Long-term safety of certolizumab pegol in plaque psoriasis: pooled analysis over 3 years from three phase III, randomized, placebo-controlled studies.

BACKGROUND: Certolizumab pegol (CZP) is an Fc-free, PEGylated anti-tumour necrosis factor biologic. OBJECTIVES: To report 3-year safety data from three phase III trials of CZP in adults with plaque psoriasis. METHODS: Data were pooled from CIMPASI-1 (NCT02326298), CIMPASI-2 (NCT02326272) and CIMPACT (NCT02346240). Included patients had moderate-to-severe plaque psoriasis of ≥ 6 months' duration; had been randomized to CZP 200 mg every 2 weeks (Q2W) (400 mg at weeks 0, 2 and 4) or CZP 400 mg Q2W; and had received at least one dose of CZP with up to 144 weeks of exposure. Treatment-emergent adverse events (TEAEs) were classified using MedDRA v18·1. Reported incidence rates (IRs) are incidence of new cases per 100 patient-years (PY). RESULTS: Over 144 weeks, 995 patients received at least one dose of CZP (exposure: 2231·3 PY); 731 and 728 received at least one dose of CZP 200 mg Q2W (1211·4 PY) and/or 400 mg Q2W (1019·9 PY), respectively. The IR [95% confidence interval (CI)] of TEAEs was 144·9 (135·3-155·0) for all patients, 134·1 (123·2-145·7) for CZP 200 mg Q2W and 158·3 (145·5-171·9) for CZP 400 mg Q2W. The IR (95% CI) of serious TEAEs for all patients was 7·5 (6·4-8·8); the IRs were 6·7 (5·2-8·3) and 8·7 (6·9-10·8) for CZP 200 mg and 400 mg Q2W, respectively. Overall, 3·2% of patients reported serious infections (2·2% within each of the CZP 200 and 400 mg Q2W groups). Overall, there was one case of active tuberculosis, 16 malignancies in 14 patients and seven deaths (two considered treatment-related). The cumulative IR of TEAEs did not increase over time. CONCLUSIONS: No new safety signals were identified compared with previously reported data. Risk did not increase with longer or higher CZP exposure.

Comparison of contrast-enhanced videofluoroscopy to unenhanced dynamic MRI in minor patients following surgical correction of velopharyngeal dysfunction.

OBJECTIVES: To compare dynamic magnetic resonance imaging (MRI) with videofluoroscopy (VFS) regarding image quality and assessment of gap size between soft palate (SP) and posterior pharyngeal wall (PPW) in children and adolescents following surgical correction of velopharyngeal dysfunction (VPD). METHODS: Twenty-one patients undergoing unenhanced 3-T MRI and contrast-enhanced VFS were included in this IRB-approved prospective study. The MRI scan protocol comprised refocused gradient-echo sequences in transverse and sagittal planes during speech, with TE 1.97 ms, TR 3.95 ms, flip angle 8°, matrix size 128 × 128, and 5-mm slice thickness. Radial k-space sampling and sliding window reconstruction were used to achieve an image acquisition rate of 28 frames per second (fps). VFS with 30 fps was similarly performed in both planes. Closure of the velopharyngeal port during phonation was evaluated by two experienced radiologists. RESULTS: Eleven (52.4%) patients displayed a complete closure, whereas ten (47.6%) patients showed a post-operative gap during speech. VFS and MRI equally identified the cases with persistent or recurrent VPD. Differences in SP-PPW distance between VFS (3.9 ± 1.6 mm) and MRI (4.1 ± 1.5 mm) were not statistically significant (p = 0.5). The subjective overall image quality of MRI was rated inferior (p < 0.001) compared with VFS, with almost perfect inter-rater agreement (κ = 0.90). The presence of susceptibility artifacts did not limit anatomical measurements. CONCLUSION: Dynamic MRI is equally reliable as VFS to assess persistent or recurrent inadequate velum closure in patients following surgical treatment of VPD. KEY POINTS: • Unenhanced 3-T dynamic MRI and contrast-enhanced videofluoroscopy are equally useful for the identification of patients with incomplete velopharyngeal closure during speech. • MRI using refocused gradient-echo acquisition with radial k-space sampling and sliding window reconstruction generates diagnostic images with 28 frames per second. • MRI can offer a radiation-free alternative to currently established videofluoroscopy for young patients.

Erratum to: After ISCHEMIA: Is cardiac MRI a reliable gatekeeper for invasive angiography and myocardial revascularization?

In the above mentioned article, the family name of the second author was not given correctly: it is Carerj instead of Careri.The authors apologize for this mistake.The original article has been ….

After ISCHEMIA: Is cardiac MRI a reliable gatekeeper for invasive angiography and myocardial revascularization?

This review surveys the findings of the International Study of Comparative Health Effectiveness with Medical and Invasive Approaches (ISCHEMIA) trial and puts them into a clinical perspective regarding its effect of the role of cardiac magnetic resonance imaging (CMR) as a well-validated gatekeeper for invasive angiography and myocardial revascularization. Noninvasive stress testing of patients with intermediate-to-high pretest likelihood for obstructive coronary artery disease (CAD) using perfusion CMR provides excellent diagnostic accuracy in detecting ischemic myocardium, and additional information from tissue characterization can guide the management of patients with stable angina toward a more individualized therapy as other non-coronary underlying causes of chest pain can be detected. Since ISCHEMIA failed to show that an invasive strategy using percutaneous coronary intervention or coronary artery bypass grafting was associated with an improved prognosis compared with initial conservative medical therapy among stable patients with moderate-to-severe ischemia, CMR as a multifaceted diagnostic imaging approach to explain patients' symptoms should be preferred over anatomical and stress testing alone. Nevertheless, the exclusion of left main coronary artery stenosis either by coronary CT or MR angiography may be required. In conclusion, the results of the ISCHEMIA trial are in good accordance with those of the MR-INFORM trial recently published in the New England Journal of Medicine, as the noninvasive management of a large proportion of patients with CAD was shown to be noninferior to current invasive strategies. Recent outcome data from trials may therefore have an impact on future guidelines to further reduce the execution of unnecessary left heart catheterizations.

Certolizumab pegol for the treatment of patients with moderate-to-severe chronic plaque psoriasis: pooled analysis of week 16 data from three randomized controlled trials.

BACKGROUND: Certolizumab pegol, an Fc-free, PEGylated, anti-tumour necrosis factor (TNF) biologic, has demonstrated favourable results in three ongoing, phase 3, randomized, double-blinded, placebo-controlled trials in adults with psoriasis. OBJECTIVE: Data were pooled from the ongoing trials to investigate efficacy in selected subgroups and add precision to estimates of treatment effects during the initial 16 weeks of treatment. METHODS: In each trial, patients ≥18 years with moderate-to-severe chronic plaque psoriasis for ≥6 months were randomized to receive certolizumab 400 mg, certolizumab 200 mg or placebo every 2 weeks for 16 weeks. Coprimary endpoints for the pooled analysis were responder rates at Week 16, defined as ≥75% reduction in psoriasis area and severity index (PASI 75) and physician global assessment (PGA) of 0/1 ('clear'/'almost clear' with ≥2-category improvement). Safety was assessed by treatment-emergent adverse events. RESULTS: A total of 850 patients treated with certolizumab 400 mg (N = 342), certolizumab 200 mg (N = 351) or placebo (N = 157) were included in the pooled analysis. At Week 16, PASI 75 and PGA 0/1 responder rates were 80.1% and 63.7% in the certolizumab 400 mg group, 74.5% and 54.6% in the certolizumab 200 mg group, and 7.5% and 2.8% in the placebo group (P < 0.0001 for each dose versus placebo). In patients with and without prior biologic therapy, both doses of certolizumab resulted in substantially higher responder rates versus placebo. The incidence of adverse events was generally similar between the 400 mg and placebo groups, and somewhat lower in the 200 mg group versus placebo. No new safety signals were identified. CONCLUSION: Certolizumab pegol 400 mg or 200 mg every 2 weeks for 16 weeks was associated with statistically significant and clinically meaningful improvements in signs and symptoms of psoriasis in patients with and without prior biologic therapy, and a safety profile consistent with the anti-TNF class in psoriasis.

Dual-energy CT in patients with abdominal malignant lymphoma: impact of noise-optimised virtual monoenergetic imaging on objective and subjective image quality.

AIM: To investigate the impact of noise-optimised virtual monoenergetic imaging (VMI+) reconstructions on quantitative and qualitative image parameters in patients with malignant lymphoma at dual-energy computed tomography (DECT) examinations of the abdomen. MATERIALS AND METHODS: Thirty-five consecutive patients (mean age, 53.8±18.6 years; range, 21-82 years) with histologically proven malignant lymphoma of the abdomen were included retrospectively. Images were post-processed with standard linear blending (M_0.6), traditional VMI, and VMI+ technique at energy levels ranging from 40 to 100 keV in 10 keV increments. Signal-to-noise (SNR) and contrast-to-noise ratios (CNR) were objectively measured in lymphoma lesions. Image quality, lesion delineation, and image noise were rated subjectively by three blinded observers using five-point Likert scales. RESULTS: Quantitative image quality parameters peaked at 40-keV VMI+ (SNR, 15.77±7.74; CNR, 18.27±8.04) with significant differences compared to standard linearly blended M_0.6 (SNR, 7.96±3.26; CNR, 13.55±3.47) and all traditional VMI series (p<0.001). Qualitative image quality assessment revealed significantly superior ratings for image quality at 60-keV VMI+ (median, 5) in comparison with all other image series (p<0.001). Assessment of lesion delineation showed the highest rating scores for 40-keV VMI+ series (median, 5), while lowest subjective image noise was found for 100-keV VMI+ reconstructions (median, 5). CONCLUSION: Low-keV VMI+ reconstructions led to improved image quality and lesion delineation of malignant lymphoma lesions compared to standard image reconstruction and traditional VMI at abdominal DECT examinations.

Certolizumab pegol in combination with dose-optimised methotrexate in DMARD-naïve patients with early, active rheumatoid arthritis with poor prognostic factors: 1-year results from C-EARLY, a randomised, double-blind, placebo-controlled phase III study.

OBJECTIVES: To assess the efficacy and safety of certolizumab pegol (CZP)+dose-optimised methotrexate (MTX) versus placebo (PBO)+dose-optimised MTX in inducing and sustaining clinical remission in DMARD-naïve patients with moderate-to-severe, active, progressive rheumatoid arthritis (RA), with poor prognostic factors over 52 weeks. METHODS: DMARD-naïve patients with ≤1 year of active RA were randomised (3:1) in a double-blind manner to CZP (400 mg Weeks 0, 2, 4, then 200 mg Q2W to Week 52)+MTX or PBO+MTX (the mean optimised-MTX dose=21 and 22 mg/week, respectively). Sustained remission (sREM) and sustained low disease activity (sLDA; DAS28(ESR)<2.6 and DAS28(ESR)≤3.2, respectively, at both Weeks 40 and 52) were the primary and secondary endpoints. RESULTS: Patients were randomised to CZP+MTX (n=660) and PBO+MTX (n=219). At Week 52, significantly more patients assigned to CZP+MTX compared with PBO+MTX achieved sREM (28.9% vs 15.0%, p<0.001) and sLDA (43.8% vs 28.6%, p<0.001). Inhibition of radiographic progression and improvements in physical functioning were significantly greater for CZP+MTX versus PBO+MTX (van der Heijde modified total Sharp score (mTSS) mean absolute change from baseline (CFB): 0.2 vs 1.8, p<0.001, rate of mTSS non-progressors: 70.3% vs 49.7%, p<0.001; least squares (LS) mean CFB in Health Assessment Questionnaire-Disability Index (HAQ-DI): -1.00 vs -0.82, p<0.001). Incidence of adverse events (AEs) and serious AEs was similar between treatment groups. Infection was the most frequent AE, with higher incidence for CZP+MTX (71.8/100 patient-years (PY)) versus PBO+MTX (52.7/100 PY); the rate of serious infection was similar between CZP+MTX (3.3/100 PY) and PBO+MTX (3.7/100 PY). CONCLUSIONS: CZP+dose-optimised MTX treatment of DMARD-naïve early RA resulted in significantly more patients achieving sREM and sLDA, improved physical function and inhibited structural damage compared with PBO+dose-optimised MTX. TRIAL REGISTRATION NUMBER: NCT01519791.

Taste preference and psychopathology.

OBJECTIVE: Excessive food intake has been linked to many factors including taste preference and the presence of psychopathology. The purpose of this study was to investigate the association between sweet and salty taste preference and psychopathology in patients with severe obesity. METHODS: A consecutive series of patients applying for bariatric surgery was recruited for the study. Taste preference was self-reported. Psychopathology was assessed using the revised version of the Minnesota Multiphasic Personality Inventory-2 (MMPI-2). 190 patients were included in the study. RESULTS: In comparison with patients who had salty taste preference, patients with sweet taste preference had significantly higher elevations on the depression (OD: 4.090, p = 0.010) and the hysteria (OD: 2.951, p = 0.026) clinical scales of the MMPI-2. CONCLUSION: The results suggest the presence of an association between taste preference and psychopathology. The findings may be of interest for clinicians who are involved in the treatment of obesity. In particular, they may wish to pay increased attention to patients with sweet taste preference or who have a strong attraction for both sweet and salty foods, in order to detect psychopathology and to adapt the treatment.

[Life-threatening macroglossia following cleft palate palatoplasty]. / Lebensbedrohliche Makroglossie nach Gaumenspaltenverschluss.

The case of a 13-month-old child who developed a life-threatening macroglossia with airway obstruction following palatoplasty for a cleft palate is reported. As direct laryngoscopy was not feasible a laryngeal mask (LM) was inserted to secure the airway. Under fiber optic guidance an endotracheal tube was then introduced via the LM. In this article the incidence, pathophysiology, clinical dynamics, options for emergency anesthesia management and organizational implications of this rare but typical complication in the field of oral and craniomaxillofacial surgery are reported.

Use of chemokine receptors by poxviruses.

Chemokine receptors serve as portals of entry for certain intracellular pathogens, most notably human immunodeficiency virus (HIV). Myxoma virus is a member of the poxvirus family that induces a lethal systemic disease in rabbits, but no poxvirus receptor has ever been defined. Rodent fibroblasts (3T3) that cannot be infected with myxoma virus could be made fully permissive for myxoma virus infection by expression of any one of several human chemokine receptors, including CCR1, CCR5, and CXCR4. Conversely, infection of 3T3-CCR5 cells can be inhibited by RANTES, anti-CCR5 polyclonal antibody, or herbimycin A but not by monoclonal antibodies that block HIV-1 infection or by pertussis toxin. These findings suggest that poxviruses, like HIV, are able to use chemokine receptors to infect specific cell subtypes, notably migratory leukocytes, but that their mechanisms of receptor interactions are distinct.

Molecular organization of the 20S proteasome gene family from Arabidopsis thaliana.

The 20S proteasome is the proteolytic complex in eukaryotes responsible for degrading short-lived and abnormal intracellular proteins, especially those targeted by ubiquitin conjugation. The 700-kD complex exists as a hollow cylinder comprising four stacked rings with the catalytic sites located in the lumen. The two outer rings and the two inner rings are composed of seven different alpha and beta polypeptides, respectively, giving an alpha7/beta7/beta7/alpha7 symmetric organization. Here we describe the molecular organization of the 20S proteasome from the plant Arabidopsis thaliana. From an analysis of a collection of cDNA and genomic clones, we identified a superfamily of 23 genes encoding all 14 of the Arabidopsis proteasome subunits, designated PAA-PAG and PBA-PBG for Proteasome Alpha and Beta subunits A-G, respectively. Four of the subunits likely are encoded by single genes, and the remaining subunits are encoded by families of at least 2 genes. Expression of the alpha and beta subunit genes appears to be coordinately regulated. Three of the nine Arabidopsis proteasome subunit genes tested, PAC1 (alpha3), PAE1 (alpha5) and PBC2 (beta3), could functionally replace their yeast orthologs, providing the first evidence for cross-species complementation of 20S subunit genes. Taken together, these results demonstrate that the 20S proteasome is structurally and functionally conserved among eukaryotes and suggest that the subunit arrangement of the Arabidopsis 20S proteasome is similar if not identical to that recently determined for the yeast complex.

Cetirizine and pseudoephedrine retard alone and in combination in the treatment of perennial allergic rhinitis: a double-blind multicentre study.

We compared the efficacy and safety of 5 mg cetirizine (CTZ), 120 mg pseudoephedrine retard (PER) and their combination (COM), given twice daily for three weeks, for the treatment of perennial allergic rhinitis. Two hundred and ten evaluable patients (97 males and 113 females) were included in the study and randomly allocated to one of three treatment groups, each of 70 patients. Nasal obstruction, sneezing, rhinorrhoea, nasal and ocular pruritus were scored each day throughout the study by patients using a symptom scale ranging from 0 (no symptom) to 3 (severe). The mean proportion of days without symptoms was higher in the COM group (11.8%) than in the CTZ (6.8%) and PER (5.1%) groups, but the differences were not statistically significant. The mean percentage of days when symptoms were absent or at most mild was significantly higher in the COM group (64.8%) than in either CTZ (45.5%; p = 0.003) or PER groups (40.6%; p = 0.0001). In addition, evaluation of symptoms by investigators and their global evaluation at the end of treatment showed statistically significant differences in favour of COM compared, to both CTZ and PER. The most frequent adverse events were somnolence in the CTZ and COM groups (8.6% and 12.9%, respectively) while insomnia was most frequent in the PER group. No clinically significant abnormalities were found in haematological or biochemical tests. These results indicate that the combined treatment was more effective than and as well tolerated as treatment with each individual agent.

Restructuring the total quality way--corporate quality leaders share their experiences. Interview by Lisa M. O'Rourke.

The pharmaceutical firm The Upjohn Company and the electronics giant and Malcolm Baldrige National Quality Award winner Westinghouse Electric Corporation have grappled with the challenge of keeping TQM on track during recent restructuring efforts. What these organizations have learned from the experience--as described here by Nicholas Andreatis, MD, Vice President of Upjohn's Corporate Quality Center, and Carl Arendt, Manager of Total Quality Services for Westinghouse's Productivity and Quality Center--can help healthcare organizations that are faced with the same challenges.

[Evaluation of cetirizine and of terfenadine in the treatment of perennial allergic rhinitis]. / Evaluation de la cetirizine et de la terfenadine dans le traitement de la rhinite allergique perannuelle.

Thirty patients suffering from perennial allergic rhinitis took part in a cross-over, double-blind study during which they were treated for 3 two-week periods with either 10 mg cetirizine nocte or 60 mg terfenadine given morning and evening, or with a placebo. Both the active products were found to significantly improve the symptoms when compared to placebo (p less than or equal to 0.001). Cetirizine helped to reduce the symptoms of a blocked nose to a significantly greater extent than terfenadine (p less than or equal to 0.05). A significantly larger number of patients (p less than or equal to 0.05) preferred cetirizine (17/30) to terfenadine (6/30). Four patients taking cetirizine, and six of those taking terfenadine, reported a mild sedative effect.

Treatment of chronic urticaria with cetirizine dihydrochloride a non-sedating antihistamine.

The efficacy of cetirizine dihydrochloride, a new H1-antagonist with minimal sedative or anticholinergic side effects was evaluated in 30 patients with chronic idiopathic urticaria. In the first part of the study, cetirizine 10 mg and placebo were compared in a double-blind cross-over trial. In the second part, patients who did not respond adequately in the first part were randomized, still double-blind, to receive 10 mg cetirizine either once daily or twice daily. In the first part, treatment was discontinued by 17 patients on placebo and two patients on cetirizine because of lack of efficacy. Cetirizine dihydrochloride was found significantly to reduce occurrence of weals, erythema and pruritus compared with placebo (P less than 0.001). Twenty-six of the patients improved on cetirizine and two on placebo. Mild sedation was noted by two patients on cetirizine and by one on placebo.

CD45 protein-tyrosine phosphatase is specifically associated with a 116-kDa tyrosine-phosphorylated glycoprotein.

CD45 is a protein-tyrosine phosphatase expressed on all cells of hematopoietic origin. In an attempt to further characterize CD45 function, we set out to identify molecule(s) that specifically associate with CD45. A 116-kDa protein was detected in immunoprecipitates from CD45+ cells but not CD45- cells. The association between CD45 and this 116-kDa protein can be reconstituted by mixing lysates from CD45- cell lines with purified CD45. p116 appears to associate with CD45 through the external, transmembrane, or membrane-proximal region of CD45 since p116 is associated with a mutant form of CD45 possessing a truncated cytoplasmic domain. The association of p116 with CD45 is not isoform-specific as p116 associates equally well with various CD45 isoforms. We have determined that p116 is a tyrosine-phosphorylated glycoprotein and that it is associated with CD45 in all hematopoietic cells examined. Because of its broad distribution, it is possible that identification of p116 will provide additional insight into the function of CD45 in lymphoid as well as non-lymphoid hematopoietic cells.

Identification of the yeast 20S proteasome catalytic centers and subunit interactions required for active-site formation.

The proteasome is responsible for degradation of substrates of the ubiquitin pathway. 20S proteasomes are cylindrical particles with subunits arranged in a stack of four heptameric rings. The outer rings are composed of alpha subunits, and the inner rings are composed of beta subunits. A well-characterized archaeal proteasome has a single type of each subunit, and the N-terminal threonine of the beta subunit is the active-site nucleophile. Yeast proteasomes have seven different beta subunits and exhibit several distinct peptidase activities, which were proposed to derive from disparate active sites. We show that mutating the N-terminal threonine in the yeast Pup1 beta subunit eliminates cleavage after basic residues in peptide substrates, and mutating the corresponding threonine of Pre3 prevents cleavage after acidic residues. Surprisingly, neither mutation has a strong effect on cell growth, and they have at most minor effects on ubiquitin-dependent proteolysis. We show that Pup1 interacts with Pup3 in each beta subunit ring. Our data reveal that different proteasome active sites contribute very differently to protein breakdown in vivo, that contacts between particular subunits in each beta subunit ring are critical for active-site formation, and that active sites in archaea and different eukaryotes are highly similar.

Two distinct domains of the beta-subunit of glucosidase II interact with the catalytic alpha-subunit.

Recent purification and cDNA cloning of the endoplasmic reticulum processing enzyme glucosidase II have revealed that it is composed of two soluble proteins: a catalytic alpha-subunit and a beta-subunit of unknown function, both of which are highly conserved in mammals. Since the beta-subunit, which contains a C-terminal His-Asp-Glu-Leu (HDEL) motif, may function to link the catalytic subunit to the KDEL receptor as a retrieval mechanism, we sought to map the regions of the mouse beta-subunit protein responsible for mediating the association with the alpha-subunit. By screening a panel of recombinant beta-subunit glutathione S-transferase fusion proteins for the ability to precipitate glucosidase II activity, we have identified two non-overlapping interaction domains (ID1 and ID2) within the beta-subunit. ID1 encompasses 118 amino acids at the N-terminus of the mature polypeptide, spanning the cysteine-rich element in this region. ID2, located near the C-terminus, is contained within amino acids 273-400, a region occupied in part by a stretch of acidic residues. Variable usage of 7 alternatively spliced amino acids within ID2 was found not to influence the association of the two sub-units. We theorize that the catalytic subunit of glucosidase II binds synergistically to ID1 and ID2, explaining the high associative stability of the enzyme complex.

Eukaryotic 20S proteasome catalytic subunit propeptides prevent active site inactivation by N-terminal acetylation and promote particle assembly.

Proteins targeted for degradation by the ubiquitin-proteasome system are degraded by the 26S proteasome. The core of this large protease is the 20S proteasome, a barrel-shaped structure made of a stack of four heptameric rings. Of the 14 different subunits that make up the yeast 20S proteasome, three have proteolytic active sites: Doa3/beta5, Pup1/beta2 and Pre3/beta1. Each of these subunits is synthesized with an N-terminal propeptide that is autocatalytically cleaved during particle assembly. We show here that the propeptides have both common and distinct functions in proteasome biogenesis. Unlike the Doa3 propeptide, which is crucial for proteasome assembly, the Pre3 and Pup1 propeptides are dispensable for cell viability and proteasome formation. However, mutants lacking these propeptide-encoding elements are defective for specific peptidase activities, are more sensitive to environmental stresses and have subtle defects in proteasome assembly. Unexpectedly, a critical function of the propeptide is the protection of the N-terminal catalytic threonine residue against Nalpha-acetylation. For all three propeptide-deleted subunits, activity of the affected catalytic center is fully restored when the Nat1-Ard1 Nalpha-acetyltransferase is mutated. In addition to delineating a novel function for proteasome propeptides, these data provide the first biochemical evidence for the postulated participation of the alpha-amino group in the proteasome catalytic mechanism.