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.

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.

[Guidelines on atopic dermatitis for Mexico (GUIDAMEX): using the ADAPTE methodology]. / Guía de dermatitis atópica para México (GUIDAMEX): lineamientos usando metodología ADAPTE.

With the advancement of knowledge in relation to the physiopathogenesis of atopic dermatitis (AD), several new therapeutic forms have been developed. There are also new guidelines for self-care. On the other hand, there is still an underdiagnosis of AD in Mexico. Thus, the need was seen to develop a national guide, with a broad base among the different medical groups that care for patients with AD. The Atopic Dermatitis Guidelines for Mexico (GUIDAMEX) was developed with the ADAPTE methodology, with the endorsement and participation of ten national medical societies, from physicians in Primary Healthcare to allergists and dermatologists. Throughout the manuscript, key clinical questions are answered that lead to recommendations and suggestions for the diagnosis of AD (including differential diagnosis with immunodeficiency syndromes), the recognition of comorbidities and complications, non-pharmacological treatment including therapeutic education, treatment of flares and maintenance therapy. The latter encompasses general measures to avoid triggering factors, first-line treatment focussed on repair of the skin barrier, second-line treatment (topical proactive therapy), and third-line phototherapy or systemic treatment, including dupilumab and JAK inhibitors.

Con el avance de los conocimientos en relación con la fisiopatogenia de la dermatitis atópica (DA) se han desarrollado varias formas terapéuticas nuevas. Asimismo, existen nuevos lineamientos para el autocuidado. Por otro lado, aún existe un subdiagnóstico de la DA en México. Así, se vio la necesidad de desarrollar una guía nacional, con base amplia entre las diferentes agrupaciones médicos que atienden pacientes con DA. Se desarrolló la Guía de DA para México (GUIDAMEX) con la metodología ADAPTE, con el aval y la participación de diez sociedades médicas nacionales, desde médicos del primer contacto hasta alergólogos y dermatólogos. A lo largo del escrito se contestan preguntas clínicas clave que llevan a recomendaciones y sugerencias para el diagnóstico de la DA (incluyendo diagnóstico diferencial con síndromes de inmunodeficiencia), el reconocer de las comorbilidades y complicaciones, las medidas generales (tratamiento no farmacológico) incluyendo la educación terapéutica, el tratamiento de los brotes y el tratamiento de mantenimiento. Este último abarca las medidas generales de evitar agravantes, el tratamiento de primera línea reparador de la barrera cutánea, de segunda línea (manejo proactivo tópico), hasta la fototerapia y el tratamiento sistémico de la tercera línea, incluyendo dupilumab y los inhibidores de la cinasa de Jano.

Guía de Práctica Clínica para el diagnóstico temprano y la referencia oportuna del cáncer de pulmón.

OBJETIVO: Proporcionar recomendaciones para la detección temprana de pacientes con alto riesgo de desarrollar cáncer de pulmón (CP) en el primer nivel de atención y su referencia oportuna. Material y métodos. Se realizó una búsqueda detallada de la evidencia científica disponible para responder las preguntas de investigación clínica y se utilizó el Panel Delphi modificado para lograr un consenso entre expertos. RESULTADOS: Se generaron 14 recomendaciones siguiendo los estándares de una GPC. Conclusión. El CP representa un problema de salud pública en México; por ello, esta guía establece recomendaciones que apoyan la toma de decisiones sobre la detección precoz y la referencia de pacientes con sospecha de CP en el primer nivel de atención.

[MIA 2021, Comprehensive Asthma Management. Guidelines for Mexico]. / MIA 2021, Manejo Integral del Asma. Lineamientos para México.

BACKGROUND: Asthma continues to be one of the most frequent chronic respiratory diseases in our country. New methods for diagnosis and treatment have been described; accordingly, the international guidelines were renewed. OBJECTIVE: To create a national platform for the development of updated guidelines, solidly based on evidence: Comprehensive Asthma Management (Spanish acronym: MIA). METHODS: MIA uses the ADAPTE method. The MIA development group consists of experts in pulmonology-allergology-methodology and representatives of 13 institutions and societies of specialties that manage asthma. The international reference guidelines (selected with AGREE-II): GINA 2020, GEMA 5.0, BTS/SIGN 2019 and ATS/ERS consensus document 2014-2019 on severe asthma. MIA covers suspected asthma, diagnosis, treatment, and special groups. Key clinical questions were formulated on treatment steps 1-3, biomarkers and severe asthma. RESULTS: Based on evidence, safety, cost and local reality, the core group developed responses. Through a Delphi process the broad MIA development group suggested adjustments until consensus was reached. CONCLUSION: A document was generated with multiple figures and algorithms, solidly based on evidence about asthma management, adjusted for Mexico with a broad base among different societies that participated in its development. It does not include guidelines for acute asthma.

Antecedentes: El asma sigue siendo una patología respiratoria crónica frecuente en México. Se han descrito nuevos métodos para el diagnóstico y tratamiento conforme se renuevan las guías internacionales. Objetivo: Crear la plataforma nacional Manejo Integral del Asma (MIA), para el desarrollo de lineamientos actualizados con base en evidencia. Métodos: Se utilizó el método ADAPTE. El grupo de desarrollo de MIA estuvo integrado por expertos en neumología, alergología y metodología y representantes de 13 instituciones y sociedades de especialidades que manejan asma. Las guías internacionales de referencia (seleccionadas con AGREE-II) fueron GINA 2020, GEMA 5.0, BTS/SIGN 2019 y consenso ATS/ERS 2014-2019. En MIA se aborda sospecha de asma, diagnóstico, tratamiento y grupos especiales. Se formularon preguntas clínicas clave sobre tratamiento en los pasos 1 a 3, biomarcadores y asma grave. Resultados: Con base en evidencia, seguridad, costo y realidad local, el grupo nuclear desarrolló respuestas. Mediante proceso Delphi, el grupo amplio de desarrollo sugirió ajustes hasta que se logró el consenso. Conclusión: El documento generado contiene múltiples figuras y algoritmos, está sólidamente basado en evidencia acerca del manejo del asma y fue ajustado para México con participación de diferentes sociedades para su desarrollo; no se incluyeron lineamientos para la crisis asmática.