Key factors in the choice of appropriate outcomes for clinical trials. / Factores clave en la elección de desenlaces apropiados para estudios clínicos.

Health research is the foundation of medical knowledge and healthcare system recommendations. Therefore, choosing appropriate outcomes in studies of therapeutic interventions is a fundamental step in producing evidence and, subsequently, for decision-making. In this article, we propose three key factors for the choice of outcomes: the inclusion of patient-reported outcomes, since they focus on the patient's perception of their health status and quality of life; the consideration of clinically relevant outcomes, which are direct measurements of the patient's health status and, therefore, will be decisive in decision-making; and the use of core outcome sets, a tool that standardizes the measurement and interpretation of outcomes, facilitating the production and synthesis of appropriate evidence for the evidence ecosystem. The correct choice of outcomes will help health decision-makers and clinicians deliver appropriate patient-centered care and optimize the use of resources in healthcare and clinical research.

La investigación en salud es la base del conocimiento médico y de las recomendaciones en los sistemas de salud. Por ello, la elección de desenlaces apropiados en estudios de intervenciones terapéuticas es un paso fundamental en la producción de evidencia y, posteriormente, para la toma de decisiones. En este artículo proponemos tres factores clave para la elección de desenlaces: la inclusión de desenlaces reportados por pacientes, ya que ponen el foco del efecto de la intervención en la percepción que tienen los propios pacientes de su estado de salud y calidad de vida; la consideración de desenlaces clínicamente relevantes, los cuales son mediciones directas del estado de salud del paciente y, por ende serán determinantes en la toma de decisiones; y la utilización de herramienta que estandariza y permite la homogeneización en la medición e interpretación de desenlaces, facilitando la producción y posterior síntesis de evidencia apropiada para el ecosistema de evidencia. La correcta elección de los desenlaces permitirá que la evidencia generada de estos estudios ayude a los tomadores de decisiones en salud y los profesionales clínicos a entregar cuidados apropiados centrados en el paciente y a optimizar el uso de recursos en salud e investigación clínica.

Discovery of Potent Glycosidases Enables Quantification of Smoke-Derived Phenolic Glycosides through Enzymatic Hydrolysis.

When grapes are exposed to wildfire smoke, certain smoke-related volatile phenols (VPs) can be absorbed into the fruit, where they can be then converted into volatile-phenol (VP) glycosides through glycosylation. These volatile-phenol glycosides can be particularly problematic from a winemaking standpoint as they can be hydrolyzed, releasing volatile phenols, which can contribute to smoke-related off-flavors. Current methods for quantitating these volatile-phenol glycosides present several challenges, including the requirement of expensive capital equipment, limited accuracy due to the molecular complexity of the glycosides, and the utilization of harsh reagents. To address these challenges, we proposed an enzymatic hydrolysis method enabled by a tailored enzyme cocktail of novel glycosidases discovered through genome mining, and the generated VPs from VP glycosides can be quantitated by gas chromatography-mass spectrometry (GC-MS). The enzyme cocktails displayed high activities and a broad substrate scope when using commercially available VP glycosides as the substrates for testing. When evaluated in an industrially relevant matrix of Cabernet Sauvignon wine and grapes, this enzymatic cocktail consistently achieved a comparable efficacy of acid hydrolysis. The proposed method offers a simple, safe, and affordable option for smoke taint analysis.

Critical behavior of cascading failures in overloaded networks.

While network abrupt breakdowns due to overloads and cascading failures have been studied extensively, the critical exponents and the universality class of such phase transitions have not been discussed. Here, we study breakdowns triggered by failures of links and overloads in networks with a spatial characteristic link length ζ. Our results indicate that this abrupt transition has features and critical exponents similar to those of interdependent networks, suggesting that both systems are in the same universality class. For weakly embedded systems (i.e., ζ of the order of the system size L) we observe a mixed-order transition, where the order parameter collapses following a long critical plateau. On the other hand, strongly embedded systems (i.e., ζ≪L) exhibit a pure first-order transition, involving nucleation and the growth of damage. The system's critical behavior in both limits is similar to that observed in interdependent networks.

Higher Synovial Immunohistochemistry Reactivity of IL-17A, Dkk1, and TGF-ß1 in Patients with Early Psoriatic Arthritis and Rheumatoid Arthritis Could Predict the Use of Biologics.

BACKGROUND: Delay in diagnosis and therapy in patients with arthritis commonly leads to progressive articular damage. The study aimed to investigate the immunohistochemical reactivity of synovial cytokines associated with inflammation and the bone erosives/neoformatives processes among individuals diagnosed with psoriatic arthritis (PsA), rheumatoid arthritis (RA), osteoarthritis (OA), and radiographic axial spondyloarthritis (r-axSpA), with the intention of identifying potential biomarkers. METHODS: Specimens were collected from the inflamed knee joints of patients referred for arthroscopic procedures, and the synovial tissue (ST) was prepared for quantifying protein expression through immunohistochemical analysis (% expressed in Ratio_Area-Intensity) for TGF-ß1, IL-17A, Dkk1, BMP2, BMP4, and Wnt5b. The collected data underwent thorough analysis and examination of their predictive capabilities utilising receiver operating characteristic (ROC) curves. RESULTS: Valid synovial tissue samples were acquired from 40 patients for IHC quantification analysis. Initially, these patients had not undergone treatment with biologics. However, after 5 years, 4 out of 13 patients diagnosed with PsA and two out of nine patients diagnosed with RA had commenced biologic treatments. Individuals with early PsA who received subsequent biologic treatment exhibited significantly elevated IHC reactivity in ST for TGF-ß1 (p = 0.015). Additionally, patients with both PsA and RA who underwent biologic therapy displayed increased IHC reactivity for IL-17A (p = 0.016), TGF-ß1 (p = 0.009), and Dkk1 (p = 0.042). ROC curve analysis of IHC reactivity for TGF-ß1, Dkk1, and IL-17A in the synovial seems to predict future treatment with biologics in the next 5 years with the area under the curve (AUC) of a combined sum of the three values: AUC: 0.828 (95% CI: 0.689-0.968; p 0.005) S 75% E 84.4%. CONCLUSIONS: Higher synovial immunohistochemistry reactivity of IL-17A, Dkk1, and TGF-ß1 in patients with early psoriatic arthritis and rheumatoid arthritis may serve as potential indicators for predicting the necessity of utilising biologic treatments.

Metabolic syndrome is not associated with erosive hand osteoarthritis: a cross-sectional study using data from the PROCOAC cohort.

To delineate the phenotype of erosive hand osteoarthritis (EHOA) in a Spanish population and assess its correlation with metabolic syndrome. We conducted a cross-sectional study using baseline data from the Prospective Cohort of Osteoarthritis from A Coruña (PROCOAC). Demographic and clinical variables, obtained through questionnaires, clinical examinations, and patient analytics, were compared among individuals with hand OA, with and without EHOA. We performed appropriate univariate and multivariate stepwise regression analyses using SPSS v28. Among 1039 subjects diagnosed with hand OA, 303 exhibited EHOA. Multivariate logistic regression analysis revealed associations with inflamed joints, nodular hand OA, and total AUSCAN. Furthermore, the association with a lower prevalence of knee OA remained significant. The influence of metabolic syndrome (MetS) on EHOA patients was analyzed by including MetS as a covariate in the model. It was observed that MetS does not significantly impact the presence of EHOA, maintaining the effect size of other factors. In conclusion, in the PROCOAC cohort, EHOA is associated with nodular hand OA, inflammatory hand OA, and a higher total AUSCAN. However, EHOA is linked to a lower prevalence of knee OA. Importantly, in our cohort, no relationship was found between EHOA and MetS.

Long term clinical outcome of sirolimus drug coated balloons in large coronary vessels.

BACKGROUND: Studies evaluating the safety and efficacy of drug coating balloons (DCB) for the treatment of lesions in large coronary vessel are limited. AIMS: Our study aimed to evaluate the performance of a sirolimus DCB in large coronary arteries. METHODS: We analyzed all the procedures included in the EASTBOURNE Registry (NCT03085823) enrolling patients with a clinical indication to percutaneous coronary intervention performed by a sirolimus DCB according to investigator judgment. In the present analysis, a cut-off of 2.75 mm was used to define large coronary arteries. Primary endpoint of the study was clinically driven target lesion revascularization (TLR) at 24 months whereas secondary endpoint included procedural success, myocardial infarction (MI), cardiac death and total mortality. RESULTS: Among the 2123 patients and 2440 lesions enrolled in the EASTBOURNE study between 2016 and 2020, 757 patients/810 lesions fulfilled the criteria for the present analysis. Mean reference vessel diameter was 3.2 ± 0.3 mm with mean lesion length of 22 ± 7 mm. Procedural success was high (96%) and at 2-year follow up the device showed a good efficacy with a TLR rate of 9%. There were 34 deaths (4.5%), 30 MIs (4%) and 8 BARC type 3-5 bleedings (1.1%). In-stent restenosis (629 lesions) and de novo lesions (181) were associated with 11% and 4% rates of TLR at 2 years, respectively (p = 0.003). CONCLUSIONS: Clinical performance of a sirolimus DCB in large coronary artery vessels shows promising signals at 2-year follow up, both in de novo and in-stent restenosis lesions.

Mitonuclear epistasis involving TP63 and haplogroup Uk: Risk of rapid progression of knee OA in patients from the OAI.

OBJECTIVE: To investigate genetic interactions between mitochondrial deoxyribonucleic acid (mtDNA) haplogroups and nuclear single nucleotide polymorphisms (nSNPs) to analyze their impact on the development of the rapid progression of knee osteoarthritis (OA). DESIGN: A total of 1095 subjects from the Osteoarthritis Initiative, with a follow-up time of at least 48-months, were included. Appropriate statistical approaches were performed, including generalized estimating equations adjusting for age, gender, body mass index, contralateral knee OA, Western Ontario and McMaster Universities Osteoarthritis Index pain, previous injury in target knee and the presence of the mtDNA variant m.16519C. Additional genomic data consisted in the genotyping of Caucasian mtDNA haplogroups and eight nSNPs previously associated with the risk of knee OA in robust genome-wide association studies. RESULTS: The simultaneous presence of the G allele of rs12107036 at TP63 and the haplogroup Uk significantly increases the risk of a rapid progression of knee OA (odds ratio = 1.670; 95% confidence interval [CI]: 1.031-2.706; adjusted p-value = 0.027). The assessment of the population attributable fraction showed that the highest proportion of rapid progressors was under the simultaneous presence of the G allele of rs12107036 and the haplogroup Uk (23.4%) (95%CI: 7.89-38.9; p-value < 0.05). The area under the curve of the cross-validation model (0.730) was very similar to the obtained for the predictive model (0.735). A nomogram was constructed to help clinicians to perform clinical trials or epidemiologic studies. CONCLUSIONS: This study demonstrates the existence of a mitonuclear epistasis in OA, providing new mechanisms by which nuclear and mitochondrial variation influence the susceptibility to develop different OA phenotypes.

Usefulness of risk scores and predictors of atrial fibrillation recurrence after elective electrical cardioversion.

INTRODUCTION: Electrical cardioversion (ECV) is a frequently used procedure for restoring sinus rhythm in atrial fibrillation (AF); however, the rate of recurrence is high. The identification of patients at high risk of recurrence could influence the decision-making process. The present study evaluates the predictive value of risk scores in atrial fibrillation recurrence after elective electrical cardioversion. METHODS: Unicentric, observational, and prospective study of adult patients who have undergone an elective ECV as rhythm control strategy between July 2017 and September 2022. RESULTS: From the 283 analyzed patients (mean age 63.95 ± 10.76212, 74.9% male); 99 had paroxysmal AF (35%) and 159 (59%) presented AF recurrence during a follow-up of 6 months. In patients with post-ECV AF recurrence, the period of time from diagnosis until the performance of the procedure was longer (393 ± 891 vs. 195 ± 527, p = .02). No paroxysmal AF (71.3% vs. 57.8%, p = .02) and LA dilatation with >40 mL/m2 (35.9% vs. 23.3%, p = .02) volumes were more frequent within these patients. AF recurrence was more frequent in patients who had previous ECV (HR = 1.32; 95% CI: 1.12-2.35; p = .01) and more than 1 shock to recover sinus rhythm (HR = 1.62; 95% CI: 1.07-1.63; p = .01). The SLAC, ALARMEc, ATLAS, and CAAP-AF scores were statistically significant, although with a moderate predictive capacity for post-ECV recurrence. CONCLUSIONS: Risk scores analyzed showed a modest value predicting AF recurrence after ECV. Previous ECV, and greater difficulty in restoring SR were independent predictors of recurrence.

Sirolimus-coated balloon in acute and chronic coronary syndromes: subanalysis of the EASTBOURNE registry.

INTRODUCTION AND OBJECTIVES: The PEACE study (Performance of a sirolimus-eluting balloon strategy in acute and chronic coronary syndromes) investigated for the first time whether a sirolimus-coated balloon (SCB) (Magic Touch, Concept Medical, India) is associated with different outcomes depending on whether it is used in acute coronary syndromes (ACS) or chronic coronary syndromes (CCS). METHODS: This was a post-hoc analysis from the all-comers EASTBOURNE Registry (NCT03085823). Out of 2083 patients enrolled, an SCB was used to treat 968 (46.5%) ACS and 1115 (53.5%) CCS patients. The primary endpoint was target lesion revascularization at 12 months, while secondary endpoints were angiographic success and major adverse cardiovascular events. RESULTS: Baseline demographics, mean reference vessel diameter and mean lesion length were comparable between ACS and CCS. Predilatation was more commonly performed in ACS (P=.007). SCB was inflated at a standard pressure in both groups with a slight trend toward longer inflation time in ACS. Angiographic success was high in both groups (ACS 97.4% vs CCS 97.7%, P=.820) with limited bailout stenting. Similarly, at 12 months the cumulative incidence of target lesion revascularization (ACS 6.6% vs CCS 5.2%, P=.258) was comparable between ACS and CCS. Conversely, a higher rate of major adverse cardiovascular events in acute presenters was mainly driven by myocardial infarction recurrencies (ACS 10.4% vs CCS 8.3%, P=.009). In-stent restenosis showed a higher proportion of target lesion revascularization and major adverse cardiovascular events than de novo lesions, independently of the type of presentation at the index procedure. CONCLUSIONS: This SCB shows good performance in terms of acute and 1-year outcomes independently of the clinical presentation.

Identifying the most important data for research in the field of infectious diseases: thinking on the basis of artificial intelligence / Identificación de los datos más importantes para el desarrollo de inteligencia artificial en el campo de las enfermedades infecciosas

Objectives. Clinical data on which artificial intelligence (AI) algorithms are trained and tested provide the basis to im prove diagnosis or treatment of infectious diseases (ID). We aimed to identify important data for ID research to prioritise efforts being undertaken in AI programmes. Material and methods. We searched for 1,000 articles from high-impact ID journals on PubMed, selecting 288 of the latest articles from 10 top journals. We classified them into structured or unstructured data. Variables were homogenised and grouped into the following categories: epidemiology, ad mission, demographics, comorbidities, clinical manifestations, laboratory, microbiology, other diagnoses, treatment, out comes and other non-categorizable variables. Results. 4,488 individual variables were collected, from the 288 articles. 3,670 (81.8%) variables were classified as structured data whilst 818 (18.2%) as unstructured data. From the structured data, 2,319 (63.2%) variables were classified as direct—retrievable from electronic health records—whilst 1,351 (36.8%) were indirect. The most frequent unstructured data were related to clinical manifestations and were repeated across articles. Data on demographics, comorbidities and mi crobiology constituted the most frequent group of variables. Conclusions. This article identified that structured vari ables have comprised the most important data in research to generate knowledge in the field of ID. Extracting these data should be a priority when a medical centre intends to start an AI programme for ID. We also documented that the most important unstructured data in this field are those related to clinical manifestations. Such data could easily undergo some structuring with the use of semi-structured medical records focusing on a few symptoms (AU)

Objetivos. Los datos clínicos sobre los que se entrenan y prueban los algoritmos de inteligencia artificial (IA) proporcio nan la base para mejorar el diagnóstico o el tratamiento de las enfermedades infecciosas (EI). Nuestro objetivo es identificar datos importantes para la investigación de las enfermedades infecciosas con el fin de priorizar los esfuerzos realizados en los programas de IA. Material y métodos. Se buscaron 1.000 artículos de re vistas de EI de alto impacto en PubMed, seleccionando 288 de los últimos artículos en 10 revistas de primer nivel. Los clasifi camos en datos estructurados o no estructurados. Las variables se homogeneizaron y agruparon en las siguientes categorías: epidemiología, ingreso, demografía, comorbilidades, manifes taciones clínicas, laboratorio, microbiología, otros diagnósticos, tratamiento, desenlace y otras variables no categorizables. Resultados. Se recogieron 4.488 variables individuales, pro cedentes de 288 artículos. 3670 (81,8%) variables se clasificaron como datos estructurados, mientras que 818 (18,2%) como da tos no estructurados. De los datos estructurados, 2.319 (63,2%) variables se clasificaron como directas -recuperables a partir de historias clínicas electrónicas-, mientras que 1.351 (36,8%) fueron indirectas. Los datos no estructurados más frecuentes estaban re lacionados con las manifestaciones clínicas y se repetían en todos los artículos. Los datos sobre demografía, comorbilidades y micro biología constituyeron el grupo más frecuente de variables Conclusiones. Este artículo identificó que las variables es tructuradas han constituido los datos más importantes en la investigación para generar conocimiento en el campo de la EI. La extracción de estos datos debería ser una prioridad cuando un centro médico pretende iniciar un programa de IA para la EI (AU)

Association between event-free survival and overall survival after neoadjuvant treatment for non-small cell lung cancer: a systematic review and meta-analysis.

BACKGROUND: We wanted to evaluate if event-free survival (EFS) is a reliable surrogate for overall survival (OS) in patients with resectable non-small cell lung cancer (r-NSCLC) receiving neoadjuvant therapy. We conducted a systematic literature review and meta-analysis to investigate the statistical association between EFS and OS. RESEARCH DESIGN AND METHODS: Electronic databases were searched on 30 July 2021 to identify sources reporting both EFS and OS data in patients with stage I-IIIB r-NSCLC receiving neoadjuvant therapy. Correlation and regression analyses evaluated the association between the effect of treatment on EFS and OS using log-hazard ratios (HRs). Sources in which the entire population had epidermal growth factor receptor mutations were excluded from the analyses. RESULTS: We identified 74 sources, of which 8 reported EFS and OS HRs from randomized controlled trials. Based on these, we found a positive linear correlation and a strong association between EFS and OS log-HRs (weighted Pearson's correlation coefficient r = 0.864; 95% confidence interval 0.809-0.992; P = 0.006; random-effects meta-regression, R2 = 0.777). CONCLUSIONS: We found a strong association between treatment effects for EFS and OS, indicating that improvements in EFS are likely to be predictive of improvements in OS. EFS may therefore be a reliable surrogate for OS after neoadjuvant therapy in r-NSCLC.

[Invasive mucormycosis during COVID-19 infection. Report of two cases]. / Mucormicosis invasora en pacientes con COVID-19: reporte de 2 casos.

COVID-19 disease is associated with a significant number of opportunistic infections, including invasive fungal infections such as mucormycosis. The prevalence of the latter is rare, estimated to be between 0.005 and 1.7 per million inhabitants. Risk factors include hematological diseases, Diabetes Mellitus with poor metabolic control, solid organ transplantation, neutropenia, and prolonged administration of systemic corticosteroids. We report two males aged 60 and 75 years with pulmonary and tracheobronchial invasive mucormycosis, respectively. Both patients had a deficient metabolic control of their diabetes as a predisposing risk factor added to severe COVID-19 infection. High suspicion and early diagnosis are essential for prompt treatment, especially considering the associated high morbidity and mortality of this fungal infection.

Spanish cardiac catheterization and coronary intervention registry. 32nd official report of the Interventional Cardiology Association of the Spanish Society of Cardiology (1990-2022).

INTRODUCTION AND OBJECTIVES: This article presents the annual activity report of the Interventional Cardiology Association of the Spanish Society of Cardiology (ACI-SEC) for the year 2022. METHODS: All Spanish centers with catheterization laboratories were invited to participate. Data were collected online and were analyzed by an external company in collaboration with the members of the board of the ACI-SEC. RESULTS: A total of 111 centers participated. The number of diagnostic studies increased by 4.8% compared with 2021, while that of percutaneous coronary interventions (PCI) remained stable. PCIs on the left main coronary artery increased by 22%. The radial approach continued to be preferred for PCI (94.9%). There was an upsurge in the use of drug-eluting balloons, as well as in intracoronary imaging techniques, which were used in 14.7% of PCIs. The use of pressure wires also increased (6.3% vs 2021) as did plaque modification techniques. Primary PCI continued to grow and was the most frequent treatment (97%) in ST-segment elevation myocardial infarction. Most noncoronary procedures maintained their upward trend, particularly percutaneous aortic valve implantation, atrial appendage closure, mitral/tricuspid edge-to-edge therapy, renal denervation, and percutaneous treatment of pulmonary arterial disease. CONCLUSIONS: The Spanish cardiac catheterization and coronary intervention registry for 2022 reveals a rise in the complexity of coronary disease, along with a notable growth in procedures for valvular and nonvalvular structural heart disease.

ß-Turn Induction by a Diastereopure Azepane-Derived Quaternary Amino Acid.

ß-Turns are one of the most common secondary structures found in proteins. In the interest of developing novel ß-turn inducers, a diastereopure azepane-derived quaternary amino acid has been incorporated into a library of simplified tetrapeptide models in order to assess the effect of the azepane position and peptide sequence on the stabilization of ß-turns. The conformational analysis of these peptides by molecular modeling, NMR spectroscopy, and X-ray crystallography showed that this azepane amino acid is an effective ß-turn inducer when incorporated at the i + 1 position. Moreover, the analysis of the supramolecular self-assembly of one of the ß-turn-containing peptide models in the solid state reveals that it forms a supramolecular helical arrangement while maintaining the ß-turn structure. The results here presented provide the basis for the use of this azepane quaternary amino acid as a strong ß-turn inducer in the search for novel peptide-based bioactive molecules, catalysts, and biomaterials.

Sirolimus-Coated Balloon in an All-Comer Population of Coronary Artery Disease Patients: The EASTBOURNE Prospective Registry.

BACKGROUND: Drug-coated balloons (DCB) represent 1 of the most promising innovations in interventional cardiology and may represent a valid alternative to drug-eluting stents. Currently, some sirolimus-coated balloons (SCB) are being investigated for several coronary artery disease applications. OBJECTIVES: This study sought to understand the role of a novel SCB for the treatment of coronary artery disease. METHODS: EASTBOURNE (All-Comers Sirolimus-Coated Balloon European Registry) is a prospective, multicenter, investigator-driven clinical study that enrolled real-world patients treated with SCB. Primary endpoint was target lesion revascularization (TLR) at 12 months. Secondary endpoints were procedural success, myocardial infarction (MI), all-cause death, and major adverse clinical events (a composite of death, MI, and TLR). All adverse events were censored and adjudicated by an independent clinical events committee. RESULTS: A total population of 2,123 patients (2,440 lesions) was enrolled at 38 study centers in Europe and Asia. The average age was 66.6 ± 11.3 years, and diabetic patients were 41.5%. De novo lesions (small vessels) were 56%, in-stent restenosis (ISR) 44%, and bailout stenting occurred in 7.7% of the patients. After 12 months, TLR occurred in 5.9% of the lesions, major adverse clinical events in 9.9%, and spontaneous MI in 2.4% of the patients. The rates of cardiac/all-cause death were 1.5% and 2.5%, respectively. The primary outcome occurred more frequently in the ISR cohort (10.5% vs 2.0%; risk ratio: 1.90; 95% CI: 1.13-3.19). After multivariate Cox regression model, the main determinant for occurrence of the primary endpoint was ISR (OR: 5.5; 95% CI: 3.382-8.881). CONCLUSIONS: EASTBOURNE, the largest DCB study in the coronary field, shows the safety and efficacy of a novel SCB in a broad population of coronary artery disease including small vessels and ISR patients at mid-term follow-up. (The All-Comers Sirolimus-Coated Balloon European Registry [EASTBOURNE]; NCT03085823).

A meta-analysis and a functional study support the influence of mtDNA variant m.16519C on the risk of rapid progression of knee osteoarthritis.

OBJECTIVES: To identify mitochondrial DNA (mtDNA) genetic variants associated with the risk of rapid progression of knee osteoarthritis (OA) and to characterise their functional significance using a cellular model of transmitochondrial cybrids. METHODS: Three prospective cohorts contributed participants. The osteoarthritis initiative (OAI) included 1095 subjects, the Cohort Hip and Cohort Knee included 373 and 326 came from the PROspective Cohort of Osteoarthritis from A Coruña. mtDNA variants were screened in an initial subset of 450 subjects from the OAI by in-depth sequencing of mtDNA. A meta-analysis of the three cohorts was performed. A model of cybrids was constructed to study the functional consequences of harbouring the risk mtDNA variant by assessing: mtDNA copy number, mitochondrial biosynthesis, mitochondrial fission and fusion, mitochondrial reactive oxygen species (ROS), oxidative stress, autophagy and a whole transcriptome analysis by RNA-sequencing. RESULTS: mtDNA variant m.16519C is over-represented in rapid progressors (combined OR 1.546; 95% CI 1.163 to 2.054; p=0.0027). Cybrids with this variant show increased mtDNA copy number and decreased mitochondrial biosynthesis; they produce higher amounts of mitochondrial ROS, are less resistant to oxidative stress, show a lower expression of the mitochondrial fission-related gene fission mitochondrial 1 and an impairment of autophagic flux. In addition, its presence modulates the transcriptome of cybrids, especially in terms of inflammation, where interleukin 6 emerges as one of the most differentially expressed genes. CONCLUSIONS: The presence of the mtDNA variant m.16519C increases the risk of rapid progression of knee OA. Among the most modulated biological processes associated with this variant, inflammation and negative regulation of cellular process stand out. The design of therapies based on the maintenance of mitochondrial function is recommended.

Meta-analysis of erosive hand osteoarthritis identifies four common variants that associate with relatively large effect.

OBJECTIVES: Erosive hand osteoarthritis (EHOA) is a severe subset of hand osteoarthritis (OA). It is unclear if EHOA is genetically different from other forms of OA. Sequence variants at ten loci have been associated with hand OA but none with EHOA. METHODS: We performed meta-analysis of EHOA in 1484 cases and 550 680 controls, from 5 populations. To identify causal genes, we performed eQTL and plasma pQTL analyses, and developed one zebrafish mutant. We analysed associations of variants with other traits and estimated shared genetics between EHOA and other traits. RESULTS: Four common sequence variants associated with EHOA, all with relatively high effect. Rs17013495 (SPP1/MEPE, OR=1.40, p=8.4×10-14) and rs11243284 (6p24.3, OR=1.35, p=4.2×10-11) have not been associated with OA, whereas rs11631127 (ALDH1A2, OR=1.46, p=7.1×10-18), and rs1800801 (MGP, OR=1.37, p=3.6×10-13) have previously been associated with hand OA. The association of rs1800801 (MGP) was consistent with a recessive mode of inheritance in contrast to its additive association with hand OA (OR homozygotes vs non-carriers=2.01, 95% CI 1.71 to 2.37). All four variants associated nominally with finger OA, although with substantially lower effect. We found shared genetic components between EHOA and other OA measures, grip strength, urate levels and gout, but not rheumatoid arthritis. We identified ALDH1A2, MGP and BMP6 as causal genes for EHOA, with loss-of-function Bmp6 zebrafish mutants displaying EHOA-like phenotypes. CONCLUSIONS: We report on significant genetic associations with EHOA. The results support the view of EHOA as a form of severe hand OA and partly separate it from OA in larger joints.

Mucormicosis invasora en pacientes con COVID-19: reporte de 2 casos / Invasive mucormycosis during COVID-19 infection. Report of two cases

COVID-19 disease is associated with a significant number of opportunistic infections, including invasive fungal infections such as mucormycosis. The prevalence of the latter is rare, estimated to be between 0.005 and 1.7 per million inhabitants. Risk factors include hematological diseases, Diabetes Mellitus with poor metabolic control, solid organ transplantation, neutropenia, and prolonged administration of systemic corticosteroids. We report two males aged 60 and 75 years with pulmonary and tracheobronchial invasive mucormycosis, respectively. Both patients had a deficient metabolic control of their diabetes as a predisposing risk factor added to severe COVID-19 infection. High suspicion and early diagnosis are essential for prompt treatment, especially considering the associated high morbidity and mortality of this fungal infection.

Active eosinophils regulate host defence and immune responses in colitis.

In the past decade, single-cell transcriptomics has helped to uncover new cell types and states and led to the construction of a cellular compendium of health and disease. Despite this progress, some difficult-to-sequence cells remain absent from tissue atlases. Eosinophils-elusive granulocytes that are implicated in a plethora of human pathologies1-5-are among these uncharted cell types. The heterogeneity of eosinophils and the gene programs that underpin their pleiotropic functions remain poorly understood. Here we provide a comprehensive single-cell transcriptomic profiling of mouse eosinophils. We identify an active and a basal population of intestinal eosinophils, which differ in their transcriptome, surface proteome and spatial localization. By means of a genome-wide CRISPR inhibition screen and functional assays, we reveal a mechanism by which interleukin-33 (IL-33) and interferon-γ (IFNγ) induce the accumulation of active eosinophils in the inflamed colon. Active eosinophils are endowed with bactericidal and T cell regulatory activity, and express the co-stimulatory molecules CD80 and PD-L1. Notably, active eosinophils are enriched in the lamina propria of a small cohort of patients with inflammatory bowel disease, and are closely associated with CD4+ T cells. Our findings provide insights into the biology of eosinophils and highlight the crucial contribution of this cell type to intestinal homeostasis, immune regulation and host defence. Furthermore, we lay a framework for the characterization of eosinophils in human gastrointestinal diseases.