Treatment of axial spondyloarthritis with biologic and targeted synthetic DMARDs: British Society for Rheumatology guideline scope.

Pharmacological management has advanced considerably since the 2015 British Society for Rheumatology axial spondyloarthritis (axSpA) guideline to incorporate new classes of biologic DMARDs (bDMARDs, including biosimilars), targeted synthetic DMARDs (tsDMARDs) and treatment strategies such as drug tapering. The aim of this guideline is to provide an evidence-based update on pharmacological management of adults with axSpA (including AS and non-radiographic axSpA) using b/tsDMARDs. This guideline is aimed at health-care professionals in the UK who care directly for people with axSpA, including rheumatologists, rheumatology specialist nurses, allied health professionals, rheumatology specialty trainees and pharmacists; people living with axSpA; and other stakeholders, such as patient organizations and charities.

IgG4-related sclerosing thyroiditis (Riedel-Struma): a review of clinicopathological features and management.

We present a thorough review of the literature on Riedel thyroiditis (RT) with emphasis on aetiology, diagnosis and management, using the PubMed, Sinomed, and China National Knowledge Infrastructure databases. Although the exact aetiology of RT remains obscure, the histopathological features are consistent with a localized form of IgG4-related systemic disease (IgG4-RSD). Nevertheless, IgG4-RSD as a systemic fibroinflammatory disorder per se rarely affects the thyroid in the context of multiorgan manifestations. The initial diagnosis of RT is based on clinical history and imaging, but confirmation by histopathological examination is mandatory. In contrast to the historical surgical approach, glucocorticosteroid therapy is currently considered first line therapy, in line with the RT currently being viewed as a manifestation of, or analogous to, IgG4-RSD. For disease relapse, immunomodulatory agents (azathioprine, methotrexate, rituximab) can be used.

The Role of Vitamin D in Autoimmune Thyroid Diseases: A Narrative Review.

Vitamin D (VitD) deficiency has garnered significant attention in contemporary medical research. Although the canonical biological activity of VitD manifests itself mainly in the regulation of calcium-phosphorus metabolism, recent studies show that, thanks to the presence of numerous receptors, VitD may also play an important role in regulating the immune system. VitD deficiency has been demonstrated to impact autoimmune disease, coeliac disease, infections (including respiratory/COVID-19), and patients with cancer. Recent studies also show that VitD plays a significant role in autoimmune thyroid diseases (AITDs). Many studies have shown a correlation between low VitD levels and chronic autoimmune thyroiditis - Hashimoto thyroiditis (HT), Graves' disease (GD), and postpartum thyroiditis (PPT). This review article, therefore, describes the current state of knowledge on the role of VitD in AITDs, including HT, GD, and PTT.

MedDRA Labeling Groupings to Improve Safety Communication in Product Labels.

The granularity and structure of the International Council for Harmonisation's (ICH) Medical Dictionary for Regulatory Activities (MedDRA) are useful for precise coding of adverse events (AEs) for data analysis. In product labeling for healthcare practitioners, however, the granularity of MedDRA Preferred Terms (PTs) can obscure the communication of adverse reactions (ARs). Driven by a focus on patient safety, business needs, and regulatory guidance, many sponsors and regulators have begun to develop institution-specific approaches to clustering similar AR terms in medical product prescribing information on a product-by-product basis. However, there are no agreed upon conventions that describe which AR terms may be appropriate to group together. In order to improve safety communication to patients and healthcare providers, there is an urgent need for a harmonized international approach to the creation and use of groups of MedDRA PTs which we refer to as "MedDRA Labeling Groupings (MLGs)" in medical product prescribing information. Given its long-standing contributions towards the design of Standardised MedDRA Queries (SMQs), the Council for International Organizations of Medical Sciences (CIOMS) convened an Expert Working Group (EWG) with involvement of multiple major stakeholders to produce a consensus document on principles and points to consider in the development of MLGs. The CIOMS MLG EWG identified variations in grouping of MedDRA PTs in product labels, and in the current document, proposes a strategy for improving the communication of drug safety labeling. It is envisaged that the use of these consensus recommendations would be voluntary and applied to product labels in a manner that is consistent with existing regulatory frameworks.

Sterile protection and transmission blockade by a multistage anti-malarial vaccine in the pre-clinical study.

The Malaria Vaccine Technology Roadmap 2013 (World Health Organization) aims to develop safe and effective vaccines by 2030 that will offer at least 75% protective efficacy against clinical malaria and reduce parasite transmission. Here, we demonstrate a highly effective multistage vaccine against both the pre-erythrocytic and sexual stages of Plasmodium falciparum that protects and reduces transmission in a murine model. The vaccine is based on a viral-vectored vaccine platform, comprising a highly-attenuated vaccinia virus strain, LC16m8Δ (m8Δ), a genetically stable variant of a licensed and highly effective Japanese smallpox vaccine LC16m8, and an adeno-associated virus (AAV), a viral vector for human gene therapy. The genes encoding P. falciparum circumsporozoite protein (PfCSP) and the ookinete protein P25 (Pfs25) are expressed as a Pfs25-PfCSP fusion protein, and the heterologous m8Δ-prime/AAV-boost immunization regimen in mice provided both 100% protection against PfCSP-transgenic P. berghei sporozoites and up to 100% transmission blocking efficacy, as determined by a direct membrane feeding assay using parasites from P. falciparum-positive, naturally-infected donors from endemic settings. Remarkably, the persistence of vaccine-induced immune responses were over 7 months and additionally provided complete protection against repeated parasite challenge in a murine model. We propose that application of the m8Δ/AAV malaria multistage vaccine platform has the potential to contribute to the landmark goals of the malaria vaccine technology roadmap, to achieve life-long sterile protection and high-level transmission blocking efficacy.

Fibromyalgia and Chronic Fatigue Syndromes: A systematic review and meta-analysis of cardiorespiratory fitness and neuromuscular function compared with healthy individuals.

OBJECTIVE: To determine cardiorespiratory fitness and neuromuscular function of people with CFS and FMS compared to healthy individuals. DESIGN: Systematic review and meta-analysis. DATA SOURCES: PubMed, Medline, CINAHL, AMED, Cochrane Central Register of Controlled Trials (CENTRAL), and PEDro from inception to June 2022. ELIGIBLE CRITERIA FOR SELECTING STUDIES: Studies were included if presenting baseline data on cardiorespiratory fitness and/or neuromuscular function from observational or interventional studies of patients diagnosed with FMS or CFS. Participants were aged 18 years or older, with results also provided for healthy controls. Risk of bias assessment was conducted using the Quality Assessment Tool for Quantitative Studies (EPHPP). RESULTS: 99 studies including 9853 participants (5808 patients; 4405 healthy controls) met our eligibility criteria. Random effects meta-analysis showed lower cardiorespiratory fitness (VO2max, anaerobic threshold, peak lactate) and neuromuscular function (MVC, fatigability, voluntary activation, muscle volume, muscle mass, rate of perceived exertion) in CFS and FMS compared to controls: all with moderate to high effect sizes. DISCUSSION: Our results demonstrate lower cardiorespiratory fitness and muscle function in those living with FMS or CFS when compared to controls. There were indications of dysregulated neuro-muscular interactions including heightened perceptions of effort, reduced ability to activate the available musculature during exercise and reduced tolerance of exercise. TRAIL REGISTRATION: PROSPERO registration number: (CRD42020184108).

Optimal Monitoring Technology for Pediatric Thyroidectomy.

This retrospective study aimed to describe, firstly, characteristics and outcomes of the intraoperative neural monitoring technology in the pediatric population, and secondarily the recurrent laryngeal nerve complication rate. Thirty-seven patients (age <18 years) operated on from 2015 to 2021 by conventional open thyroid surgery were included. Twenty-four (64.9%) total thyroidectomies and 13 (35.1%) lobectomies were performed. Seven central and six lateral lymph node dissections completed 13 bilateral procedures. Histology showed malignancy in 45.9% of the cases. The differences between the electromyographic profiles of endotracheal tubes or electrodes for continuous monitoring were not statistically significant. In our series of young patients, both adhesive (even in 4- or 5-year-olds) and embedded endotracheal tubes were used, while in patients 3 years old or younger, the use of a more invasive detection method with transcartilage placement recording electrodes was required. Overall, out of 61 total at-risk nerves, 5 (8.2%) recurrent laryngeal nerves were injured with consequent intraoperative loss of the signal; however, all these lesions were transient, restoring their normal functionality within 4 months from surgical procedure. To our knowledge, this is the first study of intraoperative neural monitoring management in a cohort of Italian pediatric patients.

A Survey of Diagnostic Delay in Axial Spondyloarthritis Across Two National Health Service (NHS) Rheumatology Services.

Introduction Diagnostic delay is an ongoing challenge in axial spondyloarthritis (axial SpA). A recent, comprehensive literature review has found a mean average of 8.7 years of delay between symptom onset and formal diagnosis in the United Kingdom (UK). The primary aim of this study was to identify delays to diagnosis experienced by patients with axial SpA under the ongoing care of two urban National Health Service (NHS) rheumatology services. The secondary aims were (a) to count healthcare professional (HCP) interactions after symptom onset but prior to the diagnosis, (b) to compare our data to published delay to diagnosis research and (c) to explore contributing factors locally and the variation between the two UK rheumatology services. Methods A 14-question survey was created to identify the delay to diagnosis and contributing factors across two urban NHS axial SpA services, from the onset of symptoms to diagnosis and commencement of treatment. Participants were recruited from clinic visits between August and November 2021 and completed the survey either on paper or via online survey software, both with HCP support. Results Those completing the survey formed a cohort of 106 participants with an established diagnosis of axial SpA who attended the axial SpA services at either Royal Free NHS Foundation Trust or Salford Care Organisation, Northern Care Alliance NHS Foundation Trust. The mean time from the onset of symptoms to the diagnosis of axial SpA was similar across centres despite the differences in demographics, with Royal Free at 5.72 years and Salford Royal at 5.96 years. When reviewing via median diagnostic delay, there was a notable difference with Royal Free at 6.09 years and Salford Royal at 4.27 years. Across the two sites, between the onset of symptoms and the diagnosis of axial SpA, 90% of the participants saw a general practitioner (GP), of which 63% of the patients saw a GP 1-5 times, 23% saw 5-10 times and 14% saw more than 10 times. Many participants also saw other HCPs, including physiotherapists, other manual therapists and hospital specialists prior to diagnosis. In addition, 32% saw one other HCP, 18% two other HCPs, 9% three, 7% four and 2.7% five other HCPs prior to diagnosis. Close to 80% of the patients stated that they had received adequate axial SpA education at diagnosis, and 76% of the patients were aware of who to contact in the event of a flare. Conclusions These data highlight that the mean average time to diagnosis for both trusts was between five and six years, somewhat lower than the 8.7-year national UK average. However, despite being specialist centres, these data are a long way from the National Axial Spondyloarthritis Society (NASS) "Gold Standard" of one year time to diagnosis. The contributors to this include lack of HCP and community awareness about axial SpA, its recognition and appropriate onwards referral. There is a need for concerted ways of working for the development of patient pathways and public and HCP education to reduce this delay to allow the ambitious NASS Gold Standard of one year time to diagnosis to be achieved.

Differences in spike generation instead of synaptic inputs determine the feature selectivity of two retinal cell types.

Retinal ganglion cells (RGCs) are the spiking projection neurons of the eye that encode different features of the visual environment. The circuits providing synaptic input to different RGC types to drive feature selectivity have been studied extensively, but there has been less research aimed at understanding the intrinsic properties and how they impact feature selectivity. We introduce an RGC type in the mouse, the Bursty Suppressed-by-Contrast (bSbC) RGC, and compared it to the OFF sustained alpha (OFFsA). Differences in their contrast response functions arose from differences not in synaptic inputs but in their intrinsic properties. Spike generation was the key intrinsic property behind this functional difference; the bSbC RGC undergoes depolarization block while the OFFsA RGC maintains a high spike rate. Our results demonstrate that differences in intrinsic properties allow these two RGC types to detect and relay distinct features of an identical visual stimulus to the brain.

Assessment of Physical Activity and Muscle Function in Adult Inflammatory Myopathies.

PURPOSE OF REVIEW: The aim is to summarize the outcome measures used in the assessment and monitoring of muscle function and physical activity in the management idiopathic inflammatory myopathy. RECENT FINDINGS: Assessment techniques have progressed and matured over the past decade, and new options are now available to clinicians working in this field. Newer outcome measures, including the Functional Index-3 and wearable motion sensors are reviewed, as well as the current application of more established measures. The available outcome measures for use in clinical practice in idiopathic inflammatory myopathies with regard to muscle function and physical activity have expanded over the past 15 years. There are valid and reliable options for several domains and methods for assessing these factors. In a busy clinical setting, efficiency is important, but there also needs to be considered the choosing of tools that work together to give the fullest picture of the status of the patient.

Ambulatory percutaneous nephrolithotomy is safe and effective in patients with extended selection criteria.

INTRODUCTION: Ambulatory percutaneous nephrolithotomy (PCNL) has been limited to highly selected patients. The objective of our study was to compare complication and stone-free rates after ambulatory PCNL in standard selection criteria vs. extended criteria patients. METHODS: We conducted a retrospective review of prospective data on all patients who underwent ambulatory PCNL at one academic center from 2007-2018. Extended criteria patients were defined as one or more of: age >75 years, body mass index (BMI) >30 kg/m2, American Society of Anesthesiologists (ASA) score >2, bilateral stones, solitary kidney, transplant kidney, complete staghorn calculi, stone burden >40 mm, multiple tracts, or prior nephrostomy tubes/stents. Primary outcomes were complication rates (Clavien-Dindo classification) and stone-free rates. RESULTS: We identified 118 patients, of which 92 (78%) met extended criteria. Mean BMI was 31 kg/m2 and 45% were ASA 3 or higher. Mean sum maximum stone diameter was 24 mm. Multiple stones were present in 25%, bilateral stones in 7%, and complete staghorn stones in 4% of patients. There was no difference in complication (12% vs. 18%, p=0.56), emergency department visit (12% vs. 18%, p=0.56), or re-admission (4% vs. 5%, p=1) rates between standard and extended criteria patients, respectively. Of the complications, 85% were Clavien-Dindo grade 1. Stone-free rates were not different between standard (84%) and extended (83%) criteria patients (p=1). No extended criteria variables were associated with complications in multivariable analysis. CONCLUSIONS: Complication and stone-free rates were not different between standard and extended selection criteria patients undergoing ambulatory PCNL. This data indicates that many of the preoperative patient and stone factors that have previously been used as exclusion criteria for ambulatory PCNL are not strictly necessary.

Splenic infarction secondary to COVID-19 complicated by Clostridium Paraputrificum infection.

A 58-year-old woman with COVID-19 presented with an acute abdomen. Her spleen was found to be infarcted with a large fluid and gas collection. Treatment included broad-spectrum antibiotics and CT-guided drainage. Definitive treatment was splenectomy. We postulate that COVID-19 related splenic infarction created ideal conditions for Clostridium paraputrificum to cause a splenic abscess.

Global Safety Database Summary of COVID-19-Related Drug Utilization-Safety Surveillance: A Sponsor's Perspective.

INTRODUCTION: Evidence-based clinical data on coronavirus disease 2019 (COVID-19) pharmacotherapies are scarce. OBJECTIVE: This study documented and characterized COVID-19 cases reported in individuals receiving treatment with Pfizer pharmaceutical products and cases that reported use of Pfizer pharmaceutical products for COVID-19 treatment. METHODS: This retrospective observational review leveraged the Pfizer safety database containing adverse event data collected in association with use of Pfizer products between 1 October, 2019, and 25 June, 2020; the database includes worldwide adverse event data from various sources. Selected Medical Dictionary for Drug Regulatory Activities (MedDRA®) Preferred Terms and subsequent clinical review were used to characterize COVID-19 cases. RESULTS: Over 1500 relevant cases were identified over an 8-month period. In cases that reported COVID-19, immunosuppressant/immunomodulating agents, followed by anticoagulant/antithrombic agents and corticosteroids, were the most frequently reported agents. The frequent reporting of immunosuppressant/immunomodulating agents among cases of COVID-19 suggests increased vulnerability to infection among treated patients, either because of immunosuppressive effects of certain agents or the nature of the underlying treated condition. In cases involving off-label pharmacotherapy use for the treatment of COVID-19-related conditions, the most frequently reported therapeutic classes included antibiotics, antimalarial agents, antivirals/antiretroviral agents, immunosuppressant/immunomodulating agents, corticosteroids, anticoagulants, and immunoglobulin/interferons. The most frequently reported pharmacotherapeutic agents were azithromycin and chloroquine/hydroxychloroquine, followed by lopinavir-ritonavir, ceftriaxone, and tofacitinib. The most frequently reported clinical adverse events associated with azithromycin (as sole therapy or combined with chloroquine/hydroxychloroquine) include electrocardiogram QT prolonged, drug interaction, hepatitis, diarrhea, and hepatitis acute. Regarding cardiac-related events, 19% (120/645) of azithromycin cases reported events associated with QT prolongation/torsade de pointes (which included seven fatal cardiac events). The most frequently reported clinical adverse events associated with other commonly used agents are also presented. CONCLUSIONS: This pharmacovigilance surveillance study provides a unique characterization of cases in which a broad range of pharmaceutical products was reported in relation to COVID-19.

Identification of retinal ganglion cell types and brain nuclei expressing the transcription factor Brn3c/Pou4f3 using a Cre recombinase knock-in allele.

Members of the POU4F/Brn3 transcription factor family have an established role in the development of retinal ganglion cell (RGCs) types, the main transducers of visual information from the mammalian eye to the brain. Our previous work using sparse random recombination of a conditional knock-in reporter allele expressing alkaline phosphatase (AP) and intersectional genetics had identified three types of Brn3c positive (Brn3c+ ) RGCs. Here, we describe a novel Brn3cCre mouse allele generated by serial Dre to Cre recombination and use it to explore the expression overlap of Brn3c with Brn3a and Brn3b and the dendritic arbor morphologies and visual stimulus response properties of Brn3c+ RGC types. Furthermore, we explore brain nuclei that express Brn3c or receive input from Brn3c+ neurons. Our analysis reveals a much larger number of Brn3c+ RGCs and more diverse set of RGC types than previously reported. Most RGCs expressing Brn3c during development are still Brn3c positive in the adult, and all express Brn3a while only about half express Brn3b. Genetic Brn3c-Brn3b intersection reveals an area of increased RGC density, extending from dorsotemporal to ventrolateral across the retina and overlapping with the mouse binocular field of view. In addition, we report a Brn3c+ RGC projection to the thalamic reticular nucleus, a visual nucleus that was not previously shown to receive retinal input. Furthermore, Brn3c+ neurons highlight a previously unknown subdivision of the deep mesencephalic nucleus. Thus, our newly generated allele provides novel biological insights into RGC type classification, brain connectivity, and cytoarchitectonic.