SARS-CoV-2 mouse adaptation selects virulence mutations that cause TNF-driven age-dependent severe disease with human correlates.

The diversity of COVID-19 disease in otherwise healthy people, from seemingly asymptomatic infection to severe life-threatening disease, is not clearly understood. We passaged a naturally occurring near-ancestral SARS-CoV-2 variant, capable of infecting wild-type mice, and identified viral genomic mutations coinciding with the acquisition of severe disease in young adult mice and lethality in aged animals. Transcriptomic analysis of lung tissues from mice with severe disease elucidated a host antiviral response dominated mainly by interferon and IL-6 pathway activation in young mice, while in aged animals, a fatal outcome was dominated by TNF and TGF-β signaling.

Simultaneous evaluation of antibodies that inhibit SARS-CoV-2 variants via multiplex assay.

The SARS-CoV-2 receptor binding domain (RBD) is both the principal target of neutralizing antibodies and one of the most rapidly evolving domains, which can result in the emergence of immune escape mutations, limiting the effectiveness of vaccines and antibody therapeutics. To facilitate surveillance, we developed a rapid, high-throughput, multiplex assay able to assess the inhibitory response of antibodies to 24 RBD natural variants simultaneously. We demonstrate how this assay can be implemented as a rapid surrogate assay for functional cell-based serological methods to measure the SARS-CoV-2 neutralizing capacity of antibodies at the angiotensin-converting enzyme 2-RBD (ACE2-RBD) interface.

Heart disease in eosinophilic granulomatosis with polyangiitis (EGPA) patients: a screening approach proposal.

Objective: To define the pattern of cardiac involvement in eosinophilic granulomatosis and polyangiitis (EGPA) and propose an algorithm for heart disease screening.

Methods: This was a retrospective study of EGPA patients attending a specialized vasculitis clinic (1989-2016). Clinical characteristics and cardiovascular evaluation (CE) results (serum troponin, ECG, echocardiography and cardiac magnetic resonance) were collected and compared according to symptoms and inflammatory cardiac disease (ICD).

Evaluation of skin irritation following weathered crude oil exposure in two mouse strains.

Petroleum crude oil spills are common and vary in size and scope. Spill response workers throughout the course of remediation are exposed to so-called weathered oil and are known to report diverse health effects, including contact dermatitis. A murine model of repeated exposure to weathered marine crude oil was employed utilizing two strains of mice, C57BL/6 and BALB/c, to investigate the pathology of this irritant and identify the principal hydrocarbon components deposited in skin.

Identification of 5-Substituted 2-Acylaminothiazoles That Activate Tat-Mediated Transcription in HIV-1 Latency Models.

The persistent reservoir of cells latently infected with human immunodeficiency virus (HIV)-integrated proviral DNA necessitates lifelong suppressive antiretroviral therapy (ART). Epigenetic targeted compounds have shown promise as potential latency-reversing agents; however, these drugs have undesirable toxicity and lack specificity for HIV. We utilized a novel HEK293-derived FlpIn dual-reporter cell line, which quantifies specific HIV provirus reactivation (LTR promoter) relative to nonspecific host cell gene expression (CMV promoter), to identify the 5-substituted 2-acylaminothiazole hit class.

Ankylosing Spondylitis Response to TNF Inhibition Is Gender Specific: A 6-Year Cohort Study.

Aim Recent studies have suggested gender-specific differences with respect to both baseline disease activity and severity in ankylosing spondylitis (AS). Tumour necrosis factor inhibitors (TNFi) have shown significant benefit in AS but there may be gender-specific differences regarding responses to TNFi therapy. Methods AS patients with active disease despite adequate trials of NSAIDs were commenced on TNFi and followed in a biologic clinic between 2004 and 2011.

HIV latency reversing agents act through Tat post translational modifications.

Background: Different classes of latency reversing agents (LRAs) are being evaluated to measure their effects in reactivating HIV replication from latently infected cells. A limited number of studies have demonstrated additive effects of LRAs with the viral protein Tat in initiating transcription, but less is known about how LRAs interact with Tat, particularly through basic residues that may be post-translationally modified to alter the behaviour of Tat for processive transcription and co-transcriptional RNA processing.

Results: Here we show that various lysine and arginine mutations reduce the capacity of Tat to induce both transcription and mRNA splicing.

International multi-centre study of pregnancy outcomes with interleukin-1 inhibitors.

Objective: To provide outcome data concerning pregnancies exposed to the Interleukin-1 (IL-1) inhibitors prior to conception in both men and women, during pregnancy and breast feeding.

Methods: Retrospective data were collected from members of the International Society for Systemic Autoinflammatory diseases and collated in a single centre. A uniform data collection sheet was used to obtain standardized data including maternal age and diagnosis, type, duration of and response to IL-1 blockade, pregnancy duration, delivery, mode of feeding and neonatal development.

Efficacy and Safety of Rituximab in Connective Tissue Disease related Interstitial Lung Disease.

Background: Pulmonary complications of connective tissue disease are being identified more frequently with the advent of more sophisticated radiological investigations. Limited previous studies have suggested Rituximab (RTX), a chimeric monoclonal antibody with activity against CD-20, may benefit connective tissue disease patients with pulmonary complications. We performed a retrospective analysis of the efficacy and safety of RTX in patients attending a tertiary referral centre.

Guideline Promotion Increases Prescription of Bone Protection with Steroids in Hospitalised Patients.

Guidelines for the prevention of glucocorticoid (GC) induced osteoporosis (GIOP) were implemented in a level 5 Irish Hospital with cross sectional audit of inpatient prescribing undertaken before and after. Prior to guideline implementation, elemental calcium (Ca) with Vitamin D (VitD) was prescribed for 11/66 (17%) of patients on GCs with 2/66 (3%) also receiving bisphosphonate (BP) therapy. Subsequent to guideline implementation, Ca with VitD was prescribed for 19/55 (35%) of patients on GCs with 11/55 (20%) also receiving BP therapy, representing a 2 and 6 fold respective increase.

Immune-mediated necrotizing myopathy, associated with antibodies to signal recognition particle, together with lupus nephritis: case presentation and management.

A male patient with limb weakness, myalgia and edema was subsequently found to have an immune-mediated necrotizing myopathy (IMNM) on biopsy. Targeted myopathic antibody analysis revealed antibodies to signal recognition particle (SRP). Anti-SRP-associated necrotizing myopathy was diagnosed.

Profound reduction in hospital admissions and musculoskeletal surgical procedures for rheumatoid arthritis with concurrent changes in clinical practice (1995-2010).

Objectives: The aims of this study were to audit the annual national incidence of inpatient days and musculoskeletal surgical procedures (MSKSPs) for RA patients and to establish concurrent changes in clinical rheumatology practice from 1995 to 2010.

Methods: Hospital inpatient enquiry systems were evaluated for 57 hospitals from 1995 to 2010. National annual TNF inhibitor (TNFi) and MTX prescriptions were analysed.

An update to returning genetic research results to individuals: perspectives of the industry pharmacogenomics working group.

The ease with which genotyping technologies generate tremendous amounts of data on research participants has been well chronicled, a feat that continues to become both faster and cheaper to perform. In parallel to these advances come additional ethical considerations and debates, one of which centers on providing individual research results and incidental findings back to research participants taking part in genetic research efforts. In 2006 the Industry Pharmacogenomics Working Group (I-PWG) offered some 'Points-to-Consider' on this topic within the context of the drug development process from those who are affiliated to pharmaceutical companies.

Comparison of remission criteria in a tumour necrosis factor inhibitor treated rheumatoid arthritis longitudinal cohort: patient global health is a confounder.

Introduction: Our objectives were to assess the frequency and sustainability of American College of Rheumatology (ACR)/European League against Rheumatism (EULAR) and Disease Activity Score (DAS)28(4v)-C-reactive protein (CRP) remission 12 months after the initiation of tumour necrosis factor inhibitor (TNFi) therapy in a rheumatoid arthritis (RA) cohort.

Methods: Data were collected of 273 biologic naive RA patients at baseline, then 3, 6 and 12 months post-TNFi therapy. Remission status was calculated using DAS28(4v)-CRP <2.

Joint tenderness and swelling in biologic-treated inflammatory arthritis patients - a tricky trade off?

Objective: To compare the pattern of joint responses in patients with rheumatoid arthritis and psoriatic arthritis treated with TNF inhibitor (TNFi) therapy.

Methods: A total of 182 PsA/Rheumatoid arthritis (RA) patients attending the rheumatology unit of a tertiary referral centre in Ireland were recruited and prospectively followed up by the attendant rheumatologists. Clinical progress of the patients was noted at baseline and 6 months after starting TNFi therapy.

Mitochondrial mutagenesis correlates with the local inflammatory environment in arthritis.

Background: To examine the association between mitochondrial mutagenesis and the proinflammatory microenvironment in patients with inflammatory arthritis.

Methods: Fifty patients with inflammatory arthritis underwent arthroscopy and synovial tissue biopsies, synovial fluid and clinical assessment were obtained. Fifteen patients pre/post-TNFi therapy were also recruited.

Synovial tissue analysis for the discovery of diagnostic and prognostic biomarkers in patients with early arthritis.

Rheumatoid arthritis (RA) is a chronic disease of unspecified etiology that is manifest by persistent inflammation of the synovium. Considerable efforts have been undertaken globally to study the microenvironment of the inflamed synovium, with many encouraging and enlightening results that bring us closer to unmasking the precise etiologies of RA. Subsequent to these efforts, it has been discovered that CD68-positive macrophages present in abundance in the synovial sublining of the inflamed synovium rescind with treatments that induce clinical improvement in RA.

How early should psoriatic arthritis be treated with a TNF-blocker?

Purpose Of Review: Psoriatic arthritis (PsA) is the second most commonly identified inflammatory arthropathy in early arthritis clinics. It is a complex multisystem disease involving the skin and joints, but may also present with inflammation of the spine - spondylitis, digits - dactylitis, eyes - uveitis and ligamentous insertions - enthesitis. The skin manifestations may be mild or patchy and often precede the joint inflammation.

Shaming, Blaming, and Maiming: Functional Links Among the Moral Emotions, Externalization of Blame, and Aggression.

Theory suggests that shame should be positively related to aggression while guilt may serve as a protective factor. Little research has examined mediators between the moral emotions and aggression. Results using path analyses in four diverse samples were consistent with a model of no direct relationship between shame-proneness and aggression.

Are inmates' subjective sleep problems associated with borderline personality, psychopathy, and antisocial personality independent of depression and substance dependence?

Previous research investigating the relationship between Borderline Personality Disorder (BPD) and sleep problems, independent of depression, has been conducted on small atypical samples with mixed results. This study extends the literature by utilizing a much larger sample and by statistically controlling for depression and substance dependence. Subjective reports of sleep problems were obtained from 513 jail inmates (70% male) incarcerated on felony charges.