EMC is required for biogenesis of Xport-A, an essential chaperone of Rhodopsin-1 and the TRP channel.

The ER membrane protein complex (EMC) is required for the biogenesis of a subset of tail anchored (TA) and polytopic membrane proteins, including Rhodopsin-1 (Rh1) and the TRP channel. To understand the physiological implications of EMC-dependent membrane protein biogenesis, we perform a bioinformatic identification of Drosophila TA proteins. From 254 predicted TA proteins, screening in larval eye discs identified two proteins that require EMC for their biogenesis: fan and Xport-A. Fan is required for male fertility in Drosophila and we show that EMC is also required for this process. Xport-A is essential for the biogenesis of both Rh1 and TRP, raising the possibility that disruption of Rh1 and TRP biogenesis in EMC mutants is secondary to the Xport-A defect. We show that EMC is required for Xport-A TMD membrane insertion and that EMC-independent Xport-A mutants rescue Rh1 and TRP biogenesis in EMC mutants. Finally, our work also reveals a role for Xport-A in a glycosylation-dependent triage mechanism during Rh1 biogenesis in the endoplasmic reticulum.

Breakthrough SARS-CoV-2 infection and disease flares in patients with rheumatoid arthritis: result from COVAD e-survey study.

COVID-19 has been suggested as a possible trigger of disease flares in patients with rheumatoid arthritis (RA). However, factors associated with disease flares remain unknown. This study aimed to identify factors associated with breakthrough infection (BIs) and disease flares in patients with RA following COVID-19. We analysed data from RA patients who participated in the COVID-19 vaccination in autoimmune diseases (COVAD) study. Demographic data, patient-reported outcomes, comorbidities, pharmacologic treatment and details regarding disease flares were extracted from the COVAD database. Factors associated with disease flare-ups were determined by multivariate logistic regression analysis. The analysis comprised 1928 patients with RA who participated in the COVAD study. Younger age, Caucasian ethnicity, comorbidities with obstructive chronic pulmonary disease and asthma were associated with COVID-19 breakthrough infection. Moreover, younger age (odds ratio (OR): 0.98, 95% CI 0.96-0.99, p < 0.001), ethnicity other than Asian, past history of tuberculosis (OR: 3.80, 95% CI 1.12-12.94, p = 0.033), treatment with methotrexate (OR: 2.55, 95% CI: 1.56-4.17, p < 0.001), poor global physical health (OR: 1.07, 95% CI 1.00-1.15, p = 0.044) and mental health (OR: 0.91, 95% CI 0.87-0.95, p < 0.001) were independent factors associated disease flares in patients with RA. Our study highlights the impact of socio-demographic factors, clinical characteristics and mental health on disease flares in patients with RA. These insights may help determine relevant strategies to proactively manage RA patients at risk of flares.

Dose-response and efficacy of 904 nm photobiomodulation on diabetic foot ulcers healing: a randomized controlled trial.

PURPOSE: This study aimed to examine the impact of a 904 nm photobiomodulation (PBM) on diabetic ulcers using varying dosages. METHODS: The study was a randomized, double-blind, placebo-controlled clinical trial that compared treatments using PBM (GaAs 904 nm 30w) with three different energy densities (4 J/cm2; 8 J/cm2; 10 J/cm2) in the healing process of non-infected diabetic foot ulcers. Eighty volunteers (48.75% female; 58.5 ± 11.1 years) were randomized into three intervention groups treated with PBM and one control group (PBM placebo). Volunteers performed up 20 interventions with PBM, either placebo or actual, in conjunction with conventional therapy, which involved dressing the wound with Helianthus annuus vegetable oil. The primary variable was the ulcer size reduction rate. RESULTS: GaAs 904 nm PBM yielded a clinically and significant ulcer size rate reduction of diabetic foot ulcers, independently of energy density range (p < 0.05). However, 10 J/cm² had 60% of completely healed ulcers and the highest proportion of patients reaching 50% of ulcer reduction rate after 5 weeks of treatment. In addition, only 10 J/cm² showed a significant difference between control group after a 10-week follow-up (p < 0.05). CONCLUSION: GaAs 904 nm PBM was effective in treating diabetic foot ulcers in this study and a dosage of 10 J/cm², after a 10-week follow-up, proved to be the most effective compared to the other groups. CLINICAL TRIAL REGISTRATION NUMBER: NCT04246814.

Polyautoimmunity in systemic lupus erythematosus: secondary Sjogren syndrome.

BACKGROUND: Sjogren's syndrome (SS) is a chronic autoimmune disease characterized by lymphocytic infiltration of the exocrine glands. It can be associated with other connective tissue diseases, including systemic lupus erythematosus (SLE). OBJECTIVE: This study aimed to determine the incidence of secondary SS (sSS) in patients diagnosed with SLE (SLE-SS) and compare the clinical and serological features of SLE-SS to SLE only. METHODS: A retrospective observational study including patients diagnosed with SLE (SLICC criteria) seen at the Rheumatology Department between 1990 and 2020 was performed. A total of 453 SLE patients were assessed for fulfilment of the criteria for SS using the European questionnaire and Schirmer test, fluorescein staining/non-stimulated whole-salivary flow, anti-Ro/La antibodies, and lip biopsy. Anti-Ro/SSA and anti-La/SSB antibodies and rheumatoid factor (RF) were measured at entry and at SS assessment. SLE-SS was defined according to the American-European Consensus Criteria (AECC). SLE-SS was defined as a case that initially only fulfilled SLE classification criteria but which exhibited disease progression during follow-up and then met classification criteria for sSS. RESULTS: SLE-SS occurred in 11% of the SLE patients. In comparison to SLE-only patients, the SLE-SS group was older at inclusion and onset, and had a longer disease course. Sicca syndrome, oral ulcers, pulmonary involvement, and peripheral neuropathy were more frequent. Anti-SSA, anti-SSB, RF, and total IgG were higher in the SLE-SS group. CONCLUSION: SLE-SS appears to be a subgroup of patients with distinct clinical and serologic features. The frequency of SLE-SS increases with age. Patients with SLE-SS have a higher frequency of oral ulcers, anti-Ro and anti-La antibodies, and a lower frequency of renal disease, anti-dsDNA antibodies, anti-SM, and lower C3 and C4 hypocomplementemia.

Factors Associated With Adverse Outcomes in Uveitis Related to Spondyloarthritis: Development of an Outcome Score (SpA-U).

BACKGROUND: Evaluating the efficacy and refractoriness to treatment and determining factors associated with adverse outcomes in uveitis associated with spondylarthritis (SpA) are complicated by the lack of validated outcome measures. OBJECTIVES: The aims of this study were to develop an outcome score SpA-U in patients with uveitis associated with SpA and to determine factors associated with adverse outcomes in patients with uveitis under systemic treatment. METHODS: The outcome score SpA-U was defined by best-corrected visual acuity, anterior chamber inflammation, macular edema and inflammation of posterior chamber, global assessment, and refractoriness to treatment. Factors associated with adverse outcomes in uveitis were studied using linear regression. For categorical factors, marginal averages and their SEs are displayed together with linear regression coefficients with 95% confidence intervals. For continuous factors, averages and SDs are reported in addition to linear regression coefficients with 95% confidence interval. Two regression coefficients are reported for each variable: unadjusted and adjusted for age at diagnosis and sex. RESULTS: One hundred ninety-seven uveitis outbreaks were included. Sixty-two uveitis outbreaks (31%) were classified as severe, 42 as moderate (21%), and 93 as mild (47%) based on the definition and construction of outcome score. The results of the linear regression model revealed that the uveitis activity was more severe in patients with smoking history ( ß = 0.34), axial and peripheral involvement ( ß = 0.43), Ankylosing Spondylitis Disease Activity Score >2.1 ( ß = 0.45), positive HLA-B27 ( ß = 0.29), female sex ( ß = 0.19), patients with C-reactive protein elevation ( ß = 0.002), and bilateral ocular involvement ( ß = 0.32). At the same time, shorter disease evolution ( ß = -0.02) was associated with less severe uveitis activity. CONCLUSION: We have determined factors associated with adverse outcomes in patients with uveitis associated with SpA by developing an outcome score SpA-U that integrates ocular inflammatory activity, visual acuity, global assessment, and refractoriness to treatment.

Anti-TNF-α-induced lupus syndrome : Two case reports and review of current literature.

Anti-tumor necrosis factor­α (TNF-α)-induced lupus (ATIL) represents a diagnostic and treatment challenge. Most cases are caused by infliximab and in some cases by etanercept and adalimumab. Symptoms can range from cutaneous manifestations to more rare and serious conditions. Diagnosis requires a temporal relationship between symptoms and positive autoantibody determination. Arthritis and cutaneous symptoms are the most common manifestations accompanied by positive antinuclear antibody (ANA) and anti-double strand DNA (dsDNA) determinations. The etiology of ATILS remains to be definitively established. Several mechanisms have been proposed for anti-TNF-α-induced lupus, including apoptosis, immunosuppression and humoral autoimmunity. Treatment includes discontinuation of anti-TNF­α agents and in some cases corticosteroids and immunosuppressors. Questions to be answered: (1) Are soluble TNF receptor fusion proteins such as etanercept and anti-TNF chimeric antibodies equally likely to cause ATIL? (2) Can patients with ATIL switch from one anti-TNF­α antagonist to another? (3) Can the concurrent use of a conventional synthetic disease-modifying antirheumatic drug (csDMARD) like methotrexate or hydroxychloroquine reduce the probability of ATIL?

Chiral Drug Analysis in Forensic Chemistry: An Overview.

Many substances of forensic interest are chiral and available either as racemates or pure enantiomers. Application of chiral analysis in biological samples can be useful for the determination of legal or illicit drugs consumption or interpretation of unexpected toxicological effects. Chiral substances can also be found in environmental samples and revealed to be useful for determination of community drug usage (sewage epidemiology), identification of illicit drug manufacturing locations, illegal discharge of sewage and in environmental risk assessment. Thus, the purpose of this paper is to provide an overview of the application of chiral analysis in biological and environmental samples and their relevance in the forensic field. Most frequently analytical methods used to quantify the enantiomers are liquid and gas chromatography using both indirect, with enantiomerically pure derivatizing reagents, and direct methods recurring to chiral stationary phases.

Cardiovascular disease in patients with systemic autoimmune diseases: The relationship between self-perceived risk and actual risk.

INTRODUCTION: Autoimmune diseases are known to be associated with an elevated risk of cardiovascular diseases; however, there exists a lack of awareness regarding this increased risk among patients. OBJECTIVE: This study aimed to assess the prevalence of cardiovascular risk factors and events in various systemic autoimmune diseases, including Systemic Sclerosis (SSc), Systemic Lupus Erythematosus (SLE), Rheumatoid Arthritis (RA), and Sjögren's syndrome (SS), matched by age, sex, and disease duration. Additionally, the study aimed to evaluate the perceived and actual risks of cardiovascular disease among patients. METHODS: A cross-sectional self-reported survey on the patient's perspective of cardiovascular risk was conducted between January and June 2023. Sociodemographic and clinical data, including disease activity, were collected through medical records and questionnaires. Traditional cardiovascular risk factors and events were assessed, alongside the perceived cardiovascular risk. The SCORE calculation and Charlson Comorbidity Index (CCI) were employed for cardiovascular risk assessment. RESULTS: Survey responses from 180 patients (45 patients each with SSc, SLE, RA, and SS) with systemic autoimmune diseases revealed that 20% perceived a low risk, 23% perceived neither lower nor higher, and 56% perceived a higher risk of developing cardiovascular diseases in the next ten years. Only 45% agreed that their autoimmune disease could increase the risk of a heart attack, even in the absence of other risk factors, and 46.7% were unaware that NSAIDs pose a cardiovascular risk. An association between cardiovascular risk measured by SCORE, comorbidities, and risk perception was observed in RA, SSc, and SS patients, with no association found in SLE patients (p=0.27). Except for SS patients (p=0.02), no association between CCI and disease activity level was found. Regarding the influence of age, working status, and education in CVD risk perception, an association between CVD risk perception and age was observed (p=0.01), with patients over 40 years exhibiting a higher perception of CVD risk. No differences were found regarding working status (p=0.19) nor education level (p=0.06). CONCLUSIONS: Patients with SS, RA, and SSc displayed a heightened perception of cardiovascular risk, correlating with their actual risk and preexisting comorbidities. However, patients exhibited unawareness of certain cardiovascular risk behaviors. This underscores the need for tailored education programs on cardiovascular risk for autoimmune disease patients, to be implemented at the time of diagnosis and during follow-up in outpatient clinics.

KL6 and IL-18 levels are negatively correlated with respiratory function tests and ILD extent assessed on HRCT in patients with systemic sclerosis-related interstitial lung disease (SSc-ILD).

BACKGROUND: Interstitial lung disease (ILD) is one of the leading causes of mortality in patients with systemic sclerosis (SSc). Serum biomarkers have been suggested as indicators for pulmonary damage with clinical value in the diagnosis and prognosis of SSc-ILD. OBJECTIVES: To investigate the role of serum biomarkers (Krebs von den Lungen-6 KL-6, IL-18 and IL-18BP) as a potential biomarker reflecting the severity of SSc-ILD as assessed through high-resolution computed tomography (HRCT) and pulmonary function tests (PFT), including forced vital capacity (%FVC) and diffusing capacity of the lung for carbon monoxide (%DLCO). METHODS: A cross-sectional study including patients with SSc fulfilling the 2013 ACR/EULAR criteria was performed. Patients were classified according to disease duration and pulmonary involvement (presence of ILD). All SSc patients underwent chest HRCT scans and pulmonary function test at baseline. Serum concentration of KL-6, IL8 and IL18BP were determined using the quantitative ELISA technique, sandwich type (solid phase sandwich Enzyme Linked-Immuno-Sorbent Assay), with kits from MyBiosource for KL-6 and from Invitrogen for IL18 and IL18BP. A semiquantitative grade of ILD extent was evaluated through HRCT scan (grade 1, 0-20%; grade 2, >20%). Extensive disease was defined as >20% lung involvement on HRCT, and FVC <70% predicted and limited lung involvement as ≤20% ILD involvement on HRCT, and an FVC ≥70% predicted. RESULTS: 74 patients were included, 27% were male. The mean age at diagnosis was 57.5±15 years and the mean time since diagnosis was 7.67±8 years. 28 patients had ILD (38%). 64% of patients had <20% ILD extent classified through HRCT scan. SSc-ILD patients had elevated serum KL-6 and IL-18 levels compared to patients without ILD (p=0.003 and p=0.04), and those findings were preserved after adjusting for age and sex. Negative correlation between KL-6 levels and%FVC (ß=-0.25, p 0.037) and% DLCO (ß=-0.28, p 0.02) and between IL-18 levels and%FVC (ß=-0.38, p 0.001) and%DLCO (ß=-0.27, p 0.03) were found. Serum KL-6 and IL-18 levels successfully differentiated grades 1 and 2 of the semiquantitative grades of ILD extent (p = 0.028 and p = 0.022). Semiquantitative grades of ILD on the HRCT scan were significantly proportional to the KL-6 (p = 0.01) and IL-18 (p = 0.03). A positive correlation between extensive lung disease and KL-6 (ß=0.42, p = 0.007) but not with IL-18 was found. CONCLUSIONS: Serum KL-6 levels and IL-18 were increased in patients with SSc-ILD and showed a positive correlation with ILD severity as measured using a semiquantitative CT grading scale and negative correlation with PFT parameters. Serum KL-6 and IL-18 could be a clinically useful biomarker in screening and evaluating SSc-ILD.

The diagnosis and management of systemic autoimmune rheumatic disease-related interstitial lung disease: British Society for Rheumatology guideline scope.

Interstitial lung disease (ILD) is a significant complication of many systemic autoimmune rheumatic diseases (SARDs), although the clinical presentation, severity and outlook may vary widely between individuals. Despite the prevalence, there are no specific guidelines addressing the issue of screening, diagnosis and management of ILD across this diverse group. Guidelines from the ACR and EULAR are expected, but there is a need for UK-specific guidelines that consider the framework of the UK National Health Service, local licensing and funding strategies. This article outlines the intended scope for the British Society for Rheumatology guideline on the diagnosis and management of SARD-ILD developed by the guideline working group. It specifically identifies the SARDs for consideration, alongside the overarching principles for which systematic review will be conducted. Expert consensus will be produced based on the most up-to-date available evidence for inclusion within the final guideline. Key issues to be addressed include recommendations for screening of ILD, identifying the methodology and frequency of monitoring and pharmacological and non-pharmacological management. The guideline will be developed according to methods and processes outlined in Creating Clinical Guidelines: British Society for Rheumatology Protocol version 5.1.

Coalition for Health and Gender Equity (CHANGE)-a protocol for a global cross-sectional survey of health and gender equity in rheumatology.

Objectives: The primary aim of the CHANGE survey is to determine the current state of gender equity within rheumatology, and secondarily, to review the physician perspective on bullying, harassment and equipoise of opportunities within rheumatology. Methods: The CHANGE e-survey is a cross-sectional self-reported questionnaire adapted from EULAR's gender equity in academic rheumatology task force. The survey was launched in January 2023; it is available in six languages and distributed widely via rheumatology organizations and social media. Eligible participants include rheumatologist physicians and rheumatology health-care professionals. Survey responses will undergo descriptive analysis and inter-group comparison aiming to explore gender-based discrimination using logistic regression, with subgroup analyses for country/continent variations. Conclusion: This e-survey represents a comprehensive global initiative led by an international consortium, aimed at exploring and investigating the gender-related disparities and obstacles encountered by rheumatologists and rheumatology health-care professionals across diverse communities and health-care environments. By pursuing this initiative, we aim to take the broader rheumatology community a step closer to understanding the underlying origins of inequities and their determinants. Such insights are pivotal in identifying viable interventions and strategies to foster gender equity within the field. Ultimately, our collective objective is to ensure equitable access to opportunities for every individual, irrespective of gender, thereby promoting inclusivity and fairness across the entire spectrum of professional practice and career development.

Atypical Debut of Granulomatosis with Polyangiitis as Acute Tonsilitis and Strawberry Gum: A Case Report.

BACKGROUND: Granulomatosis with polyangiitis (GPA) is a systemic necrotizing vasculitis characterized by necrosis, granulomatous inflammation, and vasculitis. It is characterized by the triad of the upper and lower respiratory system, lung, and kidney disease. Although it is usually a multisystemic disease, limited forms have also been described, and otolaryngological involvement is the first manifestation in up to 80-95% of the cases. CASE PRESENTATION: In this report, we describe the case of an ANCA negative patient with a limited form of GPA that presented a necrotic lesion confined to the right tonsil compatible with granulomatosis with polyangiitis, which later presented positive ANCA antibodies. Oral lesions may be the initial manifestation of GPA, and systemic involvement can be presented within weeks or months. Although the oral manifestations have been well described, the initial presentation with oral lesions is very rare, and presentation with oropharyngeal manifestation is even rarer. This disease is generally characterized by anti-neutrophil cytoplasmic antibodies (ANCA); however, there are rare cases with negative ANCA. CONCLUSION: The diagnosis was established based on the clinical presentation and the histopathological findings of the characteristic inflammatory pattern.

Clinical phenotype in scleroderma patients based on autoantibodies.

Objective: We aimed to characterize the clinical phenotype of patients with SSc based on autoantibodies (topoisomerase antibody (Scl-70), ACA and ANA). Methods: We included patients with SSc who fulfilled the 2013 ACR/EULAR criteria, with disease duration ≤15 years. Six groups of patients were defined: ACA-lcSSC, Scl-70-lcSSc, ANA-lcSSc, Scl-70-dcSSc, ANA-dcSSc and ACA-dcSSc patients. We compared the different groups of patients. In the ANA subgroup, we included patients negative for SSc-specific antibodies (Scl-70 and ACA). We assessed the following: risk of interstitial lung disease (ILD), myositis, scleroderma renal crisis, cardiac involvement, gastrointestinal involvement, pulmonary hypertension, treatment, cancer and all-cause mortality. Results: One hundred and thirteen SSc patients were included: 72 (64%) females, 82 (73%) lcSSc and 31 (27%) dcSSc. Among patients with lcSSc, 43 (52%) were ACA+, 16 (19%) Scl-70+ and 23 (28%) ANA+, and among patients with dcSSc, 13 (42%) patients were Scl-70+, 11 (35%) ANA+ and 7 (23%) ACA+. Scl-70-lcSSc patients had a significantly shorter time from RP to SSc diagnosis (P = 0.04), higher CRP (P = 0.04), renal scleroderma crisis (P = 0.02), ILD (P = 0.03) and diastolic dysfunction (P = 0.04) than ANA-lcSSc patients. Scl-70-dcSSc patients had a higher rate of myositis (P = 0.04), renal crisis (P = 0.03), CRP elevation (P = 0.002), ILD (P = 0.04), pericardial effusion (P = 0.03) and cancer (P = 0.04) than ANA-dcSSc patients. The risk of ILD was higher in Scl-70 patients during the first 10 years than in ACA+ and ANA+ patients (P = 0.03 and P = 0.02, respectively). The risk of major organ involvement was higher in Scl-70+ patients, followed by ANA+ and ACA+ patients, throughout 15 years of follow-up. All-cause mortality was higher in dcSSc patients than in lcSSc patients, but no differences were found regarding antibody positivity. Conclusion: We have characterized the clinical phenotype of patients based on autoantibodies: Scl-70 patients show the greatest risk of major organ involvement, followed by ANA+ patients and ACA+ patients. The risk of ILD in Scl-70+ patients suggests that these patients should be monitored closely, irrespective of skin involvement. These results might provide new ways to help with the early diagnosis and management and in assessment of the prognosis of the disease.

Risk factors for cardiovascular disease in primary Sjögren's syndrome (pSS): a 20-year follow-up study.

INTRODUCTION: Primary Sjögren's syndrome (pSS) is a systemic autoimmune disease characterized by a chronic grade of inflammation. Cardiovascular events represent the major causes of morbidity and mortality in patients with inflammatory rheumatic diseases; however, the significance and prevalence of cardiovascular disease in patients with pSS remain unclear. OBJECTIVE: To determine the clinical significance of cardiovascular disease in pSS and analyze the risk of cardiovascular disease according to glandular/extraglandular involvement and positivity to anti-Ro/SSA and/or anti-La/SSB autoantibodies. METHODS: A retrospective study including patients diagnosed with pSS fulfilling the 2016 ACR/EULAR classification criteria was followed and evaluated in our outpatient clinic between 2000 and 2022. The prevalence of cardiovascular risk factors with pSS was evaluated, and a possible association with clinical and immunological characteristics, the treatments received, and the impact on cardiovascular disease were determined. Univariate and multivariate regression analyses were performed in an attempt to determine potential risk factors associated with cardiovascular involvement. RESULTS: A total of 102 pSS patients were included. Eighty-two percent were female, with a mean age of 65±24 years and a disease duration of 12.5 ±6 years. Thirty-six patients (36%) had at least one cardiovascular risk factor. Arterial hypertension was diagnosed in 60 (59%) patients, dyslipidemia in 28 (27%), diabetes in 15 (15%), obesity in 22 (22%), and hyperuricemia in 19 (18%). History of arrhythmia was found in 25 (25%), conduction defects in 10 (10%), arterial peripheral vascular disease in 7 (7%), venous thrombosis in 10 (10%), coronary artery disease in 24 (24%), and cerebrovascular disease in 22 (22%) of patients. Patients with extraglandular involvement had a higher prevalence of arterial hypertension (p=0.04), dyslipidemia (p=0.003), LDL mean values (p=0.038), hyperuricemia (p=0.03), and coronary artery disease (p=0.01) after adjusting for age, sex, disease duration, and the significant variables in the univariate analysis. Patients with Ro/SSA and La/SSB autoantibodies had a substantially higher risk of hyperuricemia (p=0.01), arrhythmia (p=0.01), coronary artery disease (p=0.02), cerebrovascular disease (p=0.02), and venous thrombosis (p =0.03). In the multivariate logistic regression analysis, higher odds of cardiovascular risk factors were associated with extraglandular involvement (p=0.02), treatment with corticosteroids (p=0.02), ESSDAI>13 (p=0.02), inflammatory markers including ESR levels (p 0.007), and serologic markers such as low C3 levels (p=0.03) and hypergammaglobulinemia (p=0.02). CONCLUSIONS: Extraglandular involvement was associated with a higher prevalence of arterial hypertension, dyslipidemia, hyperuricemia, and coronary artery disease. Anti-Ro/SSA and anti-La/SSB seropositivity was associated with a higher prevalence of cardiac rhythm abnormalities, hyperuricemia, venous thrombosis, coronary artery disease, and cerebrovascular disease. Raised inflammatory markers, disease activity measured by ESSDAI, extraglandular involvement, serologic markers including hypergammaglobulinemia and low C3, and treatment with corticosteroids were associated with a higher risk for cardiovascular comorbidities. Key Points • Patients with pSS are vulnerable to cardiovascular risk factors. There is an interconnection between extraglandular involvement, disease activity, inflammatory markers, and cardiovascular risk comorbidities. • Anti-Ro/SSA and anti-La/SSB seropositivity was associated with a higher frequency of cardiac conduction abnormalities, coronary artery disease, venous thrombosis, and stroke. • Hypergammaglobulinemia, elevated ESR, and low C3 are associated with a higher prevalence of cardiovascular comorbidities. • Valid risk stratification tools to help with prevention and consensus on the management of CVDs in pSS patients are warranted.

Morphological and functional changes in skeletal muscle in type 2 diabetes mellitus: A systematic review and meta-analysis.

INTRODUCTION: Changes in the skeletal muscle are common in patients with type 2 diabetes mellitus (T2DM). These changes impair your motor skills. OBJECTIVE: This systematic review aimed to investigate changes in skeletal muscle in patients with T2DM. METHODS: The search was carried out in the PubMed, Scopus, and Web of Science databases until December 1, 2021. Observational studies that evaluated musculoskeletal changes in people with T2DM were included. The review was based on PRISMA recommendations. The primary parameters analyzed were muscle strength, muscle mass, muscle power, and muscle endurance. RESULTS: Forty-eight studies were included, with a total of 26,042 participants. The results revealed that T2DM is associated with a reduction in handgrip [-2.64 (CI 95% = -3.33 to -1.95, Z = -7.50, p < .0001], and knee extension muscle strength [-0.56 (CI 95% = -0.76 to -0.36, Z = -5.64, p < .0001)], a higher percentage of type II fibers [11.74 (CI 95% = 6.24 to 17.25, Z = 4.18, p < .0001)], and a lower percentage of type I fibers [-15.69 (CI 95% = -18.22 to -13.16, Z = -12.16, p < .0001], in addition to a greater thickness of the calcaneus tendon (p < .0001). CONCLUSION: Individuals with T2DM present skeletal muscle impairments, mainly reduced muscle strength, mass, and endurance; increase in the thickness of the calcaneus tendon, and alteration in the proportion of type I and II fibers, even in the initial stage of the disease.

Factors associated with adverse pregnancy outcomes in patients with systemic lupus erythematosus.

BACKGROUND: Pregnancies in Systemic lupus erythematosus (SLE) are considered high risk and associated with maternal and obstetric complications. OBJECTIVES: To determine the most important predictors for each of the main adverse pregnancy outcomes in SLE patients. METHODS: Patients with SLE were retrospectively analysed from 1990 to 2020. Maternal and fetal complications in pregnant women with SLE were retrieved. We compared clinical and analytical characteristics of SLE patients with adverse pregnancy outcomes to controls with SLE diagnosis without adverse pregnancy outcomes. Qualitative data were analysed by Chi-square test and Fisher's exact test. Continuous variables were analysed by using Student's t test. Multiple logistic regression was performed to determine the predictive factors for adverse pregnancy outcomes with adjustment of confounding factors. RESULTS: 135 multiparous women were included (42% with adverse pregnancy outcomes). A total of 57 pregnancies (42%) were linked to adverse outcomes. The occurrence of abortion was correlated with anti-DNAds (ß = 0.71, p = 0.04), renal involvement (ß = 0.28, p 0.03), antiphospholipid antibodies (APA) (ß = 0.29, p 0.03), erythrocyte sedimentation rate (ESR) elevation (ß = 0.81, p = 0.02) and C-reactive protein (CPR) elevation (ß = 0.91, p = 0.01). Stillbirth was also correlated with renal involvement (ß = 0.26, p = 0.04), APA (ß = 0.22, p = 0.03) and ESR elevation (ß = 0.53, p = 0.02). Preeclampsia was correlated with direct Coombs positivity (ß = 0.42, p = 0.01), serositis (ß = 0.31, p = 0.02), ESR elevation (ß = 0.52, p = 0.03) and CPR elevation (ß = 0.32, p = 0.04). Neonatal Lupus was correlated with anti-RNP (ß = 0.16, p = 0.03) and anti-Ro/SSA (ß = 0.16, p 0.02). CONCLUSIONS: The most unfavourable pregnancy outcome in women with SLE was spontaneous abortion. Renal involvement, anti-DNAds positivity, antiphospholipid antibody positivity, anti-Ro/SSA, elevated ESR and a younger age at disease onset increased the risk of pregnancy complications.

Pumilio protects Xbp1 mRNA from regulated Ire1-dependent decay.

The unfolded protein response (UPR) maintains homeostasis of the endoplasmic reticulum (ER). Residing in the ER membrane, the UPR mediator Ire1 deploys its cytoplasmic kinase-endoribonuclease domain to activate the key UPR transcription factor Xbp1 through non-conventional splicing of Xbp1 mRNA. Ire1 also degrades diverse ER-targeted mRNAs through regulated Ire1-dependent decay (RIDD), but how it spares Xbp1 mRNA from this decay is unknown. Here, we identify binding sites for the RNA-binding protein Pumilio in the 3'UTR Drosophila Xbp1. In the developing Drosophila eye, Pumilio binds both the Xbp1unspliced and Xbp1spliced mRNAs, but only Xbp1spliced is stabilized by Pumilio. Furthermore, Pumilio displays Ire1 kinase-dependent phosphorylation during ER stress, which is required for its stabilization of Xbp1spliced. hIRE1 can phosphorylate Pumilio directly, and phosphorylated Pumilio protects Xbp1spliced mRNA against RIDD. Thus, Ire1-mediated phosphorylation enables Pumilio to shield Xbp1spliced from RIDD. These results uncover an unexpected regulatory link between an RNA-binding protein and the UPR.

Immune responses to mRNA vaccines against SARS-CoV-2 in patients with immune-mediated inflammatory rheumatic diseases.

BACKGROUND: Patients with immune-mediated rheumatic diseases (IMRDs) are commonly treated with immunosuppressors and prone to infections. Recently introduced mRNA SARS-CoV-2 vaccines have demonstrated extraordinary efficacy across all ages. Immunosuppressed patients were excluded from phase III trials with SARS-CoV-2 mRNA vaccines. AIMS: To fully characterise B-cell and T-cell immune responses elicited by mRNA SARS-CoV-2 vaccines in patients with rheumatic diseases under immunotherapies, and to identify which drugs reduce vaccine's immunogenicity. METHODS: Humoral, CD4 and CD8 immune responses were investigated in 100 naïve patients with SARS-CoV-2 with selected rheumatic diseases under immunosuppression after a two-dose regimen of SARS-CoV-2 mRNA vaccine. Responses were compared with age, gender and disease-matched patients with IMRD not receiving immunosuppressors and with healthy controls. RESULTS: Patients with IMRD showed decreased seroconversion rates (80% vs 100%, p=0.03) and cellular immune responses (75% vs 100%, p=0.02). Patients on methotrexate achieved seroconversion in 62% of cases and cellular responses in 80% of cases. Abatacept decreased humoral and cellular responses. Rituximab (31% responders) and belimumab (50% responders) showed impaired humoral responses, but cellular responses were often preserved. Antibody titres were reduced with mycophenolate and azathioprine but preserved with leflunomide and anticytokines. CONCLUSIONS: Patients with IMRD exhibit impaired SARS-CoV-2 vaccine immunogenicity, variably reduced with immunosuppressors. Among commonly used therapies, abatacept and B-cell depleting therapies show deleterious effects, while anticytokines preserved immunogenicity. The effects of cumulative methotrexate and glucocorticoid doses on immunogenicity should be considered. Humoral and cellular responses are weakly correlated, but CD4 and CD8 tightly correlate. Seroconversion alone might not reflect the vaccine's immunogenicity.

A Systematic Review and Meta-Analysis of the Effects of Low-Level Laser Therapy in the Treatment of Diabetic Foot Ulcers.

Diabetic foot ulcers (DFUs) are considered one of the most aggressive and expensive complications of diabetes. Low-level laser therapy (LLLT) has been highlighted as a potential modality of treatment to accelerate the healing of ulcers. This systematic review and meta-analysis aimed to investigate the efficacy of LLLT in the treatment of DFU and identify the LLLT application parameters recommended for the treatment of DFU over the past 10 years. A systematic search was conducted in PubMed, BVS, PEDro, Scopus, Web of Science, and CINAHL up to March 31, 2019. Following the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analysis) guidelines, randomized controlled trials (RCTs) that assessed the effect of LLLT on the treatment of DFU were included. Thirteen RCTs with a total of 361 participants were included in this review. Three RCTs reported a reduction in the percentage size of the ulcers and were included in the meta-analysis. The meta-analysis of the percentage size difference demonstrated a significant reduction in ulcer size in the LLLT group compared with controls (22.96 [95% confidence interval = 18.22-27.69; z = 9.51, P < .0001]). Treatment with 632.8 to 685 nm, 50 mW/cm2, 3 to 6 J/cm2, and irradiation for 30 to 80 seconds, 3 times weekly for a month is of benefit to patients with DFU. LLLT is effective and safe for the treatment of DFU. Additionally, well-designed, high-quality studies are needed to allow its ideal parameterization for clinical practice.