Antigen-specific T cells and autoimmunity.

Autoimmune diseases (ADs) showcase the intricate balance between the immune system's protective functions and its potential for self-inflicted damage. These disorders arise from the immune system's erroneous targeting of the body's tissues, resulting in damage and disease. The ability of T cells to distinguish between self and non-self-antigens is pivotal to averting autoimmune reactions. Perturbations in this process contribute to AD development. Autoreactive T cells that elude thymic elimination are activated by mimics of self-antigens or are erroneously activated by self-antigens can trigger autoimmune responses. Various mechanisms, including molecular mimicry and bystander activation, contribute to AD initiation, with specific triggers and processes varying across the different ADs. In addition, the formation of neo-epitopes could also be implicated in the emergence of autoreactivity. The specificity of T cell responses centers on the antigen recognition sequences expressed by T cell receptors (TCRs), which recognize peptide fragments displayed by major histocompatibility complex (MHC) molecules. The assortment of TCR gene combinations yields a diverse array of T cell populations, each with distinct affinities for self and non-self antigens. However, new evidence challenges the traditional notion that clonal expansion solely steers the selection of higher-affinity T cells. Lower-affinity T cells also play a substantial role, prompting the "two-hit" hypothesis. High-affinity T cells incite initial responses, while their lower-affinity counterparts perpetuate autoimmunity. Precision treatments that target antigen-specific T cells hold promise for avoiding widespread immunosuppression. Nevertheless, detection of such antigen-specific T cells remains a challenge, and multiple technologies have been developed with different sensitivities while still harboring several drawbacks. In addition, elements such as human leukocyte antigen (HLA) haplotypes and validation through animal models are pivotal for advancing these strategies. In brief, this review delves into the intricate mechanisms contributing to ADs, accentuating the pivotal role(s) of antigen-specific T cells in steering immune responses and disease progression, as well as the novel strategies for the identification of antigen-specific cells and their possible future use in humans. Grasping the mechanisms behind ADs paves the way for targeted therapeutic interventions, potentially enhancing treatment choices while minimizing the risk of systemic immunosuppression.

Autoimmunity in centenarians. A paradox.

Autoimmune diseases (ADs) are one of the groups of chronic illnesses that impose a significant burden of disease and health costs worldwide. Age is a crucial risk factor for the onset of ADs. Theoretically, it is inferred that with organic and immune system aging, the loss of immune tolerance and specificity of immune activity becomes more intense, the probability of autoimmunity is increasing. However, there is a group of individuals whose prevalence of ADs is very low or non-existent, despite the biological aging. This paradox in autoimmunity raises questions. Centenarians, individuals who are over 100 years old, are possibly the most successful model of biological aging in humans. Most of these individuals exhibit a favorable health phenotype. To date, primary data evidence and potential hypotheses explaining this phenomenon are lacking globally, even though this paradox could provide valuable, original, and relevant information regarding the understanding of risk or protective factors, biological drivers, and biomarkers related to autoimmunity. Herein we discuss some hypothesis that may explain the absence of ADs in centenarians, including inflammaging, immunosenescence and immune resilience, immune system hyperstimulation, proteodynamics, and genetics.

Gut microbiota in centenarians: A potential metabolic and aging regulator in the study of extreme longevity.

Centenarians, those aged 100 years or older, are considered the most successful biological aging model in humans. This population is commonly characterized by a low prevalence of chronic diseases, with favorable maintenance of functionality and independence, thus determining a health phenotype of successful aging. There are many factors usually associated with extreme longevity: genetics, lifestyles, diet, among others. However, it is most likely a multifactorial condition where protective factors contribute individually to some extent. The gut microbiota (GM) has emerged as a potential factor associated with the establishment of a favorable health phenotype that allows for extreme longevity, as seen in centenarians. To understand the possible impact generated by the GM, its changes, and the probable causes for successful aging, the aim of this review was to synthesize evidence on the role of the GM as a potential protective factor for achieving extreme longevity, using its relationship with centenarians.

Global Research on Centenarians: A Historical and Comprehensive Bibliometric Analysis from 1887 to 2023.

BACKGROUND: Centenarians are considered the most successful human biological aging model. However, the characteristics and patterns of research among centenarians have not been described or analyzed. Thus, this study aimed to disclose the historical landscape of global research on centenarians. METHODS: This bibliometric study investigated historical evidence on centenarian research published in the Scopus database. The bibliometrix package in R was used to perform visual and quantitative analyses of research metrics, trends, and patterns. RESULTS: Of the 2,061 documents included between 1887 and 2023, 84.2% (n=1,736) were published as articles with primary data. We identified international collaboration and annual growth rates of 21.4% and 3.15%, respectively. The United States published the highest number of papers on centenarians (n=786), whereas the publications from Italy had the highest impact (h-index of 90). Based on the frequency of keywords, mortality, genetics, dementia, Alzheimer's disease, and immunosenescence are a few of the most studied topics among centenarians, with emerging research related to mitochondrial DNA and comparison of results between nonagenarians and centenarians. Italy, the United States, and China lead the global research collaboration network, collaborating most frequently with Japan and European countries. CONCLUSION: Global research on centenarians has grown over the last 20 years, primarily led by Italy, the United States, and China. Latin American and African countries have conducted little or no research on centenarians. The most widely studied topics include mortality, cognition, immunosenescence, and genetics.

Predictors of mortality in hospitalised patients with COVID-19: a 1-year case-control study.

BACKGROUND: A paucity of predictive models assessing risk factors for COVID-19 mortality that extend beyond age and gender in Latino population is evident in the current academic literature. OBJECTIVES: To determine the associated factors with mortality, in addition to age and sex during the first year of the pandemic. DESIGN: A case-control study with retrospective revision of clinical and paraclinical variables by systematic revision of clinical records was conducted. Multiple imputations by chained equation were implemented to account for missing variables. Classification and regression trees (CART) were estimated to evaluate the interaction of associated factors on admission and their role in predicting mortality during hospitalisation. No intervention was performed. SETTING: High-complexity centre above 2640 m above sea level (masl) in Colombia. PARTICIPANTS: A population sample of 564 patients admitted to the hospital with confirmed COVID-19 by PCR. Deceased patients (n=282) and a control group (n=282), matched by age, sex and month of admission, were included. MAIN OUTCOME MEASURE: Mortality during hospitalisation. MAIN RESULTS: After the imputation of datasets, CART analysis estimated 11 clinical profiles based on respiratory distress, haemoglobin, lactate dehydrogenase, partial pressure of oxygen to inspired partial pressure of oxygen ratio, chronic kidney disease, ferritin, creatinine and leucocytes on admission. The accuracy model for prediction was 80.4% (95% CI 71.8% to 87.3%), with an area under the curve of 78.8% (95% CI 69.63% to 87.93%). CONCLUSIONS: This study discloses new interactions between clinical and paraclinical features beyond age and sex influencing mortality in COVID-19 patients. Furthermore, the predictive model could offer new clues for the personalised management of this condition in clinical settings.

Variants in the DDX6-CXCR5 autoimmune disease risk locus influence the regulatory network in immune cells and salivary gland.

Fine mapping and bioinformatic analysis of the DDX6-CXCR5 genetic risk association in Sjögren's Disease (SjD) and Systemic Lupus Erythematosus (SLE) identified five common SNPs with functional evidence in immune cell types: rs4938573, rs57494551, rs4938572, rs4936443, rs7117261. Functional interrogation of nuclear protein binding affinity, enhancer/promoter regulatory activity, and chromatin-chromatin interactions in immune, salivary gland epithelial, and kidney epithelial cells revealed cell type-specific allelic effects for all five SNPs that expanded regulation beyond effects on DDX6 and CXCR5 expression. Mapping the local chromatin regulatory network revealed several additional genes of interest, including lnc-PHLDB1-1. Collectively, functional characterization implicated the risk alleles of these SNPs as modulators of promoter and/or enhancer activities that regulate cell type-specific expression of DDX6, CXCR5, and lnc-PHLDB1-1, among others. Further, these findings emphasize the importance of exploring the functional significance of SNPs in the context of complex chromatin architecture in disease-relevant cell types and tissues.

Kawasaki disease in Colombia: A systematic review and contrast with multisystem inflammatory syndrome in children associated with COVID-19

Introduction: Kawasaki disease (KD) is an acute vasculitis with multisystem involvement. Recently, the increasing incidence of a condition that closely resembles KD in many cases, named multisystem inflammatory syndrome in children (MIS-C), has set off alarms amid the current worldwide coronavirus disease-19 (COVID-19) pandemic. Hence, the aim is to conduct a systematic review of the literature about KD in Colombia and contrast it with COVID-19-related MIS-C. Materials and methods: A search was carried out in both international and Latin American electronic databases for publications concerning patients with KD in the Colombian population. Records were then screened by titles and/or abstracts, assessed for eligibility, and reviewed. Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines were followed. The search included studies reporting MIS-C associated with COVID-19, and compared these patients with our findings of KD in Colombia. Results: Out of 36 publications retrieved, 17 were included, representing 120 individuals. Male to female ratio was 1.6, and most patients (90.4%) were aged 5 years or less. Among the main features of KD, fever was the most frequent (96.2% of the patients), while cervical lymphadenopathy was present in only 40.6%. Intravenous immunoglobulin was administered in 91.4% cases and 6.2% were resistant. Cardiac involvement was found in around 30%, and 20% had coronary artery lesions. Comparison between MIS-C associated with COVID-19 and KD in Colombia indicates that patients affected by MIS-C were older (72.2% of MIS-C patients > 5 years), had higher rates of cardiac involvement, and required critical care more often. Conclusions: Our findings of KD in Colombia are consistent with the available descriptions of KD in the scientific literature. Given the increasing rate of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection in Colombia and Latin America, our study raises awareness about MIS-C in pediatric patients with COVID-19 and its relationship with KD.

Introducción: La enfermedad de Kawasaki (EK) es una vasculitis aguda con compromiso multisistémico. Recientemente, la incidencia creciente de una condición que se asemeja en forma considerable a la EK en muchos casos, denominada síndrome inflamatorio multisistémico (SIMS) en niños, ha encendido las alarmas en medio de la actual pandemia mundial de la enfermedad COVID-19. Por consiguiente, nos propusimos realizar una revisión sistemática de la literatura acerca de la EK en Colombia y contrastarla con el SIMS relacionado con COVID-19 en niños. Materiales y métodos: Buscamos publicaciones respecto a pacientes con EK en población colombiana, en bases de datos electrónicas tanto internacionales como latinoamericanas. Los registros hallados fueron tamizados por títulos o resúmenes, evaluados para elegibilidad y revisados. Se siguieron las guías Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA). Posteriormente, buscamos estudios que reportaran SIMS temporalmente asociado con COVID-19 en niños y comparamos estos pacientes con nuestros hallazgos de EK en Colombia. Resultados: De 36 publicaciones encontradas se incluyeron 17, las cuales representaron 120 individuos. La razón hombre a mujer fue de 1,6 y la mayoría de los pacientes (90,4%) tenía 5 anos o menos. Entre las principales características de EK, la fiebre fue la más frecuente (96,2%), mientras que la linfadenopatía cervical estuvo presente solo en el 40,6%. La inmunoglobulina intravenosa se administró en el 91,4% de los casos y 6,2% presentaron resistencia. Se encontró compromiso cardiaco en alrededor del 30% de los pacientes, en tanto que el 20% tuvo lesiones de arterias coronarias. La comparación entre las características clínicas de la EK y el SIMS asociado a COVID-19 mostró que los individuos afectados por el SIMS eran mayores (72,2% con SIMS tenían más de cinco anos), tuvieron mayores índices de compromiso cardiaco y requirieron cuidado crítico con mayor frecuencia. Conclusiones: Nuestros hallazgos de EK en Colombia son consistentes con las descripciones disponibles de esta enfermedad en la literatura científica. Debido al aumento de infección por SARS-CoV-2 en Colombia y Latinoamérica, nuestro estudio busca crear conciencia sobre el SIMS en pacientes pediátricos con COVID-19 y su relación con la EK.

Gonococcal arthritis in a healthy adult. Is it that possible?

A case report is presented of a 50-year-old woman who was seen in Accident and Emergency because of pain in the lumbar area. She was subsequently diagnosed with septic arthritis of the left hip due to being Neisseria gonorrhoeae positive for beta-lactamase. She responded to treatment with ceftriaxone, but later required a total hip replacement.

Presentamos el caso de una mujer de 50 arios, sin antecedentes de importancia, a quien se le diagnosticó inicialmente lumbago e infección de vías urinarias. Por persistencia del dolor y limitación de la movilidad en la cadera izquierda se inicia el estudio de artritis séptica, que fue provocada por Neisseria gonorrhoeae betalactamasa positiva, sensible a tratamiento con ceftriaxona, con posterior deterioro articular, el cual requirió reemplazo total de cadera.

Neutrophil extracellular traps in autoimmune diseases / Trampas extracelulares de neutrófilos en enfermedades autoinmunes

ABSTRACT Neutrophils play an important role in immune defence against several pathogens. These cells actively participate in the innate immune response through different functions, such as chemotaxis, phagocytosis, oxidative burst and degranulation, which have been widely studied. However, in the last few years, a new function has been described; activated neutrophils are able to release web-like chromatin structures known as neutrophil extracellular traps (NETs). These structures formed by DNA, histones, and proteins, immobilize and kill microorganisms. Disruption in NET formation is associated with the pathophysiology of several disorders, including the autoimmune diseases. NETs are an important source of the autoantigens involved in the production of autoantibodies and maintenance of the inflammatory milieu. This review provides a summary of the contribution of NETs to the pathogenesis of anti-neutrophil cytoplasmic antibodies-associated vasculitis, systemic lupus erythematosus, and rheumatoid arthritis. The preliminary findings on NETs components in Sjögren.'s syndrome will also be described.

RESUMEN Los neutrófilos juegan un papel muy importante en la defensa inmune contra diferentes patógenos. Estas células participan activamente en la respuesta inmune innata a través de diferentes funciones como quimiotaxis, fagocitosis, estallido oxidativo y degranulación, las cuales han sido estudiadas ampliamente. Sin embargo, en los últimos años se ha descrito una nueva función; los neutrófilos activados son capaces de liberar redes de cromatina llamadas trampas extracelulares de neutrófilos (NETs). Estas estructuras están formadas por ADN, histonas y proteínas capaces de inmovilizar y matar microorganismos. Alteraciones en la formación de estas NETs están asociadas con la fisiopatología de varios trastornos, incluyendo las enfermedades autoinmunes (EAI). Las NETs son consideradas una fuente de autoantígenos que ayudan a la producción de autoanticuerpos y al mantenimiento de un ambiente inflamatorio. Esta revisión resume la contribución de las NETs a la patogénesis de vasculitis asociada a anticuerpos contra el citoplasma de los neutrófilos, lupus eritematoso sistémico y artritis reumatoide. Adicionalmente, se describirán los resultados preliminares de la detección de componentes de las NETs en pacientes con síndrome de Sjögren.

Primer congreso colombiano de autoinmunidad / First Colombian Congress of Autoimmunity

Las enfermedades autoinmunes (EAI) representan una diversa gama de patologías en términos de su perfil demográfico y manifestaciones clínicas primarias. Se caracterizan por el daño tisular, consecuencia de la pérdida de tolerancia inmune, lo que conlleva una respuesta en contra de antígenos propios localizados en un órgano específico, o en múltiples, como es el caso de las EAI sistémicas (Figura 1) (1)

Respuesta a: Alfavirus tropicales artritogénicos / Response to: Tropical Arthritogenic Alphaviruses

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Discordancia entre métodos de detección de autoanticuerpos / Discrepancy between methods of detection of autoantibodies

Introducción: Las enfermedades autoinmunes sistémicas se caracterizan por la producción de diferentes autoanticuerpos contra antígenos intracelulares. En lupus eritematoso sistémico (LES) los autoanticuerpos son principalmente contra antígenos nucleares, los más frecuentes son los anti-ADN de doble cadena (anti-dsDNA) seguido de los antígenos nucleares extractables (ENAs) los cuales son componentes citoplasmáticos y nucleares solubles con más de 100 antígenos. Los ENAs están presentes también en el síndrome de Sjögren (SS) siendo más frecuentes los anti-Ro y anti-La. Contar con métodos fiables de detección de autoanticuerpos es necesario para el diagnóstico de estas enfermedades. Objetivo: Evaluar la concordancia de tres métodos de detección de anticuerpos antinucleares.

Ecología autoinmune en mujeres / Autoimmune ecology in women

Introducción: La exposición ambiental puede influenciar el desarrollo de enfermedades autoinmunes (EAI). El medio ambiente junto con la predisposición genética influyen en el desarrollo y severidad de estas enfermedades. Objetivo: Evaluar las exposiciones ambientales en pacientes con 4 EAI. Métodos: Se realizó un estudio exploratorio en 188 mujeres con 4 EAI: artritis reumatoide (AR) n= 51, lupus eritematoso sistémico (LES) n= 70, esclerosis sistémica (ES) n= 35 y síndrome de Sjögren (SS) n= 32. Los datos fueron recolectados mediante un cuestionario que evaluó características demográficas, clínicas, y exposición a factores ambientales. Además, se midieron 14 autoanticuerpos.

Plausibilidad genética de la infección por el virus del Zika y el síndrome de Guillain-Barré / Genetic plausibility of infection by the Zika virus syndrome Guillain - Barré Syndrome

Introducción: La infección por el virus del Zika (ZIKV) es, en la mayoría de los casos, asinto-mática o se presenta como una enfermedad leve y auto-limitada, principalmente con erupción cutánea, fiebre, artralgias y conjuntivitis. Sin embargo, en algunos pacientes puede producir efectos graves en el sistema nervioso, entre los cuales se destaca el síndrome de Guillain-Ba-rré (SGB), una polirradiculoneuropatía aguda, con características autoinmunes y, por lo ge-neral, desmielinizante. Objetivo: Realizar el primer estudio de asociación del genoma com-pleto en pacientes con infección por ZIKV y en aquellos que desarrollaron SGB post-viral.

Respuesta autoinmune en individuos infectados por el virus ZIKA (RAIZ) / Autoinmune response in people infected with ZIKA viruS (RAIZ)

En el presente artículo se presenta una revisión de los principales resultados del proyecto RAIZ, acrónimo de "Respuesta autoinmune en individuos infectados por el virus Zika", originado por dos eventos mutuamente relacionados, la asociación entre un virus emergente en el continente, el virus Zika (vZika), y una enfermedad neuromuscular poco prevalente en Colombia, el síndrome de Guillain-Barré. Después de la llegada del virus al país se observó que las zonas donde se reportaban brotes del virus, se documentaba un aumento en los casos de síndrome de Guillain-Barré y otros síndromes neurológicos, que generó un gran interés para entender los mecanismos subyacentes de la infección asociados con autoinmunidad neurológica. Mediante la realización del primer estudio de casos y controles de Zika, Guillain-Barré y otros síndromes neurológicos, se comprobó dicha asociación en Colombia. A lo largo del proyecto, además, se investigaron los principales mecanismos asociados, mediante estudios de seroprevalencia de otras infecciones, inmunológicos y genéticos

This article presents a review of the main results of the RAIZ project, acronym of "Autoimmune response in individuals infected with the Zika virus", originated by two mutually related events: the association between an emerging virus on the continent, the Zika virus (vZika), and a neuromuscular disease not very prevalent in Colombia, the Guillain-Barré syndrome. After the arrival of the virus in the country it was observed that in the areas of outbreaks an increase of cases of Guillain-Barré syndrome and other neurological syndromes was documented, which generated a great interest in the understanding of the underlying mechanisms of the infection associated with neurological autoimmunity. By conducting the first case-control study on Zika, Guillain-Barré and other neurological syndromes in Colombia, the association was verified. Throughout the project, the main associated mechanisms were addressed through analyses of other infections, immunological analysis and the first genome-wide association study

Interacciones entre citoquinas y resiliencia en pacientes con esclerosis sistémica / Interactions between Cytokines and resilience in patients with systemic sclerosis

Introducción: Resiliencia es la habilidad de responder de manera positiva a eventos adversos. Ésta puede ser influenciada por factores como el estrés crónico, la actividad física y afeccio-nes autoinmunes y/o inflamatorias como la esclerosis sistémica (ES) (1). Objetivo: Evaluar un panel de citoquinas y su asociación con resiliencia, severidad de los síntomas y actividad física en pacientes con ES. Métodos: Este fue un estudio exploratorio que incluyó 35 mujeres con ES. Las características clínicas, incluidas la severidad de los síntomas, la actividad física, la resiliencia así como un panel de 15 citoquinas fueron evaluados simultáneamente.

Estructura factorial y confiabilidad de la versión en español del cuestionario quality of life measure for rheumatoid arthritis scale (QOL-RA) en población colombiana / Factorial structure and reliability of the spanish version of thequality of life measure for rheumatoid arthritis (QOL-RA) incolombian population

Objetivo: Analizar la estructura factorial y la confiabilidad de la versión en español del cuestionario Quality of Life Measure for Rheumatoid Arthritis (QOL-RA) en población colombiana. Pacientes y métodos: Estudio de corte transversal, de alcance descriptivo y de tipo instrumental, con una cohorte de 124 pacientes diagnosticados con artritis reumatoide de la ciudad de Medellín, Colombia. Se realizó la aplicación del cuestionario QOLRA y el análisis estadístico posterior. Resultados: El análisis factorial denota dos factores independientes: factor físicopsicológico, y factor sociopsicológico, y un alfa de Cronbach de 0,885. Conclusiones: Los resultados muestran una alta confiabilidad y concordancia en la estructura factorial con la versión original, lo que implica adecuada validez de la prueba en población colombiana, recomendando su utilización en la población nacional con AR, y sugiriendo estudios transculturales en calidad de vida con ellos.

Objective: To analyze the factorial structure and reliability of the Spanish version of the Quality of Life Measure for Rheumatoid Arthritis (QOL-RA) in Colombian population. Patients and methods: Cross-sectional, descriptive and instrumental study, with a cohort of 124 patients diagnosed with rheumatoid arthritis in Medellin, Colombia. The questionnaire application QOL-RA and the subsequent statistical analysis. Results: Factor analysis indicates two independent factors: physical psychological factor, and socio-psychological factor, and a Cronbach’s alpha of 0,885. Conclusions: The results show high reliability and factor structure in accordance with the original version, which implies adequate validity of proof in Colombian population, recommending its use in the national population with RA, and cultural studies suggesting Quality of life with them.

Correlación y concordancia de la autoclinimetríaen artritis reumatoide: revisión sistemática de laliteratura y metanálisis / Patients-reported outcomes correlation and concordance in rheumatoid arthritis: systematic literature review and metaanalysis

Introducción: Existe un interés mundial en la evaluación de la artritis reumatoide (AR) desde la perspectiva del paciente mediante la autoclinimetría [en inglés patient-reported out comes(PROs)], que busca evaluar la actividad de la enfermedad, calidad de vida, pronóstico y adherencia terapéutica. Objetivo: Evaluar y analizar de manera objetiva el grado de correlación o concordancia entre las herramientas de autoclinimetría implementadas en AR con las mediciones objetivas realizadas por el equipo de salud, a través de una revisión sistemática de la literatura mundial y metanálisis. Materiales y métodos: Se realizó revisión sistemática de la literatura acerca de autoclinimetría en AR en PubMed, LILACS, Embase, SciELO y Biblioteca Virtual de la Salud, utilizando términos MeSH y DeCS, con un solo limite utilizado: humanos. Posteriormente, se realizó el metanálisis utilizando el programa Comprehensive Meta-Analysis versión 2. Resultados: Se incluyeron 85 artículos, demostrando correlaciones de moderadas a altas, entre las medidas objetivas realizadas por profesionales de la salud [DAS28, CDAI, SDAI, conteo articular inflamatorio (CAI) y doloroso (CAD), entre otros],y de autoclinimetría (RAPIDs, RADAI, RADAR, HAQ y CAI y CAD), por medio de metanálisis utilizando modelo de efectos aleatorios (p<0.0001). Conclusiones: La autoclinimetría tiene correlación y concordancia adecuadas con las medidas objetivas realizadas por el médico y su equipo entrenado. Ésta puede ser administrada tanto en la práctica clínica cotidiana como en ensayos clínicos, sin pretender que remplace el juicio clínico, pero con el ánimo de facilitar y optimizar el tiempo de consulta y los desenlaces de los paciente.

Introduction: There is a worldwide interest about the evaluation of rheumatoid arthritis (RA) from the perspective of the patient, using patient-reported outcomes (PROs), in order to assess disease activity, quality of life, prognosis, and treatment adherence. Objective: To evaluate and analyze the instruments of PROs and the degree of correlation with the objective measures done by the health practitioners through a systematic review and metaanalys.