Efficacy and safety of risankizumab vs. secukinumab in patients with moderate-to-severe plaque psoriasis (IMMerge): results from a phase III, randomized, open-label, efficacy-assessor-blinded clinical trial.

BACKGROUND: Patients with plaque psoriasis treated with biologic therapies need more efficacious, safe and convenient treatments to improve quality of life. Risankizumab and secukinumab inhibit interleukin-23 and interleukin-17A, respectively, and are effective in adult patients with moderate-to-severe plaque psoriasis but have different dosing regimens. OBJECTIVES: To compare directly the efficacy and safety of risankizumab vs. secukinumab over 52 weeks. METHODS: IMMerge was an international, phase III, multicentre, open-label, efficacy-assessor-blinded, active-comparator study, in which adult patients with chronic, moderate-to-severe plaque psoriasis were randomized in a 1 : 1 ratio to treatment with risankizumab 150 mg or secukinumab 300 mg. Primary efficacy endpoints were the proportions of patients achieving ≥ 90% improvement from baseline in Psoriasis Area and Severity Index (PASI 90) at week 16 (noninferiority comparison with margin of 12%) and week 52 (superiority comparison). RESULTS: In total 327 patients from nine countries were treated with risankizumab (n = 164) or secukinumab (n = 163). Risankizumab was noninferior to secukinumab in the proportion of patients achieving PASI 90 at week 16 [73·8% vs. 65·6%; difference of 8·2%, 96·25% confidence interval (CI)-2·2 to 18·6; within the 12% noninferiority margin] and superior to secukinumab at week 52 (86·6% vs. 57·1%; difference of 29·8%, 95% CI 20·8-38·8; P < 0·001), thus meeting both primary endpoints. All secondary endpoints (PASI 100, static Physician's Global Assessment 0 or 1, and PASI 75) at week 52 demonstrated superiority for risankizumab vs. secukinumab (P < 0·001). No new safety concerns were identified. CONCLUSIONS: At week 52, risankizumab demonstrated superior efficacy and similar safety with less frequent dosing compared with secukinumab.

[Verbal fluency among healthy elderly: a study of three complex verbal fluency tasks under healthy older people and patients with neurocognitive disorder or onset dementia of the Alzheimer type]. / Verbale fluency bij gezonde ouderen: Onderzoek met drie complexe verbale fluencytaken bij gezonde ouderen en patiënten met een lichte neurocognitieve stoornis of beginnende dementie van het Alzheimertype.

The aim of this study is to provide normative data for a phonological alternating task (FAT), a semantic alternating task (SAT) and an excluded letter task (ELT). The tasks were administered to 146 Flemish-speaking, cognitively healthy elderly. Data from 102 were used and were classified according to the significant variables. Subsequently, these tasks were administered to seven patients diagnosed with mild neurocognitive impairment (mild cognitive impairment, MCI) and seven patients with onset dementia of the Alzheimer type (DAT). Results of the standard study show that the level of education is a significant variable for all complex VFT and age for the SAT and the ELT, while age related deterioration is highest for the ELT. The error rate is highest for the ELT and lowest for the SAT. Analysis of the time duration shows that data should be collected for at least 2 min. The patients scored significantly lower than the normgroup of healthy adults. The error rate is highest for the SAT and lowest for the ELT.

NSC348884, a nucleophosmin inhibitor disrupts oligomer formation and induces apoptosis in human cancer cells.

Nucleophosmin (NPM), a multifunctional nucleolar phosphoprotein is dysregulated in human malignancies leading to anti-apoptosis and inhibition of differentiation. We evaluated the precise three-dimensional structure of NPM based on the highly conserved structure of Xenopus NO38 and its requirement to form dimers and pentamers via its N-terminal domain (residues, 1-107). We hypothesized that a small molecular inhibitor (SMI) that could disrupt the formation of dimers would inhibit aberrant NPM function(s) in cancer cells. Molecular modeling, pharmacophore design, in silico screening and interactive docking identified NSC348884 as a putative NPM SMI that disrupts a defined hydrophobic pocket required for oligomerization. NSC348884 inhibited cell proliferation at an IC(50) of 1.7-4.0 muM in distinct cancer cell lines and disrupted NPM oligomer formation by native polyacrylamide gel electrophoresis assay. Treatment of several different cancer cell types with NSC348884 upregulated p53 (increased Ser15 phosphorylation) and induced apoptosis in a dose-dependent manner that correlated with apoptotic markers: H2AX phosphorylation, poly(ADP-ribose) polymerase cleavage and Annexin V labeling. Further, NSC348884 synergized doxorubicin cytotoxicity on cancer cell viability. The data together show that NSC348884 is an SMI of NPM oligomer formation, upregulates p53, induces apoptosis and synergizes with chemotherapy. Hence, an SMI to NPM may be a useful approach to anticancer therapy.

Perioperative arrhythmia associated with aortic valve stenosis.

Peri-operative arrhythmia is one of the major complications in anaesthesia for valve replacement surgery in patients with aortic stenosis. In this retrospective study, 58 patients with sinus rhythm were investigated from induction of anaesthesia until arrival at the recovery room by close haemodynamic monitoring and Holter ECG recording. After cardiopulmonary bypass (CPB), they received either lidocaine (L, n = 35) or mexiletine (M, n = 23) via infusion for 24 hours. Pre-bypass incidence was 14% for supraventricular (SPBs) and 19% for ventricular serious arrhythmia (VPBs), i.e. high-grade forms which indicate possible deterioration and may require therapy (for all arrhythmia, incidences were 45 resp. 28%). VPBs was independently related to impaired left ventricular function (11 patients) and preoperative digitalis therapy (20 patients) but not to severity of stenosis, serum concentration of potassium (between 3.3 and 5.2 meq/l), or any other clinical parameters. Post-bypass incidence was SPBs 11% and VPBs 33%, the latter representing a significant increase compared to the first period (p < 0.03)--(all arrhythmia: 26 resp. 40%). VPBs was related to the need for multiple therapy including catecholamines and antiarrhythmic agents other than L or M, but no longer to preoperative parameters nor duration of intraoperative ischaemia. Incidences of arrhythmia for L and M were identical. While in these patients digitalis therapy may account for arrhythmia also in general anaesthesia, in valve replacement there is a post-bypass increase in VPBs which is not fully explained. Since the incidence is 33% in spite of anti-arrhythmic therapy, both administered class IB drugs may not be the best therapeutic approach.