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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 (

In many areas around the world, phreatic coastal aquifers are vulnerable to contamination and saltwater intrusion. This study aims to explore the hydrodynamic functioning of the coastal phreatic aq...

Immune-checkpoint inhibitors (ICIs) are antagonists of inhibitory receptors in the immune system, such as the cytotoxic T-lymphocyte-associated antigen-4, the programmed cell death protein-1 and its ligand PD-L1, and they are increasingly used in cancer treatment. By blocking certain suppressive pathways, ICIs promote T-cell activation and antitumor activity but may induce so-called immune-related adverse events (irAEs), which mimic traditional autoimmune disorders. With the approval of more ICIs, irAE prediction has become a key factor in improving patient survival and quality of life. Several biomarkers have been described as potential irAE predictors, some of them are already available for clinical use and others are under development; examples include circulating blood cell counts and ratios, T-cell expansion and diversification, cytokines, autoantibodies and autoantigens, serum and other biological fluid proteins, human leucocyte antigen genotypes, genetic variations and gene profiles, microRNAs, and the gastrointestinal microbiome. Nevertheless, it is difficult to generalize the application of irAE biomarkers based on the current evidence because most studies have been retrospective, time-limited and restricted to a specific type of cancer, irAE or ICI. Long-term prospective cohorts and real-life studies are needed to assess the predictive capacity of different potential irAE biomarkers, regardless of the ICI type, organ involved or cancer site.

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 asAn international, multicenter, prospective non-interventional Registry (Hp-EuReg) aimed to evaluate the decisions and outcomes ofOverall 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.Although HDDT is safe and has good compliance, it is not a good option in European first-line or rescue

Background In low transmission settings early diagnosis is the main strategy to reduce adverse outcomes of malaria in pregnancy; however, microscopy and rapid diagnostic tests (RDTs) are inadequate for detecting low-density infections. We studied the performance of the highly sensitive-RDT (hsRDT) and the loop mediated isothermal DNA amplification (LAMP) for the detection of P. falciparum in pregnant women. Methods A cross-sectional study was conducted in two malaria-endemic municipalities in Colombia. We screened pregnant women in the context of an antenatal care program in health facilities and evaluated five tests (microscopy, conventional RDT, hsRDT, LAMP and nested polymerase chain reaction-PCR) for the detection of P. falciparum in peripheral blood, using a quantitative reverse transcription PCR (qRT-PCR) as the reference standard. Diagnostic performance of hsRDT and LAMP were compared with routine testing. Results The prevalence of P. falciparum was 4.5% by qRT-PCR, half of those infections were subpatent. The sensitivity of the hsRDT (64.1%) was slightly better compared to microscopy and cRDT (59 and 53.8% respectively). LAMP had the highest sensitivity (89.7%) for detecting P. falciparum and the ability to detect very low-density infections (minimum parasite density detected 0.08 p/μL). Conclusions There is an underestimation of Plasmodium spp. infections by tests routinely used in pregnant women attending antenatal care visits. LAMP methodology can be successfully implemented at local hospitals in malaria-endemic areas. The relevance of detecting and treating this sub-patent P. falciparum infections in pregnant women should be evaluated. Trial registration ClinicalTrials.gov, Identifier: NCT03172221, Date of registration: May 29, 2017.

A 54-year-old male with a medical history of diabetes mellitus type 2 and tonsil cancer treated with radiochemotherapy years previously was admitted to hospital due to one-month progressive diarrhea, epigastric pain and 14-kg weight loss. Laboratory tests revealed mild anemia (Hb 10.8 g/dl). Upper endoscopy (UE) showed multiple ulcerated lesions with raised edges and a hard consistency on biopsy, being more evident at the duodenum and with a lower frequency and smaller diameter in the stomach.

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 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.

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.

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.To analyse the Colectomy Incidence Rate (CIR) from diagnosis to end of follow-up (31/12/2017) and identify predictive factors for colectomy.A retrospective study enrolling patients with a definitive diagnosis (DD) of UC or Unclassified Colitis (UnC) in the 2001-03 Navarra cohort.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.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.

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.

Leptin modulates insulin signaling and this involves the Akt pathway, which is influenced by changes in the inflammatory environment and with leptin regulating cytokine synthesis. We evaluated the association between activation of the insulin-signaling pathway and alterations in pro-and anti-inflammatory cytokine levels in inguinal fat and liver of chronic central leptin infused (L), pair-fed (PF), and control rats. Signal transducer and activator of transcription 3 (STAT3) phosphorylation was increased in inguinal fat and reduced in liver of L rats. Phosphorylation of c-Jun N-terminal kinase (JNK) and nuclear factor kappa B (NFkB) was increased in inguinal fat of L rats, together with a pro-inflammatory cytokine profile, while in the liver activation of JNK and NFkB were reduced and an anti-inflammatory pattern was found. Phosphorylation of the insulin receptor, Akt and mechanistic target of rapamycin was decreased in inguinal fat and increased in liver of L rats. There was a direct relationship between pSTAT3 and JNK and a negative correlation of Akt with pSTAT3 and JNK in both tissues. These results indicate that the effects of chronically increased leptin on insulin-related signaling are tissue-specific and suggest that inflammation plays a relevant role in the crosstalk between leptin and insulin signaling., This research was funded by the Spanish Ministry of Science and Innovation with the help of European FEDER funding (FIS PI19/00166), Ministerio de Economía y competitividad (BFU2017-82565-C2-1-R) and the Network Center for Biomedical Research on Obesity and Nutrition (CIBEROBN) Instituto Carlos III. S.C. was supported by CIBEROBN and A.C.-C. by Comunidad de Madrid (PEJ-2019-TL_BMD-13560)

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.

Introduction Quadruple concomitant non-bismuth therapy has recently become the most widely prescribed first-line treatment for Helicobacter pylori infection in Spain. Whether optimised conventional triple therapy can achieve comparable efficacy rates remains to be seen. Materials 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 40 mg/12 h. 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 P 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 optimised triple therapy, with rates of over 90% when the PPI prescribed is esomeprazole 40 mg/12 h.

Resumen Introduccion Recientemente la cuadruple terapia concomitante sin bismuto se ha postulado como tratamiento de primera linea para la infeccion por Helicobacter pylori en Espana. Se desconoce si la optimizacion de la triple terapia clasica puede incrementar su efectividad hasta limites aceptables. Material y metodos Estudio retrospectivo que compara la eficacia de la triple terapia con la cuadruple concomitante realizando posteriormente un subanalisis cuando ambas se administran durante 10 dias empleando esomeprazol 40 mg/12 h. Resultados Desde el 1 de enero de 2012 hasta el 31 de diciembre de 2014 recibieron al menos una primera linea de tratamiento 657 pacientes. La cuadruple combinacion (n = 371) presento una eficacia superior a la de la triple terapia clasica (n = 248) tanto «por intencion de tratar» (85,9% vs. 65,5%; p = 0,003) como «por protocolo» (92,5% vs. 74,6%; p = 0,002). Conclusiones La terapia cuadruple concomitante con dosis altas de IBP durante 10 dias consigue tasas de erradicacion significativamente superiores a las obtenidos con la triple terapia optimizada y superiores al 90% cuando se utiliza esomeprazol 40 mg/12 h.

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

This work summarizes the available data on the performance of rapid diagnostic tests (RDTs) for the detection of monoinfections due to Plasmodium species P. knowlesi, P. malariae, and P. ovale and indicates low performance of RDTs to detect these infections., 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.

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. Materials 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, quadruple 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).

Resumen Fundamento y objetivo Tras constatar que en nuestro medio la triple terapia clasica presentaba una eficacia suboptima en la erradicacion del Helicobacter pylori (H. pylori) , a mediados de 2012 decidimos implantar la cuadruple terapia concomitante sin bismuto. El objetivo de este estudio es comparar la eficacia de ambas pautas. Material y metodos Estudio retrospectivo observacional de las pautas erradicadoras administradas entre el 1 de enero de 2012 y el 5 de mayo de 2014, asi como su eficacia. Resultados En el periodo de estudio 510 pacientes recibieron al menos una primera linea de tratamiento que en 179 casos (35,1%) consistio en amoxicilina + claritromicina + IBP durante 7-14 dias, y en 298 (58,4%) en la combinacion amoxicilina + claritromicina + metronidazol + IBP 10 dias. La pauta cuadruple concomitante fue mas eficaz que la combinacion clasica, tanto «por intencion de tratar» (84,8 vs. 65,7%; p = 0,001) como «por protocolo» (86,9 vs. 67,2%; p = 0,001). La triple terapia fue mas eficaz cuando se empleaba en pautas de 10 dias que de 7 (77,9 vs. 56,5%; p: 0,005 por «intencion de tratar» y 77,9 vs. 58,5%; p: 0,011 por «protocolo»). Al comparar la eficacia de la cuadruple terapia con la triple administrada 10 dias no se encontraron diferencias significativas. Conclusiones En nuestro medio, la cuadruple terapia concomitante sin bismuto presenta una elevada eficacia como primera linea de tratamiento para la erradicacion del H. pylori , superando ampliamente la de la triple terapia en la forma en que esta viene administrandose mayoritariamente (pautas cortas de 7 dias).

Bronchodilator test measures lung function performing spirometry before and after the administration of a fast-acting bronchodilator. Recent studies reflect variability among nurses in its performance. Aims: To know the context and how nurses are performing this test -To determine how drugs are administrated (dose and type) Methods: -Descriptive multicenter cross-sectional survey study in Madrid, Spain Results: N=58.A total of 63 responses were received Socio-demographic characteristics of the sample: -Place of work:(Figure 1)Functional lab testing (46%), outpatient setting(25%), community health(16%). -Experience:97% of participant have more than a year of experience performing the bronchodilator test -Drugs administration:Figure 2 Salbutamol 100μg: 4puff(45%), 2puff(31%), 2puff(22%) and 1puff(2%) Ipratropium 20 μg: 3puff(41%),2puff(30%) and 4puff(29%) Terbutaline 500 μg: 2 puff (85%), 1 puff(8%) and 4 puff(7%) -86% of nurses know how to interpret the test Conclusions: 46% of nurses work in a functional lab testing. 97% of them perform the bronchodilator test for more than a year and 86% of them know how to interpret it Regarding to drugs administration:Salbutamol 100 μg is administered in 4 puff by 45%of participants, Ipratropium 20 μg is used by 41% of nurses (3puff), and Terbutaline 500 μg is used administering 2puff by 85% of them 86% of nurses use a spacer for pressurized inhalers. 15 minutes are normally the waiting time to interpret the test Although there is great variability, most nurses follow SEPAR criteria

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.

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. 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. 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). 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.

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.

Background: Remifentanil anesthesia enhances postopera- tive pain in animals and humans. The authors evaluated the impact of the dose (gkg 1 � min 1 ) and duration of remifen- tanil infusion, and the effects of a second surgery on postoper- ative pain sensitization. Methods: Mice received different doses of remifentanil over 30 or 60 min. The authors assessed thermal (Hargreaves) and me- chanical 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 pronocicep- tive effects with calculated ED50s of 1.7 (95% confidence interval, 1.3-2.1) and 1.26 (1.0-1.6) gkg 1 � 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 remifen- tanil when administered at a constant dose of infusion. When given during surgery, high (2.66 gkg 1 � min 1 )o r low (0.66 gkg 1 � 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 individu- ally, 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 in- duces greater postoperative hyperalgesia that is enhanced when remifentanil is used as an anesthetic. REMIFENTANIL is a potent short-acting -opioid recep- tor agonist widely used as anesthetic in humans. Its main advantage over other 4-anilidopiperidine derivatives (fentanyl, alfentanil, sufentanil) relates to its rapid inac- tivation by plasma and tissue esterases. When used as anesthetic, remifentanil has a fast and predictable onset and offset that is independent of the duration of infusion, and its metabolism is not affected by organ failure. 1 Many reports show that intraoperative remifentanil ad- ministration paradoxically enhances pain sensitization and increases analgesic requirements in the postopera- tive period. 2-5 Such opioid-induced hyperalgesia has been described in animal models and humans after sev- eral -opioid receptor agonists administered by different routes. 3,6 Animal studies also show that the magnitude of the pronociceptive effects of morphine, heroin, and methadone (among others) is influenced by the admin- istration schedule. 7-9 In humans, it has been suggested that remifentanil-induced pain sensitization is greater with higher doses. 10 -13 However, the design of such studies does not allow establishing whether the pronociceptive effects of remifentanil are related to the dose of infusion, its duration, or the total dose administered over time. This information could be useful when attempting to prevent or reduce the pronociceptive effects of remifentanil when used as the main anesthetic in humans. Another relevant aspect of the use of remifentanil during surgery is its possible contribution to the devel- opment of long-term changes in pain sensitivity, leading to chronic postsurgical pain. 14 In a previous study using the same mouse model of incisional pain, we demon- strated an increase in postoperative pain in animals re- ceiving intraoperative remifentanil. 4 However, the effect of a second surgery performed with or without remifen- tanil anesthesia was not evaluated. Therefore, the cur- rent experimental study was designed to assess the im- pact of the dose and duration of remifentanil infusion on nociceptive thresholds and to determine whether the intraoperative use of remifentanil may affect the magni- tude of the postoperative pain after a second surgery (performed after full recovery from the first one).

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.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.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).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.

Tissue injury and/or opioids induce plastic changes in the spinal cord resulting in pain hypersensitivity; the contribution of the dorsal root ganglia (DRG) is poorly understood. We evaluated DRG phenotypic changes induced by surgery and/or remifentanil in a mice model of postoperative pain using as neuronal markers ERK1/2 and c-Fos; prodynorphin mRNA and dynorphin levels were also determined. We hypothesized that a correlation between nociception and DRG reactivity would occur. Surgery and/or remifentanil induced mechanical hypersensitivity, correlated with ERK1/2 phosphorylation and c-Fos expression in the DRG; changes were greater in the remifentanil + incision group and still present on day 14 (p

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.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.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.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.

The long-lasting post-surgical changes in nociceptive thresholds in mice, indicative of latent pain sensitization, were studied. The contribution of kappa opioid and N-methyl- d -aspartate (NMDA) receptors was assessed by the administration of nor-binaltorphimine or MK-801; dynorphin levels in the spinal cord were also determined. Animals underwent a plantar incision and/or a subcutaneous infusion of remifentanil (80 μg/kg), and mechanical thresholds (von Frey) were evaluated at different times. On day 21, after complete recovery of mechanical thresholds and healing of the wound, one of the following drugs was administered subcutaneously: (−)-naloxone (1 mg/kg), (+)-naloxone (1 mg/kg), naloxone-methiodide (3 mg/kg), or nor-binaltorphimine (5 mg/kg). Another group received subcutaneous MK-801 (0.15 mg/kg) before nor-binaltorphimine administration. Dynorphin on day 21 was determined in the spinal cord by immunoassay. In mice receiving remifentanil during surgery, the administration of (−)-naloxone or nor-binaltorphimine induced significant hyperalgesia even 5 months after manipulation. Nociceptive thresholds remained unaltered after (+)-naloxone or naloxone-methiodide. On day 21 after manipulation, the administration of MK-801 prevented nor-binaltorphimine-induced hyperalgesia. No changes in dynorphin levels were observed before or after opioid antagonist administration. In conclusion, surgery produced latent pain sensitization evidenced by opioid antagonist-precipitated hyperalgesia. The effect was stereospecific, centrally originated, and mediated by kappa opioid receptors. The blockade of nor-binaltorphimine-induced hyperalgesia by MK-801, suggests that NMDA receptors are also involved. Our results show for the first time that surgery induces latent, long-lasting changes in the processing of nociceptive information that can be induced by non-nociceptive stimuli such as the administration of opioid antagonists.

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.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.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 (P0.001). 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 (P0.05) and duration (P0.01) of thermal and mechanical hyperalgesia. The latter was further enhanced after a second surgery performed in the same experimental conditions (P0.05). Surgery or remifentanil infusion, each one individually, induced significant mechanical hyperalgesia, which was greater when repeated (P0.05).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.

elaprevir 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. Supported by (in part) Instituto de Salud Carlos III (PI11/01907), Ministerio de Economía y Competitividad, co-funded by Fondo/nEuropeo de Desarrollo Regional, Unión Europea, Una manera de hacer Europa; and Roche Organ Transplantation Research/nFoundation (ROTRF, CI: 442035057) (all to Forns X).

ObjectiveThe best approach for Helicobacter pylori management remains unclear. An audit process is essential to ensure clinical practice is aligned with best standards of care.DesignInternational 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.Results30 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%).ConclusionManagement 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.