Safety and efficacy of abatacept in early diffuse cutaneous systemic sclerosis (ASSET): open-label extension of a phase 2, double-blind randomised trial

Background: Abatacept was well tolerated by patients with early diffuse cutaneous systemic sclerosis in a phase 2, double-blind randomised trial, with potential efficacy at 12 months. We report here the results of an open-label extension for 6 months. / Methods: Patients (aged ≥18 years) with diffuse cutaneous systemic sclerosis of less than 3 years' duration from their first non-Raynaud's symptom were enrolled into the ASSET trial (A Study of Subcutaneous Abatacept to Treat Diffuse Cutaneous Systemic Sclerosis), which is a double-blind trial at 22 sites in Canada, the UK, and the USA. After completion of 12 months of treatment with either abatacept or placebo, patients received a further 6 months of abatacept (125 mg subcutaneous every week) in an open-label extension. The primary endpoint of the double-blind trial was modified Rodnan Skin Score (mRSS) at 12 months, which was reassessed at 18 months in the open-label extension. The primary analysis included all participants who completed the double-blind trial and received at least one dose of open-label treatment (modified intention to treat). This trial is registered with ClinicalTrials.gov, NCT02161406. / Findings: Between Sept 22, 2014, and March 15, 2017, 88 participants were randomly allocated in the double-blind trial either abatacept (n=44) or placebo (44); 32 patients from each treatment group completed the 6-month open-label extension. Among patients assigned abatacept, a mean improvement from baseline in mRSS was noted at 12 months (−6·6 [SD 6·4]), with further improvement seen during the open-label extension period (−9·8 [8·1] at month 18). Participants assigned placebo had a mean improvement from baseline in mRSS at 12 months (−3·7 [SD 7·6]), with a further improvement at month 18 (−6·3 [9·3]). Infections during the open-label extension phase occurred in nine patients in the placebo–abatacept group (12 adverse events, one serious adverse event) and in 11 patients in the abatacept–abatacept group (14 adverse events, one serious adverse event). Two deaths occurred during the 12-month double-blind period in the abatacept group, which were related to scleroderma renal crisis; no deaths were recorded during the open-label extension. / Interpretation: During the 6-month open-label extension, no new safety signals for abatacept were identified in the treatment of diffuse cutaneous systemic sclerosis. Clinically meaningful improvements in mRSS and other outcome measures were observed in both the abatacept and placebo groups when patients transitioned to open-label treatment. These data support further studies of abatacept in diffuse cutaneous systemic sclerosis. / Funding: Bristol-Myers Squibb and National Institutes of Health

Real-time three-dimensional transthoracic echocardiography in daily practice: initial experience

<p>Abstract</p> <p>Aim of the work</p> <p>To evaluate the feasibility and possible additional value of transthoracic real-time three-dimensional echocardiography (RT3D-TTE) for the assessment of cardiac structures as compared to 2D-TTE.</p> <p>Methods</p> <p>320 patients (mean age 45 ± 8.4 years, 75% males) underwent 2D-TTE and RT3D-TTE using 3DQ-Q lab software for offline analysis. Volume quantification and functional assessment was performed in 90 patients for left ventricle and in 20 patients for right ventricle. Assessment of native (112 patients) and prosthetic (30 patients) valves morphology and functions was performed. RT3D-TTE was performed for evaluation of septal defects in 30 patients and intracardiac masses in 52 patients.</p> <p>Results</p> <p>RT3D-TTE assessment of left ventricle was feasible and reproducible in 86% of patients while for right ventricle, it was (55%). RT3D-TTE could define the surface anatomy of mitral valve optimally (100%), while for aortic and tricuspid was (88% and 81% respectively). Valve area could be planimetered in 100% for the mitral and in 80% for the aortic. RT3D-TTE provided a comprehensive anatomical and functional evaluation of prosthetic valves. RT3D-TTE enface visualization of septal defects allowed optimal assessment of shape, size, area and number of defects and evaluated the outcome post device closure. RT3D-TTE allowed looking inside the intracardiac masses through multiple sectioning, valuable anatomical delineation and volume calculation.</p> <p>Conclusion</p> <p>Our initial experience showed that the use of RT3D-TTE in the assessment of cardiac patients is feasible and allowed detailed anatomical and functional assessment of many cardiac disorders.</p

A Proposed Model

Rocha-Penedo, R., Cruz-Jesus, F., & Oliveira, T. (2021). Opposite Outcomes of Social Media Use: A Proposed Model. In S. K. Sharma, Y. K. Dwivedi, B. Metri, & N. P. Rana (Eds.), Re-imagining Diffusion and Adoption of Information Technology and Systems: A Continuing Conversation - IFIP WG 8.6 International Conference on Transfer and Diffusion of IT, TDIT 2020, Proceedings (pp. 524-537). (IFIP Advances in Information and Communication Technology; Vol. 618). Springer. https://doi.org/10.1007/978-3-030-64861-9_46Social media are probably one of the most influential and disruptive technology of the present times. It is ubiquitous and has the capability to influence virtually every aspect of one’s life while, at the same time, also influence the way firms and public organizations operate and communicate with individuals. Although there is a plethora of studies in the IS literature focused on SM adoption and outcomes, studies hypothesizing positive and negative outcomes together are scarce. We propose a comprehensive research model to shed light on SM positive and negative outcomes, and how these affect one’s happiness. We also explore how personality traits can influence these relationships.authorsversionpublishe

Impairment of Immunoproteasome Function by β5i/LMP7 Subunit Deficiency Results in Severe Enterovirus Myocarditis

Proteasomes recognize and degrade poly-ubiquitinylated proteins. In infectious disease, cells activated by interferons (IFNs) express three unique catalytic subunits β1i/LMP2, β2i/MECL-1 and β5i/LMP7 forming an alternative proteasome isoform, the immunoproteasome (IP). The in vivo function of IPs in pathogen-induced inflammation is still a matter of controversy. IPs were mainly associated with MHC class I antigen processing. However, recent findings pointed to a more general function of IPs in response to cytokine stress. Here, we report on the role of IPs in acute coxsackievirus B3 (CVB3) myocarditis reflecting one of the most common viral disease entities among young people. Despite identical viral load in both control and IP-deficient mice, IP-deficiency was associated with severe acute heart muscle injury reflected by large foci of inflammatory lesions and severe myocardial tissue damage. Exacerbation of acute heart muscle injury in this host was ascribed to disequilibrium in protein homeostasis in viral heart disease as indicated by the detection of increased proteotoxic stress in cytokine-challenged cardiomyocytes and inflammatory cells from IP-deficient mice. In fact, due to IP-dependent removal of poly-ubiquitinylated protein aggregates in the injured myocardium IPs protected CVB3-challenged mice from oxidant-protein damage. Impaired NFκB activation in IP-deficient cardiomyocytes and inflammatory cells and proteotoxic stress in combination with severe inflammation in CVB3-challenged hearts from IP-deficient mice potentiated apoptotic cell death in this host, thus exacerbating acute tissue damage. Adoptive T cell transfer studies in IP-deficient mice are in agreement with data pointing towards an effective CD8 T cell immune. This study therefore demonstrates that IP formation primarily protects the target organ of CVB3 infection from excessive inflammatory tissue damage in a virus-induced proinflammatory cytokine milieu

Local Government Revenue Mobilisation in Anglophone Africa

This paper examines opportunities and constraints facing local revenue mobilisation in anglophone Africa, with an emphasis on urban settings. It discusses specific revenue instruments and their effects on economic efficiency, income distribution and accountability. In particular, it addresses political and administrative constraints facing various revenue instruments and factors affecting citizens’ compliance. The analysis is illustrated with examples from across anglophone Africa. A general conclusion emerging from the study is that local revenues mobilised in most local government authorities in Africa are necessary but not sufficient to develop and supply adequate services for the fast-growing population. On this basis, areas for further research on local government revenue mobilisation in Africa are identifiedDfI

Distinct skill pathways to digital engagement

Digital literacy and inclusion have been two important, largely separate, areas of study that examine the relationships between Internet skills and engagement. This article brings together these areas of research by testing a model that assumes specific pathways to inclusion: specific sociodemographic factors predict specific digital skills and specific digital skills predict related types of engagement with the Internet. Analyses of nationally representative survey data of Internet use in Britain highlight considerable measurement and conceptual challenges that complicate digital literacy research. The findings suggest that linking literacy and exclusion frameworks allows for a more nuanced understanding of digital engagement. Different groups lacked different skills, which related to how their engagement with the Internet varied

Mucormycosis in the Eastern Mediterranean: a seasonal disease

Mucormycosis is a fairly rare fungal infection caused by ubiquitous fungi of the order Mucorales and primarily affects immunocompromised hosts. A series of 16 cases of invasive mucormycosis admitted to three referral centres in Beirut, Lebanon between 1981 and 1999 is described. It includes 12 patients with rhinocerebral, three with cutaneous, and one with pulmonary infection. Onset of symptoms occurred in the summer and autumn in 15 out of 16 patients, showing a statistically significant seasonal variation (P=0·007) A recent report of 19 patients from Tel Aviv describes a strikingly similar seasonal pattern. Studies on atmospheric concentration of Mucorales spores in the Eastern Mediterranean are lacking. Weather pattern analysis in Beirut revealed clustering of onset of invasive mucormycosis at the end of a dry, warm period, which begins around May and ends in October. Mucormycosis incidence appears to be seasonal in the Eastern Mediterranean

Non-vitamin K antagonist oral anticoagulants for stroke prevention in atrial fibrillation: safety issues in the elderly

INTRODUCTION: Non-vitamin K antagonist oral anticoagulants (NOACs) are increasingly used for stroke prevention in patients with atrial fibrillation (AF). Since NOACs are predominantly used in the elderly with AF at high risk for stroke and bleeding and with comorbidities requiring polypharmacy, it is important to assess their safety and efficacy in this population. AREAS COVERED: We review changes in pharmacokinetics and pharmacodynamics observed with senescence and the effect on NOACs and drug and food interactions. We also provide an update on challenges related to NOAC use in situations that increases the risk for bleeding or require temporary discontinuation and address practical issues in the elderly AF patients managed on NOACs. Clinical studies and trials with cardiovascular outcomes reported from January 1990 to August 2020 were identified through the Medline database using PubMed, Cochrane Library, and EMBASE database. EXPERT OPINION: NOACs are highly effective in preventing stroke in AF patients with non-inferior or superior efficacy to warfarin, with reduced risk of major bleeding. However, in the older-elderly, evidence comes mainly from observational studies or extrapolation from studies in populations with minimal functional limitations or comorbidities. The high upfront cost and out-of-pocket expense for copayment or deductibles also limit the use of this effective therapy in a substantial number of patients. The cost reduction may further improve long-term use for NOACs in stroke prevention in elderly patients with AF