Bismuth quadruple three-in-one single capsule three times a day increases effectiveness compared with the usual four times a day schedule: results from the European Registry on Helicobacter pylori Management (Hp-EuReg).

BACKGROUND: The recommended schedule for single capsule bismuth quadruple therapy (scBQT, Pylera) includes a proton pump inhibitor (PPI) two times a day and three scBQT capsules four times a day. Four times a day treatments are inconvenient and reduce adherence. In contrast, adherence improves with three times a day schedules. In clinical practice, many gastroenterologists use four capsule scBQT three times a day. However, the effectiveness and safety of this latter approach remain uncertain. AIM: To assess the effectiveness and safety of scBQT administered three times a day in the patients included in the European Registry on Helicobacter pylori Management (Hp-EuReg). METHODS: All Spanish adult patients registered in the Asociación Española de Gastroenterología Research Electronic Data Capture (REDCap) database from June 2013 to March 2021 receiving 10-day scBQT were analysed. Modified intention-to-treat effectiveness, adherence and the safety of scBQT given three times a day were calculated and compared with the four times a day schedule. A multivariate analysis was performed to determine independent factors predicting cure of the infection. RESULTS: Of the 3712 cases, 2516 (68%) were four times a day and 1196 (32%) three times a day. Mean age was 51 years, 63% were women and 15% had a peptic ulcer. The three times a day schedule showed significantly better overall cure rates than four times a day (1047/1112, 94%; 95% CI 92.7 to 95.6 vs 2207/2423, 91%; 95% CI 89.9 to 92.2, respectively, p=0.002). Adherence and safety data were similar for both regimens. In the multivariate analysis, three times a day dosage, first-line therapy, use of standard or high-dose PPIs and adherence over 90% were significantly associated with cure of the infection. CONCLUSIONS: ScBQT prescribed three times a day was more effective than the traditional four times a day schedule. No differences were observed in treatment adherence or safety.

Duodenal tuberculosis.

Gastrointestinal tuberculosis (TB) is a rare disease and only involves the duodenum in 2-2,5% of all cases. A 60-year-old female with no reported medical history, presented with constitutional syndrome with a 10 kg weight loss in three months, epigastric pain, bloating and vomiting. She denied fever or respiratory symptoms. Laboratory examination revealed elevated C-reactive protein levels and low prealbumin. Abdominal computed tomography (CT) showed duodenal wall thickening, mainly in its third part, with infiltration of the root of the mesentery and numerous subcentimeter adenopathies at that level.

Cumulative exposure to tacrolimus and incidence of cancer after liver transplantation.

Cancer is the leading cause of death after liver transplantation (LT). This multicenter case-control nested study aimed to evaluate the effect of maintenance immunosuppression on post-LT malignancy. The eligible cohort included 2495 LT patients who received tacrolimus-based immunosuppression. After 13 922 person/years follow-up, 425 patients (19.7%) developed malignancy (cases) and were matched with 425 controls by propensity score based on age, gender, smoking habit, etiology of liver disease, and hepatocellular carcinoma (HCC) before LT. The independent predictors of post-LT malignancy were older age (HR = 1.06 [95% CI 1.05-1.07]; p < .001), male sex (HR = 1.50 [95% CI 1.14-1.99]), smoking habit (HR = 1.96 [95% CI 1.42-2.66]), and alcoholic liver disease (HR = 1.53 [95% CI 1.19-1.97]). In selected cases and controls (n = 850), the immunosuppression protocol was similar (p = .51). An increased cumulative exposure to tacrolimus (CET), calculated by the area under curve of trough concentrations, was the only immunosuppression-related predictor of post-LT malignancy after controlling for clinical features and baseline HCC (CET at 3 months p = .001 and CET at 12 months p = .004). This effect was consistent for de novo malignancy (after excluding HCC recurrence) and for internal neoplasms (after excluding non-melanoma skin cancer). Therefore, tacrolimus minimization, as monitored by CET, is the key to modulate immunosuppression in order to prevent cancer after LT.

Empirical rescue treatment of Helicobacter pylori infection in third and subsequent lines: 8-year experience in 2144 patients from the European Registry on H. pylori management (Hp-EuReg).

OBJECTIVE: To evaluate the use, effectiveness and safety of Helicobacter pylori empirical rescue therapy in third and subsequent treatment lines in Europe. DESIGN: International, prospective, non-interventional registry of the clinical practice of European gastroenterologists. Data were collected and quality reviewed until October 2021 at Asociación Española de Gastroenterología-Research Electronic Data Capture. All cases with three or more empirical eradication attempts were assessed for effectiveness by modified intention-to-treat and per-protocol analysis. RESULTS: Overall, 2144 treatments were included: 1519, 439, 145 and 41 cases from third, fourth, fifth and sixth treatment lines, respectively. Sixty different therapies were used; the 15 most frequently prescribed encompassed >90% of cases. Overall effectiveness remained <90% in all therapies. Optimised treatments achieved a higher eradication rate than non-optimised (78% vs 67%, p<0.0001). From 2017 to 2021, only 44% of treatments other than 10-day single-capsule therapy used high proton-pump inhibitor doses and lasted ≥14 days. Quadruple therapy containing metronidazole, tetracycline and bismuth achieved optimal eradication rates only when prescribed as third-line treatment, either as 10-day single-capsule therapy (87%) or as 14-day traditional therapy with tetracycline hydrochloride (95%). Triple amoxicillin-levofloxacin therapy achieved 90% effectiveness in Eastern Europe only or when optimised. The overall incidence of adverse events was 31%. CONCLUSION: Empirical rescue treatment in third and subsequent lines achieved suboptimal effectiveness in most European regions. Only quadruple bismuth-metronidazole-tetracycline (10-day single-capsule or 14-day traditional scheme) and triple amoxicillin-levofloxacin therapies reached acceptable outcomes in some settings. Compliance with empirical therapy optimisation principles is still poor 5 years after clinical practice guidelines update. TRIAL REGISTRATION NUMBER: NCT02328131.

Controlled, double-blind, randomized trial to assess the efficacy and safety of hydroxychloroquine chemoprophylaxis in SARS CoV2 infection in healthcare personnel in the hospital setting: A structured summary of a study protocol for a randomised controlled trial.

BACKGROUND: SARS-CoV-2 infection presents a high transmission in the group of health professionals in Spain (12-15% infected). Currently there is no accepted chemoprophylaxis but hydroxychloroquine (HDQ) is known to inhibit the coronavirus in vitro. Our hypothesis is that oral administration of hydroxychloroquine to healthcare professionals can reduce the incidence and prevalence of infection as well as its severity in this group. METHODS: Design: Prospective, single center, double blind, randomised, controlled trial (RCT). PARTICIPANTS: Adult health-care professionals (18-65 years) working in areas of high exposure and high risk of transmission of SARS-COV-2 (COVID areas, Intensive Care Unit -ICUs-, Emergency, Anesthesia and all those performing aerosol-generating procedures) will be included. Exclusion criteria include previous infection with SARS CoV2 (positive SARS-CoV-2 PCR or IgG serology), pregnancy or lactation, any contraindication to hydroxychloroquine or evidence of unstable or clinically significant systemic disease. INTERVENTIONS: Patients will be randomized (1:1) to receive once-daily oral Hydroxychloroquine 200mg for two months (HC group) or placebo (P group) in addition to the protective measures appropriate to the level of exposure established by the hospital. A serological evaluation will be carried out every 15 days with PCR in case of seroconversion, symptoms or risk exposure. Primary outcome is the percentage of subjects presenting infection (seroconversion and/or PCR +ve) by the SARS-Cov-2 virus during the observation period. Additionally, both the percentage of subjects in each group presenting Pneumonia with severity criteria (Curb 65 ≥2) and that of subjects requiring admission to ICU will be determined. DISCUSSION: While awaiting a vaccine, hygiene measures, social distancing and personal protective equipment are the only primary prophylaxis measures against SARS-CoV-2, but they have not been sufficient to protect our healthcare professionals. Some evidence of the in vitro efficacy of hydroxychloroquine against this virus is known, along with some clinical data that would support the study of this drug in the chemoprophylaxis of infection. However, there are still no data from controlled clinical trials in this regard. If our hypothesis is confirmed, hydroxychloroquine can help professionals fight this infection with more guarantees. PARTICIPANTS: This is a single-center study that will be carried out at the Marqués de Valdecilla University Hospital. 450 health professionals working at the Hospital Universitario Marqués de Valdecilla in areas of high exposure and high risk of transmission of SARS COV2 (COVID hospital areas, Intensive Care Unit, Emergency, Anesthesia and all those performing aerosol-generating procedures) will be included. INCLUSION CRITERIA: 1) Health professionals aged between 18 and 65 years (inclusive) at the time of the first screening visit; 2) They must provide signed written informed consent and agree to comply with the study protocol; 3) Active work in high exposure areas during the last two weeks and during the following weeks. EXCLUSION CRITERIA: 1) Previous infection with SARS CoV2 (positive coronavirus PCR or positive serology with SARS Cov2 negative PCR and absence of symptoms); 2) Current treatment with hydroxychloroquine or chloroquine; 3) Hypersensitivity, allergy or any contraindication for taking hydroxychloroquine, in the technical sheet; 4) Previous or current treatment with tamoxifen or raloxifene; 5) Previous eye disease, especially maculopathy; 6) Known heart failure (Grade III to IV of the New York Heart Association classification) or prolonged QTc; 7) Any type of cancer (except basal cell) in the last 5 years; 6) Refusal to give informed consent; 8) Evidence of any other unstable or clinically significant untreated immune, endocrine, hematological, gastrointestinal, neurological, neoplastic or psychiatric illness; 9) Antibodies positive for the human immunodeficiency virus; 10) Significant kidney or liver disease; 11) Pregnancy or lactation. INTERVENTION AND COMPARATOR: Two groups will be analyzed with a 1: 1 randomization rate. 1)Intervention: (n = 225): One 200 mg hydroxychloroquine sulfate coated tablet once daily for two months.2)Comparator (control group) (n = 225): One hydroxychloroquine placebo tablet (identical to that of the drug) once daily for two months MAIN OUTCOMES: The primary outcome of this study will be to evaluate: number and percentage of healthcare personnel presenting symptomatic and asymptomatic infection (see "Diagnosis of SARS CoV2 infection" below) by the SARS-Cov2 virus during the study observation period (8 weeks) in both treatment arms;number and percentage of healthcare personnel in each group presenting with Pneumonia with severity criteria (Curb 65 ≥2) and number and percentage of healthcare personnel requiring admission to the Intensive Care Unit (ICU) in both treatment arms. DIAGNOSIS OF SARS COV2 INFECTION: Determination of IgA, IgM and IgG type antibodies against SARS-CoV-2 using the Anti-SARS-CoV-2 ELISA kit (EUROIMMUN Medizinische Labordiagnostika AG, Germany) every two weeks. In cases of seroconversion, a SARS-CoV-2 PCR will be performed to rule out / confirm an active infection (RT-PCR in One Step: RT performed with mastermix (Takara) and IDT probes, following protocol published and validated by the CDC Evaluation of COVID-19 in case of SARS-CoV-2 infection RANDOMISATION: Participants will be allocated to intervention and comparator groups according to a balanced randomization scheme (1: 1). The assignment will be made through a computer-generated numeric sequence for all participants BLINDING (MASKING): Both participants and investigators responsible for recruiting and monitoring participants will be blind to the assigned arm. NUMBERS TO BE RANDOMISED (SAMPLE SIZE): Taking into account the current high prevalence of infection in healthcare personnel in Spain (up to 15%), to detect a difference equal to or greater than 8% in the percentage estimates through a two-tailed 95% CI, with a statistical power of 80% and a dropout rate of 5%, a total of 450 participants will need to be included (250 in each arm). TRIAL STATUS: The protocol approved by the health authorities in Spain (Spanish Agency for Medicines and Health Products "AEMPS") and the Ethics and Research Committee of Cantabria (CEIm Cantabria) corresponds to version 1.1 of April 2, 2020. Currently, recruitment has not yet started, with the start scheduled for the second week of May 2020. TRIAL REGISTRATION: Eudra CT number: 2020-001704-42 (Registered on 29 March 2020) FULL PROTOCOL: The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol. The study protocol has been reported in accordance with the Standard Protocol Items: Recommendations for Clinical Interventional Trials (SPIRIT) guidelines (Additional file 2).

IV Conferencia Española de Consenso sobre el tratamiento de la infección por Helicobacter pylor / IV Spanish Consensus Conference on Helicobacter pyloriinfection treatment

La infección por Helicobacter pylori afecta aproximadamente al 50% de la población española y es causante de la gastritis crónica, la úlcera péptica y el cáncer gástrico. Se han llevado a cabo hasta el momento, en nuestro país, 3 reuniones de Consenso sobre el manejo de la infección por H. pylori (la última de ellas en 2012). Los cambios en los esquemas de tratamiento y la creciente evidencia disponible al respecto han justificado la organización de esta IV Conferencia Española de Consenso en marzo de 2016, centrada en el tratamiento de esta infección. Participaron 19 expertos sobre el tema, que realizaron una búsqueda sistemática de la evidencia científica y elaboraron una serie de recomendaciones que fueron sometidas a un proceso de interacción de votaciones anónimas seriadas mediante metodología Delphi. Para clasificar la evidencia científica y la fuerza de las recomendaciones se utilizó el sistema GRADE. Este consenso establece, como punto de partida, un aumento de la exigencia en la eficacia de los tratamientos recomendados, que deben alcanzar, o preferiblemente superar, el 90% de curación al ser administrados de forma empírica. De este modo, tanto en primera como en segunda línea se recomiendan tratamientos cuádruples con o sin bismuto, generalmente prescritos durante 14días. El tratamiento cuádruple sin bismuto concomitante, que incluye un inhibidor de la bomba de protones, claritromicina, amoxicilina y metronidazol, se recomienda como primera línea. En el presente consenso se revisan también con detalle otras alternativas de tratamiento tanto de primera línea como de rescate

Helicobacter pylori approximately infect 50% of Spanish population and causes chronic gastritis, peptic ulcer and gastric cancer. Until now, three consensus meetings on H. pyloriinfection had been performed in Spain (the last in 2012). The changes in the treatment schemes, and the increasing available evidence, have justified organizing the IV Spanish Consensus Conference (March 2016), focused on the treatment of this infection. Nineteen experts participated, who performed a systematic review of the scientific evidence and developed a series of recommendation that were subjected to an anonymous Delphi process of iterative voting. Scientific evidence and the strength of the recommendation were classified using GRADE guidelines. As starting point, this consensus increased the minimum acceptable efficacy of recommended treatments that should reach, or preferably surpass, the 90% cure rate when prescribed empirically. Therefore, only quadruple therapies (with or without bismuth), and generally lasting 14 days, are recommended both for first and second line treatments. Non-bismuth quadruple concomitant regimen, including a proton pump inhibitor, clarithromycin, amoxicillin and metronidazole, is recommended as first line. In the present consensus, other first line alternatives and rescue treatments are also reviewed and recommended

IV Spanish Consensus Conference on Helicobacter pylori infection treatment. / IV Conferencia Española de Consenso sobre el tratamiento de la infección por Helicobacter pylori.

Helicobacter pylori approximately infect 50% of Spanish population and causes chronic gastritis, peptic ulcer and gastric cancer. Until now, three consensus meetings on H.pylori infection had been performed in Spain (the last in 2012). The changes in the treatment schemes, and the increasing available evidence, have justified organizing the IVSpanish Consensus Conference (March 2016), focused on the treatment of this infection. Nineteen experts participated, who performed a systematic review of the scientific evidence and developed a series of recommendation that were subjected to an anonymous Delphi process of iterative voting. Scientific evidence and the strength of the recommendation were classified using GRADE guidelines. As starting point, this consensus increased the minimum acceptable efficacy of recommended treatments that should reach, or preferably surpass, the 90% cure rate when prescribed empirically. Therefore, only quadruple therapies (with or without bismuth), and generally lasting 14 days, are recommended both for first and second line treatments. Non-bismuth quadruple concomitant regimen, including a proton pump inhibitor, clarithromycin, amoxicillin and metronidazole, is recommended as first line. In the present consensus, other first line alternatives and rescue treatments are also reviewed and recommended.

First-line eradication rates comparing two shortened non-bismuth quadruple regimens against Helicobacter pylori: an open-label, randomized, multicentre clinical trial.

OBJECTIVES: Helicobacter pylori eradication remains a challenge. Non-bismuth-based quadruple regimens (NBQR) have shown high eradication rates (ER) elsewhere that need to be locally confirmed. The objective of this study was to compare the first-line ER of a hybrid therapy (20 mg of omeprazole twice daily and 1 g of amoxicillin twice daily for 10 days, adding 500 mg of clarithromycin twice daily and 500 mg of metronidazole every 8 h for the last 5 days; OA-OACM) with that of a 10 day concomitant regimen consisting of taking all four drugs twice daily every day (including 500 mg of metronidazole every 12 h; OACM). A 10 day arm with standard triple therapy (OAC; 20 mg of omeprazole/12 h, 1 g of amoxicillin/12 h and 500 mg of clarithromycin/12 h) was included. PATIENTS AND METHODS: Three hundred consecutive patients were randomized (1: 2: 2) into one of the three following regimens: (i) OAC (60); (ii) OA-OACM (120); and (iii) OACM (120). Eradication was generally confirmed by a [(13)C]urea breath test at least 4 weeks after the end of treatment. Adverse events and compliance were assessed. EudraCT: 2011-006258-99. RESULTS: ITT cure rates were: OAC, 70.0% (42/60) (95% CI: 58.3-81.7); OA-OACM, 90.8% (109/120) (95% CI: 85.6-96.0); and OACM, 90.0% (107/119) (95% CI: 84.6-95.4). PP rates were: OAC, 72.4% (42/58) (95% CI: 60.8-84.1); OA-OACM, 93.9% (108/115) (95% CI: 89.5-98.3); and OACM, 90.3% (102/113) (95% CI: 84.8-95.8). Both NBQR significantly improved ER compared with OAC (P < 0.01), but no differences were seen between them. Mean compliance was elevated [98.0% (SD = 9.8)] with no differences between groups. There were more adverse events in the quadruple arms (OACM, 65.8%; OA-OACM, 68.6%; OAC, 46.6%; P < 0.05), but no significant differences between groups in terms of severity were seen. CONCLUSIONS: Hybrid and concomitant regimens show good ER against H. pylori infection with an acceptable safety profile. They clearly displace OAC as first-line regimen in our area.

Syndrome of inappropriate antidiuresis in doxylamine overdose.

Doxylamine succinate, an H(1)-antihistamine drug, is commonly used as sleep-inducing agent as well as therapy for nausea and vomiting in pregnancy. At usual doses, it may cause impairment of cognitive and psychomotor performance, anticholinergic effects, agitation and postural hypotension. Besides, since this drug is frequently involved in either accidental or intentional overdoses, it seems relevant to bear in mind other possible toxic effects. We report a case of acute severe hyponatremia in the setting of a syndrome of inappropriate antidiuresis (SIAD), an apparent new adverse effect linked to doxylamine overdose. The Naranjo adverse drug reaction probability scale indicated a probable relationship between doxylamine intake and SIAD development. SIAD may be considered as a potential, serious adverse reaction of doxylamine overdose. Clinicians should consider this aetiological possibility when attending patients suffering from hyponatremia.

Levofloxacin versus clarithromycin in a 10 day triple therapy regimen for first-line Helicobacter pylori eradication: a single-blind randomized clinical trial.

BACKGROUND: There is growing evidence that the standard triple therapy against Helicobacter pylori infection is losing clinical effectiveness. A triple therapy regimen with levofloxacin, amoxicillin and a proton pump inhibitor has been reported to be effective and well tolerated, and this regimen has been suggested as an alternative first-line treatment. The aim of this single-blind randomized clinical trial was to compare the eradication success of two first-line triple therapy regimens in the north of Spain: clarithromycin, amoxicillin and omeprazole (CAO) versus levofloxacin, amoxicillin and omeprazole (LAO). MATERIALS AND METHODS: A total of 250 consecutive patients diagnosed by conventional methods with H. pylori infection were randomized into one of two 10 day therapeutic regimens: standard CAO (n = 128) or LAO (n = 122). Eradication was confirmed by the (13)C-urea breath test. Adverse effects and compliance were also assessed. The clinical trial registration number was HPL08001HCLAD (EudraCT: 2008-001892-31). RESULTS: Intention-to-treat cure rates were: CAO, 75.0% (96/128; 95% CI: 66.6%-82.2%) and LAO, 82.8% (101/122; 95% CI: 74.9%-89.0%). Per-protocol cure rates were: CAO, 78.0% (96/123; 95% CI: 69.7%-85.0%) and LAO, 83.1% (98/118; 95% CI: 75.0%-89.3%). There were no statistically significant differences in effectiveness between the two regimens. In addition, no relevant differences in compliance or adverse effects were demonstrated. CONCLUSIONS: Levofloxacin-based treatment for H. pylori infection did not improve upon the eradication rate of the standard clarithromycin-based triple therapy in this study. This may reflect the progressive increase in in vitro resistance rates to levofloxacin observed in our region.

Antimicrobial susceptibility of Helicobacter pylori to six antibiotics currently used in Spain.

BACKGROUND: Antibiotic resistance is directly related to the loss of efficacy of currently accepted Helicobacter pylori therapies. Knowledge of the antibiotic susceptibility in a local area can contribute to the design of specific 'à la carte' treatments. The aim of this study was to analyse the susceptibility of H. pylori isolates to six conventional antibiotics currently used in a northern region of Spain. METHODS: Seventy-one isolates were obtained from gastric biopsies of 76 consecutive adult patients suffering from peptic ulcer disease, dyspepsia or familial gastric cancer and known to be infected with H. pylori by conventional methods. Susceptibility testing was performed for amoxicillin, ciprofloxacin, levofloxacin, clarithromycin, metronidazole and tetracycline using the Etest method. RESULTS: The prevalence rates of resistance were as follows: amoxicillin, 1.4% [95% confidence interval (CI) 0.0-7.6]; clarithromycin, 14.7% (95% CI 7.3-25.4); ciprofloxacin, 14.3% (95% CI 7.1-24.7); levofloxacin, 14.5% (95% CI 7.2-25.0); metronidazole, 45.1% (95% CI 33.2-57.3); and tetracycline, 0% (95% CI 0.0-5.1). CONCLUSIONS: Our study confirms an increasing rate of resistance to levofloxacin that equals that of clarithromycin in our healthcare area. This fact may reflect a wide and indiscriminate use of the former antibiotic and could account for a loss of clinical effectiveness of levofloxacin-containing regimens. Moreover, clarithromycin resistance rates remain stable, which could allow us to maintain its use in our area.

Hepatoportal sclerosis: a cause of portal hypertension to bear in mind / Hepatoportal sclerosis: a cause of portal hypertension to bear in mind

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