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.

Colectomy rate in ulcerative colitis 15 years after diagnosis: Results from the 2001-2003 Navarra cohort. / Tasas de colectomía en colitis ulcerosa 15 años después del diagnóstico. Datos de la cohorte Navarra 2001-2003.

INTRODUCTION: Knowing the natural history of ulcerative colitis (UC) is essential to understand the course of the disease, assess the impact of different treatment strategies and identify poor prognostic factors. One of the most significant matters in this regard is the need for surgery. OBJECTIVES: To analyse the Colectomy Incidence Rate (CIR) from diagnosis to end of follow-up (31/12/2017) and identify predictive factors for colectomy. MATERIAL AND METHODS: A retrospective study enrolling patients with a definitive diagnosis (DD) of UC or Unclassified Colitis (UnC) in the 2001-03 Navarra cohort. RESULTS: We enrolled 174 patients with a DD of UC (E2 42.8%; E3 26.6%) and 5 patients with a DD of UnC: 44.1% women, median age 39.2 years (range 7-88) and median follow-up 15.7 years. A total of 8 patients underwent surgery (CIR 3 colectomies/103 patient-years: 3 at initial diagnosis (<1 month), 2 in the first 2 years, 2 at 5 years from diagnosis and 1 at 12 years from diagnosis. All had previously received steroids; 5 had received immunomodulators and 2 had received biologics. In 7 patients (87%), surgery was performed on an emergency basis. The indication was megacolon in 3 (37.5%), severe flare-up in 3 (37.5%) and medical treatment failure in 2 (25%). In 5 cases (62.5%), an ileoanal pouch was made, and in 3 cases, a definitive ileostomy was performed. In the univariate analysis, patients with loss of more than 5 kg at diagnosis and admission at diagnosis had a lower rate of colectomy-free survival. CONCLUSIONS: In our series, colectomy rates are lower than usually reported. Most colectomies were performed in the first 5 years following diagnosis and had an emergency indication.

Acceptance and perceived value of non-invasive malaria diagnostic tests in malaria-endemic countries.

BACKGROUND: The diagnosis of malaria, using microscopy or rapid diagnostic tests (RDTs), requires the collection of capillary blood. This procedure is relatively simple to perform but invasive and poses potential risks to patients and health workers, arising from the manipulation of potentially infectious bodily fluids. Less or non-invasive diagnostic tests, based on urine, saliva or requiring no sampling, have the potential to generate less discomfort for the patient and to offer simpler and less risky testing procedures that could be safely performed by untrained staff or even self-performed. To explore the potential acceptance and perceived value of such non-invasive tests, an online, international survey was conducted to gather feedback from National Malaria Control Programme (NMCP) representatives. METHODS: An online survey comprising nineteen questions, available in English, French or Spanish, was emailed to 300 individuals who work with NMCPs in malaria-endemic countries. Answers were collected between November and December 2017; responses were qualitatively analysed to identify key themes and trends and quantitatively analysed to determine average values stratified by region. RESULTS: Responses were received from 70 individuals, from 33 countries. Approximately half of the respondents (52 %) considered current blood-based tests for malaria to be minimally invasive and non-problematic in their setting. For these participants, non-invasive tests would only be of interest if they brought additional performance improvements, as compared with the performance of microscopy and RDTs. Most respondents were of the view that saliva-based (80 %) and urine-based (66 %) tests would be more readily acceptable among children than blood-based tests. Potential use-case scenarios of interest for both saliva- and urine-based tests were ease-of-testing by community health workers, additional surveillance, self-testing, and outbreak investigation. Many respondents (41 %) thought that if saliva-based tests retailed at <$0.50 per unit they could largely replace conventional RDTs, whereas only 25 % of respondents thought a similarly priced urine-based test would do so. CONCLUSIONS: Although limited to NMCP stakeholders, this survey indicated that current tests for malaria, based on capillary blood, are generally perceived to be minimally invasive and non-problematic. Non-invasive tests, especially if saliva-based, would be welcome if they could match or out-perform the price and performance of current blood-based tests.

Quantification of malaria antigens PfHRP2 and pLDH by quantitative suspension array technology in whole blood, dried blood spot and plasma.

BACKGROUND: Malaria diagnostics by rapid diagnostic test (RDT) relies primarily on the qualitative detection of Plasmodium falciparum histidine-rich protein 2 (PfHRP2) and Plasmodium spp lactate dehydrogenase (pLDH). As novel RDTs with increased sensitivity are being developed and implemented as point of care diagnostics, highly sensitive laboratory-based assays are needed for evaluating RDT performance. Here, a quantitative suspension array technology (qSAT) was developed, validated and applied for the simultaneous detection of PfHRP2 and pLDH in a variety of biological samples (whole blood, plasma and dried blood spots) from individuals living in different endemic countries. RESULTS: The qSAT was specific for the target antigens, with analytical ranges of 6.8 to 762.8 pg/ml for PfHRP2 and 78.1 to 17076.6 pg/ml for P. falciparum LDH (Pf-LDH). The assay detected Plasmodium vivax LDH (Pv-LDH) at a lower sensitivity than Pf-LDH (analytical range of 1093.20 to 187288.5 pg/ml). Both PfHRP2 and pLDH levels determined using the qSAT showed to positively correlate with parasite densities determined by quantitative PCR (Spearman r = 0.59 and 0.75, respectively) as well as microscopy (Spearman r = 0.40 and 0.75, respectively), suggesting the assay to be a good predictor of parasite density. CONCLUSION: This immunoassay can be used as a reference test for the detection and quantification of PfHRP2 and pLDH, and could serve for external validation of RDT performance, to determine antigen persistence after parasite clearance, as well as a complementary tool to assess malaria burden in endemic settings.

Keep the quality high: the benefits of lot testing for the quality control of malaria rapid diagnostic tests.

BACKGROUND: The production and use of malaria rapid diagnostic tests (RDTs) has risen dramatically over the past 20 years. In view of weak or non-existing in vitro diagnostics (IVD) regulations and post-marketing surveillance (PMS) systems in malaria endemic countries, the World Health Organization, later joined by the Foundation for Innovative New Diagnostics, established an independent, centralized performance evaluation and Lot Testing (LT) programme to safeguard against poor quality of RDTs being distributed through the public health sector of malaria endemic countries. RDT performances and manufacturer quality management systems have evolved over the past decade raising questions about the future need for a centralized LT programme. RESULTS: Between 2007 and 2017, 6056 lots have been evaluated, representing approximately 1.6 Billion RDTs. A total of 69 lots (1.1%) failed the quality control. Of these failures, 26 were detected at receipt of the RDT lot in the LT laboratory, representing an estimated 7.9 million poor quality RDTs, and LT requesters were advised that RDTs were not of sufficient quality for use in patient management. Forty-three were detected after long-term storage in the laboratory, of which 24 (56%) were found to be due to a major issue with insufficient buffer volume in single use buffer vials, others predominantly showing loss of sensitivity. The annual cost of running the programme, based on expenses recorded in years 2014-2016, an estimated volume of 700 lots per year and including replenishment of quality control samples, was estimated at US$ 178,500 ($US 255 per lot tested). CONCLUSIONS: Despite the clear benefits of the centralized LT programme and its low cost compared with the potential costs of each country establishing its own PMS system for RDTs, funding concerns have made its future beyond 2020 uncertain. In order to manage the risks of misdiagnosis due to low quality RDTs, and to ensure the continued safety and reliability of malaria case management, there is a need to ensure that an effective and implementable approach to RDT quality control continues to be available to programmes in endemic countries.

A Systematic Review: Performance of Rapid Diagnostic Tests for the Detection of Plasmodium knowlesi, Plasmodium malariae, and Plasmodium ovale Monoinfections in Human Blood.

Background: Despite the increased use and worldwide distribution of malaria rapid diagnostic tests (RDTs) that distinguish between Plasmodium falciparum and non-falciparum species, little is known about their performance detecting Plasmodium knowlesi (Pk), Plasmodium malariae (Pm), and Plasmodium ovale (Po). This review seeks to analyze the results of published studies evaluating the diagnostic accuracy of malaria RDTs in detecting Pk, Pm, and Po monoinfections. Methods: MEDLINE, EMBASE, Web of Science, and CENTRAL databases were systematically searched to identify studies that reported the performance of RDTs in detecting Pk, Pm, and Po monoinfections. Results: Among 40 studies included in the review, 3 reported on Pk, 8 on Pm, 5 on Po, 1 on Pk and Pm, and 23 on Pm and Po infections. In the meta-analysis, estimates of sensitivities of RDTs in detecting Pk infections ranged 2%-48%. Test performances for Pm and Po infections were less accurate and highly heterogeneous, mainly because of the small number of samples tested. Conclusions: Limited data available suggest that malaria RDTs show suboptimal performance for detecting Pk, Pm, and Po infections. New improved RDTs and appropriately designed cross-sectional studies to demonstrate the usefulness of RDTs in the detection of neglected Plasmodium species are urgently needed.

Diagnostic accuracy of loop-mediated isothermal amplification (LAMP) for screening malaria in peripheral and placental blood samples from pregnant women in Colombia.

BACKGROUND: Pregnant women frequently show low-density Plasmodium infections that require more sensitive methods for accurate diagnosis and early treatment of malaria. This is particularly relevant in low-malaria transmission areas, where intermittent preventive treatment is not recommended. Molecular methods, such as polymerase chain reaction (PCR) are highly sensitive, but require sophisticated equipment and advanced training. Instead, loop mediated isothermal amplification (LAMP) provides an opportunity for molecular detection of malaria infections in remote endemic areas, outside a reference laboratory. The aim of the study is to evaluate the performance of LAMP for the screening of malaria in pregnant women in Colombia. METHODS: This is a nested prospective study that uses data and samples from a larger cross-sectional project conducted from May 2016 to January 2017 in three Colombian endemic areas (El Bagre, Quibdó, and Tumaco). A total of 531 peripheral and placental samples from pregnant women self-presenting at local hospitals for antenatal care visits, at delivery or seeking medical care for suspected malaria were collected. Samples were analysed for Plasmodium parasites by light microscopy (LM), rapid diagnostic test (RDT) and LAMP. Diagnostic accuracy endpoints (sensitivity, specificity, predictive values, and kappa scores) of LM, RDT and LAMP were compared with nested PCR (nPCR) as the reference standard. RESULTS: In peripheral samples, LAMP showed an improved sensitivity (100.0%) when compared with LM 79.5% and RDT 76.9% (p < 0.01), particularly in afebrile women, for which LAMP sensitivity was two-times higher than LM and RDT. Overall agreement among LAMP and nPCR was high (kappa value = 1.0). Specificity was similar in all tests (100%). In placental blood, LAMP evidenced a four-fold improvement in sensitivity (88.9%) when compared with LM and RDT (22.2%), being the only method, together with nPCR, able to detect placental infections in peripheral blood. CONCLUSIONS: LAMP is a simple, rapid and accurate molecular tool for detecting gestational and placental malaria, being able to overcome the limited sensitivity of LM and RDT. These findings could guide maternal health programs in low-transmission settings to integrate LAMP in their surveillance systems for the active detection of low-density infections and asymptomatic malaria cases.

International survey to identify diagnostic needs to support malaria elimination: guiding the development of combination highly sensitive rapid diagnostic tests.

BACKGROUND: In malaria elimination settings, the very low levels of transmission now being attained present challenges that demand new strategies to identify and treat low-density infections in both symptomatic and asymptomatic populations. Accordingly, passive case detection activities need to be supplemented by active case detection (ACD) strategies with more sensitive diagnostic tools. Malaria rapid diagnostic tests (RDTs) have provided low- and middle-income countries with unprecedented access to malaria diagnostics. Nevertheless, conventional RDTs miss a potentially important proportion of sub-microscopic infections. Therefore, new combination highly sensitive (HS-)RDTs, able to detect low parasite densities and identify all infected individuals, could support countries implementing ACD strategies for radical cure to accelerate malaria elimination. To address this need, an on-line survey was conducted to gather information from malaria control programme representatives to guide the development of next-generation RDTs. RESULTS: Most of respondents confirmed that ACD was a common activity in their programmes (56/75; 75%). Although microscopy was the preferred method in case management and reactive case detection, RDTs were the primary diagnostic tests used in proactive case detection (31/75; 41%). In terms of preferences for species detection in a new combination HS-RDT, data was not one-directional. Survey respondents slightly preferred the Pf/Pv/Pan combination (42%; 21/50), while Pf/Pan was more popular among end-users. Survey respondents also valued a low-cost (< $1.00 USD), lightweight and portable test, able to detect asymptomatic infections and differentiate species, as well as provide immediate results that could be interpreted with the naked eye. In addition, respondents were open to new tests and even to replace the existing ones for ACD (63%; 47/75). CONCLUSIONS: This survey provided valuable information on the use and current limitations of ACD, on the primary product characteristics for a next-generation combination HS-RDT to support ACD and radical cure, and on the potential adoption of such a test, if available, to support malaria elimination.

[10-day triple therapy with esomeprazole 40 mg/12 h vs. quadruple concomitant non-bismuth therapy as first line treatment for Helicobacter pylori infection]. / Triple terapia 10 días con esomeprazol 40 mg/12 h vs. cuádruple concomitante sin bismuto como tratamiento de primera línea de la infección por Helicobacter pylori.

INTRODUCTION: Quadruple concomitant non-bismuth therapy has recently become the most widely prescribed first-line treatment for Helicobacter pylori infection in Spain. Whether optimized conventional triple therapy can achieve comparable efficacy rates remains to be seen. MATERIAL AND METHODS: Retrospective study comparing the efficacy of triple and quadruple concomitant therapy, and sub-analysis following administration of both for 10 days with esomeprazole 40mg/12h. RESULTS: A first-line therapy was administered to 657 patients from 1st January 2012 to 31st December 2014. Quadruple therapy (n=371) showed higher efficacy than triple therapy (n=248) for both intention-to-treat (85.9% vs. 65.7%; P<.001) and per protocol analysis (92.5% vs. 68.4%; P<.001). When both therapies included esomeprazole 40mg/12h administered for 10 days, quadruple concomitant therapy (n=108) also had higher efficacy than triple therapy (n=76) for intention-to-treat (90.7% vs. 73.6%; P=.003) and per protocol analysis (92.5% vs.74.6%; P=.002). CONCLUSIONS: Quadruple concomitant therapy with high dose proton pump inhibitor (PPI) for 10 days achieves a significantly higher eradication outcome than optimized triple therapy, with rates of over 90% when the PPI prescribed is esomeprazole 40mg/12h.

[COVID-19 readmissions during the first three epidemic periods in Orihuela, Spain: incidence, risk factors and letality]. / Reingresos por la COVID-19 durante los tres primeros periodos epidémicos en Orihuela, España: incidencia, factores de riesgo y letalidad.

OBJECTIVE: Readmission for COVID-19 is associated with high mortality, saturation of health services, and high costs. This study aimed to assess the incidence and risk factors of readmissions in COVID-19 patients in a regional hospital of Spain from February 2020 to March 2021. METHODS: A retrospective cohort study describing the characteristics of adult patients readmitted within thirty days of discharge after being infected with SARS-CoV-2 was carried out. Readmission associated risk factors were analysed using a binary logistic regression model. RESULTS: Of the 967 patients who survived their first COVID-19 admission, 70 (7.2%) were readmitted within thirty days. Of these, 34.3% presented pneumonia progression, 15.7% functional deterioration, and 12.9% other infections. The mortality rate during readmission was 28.6%. There were no statistically significant differences in the cumulative incidence of readmissions between the epidemic periods (p=0.241). Factors independently associated with readmission were: diabetes mellitus (aOR 1.96, 95%CI 1.07-3.57, p=0.030); acute kidney failure (aOR 2.69, 95%CI 1.43-5.07, p=0.002); not being a candidate for intensive care (aOR 7.68, 95% CI 4.28-13.80, p<0.001); and not being prescribed corticosteroids at discharge (aOR 2.15, 95% CI 1.04-4.44; p=0.039). CONCLUSIONS: A substantial proportion of patients admitted due to COVID-19 are readmitted, and they carry a high letality. Diabetes mellitus, acute kidney failure, not being a candidate for ICU admission, and not being prescribed corticosteroids on discharge are independently associated with an increased risk of readmission.

OBJECTIVE: Los reingresos por la COVID-19 se asocian a un incremento de la mortalidad, saturación de los servicios sanitarios y elevados costes. Este estudio pretendió evaluar la incidencia y los factores de riesgo de reingreso en pacientes con COVID-19 en un hospital comarcal español entre febrero de 2020 y marzo de 2021. METHODS: Se realizó un estudio sobre una cohorte que describía las características de los pacientes adultos reingresados en los treinta días siguientes al alta tras un ingreso por la COVID-19. Se analizaron los factores de riesgo asociados a reingreso mediante un modelo de regresión de logística binaria. RESULTS: De los 967 pacientes dados de alta de un primer ingreso por la COVID-19, 70 (7,2%) reingresaron en los treinta días siguientes. De ellos, el 34,3% presentó progresión de la neumonía, el 15,7% deterioro funcional y el 12,9% otras infecciones. La letalidad en el reingreso fue del 28,6%. No hubo diferencias estadísticamente significativas en la incidencia acumulada de reingreso entre los tres periodos (p=0,241). Los factores asociados de forma independiente con el reingreso fueron: diabetes mellitus (ORa: 1,96; IC 95%:1,07-3,57; p=0,030); insuficiencia renal aguda (ORa 2,69; IC del 95%: 1,43-5,07, p=0,002); no ser candidato a cuidados intensivos (ORa 7,68, IC 95% 4,28-13,80, p<0,001); y no tener prescritos corticosteroides al alta (ORa 2,15, IC 95% 1,04- 4,44; p=0,039). CONCLUSIONS: Una proporción sustancial de los pacientes ingresados por la COVID-19 reingresan, con una elevada letalidad. La diabetes mellitus, la insuficiencia renal aguda, no ser candidato a ingreso en UCI y no tener prescritos corticoides al alta se asocian con un mayor riesgo de reingreso.

Effectiveness and Safety of High-Dose Dual Therapy: Results of the European Registry on the Management of Helicobacterpylori Infection (Hp-EuReg).

BACKGROUND: Randomized clinical trials and meta-analyses, primarily from Asian countries, have reported good effectiveness with high-dose dual therapy (HDDT) including a proton pump inhibitor (PPI) and amoxicillin when prescribed as H. pylori first-line or rescue treatment. However, combining amoxicillin with PPIs in the 1990s in several European countries yielded suboptimal results. METHODS: An international, multicenter, prospective non-interventional Registry (Hp-EuReg) aimed to evaluate the decisions and outcomes of H. pylori management by European gastroenterologists. All infected adult cases treated with HDDT were registered at e-CRF AEG-REDCap platform until June 2021. Sixty patients were prescribed with HDDT (98% compliance), 19 of them received a first-line therapy and 41 a rescue treatment (second- to sixth-line). RESULTS: Overall HDDT effectiveness was 52% (per-protocol) and 51% (modified intention-to-treat). First-line and rescue treatment lines were equally effective, but the effectiveness was worse when patients had previously received metronidazole, tetracycline, or rifabutin. Adding bismuth to HDDT in rescue treatment did not yield better results. The incidence of adverse events was 30%, diarrhea being the most common (20% of patients); no serious adverse events were reported. CONCLUSION: Although HDDT is safe and has good compliance, it is not a good option in European first-line or rescue H. pylori treatment, even when adding bismuth.

A ¹8F-fluorodeoxyglucose MicroPET imaging study to assess changes in brain glucose metabolism in a rat model of surgery-induced latent pain sensitization.

BACKGROUND: Neuroplastic changes involved in latent pain sensitization after surgery are poorly defined. We assessed temporal changes in glucose brain metabolism in a postoperative rat model using positron emission tomography. We also investigated brain metabolism after naloxone administration. METHODS: Rats were given remifentanil anesthetic and underwent a plantar incision, with 1 mg/kg of (-)-naloxone subcutaneously administered on postoperative days 20 and 21. Using the von Frey test, mechanical thresholds were measured pre- and postoperatively at different time points in awake animals during F-fluorodeoxyglucose (F-FDG) uptake. Brain images were also obtained the day before mechanical testing, using a positron emission tomography R4 scanner (Concorde Microsystems, Siemens, Knoxville, TN). Differences in brain activity were assessed utilizing a statistical parametric mapping. RESULTS: Surgery induced minor changes in F-FDG uptake in the cerebellum, hippocampus, and posterior cortex, which extended to the thalamus, hypothalamus, and brainstem on days 6 and 7. Changes were still present on day 21. Maximal postoperative hypersensitivity was observed on day 2. The administration of (-)-naloxone on day 21 induced significant hypersensitivity, greatly enhancing the effect on F-FDG uptake. In sham-operated rats, naloxone induced changes limited to the striatum and the cerebellum. Nonnociceptive stimulation with von Frey filaments had no effect on F-FDG uptake. CONCLUSIONS: Surgery, remifentanil, and their combination induced long-lasting and significant metabolic changes in the pain brain matrix, with a positive correlation with hypersensitivity after naloxone. Changes in brain F-FDG precipitated by naloxone suggest that surgery under remifentanil anesthetic induces the greatest neuroplastic brain adaptations in opioid-related pathways involved in nociceptive processing and long-lasting pain sensitization.

Celsior versus University of Wisconsin preserving solutions for liver transplantation: postreperfusion syndrome and outcome of a 5-year prospective randomized controlled study.

BACKGROUND: Celsior solution (CS) is a high-sodium, low-potassium, low-viscosity extracellular solution that has been used for liver graft preservation in recent years, although experience with it is still limited. We performed an open-label randomized active-controlled trial comparing CS with the University of Wisconsin solution (UW) for liver transplantation (LT), with a follow-up period of 5 years. METHODS: Adult transplant recipients (n=102) were prospectively randomized to receive either CS (n=51) or UW (n=51). The two groups were comparable with respect to donor and recipient characteristics. The primary outcome measure was the incidence of postreperfusion syndrome (PRS). Secondary outcome measures included primary nonfunction (PNF) or primary dysfunction (PDF), liver retransplantation, and graft and patient survival. Other secondary outcome measures were days in the intensive care unit (ICU) and the rates of acute rejection, chronic rejection, infectious complications, postoperative reoperations, and vascular and biliary complications. RESULTS: In all, 14 posttransplant variables revealed no significant differences between the groups. There were no cases of PNF or PDF. The incidence of PRS was 5.9% in the CS group and 21.6% in the UW group (P=0.041). After reperfusion, CS revealed greater control of serum potassium (P=0.015), magnesium levels (P=0.005), and plasma glucose (P=0.042) than UW. Respective patient survivals at 3, 12, and 60 months were 95.7, 87.2, and 82.0% for the CS group and 95.7, 83.3, and 66.6% for the UW group (P=0.123). CONCLUSIONS: While retaining the same degree of safety and effectiveness as UW for LT, CS may yield postliver graft reperfusion benefits, as shown in this study by a significant reduction in the incidence of PRS and greater metabolic control.

Increased spinal dynorphin levels and phospho-extracellular signal-regulated kinases 1 and 2 and c-Fos immunoreactivity after surgery under remifentanil anesthesia in mice.

In humans, remifentanil anesthesia enhances nociceptive sensitization in the postoperative period. We hypothesized that activation of extracellular signal-regulated kinases 1 and 2 (ERK1/2) and the expression of c-Fos, prodynorphin (mRNA), and dynorphin in the spinal cord could participate in the molecular mechanisms underlying postoperative opioid-induced sensitization. In a mouse model of incisional pain, we evaluated thermal (Hargreaves test) and mechanical (von Frey) hyperalgesia during the first 21 postoperative days. Moreover, prodynorphin (mRNA, real-time polymerase chain reaction), dynorphin (enzymatic immunoassay), c-Fos expression, and ERK1/2 phosphorylation (both by immunohistochemistry) in the lumbar spinal cord were assessed. Surgery performed under remifentanil anesthesia induced a maximal decrease in nociceptive thresholds between 4 h and 2 days postoperatively (p < 0.001) that lasted 10 to 14 days compared with noninjured animals. In the same experimental conditions, a significant increase in prodynorphin mRNA expression (at 2 and 4 days) followed by a sustained increase of dynorphin (days 2 to 10) in the spinal cord was observed. We also identified an early expression of c-Fos immunoreactivity in the superficial laminae of the dorsal horn of the spinal cord (peak at 4 h; p < 0.001), together with a partial activation of ERK1/2 (4 h; p < 0.001). These findings suggest that activated ERK1/2 could induce c-Fos expression and trigger the transcription of prodynorphin in the spinal cord. This in turn would result in long-lasting increased levels of dynorphin that, in our model, could participate in the persistence of pain but not in the manifestation of first pain.

European Registry on Helicobacter pylori Management: Effectiveness of First and Second-Line Treatment in Spain.

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.

Pronociceptive effects of remifentanil in a mouse model of postsurgical pain: effect of a second surgery.

BACKGROUND: Remifentanil anesthesia enhances postoperative pain in animals and humans. The authors evaluated the impact of the dose (microg x kg(-1) x min(-1)) and duration of remifentanil infusion, and the effects of a second surgery on postoperative pain sensitization. METHODS: Mice received different doses of remifentanil over 30 or 60 min. The authors assessed thermal (Hargreaves) and mechanical hyperalgesia (von Frey) at 2, 4, 7, and 10 days. In other experiments, mice had a plantar incision during sevoflurane with or without remifentanil anesthesia that was repeated 27 days later, when nociceptive thresholds returned to baseline. Linear mixed models were used for statistical analysis. RESULTS: Remifentanil induced dose-dependent pronociceptive effects with calculated ED(50)s of 1.7 (95% confidence interval, 1.3-2.1) and 1.26 (1.0-1.6) microg x kg(-1) x min(-1) for thermal and mechanical hyperalgesia, respectively, which lasted longer with higher doses (P < 0.001). The duration of infusion did not alter the pronociceptive effects of remifentanil when administered at a constant dose of infusion. When given during surgery, high (2.66 microg x kg(-1) x min(-1)) or low (0.66 microg x kg(-1) x min(-1)) remifentanil increased the extent (P < 0.05) and duration (P < 0.01) of thermal and mechanical hyperalgesia. The latter was further enhanced after a second surgery performed in the same experimental conditions (P < 0.05). Surgery or remifentanil infusion, each one individually, induced significant mechanical hyperalgesia, which was greater when repeated (P < 0.05). CONCLUSIONS: In this model of incisional pain, remifentanil induces pronociceptive effects, which are dose dependent but unaltered by the duration of administration. A second surgery performed on the same site and experimental conditions induces greater postoperative hyperalgesia that is enhanced when remifentanil is used as an anesthetic.

Performance of a highly sensitive rapid diagnostic test (HS-RDT) for detecting malaria in peripheral and placental blood samples from pregnant women in Colombia.

BACKGROUND: Pregnancy poses specific challenges for the diagnosis of Plasmodium falciparum infection due to parasite sequestration in the placenta, which translates in low circulation levels in peripheral blood. The aim of this study is to assess the performance of a new highly sensitive rapid diagnostic test (HS-RDT) for the detection of malaria in peripheral and placental blood samples from pregnant women in Colombia. METHODS: This is a retrospective study using 737 peripheral and placental specimens collected from pregnant women in Colombian malaria-endemic regions. Light microscopy (LM), conventional rapid diagnostic tests (Pf/Pv RDT and Pf RDT), and HS-RDT testing were performed. Diagnostic accuracy endpoints of LM, HS-RDT and RDTs were compared with nested polymerase chain reaction (nPCR) as the reference test. RESULTS: In comparison with nPCR, the sensitivity of HS-RDT, Pf RDT, Pf/Pv RDT and LM to detect infection in peripheral samples was 85.7% (95% CI = 70.6-93.7), 82.8% (95% CI = 67.3-91.9), 77.1% (95% CI = 61.0-87.9) and 77.1% (95% CI = 61.0-87.9) respectively. The sensitivity to detect malaria in asymptomatic women, was higher with HS-RDT, where LM and Pf/Pv RDT missed half of infections detected by nPCR, but differences were not significant. Overall, specificity was similar for all tests (>99.0%). In placental blood, the prevalence of infection by P. falciparum by nPCR was 2.8% (8/286), by HS-RDT was 1% and by conventional RDTs (Pf RDT and Pf/Pv RDT) and LM was 0.7%. The HS-RDT detected placental infections in peripheral blood that were negative by LM and Pf/Pv RDT, however the number of positive placentas was low. CONCLUSIONS: The sensitivity of HS-RDT to detect P. falciparum infections in peripheral and placental samples from pregnant women was slightly better compared to routinely used tests during ANC visits and at delivery. Although further studies are needed to guide recommendations on the use of the HS-RDT for malaria case management in pregnancy, this study shows the potential value of this test to diagnose malaria in pregnancy in low-transmission settings.

[Cuadruple concomitant non-bismuth therapy vs. classical triple therapy as first line therapy for Helicobacter pylori infection]. / Comparación de cuádruple terapia concomitante sin bismuto con triple terapia clásica como primera línea de tratamiento para la erradicación del Helicobacter pylori.

BACKGROUND AND OBJECTIVE: In a previous study we found that the classical triple therapy for Helicobacter pylori (H. pylori) had low efficacy (under 70%) in our area. After this finding, in mid 2012 quadruple concomitant therapy started to be prescribed in our hospital. The aim of the present study is to compare the efficacy of classical triple therapy and quadruple concomitant therapy without bismuth. MATERIAL AND METHODS: Observational retrospective study of prescribed treatments between 1st January 2012 and 5th May 2014 and their efficacy. RESULTS: During the study period 510 patients were prescribed a first line therapy; in 179 cases (35,1%) the combination amoxiciline+clarithromicine+PPI was prescribed during 7-14 days, and 298 patients (58,4%) were treated with amoxicillin+clarithromycin+metronidazole+PPI for 10 days. The quadruple concomitant therapy had a higher efficacy than the classical triple therapy, both in an "intention to treat" (84.8% vs. 65.7%, P=.001) and "per protocol" (86.9% vs. 67.2%, P=.001) analysis. Triple therapy had a higher efficacy when it was prescribed for 10 days compared to 7 days (77.9% vs. 56.5%, P=.005 per "intention to treat" and 77.9% vs. 58.5%, P=.011 "per protocol"). When quadruple concomitant therapy was compared with classical triple therapy prescribed over 10 days no significant differences were found. CONCLUSIONS: In our setting, cuadruple concomitant therapy without bismuth has a high efficacy as first line therapy for H. pylori eradication, with much better results than classical triple therapy in the way that it is most widely prescribed (short courses of 7-day with a single dose of omeprazole).

Aplastic anemia and severe pancytopenia during treatment with peg-interferon, ribavirin and telaprevir for chronic hepatitis C.

Telaprevir and Boceprevir are the first direct acting antivirals approved for chronic hepatitis C in combination with peg-interferon alfa and ribavirin. Pancytopenia due to myelotoxicity caused by these drugs may occur, but severe hematological abnormalities or aplastic anemia (AA) have not been described. We collected all cases of severe pancytopenia observed during triple therapy with telaprevir in four Spanish centers since approval of the drug in 2011. Among 142 cirrhotic patients receiving treatment, 7 cases of severe pancytopenia (5%) were identified and three were consistent with the diagnosis of AA. Mean age was 59 years, five patients had compensated cirrhosis and two patients had severe hepatitis C recurrence after liver transplantation. Severe pancytopenia was diagnosed a median of 10 wk after the initiation of therapy. Three patients had pre-treatment hematological abnormalities related to splenomegaly. In six patients, antiviral treatment was interrupted at the onset of hematological abnormalities. Two patients died due to septic complications and one patient due to acute alveolar hemorrhage. The remaining patients recovered. Severe pancytopenia and especially AA, are not rare during triple therapy with telaprevir in patients with advanced liver disease. Close monitoring is imperative in this setting to promptly detect serious hematological disorders and to prevent further complications.

Angiogenesis and proliferation markers in adjacent cirrhotic tissue could predict hepatocellular carcinoma outcome after liver transplantation.

INTRODUCTION: The current staging systems for hepatocellular carcinoma (HCC) do not sufficiently predict outcomes after liver transplantation (LT). The present study assessed whether some tissue markers related to proliferation and angiogenesis have prognostic value. PATIENTS AND METHODS: The expression of CD34, vascular endothelial growth factor (VEGF), VEGFR2, VEGFR1, angiopoietin-1, angiopoietin-2, TIE2, COX-2, and proliferating cell nuclear antigen (PCNA) in tumor and adjacent cirrhotic tissue samples from 36 patients with HCC (n=10 with tumor recurrence after LT) was determined by immunochemistry. Microvessel density was assessed by CD34 staining and the PCNA labeling index calculated as the percentage of positive cells among at least 1000 hepatocyte nuclei studied in each sample using the computer program ContimUZ. VEGF, VEGFR2, VEGFR-1, angiopoietin-1, angiopoietin-2, TIE2, and COX-2 staining were evaluated by two blinded pathologists. The tumor recurrence rate was analyzed after a minimum follow-up of 36 months. RESULTS: A higher proliferation index in both tumor and adjacent cirrhotic tissue was related to HCC recurrence. The proliferation index in tumor tissue was also related to microvascular invasion. High expression (staining in ≥50% of hepatocytes) of COX2 [P=0.025, odds ratio (OR)=7.5, 95% confidence interval (CI) 1.3-43.4], VEGF (P=0.01, OR=12, 95% CI 1.8-80.4), and its receptor VEGFR-2 (P=0.02, OR=8.5, 95% CI 1.4-49.5) in cirrhotic liver tissue, but not tumor tissue, was related to HCC recurrence after LT. CONCLUSION: A high proliferation index in tumor and cirrhotic tissue and high expression levels of some angiogenic markers in adjacent cirrhotic tissue could be predictive of tumor recurrence after LT.