group with traditional drug Tongre Decoction. Degree of breast engorge, lactating volume, prolactin, neonate body weight, artificial feeding frequency and volume, urination frequency and crying time of neonate were recorded for comparison of therapeutic effects. After treatment, degree of breast engorge, lactating volume, neonate body weight, artificial feeding frequency and volume, urination frequency and crying time of neonate were significantly improved in the two groups, with no significant difference between the two groups. Acupuncture at Tanzhong (CV 17) can effectively promote lactation with a same therapeutic effect as the traditional Chinese drug Tongru Decocnon.

  12. Phase transitions for information diffusion in random clustered networks

    NASA Astrophysics Data System (ADS)

    Lim, Sungsu; Shin, Joongbo; Kwak, Namju; Jung, Kyomin

    2016-09-01

    We study the conditions for the phase transitions of information diffusion in complex networks. Using the random clustered network model, a generalisation of the Chung-Lu random network model incorporating clustering, we examine the effect of clustering under the Susceptible-Infected-Recovered (SIR) epidemic diffusion model with heterogeneous contact rates. For this purpose, we exploit the branching process to analyse information diffusion in random unclustered networks with arbitrary contact rates, and provide novel iterative algorithms for estimating the conditions and sizes of global cascades, respectively. Showing that a random clustered network can be mapped into a factor graph, which is a locally tree-like structure, we successfully extend our analysis to random clustered networks with heterogeneous contact rates. We then identify the conditions for phase transitions of information diffusion using our method. Interestingly, for various contact rates, we prove that random clustered networks with higher clustering coefficients have strictly lower phase transition points for any given degree sequence. Finally, we confirm our analytical results with numerical simulations of both synthetically-generated and real-world networks.

  13. Random phase-free computer holography and its applications

    NASA Astrophysics Data System (ADS)

    Shimobaba, Tomoyoshi; Kakue, Takashi; Ito, Tomoyoshi

    2016-06-01

    Random phase is required in computer-generated hologram (CGH) to widely diffuse object light and to avoid its concentration on the CGH; however, the random phase causes considerable speckle noise in the reconstructed image and degrades the image quality. We introduce a simple and computationally inexpensive method that improves the image quality and reduces the speckle noise by multiplying the object light with the designed convergence light. We furthermore propose the improved method of the designed convergence light with iterative method to reduce ringing artifacts. Subsequently, as the application, a lensless zoomable holographic projection is introduced.

  14. Ultrafast quantum random number generation based on quantum phase fluctuations.

    PubMed

    Xu, Feihu; Qi, Bing; Ma, Xiongfeng; Xu, He; Zheng, Haoxuan; Lo, Hoi-Kwong

    2012-05-21

    A quantum random number generator (QRNG) can generate true randomness by exploiting the fundamental indeterminism of quantum mechanics. Most approaches to QRNG employ single-photon detection technologies and are limited in speed. Here, we experimentally demonstrate an ultrafast QRNG at a rate over 6 Gbits/s based on the quantum phase fluctuations of a laser operating near threshold. Moreover, we consider a potential adversary who has partial knowledge on the raw data and discuss how one can rigorously remove such partial knowledge with postprocessing. We quantify the quantum randomness through min-entropy by modeling our system and employ two randomness extractors--Trevisan's extractor and Toeplitz-hashing--to distill the randomness, which is information-theoretically provable. The simplicity and high-speed of our experimental setup show the feasibility of a robust, low-cost, high-speed QRNG.

  15. Azathioprine versus Beta Interferons for Relapsing-Remitting Multiple Sclerosis: A Multicentre Randomized Non-Inferiority Trial

    PubMed Central

    Massacesi, Luca; Tramacere, Irene; Amoroso, Salvatore; Battaglia, Mario A.; Benedetti, Maria Donata; Filippini, Graziella; La Mantia, Loredana; Repice, Anna; Solari, Alessandra; Tedeschi, Gioacchino; Milanese, Clara

    2014-01-01

    For almost three decades in many countries azathioprine has been used to treat relapsing-remitting multiple sclerosis. However its efficacy was usually considered marginal and following approval of β interferons for this indication it was no longer recommended as first line treatment, even if presently no conclusive direct β interferon-azathioprine comparison exists. To compare azathioprine efficacy versus the currently available β interferons in relapsing-remitting multiple sclerosis, a multicenter, randomized, controlled, single-blinded, non-inferiority trial was conducted in 30 Italian multiple sclerosis centers. Eligible patients (relapsing-remitting course; ≥2 relapses in the last 2 years) were randomly assigned to azathioprine or β interferons. The primary outcome was annualized relapse rate ratio (RR) over 2 years. Key secondary outcome was number of new brain MRI lesions. Patients (n = 150) were randomized in 2 groups (77 azathioprine, 73 β interferons). At 2 years, clinical evaluation was completed in 127 patients (62 azathioprine, 65 β interferons). Annualized relapse rate was 0.26 (95% Confidence Interval, CI, 0.19–0.37) in the azathioprine and 0.39 (95% CI 0.30–0.51) in the interferon group. Non-inferiority analysis showed that azathioprine was at least as effective as β interferons (relapse RRAZA/IFN 0.67, one-sided 95% CI 0.96; p<0.01). MRI outcomes were analyzed in 97 patients (50 azathioprine and 47 β interferons). Annualized new T2 lesion rate was 0.76 (95% CI 0.61–0.95) in the azathioprine and 0.69 (95% CI 0.54–0.88) in the interferon group. Treatment discontinuations due to adverse events were higher (20.3% vs. 7.8%, p = 0.03) in the azathioprine than in the interferon group, and concentrated within the first months of treatment, whereas in the interferon group discontinuations occurred mainly during the second year. The results of this study indicate that efficacy of azathioprine is not inferior to that of

  16. Azathioprine versus beta interferons for relapsing-remitting multiple sclerosis: a multicentre randomized non-inferiority trial.

    PubMed

    Massacesi, Luca; Tramacere, Irene; Amoroso, Salvatore; Battaglia, Mario A; Benedetti, Maria Donata; Filippini, Graziella; La Mantia, Loredana; Repice, Anna; Solari, Alessandra; Tedeschi, Gioacchino; Milanese, Clara

    2014-01-01

    For almost three decades in many countries azathioprine has been used to treat relapsing-remitting multiple sclerosis. However its efficacy was usually considered marginal and following approval of β interferons for this indication it was no longer recommended as first line treatment, even if presently no conclusive direct β interferon-azathioprine comparison exists. To compare azathioprine efficacy versus the currently available β interferons in relapsing-remitting multiple sclerosis, a multicenter, randomized, controlled, single-blinded, non-inferiority trial was conducted in 30 Italian multiple sclerosis centers. Eligible patients (relapsing-remitting course; ≥ 2 relapses in the last 2 years) were randomly assigned to azathioprine or β interferons. The primary outcome was annualized relapse rate ratio (RR) over 2 years. Key secondary outcome was number of new brain MRI lesions. Patients (n = 150) were randomized in 2 groups (77 azathioprine, 73 β interferons). At 2 years, clinical evaluation was completed in 127 patients (62 azathioprine, 65 β interferons). Annualized relapse rate was 0.26 (95% Confidence Interval, CI, 0.19-0.37) in the azathioprine and 0.39 (95% CI 0.30-0.51) in the interferon group. Non-inferiority analysis showed that azathioprine was at least as effective as β interferons (relapse RRAZA/IFN 0.67, one-sided 95% CI 0.96; p<0.01). MRI outcomes were analyzed in 97 patients (50 azathioprine and 47 β interferons). Annualized new T2 lesion rate was 0.76 (95% CI 0.61-0.95) in the azathioprine and 0.69 (95% CI 0.54-0.88) in the interferon group. Treatment discontinuations due to adverse events were higher (20.3% vs. 7.8%, p = 0.03) in the azathioprine than in the interferon group, and concentrated within the first months of treatment, whereas in the interferon group discontinuations occurred mainly during the second year. The results of this study indicate that efficacy of azathioprine is not inferior to that of β interferons for patients

  17. Magnetic phases of spin-1 lattice gases with random interactions

    NASA Astrophysics Data System (ADS)

    McAlpine, Kenneth D.; Paganelli, Simone; Ciuchi, Sergio; Sanpera, Anna; De Chiara, Gabriele

    2017-06-01

    A spin-1 atomic gas in an optical lattice, in the unit-filling Mott insulator (MI) phase and in the presence of disordered spin-dependent interaction, is considered. In this regime, at zero temperature, the system is well described by a disordered rotationally invariant spin-1 bilinear-biquadratic model. We study, via the density matrix renormalization group algorithm, a bounded disorder model such that the spin interactions can be locally either ferromagnetic or antiferromagnetic. Random interactions induce the appearance of a disordered ferromagnetic phase characterized by a nonvanishing value of the spin glass order parameter across the boundary between a ferromagnetic phase and a dimer phase exhibiting random singlet order. We also study the distribution of the block entanglement entropy in the different regions.

  18. A multicentre, randomized, controlled trial of oseltamivir in the treatment of influenza in a high-risk Chinese population.

    PubMed

    Lin, Jiang-Tao; Yu, Xue-Zhong; Cui, De-Jian; Chen, Xu-Yan; Zhu, Ji-Hong; Wang, Yu-Zhen; Wu, Xiao-di

    2006-01-01

    To evaluate the efficacy and safety of oseltamivir treatment in a population at high risk for influenza. This was a randomized, open-label, controlled trial involving Chinese patients with chronic respiratory diseases (chronic bronchitis, obstructive emphysema, bronchial asthma or bronchiectasis) or chronic cardiac disease. Patients showing symptoms of influenza were randomly assigned to receive oral oseltamivir 75 mg twice daily for 5 days (oseltamivir group), or symptomatic treatment (control group) within 48 h after symptom onset. The main outcome measures were duration and severity of illness in influenza-infected patients. Other outcome measures included incidence of complications, antibiotic use, hospitalization and total medical cost. Of the 118 recruited patients, 56 were identified as influenza-infected through laboratory tests (oseltamivir, N = 27; control, N = 29). Relative to symptomatic treatment, oseltamivir significantly reduced the duration of influenza symptoms by 36.8% (p = 0.0479), and the severity by 43.1% (p = 0.0002). In addition, oseltamivir significantly reduced the duration of fever by 45.2% (p = 0.0051), and the time to return to baseline health status by 5 days (p = 0.0011). The incidence of complications (11% vs. 45%, p = 0.0053) and antibiotic use (37% vs. 69%, p = 0.0167) were also significantly lower in the oseltamivir group compared with the control group. The cost of treating influenza and its complications was comparable between the two groups (p = 0.2462). Oseltamivir is effective and well tolerated in high-risk patients with chronic respiratory or cardiac diseases. It can reduce the duration and severity of influenza symptoms and decrease the incidence of secondary complications and antibiotic use, without increasing the total medical cost.

  19. Randomized, controlled, multicentre clinical trial of the antipyretic effect of intravenous paracetamol in patients admitted to hospital with infection

    PubMed Central

    Tsaganos, Thomas; Tseti, Ioulia K.; Tziolos, Nikolaos; Soumelas, Georgios‐Stefanos; Koupetori, Marina; Pyrpasopoulou, Athina; Akinosoglou, Karolina; Gogos, Charalambos; Tsokos, Nikolaos; Karagiannis, Asterios; Sympardi, Styliani

    2016-01-01

    Aim No randomized study has been conducted to investigate the use of intravenous paracetamol (acetaminophen, APAP) for the management of fever due to infection. The present study evaluated a new ready‐made infusion of paracetamol. Methods Eighty patients with a body temperature onset ≥38.5°C in the previous 24 h due to infection were randomized to a single administration of placebo (n = 39) or 1 g paracetamol (n = 41), and their temperature was recorded at standard intervals. Rescue medication with 1 g paracetamol was allowed. Serum samples were collected for the measurement of APAP and its metabolites. The primary endpoint was defervescence, defined as a core temperature ≤37.1°C. Results During the first 6 h, defervescence was achieved in 15 (38.5%) patients treated with placebo compared with 33 (80.5%) patients treated with paracetamol 1 g (P < 0.0001). The median time to defervescence with paracetamol 1 g was 3 h. Rescue medication was given to 15 (38.5%) and five (12.2%) patients allocated to placebo and paracetamol, respectively (P = 0.007); nine (60.0%) and two (40.0%) of these patients, respectively, experienced defervescence. No further antipyretic medication was needed for patients becoming afebrile with rescue medication. Serum glucuronide‐APAP concentrations were significantly greater in the serum of patients who did not experience defervescence with paracetamol. The efficacy of paracetamol was not affected by serum creatinine. No drug‐related adverse events were reported. Conclusions The 1 g paracetamol formulation has a rapid and sustainable antipyretic effect on fever due to infection. Its efficacy is dependent on hepatic metabolism. PMID:27792836

  20. Single-random-phase holographic encryption of images

    NASA Astrophysics Data System (ADS)

    Tsang, P. W. M.

    2017-02-01

    In this paper, a method is proposed for encrypting an optical image onto a phase-only hologram, utilizing a single random phase mask as the private encryption key. The encryption process can be divided into 3 stages. First the source image to be encrypted is scaled in size, and pasted onto an arbitrary position in a larger global image. The remaining areas of the global image that are not occupied by the source image could be filled with randomly generated contents. As such, the global image as a whole is very different from the source image, but at the same time the visual quality of the source image is preserved. Second, a digital Fresnel hologram is generated from the new image, and converted into a phase-only hologram based on bi-directional error diffusion. In the final stage, a fixed random phase mask is added to the phase-only hologram as the private encryption key. In the decryption process, the global image together with the source image it contained, can be reconstructed from the phase-only hologram if it is overlaid with the correct decryption key. The proposed method is highly resistant to different forms of Plain-Text-Attacks, which are commonly used to deduce the encryption key in existing holographic encryption process. In addition, both the encryption and the decryption processes are simple and easy to implement.

  1. Combined nivolumab and ipilimumab versus ipilimumab alone in patients with advanced melanoma: 2-year overall survival outcomes in a multicentre, randomised, controlled, phase 2 trial.

    PubMed

    Hodi, F Stephen; Chesney, Jason; Pavlick, Anna C; Robert, Caroline; Grossmann, Kenneth F; McDermott, David F; Linette, Gerald P; Meyer, Nicolas; Giguere, Jeffrey K; Agarwala, Sanjiv S; Shaheen, Montaser; Ernstoff, Marc S; Minor, David R; Salama, April K; Taylor, Matthew H; Ott, Patrick A; Horak, Christine; Gagnier, Paul; Jiang, Joel; Wolchok, Jedd D; Postow, Michael A

    2016-11-01

    Results from phase 2 and 3 trials in patients with advanced melanoma have shown significant improvements in the proportion of patients achieving an objective response and prolonged progression-free survival with the combination of nivolumab (an anti-PD-1 antibody) plus ipilimumab (an anti-CTLA-4 antibody) compared with ipilimumab alone. We report 2-year overall survival data from a randomised controlled trial assessing this treatment in previously untreated advanced melanoma. In this multicentre, double-blind, randomised, controlled, phase 2 trial (CheckMate 069) we recruited patients from 19 specialist cancer centres in two countries (France and the USA). Eligible patients were aged 18 years or older with previously untreated, unresectable stage III or IV melanoma and an Eastern Cooperative Oncology Group performance status of 0 or 1. Patients were randomly assigned 2:1 to receive an intravenous infusion of nivolumab 1 mg/kg plus ipilimumab 3 mg/kg or ipilimumab 3 mg/kg plus placebo, every 3 weeks for four doses. Subsequently, patients assigned to nivolumab plus ipilimumab received nivolumab 3 mg/kg every 2 weeks until disease progression or unacceptable toxicity, whereas patients allocated to ipilimumab alone received placebo every 2 weeks during this phase. Randomisation was done via an interactive voice response system with a permuted block schedule (block size of six) and stratification by BRAF mutation status. The study funder, patients, investigators, and study site staff were masked to treatment assignment. The primary endpoint, which has been reported previously, was the proportion of patients with BRAF(V600) wild-type melanoma achieving an investigator-assessed objective response. Overall survival was an exploratory endpoint and is reported in this Article. Efficacy analyses were done on the intention-to-treat population, whereas safety was assessed in all treated patients who received at least one dose of study drug. This study is registered with

  2. A large, prospective, randomized, open-label, multicentre study of corticosteroid withdrawal in SPK transplantation: a 3-year report.

    PubMed

    Nakache, Richard; Malaise, Jacques; Van Ophem, Dominique

    2005-05-01

    Simultaneous pancreas-kidney (SPK) transplantation is the treatment of choice for selected diabetic patients. Corticosteroids are an important element of immunosuppressive protocols, but their long-term use has detrimental effects on patients' health, necessitating eventual discontinuation. This prospective study evaluated the safety and feasibility of corticosteroid withdrawal in 205 SPK transplant recipients randomized to immunosuppressive treatment with either tacrolimus and mycophenolate mofetil (MMF) (n = 103) or cyclosporin microemulsion (ME) and MMF (n = 102). Corticosteroid withdrawal was successful in the majority of in-study patients (66% tacrolimus, 73% cyclosporin-ME). Compared with out-of-study patients or those continuing corticosteroid therapy, in-study patients withdrawn from corticosteroids experienced fewer pancreas or kidney graft losses, fewer episodes of acute rejection and were less likely to be withdrawn from the study. Acute rejection occurred after corticosteroid withdrawal in two patients who had a previous rejection and in five patients who were rejection-free before corticosteroid withdrawal. No rejection episodes were associated with graft loss or immediate serious consequences. Overall, corticosteroid withdrawal was achieved with an increase in the dose of both MMF and tacrolimus. A long-term survey of corticosteroid withdrawal in SPK transplantation with multifactorial analyses is necessary to confirm these early results and to evaluate the positive effects on glucose metabolism and hypertension.

  3. Randomized multicentre trial of gadoxetic acid-enhanced MRI versus conventional MRI or CT in the staging of colorectal cancer liver metastases

    PubMed Central

    Zech, C J; Korpraphong, P; Huppertz, A; Denecke, T; Kim, M-J; Tanomkiat, W; Jonas, E; Ba-Ssalamah, A

    2014-01-01

    Background This multicentre international randomized trial compared the impact of gadoxetic acid-enhanced magnetic resonance imaging (MRI), MRI with extracellular contrast medium (ECCM-MRI) and contrast-enhanced computed tomography (CE-CT) as a first-line imaging method in patients with suspected colorectal cancer liver metastases (CRCLM). Methods Between October 2008 and September 2010, patients with suspected CRCLM were randomized to one of the three imaging modalities. The primary endpoint was the proportion of patients for whom further imaging after initial imaging was required for a confident diagnosis. Secondary variables included confidence in the therapeutic decision, intraoperative deviations from the initial imaging-based surgical plan as a result of additional operative findings, and diagnostic efficacy of the imaging modalities versus intraoperative and pathological extent of the disease. Results A total of 360 patients were enrolled. Efficacy was analysed in 342 patients (118, 112 and 112 with gadoxetic acid-enhanced MRI, ECCM-MRI and CE-CT respectively as the initial imaging procedure). Further imaging was required in 0 of 118, 19 (17·0 per cent) of 112 and 44 (39·3 per cent) of 112 patients respectively (P < 0·001). Diagnostic confidence was high or very high in 98·3 per cent of patients for gadoxetic acid-enhanced MRI, 85·7 per cent for ECCM-MRI and 65·2 per cent for CE-CT. Surgical plans were changed during surgery in 28, 32 and 47 per cent of patients in the respective groups. Conclusion The diagnostic performance of gadoxetic acid-enhanced MRI was better than that of CE-CT and ECCM-MRI as the initial imaging modality. No further imaging was needed in the gadoxetic acid-enhanced MRI group and comparison of diagnostic efficacy parameters demonstrated the diagnostic superiority of gadoxetic acid-enhanced MRI. Registration number: NCT00764621( http://clinicaltrials.gov ); EudraCT number: 2008-000583-16 ( https://eudract.ema.europa.eu/ ). PMID

  4. Atrial antitachycardia pacing and managed ventricular pacing in bradycardia patients with paroxysmal or persistent atrial tachyarrhythmias: the MINERVA randomized multicentre international trial.

    PubMed

    Boriani, Giuseppe; Tukkie, Raymond; Manolis, Antonis S; Mont, Lluis; Pürerfellner, Helmut; Santini, Massimo; Inama, Giuseppe; Serra, Paolo; de Sousa, João; Botto, Giovanni Luca; Mangoni, Lorenza; Grammatico, Andrea; Padeletti, Luigi

    2014-09-14

    Atrial fibrillation (AF) is a common comorbidity in bradycardia patients. Advanced pacemakers feature atrial preventive pacing and atrial antitachycardia pacing (DDDRP) and managed ventricular pacing (MVP), which minimizes unnecessary right ventricular pacing. We evaluated whether DDDRP and MVP might reduce mortality, morbidity, or progression to permanent AF when compared with standard dual-chamber pacing (Control DDDR). In a randomized, parallel, single-blind, multi-centre trial we enrolled 1300 patients with bradycardia and previous atrial tachyarrhythmias, in whom a DDDRP pacemaker had recently been implanted. History of permanent AF and third-degree atrioventricular block were exclusion criteria. After a 1-month run-in period, 1166 eligible patients, aged 74 ± 9 years, 50% females, were randomized to Control DDDR, DDDRP + MVP, or MVP. Analysis was intention-to-treat. The primary outcome, i.e. the 2-year incidence of a combined endpoint composed of death, cardiovascular hospitalizations, or permanent AF, occurred in 102/385 (26.5%) Control DDDR patients, in 76/383 (19.8%) DDDRP + MVP patients [hazard ratio (HR) = 0.74, 95% confidence interval 0.55-0.99, P = 0.04 vs. Control DDDR] and in 85/398 (21.4%) MVP patients (HR = 0.89, 95% confidence interval 0.77-1.03, P = 0.125 vs. Control DDDR). When compared with Control DDDR, DDDRP + MVP reduced the risk for AF longer than 1 day (HR = 0.66, 95% CI 0.52-0.85, P < 0.001), AF longer than 7 days (HR = 0.52, 95% CI 0.36-0.73, P < 0.001), and permanent AF (HR = 0.39, 95% CI 0.21-0.75, P = 0.004). In patients with bradycardia and atrial tachyarrhythmias, DDDRP + MVP is superior to standard dual-chamber pacing. The primary endpoint was significantly lowered through the reduction of the progression of atrial tachyarrhythmias to permanent AF. NCT00262119. © The Author 2014. Published by Oxford University Press on behalf of the European Society of Cardiology.

  5. Fusion and failure following anterior cervical plating with dynamic or rigid plates: 6-months results of a multi-centric, prospective, randomized, controlled study

    PubMed Central

    Stulik, Jan; Chrobok, Jan; Ruffing, Sabine; Drumm, Jörg; Sova, Laurentius; Kucera, Ravel; Vyskocil, Tomas; Steudel, Wolf Ingo

    2007-01-01

    Anterior cervical plate fixation is an approved surgical technique for cervical spine stabilization in the presence of anterior cervical instability. Rigid plate design with screws rigidly locked to the plate is widely used and is thought to provide a better fixation for the treated spinal segment than a dynamic design in which the screws may slide when the graft is settling. Recent biomechanical studies showed that dynamic anterior plates provide a better graft loading possibly leading to accelerated spinal fusion with a lower incidence of implant complications. This, however, was investigated in vitro and does not necessarily mean to be the case in vivo, as well. Thus, the two major aspects of this study were to compare the speed of bone fusion and the rate of implant complications using either rigid- or dynamic plates. The study design is prospective, randomized, controlled, and multi-centric, having been approved by respective ethic committees of all participating sites. One hundred and thirty-two patients were included in this study and randomly assigned to one of the two groups, both undergoing routine level-1- or level-2 anterior cervical discectomy with autograft fusion receiving either a dynamic plate with screws being locked in ap - position (ABC, Aesculap, Germany), or a rigid plate (CSLP, Synthes, Switzerland). Segmental mobility and implant complications were compared after 3- and 6 months, respectively. All measurements were performed by an independent radiologist. Mobility results after 6 months were available for 77 patients (43 ABC/34 CSLP). Mean segmental mobility for the ABC group was 1.7 mm at the time of discharge, 1.4 mm after 3 months, and 0.8 mm after 6 months. For the CSLP- group the measurements were 1.0, 1.8, and 1.7 mm, respectively. The differences of mean segmental mobility were statistically significant between both groups after 6 months (P = 0.02). Four patients of the CSLP-group demonstrated surgical hardware complications

  6. Design of a multicentre randomized controlled trial to evaluate the effectiveness of a tailored clinical support intervention to enhance return to work for gastrointestinal cancer patients.

    PubMed

    Zaman, AnneClaire G N M; Tytgat, Kristien M A J; Klinkenbijl, Jean H G; Frings-Dresen, Monique H W; de Boer, Angela G E M

    2016-05-10

    Gastrointestinal (GI) cancer is frequently diagnosed in people of working age, and many GI cancer patients experience work-related problems. Although these patients often experience difficulties returning to work, supportive work-related interventions are lacking. We have therefore developed a tailored work-related support intervention for GI cancer patients, and we aim to evaluate its cost-effectiveness compared with the usual care provided. If this intervention proves effective, it can be implemented in practice to support GI cancer patients after diagnosis and to help them return to work. We designed a multicentre randomized controlled trial with a follow-up of twelve months. The study population (N = 310) will include individuals aged 18-63 years diagnosed with a primary GI cancer and employed at the time of diagnosis. The participants will be randomized to the intervention or to usual care. 'Usual care' is defined as psychosocial care in which work-related issues are not discussed. The intervention group will receive tailored work-related support consisting of three face-to-face meetings of approximately 30 min each. Based on the severity of their work-related problems, the intervention group will be divided into groups receiving three types of support (A, B or C). A different supportive healthcare professional will be available for each group: an oncological nurse (A), an oncological occupational physician (B) and a multidisciplinary team (C) that includes an oncological nurse, oncological occupational physician and treating oncologist/physician. The primary outcome measure is return to work (RTW), defined as the time to a partial or full RTW. The secondary outcomes are work ability, work limitations, quality of life, and direct and indirect costs. The hypothesis is that tailored work-related support for GI cancer patients is more effective than usual care in terms of the RTW. The intervention is innovative in that it combines oncological and

  7. Stop or go? Preventive cognitive therapy with guided tapering of antidepressants during pregnancy: study protocol of a pragmatic multicentre non-inferiority randomized controlled trial.

    PubMed

    Molenaar, Nina M; Brouwer, Marlies E; Bockting, Claudi L H; Bonsel, Gouke J; van der Veere, Christine N; Torij, Hanneke W; Hoogendijk, Witte J G; Duvekot, Johannes J; Burger, Huibert; Lambregtse-van den Berg, Mijke P

    2016-03-18

    Approximately 6.2 % of women in the USA and 3.7 % of women in the UK, use Selective Serotonin Reuptake Inhibitors (SSRIs) during their pregnancies because of depression and/or anxiety. In the Netherlands, this prevalence is around 2 %. Nonetheless, SSRI use during pregnancy is still controversial. On the one hand SSRIs may be toxic to the intrauterine developing child, while on the other hand relapse or recurrence of depression during pregnancy poses risks for both mother and child. Among patients and professionals there is an urgent need for evidence from randomized studies to make rational decisions regarding continuation or tapering of SSRIs during pregnancy. At present, no such studies exist. 'Stop or Go' is a pragmatic multicentre randomized non-inferiority trial among 200 pregnant women with a gestational age of less than 16 weeks who use SSRIs without clinically relevant depressive symptoms. Women allocated to the intervention group will receive preventive cognitive therapy with gradual, guided discontinuation of SSRIs under medical management (STOP). Women in the control group will continue the use of SSRIs (GO). Primary outcome will be the (cumulative) incidence of relapse or recurrence of maternal depressive disorder (as assessed by the Structured Clinical Interview for DSM disorders) during pregnancy and up to three months postpartum. Secondary outcomes will be child outcome (neonatal outcomes and psychomotor and behavioural outcomes up to 24 months postpartum), and health-care costs. Total study duration for participants will be therefore be 30 months. We specified a non-inferiority margin of 15 % difference in relapse risk. This study is the first to investigate the effect of guided tapering of SSRIs with preventive cognitive therapy from early pregnancy onwards as compared to continuation of SSRIs during pregnancy. We will study the effects on both mother and child with a pragmatic approach. Additionally, the study examines cost effectiveness. If non

  8. Early class III protraction facemask treatment reduces the need for orthognathic surgery: a multi-centre, two-arm parallel randomized, controlled trial

    PubMed Central

    Mandall, Nicky; Cousley, Richard; DiBiase, Andrew; Dyer, Fiona; Littlewood, Simon; Mattick, Rye; Nute, Spencer J.; Doherty, Barbara; Stivaros, Nadia; McDowall, Ross; Shargill, Inderjit; Worthington, Helen V.

    2016-01-01

    Objective: To evaluate whether patients who had received early class III protraction facemask treatment were less likely to need orthognathic surgery compared with untreated controls. This paper is a 6-year follow-up of a previous clinical trial. Design: Multi-centre 2-arm parallel randomized controlled trial. Setting: Eight United Kingdom hospital orthodontic departments. Participants: Seventy three 7- to 9–year-old children. Method: Patients were randomly allocated, stratified for gender, into an early class III protraction facemask group (PFG) (n = 35) and a control/no treatment group (CG) (n = 38). The primary outcome, need for orthognathic surgery was assessed by panel consensus. Secondary outcomes were changed in skeletal pattern, overjet, Peer Assessment Rating (PAR), self-esteem and the oral aesthetic impact of malocclusion. The data were compared between baseline (DC1) and 6-year follow-up (DC4). A per-protocol analysis was carried out with n = 32 in the CG and n = 33 in the PFG. Results: Thirty six percent of the PFG needed orthognathic surgery, compared with 66% of the CG (P = 0.027). The odds of needing surgery was 3.5 times more likely when protraction facemask treatment was not used (odds ratio = 3.34 95% CI 1.21–9.24). The PFG exhibited a clockwise rotation and the CG an anti-clockwise rotation in the maxilla (regression coefficient 8.24 (SE 0.75); 95% CI 6.73–9.75; P < 0.001) and the mandible (regression coefficient 6.72 (SE 0.73); 95% CI 5.27–8.18; P < 0.001). Sixty eight per cent of the PFG maintained a positive overjet at 6-year follow-up. There were no statistically significant differences between the PFG and CG for skeletal/occlusal improvement, self-esteem or oral aesthetic impact. Conclusions: Early class III protraction facemask treatment reduces the need for orthognathic surgery. However, this effect cannot be explained by the maintenance of skeletal cephalometric change. PMID:27564126

  9. Treatment of severe, nonfulminant acute hepatitis B with lamivudine vs placebo: a prospective randomized double-blinded multicentre trial.

    PubMed

    Wiegand, J; Wedemeyer, H; Franke, A; Rößler, S; Zeuzem, S; Teuber, G; Wächtler, M; Römmele, U; Ruf, B; Spengler, U; Trautwein, C; Bock, C T; Fiedler, G M; Thiery, J; Manns, M P; Brosteanu, O; Tillmann, H L

    2014-10-01

    Acute hepatitis B virus (aHBV) infection can lead to fulminant liver failure, which likely is prevented by early lamivudine therapy. Even nonfulminant but severe acute hepatitis B can lead to significant morbidity and impaired quality of life. Therefore, lamivudine was evaluated in patients with severe aHBV in a placebo-controlled trial. Patients with severe aHBV infection (ALT >10× ULN, bilirubin >85 μm, prothrombin time >50%) were prospectively treated with lamivudine 100 mg/day or with placebo within 8 days after the diagnosis. The primary end point was time to bilirubin <34.2 μm. Secondary end points were time to clear HBsAg and HBV-DNA, development of anti-HBs and normalization of ALT. Eighteen cases were randomized to lamivudine, 17 to placebo. 94% of patients were hospitalized. No individual progressed to hepatic failure; all but one patient achieved the primary end point. Due to smaller than expected patient numbers, all study end points did not become statistically significant between treatment arms. Median time end points [in days] were bilirubin <34.2 μm (26.5 vs 32), ALT normalization (35 vs 48) and HBsAg clearance (48 vs 67) referring to earlier recovery under lamivudine, in contrast to loss of HBV-DNA (62 vs 54) and development of anti-HBs (119 vs 109). In all but two patients (one in every group), HBsAg clearance was reached in the study. Adverse events occurred more frequently during lamivudine therapy, but did not reach statistical significance. Lamivudine may ameliorate severe aHBV infection, but limited patient numbers prevented definite conclusions.

  10. Random and systematic medication errors in routine clinical practice: a multicentre study of infusions, using acetylcysteine as an example

    PubMed Central

    Ferner, R E; Langford, N J; Anton, C; Hutchings, A; Bateman, D N; Routledge, P A

    2001-01-01

    Aims The nature and incidence of errors in prescribing and giving medicines have previously been estimated by trained observers, or by retrospective analysis of incidents in which patients have come to harm. We have examined prospectively in routine clinical practice the concentrations of intravenous infusions of a drug (acetylcysteine) which is given according to a complicated dosing schedule. Methods We prospectively collected samples before and, where possible, after the infusion of acetylcysteine in 66 anonymous patients requiring treatment for acetaminophen (paracetamol) overdose in four centres in the United Kingdom. We measured the concentration in each infusion bag, and deduced from the weight of the patient the percentage of the anticipated dose that had actually been given. Results The experimentally determined dose was within 10% of the anticipated dose in 68 of 184 individual bags (37%), and within 20% of the anticipated dose in 112 bags (61%). Doses in 17 bags were more than 50% from the anticipated doses. In three patients, values in all three bags appeared to be systematically wrong by 50% or more; in a further seven cases, individual bags differed by 50% or more from the anticipated value. The median difference between pre- and post-infusion samples was 0% [interquartile range −5.2% to +14.6%], but 9% showed a disparity of greater than ± 50%. Conclusions Our data suggest that there is large random variation in administered dosage of intravenous infusions. Systematic calculation errors occur in about 5% [95% confidence interval 2, 8%] of cases, and major errors in drawing up in a further 3% [1, 7%], with inadequate mixing in 9% [4, 14%]. While we have no evidence that patients were adversely affected, and while the regime of administration of the drug studied (acetylcysteine) is complicated, these data suggest that the delivered dose often deviates from the intended dose, and that methods of quality control are needed. PMID:11736866

  11. Prospective randomized multicentre study comparing stapler haemorrhoidopexy with Doppler-guided transanal haemorrhoid dearterialization for third-degree haemorrhoids.

    PubMed

    Infantino, A; Altomare, D F; Bottini, C; Bonanno, M; Mancini, S; Yalti, T; Giamundo, P; Hoch, J; El Gaddal, A; Pagano, C

    2012-02-01

    Doppler-guided transanal haemorrhoid dearterialization (THD) and stapler haemorrhoidopexy (SH) have been demonstrated to be less painful than the Milligan-Morgan procedure. The aim of this study was to compare the effectiveness of THD vs SH in the treatment of third-degree haemorrhoids in an equivalent trial. One hundred and sixty-nine patients with third-degree haemorrhoids were randomized online to receive THD (n = 85) or SH (n = 84) in 10 Colorectal Units in which the staff were well trained in both techniques. The mean follow-up period was 17 (range 15-20) months. Early minor postoperative complications occurred in 30.6% of patients in the THD group and in 32.1% of patients in the SH group. Milder spontaneous pain and pain on defecation were reported in the THD group in the first postoperative week, but this was not statistically significant. Late complications were significantly higher (P = 0.028) in the SH group. Residual haemorrhoids persisted in 12 patients in the THD group and in six patients in the SH group (P = 0.14). Six patients in the SH group and 10 in the THD group underwent further treatment of haemorrhoids (P = 0.34). No differences were found in postoperative incontinence. The obstructed defecation score (ODS) was significantly higher in the SH group (P < 0.02). Improvement in quality of life was similar in both groups. Postoperative in-hospital stay was 1.14 days in the THD group and 1.31 days in the SH group (P = 0.03). Both THD and SH techniques are effective for the treatment of third-degree haemorrhoids in the medium term. THD has a better cost-effective ratio and lower (not significant) pain compared with SH. Postoperative pain and recurrence did not differ significantly between the two groups. © 2011 The Authors. Colorectal Disease © 2011 The Association of Coloproctology of Great Britain and Ireland.

  12. Zero-temperature second random phase approximation and its formal properties

    SciTech Connect

    Yannouleas, C.

    1987-03-01

    We derive the zero-temperature second random phase approximation using Rowe's double-commutator equation. Subsequently, we show that the zero-temperature second random phase approximation exhibits formal properties in analogy with the usual 1p-1h random phase approximation. In particular, the second random phase approximation preserves the energy-weighted sum rule.

  13. Lenalidomide versus investigator's choice in relapsed or refractory mantle cell lymphoma (MCL-002; SPRINT): a phase 2, randomised, multicentre trial.

    PubMed

    Trněný, Marek; Lamy, Thierry; Walewski, Jan; Belada, David; Mayer, Jiri; Radford, John; Jurczak, Wojciech; Morschhauser, Franck; Alexeeva, Julia; Rule, Simon; Afanasyev, Boris; Kaplanov, Kamil; Thyss, Antoine; Kuzmin, Alexej; Voloshin, Sergey; Kuliczkowski, Kazimierz; Giza, Agnieszka; Milpied, Noel; Stelitano, Caterina; Marks, Reinhard; Trümper, Lorenz; Biyukov, Tsvetan; Patturajan, Meera; Bravo, Marie-Laure Casadebaig; Arcaini, Luca

    2016-03-01

    Lenalidomide, an immunomodulatory drug with antineoplastic and antiproliferative effects, showed activity in many single-group studies in relapsed or refractory mantle cell lymphoma. The aim of this randomised study was to examine the efficacy and safety of lenalidomide versus best investigator's choice of single-agent therapy in relapsed or refractory mantle cell lymphoma. The MCL-002 (SPRINT) study was a randomised, phase 2 study of patients with mantle cell lymphoma aged 18 years or older at 67 clinics and academic centres in 12 countries who relapsed one to three times, had Eastern Cooperative Oncology Group performance status of 0-2, at least one measurable lesion to be eligible, and who were ineligible for intensive chemotherpy or stem-cell transplantation. Using a centralised interactive voice response system, we randomly assigned (2:1) patients in a permuted block size of six to receive lenalidomide (25 mg orally on days 1-21 every 28 days) until progressive disease or intolerability, or single-agent investigator's choice of either rituximab, gemcitabine, fludarabine, chlorambucil, or cytarabine. Randomisation was stratified by time from diagnosis, time from last anti-lymphoma therapy, and previous stem-cell transplantation. Individual treatment assignment between lenalidomide and investigator's choice was open label, but investigators had to register their choice of comparator drug before randomly assigning a patient. Patients who progressed on investigator's choice could cross over to lenalidomide treatment. We present the prespecified primary analysis results in the intention-to-treat population for the primary endpoint of progression-free survival, defined as the time from randomisation to progressive disease or death, whichever occurred first. Patient enrolment is complete, although treatment and collection of additional time-to-event data are ongoing. This study is registered with ClinicalTrials.gov, number NCT00875667. Between April 30, 2009, and

  14. The Norwegian dietary guidelines and colorectal cancer survival (CRC-NORDIET) study: a food-based multicentre randomized controlled trial.

    PubMed

    Henriksen, Hege Berg; Ræder, Hanna; Bøhn, Siv Kjølsrud; Paur, Ingvild; Kværner, Ane Sørlie; Billington, Siv Åshild; Eriksen, Morten Tandberg; Wiedsvang, Gro; Erlund, Iris; Færden, Arne; Veierød, Marit Bragelien; Zucknick, Manuela; Smeland, Sigbjørn; Blomhoff, Rune

    2017-01-30

    Colorectal cancer survivors are not only at risk for recurrent disease but also at increased risk of comorbidities such as other cancers, cardiovascular disease, diabetes, hypertension and functional decline. In this trial, we aim at investigating whether a diet in accordance with the Norwegian food-based dietary guidelines and focusing at dampening inflammation and oxidative stress will improve long-term disease outcomes and survival in colorectal cancer patients. This paper presents the study protocol of the Norwegian Dietary Guidelines and Colorectal Cancer Survival study. Men and women aged 50-80 years diagnosed with primary invasive colorectal cancer (Stage I-III) are invited to this randomized controlled, parallel two-arm trial 2-9 months after curative surgery. The intervention group (n = 250) receives an intensive dietary intervention lasting for 12 months and a subsequent maintenance intervention for 14 years. The control group (n = 250) receives no dietary intervention other than standard clinical care. Both groups are offered equal general advice of physical activity. Patients are followed-up at 6 months and 1, 3, 5, 7, 10 and 15 years after baseline. The study center is located at the Department of Nutrition, University of Oslo, and patients are recruited from two hospitals within the South-Eastern Norway Regional Health Authority. Primary outcomes are disease-free survival and overall survival. Secondary outcomes are time to recurrence, cardiovascular disease-free survival, compliance to the dietary recommendations and the effects of the intervention on new comorbidities, intermediate biomarkers, nutrition status, physical activity, physical function and quality of life. The current study is designed to gain a better understanding of the role of a healthy diet aimed at dampening inflammation and oxidative stress on long-term disease outcomes and survival in colorectal cancer patients. Since previous research on the role of diet for

  15. Ursodeoxycholic acid counteracts celecoxib in reduction of duodenal polyps in patients with familial adenomatous polyposis: a multicentre, randomized controlled trial

    PubMed Central

    2013-01-01

    Background Due to prophylactic colectomy, mortality in patients with familial adenomatous polyposis (FAP) has changed, with duodenal cancer currently being the main cause of death. Although celecoxib reduces duodenal polyp density in patients with FAP, its long-term use may increase the risk of cardiovascular events and alternatives need to be explored. Preclinical studies suggest that the combination of celecoxib with ursodeoxycholic acid (UDCA) is a potentially effective strategy. We performed a randomized, double-blind, placebo-controlled trial to investigate the effect of celecoxib and UDCA co-treatment on duodenal adenomatosis in patients with FAP. Methods Patients with FAP received celecoxib (400 mg twice daily) and UDCA (1000-2000 mg daily, ~20-30 mg/kg/day, n=19) or celecoxib and placebo (n=18) orally for 6 months. Primary outcome was drug efficacy, assessed by comparing duodenal polyp density at pre- and post-intervention by blinded review of endoscopic recordings. As secondary outcomes, cell proliferation, apoptosis, and COX-2 levels in normal duodenal mucosa were assessed by immunohistochemistry or real-time quantitative polymerase chain reaction. Results In intention-to-treat analysis, deceased polyp density was observed after celecoxib/placebo treatment (p=0.029), whereas increased polyp density was observed after celecoxib/UDCA treatment (p=0.014). The difference in change in duodenal polyp density was statistically significant between the groups (p=0.011). No changes in secondary outcomes were observed. Thirty patients (81%) reported one or more adverse events, 16 patients (84%, Common Toxicity Criteria for Adverse Events version 3.0 (CTCAE) grade 1–3) treated with celecoxib/UDCA and 14 patients (78%, CTCAE grade 1–2) treated with celecoxib/placebo. Nine patients (24%) discontinued intervention prematurely, 5 patients (26%) treated with celecoxib/UDCA and 4 patients (22%) treated with celecoxib/placebo. Conclusions Celecoxib reduces duodenal

  16. MD-Logic overnight type 1 diabetes control in home settings: A multicentre, multinational, single blind randomized trial.

    PubMed

    Nimri, Revital; Bratina, Natasa; Kordonouri, Olga; Avbelj Stefanija, Magdalena; Fath, Maryam; Biester, Torben; Muller, Ido; Atlas, Eran; Miller, Shahar; Fogel, Aviel; Phillip, Moshe; Danne, Thomas; Battelino, Tadej

    2017-04-01

    To evaluate the safety, efficacy and need for remote monitoring of the MD-Logic closed-loop system during short-term overnight use at home. Seventy-five patients (38 male; aged 10-54 years; average A1c, 7.8% ± 0.7%, 61.8 ± 7.2 mmol/mol) were enrolled from 3 clinical sites. Patients were randomly assigned to participate in 2 overnight crossover periods, each including 4 consecutive nights, 1 under closed-loop control and 1 under sensor-augmented pump (SAP) therapy in the patient's home. Both study arms were supervised using a remote-monitoring system in a blinded manner. Primary endpoints were time spent with glucose levels below 70 mg/dL and percentage of nights in which mean overnight glucose levels were within 90 to 140 mg/dL. The median [interquartile range] percentage of time spent in hypoglycaemia was significantly lower on nights when MD-Logic was used, compared to SAP therapy (2.07 [0, 4.78] and 2.6 [0, 10.34], respectively; P = .004) and the percentage of individual nights with a mean overnight glucose level in target was significantly greater (75 [42, 75] and 50 [25,75], respectively; P = .008). The time spent in target range was increased by a median of 28% (P = .001), with the same amount of insulin (10.69 [7.28, 13.94] and 10.41[6.9, 14.07], respectively; P = .087). The remote monitoring triggered calls for hypoglycaemia at twice the rate during SAP therapy compared to closed-loop control (62 and 29, respectively; P = .002). The MD-Logic system demonstrated a safe and efficient profile during overnight use by children, adolescents and adults with type 1 diabetes and, therefore, provides an effective means of mitigating the risk of nocturnal hypoglycaemia. © 2016 John Wiley & Sons Ltd.

  17. Partially coherent transducers: the random phase transducer approach.

    PubMed

    Mallart, R; Fink, M; Laugier, P; Abouelkaram, S

    1990-07-01

    Ultrasound speckle is a consequence of the stochastic nature of the reflectivity of scattering media (e.g., biological tissue) and of the coherent nature of piezoelectric transducers. This speckle noise can be reduced by the use of incoherent processing techniques (e.g., spatial compounding, incoherent summation, random phase and phase insensitive transducers). We present a unified framework that explains the limitations of incoherent processing in terms of the information grain theory. This theory predicts the gains in SNR as well as the losses in directivity. We also present the random phase transducer approach to incoherence to total coherence. We present applications to speckle reduction, detection of specular reflectors, attenuation estimation and ultrasound imaging. We show that totally incoherent transducers completely remove diffraction effects. They might be used in attenuation estimation, in which case, correction for diffraction is no longer required, in order to obtain unbiased estimates. Partially coherent transducers might also be useful in imaging to reduce speckle noise.

  18. Intermittent Preventive Treatment of Malaria in Pregnancy with Mefloquine in HIV-Negative Women: A Multicentre Randomized Controlled Trial

    PubMed Central

    Abdulla, Salim; Accrombessi, Manfred; Aponte, John J.; Akerey-Diop, Daisy; Basra, Arti; Briand, Valérie; Capan, Meskure; Cot, Michel; Kabanywanyi, Abdunoor M.; Kleine, Christian; Kremsner, Peter G.; Macete, Eusebio; Mackanga, Jean-Rodolphe; Massougbodgi, Achille; Mayor, Alfredo; Nhacolo, Arsenio; Pahlavan, Golbahar; Ramharter, Michael; Rupérez, María; Sevene, Esperança; Vala, Anifa; Zoleko-Manego, Rella; Menéndez, Clara

    2014-01-01

    Background Intermittent preventive treatment in pregnancy (IPTp) with sulfadoxine-pyrimethamine (SP) is recommended by WHO to prevent malaria in African pregnant women. The spread of SP parasite resistance has raised concerns regarding long-term use for IPT. Mefloquine (MQ) is the most promising of available alternatives to SP based on safety profile, long half-life, and high efficacy in Africa. We evaluated the safety and efficacy of MQ for IPTp compared to those of SP in HIV-negative women. Methods and Findings A total of 4,749 pregnant women were enrolled in an open-label randomized clinical trial conducted in Benin, Gabon, Mozambique, and Tanzania comparing two-dose MQ or SP for IPTp and MQ tolerability of two different regimens. The study arms were: (1) SP, (2) single dose MQ (15 mg/kg), and (3) split-dose MQ in the context of long lasting insecticide treated nets. There was no difference on low birth weight prevalence (primary study outcome) between groups (360/2,778 [13.0%]) for MQ group and 177/1,398 (12.7%) for SP group; risk ratio [RR], 1.02 (95% CI 0.86–1.22; p = 0.80 in the ITT analysis). Women receiving MQ had reduced risks of parasitemia (63/1,372 [4.6%] in the SP group and 88/2,737 [3.2%] in the MQ group; RR, 0.70 [95% CI 0.51–0.96]; p = 0.03) and anemia at delivery (609/1,380 [44.1%] in the SP group and 1,110/2743 [40.5%] in the MQ group; RR, 0.92 [95% CI 0.85–0.99]; p = 0.03), and reduced incidence of clinical malaria (96/551.8 malaria episodes person/year [PYAR] in the SP group and 130/1,103.2 episodes PYAR in the MQ group; RR, 0.67 [95% CI 0.52–0.88]; p = 0.004) and all-cause outpatient attendances during pregnancy (850/557.8 outpatients visits PYAR in the SP group and 1,480/1,110.1 visits PYAR in the MQ group; RR, 0.86 [0.78–0.95]; p = 0.003). There were no differences in the prevalence of placental infection and adverse pregnancy outcomes between groups. Tolerability was poorer in the two MQ groups compared to SP

  19. A prospective randomized multicentre study comparing vaginal progesterone gel and vaginal micronized progesterone tablets for luteal support after in vitro fertilization/intracytoplasmic sperm injection.

    PubMed

    Bergh, Christina; Lindenberg, Svend

    2012-12-01

    SUMMARY QUESTION: Is vaginal progesterone gel equivalent to vaginal micronized progesterone tablets concerning ongoing pregnancy rate and superior concerning patient convenience when used for luteal support after IVF/ICSI? Equivalence of treatments in terms of ongoing live intrauterine pregnancy rate has not been demonstrated; the 95% confidence interval (CI) for the difference in ongoing pregnancy rate (-8.2 to 0.1%) did not lie entirely within the pre-specified equivalence interval -7 to 7%. No significant differences in clinical pregnancy rates have been observed between vaginal progesterone gel and other vaginal progesterone products in earlier studies. However, all previous studies included a limited number of patients. This was a randomized, multicentre, controlled, assessor-blinded equivalence trial in 18 fertility centres in Denmark and Sweden between March 2006 and January 2010. A web-based randomization program was used with concealed allocation of patients. Patients were randomized to one of two groups: vaginal progesterone gel or vaginal micronized progesterone tablets. There was no blinding of patients. A total of 2057 women ≤ 40 years of age were included and down-regulated, using the long agonist protocol and rFSH for stimulation. Luteal support was given for 19 days after embryo transfer or until a negative pregnancy test Day 14 after embryo transfer. Patient convenience was assessed using questionnaires to be filled in 14 days after embryo transfer, before pregnancy test. Ongoing intrauterine pregnancy rates were 299/991 (30.2%) (95% CI 27.3-33.0%) in the progesterone gel group and 324/992 (32.7%) (29.7-35.6%) in the micronized progesterone tablet group. The difference in ongoing pregnancy rates between the groups was -4.1% (-8.2 to 0.1%) and the difference in live birth rates was -3.4% (-7.4 to 0.7%), both calculated after correction for significant confounders. Patient convenience and ease of use (1 = very convenient, 10 = very inconvenient

  20. [Rengalin, a novel drug for treatment of cough in children. Intermediate data on multicentre, comparative randomized clinical trial].

    PubMed

    Geppe, N A; Kondyurina, E G; Galustyan, A N; Pak, T E; Baltserovich, N B; Zhiglinskaya, O V; Kamaev, A V; Lazareva, S G; Laleko, S L; Melnikova, I M; Mikhalkova, E V; Perminova, O A; Sabitov, A U; Spivakovsky, Yu M

    2014-01-01

    Rengalin liquid formulation on the basis of antibodies to bradikinin histamine and morphine was specially designed for the treatment of cough in children. The three-component combination in therapeutically active against both dry and wet cough due to effect on diverse pathogenetic aspects of the cough reflex. The aim of the multicenter, comparative, randomized clinical trial was to estimate the efficacy and safety of rengalin in the treatment of cough in patients with acute respiratory infection (ARI) of the upper respiratory tract. One hundred forty six patients at the age of 3 to 17 years (the average age of 8.2 ± 3.6 years) from 14 medical centres of Russia were observed. The patients suffered from dry/nonproductive, frequent, sore cough preventing from day-time activity and/or night sleep (≥ 4 by the Cough Severity Scale). The cough duration ranged from 12 hours to 3 days. For 3 days the patients of group 1 (n = 71) and group 2 (n = 75) were treated with rengalin and sinekod (butamirate) respectively. For the following 4 days the patients (in case of viscid expectoration were treated with ambroxole in the age doses. The results of the Per Protokol Analysis (n = 67 rengalin group and n = 73 sinekod group) with an account of the Non-Infectiority Design are presented. In 3 days the number of the group 1 patients with significant improvement/recovery by the day and night estimates amounted to 90% and 88% respectively (vs. 81% and 88% in the group 2 patients, no night opisodes of cough after 3-days rengalin use being recorded in 52% of the patients vs. 34% in the sinekod group patients (p = 0.0003). On the 7th day of the treatment with rengalin the number of the children with significant improvement of or recovery from day-time cought amounted to 99%and that of the patients with significant improvement of or recovery from night-time cough amounted to 93%, in 90% of them no night-time cough being recorded (p = 0.0008). As for the patients of the reference group

  1. Noise radar using random phase and frequency modulation

    NASA Astrophysics Data System (ADS)

    Axelsson, Sune R. J.

    2004-01-01

    Pulse compression radar is used in a great number of radar applications. Excellent range resolution and high ECCM performance can be achieved by wide-band modulated long pulses, which spread out the transmitted energy in frequency and time. By using random noise as waveform, the range ambiguity can be suppressed as well. The same limit in doppler resolution is achieved as for a coherent doppler radar when the time compression of the reference is tuned to that of the target. Mostly, the random signal is transmitted directly from a noise generating HF-source. A sine wave, which is phase or frequency modulated by random noise, is an alternative giving similar performance but higher transmitted mean power when peak-limited transmitters are applied. A narrower modulation noise bandwidth can also be applied to generate the same output bandwidth. For phase modulation, the bandwidth amplifying factor is simply the rms value of the phase modulation, and for a frequency modulating waveform the output rms bandwidth equals the rms value of the frequency modulation. The results also show that the range sidelobes can be highly suppressed compared with the sidelobes of the modulating signal. The mean and variance of the correlation integral are derived in terms of the autocorrelation function of the modulation. Finally, random bi-phase modulation and the effects of low-bit ADC at the correlation processing are analyzed and described. The advantages of low range sidelobes and enhanced range resolution make frequency and phase modulation attractive for a great number of applications.

  2. A multilayer biomaterial for osteochondral regeneration shows superiority vs microfractures for the treatment of osteochondral lesions in a multicentre randomized trial at 2 years.

    PubMed

    Kon, Elizaveta; Filardo, Giuseppe; Brittberg, Mats; Busacca, Maurizio; Condello, Vincenzo; Engebretsen, Lars; Marlovits, Stefan; Niemeyer, Philipp; Platzer, Patrik; Posthumus, Michael; Verdonk, Peter; Verdonk, Renè; Victor, Jan; van der Merwe, Willem; Widuchowski, Wojciech; Zorzi, Claudio; Marcacci, Maurilio

    2017-09-14

    The increasing awareness on the role of subchondral bone in the etiopathology of articular surface lesions led to the development of osteochondral scaffolds. While safety and promising results have been suggested, there are no trials proving the real potential of the osteochondral regenerative approach. Aim was to assess the benefit provided by a nanostructured collagen-hydroxyapatite (coll-HA) multilayer scaffold for the treatment of chondral and osteochondral knee lesions. In this multicentre randomized controlled clinical trial, 100 patients affected by symptomatic chondral and osteochondral lesions were treated and evaluated for up to 2 years (51 study group and 49 control group). A biomimetic coll-HA scaffold was studied, and bone marrow stimulation (BMS) was used as reference intervention. Primary efficacy measurement was IKDC subjective score at 2 years. Secondary efficacy measurements were: KOOS, IKDC Knee Examination Form, Tegner and VAS Pain scores evaluated at 6, 12 and 24 months. Tissue regeneration was evaluated with MRI MOCART scoring system at 6, 12 and 24 months. An external independent agency was involved to ensure data correctness and objectiveness. A statistically significant improvement of all clinical scores was obtained from basal evaluation to 2-year follow-up in both groups, although no overall statistically significant differences were detected between the two treatments. Conversely, the subgroup of patients affected by deep osteochondral lesions (i.e. Outerbridge grade IV and OCD) showed a statistically significant better IKDC subjective outcome (+12.4 points, p = 0.036) in the coll-HA group. Statistically significant better results were also found for another challenging group: sport active patients (+16.0, p = 0.027). Severe adverse events related to treatment were documented only in three patients in the coll-HA group and in one in the BMS group. The MOCART score showed no statistical difference between the two groups. This

  3. A multicentre randomized controlled trial of an empowerment-inspired intervention for adolescents starting continuous subcutaneous insulin infusion--a study protocol.

    PubMed

    Brorsson, Anna Lena; Leksell, Janeth; Viklund, Gunnel; Lindholm Olinder, Anna

    2013-12-20

    Continuous subcutaneous insulin infusion (CSII) treatment among children with type 1 diabetes is increasing in Sweden. However, studies evaluating glycaemic control in children using CSII show inconsistent results. The distribution of responsibility for diabetes self-management between children and parents is often unclear and needs clarification. There is much published support for continued parental involvement and shared diabetes management during adolescence. Guided Self-Determination (GSD) is an empowerment-based, person-centred, reflection and problem solving method intended to guide the patient to become self-sufficient and develop life skills for managing difficulties in diabetes self-management. This method has been adapted for adolescents and parents as Guided Self-Determination-Young (GSD-Y). This study aims to evaluate the effect of an intervention with GSD-Y in groups of adolescents starting on insulin pumps and their parents on diabetes-related family conflicts, perceived health and quality of life (QoL), and metabolic control. Here, we describe the protocol and plans for study enrollment. This study is designed as a randomized, controlled, prospective, multicentre study. Eighty patients between 12-18 years of age who are planning to start CSII will be included. All adolescents and their parents will receive standard insulin pump training. The education intervention will be conducted when CSII is to be started and at four appointments in the first 4 months after starting CSII. The primary outcome is haemoglobin A1c levels. Secondary outcomes are perceived health and QoL, frequency of blood glucose self-monitoring and bolus doses, and usage of carbohydrate counting. The following instruments will be used: Disabkids, 'Check your health', the Diabetes Family Conflict Scale and the Swedish Diabetes Empowerment Scale. Outcomes will be evaluated within and between groups by comparing data at baseline, and at 6 and 12 months after starting treatment. In this

  4. Gemifloxacin once daily for 5 days versus 7 days for the treatment of community-acquired pneumonia: a randomized, multicentre, double-blind study.

    PubMed

    File, Thomas M; Mandell, Lionel A; Tillotson, Glenn; Kostov, Kosta; Georgiev, Ognian

    2007-07-01

    Short-course therapy has been advocated for the treatment of community-acquired pneumonia (CAP). We compared the efficacy and safety of 5 and 7 day courses of gemifloxacin for outpatient treatment of mild-moderate CAP. In a multicentre, double-blind, parallel group study, patients were randomized to receive 320 mg of oral gemifloxacin once daily for 5 or 7 days. Over 95% of all patients in each cohort had a Fine score of

  5. HairMax LaserComb laser phototherapy device in the treatment of male androgenetic alopecia: A randomized, double-blind, sham device-controlled, multicentre trial.

    PubMed

    Leavitt, Matt; Charles, Glenn; Heyman, Eugene; Michaels, David

    2009-01-01

    The use of low levels of visible or near infrared light for reducing pain, inflammation and oedema, promoting healing of wounds, deeper tissue and nerves, and preventing tissue damage has been known for almost 40 years since the invention of lasers. The HairMax LaserComb is a hand-held Class 3R lower level laser therapy device that contains a single laser module that emulates 9 beams at a wavelength of 655 nm (+/-5%). The device uses a technique of parting the user's hair by combs that are attached to the device. This improves delivery of distributed laser light to the scalp. The combs are designed so that each of the teeth on the combs aligns with a laser beam. By aligning the teeth with the laser beams, the hair can be parted and the laser energy delivered to the scalp of the user without obstruction by the individual hairs on the scalp. The primary aim of the study was to assess the safety and effectiveness of the HairMax LaserComb laser phototherapy device in the promotion of hair growth and in the cessation of hair loss in males diagnosed with androgenetic alopecia (AGA). This double-blind, sham device-controlled, multicentre, 26-week trial randomized male patients with Norwood-Hamilton classes IIa-V AGA to treatment with the HairMax LaserComb or the sham device (2 : 1). The sham device used in the study was identical to the active device except that the laser light was replaced by a non-active incandescent light source. Of the 110 patients who completed the study, subjects in the HairMax LaserComb treatment group exhibited a significantly greater increase in mean terminal hair density than subjects in the sham device group (p < 0.0001). Consistent with this evidence for primary effectiveness, significant improvements in overall hair regrowth were demonstrated in terms of patients' subjective assessment (p < 0.015) at 26 weeks over baseline. The HairMax LaserComb was well tolerated with no serious adverse events reported and no statistical difference in

  6. Evaluations of phase-only double random phase encoding based on key-space analysis.

    PubMed

    Nakano, Kazuya; Takeda, Masafumi; Suzuki, Hiroyuki; Yamaguchi, Masahiro

    2013-02-20

    Although initial research shows that double-random phase encoding (DRPE) is vulnerable to known-plaintext attacks that use phase retrieval algorithms, subsequent research has shown that phase-only DRPE, in which the Fourier amplitude component of an image encrypted with classical DRPE remains constant, is resistant to attacks that apply phase retrieval algorithms. Herein, we numerically analyze the key-space of DRPE and investigate the distribution property of decryption keys for classical and phase-only DRPE. We determine the difference in the distribution property of successful decryption keys for these DRPE techniques from the numerical analysis results and then discuss the security offered by them.

  7. Third-order phase transition in random tilings

    NASA Astrophysics Data System (ADS)

    Colomo, F.; Pronko, A. G.

    2013-10-01

    We consider the domino tilings of an Aztec diamond with a cut-off corner of macroscopic square shape and given size and address the bulk properties of tilings as the size is varied. We observe that the free energy exhibits a third-order phase transition when the cut-off square, increasing in size, reaches the arctic ellipse—the phase separation curve of the original (unmodified) Aztec diamond. We obtain this result by studying the thermodynamic limit of a certain nonlocal correlation function of the underlying six-vertex model with domain wall boundary conditions, the so-called emptiness formation probability (EFP). We consider EFP in two different representations: as a τ function for Toda chains and as a random matrix model integral. The latter has a discrete measure and a linear potential with hard walls; the observed phase transition shares properties with both Gross-Witten-Wadia and Douglas-Kazakov phase transitions.

  8. Zoledronate in combination with chemotherapy and surgery to treat osteosarcoma (OS2006): a randomised, multicentre, open-label, phase 3 trial.

    PubMed

    Piperno-Neumann, Sophie; Le Deley, Marie-Cécile; Rédini, Françoise; Pacquement, Hélène; Marec-Bérard, Perrine; Petit, Philippe; Brisse, Hervé; Lervat, Cyril; Gentet, Jean-Claude; Entz-Werlé, Natacha; Italiano, Antoine; Corradini, Nadège; Bompas, Emmanuelle; Penel, Nicolas; Tabone, Marie-Dominique; Gomez-Brouchet, Anne; Guinebretière, Jean-Marc; Mascard, Eric; Gouin, François; Chevance, Aurélie; Bonnet, Naïma; Blay, Jean-Yves; Brugières, Laurence

    2016-08-01

    Based on preclinical data for the antitumour effect of zoledronate in osteosarcoma, we assessed whether zoledronate combined with chemotherapy and surgery improved event-free survival in children and adults with osteosarcoma. In this randomised, multicentre, open-label, phase 3 trial (OS2006), patients aged between 5 years and 50 years with newly diagnosed high-grade osteosarcoma were randomly assigned to receive standard chemotherapy with or without ten zoledronate intravenous infusions (four preoperative and six postoperative). Adults older than 25 years received 4 mg zoledronate per infusion, patients aged 18-25 years received 0·05 mg/kg for the first two infusions and 4 mg for the remaining eight infusions, and younger patients received 0·05 mg/kg per infusion. Chemotherapy comprised high-dose methotrexate based chemotherapy in patients younger than 18 years, and doxorubicin, ifosfamide, and cisplatin in adults older than 25 years; patients aged 18-25 years were treated with either regime at the discretion of the treating centre. Balanced randomisation between the two groups was done centrally with online randomisation software, based on a minimisation algorithm taking into account centre, age, combined with chemotherapy regimen, and risk group (resectable primary and no metastasis vs other). Patients and investigators were not masked to treatment assignment, but the endpoint adjudication committee members who reviewed suspected early progressions were masked to group allocation. The primary endpoint was event-free survival, estimated from the randomisation to the time of first failure (local or distant relapse, progression, death) or to the last follow-up visit for the patients in first complete remission, analysed on a modified intention-to-treat population, which excluded patients found not to have a malignant tumour after central review. Three interim analyses were planned. This trial is registered with ClinicalTrials.gov, number NCT00470223. Between

  9. Correlation Energies from the Two-Component Random Phase Approximation.

    PubMed

    Kühn, Michael

    2014-02-11

    The correlation energy within the two-component random phase approximation accounting for spin-orbit effects is derived. The resulting plasmon equation is rewritten-analogously to the scalar relativistic case-in terms of the trace of two Hermitian matrices for (Kramers-restricted) closed-shell systems and then represented as an integral over imaginary frequency using the resolution of the identity approximation. The final expression is implemented in the TURBOMOLE program suite. The code is applied to the computation of equilibrium distances and vibrational frequencies of heavy diatomic molecules. The efficiency is demonstrated by calculation of the relative energies of the Oh-, D4h-, and C5v-symmetric isomers of Pb6. Results within the random phase approximation are obtained based on two-component Kohn-Sham reference-state calculations, using effective-core potentials. These values are finally compared to other two-component and scalar relativistic methods, as well as experimental data.

  10. Relativistic continuum quasiparticle random-phase approximation in spherical nuclei

    SciTech Connect

    Daoutidis, I.; Ring, P.

    2011-04-15

    We have calculated the strength distributions of the dipole response in spherical nuclei, ranging all over the periodic table. The calculations were performed within two microscopic models: the discretized quasiparticle random-phase approximation and the continuum quasiparticle random-phase approximation, which takes into account the coupling of the single-particle continuum in an exact way. Pairing correlations are treated with the BCS model. In the calculations, two density functionals were used, namely, the PC-F1 and the DD-PC1. Both are based on relativistic point-coupling Lagrangians. It is explicitly shown that this model is capable of reproducing the giant- as well as the pygmy-dipole resonance for open-shell nuclei in a high level of quantitative agreement with the available experimental observations.

  11. [Occult multicentric breast cancer].

    PubMed

    Vtorushin, S V; Zab'ialova, M V; Glushchenko, S A; Perel'muter, V M; Slonimskaia, E M

    2009-01-01

    The study included 92 patients with invasive ductal breast cancer (T2-4N0-2M0-1). In 38 cases, tumor growth was unicentric while histologically identifiable ones as multicentric in 44. Multicentricity mostly occurred in cases of macroscopically-identifiable nodes located in the central segments of the breast. Clinically-identifiable nodes of multicentric tumor growth measured more than 3 cm. Multicentric tumors were mostly grade III, featured lower expression of sex hormone receptors and positive Her2 status.

  12. A multicentre phase II study of vorinostat in patients with relapsed or refractory indolent B-cell non-Hodgkin lymphoma and mantle cell lymphoma.

    PubMed

    Ogura, Michinori; Ando, Kiyoshi; Suzuki, Tatsuya; Ishizawa, Kenichi; Oh, Sung Yong; Itoh, Kuniaki; Yamamoto, Kazuhito; Au, Wing Yan; Tien, Hwei-Fang; Matsuno, Yoshihiro; Terauchi, Takashi; Yamamoto, Keiko; Mori, Masahiko; Tanaka, Yoshinobu; Shimamoto, Takashi; Tobinai, Kensei; Kim, Won Seog

    2014-06-01

    Although initial rituximab-containing chemotherapies achieve high response rates, indolent B-cell non-Hodgkin lymphoma (B-NHL), such as follicular lymphoma (FL), is still incurable. Therefore, new effective agents with novel mechanisms are anticipated. In this multicentre phase II study, patients with relapsed/refractory indolent B-NHL and mantle cell lymphoma (MCL) received vorinostat 200 mg twice daily for 14 consecutive days in a 21-d cycle until disease progression or unacceptable toxicity occurred. The primary endpoint was overall response rate (ORR) in FL patients and safety and tolerability in all patients. Secondary endpoints included progression-free survival (PFS). Fifty-six eligible patients were enrolled; 50 patients (39 with FL, seven with other B-NHL, and four with MCL) were evaluable for ORR, and 40 patients had received rituximab-containing prior chemotherapeutic regimens. For the 39 patients with FL, the ORR was 49% [95% confidence interval (CI): 32·4, 65·2] and the median PFS was 20 months (95% CI: 11·2, 29·7). Major toxicities were manageable grade 3/4 thrombocytopenia and neutropenia. Vorinostat offers sustained antitumour activity in patients with relapsed or refractory FL with an acceptable safety profile. Further investigation of vorinostat for clinical efficacy is warranted.

  13. Autocorrelations of Random Fractal Apertures and Phase Screens

    NASA Astrophysics Data System (ADS)

    Schonfeld, Jonathan F.

    We introduce a new product representation for general random binary fractal apertures defined by removing voids from Euclidean space, and use it to derive a simple closed-form expression for ensemble-averaged correlations. Power-law scaling at short distance follows almost immediately. Similar techniques provide easy constructions of objects with fractional Brownian short-distance behavior for phase screens and other applications.

  14. Comparison of cinnarizine/dimenhydrinate fixed combination with the respective monotherapies for vertigo of various origins: a randomized, double-blind, active-controlled, multicentre study.

    PubMed

    Hahn, Ales; Novotný, Miroslav; Shotekov, Penko M; Cirek, Zdenek; Bognar-Steinberg, Irene; Baumann, Wolfgang

    2011-01-01

    Vertigo may arise from dysfunction in the peripheral and/or the central vestibular system. Simultaneous activity of a medication at both sites will serve to improve the efficacy of antivertigo treatment. The aim of this study was to compare the efficacy and tolerability of a fixed combination of the peripherally acting cinnarizine (20 mg) plus the centrally acting dimenhydrinate (40 mg) with those of equally dosed monotherapies in the treatment of vertigo of various origins. This prospective, randomized, double-blind, active-controlled, multicentre study included patients who assessed at least one vertigo symptom as being of at least medium intensity (≥2) on a 5-point visual analogue scale (VAS; ranging from 0 = not present to 4 = very strong) and who had pathological vestibulospinal movement patterns and/or nystagmus reactions. Patients were randomly assigned to receive either cinnarizine 20 mg/dimenhydrinate 40 mg as a fixed combination, cinnarizine 20 mg as monotherapy or dimenhydrinate 40 mg as monotherapy, each three times daily for 4 weeks. Patients were examined at baseline (t(0)), and after 1 week (t(1w)) and 4 weeks (t(4w)) of treatment. The primary efficacy endpoint was the decrease in mean vertigo score (MVS) at t(4w), which was calculated by averaging the total score for 12 individual vertigo symptoms, each assessed using the 5-point VAS. The study included 182 patients, of whom 177 were evaluable for efficacy. The mean ± SD reduction in MVS after 4 weeks of treatment with the fixed combination (-1.44 ± 0.56) was significantly greater than the reductions with each of the active treatments alone (cinnarizine -1.04 ± 0.53; dimenhydrinate -1.06 ± 0.56; p = 0.0001, both comparisons). Cinnarizine 20 mg/dimenhydrinate 40 mg as a fixed combination was associated with a significantly higher responder rate (78% of patients with MVS ≤0.5 at t(4w)) than the monotherapies. The odds ratios for MVS ≤0.5 at t(4w

  15. Cascading dynamics on random networks: crossover in phase transition.

    PubMed

    Liu, Run-Ran; Wang, Wen-Xu; Lai, Ying-Cheng; Wang, Bing-Hong

    2012-02-01

    In a complex network, random initial attacks or failures can trigger subsequent failures in a cascading manner, which is effectively a phase transition. Recent works have demonstrated that in networks with interdependent links so that the failure of one node causes the immediate failures of all nodes connected to it by such links, both first- and second-order phase transitions can arise. Moreover, there is a crossover between the two types of transitions at a critical system-parameter value. We demonstrate that these phenomena can occur in the more general setting where no interdependent links are present. A heuristic theory is derived to estimate the crossover and phase-transition points, and a remarkable agreement with numerics is obtained.

  16. Cascading dynamics on random networks: Crossover in phase transition

    NASA Astrophysics Data System (ADS)

    Liu, Run-Ran; Wang, Wen-Xu; Lai, Ying-Cheng; Wang, Bing-Hong

    2012-02-01

    In a complex network, random initial attacks or failures can trigger subsequent failures in a cascading manner, which is effectively a phase transition. Recent works have demonstrated that in networks with interdependent links so that the failure of one node causes the immediate failures of all nodes connected to it by such links, both first- and second-order phase transitions can arise. Moreover, there is a crossover between the two types of transitions at a critical system-parameter value. We demonstrate that these phenomena can occur in the more general setting where no interdependent links are present. A heuristic theory is derived to estimate the crossover and phase-transition points, and a remarkable agreement with numerics is obtained.

  17. Phase diffusion and random walk interpretation of electromagnetic scattering.

    PubMed

    Bahcivan, Hasan; Hysell, David L; Kelley, Michael C

    2003-08-01

    The relaxation behavior of phase observables for different particle diffusion models is found to establish a ground for radioscience interpretations of coherent backscatter spectra. The characteristic function for a random walk process at twice the incident radiation wave number is associated with the complex amplitude of the scattered field from a medium containing refractive index fluctuations. The phase relaxation function can be connected to the evolution of the characteristic function and may describe the average regression of the scattered field from a spontaneous fluctuation undergoing turbulent mixing. This connection holds when we assume that the stochastic description of particle movements based on a diffusion model is valid. The phase relaxation function, when identified as the generalized susceptibility function of the fluctuation dissipation theorem, is related to the spectral density of the scattered field from steady-state fluctuations.

  18. Phase Transitions and Equilibrium Measures in Random Matrix Models

    NASA Astrophysics Data System (ADS)

    Martínez-Finkelshtein, A.; Orive, R.; Rakhmanov, E. A.

    2015-02-01

    The paper is devoted to a study of phase transitions in the Hermitian random matrix models with a polynomial potential. In an alternative equivalent language, we study families of equilibrium measures on the real line in a polynomial external field. The total mass of the measure is considered as the main parameter, which may be interpreted also either as temperature or time. Our main tools are differentiation formulas with respect to the parameters of the problem, and a representation of the equilibrium potential in terms of a hyperelliptic integral. Using this combination we introduce and investigate a dynamical system (system of ODEs) describing the evolution of families of equilibrium measures. On this basis we are able to systematically derive a number of new results on phase transitions, such as the local behavior of the system at all kinds of phase transitions, as well as to review a number of known ones.

  19. Multiple image encryption and watermarking by random phase matching

    NASA Astrophysics Data System (ADS)

    He, M. Z.; Cai, L. Z.; Liu, Q.; Wang, X. C.; Meng, X. F.

    2005-03-01

    Usually a set of transmitted patterns can realize encryption and/or watermarking just for one hidden image. In this paper, we propose a novel method of multiple image encryption and watermarking by random phase matching, which can encrypt and then decrypt more than one image with the same set of transmitted patterns based on the idea of double phase encoding and the wave field superposition. The principle and procedure of this method are explained. A series of computer simulations with phase-shifting interferometry have shown that two or four independent images can be encrypted and decrypted without or with watermarking successfully with one set of composite interferograms. The ability of this method to retrieve hidden image(s) from part of the transmitted patterns has also been verified. This technique can considerably raise the efficiency of data transmission, and it is particularly suitable for the image transmission via Internet.

  20. Randomized Phase II Trial of Sulindac for Lung Cancer Chemoprevention

    PubMed Central

    Limburg, Paul J.; Mandrekar, Sumithra J.; Aubry, Marie Christine; Ziegler, Katie L. Allen; Zhang, Jun; Yi, Joanne E.; Henry, Michael; Tazelaar, Henry D.; Lam, Stephen; McWilliams, Annette; Midthun, David E.; Edell, Eric S.; Rickman, Otis B.; Mazzone, Peter; Tockman, Melvyn; Beamis, John F.; Lamb, Carla; Simoff, Michael; Loprinzi, Charles; Szabo, Eva; Jett, James

    2012-01-01

    Introduction Sulindac represents a promising candidate agent for lung cancer chemoprevention, but clinical trial data have not been previously reported. We conducted a randomized, phase II chemoprevention trial involving current or former cigarette smokers (≥ 30 pack-years) utilizing the multi-center, inter-disciplinary infrastructure of the Cancer Prevention Network (CPN). Methods At least 1 bronchial dysplastic lesion identified by fluorescence bronchoscopy was required for randomization. Intervention assignments were sulindac 150 mg bid or an identical placebo bid for six months. Trial endpoints included changes in histologic grade of dysplasia (per-participant as primary endpoint and per lesion as secondary endpoint), number of dysplastic lesions (per-participant), and Ki67 labeling index. Results Slower than anticipated recruitment led to trial closure after randomizing participants (n = 31 and n = 30 in the sulindac and placebo arms, respectively). Pre- and post-intervention fluorescence bronchoscopy data were available for 53/61 (87%) randomized, eligible participants. The median (range) of dysplastic lesions at baseline was 2 (1-12) in the sulindac arm and 2 (1-7) in the placebo arm. Change in dysplasia was categorized as regression:stable:progression for 15:3:8 (58%:12%:31%) subjects in the sulindac arm and 15:2:10 (56%:7%:37%) subjects in the placebo arm; these distributions were not statistically different (p=0.85). Median Ki67 expression (% cells stained positive) was significantly reduced in both the placebo (30 versus 5; p = 0.0005) and sulindac (30 versus 10; p = 0.0003) arms, but the difference between arms was not statistically significant (p = 0.92). Conclusions Data from this multi-center, phase II squamous cell lung cancer chemoprevention trial do not demonstrate sufficient benefits from sulindac 150 mg bid for 6 months to warrant additional phase III testing. Investigation of pathway-focused agents is necessary for lung cancer chemoprevention

  1. Randomized phase II trial of sulindac for lung cancer chemoprevention.

    PubMed

    Limburg, Paul J; Mandrekar, Sumithra J; Aubry, Marie Christine; Ziegler, Katie L Allen; Zhang, Jun; Yi, Joanne E; Henry, Michael; Tazelaar, Henry D; Lam, Stephen; McWilliams, Annette; Midthun, David E; Edell, Eric S; Rickman, Otis B; Mazzone, Peter; Tockman, Melvyn; Beamis, John F; Lamb, Carla; Simoff, Michael; Loprinzi, Charles; Szabo, Eva; Jett, James

    2013-03-01

    Sulindac represents a promising candidate agent for lung cancer chemoprevention, but clinical trial data have not been previously reported. We conducted a randomized, phase II chemoprevention trial involving current or former cigarette smokers (≥30 pack-years) utilizing the multi-center, inter-disciplinary infrastructure of the Cancer Prevention Network (CPN). At least 1 bronchial dysplastic lesion identified by fluorescence bronchoscopy was required for randomization. Intervention assignments were sulindac 150mg bid or an identical placebo bid for 6 months. Trial endpoints included changes in histologic grade of dysplasia (per-participant as primary endpoint and per lesion as secondary endpoint), number of dysplastic lesions (per-participant), and Ki67 labeling index. Slower than anticipated recruitment led to trial closure after randomizing participants (n=31 and n=30 in the sulindac and placebo arms, respectively). Pre- and post-intervention fluorescence bronchoscopy data were available for 53/61 (87%) randomized, eligible participants. The median (range) of dysplastic lesions at baseline was 2 (1-12) in the sulindac arm and 2 (1-7) in the placebo arm. Change in dysplasia was categorized as regression:stable:progression for 15:3:8 (58%:12%:31%) subjects in the sulindac arm and 15:2:10 (56%:7%:37%) subjects in the placebo arm; these distributions were not statistically different (p=0.85). Median Ki67 expression (% cells stained positive) was significantly reduced in both the placebo (30 versus 5; p=0.0005) and sulindac (30 versus 10; p=0.0003) arms, but the difference between arms was not statistically significant (p=0.92). Data from this multi-center, phase II squamous cell lung cancer chemoprevention trial do not demonstrate sufficient benefits from sulindac 150mg bid for 6 months to warrant additional phase III testing. Investigation of pathway-focused agents is necessary for lung cancer chemoprevention. Copyright © 2012 Elsevier Ireland Ltd. All rights

  2. A 3-year multicentre randomized controlled trial of etonogestrel- and levonorgestrel-releasing contraceptive implants, with non-randomized matched copper-intrauterine device controls.

    PubMed

    Bahamondes, Luis; Brache, Vivian; Meirik, Olav; Ali, Moazzam; Habib, Ndema; Landoulsi, Sihem

    2015-11-01

    Is there any difference in the clinical performance of the 3-year one-rod etonogestrel (ENG)- and the 5-year two-rod levonorgestrel (LNG)-releasing contraceptive implants during 3 years of insertion, and between implant and intrauterine device (IUD) contraception, in particular complaints possibly related to hormonal contraceptives? The cumulative contraceptive effectiveness after 3 years and method continuation through 2.5 years were not significantly different between ENG and LNG implants, but both outcomes were significantly worse in the non-randomized age-matched group of IUD users than in the combined implant group. ENG- and LNG-releasing implants are safe and highly efficacious contraceptives with pregnancy rates reported to be 0.0-0.5 per 100 women-years (W-Y). No head-to-head comparative study of the two implants has been undertaken, and little information is available on comparisons of complaints of side effects of implant and copper IUD users. This was an open parallel group RCT with 1:1 allocation ratio of the ENG and the LNG implants with non-randomized control group of women choosing TCu380A IUD to address lack of reliable data on common side effects typically attributed to the use of progestogen-only contraceptives. After device(s) placement, follow-ups were at 2 weeks, 3 and 6 months, and semi-annually thereafter for 3 years or until pregnancy, removal or expulsion of the implant/IUD occurred. The study took place in family planning clinics in Brazil, Chile, Dominican Republic, Hungary, Thailand, Turkey and Zimbabwe. Women seeking long-term contraception were enlisted after an eligibility check and informed consent, and 2982 women were enrolled: 1003, 1005 and 974 in the ENG-implant, LNG-implant and IUD groups, respectively; 995, 997 and 971, respectively, were included in the per protocol analysis reported here. ENG and LNG implants each had the same 3-year cumulative pregnancy rate of 0.4 per 100 W-Y [95% confidence interval (CI) 0.1-1.4]. A weight

  3. Fully phase image encryption using double random-structured phase masks in gyrator domain.

    PubMed

    Singh, Hukum; Yadav, A K; Vashisth, Sunanda; Singh, Kehar

    2014-10-01

    We propose a method for fully phase image encryption based on double random-structured phase mask encoding in the gyrator transform (GT) domain. The security of the system is strengthened by parameters used in the construction of a structured phase mask (SPM) based on a devil's vortex Fresnel lens (DVFL). The input image is recovered using the correct parameters of the SPMs, transform orders of the GT, and conjugate of the random phase masks. The use of a DVFL-based SPM enhances security by increasing the key space for encryption, and also overcomes the problem of axis alignment associated with an optical setup. The proposed scheme can also be implemented optically. The computed values of mean squared error between the retrieved and the original image show the efficacy of the proposed scheme. We have also investigated the scheme's sensitivity to the encryption parameters, and robustness against occlusion and multiplicative Gaussian noise attacks.

  4. Glassy phases and driven response of the phase-field-crystal model with random pinning.

    PubMed

    Granato, E; Ramos, J A P; Achim, C V; Lehikoinen, J; Ying, S C; Ala-Nissila, T; Elder, K R

    2011-09-01

    We study the structural correlations and the nonlinear response to a driving force of a two-dimensional phase-field-crystal model with random pinning. The model provides an effective continuous description of lattice systems in the presence of disordered external pinning centers, allowing for both elastic and plastic deformations. We find that the phase-field crystal with disorder assumes an amorphous glassy ground state, with only short-ranged positional and orientational correlations, even in the limit of weak disorder. Under increasing driving force, the pinned amorphous-glass phase evolves into a moving plastic-flow phase and then, finally, a moving smectic phase. The transverse response of the moving smectic phase shows a vanishing transverse critical force for increasing system sizes.

  5. The efficacy and safety of Tanacetum parthenium (feverfew) in migraine prophylaxis--a double-blind, multicentre, randomized placebo-controlled dose-response study.

    PubMed

    Pfaffenrath, V; Diener, H C; Fischer, M; Friede, M; Henneicke-von Zepelin, H H

    2002-09-01

    Tanacetum parthenium (feverfew), is a well-known herb for the prophylactic treatment of migraine. The primary objective was to show a dose-response of a new stable extract (MIG-99) reproducibly manufactured with supercritical CO2 from feverfew (T. parthenium). Furthermore, the study should provide data on the safety and tolerability of MIG-99. In a randomized, double-blind, multicentre, controlled trial with an adaptive design, the clinical efficacy and safety of three dosages of MIG-99 (2.08 mg; 6.25 mg; 18.75 mg t.i.d.) were compared with placebo. The patients (n = 147) suffered from migraine with and without aura according to International Headache Society (IHS) criteria and were treated with one of the study medications for 12 weeks after a 4-week baseline period. The primary efficacy parameter was the number of migraine attacks during the last 28 days of the treatment period compared with baseline. Secondary endpoints were total and average duration and intensity of migraine attacks, mean duration of the single attack, number of days with accompanying migraine symptoms, number of days with inability to work due to migraine as well as type and amount of additionally taken medications for the treatment of migraine attacks. The design of the study included a pre-planned adaptive interim analysis for patients with at least four migraine attacks within the baseline period. With respect to the primary and secondary efficacy parameter, a statistically significant difference was not found between the overall and the confirmatory intention-to-treat (ITT) sample in the exploratorily analysed four treatment groups. The frequency of migraine attacks for the predefined confirmatory subgroup of patients (n = 49) with at least four migraine attacks during the baseline period decreased in a dose-dependent manner (P = 0.001). The highest absolute change of migraine attacks was observed under treatment with 6.25 mg t.i.d. (mean +/- SD = -1.8 +/- 1.5 per 28 days) compared with

  6. Doorway states in the random-phase approximation

    SciTech Connect

    De Pace, A.; Molinari, A.; Weidenmüller, H.A.

    2014-12-15

    By coupling a doorway state to a sea of random background states, we develop the theory of doorway states in the framework of the random-phase approximation (RPA). Because of the symmetry of the RPA equations, that theory is radically different from the standard description of doorway states in the shell model. We derive the Pastur equation in the limit of large matrix dimension and show that the results agree with those of matrix diagonalization in large spaces. The complexity of the Pastur equation does not allow for an analytical approach that would approximately describe the doorway state. Our numerical results display unexpected features: The coupling of the doorway state with states of opposite energy leads to strong mutual attraction.

  7. Finite amplitude method for the quasiparticle random-phase approximation

    SciTech Connect

    Avogadro, Paolo; Nakatsukasa, Takashi

    2011-07-15

    We present the finite amplitude method (FAM), originally proposed in Ref. [17], for superfluid systems. A Hartree-Fock-Bogoliubov code may be transformed into a code of the quasiparticle-random-phase approximation (QRPA) with simple modifications. This technique has advantages over the conventional QRPA calculations, such as coding feasibility and computational cost. We perform the fully self-consistent linear-response calculation for the spherical neutron-rich nucleus {sup 174}Sn, modifying the hfbrad code, to demonstrate the accuracy, feasibility, and usefulness of the FAM.

  8. Qubit Metrology of Ultralow Phase Noise Using Randomized Benchmarking

    NASA Astrophysics Data System (ADS)

    O'Malley, P. J. J.; Kelly, J.; Barends, R.; Campbell, B.; Chen, Y.; Chen, Z.; Chiaro, B.; Dunsworth, A.; Fowler, A. G.; Hoi, I.-C.; Jeffrey, E.; Megrant, A.; Mutus, J.; Neill, C.; Quintana, C.; Roushan, P.; Sank, D.; Vainsencher, A.; Wenner, J.; White, T. C.; Korotkov, A. N.; Cleland, A. N.; Martinis, John M.

    2015-04-01

    A precise measurement of dephasing over a range of time scales is critical for improving quantum gates beyond the error correction threshold. We present a metrological tool based on randomized benchmarking capable of greatly increasing the precision of Ramsey and spin-echo sequences by the repeated but incoherent addition of phase noise. We find our superconducting-quantum-interference-device-based qubit is not limited by 1 /f flux noise at short time scales but instead observe a telegraph noise mechanism that is not amenable to study with standard measurement techniques.

  9. Range sidelobe reduction for the random binary phase codes

    NASA Astrophysics Data System (ADS)

    Gu, Hong; Liu, Guosui; Sun, Guangmin; Li, Xi; Su, Weimin

    1997-06-01

    Based on the statistics theory and the pulse compression technique, a statistical method of reducing the range sidelobe (RSL) of the random binary phase codes (RBPC) is presented, which is different from those of decreasing the RSL of the pseudorandom binary phase codes. The theoretical analysis and computer simulation show that it is possible to suppress the peak RSL to lower than -30 dB, which can effectively guarantee the RBPC radar with good electronic counter-countermeasures feature applicable. Additionally, owing to the Doppler of the target, the maximum loss of the ratio of the mainlobe and sidelobe (MSR) is also discussed. In the meantime, the approach to realization of the RSL reduction with digital signal processors is given.

  10. A multi-centre phase IIa clinical study of predictive testing for preeclampsia: improved pregnancy outcomes via early detection (IMPROvED)

    PubMed Central

    2013-01-01

    Background 5% of first time pregnancies are complicated by pre-eclampsia, the leading cause of maternal death in Europe. No clinically useful screening test exists; consequentially clinicians are unable to offer targeted surveillance or preventative strategies. IMPROvED Consortium members have pioneered a personalised medicine approach to identifying blood-borne biomarkers through recent technological advancements, involving mapping of the blood metabolome and proteome. The key objective is to develop a sensitive, specific, high-throughput and economically viable early pregnancy screening test for pre-eclampsia. Methods/Design We report the design of a multicentre, phase IIa clinical study aiming to recruit 5000 low risk primiparous women to assess and refine innovative prototype tests based on emerging metabolomic and proteomic technologies. Participation involves maternal phlebotomy at 15 and 20 weeks’ gestation, with optional testing and biobanking at 11 and 34 weeks. Blood samples will be analysed using two innovative, proprietary prototype platforms; one metabolomic based and one proteomic based, both of which outperform current biomarker based screening tests at comparable gestations. Analytical and clinical data will be collated and analysed via the Copenhagen Trials Unit. Discussion The IMPROvED study is expected to refine proteomic and metabolomic panels, combined with clinical parameters, and evaluate clinical applicability as an early pregnancy predictive test for pre-eclampsia. If ‘at risk’ patients can be identified, this will allow stratified care with personalised fetal and maternal surveillance, early diagnosis, timely intervention, and significant health economic savings. The IMPROvED biobank will be accessible to the European scientific community for high quality research into the cause and prevention of adverse pregnancy outcome. Trial registration Trial registration number NCT01891240 The IMPROvED project is funded by the seventh framework

  11. Pegylated liposomal doxorubicin and gemcitabine in the front-line treatment of recurrent/metastatic breast cancer: a multicentre phase II study.

    PubMed

    Adamo, V; Lorusso, V; Rossello, R; Adamo, B; Ferraro, G; Lorusso, D; Condemi, G; Priolo, D; Di Lullo, L; Paglia, A; Pisconti, S; Scambia, G; Ferrandina, G

    2008-06-17

    This multicentre phase II study was aimed at investigating the activity and safety of pegylated liposomal doxorubicin (PLD) and gemcitabine (GEM) as front-line therapy in a large series of chemotherapy-naïve recurrent/metastatic breast cancer patients. From June 2003 to December 2006, a total of 71 recurrent/metastatic breast cancer patients were enrolled. Median age was 63 years (range=37-79), and 31 patients (43.7%) were > or =65 years old. Patients received PLD, 25 mg m(-2), day 1, followed by GEM, 800 mg m(-2), days 1 and 8, q21. Response was evaluable in 64 cases. Eight complete (12.5%) and 17 partial responses (26.6%) were registered, with an overall response rate of 39.1%. Thirty patients (46.9%) experienced stable disease, with an overall clinical benefit of 85.9%. Median time to progression (TTP) was 11 months, whereas median overall survival (OS) was not reached. The rate of 1- and 2-year OS was 79 and 61%, respectively. A total of 443 courses were evaluable for toxicity: grade 3 and 4 neutropaenia affected 14 patients (20.3%) and 3 patients (4.3%), respectively. Grade 3 and 4 palmar-plantar erythrodysesthesia syndrome was documented in five cases (7.2%) and one case (1.4%), whereas grade 3 and 4 mucositis occurred in six cases (8.7%) and two cases (2.9%), respectively. Grade 2 cardiac toxicity was observed in only one case. Interestingly enough, there was no difference in the percentage and severity of either haematological or non-haematological toxicity according to the age of the patients (<65 vs > or =65 years). We confirmed in a large, very homogenous study sample of chemotherapy-naïve recurrent/metastatic breast cancer patients the efficacy and safety of PLD/GEM combination, providing response rates, median TTP and OS values comparable with those achieved with more toxic combinations.

  12. Vorinostat in refractory soft tissue sarcomas - Results of a multi-centre phase II trial of the German Soft Tissue Sarcoma and Bone Tumour Working Group (AIO).

    PubMed

    Schmitt, Thomas; Mayer-Steinacker, Regine; Mayer, Frank; Grünwald, Viktor; Schütte, Jochen; Hartmann, Jörg T; Kasper, Bernd; Hüsing, Johannes; Hajda, Jacek; Ottawa, Gregor; Mechtersheimer, Gunhild; Mikus, Gerd; Burhenne, Jürgen; Lehmann, Lorenz; Heilig, Christoph E; Ho, Anthony D; Egerer, Gerlinde

    2016-09-01

    New treatment options for patients with metastatic Soft Tissue Sarcoma are urgently needed. Preclinical studies suggested activity of vorinostat, a histone deacetylase inhibitor. A multi-centre, open-label, non-randomised phase II trial to investigate the efficacy and safety of vorinostat in patients with locally advanced or metastatic Soft Tissue Sarcoma failing 1st-line anthracycline-based chemotherapy was initiated. Patients were treated with vorinostat 400 mg po qd for 28 d followed by a treatment-free period of 7 d, representing a treatment cycle of 5 weeks. Restaging was performed every three cycles or at clinical progression. Between 06/10 and 09/13, 40 Soft Tissue Sarcoma patients were treated with vorinostat at seven participating centres. Patients had received 1 (n=8, 20%), 2 (n=10, 25%) or ≥3 (n=22, 55%) previous lines of chemotherapy. Best response after three cycles of treatment was stable disease (n=9, 23%). Median progression-free survival and overall survival were 3.2 and 12.3 months, respectively. Six patients showed long-lasting disease stabilisation for up to ten cycles. Statistical analyses failed to identify baseline predictive markers in this subgroup. Major toxicities (grade ≥III) included haematological toxicity (n=6, 15%) gastrointestinal disorders (n=5, 13%), fatigue (n=4, 10%), musculoskeletal pain (n=4, 10%), and pneumonia (n=2, 5%). In a heavily pre-treated patient population, objective response to vorinostat was low. However, a small subgroup of patients had long-lasting disease stabilisation. Further studies aiming to identify predictive markers for treatment response as well as exploration of combination regimens are warranted. NCT00918489 (ClinicalTrials.gov) EudraCT-number: 2008-008513-19. Copyright © 2016 Elsevier Ltd. All rights reserved.

  13. Second-line pazopanib in patients with relapsed and refractory small-cell lung cancer: a multicentre phase II study of the Hellenic Oncology Research Group.

    PubMed

    Koinis, F; Agelaki, S; Karavassilis, V; Kentepozidis, N; Samantas, E; Peroukidis, S; Katsaounis, P; Hartabilas, E; Varthalitis, I I; Messaritakis, I; Fountzilas, G; Georgoulias, V; Kotsakis, A

    2017-06-27

    Pazopanib is a tyrosine kinase inhibitor with antiangiogenic activity. Vascular endothelial growth factor expression is increased in SCLC and is correlated with poor prognosis. The efficacy and tolerance of second-line pazopanib in SCLC was evaluated. Patients with platinum-sensitive (cohort A; n=39) and -resistant/refractory (cohort B; n=19) SCLC were enrolled in a multicentre phase II study. The primary end point was the progression-free survival rate (PFS-R) at week 8 in each cohort. Pazopanib (800 mg per day per os) was administered until progressive disease (PD). Circulating tumour cells (CTCs) were enumerated using the Cellsearch assay. All patients were evaluable for response and toxicity. In the intention-to-treat analysis, eight (13.8%) patients achieved partial response (PR) (95% confidence interval (CI): 5.0-22.7), 20 (34.5%) stable disease (SD) and 30 (51.7%) PD. Accrual in cohort B was halted because the hard-stop rule was met; in cohort A, the PFS-R was 59% (95% CI: 43.5-74.4; PR=7, SD=16). Nine (23.1%) patients received pazopanib for >6 months and 3 of them for >12 months. One pazopanib cycle resulted to a significant decrease to the number of patients with ⩾5 CTCs/7.5 ml of blood (20%) compared with baseline (50%). The median PFS and OS for all patients was 2.5 months (95% CI: 1.9-3.1 months) and 6.0 months (95% CI: 3.8-8.2 months), respectively (cohort A: PFS=3.7 months and OS=8.0 months). No unexpected toxicity was observed. Second-line treatment with pazopanib in platinum-sensitive SCLC is well tolerated and resulted in promising objective responses and disease control; CTC enumeration might serve as a reliable surrogate biomarker of response.

  14. Antiproliferative effects of lanreotide autogel in patients with progressive, well-differentiated neuroendocrine tumours: a Spanish, multicentre, open-label, single arm phase II study.

    PubMed

    Martín-Richard, Marta; Massutí, Bartomeu; Pineda, Eva; Alonso, Vicente; Marmol, Maribel; Castellano, Daniel; Fonseca, Emilio; Galán, Antonio; Llanos, Marta; Sala, Maria Angeles; Pericay, Carlos; Rivera, Fernando; Sastre, Javier; Segura, Angel; Quindós, Maria; Maisonobe, Pascal

    2013-09-20

    Somatostatin analogues (SSAs) are indicated to relieve carcinoid syndrome but seem to have antiproliferative effects on neuroendocrine tumours (NETs). This is the first prospective study investigating tumour stabilisation with the long-acting SSA lanreotide Autogel in patients with progressive NETs. This was a multicentre, open-label, phase II trial conducted in 17 Spanish specialist centres. Patients with well-differentiated NETs and radiologically confirmed progression within the previous 6 months received lanreotide Autogel, 120 mg every 28 days over ≤92 weeks. The primary endpoint was progression-free survival (PFS). Secondary endpoints were response rate, tumour biomarkers, symptom control, quality of life (QoL), and safety. Radiographic imaging was assessed by a blinded central radiologist. Of 30 patients included in the efficacy and safety analyses, 40% had midgut tumours and 27% pancreatic tumours; 63% of tumours were functioning. Median PFS time was 12.9 (95% CI: 7.9, 16.5) months, and most patients achieved disease stabilisation (89%) or partial response (4%). No deterioration in QoL was observed. Nineteen patients (63%) experienced treatment-related adverse events, most frequently diarrhoea and asthenia; only one treatment-related adverse event (aerophagia) was severe. Lanreotide Autogel provided effective tumour stabilisation and PFS >12 months in patients with progressive NETs ineligible for surgery or chemotherapy, with a safety profile consistent with the pharmacology of the class. ClinicalTrials.gov Identifier NCT00326469; EU Clinical Trial Register EudraCT no 2004-002871-18.

  15. The quality of the extra-analytical phase of laboratory practice in some developing European countries and Mexico - a multicentric study.

    PubMed

    Simundic, Ana-Maria; Bilic-Zulle, Lidija; Nikolac, Nora; Supak-Smolcic, Vesna; Honovic, Lorena; Avram, Sanja; Beregovaja, Elena; Dobreanu, Minodora; Guimaraes, Joao-Tiago; Kovacs, Gabor L; Singh, Nada Majkic; Sierra-Amor, Rosa Isabel; Sypniewska, Grazyna; Zima, Tomas

    2011-02-01

    This cross-sectional multicentric survey study aimed to assess the quality of the extra-analytical phase of laboratory activities in some developing European countries and Mexico. We assessed the quality of the extra-analytical practices in participating laboratories regarding the: a) sample acceptance criteria; b) phlebotomy procedures; c) test results reporting and d) recording non-conformities. A survey was performed during the April-May 2009. A total of 15 clinical laboratories from the following countries were included: Bosnia, Croatia, Czech Republic, Hungary, Mexico, Poland, Portugal, Romania, Serbia and Ukraine. Questions were scored (scores from 1-4) and average scores was calculated for each category. The overall score for all respondents (n = 443) was 3.10 ± 0.33. The average score was 3.11 ± 0.56 for sample acceptance criteria, 2.76 ± 0.58 for phlebotomy and 3.34 ± 0.53, for test results reporting (F = 116.49; p < 0.001). Laboratory accreditation was associated with better practices and higher overall quality of the extra-analytical procedures (F = 16.62; p < 0.001). Moreover, the highest scores for sample acceptance criteria (F = 8.32; p < 0.001), phlebotomy procedures (F = 13.28; p < 0.001) and for reporting non-conformities (F = 33.62; p < 0.001) were observed for accredited laboratories or laboratories under preparation for accreditation. The overall quality of the extra-analytical practices in countries in this survey is not satisfactory. Phlebotomy practices are the most critical extra-analytical activity. Since laboratory accreditation was associated with better practices and higher overall quality of the extra-analytical procedures, we believe that the most significant improvement could be made by implementing the total quality management system and standardizing laboratory procedures.

  16. A phase II, single-arm, multicentre study of coltuximab ravtansine (SAR3419) and rituximab in patients with relapsed or refractory diffuse large B-cell lymphoma.

    PubMed

    Coiffier, Bertrand; Thieblemont, Catherine; de Guibert, Sophie; Dupuis, Jehan; Ribrag, Vincent; Bouabdallah, Réda; Morschhauser, Franck; Navarro, Robert; Le Gouill, Steven; Haioun, Corinne; Houot, Roch; Casasnovas, Olivier; Holte, Harald; Lamy, Thierry; Broussais, Florence; Payrard, Sandrine; Hatteville, Laurence; Tilly, Hervé

    2016-06-01

    In this phase II, multicentre, single-arm study, 52 patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL) received the anti-CD19 antibody-drug conjugate coltuximab ravtansine (55 mg/m(2) ) and rituximab (375 mg/m(2) ) weekly for 4 weeks, then every 2 weeks for 8 weeks. The primary endpoint was objective response rate (ORR) by International Working Group Criteria. The primary objective was to reject the null hypothesis of an ORR of ≤40%. Among 45 evaluable patients, the ORR was 31·1% (80% confidence interval [CI]: 22·0-41·6%) and the primary objective was not met. The ORR appeared higher in patients with relapsed disease (58·3% [80% CI: 36·2-78·1%]) versus those refractory to their last (42·9% [80% CI: 17·0-72·1%]) or first-line therapy (15·4% [80% CI: 6·9-28·4%]). Median progression-free survival, overall survival and duration of response were 3·9 [80% CI: 3·22-3·98], 9·0 [80% CI: 6·47-13·67] and 8·6 (range: 0-18) months, respectively. The pharmacokinetics of both drugs were unaffected by co-administration. Common adverse events included gastrointestinal disorders (52%) and asthenia (25%). No patients discontinued due to adverse events. In conclusion, coltuximab ravtansine with rituximab was well tolerated and yielded clinical responses in a subset of patients with relapsed/refractory DLBCL. © 2016 John Wiley & Sons Ltd.

  17. Drugs, Women and Violence in the Americas: U.S. Results of a Multi-Centric Pilot Project (Phase 1)

    PubMed Central

    González-Guarda, Rosa María; Peragallo, Nilda; Lynch, Ami; Nemes, Susanna

    2011-01-01

    Objectives To explore the collective and individual experiences that Latin American females in the U. S. have with substance abuse, violence and risky sexual behaviors. Methods This study was conducted in two phases that were carried out from July 2006 to June 2007 in south Florida. This paper covers Phase 1. In Phase 1, focus groups were conducted among 93 women in English, Spanish and Portuguese. Through content analyses of the focus group transcriptions, major themes were identified. Results Participants identified substance abuse, violence and risky sexual behaviors as closely related problems of great concern in Latina women in the U.S. Three important themes emerged from the focus groups. These included “Living in the US and the Devaluing of Latino Culture,” the “Vicious Cycle of Abuse” and “Breaking the Silence”. Conclusions The results from this study suggest that substance abuse, violence and HIV should be addressed in an integrative and comprehensive manner. Recommendations for the development of policies, programs and services addressing substance abuse, violence and risk for HIV among Latinos are provided. PMID:21593995

  18. A new phase of disordered phonons modelled by random matrices

    NASA Astrophysics Data System (ADS)

    Schmittner, Sebastian; Zirnbauer, Martin

    2015-03-01

    Starting from the clean harmonic crystal and not invoking two-level systems, we propose a model for phonons in a disordered solid. In this model the strength of mass and spring constant disorder can be increased separately. Both types of disorder are modelled by random matrices that couple the degrees of freedom locally. Treated in coherent potential approximation (CPA), the speed of sound decreases with increasing disorder until it reaches zero at finite disorder strength. There, a critical transition to a strong disorder phase occurs. In this novel phase, we find the density of states at zero energy in three dimensions to be finite, leading to a linear temperature dependence of the heat capacity, as observed experimentally for vitreous systems. For any disorder strength, our model is stable, i.e. masses and spring constants are positive, and there are no runaway dynamics. This is ensured by using appropriate probability distributions, inspired by Wishart ensembles, for the random matrices. The CPA self-consistency equations are derived in a very accessible way using planar diagrams. The talk focuses on the model and the results. The first author acknowledges financial support by the Deutsche Telekom Stiftung.

  19. Nonergodic Phases in Strongly Disordered Random Regular Graphs.

    PubMed

    Altshuler, B L; Cuevas, E; Ioffe, L B; Kravtsov, V E

    2016-10-07

    We combine numerical diagonalization with semianalytical calculations to prove the existence of the intermediate nonergodic but delocalized phase in the Anderson model on disordered hierarchical lattices. We suggest a new generalized population dynamics that is able to detect the violation of ergodicity of the delocalized states within the Abou-Chakra, Anderson, and Thouless recursive scheme. This result is supplemented by statistics of random wave functions extracted from exact diagonalization of the Anderson model on ensemble of disordered random regular graphs (RRG) of N sites with the connectivity K=2. By extrapolation of the results of both approaches to N→∞ we obtain the fractal dimensions D_{1}(W) and D_{2}(W) as well as the population dynamics exponent D(W) with the accuracy sufficient to claim that they are nontrivial in the broad interval of disorder strength W_{E}10^{5} reveals a singularity in D_{1,2}(W) dependencies which provides clear evidence for the first order transition between the two delocalized phases on RRG at W_{E}≈10.0. We discuss the implications of these results for quantum and classical nonintegrable and many-body systems.

  20. Nonergodic Phases in Strongly Disordered Random Regular Graphs

    NASA Astrophysics Data System (ADS)

    Altshuler, B. L.; Cuevas, E.; Ioffe, L. B.; Kravtsov, V. E.

    2016-10-01

    We combine numerical diagonalization with semianalytical calculations to prove the existence of the intermediate nonergodic but delocalized phase in the Anderson model on disordered hierarchical lattices. We suggest a new generalized population dynamics that is able to detect the violation of ergodicity of the delocalized states within the Abou-Chakra, Anderson, and Thouless recursive scheme. This result is supplemented by statistics of random wave functions extracted from exact diagonalization of the Anderson model on ensemble of disordered random regular graphs (RRG) of N sites with the connectivity K =2 . By extrapolation of the results of both approaches to N →∞ we obtain the fractal dimensions D1(W ) and D2(W ) as well as the population dynamics exponent D (W ) with the accuracy sufficient to claim that they are nontrivial in the broad interval of disorder strength WE1 05 reveals a singularity in D1 ,2(W ) dependencies which provides clear evidence for the first order transition between the two delocalized phases on RRG at WE≈10.0 . We discuss the implications of these results for quantum and classical nonintegrable and many-body systems.

  1. The decryption of random phase multiplexing encoding system

    NASA Astrophysics Data System (ADS)

    Lee, Hsiao-Yi; Liu, Jung-Ping; Chang, Chi-Ching; Yau, Hon-Fai; Chang, Tsung-Chien

    2004-10-01

    Random-phase-multiplexing storage using photorefractive crystals is one of the most important topics in the field of photorefractive optics. To achieve random phase recording, we can use a diffuser to encrypt the reference light in a holographic recording setup. To decrypt the recorded pattern, the same diffuser used in encryption must be used in the reconstruction light, and it must be set in the original orientation. In this way, a number of 2-D patterns can be stored in a single photorefractive crystal with a single diffuser set at different orientations for different patterns. A merit in this recording method is that the encryption is virtually not possible to be decrypted if the original diffuser for encrypting is not available. In this paper, we proposed a way to decrypt the encrypted information in a photorefractive lithium niobate crystal without the possession of the original diffuser. In this method, we suppose somehow we know one of the patterns stored in the crystal, and then we retrieve the original diffuser with this pattern. And ultimately all the other patterns stored in the crystal are decrypted and retrieved with this retrieved diffuser.

  2. The peculiar phase structure of random graph bisection

    SciTech Connect

    Percus, Allon G; Istrate, Gabriel; Goncalves, Bruno T; Sumi, Robert Z

    2008-01-01

    The mincut graph bisection problem involves partitioning the n vertices of a graph into disjoint subsets, each containing exactly n/2 vertices, while minimizing the number of 'cut' edges with an endpoint in each subset. When considered over sparse random graphs, the phase structure of the graph bisection problem displays certain familiar properties, but also some surprises. It is known that when the mean degree is below the critical value of 2 log 2, the cutsize is zero with high probability. We study how the minimum cutsize increases with mean degree above this critical threshold, finding a new analytical upper bound that improves considerably upon previous bounds. Combined with recent results on expander graphs, our bound suggests the unusual scenario that random graph bisection is replica symmetric up to and beyond the critical threshold, with a replica symmetry breaking transition possibly taking place above the threshold. An intriguing algorithmic consequence is that although the problem is NP-hard, we can find near-optimal cutsizes (whose ratio to the optimal value approaches 1 asymptotically) in polynomial time for typical instances near the phase transition.

  3. Calcium supplementation reducing the risk of hypertensive disorders of pregnancy and related problems: A meta-analysis of multicentre randomized controlled trials.

    PubMed

    An, Li-bin; Li, Wen-tao; Xie, Tie-nan; Peng, Xin; Li, Bo; Xie, Shu-hong; Xu, Jing; Zhou, Xiao-hua; Guo, Shao-ning

    2015-05-01

    Hypertensive disorders of pregnancy are closely related to maternal mortality and morbidity. Calcium supplementation during pregnancy seems to reduce the risk of hypertensive disorders. No systematic review on multicentre RCTs of calcium supplementation during pregnancy has been published. The purpose of this study was to report a quantitative systematic review of the effectiveness of calcium supplementation during pregnancy on reducing the risk of hypertensive disorders of pregnancy and related problems. Publications over the years of 1991-2012 were searched through PubMed, Science Direct, EMBASE, CINAHL and Web of Science. The literatures were selected of the multicentre RCTs on calcium supplementation during pregnancy in prevention of hypertensive disorders and related problems. Reference lists from the studies were also examined for additional references. Studies were critically appraised by three independent reviewers, and the Cochrane Handbook was used to assess the quality of those included trials. Four studies were included in this systematic review. All included studies were high quality, with low risk of bias. There was an observed risk reduction in hypertension in calcium group. However, there was no reduction in the risk of severe gestational hypertension, pre-eclampsia, severe pre-eclampsia, preterm birth and low birthweight. Calcium supplementation appears to reduce the risk of hypertension in pregnancy.

  4. Raltegravir for the treatment of patients co-infected with HIV and tuberculosis (ANRS 12 180 Reflate TB): a multicentre, phase 2, non-comparative, open-label, randomised trial.

    PubMed

    Grinsztejn, Beatriz; De Castro, Nathalie; Arnold, Vincent; Veloso, Valdiléa G; Morgado, Mariza; Pilotto, José Henrique; Brites, Carlos; Madruga, José Valdez; Barcellos, Nêmora Tregnago; Santos, Breno Riegel; Vorsatz, Carla; Fagard, Catherine; Santini-Oliveira, Marilia; Patey, Olivier; Delaugerre, Constance; Chêne, Geneviève; Molina, Jean-Michel

    2014-06-01

    Concurrent treatment of HIV and tuberculosis is complicated by drug interactions. We explored the safety and efficacy of raltegravir as an alternative to efavirenz for patients co-infected with HIV and tuberculosis. We did a multicentre, phase 2, non-comparative, open-label, randomised trial at eight sites in Brazil and France. Using a computer-generated randomisation sequence, we randomly allocated antiretroviral-naive adult patients with HIV-1 and tuberculosis (aged ≥18 years with a plasma HIV RNA concentration of >1000 copies per mL) to receive raltegravir 400 mg twice a day, raltegravir 800 mg twice daily, or efavirenz 600 mg once daily plus tenofovir and lamivudine (1:1:1; stratified by country). Patients began study treatment after the start of tuberculosis treatment. The primary endpoint was virological suppression at 24 weeks (HIV RNA <50 copies per mL) in all patients who received at least one dose of study drug (modified intention-to-treat analysis). We recorded death, study drug discontinuation, and loss to follow-up as failures to achieve the primary endpoint. We assessed safety in all patients who received study drugs. This study is registered in ClinicalTrials.gov, number NCT00822315. Between July 3, 2009, and June 6, 2011, we enrolled and randomly assigned treatment to 155 individuals; 153 (51 in each group) received at least one dose of the study drug and were included in the primary analysis. 133 patients (87%) completed follow-up at week 48. At week 24, virological suppression was achieved in 39 patients (76%, 95% CI 65-88) in the raltegravir 400 mg group, 40 patients (78%, 67-90) in the raltegravir 800 mg group, and 32 patients (63%, 49-76) in the efavirenz group. The adverse-event profile was much the same across the three groups. Three (6%) patients allocated to efavirenz and three (6%) patients allocated to raltegravir 800 mg twice daily discontinued the study drugs due to adverse events. Seven patients died during the study (one in the

  5. Masitinib in the treatment of active rheumatoid arthritis: results of a multicentre, open-label, dose-ranging, phase 2a study

    PubMed Central

    Tebib, Jacques; Mariette, Xavier; Bourgeois, Pierre; Flipo, René-Marc; Gaudin, Philippe; Le Loët, Xavier; Gineste, Paul; Guy, Laurent; Mansfield, Colin D; Moussy, Alain; Dubreuil, Patrice; Hermine, Olivier; Sibilia, Jean

    2009-01-01

    Introduction Since current treatment options for patients suffering from active rheumatoid arthritis (RA) remain inadequate, especially for those unresponsive to disease-modifying antirheumatic drugs (DMARDs), new and improved medication is needed. This study evaluates the safety and efficacy of masitinib (AB1010), a potent and selective protein tyrosine kinase inhibitor of c-KIT, in the monotherapy treatment of DMARD-refractory RA. Methods This was a multicentre, uncontrolled, open-label, randomised, dose-ranging, phase 2a trial. Masitinib was administered orally to 43 patients who had inadequate response to DMARDs, at initial randomised dosing levels of 3 and 6 mg/kg per day over a 12-week period. Dose adjustment was permitted based upon tolerability and response criteria. Efficacy was assessed via American College of Rheumatology 20%/50%/70% improvement criteria (ACR20/50/70) responses, disease activity score using 28 joint counts (DAS28), index of improvement in RA (ACRn) and C-reactive protein (CRP) improvement, relative to baseline at week 12. Results Improvement was observed in all efficacy endpoints, including ACR20/50/70 scores of 54%, 26% and 8%, respectively, and a reduction in CRP level by greater than 50% for approximately half the population. This improvement was sustainable throughout an extension phase (> 84 weeks) and was also independent of initial DMARD resistance (anti-tumour necrosis factor-alpha and/or methotrexate). A relatively high patient withdrawal rate (37%) required the use of last observation carried forward (LOCF) data imputation. Incidence of adverse events was high (95%), although the majority were of mild or moderate severity with a considerable decline in frequency observed after 12 weeks of treatment. Two nonfatal serious adverse events were reported. Dose-response analyses tentatively indicate that an initial dosing level of 6.0 mg/kg per day administered orally in two daily intakes is the most appropriate, based upon potency

  6. Testing a random phase approximation for bounded turbulent flow.

    PubMed

    Ulitsky, M; Clark, T; Turner, L

    1999-05-01

    Tractable implementation of a spectral closure requires that the modal representation of the energy satisfy a restricted random phase approximation (RRPA). This condition is exactly satisfied when the statistical system is homogeneous and the basis functions are Fourier modes. In this case, the ensemble average of the spectral covariance diagonalizes, i.e., =delta(k(1)+k(2)), where c(k,t) is a Fourier coefficient in a Galerkin representation of the velocity field. However, for inhomogeneous statistical systems in which the Fourier system is inappropriate, the RRPA requires validation. We use direct numerical simulations (DNSs) of the Navier-Stokes and truncated Euler equations to test the degree to which the RRPA is satisfied when applied to a recent representation due to Turner (LANL Unclassified Report No. LA-UR-96-3257) of a bounded turbulent rectangular channel flow with free slip, stress free walls. It is shown that a complete test of the RRPA for a fully inhomogeneous DNS with N3 grid points actually requires N3+1 members in the ensemble. The "randomness" of the phase can be characterized by a probability density function (PDF) of the modulus of the normalized spectral covariance. Results reveal that for both the Navier-Stokes and Euler systems the PDF does not change in time as the turbulence decays, and that the PDF for the Euler system is virtually identical to the one produced from an ensemble of random fields. This result is consistent with the equipartition of energy for the Euler system, in which the RRPA becomes an exact result rather than an approximation as the number of realizations approaches N3+1. The slight differences observed between the PDF produced from the random fields and the one from the Navier-Stokes system are thus shown to be entirely a result of the presence of a finite viscosity. It is also shown that there is great variation between statistics computed over the ensemble and those for a single

  7. Testing a random phase approximation for bounded turbulent flow

    NASA Astrophysics Data System (ADS)

    Ulitsky, Mark; Clark, Tim; Turner, Leaf

    1999-05-01

    Tractable implementation of a spectral closure requires that the modal representation of the energy satisfy a restricted random phase approximation (RRPA). This condition is exactly satisfied when the statistical system is homogeneous and the basis functions are Fourier modes. In this case, the ensemble average of the spectral covariance diagonalizes, i.e., =δ(k1+k2), where c(k,t) is a Fourier coefficient in a Galerkin representation of the velocity field. However, for inhomogeneous statistical systems in which the Fourier system is inappropriate, the RRPA requires validation. We use direct numerical simulations (DNSs) of the Navier-Stokes and truncated Euler equations to test the degree to which the RRPA is satisfied when applied to a recent representation due to Turner (LANL Unclassified Report No. LA-UR-96-3257) of a bounded turbulent rectangular channel flow with free slip, stress free walls. It is shown that a complete test of the RRPA for a fully inhomogeneous DNS with N3 grid points actually requires N3+1 members in the ensemble. The ``randomness'' of the phase can be characterized by a probability density function (PDF) of the modulus of the normalized spectral covariance. Results reveal that for both the Navier-Stokes and Euler systems the PDF does not change in time as the turbulence decays, and that the PDF for the Euler system is virtually identical to the one produced from an ensemble of random fields. This result is consistent with the equipartition of energy for the Euler system, in which the RRPA becomes an exact result rather than an approximation as the number of realizations approaches N3+1. The slight differences observed between the PDF produced from the random fields and the one from the Navier-Stokes system are thus shown to be entirely a result of the presence of a finite viscosity. It is also shown that there is great variation between statistics computed over the ensemble and those for a single realization.

  8. Optical double image security using random phase fractional Fourier domain encoding and phase-retrieval algorithm

    NASA Astrophysics Data System (ADS)

    Rajput, Sudheesh K.; Nishchal, Naveen K.

    2017-04-01

    We propose a novel security scheme based on the double random phase fractional domain encoding (DRPE) and modified Gerchberg-Saxton (G-S) phase retrieval algorithm for securing two images simultaneously. Any one of the images to be encrypted is converted into a phase-only image using modified G-S algorithm and this function is used as a key for encrypting another image. The original images are retrieved employing the concept of known-plaintext attack and following the DRPE decryption steps with all correct keys. The proposed scheme is also used for encryption of two color images with the help of convolution theorem and phase-truncated fractional Fourier transform. With some modification, the scheme is extended for simultaneous encryption of gray-scale and color images. As a proof-of-concept, simulation results have been presented for securing two gray-scale images, two color images, and simultaneous gray-scale and color images.

  9. Cilengitide combined with standard treatment for patients with newly diagnosed glioblastoma with methylated MGMT promoter (CENTRIC EORTC 26071-22072 study): a multicentre, randomised, open-label, phase 3 trial.

    PubMed

    Stupp, Roger; Hegi, Monika E; Gorlia, Thierry; Erridge, Sara C; Perry, James; Hong, Yong-Kil; Aldape, Kenneth D; Lhermitte, Benoit; Pietsch, Torsten; Grujicic, Danica; Steinbach, Joachim Peter; Wick, Wolfgang; Tarnawski, Rafał; Nam, Do-Hyun; Hau, Peter; Weyerbrock, Astrid; Taphoorn, Martin J B; Shen, Chiung-Chyi; Rao, Nalini; Thurzo, László; Herrlinger, Ulrich; Gupta, Tejpal; Kortmann, Rolf-Dieter; Adamska, Krystyna; McBain, Catherine; Brandes, Alba A; Tonn, Joerg Christian; Schnell, Oliver; Wiegel, Thomas; Kim, Chae-Yong; Nabors, Louis Burt; Reardon, David A; van den Bent, Martin J; Hicking, Christine; Markivskyy, Andriy; Picard, Martin; Weller, Michael

    2014-09-01

    Cilengitide is a selective αvβ3 and αvβ5 integrin inhibitor. Data from phase 2 trials suggest that it has antitumour activity as a single agent in recurrent glioblastoma and in combination with standard temozolomide chemoradiotherapy in newly diagnosed glioblastoma (particularly in tumours with methylated MGMT promoter). We aimed to assess cilengitide combined with temozolomide chemoradiotherapy in patients with newly diagnosed glioblastoma with methylated MGMT promoter. In this multicentre, open-label, phase 3 study, we investigated the efficacy of cilengitide in patients from 146 study sites in 25 countries. Eligible patients (newly diagnosed, histologically proven supratentorial glioblastoma, methylated MGMT promoter, and age ≥18 years) were stratified for prognostic Radiation Therapy Oncology Group recursive partitioning analysis class and geographic region and centrally randomised in a 1:1 ratio with interactive voice response system to receive temozolomide chemoradiotherapy with cilengitide 2000 mg intravenously twice weekly (cilengitide group) or temozolomide chemoradiotherapy alone (control group). Patients and investigators were unmasked to treatment allocation. Maintenance temozolomide was given for up to six cycles, and cilengitide was given for up to 18 months or until disease progression or unacceptable toxic effects. The primary endpoint was overall survival. We analysed survival outcomes by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00689221. Overall, 3471 patients were screened. Of these patients, 3060 had tumour MGMT status tested; 926 patients had a methylated MGMT promoter, and 545 were randomly assigned to the cilengitide (n=272) or control groups (n=273) between Oct 31, 2008, and May 12, 2011. Median overall survival was 26·3 months (95% CI 23·8-28·8) in the cilengitide group and 26·3 months (23·9-34·7) in the control group (hazard ratio 1·02, 95% CI 0·81-1·29, p=0·86). None of the predefined

  10. Pazopanib and depot octreotide in advanced, well-differentiated neuroendocrine tumours: a multicentre, single-group, phase 2 study

    PubMed Central

    Phan, Alexandria T; Halperin, Daniel M; Chan, Jennifer A; Fogelman, David R; Hess, Kenneth R; Malinowski, Paige; Regan, Eileen; Ng, Chaan S; Yao, James C; Kulke, Matthew H

    2015-01-01

    Summary Background Treatment options for advanced, well-differentiated neuroendocrine tumours (NETs) remain scarce. Pazopanib is an orally bioavailable, small molecule, multitargeted kinase inhibitor that inhibits VEGF receptors 1, 2, and 3. We did a study of the efficacy of pazopanib with depot octreotide in patients with advanced NETs. Methods We did a parallel cohort study of patients with metastatic or locally advanced grade 1–2 carcinoid tumours or pancreatic NETs, by use of a single-group, two-stage design. Patients received pazopanib 800 mg orally once per day and octreotide at their preprotocol dosage. The primary endpoint was the proportion of patients achieving an objective response, as assessed by investigators, by intention-to-treat analysis. This study is registered with ClinicalTrials.gov, identifier NCT00454363, and was completed in March, 2014. Findings Between April 12, 2007, and July 2, 2009, we enrolled 52 patients, including 32 individuals with pancreatic NETs and 20 individuals with carcinoid tumours. Seven (21.9%, 95% CI 11.0–38.8) of 32 patients with pancreatic NETs achieved an objective response. We detected no responses in the first stage of the cohort with carcinoid tumours, and we terminated accrual at 20 patients. Toxic effects included one patient with grade 4 hypertriglyceridaemia and one with grade 4 thrombosis, with the most common grade three events being aminotransferase increases and neutropenia, each of which happened in 3 patients. In all 52 patients, the most frequently observed toxic effects were fatigue (39 [75%]), nausea (33 [63%]), diarrhoea (33 [63%]), and hypertension (28 [54%]). Interpretation Treatment with pazopanib is associated with tumour response for patients with pancreatic NETs, but not for carcinoid tumours; a randomised controlled phase 3 study to assess pazopanib in advanced pancreatic NETs is warranted. Funding US National Cancer Institute of the National Institutes of Health. PMID:25956795

  11. Exploring the Random Phase Approximately for materials chemistry and physics

    SciTech Connect

    Ruzsinsky, Adrienn

    2015-03-23

    This proposal focuses on improved accuracy for the delicate energy differences of interest in materials chemistry with the fully nonlocal random phase approximation (RPA) in a density functional context. Could RPA or RPA-like approaches become standard methods of first-principles electronic-structure calculation for atoms, molecules, solids, surfaces, and nano-structures? Direct RPA includes the full exact exchange energy and a nonlocal correlation energy from the occupied and unoccupied Kohn-Sham orbitals and orbital energies, with an approximate but universal description of long-range van der Waals attraction. RPA also improves upon simple pair-wise interaction potentials or vdW density functional theory. This improvement is essential to capture accurate energy differences in metals and different phases of semiconductors. The applications in this proposal are challenges for the simpler approximations of Kohn-Sham density functional theory, which are part of the current “standard model” for quantum chemistry and condensed matter physics. Within this project we already applied RPA on different structural phase transitions on semiconductors, metals and molecules. Although RPA predicts accurate structural parameters, RPA has proven not equally accurate in all kinds of structural phase transitions. Therefore a correction to RPA can be necessary in many cases. We are currently implementing and testing a nonempirical, spatially nonlocal, frequency-dependent model for the exchange-correlation kernel in the adiabatic-connection fluctuation-dissipation context. This kernel predicts a nearly-exact correlation energy for the electron gas of uniform density. If RPA or RPA-like approaches prove to be reliably accurate, then expected increases in computer power may make them standard in the electronic-structure calculations of the future.

  12. Analytic Interatomic Forces in the Random Phase Approximation

    NASA Astrophysics Data System (ADS)

    Ramberger, Benjamin; Schäfer, Tobias; Kresse, Georg

    2017-03-01

    We discuss that in the random phase approximation (RPA) the first derivative of the energy with respect to the Green's function is the self-energy in the G W approximation. This relationship allows us to derive compact equations for the RPA interatomic forces. We also show that position dependent overlap operators are elegantly incorporated in the present framework. The RPA force equations have been implemented in the projector augmented wave formalism, and we present illustrative applications, including ab initio molecular dynamics simulations, the calculation of phonon dispersion relations for diamond and graphite, as well as structural relaxations for water on boron nitride. The present derivation establishes a concise framework for forces within perturbative approaches and is also applicable to more involved approximations for the correlation energy.

  13. Continuum random-phase approximation for relativistic point coupling models

    SciTech Connect

    Daoutidis, J.; Ring, P.

    2009-08-15

    Continuum relativistic random-phase approximation (CRPA) is used to investigate collective excitation phenomena in several spherical nuclei along the periodic table. We start from relativistic mean-field calculations based on a covariant density functional with density-dependent zero-range forces. From the same functional an effective interaction is obtained as the second derivative with respect to the density. This interaction is used in relativistic CRPA calculations for the investigation of isoscalar monopole, isovector dipole, and isoscalar quadrupole resonances of spherical nuclei. In particular we study the low-lying E1 strength in the vicinity of the neutron evaporation threshold. The properties of the resonances, such as centroid energies and strengths distributions are compared with results of discrete RPA calculations for the same model as well as with experimental data.

  14. Orientation dynamics of asymmetric rotors using random phase wave functions

    NASA Astrophysics Data System (ADS)

    Kallush, Shimshon; Fleischer, Sharly

    2015-06-01

    Intense terahertz-frequency pulses induce coherent rotational dynamics and orientation of polar molecular ensembles. Exact numerical methods for rotational dynamics at room temperature are computationally not feasible for the vast majority of molecular rotors: the asymmetric top molecules at ambient temperatures. We exemplify the use of random phase wave functions (RPWFs) by calculating the terahertz-induced rotational dynamics of sulfur dioxide at ambient temperatures and high-field strengths and show that the RPWF method gains efficiency with the increase in temperature and in the terahertz-field strengths. The present method provides wide-ranging computational access to rotational dynamical responses of molecules at experimental conditions that are far beyond the reach of exact numerical methods.

  15. Correlated random-phase-approximation study of an anyon gas

    NASA Astrophysics Data System (ADS)

    Liu, B. H.; Wang, X. Q.; McLerran, L.

    1991-06-01

    The correlated random-phase-approximation (CRPA) method is applied to study the ground-state and excited-state properties of an anyon gas. We perform a systematic 1/N expansion to the calculation of elementary excitations, where N is the statistical parameter. We find that the leading-(1/N)-order contributions are the same as those obtained by calculations of the RPA response functions. We then consider corrections to the RPA by a perturbation of the exchange interactions, and show that these higher-order corrections are important at large wave vectors. Our calculation gives an excitation spectrum in good agreement with that obtained by the exact solution of a small system.

  16. Key-space analysis of double random phase encryption technique

    NASA Astrophysics Data System (ADS)

    Monaghan, David S.; Gopinathan, Unnikrishnan; Naughton, Thomas J.; Sheridan, John T.

    2007-09-01

    We perform a numerical analysis on the double random phase encryption/decryption technique. The key-space of an encryption technique is the set of possible keys that can be used to encode data using that technique. In the case of a strong encryption scheme, many keys must be tried in any brute-force attack on that technique. Traditionally, designers of optical image encryption systems demonstrate only how a small number of arbitrary keys cannot decrypt a chosen encrypted image in their system. However, this type of demonstration does not discuss the properties of the key-space nor refute the feasibility of an efficient brute-force attack. To clarify these issues we present a key-space analysis of the technique. For a range of problem instances we plot the distribution of decryption errors in the key-space indicating the lack of feasibility of a simple brute-force attack.

  17. Limitations of the number self-consistent random phase approximation

    NASA Astrophysics Data System (ADS)

    Mariano, Alejandro; Hirsch, Jorge G.

    2000-05-01

    The quasiparticle random phase approximation (QRPA) equations are solved taking into account the Pauli principle at the expectation value level, and allowing changes in the mean field occupation numbers to minimize the energy while having the correct number of particles in the correlated vacuum. The study of Fermi pn excitations in 76Ge using a realistic Hilbert space shows that the pairing energy gaps in the modified mean field are diminished up to one half of the experimental value when strong proton-neutron correlations are present. Additionally, the Ikeda sum rule for Fermi transitions is violated due to the lack of scattering terms in the phonon operators. These results call for a critical revision of the double β decay half-lives estimated using the QRPA extensions when standard QRPA calculations collapse.

  18. Surface wake in the random-phase approximation

    SciTech Connect

    Garcia de Abajo, F.J. ); Echenique, P.M. )

    1993-11-01

    The scalar-electric-potential distribution set up by an ion traveling in the vicinity of a plane solid-vacuum interface, that is, the surface-wake potential, is investigated with the specular-reflection model to describe the response of the surface and with the random-phase approximation for the dielectric function of the bulk material. This permits us to address the study of the low-velocity surface wake: the static potential is found to have a dip at the position of the ion; that dip is shifted towards the direction opposite to the velocity vector for velocities smaller than the threshold of creation of plasmons ([approx]1.3[ital v][sub [ital F

  19. Intravenous immunoglobulin for maintenance treatment of chronic inflammatory demyelinating polyneuropathy: a multicentre, open-label, 52-week phase III trial.

    PubMed

    Kuwabara, Satoshi; Mori, Masahiro; Misawa, Sonoko; Suzuki, Miki; Nishiyama, Kazutoshi; Mutoh, Tatsuro; Doi, Shizuki; Kokubun, Norito; Kamijo, Mikiko; Yoshikawa, Hiroo; Abe, Koji; Nishida, Yoshihiko; Okada, Kazumasa; Sekiguchi, Kenji; Sakamoto, Ko; Kusunoki, Susumu; Sobue, Gen; Kaji, Ryuji

    2017-10-01

    Short-term efficacy of induction therapy with intravenous immunoglobulin (Ig) in patients with chronic inflammatory demyelinating polyneuropathy (CIDP) is well established. However, data of previous studies on maintenance therapy were limited up to 24-week treatment period. We aimed to investigate the efficacy and safety of longer-term intravenous Ig therapy for 52 weeks. This study was an open-label phase 3 clinical trial conducted in 49 Japanese tertiary centres. 49 patients with CIDP who fulfilled diagnostic criteria were included. After an induction intravenous Ig therapy (0.4 g/kg/day for five consecutive days), maintenance dose intravenous Ig (1.0 g/kg) was given every 3 weeks for up to 52 weeks. The primary outcome measures were the responder rate at week 28 and relapse rate at week 52. The response and relapse were defined with the adjusted Inflammatory Neuropathy Cause and Treatment scale. At week 28, the responder rate was 77.6% (38/49 patients; 95% CI 63% to 88%), and the 38 responders continued the maintenance therapy. At week 52, 4 of the 38 (10.5%) had a relapse (95% CI 3% to 25%). During 52 weeks, 34 (69.4%) of the 49 enrolled patients had a maintained improvement. Adverse events were reported in 94% of the patients; two patients (66-year-old and 76-year-old men with hypertension or diabetes) developed cerebral infarction (lacunar infarct with good recovery), and the other adverse effects were mild and resolved by the end of the study period. Maintenance treatment with 1.0 g/kg intravenous Ig every 3 weeks is an efficacious therapy for patients with CIDP, and approximately 70% of them had a sustained remission for 52 weeks. Thrombotic complications should be carefully monitored, particularly in elderly patients with vascular risk factors. ClinicalTrials.gov (NCT01824251). © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise

  20. Immunoablation and autologous haemopoietic stem-cell transplantation for aggressive multiple sclerosis: a multicentre single-group phase 2 trial.

    PubMed

    Atkins, Harold L; Bowman, Marjorie; Allan, David; Anstee, Grizel; Arnold, Douglas L; Bar-Or, Amit; Bence-Bruckler, Isabelle; Birch, Paul; Bredeson, Christopher; Chen, Jacqueline; Fergusson, Dean; Halpenny, Mike; Hamelin, Linda; Huebsch, Lothar; Hutton, Brian; Laneuville, Pierre; Lapierre, Yves; Lee, Hyunwoo; Martin, Lisa; McDiarmid, Sheryl; O'Connor, Paul; Ramsay, Timothy; Sabloff, Mitchell; Walker, Lisa; Freedman, Mark S

    2016-08-06

    Strong immunosuppression, including chemotherapy and immune-depleting antibodies followed by autologous haemopoietic stem-cell transplantation (aHSCT), has been used to treat patients with multiple sclerosis, improving control of relapsing disease. We addressed whether near-complete immunoablation followed by immune cell depleted aHSCT would result in long-term control of multiple sclerosis. We did this phase 2 single-arm trial at three hospitals in Canada. We enrolled patients with multiple sclerosis, aged 18-50 years with poor prognosis, ongoing disease activity, and an Expanded Disability Status Scale of 3.0-6.0. Autologous CD34 selected haemopoietic stem-cell grafts were collected after mobilisation with cyclophosphamide and filgrastim. Immunoablation with busulfan, cyclophosphamide, and rabbit anti-thymocyte globulin was followed by aHSCT. The primary outcome was multiple sclerosis activity-free survival (events were clinical relapse, appearance of a new or Gd-enhancing lesion on MRI, and sustained progression of Expanded Disability Status Scale score). This study was registered at ClinicalTrials.gov, NCT01099930. Between diagnosis and aHSCT, 24 patients had 167 clinical relapses over 140 patient-years with 188 Gd-enhancing lesions on 48 pre-aHSCT MRI scans. Median follow-up was 6.7 years (range 3.9-12.7). The primary outcome, multiple sclerosis activity-free survival at 3 years after transplantation was 69.6% (95% CI 46.6-84.2). With up to 13 years of follow-up after aHSCT, no relapses occurred and no Gd enhancing lesions or new T2 lesions were seen on 314 MRI sequential scans. The rate of brain atrophy decreased to that expected for healthy controls. One of 24 patients died of transplantation-related complications. 35% of patients had a sustained improvement in their Expanded Disability Status Scale score. We describe the first treatment to fully halt all detectable CNS inflammatory activity in patients with multiple sclerosis for a prolonged period in the

  1. Inhomogeneous random phase approximation for nuclear and atomic reactions

    SciTech Connect

    Lemm, J.C.

    1995-11-15

    A random phase approximation (RPA) of the inhomogeneous time-independent mean field (TIMF) equations for reactions is developed. The TIMF method is based on a general variational principle for calculating matrix elements of operator inverses as, for example, matrix elements of the resolvent of a Hamiltonian or the scattering T-operator. In the case of nuclear or atomic reactions, these matrix elements are calculated with respect to the asymptotic channel wave functions which also define the inhomogeneous terms in the variational equations. For inhomogeneous equations a direct RPA-like treatment, analogous to the standard RPA used for diagonalization problems, is not possible. Hence the starting point to obtain an RPA extension for the inhomogeneous mean field. equations is a transformation of the inhomogeneous into homogeneous variational equations. The problem of operator inversion is then transformed into the inversion of a function which is obtained by the diagonalization of an auxiliary operator. This auxiliary operator consists of the operator to be inverted and an additional term incorporating the inhomogeneities. Taking into account particle-hole correlations for the nonhermitian diagonalization problem, the standard random phase approximation for hermitian operators can be generalized to a nonhermitian RPA built on top of TIME For that purpose, the antisymmetric TIMF theory for operator inversion is formulated in second quantization. Complications are discussed, which result from the use of several biorthogonal bases and of only intra-fragment antisymmetrized channel wave functions, as needed in antisymmetric scattering theories. In this framework it is shown how particle-hole correlations can be used to generalize the inhomogeneous TIMF method, thus going beyond the mean field approximation. 62 refs., 8 figs.

  2. Coulomb glass in the restricted random phase approximation

    NASA Astrophysics Data System (ADS)

    Basylko, S. A.; Onischouk, V. A.; Rosengren, A.

    2002-06-01

    A three-dimensional model of N/2 electrons localized on N randomly distributed donor sites of density n and with the acceptor charge uniformly smeared on these sites, - e/2 on each, has been considered in the restricted random phase approximation (RRPA) which uses the set of 3 N Fourier components of the local charge density as the independent collective variables. The energy e( T) per site and the density of one-site excitation energy (DOSE) g( ɛ) are shown to be, respectively, in excellent quantitative and in good qualitative agreement with the Monte Carlo simulation data in the whole temperature region 0.1< T<100, where these simulations were performed ( e2n1/3/ kB being the temperature scale). The pair correlator for the one-site energies g( ɛ,± ɛ, r) is found to have the slow decoupling law ˜(±1/ r) for T≲1 and r≫ rd ( rd, Debye screening radius). The status of the commonly accepted asymptotic g( ɛ)˜( ɛ- μ) d-1 ( d and μ being, respectively, the spatial dimension and the Fermi energy) is discussed. The “deduction” of this asymptotic is shown to be based on the strong and questionable conjecture about decoupling of correlations between one-site excitation energies in the vicinity of μ.

  3. Efficacy and safety of dapagliflozin in patients with inadequately controlled type 1 diabetes (DEPICT-1): 24 week results from a multicentre, double-blind, phase 3, randomised controlled trial.

    PubMed

    Dandona, Paresh; Mathieu, Chantal; Phillip, Moshe; Hansen, Lars; Griffen, Steven C; Tschöpe, Diethelm; Thorén, Fredrik; Xu, John; Langkilde, Anna Maria

    2017-09-13

    Dapagliflozin is a sodium-glucose cotransporter-2 inhibitor approved for the treatment of type 2 diabetes. We aimed to assess the efficacy and safety of dapagliflozin as an add-on to adjustable insulin in patients with inadequately controlled type 1 diabetes. DEPICT-1 was a double-blind, randomised, parallel-controlled, three-arm, phase 3, multicentre study done at 143 sites in 17 countries. Eligible patients were aged 18-75 years and had inadequately controlled type 1 diabetes (HbA1c between ≥7·7% and ≤11·0% [≥61·0 mmol/mol and ≤97·0 mmol/mol]) and had been prescribed insulin for at least 12 months before enrolment. After an 8 week lead-in period to optimise diabetes management, patients were randomly assigned (1:1:1) using an interactive voice response system to dapagliflozin 5 mg or 10 mg once daily, given orally, or matched placebo. Randomisation was stratified by current use of continuous glucose monitoring, method of insulin administration, and baseline HbA1c. The primary efficacy outcome was the change from baseline in HbA1c after 24 weeks of treatment in the full analysis set, which consisted of all randomly assigned patients who received at least one dose of study drug. An additional 55 patients who were incorrectly and non-randomly allocated to only dapagliflozin treatment groups were included in the safety analysis set. This study was registered with ClinicalTrials.gov, number NCT02268214; data collection for the present analysis was completed on Jan 4, 2017, and a 28 week extension phase is ongoing. Between Nov 11, 2014, and April 16, 2016, 833 patients were assigned to treatment groups and included in safety analyses (dapagliflozin 5 mg [n=277] vs dapagliflozin 10 mg [n=296] vs placebo [n=260]; 778 of these patients were randomly assigned and included in the full analysis set for efficacy analyses (259 vs 259 vs 260; difference due to randomisation error affecting 55 patients). Mean baseline HbA1c was 8·53% (70 mmol/mol; SD 0·67% [7·3

  4. Patient adherence to and tolerability of self-administered interferon β-1a using an electronic autoinjection device: a multicentre, open-label, phase IV study

    PubMed Central

    2012-01-01

    Background Achieving good adherence to self-injected treatments for multiple sclerosis can be difficult. Injection devices may help to overcome some of the injection-related barriers to adherence that can be experienced by patients. We sought to assess short-term adherence to, and tolerability of, interferon (IFN) β-1a administered via electronic autoinjection device in patients with relapsing-remitting multiple sclerosis (RRMS). Methods BRIDGE (RebiSmart to self-inject Rebif serum-free formulation in a multidose cartridge) was a 12-week, multicentre, open-label, single-arm, observational, Phase IV study in which patients self-administered IFN β-1a (titrated to 44 μg), subcutaneously (sc), three times weekly, via electronic autoinjection device. Patients were assessed at baseline and 4-weekly intervals to Week 12 or early termination (ET) for: physical examinations; diary card completion (baseline, Weeks 4, 8 only); neurological examinations (baseline, Week 12/ET only); MS Treatment Concern Questionnaire (MSTCQ; Weeks 4, 8, 12 only); Convenience Questionnaire (Week 12 only); Hospital Anxiety and Depression Scale (HADS); and Paced Auditory Serial Addition Task (PASAT; baseline only). Adherence was defined as administration of ≥ 80% of scheduled injections, recorded by the autoinjection device. Results Overall, 88.2% (105/119; intent-to-treat population) of patients were adherent; 67.2% (80/119) administered all scheduled injections. Medical reasons accounted for 35.6% (31/87) of missed injections, forgetfulness for 20.6% (18/87). Adherence did not correlate with baseline Expanded Disability Status Scale (P = 0.821) or PASAT (P = 0.952) scores, or pre-study therapy (P = 0.303). No significant changes (baseline-Week 12) in mean HADS depression (P = 0.482) or anxiety (P = 0.156) scores were observed. 'Overall convenience' was the most important reported benefit of the autoinjection device. Device features associated with handling and ease of use were highly rated

  5. Patient adherence to and tolerability of self-administered interferon β-1a using an electronic autoinjection device: a multicentre, open-label, phase IV study.

    PubMed

    Lugaresi, Alessandra; Florio, Ciro; Brescia-Morra, Vincenzo; Cottone, Salvatore; Bellantonio, Paolo; Clerico, Marinella; Centonze, Diego; Uccelli, Antonio; di Ioia, Maria; De Luca, Giovanna; Marcellusi, Andrea; Paolillo, Andrea

    2012-03-05

    Achieving good adherence to self-injected treatments for multiple sclerosis can be difficult. Injection devices may help to overcome some of the injection-related barriers to adherence that can be experienced by patients. We sought to assess short-term adherence to, and tolerability of, interferon (IFN) β-1a administered via electronic autoinjection device in patients with relapsing-remitting multiple sclerosis (RRMS). BRIDGE (RebiSmart to self-inject Rebif serum-free formulation in a multidose cartridge) was a 12-week, multicentre, open-label, single-arm, observational, Phase IV study in which patients self-administered IFN β-1a (titrated to 44 μg), subcutaneously (sc), three times weekly, via electronic autoinjection device. Patients were assessed at baseline and 4-weekly intervals to Week 12 or early termination (ET) for: physical examinations; diary card completion (baseline, Weeks 4, 8 only); neurological examinations (baseline, Week 12/ET only); MS Treatment Concern Questionnaire (MSTCQ; Weeks 4, 8, 12 only); Convenience Questionnaire (Week 12 only); Hospital Anxiety and Depression Scale (HADS); and Paced Auditory Serial Addition Task (PASAT; baseline only). Adherence was defined as administration of ≥ 80% of scheduled injections, recorded by the autoinjection device. Overall, 88.2% (105/119; intent-to-treat population) of patients were adherent; 67.2% (80/119) administered all scheduled injections. Medical reasons accounted for 35.6% (31/87) of missed injections, forgetfulness for 20.6% (18/87). Adherence did not correlate with baseline Expanded Disability Status Scale (P = 0.821) or PASAT (P = 0.952) scores, or pre-study therapy (P = 0.303). No significant changes (baseline-Week 12) in mean HADS depression (P = 0.482) or anxiety (P = 0.156) scores were observed. 'Overall convenience' was the most important reported benefit of the autoinjection device. Device features associated with handling and ease of use were highly rated. Mean MSTCQ scores for 'flu

  6. Safety and activity of blinatumomab for adult patients with relapsed or refractory B-precursor acute lymphoblastic leukaemia: a multicentre, single-arm, phase 2 study.

    PubMed

    Topp, Max S; Gökbuget, Nicola; Stein, Anthony S; Zugmaier, Gerhard; O'Brien, Susan; Bargou, Ralf C; Dombret, Hervé; Fielding, Adele K; Heffner, Leonard; Larson, Richard A; Neumann, Svenja; Foà, Robin; Litzow, Mark; Ribera, Josep-Maria; Rambaldi, Alessandro; Schiller, Gary; Brüggemann, Monika; Horst, Heinz A; Holland, Chris; Jia, Catherine; Maniar, Tapan; Huber, Birgit; Nagorsen, Dirk; Forman, Stephen J; Kantarjian, Hagop M

    2015-01-01

    Adults with relapsed or refractory B-precursor acute lymphoblastic leukaemia have an unfavourable prognosis. Blinatumomab is a bispecific T-cell engager antibody construct targeting CD19, an antigen consistently expressed on B-lineage acute lymphoblastic leukaemia cells. We aimed to confirm the activity and safety profile of blinatumomab for acute lymphoblastic leukaemia. In a multicentre, single-arm, open-label phase 2 study, we enrolled adult patients with Philadelphia-chromosome-negative, primary refractory or relapsed (first relapse within 12 months of first remission, relapse within 12 months after allogeneic haemopoietic stem-cell transplantation [HSCT], or no response to or relapse after first salvage therapy or beyond) leukaemia. Patients received blinatumomab (9 μg/day for the first 7 days and 28 μg/day thereafter) by continuous intravenous infusion over 4 weeks every 6 weeks (up to five cycles), per protocol. The primary endpoint was complete remission (CR) or CR with partial haematological recovery of peripheral blood counts (CRh) within the first two cycles. Analysis was by intention to treat. This trial is registered at ClinicalTrials.gov, number NCT01466179. Between Jan 13, 2012, and Oct 10, 2013, 189 patients were enrolled and treated with blinatumomab. After two cycles, 81 (43%, 95% CI 36-50) patients had achieved a CR or CRh: 63 (33%) patients had a CR and 18 (10%) patients had a CRh. 32 (40%) of patients who achieved CR/CRh underwent subsequent allogeneic HSCT. The most frequent grade 3 or worse adverse events were febrile neutropenia (48 patients, 25%), neutropenia (30 patients, 16%), and anaemia (27 patients, 14%). Three (2%) patients had grade 3 cytokine release syndrome. Neurologic events of worst grade 3 or 4 occurred in 20 (11%) and four (2%) patients, respectively. Three deaths (due to sepsis, Escherichia coli sepsis, and Candida infection) were thought to be treatment-related by the investigators. Single-agent blinatumomab showed

  7. Ledipasvir-sofosbuvir in patients with hepatitis C virus genotype 5 infection: an open-label, multicentre, single-arm, phase 2 study.

    PubMed

    Abergel, Armand; Asselah, Tarik; Metivier, Sophie; Kersey, Kathryn; Jiang, Deyuan; Mo, Hongmei; Pang, Phillip S; Samuel, Didier; Loustaud-Ratti, Véronique

    2016-04-01

    Data about the response of hepatitis C virus (HCV) genotype 5 to approved and experimental treatment regimens are scarce. We assessed the efficacy and safety of combination therapy with the NS5A inhibitor ledipasvir and the NS5B polymerase inhibitor sofosbuvir in patients with HCV genotype 5. We did this open-label, multicentre, single-arm, phase 2 trial at five hospitals in France. Eligible patients were at least 18 years old and had chronic infection with HCV genotype 5, with plasma HCV RNA of at least 10,000 IU/mL. We used BLAST analyses of NS5B partial sequences to establish the genotype and subtype at screening. Patients were given a fixed-dose combination tablet of 90 mg ledipasvir and 400 mg sofosbuvir orally once per day for 12 weeks. The primary endpoint was the proportion of patients with a sustained viral response, defined as HCV RNA concentration less than 15 IU/mL at 12 weeks after the end of treatment (SVR12). We analysed efficacy and safety in all patients who received at least one dose of ledipasvir-sofosbuvir. This trial is registered with EudraCT, number 2013-003978-27, and with ClinicalTrials.gov, number NCT02081079. From March 7 to June 10, 2014, we recruited 41 patients, including 21 who were treatment naive and 20 who were treatment experienced. All patients were of white ethnic origins. All 41 patients who started treatment completed the full 12 weeks of treatment and had undetectable HCV RNA at their final treatment visit. In the overall study population, 39 (95%, 95% CI 83-99) of 41 patients achieved SVR12. SVR12 was achieved by 20 (95%, 76-100) of the 21 patients who were treatment naive and 19 (95%, 75-100) of the 20 patients who were treatment experienced. Eight (89%) of nine patients with cirrhosis achieved SVR12, whereas 31 (97%) of the 32 patients without cirrhosis achieved SVR12. The two patients who did not reach SVR12 both had IL28B TT genotype and had viral relapse within 4 weeks of the end of treatment. The most common adverse

  8. Preoperative hyperfractionated chemoradiation for locally recurrent rectal cancer in patients previously irradiated to the pelvis: A multicentric phase II study

    SciTech Connect

    Valentini, Vincenzo . E-mail: vvalentini@rm.unicatt.it; Morganti, Alessio G.; Gambacorta, M. Antonietta; Mohiuddin, Mohammed; Doglietto, G. Battista; Coco, Claudio; De Paoli, Antonino; Rossi, Carlo; Di Russo, Annamaria; Valvo, Francesca; Bolzicco, Giampaolo; Dalla Palma, Maurizio

    2006-03-15

    Purpose: The combination of irradiation and total mesorectal excision for rectal carcinoma has significantly lowered the incidence of local recurrence. However, a new problem is represented by the patient with locally recurrent cancer who has received previous irradiation to the pelvis. In these patients, local recurrence is very often not easily resectable and reirradiation is expected to be associated with a high risk of late toxicity. The aim of this multicenter phase II study is to evaluate the response rate, resectability rate, local control, and treatment-related toxicity of preoperative hyperfractionated chemoradiation for locally recurrent rectal cancer in patients previously irradiated to the pelvis. Methods and Materials: Patients with histologically proven pelvic recurrence of rectal carcinoma, with the absence of extrapelvic disease or bony involvement and previous pelvic irradiation with doses {<=}55 Gy; age {>=}18 years; performance status (PS) (Karnofsky) {>=}60, and who gave institutional review board-approved written informed consent were treated by preoperative chemoradiation. Radiotherapy was delivered to a planning target volume (PTV2) including the gross tumor volume (GTV) plus a 4-cm margin, with a dose of 30 Gy (1.2 Gy twice daily with a minimum 6-h interval). A boost was delivered, with the same fractionation schedule, to a PTV1 including the GTV plus a 2-cm margin (10.8 Gy). During the radiation treatment, concurrent chemotherapy was delivered (5-fluorouracil, protracted intravenous infusion, 225 mg/m{sup 2}/day, 7 days per week). Four to 6 weeks after the end of chemoradiation, patients were evaluated for tumor resectability, and, when feasible, surgical resection of recurrence was performed between 6-8 weeks from the end of chemoradiation. Adjuvant chemotherapy was prescribed to all patients, using Raltitrexed, 3 mg/square meter (sm), every 3 weeks, for a total of 5 cycles. Patients were staged using the computed tomography (CT)-based F

  9. Evaluations of liquid crystal panel as a random phase modulator for optical encryption systems based on the double random phase encoding

    NASA Astrophysics Data System (ADS)

    Harada, Yasuhiro; Fukuyama, Shingo

    2010-02-01

    A use of liquid crystal panels (LCPs) as a random phase modulator in the optical encryption system based on the double random phase coding (DRPC) [Optics Letters, Vol.20, 767(1995)] is considered in the present paper. Required phase modulation property of LCPs as random phase modulators in the DRPC are investigated by computer simulations. It is found from simulation results that the required number of independent patches for phase modulations must be greater than 128 × 128 pixels for LCPs with the maximum phase modulation of 1.55π radians. It is also found that the required maximum phase modulation can be reduced to 1.25π radians by increasing the number of independent patches to 1024 × 1024 pixles. Experimental study using a commercially available LCP (EPSON, HTPS LCP, L3P14Y-55G00) verified partially these simulation results.

  10. Statistics of light deflection in a random two-phase medium

    SciTech Connect

    Sviridov, A P

    2007-01-31

    The statistics of the angles of light deflection during its propagation in a random two-phase medium with randomly oriented phase interfaces is considered within the framework of geometrical optics. The probabilities of finding a randomly walking photon in different phases of the inhomogeneous medium are calculated. Analytic expressions are obtained for the scattering phase function and the scattering phase matrix which relates the Stokes vector of the incident light beam with the Stokes vectors of deflected beams. (special issue devoted to multiple radiation scattering in random media)

  11. Pre-Study protocol MagPEP: a multicentre randomized controlled trial of magnesium sulphate in the prevention of post-ERCP pancreatitis

    PubMed Central

    2013-01-01

    Background Acute pancreatitis is the most common complication of diagnostic and therapeutic endoscopic retrograde cholangiopancreatography (ERCP). In spite of continuing research, no pharmacologic agent capable of effectively reducing the incidence of ERCP-induced pancreatitis has found its way into clinical practise. A number of experimental studies suggest that intrapancreatic calcium concentrations play an important role in the initiation of intracellular protease activation, an initiating step in the course of acute pancreatitis. Magnesium can act as a calcium-antagonist and counteracts effects in calcium signalling. It can thereby attenuate the intracellular activation of proteolytic digestive enzymes in the pancreas and reduces the severity of experimental pancreatitis when administered either intravenously or as a food supplement. Methods We designed a randomized, double-blind, placebo-controlled phase III study to test whether the administration of intravenous magnesium sulphate before and after ERCP reduces the incidence and the severity of post-ERCP pancreatitis. A total of 502 adult patients with a medical indication for ERCP are to be randomized to receive either 4930 mg magnesium sulphate (= 20 mmol magnesium) or placebo 60 min before and 6 hours after ERCP. The incidence of clinical post-ERCP pancreatitis, hyperlipasemia, pain levels, use of analgetics and length of hospital stay will be evaluated. Conclusions If magnesium sulphate is found to be effective in preventing post-ERCP pancreatitis, this inexpensive agent with limited adverse effects could be used as a routine pharmacological prophylaxis. Trial registration Current Controlled Trials ISRCTN46556454 PMID:23320650

  12. The Power of Randomization Tests for Single-Case Phased Designs.

    ERIC Educational Resources Information Center

    Ferron, John; Onghena, Patrick

    1996-01-01

    Monte Carlo methods were used to estimate the power of randomization tests used with single-case designs involving random assignment of treatments to phases. Simulations of two treatments and six phases showed an adequate level of power when effect sizes were large, phase lengths exceeded five, and autocorrelation was not negative. (SLD)

  13. A prospective, multicentre, randomized, double-blind, placebo-controlled trial of onabotulinumtoxinA to treat plantarflexor/invertor overactivity after stroke.

    PubMed

    Dunne, John Walter; Gracies, Jean-Michel; Hayes, Michael; Zeman, Brian; Singer, Barbara Jennifer

    2012-09-01

    To examine the safety and efficacy of onabotulinumtoxinA (Botox) for plantarflexor overactivity following stroke. Double-blind randomized controlled trial, open-label extension phase. Neurology rehabilitation facilities. Eighty-five subjects with lower limb hypertonia received 200 U (n = 28) or 300 U (n = 28) of onabotulinumtoxinA or saline (n = 29) injection. Plantarflexor Ashworth scores at 12 weeks post injection and adverse events. Secondary measures: self-reported spasm frequency and pain, physician rating of hypertonia severity, gait quality and active dorsiflexion. Differences were not seen between onabotulinumtoxinA groups; hence data were pooled. Incidence of adverse events was not different between groups (P = 0.61). Reduction in hypertonia was not different between groups at 12 weeks (P = 0.53); however for subjects with Ashworth scores of >3 at baseline, 14/31 in the onabotulinumtoxinA group demonstrated a reduction of >1 grade versus 1/17 receiving placebo injection (P = 0.01). Overall, onabotulinumtoxinA-injected subjects demonstrated significantly greater improvement in spasm frequency (22/54 versus 4/29, P = 0.01), pain reduction (8/54 versus 1/29, P = 0.02), active dorsiflexion (8/54 versus 1/29 P = 0.03) and gait quality (17/54 versus 6/29, P = 0.02) than controls. In the open-label phase, a second onabotulinumtoxinA injection was associated with greater hypertonia reduction (P = 0.005) and gait quality (P = 0.002) compared with single injection. OnabotulinumtoxinA injection for ankle flexor overactivity after stroke was safe and well tolerated but did not alter local spasticity at 12 weeks; it did reduce spasms and improve gait quality. There were no detectable differences between higher and lower doses. A second injection may be associated with greater change.

  14. Optimal duration of adjuvant chemotherapy for high-risk node-negative (N-) breast cancer patients: 6-year results of the prospective randomised multicentre phase III UNICANCER-PACS 05 trial (UCBG-0106).

    PubMed

    Kerbrat, Pierre; Desmoulins, Isabelle; Roca, Lise; Levy, Christelle; Lortholary, Alain; Marre, Alain; Delva, Rémy; Rios, Maria; Viens, Patrice; Brain, Étienne; Serin, Daniel; Edel, Magali; Debled, Marc; Campone, Mario; Mourret-Reynier, Marie-Ange; Bachelot, Thomas; Foucher-Goudier, Marie-Josèphe; Asselain, Bernard; Lemonnier, Jérôme; Martin, Anne-Laure; Roché, Henri

    2017-07-01

    Optimal duration of adjuvant chemotherapy in the treatment of early-stage breast cancer remained to be investigated rigorously for the standard regimens in widespread use in North America (doxorubicin/cyclophosphamide, AC) and Europe (5-fluorouracil/epirubicin/cyclophosphamide, FEC). Whether six cycles of FEC 100 present an advantage, or not, compared with only four cycles was tested directly in a phase III prospective multicentre trial. Between 2002 and 2006, 1515 women between 18 and 65°years of age, with node negative N(-) high-risk early-stage breast cancer, were included in the study following breast surgery and axillary lymph node dissection or procedure by sentinel node technique. Inclusion in the study required tumour size T ≥ 1 cm and at least one of the high-risk factors: T > 2 cm, negative oestrogen receptor/progesterone receptor (ER- and PR-), Scarff-Bloom-Richardson (SBR) grade II or III and age ≤ 35°years. Patients were randomly assigned to either six FEC 100 (Arm A) or four FEC 100 (Arm B). The trial was powered to detect an absolute difference ≥6% in disease-free survival (DFS) at 5°years. At 6.1°years median follow-up, with 91 (12%) events recorded in Arm A versus 106 (14%) in Arm B, no statistically significant risk increase was associated with four versus six FEC 100: DFS (hazard ratio (HR) = 1.18; CI 95% [0.89-1.56], P = .24) and overall survival (OS) (HR = 1.39; CI 95% [0.91-2.13], P = .12). Differences in chemotherapy duration did not induce notably different outcomes in our cohort of high-risk patients. NCT00055679, Agence National de Sécurité du Médicament (ANSM) - France. Copyright © 2017 Elsevier Ltd. All rights reserved.

  15. Dabrafenib plus trametinib in patients with BRAF(V600)-mutant melanoma brain metastases (COMBI-MB): a multicentre, multicohort, open-label, phase 2 trial.

    PubMed

    Davies, Michael A; Saiag, Philippe; Robert, Caroline; Grob, Jean-Jacques; Flaherty, Keith T; Arance, Ana; Chiarion-Sileni, Vanna; Thomas, Luc; Lesimple, Thierry; Mortier, Laurent; Moschos, Stergios J; Hogg, David; Márquez-Rodas, Iván; Del Vecchio, Michele; Lebbé, Céleste; Meyer, Nicolas; Zhang, Ying; Huang, Yingjie; Mookerjee, Bijoyesh; Long, Georgina V

    2017-07-01

    Dabrafenib plus trametinib improves clinical outcomes in BRAF(V600)-mutant metastatic melanoma without brain metastases; however, the activity of dabrafenib plus trametinib has not been studied in active melanoma brain metastases. Here, we report results from the phase 2 COMBI-MB trial. Our aim was to build on the current body of evidence of targeted therapy in melanoma brain metastases through an evaluation of dabrafenib plus trametinib in patients with BRAF(V600)-mutant melanoma brain metastases. This ongoing, multicentre, multicohort, open-label, phase 2 study evaluated oral dabrafenib (150 mg twice per day) plus oral trametinib (2 mg once per day) in four patient cohorts with melanoma brain metastases enrolled from 32 hospitals and institutions in Europe, North America, and Australia: (A) BRAF(V600E)-positive, asymptomatic melanoma brain metastases, with no previous local brain therapy, and an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1; (B) BRAF(V600E)-positive, asymptomatic melanoma brain metastases, with previous local brain therapy, and an ECOG performance status of 0 or 1; (C) BRAF(V600D/K/R)-positive, asymptomatic melanoma brain metastases, with or without previous local brain therapy, and an ECOG performance status of 0 or 1; and (D) BRAF(V600D/E/K/R)-positive, symptomatic melanoma brain metastases, with or without previous local brain therapy, and an ECOG performance status of 0, 1, or 2. The primary endpoint was investigator-assessed intracranial response in cohort A in the all-treated-patients population. Secondary endpoints included intracranial response in cohorts B, C, and D. This study is registered with ClinicalTrials.gov, number NCT02039947. Between Feb 28, 2014, and Aug 5, 2016, 125 patients were enrolled in the study: 76 patients in cohort A; 16 patients in cohort B; 16 patients in cohort C; and 17 patients in cohort D. At the data cutoff (Nov 28, 2016) after a median follow-up of 8·5 months (IQR 5·5-14·0), 44 (58

  16. Expectation values of single-particle operators in the random phase approximation ground state.

    PubMed

    Kosov, D S

    2017-02-07

    We developed a method for computing matrix elements of single-particle operators in the correlated random phase approximation ground state. Working with the explicit random phase approximation ground state wavefunction, we derived a practically useful and simple expression for a molecular property in terms of random phase approximation amplitudes. The theory is illustrated by the calculation of molecular dipole moments for a set of representative molecules.

  17. Expectation values of single-particle operators in the random phase approximation ground state

    NASA Astrophysics Data System (ADS)

    Kosov, D. S.

    2017-02-01

    We developed a method for computing matrix elements of single-particle operators in the correlated random phase approximation ground state. Working with the explicit random phase approximation ground state wavefunction, we derived a practically useful and simple expression for a molecular property in terms of random phase approximation amplitudes. The theory is illustrated by the calculation of molecular dipole moments for a set of representative molecules.

  18. Communication: Random phase approximation renormalized many-body perturbation theory

    SciTech Connect

    Bates, Jefferson E.; Furche, Filipp

    2013-11-07

    We derive a renormalized many-body perturbation theory (MBPT) starting from the random phase approximation (RPA). This RPA-renormalized perturbation theory extends the scope of single-reference MBPT methods to small-gap systems without significantly increasing the computational cost. The leading correction to RPA, termed the approximate exchange kernel (AXK), substantially improves upon RPA atomization energies and ionization potentials without affecting other properties such as barrier heights where RPA is already accurate. Thus, AXK is more balanced than second-order screened exchange [A. Grüneis et al., J. Chem. Phys. 131, 154115 (2009)], which tends to overcorrect RPA for systems with stronger static correlation. Similarly, AXK avoids the divergence of second-order Møller-Plesset (MP2) theory for small gap systems and delivers a much more consistent performance than MP2 across the periodic table at comparable cost. RPA+AXK thus is an accurate, non-empirical, and robust tool to assess and improve semi-local density functional theory for a wide range of systems previously inaccessible to first-principles electronic structure calculations.

  19. Communication: Random phase approximation renormalized many-body perturbation theory

    NASA Astrophysics Data System (ADS)

    Bates, Jefferson E.; Furche, Filipp

    2013-11-01

    We derive a renormalized many-body perturbation theory (MBPT) starting from the random phase approximation (RPA). This RPA-renormalized perturbation theory extends the scope of single-reference MBPT methods to small-gap systems without significantly increasing the computational cost. The leading correction to RPA, termed the approximate exchange kernel (AXK), substantially improves upon RPA atomization energies and ionization potentials without affecting other properties such as barrier heights where RPA is already accurate. Thus, AXK is more balanced than second-order screened exchange [A. Grüneis et al., J. Chem. Phys. 131, 154115 (2009)], which tends to overcorrect RPA for systems with stronger static correlation. Similarly, AXK avoids the divergence of second-order Møller-Plesset (MP2) theory for small gap systems and delivers a much more consistent performance than MP2 across the periodic table at comparable cost. RPA+AXK thus is an accurate, non-empirical, and robust tool to assess and improve semi-local density functional theory for a wide range of systems previously inaccessible to first-principles electronic structure calculations.

  20. Phase Transitions in the Dynamics of Slow Random Monads

    NASA Astrophysics Data System (ADS)

    Ramos, A. D.; Toom, A.

    2011-12-01

    Let us have a finite set B (basin) with n>1 elements, which we call points, and a map M: B→ B. Following Vladimir Arnold, we call such pairs ( B, M) monads. Here we study a class of random monads, where the values of M(ṡ) are independently distributed in B as follows: for all a, b∈ B the probability of M( a)= a is s and the probability of M( a)= b, where a≠ b, is (1- s)/( n-1). Here s is a parameter in [0,1]. We fix a point ⊙∈ B and consider the sequence M t (⊙), t=0,1,2,… . A point is called visited if it coincides with at least one term of this sequence. A visited point is called recurrent if it appears in this sequence at least twice; if a visited point appears in this sequence only once, it is called transient. We denote by Vis, Rec, Tra the numbers of visited, recurrent and transient points respectively and study their distributions depending on parameters n and s. In this study we define the term "mode" as we need. These are our main results showing existence of two phases in the following cases: On the one hand, if s ge1 / sqrt{n}, the mode of Vis equals 1 (which is the minimal value of Vis).

  1. Safety and efficacy of oral febuxostat for treatment of HLA-B*5801-negative gout: a randomized, open-label, multicentre, allopurinol-controlled study

    PubMed Central

    Yu, K-H; Lai, J-H; Hsu, P-N; Chen, D-Y; Chen, C-J; Lin, H-Y

    2016-01-01

    Objectives: This phase IIIB study compared the efficacy and safety of febuxostat and allopurinol in gout patients with or without tophi who were HLA-B*5801 negative. Method: Eligible patients were randomized to a febuxostat group (80 mg QD) or an allopurinol group (300 mg QD). Following an initial 2-week washout period, over the next 12 weeks we made five measurements of serum urate levels along with assessments of adverse events (AEs). Results: Forty-three out of 152 screened subjects (28.3%) were ineligible either because of the presence of the HLA-B*5801 allele or for various other reasons. The febuxostat group (n = 54) and the allopurinol group (n = 55) had no significant differences in demographic or baseline characteristics. From week 2 to week 12, the febuxostat group had a significantly lower serum urate level than the allopurinol group (p ≤ 0.001 for all comparisons) and significantly more patients with serum urate levels less than 6.0 mg/dL. The serum urate levels of the febuxostat group declined by more than 40% from week 2 to week 12 and this decrease was greater than that in the allopurinol group (~30%). The two groups were similar in terms of AEs. Conclusions: Febuxostat was more effective than allopurinol in reducing the serum urate levels of Han Chinese patients with gout or tophaceous gout who were HLA-B*5801 negative, without causing any serious skin reactions. Febuxostat should be considered for treatment of Han Chinese patients with gout who are HLA-B*5801 negative. PMID:26771445

  2. A multicentre randomized/controlled trial of a conventional versus modestly accelerated radiotherapy in the laryngeal cancer: influence of a 1 week shortening overall time.

    PubMed

    Hliniak, A; Gwiazdowska, B; Szutkowski, Z; Kraszewska, E; Kukolowicz, P; Jarzabski, A; Sochacka, B; Mazurkiewicz, M; Paprota, K; Oliskiewicz, W; Zadrozna, O; Milecki, P; Kubiak, M; Czopkiewicz, L; Jagas, M; Góźdź, S; Wieczorek, A; Woytowicz, A; Cisowska, B; Magdziarz, H; Nowakowski, S; Kośniewski, W; Laskosz, I; Serafin, A; Gradoń, E

    2002-01-01

    To compare in a phase III study the loco-regional control, disease-free survival and overall survival induced by an accelerated regimen (AF) as compared with conventional regimen (CF) and to analyze the early and late post-radiation morbidity in both arms. Patients with age < or = 75, WHO 0-1, suitable for a radical course of radiotherapy T1-T3, N0, M0, stage of glottic and supraglottic laryngeal cancer were randomized to either CF: 66Gy given in 33 fractions over 45 days or AF: 66Gy given in 33 fractions over 38 days (2 fractions every Thursday). A total of 395 patients were included from 05.1995 to 12.1998. Early toxicity: At the end of radiotherapy patients treated with AF complained for more severe reactions than patients treated with CF. In 8 weeks after treatment completion patients treated with AF complained only for more severe pain on swallowing (P=0.027). In 4 months after treatment completion all types of toxicity except for skin teleangiectasia (P=0.001) were similar in the two groups. Loco-regional control: comparison between CF and AF showed no difference in terms of loco-regional control (P=0.37). The improvement in AF in terms of loco-regional control is estimated to be 3-5% in comparison with conventional regimen and is not significant. The intensity of reactions after 4 months was similar in both arms, what suggests the possibility of further shortening of the overall time by few days or enhancing the total dose within the limits of acceptable morbidity.

  3. Safety and efficacy of oral febuxostat for treatment of HLA-B*5801-negative gout: a randomized, open-label, multicentre, allopurinol-controlled study.

    PubMed

    Yu, K-H; Lai, J-H; Hsu, P-N; Chen, D-Y; Chen, C-J; Lin, H-Y

    2016-07-01

    This phase IIIB study compared the efficacy and safety of febuxostat and allopurinol in gout patients with or without tophi who were HLA-B*5801 negative. Eligible patients were randomized to a febuxostat group (80 mg QD) or an allopurinol group (300 mg QD). Following an initial 2-week washout period, over the next 12 weeks we made five measurements of serum urate levels along with assessments of adverse events (AEs). Forty-three out of 152 screened subjects (28.3%) were ineligible either because of the presence of the HLA-B*5801 allele or for various other reasons. The febuxostat group (n = 54) and the allopurinol group (n = 55) had no significant differences in demographic or baseline characteristics. From week 2 to week 12, the febuxostat group had a significantly lower serum urate level than the allopurinol group (p ≤ 0.001 for all comparisons) and significantly more patients with serum urate levels less than 6.0 mg/dL. The serum urate levels of the febuxostat group declined by more than 40% from week 2 to week 12 and this decrease was greater than that in the allopurinol group (~30%). The two groups were similar in terms of AEs. Febuxostat was more effective than allopurinol in reducing the serum urate levels of Han Chinese patients with gout or tophaceous gout who were HLA-B*5801 negative, without causing any serious skin reactions. Febuxostat should be considered for treatment of Han Chinese patients with gout who are HLA-B*5801 negative.

  4. Ipilimumab versus placebo after radiotherapy in patients with metastatic castration-resistant prostate cancer that had progressed after docetaxel chemotherapy (CA184-043): a multicentre, randomised, double-blind, phase 3 trial

    PubMed Central

    Kwon, Eugene D; Drake, Charles G; Scher, Howard I; Fizazi, Karim; Bossi, Alberto; van den Eertwegh, Alfons J M; Krainer, Michael; Houede, Nadine; Santos, Ricardo; Mahammedi, Hakim; Ng, Siobhan; Maio, Michele; Franke, Fabio A; Sundar, Santhanam; Agarwal, Neeraj; Bergman, Andries M; Ciuleanu, Tudor E; Korbenfeld, Ernesto; Sengeløv, Lisa; Hansen, Steinbjorn; Logothetis, Christopher; Beer, Tomasz M; McHenry, M Brent; Gagnier, Paul; Liu, David; Gerritsen, Winald R

    2015-01-01

    Summary Background Ipilimumab is a fully human monoclonal antibody that binds cytotoxic T-lymphocyte antigen 4 to enhance antitumour immunity. Our aim was to assess the use of ipilimumab after radiotherapy in patients with metastatic castration-resistant prostate cancer that progressed after docetaxel chemotherapy. Methods We did a multicentre, randomised, double-blind, phase 3 trial in which men with at least one bone metastasis from castration-resistant prostate cancer that had progressed after docetaxel treatment were randomly assigned in a 1:1 ratio to receive bone-directed radiotherapy (8 Gy in one fraction) followed by either ipilimumab 10 mg/kg or placebo every 3 weeks for up to four doses. Non-progressing patients could continue to receive ipilimumab at 10 mg/kg or placebo as maintenance therapy every 3 months until disease progression, unacceptable toxic effect, or death. Patients were randomly assigned to either treatment group via a minimisation algorithm, and stratified by Eastern Cooperative Oncology Group performance status, alkaline phosphatase concentration, haemoglobin concentration, and investigator site. Patients and investigators were masked to treatment allocation. The primary endpoint was overall survival, assessed in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, number NCT00861614. Findings From May 26, 2009, to Feb 15, 2012, 799 patients were randomly assigned (399 to ipilimumab and 400 to placebo), all of whom were included in the intention-to-treat analysis. Median overall survival was 11·2 months (95% CI 9·5–12·7) with ipilimumab and 10·0 months (8·3–11·0) with placebo (hazard ratio [HR] 0·85, 0·72–1·00; p=0·053). However, the assessment of the proportional hazards assumption showed that it was violated (p=0·0031). A piecewise hazard model showed that the HR changed over time: the HR for 0–5 months was 1·46 (95% CI 1·10–1·95), for 5–12 months was 0·65 (0·50–0·85), and

  5. Erlotinib and bevacizumab in patients with advanced non-small-cell lung cancer and activating EGFR mutations (BELIEF): an international, multicentre, single-arm, phase 2 trial.

    PubMed

    Rosell, Rafael; Dafni, Urania; Felip, Enriqueta; Curioni-Fontecedro, Alessandra; Gautschi, Oliver; Peters, Solange; Massutí, Bartomeu; Palmero, Ramon; Aix, Santiago Ponce; Carcereny, Enric; Früh, Martin; Pless, Miklos; Popat, Sanjay; Kotsakis, Athanasios; Cuffe, Sinead; Bidoli, Paolo; Favaretto, Adolfo; Froesch, Patrizia; Reguart, Noemí; Puente, Javier; Coate, Linda; Barlesi, Fabrice; Rauch, Daniel; Thomas, Michael; Camps, Carlos; Gómez-Codina, Jose; Majem, Margarita; Porta, Rut; Shah, Riyaz; Hanrahan, Emer; Kammler, Roswitha; Ruepp, Barbara; Rabaglio, Manuela; Kassapian, Marie; Karachaliou, Niki; Tam, Rachel; Shames, David S; Molina-Vila, Miguel A; Stahel, Rolf A

    2017-05-01

    The tyrosine kinase inhibitor erlotinib improves the outcomes of patients with advanced non-small-cell lung carcinoma (NSCLC) harbouring epidermal growth factor receptor (EGFR) mutations. The coexistence of the T790M resistance mutation with another EGFR mutation in treatment-naive patients has been associated with a shorter progression-free survival to EGFR inhibition than in the absence of the T790M mutation. To test this hypothesis clinically, we developed a proof-of-concept study, in which patients with EGFR-mutant NSCLC were treated with the combination of erlotinib and bevacizumab, stratified by the presence of the pretreatment T790M mutation. BELIEF was an international, multicentre, single-arm, phase 2 trial done at 29 centres in eight European countries. Eligible patients were aged 18 years or older and had treatment-naive, pathologically confirmed stage IIIB or stage IV lung adenocarcinoma with a confirmed, activating EGFR mutation (exon 19 deletion or L858R mutation). Patients received oral erlotinib 150 mg per day and intravenous bevacizumab 15 mg/kg every 21 days and were tested centrally for the pretreatment T790M resistance mutation with a peptide nucleic acid probe-based real-time PCR. The primary endpoint was progression-free survival. The primary efficacy analysis was done in the intention-to-treat population and was stratified into two parallel substudies according to the centrally confirmed pretreatment T790M mutation status of enrolled patients (T790M positive or negative). The safety analysis was done in all patients that have received at least one dose of trial treatment. This trial was registered with ClinicalTrials.gov, number NCT01562028. Between June 11, 2012, and Oct 28, 2014, 109 patients were enrolled and included in the efficacy analysis. 37 patients were T790M mutation positive and 72 negative. The overall median progression-free survival was 13·2 months (95% CI 10·3-15·5), with a 12 month progression-free survival of 55% (95% CI

  6. Single-dose, subcutaneous recombinant phenylalanine ammonia lyase conjugated with polyethylene glycol in adult patients with phenylketonuria: an open-label, multicentre, phase 1 dose-escalation trial.

    PubMed

    Longo, Nicola; Harding, Cary O; Burton, Barbara K; Grange, Dorothy K; Vockley, Jerry; Wasserstein, Melissa; Rice, Gregory M; Dorenbaum, Alejandro; Neuenburg, Jutta K; Musson, Donald G; Gu, Zhonghua; Sile, Saba

    2014-07-05

    Phenylketonuria is an inherited disease caused by impaired activity of phenylalanine hydroxylase, the enzyme that converts phenylalanine to tyrosine, leading to accumulation of phenylalanine and subsequent neurocognitive dysfunction. Phenylalanine ammonia lyase is a prokaryotic enzyme that converts phenylalanine to ammonia and trans-cinnamic acid. We aimed to assess the safety, tolerability, pharmacokinetic characteristics, and efficacy of recombinant Anabaena variabilis phenylalanine ammonia lyase (produced in Escherichia coli) conjugated with polyethylene glycol (rAvPAL-PEG) in reducing phenylalanine concentrations in adult patients with phenylketonuria. In this open-label, phase 1, multicentre trial, single subcutaneous injections of rAvPAL-PEG were given in escalating doses (0·001, 0·003, 0·010, 0·030, and 0·100 mg/kg) to adults with phenylketonuria. Participants aged 18 years or older with blood phenylalanine concentrations of 600 μmol/L or higher were recruited from among patients attending metabolic disease clinics in the USA. The primary endpoints were safety and tolerability of rAvPAL-PEG. Secondary endpoints were the pharmacokinetic characteristics of the drug and its effect on concentrations of phenylalanine. Participants and investigators were not masked to assigned dose group. This study is registered with ClinicalTrials.gov, number NCT00925054. 25 participants were recruited from seven centres between May 6, 2008, and April 15, 2009, with five participants assigned to each escalating dose group. All participants were included in the safety population. The most frequently reported adverse events were injection-site reactions and dizziness, which were self-limited and without sequelae. Two participants had serious adverse reactions to intramuscular medroxyprogesterone acetate, a drug that contains polyethylene glycol as an excipient. Three of five participants given the highest dose of rAvPAL-PEG (0·100 mg/kg) developed a generalised skin rash

  7. Treatment with two different doses of sonidegib in patients with locally advanced or metastatic basal cell carcinoma (BOLT): a multicentre, randomised, double-blind phase 2 trial.

    PubMed

    Migden, Michael R; Guminski, Alexander; Gutzmer, Ralf; Dirix, Luc; Lewis, Karl D; Combemale, Patrick; Herd, Robert M; Kudchadkar, Ragini; Trefzer, Uwe; Gogov, Sven; Pallaud, Celine; Yi, Tingting; Mone, Manisha; Kaatz, Martin; Loquai, Carmen; Stratigos, Alexander J; Schulze, Hans-Joachim; Plummer, Ruth; Chang, Anne Lynn S; Cornélis, Frank; Lear, John T; Sellami, Dalila; Dummer, Reinhard

    2015-06-01

    Patients with advanced basal cell carcinoma have limited treatment options. Hedgehog pathway signalling is aberrantly activated in around 95% of tumours. We assessed the antitumour activity of sonidegib, a Hedgehog signalling inhibitor, in patients with advanced basal cell carcinoma. BOLT is an ongoing multicentre, randomised, double-blind, phase 2 trial. Eligible patients had locally advanced basal cell carcinoma not amenable to curative surgery or radiation or metastatic basal cell carcinoma. Patients were randomised via an automated system in a 1:2 ratio to receive 200 mg or 800 mg oral sonidegib daily, stratified by disease, histological subtype, and geographical region. The primary endpoint was the proportion of patients who achieved an objective response, assessed in the primary efficacy analysis population (patients with fully assessable locally advanced disease and all those with metastatic disease) with data collected up to 6 months after randomisation of the last patient. This trial is registered with ClinicalTrials.gov, number NCT01327053. Between July 20, 2011, and Jan 10, 2013, we enrolled 230 patients, 79 in the 200 mg sonidegib group, and 151 in the 800 mg sonidegib group. Median follow-up was 13·9 months (IQR 10·1-17·3). In the primary efficacy analysis population, 20 (36%, 95% CI 24-50) of 55 patients receiving 200 mg sonidegib and 39 (34%, 25-43) of 116 receiving 800 mg sonidegib achieved an objective response. In the 200 mg sonidegib group, 18 (43%, 95% CI 28-59) patients who achieved an objective response, as assessed by central review, were noted among the 42 with locally advanced basal cell carcinoma and two (15%, 2-45) among the 13 with metastatic disease. In the 800 mg group, 35 (38%, 95% CI 28-48) of 93 patients with locally advanced disease had an objective response, as assessed by central review, as did four (17%, 5-39) of 23 with metastatic disease. Fewer adverse events leading to dose interruptions or reductions (25 [32%] of 79

  8. Partially random phase attack to the practical two-way quantum-key-distribution system

    NASA Astrophysics Data System (ADS)

    Sun, Shi-Hai; Gao, Ming; Jiang, Mu-Sheng; Li, Chun-Yan; Liang, Lin-Mei

    2012-03-01

    Phase randomization is a very important assumption in the Bennett-Brassard 1984 quantum key distribution (QKD) system with a weak coherent source. Thus an active phase modulator is needed to randomize the phase of source. However, it is hard to check whether the phase of source is randomized totally or not in practical QKD systems. In this paper a partially random phase attack is proposed to exploit this imperfection. Our analysis shows that Eve can break the security of a two-way QKD system by using our attack, even if an active phase randomization is adopted by Alice. Furthermore, the numerical simulation shows that in some parameter regimes, our attack is immune to the one-decoy-state method.

  9. Evaluation of Clensia(®), a new low-volume PEG bowel preparation in colonoscopy: Multicentre randomized controlled trial versus 4L PEG.

    PubMed

    Spada, Cristiano; Cesaro, Paola; Bazzoli, Franco; Saracco, Giorgio Maria; Cipolletta, Livio; Buri, Luigi; Crosta, Cristiano; Petruzziello, Lucio; Ceroni, Liza; Fuccio, Lorenzo; Giordanino, Chiara; Elia, Chiara; Rotondano, Gianluca; Bianco, Maria A; Simeth, Catrin; Consalvo, Danilo; De Roberto, Giuseppe; Fiori, Giancarla; Campanale, Mariachiara; Costamagna, Guido

    2017-06-01

    Success of colonoscopy is linked to the adequacy of bowel cleansing. Polyethylene glycol 4L (PEG 4L) solutions are widely used for colonic cleansing but with limitations concerning tolerability and acceptability. To demonstrate the equivalence of a new low-volume PEG containing citrates and simeticone (Clensia) versus a standard PEG 4L. In this, multicentre, randomised, observer-blind trial, patients received either Clensia 2L or PEG 4L solution. Primary endpoint was the proportion of patients with colon cleansing evaluated as excellent or good. 422 patients received Clensia (n=213) or PEG 4L (n=209). Rate of excellent/good bowel cleansing was 73.6% and 72.3% in Clensia and PEG 4L group respectively. Clensia was demonstrated to be equivalent to PEG 4L. No SAEs were observed. Clensia showed better gastrointestinal tolerability (37.0% vs 25.4%). The acceptability was significantly better with Clensia in terms of proportion of subjects who felt no distress (Clensia 72.8% vs PEG 4L 63%, P=0.0314) and willingness-to-repeat (93.9% vs 82.2%, P=0.0002). The rate of optimal compliance was similar with both formulations (91.1% for Clensia vs 90.9% for PEG 4L, P=0.9388). The low-volume Clensia is equally effective and safe in bowel cleansing compared to the standard PEG 4L, with better gastrointestinal tolerability and acceptability. Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.

  10. Safety of intramuscular influenza vaccine in patients receiving oral anticoagulation therapy: a single blinded multi-centre randomized controlled clinical trial

    PubMed Central

    Casajuana, Josep; Iglesias, Begoña; Fàbregas, Mireia; Fina, Francesc; Vallès, Joan-Antoni; Aragonès, Rosa; Benítez, Mència; Zabaleta, Edurne

    2008-01-01

    Background Influenza vaccines are recommended for administration by the intramuscular route. However, many physicians use the subcutaneous route for patients receiving an oral anticoagulant because this route is thought to induce fewer hemorrhagic side effects. Our aim is to assess the safety of intramuscular administration of influenza vaccine in patients on oral anticoagulation therapy. Methods Design: Randomised, controlled, single blinded, multi-centre clinical trial. Setting: 4 primary care practices in Barcelona, Spain. Participants: 229 patients on oral anticoagulation therapy eligible for influenza vaccine during the 2003–2004 season. Interventions: intramuscular administration of influenza vaccine in the experimental group (129 patients) compared to subcutaneous administration in the control group (100 patients). Primary outcome: change in the circumference of the arm at the site of injection at 24 hours. Secondary outcomes: appearance of local reactions and pain at 24 hours and at 10 days; change in INR (International Normalized Ratio) at 24 hours and at 10 days. Analysis was by intention to treat using the 95% confidence intervals of the proportions or mean differences. Results Baseline variables in the two groups were similar. No major side effects or major haemorrhage during the follow-up period were reported. No significant differences were observed in the primary outcome between the two groups. The appearance of local adverse reactions was more frequent in the subcutaneous administration group (37,4% vs. 17,4%, 95% confidence interval of the difference 8,2% to 31,8%). Conclusion This study shows that the intramuscular administration route of influenza vaccine in patients on anticoagulant therapy does not have more side effects than the subcutaneous administration route. Registration number NCT00137579 at clinicaltrials.gov PMID:18507871

  11. Crenobalneotherapy (spa therapy) in patients with knee and generalized osteoarthritis: a post-hoc subgroup analysis of a large multicentre randomized trial.

    PubMed

    Forestier, R; Genty, C; Waller, B; Françon, A; Desfour, H; Rolland, C; Roques, C-F; Bosson, J-L

    2014-06-01

    To determine whether the addition of spa therapy to home exercises provides any benefit over exercises and the usual treatment alone in the management of generalised osteoarthritis associated with knee osteoarthritis. This study was a post-hoc subgroup analysis of our randomised multicentre trial (www.clinicaltrial.gov: NCT00348777). Participants who met the inclusion criteria of generalized osteoarthritis (Kellgren, American College of Rheumatology, or Dougados criteria) were extracted from the original randomised controlled trial. They had been randomised using Zelen randomisation. The treatment group received 18days of spa treatment in addition to a home exercise programme. Main outcome was number of patients achieving minimal clinically important improvement at six months (MCII) (≥-19.9mm on the VAS pain scale and/or ≥-9.1 points in a WOMAC function subscale), and no knee surgery. Secondary outcomes included the "patient acceptable symptom state" (PASS) defined as VAS pain ≤32.3mm and/or WOMAC function subscale ≤31 points. From the original 462 participants, 214 patients could be categorized as having generalised osteoarthritis. At sixth month, 182 (88 in control and 94 in SA group) patients, were analysed for the main criteria. MCII was observed more often in the spa group (n=52/94 vs. 38/88, P=0.010). There was no difference for the PASS (n=19/88 vs. 26/94, P=0.343). This study indicates that spa therapy with home exercises may be superior to home exercise alone in the management of patients with GOA associated with knee OA. Copyright © 2014 Elsevier Masson SAS. All rights reserved.

  12. Increasing exercise capacity and quality of life of patients with heart failure through Wii gaming: the rationale, design and methodology of the HF-Wii study; a multicentre randomized controlled trial.

    PubMed

    Jaarsma, Tiny; Klompstra, Leonie; Ben Gal, Tuvia; Boyne, Josiane; Vellone, Ercole; Bäck, Maria; Dickstein, Kenneth; Fridlund, Bengt; Hoes, Arno; Piepoli, Massimo F; Chialà, Oronzo; Mårtensson, Jan; Strömberg, Anna

    2015-07-01

    Exercise is known to be beneficial for patients with heart failure (HF), and these patients should therefore be routinely advised to exercise and to be or to become physically active. Despite the beneficial effects of exercise such as improved functional capacity and favourable clinical outcomes, the level of daily physical activity in most patients with HF is low. Exergaming may be a promising new approach to increase the physical activity of patients with HF at home. The aim of this study is to determine the effectiveness of the structured introduction and access to a Wii game computer in patients with HF to improve exercise capacity and level of daily physical activity, to decrease healthcare resource use, and to improve self-care and health-related quality of life. A multicentre randomized controlled study with two treatment groups will include 600 patients with HF. In each centre, patients will be randomized to either motivational support only (control) or structured access to a Wii game computer (Wii). Patients in the control group will receive advice on physical activity and will be contacted by four telephone calls. Patients in the Wii group also will receive advice on physical activity along with a Wii game computer, with instructions and training. The primary endpoint will be exercise capacity at 3 months as measured by the 6 min walk test. Secondary endpoints include exercise capacity at 6 and 12 months, level of daily physical activity, muscle function, health-related quality of life, and hospitalization or death during the 12 months follow-up. The HF-Wii study is a randomized study that will evaluate the effect of exergaming in patients with HF. The findings can be useful to healthcare professionals and improve our understanding of the potential role of exergaming in the treatment and management of patients with HF. NCT01785121. © 2015 The Authors. European Journal of Heart Failure © 2015 European Society of Cardiology.

  13. Nivolumab alone and nivolumab plus ipilimumab in recurrent small-cell lung cancer (CheckMate 032): a multicentre, open-label, phase 1/2 trial.

    PubMed

    Antonia, Scott J; López-Martin, José A; Bendell, Johanna; Ott, Patrick A; Taylor, Matthew; Eder, Joseph Paul; Jäger, Dirk; Pietanza, M Catherine; Le, Dung T; de Braud, Filippo; Morse, Michael A; Ascierto, Paolo A; Horn, Leora; Amin, Asim; Pillai, Rathi N; Evans, Jeffry; Chau, Ian; Bono, Petri; Atmaca, Akin; Sharma, Padmanee; Harbison, Christopher T; Lin, Chen-Sheng; Christensen, Olaf; Calvo, Emiliano

    2016-07-01

    Treatments for small-cell lung cancer (SCLC) after failure of platinum-based chemotherapy are limited. We assessed safety and activity of nivolumab and nivolumab plus ipilimumab in patients with SCLC who progressed after one or more previous regimens. The SCLC cohort of this phase 1/2 multicentre, multi-arm, open-label trial was conducted at 23 sites (academic centres and hospitals) in six countries. Eligible patients were 18 years of age or older, had limited-stage or extensive-stage SCLC, and had disease progression after at least one previous platinum-containing regimen. Patients received nivolumab (3 mg/kg bodyweight intravenously) every 2 weeks (given until disease progression or unacceptable toxicity), or nivolumab plus ipilimumab (1 mg/kg plus 1 mg/kg, 1 mg/kg plus 3 mg/kg, or 3 mg/kg plus 1 mg/kg, intravenously) every 3 weeks for four cycles, followed by nivolumab 3 mg/kg every 2 weeks. Patients were either assigned to nivolumab monotherapy or assessed in a dose-escalating safety phase for the nivolumab/ipilimumab combination beginning at nivolumab 1 mg/kg plus ipilimumab 1 mg/kg. Depending on tolerability, patients were then assigned to nivolumab 1 mg/kg plus ipilimumab 3 mg/kg or nivolumab 3 mg/kg plus ipilimumab 1 mg/kg. The primary endpoint was objective response by investigator assessment. All analyses included patients who were enrolled at least 90 days before database lock. This trial is ongoing; here, we report an interim analysis of the SCLC cohort. This study is registered with ClinicalTrials.gov, number NCT01928394. Between Nov 18, 2013, and July 28, 2015, 216 patients were enrolled and treated (98 with nivolumab 3 mg/kg, three with nivolumab 1 mg/kg plus ipilimumab 1 mg/kg, 61 with nivolumab 1 mg/kg plus ipilimumab 3 mg/kg, and 54 with nivolumab 3 mg/kg plus ipilimumab 1 mg/kg). At database lock on Nov 6, 2015, median follow-up for patients continuing in the study (including those who had died or discontinued treatment) was 198·5 days (IQR 163

  14. Electron correlation effects beyond the random phase approximation

    NASA Astrophysics Data System (ADS)

    Fan, J. D.; Malozovsky, Y. M.

    2016-04-01

    The methods that have been used to deal with a many-particle system can be basically sorted into three types: Hamiltonian, field theory and phenomenological method. The first two methods are more popular. Traditionally, the Hamiltonian method has been widely adopted in the conventional electronic theory for metals, alloys and semiconductors. Basically, the mean-field approximation (MFA) that has been working well for a weakly coupled system like a metal is employed to simplify a Hamiltonian corresponding to a particular electron system. However, for a strongly coupled many-particle system like a cuprate superconductor MFA should in principle not apply. Therefore, the field theory on the basis of Green’s function and the Feynman diagrams must be invoked. In this method, one is however more familiar with the random phase approximation (RPA) that gives rise to the same results as MFA because of being short of the information for higher-order terms of interaction. For a strongly coupled electron system, it is obvious that one has to deal with higher-order terms of a pair interaction to get a correct solution. Any ignorance of the higher-order terms implies that the more sophisticated information contained in those terms is discarded. However, to date one has not reached a consensus on how to deal with the higher-order terms beyond RPA. We preset here a method that is termed the diagrammatic iteration approach (DIA) and able to derive higher-order terms of the interaction from the information of lower-order ones on the basis of Feynman diagram, with which one is able to go beyond RPA step by step. It is in principle possible that all of higher-order terms can be obtained, and then sorted to groups of diagrams. It turns out that each of the groups can be replaced by an equivalent one, forming a diagrammatic Dyson-equation-like relation. The diagrammatic solution is eventually “translated” to a four-dimensional integral equation. The method can be applied to a

  15. Doxorubicin plus evofosfamide versus doxorubicin alone in locally advanced, unresectable or metastatic soft-tissue sarcoma (TH CR-406/SARC021): an international, multicentre, open-label, randomised phase 3 trial.

    PubMed

    Tap, William D; Papai, Zsuzsanna; Van Tine, Brian A; Attia, Steven; Ganjoo, Kristen N; Jones, Robin L; Schuetze, Scott; Reed, Damon; Chawla, Sant P; Riedel, Richard F; Krarup-Hansen, Anders; Toulmonde, Maud; Ray-Coquard, Isabelle; Hohenberger, Peter; Grignani, Giovanni; Cranmer, Lee D; Okuno, Scott; Agulnik, Mark; Read, William; Ryan, Christopher W; Alcindor, Thierry; Del Muro, Xavier F Garcia; Budd, G Thomas; Tawbi, Hussein; Pearce, Tillman; Kroll, Stew; Reinke, Denise K; Schöffski, Patrick

    2017-08-01

    Evofosfamide is a hypoxia-activated prodrug of bromo-isophosphoramide mustard. We aimed to assess the benefit of adding evofosfamide to doxorubicin as first-line therapy for advanced soft-tissue sarcomas. We did this international, open-label, randomised, phase 3, multicentre trial (TH CR-406/SARC021) at 81 academic or community investigational sites in 13 countries. Eligible patients were aged 15 years or older with a diagnosis of an advanced unresectable or metastatic soft-tissue sarcoma, of intermediate or high grade, for which no standard curative therapy was available, an Eastern Cooperative Oncology Group performance status of 0-1, and measurable disease by Response Evaluation Criteria in Solid Tumors version 1.1. Patients were randomly assigned (1:1) to receive doxorubicin alone (75 mg/m(2) via bolus injection administered over 5-20 min or continuous intravenous infusion for 6-96 h on day 1 of every 21-day cycle for up to six cycles) or doxorubicin (given via the same dose procedure) plus evofosfamide (300 mg/m(2) intravenously for 30-60 min on days 1 and 8 of every 21-day cycle for up to six cycles). After six cycles of treatment, patients in the single-drug doxorubicin group were followed up expectantly whereas patients with stable or responsive disease in the combination group were allowed to continue with evofosfamide monotherapy until documented disease progression. A web-based central randomisation with block sizes of two and four was stratified by extent of disease, doxorubicin administration method, and previous systemic therapy. Patients and investigators were not masked to treatment assignment. The primary endpoint was overall survival, analysed in the intention-to-treat population. Safety analyses were done in all patients who received any amount of study drug. This study was registered with ClinicalTrials.gov, number NCT01440088. Between Sept 26, 2011, and Jan 22, 2014, 640 patients were enrolled and randomly assigned to a treatment group (317 to

  16. Afatinib alone or afatinib plus vinorelbine versus investigator's choice of treatment for HER2-positive breast cancer with progressive brain metastases after trastuzumab, lapatinib, or both (LUX-Breast 3): a randomised, open-label, multicentre, phase 2 trial.

    PubMed

    Cortés, Javier; Dieras, Véronique; Ro, Jungsil; Barriere, Jérôme; Bachelot, Thomas; Hurvitz, Sara; Le Rhun, Emilie; Espié, Marc; Kim, Sung-Bae; Schneeweiss, Andreas; Sohn, Joo Hyuk; Nabholtz, Jean-Marc; Kellokumpu-Lehtinen, Pirkko-Liisa; Taguchi, Julie; Piacentini, Federico; Ciruelos, Eva; Bono, Petri; Ould-Kaci, Mahmoud; Roux, Flavien; Joensuu, Heikki

    2015-12-01

    Patients with advanced HER2-positive breast cancer frequently develop CNS metastases. The metastases that progress after brain radiotherapy and HER2-targeted systemic therapy are a difficult therapeutic challenge. We aimed to assess the efficacy and safety of afatinib, an irreversible blocker of the ErbB protein family, alone or combined with vinorelbine, compared with treatment of the investigator's choice in women with HER2-positive breast cancer with progressive brain metastases during or after treatment with trastuzumab, lapatinib, or both. We did this randomised, open-label, multicentre, phase 2 trial in 40 hospitals in Canada, Finland, France, Germany, Italy, Spain, South Korea, and the USA. Women older than 18 years with histologically confirmed HER2-overexpressing breast cancer and CNS recurrence or progression as determined by Response Evaluation Criteria in Solid Tumors (RECIST version 1.1) during or after treatment with trastuzumab, lapatinib, or both, were eligible. We randomly assigned patients (1:1:1) centrally to afatinib 40 mg orally once per day, afatinib 40 mg per day plus intravenous vinorelbine 25 mg/m(2) once per week, or investigator's choice of treatment in cycles of 3 weeks until disease progression, patient withdrawal, or unacceptable toxicity. Treatment assignment was not masked for clinicians or patients, but the trial team was masked until database lock to reduce bias. The primary endpoint, assessed in the intention-to-treat population, was patient benefit at 12 weeks, defined by an absence of CNS or extra-CNS disease progression, no tumour-related worsening of neurological signs or symptoms, and no increase in corticosteroid dose. Safety was assessed in all patients who received at least one dose of a study drug. This completed trial is registered with ClinicalTrials.gov, number NCT01441596. Between Dec 22, 2011, and Feb 12, 2013, we screened 132 patients, of whom 121 were eligible and randomly assigned to treatment: 40 to afatinib

  17. Oral all-trans retinoic acid plus danazol versus danazol as second-line treatment in adults with primary immune thrombocytopenia: a multicentre, randomised, open-label, phase 2 trial.

    PubMed

    Feng, Fei-Er; Feng, Ru; Wang, Min; Zhang, Jia-Min; Jiang, Hao; Jiang, Qian; Lu, Jin; Liu, Hui; Peng, Jun; Hou, Ming; Shen, Jian-Liang; Wang, Jing-Wen; Xu, Lan-Ping; Liu, Kai-Yan; Huang, Xiao-Jun; Zhang, Xiao-Hui

    2017-10-01

    Primary immune thrombocytopenia is a severe bleeding disorder. About 50-85% of patients achieve initial remission from first-line therapies, but optimal second-line treatment remains a challenge. All-trans retinoic acid (ATRA) has an immunomodulatory effect on haemopoiesis, making it a possible treatment option. We aimed to evaluate the efficacy and safety of ATRA plus danazol versus danazol in non-splenectomised patients with corticosteroid-resistant or relapsed primary immune thrombocytopenia. We did a multicentre, randomised, open-label, phase 2 study of adult patients (≥18 years) with primary immune thrombocytopenia from five different tertiary medical centres in China. Those eligible were non-splenectomised, resistant to corticosteroid treatment or relapsed, and had a platelet count less than 30 × 10(9) per L. Masked statisticians used simple randomisation to assign patients (1:1) to receive oral ATRA (10 mg twice daily) plus oral danazol (200 mg twice daily) or oral danazol monotherapy (200 mg twice daily) for 16 weeks. Neither clinicians nor patients were masked to group assignments. All patients were assessed every week during the first 8 weeks of treatment, and at 2-week intervals thereafter. The primary endpoint was 12-month sustained response defined as platelet count of 30 × 10(9) per L or more and at least a doubling of baseline platelet count (partial response), or a platelet count of 100 × 10(9) per L or more (complete response) and the absence of bleeding without rescue medication at the 12-month follow-up. All randomly allocated patients, except for those who withdrew consent, were included in the modified intention-to-treat population and efficacy assessment, and all patients who received at least one dose of the study agents were included in the safety analysis. Study enrolment was stopped early because the trial results crossed the interim analysis efficacy boundary for sustained response. This trial is registered with Clinical

  18. Etirinotecan pegol (NKTR-102) versus treatment of physician's choice in women with advanced breast cancer previously treated with an anthracycline, a taxane, and capecitabine (BEACON): a randomised, open-label, multicentre, phase 3 trial.

    PubMed

    Perez, Edith A; Awada, Ahmad; O'Shaughnessy, Joyce; Rugo, Hope S; Twelves, Chris; Im, Seock-Ah; Gómez-Pardo, Patricia; Schwartzberg, Lee S; Diéras, Veronique; Yardley, Denise A; Potter, David A; Mailliez, Audrey; Moreno-Aspitia, Alvaro; Ahn, Jin-Seok; Zhao, Carol; Hoch, Ute; Tagliaferri, Mary; Hannah, Alison L; Cortes, Javier

    2015-11-01

    New options are needed for patients with heavily pretreated breast cancer. Etirinotecan pegol is a long-acting topoisomerase-I inhibitor that prolongs exposure to, but reduces the toxicity of, SN38 (the active metabolite of irinotecan). We assessed whether etirinotecan pegol is superior to currently available treatments for patients with previously treated, locally recurrent or metastatic breast cancer. In this open-label, multicentre, randomised phase 3 study (BEACON; BrEAst Cancer Outcomes with NKTR-102), conducted at 135 sites in 11 countries, patients with locally recurrent or metastatic breast cancer previously treated with an anthracycline, a taxane, and capecitabine (and two to five previous regimens for advanced disease) were randomly assigned (1:1) centrally via an interactive response system to etirinotecan pegol (145 mg/m(2) as a 90-min intravenous infusion every 3 weeks) or single-drug treatment of physician's choice. Patients with stable brain metastases and an Eastern Cooperative Oncology Group performance status of 0-1 were eligible. Randomisation was stratified with a permuted block scheme by region, previous eribulin, and receptor status. After randomisation, patients and investigators were aware of treatment assignments. The primary endpoint was overall survival in the intention-to-treat population. This study is registered with ClinicalTrials.gov, number NCT01492101. Between Dec 19, 2011, and Aug 20, 2013, 852 patients were randomly assigned; 429 to etirinotecan pegol and 423 to treatment of physician's choice. There was no significant difference in overall survival between groups (median 12·4 months [95% CI 11·0-13·6] for the etirinotecan pegol group vs 10·3 months [9·0-11·3] for the treatment of physician's choice group; hazard ratio 0·87 [95% CI 0·75-1·02]; p=0·084). The safety population includes the 831 patients who received at least one dose of assigned treatment (425 assigned to etirinotecan pegol and 406 to treatment of

  19. Salvage radiotherapy with or without short-term hormone therapy for rising prostate-specific antigen concentration after radical prostatectomy (GETUG-AFU 16): a randomised, multicentre, open-label phase 3 trial.

    PubMed

    Carrie, Christian; Hasbini, Ali; de Laroche, Guy; Richaud, Pierre; Guerif, Stéphane; Latorzeff, Igor; Supiot, Stéphane; Bosset, Mathieu; Lagrange, Jean-Léon; Beckendorf, Véronique; Lesaunier, François; Dubray, Bernard; Wagner, Jean-Philippe; N'Guyen, Tan Dat; Suchaud, Jean-Philippe; Créhange, Gilles; Barbier, Nicolas; Habibian, Muriel; Ferlay, Céline; Fourneret, Philippe; Ruffion, Alain; Dussart, Sophie

    2016-06-01

    How best to treat rising prostate-specific antigen (PSA) concentration after radical prostatectomy is an urgent clinical question. Salvage radiotherapy delays the need for more aggressive treatment such as long-term androgen suppression, but fewer than half of patients benefit from it. We aimed to establish the effect of adding short-term androgen suppression at the time of salvage radiotherapy on biochemical outcome and overall survival in men with rising PSA following radical prostatectomy. This open-label, multicentre, phase 3, randomised controlled trial, was done in 43 French study centres. We enrolled men (aged ≥18 years) who had received previous treatment for a histologically confirmed adenocarcinoma of the prostate (but no previous androgen deprivation therapy or pelvic radiotherapy), and who had stage pT2, pT3, or pT4a (bladder neck involvement only) in patients who had rising PSA of 0·2 to less than 2·0 μg/L following radical prostatectomy, without evidence of clinical disease. Patients were randomly assigned (1:1) centrally via an interactive web response system to standard salvage radiotherapy (three-dimensional [3D] conformal radiotherapy or intensity modulated radiotherapy, of 66 Gy in 33 fractions 5 days a week for 7 weeks) or radiotherapy plus short-term androgen suppression using 10·8 mg goserelin by subcutaneous injection on the first day of irradiation and 3 months later. Randomisation was stratified using a permuted block method according to investigational site, radiotherapy modality, and prognosis. The primary endpoint was progression-free survival, analysed in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, number NCT00423475. Between Oct 19, 2006, and March 30, 2010, 743 patients were randomly assigned, 374 to radiotherapy alone and 369 to radiotherapy plus goserelin. Patients assigned to radiotherapy plus goserelin were significantly more likely than patients in the radiotherapy alone group to be

  20. Adalimumab for prevention of uveitic flare in patients with inactive non-infectious uveitis controlled by corticosteroids (VISUAL II): a multicentre, double-masked, randomised, placebo-controlled phase 3 trial.

    PubMed

    Nguyen, Quan Dong; Merrill, Pauline T; Jaffe, Glenn J; Dick, Andrew D; Kurup, Shree Kumar; Sheppard, John; Schlaen, Ariel; Pavesio, Carlos; Cimino, Luca; Van Calster, Joachim; Camez, Anne A; Kwatra, Nisha V; Song, Alexandra P; Kron, Martina; Tari, Samir; Brézin, Antoine P

    2016-09-17

    Non-infectious uveitis is a potentially sight-threatening ocular disorder caused by chronic inflammation and its complications. Therapeutic success is limited by systemic adverse effects associated with long-term corticosteroid and immunomodulator use if topical medication is not sufficient to control the inflammation. We aimed to assess the efficacy and safety of adalimumab in patients with inactive, non-infectious uveitis controlled by systemic corticosteroids. We did this multicentre, double-masked, randomised, placebo-controlled phase 3 trial at 62 study sites in 21 countries in the USA, Canada, Europe, Israel, Australia, and Latin America. Patients (aged ≥18 years) with inactive, non-infectious intermediate, posterior, or panuveitic uveitis controlled by 10-35 mg/day of prednisone were randomly assigned (1:1), via an interactive voice and web response system with a block size of four, to receive either subcutaneous adalimumab (loading dose 80 mg; biweekly dose 40 mg) or placebo, with a mandatory prednisone taper from week 2. Randomisation was stratified by baseline immunosuppressant treatment. Sponsor personnel with direct oversight of the conduct and management of the study, investigators, study site personnel, and patients were masked to treatment allocation. The primary efficacy endpoint was time to treatment failure, a multicomponent endpoint encompassing new active inflammatory chorioretinal or inflammatory retinal vascular lesions, anterior chamber cell grade, vitreous haze grade, and visual acuity. Analysis was done in the intention-to-treat population. This trial is registered with ClinicalTrials.gov number NCT01124838. Between Aug 10, 2010, and May 14, 2015, we randomly assigned 229 patients to receive placebo (n=114) or adalimumab (n=115); 226 patients comprised the intention-to-treat population. Median follow-up time was 155 days (IQR 77-357) in the placebo group and 245 days (119-564) in the adalimumab group. Treatment failure occurred in 61 (55

  1. Efficacy of mepolizumab add-on therapy on health-related quality of life and markers of asthma control in severe eosinophilic asthma (MUSCA): a randomised, double-blind, placebo-controlled, parallel-group, multicentre, phase 3b trial.

    PubMed

    Chupp, Geoffrey L; Bradford, Eric S; Albers, Frank C; Bratton, Daniel J; Wang-Jairaj, Jie; Nelsen, Linda M; Trevor, Jennifer L; Magnan, Antoine; Ten Brinke, Anneke

    2017-05-01

    Mepolizumab, an anti-interleukin-5 monoclonal antibody approved as add-on therapy to standard of care for patients with severe eosinophilic asthma, has been shown in previous studies to reduce exacerbations and dependency on oral corticosteroids compared with placebo. We aimed to further assess mepolizumab in patients with severe eosinophilic asthma by examining its effect on health-related quality of life (HRQOL). We did a randomised, double-blind, placebo-controlled, parallel-group, multicentre, phase 3b trial (MUSCA) in 146 hospitals or research centres in 19 countries worldwide. Eligible participants were patients aged 12 years or older with severe eosinophilic asthma and a history of at least two exacerbations requiring treatment in the previous 12 months before screening despite regular use of high-dose inhaled corticosteroids plus other controller medicines. Exclusion criteria included current smokers or former smokers with a history of at least ten pack-years. We randomly assigned participants (1:1) by country to receive a subcutaneous injection of either mepolizumab 100 mg or placebo, plus standard of care, every 4 weeks for 24 weeks (the final dose was given at week 20). We did the randomisation using an interactive voice response system and a centralised, computer-generated, permuted-block design of block size six. The two treatments were identical in appearance and administered in a masked manner; patients, investigators, other site staff and the entire study team including those assessing outcomes data were also masked to group assignment. The primary endpoint was the mean change from baseline in the St George's Respiratory Questionnaire (SGRQ) total score at week 24 in the modified intention-to-treat (modified ITT) population (analysed according to their randomly assigned treatment). Safety was assessed in all patients who received at least one dose of trial medication (analysed according to the actual treatment received). This trial is registered

  2. Hydroxycarbamide versus chronic transfusion for maintenance of transcranial doppler flow velocities in children with sickle cell anaemia-TCD With Transfusions Changing to Hydroxyurea (TWiTCH): a multicentre, open-label, phase 3, non-inferiority trial.

    PubMed

    Ware, Russell E; Davis, Barry R; Schultz, William H; Brown, R Clark; Aygun, Banu; Sarnaik, Sharada; Odame, Isaac; Fuh, Beng; George, Alex; Owen, William; Luchtman-Jones, Lori; Rogers, Zora R; Hilliard, Lee; Gauger, Cynthia; Piccone, Connie; Lee, Margaret T; Kwiatkowski, Janet L; Jackson, Sherron; Miller, Scott T; Roberts, Carla; Heeney, Matthew M; Kalfa, Theodosia A; Nelson, Stephen; Imran, Hamayun; Nottage, Kerri; Alvarez, Ofelia; Rhodes, Melissa; Thompson, Alexis A; Rothman, Jennifer A; Helton, Kathleen J; Roberts, Donna; Coleman, Jamie; Bonner, Melanie J; Kutlar, Abdullah; Patel, Niren; Wood, John; Piller, Linda; Wei, Peng; Luden, Judy; Mortier, Nicole A; Stuber, Susan E; Luban, Naomi L C; Cohen, Alan R; Pressel, Sara; Adams, Robert J

    2016-02-13

    For children with sickle cell anaemia and high transcranial doppler (TCD) flow velocities, regular blood transfusions can effectively prevent primary stroke, but must be continued indefinitely. The efficacy of hydroxycarbamide (hydroxyurea) in this setting is unknown; we performed the TWiTCH trial to compare hydroxyurea with standard transfusions. TWiTCH was a multicentre, phase 3, randomised, open-label, non-inferiority trial done at 26 paediatric hospitals and health centres in the USA and Canada. We enrolled children with sickle cell anaemia who were aged 4-16 years and had abnormal TCD flow velocities (≥ 200 cm/s) but no severe vasculopathy. After screening, eligible participants were randomly assigned 1:1 to continue standard transfusions (standard group) or hydroxycarbamide (alternative group). Randomisation was done at a central site, stratified by site with a block size of four, and an adaptive randomisation scheme was used to balance the covariates of baseline age and TCD velocity. The study was open-label, but TCD examinations were read centrally by observers masked to treatment assignment and previous TCD results. Participants assigned to standard treatment continued to receive monthly transfusions to maintain 30% sickle haemoglobin or lower, while those assigned to the alternative treatment started oral hydroxycarbamide at 20 mg/kg per day, which was escalated to each participant's maximum tolerated dose. The treatment period lasted 24 months from randomisation. The primary study endpoint was the 24 month TCD velocity calculated from a general linear mixed model, with the non-inferiority margin set at 15 cm/s. The primary analysis was done in the intention-to-treat population and safety was assessed in all patients who received at least one dose of assigned treatment. This study is registered with ClinicalTrials.gov, number NCT01425307. Between Sept 20, 2011, and April 17, 2013, 159 patients consented and enrolled in TWiTCH. 121 participants passed

  3. Efficacy and safety of 6.25 mg t.i.d. feverfew CO2-extract (MIG-99) in migraine prevention--a randomized, double-blind, multicentre, placebo-controlled study.

    PubMed

    Diener, H C; Pfaffenrath, V; Schnitker, J; Friede, M; Henneicke-von Zepelin, H-H

    2005-11-01

    The efficacy and tolerability of a CO(2)-extract of feverfew (MIG-99, 6.25 mg t.i.d.) for migraine prevention were investigated in a randomized, double-blind, placebo-controlled, multicentre, parallel-group study. Patients (N = 170 intention-to-treat; MIG-99, N = 89; placebo, N = 81) suffering from migraine according to International Headache Society criteria were treated for 16 weeks after a 4-week baseline period. The primary endpoint was the average number of migraine attacks per 28 days during the treatment months 2 and 3 compared with baseline. Safety parameters included adverse events, laboratory parameters, vital signs and physical examination. The migraine frequency decreased from 4.76 by 1.9 attacks per month in the MIG-99 group and by 1.3 attacks in the placebo group (P = 0.0456). Logistic regression of responder rates showed an odds ratio of 3.4 in favour of MIG-99 (P = 0.0049). Adverse events possibly related to study medication were 9/107 (8.4%) with MIG-99 and 11/108 (10.2%) with placebo (P = 0.654). MIG-99 is effective and shows a favourable benefit-risk ratio.

  4. Deep Learning the Quantum Phase Transitions in Random Two-Dimensional Electron Systems

    NASA Astrophysics Data System (ADS)

    Ohtsuki, Tomoki; Ohtsuki, Tomi

    2016-12-01

    Random electron systems show rich phases such as Anderson insulator, diffusive metal, quantum Hall and quantum anomalous Hall insulators, Weyl semimetal, as well as strong/weak topological insulators. Eigenfunctions of each matter phase have specific features, but owing to the random nature of systems, determining the matter phase from eigenfunctions is difficult. Here, we propose the deep learning algorithm to capture the features of eigenfunctions. Localization-delocalization transition, as well as disordered Chern insulator-Anderson insulator transition, is discussed.

  5. Vulnerability of impulse attack-free four random phase mask cryptosystems to chosen-plaintext attack

    NASA Astrophysics Data System (ADS)

    Li, Tuo; Shi, Yishi

    2016-03-01

    An attack-free four random phase mask cryptosystem is breached in the paper. The decryption key of the system can be easily accessed by the opponent by using a new type of powerful three-dimensional phase retrieval method. Our result, to the best of our knowledge, is the first work to show this security flaw in the attack-free four random phase mask cryptosystem. Meanwhile, a set of numerical simulations is provided to demonstrate the robustness of the presented method.

  6. Shaping the spectrum of random-phase radar waveforms

    DOEpatents

    Doerry, Armin W.; Marquette, Brandeis

    2017-05-09

    The various technologies presented herein relate to generation of a desired waveform profile in the form of a spectrum of apparently random noise (e.g., white noise or colored noise), but with precise spectral characteristics. Hence, a waveform profile that could be readily determined (e.g., by a spoofing system) is effectively obscured. Obscuration is achieved by dividing the waveform into a series of chips, each with an assigned frequency, wherein the sequence of chips are subsequently randomized. Randomization can be a function of the application of a key to the chip sequence. During processing of the echo pulse, a copy of the randomized transmitted pulse is recovered or regenerated against which the received echo is correlated. Hence, with the echo energy range-compressed in this manner, it is possible to generate a radar image with precise impulse response.

  7. Anomalously elastic intermediate phase in randomly layered superfluids, superconductors, and planar magnets.

    PubMed

    Mohan, Priyanka; Goldbart, Paul M; Narayanan, Rajesh; Toner, John; Vojta, Thomas

    2010-08-20

    We show that layered quenched randomness in planar magnets leads to an unusual intermediate phase between the conventional ferromagnetic low-temperature and paramagnetic high-temperature phases. In this intermediate phase, which is part of the Griffiths region, the spin-wave stiffness perpendicular to the random layers displays anomalous scaling behavior, with a continuously variable anomalous exponent, while the magnetization and the stiffness parallel to the layers both remain finite. Analogous results hold for superfluids and superconductors. We study the two phase transitions into the anomalous elastic phase, and we discuss the universality of these results, and implications of finite sample size as well as possible experiments.

  8. From open to large-scale randomized cell transplantation trials in Huntington's disease: Lessons from the multicentric intracerebral grafting in Huntington's disease trial (MIG-HD) and previous pilot studies.

    PubMed

    Bachoud-Lévi, Anne-Catherine

    2017-01-01

    Fifty-one patients from open-label pilot trials have been transplanted in Huntington's disease (HD) using human fetal cells; clinical data and follow-up are available in 30 of them. These open-label studies were mostly designed for safety and feasibility. However, signs of long-term efficacy have been reported in 4 out of 30 patients, differences in tissue preparation, surgical procedure, patients characteristics, immunosuppression regimens, clinical, and imaging assessments, makes it difficult to define the optimal procedure for future trials. Forty-five patients have now been grafted in the multicentric intracerebral grafting trial in Huntington's in France (MIG-HD) and Belgium, and 22 in Germany in a randomized delayed start design. Whereas the 10 patients published from the German cohort showed no improvement, the results from the MIG-HD trial are still under analysis. However, the MIG-HD trial has already changed cell transplantation for HD by showing alloimmunization with graft rejection in one patient and HLA antibodies against the transplant in others. Moreover, MIG-HD has established a new surgical procedure to avoid subdural hematoma, the most frequent adverse effect in transplant in HD, and a surgical strategy to eradicate eventual choroid cysts. By reviewing all the published results, new avenues are provided for optimization for cell preparation, delivery methods, standardization of clinical assessment, and surgical procedure with blind video scoring, imaging, and electrophysiology. Future trials should capitalize on a new CAPIT-HD2 battery to determine efficacy with sufficiently long pre and postgraft follow-up, using patient stratification and randomization, control of alloimmunization, HLA monitoring, and standardization of the consent procedure. © 2017 Elsevier B.V. All rights reserved.

  9. Predictors of haemoglobin levels and resistance to erythropoiesis-stimulating agents in patients treated with low-flux haemodialysis, haemofiltration and haemodiafiltration: results of a multicentre randomized and controlled trial

    PubMed Central

    Locatelli, Francesco; Altieri, Paolo; Andrulli, Simeone; Sau, Giovanna; Bolasco, Piergiorgio; Pedrini, Luciano A.; Basile, Carlo; David, Salvatore; Feriani, Mariano; Nebiolo, Pier Eugenio; Ferrara, Rocco; Casu, Domenica; Logias, Francesco; Tarchini, Renzo; Cadinu, Francesco; Passaghe, Mario; Fundoni, Gianfranco; Villa, Giuseppe; Di Iorio, Biagio Raffaele; Zoccali, Carmine

    2012-01-01

    Background Predictors of haemoglobin (Hb) levels and resistance to erythropoiesis-stimulating agents (ESAs) in dialysis patients have not yet been clearly defined. Some mainly uncontrolled studies suggest that online haemodiafiltration (HDF) may have a beneficial effect on Hb, whereas no data are available concerning online haemofiltration (HF). The objectives of this study were to evaluate the effects of convective treatments (CTs) on Hb levels and ESA resistance in comparison with low-flux haemodialysis (HD) and to evaluate the predictors of these outcomes. Methods Primary multivariate analysis was made of a pre-specified secondary outcome of a multicentre, open-label, randomized controlled study in which 146 chronic HD patients from 27 Italian centres were randomly assigned to HD (70 patients) or CTs: online pre-dilution HF (36 patients) or online pre-dilution HDF (40 patients). Results CTs did not affect Hb levels (P = 0.596) or ESA resistance (P = 0.984). Hb correlated with polycystic kidney disease (P = 0.001), C-reactive protein (P = 0.025), ferritin (P = 0.018), ESA dose (P < 0.001) and total cholesterol (P = 0.021). The participating centres were the main source of Hb variability (partial eta2 0.313, P < 0.001). ESA resistance directly correlated with serum ferritin (P = 0.030) and beta2 microglobulin (P = 0.065); participating centres were again a major source of variance (partial eta2 0.367, P < 0.001). Transferrin saturation did not predict either outcome variables (P = 0.277 and P = 0.170). Conclusions In comparison with low-flux HD, CTs did not significantly improve Hb levels or ESA resistance. The main sources of variability were participating centres, ESA dose and the underlying disease. PMID:22622452

  10. One-year follow-up results from AUGMENT-HF: a multicentre randomized controlled clinical trial of the efficacy of left ventricular augmentation with Algisyl in the treatment of heart failure.

    PubMed

    Mann, Douglas L; Lee, Randall J; Coats, Andrew J S; Neagoe, Gheorghe; Dragomir, Dinu; Pusineri, Enrico; Piredda, Massimo; Bettari, Luca; Kirwan, Bridget-Anne; Dowling, Robert; Volterrani, Maurizio; Solomon, Scott D; Sabbah, Hani N; Hinson, Andy; Anker, Stefan D

    2016-03-01

    AUGMENT-HF was an international, multicentre, prospective, open-label, randomized, controlled evaluation testing the hypothesis that Algisyl (injectable calcium alginate hydrogel) is superior to standard medical therapy (SMT) for improving functional capacity and clinical outcomes in patients with advanced heart failure (HF). We previously reported results following 6 months of follow-up. This report presents the results from 1 year of extended follow up for this clinical trial. We enrolled 78 patients with advanced HF, randomized (1:1), to Algisyl with SMT or SMT alone as previously reported. Patient inclusion criteria were LVEF ≤35%, peak VO2 of 9.0-14.5 mL/min/kg and LV end-diastolic diameter (LVEDD) index 30-40 mm/m(2) (LVEDD/body surface area). Patients must have been on stable, evidence-based therapy for HF. A total of 58 patients, mean age 62.3 ± 9.6 years, with ischaemic (57.7%) or non-ischaemic (42.3%) HF completed 12 months of follow-up. Treatment with Algisyl was associated with improved peak VO2 at 12 months; treatment effect vs. control of +2.10 mL/kg/min (95% confidence interval 0.96-3.24, P < 0.001). Statistically significant improvements were observed for VO2 at anaerobic threshold, 6-min walk test distance, and NYHA functional class (all P < 0.001). Through 12 months of follow-up there were 4 (10.5%) deaths in the control group and 9 (22.5%) deaths in the Algisyl group. Algisyl in addition to SMT was more effective than SMT alone for providing sustained 1-year benefits in exercise capacity, symptoms, and clinical status for patients with advanced HF. These data support larger clinical evaluations of this novel therapy. © 2015 The Authors European Journal of Heart Failure © 2015 European Society of Cardiology.

  11. Hormone-Balancing Effect of Pre-Gelatinized Organic Maca (Lepidium peruvianum Chacon): (II) Physiological and Symptomatic Responses of Early-Postmenopausal Women to Standardized doses of Maca in Double Blind, Randomized, Placebo-Controlled, Multi-Centre Clinical Study.

    PubMed

    Meissner, H O; Mscisz, A; Reich-Bilinska, H; Kapczynski, W; Mrozikiewicz, P; Bobkiewicz-Kozlowska, T; Kedzia, B; Lowicka, A; Barchia, I

    2006-12-01

    This was a double-blind, randomized, placebo-corrected, outpatient, multi-centre (five sites) clinical study, in which a total of 168 Caucasian early-postmenopausal women volunteers (age>49 years) participated after fulfilling the criteria: follicle stimulating hormone (FSH) >30 IU/ml and estrogen (E2) <40 pg/ml levels at admission. They were randomly allocated to Placebo and Pre-Gelatinized Organic Maca (Maca-GO) treatment, according to different monthly treatment sequences scheduled for each site. Two 500 mg vegetable hard gel capsules with Maca-GO or Placebo powder were self-administered twice daily with meals (total 2 g/day) during three (Trial I; n=102) or four (Trial II; n=66) months study periods. At the baseline and follow- up monthly intervals, blood levels of FSH, E2, progesterone (PRG) and lutinizing hormone (LH), as well as serum cholesterol (CHOL), triglycerides (TRG), high- and low density lipoproteins (HDL and LDL) were measured. Menopausal symptoms were assessed according to Greene's Score (GMS) and Kupperman's Index (KMI). Data were analyzed using multivariate technique on blocs of monthly results in one model and Maca versus Placebo contrast in another model. A total of 124 women concluded the study. Maca-GO significantly stimulated production of E2 (P<0.001) with a simultaneous suppression (P<0.05) of blood FSH, increase (P<0.05) in HDL. Maca-GO significantly reduced both frequency and severity of individual menopausal symptoms (hot flushes and night sweating in particular) resulting in significant (P<0.001) alleviation of KMI (from 22 to 10), thus, offering an attractive non-hormonal addition to the choices available to early-postmenopausal women in the form of a natural plant alternative to Hormone Replacement Therapy (HRT) - hence, reducing dependence on hormone therapy programs.

  12. Efficacy of intensified hyperfractionated and accelerated radiotherapy and concurrent chemotherapy with carboplatin and 5-fluorouracil: Updated results of a randomized multicentric trial in advanced head-and-neck cancer

    SciTech Connect

    Semrau, Robert . E-mail: Robert.Semrau@uk-koeln.de; Mueller, Rolf-Peter; Stuetzer, Hartmut; Staar, Susanne; Schroeder, Ursula; Guntinas-Lichius, Orlando; Kocher, Martin; Eich, Hans Theodor; Dietz, Andreas; Flentje, Michael; Rudat, Volker; Volling, Peter; Schroeder, Michael; Eckel, Hans Edmund

    2006-04-01

    Purpose: To prove an expected benefit of concurrent radiochemotherapy (RCT), a two-arm randomized multicentric study was performed. In a subgroup analysis the influence of pretherapeutical hemoglobin level (p-Hb) on survival under locoregional control (SLC) was tested. Patients and Methods: The study included primarily untreated Stage III/IV (International Union Against Cancer [UICC]) oropharyngeal and hypopharyngeal carcinomas. Patients were randomized to receive either hyperfractionated (hf) and accelerated (acc) RCT with two cycles 5-fluorouracil (600 mg/m{sup 2}/day) and carboplatin (70 mg/m{sup 2}/day) on Days 1-5 and 29-33 or hf-acc radiotherapy (RT) alone. Total RT dose in both arms was 69.9 Gy in 38 days in concomitant boost technique. Results: After a median follow-up time of 57 months, SLC is significantly better in RCT than in RT (p = 0.01), with median SLC of 17 months and 11 months, respectively. Also overall survival (OS) shows a benefit for RCT (p 0.016), with a median survival of 23 months for RCT and 16 months for RT. However, the benefit in SLC and OS is not seen in hypopharyngeal carcinomas. In a multivariate analysis of oropharyngeal cancer patients, p-Hb levels lower than 12.7 g/dL resulted in lower SLC compared with higher p-Hb levels up to 13.8 g/dL. P-Hb levels >13.8 g/dL did not further improve SLC. Conclusions: Hyperfractionated-accelerated RCT is superior to hf-acc RT in oropharyngeal carcinomas. P-Hb levels >13.8 g/dL do not further improve SLC.

  13. Eribulin versus dacarbazine in previously treated patients with advanced liposarcoma or leiomyosarcoma: a randomised, open-label, multicentre, phase 3 trial.

    PubMed

    Schöffski, Patrick; Chawla, Sant; Maki, Robert G; Italiano, Antoine; Gelderblom, Hans; Choy, Edwin; Grignani, Giovanni; Camargo, Veridiana; Bauer, Sebastian; Rha, Sun Young; Blay, Jean-Yves; Hohenberger, Peter; D'Adamo, David; Guo, Matthew; Chmielowski, Bartosz; Le Cesne, Axel; Demetri, George D; Patel, Shreyaskumar R

    2016-04-16

    A non-randomised, phase 2 study showed activity and tolerability of eribulin in advanced or metastatic soft-tissue sarcoma. In this phase 3 study, we aimed to compare overall survival in patients with advanced or metastatic soft-tissue sarcoma who received eribulin with that in patients who received dacarbazine (an active control). We did this randomised, open-label, phase 3 study across 110 study sites in 22 countries. We enrolled patients aged 18 years or older with intermediate-grade or high-grade advanced liposarcoma or leiomyosarcoma who had received at least two previous systemic regimens for advanced disease (including an anthracycline). Using an interactive voice and web response system, an independent statistician randomly assigned (1:1) patients to receive eribulin mesilate (1·4 mg/m(2) intravenously on days 1 and 8) or dacarbazine (850 mg/m(2), 1000 mg/m(2), or 1200 mg/m(2) [dose dependent on centre and clinician] intravenously on day 1) every 21 days until disease progression. Randomisation was stratified by disease type, geographical region, and number of previous regimens for advanced soft-tissue sarcoma and in blocks of six. Patients and investigators were not masked to treatment assignment. The primary endpoint was overall survival in the intention-to-treat population. The study is registered with ClinicalTrials.gov, number NCT01327885, and is closed to recruitment, but treatment and follow-up continue. Between March 10, 2011 and May 22, 2013, we randomly assigned patients to eribulin (n=228) or dacarbazine (n=224). Overall survival was significantly improved in patients assigned to eribulin compared with those assigned to dacarbazine (median 13·5 months [95% CI 10·9-15·6] vs 11·5 months [9·6-13·0]; hazard ratio 0·77 [95% CI 0·62-0·95]; p=0·0169). Treatment-emergent adverse events occurred in 224 (99%) of 226 patients who received eribulin and 218 (97%) of 224 who received dacarbazine. Grade 3 or higher adverse events were more common in

  14. Atezolizumab in patients with locally advanced and metastatic urothelial carcinoma who have progressed following treatment with platinum-based chemotherapy: a single-arm, multicentre, phase 2 trial.

    PubMed

    Rosenberg, Jonathan E; Hoffman-Censits, Jean; Powles, Tom; van der Heijden, Michiel S; Balar, Arjun V; Necchi, Andrea; Dawson, Nancy; O'Donnell, Peter H; Balmanoukian, Ani; Loriot, Yohann; Srinivas, Sandy; Retz, Margitta M; Grivas, Petros; Joseph, Richard W; Galsky, Matthew D; Fleming, Mark T; Petrylak, Daniel P; Perez-Gracia, Jose Luis; Burris, Howard A; Castellano, Daniel; Canil, Christina; Bellmunt, Joaquim; Bajorin, Dean; Nickles, Dorothee; Bourgon, Richard; Frampton, Garrett M; Cui, Na; Mariathasan, Sanjeev; Abidoye, Oyewale; Fine, Gregg D; Dreicer, Robert

    2016-05-07

    Patients with metastatic urothelial carcinoma have few treatment options after failure of platinum-based chemotherapy. In this trial, we assessed treatment with atezolizumab, an engineered humanised immunoglobulin G1 monoclonal antibody that binds selectively to programmed death ligand 1 (PD-L1), in this patient population. For this multicentre, single-arm, two-cohort, phase 2 trial, patients (aged ≥18 years) with inoperable locally advanced or metastatic urothelial carcinoma whose disease had progressed after previous platinum-based chemotherapy were enrolled from 70 major academic medical centres and community oncology practices in Europe and North America. Key inclusion criteria for enrolment were Eastern Cooperative Oncology Group performance status of 0 or 1, measurable disease defined by Response Evaluation Criteria In Solid Tumors version 1.1 (RECIST v1.1), adequate haematological and end-organ function, and no autoimmune disease or active infections. Formalin-fixed paraffin-embedded tumour specimens with sufficient viable tumour content were needed from all patients before enrolment. Patients received treatment with intravenous atezolizumab (1200 mg, given every 3 weeks). PD-L1 expression on tumour-infiltrating immune cells (ICs) was assessed prospectively by immunohistochemistry. The co-primary endpoints were the independent review facility-assessed objective response rate according to RECIST v1.1 and the investigator-assessed objective response rate according to immune-modified RECIST, analysed by intention to treat. A hierarchical testing procedure was used to assess whether the objective response rate was significantly higher than the historical control rate of 10% at an α level of 0·05. This study is registered with ClinicalTrials.gov, number NCT02108652. Between May 13, 2014, and Nov 19, 2014, 486 patients were screened and 315 patients were enrolled into the study. Of these patients, 310 received atezolizumab treatment (five enrolled patients

  15. Random fields and phase transitions in model magnetic systems

    NASA Astrophysics Data System (ADS)

    Birgeneau, R. J.

    1998-01-01

    Random fields occur in a wide variety of physical systems varying from type II superconductors to two-component fluids in a random medium. However, only in model magnetic systems have systematic studies as a function of both temperature and random-field strength been possible. In this article we review recent neutron and magnetic X-ray scattering studies of the magnetic ordering processes in the antiferromagnets Mn 0.75Zn 0.25F 2, Fe 0.5Zn 0.5F 2 and Fe 0.75Co 0.25TiO 3 in an applied magnetic field. These systems should all represent realizations of the three-dimensional random-field Ising model which is the simplest version of the random-field problem in models with discrete symmetry. In all cases on field cooling (FC) the systems evolve continuously from a high-temperature paramagnetic state to a low-temperature antiferromagnetic domain state. However, on cooling to low temperatures in zero field and then applying a field (ZFC) long-range order (LRO) is obtained. On subsequent heating in the three systems the LRO vanishes continuously with a rounded power-law behavior which has been labelled trompe l'oeil critical behavior. The width of the transition region scales as H2. Reconsideration of indirect ZFC specific-heat measurements shows that the observed peaks, previously attributed to equilibrium critical fluctuations, instead arise entirely from a LRO contribution, scaling like dM s2/dT , to the measured quantity. Here Ms is the staggered magnetization. These results thus reconcile scattering and bulk property measurements of random-field Ising systems.

  16. Phase transitions, magnetism and surface adsorptions assessed by meta-GGA functionals and random phase approximation

    NASA Astrophysics Data System (ADS)

    Xiao, Bing

    The meta-GGA functionals and random phase approximation are tested for phase transitions and a strongly correlated transition metal oxide in this dissertation. One of the latest meta-GGA functionals is also employed to study the van der Waals bound system in surface science. Our main purpose is to reveal the performance of new exchange-correlation functionals on various properties and systems. We are also interested in seeking the possible relationship between the performance of a semilocal functional and its exchange enhancement factor. We have studied the structural phase transitions in crystalline Si (insulator to metal), SiO2 (insulator to insulator) and Zr (metal to metal) systems, as a test of exchange energy semilocal functionals on Jacob's ladder. Our results confirm the energy-geometry delimma of GGAs in three systems. The most sophisticated non-empirical meta-generalized gradient approximations (meta-GGAs) such as TPSS (Tao-Perdew-Staroveov-Scuseria) and revTPSS (revised TPSS) give better lattice constants than PBE, but the phase transition parameters (energy difference and transition pressure) are smaller and less realistic than those from the latter GGA. However, the recent functionals of meta-GGA made simple family (MGGA_MS) behave differently to those previous meta-GGAs, predicting larger and more realistic phase transition parameters. Meanwhile, MGGA_MS also delivers the equilibrium geometry of crystalline materials similar to previous non-empirical meta-GGAs. In contrast to semilocal functionals, the nonlocal functionals such as the range-separated hybrid functional HSE06 (Heyd-Scuseria-Ernzerhof) and non-self consistent random phase approximation (RPA) are not only able to give the accurate equilibrium geometry , but also predict the realistic phase transition parameters for Si and SiO2 systems. The ground state of rutile-type vanadium dioxide (R-VO2) represents a great challenge to the current density functional theory. In this dissertation, we

  17. Partition function for a two dimensional plasma in the random phase approximation

    NASA Technical Reports Server (NTRS)

    Seyler, C. E., Jr.

    1974-01-01

    The partition function for a two-dimensional plasma is evaluated within the random phase approximation. The periodic boundary conditions are fully taken into account by including the periodic image interactions. In the guiding-center limit, the negative temperature threshold energy is evaluated, and a value different from previous calculations results. When an identical random phase evaluated, and a value different from previous calculations results. When an identical random phase evaluation is applied to the finite gyroradius plasma, the Salzberg-Prager-May equation of state is recovered.

  18. Number-conserving random phase approximation with analytically integrated matrix elements

    SciTech Connect

    Kyotoku, M. ); Schmid, K.W. ); Gruemmer, F. ); Faessler, A. )

    1990-01-01

    In the present paper a number conserving random phase approximation is derived as a special case of the recently developed random phase approximation in general symmetry projected quasiparticle mean fields. All the occurring integrals induced by the number projection are performed analytically after writing the various overlap and energy matrices in the random phase approximation equation as polynomials in the gauge angle. In the limit of a large number of particles the well-known pairing vibration matrix elements are recovered. We also present a new analytically number projected variational equation for the number conserving pairing problem.

  19. A multicentre randomized controlled trial of gentle assisted pushing in the upright posture (GAP) or upright posture alone compared with routine practice to reduce prolonged second stage of labour (the Gentle Assisted Pushing study): study protocol.

    PubMed

    Hofmeyr, G Justus; Singata, Mandisa; Lawrie, Theresa; Vogel, Joshua P; Landoulsi, Sihem; Seuc, Armando H; Gülmezoglu, A Metin

    2015-12-16

    Fundal pressure (pushing on the upper part of the uterus in the direction of the birth canal) is often performed in routine practice, however the benefit and indications for its use are unclear and vigorous pressure is potentially harmful. There is some evidence that it may be applied routinely or to expedite delivery in some situations (e.g. fetal distress or maternal exhaustion), particularly in settings where other methods of achieving delivery (forceps, vacuum) are not available. Gentle assisted pushing (GAP) is an innovative method of applying gentle but steady pressure to the uterine fundus with the woman in an upright posture. This trial aims to evaluate the use of GAP in an upright posture, or upright posture alone, on reducing the mean time of delivery and the associated maternal and neonatal complications in women not having delivered following 15-30 min in the second stage of labour. We will conduct a multicentre, randomized, unblinded, controlled trial with three parallel arms (1:1:1). 1,145 women will be randomized at three hospitals in South Africa. Women will be eligible for inclusion if they are ≥18 years old, nulliparous, gestational age ≥ 35 weeks, have a singleton pregnancy in cephalic presentation and vaginal delivery anticipated. Women with chronic medical conditions or obstetric complications are not eligible. If eligible women are undelivered following 15-30 min in the second stage of labour, they will be randomly assigned to: 1) GAP in the upright posture, 2) upright posture only and 3) routine practice (recumbent/supine posture). The primary outcome is the mean time from randomization to complete delivery. Secondary outcomes include operative delivery, adverse neonatal outcomes, maternal adverse events and discomfort. This trial will establish whether upright posture and/or a controlled method of applying fundal pressure (GAP) can improve labour outcomes for women and their babies. If fundal pressure is found to have a measurable

  20. Nab-paclitaxel plus either gemcitabine or simplified leucovorin and fluorouracil as first-line therapy for metastatic pancreatic adenocarcinoma (AFUGEM GERCOR): a non-comparative, multicentre, open-label, randomised phase 2 trial.

    PubMed

    Bachet, Jean-Baptiste; Hammel, Pascal; Desramé, Jérôme; Meurisse, Aurélia; Chibaudel, Benoist; André, Thierry; Debourdeau, Philippe; Dauba, Jérome; Lecomte, Thierry; Seitz, Jean-François; Tournigand, Christophe; Aparicio, Thomas; Meyer, Véronique Guerin; Taieb, Julien; Volet, Julien; Monier, Amandine; Bonnetain, Franck; Louvet, Christophe

    2017-05-01

    Nab-paclitaxel plus gemcitabine has become a standard treatment regimen in patients with metastatic pancreatic adenocarcinoma; however, retrospective data suggest that gemcitabine might be inefficient in 50-60% of patients and thus not an optimum regimen in combination with nab-paclitaxel. We did a phase 2 trial to assess the activity and safety of a new regimen of nab-paclitaxel plus simplified leucovorin and fluorouracil. We did a non-comparative, multicentre, open-label, randomised phase 2 trial in 15 hospitals and institutions in France. Eligible participants were previously untreated patients with metastatic pancreatic adenocarcinoma (previous adjuvant chemotherapy after curative intent resection was allowed if the interval between the end of chemotherapy and relapse was more than 12 months). Patients had to have at least one measurable lesion assessed by CT scan or MRI and an Eastern Cooperative Oncology Group (ECOG) performance status of 2 or less. We randomly assigned participants (1:2) centrally to 28-day cycles of either gemcitabine plus nab-paclitaxel or simplified leucovorin and fluorouracil plus nab-paclitaxel. The randomisation was by minimisation, stratified by centre and ECOG performance status. Drugs were administered in each cycle as follows: nab-paclitaxel (125 mg/m(2)) and gemcitabine (1000 mg/m(2)) as 30-min intravenous infusions on days 1, 8, and 15; leucovorin (400 mg/m(2)) as a 120-min intravenous infusion on days 1 and 15; and fluorouracil (400 mg/m(2)) as a 5-min bolus intravenous infusion followed by a 46-h continuous intravenous infusion of 2400 mg/m(2) on days 1 and 15. Patients continued treatment until unacceptable toxicity, disease progression, or patient withdrawal. The primary endpoint was progression-free survival at 4 months in the first 72 assessable patients in the leucovorin and fluorouracil group, with a target of 50% for the regimen to be deemed sufficiently active to warrant further study. We did the primary analysis on the

  1. Ramucirumab versus placebo as second-line treatment in patients with advanced hepatocellular carcinoma following first-line therapy with sorafenib (REACH): a randomised, double-blind, multicentre, phase 3 trial.

    PubMed

    Zhu, Andrew X; Park, Joon Oh; Ryoo, Baek-Yeol; Yen, Chia-Jui; Poon, Ronnie; Pastorelli, Davide; Blanc, Jean-Frederic; Chung, Hyun Cheol; Baron, Ari D; Pfiffer, Tulio Eduardo Flesch; Okusaka, Takuji; Kubackova, Katerina; Trojan, Jorg; Sastre, Javier; Chau, Ian; Chang, Shao-Chun; Abada, Paolo B; Yang, Ling; Schwartz, Jonathan D; Kudo, Masatoshi

    2015-07-01

    VEGF and VEGF receptor-2-mediated angiogenesis contribute to hepatocellular carcinoma pathogenesis. Ramucirumab is a recombinant IgG1 monoclonal antibody and VEGF receptor-2 antagonist. We aimed to assess the safety and efficacy of ramucirumab in advanced hepatocellular carcinoma following first-line therapy with sorafenib. In this randomised, placebo-controlled, double-blind, multicentre, phase 3 trial (REACH), patients were enrolled from 154 centres in 27 countries. Eligible patients were aged 18 years or older, had hepatocellular carcinoma with Barcelona Clinic Liver Cancer stage C disease or stage B disease that was refractory or not amenable to locoregional therapy, had Child-Pugh A liver disease, an Eastern Cooperative Oncology Group performance status of 0 or 1, had previously received sorafenib (stopped because of progression or intolerance), and had adequate haematological and biochemical parameters. Patients were randomly assigned (1:1) to receive intravenous ramucirumab (8 mg/kg) or placebo every 2 weeks, plus best supportive care, until disease progression, unacceptable toxicity, or death. Randomisation was stratified by geographic region and cause of liver disease with a stratified permuted block method. Patients, medical staff, investigators, and the funder were masked to treatment assignment. The primary endpoint was overall survival in the intention-to-treat population. This study is registered with ClinicalTrials.gov, number NCT01140347. Between Nov 4, 2010, and April 18, 2013, 565 patients were enrolled, of whom 283 were assigned to ramucirumab and 282 were assigned to placebo. Median overall survival for the ramucirumab group was 9·2 months (95% CI 8·0-10·6) versus 7·6 months (6·0-9·3) for the placebo group (HR 0·87 [95% CI 0·72-1·05]; p=0·14). Grade 3 or greater adverse events occurring in 5% or more of patients in either treatment group were ascites (13 [5%] of 277 patients treated with ramucirumab vs 11 [4%] of 276 patients treated

  2. Calcium imaging and selective computed tomography angiography in comparison to functional testing for suspected coronary artery disease: the multicentre, randomized CRESCENT trial.

    PubMed

    Lubbers, Marisa; Dedic, Admir; Coenen, Adriaan; Galema, Tjebbe; Akkerhuis, Jurgen; Bruning, Tobias; Krenning, Boudewijn; Musters, Paul; Ouhlous, Mohamed; Liem, Ahno; Niezen, Andre; Hunink, Miriam; de Feijter, Pim; Nieman, Koen

    2016-04-14

    To compare the effectiveness and safety of a cardiac computed tomography (CT) algorithm with functional testing in patients with symptoms suggestive of coronary artery disease (CAD). Between April 2011 and July 2013, 350 patients with stable angina, referred to the outpatient clinic of four Dutch hospitals, were prospectively randomized between cardiac CT and functional testing (2 : 1 ratio). The tiered cardiac CT protocol included a calcium scan followed by CT angiography if the Agatston calcium score was between 1 and 400. Patients with test-specific contraindications were not excluded from study participation. By 1 year, fewer patients randomized to cardiac CT reported anginal complaints (P = 0.012). The cumulative radiation dose was slightly higher in the CT group (6.6 ± 8.7 vs. 6.1 ± 9.3 mSv; P < 0.0001). After 1.2 years, event-free survival was 96.7% for patients randomized to CT and 89.8% for patients randomized to functional testing (P = 0.011). After CT, the final diagnosis was established sooner (P < 0.0001), and additional downstream testing was required less frequently (25 vs. 53%, P < 0.0001), resulting in lower cumulative diagnostic costs (€369 vs. €440; P < 0.0001). For patients with suspected stable CAD, a tiered cardiac CT protocol offers an effective and safe alternative to functional testing. Incorporating the calcium scan into the diagnostic workup was safe and lowered diagnostic expenses and radiation exposure. Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2016. For permissions please email: journals.permissions@oup.com.

  3. Prospective, multicentre, randomized, double-blind study of the efficacy of escitalopram versus citalopram in outpatient treatment of major depressive disorder.

    PubMed

    Moore, Nicholas; Verdoux, Hélène; Fantino, Bruno

    2005-05-01

    Pre-clinical studies, active-control clinical trials and meta-analyses indicate that escitalopram (S-citalopram) might be more effective than citalopram, the racemic mixture of S- and R-citalopram. The present study aimed to confirm the superior efficacy of escitalopram over citalopram. A double-blind, randomized clinical trial was performed in which general practitioners and psychiatrists compared fixed doses of escitalopram (20 mg/day) with citalopram (40 mg/day) over 8 weeks in outpatients with major depressive disorder (MDD) [baseline Montgomery-Asberg Depression Rating Scale (MADRS) score > or =30]. Primary efficacy parameter was change from baseline to last assessment in the MADRS total score. Out of 138 (aged 44.1+/-10.9 years; initial MADRS score 36.3+/-4.8) and 142 (aged 46.2+/-11.1 years; initial MADRS score 35.7+/-4.4) evaluable patients who were randomized to escitalopram and citalopram, respectively, six and 15 withdrew prematurely (P=0.05). The MADRS score decreased more in the escitalopram than in the citalopram arm (-22.4+/-12.9 versus -20.3+/-12.7; P<0.05). There were more treatment responders with escitalopram (76.1%) than with citalopram (61.3%, P<0.01). Adjusted remitter rates were 56.1% and 43.6%, respectively (P<0.05). Tolerability was similar in both groups. This randomized double-blind trial confirms that escitalopram has a superior effect to citalopram in MDD.

  4. The CHOLEGAS study: multicentric randomized, blinded, controlled trial of gastrectomy plus prophylactic cholecystectomy versus gastrectomy only, in adults submitted to gastric cancer surgery with curative intent.

    PubMed

    Farsi, Marco; Bernini, Marco; Bencini, Lapo; Miranda, Egidio; Manetti, Roberto; de Manzoni, Giovanni; Verlato, Giuseppe; Marrelli, Daniele; Pedrazzani, Corrado; Roviello, Francesco; Marchet, Alberto; Cristadoro, Luigi; Gerard, Leonardo; Moretti, Renato

    2009-05-15

    The incidence of gallstones and gallbladder sludge is known to be higher in patients after gastrectomy than in general population. This higher incidence is probably related to surgical dissection of the vagus nerve branches and the anatomical gastrointestinal reconstruction. Therefore, some surgeons perform routine concomitant cholecystectomy during standard surgery for gastric malignancies. However, not all the patients who are diagnosed to have cholelithiasis after gastric cancer surgery will develop symptoms or require additional surgical treatments and a standard laparoscopic cholecystectomy is feasible even in those patients who underwent previous gastric surgery. At the present, no randomized study has been published and the decision of gallbladder management is left to each surgeon preference. The study is a randomized controlled investigation. The study will be performed in the General and Oncologic Surgery, Department of Oncology-Azienda Ospedaliero-Universitaria Careggi-Florence-Italy, a large teaching institution, with the participation of all surgeons who accept to be involved in, together with other Italian Surgical Centers, on behalf of the GIRCG (Italian Research Group for Gastric Cancer).The patients will be randomized into two groups: in the first group the patient will be submitted to prophylactic cholecystectomy during standard surgery for curable gastric cancer (subtotal or total gastrectomy), while in the second group he/she will be submitted to standard gastric surgery only. ClinicalTrials.gov ID. NCT00757640.

  5. SixSb2Te materials with stable phase for phase change random access memory applications

    NASA Astrophysics Data System (ADS)

    Gu, Yifeng; Song, Sannian; Song, Zhitang; Cheng, Yan; Du, Xiaofeng; Liu, Bo; Feng, Songlin

    2012-03-01

    The physical and electrical properties of SixSb2Te system materials with various Si contents have been systemically studied with the aim of finding the most suitable composition for the phase change random access memory (PCRAM) applications. SixSb2Te shows better thermal stability than Ge2Sb2Te5 due to no Te separation under high annealing temperatures. The increase of Si content can enhance the data retention ability of SixSb2Te materials. When the value of x is larger than 0.44, the 10-year data retention temperature for SixSb2Te will exceed 110 °C, which meets the long-term data retention requirement. Furthermore, Si-rich SixSb2Te materials exhibit the improvement on thickness change after annealing compared with Ge2Sb2Te5. In addition, the PCRAM devices based on SixSb2Te (x = 0.31, 0.44) were fabricated and the electrical operations were carried out. Both of them show the outstanding performances with long-term operations.

  6. Optical security system using jigsaw transforms of the second random phase mask and the encrypted image in a double random phase encoding system

    NASA Astrophysics Data System (ADS)

    Singh, Madan; Kumar, Arvind; Singh, Kehar

    2008-10-01

    In this paper, we have described a simple and secure double random phase encoding and decoding system to encrypt and decrypt a two-dimensional gray scale image. We have used jigsaw transforms of the second random phase mask and the encrypted image. The random phase mask placed in the Fourier plane is broken into independent non-overlapping segments by applying the jigsaw transform. To make the system more secure, a jigsaw transform on the encrypted image is also carried out. The encrypted image is also broken into independent non-overlapping segments. The jigsaw transform indices of random phase code and the encrypted image form the keys for the successful retrieval of the data. Encrypting with this technique makes it almost impossible to retrieve the image without using both the right keys. Results of computer simulation have been presented in support of the proposed idea. Mean square error (MSE) between the decrypted and the original image has also been calculated in support of the technique.

  7. Variance of phase fluctuations of waves propagating through a random medium

    NASA Technical Reports Server (NTRS)

    Chu, Nelson C.; Kong, Jin AU; Yueh, Simon H.; Nghiem, Son V.; Fleischman, Jack G.; Ayasli, Serpil; Shin, Robert T.

    1992-01-01

    As an electromagnetic wave propagates through a random scattering medium, such as a forest, its energy is attenuated and random phase fluctuations are induced. The magnitude of the random phase fluctuations induced is important in estimating how well a Synthetic Aperture Radar (SAR) can image objects within the scattering medium. The two-layer random medium model, consisting of a scattering layer between free space and ground, is used to calculate the variance of the phase fluctuations induced between a transmitter located above the random medium and a receiver located below the random medium. The scattering properties of the random medium are characterized by a correlation function of the random permittivity fluctuations. The effective permittivity of the random medium is first calculated using the strong fluctuation theory, which accounts for large permittivity fluctuations of the scatterers. The distorted Born approximation is used to calculate the first-order scattered field. A perturbation series for the phase of the received field in the Rytov approximation is then introduced and the variance of the phase fluctuations is also calculated assuming that the transmitter and receiver are in the paraxial limit of the random medium, which allows an analytic solution to be obtained. Results are compared using the paraxial approximation, scalar Green's function formulation, and dyadic Green's function formulation. The effects studied are the dependence of the variance of the phase fluctuations on receiver location in lossy and lossless regions, medium thickness, correlation length and fractional volume of scatterers, depolarization of the incident wave, ground layer permittivity, angle of incidence, and polarization.

  8. Long-term survival of stage I multiple myeloma given chemotherapy just after diagnosis or at progression of the disease: a multicentre randomized study

    PubMed Central

    Riccardi, A; Mora, O; Tinelli, C; Valentini, D; Brugnatelli, S; Spanedda, R; De Paoli, A; Barbarano, L; Di Stasi, M; Giordano, M; Delfini, C; Nicoletti, G; Bergonzi, C; Rinaldi, E; Piccinini, L; Ascari, E

    2000-01-01

    We conducted a randomized trial to evaluate whether melphalan-prednisone (MPH-P) treatment administered just after diagnosis improves survival of stage I multiple myeloma (MM). Between January 1987 and March 1993, 145 consecutive previously untreated patients with stage I MM were randomized between treatment with MPH-P (administered for 4 days every 6 weeks) just after diagnosis and treatment only at disease progression. Survival was not influenced by MPH-P treatment either administered just after diagnosis or at disease progression (64 vs 71 months respectively). Comparing the first with the second group the odds ratio of death is 1.17 (95% confidence interval 0.57–2.42;P = 0.64). Disease progression occurred within a year in about 50% of patients who were initially untreated. Response rate was similar in both groups, but duration of response was shorter in patients who were treated at disease progression (48 vs 79 months, P = 0.044). Patients actually treated at disease progression (34/70) survived shorter than those who had neither disease progression nor treatment (56 vs > 92 months;P = 0.005). Starting MPH-P just after diagnosis does not improve survival and response rate in stage I MM, with respect to deferring therapy until disease progression. However, patients with stage I MM randomized to have treatment delayed and who actually progressed and were treated had shorter survival than those with stable disease and no treatment. Biologic or other disease features could identify these subgroups of patients. © 2000 Cancer Research Campaign PMID:10755397

  9. [Cycloferon, as an agent in the therapy and urgent prophylaxis of influenza and acute respiratory tract viral infection (multicentre randomized controlled comparative study)].

    PubMed

    Sologub, T V; Shul'diakov, A A; Romantsov, M G; Zhekalov, A N; Petlenko, S V; Erofeeva, M K; Maksakova, V L; Isakov, V A; Zarubaev, V V; Gatsan, V V; Kovalenko, A L

    2009-01-01

    Data on the study of the efficacy of the tablets of cycloferon, an early inductor of types 1 and 2 interferon, in the treatment of influenza and acute respiratory tract viral infections in adults are presented. The study enrolled 522 patients with moderate influenza of type A (H1N1) verified in 61% of the patients and type A (H3N2) verified in 7.5% of the cases. The patients were randomized with the envelope procedure. In the patients treated with cycloferon the intensity and period of the fever were stopped earlier and averaged from 1.8 to 3 days vs. 5 days in the reference group (symptomatic therapy). The improvement signs in the general state of the patients treated with cycloferon were noted on the 2nd day. The influenza complication as pneumonia was recorded in 2.2% of the patients treated with cycloferon, whereas in the patients under the symptomatic therapy the complications as bronchitis, pneumonia, angina were stated in 21.4% of the cases. For urgent prophylaxis of the influenza and respiratory tract viral infections (epidemiologic study) a group of 3717 subjects randomized with the table of random numbers was observed. 2080 patients were treated with cycloferon and 1637 patients were under the symptomatic therapy. The results were evaluated by the efficacy index and the protection estimate (T. A. Semenenko, 1991). The total efficacy index and the protection estimate in all the patients of the group were 4.9 and 79.8% respectively. The complicated forms of the disease were recorded in 1.5% of the patients treated with cycloferon and in 10.5 and 11.3% of the patients not treated with cycloferon.

  10. A randomized controlled multicentre trial on the treatment for ADHD in mothers and children: enrolment and basic characteristics of the study sample.

    PubMed

    Jans, Thomas; Graf, Erika; Jacob, Christian; Zwanzger, Ulrike; Gross-Lesch, Silke; Matthies, Swantje; Perlov, Evgeniy; Hennighausen, Klaus; Jung, Melanie; Rösler, Michael; Schulte-Altedorneburg, Monika; von Gontard, Alexander; Hänig, Susann; Sobanski, Esther; Alm, Barbara; Poustka, Luise; Bliznak, Lucia; Colla, Michael; Gentschow, Laura; Burghardt, Roland; Salbach-Andrae, Harriet; Becker, Katja; Holtmann, Martin; Freitag, Christine; Warnke, Andreas; Philipsen, Alexandra

    2013-03-01

    Parental ADHD may be a significant barrier to a successful treatment for the child's ADHD. The objective of our randomized controlled trial was to evaluate whether the treatment for maternal ADHD improves the efficacy of a behavioural parent training for children's ADHD. Patient enrolment and a description of the full analysis set (FAS) of mother-child pairs with non-missing baseline data are presented. One hundred and forty-four mother-child pairs were randomized to two treatments for maternal ADHD: cognitive behavioural group psychotherapy plus open methylphenidate treatment or control treatment (supportive counselling). After 3 months of treatment for maternal ADHD, mother-child pairs participated in a behavioural parent-child training. Assessment for eligibility included standardized instruments. After pre-screening out of 444 mother-child pairs, 206 were evaluated for trial participation and 144 were randomized. The FAS was built up by 143 dyads (children: mean age 9.4 years, 73 % males; mothers: mean age: 38.3 years). Fifty-two per cent of the children and 66 % of the mothers had combined ADHD subtype. Current axis-I co-morbidity rates were 48 % in children and 31 % in mothers. Maternal axis-II co-morbidity was 20.1 %. Fifty-seven per cent of the mothers lived together with the father of the index-child, and 29 % were single mothers. Sixty-two per cent had part-time or full-time employment. There was a selection bias excluding mothers with lack of time and effort for participation and mothers affected by coexisting mental and physical illness. Nevertheless, for our trial we were able to collect a sample comparable to routine psychiatric outpatient settings (registration: CCT-ISRCTN73911400, funding: BMBF-01GV0605).

  11. A prospective, randomized, double-blind, multicentre, parallel-group, active controlled study to compare efficacy and safety of biosimilar adalimumab (Exemptia; ZRC-3197) and adalimumab (Humira) in patients with rheumatoid arthritis.

    PubMed

    Jani, Rajendrakumar H; Gupta, Rajiv; Bhatia, Girish; Rathi, Gaurav; Ashok Kumar, Patnala; Sharma, Reena; Kumar, Uma; Gauri, Liyakat A; Jadhav, Praveen; Bartakke, Girishchandra; Haridas, Vikram; Jain, Dinesh; Mendiratta, Sanjeev K

    2016-11-01

    In this study, efficacy, tolerability and safety of biosimilar adalimumab (Exemptia; Zydus Cadila) was compared with reference adalimumab (Humira; AbbVie) in patients with moderate to severe rheumatoid arthritis (RA). In this multicentre, prospective, randomized, double-blind, active controlled parallel arm study, 120 patients with moderate to severe RA were given 40 mg of either test adalimumab (Exemptia) or reference adalimumab (Humira) by subcutaneous route every other week for 12 weeks. The primary endpoint was proportion of responders in two tretament groups by American College of Rheumatology 20 (ACR20) at week 12. The secondary endpoints were change in Disease Activity Score of 28 joints - C-reactive protein (DAS28-CRP) and proportion of patients with an ACR50 and ACR70 response in two treatment groups at week 12. Safety outcomes were also assessed. After 12 weeks, patients treated every other week with test adalimumab (Zydus Cadila) had statistically similar response rates as compared to reference adalimumab (AbbVie): ACR20 (82% vs. 79.2%; P > 0.7); ACR50 (46%, vs. 43.4%; P > 0.7); ACR70 (14% vs. 15.1%; P > 0.8). The change in DAS28-CRP score was -2.1 ± 1.09 and -2.1 ± 1.21, in test and reference products, respectively. It was statistically significant compared to baseline, but not significantly different between the two products. Three serious adverse events and no death was reported during the study. Both adalimumab preparations were safe and well tolerated in this study. The results demonstrated biosimilarity with respect to efficacy, tolerability and safety of test adalimumab (Exemptia) and reference adalimumab (Humira) in patients with moderate to severe RA. © 2015 The Authors. International Journal of Rheumatic Diseases published by Asia Pacific League of Associations for Rheumatology and Wiley Publishing Asia Pty Ltd.

  12. Cyclosporin A is superior to cyclophosphamide in children with steroid-resistant nephrotic syndrome-a randomized controlled multicentre trial by the Arbeitsgemeinschaft für Pädiatrische Nephrologie.

    PubMed

    Plank, Christian; Kalb, Veronica; Hinkes, Bernward; Hildebrandt, Friedhelm; Gefeller, Olaf; Rascher, Wolfgang

    2008-09-01

    First line immunosuppressive treatment in steroid-resistant nephrotic syndrome in children is still open to discussion. We conducted a controlled multicentre randomized open label trial to test the efficacy and safety of cyclosporin A (CSA) versus cyclophosphamide pulses (CPH) in the initial therapy of children with newly diagnosed primary steroid-resistant nephrotic syndrome and histologically proven minimal change disease, focal segmental glomerulosclerosis or mesangial hypercellularity. Patients in the CSA group (n = 15) were initially treated with 150 mg/m(2) CSA orally to achieve trough levels of 120-180 ng/ml, while patients in the CPH group (n = 17) received CPH pulses (500 mg/m(2) per month intravenous). All patients were on alternate prednisone therapy. Patients with proteinuria >40 mg/m(2) per hour at 12 weeks of therapy were allocated to a non-responder protocol with high-dose CSA therapy or methylprednisolone pulses. At week 12, nine of the 15 (60%) CSA patients showed at least partial remission, evidences by a reduction of proteinuria <40 mg/h per m(2). In contrast, three of the 17 (17%) CPH patients responded (p < 0.05, intention-to-treat). Given these results, the study was stopped, in accordance with the protocol. After 24 weeks, complete remission was reached by two of the 15 (13%) CSA and one of the 17 (5%) CPH patients (p = n.s.). Partial remission was achieved by seven of the 15 (46%) CSA and two of the 15 (11%) CPH patients (p <0.05). Five patients in the CSA group and 14 patients in the CPH group were withdrawn from the study, most of them during the non-responder protocol. The number of adverse events was comparable between both groups. We conclude that CSA is more effective than CPH in inducing at least partial remission in steroid-resistant nephrotic syndrome in children.

  13. Comparative assessment of image quality for coronary CT angiography with iobitridol and two contrast agents with higher iodine concentrations: iopromide and iomeprol. A multicentre randomized double-blind trial.

    PubMed

    Achenbach, Stephan; Paul, Jean-François; Laurent, François; Becker, Hans-Christoph; Rengo, Marco; Caudron, Jerome; Leschka, Sebastian; Vignaux, Olivier; Knobloch, Gesine; Benea, Giorgio; Schlosser, Thomas; Andreu, Jordi; Cabeza, Beatriz; Jacquier, Alexis; Souto, Miguel; Revel, Didier; Qanadli, Salah Dine; Cademartiri, Filippo

    2017-02-01

    To demonstrate non-inferiority of iobitridol 350 for coronary CT angiography (CTA) compared to higher iodine content contrast media regarding rate of patients evaluable for the presence of coronary artery stenoses. In this multicentre trial, 452 patients were randomized to receive iobitridol 350, iopromide 370 or iomeprol 400 and underwent coronary CTA using CT systems with 64-detector rows or more. Two core lab readers assessed 18 coronary segments per patient regarding image quality (score 0 = non diagnostic to 4 = excellent quality), vascular attenuation, signal and contrast to noise ratio (SNR, CNR). Patients were considered evaluable if no segment had a score of 0. Per-patient, the rate of fully evaluable CT scans was 92.1, 95.4 and 94.6 % for iobitridol, iopromide and iomeprol, respectively. Non-inferiority of iobitridol over the best comparator was demonstrated with a 95 % CI of the difference of [-8.8 to 2.1], with a pre-specified non-inferiority margin of -10 %. Although average attenuation increased with higher iodine concentrations, average SNR and CNR did not differ between groups. With current CT technology, iobitridol 350 mg iodine/ml is not inferior to contrast media with higher iodine concentrations in terms of image quality for coronary stenosis assessment. • Iodine concentration is an important parameter for image quality in coronary CTA. • Contrast enhancement must be balanced against the amount of iodine injected. • Iobitridol 350 is non-inferior compared to CM with higher iodine concentrations. • Higher attenuation with higher iodine concentrations, but no SNR or CNR differences.

  14. Non-equilibrium Phase Transitions: Activated Random Walks at Criticality

    NASA Astrophysics Data System (ADS)

    Cabezas, M.; Rolla, L. T.; Sidoravicius, V.

    2014-06-01

    In this paper we present rigorous results on the critical behavior of the Activated Random Walk model. We conjecture that on a general class of graphs, including , and under general initial conditions, the system at the critical point does not reach an absorbing state. We prove this for the case where the sleep rate is infinite. Moreover, for the one-dimensional asymmetric system, we identify the scaling limit of the flow through the origin at criticality. The case remains largely open, with the exception of the one-dimensional totally-asymmetric case, for which it is known that there is no fixation at criticality.

  15. Web-based screening and brief intervention for poly-drug use among teenagers: study protocol of a multicentre two-arm randomized controlled trial

    PubMed Central

    2012-01-01

    Background Mid to late adolescence is characterised by a vulnerability to problematic substance use since the consumption of alcohol and illicit drugs is frequently initiated and increased in this life period. While the detrimental long- and short-term effects of problematic consumption patterns in adolescence pose a major public health concern, current prevention programs targeting alcohol- and other substance-using adolescents are scarce. The study described in this protocol will test the effectiveness of a web-based brief intervention aimed at reducing problematic alcohol use and promoting abstinence from illegal drugs in adolescents with risky substance use aged 16 to 18 years old in four EU-countries. Methods/design To determine the effectiveness of our web-BI, we apply a two-arm randomized controlled trial (RCT) study design, with baseline assessment at study entry and a three month follow-up assessment. Adolescents aged 16 to 18 years from Belgium, the Czech Republic, Germany, and Sweden will be randomly assigned to either the fully electronically delivered brief intervention group (N = 400) or an assessment only control group (N = 400) depending on their screening for risky substance use (using the CRAFFT). Recruitment, informed consent, randomization, intervention and follow-up will be implemented online. Primary outcomes are reductions in frequency and quantity of use of alcohol and drugs other than alcohol over a 30 day period, as well as consumption per typical occasion. Secondary outcomes concern changes in substance use related cognitions including the constructs of the Theory of Planned Behaviour, implementation intentions, and stages of change. Moreover the study addresses a number of moderator variables, including age of first use, general psychopathology and quality of parent–child relationship. Discussion The trial is expected to contribute to the growing literature on theory- and web-based brief interventions for adolescents. We will

  16. Web-based screening and brief intervention for poly-drug use among teenagers: study protocol of a multicentre two-arm randomized controlled trial.

    PubMed

    Arnaud, Nicolas; Bröning, Sonja; Drechsel, Magdalena; Thomasius, Rainer; Baldus, Christiane

    2012-09-26

    Mid to late adolescence is characterised by a vulnerability to problematic substance use since the consumption of alcohol and illicit drugs is frequently initiated and increased in this life period. While the detrimental long- and short-term effects of problematic consumption patterns in adolescence pose a major public health concern, current prevention programs targeting alcohol- and other substance-using adolescents are scarce. The study described in this protocol will test the effectiveness of a web-based brief intervention aimed at reducing problematic alcohol use and promoting abstinence from illegal drugs in adolescents with risky substance use aged 16 to 18 years old in four EU-countries. To determine the effectiveness of our web-BI, we apply a two-arm randomized controlled trial (RCT) study design, with baseline assessment at study entry and a three month follow-up assessment. Adolescents aged 16 to 18 years from Belgium, the Czech Republic, Germany, and Sweden will be randomly assigned to either the fully electronically delivered brief intervention group (N = 400) or an assessment only control group (N = 400) depending on their screening for risky substance use (using the CRAFFT). Recruitment, informed consent, randomization, intervention and follow-up will be implemented online. Primary outcomes are reductions in frequency and quantity of use of alcohol and drugs other than alcohol over a 30 day period, as well as consumption per typical occasion. Secondary outcomes concern changes in substance use related cognitions including the constructs of the Theory of Planned Behaviour, implementation intentions, and stages of change. Moreover the study addresses a number of moderator variables, including age of first use, general psychopathology and quality of parent-child relationship. The trial is expected to contribute to the growing literature on theory- and web-based brief interventions for adolescents. We will explore the potential of using web

  17. Lamivudine in late pregnancy to prevent perinatal transmission of hepatitis B virus infection: a multicentre, randomized, double-blind, placebo-controlled study.

    PubMed

    Xu, W-M; Cui, Y-T; Wang, L; Yang, H; Liang, Z-Q; Li, X-M; Zhang, S-L; Qiao, F-Y; Campbell, F; Chang, C-N; Gardner, S; Atkins, M

    2009-02-01

    This randomized, double-blind, placebo-controlled study evaluated whether lamivudine given during late pregnancy can reduce hepatitis B virus (HBV) perinatal transmission in highly viraemic mothers. Mothers were randomized to either lamivudine 100 mg or placebo from week 32 of gestation to week 4 postpartum. At birth, infants received recombinant HBV vaccine with or without HBIg and were followed until week 52. One hundred and fifty mothers, with a gestational age of 26-30 weeks and serum HBV DNA >1000 MEq/mL (bDNA assay), were treated. A total of 141 infants received immunoprophylaxis at birth. In lamivudine-treated mothers, 56 infants received vaccine + HBIg (lamivudine + vaccine + HBIg) and 26 infants received vaccine (lamivudine + vaccine). In placebo-treated mothers, 59 infants received vaccine + HBIg (placebo + vaccine + HBIg). At week 52, in the primary analyses where missing data was counted as failures, infants in the lamivudine + vaccine + HBIg group had a significant decrease in incidence of HBsAg seropositivity (10/56, 18%vs 23/59, 39%; P = 0.014) and in detectable HBV DNA (11/56, 20%vs 27/59, 46%; P = 0.003) compared to infants in the placebo + vaccine + HBIg group. Sensitivity analyses to evaluate the impact of missing data at week 52 resulting from a high dropout rate (13% in the lamivudine + vaccine + HBIg group and 31% in the placebo + vaccine + HBIg group) remained consistent with the primary analysis in that lower transmission rates were still observed in the infants of lamivudine-treated mothers, but the differences were not statistically significant. No safety concerns were noted in the lamivudine-treated mothers or their infants. Results of this study suggest that lamivudine reduced HBV transmission from highly viraemic mothers to their infants who received passive/active immunization.

  18. A prospective randomized controlled multicentre trial comparing intravesical DMSO and chondroïtin sulphate 2% for painful bladder syndrome/interstitial cystitis

    PubMed Central

    Tutolo, Manuela; Ammirati, Enrico; Castagna, Giulia; Klockaerts, Katrien; Plancke, Hendrik; Ost, Dieter; der Aa, Frank Van; Ridder, Dirk De

    2017-01-01

    ABSTRACT Objective To compare effectiveness of intravesical chondroïtin sulphate (CS) 2% and dimethyl sulphoxide (DMSO) 50% in patients with painful bladder syndrome/interstitial cystitis (PBS/IC). Materials and methods Patients were randomized to receive either 6 weekly instillations of CS 2% or 50% DMSO. Primary endpoint was difference in proportion of patients achieving score 6 (moderately improved) or 7 (markedly improved) in both groups using the Global Response Assessment (GRA) scale. Secondary parameters were mean 24-hours frequency and nocturia on a 3-day micturition dairy, changes from baseline in O’Leary-Sant questionnaire score and visual analog scale (VAS) for suprapubic pain. Results Thirty-six patients were the intention to treat population (22 in CS and 14 in DMSO group). In DMSO group, 57% withdrew consent and only 6 concluded the trial. Major reasons were pain during and after instillation, intolerable garlic odor and lack of efficacy. In CS group, 27% withdrew consent. Compared with DMSO group, more patients in CS group (72.7% vs. 14%) reported moderate or marked improvement (P=0.002, 95% CI 0.05-0.72) and achieved a reduction in VAS scores (20% vs. 8.3%). CS group performed significantly better in pain reduction (-1.2 vs. -0.6) and nocturia (-2.4 vs. -0.7) and better in total O’Leary reduction (-9.8 vs. -7.2). CS was better tolerated. The trial was stopped due to high number of drop-outs with DMSO. Conclusions Intravesical CS 2% is viable treatment for PBS/IC with minimal side effects. DMSO should be used with caution and with active monitoring of side effects. More randomized controlled studies on intravesical treatments are needed. PMID:28124536

  19. Single daily dose of moxifloxacin versus ofloxacin plus metronidazole as a new treatment approach to uncomplicated pelvic inflammatory disease: a multicentre prospective randomized trial.

    PubMed

    Aşicioğlu, Osman; Gungorduk, Kemal; Ozdemir, Aykut; Ertas, Ibrahim Egemen; Yildirim, Gökhan; Sanci, Muzaffer; Ark, Cemal

    2013-11-01

    To evaluate the efficacy and safety of moxifloxacin versus ofloxacin plus metronidazole in patients with uncomplicated pelvic inflammatory disease (uPID; defined as PID symptoms and signs, but no complications such as septicemia, perihepatitis, and tubo-ovarian abscess) in Turkey. This was a multicenter, prospective, randomized, parallel-group study conducted between June 2010 and March 2013 in four hospitals in Turkey. Women received a 14-day course of either oral moxifloxacin at 400mg once daily (n = 560) or oral ofloxacin at 400mg twice daily plus oral metronidazole at 500 mg twice daily (n = 543). A total of 1156 women were randomized to the study. Total compliance was achieved in 1103 patients. For the primary measure of efficacy (clinical cure), moxifloxacin showed no difference compared with ofloxacin plus metronidazole (445/560 [79.5%] vs. 449/543 [82.7%]; p = 0.172). Bacteriological cure rates were high and comparable between treatment arms (99/119 [83.2%] vs. 93/110 [84.5%]; p = 0.781). Drug-related adverse events occurred less frequently with moxifloxacin than with ofloxacin plus metronidazole (210/560 [37.5%] vs. 252/543 [46.4%]; p = 0.003). Furthermore, moxifloxacin treatment was lower in cost and achieved higher patient compliance compared with ofloxacin plus metronidazole (31.4 Euros vs. 23.4 Euros and 7/578 (1.2%) vs. 22/578 (3.8%), respectively; p = 0.005). In patients with uPID, once-daily moxifloxacin monotherapy was clinically and microbiologically as efficacious as twice-daily ofloxacin plus metronidazole therapy and was associated with fewer drug-related adverse events, lower patient non-compliance, and a lower treatment cost. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

  20. Security enhancement of the phase-shifting interferometry-based cryptosystem by independent random phase modulation in each exposure

    NASA Astrophysics Data System (ADS)

    Liao, Meihua; He, Wenqi; Lu, Dajiang; Wu, Jiachen; Peng, Xiang

    2017-02-01

    The traditional phase-shifting interferometry (PSI)-based cryptosystem is one of the most classical optical cryptosystems. It employs the Mach-Zahnder interferometer to record the intensity distributions to partly overcome the inconvenience while storing the complex-valued ciphertext in some other optical cryptosystems (e.g., double random phase encoding technique). However, it has been proven to be vulnerable to chosen-plaintext attack and known-plaintext attack. In this manuscript, we propose an alternative method to enhance the security strength of the traditional PSI-based cryptosystem. By substituting the fixed random phase mask (RPM) and the phase retarder in the reference arm with four independent and different RPMs (served as secret keys) in four exposures, we can correspondingly capture four intensity-only patterns (regarded as ciphertexts). Theoretical analysis, especially with respect to security characteristics, as well as the numerical simulations are presented to verify the feasibility and reliability of the proposed cryptosystem.

  1. Postradiation multicentric osteosarcoma

    SciTech Connect

    Tillotson, C.; Rosenberg, A.; Gebhardt, M.; Rosenthal, D.I.

    1988-07-01

    The oncogenic effects of radiation are well-established. Osteosarcomas and fibrosarcomas are the two most common histologic types of secondary sarcoma. In this article a case of postradiation osteosarcoma is presented in which four discrete foci of sarcomatous transformation have occurred in the tibia and fibula after irradiation for a rhabdomyosarcoma of the calf 8 years earlier. A review of the literature reveals no similar case. Although synchronous, multifocal osteosarcoma without prior radiation has been described, this case differs in clinical, radiographic, and pathologic features; it best fits the description of postradiation multicentric osteosarcoma.

  2. Postradiation multicentric osteosarcoma.

    PubMed

    Tillotson, C; Rosenberg, A; Gebhardt, M; Rosenthal, D I

    1988-07-01

    The oncogenic effects of radiation are well-established. Osteosarcomas and fibrosarcomas are the two most common histologic types of secondary sarcoma. In this article a case of postradiation osteosarcoma is presented in which four discrete foci of sarcomatous transformation have occurred in the tibia and fibula after irradiation for a rhabdomyosarcoma of the calf 8 years earlier. A review of the literature reveals no similar case. Although synchronous, multifocal osteosarcoma without prior radiation has been described, this case differs in clinical, radiographic, and pathologic features; it best fits the description of postradiation multicentric osteosarcoma.

  3. Experimental demonstration of an active phase randomization and monitor module for quantum key distribution

    NASA Astrophysics Data System (ADS)

    Sun, Shi-Hai; Liang, Lin-Mei

    2012-08-01

    Phase randomization is a very important assumption in the BB84 quantum key distribution (QKD) system with weak coherent source; otherwise, eavesdropper may spy the final key. In this Letter, a stable and monitored active phase randomization scheme for the one-way and two-way QKD system is proposed and demonstrated in experiments. Furthermore, our scheme gives an easy way for Alice to monitor the degree of randomization in experiments. Therefore, we expect our scheme to become a standard part in future QKD systems due to its secure significance and feasibility.

  4. Tafenoquine plus chloroquine for the treatment and relapse prevention of Plasmodium vivax malaria (DETECTIVE): a multicentre, double-blind, randomised, phase 2b dose-selection study.

    PubMed

    Llanos-Cuentas, Alejandro; Lacerda, Marcus V; Rueangweerayut, Ronnatrai; Krudsood, Srivicha; Gupta, Sandeep K; Kochar, Sanjay K; Arthur, Preetam; Chuenchom, Nuttagarn; Möhrle, Jörg J; Duparc, Stephan; Ugwuegbulam, Cletus; Kleim, Jörg-Peter; Carter, Nick; Green, Justin A; Kellam, Lynda

    2014-03-22

    Clinical effectiveness of previous regimens to treat Plasmodium vivax infection have been hampered by compliance. We aimed to assess the dose-response, safety, and tolerability of single-dose tafenoquine plus 3-day chloroquine for P vivax malaria radical cure. In this double-blind, randomised, dose-ranging phase 2b study, men and women (aged ≥16 years) with microscopically confirmed P vivax monoinfection (parasite density >100 to <100,000 per μL blood) were enrolled from community health centres and hospitals across seven sites in Brazil, Peru, India, and Thailand. Patients with glucose-6-phosphate dehydrogenase enzyme activity of less than 70% were excluded. Eligible patients received chloroquine (days 1-3) and were randomly assigned (1:1:1:1:1:1) by a computer-generated randomisation schedule to receive single-dose tafenoquine 50 mg, 100 mg, 300 mg, or 600 mg, primaquine 15 mg for 14 days, or chloroquine alone. Randomisation was stratified by baseline parasite count (≤7500 and >7500 per μL blood). The primary efficacy endpoint was relapse-free efficacy at 6 months from initial dose (ie, clearance of initial infection without subsequent microscopically confirmed infection), analysed by intention to treat. This study is registered with ClinicalTrials.gov, number NCT01376167. Between Sept 19, 2011, and March 25, 2013, 329 patients were randomly assigned to a treatment group (chloroquine plus tafenoquine 50 mg [n=55], 100 mg [n=57], 300 mg [n=57], 600 mg [n=56]; or to chloroquine plus primaquine [n=50]; or chloroquine alone [n=54]). Relapse-free efficacy at 6 months was 57·7% (95% CI 43-70) with tafenoquine 50 mg, 54·1% (40-66) with tafenoquine 100 mg, 89·2% (77-95) with tafenoquine 300 mg, 91·9% (80-97) with tafenoquine 600 mg, 77·3% (63-87) with primaquine, and 37·5% (23-52) with chloroquine alone. Tafenoquine 300 mg and 600 mg had better efficacy than chloroquine alone (treatment differences 51·7% [95% CI 35-69], p<0·0001, with tafenoquine 300 mg and

  5. Characteristics of phase transitions via intervention in random networks

    NASA Astrophysics Data System (ADS)

    Jia, Xiao; Hong, Jin-Song; Yang, Hong-Chun; Yang, Chun; Shi, Xiao-Hong; Hu, Jian-Quan

    2014-07-01

    We present a percolation process in which the classical Erdös—Rényi (ER) random evolutionary network is intervened by the product rule (PR) from some moment t0. The parameter t0 is continuously tunable over the real interval [0, 1]. This model becomes the random network under the Achlioptas process at t0 = 0 and the ER network at t0 = 1. For the percolation process at t0 <= 1, we introduce a relatively slow-growing point, after which the largest cluster begins growing faster than that in the ER model. A weakly discontinuous transition is generated in the percolation process at t0 <= 0.5. We take the relatively slow-growing point as the lower pseudotransition point and the maximum gap point of the order parameter as the upper pseudotransition point. The critical point can be approximately predicted by each fitting function of the two points about t0. This contributes to understanding the rapid mergence of the large clusters at the critical point. The numerical simulations indicate that the lower pseudotransition point and the upper pseudotransition point are equal in the thermodynamic limit. When t0 > 0.5, the percolation processes generate a continuous transition. The scaling analyses of several quantities are presented, including the relatively slow-growing point, the duration of the relatively slow-growing process, as well as the relatively maximum strength between the percolation percolation at t0 < 1 and the ER network about different t0. The presented mechanism can be viewed as a two-stage percolation process that has many potential applications in the growth processes of real networks.

  6. Efficacy of degarelix in prostate cancer patients following failure on luteinizing hormone-releasing hormone agonist treatment: results from an open-label, multicentre, uncontrolled, phase II trial (CS27)

    PubMed Central

    Simson, Gabriele; Goble, Sandra; Persson, Bo-Eric

    2015-01-01

    Objective: To evaluate the efficacy of second-line degarelix in patients with prostate cancer (PCa) after treatment failure with a luteinizing hormone-releasing hormone (LHRH) agonist. Methods: This 1-year exploratory, multicentre, open-label phase II trial was performed in 2 patient cohorts (Cohort 1, n = 25; Cohort 2, n = 12) in Germany. Patients with castrate-resistant PCa after primary hormonal treatment received degarelix 240 mg, followed by 11 monthly maintenance doses of 80 mg. The primary endpoint was the proportion of patients with decreasing/stable prostate-specific antigen (PSA) (relative change ⩽+10% of baseline PSA) after 3 months. Results: At Month 3, the response rate (intention-to-treat, last observation carried forward analysis) was 16.7% [95% confidence interval (CI): 4.74–37.38] in Cohort 1 and 33.3% (95% CI: 9.92–65.11) in Cohort 2. The probability of completing 12 months without PSA progression was 8.8% (95% CI: 1.51–24.3) in Cohort 1 and 8.3% (95% CI: 0.5–31.1) in Cohort 2. Degarelix was well tolerated; the most frequently reported adverse events were local injection-site reactions. Conclusions: In PCa patients who failed LHRH therapy, degarelix was well tolerated and achieved a limited PSA response. Phase III trials show that disease control benefits with degarelix versus agonists are more clearly demonstrated as first-line therapy. PMID:26161141

  7. Prolonged impact of home versus clinic-based management of chronic heart failure: extended follow-up of a pragmatic, multicentre randomized trial cohort.

    PubMed

    Stewart, Simon; Carrington, Melinda J; Horowitz, John D; Marwick, Thomas H; Newton, Phillip J; Davidson, Patricia M; Macdonald, Peter; Thompson, David R; Chan, Yih-Kai; Krum, Henry; Reid, Christopher; Scuffham, Paul A

    2014-07-01

    We compared the longer-term impact of the two most commonly applied forms of post-discharge management designed to minimize recurrent hospitalization and prolong survival in typically older patients with chronic heart failure (CHF). We followed a multi-center randomized controlled trial cohort of Australian patients hospitalized with CHF and initially allocated to home-based or specialized CHF clinic-based intervention for 1368 ± 216 days. Blinded endpoints included event-free survival from all-cause emergency hospitalization or death, all-cause mortality and rate of all-cause hospitalization and stay. 280 patients (73% male, aged 71 ± 14 years and 73% left ventricular systolic dysfunction) were initially randomized to home-based (n=143) or clinic-based (n=137) intervention. During extended follow-up (complete for 274 patients), 1139 all-cause hospitalizations (7477 days of hospital stay) and 121 (43.2%) deaths occurred. There was no difference in the primary endpoint; 20 (14.0%) home-based versus 13 (7.4%) clinic-based patients remained event-free (adjusted HR 0.89, 95% CI 0.70 to 1.15; p=0.378). Significantly fewer home-based (51/143, 35.7%) than clinic-based intervention (71/137, 51.8%) patients died (adjusted HR 0.62, 95% CI 0.42 to 0.90: p=0.012). Home-based versus clinic-based intervention patients accumulated 592 and 547 all-cause hospitalizations (p=0.087) associated with 3067 (median 4.0, IQR 2.0 to 6.8) versus 4410 (6.0, IQR 3.0 to 12.0) days of hospital stay (p<0.01 for rate and duration of hospital stay). Relative to clinic-based intervention, home-based intervention was not associated with prolonged event-free survival. Home-based intervention was, however, associated with significantly fewer all-cause deaths and significantly fewer days of hospital stay in the longer-term. Australian New Zealand Clinical Trials Registry number 12607000069459 (http://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=81803). Copyright © 2013 Elsevier Ireland

  8. Hepatic intra-arterial versus intravenous fotemustine in patients with liver metastases from uveal melanoma (EORTC 18021): a multicentric randomized trial.

    PubMed

    Leyvraz, S; Piperno-Neumann, S; Suciu, S; Baurain, J F; Zdzienicki, M; Testori, A; Marshall, E; Scheulen, M; Jouary, T; Negrier, S; Vermorken, J B; Kaempgen, E; Durando, X; Schadendorf, D; Gurunath, R Karra; Keilholz, U

    2014-03-01

    In uveal melanoma (UM) with metastatic disease limited to the liver, the effect of an intrahepatic treatment on survival is unknown. We investigated prospectively the efficacy and toxicity of hepatic intra-arterial (HIA) versus systemic (IV) fotemustine in patients with liver metastases from UM. Patients were randomly assigned to receive either IV or HIA fotemustine at 100 mg/m(2) on days 1, 8, 15 (and 22 in HIA arm only) as induction, and after a 5-week rest period every 3 weeks as maintenance. Primary end point was overall survival (OS). Response rate (RR), progression-free survival (PFS) and safety were secondary end points. Accrual was stopped after randomization of 171 patients based on the results of a futility OS analysis. A total of 155 patients died and 16 were still alive [median follow-up 1.6 years (range 0.25-6 years)]. HIA did not improve OS (median 14.6 months) when compared with the IV arm (median 13.8 months), hazard ratio (HR) 1.09; 95% confidence interval (CI) 0.79-1.50, log-rank P = 0.59. However, there was a significant benefit on PFS for HIA compared with IV with a median of 4.5 versus 3.5 months, respectively (HR 0.62; 95% CI 0.45-0.84, log-rank P = 0.002). The 1-year PFS rate was 24% in the HIA arm versus 8% in the IV arm. An improved RR was seen in the HIA (10.5%) compared with IV treatment (2.4%). In the IV arm, the most frequent grade ≥3 toxicity was thrombocytopenia (42.1%) and neutropenia (62.6%), compared with 21.2% and 28.7% in the HIA arm. The main grade ≥3 toxicity related to HIA was catheter complications (12%) and liver toxicity (4.5%) apart from two toxic deaths. HIA treatment with fotemustine did not translate into an improved OS compared with IV treatment, despite better RR and PFS. Intrahepatic treatment should still be considered as experimental. 2004-002245-12 and NCT00110123.

  9. Hepatic intra-arterial versus intravenous fotemustine in patients with liver metastases from uveal melanoma (EORTC 18021): a multicentric randomized trial

    PubMed Central

    Leyvraz, S.; Piperno-Neumann, S.; Suciu, S.; Baurain, J. F.; Zdzienicki, M.; Testori, A.; Marshall, E.; Scheulen, M.; Jouary, T.; Negrier, S.; Vermorken, J. B.; Kaempgen, E.; Durando, X.; Schadendorf, D.; Gurunath, R. Karra; Keilholz, U.

    2014-01-01

    Background In uveal melanoma (UM) with metastatic disease limited to the liver, the effect of an intrahepatic treatment on survival is unknown. We investigated prospectively the efficacy and toxicity of hepatic intra-arterial (HIA) versus systemic (IV) fotemustine in patients with liver metastases from UM. Patients and methods Patients were randomly assigned to receive either IV or HIA fotemustine at 100 mg/m2 on days 1, 8, 15 (and 22 in HIA arm only) as induction, and after a 5-week rest period every 3 weeks as maintenance. Primary end point was overall survival (OS). Response rate (RR), progression-free survival (PFS) and safety were secondary end points. Results Accrual was stopped after randomization of 171 patients based on the results of a futility OS analysis. A total of 155 patients died and 16 were still alive [median follow-up 1.6 years (range 0.25–6 years)]. HIA did not improve OS (median 14.6 months) when compared with the IV arm (median 13.8 months), hazard ratio (HR) 1.09; 95% confidence interval (CI) 0.79–1.50, log-rank P = 0.59. However, there was a significant benefit on PFS for HIA compared with IV with a median of 4.5 versus 3.5 months, respectively (HR 0.62; 95% CI 0.45–0.84, log-rank P = 0.002). The 1-year PFS rate was 24% in the HIA arm versus 8% in the IV arm. An improved RR was seen in the HIA (10.5%) compared with IV treatment (2.4%). In the IV arm, the most frequent grade ≥3 toxicity was thrombocytopenia (42.1%) and neutropenia (62.6%), compared with 21.2% and 28.7% in the HIA arm. The main grade ≥3 toxicity related to HIA was catheter complications (12%) and liver toxicity (4.5%) apart from two toxic deaths. Conclusion HIA treatment with fotemustine did not translate into an improved OS compared with IV treatment, despite better RR and PFS. Intrahepatic treatment should still be considered as experimental. EudraCT number and ClinicalTrials.gov identifier 2004-002245-12 and NCT00110123. PMID:24510314

  10. Preventive effect of Malva on urinary toxicity after radiation therapy in prostate cancer patients: A multi-centric, double-blind, randomized clinical trial

    PubMed Central

    Mofid, Bahram; Rezaeizadeh, Hossein; Jaladat, Amir Mohammad; Atarzadeh, Fatemeh; Moeini, Reihane; Motevalian, Abbas; Mosalaie, Ahmad; Farhan, Farshid; Rakhsha, Afshin; Kashi, Amir Shahram Yousefi

    2015-01-01

    Background: For patients receiving external beam radiation therapy (EBRT) after radical prostatectomy as adjuvant treatment or patients receiving EBRT as definitive treatment, partial irradiation of the urinary bladder is common. Many of such patients experience some degree of radiation-induced cystitis during or after EBRT. There is currently no efficient treatment for preventing radiation cystitis. Objective: The aim of this study was to evaluate the effectiveness of one of the safe mucilaginous herbs (Malva) in preventing radiation-induced dysuria in patients who are undergoing EBRT for prostate cancer. Methods: From April 2013 to August 2014, 68 patients were randomized into two groups using four block randomization, 34 to the drug (Malva) group and 34 to the placebo group. Of the 68 patients who began the study, 60 completed it. They were instructed to use the medication, i.e., Malva or the placebo, three times a day for six weeks. They were followed by a physician every two weeks for eight weeks, and urinary function was assessed in each visit by asking questions based on the Visual Prostate Symptom Score (VPSS) and a dysuria severity score. The changes in the VPSS and dysuria severity score between baseline and each follow-up visit were compared between the two groups in the study using repeated measures analysis of variance (ANOVA) and t-tests. Results: The median age of the 68 patients was 66. Twenty-one of 27 patients in the control group (77.7%) suffered from dysuria, while dysuria was detected in 23 of 33 patients (69.6%) who received Malva (odds ratio=2.70 for dysuria). After two weeks, four weeks, and six weeks of treatment with Malva, dysuria due to EBRT was milder in the treatment group than in the control group, and the differences were statistically significant (p = 0.005, p = 0.004, p = 0.001, respectively). Conclusion: To the best of our knowledge, our study is the first study to assess the protective effect of a mucilaginous herb (Malva

  11. Efficacy of octreotide and sclerotherapy in the treatment of acute variceal bleeding in cirrhotic patients. A prospective, multicentric, and randomized clinical trial.

    PubMed

    Bildozola, M; Kravetz, D; Argonz, J; Romero, G; Suarez, A; Jmelnitzky, A; Fainberg, M; Fassio, E; Berreta, J; Romero, G; Landeira, G; Martinez, H; Bosco, A; Guevara, M; Valero, J; Chopita, N; Berenstein, G; Terg, R

    2000-04-01

    Sclerotherapy is the most widely used method for treatment of acute variceal bleeding. Previous reports have suggested that octreotide infusion is as effective as sclerotherapy. Our aim was to investigate the efficacy and safety of octreotide in comparison with sclerotherapy in controlling variceal bleeding. Seventy-six cirrhotic patients were randomized to receive either sclerotherapy (n = 37) or octreotide (n = 39) infusion of 50 microg/h intravenously for 48 h after a bolus of 100 microg, followed by subcutaneous injection of 100 microg/8 h for an additional 72 h. The two groups were similar in base-line data. A similar initial control of bleeding was obtained in 94.6% for sclerotherapy and 84.6% for octreotide (NS). No difference was observed between sclerotherapy and octreotide in rebleeding (23% versus 33%) and treatment failure (22% versus 36%, respectively). Furthermore, the overall success of treatment was 78% for sclerotherapy and 64% for octreotide. No significant difference in mortality was observed between treatments (eight patients for octreotide and three patients for sclerotherapy, NS). These results show that both treatments present a very high and similar initial and final control of bleeding. However, there is a trend that could be clinically important towards better results in the patients treated with sclerotherapy.

  12. Switching to aripiprazole in outpatients with schizophrenia experiencing insufficient efficacy and/or safety/tolerability issues with risperidone: a randomized, multicentre, open-label study.

    PubMed

    Ryckmans, V; Kahn, J P; Modell, S; Werner, C; McQuade, R D; Kerselaers, W; Lissens, J; Sanchez, R

    2009-05-01

    This study evaluated the safety/tolerability and effectiveness of aripiprazole titrated-dose versus fixed-dose switching strategies from risperidone in patients with schizophrenia experiencing insufficient efficacy and/or safety/tolerability issues. Patients were randomized to an aripiprazole titrated-dose (starting dose 5 mg/day) or fixed-dose (dose 15 mg/day) switching strategy with risperidone down-tapering. Primary endpoint was rate of discontinuation due to adverse events (AEs) during the 12-week study. Secondary endpoints included positive and negative syndrome scale (PANSS), clinical global impressions - improvement of illness scale (CGI-I), preference of medication (POM), subjective well-being under neuroleptics (SWN-K) and GEOPTE (Grupo Español para la Optimización del Tratamiento de la Esquizofrenia) scales. Rates of discontinuations due to AEs were similar between titrated-dose and fixed-dose strategies (3.5% vs. 5.0%; p=0.448). Improvements in mean PANSS total scores were similar between aripiprazole titrated-dose and fixed-dose strategies (-14.8 vs. -17.2; LOCF), as were mean CGI-I scores (2.9 vs. 2.8; p=0.425; LOCF) and SWN-K scores (+8.6 vs.+10.3; OC,+7.8 vs.+9.8; LOCF). Switching can be effectively and safely achieved through a titrated-dose or fixed-dose switching strategy for aripiprazole, with down-titration of risperidone.

  13. Effect of platform switching on crestal bone levels around implants in the posterior mandible: 3 years results from a multicentre randomized clinical trial.

    PubMed

    Rocha, Salomão; Wagner, Wilfried; Wiltfang, Jörg; Nicolau, Pedro; Moergel, Maximilian; Messias, Ana; Behrens, Eleonore; Guerra, Fernando

    2016-04-01

    Evaluation of differences in the clinical performance and crestal bone levels between implants restored with single crowns with platform-matched or platform-switched abutments after 3 years. The study enrolled adult patients missing two or more adjacent teeth in the posterior mandible with natural teeth mesial to the implant site. Randomization followed open-flap implant insertion and the corresponding matching or switching healing abutments placed at surgery. Conventional loading was made with cemented crowns. Clinical follow-up took place annually after loading up to 3 years. Bone level changes were measured in standardized radiographs as the variation in crestal bone from one evaluation to the next. Sixty-three patients with a total of 135 implants (66 platform matching, 69 platform switching) were analysed. From surgery to 36 months, mean bone loss was 0.28 ± 0.56 mm for the platform-switching group and 0.68 ± 0.64 mm for the platform-matching group. A statistically significant difference was found between groups (p = 0.002) with an estimate of 0.39 mm (0.15-0.64, 95% CI) in favour of platform switching. After 3 years, platform-switching restorations showed a significant effect in the preservation of marginal bone levels compared to platform-matching restorations. © 2016 The Authors. Journal of Clinical Periodontology Published by John Wiley & Sons Ltd.

  14. Efficacy of Diosmectite (Smecta)® in the Treatment of Acute Watery Diarrhoea in Adults: A Multicentre, Randomized, Double-Blind, Placebo-Controlled, Parallel Group Study

    PubMed Central

    Khediri, Faouzi; Mrad, Abdennebi Ilhem; Azzouz, Moussadek; Doughi, Hedi; Najjar, Taoufik; Mathiex-Fortunet, Hélène; Garnier, Philippe; Cortot, Antoine

    2011-01-01

    Background. Although diosmectite has demonstrated efficacy in the treatment of acute watery diarrhoea in children, its efficacy in adults still needs to be assessed. The objective of this study was therefore to assess the efficacy of diosmectite on the time to recovery in adults with acute diarrhoea. Methods. A total of 346 adults with at least three watery stools per day over a period of less than 48 hours were prospectively randomized to diosmectite (6 g tid) or placebo during four days. The primary endpoint was time to diarrhoea recovery. Results. In the intention-to-treat population, median time to recovery was 53.8 hours (range [3.7–167.3]) with diosmectite (n = 166) versus 69.0 hours [2.2–165.2] with placebo, (n = 163; P = .029), which corresponds to a difference of 15.2 hours. Diosmectite was well tolerated. Conclusion. Diosmectite at 6 g tid was well tolerated and reduced the time to recovery of acute watery diarrhoea episode in a clinically relevant manner. PMID:21760777

  15. Efficacy and safety of tofogliflozin in Japanese patients with type 2 diabetes mellitus with inadequate glycaemic control on insulin therapy (J-STEP/INS): Results of a 16-week randomized, double-blind, placebo-controlled multicentre trial.

    PubMed

    Terauchi, Yasuo; Tamura, Masahiro; Senda, Masayuki; Gunji, Ryoji; Kaku, Kohei

    2017-10-01

    To assess the effects of 16 weeks of tofogliflozin (sodium-glucose co-transporter-2 [SGLT2] inhibitor) treatment vs placebo on glycated haemoglobin (HbA1c) levels in Japanese patients with type 2 diabetes mellitus (T2DM) inadequately controlled with insulin monotherapy or insulin plus a dipeptidyl peptidase-4 (DPP-4) inhibitor. The study comprised a 16-week, multicentre, double-blind, placebo-controlled period and a 36-week extension (NCT02201004). Men and women (aged ≥20 and ≤75 years) with T2DM (HbA1c ≥7.5% and ≤10.5%) were randomized 2:1 to tofogliflozin 20 mg once/day or placebo. The primary endpoint was change in HbA1c from baseline. Insulin reduction was not permitted during this study. A total of 211 patients were randomized (141 tofogliflozin, 70 placebo). Addition of tofogliflozin to insulin therapy was significantly superior to placebo for lowering HbA1c (-0.59 vs +0.48%; P < .0001), fasting plasma glucose (-27.2 vs +5.3 mg/dL; P < .0001), postprandial plasma glucose (-65.0 vs +3.2 mg/dL; P < 0.0001), serum uric acid (-0.18 vs +0.07 mg/dL; P = .0062), body weight (-1.34 vs +0.03 kg; P < .0001) and daily insulin dose (-1.3 vs -0.2 U, P = .0152). Hypoglycaemia occurred in 30.7% of patients receiving tofogliflozin vs 21.4% for placebo. Two patients treated with tofogliflozin each had a genital or urinary tract infection. This 16-week double-blind study indicated that, in patients with T2DM whose HbA1c levels were poorly controlled with insulin monotherapy or insulin plus a DPP-4 inhibitor, addition of tofogliflozin was an effective treatment option with an acceptable safety profile. © 2017 Sanofi K.K. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.

  16. The effect of an education programme (MEDIAS 2 BSC) of non-intensive insulin treatment regimens for people with Type 2 diabetes: a randomized, multi-centre trial.

    PubMed

    Hermanns, N; Ehrmann, D; Schall, S; Maier, B; Haak, T; Kulzer, B

    2017-08-01

    A self-management oriented education programme (MEDIAS 2 BSC) for people with Type 2 diabetes who are on a non-intensive insulin treatment regimen was developed. In a randomized, multi-centre trial, the effect of MEDIAS 2 BSC was compared with an established education programme that acted as a control group. The primary outcome was the impact of MEDIAS 2 BSC on glycaemic control. Secondary outcomes included the incidence of severe hypoglycaemia, hypoglycaemia unawareness, diabetes-related distress, diabetes knowledge, quality of life and self-care behaviour. In total, 182 participants were randomized to the control group or MEDIAS 2 BSC [median age 64.0 (interquartile range 58.0-68.5) vs. 63.5 (57.0-70.0) years; HbA1c 62.8 ± 12.7 mmol/mol vs. 63.7 ± 14.0 mmol/mol; 7.9% ± 1.2% vs. 8.0% ± 1.3%]. After a 6-month follow-up, there was a mean decrease in HbA1c of 3.5 mmol/mol (0.32%) in the control group and 6.7 mmol/mol (0.61%) in MEDIAS 2 BSC. After adjusting for baseline differences and study centre, the mean difference between the groups was -3.3 mmol/mol [95% confidence interval (CI) -0.54 to -5.90 mmol/mol] [-0.30% (95% CI -0.05 to -0.54)] in favour of MEDIAS 2 BSC (P = 0.018). There were no increases in severe hypoglycaemia or hypoglycaemia unawareness. The education programmes had no significant effects on psychosocial outcome variables. MEDIAS 2 BSC was more effective in lowering HbA1c than the control condition. MEDIAS 2 BSC is a safe educational tool that improves glycaemic control without increasing the risk for hypoglycaemia. (Clinical Trials Registry No; NCT 02748239). © 2017 Diabetes UK.

  17. Betamethasone valerate dressing is non-inferior to calcipotriol–betamethasone dipropionate ointment in the treatment of patients with mild-to-moderate chronic plaque psoriasis: results of a randomized assessor-blinded multicentre trial

    PubMed Central

    Ortonne, J-P; Esposito, M; Chimenti, S; Kapińska-Mrowiecka, M; Grodzińska, A; Naldi, L; Frangione, V

    2014-01-01

    Background A ready-to-use betamethasone valerate 0.1% (BMV) dressing was found to be superior to placebo dressing and a reference 0.1% BMV cream in the treatment of patients with chronic plaque psoriasis (CPP). Methods This multicentre, prospective, randomized, investigator-blinded, controlled, non-inferiority trial compared the efficacy and safety of the BMV dressing to the calcipotriol–betamethasone dipropionate (CBD) ointment during a 4-week treatment of patients with mild to moderate CPP. The primary efficacy endpoint was the 4-item psoriasis total severity score (TSS-4) at week 4, and the associated non-inferiority margin was 1 point. Secondary outcome measures included the psoriasis global assessment (PGA) score and patients’ quality of life (QoL). Safety was assessed through adverse events (AE) reporting in each treatment group. Results Of 325 screened patients, 324 were randomized to BMV (N = 165) or CBD (N = 159), and were considered evaluable for the safety and intention-to-treat (ITT) efficacy analyses. Per protocol (PP) populations included 133 and 131 patients in the BMV and CBD groups respectively. The mean adjusted TSS-4 significantly decreased through the study from baseline in both groups. The PP (primary) analysis of week 4 data revealed a −0.288 (95% CI: −0.610 to 0.034) not significant between-group difference in adjusted means, demonstrating non-inferiority of BMV to CBD. Non-inferiority was also demonstrated in the ITT analysis. The PGA and other secondary outcomes were significantly improved from baseline in both groups at week 4. The QoL score was slightly better in the CBD group at week 4, but no difference was observed at follow-up. No safety or tolerability concerns were observed in either group. Conflicts of interest Centro Studi GISED, the centre led by LN, received a grant from IBSA Institut Biochimique SA. VF is an employee of IBSA Institut Biochimique SA. PMID:24256460

  18. Betamethasone valerate dressing is non-inferior to calcipotriol-betamethasone dipropionate ointment in the treatment of patients with mild-to-moderate chronic plaque psoriasis: results of a randomized assessor-blinded multicentre trial.

    PubMed

    Ortonne, J-P; Esposito, M; Chimenti, S; Kapińska-Mrowiecka, M; Grodzińska, A; Naldi, L; Frangione, V

    2014-09-01

    A ready-to-use betamethasone valerate 0.1% (BMV) dressing was found to be superior to placebo dressing and a reference 0.1% BMV cream in the treatment of patients with chronic plaque psoriasis (CPP). This multicentre, prospective, randomized, investigator-blinded, controlled, non-inferiority trial compared the efficacy and safety of the BMV dressing to the calcipotriol-betamethasone dipropionate (CBD) ointment during a 4-week treatment of patients with mild to moderate CPP. The primary efficacy endpoint was the 4-item psoriasis total severity score (TSS-4) at week 4, and the associated non-inferiority margin was 1 point. Secondary outcome measures included the psoriasis global assessment (PGA) score and patients' quality of life (QoL). Safety was assessed through adverse events (AE) reporting in each treatment group. Of 325 screened patients, 324 were randomized to BMV (N = 165) or CBD (N = 159), and were considered evaluable for the safety and intention-to-treat (ITT) efficacy analyses. Per protocol (PP) populations included 133 and 131 patients in the BMV and CBD groups respectively. The mean adjusted TSS-4 significantly decreased through the study from baseline in both groups. The PP (primary) analysis of week 4 data revealed a -0.288 (95% CI: -0.610 to 0.034) not significant between-group difference in adjusted means, demonstrating non-inferiority of BMV to CBD. Non-inferiority was also demonstrated in the ITT analysis. The PGA and other secondary outcomes were significantly improved from baseline in both groups at week 4. The QoL score was slightly better in the CBD group at week 4, but no difference was observed at follow-up. No safety or tolerability concerns were observed in either group. BMV dressing is non-inferior to CBD ointment in patients with mild to moderate CPP. Both treatments significantly improve patients' psoriasis and QoL. © 2013 Laboratoires Genevrier/IBSA Institut Biochimique SA (Switzerland). Journal of the European Academy of

  19. A multicentre, randomized, single-blind, parallel-group study comparing the efficacy and tolerability of benzoyl peroxide 3%/clindamycin 1% with azelaic acid 20% in the topical treatment of mild-to-moderate acne vulgaris.

    PubMed

    Schaller, M; Sebastian, M; Ress, C; Seidel, D; Hennig, M

    2016-06-01

    Mild-to-moderate acne vulgaris is treated with a range of mono- and combination therapies; however, clinical evidence is still required to optimize treatment recommendations. To compare the efficacy, tolerability and safety of a combination of benzoyl peroxide 3% and clindamycin 1% (BPO + CLN) with azelaic acid 20% (AzA) for the topical treatment of mild-to-moderate acne vulgaris. This was a randomized, assessor-blinded, parallel-group, multicentre study conducted in Germany. Patients with a confirmed diagnosis of acne vulgaris, aged 12-45 years, were randomized 1 : 1 to once-daily BPO + CLN gel or twice-daily AzA cream for up to 12 weeks. The primary endpoint was the percentage change in inflammatory lesions from baseline at Week 4. Secondary endpoints included total and inflammatory lesion counts and tolerability assessments. For selected secondary endpoints, inductive statistical analysis was performed post hoc. Patient safety was assessed by adverse event (AE) monitoring. Efficacy was assessed in the modified intent-to-treat (mITT) population [patients using ≥1 dose of study medication (ITT), plus baseline and ≥1 post-baseline lesion count (n = 215)]. There was a statistically significant difference in the primary endpoint, with a median decrease of -52.6% for BPO + CLN (n = 107) vs.-38.8% for AzA (n = 108; P = 0.0004). There was also a greater difference in secondary lesion endpoints at Week 12, with a median decrease in inflammatory lesions of -78.8% and -65.3% and total lesions of -69.0% and -53.9% with BPO + CLN and AzA, respectively (both P < 0.0001). Tolerability was acceptable for both treatments. Overall, 55.6% (BPO + CLN) and 69.7% (AzA) of patients reported treatment-emergent AEs, and 15.7% and 35.8% of patients experienced application site reactions with BPO + CLN (24 events; 17 patients) and AzA (60 events; 39 patients) treatment, respectively (ITT population). BPO + CLN demonstrated greater efficacy than AzA in the treatment of mild

  20. Image encryption using the Gyrator transform and random phase masks generated by using chaos

    NASA Astrophysics Data System (ADS)

    Vilardy, Juan M.; Jimenez, Carlos J.; Perez, Ronal

    2017-06-01

    The Gyrator transform (GT), chaotic random phase masks (CRPMs) and a random permutation of the Jigsaw transform (JT) are utilized to design an images encryption-decryption system. The encryption-decryption system is based on the double random phase encoding (DRPE) in the Gyrator domain (GD), this technique uses two random phase masks (RPMs) to encode the image to encrypt (original image) into a random noise. The RPMs are generated by using chaos, these masks are CRPMs. The parameters of the chaotic function have the control of the generation of the CRPMs. We apply a random permutation to the resulting image of the DRPE technique, with the purpose of obtaining an encrypted image with a higher randomness. In order to successfully retrieve the original image (without errors or noise-free) at the output of the decryption system is necessary to have all the proper keys, which are: the rotation angles of the GTs, the parameters of the chaotic function utilized to generate the two CRPMs and the random permutation of the JT. We check and analyze the validity of the image encryption and decryption systems by means of computing simulations.

  1. Phase diagram of the transverse Ising model in a random field

    NASA Astrophysics Data System (ADS)

    Milman, F. S.; Hauser, P. R.; Figueiredo, W.

    1991-06-01

    We determine the phase diagram of the transverse Ising model with a trimodal distribution (sum of three δ functions) for a longitudinal random field at T=0, using a mean-field approximation. The phase diagram includes tricritical points, ordered critical points, a fourth-order point, critical end points, and a double critical end point. Our T=0 phase diagram is completely equivalent to the one obtained by Kaufman, Klunzinger, and Khurana for the random-field Ising model. We show that the temperature and the magnitude of the transverse field play a similar role.

  2. Randomness-driven Quantum Phase Transition in Bond-alternating Haldane Chain

    NASA Astrophysics Data System (ADS)

    Arakawa, Takayuki; Todo, Synge; Takayama, Hajime

    2005-04-01

    The effect of bond randomness on the spin-gapped ground state of the spin-1 bond-alternating antiferromagnetic Heisenberg chain is discussed. By using the loop cluster quantum Monte Carlo method, we investigate the stability of topological order in terms of the recently proposed twist order parameter [M. Nakamura and S. Todo: Phys. Rev. Lett. 89 (2002) 077204]. It is observed that the dimer phases as well as the Haldane phase of the spin-1 Heisenberg chain are robust against a weak randomness, though the valence-bond-solid-like topological order in the latter phase is destroyed by introducing a disorder stronger than the critical value.

  3. Hydrogen multicentre bonds.

    PubMed

    Janotti, Anderson; Van de Walle, Chris G

    2007-01-01

    The concept of a chemical bond stands out as a major development in the process of understanding how atoms are held together in molecules and solids. Lewis' classical picture of chemical bonds as shared-electron pairs evolved to the quantum-mechanical valence-bond and molecular-orbital theories, and the classification of molecules and solids in terms of their bonding type: covalent, ionic, van der Waals and metallic. Along with the more complex hydrogen bonds and three-centre bonds, they form a paradigm within which the structure of almost all molecules and solids can be understood. Here, we present evidence for hydrogen multicentre bonds-a generalization of three-centre bonds-in which a hydrogen atom equally bonds to four or more other atoms. When substituting for oxygen in metal oxides, hydrogen bonds equally to all the surrounding metal atoms, becoming fourfold coordinated in ZnO, and sixfold coordinated in MgO. These multicentre bonds are remarkably strong despite their large hydrogen-metal distances. The calculated local vibration mode frequency in MgO agrees with infrared spectroscopy measurements. Multicoordinated hydrogen also explains the dependence of electrical conductivity on oxygen partial pressure, resolving a long-standing controversy on the role of point defects in unintentional n-type conductivity of ZnO (refs 8-10).

  4. Mathematic model analysis of Gaussian beam propagation through an arbitrary thickness random phase screen.

    PubMed

    Tian, Yuzhen; Guo, Jin; Wang, Rui; Wang, Tingfeng

    2011-09-12

    In order to research the statistical properties of Gaussian beam propagation through an arbitrary thickness random phase screen for adaptive optics and laser communication application in the laboratory, we establish mathematic models of statistical quantities, which are based on the Rytov method and the thin phase screen model, involved in the propagation process. And the analytic results are developed for an arbitrary thickness phase screen based on the Kolmogorov power spectrum. The comparison between the arbitrary thickness phase screen and the thin phase screen shows that it is more suitable for our results to describe the generalized case, especially the scintillation index.

  5. Smeared quantum phase transition in the dissipative random quantum Ising model

    NASA Astrophysics Data System (ADS)

    Vojta, Thomas; Hoyos, José A.

    2010-01-01

    We investigate the quantum phase transition in the random transverse-field Ising model under the influence of Ohmic dissipation. To this end, we numerically implement a strong-disorder renormalization-group scheme. We find that Ohmic dissipation destroys the quantum critical point and the associated quantum Griffiths phase by smearing. Our results quantitatively confirm a recent theory [J.A. Hoyos, T. Vojta, Phys. Rev. Lett. 100 (2008) 240601] of smeared quantum phase transitions.

  6. Amplitude-phase retrieval attack free image encryption based on two random masks and interference

    NASA Astrophysics Data System (ADS)

    Liansheng, Sui; bei, Zhou; Zhanmin, Wang; qindong, Sun

    2016-11-01

    An amplitude-phase retrieval attack free encryption scheme is proposed by using two random masks, where one is considered as the random image and other as the public key. Initially, the random image is encrypted to two phase-only masks based on interference technique with the help of the public key. These two phase-only masks are real-valued functions and used as the encryption keys. Then, the plain image is encrypted to the ciphertext with the white noise distribution by using the phase-truncated Fourier-transform-based encoding scheme with the previous encryption keys. The encryption process is nonlinear in which no iterative calculation is involved, while the decryption process is linear which can be easily implemented with the 4 f optical system. Moreover, less constraints makes the specific attack unusable. Simulation results are given to verify the feasibility and robustness of the proposed encryption scheme.

  7. Experimental study on optical image encryption with asymmetric double random phase and computer-generated hologram.

    PubMed

    Xi, Sixing; Wang, Xiaolei; Song, Lipei; Zhu, Zhuqing; Zhu, Bowen; Huang, Shuai; Yu, Nana; Wang, Huaying

    2017-04-03

    Optical image encryption, especially double-random-phase-based, is of great interest in information security. In this work, we experimentally demonstrate the security and feasibility of optical image encryption with asymmetric double random phase and computer-generated hologram (CGH) by using spatial light modulator. First of all, the encrypted image modulated by asymmetric double random phase is numerically encoded into real-value CGH. Then, the encoded real-value CGH is loaded on the spatial light modulator and optically decrypted in self-designed experimental system. Experimental decryption results are in agreement with numerical calculations under the prober/mistaken phase keys condition. This optical decryption technology opens a window of optical encryption practical application and shows great potential for digital multimedia product copyright protection and holographic false trademark.

  8. Wound Infections Following Implant removal below the knee: the effect of antibiotic prophylaxis; the WIFI-trial, a multi-centre randomized controlled trial.

    PubMed

    Backes, Manouk; Dingemans, Siem A; Schep, Niels W L; Bloemers, Frank W; Van Dijkman, Bart; Garssen, Frank P; Haverlag, Robert; Hoogendoorn, Jochem M; Joosse, Pieter; Mirck, Boj; Postma, Victor; Ritchie, Ewan; Roerdink, W Herbert; Sintenie, Jan Bernard; Soesman, Nicolaj M R; Sosef, Nico L; Twigt, Bas A; Van Veen, Ruben N; Van der Veen, Alexander H; Van Velde, Romuald; Vos, Dagmar I; De Vries, Mark R; Winkelhagen, Jasper; Goslings, J Carel; Schepers, Tim

    2015-02-06

    In the Netherlands about 18,000 procedures with implant removal are performed annually following open or closed reduction and fixation of fractures, of which 30-80% concern the foot, ankle and lower leg region. For clean surgical procedures, the rate of postoperative wound infections (POWI) should be less than ~2%. However, rates of 10-12% following implant removal have been reported, specifically after foot, ankle and lower leg fractures. Currently, surgeons individually decide if antibiotics prophylaxis is given, since no guideline exists. This leads to undesirable practice variation. The aim of the study is to assess the (cost-)effectiveness of a single intravenous gift of Cefazolin prior to implant removal following surgical fixation of foot, ankle and/or lower leg fractures. This is a double-blind randomized controlled trial in patients scheduled for implant removal following a foot, ankle or lower leg fracture. Primary outcome is a POWI within 30 days after implant removal. Secondary outcomes are quality of life, functional outcome and costs at 30 days and 6 months after implant removal. With 2 x 250 patients a decrease in POWI rate from 10% to 3.3% (expected rate in clean-contaminated elective orthopaedic trauma procedures) can be detected (Power = 80%, 2-sided alpha = 5%, including 15% lost to follow up). If administration of prophylactic antibiotics prior to implant removal reduces the infectious complication rate, this will offer a strong argument to adopt this as standard practice of care. This will consequently lead to less physical and social disabilities and health care use. A preliminary, conservative estimation suggests yearly cost savings in the Netherlands of € 3.5 million per year. This study is registered at Clinicaltrials.gov ( NCT02225821 ) and the Netherlands Trial Register ( NTR4393 ) and was granted permission by the Medical Ethical Review Committee of the Academic Medical Centre on October 7 2014.

  9. Multiscale assessment of treatment efficacy in adults with ADHD: A randomized placebo-controlled, multi-centre study with extended-release methylphenidate

    PubMed Central

    Retz, Wolfgang; Rösler, Michael; Ose, Claudia; Scherag, André; Alm, Barbara; Philipsen, Alexandra; Fischer, Roland; Ammer, Richard

    2012-01-01

    Objectives This trial was performed to test the efficacy and safety of an extended-release formulation of methylphenidate (MPH ER). Methods A total of 162 adults with ADHD according to DSM-IV were treated for 8 weeks with either two daily individually body weight-adjusted doses of MPH ER up to 1 mg/kg per day (N = 84) or placebo (N = 78). The primary efficacy outcome was the Wender-Reimherr Adult Attention Deficit Disorder Scale (WRAADDS) 8 weeks after randomization. Secondary efficacy measures were the ADHD Diagnostic Checklist (ADHD-DC), the Conners Adult Attention Deficit Disorder Scale (CAARS-S:L), the Clinical Global Impression (CGI) and the Sheehan Disability Scale (SDS). Results At week 8 a significantly higher decline of the total WRAADDS score was found in the MPH ER group as compared to the placebo group (P = 0.0003). The rates of responders were 50% in the MPH ER and 18% in the placebo group (P < 0.0001). Furthermore, similar effects were observed for the secondary efficacy variable: ADHD-DC score (P = 0.004), CAARS-S:L score (P = 0.008) and the SDS score (P = 0.017). 50% of the MPH ER group and 24.4% of the placebo group were improved “much” or “very much” according to the CGI rating (P = 0.0001). MPH ER treatment was well tolerated. At week 2 also the mean heart rate was significantly higher in the MPH ER group as compared to the placebo group (P = 0.01). No differences between the study groups were observed regarding mean blood pressure at any visit. Conclusions This clinical trial demonstrated statistically significant and clinical relevant effects of MPH ER in adults with ADHD for several self- and investigator-rated ADHD psychopathology and also functional efficacy measures. PMID:21155632

  10. Combination therapy with adapalene-benzoyl peroxide and oral lymecycline in the treatment of moderate to severe acne vulgaris: a multicentre, randomized, double-blind controlled study.

    PubMed

    Dréno, B; Kaufmann, R; Talarico, S; Torres Lozada, V; Rodríguez-Castellanos, M A; Gómez-Flores, M; De Maubeuge, J; Berg, M; Foley, P; Sysa-Jedrzejowska, A; Kerrouche, N; Paliargues, F; Bettoli, V

    2011-08-01

    Oral antibiotics in association with a topical retinoid with or without benzoyl peroxide (BPO) are the recommended first-line option in the treatment of moderate to severe acne vulgaris. To evaluate the efficacy and safety of oral lymecycline 300 mg with adapalene 0·1%-BPO 2·5% (A/BPO) fixed-dose gel in comparison with oral lymecycline 300 mg with a vehicle gel in subjects with moderate to severe acne vulgaris. A total of 378 subjects were randomized in a double-blind, controlled trial to receive once-daily lymecycline with either A/BPO or vehicle for 12 weeks. Evaluations included percentage changes from baseline in lesion counts, success rate (subjects 'clear' or 'almost clear'), skin tolerability, adverse events and patients' satisfaction. The median percentage reduction from baseline in total lesion counts at week 12 was significantly higher (P < 0·001) in the lymecycline with A/BPO group (-74·1%) than in the lymecycline with vehicle group (-56·8%). The success rate was significantly higher (47·6% vs. 33·7%, P = 0·002) in subjects treated with lymecycline and A/BPO. Both inflammatory and noninflammatory lesions were significantly reduced at week 12 (both P < 0·001) with a rapid onset of action from week 2 for noninflammatory lesions (P < 0·001) and week 4 for inflammatory lesions (P = 0·005). The A/BPO and lymecycline combination was well tolerated. The proportion of satisfied and very satisfied subjects was similar in both groups, but the number in the A/BPO group who were 'very satisfied' was significantly greater (P = 0·031). These results demonstrate the clinical benefit of combining A/BPO with lymecycline in the treatment of moderate to severe acne vulgaris. © 2011 The Authors. BJD © 2011 British Association of Dermatologists 2011.

  11. Dosage effect on uropathogenic Escherichia coli anti-adhesion activity in urine following consumption of cranberry powder standardized for proanthocyanidin content: a multicentric randomized double blind study

    PubMed Central

    2010-01-01

    Background Ingestion of cranberry (Vaccinium macrocarpon Ait.) has traditionally been utilized for prevention of urinary tract infections. The proanthocyanidins (PACs) in cranberry, in particular the A-type linkages have been implicated as important inhibitors of primarily P-fimbriated E. coli adhesion to uroepithelial cells. Additional experiments were required to investigate the persistence in urine samples over a broader time period, to determine the most effective dose per day and to determine if the urinary anti-adhesion effect following cranberry is detected within volunteers of different origins. Methods Two separate bioassays (a mannose-resistant hemagglutination assay and an original new human T24 epithelial cell-line assay) have assessed the ex-vivo urinary bacterial anti-adhesion activity on urines samples collected from 32 volunteers from Japan, Hungary, Spain and France in a randomized, double-blind versus placebo study. An in vivo Caenorhabditis elegans model was used to evaluate the influence of cranberry regimen on the virulence of E. coli strain. Results The results indicated a significant bacterial anti-adhesion activity in urine samples collected from volunteers that consumed cranberry powder compared to placebo (p < 0.001). This inhibition was clearly dose-dependent, prolonged (until 24 h with 72 mg of PAC) and increasing with the amount of PAC equivalents consumed in each cranberry powder regimen. An in vivo Caenorhabditis elegans model showed that cranberry acted against bacterial virulence: E. coli strain presented a reduced ability to kill worms after a growth in urines samples of patients who took cranberry capsules. This effect is particularly important with the regimen of 72 mg of PAC. Conclusions Administration of PAC-standardized cranberry powder at dosages containing 72 mg of PAC per day may offer some protection against bacterial adhesion and virulence in the urinary tract. This effect may offer a nyctohemeral protection. PMID

  12. A multicentre randomized controlled trial of ion-exchange water softeners for the treatment of eczema in children: protocol for the Softened Water Eczema Trial (SWET) (ISRCTN: 71423189).

    PubMed

    Thomas, K S; Sach, T H

    2008-09-01

    There is epidemiological evidence linking increased water hardness with increased eczema prevalence. A number of plausible mechanisms can be forwarded to suggest why hard water could exacerbate eczema. The most likely explanation is increased soap usage in hard water areas, the deposits of which can cause skin irritation in individuals with eczema. To assess the cost and cost-effectiveness of ion-exchange water softeners for the treatment of eczema in children. Three hundred and ten children aged 6 months to 16 years, with moderate to severe eczema. The children must live in hard water areas (>or= 200 mg L(-1) of calcium carbonate) and have a home that is suitable for the installation of a water softener. This is a single-blind, parallel-group, randomized controlled trial of 12 weeks duration followed by a 4-week cross-over period. RESULTS/ANALYSIS PLAN: difference in the mean change in disease severity (Six Area, Six Sign Atopic Dermatitis score) at 12 weeks compared with baseline. (i) proportion of time spent moving during the night; (ii) self-reported global changes in eczema severity; (iii) amount of topical treatment used; (iv) Patient Oriented Eczema Measure; (v) number of totally controlled and well controlled weeks; (vi) impact on health-related quality of life for the child (EQ-5D) and the family (Dermatitis Family Impact questionnaire); and (vii) cost-effectiveness. It is planned that recruitment will be completed by the end of 2008 and results will be available towards the end of 2009.

  13. Anrukinzumab, an anti-interleukin 13 monoclonal antibody, in active UC: efficacy and safety from a phase IIa randomised multicentre study.

    PubMed

    Reinisch, Walter; Panés, Julián; Khurana, Sunil; Toth, Gabor; Hua, Fei; Comer, Gail M; Hinz, Michelle; Page, Karen; O'Toole, Margot; Moorehead, Tara McDonnell; Zhu, Hua; Sun, YanHui; Cataldi, Fabio

    2015-06-01

    Interleukin 13 (IL-13) is thought to play a key role as an effector cytokine in UC. Anrukinzumab, a humanised antibody that inhibits human IL-13, was evaluated for the treatment of UC. In a multicentre, randomised, double-blind, placebo-controlled study, patients with active UC (Mayo score ≥4 and <10) were randomised to anrukinzumab 200, 400 or 600 mg or placebo. Patients received five intravenous administrations over 14 weeks. The primary endpoint was fold change from baseline in faecal calprotectin (FC) at Week 14. Secondary endpoints included safety, pharmacokinetics and IL-13 levels. The modified intention-to-treat population included 84 patients (21 patients/arm). Fold change of FC from baseline at Week 14 was not significantly different for any treatment groups compared with the placebo. The study had a high dropout rate, in part, related to lack of efficacy. The exploratory comparisons of each dose were not significantly different from placebo in terms of change from baseline in total Mayo score, clinical response, clinical remission and proportion of subjects with mucosal healing. An increase in serum total IL-13 (free and bound to anrukinzumab) was observed for all anrukinzumab groups but not with placebo. This suggests significant binding of anrukinzumab to IL-13. The safety profile was not different between the anrukinzumab and placebo groups. A statistically significant therapeutic effect of anrukinzumab could not be demonstrated in patients with active UC in spite of binding of anrukinzumab to IL-13. ClinicalTrials.gov number NCT01284062. 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.

  14. ‘Placement budgets’ for supported employment – improving competitive employment for people with mental illness: study protocol of a multicentre randomized controlled trial

    PubMed Central

    2012-01-01

    Background Vocational integration of people with mental illness is poor despite their willingness to work. The ‘Individual Placement and Support’ (IPS) model which emphasises rapid and direct job placement and continuing support to patient and employer has proven to be the most effective vocational intervention programme. Various studies have shown that every second patient with severe mental illness was able to find competitive employment within 18 months. However, the goal of taking up employment within two months was rarely achieved. Thus, we aim to test whether the new concept of limited placement budgets increases the effectiveness of IPS. Methods/Design Six job coaches in six out-patients psychiatric clinics in the Canton of Zurich support unemployed patients of their clinic who seek competitive employment. Between June 2010 and May 2011 patients (N=100) are randomly assigned to three different placement budgets of 25h, 40h, or 55h working hours of job coaches. Support lasts two years for those who find a job. The intervention ends for those who fail to find competitive employment when the respective placement budgets run out. The primary outcome measure is the time between study inclusion and first competitive employment that lasted three months or longer. Over a period of three years interviews are carried out every six months to measure changes in motivation, stigmatization, social network and social support, quality of life, job satisfaction, financial situation, and health conditions. Cognitive and social-cognitive tests are conducted at baseline to control for confounding variables. Discussion This study will show whether the effectiveness of IPS can be increased by the new concept of limited placement budgets. It will also be examined whether competitive employment leads in the long term to an improvement of mental illness, to a transfer of the psychiatric support system to private and vocational networks, to an increase in financial independence

  15. First-line eradication rates comparing two shortened non-bismuth quadruple regimens against Helicobacter pylori: an open-label, randomized, multicentre clinical trial.

    PubMed

    Cuadrado-Lavín, Antonio; Salcines-Caviedes, J Ramón; Diaz-Perez, Ainhoa; Carrascosa, Miguel F; Ochagavía, María; Fernandez-Forcelledo, José Luis; Cobo, Marta; Fernández-Gil, Pedro; Ayestarán, Blanca; Sánchez, Blanca; Campo, Cristina; Llorca, Javier; Lorenzo, Silvia; Illaro, Aitziber

    2015-08-01

    Helicobacter pylori eradication remains a challenge. Non-bismuth-based quadruple regimens (NBQR) have shown high eradication rates (ER) elsewhere that need to be locally confirmed. The objective of this study was to compare the first-line ER of a hybrid therapy (20 mg of omeprazole twice daily and 1 g of amoxicillin twice daily for 10 days, adding 500 mg of clarithromycin twice daily and 500 mg of metronidazole every 8 h for the last 5 days; OA-OACM) with that of a 10 day concomitant regimen consisting of taking all four drugs twice daily every day (including 500 mg of metronidazole every 12 h; OACM). A 10 day arm with standard triple therapy (OAC; 20 mg of omeprazole/12 h, 1 g of amoxicillin/12 h and 500 mg of clarithromycin/12 h) was included. Three hundred consecutive patients were randomized (1: 2: 2) into one of the three following regimens: (i) OAC (60); (ii) OA-OACM (120); and (iii) OACM (120). Eradication was generally confirmed by a [(13)C]urea breath test at least 4 weeks after the end of treatment. Adverse events and compliance were assessed. EudraCT: 2011-006258-99. ITT cure rates were: OAC, 70.0% (42/60) (95% CI: 58.3-81.7); OA-OACM, 90.8% (109/120) (95% CI: 85.6-96.0); and OACM, 90.0% (107/119) (95% CI: 84.6-95.4). PP rates were: OAC, 72.4% (42/58) (95% CI: 60.8-84.1); OA-OACM, 93.9% (108/115) (95% CI: 89.5-98.3); and OACM, 90.3% (102/113) (95% CI: 84.8-95.8). Both NBQR significantly improved ER compared with OAC (P < 0.01), but no differences were seen between them. Mean compliance was elevated [98.0% (SD = 9.8)] with no differences between groups. There were more adverse events in the quadruple arms (OACM, 65.8%; OA-OACM, 68.6%; OAC, 46.6%; P < 0.05), but no significant differences between groups in terms of severity were seen. Hybrid and concomitant regimens show good ER against H. pylori infection with an acceptable safety profile. They clearly displace OAC as first-line regimen in our area. © The Author 2015. Published by Oxford

  16. 'Placement budgets' for supported employment--improving competitive employment for people with mental illness: study protocol of a multicentre randomized controlled trial.

    PubMed

    Nordt, Carlos; Brantschen, Elisabeth; Kawohl, Wolfram; Bärtsch, Bettina; Haker, Helene; Rüsch, Nicolas; Rössler, Wulf

    2012-10-04

    Vocational integration of people with mental illness is poor despite their willingness to work. The 'Individual Placement and Support' (IPS) model which emphasises rapid and direct job placement and continuing support to patient and employer has proven to be the most effective vocational intervention programme. Various studies have shown that every second patient with severe mental illness was able to find competitive employment within 18 months. However, the goal of taking up employment within two months was rarely achieved. Thus, we aim to test whether the new concept of limited placement budgets increases the effectiveness of IPS. Six job coaches in six out-patients psychiatric clinics in the Canton of Zurich support unemployed patients of their clinic who seek competitive employment. Between June 2010 and May 2011 patients (N=100) are randomly assigned to three different placement budgets of 25h, 40h, or 55h working hours of job coaches. Support lasts two years for those who find a job. The intervention ends for those who fail to find competitive employment when the respective placement budgets run out. The primary outcome measure is the time between study inclusion and first competitive employment that lasted three months or longer. Over a period of three years interviews are carried out every six months to measure changes in motivation, stigmatization, social network and social support, quality of life, job satisfaction, financial situation, and health conditions. Cognitive and social-cognitive tests are conducted at baseline to control for confounding variables. This study will show whether the effectiveness of IPS can be increased by the new concept of limited placement budgets. It will also be examined whether competitive employment leads in the long term to an improvement of mental illness, to a transfer of the psychiatric support system to private and vocational networks, to an increase in financial independence, to a reduction of perceived and

  17. Endoscopic sclerotherapy compared with no specific treatment for the primary prevention of bleeding from esophageal varices. A randomized controlled multicentre trial [ISRCTN03215899].

    PubMed

    van Buuren, Henk R; Rasch, Marijke C; Batenburg, Piet L; Bolwerk, Clemens J M; Nicolai, Jan J; van der Werf, Sjoerd D J; Scherpenisse, Joost; Arends, Lidia R; van Hattum, Jan; Rauws, Erik A J; Schalm, Solko W

    2003-08-15

    Since esophageal variceal bleeding is associated with a high mortality rate, prevention of bleeding might be expected to result in improved survival. The first trials to evaluate prophylactic sclerotherapy found a marked beneficial effect of prophylactic treatment. These results, however, were not generally accepted because of methodological aspects and because the reported incidence of bleeding in control subjects was considered unusually high. The objective of this study was to compare endoscopic sclerotherapy (ES) with nonactive treatment for the primary prophylaxis of esophageal variceal bleeding in patients with cirrhosis. 166 patients with esophageal varices grade II, III of IV according to Paquet's classification, with evidence of active or progressive liver disease and without prior variceal bleeding, were randomized to groups receiving ES (n = 84) or no specific treatment (n = 82). Primary end-points were incidence of bleeding and mortality; secondary end-points were complications and costs. During a mean follow-up of 32 months variceal bleeding occurred in 25% of the patients of the ES group and in 28% of the control group. The incidence of variceal bleeding for the ES and control group was 16% and 16% at 1 year and 33% and 29% at 3 years, respectively. The 1-year survival rate was 87% for the ES group and 84% for the control group; the 3-year survival rate was 62% for each group. In the ES group one death occurred as a direct consequence of variceal bleeding compared to 9 in the other group (p = 0.01, log-rank test). Complications were comparable for the two groups. Health care costs for patients assigned to ES were estimated to be higher. Meta-analysis of a large number of trials showed that the effect of prophylactic sclerotherapy is significantly related to the baseline bleeding risk. In the present trial, prophylactic sclerotherapy did not reduce the incidence of bleeding from varices in patients with liver cirrhosis and a low to moderate bleeding

  18. Chlorambucil plus ofatumumab versus chlorambucil alone in previously untreated patients with chronic lymphocytic leukaemia (COMPLEMENT 1): a randomised, multicentre, open-label phase 3 trial.

    PubMed

    Hillmen, Peter; Robak, Tadeusz; Janssens, Ann; Babu, K Govind; Kloczko, Janusz; Grosicki, Sebastian; Doubek, Michael; Panagiotidis, Panagiotis; Kimby, Eva; Schuh, Anna; Pettitt, Andrew R; Boyd, Thomas; Montillo, Marco; Gupta, Ira V; Wright, Oliver; Dixon, Iestyn; Carey, Jodi L; Chang, Chai-Ni; Lisby, Steen; McKeown, Astrid; Offner, Fritz

    2015-05-09

    Treatment for patients with chronic lymphocytic leukaemia who are elderly or who have comorbidities is challenging because fludarabine-based chemoimmunotherapies are mostly not suitable. Chlorambucil remains the standard of care in many countries. We aimed to investigate whether the addition of ofatumumab to chlorambucil could lead to better clinical outcomes than does treatment with chlorambucil alone, while also being tolerable for patients who have few treatment options. We carried out a randomised, open-label, phase 3 trial for treatment-naive patients with chronic lymphocytic leukaemia in 109 centres in 16 countries. We included patients who had active disease needing treatment, but in whom fludarabine-based treatment was not possible. We randomly assigned patients (1:1) to receive oral chlorambucil (10 mg/m(2)) on days 1-7 of a 28 day treatment course or to receive chlorambucil by this schedule plus intravenous ofatumumab (cycle 1: 300 mg on day 1 and 1000 mg on day 8; subsequent cycles: 1000 mg on day 1) for three to 12 cycles. Assignment was done with a randomisation list that was computer generated at GlaxoSmithKline, and was stratified, in a block size of two, by age, disease stage, and performance status. The primary endpoint was progression-free survival in the intention-to-treat population and assessment was done by an independent review committee that was masked to group assignment. The study is registered with ClinicalTrials.gov, number NCT00748189. We enrolled 447 patients, median age 69 years (range 35-92). Between Dec 22, 2008, and May 26, 2011, we randomly assigned 221 patients to chlorambucil plus ofatumumab and 226 patients to chlorambucil alone. Median progression-free survival was 22·4 months (95% CI 19·0-25·2) in the group assigned to chlorambucil plus ofatumumab compared with 13·1 months (10·6-13·8) in the group assigned to chlorambucil only (hazard ratio 0·57, 95% CI 0·45-0·72; p<0·0001). Grade 3 or greater adverse events were

  19. Phase transitions in optimal search times: How random walkers should combine resetting and flight scales.

    PubMed

    Campos, Daniel; Méndez, Vicenç

    2015-12-01

    Recent works have explored the properties of Lévy flights with resetting in one-dimensional domains and have reported the existence of phase transitions in the phase space of parameters which minimizes the mean first passage time (MFPT) through the origin [L. Kusmierz et al., Phys. Rev. Lett. 113, 220602 (2014)]. Here, we show how actually an interesting dynamics, including also phase transitions for the minimization of the MFPT, can also be obtained without invoking the use of Lévy statistics but for the simpler case of random walks with exponentially distributed flights of constant speed. We explore this dynamics both in the case of finite and infinite domains, and for different implementations of the resetting mechanism to show that different ways to introduce resetting consistently lead to a quite similar dynamics. The use of exponential flights has the strong advantage that exact solutions can be obtained easily for the MFPT through the origin, so a complete analytical characterization of the system dynamics can be provided. Furthermore, we discuss in detail how the phase transitions observed in random walks with resetting are closely related to several ideas recurrently used in the field of random search theory, in particular, to other mechanisms proposed to understand random search in space as mortal random walks or multiscale random walks. As a whole, we corroborate that one of the essential ingredients behind MFPT minimization lies in the combination of multiple movement scales (regardless of their specific origin).

  20. Masking property of quantum random cipher with phase mask encryption

    NASA Astrophysics Data System (ADS)

    Sohma, Masaki; Hirota, Osamu

    2014-10-01

    The security analysis of physical encryption protocol based on coherent pulse position modulation (CPPM) originated by Yuen is one of the most interesting topics in the study of cryptosystem with a security level beyond the Shannon limit. Although the implementation of CPPM scheme has certain difficulty, several methods have been proposed recently. This paper deals with the CPPM encryption in terms of symplectic transformation, which includes a phase mask encryption as a special example, and formulates a unified security analysis for such encryption schemes. Specifically, we give a lower bound of Eve's symbol error probability using reliability function theory to ensure that our proposed system exceeds the Shannon limit. Then we assume the secret key is given to Eve after her heterodyne measurement. Since this assumption means that Eve has a great advantage in the sense of the conventional cryptography, the lower bound of her error indeed ensures the security level beyond the Shannon limit. In addition, we show some numerical examples of the security performance.

  1. Binimetinib versus dacarbazine in patients with advanced NRAS-mutant melanoma (NEMO): a multicentre, open-label, randomised, phase 3 trial.

    PubMed

    Dummer, Reinhard; Schadendorf, Dirk; Ascierto, Paolo A; Arance, Ana; Dutriaux, Caroline; Di Giacomo, Anna Maria; Rutkowski, Piotr; Del Vecchio, Michele; Gutzmer, Ralf; Mandala, Mario; Thomas, Luc; Demidov, Lev; Garbe, Claus; Hogg, David; Liszkay, Gabriella; Queirolo, Paola; Wasserman, Ernesto; Ford, James; Weill, Marine; Sirulnik, L Andres; Jehl, Valentine; Bozón, Viviana; Long, Georgina V; Flaherty, Keith

    2017-04-01

    There are no established therapies specific for NRAS-mutant melanoma despite the emergence of immunotherapy. We aimed to assess the efficacy and safety of the MEK inhibitor binimetinib versus that of dacarbazine in patients with advanced NRAS-mutant melanoma. NEMO is an ongoing, randomised, open-label phase 3 study done at 118 hospitals in 26 countries. Patients with advanced, unresectable, American Joint Committee on Cancer stage IIIC or stage IV NRAS-mutant melanoma who were previously untreated or had progressed on or after previous immunotherapy were randomised (2:1) to receive either binimetinib 45 mg orally twice daily or dacarbazine 1000 mg/m(2) intravenously every 3 weeks. Randomisation was stratified by stage, performance status, and previous immunotherapy. The primary endpoint was progression-free survival assessed by blinded central review in the intention-to-treat population. Safety analyses were done in the safety population, consisting of all patients who received at least one study drug dose and one post-baseline safety assessment. This study is registered with ClinicalTrials.gov, number NCT01763164 and with EudraCT, number 2012-003593-51. Between Aug 19, 2013, and April 28, 2015, 402 patients were enrolled and randomly assigned, 269 to binimetinib and 133 to dacarbazine. Median follow-up was 1·7 months (IQR 1·4-4·1). Median progression-free survival was 2·8 months (95% CI 2·8-3·6) in the binimetinib group and 1·5 months (1·5-1·7) in the dacarbazine group (hazard ratio 0·62 [95% CI 0·47-0·80]; one-sided p<0·001). Grade 3-4 adverse events seen in at least 5% of patients the safety population in either group were increased creatine phosphokinase (52 [19%] of 269 patients in the binimetinib group vs none of 114 in the dacarbazine group), hypertension (20 [7%] vs two [2%]), anaemia (five [2%] vs six [5%]), and neutropenia (two [1%] vs ten [9%]). Serious adverse events (all grades) occurred in 91 (34%) patients in the binimetinib group and 25

  2. The second (main) phase of an open, randomised, multicentre study to investigate the effectiveness of an intensive blood pressure reduction in acute cerebral haemorrhage trial (INTERACT2).

    PubMed

    Delcourt, C; Huang, Y; Wang, J; Heeley, E; Lindley, R; Stapf, C; Tzourio, C; Arima, H; Parsons, M; Sun, J; Neal, B; Chalmers, J; Anderson, C

    2010-04-01

    The INTERACT pilot study demonstrated the feasibility of the protocol, safety of early intensive blood pressure lowering and effects on haematoma expansion within 6 h of onset of intracerebral haemorrhage. This article describes the design of the second, main phase, INTERACT2. To compare the effects of a management strategy of early intensive blood pressure lowering with a more conservative guideline-based blood pressure management policy in patients with acute intracerebral hemorrhage. INTERACT2 is a prospective, randomized, open label, assessor-blinded end-point (PROBE). Patients with a systolic blood pressure greater than 150 mmHg and no definite indication for or contraindication to blood pressure-lowering treatment are centrally randomised to either of two treatment groups within 6 h onset of intracerebral haemorrhage. Those allocated to intensive blood pressure lowering will receive primarily intravenous, hypotensive agents to achieve a systolic blood pressure target of <140 mmHg within 1 h of randomisation and to maintain this level for up to 7 days in hospital. The control group will receive blood pressure-lowering treatment to a target systolic blood pressure of <180 mmHg. Both groups are to receive similar acute stroke unit care, therapy and active management. Oral antihypertensive therapy is recommended in patients before hospital discharge with a long-term systolic blood pressure goal of 140 mmHg according to secondary stroke prevention guidelines. A projected 2800 subjects are to be enrolled from approximately 140 centres worldwide to provide 90% power (alpha 0.05) to detect a 14% difference in the risk of death and dependency between the groups, which equates to one or more cases of a poor outcome prevented in every 15 patients treated. The primary outcome is the combined end-point of death and dependency according to the modified Rankin Scale at 90 days. The secondary outcomes are the separate components of the primary end-point in patients treated

  3. Improvement in holographic storage capacity by use of double-random phase encryption.

    PubMed

    Tan, X; Matoba, O; Shimura, T; Kuroda, K

    2001-09-10

    We show that a double-random encryption technique can improve the storage capacity of an angular-multiplexed holographic memory system. In the holographic memory system, input binary images are encrypted into white-noise-like images by use of two random phase masks located at the input and the Fourier planes. These encrypted images are stored as holograms in a photorefractive medium by use of angular multiplexing. All the images are encrypted by different sets of random phase masks. Even when the angle separation between adjacent images is small enough to cause cross talk between adjacent images, original binary data can be recovered with the correct phase mask; the other reconstructed images remain white-noise-like images because incorrect masks are used. Therefore the capacity of the proposed system can be larger than that of a conventional holographic memory system without the random phase encryption technique. Numerical evaluation and experimental results are presented to confirm that the capacity of the system with random phase masks is larger than that of the conventional memory system.

  4. Color image security system using double random-structured phase encoding in gyrator transform domain.

    PubMed

    Abuturab, Muhammad Rafiq

    2012-05-20

    A novel method for encoding color information based on a double random phase mask and a double structured phase mask in a gyrator transform domain is proposed. The amplitude transmittance of the Fresnel zone plate is used as structured phase-mask encoding. A color image is first segregated into red, green, and blue component images. Each of these component images are then independently encrypted using first a random phase mask placed at the image plane and transmitted through the first structured phase mask. They are then encoded by the first gyrator transform. The resulting information is again encrypted by a second random phase mask placed at the gyrator transform plane and transmitted through the second structured phase mask, and then encoded by the second gyrator transform. The system parameters of the structured phase mask and gyrator transform in each channel serve as additional encryption keys and enlarge the key space. The encryption process can be realized with an electro-optical hybrid system. The proposed system avoids problems arising from misalignment and benefits of a higher space-bandwidth product. Numerical simulations are presented to confirm the security, validity, and possibility of the proposed idea.

  5. Atezolizumab versus docetaxel in patients with previously treated non-small-cell lung cancer (OAK): a phase 3, open-label, multicentre randomised controlled trial.

    PubMed

    Rittmeyer, Achim; Barlesi, Fabrice; Waterkamp, Daniel; Park, Keunchil; Ciardiello, Fortunato; von Pawel, Joachim; Gadgeel, Shirish M; Hida, Toyoaki; Kowalski, Dariusz M; Dols, Manuel Cobo; Cortinovis, Diego L; Leach, Joseph; Polikoff, Jonathan; Barrios, Carlos; Kabbinavar, Fairooz; Frontera, Osvaldo Arén; De Marinis, Filippo; Turna, Hande; Lee, Jong-Seok; Ballinger, Marcus; Kowanetz, Marcin; He, Pei; Chen, Daniel S; Sandler, Alan; Gandara, David R

    2017-01-21

    Atezolizumab is a humanised antiprogrammed death-ligand 1 (PD-L1) monoclonal antibody that inhibits PD-L1 and programmed death-1 (PD-1) and PD-L1 and B7-1 interactions, reinvigorating anticancer immunity. We assessed its efficacy and safety versus docetaxel in previously treated patients with non-small-cell lung cancer. We did a randomised, open-label, phase 3 trial (OAK) in 194 academic or community oncology centres in 31 countries. We enrolled patients who had squamous or non-squamous non-small-cell lung cancer, were 18 years or older, had measurable disease per Response Evaluation Criteria in Solid Tumors, and had an Eastern Cooperative Oncology Group performance status of 0 or 1. Patients had received one to two previous cytotoxic chemotherapy regimens (one or more platinum based combination therapies) for stage IIIB or IV non-small-cell lung cancer. Patients with a history of autoimmune disease and those who had received previous treatments with docetaxel, CD137 agonists, anti-CTLA4, or therapies targeting the PD-L1 and PD-1 pathway were excluded. Patients were randomly assigned (1:1) to intravenously receive either atezolizumab 1200 mg or docetaxel 75 mg/m(2) every 3 weeks by permuted block randomisation (block size of eight) via an interactive voice or web response system. Coprimary endpoints were overall survival in the intention-to-treat (ITT) and PD-L1-expression population TC1/2/3 or IC1/2/3 (≥1% PD-L1 on tumour cells or tumour-infiltrating immune cells). The primary efficacy analysis was done in the first 850 of 1225 enrolled patients. This study is registered with ClinicalTrials.gov, number NCT02008227. Between March 11, 2014, and April 29, 2015, 1225 patients were recruited. In the primary population, 425 patients were randomly assigned to receive atezolizumab and 425 patients were assigned to receive docetaxel. Overall survival was significantly longer with atezolizumab in the ITT and PD-L1-expression populations. In the ITT population, overall

  6. Neratinib after trastuzumab-based adjuvant therapy in patients with HER2-positive breast cancer (ExteNET): a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial.

    PubMed

    Chan, Arlene; Delaloge, Suzette; Holmes, Frankie A; Moy, Beverly; Iwata, Hiroji; Harvey, Vernon J; Robert, Nicholas J; Silovski, Tajana; Gokmen, Erhan; von Minckwitz, Gunter; Ejlertsen, Bent; Chia, Stephen K L; Mansi, Janine; Barrios, Carlos H; Gnant, Michael; Buyse, Marc; Gore, Ira; Smith, John; Harker, Graydon; Masuda, Norikazu; Petrakova, Katarina; Zotano, Angel Guerrero; Iannotti, Nicholas; Rodriguez, Gladys; Tassone, Pierfrancesco; Wong, Alvin; Bryce, Richard; Ye, Yining; Yao, Bin; Martin, Miguel

    2016-03-01

    Neratinib, an irreversible tyrosine-kinase inhibitor of HER1, HER2, and HER4, has clinical activity in patients with HER2-positive metastatic breast cancer. We aimed to investigate the efficacy and safety of 12 months of neratinib after trastuzumab-based adjuvant therapy in patients with early-stage HER2-positive breast cancer. We did this multicentre, randomised, double-blind, placebo-controlled, phase 3 trial at 495 centres in Europe, Asia, Australia, New Zealand, and North and South America. Eligible women (aged ≥18 years, or ≥20 years in Japan) had stage 1-3 HER2-positive breast cancer and had completed neoadjuvant and adjuvant trastuzumab therapy up to 2 years before randomisation. Inclusion criteria were amended on Feb 25, 2010, to include patients with stage 2-3 HER2-positive breast cancer who had completed trastuzumab therapy up to 1 year previously. Patients were randomly assigned (1:1) to receive oral neratinib 240 mg per day or matching placebo. The randomisation sequence was generated with permuted blocks stratified by hormone receptor status (hormone receptor-positive [oestrogen or progesterone receptor-positive or both] vs hormone receptor-negative [oestrogen and progesterone receptor-negative]), nodal status (0, 1-3, or ≥4), and trastuzumab adjuvant regimen (sequentially vs concurrently with chemotherapy), then implemented centrally via an interactive voice and web-response system. Patients, investigators, and trial sponsors were masked to treatment allocation. The primary outcome was invasive disease-free survival, as defined in the original protocol, at 2 years after randomisation. Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00878709. Between July 9, 2009, and Oct 24, 2011, we randomly assigned 2840 women to receive neratinib (n=1420) or placebo (n=1420). Median follow-up time was 24 months (IQR 20-25) in the neratinib group and 24 months (22-25) in the placebo group. At 2 year follow-up, 70

  7. Frequency domain phase extraction algorithm for phase-shifting interferometry with random phase-shifting amount and low-sampling rate

    NASA Astrophysics Data System (ADS)

    Liu, Shengde; Zhong, Liyun; Zhang, Fengjie; Lu, Xiaoxu

    2013-03-01

    To extract the exact phase of the measured object in the environmental conditions with random noise, a novel kind of frequency domain phase extraction method for phase-shifting interferometry with random phase-shifting amount and low-sampling rate is proposed, in which the time-varied intensity signal of an arbitrary pixel of phase-shifting interferograms is cut into a lot of sub-sections intensity signals with the same length, and then the frequency domain weighted stack operation is performed for the corresponding Fourier spectrum of these sub-section intensity signals. Importantly, the phase obtained from the proposed method coincides well with the conventional four-step phase-shifting algorithm, but the requirement for the environmental conditions in the former are greatly lowered than that in the latter, moreover, while the same number of phase-shifting interferograms is employed to perform the phase extraction, the phase measuring accuracy in the proposed method is greatly higher than that in the time domain Fourier transform (TFT) method.

  8. A combination of gefitinib and FOLFOX-4 as first-line treatment in advanced colorectal cancer patients. A GISCAD multicentre phase II study including a biological analysis of EGFR overexpression, amplification and NF-kB activation

    PubMed Central

    Cascinu, S; Berardi, R; Salvagni, S; Beretta, G D; Catalano, V; Pucci, F; Sobrero, A; Tagliaferri, P; Labianca, R; Scartozzi, M; Crocicchio, F; Mari, E; Ardizzoni, A

    2007-01-01

    Interesting activity has been reported by combining chemotherapy with cetuximab. An alternative approach for blocking EGFR function has been the development of small-molecule inhibitors of tyrosine kinase domain such as gefitinib. We designed a multicentre phase II study in advanced colorectal cancer combining gefitinib+FOLFOX in order to determine the activity and to relate EGFR expression and gene amplification and NF-kB activation to therapeutic results. Patients received FOLFOX-4 regimen plus gefitinib as first-line treatment. Tumour samples were analysed for EGFR protein expression by immunohistochemical analysis and for EGFR gene amplification by fluorescence in situ hybridisation (FISH), chromogenic in situ hybridisation (CISH) and NF-kB activation. Forty-three patients were enrolled into this study; 15 patients experienced a partial response (response rate=34.9%), whereas other 12 (27.9%) had a stable disease. Median progression-free survival (PFS) was 7.8 months and median overall survival (OS) was 13.9 months. We did not find any relationship with EGFR overexpression, gene amplification, while NF-kB activation was associated with a resistance to therapy. Gefitinib does not seem to increase the activity of FOLFOX in advanced colorectal cancer even in patients overexpressing EGFR or with EGFR amplification. Furthermore, while NF-kB activation seems to predict resistance to chemotherapy as demonstrated ‘in vitro' models, gefitinib does not overcome this mechanism of resistance, as reported for cetuximab. PMID:18059397

  9. A randomized phase 2b study of peginterferon lambda-1a for the treatment of chronic HCV infection.

    PubMed

    Muir, Andrew J; Arora, Sanjeev; Everson, Gregory; Flisiak, Robert; George, Jacob; Ghalib, Reem; Gordon, Stuart C; Gray, Todd; Greenbloom, Susan; Hassanein, Tarek; Hillson, Jan; Horga, Maria Arantxa; Jacobson, Ira M; Jeffers, Lennox; Kowdley, Kris V; Lawitz, Eric; Lueth, Stefan; Rodriguez-Torres, Maribel; Rustgi, Vinod; Shemanski, Lynn; Shiffman, Mitchell L; Srinivasan, Subasree; Vargas, Hugo E; Vierling, John M; Xu, Dong; Lopez-Talavera, Juan C; Zeuzem, Stefan

    2014-12-01

    Peginterferon lambda-1a (Lambda) is a type-III interferon with similar antiviral activity to alfa interferons but with a diminished extrahepatic receptor distribution, reducing the risk for extrahepatic adverse events. This was a randomized, blinded, actively-controlled, multicentre phase 2b dose-ranging study in patients chronically infected with HCV genotypes 1-4. Treatment-naive patients received Lambda (120/180/240 μg) or peginterferon alfa-2a (alfa; 180 μg) once-weekly with ribavirin for 24 (genotypes [GT] 2,3) or 48 (GT1,4) weeks. Rates of undetectable HCV-RNA at week 12 (complete early virologic response [cEVR]; primary end point) were significantly higher in GT1,4 patients receiving Lambda vs. alfa (170/304, 56% vs. 38/103, 37%); with similar cEVR rates for GT2,3 (80/88, 91% vs. 26/30, 87%). Rates of undetectable HCV-RNA at week 4 were significantly higher on 180 μg (15/102, 15% GT1,4; 22/29, 76% GT2,3) and 240 μg (17/104, 16% GT1,4; 20/30, 67% GT2,3) Lambda than alfa (6/103, 6% GT1,4; 9/30, 30% GT2,3). Sustained virologic responses (post-treatment week 24) were comparable between Lambda and alfa for GT1,4 (37-46% Lambda; 37% alfa) and GT2,3 (60-76% Lambda; 53% alfa). Aminotransferase and/or bilirubin elevations were the primary dose-limiting abnormalities for Lambda; a sponsor-mandated 240 to 180 μg dose reduction was therefore implemented. Serious adverse events were comparable (3-13% Lambda; 3-7% alfa). Grade 3-4 haemoglobin, neutrophil, and platelet reductions were lower on Lambda than alfa. Among alfa patients, 28/133 (21%) had peginterferon and 31/133 (23%) had ribavirin dose reductions for haematologic abnormalities vs. 0/392 and 8/392 (2%) on Lambda. Lambda demonstrated fewer musculoskeletal (16-28% vs. 47-63%) and influenza-like events (8-23% vs. 40-46%) than alfa. Lambda was associated with improved or similar rates of virologic response with fewer extrahepatic adverse events than alfa in chronic HCV infection. Copyright © 2014 European

  10. All-optical quantum random bit generation from intrinsically binary phase of parametric oscillators.

    PubMed

    Marandi, Alireza; Leindecker, Nick C; Vodopyanov, Konstantin L; Byer, Robert L

    2012-08-13

    We demonstrate a novel all-optical quantum random number generator (RNG) based on above-threshold binary phase state selection in a degenerate optical parametric oscillator (OPO). Photodetection is not a part of the random process, and no post processing is required for the generated bit sequence. We show that the outcome is statistically random with 99% confidence, and verify that the randomness is due to the phase of initiating photons generated through spontaneous parametric down conversion of the pump, with negligible contribution of classical noise sources. With the use of micro- and nanoscale OPO resonators, this technique offers a promise for simple, robust, and high-speed on-chip all-optical quantum RNGs.

  11. N-terminal pro brain natriuretic peptide in the management of patients in the medical emergency department (PROMPT): correlation with disease severity, utilization of hospital resources, and prognosis in a large, prospective, randomized multicentre trial.

    PubMed

    Luchner, Andreas; Möckel, Martin; Spanuth, Eberhard; Möcks, Joachim; Peetz, Dirk; Baum, Hannsjörg; Spes, Christoph; Wrede, Christian E; Vollert, Jörn; Müller, Reinhold; Katus, Hugo; Giannitsis, Evangelos

    2012-03-01

    N-terminal pro brain natriuretic peptide (NT-proBNP) is a potent marker of heart failure and other cardiac diseases. The value of NT-proBNP testing in the medical emergency department (ED) was assessed in patients >65 years old. This large, prospective, randomized, controlled, multicentre trial was conducted in six medical EDs. Data for evaluation of the primary endpoint of hospitalization were available for 1086 patients. Median NT-proBNP was 582 pg/mL. A total of 16% of patients presented with NT-proBNP <150 pg/mL (low), 55% with NT-proBNP between 150 and 1800 pg/mL (intermediate), and 29% with NT-proBNP >1800 pg/mL (high). NT-proBNP was positively correlated with hospital admission [ odds ratio (OR) for high vs. low 2.9, P < 0.0001], length of stay (8.5 days vs. 3.5 days for high vs. low, P < 0.01), in-hospital death (3.9% vs. 0% for high vs. low, P < 0.01), 6 months re-hospitalization (OR for high vs. low 5.1, P < 0.0001), and 6 months death or re-hospitalization (OR for high vs. low 5.7, P < 0.0001). Knowledge of NT-proBNP had no significant effect on the primary endpoint hospital admission and the secondary endpoints intermediate/intensive care unit (IMC/ICU) admission, length of stay, re-hospitalization and death, or re-hospitalization in the total cohort. However, patients with high open NT-proBNP (>1800 pg/mL) were more likely to be admitted to the hospital (P < 0.05) and IMC/ICU (P < 0.05), whereas patients with low open NT-proBNP (<150 pg/mL) were less likely to be admitted (P < 0.05) compared with patients with blinded NT-proBNP. Although NT-proBNP does not affect overall hospitalization, it is associated with better stratification of patient care and is strongly correlated with subsequent utilization of hospital resources and prognosis.

  12. Simultaneous transmission for an encrypted image and a double random-phase encryption key.

    PubMed

    Yuan, Sheng; Zhou, Xin; Li, Da-hai; Zhou, Ding-fu

    2007-06-20

    We propose a method to simultaneously transmit double random-phase encryption key and an encrypted image by making use of the fact that an acceptable decryption result can be obtained when only partial data of the encrypted image have been taken in the decryption process. First, the original image data are encoded as an encrypted image by a double random-phase encryption technique. Second, a double random-phase encryption key is encoded as an encoded key by the Rivest-Shamir-Adelman (RSA) public-key encryption algorithm. Then the amplitude of the encrypted image is modulated by the encoded key to form what we call an encoded image. Finally, the encoded image that carries both the encrypted image and the encoded key is delivered to the receiver. Based on such a method, the receiver can have an acceptable result and secure transmission can be guaranteed by the RSA cipher system.

  13. Effects of closed-loop stimulation vs. DDD pacing on haemodynamic variations and occurrence of syncope induced by head-up tilt test in older patients with refrac\\tory cardioinhibitory vasovagal syncope: the Tilt test-Induced REsponse in Closed-loop Stimulation multicentre, prospective, single blind, randomized study.

    PubMed

    Palmisano, Pietro; Dell'Era, Gabriele; Russo, Vincenzo; Zaccaria, Maria; Mangia, Rolando; Bortnik, Miriam; De Vecchi, Federica; Giubertoni, Ailia; Patti, Fabiana; Magnani, Andrea; Nigro, Gerardo; Rago, Anna; Occhetta, Eraldo; Accogli, Michele

    2017-04-12

    Closed-loop stimulation (CLS) seemed promising in preventing the recurrence of vasovagal syncope (VVS) in patients with a cardioinhibitory response to head-up tilt test (HUTT) compared with conventional pacing. We hypothesized that the better results of this algorithm are due to its quick reaction in high-rate pacing delivered in the early phase of vasovagal reflex, which increase the cardiac output and the blood pressure preventing loss of consciousness. This prospective, randomized, single-blind, multicentre study was designed as an intra-patient comparison and enrolled 30 patients (age 62.2 ± 13.5 years, males 60.0%) with cardioinhibitory VVS, carrying a dual-chamber pacemaker incorporating CLS algorithm. Two HUTTs were performed one week apart: one during DDD-CLS 60-130/min pacing and the other during DDD 60/min pacing; patients were randomly and blindly assigned to two groups: in one the first HUTT was performed in DDD-CLS (n = 15), in the other in DDD (n = 15). Occurrence of syncope and haemodynamic variations induced by HUTT was recorded during the tests. Compared with DDD, DDD-CLS significantly reduced the occurrence of syncope induced by HUTT (30.0% vs. 76.7%; P < 0.001). In the patients who had syncope in both DDD and DDD-CLS mode, DDD-CLS significantly delayed the onset of syncope during HUTT (from 20.8 ± 3.9 to 24.8 ± 0.9 min; P = 0.032). The maximum fall in systolic blood pressure recorded during HUTT was significantly lower in DDD-CLS compared with DDD (43.2 ± 30.3 vs. 65.1 ± 25.8 mmHg; P = 0.004). In patients with cardioinhibitory VVS, CLS reduces the occurrence of syncope induced by HUTT, compared with DDD pacing. When CLS is not able to abort the vasovagal reflex, it seems to delay the onset of syncope.

  14. Color image encoding in dual fractional Fourier-wavelet domain with random phases

    NASA Astrophysics Data System (ADS)

    Chen, Linfei; Zhao, Daomu

    2009-09-01

    A new cryptology in dual fractional Fourier-wavelet domain is proposed in this paper, which is calculated by discrete fractional Fourier transform and wavelet decomposition. Different random phases are used in different wavelet subbands in encryption. A new color image encoding method is also presented with basic color decomposition and encryption respectively. All the keys, including random phases and fractional orders in R, G and B three channels, should be correctly used in decryption, otherwise people cannot obtain the totally correct information. Some numerical simulations are presented to demonstrate the possibility of the method. It would have widely potential applications in digital color image processing and protection.

  15. Phase retrieval and diffractive imaging based on Babinet's principle and complementary random sampling.

    PubMed

    Cheng, Zhen-Jia; Wang, Ben-Yi; Xie, Yi-Yan; Lu, Yu-Jie; Yue, Qing-Yang; Guo, Cheng-Shan

    2015-11-02

    We proposed an iterative method for phase retrieval and diffractive imaging based on Babinet's principle and complementary random sampling (CRS). We demonstrated that the whole complex amplitude (not sieved) of an object wave can be accurately retrieved from the diffraction intensities of the object wave sampled by a group of binary CRS masks and the diffractive imaging for the object can be realized through a single digital inverse diffraction. Some experimental results are given for the demonstration. Our experimental results reveal that, using CRS, the influence of a binary random sampling mask on the retrieved field can be well eliminated, and the accuracy and efficiency of the phase retrieval can be greatly improved.

  16. Quantum image encryption based on generalized Arnold transform and double random-phase encoding

    NASA Astrophysics Data System (ADS)

    Zhou, Nan Run; Hua, Tian Xiang; Gong, Li Hua; Pei, Dong Ju; Liao, Qing Hong

    2015-04-01

    A quantum realization of the generalized Arnold transform is designed. A novel quantum image encryption algorithm based on generalized Arnold transform and double random-phase encoding is proposed. The pixels are scrambled by the generalized Arnold transform, and the gray-level information of images is encoded by the double random-phase operations. The keys of the encryption algorithm include the independent parameters of coefficients matrix, iterative times and classical binary sequences, and thus, the key space is extremely large. Numerical simulations and theoretical analyses demonstrate that the proposed algorithm with good feasibility and effectiveness has lower computational complexity than its classical counterpart.

  17. Random exchange interaction effects on the phase transitions in frustrated classical Heisenberg model

    SciTech Connect

    Li, W. C.; Song, X.; Feng, J. J.; Zeng, M.; Gao, X. S.; Qin, M. H.; Jia, X. T.

    2015-07-07

    In this work, the effects of the random exchange interaction on the phase transitions and phase diagrams of classical frustrated Heisenberg model are investigated by Monte Carlo simulation in order to simulate the chemical doping effect in real materials. It is observed that the antiferromagnetic transitions shift toward low temperature with the increasing magnitude of the random exchange interaction, which can be qualitatively understood from the competitions among local spin states. This study is related to the magnetic properties in the doped iron-based superconductors.

  18. Atezolizumab versus docetaxel for patients with previously treated non-small-cell lung cancer (POPLAR): a multicentre, open-label, phase 2 randomised controlled trial.

    PubMed

    Fehrenbacher, Louis; Spira, Alexander; Ballinger, Marcus; Kowanetz, Marcin; Vansteenkiste, Johan; Mazieres, Julien; Park, Keunchil; Smith, David; Artal-Cortes, Angel; Lewanski, Conrad; Braiteh, Fadi; Waterkamp, Daniel; He, Pei; Zou, Wei; Chen, Daniel S; Yi, Jing; Sandler, Alan; Rittmeyer, Achim

    2016-04-30

    Outcomes are poor for patients with previously treated, advanced or metastatic non-small-cell lung cancer (NSCLC). The anti-programmed death ligand 1 (PD-L1) antibody atezolizumab is clinically active against cancer, including NSCLC, especially cancers expressing PD-L1 on tumour cells, tumour-infiltrating immune cells, or both. We assessed efficacy and safety of atezolizumab versus docetaxel in previously treated NSCLC, analysed by PD-L1 expression levels on tumour cells and tumour-infiltrating immune cells and in the intention-to-treat population. In this open-label, phase 2 randomised controlled trial, patients with NSCLC who progressed on post-platinum chemotherapy were recruited in 61 academic medical centres and community oncology practices across 13 countries in Europe and North America. Key inclusion criteria were Eastern Cooperative Oncology Group performance status 0 or 1, measurable disease by Response Evaluation Criteria In Solid Tumors version 1.1 (RECIST v1.1), and adequate haematological and end-organ function. Patients were stratified by PD-L1 tumour-infiltrating immune cell status, histology, and previous lines of therapy, and randomly assigned (1:1) by permuted block randomisation (with a block size of four) using an interactive voice or web system to receive intravenous atezolizumab 1200 mg or docetaxel 75 mg/m(2) once every 3 weeks. Baseline PD-L1 expression was scored by immunohistochemistry in tumour cells (as percentage of PD-L1-expressing tumour cells TC3≥50%, TC2≥5% and <50%, TC1≥1% and <5%, and TC0<1%) and tumour-infiltrating immune cells (as percentage of tumour area: IC3≥10%, IC2≥5% and <10%, IC1≥1% and <5%, and IC0<1%). The primary endpoint was overall survival in the intention-to-treat population and PD-L1 subgroups at 173 deaths. Biomarkers were assessed in an exploratory analysis. We assessed safety in all patients who received at least one dose of study drug. This study is registered with ClinicalTrials.gov, number NCT

  19. Encrypted optical storage with wavelength-key and random phase codes.

    PubMed

    Matoba, O; Javidi, B

    1999-11-10

    An encrypted optical memory system that uses a wavelength code as well as input and Fourier-plane random phase codes is proposed. Original data are illuminated by a coherent light source with a specified wavelength and are then encrypted with two random phase codes before being stored holographically in a photorefractive material. Successful decryption requires the use of a readout beam with the same wavelength as that used in the recording, in addition to the correct phase key in the Fourier plane. The wavelength selectivity of the proposed system is evaluated numerically. We show that the number of available wavelength keys depends on the correlation length of the phase key in the Fourier plane. Preliminary experiments of encryption and decryption of optical memory in a LiNbO(3):Fe photorefractive crystal are demonstrated.

  20. Phase diagram of the random field Ising model on the Bethe lattice

    NASA Astrophysics Data System (ADS)

    Nowotny, Thomas; Patzlaff, Heiko; Behn, Ulrich

    2002-01-01

    The phase diagram of the random field Ising model on the Bethe lattice with a symmetric dichotomous random field is closely investigated with respect to the transition between the ferromagnetic and paramagnetic regimes. Refining arguments of Bleher, Ruiz, and Zagrebnov [J. Stat. Phys. 93, 33 (1998)], an exact upper bound for the existence of a unique paramagnetic phase is found, which considerably improves the earlier results. Several numerical estimates of transition lines between a ferromagnetic and a paramagnetic regime are presented. The results obtained do not coincide with the lower bound for the onset of ferromagnetism proposed by Bruinsma [Phys. Rev. B 30, 289 (1984)]. If Bruinsma's estimate proves correct, this would hint at a region of coexistence of stable ferromagnetic phases and a stable paramagnetic phase.

  1. Ibrutinib for patients with rituximab-refractory Waldenström's macroglobulinaemia (iNNOVATE): an open-label substudy of an international, multicentre, phase 3 trial.

    PubMed

    Dimopoulos, Meletios A; Trotman, Judith; Tedeschi, Alessandra; Matous, Jeffrey V; Macdonald, David; Tam, Constantine; Tournilhac, Olivier; Ma, Shuo; Oriol, Albert; Heffner, Leonard T; Shustik, Chaim; García-Sanz, Ramón; Cornell, Robert F; de Larrea, Carlos Fernández; Castillo, Jorge J; Granell, Miquel; Kyrtsonis, Marie-Christine; Leblond, Veronique; Symeonidis, Argiris; Kastritis, Efstathios; Singh, Priyanka; Li, Jianling; Graef, Thorsten; Bilotti, Elizabeth; Treon, Steven; Buske, Christian

    2017-02-01

    In the era of widespread rituximab use for Waldenström's macroglobulinaemia, new treatment options for patients with rituximab-refractory disease are an important clinical need. Ibrutinib has induced durable responses in previously treated patients with Waldenström's macroglobulinaemia. We assessed the efficacy and safety of ibrutinib in a population with rituximab-refractory disease. This multicentre, open-label substudy was done at 19 sites in seven countries in adults aged 18 years and older with confirmed Waldenström's macroglobulinaemia, refractory to rituximab and requiring treatment. Disease refractory to the last rituximab-containing therapy was defined as either relapse less than 12 months since last dose of rituximab or failure to achieve at least a minor response. Key exclusion criteria included: CNS involvement, a stroke or intracranial haemorrhage less than 12 months before enrolment, clinically significant cardiovascular disease, hepatitis B or hepatitis C viral infection, and a known bleeding disorder. Patients received oral ibrutinib 420 mg once daily until progression or unacceptable toxicity. The substudy was not prospectively powered for statistical comparisons, and as such, all the analyses are descriptive in nature. This study objectives were the proportion of patients with an overall response, progression-free survival, overall survival, haematological improvement measured by haemoglobin, time to next treatment, and patient-reported outcomes according to the Functional Assessment of Cancer Therapy-Anemia (FACT-An) and the Euro Qol 5 Dimension Questionnaire (EQ-5D-5L). All analyses were per protocol. The study is registered at ClinicalTrials.gov, number NCT02165397, and follow-up is ongoing but enrolment is complete. Between Aug 18, 2014, and Feb 18, 2015, 31 patients were enrolled. Median age was 67 years (IQR 58-74); 13 (42%) of 31 patients had high-risk disease per the International Prognostic Scoring System Waldenstr

  2. QCD phase structure at finite temperature in three-flavor random matrix theory

    SciTech Connect

    Arai, Ryoichi; Yoshinaga, Naotaka

    2009-07-01

    The QCD phase structure is studied at finite temperature in a three-flavor random matrix model formulated with nonzero quark chemical potentials. In the case of no flavor mixing, we analytically obtain temperature dependent critical chemical potentials for finite quark masses. Numerical results show that the QCD phase diagram as a function of temperature is qualitatively in agreement with the prediction of the Nambu-Jona-Lasinio model.

  3. Efficacy and safety of epratuzumab in patients with moderate/severe active systemic lupus erythematosus: results from EMBLEM, a phase IIb, randomised, double-blind, placebo-controlled, multicentre study

    PubMed Central

    Wallace, Daniel J; Kalunian, Kenneth; Petri, Michelle A; Strand, Vibeke; Houssiau, Frederic A; Pike, Marilyn; Kilgallen, Brian; Bongardt, Sabine; Barry, Anna; Kelley, Lexy; Gordon, Caroline

    2014-01-01

    Objective To identify a suitable dosing regimen of the CD22-targeted monoclonal antibody epratuzumab in adults with moderately to severely active systemic lupus erythematosus (SLE). Methods A phase IIb, multicentre, randomised controlled study (NCT00624351) was conducted with 227 patients (37–39 per arm) receiving either: placebo, epratuzumab 200 mg cumulative dose (cd) (100 mg every other week (EOW)), 800 mg cd (400 mg EOW), 2400 mg cd (600 mg weekly), 2400 mg cd (1200 mg EOW), or 3600 mg cd (1800 mg EOW). The primary endpoint (not powered for significance) was the week 12 responder rate measured using a novel composite endpoint, the British Isles Lupus Assessment Group (BILAG)-based Combined Lupus Assessment (BICLA). Results Proportion of responders was higher in all epratuzumab groups than with placebo (overall treatment effect test p=0.148). Exploratory pairwise analysis demonstrated clinical improvement in patients receiving a cd of 2400 mg epratuzumab (OR for 600 mg weekly vs placebo: 3.2 (95% CI 1.1 to 8.8), nominal p=0.03; OR for 1200 mg EOW vs placebo: 2.6 (0.9 to 7.1), nominal p=0.07). Post-hoc comparison of all 2400 mg cd patients versus placebo found an overall treatment effect (OR=2.9 (1.2 to 7.1), nominal p=0.02). Incidence of adverse events (AEs), serious AEs and infusion reactions was similar between epratuzumab and placebo groups, without decreases in immunoglobulin levels and only partial reduction in B-cell levels. Conclusions Treatment with epratuzumab 2400 mg cd was well tolerated in patients with moderately to severely active SLE, and associated with improvements in disease activity. Phase III studies are ongoing. PMID:23313811

  4. Security enhancement of double-random phase encryption by iterative algorithm

    NASA Astrophysics Data System (ADS)

    Qian, Sheng-Xia; Li, Yongnan; Kong, Ling-Jun; Li, Si-Min; Ren, Zhi-Cheng; Tu, Chenghou; Wang, Hui-Tian

    2014-08-01

    We propose an approach to enhance the security of optical encryption based on double-random phase encryption in a 4f system. The phase key in the input plane of the 4f system is generated by the Yang-Gu algorithm to control the phase of the encrypted information in the output plane of the 4f system, until the phase in the output plane converges to a predesigned distribution. Only the amplitude of the encrypted information must be recorded as a ciphertext. The information, which needs to be transmitted, is greatly reduced. We can decrypt the ciphertext with the aid of the predesigned phase distribution and the phase key in the Fourier plane. Our approach can resist various attacks.

  5. Optical information authentication using compressed double-random-phase-encoded images and quick-response codes.

    PubMed

    Wang, Xiaogang; Chen, Wen; Chen, Xudong

    2015-03-09

    In this paper, we develop a new optical information authentication system based on compressed double-random-phase-encoded images and quick-response (QR) codes, where the parameters of optical lightwave are used as keys for optical decryption and the QR code is a key for verification. An input image attached with QR code is first optically encoded in a simplified double random phase encoding (DRPE) scheme without using interferometric setup. From the single encoded intensity pattern recorded by a CCD camera, a compressed double-random-phase-encoded image, i.e., the sparse phase distribution used for optical decryption, is generated by using an iterative phase retrieval technique with QR code. We compare this technique to the other two methods proposed in literature, i.e., Fresnel domain information authentication based on the classical DRPE with holographic technique and information authentication based on DRPE and phase retrieval algorithm. Simulation results show that QR codes are effective on improving the security and data sparsity of optical information encryption and authentication system.

  6. Deterministic matrices matching the compressed sensing phase transitions of Gaussian random matrices

    PubMed Central

    Monajemi, Hatef; Jafarpour, Sina; Gavish, Matan; Donoho, David L.; Ambikasaran, Sivaram; Bacallado, Sergio; Bharadia, Dinesh; Chen, Yuxin; Choi, Young; Chowdhury, Mainak; Chowdhury, Soham; Damle, Anil; Fithian, Will; Goetz, Georges; Grosenick, Logan; Gross, Sam; Hills, Gage; Hornstein, Michael; Lakkam, Milinda; Lee, Jason; Li, Jian; Liu, Linxi; Sing-Long, Carlos; Marx, Mike; Mittal, Akshay; Monajemi, Hatef; No, Albert; Omrani, Reza; Pekelis, Leonid; Qin, Junjie; Raines, Kevin; Ryu, Ernest; Saxe, Andrew; Shi, Dai; Siilats, Keith; Strauss, David; Tang, Gary; Wang, Chaojun; Zhou, Zoey; Zhu, Zhen

    2013-01-01

    In compressed sensing, one takes samples of an N-dimensional vector using an matrix A, obtaining undersampled measurements . For random matrices with independent standard Gaussian entries, it is known that, when is k-sparse, there is a precisely determined phase transition: for a certain region in the (,)-phase diagram, convex optimization typically finds the sparsest solution, whereas outside that region, it typically fails. It has been shown empirically that the same property—with the same phase transition location—holds for a wide range of non-Gaussian random matrix ensembles. We report extensive experiments showing that the Gaussian phase transition also describes numerous deterministic matrices, including Spikes and Sines, Spikes and Noiselets, Paley Frames, Delsarte-Goethals Frames, Chirp Sensing Matrices, and Grassmannian Frames. Namely, for each of these deterministic matrices in turn, for a typical k-sparse object, we observe that convex optimization is successful over a region of the phase diagram that coincides with the region known for Gaussian random matrices. Our experiments considered coefficients constrained to for four different sets , and the results establish our finding for each of the four associated phase transitions. PMID:23277588

  7. Single-random phase encoding architecture using a focus tunable lens

    NASA Astrophysics Data System (ADS)

    Mosso, E. F.; Bolognini, N.; Pérez, D. G.

    2016-02-01

    We propose a new nonlinear optical architecture based on a focus tunable lens and an iterative phase retrieva