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1.
CJC Open ; 6(6): 798-804, 2024 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-39022171

RESUMEN

Background: Inaccurate blood pressure (BP) classification results in inappropriate treatment. We tested whether machine learning (ML), using routine clinical data, can serve as a reliable alternative to ambulatory BP monitoring (ABPM) in classifying BP status. Methods: This study employed a multicentre approach involving 3 derivation cohorts from Glasgow, Gdansk, and Birmingham, and a fourth independent evaluation cohort. ML models were trained using office BP, ABPM, and clinical, laboratory, and demographic data, collected from patients referred for hypertension assessment. Seven ML algorithms were trained to classify patients into 5 groups, named as follows: Normal/Target; Hypertension-Masked; Normal/Target-White-Coat (WC); Hypertension-WC; and Hypertension. The 10-year cardiovascular outcomes and 27-year all-cause mortality risks were calculated for the ML-derived groups using the Cox proportional hazards model. Results: Overall, extreme gradient boosting (using XGBoost open source software) showed the highest area under the receiver operating characteristic curve of 0.85-0.88 across derivation cohorts, Glasgow (n = 923; 43% female; age 50.7 ± 16.3 years), Gdansk (n = 709; 46% female; age 54.4 ± 13 years), and Birmingham (n = 1222; 56% female; age 55.7 ± 14 years). But accuracy (0.57-0.72) and F1 (harmonic mean of precision and recall) scores (0.57-0.69) were low across the 3 patient cohorts. The evaluation cohort (n = 6213; 51% female; age 51.2 ± 10.8 years) indicated elevated 10-year risks of composite cardiovascular events in the Normal/Target-WC and the Hypertension-WC groups, with heightened 27-year all-cause mortality observed in all groups, except the Hypertension-Masked group, compared to the Normal/Target group. Conclusions: ML has limited potential in accurate BP classification when ABPM is unavailable. Larger studies including diverse patient groups and different resource settings are warranted.


Contexte: Les erreurs dans la classification des valeurs de la pression artérielle (PA) entraînent une inadéquation du traitement. Nous avons tâché de déterminer si l'apprentissage machine, à l'aide de données cliniques routinières, constituait une solution de rechange fiable à la surveillance ambulatoire de la PA pour définir le statut de la PA. Méthodologie: Cette étude a utilisé une approche multicentrique incluant trois cohortes de dérivation de Glasgow, Gdansk et Birmingham, et une quatrième cohorte d'évaluation indépendante. Les modèles d'apprentissage machine ont été développés en analysant les données démographiques, les valeurs de la PA mesurée au cabinet, les données relatives à la surveillance ambulatoire de la PA et aux épreuves de laboratoire recueillies auprès de patients adressés pour une évaluation de l'hypertension. Sept algorithmes d'apprentissage machine ont été appliqués pour classer les patients en cinq groupes : Normale/Cible; Hypertension-Masquée; Normal/Cible-Blouse blanche; Hypertension-Blouse blanche; Hypertension. Les événements cardiovasculaires sur 10 ans et le risque de mortalité toutes causes confondues sur 27 ans ont été calculés dans les groupes dérivés de l'apprentissage machine à l'aide d'un modèle de risques proportionnels de Cox. Résultats: D'une manière générale, l'amplification de gradient extrême (à l'aide du logiciel ouvert XGBoost) a mis en évidence l'aire sous la courbe de la fonction d'efficacité du récepteur (courbe ROC pour Receiver Operating Characteristic) la plus haute, soit 0,85 à 0,88, pour toutes les cohortes de dérivation : Glasgow (n = 923; 43 % de femmes; âge : 50,7 ± 16,3 ans); Gdansk (n = 709; 46 % de femmes; âge : 54,4 ± 13 ans); Birmingham (n = 1 222; 56 % de femmes; âge : 55,7 ± 14 ans). La précision (0,57 ­ 0,72) et le score F1 (moyenne harmonique de la précision et du rappel) (0,57 ­ 0,69) ont été faibles dans les trois cohortes de patients. La cohorte d'évaluation (n = 6 213; 51 % de femmes; âge : 51,2 ± 10,8 ans) a indiqué un risque d'événements cardiovasculaires composites sur 10 ans élevé dans les groupes Normale/Cible-Blouse blanche et Hypertension-Blouse blanche, tandis qu'une hausse de la mortalité toutes causes confondues sur 27 ans a été observée dans tous les groupes, sauf dans le groupe Hypertension-Masquée, comparativement au groupe Normale/Cible. Conclusions: Le potentiel d'exactitude de la classification de la PA à l'aide de l'apprentissage machine lorsque la surveillance ambulatoire de la PA n'est pas possible est limité. Des études de plus grande envergure portant sur des groupes de patients et des niveaux de ressources diversifiés s'imposent.

4.
Hypertension ; 81(6): 1218-1232, 2024 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-38511317

RESUMEN

Inflammatory responses in small vessels play an important role in the development of cardiovascular diseases, including hypertension, stroke, and small vessel disease. This involves various complex molecular processes including oxidative stress, inflammasome activation, immune-mediated responses, and protein misfolding, which together contribute to microvascular damage. In addition, epigenetic factors, including DNA methylation, histone modifications, and microRNAs influence vascular inflammation and injury. These phenomena may be acquired during the aging process or due to environmental factors. Activation of proinflammatory signaling pathways and molecular events induce low-grade and chronic inflammation with consequent cardiovascular damage. Identifying mechanism-specific targets might provide opportunities in the development of novel therapeutic approaches. Monoclonal antibodies targeting inflammatory cytokines and epigenetic drugs, show promise in reducing microvascular inflammation and associated cardiovascular diseases. In this article, we provide a comprehensive discussion of the complex mechanisms underlying microvascular inflammation and offer insights into innovative therapeutic strategies that may ameliorate vascular injury in cardiovascular disease.


Asunto(s)
Inflamación , Animales , Humanos , Arterias/metabolismo , Enfermedades Cardiovasculares/metabolismo , Epigénesis Genética , Inflamación/metabolismo , Inflamación/inmunología , Estrés Oxidativo/fisiología , Transducción de Señal/fisiología , Vasculitis/metabolismo , Vasculitis/inmunología
6.
Glob Heart ; 19(1): 18, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38371656

RESUMEN

Two recent large trials showed the potential of single pill combinations (SPCs) with ≥3 low-dose components among people with hypertension who were untreated or receiving monotherapy. In both trials, these 'hypertension polypills' were superior to usual care, achieving >80% BP control without increasing withdrawal due to side effects. However, there are no such products available for prescribers. To address this unmet need, George Medicines developed GMRx2 with telmisartan/amlodipine/indapamide in three strengths (mg): 10/1.25/0.625, 20/2.5/1.25; 40/5/2.5. Two pivotal trials are ongoing to support FDA submission for the treatment of hypertension, including initial treatment. These assess efficacy and safety of GMRx2 compared to: placebo, and each of the three possible dual combinations. Regulatory submissions are planned for 2024, with the aim of providing access to GMRx2 in developed and developing regions. Wider implementation of GMRx2-based treatment strategies will be guided by further research to inform access and appropriate scale up.


Asunto(s)
Hipertensión , Indapamida , Humanos , Antihipertensivos/uso terapéutico , Hipertensión/tratamiento farmacológico , Indapamida/farmacología , Indapamida/uso terapéutico , Presión Sanguínea , Resultado del Tratamiento
7.
Cerebrovasc Dis ; 53(2): 216-223, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-37591226

RESUMEN

INTRODUCTION: Intracranial carotid artery calcification (ICAC), as a strong contributor to the occurrence of ischemic stroke, might be present in the medial or intimal arterial layer. Traditional cardiovascular risk factors (CVRFs) are associated with ICAC; however, its association with new markers of vascular function is less understood. The paper aimed to evaluate the relationship between carotid-femoral pulse wave velocity (CF-PWV) and ICAC subtypes. METHODS: We enrolled 65 patients with ischemic stroke. CF-PWV, systolic, diastolic, mean blood pressure, and pulse pressure were measured within 6 ± 2 days after stroke onset, and CT was performed within 24 h. ICAC on the stroke site was classified by two methods: volume and score based. Tertiles of ICAC volume were determined, and low-grade ICAC (T1) was regarded as a reference. According to the score-based method, (dominant) medial and (dominant) intimal ICAC subtypes were determined. Data were analyzed with multivariate logistic regression. RESULTS: Medial and intimal ICAC subtypes were found in 34 (52%) and 24 (37%) patients, respectively. In 11% of patients, no ICAC calcifications were found. CF-PWV was higher in patients with high-grade ICAC (OR = 1.56, 95% CI = 1.03-2.35, p = 0.035). CF-PWV was higher in patients with the medial ICAC subtype (OR = 1.60, 95% CI = 1.00-2.55, p = 0.049) after adjustment for traditional CVRFs. CONCLUSION: Our study demonstrates that among patients with ischemic stroke, aortic stiffness is independently associated with ICAC and that medial ICAC, compared with intimal ICAC, is accompanied by more advanced aortic stiffness.


Asunto(s)
Enfermedades de las Arterias Carótidas , Accidente Cerebrovascular Isquémico , Accidente Cerebrovascular , Rigidez Vascular , Humanos , Accidente Cerebrovascular Isquémico/complicaciones , Análisis de la Onda del Pulso , Factores de Riesgo , Enfermedades de las Arterias Carótidas/complicaciones , Enfermedades de las Arterias Carótidas/diagnóstico por imagen , Accidente Cerebrovascular/diagnóstico por imagen , Accidente Cerebrovascular/etiología , Arterias Carótidas
9.
10.
Blood Press ; 32(1): 2269431, 2023 12.
Artículo en Inglés | MEDLINE | ID: mdl-37837345

RESUMEN

PURPOSE: To describe the history of the Excellence Centre (EC) programme of the European Society of Hypertension (ESH) since the beginning in 2006, its achievements, and its future developments. MATERIALS AND METHODS: We list the number of ECs per country, the research projects performed so far, and the organisational steps needed to reshape the EC programme for the future. RESULTS: In August 2023, the ESH EC programme includes 118 registered ECs in 21 European and 7 non-European countries. Updates about the formal steps for application, re-application, transfer of EC and retirement of EC heads are given. CONCLUSIONS: The EC programme of the ESH has been a success from the beginning. Further refinements will make it fit for the next decades.


Asunto(s)
Hipertensión , Humanos , Hipertensión/terapia
11.
Chaos ; 33(10)2023 Oct 01.
Artículo en Inglés | MEDLINE | ID: mdl-37889953

RESUMEN

We introduce an entropy-based classification method for pairs of sequences (ECPS) for quantifying mutual dependencies in heart rate and beat-to-beat blood pressure recordings. The purpose of the method is to build a classifier for data in which each item consists of two intertwined data series taken for each subject. The method is based on ordinal patterns and uses entropy-like indices. Machine learning is used to select a subset of indices most suitable for our classification problem in order to build an optimal yet simple model for distinguishing between patients suffering from obstructive sleep apnea and a control group.


Asunto(s)
Apnea Obstructiva del Sueño , Humanos , Frecuencia Cardíaca/fisiología , Presión Sanguínea , Entropía , Apnea Obstructiva del Sueño/diagnóstico , Aprendizaje Automático
12.
Kardiol Pol ; 81(10): 944-949, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-37718589

RESUMEN

Considering the pathophysiology and clinical presentation of heart failure, using diuretics or drugs with diuretic properties is indispensable for adequate management of heart failure patients. However, in clinical practice, fluid expansion is often undiagnosed, and diuretic therapy is not always adequately titrated. Today, several drug classes with diuretic properties are available in addition to classical thiazides, thiazide-like, and loop diuretics. The purpose of this short review is to discuss different ways to optimize diuretic therapy using currently available drugs. Several approaches are considered, including a combination of diuretics to obtain a sequential nephron blockade, use of a drug combining a blocker of the renin-angiotensin system (RAS) and an inhibitor of the metabolism of natriuretic peptides (ARNI), prescription of potassium binders to maintain and up-titrate RAS blockers and mineralocorticoid antagonists, and finally use of inhibitors of renal reabsorption of glucose through the sodium-glucose cotransporter 2 system. Optimal use of these various drug classes should improve the quality of life and reduce the need for hospital admissions and mortality in heart failure patients.


Asunto(s)
Diuréticos , Insuficiencia Cardíaca , Humanos , Diuréticos/uso terapéutico , Calidad de Vida , Inhibidores de los Simportadores del Cloruro de Sodio/efectos adversos , Glucosa/uso terapéutico
13.
Curr Atheroscler Rep ; 25(9): 605-612, 2023 09.
Artículo en Inglés | MEDLINE | ID: mdl-37594602

RESUMEN

PURPOSE OF REVIEW: The goal of this article is to characterize the endothelium's role in the development of hypertension and dyslipidemia and to point out promising therapeutic directions. RECENT FINDINGS: Dyslipidemia may facilitate the development of hypertension, whereas the collaboration of these two silent killers potentiates the risk of atherosclerosis. The common pathophysiological denominator for hypertension and dyslipidemia is endothelial cell dysfunction, which manifests as dysregulation of homeostasis, redox balance, vascular tone, inflammation, and thrombosis. Treatment focused on mediators acting in these processes might be groundbreaking. Metabolomic research on hypertension and dyslipidemia has revealed new therapeutic targets. State-of-the-art solutions integrating interview, clinical examination, innovative imaging, and omics profiles along with artificial intelligence have been already shown to improve patients' risk stratification and treatment. Pathomechanisms underlying hypertension and dyslipidemia take place in the endothelium. Novel approaches involving endothelial biomarkers and bioinformatics advances could open new perspectives in patient management.


Asunto(s)
Dislipidemias , Hipertensión , Humanos , Inteligencia Artificial , Dislipidemias/epidemiología , Crimen , Endotelio
14.
Hypertension ; 80(9): 1949-1959, 2023 09.
Artículo en Inglés | MEDLINE | ID: mdl-37470187

RESUMEN

BACKGROUND: Aortic pulse wave velocity (PWV) predicts cardiovascular events (CVEs) and total mortality (TM), but previous studies proposing actionable PWV thresholds have limited generalizability. This individual-participant meta-analysis is aimed at defining, testing calibration, and validating an outcome-driven threshold for PWV, using 2 populations studies, respectively, for derivation IDCARS (International Database of Central Arterial Properties for Risk Stratification) and replication MONICA (Monitoring of Trends and Determinants in Cardiovascular Disease Health Survey - Copenhagen). METHODS: A risk-carrying PWV threshold for CVE and TM was defined by multivariable Cox regression, using stepwise increasing PWV thresholds and by determining the threshold yielding a 5-year risk equivalent with systolic blood pressure of 140 mm Hg. The predictive performance of the PWV threshold was assessed by computing the integrated discrimination improvement and the net reclassification improvement. RESULTS: In well-calibrated models in IDCARS, the risk-carrying PWV thresholds converged at 9 m/s (10 m/s considering the anatomic pulse wave travel distance). With full adjustments applied, the threshold predicted CVE (hazard ratio [CI]: 1.68 [1.15-2.45]) and TM (1.61 [1.01-2.55]) in IDCARS and in MONICA (1.40 [1.09-1.79] and 1.55 [1.23-1.95]). In IDCARS and MONICA, the predictive accuracy of the threshold for both end points was ≈0.75. Integrated discrimination improvement was significant for TM in IDCARS and for both TM and CVE in MONICA, whereas net reclassification improvement was not for any outcome. CONCLUSIONS: PWV integrates multiple risk factors into a single variable and might replace a large panel of traditional risk factors. Exceeding the outcome-driven PWV threshold should motivate clinicians to stringent management of risk factors, in particular hypertension, which over a person's lifetime causes stiffening of the elastic arteries as waypoint to CVE and death.


Asunto(s)
Enfermedades Cardiovasculares , Hipertensión , Rigidez Vascular , Humanos , Análisis de la Onda del Pulso/efectos adversos , Aorta , Enfermedades Cardiovasculares/diagnóstico , Enfermedades Cardiovasculares/epidemiología , Enfermedades Cardiovasculares/etiología , Hipertensión/diagnóstico , Hipertensión/epidemiología , Hipertensión/complicaciones , Arterias , Factores de Riesgo , Rigidez Vascular/fisiología
15.
Blood Press ; 32(1): 2232873, 2023 12.
Artículo en Inglés | MEDLINE | ID: mdl-37470450

RESUMEN

Uncontrolled hypertension drives the global burden of increased cardiovascular disease (CVD) morbidity and mortality. Although high blood pressure (BP) is treatable and preventable, only half of the patients with hypertension undergoing treatment have their BP controlled. The failure of polypharmacy to attain adequate BP control may be due to a lack of physiological response, however, medication non-adherence and clinician inertia to increase treatment intensity are critical factors associated with poor hypertension management. The long-time medication titration, lifelong drug therapy, and often multi-drug treatment strategy are frustrating when the BP goal is not achieved, leading to increased CVD risk and a substantial burden on the healthcare system. Growing evidence indicates that neurohumoral activation is critical in initiating and maintaining elevated BP and its adverse consequences. Over the past decades, device-based therapies targeting the mechanisms underlying hypertension pathophysiology have been extensively studied. Among these, robust clinical experience for hypertension management exists for renal denervation (RDN) and baroreflex activation therapy (BAT), carotid body denervation (CBD), central arteriovenous anastomosis, and to a lesser extent, deep brain stimulation. Future studies are warranted to define the role of device-based approaches as an alternative or adjunctive treatment option to treat hypertension.


Systemic hypertension is a growing contributor to global disease burden and premature cause of death worldwide.The percentage of patients achieving target BP levels remains largely inadequate.Hypertension is characterised by activation of the sympathetic nervous system, with the magnitude depending on age and the disease severity.Device-based interventions have been extensively studied to directly target the relevant sympathetic neural pathophysiological mechanisms involved in BP control.Modulation of the chronic sympathetic outflow with CBD or BAT shows promise for the treatment of poorly controlled hypertension in addition to antihypertensive medicines.The BP response to device-based therapies appears variable and cannot be predicted before the procedure.Until more robust evidence related to patient selection, procedural and technical aspects is available, chemoreflex and baroreflex neuromodulation therapy should be restricted to randomised sham-controlled trials performed in experienced centres.


Asunto(s)
Enfermedades Cardiovasculares , Hipertensión , Humanos , Antihipertensivos/uso terapéutico , Antihipertensivos/farmacología , Presión Sanguínea/fisiología , Enfermedades Cardiovasculares/etiología , Seno Carotídeo , Riñón , Resultado del Tratamiento
16.
J Hypertens ; 41(10): 1521-1543, 2023 10 01.
Artículo en Inglés | MEDLINE | ID: mdl-37382158

RESUMEN

Microcirculation is pervasive and orchestrates a profound regulatory cross-talk with the surrounding tissue and organs. Similarly, it is one of the earliest biological systems targeted by environmental stressors and consequently involved in the development and progression of ageing and age-related disease. Microvascular dysfunction, if not targeted, leads to a steady derangement of the phenotype, which cumulates comorbidities and eventually results in a nonrescuable, very high-cardiovascular risk. Along the broad spectrum of pathologies, both shared and distinct molecular pathways and pathophysiological alteration are involved in the disruption of microvascular homeostasis, all pointing to microvascular inflammation as the putative primary culprit. This position paper explores the presence and the detrimental contribution of microvascular inflammation across the whole spectrum of chronic age-related diseases, which characterise the 21st-century healthcare landscape. The manuscript aims to strongly affirm the centrality of microvascular inflammation by recapitulating the current evidence and providing a clear synoptic view of the whole cardiometabolic derangement. Indeed, there is an urgent need for further mechanistic exploration to identify clear, very early or disease-specific molecular targets to provide an effective therapeutic strategy against the otherwise unstoppable rising prevalence of age-related diseases.


Asunto(s)
Arterias , Inflamación , Humanos , Enfermedad Crónica , Microcirculación
17.
Hypertension ; 80(8): 1759-1770, 2023 08.
Artículo en Inglés | MEDLINE | ID: mdl-37317866

RESUMEN

BACKGROUND: The Global SYMPLICITY Registry DEFINE (Denervation Findings in Real World) investigates radiofrequency renal denervation (RDN) in a broad range of patients with hypertension. We evaluated whether the number or type of antihypertensive medications were associated with increased long-term blood pressure (BP) reductions and cardiovascular outcomes following radiofrequency RDN. METHODS: Patients underwent radiofrequency RDN and were categorized by baseline number (0-3 and ≥4) and different combinations of medication classes. BP changes were compared between groups through 36 months. Individual and composite major adverse cardiovascular events were analyzed. RESULTS: Of 2746 evaluable patients, 18% were prescribed 0 to 3 and 82% prescribed ≥4 classes. At 36 months, office systolic BP significantly decreased (P<0.0001) by -19.0±28.3 and -16.2±28.6 mm Hg in the 0 to 3 and ≥4 class groups, respectively. Twenty-four-hour mean systolic BP significantly decreased (P<0.0001) by -10.7±19.7 and -8.9±20.5 mm Hg, respectively. BP reduction was similar between the medication subgroups. Antihypertensive medication classes decreased from 4.6±1.4 to 4.3±1.5 (P<0.0001). Most decreased (31%) or had no changes (47%) to the number of medications, while 22% increased. The number of baseline antihypertensive medication classes was inversely related to the change in prescribed classes at 36 months (P<0.001). Cardiovascular event rates were generally low. More patients in the ≥4 compared with 0 to 3 medication classes had myocardial infarction at 36 months (2.8% versus 0.3%; P=0.009). CONCLUSIONS: Radiofrequency RDN reduced BP safely through 36 months, independent of the number and type of baseline antihypertensive medication classes. More patients decreased than increased their number of medications. Radiofrequency RDN is a safe and effective adjunctive therapy regardless of antihypertensive medication regimen. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT01534299.


Asunto(s)
Antihipertensivos , Hipertensión , Humanos , Antihipertensivos/uso terapéutico , Antihipertensivos/farmacología , Resultado del Tratamiento , Monitoreo Ambulatorio de la Presión Arterial , Riñón , Hipertensión/diagnóstico , Hipertensión/tratamiento farmacológico , Hipertensión/cirugía , Presión Sanguínea/fisiología , Simpatectomía , Sistema de Registros , Desnervación
18.
J Clin Hypertens (Greenwich) ; 25(6): 521-533, 2023 06.
Artículo en Inglés | MEDLINE | ID: mdl-37147930

RESUMEN

High blood pressure (BP) and type-2 diabetes (T2DM) are forerunners of chronic kidney disease and left ventricular dysfunction. Home BP telemonitoring (HTM) and urinary peptidomic profiling (UPP) are technologies enabling risk stratification and personalized prevention. UPRIGHT-HTM (NCT04299529) is an investigator-initiated, multicenter, open-label, randomized trial with blinded endpoint evaluation designed to assess the efficacy of HTM plus UPP (experimental group) over HTM alone (control group) in guiding treatment in asymptomatic patients, aged 55-75 years, with ≥5 cardiovascular risk factors. From screening onwards, HTM data can be freely accessed by all patients and their caregivers; UPP results are communicated early during follow-up to patients and caregivers in the intervention group, but at trial closure in the control group. From May 2021 until January 2023, 235 patients were screened, of whom 53 were still progressing through the run-in period and 144 were randomized. Both groups had similar characteristics, including average age (62.0 years) and the proportions of African Blacks (81.9%), White Europeans (16.7%), women 56.2%, home (31.2%), and office (50.0%) hypertension, T2DM (36.4%), micro-albuminuria (29.4%), and ECG (9.7%) and echocardiographic (11.5%) left ventricular hypertrophy. Home and office BP were 128.8/79.2 mm Hg and 137.1/82.7 mm Hg, respectively, resulting in a prevalence of white-coat, masked and sustained hypertension of 40.3%, 11.1%, and 25.7%. HTM persisted after randomization (48 681 readings up to 15 January 2023). In conclusion, results predominantly from low-resource sub-Saharan centers proved the feasibility of this multi-ethnic trial. The COVID-19 pandemic caused delays and differential recruitment rates across centers.


Asunto(s)
COVID-19 , Diabetes Mellitus Tipo 2 , Hipertensión , Humanos , Femenino , Persona de Mediana Edad , Presión Sanguínea , Hipertensión/diagnóstico , Hipertensión/epidemiología , Informe de Investigación , Pandemias , Reforma de la Atención de Salud , Proteómica , Monitoreo Ambulatorio de la Presión Arterial/métodos , Diabetes Mellitus Tipo 2/diagnóstico , Diabetes Mellitus Tipo 2/epidemiología
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