Contribution of Telomere Length to Systemic Sclerosis Onset: A Mendelian Randomization Study

Mendelian randomization; Systemic sclerosis; Telomere lengthAleatorització mendeliana; Esclerosi sistèmica; Longitud dels telòmersAleatorización mendeliana; Esclerosis sistémica; Longitud de los telómerosAlthough previous studies have suggested a relationship between telomere shortening and systemic sclerosis (SSc), the association between these two traits remains poorly understood. The objective of this study was to assess the causal relationship between telomere length in leukocytes (LTL) and SSc using the two-sample Mendelian randomization approach, with the genome-wide association study data for both LTL and SSc. The results of inverse-variance weighted regression (OR = 0.716 [95% CI 0.528–0.970], p = 0.031) and the Mendelian randomization pleiotropy residual sum and outlier method (OR = 0.716 [95% CI 0.563–0.911], p = 0.035) indicate an association between telomere length and SSc. Specifically, longer genetically predicted LTL is associated with a reduced risk of SSc. Sensitivity tests highlight the significant roles of the variants rs10936599 and rs2736100 annotated to the TERC and TERT genes, respectively. Our findings suggest an influence of telomere length in leukocytes on the development of SSc.This work was supported by Redes de Investigación Cooperativa Orientadas a Resultados en Salud (RICORS) (RD21/0002/0039) funded by Instituto de Salud Carlos III (ISCIII) from the Spanish Ministry of Science and Innovation. M.A.H. is a recipient of a Miguel Servet fellowship (CP21/00132) from ISCIII. G.V.M was funded by Grant PRE2019-087586 funded by MCIN/AEI/10.13039/501100011033 and by “ESF Investing in your future”. I.R.M was supported by the program FPU (FPU21/02746) funded by the Spanish Ministry of University

High sensitivity and negative predictive value of the DETECT algorithm for an early diagnosis of pulmonary arterial hypertension in systemic sclerosis : application in a single center

Pulmonary arterial hypertension (PAH) is one of the most relevant causes of death in systemic sclerosis. The aims of this study were to analyse the recently published DETECT algorithm comparing it with European Society of Cardiology/European Respiratory Society (ESC/ERS) 2009 guidelines: as screening of PAH; (2) identifying median pulmonary arterial pressure (mPAP) ≥21 mmHg; and (3) determining any group of pulmonary hypertension (PH). Eighty-three patients fulfilling LeRoy's systemic sclerosis diagnostic criteria with at least right heart catheterization were studied retrospectively. Clinical data, serological biomarkers, echocardiographic and hemodynamic features were collected. SPSS 20.0 was used for statistical analysis. According to right heart catheterization findings, 35 patients with PAH and 28 with no PH met the standards for DETECT algorithm analysis: 27.0% of patients presented with functional class III/IV. Applying DETECT, the sensitivity was 100%, specificity 42.9%, the positive predictive value 68.6% and the negative predictive value 100%, whereas employing the ESC/ERS guidelines these were 91.4%, 85.7%, 88.9% and 89.3%, respectively. There were no missed diagnoses of PAH using DETECT compared with three patients missed (8.5%) using ESC/ERS guidelines. The DETECT algorithm also showed greater sensitivity and negative predictive value to identify patients with mPAP ≥21 mmHg or with any type of PH. The DETECT algorithm is confirmed as an excellent screening method due to its high sensitivity and negative predictive value, minimizing missed diagnosis of PAH. DETECT would be accurate either for early diagnosis of borderline mPAP or any group of PH

A computer-aided diagnosis of multiple sclerosis based on mfVEP recordings.

Introduction: The aim of this study is to develop a computer-aided diagnosis system to identify subjects at differing stages of development of multiple sclerosis (MS) using multifocal visual-evoked potentials (mfVEPs). Using an automatic classifier, diagnosis is performed first on the eyes and then on the subjects. Patients: MfVEP signals were obtained from patients with Radiologically Isolated Syndrome (RIS) (n = 30 eyes), patients with Clinically Isolated Syndrome (CIS) (n = 62 eyes), patients with definite MS (n = 56 eyes) and 22 control subjects (n = 44 eyes). The CIS and MS groups were divided into two subgroups: those with eyes affected by optic neuritis (ON) and those without (non-ON). Methods: For individual eye diagnosis, a feature vector was formed with information about the intensity, latency and singular values of the mfVEP signals. A flat multiclass classifier (FMC) and a hierarchical classifier (HC) were tested and both were implemented using the k-Nearest Neighbour (k-NN) algorithm. The output of the best eye classifier was used to classify the subjects. In the event of divergence, the eye with the best mfVEP recording was selected. Results: In the eye classifier, the HC performed better than the FMC (accuracy = 0.74 and extended Matthew Correlation Coefficient (MCC) = 0.68). In the subject classification, accuracy = 0.95 and MCC = 0.93, confirming that it may be a promising tool for MS diagnosis. Chirped-pulse φOTDR provides distributed strain measurement via a time-delay estimation process. We propose a lower bound for performance, after reducing sampling error and compensating phase-noise. We attempt to reach the limit, attaining unprecedented pε/√Hz sensitivities. Conclusion: In addition to amplitude (axonal loss) and latency (demyelination), it has shown that the singular values of the mfVEP signals provide discriminatory information that may be used to identify subjects with differing degrees of the disease.Secretaría de Estado de Investigación, Desarrollo e InnovaciónInstituto de Salud Carlos II

Standardized incidence ratios and risk factors for cancer in patients with systemic sclerosis: Data from the Spanish Scleroderma Registry (RESCLE)

Aim: Patients with systemic sclerosis (SSc) are at increased risk of cancer, a growing cause of non-SSc-related death among these patients. We analyzed the increased cancer risk among Spanish patients with SSc using standardized incidence ratios (SIRs) and identified independent cancer risk factors in this population. Material and methods: Spanish Scleroderma Registry data were analyzed to determine the demographic characteristics of patients with SSc, and logistic regression was used to identify cancer risk factors. SIRs with 95% confidence intervals (CIs) relative to the general Spanish population were calculated. Results: Of 1930 patients with SSc, 206 had cancer, most commonly breast, lung, hematological, and colorectal cancers. Patients with SSc had increased risks of overall cancer (SIR 1.48, 95% CI 1.36-1.60; P < 0.001), and of lung (SIR 2.22, 95% CI 1.77-2.73; P < 0.001), breast (SIR 1.31, 95% CI 1.10-1.54; P = 0.003), and hematological (SIR 2.03, 95% CI 1.52-2.62; P < 0.001) cancers. Cancer was associated with older age at SSc onset (odds ratio [OR] 1.22, 95% CI 1.01-1.03; P < 0.001), the presence of primary biliary cholangitis (OR 2.35, 95% CI 1.18-4.68; P = 0.015) and forced vital capacity <70% (OR 1.8, 95% CI 1.24-2.70; P = 0.002). The presence of anticentromere antibodies lowered the risk of cancer (OR 0.66, 95% CI 0.45-0.97; P = 0.036). Conclusions: Spanish patients with SSc had an increased cancer risk compared with the general population. Some characteristics, including specific autoantibodies, may be related to this increased risk

Impact of interstitial lung disease on the survival of systemic sclerosis with pulmonary arterial hypertension

To assess severity markers and outcomes of patients with systemic sclerosis (SSc) with or without pulmonary arterial hypertension (PAH-SSc/non-PAH-SSc), and the impact of interstitial lung disease (ILD) on PAH-SSc. Non-PAH-SSc patients from the Spanish SSc registry and PAH-SSc patients from the Spanish PAH registry were included. A total of 364 PAH-SSc and 1589 non-PAH-SSc patients were included. PAH-SSc patients had worse NYHA-functional class (NYHA-FC), worse forced vital capacity (FVC) (81.2 ± 20.6% vs 93.6 ± 20.6%, P &lt; 0.001), worse tricuspid annular plane systolic excursion (TAPSE) (17.4 ± 5.2 mm vs 19.9 ± 6.7 mm, P &lt; 0.001), higher incidence of pericardial effusion (30% vs 5.2%, P &lt; 0.001) and similar prevalence of ILD (41.8% vs. 44.9%). In individuals with PAH-SSc, ILD was associated with worse hemodynamics and pulmonary function tests (PFT). Up-front combination therapy was used in 59.8% and 61.7% of patients with and without ILD, respectively. Five-year transplant-free survival rate was 41.1% in PAH-SSc patients and 93.9% in non-PAH-SSc patients (P &lt; 0.001). Global survival of PAH-SSc patients was not affected by ILD regardless its severity. The multivariate survival analysis in PAH-SSc patients confirmed age at diagnosis, worse NYHA-FC, increased PVR, reduced DLCO, and lower management with up-front combination therapy as major risk factors. In conclusion, in PAH-SSc cohort risk of death was greatly increased by clinical, PFT, and hemodynamic factors, whereas it was decreased by up-front combination therapy. Concomitant ILD worsened hemodynamics and PFT in PAH-SSc but not survival regardless of FVC impairment

Impact of interstitial lung disease on the survival of systemic sclerosis with pulmonary arterial hypertension

To assess severity markers and outcomes of patients with systemic sclerosis (SSc) with or without pulmonary arterial hypertension (PAH-SSc/non-PAH-SSc), and the impact of interstitial lung disease (ILD) on PAH-SSc. Non-PAH-SSc patients from the Spanish SSc registry and PAH-SSc patients from the Spanish PAH registry were included. A total of 364 PAH-SSc and 1589 non-PAH-SSc patients were included. PAH-SSc patients had worse NYHA-functional class (NYHA-FC), worse forced vital capacity (FVC) (81.2 +/- 20.6% vs 93.6 +/- 20.6%, P < 0.001), worse tricuspid annular plane systolic excursion (TAPSE) (17.4 +/- 5.2 mm vs 19.9 +/- 6.7 mm, P < 0.001), higher incidence of pericardial effusion (30% vs 5.2%, P < 0.001) and similar prevalence of ILD (41.8% vs. 44.9%). In individuals with PAH-SSc, ILD was associated with worse hemodynamics and pulmonary function tests (PFT). Up-front combination therapy was used in 59.8% and 61.7% of patients with and without ILD, respectively. Five-year transplant-free survival rate was 41.1% in PAH-SSc patients and 93.9% in non-PAH-SSc patients (P < 0.001). Global survival of PAH-SSc patients was not affected by ILD regardless its severity. The multivariate survival analysis in PAH-SSc patients confirmed age at diagnosis, worse NYHA-FC, increased PVR, reduced DLCO, and lower management with up-front combination therapy as major risk factors. In conclusion, in PAH-SSc cohort risk of death was greatly increased by clinical, PFT, and hemodynamic factors, whereas it was decreased by up-front combination therapy. Concomitant ILD worsened hemodynamics and PFT in PAH-SSc but not survival regardless of FVC impairment

Complement component C4 structural variation and quantitative traits contribute to sex-biased vulnerability in systemic sclerosis

Altres ajuts: Fondo Europeo de Desarrollo Regional (FEDER), "A way of making Europe".Copy number (CN) polymorphisms of complement C4 play distinct roles in many conditions, including immune-mediated diseases. We investigated the association of C4 CN with systemic sclerosis (SSc) risk. Imputed total C4, C4A, C4B, and HERV-K CN were analyzed in 26,633 individuals and validated in an independent cohort. Our results showed that higher C4 CN confers protection to SSc, and deviations from CN parity of C4A and C4B augmented risk. The protection contributed per copy of C4A and C4B differed by sex. Stronger protection was afforded by C4A in men and by C4B in women. C4 CN correlated well with its gene expression and serum protein levels, and less C4 was detected for both in SSc patients. Conditioned analysis suggests that C4 genetics strongly contributes to the SSc association within the major histocompatibility complex locus and highlights classical alleles and amino acid variants of HLA-DRB1 and HLA-DPB1 as C4-independent signals

Reducing the environmental impact of surgery on a global scale: systematic review and co-prioritization with healthcare workers in 132 countries

Abstract Background Healthcare cannot achieve net-zero carbon without addressing operating theatres. The aim of this study was to prioritize feasible interventions to reduce the environmental impact of operating theatres. Methods This study adopted a four-phase Delphi consensus co-prioritization methodology. In phase 1, a systematic review of published interventions and global consultation of perioperative healthcare professionals were used to longlist interventions. In phase 2, iterative thematic analysis consolidated comparable interventions into a shortlist. In phase 3, the shortlist was co-prioritized based on patient and clinician views on acceptability, feasibility, and safety. In phase 4, ranked lists of interventions were presented by their relevance to high-income countries and low–middle-income countries. Results In phase 1, 43 interventions were identified, which had low uptake in practice according to 3042 professionals globally. In phase 2, a shortlist of 15 intervention domains was generated. In phase 3, interventions were deemed acceptable for more than 90 per cent of patients except for reducing general anaesthesia (84 per cent) and re-sterilization of ‘single-use’ consumables (86 per cent). In phase 4, the top three shortlisted interventions for high-income countries were: introducing recycling; reducing use of anaesthetic gases; and appropriate clinical waste processing. In phase 4, the top three shortlisted interventions for low–middle-income countries were: introducing reusable surgical devices; reducing use of consumables; and reducing the use of general anaesthesia. Conclusion This is a step toward environmentally sustainable operating environments with actionable interventions applicable to both high– and low–middle–income countries

Enfermedad pulmonar intersticial en Esclerosis Sistémica: diferencia en la presentación clínica y evolución clínica y evolución entre pacientes con anticuerpos Scl-70 frente PM-Scl

La esclerosis sistémica (ES) es una enfermedad autoinmune multisistémica que afecta de forma variable a diferentes órganos. En el pulmón produce la enfermedad pulmonar intersticial difusa (EPID), cuyo pronóstico difiere según el autoanticuerpo asociado. Se estudiaron las características clínicas y espirométricas de 63 pacientes diagnosticados de ES y EPID, con positividad para anti-Scl-70 o anti-PM-Scl. En el grupo anti-Scl-70 se documentó mayor prevalencia de úlceras digitales y afección gastrointestinal, con mayor pérdida de capacidad vital forzada (CVF) al final del seguimiento y mayor proporción de patrón restrictivo grave. El grupo anti-PM-Scl presentó mayor miopatía inflamatoria y mejor evolución espirométrica.L'esclerosi sistèmica (ES) és una malaltia autoimmune multisistèmica que afecta de forma variable a diferents òrgans. Al pulmó produeix la malaltia pulmonar intersticial difusa (EPID), el pronòstic difereix segons el autoanticos associat. Es van estudiar les característiques clíniques i espiromètriques de 63 pacients diagnosticats d'ES i EPID, amb positivitat a l’anti-Scl-70 o anti-PM-Scl. En el grup anti-Scl-70 es va documentar major prevalença d'úlceres digitals i d’afecció gastrointestinal, amb major pèrdua de capacitat vital forçada (CVF) al final del seguiment i major proporció de patró restrictiu greu. El grup d’anti-PM-Scl va presentar major miopatia inflamatòria i millor evolució espiromètric

Estudio de la afección pulmonar asociada a esclerodermia sistémica: biomarcadores pronósticos y detección precoz

La esclerodermia (ES) es una enfermedad autoinmune sistémica, poco prevalente, suponiendo la afección pulmonar asociada a la enfermedad la primera causa de muerte tanto la enfermedad pulmonar intersticial (EPI) como la hipertensión arterial pulmonar (HAP). Es por tanto, de vital importancia estudiar tanto factores asociados al pronóstico de las afecciones respiratorias así como poder diagnosticar precozmente las mismas. En el caso de la EPI es ampliamente conocido que los pacientes con anticuerpos anti-Scl-70 presentan un curso evolutivo de la fibrosis más agresivo, y con una supervivencia reducida. Sin embargo, no se ha estudiado específicamente la evolución de los pacientes con anticuerpos anti-PM/Scl, ni se ha evaluado de forma completa el valor pronóstico de biomarcadores no invasivos en el condensado de aire exhalado (CAE), ni en el aire exhalado (AE). Los objetivos de los dos primeros estudios fueron establecer el curso de la EPI asociada a los anticuerpos anti-PM/Scl comparándolos con pacientes con anti-Scl-70, así como analizar los biomarcadores en CAE y AE para valorar su correlación con las pruebas de función respiratoria y su valor pronóstico. El primer artículo mostró como los pacientes con anti-PM/Scl presentaban unas características clínicas diferentes al grupo con anti-Scl-70, con mayor frecuencia de subtipo cutáneo ES limitada y miopatía inflamatoria y menor prevalencia de vasculopatía periférica y afección gastrointestinal. Además los pacientes con anticuerpos anti-PM/Scl presentaron una estabilización de la capacidad vital forzada (FVC) durante el seguimiento, una mayor supervivencia libre de progresión y una menor supervivencia libre de enfermedad respiratoria restrictiva grave. En el segundo artículo se identificó que valores en el CAE de pH inferiores a 7.88 se relacionaron con una menor supervivencia libre de progresión de la enfermedad. Del mismo modo, valores de FeNO en el AE menores a 10.75 ppb se asociaron a una peor supervivencia libre de progresión de la enfermedad. En los pacientes con EPI asociada a esclerodermia se documentó una correlación inversa entre cifras elevadas de CO en AE tanto con niveles disminuidos de FVC de forma basal como al final del seguimiento. En el caso de la HAP, se ha comprobado la importancia de los métodos de cribaje en el aumento de la supervivencia debido a la instauración temprana del tratamiento vasodilatador específico. Recientemente se ha publicado un nuevo algoritmo de diagnóstico precoz de HAP específico para los pacientes con esclerodermia denominado DETECT, sin embargo, no ha sido validado ampliamente en cohortes externas. Además, los pacientes con ES que presentan valores de hipertensión pulmonar (HP) limítrofe se encuentran en un alto riesgo de desarrollar HAP establecida y una mayor mortalidad. Así mismo, los pacientes con HP relacionada con la EPI o por cardiopatía izquierda también presentan un peor pronóstico. De este modo, es importante investigar la capacidad de dicho algoritmo en el diagnóstico temprano de la HP limítrofe y en otros tipos de HP. Por ello, los objetivos del tercer estudio fueron validar el algoritmo DETECT en una cohorte externa, comprobar la capacidad del algoritmo en identificar precozmente la HP limítrofe o la HAP establecida y por último, valorar la capacidad del algoritmo DETECT en detectar de forma precoz cualquier tipo de HP. Se realizó una validación del algoritmo DETECT, objetivando que en nuestra cohorte de enfermos presentó una alta sensibilidad y valor predictivo negativo, disminuyendo el número de falsos negativos superando la capacidad diagnóstica de las recomendaciones previas. Con el algoritmo DETECT también se identificaron el grupo de enfermos con HP limítrofe y HAP, así como los pacientes con HP del Grupo 2 y 3 de la clasificación de la OMS.The systemic sclerosis (SSc) is a systemic autoimmune disease, with a low prevalence in the population. The pulmonary involvement related to SSc is the leading cause of death, as interstitial lung disease (ILD) or pulmonary arterial hypertension (PAH). Then, it is very important the study of factors associated to the prognostic of pulmonary involvement and a screening of them. It is well known that patients with SSc-ILD and anti-Scl-70 antibodies have a more aggressive fibrosis outcome and a reduced survival. However, the outcome of patients with SSc-ILD and anti-PM/Scl has not been established, neither the prognostic value of non-invasive biomarkers in EBC and EB. The aims of the two first works were study the outcome of ILD associated to the anti-PM/Scl antibodies compared with patients with anti-Scl-70, and analyse the biomarkers in EBC and EB to evaluate their correlation with the pulmonary function test and their prognostic value. The first study showed that the patients with anti-PM/Scl had different clinic characteristics than anti-Scl-70 group, with higher frequency of limited cutaneous SSc, inflammatory myopathy, and lower prevalence of peripheral vascular disease and gastrointestinal disease. The patients with anti-PM/Scl antibodies presented stabilization in forced vital capacity (FVC) during the follow-up, a greater progression-free survival and lower severe restrictive free survival. In the second study was identified that in the EBC pH values lower than 7.88 were related with reduced progression-free survival. Moreover, FeNO values in the EB lower than 10.75 ppb were associated with a worse progression-free survival. In the patients with SSc-ILD was documented an inverse correlation between elevated values of CO in EB and diminished FVC at baseline and the end of follow-up. In the case of PAH, it has been determined the relevance of screening methods for the increase of the survival secondary to the initiation of early vasodilator specific treatment. Recently, a new algorithm for the early diagnosis of PAH in SSc patients has been published, although it has not widely validated in external cohorts. SSc patients with borderline pulmonary hypertension (PH) have a high risk to develop PAH and higher mortality. Patients with PH related with ILD or left heart disease also has worse prognosis. In this way, it would be relevant study the capacity of this algorithm in the early diagnosis of borderline PH and other groups of PH. The aims of the third study were to validate the DETECT algorithm in an external cohort, determine the capacity of the algorithm for an early identification of borderline PH and PAH, and finally to value the DETECT algorithm capacity to an early identification of any sort of PH. A validation of DETECT algorithm was performed, objectifying that in our cohort presented a high sensibility and negative predictive value, reducing the number of false negative improving the diagnostic capacity than the previous recommendations. With the DETECT algorithm also were identified the group of patients with borderline PH and HAP, and also the patients with group 2 and 3 PH of the WHO classification