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MLKL and RIPK3 are the core signaling proteins of the inflammatory cell death pathway, necroptosis, which is a known mediator and modifier of human disease. Necroptosis has been implicated in the progression of disease in almost every physiological system and recent reports suggest a role for necroptosis in aging. Here, we present the first comprehensive analysis of age-related histopathological and immunological phenotypes in a cohort of Mlkl–/– and Ripk3–/– mice on a congenic C57BL/6 J genetic background. We show that genetic deletion of Mlkl in female mice interrupts immune system aging, specifically delaying the age-related reduction of circulating lymphocytes. -Seventeen-month-old Mlkl–/– female mice were also protected against age-related chronic sterile inflammation in connective tissue and skeletal muscle relative to wild-type littermate controls, exhibiting a reduced number of immune cell infiltrates in these sites and fewer regenerating myocytes. These observations implicate MLKL in age-related sterile inflammation, suggesting a possible application for long-term anti-necroptotic therapy in humans.

Objectives The assessment of physical function is fundamental in the management of patients with idiopathic inflammatory myopathies (IIMs). We aimed to investigate the physical function of patients with IIMs compared with those with non-IIM autoimmune rheumatic diseases (AIRDs) utilizing Patient-Reported Outcome Measurement Information System (PROMIS) Physical Function (PF) data obtained in the COVAD study, an international self-reported e-survey assessing the safety of COVID-19 vaccines in AIRDs. Methods Demographics, AIRD diagnosis, disease activity, and PROMIS PF short form-10a data were extracted from the COVAD database. PROMIS PF-10a scores were compared between disease categories and stratified by disease activity. Factors affecting PROMIS PF-10a scores other than disease activity were identified by multivariable regression analysis in patients with inactive disease. Results A total of 1057 IIM patients, 3635 non-IIM AIRD patients and 3981 healthy controls (HCs) responded to the COVAD e-survey from April to August 2021. Using a binomial regression model, the predicted mean of PROMIS PF-10a scores was significantly lower in IIM patients compared with non-IIM AIRD patients or HCs [36.3 (95% CI 35.5, 37.1) vs 41.3 (95% CI 40.2, 42.5) vs 46.2 (95% CI 45.8, 46.6), P Conclusion Physical function is significantly impaired in IIMs compared with non-IIM AIRDs or HCs, even in patients with inactive disease. Our study highlights a critical need for better strategies to minimize functional disability in patients with IIMs.

Medical personnel play a critical role in caregiver safe infant sleep education. However, training outcomes in the safe infant sleep training literature have been mixed. Promising approaches that warrant further investigation are the use of behavioral skills training and pyramidal training. The current study consisted of two experiments. Experiment 1 extended Carrow et al. (2020) and Vladescu et al. (2020) by teaching medical students safe infant sleep practices using behavioral skills training. Discriminated responding was examined across trained and untrained environmental arrangements using a multiple-baseline design. All participants arranged safe sleep environments following behavioral skills training. In Experiment 2, we used pyramidal behavioral skills training to train medical students to teach others safe sleep practices. Results indicated high procedural integrity scores following training and generalization of skills.

Cardiovascular involvement in idiopathic inflammatory myopathies (IIM) is an understudied area which is gaining increasing recognition in recent times. Recent advances in imaging modalities and biomarkers have allowed the detection of subclinical cardiovascular manifestations in IIM. However, despite the availability of these tools, the diagnostic challenges and underestimated prevalence of cardiovascular involvement in these patients remain significant. Notably, cardiovascular involvement remains one of the leading causes of mortality in patients with IIM. In this narrative literature review, we outline the prevalence and characteristics of cardiovascular involvement in IIM. Additionally, we explore investigational modalities for early detection of cardiovascular involvement, as well as newer approaches in screening to facilitate timely management. Key points• Cardiac involvement in IIM in majority cases is subclinical and a major cause of mortality.• Cardiac magnetic resonance imaging is sensitive for detection of subclinical cardiac involvement.

To reduce sleep-related infant deaths, the American Academy of Pediatrics (AAP) has identified safe infant sleep recommendations; however, it is unclear which training strategies to teach safe infant sleep practices are most effective. Since the AAP released updated safe sleep recommendations in 2016, no analysis of the safe infant sleep training literature has been conducted. The purpose of the present review was to evaluate the safe infant sleep training literature of relevant populations such as caregivers and medical personnel, and provide recommendations for future research. The overall efficacy of training strategies was found to be positive or mixed where experiments most commonly implemented an educational session, followed by use of instructional materials, distribution of safe materials, and hospital-wide policy change. Methodological limitations were also identified.

COVID-19; Registries; Vaccination COVID-19; Registros; Vacunación COVID-19; Registres; Vacunació Vaccine hesitancy is considered a major barrier to achieving herd immunity against COVID-19. While multiple alternative and synergistic approaches including heterologous vaccination, booster doses, and antiviral drugs have been developed, equitable vaccine uptake remains the foremost strategy to manage pandemic. Although none of the currently approved vaccines are live-attenuated, several reports of disease flares, waning protection, and acute-onset syndromes have emerged as short-term adverse events after vaccination. Hence, scientific literature falls short when discussing potential long-term effects in vulnerable cohorts. The COVAD-2 survey follows on from the baseline COVAD-1 survey with the aim to collect patient-reported data on the long-term safety and tolerability of COVID-19 vaccines in immune modulation. The e-survey has been extensively pilot-tested and validated with translations into multiple languages. Anticipated results will help improve vaccination efforts and reduce the imminent risks of COVID-19 infection, especially in understudied vulnerable groups. HC is supported by the National Institution for Health Research Manchester Biomedical Research Centre Funding Scheme. The views expressed in this publication are those of the authors and not necessarily those of the NHS, the National Institute for Health Research or the Department of Health.

Objectives The COVID-19 vaccination in autoimmune diseases (COVAD) study aimed to assess short-term COVID-19 vaccination-related adverse events (AEs) in RA patients. Methods An online self-reported questionnaire (March–December 2021) was used to capture data related to COVID-19 vaccination-related AEs in RA, other autoimmune rheumatic diseases (AIRDs) (excluding RA and inflammatory myositis), non-rheumatic autoimmune diseases (nrAIDs) and healthy controls (HCs). Descriptive and multivariable regression analyses were performed. Results Of the 9462 complete respondents, 14.2% (n = 1347) had been diagnosed with RA; they had a mean (s.d.) age of 50.7 (13.7) years, 74.2% were women and 49.3% were Caucasian. In total, 76.9% and 4.2% of patients with RA reported minor and major AEs, respectively. Patients with active and inactive RA had similar AE and hospitalization frequencies. Overall, AEs were reported more frequently by BNT162b2 and mRNA-1273 recipients and less frequently by BBV152 recipients compared with the rest. Major AE and hospitalization frequencies were similar across recipients of different vaccines. Patients receiving methotrexate and hydroxychloroquine reported fewer minor AEs than those patients not on them. Compared with HCs and patients with other AIRDs, patients with RA reported similar total AEs, overall minor AEs, and hospitalizations. Compared with nrAIDs, patients with RA reported lower frequencies of overall AEs, minor AEs (both odds ratio [OR] = 0.7; 95% CI: 0.5, 0.9), and injection site pain (OR = 0.6; 95% CI: 0.5, 0.8) with similar major AE and hospitalization frequencies. Conclusion Despite the differences in AE frequency across different COVID-19 vaccines, all were well tolerated in patients with RA and were comparable to HCs, providing reassurance as to the safety of COVID-19 vaccination.

Positron emission tomography (PET), often combined with computed tomography (CT), is a well-established tool for diagnosing malignancy and inflammatory disease. The idiopathic inflammatory myopathies (IIM) are chronic, multi-system diseases characterised by skeletal muscle inflammation, the potential for extramuscular manifestations such as interstitial lung disease (ILD) and an increased risk of malignancy. We performed a systematic literature review to evaluate the utility of PET or PET-CT in evaluation of IIM.A search of Medline and EMBASE from 1990 to 2022 using keywords related to IIM and PET was performed. English language studies of adults with IIM who had PET or PET-CT were included.Our search identified 1173 potentially relevant abstracts, 19 of which were included. The majority of studies used [18F] fluorodeoxyglucose (FDG) PET or PET-CT scans, while the remainder used [18F] florbetapir and [PET-CT holds promise as a single tool that can simultaneously evaluate multiple aspects of IIM. These include screening for associated malignancy, achieving an early diagnosis of ILD and evaluating muscle inflammation.

Both Legionella pneumophila and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can cause pneumonia. L. pneumophila is acquired from water sources, sometimes in healthcare settings. We report 2 fatal cases of L. pneumophila and SARS-CoV-2 co-infection in England. Clinicians should be aware of possible L. pneumophila infections among SARS-CoV-2 patients.

Open skeletal muscle biopsy has been the mainstay of sample retrieval in patients with suspected muscle diseases. However, this technique is limited by surgeon and theatre availability, potentially resulting in delayed diagnosis and increasing hospital stay.To compare the effectiveness and timeliness of ultrasound guided 14-gauge needle percutaneous muscle biopsy in comparison with open biopsy.We performed a retrospective chart review on 19 inpatients who underwent ultrasound-guided percutaneous muscle biopsy using a 14-gauge needle and 19 consecutive inpatients who underwent open surgical muscle biopsy between January 2017 and June 2019. Patient demographics, length of stay, biopsy sample size and the correlation between histological and clinical diagnosis were compared between groups.The median age of both groups was 64 years. Seventy-nine percent of surgical patients were female compared with 58% who had percutaneous biopsy. Surgical biopsies yielded larger samples (median 864 mmUltrasound guided percutaneous muscle biopsies were performed faster and a wider range of muscles were targeted. However, this technique yielded smaller samples, which were non-diagnostic in 26% of cases. Increasing the needle gauge or number of passes may improve the diagnostic yield of this technique.

Objectives COVID-19 vaccines have been proven to be safe in the healthy population. However, gaps remain in the evidence of their safety in patients with systemic autoimmune and inflammatory disorders (SAIDs). COVID-19 vaccination-related adverse events (AEs) in patients with SAIDs and healthy controls (HC) seven days post-vaccination were assessed in the COVAD study, a patient self-reported cross-sectional survey. Methods The survey was circulated in early 2021 by >110 collaborators (94 countries) to collect SAID details, COVID-19 vaccination details and 7-day vaccine AEs, irrespective of respondent vaccination status. Analysis was performed based on data distribution and variable type. Results Ten thousand nine hundred respondents [median (interquartile range) age 42 (30–55) years, 74% females and 45% Caucasians] were analysed; 5867 patients (54%) with SAIDs were compared with 5033 HCs. Seventy-nine percent had minor and only 3% had major vaccine AEs requiring urgent medical attention (but not hospital admission) overall. Headache [SAIDs = 26%, HCs = 24%; odds ratio (OR) = 1.1 (95% CI: 1.03, 1.3); P = 0.014], abdominal pain [SAIDs = 2.6%, HCs = 1.4%; OR = 1.5 (95% CI: 1.1, 2.3); P = 0.011], and dizziness [SAIDs = 6%, HCs = 4%; OR = 1.3 (95% CI: 1.07, 1.6); P = 0.011], were slightly more frequent in SAIDs. Overall, major AEs [SAIDs = 4%, HCs = 2%; OR = 1.9 (95% CI: 1.6, 2.2); P Conclusion Vaccination against COVID-19 is safe in SAID patients. SAIDs were at a higher risk of major AEs than HCs, though absolute risk was small. There are small differences in minor AEs between vaccine types in SAID patients.

Objectives To determine the prevalence and associations of autoantibodies targeting a muscle-specific autoantigen, four-and-a-half-LIM-domain 1 (FHL1), in South Australian patients with histologically-confirmed idiopathic inflammatory myopathies (IIM) and in patients with SSc. Material and methods Sera from patients with IIM (n = 267) from the South Australian Myositis Database (SAMD), SSc (n = 174) from the Australian Scleroderma Cohort Study (ASCS) and healthy controls (HC, n = 100) were analysed for anti-FHL1 autoantibodies by Enzyme-Linked ImmunoSorbent Assay (ELISA). Results Autoantibodies to FHL1 were more frequent in patients with IIM (37/267, 13.8%) compared with SSc (12/174, 7%) (P Conclusions We report a substantial prevalence (13.8%) of anti-FHL1 autoantibodies in a large cohort of patients with histologically confirmed IIM; 75% of these cases did not have a detectable myositis-specific autoantibody. Anti-FHL1 autoantibodies were also detected in a subgroup of patients with SSc (7%), indicating that anti-FHL1 autoantibodies may not be myositis-specific. The trend towards an HLA-DR association might indicate a specific immune response to the FHL1 protein.

Annually, thousands of infant deaths are classified as sudden unexpected infant deaths (SUIDs). In an effort to reduce the risk of SUIDs, the American Academy of Pediatrics has made a number of recommendations to educate caregivers, childcare providers, and healthcare professionals on safe infant sleep practices. The purpose of the current study was to extend the literature on safe infant sleep practices by teaching caregivers to arrange safe infant sleep environments using a mannequin and common infant items. We partnered with community-based agencies to evaluate the effectiveness of behavioral skills training delivered in a single training session as part of the ongoing pre- or postnatal care these agencies provided. Following training, all participants demonstrated a substantial change in responding and returned favorable social validity ratings. We discuss these outcomes in light of previous studies, limitations, and future directions.

Immune-mediated necrotising myopathy (IMNM) is a recently described entity. We describe a cohort of South Australian IMNM patients in order to define the spectrum of disease, characterise features that distinguish IMNM from other idiopathic inflammatory myopathy (IIM) subtypes and identify factors associated with clinically severe disease. Subjects were identified from the South Australian Myositis Database(SAMD), a histologically defined registry. Consecutive muscle sections from patients with IMNM (n=62), other forms of IIM (n=60) and histologically normal muscle (n=17) were stained using immunohistochemistry and graded. Clinical information was collected from the SAMD and through retrospective chart review. IMNM patients displayed clinical and histological heterogeneity. While most (67%) were profoundly weak at presentation, 24% exhibited mild to moderate weakness and 9% had normal power. Histological myonecros is ranged from minor to florid. The amount of myofibre complement deposition was closely associated with clinical severity. Patients of Aboriginal and Torres Strait Islander heritage and those with anti-SRP auto antibodies present with a severe phenotype. Despite intense immunotherapy,few IMNM patients recovered full power at one year follow up. The identification of clinical, serological and histological features which are associated with severe forms of the disease may have diagnostic and therapeutic utility. Refereed/Peer-reviewed

Immune-mediated necrotising myopathy (IMNM)is a relatively recently described form of idiopathic inflammatory myopathy (IIM)that is characterised by progressive proximal weakness and few extra-muscular manifestations. Prominent myonecrosis, muscle fibre regeneration and a relative paucity of intramuscular lymphocytes are seen histologically. Immunological mechanisms are believed to underpin the pathogenesis, and intense immunotherapy is frequently required. Disease is often severe and neuromuscular recovery may be poor. Recently there has been an impressive international research effort to understand and characterise this emerging condition, although much remains unknown. Significant advances in the field include the discovery of specific autoantibodies, increased understanding of the risk factors, clinical characteristics and treatment options owing to a wealth of observational studies, and the development of novel classification criteria. Herein we review the current evidence regarding the pathophysiology, clinical presentation, histological features and serological profiles associated with this condition. Diagnostic approaches are discussed, including the role of muscle MRI and antibodies targeting 3‑hydroxy-3-methylglutaryl-CoA reductase (HMGCR)and signal-recognition peptide (SRP), and a review of current treatment recommendations is provided Refereed/Peer-reviewed

Objective Recent advances in cardiac MRI (CMR) and other diagnostic techniques have made it easier to identify subclinical cardiac inflammation and dysfunction in the idiopathic inflammatory myopathies (IIM). Herein, we systematically review the literature regarding cardiac involvement in IIM. Methods We searched Medline and EMBASE from 1990 to 2020 using keywords related to IIM and cardiac disease. We included English language studies in adults with any immune-mediated, inflammatory muscle pathology. Results We identified 10 425 potentially relevant abstracts, of which 29 were included. Most frequently these included patients with PM or DM without symptomatic myocarditis. Five categories of cardiac investigation were used in these patients: cardiac enzyme testing, ECG, transthoracic echocardiography, CMR and nuclear medicine testing. Patients with clinical myocarditis had universally abnormal cardiac troponin levels and ECG. Elevated cardiac troponin T was more common than cardiac troponin I and may correlate with disease activity, whereas cardiac troponin I was more specific for cardiac involvement. Non-specific ECG changes were common. The major finding on transthoracic echocardiography was abnormal ejection fraction. Gross systolic dysfunction was unusual, but subclinical systolic dysfunction was reported in several studies. Abnormal diastolic function was common and may be associated with disease duration. Late gadolinium enhancement (reflecting regional necrosis or scarring) and abnormal myocardial mapping parameters (reflecting myocardial inflammation, fibrosis and oedema) were frequently identified on CMR, suggesting significant subclinical myocardial pathology (despite typically normal ejection fraction). Conclusion Abnormal cardiac investigations are commonly found in asymptomatic IIM patients, which has potential prognostic and treatment implications.

This study evaluated the effectiveness of an adaptive, computer-based staff training software program called Train-to-Code (TTC) to teach the administration of a social skills intervention. The software program actively trained participants to identify whether video models illustrated each step of the procedure effectively or ineffectively. Multiple exemplars of each step of the social skills task analysis were represented. Most-to-least prompting as well as feedback and error correction were embedded into the software program and prompts were faded through seven levels as the participant reached criterion accuracy. A multiple-probe across participants design was used to evaluate the effectiveness of this program by comparing pre- and post-training in vivo probes conducted with a confederate learner. All participant scores increased from pre-training to post-training, indicating that Train-to-Code was effective at teaching administration of the social skills intervention. These results have implications for training staff in applied community settings. Due to Train-to-Code’s ability to be internet-based and to measure actual viewing performance, it has the potential for “distance training” deliveries.

Objective To externally validate the European League Against Rheumatism/American College of Rheumatism (EULAR/ACR) classification criteria for idiopathic inflammatory myositis (IIM) and determine the optimal cut points for Australian patients. To determine the level of agreement with traditional criteria and assess the effect of including magnetic resonance imaging (MRI) and an extended myositis antibody panel as well as extending histological criteria to include myofiber invasion. Methods Data were collected on adult patients referred for muscle biopsy to two Australian teaching hospitals. Patients were scored for "risk of IIM" according to EULAR/ACR criteria, using clinician diagnosis as the gold standard. Results Overall, 87 of 204 patients had IIM. For patients with muscle biopsy, the optimal cut point of 5.25 (sensitivity 90%, specificity 89%) was lower than the EULAR/ACR cut point of 6.7, which in our cohort showed reduced sensitivity (71% vs 93%) but comparable specificity (89% vs 88%). We found moderate agreement between the EULAR/ACR criteria and Bohan and Peter (κ = 0.45, 95% confidence interval [CI] = 0.28, 0.62, P < 0.001) and Targoff (κ = 0.40, 95% CI = 0.23, 0.57, P < 0.001). Inclusion of MRI (area under curve [AUC] = 0.86, 95% CI = 0.79, 0.93) or non-Jo1 antibodies (AUC = 0.84, 95% CI = 0.77, 0.91) as covariates improved the probability of IIM diagnosis (AUC = 0.80, 95% CI = 0.75, 0.86). Extending histologic criteria to include myofiber invasion slightly improved sensitivity (75% vs 71%) with the same level of specificity (89% vs 89%). Conclusion Application of the EULAR/ACR criteria to an Australian cohort showed comparable specificity but lower sensitivity, and a lower optimal cut point. Inclusion of MRI or non-Jo1 antibodies as covariates may improve the accuracy of determining the probability of IIM diagnoses. Extending the histologic criteria to include myofiber invasion did not reduce specificity.

Natural killer (NK) cells are a specialised population of innate lymphoid cells (ILCs) that help control local immune responses. Through natural cytotoxicity, production of cytokines and chemokines, and migratory capacity, NK cells play a vital immunoregulatory role in the initiation and chronicity of inflammatory and autoimmune responses. Our understanding of their functional differences and contributions in disease settings is evolving owing to new genetic and functional murine proof‐of‐concept studies. Here, we summarise current understanding of NK cells in several classic autoimmune disorders, particularly in rheumatoid arthritis (RA), multiple sclerosis (MS), systemic lupus erythematosus (SLE) and type 1 diabetes mellitus (T1DM), but also less understood diseases such as idiopathic inflammatory myopathies (IIMs). A better understanding of how NK cells contribute to these autoimmune disorders may pave the way for NK cell‐targeted therapeutics., In this review, we summarise current understanding of NK cells in several classic autoimmune disorders, particularly in rheumatoid arthritis (RA), multiple sclerosis (MS), systemic lupus erythematosus (SLE) and type 1 diabetes mellitus (T1DM), but also less understood diseases such as idiopathic inflammatory myopathies. We also discuss how a better understanding of the contribution of NK cells to these autoimmune disorders may pave the way for NK cell‐targeted therapeutics.