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Exosomes are a subset of Extracellular vesicles (EVs) released by most cells in the body and can play a significant role in the intercellular connection. Researchers today claim that exosomes secreted by induced pluripotent stem cells (iPSCs) alone can play the same role as direct cell transplantation and, unlike iPSCs, do not lead to tumorigenesis. As a result, iPSC-derived exosomes (iPSC-Exos) have many applications in cell-free treatments and therapeutic effects on various diseases. Male infertility due to a defect or deficiency of spermatogonia to maintain spermatogenesis is one of the diseases that iPSC-Exos seems to be a new way to cure. However, the studies on the effect of iPSC-Exos on male infertility are very limited. In this review, we intend to provide a broader perspective on understanding the mechanisms of iPSC-Exos on spermatogenesis by collecting and reviewing some of the research conducted in this field. [ABSTRACT FROM AUTHOR]

Purpose: This study aims to investigate why and how shared service centres (SSCs) are implemented as well as how they affect audit firm practice and audit quality. Design/methodology/approach: In this qualitative study guided by the theoretical framework of institutional theory, the authors conducted 25 semi-structured interviews in seven European countries, including 16 interviews with audit partners from Big 4 firms, 6 with audit team members, 2 with interviewees from second-tier audit firms and 1 with a member of an oversight body. Findings: The authors show that the central rationale for audit firms to implement SSCs is economic rather than external legitimacy. The authors find that SSC implementation has substantial effects on audit practices, particularly those related to standardisation, coordination and monitoring activities. The authors also highlight the potential impacts on audit quality. Originality/value: By exploring the motivation for and effects of SSC implementation amongst audit firms, the authors offer insights into the best practices related to subsequent change processes and audit quality. [ABSTRACT FROM AUTHOR]

Purpose: The present research is aimed to determine the acute effect of post-activation potentiation (PAP) with squat and leg extension machine, static, dynamic, and no stretching warm up on stretch–shortening cycle (SSC) of knee extensors muscles during countermovement jump (CMJ) and soccer instep kicking (SIK) in female soccer players. Methods: Thirty semi-professional female soccer players with a mean age of 24.5 ± 2.63 years, were chosen randomly. Then, during non-successive days, all groups performed one of the warm-up programs regularly on working days (static, dynamic and no-stretching and PAPs). Then they performed CMJ and SIK in order to measure the eccentric knee angular velocity (EKAV), concentric knee angular velocity (CKAV), knee extension power (KEP), jump height (JH), and ball velocity (BV) through biomechanical evaluation. Results: Findings showed that there was a significant increase in EKAV, CKAV, KEP, HJ, and BV after warm up PAPs compared to other methods in both CMJ and SIK. Conclusion: Based on obtained results, it can be said that among the warm up methods and their effects on SSC of the knee for the extensor muscles, both PAP methods were the most effective methods in improving and increasing EKAV, CKAV, KEP, JH, BV during CMJ and SIK in professional female soccer players. [ABSTRACT FROM AUTHOR]

OBJECTIVES: SSc is associated with increased health-care resource utilization and economic burden. The Collaborative National Quality and Efficacy Registry (CONQUER) is a US-based collaborative that collects longitudinal follow-up data on SSc patients with

Objective The objective of this study was to assess the incidence and risk factors of major adverse cardiovascular events (MACEs) in patients with systemic sclerosis (SSc). Methods We conducted a nationwide, population-based, cohort study using Taiwan's National Health Insurance Research Database. We performed propensity score matching (PSM) using a 1:2 ratio, resulting in inclusion of 1379 patients with SSc and 2758 non-SSc individuals in the analysis. We assessed the association between SSc and MACEs, using the multivariable Cox proportional hazard regression model with adjustment of time-dependent covariates, and investigated risk factors for MACEs in patients with SSc, shown as adjusted hazard ratios (aHRs) with 95% CIs. Results SSc was not significantly associated with the risk of MACEs (aHR 1.04; 95% CI 0.77–1.42). Nevertheless, SSc was associated with increased risk of myocardial infarction [incidence rate ratio (IRR) 1.76; 95% CI 1.08–2.86] and peripheral arterial occlusion disease (IRR 3.67; 95% CI 2.84–4.74) but not of ischaemic stroke (IRR 0.89; 95% CI 0.61–1.29). Factors independently associated with MACEs in SSc patients included age (aHR 1.02), male gender (aHR 2.01), living in a suburban area (aHR 2.09), living in a rural area (aHR 3.00), valvular heart disease (aHR 4.26), RA (aHR 2.14), use of clopidogrel (aHR 26.65), and use of aspirin (aHR 5.31). Conclusions The risk of MACEs was not significantly increased in Taiwanese patients with SSc, and our investigation effectively identified the factors independently associated with MACEs in SSc patients. Additionally, patients with SSc exhibited higher risks of myocardial infarction and peripheral arterial occlusion disease but not of ischaemic stroke. [ABSTRACT FROM AUTHOR]

Objective To describe the frequency of progressive pulmonary fibrosis (PPF) in an incident cohort of systemic sclerosis (SSc)-related interstitial lung disease (ILD) and its impact on survival. Methods Incident ILD was defined as the new development of characteristic fibrotic changes on chest HRCT scan. PPF was defined as per the 2022 American Thoracic Society. Determinants of PPF were identified using generalised estimating equations. Impact on survival was analysed using accelerated failure time regression modelling. Results Of our incident SSc-ILD cases, 38.8% (n  = 180) experienced PPF within a 12-month period after ILD diagnosis. Determinants of PPF included older age (OR 1.02, 95%CI 1.00–1.03, P  = 0.011), dcSSc (OR 1.54, 95% CI 1.06–2.25, P  = 0.024) and SSc-specific antibodies (anticentomere antibody OR 0.51, 95%CI 0.29–0.91, P  = 0.021 and anti-Scl-70 antibody OR 1.46, 95%CI 1.01–2.09, P  = 0.043). Raised CRP was numerically associated with PPF but did not reach statistical significance (OR 1.29, 95%CI 0.99–1.68, P  = 0.064) nor did GORD or dysphagia (OR 1.18, 95%CI 0.57–2.42, P  = 0.658 and OR 1.17, 95%CI 0.57–2.40, P  = 0.664, respectively). The presence of PPF significantly impacted survival in SSc-ILD (hazard ratio 2.66, 95%CI 1.59–4.41, P  < 0.001). Conclusions PPF occurred in a third of our incident SSc-ILD cohort; however, its occurrence was significantly associated with mortality indicating an at-risk group who may be suitable for earlier introduction of immunosuppressive and/or antifibrotic therapy. [ABSTRACT FROM AUTHOR]

Objectives Pulmonary arterial hypertension associated with systemic sclerosis (PAH-SSc) sometimes accompanies pulmonary veno-occlusive disease (PVOD). We aimed to reveal the relationship between clinical signs of PVOD and severity of pulmonary vasculopathy in SSc. Methods This study included 52 consecutive SSc patients who had pulmonary haemodynamic abnormalities [mean pulmonary arterial pressure (mPAP) >20 mmHg, pulmonary vascular resistance >2 WU or pulmonary artery wedge pressure (PAWP) >15 mmHg]. A chest CT scan was evaluated in all patients. Patients were divided into two groups, the 0–1 group and the 2–3 group, according to the number of chest CT signs for PVOD, including mediastinal lymph node enlargement, thickened interlobular septal wall and ground glass opacity. Pulmonary haemodynamics, echocardiography and MRI-based cardiac function, pulmonary function and serum biomarkers were compared between the two groups. Results Mediastinal lymph node enlargement, thickened interlobular septal wall and ground glass opacity were observed in 11 (21%), 32 (62%) and 11 (21%) patients, respectively. The 2–3 group (n  = 15) had higher mPAP (P  = 0.02) but lower diffusing capacity of carbon monoxide (DLCO)/alveolar volume (P  = 0.02) compared with the 0–1 group (n  = 37). Other parameters, including PAWP, cardiac output, left ventricular ejection fraction, left atrial diameter, forced vital capacity, brain natriuretic peptide and Krebs von den Lunge-6 were not different between the two groups. Conclusions The CT signs for PVOD had a positive correlation with mPAP but a negative correlation with DLCO in SSc patients, indicating that PAH-SSc may reflect a spectrum of pulmonary vascular disease that ranges from the pulmonary artery to the vein. [ABSTRACT FROM AUTHOR]

Objectives Autologous hematopoietic stem cell transplantation (AHSCT) has been shown to improve long-term survival for early diffuse progressive SSc compared with CYC. CYC, however, does not provide a long-term benefit in SSc. The combination of MMF and rituximab is a potent alternative regimen. We aimed to retrospectively compare the outcomes of SSc patients who underwent AHSCT to patients who met the eligibility criteria for AHSCT but received upfront combination therapy with MMF and rituximab. Methods Repeated assessments of modified Rodnan Skin Score (mRSS), forced vital capacity (FVC), and diffusing capacity (DLCO) values were conducted. Clinical improvement was defined as an mRSS decrease >25% or an FVC increase >10%. Event-free survival (EFS) was defined in the absence of persistent major organ failure or death. Results Twenty-one SSc patients in the combination therapy group were compared with 16 in the AHSCT group. Age, sex and disease duration were similar between the two groups. Clinical improvement at 12 months was seen in 18 (86%) patients in the combination group compared with 13 (81%) in the AHSCT group (P  = 0.7). The hazard ratio for EFS at 24 months favoured the combination group (HR = 0.09, P  = 0.04). During follow-up, both groups exhibited a significant and comparable reduction in mRSS and an increase in FVC values at each time interval up to 24 months. Conclusion MMF and rituximab compared with AHSCT in SSc patients eligible for AHSCT resulted in similar skin and lung clinical improvement with a better safety profile at 24 months. [ABSTRACT FROM AUTHOR]

Objectives Innate immunity significantly contributes to SSc pathogenesis. TLR8 is an important innate immune mediator that is implicated in autoimmunity and fibrosis. However, the expression, mechanism of action, and pathogenic role of TLR8 in SSc remain unclear. The aim of this study was to explore the roles and underlying mechanisms of TLR8 in SSc. Methods The expression of TLR8 was analysed, based on a public dataset, and then verified in skin tissues and skin fibroblasts of SSc patients. The role of TLR8 in inflammation and fibrosis was investigated using a TLR8-overexpression vector, activator (VTX-2337), inhibitor (cu-cpt-8m), and TLR8 siRNA in skin fibroblasts. The pathogenic role of TLR8 in skin inflammation and fibrosis was further validated in a bleomycin (BLM)-induced mouse skin inflammation and fibrosis model. Results TLR8 levels were significantly elevated in SSc skin tissues and myofibroblasts, along with significant activation of the TLR8 pathway. In vitro studies showed that overexpression or activation of TLR8 by a recombinant plasmid or VTX-2337 upregulated IL-6, IL-1β, COL I, COL III and α-SMA in skin fibroblasts. Consistently, both TLR8-siRNA and cu-cpt-8m reversed the phenotypes observed in TLR8-activating fibroblasts. Mechanistically, TLR8 induces skin fibrosis and inflammation in a manner dependent on the MAPK, NF-κB and SMAD2/3 pathways. Subcutaneous injection of cu-cpt-8m significantly alleviated BLM-induced skin inflammation and fibrosis in vivo. Conclusion TLR8 might be a promising therapeutic target for improving the treatment strategy for skin inflammation and fibrosis in SSc. [ABSTRACT FROM AUTHOR]

Objectives To evaluate the effectiveness of early initiation of angiotensin-converting enzyme inhibitor (ACEi) in patients with scleroderma renal crisis (SRC). Methods This was a retrospective cohort study using a nationwide inpatient database in Japan from July 2010 to March 2020. All hospitalized patients with SRC were divided into those who received ACEi within 2 days of admission (early ACEi group) and those who did not (control group). Propensity-score overlap weighting analysis was performed to adjust for confounding factors. The primary outcome was the composite of in-hospital mortality or haemodialysis dependence at discharge. Results Of the 475 eligible patients, 248 (52.2%) were in the early ACEi group and 227 (47.8%) were in the control group. After overlap weighting, the primary outcome was significantly lower in the early ACEi group than in the control group (40.1% vs 49.0%; odds ratio, 0.69; 95% CI: 0.48, 1.00; P  = 0.049). Conclusions The present study showed that early initiation of ACEi was associated with lower composite outcome of in-hospital mortality or haemodialysis dependence at discharge in patients with SRC. Further prospective studies are warranted to verify the present findings. [ABSTRACT FROM AUTHOR]

Objectives Measurement of digital perfusion, sometimes coupled with a cold challenge, has been widely used as an objective outcome in trials evaluating drug therapies in RP, in addition to patient-reported outcomes or to establish the proof-of-concept in preliminary studies. However, whether digital perfusion is a valid surrogate for clinical outcomes in RP trials has never been explored. The principal aim of this study was to evaluate the potential surrogacy of digital perfusion, by combining individual-level and trial-level data. Methods We used individual data from a series of n -of-1 trials, and trial data from a network meta-analysis. We estimated individual-level surrogacy through coefficients of determination between digital perfusion and clinical outcomes (R 2ind). We further calculated the coefficients of determination between treatment effect on the clinical outcomes and on digital perfusion, at the individual level (R 2TEind) and at the trial level (R 2trial), using non-weighted linear regression, with their 95% CI calculated through bootstrapping. Results Results from 33 patients and 24 trials were included in the final analysis. At the individual level, there was no correlation between digital perfusion and clinical outcomes at rest and in response to various cooling tests (the highest R 2ind was 0.03 [−0.07, 0.09]), and R 2TEind was also very low 0.07 (0, 0.29). At the trial level, the highest value of R 2trial was 0.1 (0, 0.477). Conclusions Digital perfusion, at rest or in response to a cold challenge, and whatever the method used, does not fulfil the criteria of a valid surrogate for existing patient-reported outcomes in RP trials. [ABSTRACT FROM AUTHOR]

The main criteria used in NEI 18–04 to define SSCs as risk-significant include (1) the SSC is required to keep all LBEs within the F–C target, and (2) the total frequency with the SSC failed exceeds 1% of the limit for at least one of the three cumulative risk metrics used for evaluating the integrated plant risk. The first one is a reasonable criterion in determining the risk significant SSCs. However, the second criterion may not be adequate to serve the purpose of determining the risk significance of SSCs. In the second criterion, the cumulative risk metric values representing the integrated plant risk (less the preventive and mitigative effects of the SSC being evaluated) are compared to a risk limit that represents a very small contribution to the overall integrated plant risk, which corresponds appropriately to the contributions from individual SSCs. The easiest approach to redefine the NEI 18-04 definition of risk-significant SSCs in relation to the integrated plant risk metrics is to compare the difference, between the risk metric value calculated with the SSC failed and the risk metric value calculated with the SSC credited, with 1% of the risk limit established for the integrated plant risk metrics.

Objectives Assessment of construct validity and reliability of a novel patient-reported outcome (PRO) instrument for assessing the severity and impact of RP in SSc. Methods An international multicentre study validation study of the 27-item Assessment of Systemic Sclerosis-Associated Raynaud's Phenomenon (ASRAP) and 10-item short-form (ASRAP-SF) questionnaires. The relationship between ASRAP questionnaires and demographics, clinical phenotype and legacy instruments for assessing SSc-RP severity, disability and pain was assessed. Repeatability was evaluated at 1 week. Anchor-based statements of health status facilitated assessment of ASRAP thresholds of meaning. Results A total of 420 SSc subjects were enrolled. There was good correlation between ASRAP (and ASRAP-SF) with RP visual analogue scale (VAS) and Scleroderma Health Assessment Questionnaire RP VAS (rho range 0.648–0.727, P  < 0.001). Correlation with diary-based assessment of SSc-RP attack frequency and duration was lower (rho range 0.258–0.504, P  < 0.001). ASRAP questionnaires had good correlation with instruments for assessing disability, hand function, pain and global health assessment (rho range 0.427–0.575, P  < 0.001). Significantly higher ASRAP scores were identified in smokers, patients with active digital ulceration (DU), previous history of DU and calcinosis (P  < 0.05 for all comparisons). There was excellent repeatability at 1 week among patients with stable SSc-RP symptoms (intra-class coefficients of 0.891 and 0.848, P  < 0.001). Patient-acceptable symptom state thresholds for ASRAP and ASRAP-SF were 45.34 and 45.77, respectively. A preliminary Minimally Important Clinical Difference threshold of 4.17 (95% CI 0.53, 7.81, P  = 0.029) was estimated. Conclusion ASRAP and ASRAP-SF questionnaires are valid and reliable novel PRO instruments for assessing the severity and impact of SSc-RP. [ABSTRACT FROM AUTHOR]

Objectives Pulmonary hypertension (PH) is a leading cause of death in patients with SSc. The purpose of this study was to determine the prognostic significance of pericardial effusion in patients with SSc-PH. Methods Pulmonary Hypertension Assessment and Recognition of Outcomes in Scleroderma (PHAROS) is a prospective multicentre registry which enrolled patients with newly diagnosed SSc-PH from 2005 to 2016. The prognostic impact of pericardial effusion status, including those who ever or never had pericardial effusion, and those who had persistent or intermittent pericardial effusion, was analysed. Kaplan–Meier survival analyses, log-rank test, and multivariable Cox proportional hazards regression were performed. Results Of the 335 patients with SSc-PH diagnosed by right heart catheterization and documentation of pericardial effusion presence or absence on echocardiogram, 166 (50%) ever had pericardial effusion. Ever having pericardial effusion was not predictive of survival (log-rank test P  = 0.49). Of the 245 SSc-PH patients who had at least two echocardiograms, 44% had a change in pericardial effusion status over an average of 4.3 years of follow up. Having a persistent pericardial effusion was an independent predictor of survival [adjusted hazard ratio (aHR)=2.34, 95% CI 1.20, 4.64, P  = 0.002], while intermittent pericardial effusion was not a predictor of survival (aHR = 0.89, 95% CI 0.52, 1.56, P  = 0.68), in a multivariable-adjusted analysis. Conclusion Persistent pericardial effusion, but not ever having had pericardial effusion or intermittent pericardial effusion, was independently associated with poorer survival. Incorporating information from serial echocardiograms may help clinicians better prognosticate survival in their SSc-PH patients. [ABSTRACT FROM AUTHOR]

Hydrocarbons, water, carbon dioxide, hydrogen sulfide, chloride, high temperatures and pressures are all involved in the oil and gas production. Thus, corrosion, particularly sulfide stress cracking (SSC), poses a great threat to the integrity of well components such as tubing, casing, packer, and wellhead assembly. Sometimes, SSC can lead to catastrophic failures and must be addressed due to operational security and environmental concerns. Localized corrosion, including SSC can be reduced greatly with the appropriate material selection and optimization of critical operational parameters. The material selection is performed according to service environments vis-a-vis mechanical/ metallurgical attributes of the alloys as prescribed in standards such as API 5CT and ANSI/NACE MR0175/ISO 15156. Currently, corrosion-resistant alloys (CRAs) such as martensitic and duplex stainless steels, nickel, titanium and other precipitation hardened alloys are available and used in oil and gas industries because of their superior mechanical and corrosion properties. Owing to the operating environmental reasons, designer often opt for more expensive CRAs as compared to relatively less expensive materials which fall close to the performance boundary of materials selection criteria, thereby increasing overall cost of crude oil production. Thus, there is a paramount requirement to ascertain the candidate materials appropriately without bearing the cost penalties of over-specifications or the performance shortfalls of under-specified alloys when new fields are discovered. In this paper the application domains of 13Cr martensitic stainless steels are reviewed vis-a-vis limits prescribed in ANSI/NACE MR0175/ISO 15156 standard. The paper will aid in the selection of cost-effective materials for oil and gas production when temperature, pressure, hydrogen sulfide concentration, pH, and salinity vary in different directions and cannot be well defined within standard limits. [ABSTRACT FROM AUTHOR]

Objective Interstitial lung disease (ILD) is the leading cause of mortality in SSc. Novel biomarkers are crucial to improve outcomes in SSc-ILD. We aimed to compare the performance of potential serum biomarkers of SSc-ILD that reflect different pathogenic processes: KL-6 and SP-D (epithelial injury), CCL18 (type 2 immune response), YKL-40 (endothelial injury and matrix remodelling) and MMP-7 (ECM remodelling). Methods Baseline and follow-up serum samples from 225 SSc patients were analysed by ELISA. Progressive ILD was defined according to the 2022-ATS/ERS/JRS/ALAT guidelines. Linear mixed models and random forest models were used for statistical analyses. Results Serum levels of KL-6 [MD 35.67 (95% CI 22.44–48.89, P  < 0.01)], SP-D [81.13 (28.46–133.79, P  < 0.01)], CCL18 [17.07 (6.36–27.77, P  < 0.01)], YKL-40 [22.81 (7.19–38.44, P  < 0.01)] and MMP-7 [2.84 (0.88–4.80, P  < 0.01)] were independently associated with the presence of SSc-ILD. A machine-learning model including all candidates classified patients with or without ILD with an accuracy of 85%. The combination of KL-6 and SP-D was associated with the presence [0.77 (0.53–1.00, P'  <0.01)] and previous progression of SSc-ILD [OR 1.28 (1.01–1.61, P'  =0.047)]. Higher baseline levels of KL-6 [OR 3.70 (1.52–9.03, P  < 0.01)] or SP-D [OR 2.00 (1.06–3.78, P  = 0.03)] increased the odds of future SSc-ILD progression, independent of other conventional risk factors, and the combination of KL-6 and SP-D [1.109 (0.665–1.554, P  < 0.01)] showed improved performance compared with KL-6 and SP-D alone. Conclusion All candidates performed well as diagnostic biomarkers for SSc-ILD. The combination of KL-6 and SP-D might serve as biomarker for the identification of SSc patients at risk of ILD progression. [ABSTRACT FROM AUTHOR]

Background: SARS-CoV-2 infection and associated COVID-19 disease can lead to critical illness with a risk of developing a multiple organ failure. Subsequently, this may lead to various pathological sequelae, such as secondary sclerosing cholangitis after surviving COVID-19 (SSC-COVID). Objective: The aim is to retrospectively analyze a cohort of hospitalized patients with first-wave (February 2020–June 2020) SARS-CoV-2 infection and persisting unclear cholangiopathy to determine the incidence of SSC-COVID and its risk factors. Results: A total of 249 patients were hospitalized at the university hospital in Tübingen, Germany, with SARS-CoV-2 infection during the first wave of the pandemic. Of these, 35.3% (88/249) required intensive care treatment; 16.5% (41/249) of them died due to the complications of COVID-19; 30.8% (64/208) of surviving patients could be followed up und were retrospectively analyzed at our center. The incidence of confirmed SSC-COVID was 7.8% (5/64). All SSC-COVID patients had an ICU stay >20 days, for invasive ventilation, positioning treatment, vasopressor treatment, but possible risk factors for SSC were not significant due to the small number of patients. Conclusions: SSC-COVID is an emerging disease in post-COVID patients with a high incidence in our single-center cohort. SSC-COVID should be considered as a differential diagnosis, if unclear cholangiopathy or cholestasis persists after SARS-CoV-2 infection. [ABSTRACT FROM AUTHOR]

The influence of Ni content on corrosion and trench formation of low alloy steel in a low H2S containing sour corrosion environment was investigated. The results show that Ni decreases the total amount of corrosion by forming a passive film containing Ni components, such as NiS and Ni3S2 on the steel surface as a result of long‐term corrosion and suppressing the anodic dissolution reaction, while increasing the trench depth. It was also identified that the Ni content had a more dominant effect on trench formation in steel regardless of the tested sour environments with 0.01 bar H2S gas (pH 4.0) and 0.001 M Na2S2O3 (pH 2.7) in this study. Based on the experimental findings, the mechanism of trenching propagation by Ni was discussed from the viewpoint of changes in surface film properties and associated difference of corrosion resistance between trench‐tip and bulk surface due to the variation in Ni content. [ABSTRACT FROM AUTHOR]

Hyponatremia is associated with considerable morbidity and mortality, but causal links have been difficult to establish. Here, we describe the establishment and representativeness of the Stockholm Sodium Cohort (SSC), designed to study etiologies and outcomes of hyponatremia. All residents of Stockholm County undertaking at least one serum sodium test between 2005–2018 were included in the SSC. Individual-level test results from over 100 laboratory parameters relevant to hyponatremia were collected and linked to data on demographics, socioeconomic status, healthcare contacts, diagnoses and dispensed prescription medications using national registers. A total of 1,632,249 individuals, corresponding to 64% of the population of Stockholm County, were included in the SSC. Coverage increased with advancing age, ranging from 32% in children and adolescents (≤18 years) to 97% among the oldest (≥80 years). The coverage of SSC included the vast majority of patients in Stockholm County diagnosed with diabetes mellitus (93%), myocardial infarction (98%), ischemic stroke (97%), cancer (85%), pneumonias requiring inpatient care (95%) and deaths (88%). SSC is the first cohort specifically designed to investigate sodium levels in a large, population-based setting. It includes a wide range of administrative health data and laboratory analyses. The coverage is high, particularly among elderly and individuals with comorbidities. Consequently, the cohort has a large potential for exploration of various aspects of hyponatremia. • Hyponatremia is associated with considerable mortality and morbidity, but the etiology is complex. • The Stockholm Sodium Cohort facilitates studies on the etiology and consequences of hyponatremia. • SSC includes over 1.6 million individuals and a wide range of administrative health data and laboratory analyses. • The coverage of SSC is high, particularly among the elderly and among individuals with comorbidities. [ABSTRACT FROM AUTHOR]

Objectives Our previous studies have demonstrated that the Damage Associated Molecular Pattern (DAMP) protein, S100A4, is overexpressed in the involved skin and peripheral blood of patients with SSc. It is associated with skin and lung involvement, and disease activity. By contrast, lack of S100A4 prevented the development of experimental dermal fibrosis. Herein we aimed to evaluate the effect of murine anti-S100A4 mAb 6B12 in the treatment of preestablished experimental dermal fibrosis. Methods The effects of 6B12 were assessed at therapeutic dosages in a modified bleomycin-induced dermal fibrosis mouse model by evaluating fibrotic (dermal thickness, proliferation of myofibroblasts, hydroxyproline content, phosphorylated Smad3-positive cell count) and inflammatory (leukocytes infiltrating the lesional skin, systemic levels of selected cytokines and chemokines) outcomes, and transcriptional profiling (RNA sequencing). Results Treatment with 7.5 mg/kg 6B12 attenuated and might even reduce pre-existing dermal fibrosis induced by bleomycin as evidenced by reduction in dermal thickness, myofibroblast count and collagen content. These antifibrotic effects were mediated by the downregulation of TGF-β/Smad signalling and partially by reducing the number of leukocytes infiltrating the lesional skin and decrease in the systemic levels of IL-1α, eotaxin, CCL2 and CCL5. Moreover, transcriptional profiling demonstrated that 7.5 mg/kg 6B12 also modulated several profibrotic and proinflammatory processes relevant to the pathogenesis of SSc. Conclusion Targeting S100A4 by the 6B12 mAb demonstrated potent antifibrotic and anti-inflammatory effects on bleomycin-induced dermal fibrosis and provided further evidence for the vital role of S100A4 in the pathophysiology of SSc. [ABSTRACT FROM AUTHOR]

Objective Multiple observations indicate a role for lymphocytes in driving autoimmunity in SSc. While T and NK cells have been studied in SSc whole blood and bronchoalveolar lavage fluid, their role remains unclear, partly because no studies have analysed these cell types in SSc-interstitial lung disease (ILD) lung tissue. This research aimed to identify and analyse the lymphoid subpopulations in SSc-ILD lung explants. Methods Lymphoid populations from 13 SSc-ILD and 6 healthy control (HC) lung explants were analysed using Seurat following single-cell RNA sequencing. Lymphoid clusters were identified by their differential gene expression. Absolute cell numbers and cell proportions in each cluster were compared between cohorts. Additional analyses were performed using pathway analysis, pseudotime and cell ligand-receptor interactions. Results Activated CD16+ NK cells, CD8+ tissue resident memory T cells and Treg cells were proportionately higher in SSc-ILD compared with HC lungs. Activated CD16+ NK cells in SSc-ILD showed upregulated granzyme B, IFN-γ and CD226. Amphiregulin, highly upregulated by NK cells, was predicted to interact with epidermal growth factor receptor on several bronchial epithelial cell populations. Shifts in CD8+ T cell populations indicated a transition from resting to effector to tissue resident phenotypes in SSc-ILD. Conclusions SSc-ILD lungs show activated lymphoid populations. Activated cytotoxic NK cells suggest they may kill alveolar epithelial cells, while their expression of amphiregulin suggests they may also induce bronchial epithelial cell hyperplasia. CD8+ T cells in SSc-ILD appear to transition from resting to the tissue resident memory phenotype. [ABSTRACT FROM AUTHOR]

In the study carried out to determine the pomological characteristics of local pomegranate genotypes grown in Kahta district center and Bostanli, Eceler, Balli, Kilisk, Sarica, and Narince villages of Adıyaman province, one orchard belonging to a grower in each region and 1 genotype in each orchard were determined. 10 fruits in each genotype were harvested, and pomological measurements and biochemical analyses were performed. The largest fruit was obtained with the Sarıca genotype and Narince was the genotype with the smallest fruit. In genotypes, the fruit weight was between 196.300-328.909 g, the fruit length 61.528-72.801 mm, and the fruit width between 73.047-86.613 mm. Total aril weight was between 94.144-203.567 g and the fruit volume was between 188.333-327.000. The Sarıca genotype had the highest juice volume and the lowest juice ratio was recorded in the Eceler genotype. Calyx length was longer in the Sarıca genotype and the highest values in terms of calyx radius were recorded with the Kilisk genotype. The Eceler genotype had thicker shells and the Narince genotype had thinner shells. The number of chambers in the genotypes was between 5 and 6. There were significant differences between genotypes in terms of fruit skin and aril color. The soluble solids content (SSC) in genotypes was determined between 12.011-17.267, pH was 3.583-4.073 and total acidity (TA) was 0.736-1.489%. Phenolic compounds such as protocatechuic acid, rutin, gallic acid, chlorogenic acid, epicatechin, ferulic acid, floridzin, vanillic acid, hydroxycinnamic acid, catechin, caffeic acid, syringic acid, and p-coumaric acid were detected in pomegranate fruit, and rutin was phenolic compound with the highest concentration. [ABSTRACT FROM AUTHOR]

Soluble solids content (SSC) and pH of red globe grapes are crucial measures of quality. In this paper, we used hyperspectral imaging technology to achieve nondestructive detection and distribution visualization of SSC and pH of red globe grapes. First, the hyperspectral images of samples were collected. Then, CARS, SPA, GA, IRIV were used to extract feature variables from raw spectral (RAW) information. The PLSR prediction models of samples were developed. By comparing the different prediction models, RAW-IRIV-PLSR was selected as the optimal model. Finally, the SSC and pH of the samples were calculated to obtain a grayscale image and perform a pseudo-color transformation to visualize the distribution of SSC and pH. By studying the classification of the maturity of samples, it was concluded that the best discriminant classification model of maturity was RAW-IRIV-ELM. Hyperspectral also provided a new method for maturity stage classification of red globe grapes.

Systemic sclerosis is a chronic disease involving the connective tissue of the skin and internal organs. It is characterised by disorders of peripheral microcirculation, immune dysregulation, and deposition of collagen fibres and other substances in connective tissue. The most common organ complications in systemic sclerosis include interstitial lung disease, pulmonary arterial hypertension, renal tubular hypertrophy, and arthritis. Imaging findings often precede clinical symptoms, so all patients should be screened as soon as possible, preferably in the asymptomatic phase of the disease. Treatment options for systemic sclerosis include immunomodulatory therapies as well as therapeutic modalities targeting vascular mechanics and connective tissue fibrosis. Efforts are underway to discover new, more sensitive and specific prognostic factors that would help to personalize therapies and thus improve the final treatment outcomes. Identified biomarkers would accelerate the implementation of appropriate treatments, delaying the progression of irreversible complications and decreasing mortality rates in patients.

Abstract Background Nintedanib was approved for the treatment of scleroderma and scleroderma-related interstitial lung disease, as it decrease the forced expiratory volume. Case presentation A 48-year-old Asian female patient with systemic scleroderma 6 years ago developed breathlessness, nausea, heart palpation, and sudden severe occipital headache over the preceding week. She was receiving aspirin 81 mg/day and amlodipine 5 mg/day. Her diagnosis was diffuse scleroderma with pulmonary hypertension, interstitial lung involvement, and renal crisis. The modified Rodnan score was 18. We begin captopril at a dose of 12.5 mg, progressively escalating to 200 mg/day, and oral nintedanib was started at 150 mg. A total of 12 months after initiation of treatment, the patient’s kidney function was normal. The pulmonary function tests improved. The modified Rodnan score was reduced to 10. We did not encounter any side effects in our case due to nintedanib treatment. Conclusion Treatment with nintedanib is crucial for slowing lung function decline. Diarrhea was the most common adverse event. Scleroderma renal crisis occurs in 10% of patients and typically presents with an abrupt onset of hypertension and kidney failure. The optimal antihypertensive agent for scleroderma renal crisis is an ACE inhibitor. The mainstay of therapy in scleroderma renal crisis has been shown to improve or stabilize renal function in approximately 70% of patients and improve survival in nearly 80% at 1 year. Nintedanib may be effective, and fairly safe to use. Further exploration is anticipated to advance a new period of systemic sclerosis treatment.

Abstract Background This work aims to develop clinical practice recommendations for the management of systemic sclerosis (SSc). Results Fourteen expert panels had completed the two rounds of surveys. After the end of round 2, recommendations were released and distributed on 11 domains. The percentage of the agreement on the recommendations was 92.3% to 100%. All 11 key questions were answered at the end of the second round with agreement. Conclusion This guideline tried to tackle the gaps in research that limit treatment options. Stratifying the patients according to their disease domains has helped to set up sequential management pathways for each domain.

Background: Nintedanib was approved for the treatment of scleroderma and scleroderma-related interstitial lung disease, as it decrease the forced expiratory volume. Case presentation: A 48-year-old Asian female patient with systemic scleroderma 6 years ago developed breathlessness, nausea, heart palpation, and sudden severe occipital headache over the preceding week. She was receiving aspirin 81 mg/day and amlodipine 5 mg/day. Her diagnosis was diffuse scleroderma with pulmonary hypertension, interstitial lung involvement, and renal crisis. The modified Rodnan score was 18. We begin captopril at a dose of 12.5 mg, progressively escalating to 200 mg/day, and oral nintedanib was started at 150 mg. A total of 12 months after initiation of treatment, the patient's kidney function was normal. The pulmonary function tests improved. The modified Rodnan score was reduced to 10. We did not encounter any side effects in our case due to nintedanib treatment. Conclusion: Treatment with nintedanib is crucial for slowing lung function decline. Diarrhea was the most common adverse event. Scleroderma renal crisis occurs in 10% of patients and typically presents with an abrupt onset of hypertension and kidney failure. The optimal antihypertensive agent for scleroderma renal crisis is an ACE inhibitor. The mainstay of therapy in scleroderma renal crisis has been shown to improve or stabilize renal function in approximately 70% of patients and improve survival in nearly 80% at 1 year. Nintedanib may be effective, and fairly safe to use. Further exploration is anticipated to advance a new period of systemic sclerosis treatment. [ABSTRACT FROM AUTHOR]

Background: This work aims to develop clinical practice recommendations for the management of systemic sclerosis (SSc). Results: Fourteen expert panels had completed the two rounds of surveys. After the end of round 2, recommendations were released and distributed on 11 domains. The percentage of the agreement on the recommendations was 92.3% to 100%. All 11 key questions were answered at the end of the second round with agreement. Conclusion: This guideline tried to tackle the gaps in research that limit treatment options. Stratifying the patients according to their disease domains has helped to set up sequential management pathways for each domain. [ABSTRACT FROM AUTHOR]

Objectives We aimed to perform a comprehensive analysis of the ECG, two-dimensional echocardiography (2DE) and cardiac MRI (CMR) findings in patients with systemic sclerosis (SSc), and also to investigate correlations between CMR findings and some ECG and echocardiography (ECHO) results. Methods We retrospectively analysed data from patients with SSc who were regularly seen at our outpatient referral centre, all assessed with ECG, Doppler ECHO and CMR. Results Ninety-three patients were included; mean (s. d.) age of 48.5 (10.3) years, 86% female, 52% diffuse SSc. Eighty-four (90%) of the patients had sinus rhythm. The most common ECG finding was the left anterior fascicular block, recorded in 26 patients (28%). The abnormal septal motion (ASM) was found in 43 (46%) patients on ECHO. Myocardial involvement (inflammation or fibrosis), as assessed by multiparametric CMR, was present in >50% of our patients. The age- and sex-adjusted model showed that ASM on ECHO increased significantly the odds of increased extracellular volume [odds ratio (OR) 4.43, 95% CI 1.73, 11.38], increased T1 Relaxation time (OR 2.67, 95% CI 1.09, 6.54), increased T2 Relaxation time (OR 2.56, 95% CI 1.05, 6.22), increased signal intensity ratio in T2-weighted imaging (OR 2.56, 95% CI 1.05, 6.22), presence of late gadolinium enhancement (OR 3.85, 95% CI 1.52, 9.76) and mid-wall fibrosis (OR 3.64, 95% CI 1.48, 8.96). Conclusion This study indicates that the presence of ASM on ECHO is a predictor of abnormal CMR in SSc patients, and a precise assessment of ASM may serve as an important point for selecting the patients that should be evaluated by CMR for early detection of myocardial involvement. [ABSTRACT FROM AUTHOR]

Objective We aimed to assess SSc mortality by age in the general population over the past five decades. Methods This is a population-based study using a national mortality database and the census data for all US residents. We calculated the proportions of deaths for SSc and for all other causes (non-SSc) by age, and calculated age-standardized mortality rates (ASMRs) for SSc and non-SSc, and the ratio of SSc-ASMR to non-SSc-ASMR by age groups for each year from 1968 through 2015. We performed joinpoint regression to estimate the average annual percent change (AAPC) for each of these parameters. Results SSc was recorded as the underlying cause of death in 5457 decedents aged ≤44 years, 18 395 aged 45–64, and 22 946 aged ≥65 from 1968 through 2015. At ages ≤44, the proportion of annual deaths decreased more for SSc than for non-SSc: AAPC, –2.2% (95% CI, –2.4% to –2.0%) for SSc vs –1.5% (–1.9% to –1.1%) for non-SSc. Consistently, SSc-ASMR decreased from 1.0 (95% CI, 0.8–1.2) in 1968 to 0.4 (0.3–0.5) per million persons in 2015, a cumulative decrease of 60% at an AAPC of –1.9% (95% CI, –2.5% to –1.2%) at ages ≤44. The SSc-ASMR:non-SSc-ASMR ratio also decreased [cumulative –20%; AAPC –0.3% (95% CI, –1.15% to 0.55%)] in the ≤44-years group. In contrast, those aged ≥65 experienced a steep increase in the SSc-ASMR [cumulative 187.0%; AAPC 2.0% (95% CI, 1.8–2.2)] and the SSc-ASMR:non-SSc-ASMR ratio [cumulative 395.4%; AAPC 3.3% (95% CI, 2.9–3.7)]. Conclusion Mortality for SSc has steadily decreased at younger ages over the past five decades. [ABSTRACT FROM AUTHOR]

Objective To investigate the evolution of nailfold capillary density in patients with SSc in relation to immunosuppressive treatment and autoantibodies. Methods This was a prospective study cohort. Consecutive newly diagnosed SSc patients were included into this study who, in a retrospective review, had at least two nailfold capillary microscopy measurements performed during the first 48 months of follow-up. Capillary density per 3 mm was measured with widefield nailfold capillary microscopy. Improvement of capillary density per finger and mean capillary density were analysed. Longitudinal measurements of mean capillary density were analysed by generalized estimating equation. Results Eighty patients (68 women, 12 men) met the inclusion criteria. The median follow-up time was 27 months. Twenty-eight patients had an improved capillary density in per-finger analysis. MMF was associated with fewer numbers of fingers that had worsened in capillary density. Anti-topoisomerase antibodies were associated with low mean capillary density. Anti-RNA polymerase III antibodies were associated with improvement and anti-centromere antibodies with worsening of capillary density in per-finger analysis. MMF treatment was associated with less steep capillary density decline in a moderated generalized estimating equation model including presence of anti-topoisomerase antibodies and the interaction of MMF with follow-up time. Conclusion Nailfold capillary density improved over time in a substantial proportion of SSc patients. MMF treatment had a positive impact on the evolution of capillary density in these patients. SSc autoantibody phenotype may affect the capillary density development. The data support previous hypotheses that early immunosuppression may favourably affect vascular regeneration in SSc. [ABSTRACT FROM AUTHOR]

The aim of this study was in-line, rapid, and non-destructive detection for soluble solid content (SSC) in pomelos using visible and near-infrared spectroscopy (Vis-NIRS). However, the large size and thick rind of pomelo affect the stability of spectral acquisition and the biological variabilities affect the robustness of models. Given these issues, in this study, an efficient prototype in-line detection system in transmittance mode was designed and evaluated in comparison with an off-line detection system. Data from the years 2019 and 2020 were used for modeling and the external validation data were obtained by the inline detection system in 2021. The wavelength selection methods of changeable size moving window (CSMW), random frog (RF), and competitive adaptive reweighted sampling (CARS) were used to improve the prediction accuracy of partial least squares regression (PLSR) models. The best performance of internal prediction was obtained by CARS-PLSR and the determination coefficient of prediction (R²p), root mean square error of prediction (RMSEP), and residual predictive deviation (RPD) were 0.958, 0.204%, and 4.821, respectively. However, all models obtained large prediction biases in external validation. The latent variable updating (LVU) method was proposed to update models and improve the performance in external validation. Ten samples from the external validation set were randomly selected to update the models. Compared with the recalibration method, LVU could effectively modify the original models which matched the SSC range of the external validation set. The CSMW-PLSR models were more robust in external validations. The off-line model with LVU performed best with a root mean square error of validation (RMSEV) of 0.599% and the in-line model with recalibration obtained RMSEV of 0.864%. These results demonstrated the application potential of the transmittance Vis-NIRS for in-line rapid prediction of SSC in pomelos and the modeling and updating methods could be applied to samples with biological variabilities. [ABSTRACT FROM AUTHOR]

Neuropathic pain, which is initiated by a malfunction of the somatosensory cortex system, elicits inflammation and simultaneously activates glial cells that initiate neuroinflammation. Electroacupuncture (EA) has been shown to have therapeutic effects for neuropathic pain, although with uncertain mechanisms. We suggest that EA can reliably cure neuropathic disease through anti-inflammation and transient receptor potential V1 (TRPV1) signaling pathways from the peripheral to the central nervous system. To explore this, we used EA to treat the mice spared nerve injury (SNI) model and explore the underlying molecular mechanisms through novel chemogenetics techniques. Both mechanical and thermal pain were found in SNI mice at four weeks (mechanical: 3.23 ± 0.29 g; thermal: 4.9 ± 0.14 s). Mechanical hyperalgesia was partially attenuated by 2 Hz EA (mechanical: 4.05 ± 0.19 g), and thermal hyperalgesia was fully reduced (thermal: 6.22 ± 0.26 s) but not with sham EA (mechanical: 3.13 ± 0.23 g; thermal: 4.58 ± 0.37 s), suggesting EA's specificity. In addition, animals with Trpv1 deletion showed partial mechanical hyperalgesia and no significant induction of thermal hyperalgesia in neuropathic pain mice (mechanical: 4.43 ± 0.26 g; thermal: 6.24 ± 0.09 s). Moreover, we found increased levels of inflammatory factors such as interleukin-1 beta (IL1-β), IL-3, IL-6, IL-12, IL-17, tumor necrosis factor alpha, and interferon gamma after SNI modeling, which decreased in the EA and Trpv1−/− groups rather than the sham group. Western blot and immunofluorescence analysis showed similar tendencies in the dorsal root ganglion, spinal cord dorsal horn, somatosensory cortex (SSC), and anterior cingulate cortex (ACC). In addition, a novel chemogenetics method was used to precisely inhibit SSC to ACC activity, which showed an analgesic effect through the TRPV1 pathway. In summary, our findings indicate a novel mechanism underlying neuropathic pain as a beneficial target for neuropathic pain. [ABSTRACT FROM AUTHOR]

Background The aim of this systematic review and meta-analysis was to summarize current evidence regarding body composition (BC) in SSc in order to gain new insights and improve clinical care in the context of the nutritional status of SSc patients. Methods The databases Web of Science, PubMed, Scopus and Cochrane Library were searched on 4 January 2023. Studies were included if they provided data regarding BC obtained by dual-energy X-ray absorptiometry (DXA) or bioelectrical impedance analysis (BIA) in patients with SSc and healthy controls (HC). The study design criteria for inclusion were cohort and observational studies. The risk of bias assessment was performed using the Newcastle–Ottawa scale. For meta-analysis, mean difference with a 95% confidence interval was obtained and all results were depicted as forest plots. Results The number of retrieved publications was 593, of which nine were included in a random-effects meta-analysis totalling 489 SSc patients and 404 HC. Overall, significantly lower body mass index, lean mass (LM), fat mass (FM) and phase angle values were found in SSc patients when compared with HC. Furthermore, FM and LM were significantly lower in SSc patients when the DXA method was applied, whereas the same parameters were comparable between two groups of participants when BIA was applied. Conclusion Altered BC is characteristic of SSc patients indicating the need for regular nutritional status assessment in order to improve the quality of life and clinical care of patients with SSc. [ABSTRACT FROM AUTHOR]

Objectives We characterized the microbiota in SSc, focusing on the skin–oral–gut axis and the serum and faecal free fatty acid (FFA) profile. Methods Twenty-five SSc patients with ACA or anti-Scl70 autoantibodies were enrolled. The microbiota of faecal, saliva and superficial epidermal samples was assessed through next-generation sequencing analysis. GC-MS was used to quantify faecal and serum FFAs. Gastrointestinal symptoms were investigated with the University of California Los Angeles Scleroderma Clinical Trial Consortium Gastrointestinal Tract Instrument (UCLA GIT-2.0) questionnaire. Results The ACA+ and anti-Scl70+ groups displayed different cutaneous and faecal microbiota profiles. The classes of cutaneous Sphingobacteriia and Alphaproteobacteria, the faecal phylum Lentisphaerae, the levels of the classes Lentisphaeria and Opitutae, and the genus NA-Acidaminococcaceae were significantly higher in faecal samples from the ACA+ patients than in samples from the anti-Scl70+ patients. The cutaneous Sphingobacteria and the faecal Lentisphaerae were significantly correlated (rho = 0.42; P  = 0.03). A significant increase in faecal propionic acid was observed in ACA+ patients. Moreover, all levels of faecal medium-chain FFAs and hexanoic acids were significantly higher in the ACA+ group than in the anti-Scl70+ group (P  < 0.05 and P  < 0.001, respectively). In the ACA+ group, the analysis of the serum FFA levels showed an increasing trend in valeric acid. Conclusion Different microbiota signatures and FFA profiles were found for the two groups of patients. Despite being in different body districts, the cutaneous Sphingobacteria and faecal Lentisphaerae appear interdependent. [ABSTRACT FROM AUTHOR]

Objective Stratifying the risk of death in SSc-related interstitial lung disease (SSc-ILD) is a challenging issue. The extent of lung fibrosis on high-resolution CT (HRCT) is often assessed by a visual semiquantitative method that lacks reliability. We aimed to assess the potential prognostic value of a deep-learning–based algorithm enabling automated quantification of ILD on HRCT in patients with SSc. Methods We correlated the extent of ILD with the occurrence of death during follow-up, and evaluated the additional value of ILD extent in predicting death based on a prognostic model including well-known risk factors in SSc. Results We included 318 patients with SSc, among whom 196 had ILD; the median follow-up was 94 months (interquartile range 73–111). The mortality rate was 1.6% at 2 years and 26.3% at 10 years. For each 1% increase in the baseline ILD extent (up to 30% of the lung), the risk of death at 10 years was increased by 4% (hazard ratio 1.04, 95% CI 1.01, 1.07, P  = 0.004). We constructed a risk prediction model that showed good discrimination for 10-year mortality (c index 0.789). Adding the automated quantification of ILD significantly improved the model for 10-year survival prediction (P  = 0.007). Its discrimination was only marginally improved, but it improved prediction of 2-year mortality (difference in time-dependent area under the curve 0.043, 95% CI 0.002, 0.084, P  = 0.040). Conclusion The deep-learning–based, computer-aided quantification of ILD extent on HRCT provides an effective tool for risk stratification in SSc. It might help identify patients at short-term risk of death. [ABSTRACT FROM AUTHOR]

Pulmonary involvement is the leading cause of death in systemic sclerosis (SSc) and may manifest as interstitial lung disease (ILD), pulmonary arterial hypertension (PAH), or in combination of both (ILD with pulmonary hypertension [ILD-PH]). The aim of this analysis was to determine prevalence, clinical characteristics, and survival of these different forms within the registry of the German Network for Systemic Sclerosis. Does SSc-associated ILD-PH or ILD without PH affect survival differently, and are there any risk factors that have an additional impact? Clinical data of 5,831 patients with SSc were collected in the German Network for Systemic Sclerosis registry. Kaplan-Meier estimates were used to compare overall survival in patients with SSc-associated ILD-PH and ILD without PH with patients without pulmonary involvement and those with PAH. The Cox proportional hazard model was used to analyze the influence of pulmonary involvement and other potential predictors on patient survival. Clinical data of 3,257 patients with a mean follow-up time of 3.45 ± 1.63 years have been included in our analysis. At baseline, ILD was present in 34.5%, whereas PH without ILD had a lower prevalence with 4.5%. At the end of follow-up, 47.6% of patients with SSc had ILD, 15.2% had ILD-PH, and 6.5% had PAH. ILD was more frequent in the diffuse cutaneous form (57.3%), whereas PAH did not differ significantly between SSc subtypes. Significant differences in baseline characteristics between PAH vs ILD-PH vs ILD without PH were found for age at diagnosis, sex, SSc subsets, antibody status, FVC, diffusing capacity of the lung for carbon monoxide, and therapy. Overall survival at 5 years was 96.4% for patients without pulmonary involvement and differed significantly between patients with ILD without PH, PAH, and being worst in patients with ILD-PH. Female sex (hazard ratio [HR], 0.3), higher BMI (HR, 0.9), and higher diffusing capacity of the lung for carbon monoxide values (HR, 0.98) were associated with a lower mortality risk. ILD is the most prevalent pulmonary involvement in SSc, whereas the combination of ILD and PH is associated with the most detrimental survival. [Display omitted] [ABSTRACT FROM AUTHOR]

Rationale: The American Thoracic Society convened an international, multidisciplinary panel to develop clinical practice guidelines for the treatment of systemic sclerosis-associated interstitial lung disease (SSc-ILD). Objective: To conduct a systematic review and evaluate the literature to determine whether patients with SSc-ILD should be treated with mycophenolate. Methods: A literature search was conducted across the MEDLINE, EMBASE, and CENTRAL databases through June 2022 for studies using mycophenolate to treat patients with SSc-ILD. Mortality, disease progression, quality of life, and adverse event data were extracted, and meta-analyses were performed when possible. The Grading of Recommendations, Assessment, Development and Evaluation (GRADE) Working Group method was used to assess the quality of evidence. Results: The literature review resulted in seven studies fitting the inclusion criteria. The systematic review and meta-analyses revealed changes in forced vital capacity % predicted (mean difference [MD], 5.4%; 95% confidence interval [95% CI]: 3.3%, 7.5%), diffusing capacity of the lung for carbon monoxide % predicted (MD, 4.64%; 95% CI: 0.54%, 8.74%), and breathlessness score (MD, 1.99; 95% CI: 0.36, 3.62) favored mycophenolate over placebo. The risk of anemia (relative risk [RR], 2.3; 95% CI: 1.2, 71.4) was higher with mycophenolate. There were no significant differences between mycophenolate and cyclophosphamide, except risk of premature discontinuation (RR, 0.6; 95% CI: 0.4, 0.9), and leukopenia (RR, 0.1; 95% CI: 0.05, 0.4) favored mycophenolate. The quality of evidence was moderate to very low per GRADE. Conclusions: Mycophenolate use in patients with SSc-ILD is associated with statistically significant improvements in disease progression and quality-of-life measures compared with placebo. There were no differences in mortality, disease progression, or quality of life compared with cyclophosphamide, but there were fewer adverse events. The quality of evidence is very low. [ABSTRACT FROM AUTHOR]

Background: The American Thoracic Society convened an international, multidisciplinary panel to develop clinical practice guidelines for the treatment of systemic sclerosis-associated interstitial lung disease (SSc-ILD). Objective: To conduct a systematic review and evaluate the literature to determine whether patients with SSc-ILD should be treated with cyclophosphamide. Data Sources: A literature search was conducted across the MEDLINE, EMBASE, and Cochrane Central Register of Controlled Trials databases through June 2022 for studies using cyclophosphamide to treat patients with SSc-ILD. Data Extraction: Mortality, disease progression, quality of life, and adverse event data were extracted, and meta-analyses were performed when possible. The Grading of Recommendations, Assessment, Development and Evaluation Working Group method was used to assess the quality of evidence. Synthesis: Five studies were included; two randomized controlled trials compared cyclophosphamide versus placebo, and one randomized controlled trial and two retrospective casecontrol studies compared cyclophosphamide versus mycophenolate. Compared with placebo, there was a 2.83% reduction in the decline at 12 months for forced vital capacity (FVC) % predicted using cyclophosphamide (95% confidence interval [CI], 0.80-4.87; low evidence). There were improvements in breathlessness (Transition Dyspnea Index mean difference [MD], 2.90; 95% CI, 1.94-3.86; minimum clinically important difference, 1; moderate evidence) and disability (Health Assessment Questionnaire-Disability Index MD, 20.16; 95% CI, 20.28 to 20.04; minimum clinically important difference, 20.14; moderate evidence). There were increased risks of leukopenia and constitutional symptoms using cyclophosphamide, but no difference in mortality. When cyclophosphamide was compared with mycophenolate, there were differences in diffusing capacity of the lung for carbon monoxide % predicted favoring mycophenolate at 6 months (MD, 23.67%; 95% CI, 26.3% to 21.1% unadjusted; MD, 24.88%; 95% CI, 27.3% to 22.5% adjusted for alveolar volume; moderate evidence), 12 months (MD, 25.90%; 95% CI, 28.4% to 23.4% adjusted for alveolar volume; moderate evidence), and 18 months (MD, 23.26%; 95% CI, 26.1% to 20.4%; moderate evidence), but not at 24 months. There were no differences in FVC % predicted, mortality, or quality-of-life outcomes, but participants were more likely to prematurely discontinue cyclophosphamide compared with mycophenolate (relative risk, 1.70; 95% CI, 1.10-2.63; highcertainty evidence). Conclusions: A review of the published evidence shows that cyclophosphamide is effective in SSc-ILD compared with placebo, with an increased risk of side effects. However, mycophenolate may be equivocal or better than cyclophosphamide. Clinicians and patients should weigh the potential benefits and risks with respect to individual patient circumstances and preferences. [ABSTRACT FROM AUTHOR]

Offshore wind farms (OWFs), built extensively in recent years, induce changes in the surrounding water environment. The changes in the suspended sediment concentration (SSC) and chlorophyll-a concentration (Chl-aC) induced by an OWF in the Yangtze River Estuary were analyzed based on Chinese Gaofen (GF) satellite data. The results show the following: (1) The flow near the wind turbines makes the bottom water surge, driving the sediment to "re-suspend" and be lost, deepening the scour pit around the bottom of the wind turbines, which is known as "self-digging". The interaction between the pillar of a wind turbine and tidal currents makes hydrodynamic factors more complicated. Blocking by wind turbines promoting the scour of the bottom seabed of the OWF results in speeding up the circulation rate of sediment loss and "re-suspension", which contributes to the change in the SSC and Chl-aC. This kind of change in sediment transport in estuarine areas due to human construction affects the balance of the ecological environment. Long-term sediment loss around wind turbines also influences the safety of wind turbines. (2) The SSC and Chl-aC are mainly in the range of 200–600 mg/L and 3–7 μg/L, respectively, in the OWF area, higher than the values obtained in surrounding waters. The SSC and Chl-aC downstream of the OWF are higher than those upstream, with differences of 100–300 mg/L and 0.5–2 μg/L. High SSC and Chl-aC "tails" appear downstream of wind turbines, consistent with the direction of local tidal currents, with lengths in the range of 2–4 km. In addition, the water environment in the vicinity of a wind turbine array, with a roughly 2–5 km scope (within 4 km during flooding and around 2.5 km during ebbing approximately) downstream of the wind turbine array, is impacted by the OWF. (3) In order to solve the problem of "self-digging" induced by OWFs, it is suggested that the distance between two wind turbines should be controlled within 2–3.5 km in the main flow direction, promising that the second row of wind turbines will be placed on the suspended sediment deposition belt induced by the first row. In this way, the problems of ecosystem imbalance and tidal current structure change caused by sediment loss because of local scouring can be reduced. Furthermore, mutual compensation between wind turbines can solve the "self-digging" problem to a certain extent and ensure the safety of OWFs. [ABSTRACT FROM AUTHOR]

Badminton, a dynamic racquet sport demanding agility and power, features the overhead forehand smash as a pivotal offensive shot. Utilizing 3D motion analysis, this research delves into the intricate biomechanical facets underpinning this pivotal shot, with a dual focus on both novice and proficient players. Through a comparative analysis of these two player cohorts, the investigation aims to elucidate the fundamental factors influencing the quality of the forehand smash. Our findings reveal that skilled players exhibit significant improvements in smash quality, including a 60.2% increase in shuttlecock speed, reduced clearance height, and flight angle at release. These enhancements are associated with specific determinants, such as consistent positioning, racket angle at impact, and range of motion (ROM) in various joints. More crucially, full-body tension-arc formation and a four-segment whip-like smash contribute to these improvements. Unique to the whip-like smash is the rapid trunk and shoulder rotations in early whip-like control inducing passive elbow flexion and wrist over-extension, enhancing the stretch-shortening cycle (SSC) effect of muscles for a more powerful smash. Emphasizing this uniqueness and the determinants simplify smash learning, potentially boosting training effectiveness. This research contributes to a deeper understanding of badminton's biomechanics and offers practical implications for coaches and players to enhance their forehand smashes, especially among beginners. [ABSTRACT FROM AUTHOR]

Objectives Ectopic calcification (calcinosis) is a common complication of SSc, but a subset of SSc patients has a heavy burden of calcinosis. We examined whether there are unique risk factors for a heavy burden of calcinosis, as compared with a light burden or no calcinosis. Methods We reviewed the medical records of all patients in the Johns Hopkins Scleroderma Center Research Registry with calcinosis to quantify calcinosis burden using pre-specified definitions. We performed latent class analysis to identify SSc phenotypic classes. We used multinomial logistic regression to determine whether latent phenotypic classes and autoantibodies were independent risk factors for calcinosis burden. Results Of all patients, 29.4% (997/3388) had calcinosis, and 13.5% (130/963) of those with calcinosis had a heavy burden. The latent phenotypic class with predominantly diffuse skin disease and higher disease severity (characterized by pulmonary hypertension, interstitial lung disease, cardiomyopathy, severe RP, gastrointestinal involvement, renal crisis, myopathy and/or tendon friction rubs) was associated with an increased risk of both a heavy burden [odds ratio (OR) 6.92, 95% CI 3.66, 13.08; P  < 0.001] and a light burden (OR 2.88, 95% CI 2.11, 3.95; P  < 0.001) of calcinosis compared with the phenotypic class with predominantly limited skin disease. Autoantibodies to PM/Scl were strongly associated with a heavy burden of calcinosis (OR 17.31, 95% CI 7.72, 38.81; P  < 0.001) and to a lesser degree a light burden of calcinosis (OR 3.59, 95% CI 1.84, 7.00; P  < 0.001). Conclusions Calcinosis burden is associated with cumulative SSc-related tissue damage. Independent of disease severity, autoantibodies to PM/Scl are also associated with a heavy burden of calcinosis. [ABSTRACT FROM AUTHOR]

With the high production of apples in Poland, the priority actions include increasing their export volume. The main objective of the presented research was to maintain sufficient firmness in the apple cultivar Gala Schniga® SchniCo Red(s) transported to distant markets immediately after harvest or after long-term storage under ULO conditions (1.2% CO2 and 1.2% O2). In the study conducted during the 2021/2022 storage season on apples from the experimental orchard of the Warsaw University of Life Sciences (SGGW-WULS; Warsaw-52°14′ N, 21°1′ E), the effect of the pre- and post-harvest application of 1-MCP, harvest date, and simulated transport duration on the quality of apples in target retail trading conditions was evaluated. Apples collected on a given harvest date were divided into four samples: control (without the use of 1-MCP), Harvista™-sprayed, SmartFresh™-treated, and Harvista™-sprayed + SmartFresh™-treated. Immediately after harvest and after 9 months of storage, the apples were packed in boxes and stored at 1 °C for 6 and 8 weeks (simulated transport conditions). Directly after the simulated transport and after an additional 7 and 14 days at 25 °C (handling conditions in hot countries), the following parameters were determined: firmness, SSC, TA, and ethylene production. The study noted a significant effect of the use of 1-MCP, harvest time, and simulated transport period on all tested parameters. Apples from trees sprayed with Harvista™ maintained a firmness of >55 N for 14 days of shelf-life only if they were harvested at the optimal date and transported immediately after harvest, and if their shipping lasted 6 weeks. Such firmness could be preserved after 8 weeks of the transport of SmartFresh™-treated apples harvested at the optimal date, and of Harvista™-sprayed + SmartFresh™-treated apples harvested at a delayed date. In the latter combination, apples also maintained the desired firmness after 9 months of storage + 6 weeks of transport regardless of the harvest date. [ABSTRACT FROM AUTHOR]

Mixed connective tissue disease (MCTD) is a very rare disorder that belongs in the rare and clinically multifactorial groups of diseases. The pathogenesis of MCTD is still unclear. The best understood epigenetic alteration is DNA methylation whose role is to regulate gene expression. In the literature, there are ever-increasing assumptions that DNA methylation can be one of the possible reasons for the development of Autoimmune Connective Tissue Diseases (ACTDs) such as systemic sclerosis (SSc) and systemic lupus erythematosus (SLE). The aim of this study was to define the global DNA methylation changes between MCTD and other ACTDs patients in whole blood samples. The study included 54 MCTD patients, 43 SSc patients, 45 SLE patients, and 43 healthy donors (HC). The global DNA methylation level was measured by ELISA. Although the global DNA methylation was not significantly different between MCTD and control, we observed that hypomethylation distinguishes the MCTD patients from the SSc and SLE patients. The present analysis revealed a statistically significant difference of global methylation between SLE and MCTD (p < 0.001), SLE and HC (p = 0.008), SSc and MCTD (p ≤ 0.001), and SSc and HC (p < 0.001), but neither between MCTD and HC (p = 0.09) nor SSc and SLE (p = 0.08). The highest % of global methylation (median, IQR) has been observed in the group of patients with SLE [0.73 (0.43, 1.22] and SSc [0,91 (0.59, 1.50)], whereas in the MCTD [0.29 (0.20, 0.54)], patients and healthy subjects [0.51 (0.24, 0.70)] were comparable. In addition, our study provided evidence of different levels of global DNA methylation between the SSc subtypes (p = 0.01). Our study showed that patients with limited SSc had a significantly higher global methylation level when compared to diffuse SSc. Our data has shown that the level of global DNA methylation may not be a good diagnostic marker to distinguish MCTD from other ACTDs. Our research provides the groundwork for a more detailed examination of the significance of global DNA methylation as a distinguishing factor in patients with MCTD compared to other ACTDs patients. [ABSTRACT FROM AUTHOR]

Introduction: The inflammatory involvement of joints and tendons is common in Systemic Sclerosis (SSc). Ultrasonography (US) is a non-invasive tool commonly applied for the assessment of the main inflammatory arthropathies and could be also used in identifying pathological features in SSc patients, even without clinical evidence of joint complaint. So, the aim of this study was to assess the prevalence of US pathological features in a cohort of SSc patients and assessed the role of US in the detection of subclinical joint involvement. Methods: In this retrospective study, we collected data about the prevalence of US pathological features at the level of hands and wrists in a cohort of patients with a definite diagnosis of SSc, submitted to an ultrasound examination of hands and wrists according to the clinician's opinion, with or without joint involvement symptoms, in order to assess the US ability in detecting subclinical inflammatory signs in SSc patients. Results: In total, 47.5% of patients reported at least one US pathological feature. The most common was synovial hypertrophy (62.1%). Other assessed lesions were effusion (48%), tenosynovitis (37.9%), power Doppler (PD) signal (31.0%), and erosions (0.7%). Effusion and PD signal appeared significantly higher in symptomatic patients, with a p<0.01 and p=0.045, respectively. Conclusions: In this cohort of SSc subjects, almost the half of the US-positive patients were clinically asymptomatic. Therefore, the application of US could be useful to detect the musculoskeletal involvement of SSc patients, a potential markers of disease severity. Further studies are required to assess the role of US in monitoring SSc patients. Key Points • The inflammatory involvement of joints and/or tendons is common in systemic sclerosis (SSc) but could be partially covered by other disease features. • Among the diagnostic methods able to increase the sensitivity of the musculoskeletal evaluation, Ultrasonography (US) is one of the most promising to reveal subclinical inflammation and predict the joint damage progression. • We retrospectively investigated the prevalence of US pathological features in a cohort of SSc patients, with or without symptoms of joint involvement, assessing the role of US in the detection of subclinical joint involvement. • We found that joint and tendon involvement, a potential marker of disease severity, is common in SSc. [ABSTRACT FROM AUTHOR]

Objective Pulmonary arterial hypertension (PAH) is a leading cause of death in MCTD. We aimed to describe PAH in well-characterized MCTD patients. Methods MCTD patients enrolled in the French Pulmonary Hypertension Registry with a PAH diagnosis confirmed by right heart catheterization were included in the study and compared with matched controls: MCTD patients without PAH, SLE patients with PAH and SSc patients with PAH. Survival rates were estimated by the Kaplan–Meier method and risk factors for PAH in MCTD patients and risk factors for mortality in MCTD-PAH were sought using multivariate analyses. Results Thirty-six patients with MCTD-PAH were included in the study. Comparison with MCTD patients without PAH and multivariate analysis revealed that pericarditis, polyarthritis, thrombocytopenia, interstitial lung disease (ILD) and anti-Sm antibodies were independent predictive factors of PAH/PH in MCTD. Estimated survival rates at 1, 5 and 10 years following PAH diagnosis were 83%, 67% and 56%, respectively. MCTD-PAH presentation and survival did not differ from SLE-PAH and SSc-PAH. Multivariate analysis revealed that tobacco exposure was an independent factor predictive of mortality in MCTD-PAH. Conclusion PAH is a rare and severe complication of MCTD associated with a 56% 10-year survival. We identified ILD, pericarditis, thrombocytopenia and anti-Sm antibodies as risk factors for PAH in MCTD and tobacco exposure as a predictor of mortality in MCTD-PAH. [ABSTRACT FROM AUTHOR]

Objective To evaluate the role of induced immunosuppressive T regulatory (iTr) 35 cells in SSc-related inflammation and fibrosis. Methods Sixty-eight SSc patients were enrolled in this study. Subsets of iTr35 and Tr1 were measured by flow cytometry. IL-35 and IL-10 levels were measured using ELISA. Expressions of iTr35, Tr1, fibrosis-related genes and proteins associated with signalling pathways were determined using immunofluorescence, western blot and immunohistochemistry assays. Results In peripheral blood, the proportions of the iTr35 cells were higher and Tr1 cells were lower than the control group. Similarly, IL-35 expression was increased, while IL-10 levels were decreased. In fibroblasts from skin tissue, the expression levels of EBI3, IL-12Ap35, Foxp3 and IL-10 were decreased, but collagen I, TGF-β, alpha smooth muscle actin (α-SMA) and fibronectin levels were increased. Phosphorylated STAT3/6 were increased, but iTr35 and Tr1 cell levels were significantly decreased. When CD4+ cells were incubated with both recombinant human (rh)IL-35 and rhIL-10, the cell numbers of iTr35 and Tr1 were greater than the same type of cells treated with rhIL-35 or rhIL-10 alone. However, the viability of conventional CD4+ T cells was decreased by gradually increasing iTr35 cells. Moreover, iTr35 cells affected α-SMA expression through the STAT3/6 signalling pathway. Conclusion Both iTr35 and Tr1 cells are involved in SSc-related inflammation and fibrosis. IL-35 can induce iTr35 cells, showing a synergistic effect with IL-10. We also found that iTr35 cells can inhibit T cell proliferation and differentiation via the STAT3/6 signalling pathway, thereby causing fibrosis. [ABSTRACT FROM AUTHOR]