A multi-centre,randomised, double-blind,placebo-controlled clinical trial of methylphenidate in the initial treatment of acute mania (MEMAP study)

Based on many clinical and preclinical findings the ‘vigilance regulation model of mania’ postulates that an unstable regulation of wakefulness is a pathogenetic factor in both mania and Attention Deficit Hyperactivity Disorder (ADHD) and induces hyperactivity and sensation seeking as an autoregulatory attempt to stabilize wakefulness. Accordingly, stimulant medications with their vigilance stabilizing properties could have rapid antimanic effects similar to their beneficial effects in ADHD. The MEMAP study – a multi-center, double-blind, placebo-controlled and randomized clinical trial (RCT) – assessed the antimanic efficacy and safety of a 2.5-day treatment with methylphenidate (20–40 mg/day). Of 157 screened patients with acute mania, 42 were randomly assigned to receive 20–40 mg per day of methylphenidate in one or two applications, or placebo. The primary outcome was the change in Young Mania Rating Scale (YMRS) sum scores from baseline to day 2.5 in the methylphenidate group compared to the placebo group. A group sequential design was chosen to justify early RCT termination based on efficacy or futility at an interim analysis after inclusion of 40 patients. In the interim analysis, the change from baseline in the YMRS total score at day 2.5 was not significantly different between both groups (F(1,37)=0.23; p=0.64). Thus, futility was declared for methylphenidate and the RCT was stopped. In summary, although methylphenidate was well tolerated and safe in the full analysis set, it failed to show efficacy in the treatment of acute mania. Trial registration: clinicaltrials.gov (URL: http://www.clinicaltrials.gov; registration number: NCT01541605).     

Referral,Genetic Counselling,and BRCA Testing in the Manitoba High-Grade Serous Ovarian Cancer Population, 2004–2019

Simple SummaryThis study was performed to better understand rates and factors that influence patients in accepting a referral to genetics or testing for genes that predispose them to ovarian cancer (BRCA1/2). Using multiple provincial databases and registries, the study team looked at data from 944 patients with high-grade ovarian cancer between 2004–2019. We found that the rate of genetic referrals fluctuated over time; however, the rate of genetic testing increased over the entire timeframe. Factors found to increase rates of referral and testing included age, cancer histology, history of oral contraceptive use, and family history of ovarian cancer. Increasing the rate of genetic testing will help patients and their health care team plan clinical management and treatment.Abstract(1) Background: The primary objective of this study was to examine the rate of genetic referral, BRCA testing, and BRCA positivity amongst all patients with high-grade serous ovarian cancers (HGSOC) from 2004–2019. The secondary objective was to analyze secondary factors that may affect the rates of referral and testing. (2) Methods: This population-based cohort study included all women diagnosed with HGSOC using the Manitoba Cancer Registry, CervixCheck registry, Medical Claims database at Manitoba Health, the Hospital Discharge abstract, the Population Registry, and Winnipeg Regional Health Authority genetics data. Data were examined for three different time cohorts (2004–2013, 2014–2016; 2017–2019) correlating to practice pattern changes. (3) Results: A total of 944 patients were diagnosed with HGSOC. The rate of genetic referrals changed over the three timeframes (20.0% → 56.7% → 36.6%) and rate of genetic testing increased over the entire timeframe. Factors found to increase rates of referral and testing included age, histology, history of oral contraceptive use, and family history of ovarian cancer. Prior health care utilization indicators did not affect genetic referral or testing. (4) Conclusion: The rate of genetic referral (2004–2016) and BRCA1/2 testing (2004–2019) for patients with a diagnosis of HGSOC increased over time. A minority of patients received a consultation for genetics counselling, and even fewer received testing for a BRCA1/2. Without a genetic result, it is difficult for clinicians to inform treatment decisions. Additional efforts are needed to increase genetics consultation and testing for Manitoban patients with HGSOC. Effects of routine tumour testing on rates of genetic referral will have to be examined in future studies.     

The Role of Intramedullary Nailing for Proximal Humerus Fractures: What Works and What Does Not

Purpose of ReviewThe evaluation of proximal humerus fractures (PHFs) should be aimed to answer the following four questions: (1) does the fracture need surgery in each particular patient? (2) if surgery is recommended, is it better to proceed with internal fixation or shoulder arthroplasty, (3) if internal fixation is recommended, what is the ideal fixation device strategy, and (4) how can outcomes be optimized? This review article tries to answer these questions and provides some clarity regarding what works and what does not in PHFs treated with intramedullary nailing.Recent FindingsAccording to published articles on the treatment of PHFs with intramedullary nails, it is difficult to draw conclusions about outcomes and complications due to great variation in age, type of fracture, and nail designs included in the studies. However, the literature seems to support the use of modern nail designs for PHFs, especially in fractures of the surgical neck as well as varus posteromedial and valgus fractures with no tuberosity involvement.SummaryAlthough the results of IMN in PHF seem to be better in two-part fractures, in more complex fractures, the quality of the reduction achieved seems to influence functional outcomes. Tuberosity malreduction leads to poor clinical outcomes, high rate of complications, and an increased risk of avascular necrosis. Malreduction of the humeral head increases the risk of postoperative loss of reduction, especially for varus posteromedial impacted fractures. A medial nail entry point decreases the risk of postoperative varus malunion, preserves the rotator cuff tendon, and avoids iatrogenic fractures of the GT. To decrease the risk of postoperative stiffness, fracture fixation should be stable enough to allow early mobilization.     

Inhibitors of Activin Receptor-like Kinase 5 Interfere with SARS-CoV-2 S-Protein Processing and Spike-Mediated Cell Fusion via Attenuation of Furin Expression

Screening of a protein kinase inhibitor library identified SB431542, targeting activin receptor-like kinase 5 (ALK5), as a compound interfering with SARS-CoV-2 replication. Since ALK5 is implicated in transforming growth factor β (TGF-β) signaling and regulation of the cellular endoprotease furin, we pursued this research to clarify the role of this protein kinase for SARS-CoV-2 infection. We show that TGF-β1 induces the expression of furin in a broad spectrum of cells including Huh-7 and Calu-3 that are permissive for SARS-CoV-2. The inhibition of ALK5 by incubation with SB431542 revealed a dose-dependent downregulation of both basal and TGF-β1 induced furin expression. Furthermore, we demonstrate that the ALK5 inhibitors SB431542 and Vactosertib negatively affect the proteolytic processing of the SARS-CoV-2 Spike protein and significantly reduce spike-mediated cell–cell fusion. This correlated with an inhibitory effect of ALK5 inhibition on the production of infectious SARS-CoV-2. Altogether, our study shows that interference with ALK5 signaling attenuates SARS-CoV-2 infectivity and cell–cell spread via downregulation of furin which is most pronounced upon TGF-β stimulation. Since a TGF-β dominated cytokine storm is a hallmark of severe COVID-19, ALK5 inhibitors undergoing clinical trials might represent a potential therapy option for COVID-19.     

Correction to: Diagnostic performance of four SARS-CoV-2 antibody assays in patients with COVID-19 or with bacterial and non-SARS-CoV-2 viral respiratory infections

European Journal of Clinical Microbiology & Infectious Diseases -