La adecuada limpieza mucosa es esencial para una exploración diagnóstica de calidad en la esofagogastroduodenoscopia (EGD). La escala de Barcelona, un sistema sencillo de puntuación de 0 a 2 en cinco segmentos del tracto digestivo superior, se diseñó para evaluar de forma objetiva la limpieza tras las maniobras endoscópicas. En este estudio prospectivo multicéntrico realizado en 14 hospitales españoles (2022–2023), se incluyeron 641 pacientes adultos sometidos a EGD diagnóstica. En total se valoraron 3205 segmentos: el 81% obtuvo puntuación 2, el 19% puntuación 1 y menos del 1% puntuación 0, con una mediana global de 9 puntos. Se identificaron 327 lesiones clínicamente significativas (LCS) en 272 pacientes (42%), localizadas principalmente en el estómago (68%) y esófago (28%). Todos los casos de neoplasia (n=5) se detectaron en segmentos puntuados como 2. La tasa de detección de LCS aumentó progresivamente con la limpieza (0% en puntuación 0, 5,3% en 1 y 11,4% en 2; p<0,001), con un riesgo significativamente mayor para puntuación 2 frente a 1 (OR 2,29; IC95% 1,57–3,34). Además, la detección de LCS se asoció de forma independiente con edad ≥50 años, sexo masculino, uso de endoscopios de alta definición y empleo de cromoendoscopia. No se registraron eventos adversos graves. En conclusión, la escala de Barcelona es una herramienta válida, reproducible y segura para evaluar la limpieza mucosa durante la EGD en la práctica clínica real, y su aplicación puede contribuir a mejorar la calidad de la endoscopia digestiva alta y la detección de lesiones relevantes.

Referencia: Córdova H, Luzko I, Tejedor-Tejada J, Castillo-Regalado E, Barreiro-Alonso E, Delgado-Guillena P, Díez Redondo P, Galdin M, García-Rodríguez A, Hernández L, Núñez Rodríguez MH, Seoane A, Jiménez Sánchez J, Cubiella J, Jover R, Rodríguez-D’Jesús A, El Maimouni C, Moreira L, Ortiz O, Llach J, Fernández-Esparrach G. Prospective validation of the Barcelona scale for the assessment of mucosal cleanliness during upper gastrointestinal endoscopy. Ther Adv Gastroenterol. 2025;18:1–14. doi:10.1177/17562848251363873

Estremera‑Arévalo F, Bravo‑Meléndez S, Hijos‑Mallada G, et al. Clinical outcomes in the implementation of peroral endoscopic myotomy (POEM): Results from the Spanish multicenter registry. Gastroenterol Hepatol. 2025 Aug 5:502527. doi:10.1016/j.gastrohep.2025.502527

La miotomía endoscópica peroral (POEM) se ha consolidado como un tratamiento endoscópico destacado para la acalasia y otros trastornos motores esofágicos (TME). El propósito de este estudio fue evaluar su eficacia clínica y seguridad tras su implementación en España. Se llevó a cabo un registro multicéntrico, prospectivo, en 13 hospitales de España. Se incluyeron pacientes sintomáticos sometidos a POEM por cualquier TME entre junio de 2016 y febrero de 2023. Se analizaron características basales, detalles del procedimiento y resultados relacionados con eficacia y seguridad en seguimiento a corto y largo plazo. Se reclutaron 441 pacientes, siendo la acalasia tipo II el diagnóstico más frecuente (62,1 %). La POEM fue el tratamiento primario en 277 pacientes (62,8 %). Se disponía de datos de éxito clínico en 396 pacientes, con una tasa de éxito del 94,4 % en el último seguimiento disponible. El reflujo sintomático se observó en el 4,7 % de los pacientes, y la tasa de esofagitis significativa fue del 11,3 %. La incidencia de complicaciones fue del 9,3 % (41/441). Edad avanzada, mayor duración del procedimiento y lesión mucosa fueron predictores de complicaciones. Conclusiones: Estos hallazgos confirman la eficacia clínica y la seguridad de la POEM durante su fase de implementación para todos los TME en España.

Autores: Henry Córdova, Eva Barreiro‑Alonso, Edgar Castillo‑Regalado, Joaquín Cubiella, Pedro Delgado‑Guillena, Pilar Díez Redondo, Martin Galdín, Ana García‑Rodríguez, Luis Hernández, Alain Huerta, Rodrigo Jover, Henar Núñez, Antonio Rodríguez‑D’Jesús, Agustín Seoane, Gerard Surís, Javier Tejedor‑Tejada, Javier Jiménez Sánchez, Francisco Martín, Leticia Moreira, Sabela Carballal, Liseth Rivero, Angella Da Fieno, Gherzon Casanova, Irina Luzko Scheid, Joan Llach, Glòria Fernández‑Esparrach.

Resumen: Se validó la escala de limpieza (Barcelona scale) para la esofagogastroduodenoscopia, puntuando de 0‑2 en cinco segmentos digestivos. En 1500 valoraciones, la concordancia con el consenso fue del 89 %, con kappa medio de 0,83 para inter‑observador y 0,89 para intra‑observador. Es una herramienta válida y reproducible con formación mínima.

Citación: Córdova H, Barreiro‑Alonso E, Castillo‑Regalado E, Cubiella J, Delgado‑Guillena P, Díez Redondo P, Galdín M, García‑Rodríguez A, Hernández L, Huerta A, Jover R, Núñez H, Rodríguez‑D’Jesús A, Seoane A, Surís G, Tejedor‑Tejada J, Jiménez Sánchez J, Martín F, Moreira L, Carballal S, Rivero L, Da Fieno A, Casanova G, Luzko Scheid I, Llach J, Fernández‑Esparrach G. Applicability of the Barcelona scale to assess the quality of cleanliness of mucosa at esophagogastroduodenoscopy. Gastroenterol Hepatol. 2024;47(3):246‑252. doi:10.1016/j.gastrohep.2023.05.011

Autores: Albert Martín‑Cardona, Anna Carrasco, Beatriz Arau, Judith Vidal, Eva Tristán, Carme Ferrer, Gerardo Gonzalez‑Puglia, Natàlia Pallarès, Cristian Tebé, Sergio Farrais, Concepción Núñez, Fernando Fernández‑Bañares, Maria Esteve.

Resumen: Antecedentes: El diagnóstico diferencial entre pacientes con enfermedad celíaca (EC) y sensibilidad al gluten no celíaca (SGNC) es difícil cuando se ha iniciado una dieta sin gluten (DSG) antes de completar el proceso diagnóstico. El aumento aislado de TCRγδ+ y el linfograma celíaco (incremento de TCRγδ+ junto con disminución de CD3−) pueden permitir un diagnóstico diferencial en este contexto clínico complejo. Este estudio evaluó: (1) la precisión del %TCRγδ+ y del linfograma celíaco para diagnosticar EC antes y después de la DSG y para diferenciarla de la SGNC; (2) la cinética de TCRγδ+ al inicio y tras comenzar la DSG tanto en EC como en SGNC. Métodos: Los criterios de inclusión fueron pacientes con EC (n = 104), SGNC (n = 37) y voluntarios sanos (n = 18). Se realizó una biopsia intestinal para el linfograma intraepitelial mediante citometría de flujo al inicio y después de la DSG. El punto de corte óptimo para la precisión diagnóstica de la EC se estableció maximizando el índice de Youden y mediante regresión logística. Resultados: El %TCRγδ+ mostró mejor precisión diagnóstica que el linfograma celíaco para identificar la EC antes y después de iniciar la DSG. Con un punto de corte >13,31, la precisión para diagnosticar EC en pacientes bajo DSG fue de 0,88 [0,80–0,93], mientras que la precisión para diagnosticar SGNC (%TCRγδ+ ≤13,31) fue de 0,84 [0,76–0,89]. El porcentaje de células TCRγδ+ mostró una cinética diferencial entre la EC (inicio 22,7% [IQR, 16,4–33,6] frente a después de DSG 26,4% [IQR, 17,8–36,8]; p = 0,026) y la SGNC (inicio 9,4% [IQR, 4,1–14,6] frente a después de DSG 6,4% [IQR, 3,2–11]; p = 0,022). Conclusión: La evaluación de linfocitos TCRγδ+ permite diagnosticar con precisión la EC antes y después de una DSG. El incremento de TCRγδ+ se mantiene a largo plazo tras la DSG en la EC, pero no en la SGNC. En conjunto, esto sugiere la utilidad potencial de este marcador para el diagnóstico diferencial de estas dos entidades en pacientes bajo DSG.

Citación: Martín‑Cardona A, Carrasco A, Arau B, Vidal J, Tristán E, Ferrer C, Gonzalez‑Puglia G, Pallarès N, Tebé C, Farrais S, Núñez C, Fernández‑Bañares F, Esteve M. γδ+ T‑Cells Is a Useful Biomarker for the Differential Diagnosis between Celiac Disease and Non‑Celiac Gluten Sensitivity in Patients under Gluten Free Diet. Nutrients. 2024;16(14):2294. doi:10.3390/nu16142294

Autores: Joaquín Cubiella et al., en representación de AEG, SEED y SEAP.

Resumen: Declaración de posicionamiento sobre el cribado de cáncer gástrico en poblaciones de baja incidencia. Incluye contexto, criterios y recomendaciones basadas en evidencia para definir estrategias de cribado, indicando cuándo es coste‑efectivo y en qué grupos poblacionales puede considerarse.

Citación: Cubiella J, et al. Gastric cancer screening in low incidence populations: Position statement of AEG, SEED and SEAP. Gastroenterol Hepatol. 2021;44(1):67‑86. doi:10.1016/j.gastrohep.2020.08.004

Gastroenterologists' attitudes on the detection and management of gastric premalignant conditions: results of a nationwide survey in Spain.

Delgado-Guillena PG, Morales-Alvarado VJ, Elosua-González A, Murcia Pomares O, Pérez-Aisa A, Córdova H, Alcedo J, Calvet X, Fernández-Esparrach G. Eur J Cancer Prev. 2021 Nov 1;30(6):431-436. doi: 10.1097/CEJ.0000000000000648.

PMID: 33369947

Gastric cancer screening in low incidence populations: Position statement of AEG, SEED and SEAP.

Cubiella J, Pérez Aisa Á, Cuatrecasas M, Díez Redondo P, Fernández Esparrach G, Marín-Gabriel JC, Moreira L, Núñez H, Pardo López ML, Rodríguez de Santiago E, Rosón P, Sanz Anquela JM, Calvet X; en representación de la Asociación Española de Gastroenterología, la Sociedad Española de Endoscopia Digestiva y la Sociedad Española de Anatomía Patológica.

Gastroenterol Hepatol. 2021 Jan;44(1):67-86. doi: 10.1016/j.gastrohep.2020.08.004. Epub 2020 Oct 24.

PMID: 33252332

Quality in diagnostic upper gastrointestinal endoscopy for the detection and surveillance of gastric cancer precursor lesions: Position paper of AEG, SEED and SEAP.

Fernández-Esparrach G, Marín-Gabriel JC, Díez Redondo P, Núñez H, Rodríguez de Santiago E, Rosón P, Calvet X, Cuatrecasas M, Cubiella J, Moreira L, Pardo López ML, Pérez Aisa Á, Sanz Anquela JM; en representación de la Asociación Española de Gastroenterología, la Sociedad Española de Endoscopia Digestiva y la Sociedad Española de Anatomía Patológica.

Gastroenterol Hepatol. 2021 Jun-Jul;44(6):448-464. doi: 10.1016/j.gastrohep.2021.01.002. Epub 2021 Feb 17.

PMID: 33609597

Room for Improvement in the Treatment of Helicobacter pylori Infection: Lessons from the European Registry on H. pylori Management (Hp-EuReg).

Nyssen OP, Vaira D, Tepes B, Kupcinskas L, Bordin D, Pérez-Aisa Á, Gasbarrini A, Castro-Fernández M, Bujanda L, Garre A, Lucendo A, Vologzhanina L, Jurecic NB, Rodrigo-Sáez L, Huguet JM, Voynovan I, Perez-Lasala J, Romero PM, Vujasinovic M, Abdulkhakov R, Barrio J, Fernandez-Salazar L, Mégraud F, O'Morain C, Gisbert JP.

J Clin Gastroenterol. 2021 Jan 5;Publish Ahead of Print. doi: 10.1097/MCG.0000000000001482. Online ahead of print. PMID: 33405435

European Registry on Helicobacter pylori management (Hp-EuReg): First-line Therapy in Israel.
Boltin D, Beniashvili Z, Lahat A, Hirsch J, Nyssen OP, Mégraud F, O'Morain C, Gisbert JP, Niv Y.

Isr Med Assoc J. 2021 Jan;23(1):38-42. PMID: 33443341

Comparative Effectiveness of Multiple Different First-Line Treatment Regimens for Helicobacter pylori Infection: A Network Meta-analysis.

Rokkas T, Gisbert JP, Malfertheiner P, Niv Y, Gasbarrini A, Leja M, Megraud F, O'Morain C, Graham DY.

Gastroenterology. 2021 Aug;161(2):495-507.e4. doi: 10.1053/j.gastro.2021.04.012. Epub 2021 Apr 8. PMID: 33839101

Follow-Up Study Confirms the Presence of Gastric Cancer DNA Methylation Hallmarks in High-Risk Precursor Lesions.
Gómez A, Pato ML, Bujanda L, Sala N, Companioni O, Cosme Á, Tufano M, Hanly DJ, García N, Sanz-Anquela JM, Gisbert JP, López C, Elizalde JI, Cuatrecasas M, Andreu V, Paules MJ, Martín-Arranz MD, Ortega L, Poves E, Barrio J, Torres MÁ, Muñoz G, Ferrández Á, Ramírez-Lázaro MJ, Lario S, González CA, Esteller M, Berdasco M.

Cancers (Basel). 2021 Jun 2;13(11):2760. doi: 10.3390/cancers13112760.

European Registry on Helicobacter pylori management (Hp-EuReg): patterns and trends in first-line empirical eradication prescription and outcomes of 5 years and 21 533 patients.

Nyssen OP, Bordin D, Tepes B, Pérez-Aisa Á, Vaira D, Caldas M, Bujanda L, Castro-Fernandez M, Lerang F, Leja M, Rodrigo L, Rokkas T, Kupcinskas L, Pérez-Lasala J, Jonaitis L, Shvets O, Gasbarrini A, Simsek H, Axon ATR, Buzás G, Machado JC, Niv Y, Boyanova L, Goldis A, Lamy V, Tonkic A, Przytulski K, Beglinger C, Venerito M, Bytzer P, Capelle L, Milosavljević T, Milivojevic V, Veijola L, Molina-Infante J, Vologzhanina L, Fadeenko G, Ariño I, Fiorini G, Garre A, Garrido J, F Pérez C, Puig I, Heluwaert F, Megraud F, O'Morain C, Gisbert JP; Hp-EuReg Investigators.

Gut. 2021 Jan;70(1):40-54. doi: 10.1136/gutjnl-2020-321372. Epub 2020 Sep 21. PMID: 32958544 

Abstract

Objective: The best approach for Helicobacter pylori management remains unclear. An audit process is essential to ensure clinical practice is aligned with best standards of care.

Design: International multicentre prospective non-interventional registry starting in 2013 aimed to evaluate the decisions and outcomes in H. pylori management by European gastroenterologists. Patients were registered in an e-CRF by AEG-REDCap. Variables included demographics, previous eradication attempts, prescribed treatment, adverse events and outcomes. Data monitoring was performed to ensure data quality. Time-trend and geographical analyses were performed.

Results: 30 394 patients from 27 European countries were evaluated and 21 533 (78%) first-line empirical H. pylori treatments were included for analysis. Pretreatment resistance rates were 23% to clarithromycin, 32% to metronidazole and 13% to both. Triple therapy with amoxicillin and clarithromycin was most commonly prescribed (39%), achieving 81.5% modified intention-to-treat eradication rate. Over 90% eradication was obtained only with 10-day bismuth quadruple or 14-day concomitant treatments. Longer treatment duration, higher acid inhibition and compliance were associated with higher eradication rates. Time-trend analysis showed a region-dependent shift in prescriptions including abandoning triple therapies, using higher acid-inhibition and longer treatments, which was associated with an overall effectiveness increase (84%-90%).

Conclusion: Management of H. pylori infection by European gastroenterologists is heterogeneous, suboptimal and discrepant with current recommendations. Only quadruple therapies lasting at least 10 days are able to achieve over 90% eradication rates. European recommendations are being slowly and heterogeneously incorporated into routine clinical practice, which was associated with a corresponding increase in effectiveness.

Keywords: helicobacter pylori; helicobacter pylori - treatment.

 European Registry on Helicobacter pylori management: Single-capsule bismuth quadruple therapy is effective in real-world clinical practice

Olga P Nyssen  1 , Angeles Perez-Aisa  2 , Manuel Castro-Fernandez  3 , Rinaldo Pellicano  4 , Jose M Huguet  5 , Luis Rodrigo  6 , Juan Ortuñ, O  7 , Blas J Gomez-Rodriguez  8 , Ricardo M Pinto  9   10 , Miguel Areia  10   11 , Monica Perona  12 , Oscar Nuñez  13 , Marco Romano  14 , Antonietta G Gravina  14 , Liliana Pozzati  15 , Miguel Fernandez-Bermejo  16 , Marino Venerito  17 , Peter Malfertheiner  17 , Luis Fernanadez-Salazar  18 , Antonio Gasbarrini  19 , Dino Vaira  20 , Ignasi Puig  21 , Francis Megraud  22 , Colm O'Morain  23 , Javier P Gisbert  1 , Hp-EuReg investigators

United European Gastroenterol J. 2021 Feb;9(1):38-46. doi: 10.1177/2050640620972615.

Abstract

Background: There has been resurgence in the use of bismuth quadruple therapy (proton pump inhibitor, bismuth, tetracycline and metronidazole) for treating Helicobacter pylori infection thanks to a three-in-one single-capsule formulation.

Objective: To evaluate the effectiveness and safety of the single-capsule bismuth quadruple therapy.

Methods: Data were collected in a multicentre, prospective registry of the clinical practice of gastroenterologists on the management of H. pylori infection, where patients were registered at the Asociación Española de Gastroenterologia REDCap database on an electronic case report form until January 2020. Effectiveness by modified intention-to-treat and per-protocol as well as multivariable analysis were performed. Independent factors evaluated were: age, gender, indication, compliance, proton pump inhibitor dose and treatment line.

Results: Finally, 2100 patients were prescribed single-capsule bismuth quadruple therapy following the technical sheet (i.e., three capsules every 6 h for 10 days). The majority of these patients were naive (64%), with an average age of 50 years, 64% women and 16% with peptic ulcer. An overall modified intention-to-treat effectiveness of 92% was achieved. Eradication was over 90% in first-line treatment (95% modified intention-to-treat, n = 1166), and this was maintained as a rescue therapy, both in second (89% modified intention-to-treat, n = 375) and subsequent lines of therapy (third to sixth line: 92% modified intention-to-treat, n = 236). Compliance was the factor most closely associated with treatment effectiveness. Adverse events were generally mild to moderate, and 3% of patients reported a severe adverse event, leading to discontinuation of treatment in 1.7% of cases.

Conclusions: Single-capsule bismuth quadruple therapy achieved H. pylori eradication in approximately 90% of patients in real-world clinical practice, both as a first-line and rescue treatment, with good compliance and a favourable safety profile.

Trial registration: ClinicalTrials.gov NCT02328131.

Keywords: Helicobacter pylori; Pylera; bismuth; eradication; quadruple.

 Adverse Event Profile During the Treatment of Helicobacter pylori: A Real-World Experience of 22,000 Patients From the European Registry on H. pylori Management (Hp-EuReg)

Olga P Nyssen  1 , Angeles Perez-Aisa  2 , Bojan Tepes  3 , Manuel Castro-Fernandez  4 , Juozas Kupcinskas  5 , Laimas Jonaitis  5 , Luis Bujanda  6 , Alfredo Lucendo  7 , Natasa Brglez Jurecic  8 , Jorge Perez-Lasala  9 , Oleg Shvets  10 , Galina Fadeenko  11 , Jose M Huguet  12 , Zdenki Kikec  13 , Dmitry Bordin  14   15   16 , Irina Voynovan  14 , Marcis Leja  17 , Jose Carlos Machado  18 , Miguel Areia  19 , Luis Fernandez-Salazar  20 , Luis Rodrigo  21 , Sergey Alekseenko  22 , Jesus Barrio  23 , Juan Ortuño  24 , Monica Perona  25 , Liudmila Vologzhanina  26 , Pilar Mata Romero  27 , Oleg Zaytsev  28 , Theodore Rokkas  29 , Sotirios Georgopoulos  30 , Rinaldo Pellicano  31 , Gyorgy M Buzas  32 , Ines Modolell  33 , Blas Jose Gomez Rodriguez  34 , Ilkay Simsek  35 , Cem Simsek  36 , Marina Roldan Lafuente  37 , Tatiana Ilchishina  38 , Judith Gomez Camarero  39 , Manuel Dominguez-Cajal  40 , Vassiliki Ntouli  41 , Natalia Nikolaevna Dekhnich  42 , Perminder Phull  43 , Oscar Nuñez  44 , Frode Lerang  45 , Marino Venerito  46 , Frederic Heluwaert  47 , Ante Tonkic  48 , Maria Caldas  1 , Ignasi Puig  49 , Francis Megraud  50 , Colm O'Morain  51 , Javier P Gisbert  1 , Hp-EuReg Investigators

Am J Gastroenterol . 2021 Jun 1;116(6):1220-1229.

Abstract

Introduction: The safety of Helicobacter pylori eradication treatments and to what extent adverse events (AEs) influence therapeutic compliance in clinical practice are hardly known. Our aim was to assess the frequency, type, intensity, and duration of AEs, and their impact on compliance, for the most frequently used treatments in the "European Registry on Helicobacter pylori management."

Methods: Systematic prospective noninterventional registry of the clinical practice of European gastroenterologists (27 countries, 300 investigators) on the management of H. pylori infection in routine clinical practice. All prescribed eradication treatments and their corresponding safety profile were recorded. AEs were classified depending on the intensity of symptoms as mild/moderate/severe and as serious AEs. All data were subject to quality control.

Results: The different treatments prescribed to 22,492 patients caused at least 1 AE in 23% of the cases; the classic bismuth-based quadruple therapy was the worst tolerated (37% of AEs). Taste disturbance (7%), diarrhea (7%), nausea (6%), and abdominal pain (3%) were the most frequent AEs. The majority of AEs were mild (57%), 6% were severe, and only 0.08% were serious, with an average duration of 7 days. The treatment compliance rate was 97%. Only 1.3% of the patients discontinued treatment due to AEs. Longer treatment durations were significantly associated with a higher incidence of AEs in standard triple, concomitant, bismuth quadruple, and levofloxacin triple or quadruple therapies.

Discussion: Helicobacter pylori eradication treatment frequently induces AEs, although they are usually mild and of limited duration. Their appearance does not interfere significantly with treatment compliance.

Trial registration: ClinicalTrials.gov NCT02328131.

 Evaluation of the Effectiveness of Helicobacter pylori Eradication Regimens in Lithuania during the Years 2013-2020: Data from the European Registry on Helicobacter pylori Management (Hp-EuReg)

Paulius Jonaitis  1 , Juozas Kupcinskas  1 , Olga P Nyssen  2   3 , Ignasi Puig  4   5 , Javier P Gisbert  2   3 , Laimas Jonaitis  1

Medicina (Kaunas). 2021 Jun 23;57(7):642. doi: 10.3390/medicina57070642.

Abstract

Background and Objectives: The prevalence of H. pylori in Eastern Europe remains quite high; however, there is insufficient data on the eradication regimens and their effectiveness. Therefore, the objective of the study was to evaluate the diagnostic methods and treatment of H. pylori infection as well as their adherence to Maastricht V/Florence consensus during the years 2013-2020 in Lithuania. Materials and Methods: Sub-study of the "European Registry on H. pylori Management" (Hp-EuReg), international multicenter prospective non-interventional registry of the routine clinical practice. Lithuanian data from the years 2013-2020 were analyzed for effectiveness on a modified intention-to-treat (mITT) basis. 2000 adult patients, diagnosed with H. pylori infection, were included. Data were compared to the European Maastricht V guidelines. Results: Triple-therapy was used in 90% of the cases. In 91% of the first-line prescriptions, standard triple therapy (STT) was used. The most common second-line treatment was a combination of PPI, amoxicillin and levofloxacin (PPI+A+L) (47%). The overall effectiveness in 552 cases valid for analysis was 90% by mITT. In first-line treatment, the STT effectiveness was 90% and second-line treatment with PPI+A+L achieved 92% by mITT. Increasing overall H. pylori eradication rates were observed: from 72% in 2013 to more than 90% in 2018-2020, as well as a shift from 7 to 10-14 days treatments duration throughout 2013-2020. Conclusions: In Lithuania, the prescribed eradication regimens for H. pylori were in accordance with the international guidelines but diagnostic methods and treatment duration only partially met Maastricht V/Florence guidelines. The eradication effectiveness was improved progressively during the years 2018-2020, reaching ≥90% cure rates.

Keywords: Helicobacter pylori; Hp-EuReg; Lithuania; effectiveness; eradication.

 The Role of Statins on Helicobacter pylori Eradication: Results from the European Registry on the Management of H. pylori (Hp-EuReg)

María Caldas  1 , Ángeles Pérez-Aisa  2 , Bojan Tepes  3 , Alma Keco-Huerga  4 , Luis Bujanda  5 , Alfredo J Lucendo  6 , Luis Rodrigo  7 , Dino Vaira  8 , Luis Fernández-Salazar  9 , Jose M Huguet  10 , Jorge Pérez-Lasala  11 , Natasa Brglez Jurecic  12 , Galina Fadeenko  13 , Jesús Barrio  14 , Miguel Areia  15 , Juan Ortuño  16 , Rinaldo Pellicano  17 , Marcis Leja  18 , Javier Molina-Infante  19 , Pavel Bogomolov  20 , Sergey Alekseenko  21 , Manuel Domínguez-Cajal  22 , Judith Gómez-Camarero  23 , Vassiliki Ntouli  24 , Samuel J Martínez-Domínguez  25 , Rafael Ruiz-Zorrilla  26 , Oscar Núñez  27 , Aiman Silkanovna Sarsenbaeva  28 , Pedro Almela  29 , Perminder Phull  30 , Marta Espada  1 , Ignasi Puig  31 , Olga P Nyssen  1 , Francis Mégraud  32 , Colm O'Morain  33 , Javier P Gisbert  1 , the Hp-EuReg Investigators

Antibiotics (Basel). 2021 Aug 11;10(8):965. doi: 10.3390/antibiotics10080965.

Abstract

Statins could increase the effectiveness of Helicobacter pylori eradication therapies due to their anti-inflammatory effect. The aim of this study was to analyze the impact of this therapeutic association in real life. This is a multicenter, prospective, non-interventional study aimed at evaluating the management of H. pylori by European gastroenterologists. Patients were registered in an e-CRF by AEG-REDCap from 2013 to 2020. The association between statin use and H. pylori eradication effectiveness was evaluated through multivariate analysis. Overall, 9988 and 705 patients received empirical and culture-guided treatment, respectively. Overall, statin use was associated with higher effectiveness in the empirical group (OR = 1.3; 95%CI = 1.1-1.5), but no association was found with first-line treatment effectiveness (N = 7738); as an exception, statin use was specifically associated with lower effectiveness of standard triple therapy (OR = 0.76; 95%CI = 0.59-0.99). In the rescue therapy empirical group (N = 2228), statins were associated with higher overall effectiveness (OR = 1.9; 95%CI = 1.4-2.6). However, sub-analyses by treatment schemes only confirmed this association for the single-capsule bismuth quadruple therapy (OR = 2.8; 95%CI = 1.3-5.7). No consistent association was found between statin use and H. pylori therapy effectiveness. Therefore, the addition of statins to the usual H. pylori treatment cannot be currently recommended to improve cure rates.

Keywords: Helicobacter pylori; statins; treatment.

 Antibiotic Resistance Prevalence and Trends in Patients Infected with Helicobacter pylori in the Period 2013-2020: Results of the European Registry on H. pylori Management (Hp-EuReg)

Luis Bujanda  1 , Olga P Nyssen  2 , Dino Vaira  3 , Ilaria M Saracino  3 , Giulia Fiorini  3 , Frode Lerang  4 , Sotirios Georgopoulos  5 , Bojan Tepes  6 , Frederic Heluwaert  7 , Antonio Gasbarrini  8 , Theodore Rokkas  9 , Dmitry Bordin  10   11   12 , Sinead Smith  13 , Vincent Lamy  14 , María Caldas  2 , Elena Resina  2 , Raquel Muñoz  2 , Ángel Cosme  1 , Ignasi Puig  15 , Francis Megraud  16 , Colm O'Morain  13 , Javier P Gisbert  2 , The Hp-EuReg Investigators
Antibiotics (Basel). 2021 Sep 1;10(9):1058.
doi: 10.3390/antibiotics10091058.

Abstract

Background: Bacterial antibiotic resistance changes over time depending on multiple factors; therefore, it is essential to monitor the susceptibility trends to reduce the resistance impact on the effectiveness of various treatments. Objective: To conduct a time-trend analysis of Helicobacter pylori resistance to antibiotics in Europe. Methods: The international prospective European Registry on Helicobacter pylori Management (Hp-EuReg) collected data on all infected adult patients diagnosed with culture and antimicrobial susceptibility testing positive results that were registered at AEG-REDCap e-CRF until December 2020. Results: Overall, 41,562 patients were included in the Hp-EuReg. Culture and antimicrobial susceptibility testing were performed on gastric biopsies of 3974 (9.5%) patients, of whom 2852 (7%) were naive cases included for analysis. The number of positive cultures decreased by 35% from the period 2013-2016 to 2017-2020. Concerning naïve patients, no antibiotic resistance was found in 48% of the cases. The most frequent resistances were reported against metronidazole (30%), clarithromycin (25%), and levofloxacin (20%), whereas resistances to tetracycline and amoxicillin were below 1%. Dual and triple resistances were found in 13% and 6% of the cases, respectively. A decrease (p < 0.001) in the metronidazole resistance rate was observed between the 2013-2016 (33%) and 2017-2020 (24%) periods. Conclusion: Culture and antimicrobial susceptibility testing for Helicobacter pylori are scarcely performed (<10%) in Europe. In naïve patients, Helicobacter pylori resistance to clarithromycin remained above 15% throughout the period 2013-2020 and resistance to levofloxacin, as well as dual or triple resistances, were high. A progressive decrease in metronidazole resistance was observed.

Keywords: Helicobacter pylori; amoxicillin; antibiotic resistance; clarithromycin; levofloxacin; metronidazole; tetracycline.

V Spanish Consensus Conference on Helicobacter pylori infection treatment.

Gisbert JP, Alcedo J, Amador J, Bujanda L, Calvet X, Castro-Fernández M, Fernández-Salazar L, Gené E, Lanas Á, Lucendo AJ, Molina-Infante J, Nyssen OP, Pérez-Aisa A, Puig I. Gastroenterol Hepatol. 2021 Oct 7:S0210-5705(21)00229-6. doi: 10.1016/j.gastrohep.2021.07.011. Online ahead of print. PMID: 34629204 English, Spanish

Abstract

Helicobacter pylori infection is very common in the Spanish population and represents the main cause of chronic gastritis, peptic ulcer, and gastric cancer. The last iteration of Spanish consensus guidelines on H. pylori infection was conducted in 2016. Recent changes in therapeutic schemes along with increasing supporting evidence were key for developing the V Spanish Consensus Conference (May 2021). Fourteen experts performed a systematic review of the scientific evidence and developed a series of recommendations that were subjected to an anonymous Delphi process of iterative voting. Scientific evidence and the strength of the recommendation were classified using GRADE guidelines. An eradication therapy, when prescribed empirically, is considered acceptable when it reliably achieves, or preferably surpass, 90% cure rates. Currently, only quadruple therapies (with or without bismuth) and generally lasting 14 days, accomplish this goal in first- and second-line therapies. A non-bismuth quadruple concomitant regimen (proton pump inhibitor, clarithromycin, amoxicillin, and metronidazole) or a quadruple bismuth-based combination (proton pump inhibitor, bismuth, tetracycline, and metronidazole), are recommended as first-line regimens. Rescue therapies after eradication failure and management of H. pylori infection in peptic ulcer disease were also reviewed.

Keywords: Bismuth; Bismuto, Claritromicina, Helicobacter pylori; Clarithromycin; Helicobacter pylori; Inhibidor de la bomba de protones; Levofloxacin; Levofloxacino; Metronidazol; Metronidazole; Omeprazol; Omeprazole; Proton pump inhibitor; Tetraciclina; Tetracycline.

[European registry on Helicobacter pylori management (Hp-EuReg) as a tool to evaluate and improve clinical practice in Moscow].

Bordin DS, Voynovan IN, Embutnieks YV, Nyssen OP, Megraud F, O Morain C, Perez-Gisbert J.

Ter Arkh. 2020 Apr 27;92(2):12-18. doi: 10.26442/00403660.2020.02.000567.

PMID: 32598712 

[European Registry on the management of Helicobacter pylori infection: features of diagnosis and treatment in Kazan].

Abdulkhakov SR, Bordin DS, Abdulkhakov RA, Safina DD, Gizdatullina AR, Gimadieva LZ, Safina GM, Ziyatdinov AI, Maturina AM, Nyssen OP, Megraud F, O'Morain C, Perez-Gisbert J.

Ter Arkh. 2020 Sep 3;92(8):52-59. doi: 10.26442/00403660.2020.08.000758.

PMID: 33346462 

Combination of Bismuth and Standard Triple Therapy Eradicates Helicobacter pylori Infection in More than 90% of Patients.

McNicholl AG, Bordin DS, Lucendo A, Fadeenko G, Fernandez MC, Voynovan I, Zakharova NV, Sarsenbaeva AS, Bujanda L, Perez-Aisa Á, Vologzhanina L, Zaytsev O, Ilchishina T, Coba C, Lasala JP, Alekseenko S, Modolell I, Molina-Infante J, Ruiz-Zorrilla Lopez R, Alonso-Galan H, Moreno NF, Hinojosa J, Santaella I, Varela P, Gonzalez-Cordero PL, Barrio J, Dominguez-Jimenez JL, Nuñez O, Alcedo J, Nyssen OP, Caldas M, Donday MG, Shvetz O, Megraud F, O'Morain C, Gisbert JP.

Clin Gastroenterol Hepatol. 2020 Jan;18(1):89-98. doi: 10.1016/j.cgh.2019.03.048. Epub 2019 Apr 10. PMID: 30978536

Prospective, study comparing the accuracy of two different stool antigen tests (Premier Platinum HpSA and novel ImmunoCard STAT! rapid test) for the diagnosis of Helicobacter pylori infection.

McNicholl AG, Garre A, Llorca L, Bujanda L, Molina-Infante J, Barenys M, Perez J, Guerrero-Torres MD, Tamayo E, Montes M, Prados-Manzano R, Sanchez-Garcia A, Ramas M, Valdez Blanco VB, Montoro M, Calvet X, Figuerola A, Lario S, Quilez E, Lanas A, Silva-Pomarino P, Perez-Aisa A, Donday MG, Belloc B, Montserrat-Torres A, Fernandez-Moreno N, Ramírez MJ, Alarcon T, Gisbert JP.

Gastroenterol Hepatol. 2020 Mar;43(3):117-125. doi: 10.1016/j.gastrohep.2019.09.009. Epub 2019 Dec 4. PMID: 31810793

Helicobacter pylori first-line and rescue treatments in patients allergic to penicillin: Experience from the European Registry on H pylori management (Hp-EuReg).

Nyssen OP, Pérez-Aisa Á, Tepes B, Rodrigo-Sáez L, Romero PM, Lucendo A, Castro-Fernández M, Phull P, Barrio J, Bujanda L, Ortuño J, Areia M, Brglez Jurecic N, Huguet JM, Alcaide N, Voynovan I, María Botargues Bote J, Modolell I, Pérez Lasala J, Ariño I, Jonaitis L, Dominguez-Cajal M, Buzas G, Lerang F, Perona M, Bordin D, Axon T, Gasbarrini A, Marcos Pinto R, Niv Y, Kupcinskas L, Tonkic A, Leja M, Rokkas T, Boyanova L, Shvets O, Venerito M, Bytzer P, Goldis A, Simsek I, Lamy V, Przytulski K, Kunovský L, Capelle L, Milosavljevic T, Caldas M, Garre A, Mégraud F, O'Morain C, Gisbert JP; Hp-EuReg Investigators.

Helicobacter. 2020 Jun;25(3):e12686. doi: 10.1111/hel.12686. Epub 2020 Mar 16. PMID: 32173974

Poor Sensitivity of Fecal Gluten Immunogenic Peptides and Serum Antibodies to Detect Duodenal Mucosal Damage in Celiac Disease Monitoring.

Laserna-Mendieta EJ, Casanova MJ, Arias Á, Arias-González L, Majano P, Mate LA, Gordillo-Vélez CH, Jiménez M, Angueira T, Tébar-Romero E, Carrillo-Ramos MJ, Tejero-Bustos MÁ, Gisbert JP, Santander C, Lucendo AJ. Nutrients. 2020 Dec 30;13(1):98. doi: 10.3390/nu13010098. PMID: 33396719

Heterogeneity of clinical management of low-grade gastric lymphoma of mucosa-associated lymphoid tissue. An audit of 198 patients in Spain.

Puig I, Sanabria E, Feu F, Couto I, Blanco M, Alonso P, Gisbert JP, McNicholl AG, Seoane A, Bory F, Polo F, Orivé V, Ponce J, Borda F, Hervás A, Pérez-Aisa Á, Rivera R, Quintero E, Nicolás-Pérez D, Bujanda L, Rodrigo L, Calvet X; Spanish Gastroenterological Association Gastroduodenal Diseases Study Group.

Gastroenterol Hepatol. 2020 Feb;43(2):79-86. doi: 10.1016/j.gastrohep.2019.08.012. Epub 2019 Nov 29. PMID: 31787375

Abstract

Introduction: Cure of Helicobacter pylori infection in patients with gastric lymphoma of mucosa-associated lymphoid tissue (MALT) leads to long-term clinical remission in the initial stages. As it is a rare disease, its management in clinical practice remains largely unknown and heterogeneity of care remains a concern. The aim was to audit the management and evolution of a large series of low-grade gastric MALT lymphomas from thirteen Spanish hospitals.

Materials and methods: Multicentre retrospective study including data on the diagnosis and follow-up of patients with gastric low-grade MALT lymphoma from January 1998 to December 2013. Clinical, biological and pathological data were analyzed and survival curves were drawn.

Results: One-hundred and ninety-eight patients were included. Helicobacter pylori was present in 132 (69%) patients and 103 (82%) in tumors confined to the stomach (stage EI) and was eradicated in 92% of patients. Chemotherapy was given in 90 (45%) patients and 43 (33%) with stage EI. Marked heterogeneity in the use of diagnostic methods and chemotherapy was observed. Five-year overall survival was 86% (89% in EI). Survival was similar in EI patients receiving aggressive treatment and in those receiving only antibiotics (p=0.577).

Discussion: Gastric MALT lymphoma has an excellent prognosis. We observed, however, a marked heterogeneity in the use of diagnostic methods or chemotherapy in early-stage patients.

Keywords: Disease management; Estudios de seguimiento; Follow-up studies; Linfoma; Lymphoma; Mortalidad; Mortality; Neoplasias malignas; Stomach neoplasms; Tratamiento de la enfermedad.

Bismuth quadruple regimen with tetracycline or doxycycline versus three-in-one single capsule as third-line rescue therapy for Helicobacter pylori infection: Spanish data of the European Helicobacter pylori Registry (Hp-EuReg).

Nyssen OP, Perez-Aisa A, Rodrigo L, Castro M, Mata Romero P, Ortuño J, Barrio J, Huguet JM, Modollel I, Alcaide N, Lucendo A, Calvet X, Perona M, Gomez B, Gomez Rodriguez BJ, Varela P, Jimenez-Moreno M, Dominguez-Cajal M, Pozzati L, Burgos D, Bujanda L, Hinojosa J, Molina-Infante J, Di Maira T, Ferrer L, Fernández-Salazar L, Figuerola A, Tito L, de la Coba C, Gomez-Camarero J, Fernandez N, Caldas M, Garre A, Resina E, Puig I, O'Morain C, Megraud F, Gisbert JP.

Helicobacter. 2020 Oct;25(5):e12722. doi: 10.1111/hel.12722. Epub 2020 Jul 13. PMID: 32656898

Abstract

Background: Different bismuth quadruple therapies containing proton-pump inhibitors, bismuth salts, metronidazole, and a tetracycline have been recommended as third-line Helicobacter pylori eradication treatment after failure with clarithromycin and levofloxacin.

Aim: To evaluate the efficacy and safety of third-line treatments with bismuth, metronidazole, and either tetracycline or doxycycline.

Methods: Sub-study with Spanish data of the "European Registry on H pylori Management" (Hp-EuReg), international multicenter prospective non-interventional Registry of the routine clinical practice of gastroenterologists. After previous failure with clarithromycin- and levofloxacin-containing therapies, patients receiving a third-line regimen with 10/14-day bismuth salts, metronidazole, and either tetracycline (BQT-Tet) or doxycycline (BQT-Dox), or single capsule (BQT-three-in-one) were included. Data were registered at AEG-REDCap database. Univariate and multivariate analyses were performed.

Results: Four-hundred and fifty-four patients have been treated so far: 85 with BQT-Tet, 94 with BQT-Dox, and 275 with BQT-three-in-one. Average age was 53 years, 68% were women. Overall modified intention-to-treat and per-protocol eradication rates were 81% (BQT-Dox: 65%, BQT-Tet: 76%, BQT-three-in-one: 88%) and 82% (BQT-Dox: 66%, BQT-Tet: 77%, BQT-three-in-one: 88%), respectively. By logistic regression, higher eradication rates were associated with compliance (OR = 2.96; 95% CI = 1.01-8.84) and no prior metronidazole use (OR = 1.96; 95% CI = 1.15-3.33); BQT-three-in-one was superior to BQT-Dox (OR = 4.46; 95% CI = 2.51-8.27), and BQT-Tet was marginally superior to BQT-Dox (OR = 1.67; 95% CI = 0.85-3.29).

Conclusion: Third-line H pylori eradication with bismuth quadruple treatment (after failure with clarithromycin and levofloxacin) offers acceptable efficacy and safety. Highest efficacy was found in compliant patients and those taking 10-day BQT-three-in-one or 14-day BQT-Tet. Doxycycline seems to be less effective and therefore should not be recommended.

Keywords: Helicobacter pylori; Pylera®; bismuth; doxycycline; metronidazole; tetracycline.

  European Registry on Helicobacter pylori Management: Effectiveness of First and Second-Line Treatment in Spain
María Caldas  1 , Ángeles Pérez-Aisa  2 , Manuel Castro-Fernández  3 , Luis Bujanda  4 , Alfredo J Lucendo  5 , Luis Rodrigo  6 , Jose M Huguet  7 , Jorge Pérez-Lasala  8 , Javier Molina-Infante  9 , Jesús Barrio  10 , Luis Fernández-Salazar  11 , Ángel Lanas  12 , Mónica Perona  13 , Manuel Domínguez-Cajal  14 , Juan Ortuño  15 , Blas José Gómez-Rodríguez  16 , Pedro Almela  17 , Josep María Botargués  18 , Óscar Núñez  19 , Inés Modolell  20 , Judith Gómez  21 , Rafael Ruiz-Zorrilla  22 , Cristóbal De la Coba  23 , Alain Huerta  24 , Eduardo Iyo  25 , Liliana Pozzati  26 , Rosario Antón  27 , Mercé Barenys  28 , Teresa Angueira  5 , Miguel Fernández-Bermejo  29 , Ana Campillo  30 , Javier Alcedo  31 , Ramón Pajares-Villaroya  32 , Marianela Mego  33 , Fernando Bermejo  34 , José Luis Dominguez-Jiménez  35 , Llúcia Titó  36 , Nuria Fernández  2 , Manuel Pabón-Carrasco  37 , Ángel Cosme  4 , Pilar Mata-Romero  9 , Noelia Alcaide  11 , Inés Ariño  12 , Tommaso Di Maira  15 , Ana Garre  1 , Ignasi Puig  38 , Olga P Nyssen  1 , Francis Megraud  39 , Colm O'Morain  40 , Javier P Gisbert  1 , Hp-EuReg Investigators

Antibiotics (Basel). 2020 Dec 25;10(1):13. doi: 10.3390/antibiotics10010013.

Abstract

The management of Helicobacter pylori infection has to rely on previous local effectiveness due to the geographical variability of antibiotic resistance. The aim of this study was to evaluate the effectiveness of first and second-line H. pylori treatment in Spain, where the empirical prescription is recommended. A multicentre prospective non-interventional registry of the clinical practice of European gastroenterologists concerning H. pylori infection (Hp-EuReg) was developed, including patients from 2013 until June 2019. Effectiveness was evaluated descriptively and through a multivariate analysis concerning age, gender, presence of ulcer, proton-pump inhibitor (PPI) dose, therapy duration and compliance. Overall, 53 Spanish hospitals were included, and 10,267 patients received a first-line therapy. The best results were obtained with the 10-day bismuth single-capsule therapy (95% cure rate by intention-to-treat) and with both the 14-day bismuth-clarithromycin quadruple (PPI-bismuth-clarithromycin-amoxicillin, 91%) and the 14-day non-bismuth quadruple concomitant (PPI-clarithromycin-amoxicillin-metronidazole, 92%) therapies. Second-line therapies were prescribed to 2448 patients, with most-effective therapies being the triple quinolone (PPI-amoxicillin-levofloxacin/moxifloxacin) and the bismuth-levofloxacin quadruple schemes (PPI-bismuth-levofloxacin-amoxicillin) prescribed for 14 days (92%, 89% and 90% effectiveness, respectively), and the bismuth single-capsule (10 days, 88.5%). Compliance, longer duration and higher acid inhibition were associated with higher effectiveness. "Optimized" H. pylori therapies achieve over 90% success in Spain.

Keywords: Helicobacter pylori; Spain; first-line; second-line; treatment.

[European registry Helicobacter pylori (Hp-EuReg): how has clinical practice changed in Russia from 2013 to 2018 years].

Bordin DS, Embutnieks YV, Vologzhanina LG, Ilchishina TA, Voynovan IN, Sarsenbaeva AS, Zaitsev OV, Alekseenko SA, Abdulkhakov RA, Dehnich NN, Osipenko MF, Livzan MA, Tsukanov VV, Burkov SG, Bakulina NV, Plotnikova EY, Tarasova LV, Maev IV, Kucheryavyi YA, Baryshnikova NV, Butov MA, Kolbasnikov SV, Pakhomova AL, Zhestkova TV, Baranovsky AY, Abdulhakov SR, Ageeva EA, Lyalyukova EA, Vasyutin AV, Golubev NN, Savilova IV, Morkovkina LV, Kononova AG, Megraud F, O'Morain C, Ramas M, Nyssen OP, McNicholl AG, Gisbert JP.

Ter Arkh. 2019 Feb 15;91(2):16-24. doi: 10.26442/00403660.2019.02.000156. PMID: 32598623

Spanish primary care survey on the management of Helicobacter pylori infection and dyspepsia: Information, attitudes, and decisions.

McNicholl AG, Amador J, Ricote M, Cañones-Garzón PJ, Gene E, Calvet X, Gisbert JP; Spanish Primary Care Societies SEMFyC; SEMERGEN and SEMG, the Spanish Association of Gastroenterology; OPTICARE Long-Term Educational Project.

Helicobacter. 2019 Aug;24(4):e12593. doi: 10.1111/hel.12593. Epub 2019 May 20. PMID: 31111627

Protocol of the European Registry on the management of Helicobacter pylori infection (Hp-EuReg).

McNicholl AG, O'Morain CA, Megraud F, Gisbert JP; As Scientific Committee of the Hp-Eureg on Behalf of the National Coordinators.

Helicobacter. 2019 Oct;24(5):e12630. doi: 10.1111/hel.12630. Epub 2019 Jul 8. PMID: 31282060

[Pan-European Registry on Helicobacter pylori management. Results from Ferencváros, Budapest, 2013-2019].

Buzás GM, Nyssen OP, Mégraud F, O'Morain C, Gisbert JP.

Orv Hetil. 2019 Nov;160(47):1856-1863. doi: 10.1556/650.2019.31553. PMID: 31736344

European Registry on the management of Helicobacter pylori infection (Hp-EuReg): analysis of 2360 patients receiving first-line therapy in Russia.

Bordin DS, Embutnieks YV, Vologzhanina LG, Il'chishina TA, Voinovan IN, Sarsenbaeva AS, Alekseenko SA, Zaitsev OV, Abdulkhakov RA, Osipenko MF, Livzan MA, Tsukanov VV, Burkov SG, Bakulina NV, Dekhnich NN, Tarasova LV, Plotnikova EY, Maev IV, Kucheryavyi YA, Baryshnikova NV, Butov MA, Kolbasnikov SV, Pakhomova AL, Zhestkova TV, Baranovskii AY, Abdulkhakov SR, Ageeva EA, Lyalyukova EA, Vasyutin AV, Golubev NN, Savilova IV, Morkovkina LV, Kononova AG, Megraud F, O'Morain C, Ramas M, Nyssen OP, McNicholl AG, Gisbert JP.

Ter Arkh. 2018 Feb 15;90(2):35-42. doi: 10.26442/terarkh201890235-42. PMID: 30701770