HpARI Protein Secreted by a Helminth Parasite Suppresses Interleukin-33.

Infection by helminth parasites is associated with amelioration of allergic reactivity, but mechanistic insights into this association are lacking. Products secreted by the mouse parasite Heligmosomoides polygyrus suppress type 2 (allergic) immune responses through interference in the interleukin-33 (IL-33) pathway. Here, we identified H. polygyrus Alarmin Release Inhibitor (HpARI), an IL-33-suppressive 26-kDa protein, containing three predicted complement control protein (CCP) modules. In vivo, recombinant HpARI abrogated IL-33, group 2 innate lymphoid cell (ILC2) and eosinophilic responses to Alternaria allergen administration, and diminished eosinophilic responses to Nippostrongylus brasiliensis, increasing parasite burden. HpARI bound directly to both mouse and human IL-33 (in the cytokine's activated state) and also to nuclear DNA via its N-terminal CCP module pair (CCP1/2), tethering active IL-33 within necrotic cells, preventing its release, and forestalling initiation of type 2 allergic responses. Thus, HpARI employs a novel molecular strategy to suppress type 2 immunity in both infection and allergy.

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.

Myocarditis Associated with Immune Checkpoint Inhibitors: An Expert Consensus on Data Gaps and a Call to Action.

Immune checkpoint inhibitors (ICIs) have transformed the treatment landscape for cancer. Due to the mechanism of action of ICIs, inflammatory reactions against normal tissue were an anticipated side effect of these agents; these immune-related adverse events have been documented and are typically low grade and manageable. Myocarditis has emerged as an uncommon but potentially life-threatening adverse reaction in patients treated with ICIs. Assessment and characterization of ICI-associated myocarditis is challenging because of its low incidence and protean manifestations. Nevertheless, the seriousness of ICI-associated myocarditis justifies a coordinated effort to increase awareness of this syndrome, identify patients who may be at risk, and enable early diagnosis and appropriate treatment. The "Checkpoint Inhibitor Safety Working Group," a multidisciplinary committee of academic, industry, and regulatory partners, convened at a workshop hosted by Project Data Sphere, LLC, on December 15, 2017. This meeting aimed to evaluate the current information on ICI-associated myocarditis, determine methods to collect and share data on this adverse reaction, and establish task forces to close the identified knowledge gaps. In this report, we summarize the workshop findings and proposed steps to address the impact of ICI-associated myocarditis in patients with cancer.

Patterns and predictors of skin score change in early diffuse systemic sclerosis from the European Scleroderma Observational Study.

OBJECTIVES: Our aim was to use the opportunity provided by the European Scleroderma Observational Study to (1) identify and describe those patients with early diffuse cutaneous systemic sclerosis (dcSSc) with progressive skin thickness, and (2) derive prediction models for progression over 12 months, to inform future randomised controlled trials (RCTs). METHODS: The modified Rodnan skin score (mRSS) was recorded every 3 months in 326 patients. 'Progressors' were defined as those experiencing a 5-unit and 25% increase in mRSS score over 12 months (±3 months). Logistic models were fitted to predict progression and, using receiver operating characteristic (ROC) curves, were compared on the basis of the area under curve (AUC), accuracy and positive predictive value (PPV). RESULTS: 66 patients (22.5%) progressed, 227 (77.5%) did not (33 could not have their status assessed due to insufficient data). Progressors had shorter disease duration (median 8.1 vs 12.6 months, P=0.001) and lower mRSS (median 19 vs 21 units, P=0.030) than non-progressors. Skin score was highest, and peaked earliest, in the anti-RNA polymerase III (Pol3+) subgroup (n=50). A first predictive model (including mRSS, duration of skin thickening and their interaction) had an accuracy of 60.9%, AUC of 0.666 and PPV of 33.8%. By adding a variable for Pol3 positivity, the model reached an accuracy of 71%, AUC of 0.711 and PPV of 41%. CONCLUSIONS: Two prediction models for progressive skin thickening were derived, for use both in clinical practice and for cohort enrichment in RCTs. These models will inform recruitment into the many clinical trials of dcSSc projected for the coming years. TRIAL REGISTRATION NUMBER: NCT02339441.

Disability, fatigue, pain and their associates in early diffuse cutaneous systemic sclerosis: the European Scleroderma Observational Study.

Objectives: Our aim was to describe the burden of early dcSSc in terms of disability, fatigue and pain in the European Scleroderma Observational Study cohort, and to explore associated clinical features. Methods: Patients completed questionnaires at study entry, 12 and 24 months, including the HAQ disability index (HAQ-DI), the Cochin Hand Function Scale (CHFS), the Functional Assessment of Chronic Illness Therapy-fatigue and the Short Form 36 (SF36). Associates examined included the modified Rodnan skin score (mRSS), current digital ulcers and internal organ involvement. Correlations between 12-month changes were also examined. Results: The 326 patients recruited (median disease duration 11.9 months) displayed high levels of disability [mean (s.d.) HAQ-DI 1.1 (0.83)], with 'grip' and 'activity' being most affected. Of the 18 activities assessed in the CHFS, those involving fine finger movements were most affected. High HAQ-DI and CHFS scores were both associated with high mRSS (ρ = 0.34, P < 0.0001 and ρ = 0.35, P < 0.0001, respectively). HAQ-DI was higher in patients with digital ulcers (P = 0.004), pulmonary fibrosis (P = 0.005), cardiac (P = 0.005) and muscle involvement (P = 0.002). As anticipated, HAQ-DI, CHFS, the Functional Assessment of Chronic Illness Therapy and SF36 scores were all highly correlated, in particular the HAQ-DI with the CHFS (ρ = 0.84, P < 0.0001). Worsening HAQ-DI over 12 months was strongly associated with increasing mRSS (ρ = 0.40, P < 0.0001), decreasing hand function (ρ = 0.57, P < 0.0001) and increasing fatigue (ρ = -0.53, P < 0.0001). Conclusion: The European Scleroderma Observational Study highlights the burden of disability in early dcSSc, with high levels of disability and fatigue, associating with the degree of skin thickening (mRSS). Impaired hand function is a major contributor to overall disability.

Treatment outcome in early diffuse cutaneous systemic sclerosis: the European Scleroderma Observational Study (ESOS).

OBJECTIVES: The rarity of early diffuse cutaneous systemic sclerosis (dcSSc) makes randomised controlled trials very difficult. We aimed to use an observational approach to compare effectiveness of currently used treatment approaches. METHODS: This was a prospective, observational cohort study of early dcSSc (within three years of onset of skin thickening). Clinicians selected one of four protocols for each patient: methotrexate, mycophenolate mofetil (MMF), cyclophosphamide or 'no immunosuppressant'. Patients were assessed three-monthly for up to 24 months. The primary outcome was the change in modified Rodnan skin score (mRSS). Confounding by indication at baseline was accounted for using inverse probability of treatment (IPT) weights. As a secondary outcome, an IPT-weighted Cox model was used to test for differences in survival. RESULTS: Of 326 patients recruited from 50 centres, 65 were prescribed methotrexate, 118 MMF, 87 cyclophosphamide and 56 no immunosuppressant. 276 (84.7%) patients completed 12 and 234 (71.7%) 24 months follow-up (or reached last visit date). There were statistically significant reductions in mRSS at 12 months in all groups: -4.0 (-5.2 to -2.7) units for methotrexate, -4.1 (-5.3 to -2.9) for MMF, -3.3 (-4.9 to -1.7) for cyclophosphamide and -2.2 (-4.0 to -0.3) for no immunosuppressant (p value for between-group differences=0.346). There were no statistically significant differences in survival between protocols before (p=0.389) or after weighting (p=0.440), but survival was poorest in the no immunosuppressant group (84.0%) at 24 months. CONCLUSIONS: These findings may support using immunosuppressants for early dcSSc but suggest that overall benefit is modest over 12 months and that better treatments are needed. TRIAL REGISTRATION NUMBER: NCT02339441.

Effect of energy-based devices on voice quality after total thyroidectomy.

Voice alteration is an important complication of thyroid surgery and is closely related to patients' quality of life. There are no studies analyzing effect of energy-based devices (EBD) on voice quality (VQ). Aim of this prospective study is to evaluate impact of sutureless total thyroidectomy performed with EBDs on objective voice parameters of patients without recurrent laryngeal nerve (RLN) and/or external branch of superior laryngeal nerve (EBSLN) injury. Sixty patients underwent total thyroidectomy with meticulous dissection of EBSLN. Patients were assigned to Group L (Ligasure™), Group H (Harmonic), or Group C (Conventional) through random ballot. For analysis of alteration in VQ, digital videolaryngostroboscopy (VLS), voice handicap index (VHI), multidimensional voice program (MDVP), and electroglottography (EGG) were used. VLS was performed by 70°-angled indirect laryngoscopy and evaluation was standardized by VLS scale and laryngeal function scoring. This study is registered on clinicaltrials.gov with number NCT01865006. Forty eight patients were female. There was no difference on demographic data. On post-operative laryngoscopic examination, none of the patients had vocal fold palsy. When mean VHI scores at post-operative 1st week and 2nd month were compared to pre-operative values for each groups, groups L and H demonstrated a significant increase in VHI in the early post-operative evaluation, while there was no significant increase for group C. No significant increase was seen in late post-operative period compared to pre-operative period for any groups. In the early post-operative period, VQ is better with the conventional technique than EBDs; however, in late post-operative period, VQ is detected better in EBDs (especially in Group L) than the conventional technique, but no statistical difference was observed.

Latency to vaginal mesh exposure with mesh placed abdominally versus vaginally in pelvic floor surgery: A retrospective comparative study.

The primary aim was to compare the difference in time to mesh exposure between mesh placed abdominally versus vaginally. This is a retrospective comparative study of patients presented with vaginal mesh exposure between January 2001 and July 2012. This study compares patients who had undergone vaginally placed mesh procedures to those who had had abdominally placed mesh. Kaplan-Meier survival analysis was used to measure the time to mesh exposure. There were 68 patients with mesh exposure in our cohort. Thirty eight patients had undergone vaginal placement of mesh and 30 patients had abdominal mesh. There was a statistically significant difference in time to mesh exposure between abdominal and vaginal meshes (p≤.0001). Mean time to vaginal mesh exposure with abdominal mesh was 59.8 months (95%CI 46.2-73.3) compared to 23 months (95%CI 15.9-30.2) for vaginal mesh. When controlling for age, BMI and surgeon at index surgery, the Hazard Ratio for mesh exposure in our Cox Regression model was 0.53 (95%CI 0.39-0.71) (p ≤.0001). The mean time to vaginal mesh exposure after abdominal mesh was longer compared to the time to exposure with vaginally placed mesh (60 versus 23 months, p ≤.0001). These results support the evolving evidence that mesh exposures can occur many years distant from the procedure and warrant some level of surveillance or provision of warning signs by the providers who perform procedures with mesh.

Evaluation of Viremia Frequencies of a Novel Human Pegivirus by Using Bioinformatic Screening and PCR.

Next-generation sequencing has critical applications in virus discovery, diagnostics, and environmental surveillance. We used metagenomic sequence libraries for retrospective screening of plasma samples for the recently discovered human hepegivirus 1 (HHpgV-1). From a cohort of 150 hepatitis C virus (HCV)-positive case-patients, we identified 2 persons with HHpgV-1 viremia and a high frequency of human pegivirus (HPgV) viremia (14%). Detection of HHpgV-1 and HPgV was concordant with parallel PCR-based screening using conserved primers matching groups 1 (HPgV) and 2 (HHPgV-1) nonstructural 3 region sequences. PCR identified 1 HHPgV-1-positive person with viremia from a group of 195 persons with hemophilia who had been exposed to nonvirally inactivated factor VII/IX; 18 (9%) were HPgV-positive. Relative to HCV and HPgV, active infections with HHpgV-1 were infrequently detected in blood, even in groups that had substantial parenteral exposure. Our findings are consistent with lower transmissibility or higher rates of virus clearance for HHpgV-1 than for other bloodborne human flaviviruses.

Interaction of rabies virus P-protein with STAT proteins is critical to lethal rabies disease.

BACKGROUND: Rabies virus (RABV) causes rabies disease resulting in >55,000 human deaths/year. The multifunctional RABV P-protein has essential roles in genome replication, and forms interactions with cellular STAT proteins that are thought to underlie viral antagonism of interferon-dependent immunity. However, the molecular details of P-protein-STAT interaction, and its importance to disease are unresolved. METHODS: Studies were performed using sequence/structure analysis, mutagenesis, immunoprecipitation, luciferase and qRT-PCR-based signaling assays, confocal microscopy and reverse genetics/in vivo infection. RESULTS: We identified a hydrophobic pocket of the P-protein C-terminal domain as critical to STAT-binding/antagonism. This interface was found to be functionally and spatially independent of the region responsible for N-protein interaction, which is critical to genome replication. Based on these findings, we generated the first mutant RABV lacking STAT-association. Growth of the virus in vitro was unimpaired, but it lacked STAT-antagonist function and was highly sensitive to interferon. Importantly, growth of the virus was strongly attenuated in brains of infected mice, producing no major neurological symptoms, compared with the invariably lethal wild-type virus. CONCLUSIONS: These data represent direct evidence that P-protein-STAT interaction is critical to rabies, and provide novel insights into the mechanism by which RABV coordinates distinct functions in interferon antagonism and replication.

Examining mechanisms of brain control of bladder function with resting state functional connectivity MRI.

AIMS: This aim of this study is to identify the brain mechanisms involved in bladder control. METHODS: We used fMRI to identify brain regions that are activated during bladder filling. We then used resting state connectivity fMRI (rs-fcMRI) to assess functional connectivity of regions identified by fMRI with the rest of the brain as the bladder is filled to capacity. RESULTS: Female participants (n = 20) were between ages 40 and 64 with no significant history of symptomatic urinary incontinence. Main effect of time (MET) fMRI analysis resulted in 20 regions of interest (ROIs) that have significant change in BOLD signal (z = 3.25, P <0.05) over the course of subtle bladder filling and emptying regardless of full versus empty bladder state. Bladder-state by time (BST) fMRI analysis resulted in three ROIs that have significant change in BOLD signal (z = 3.25, P <0.05) over the course of bladder runs comparing full versus empty bladder state. Rs-fcMRI fixed effects analysis identified significant changes in connectivity between full and empty bladder states in seven brain regions (z = 4.0) using the three BST ROIs and sixteen brain regions (z = 7) using the twenty MET ROIs. Regions identified include medial frontal gyrus, posterior cingulate (PCC), inferiolateral temporal and post-central gyrus, amygdale, the caudate, inferior parietal lobe as well as anterior and middle cingulate gyrus. CONCLUSIONS: There is significant and vast changes in the brain's functional connectivity when bladder is filled suggesting that the central process responsible for the increased control during the full bladder state appears to largely rely on the how distributed brain systems are functionally integrated.

Scalable interpolation of satellite altimetry data with probabilistic machine learning.

We present GPSat; an open-source Python programming library for performing efficient interpolation of non-stationary satellite altimetry data, using scalable Gaussian process techniques. We use GPSat to generate complete maps of daily 50 km-gridded Arctic sea ice radar freeboard, and find that, relative to a previous interpolation scheme, GPSat offers a 504 × computational speedup, with less than 4 mm difference on the derived freeboards on average. We then demonstrate the scalability of GPSat through freeboard interpolation at 5 km resolution, and Sea-Level Anomalies (SLA) at the resolution of the altimeter footprint. Interpolated 5 km radar freeboards show strong agreement with airborne data (linear correlation of 0.66). Footprint-level SLA interpolation also shows improvements in predictive skill over linear regression. In this work, we suggest that GPSat could overcome the computational bottlenecks faced in many altimetry-based interpolation routines, and hence advance critical understanding of ocean and sea ice variability over short spatio-temporal scales.

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.

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.

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.

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.