Atrial fibrillation in the elderly

Atrial fibrillation(AF)is the most common arrhythmia in elderly population,with age being one of the most important factors involved in its pathogenesis.Conduction disturbances may be present on the surface electrocardiogram before AF onset in some patients.Once this arrhythmia is diagnosed,antithrombotic therapy is mandatory in most cases,as this is the only treatment that has demonstrated to improve survival.Age increases both the risk of thromboembolic and bleeding complications,while benefits from anticoagulant therapy outweigh that from bleeding in most scenarios,also in very elderly patients.However,elderly patients with AF are often undertreated.Non-vitamin K antagonist oral anticoagulants have emerged as an alternative to vitamin K antagonists,with significant less adverse events and better profile in terms of efficacy and safety.Other conditions related to age should be carefully evaluated in these patients(including frailty,comorbidity and polypharmacy)to ensure an individualized clinical and therapeutic approach.

Tenofovir vs lamivudine plus adefovir in chronic hepatitis B:TENOSIMP-B study

AIM To demonstrate the non-inferiority(15% non-inferiority limit) of monotherapy with tenofovir disoproxil fumarate(TDF) vs the combination of lamivudine(LAM) plus adefovir dipivoxil(ADV) in the maintenance of virologic response in patients with chronic hepatitis B(CHB) and prior failure with LAM.METHODS This study was a Phase IV prospective, randomized, open, controlled study with 2 parallel groups(TDF and LAM+ADV) of adult patients with hepatitis B e antigen(HBe Ag)-negative CHB, prior failure with LAM, on treatment with LAM+ADV for at least 6 mo, without prior resistance to ADV and with an undetectable viral load at the start of the study, in 14 Spanish hospitals. The follow-up time for each patient was 48 wk after randomization, with quarterly visits in which the viral load, biochemical and serological parameters, adverse effects, adherence to treatment and consumption of hospital resources were analysed.RESULTS Forty-six patients were evaluated [median age: 55.4 years(30.2-75.2); 84.8% male], including 22 patients with TDF and 24 with LAM+ADV. During study development, hepatitis B virus DNA(HBV-DNA) remained undetectable, all patients remained HBe Ag negative, and hepatitis B surface antigen(HBs Ag) positive. Alanine aminotransferase(ALT) values at the end of the study were similar in the 2 groups(25.1± 7.65, TDF vs 24.22 ± 8.38, LAM+ADV, P = 0.646). No significant changes were observed in creatinine or serum phosphorus values in either group. No significant differences between the 2 groups were noted in the identification of adverse effects(AEs)(53.8%, TDF vs 37.5%, LAM+ADV, P = 0.170), and none of the AEs which occurred were serious. Treatment adherence was 95.5% and 83.3% in the TDF and the LAM+ADV groups, respectively(P = 0.488). The costs associated with hospital resource consumption were significantly lower with the TDF treatment than the LAM+ADV treatment(€4943 ± 1059 vs €5811 ± 1538, respectively, P < 0.001).CONCLUSION TDF monotherapy proved to be safe and not inferior to the LAM+ADV combination therapy in maintaining virologic response in patients with CHB and previous LAM failure. In addition, the use of TDF generated a significant savings in hospital costs.

Clinical characteristics and type of antithrombotic treatment in a Spanish cohort of elderly patients with atrial fibrillation according to dependency, frailty and cognitive impairment

Background Available data regarding clinical profile and management of elderly patients with atrial fibrillation （AF） according to dependency, fragility and cognitive impairment are scarce. The objective of the study was to analyze the biodemographic data, clinical profile and antithrombotic treatment according to dependency, fragility and cognitive impairment in elderly AF patients. Methods Cross- sectional and multi-center study performed in consecutive AF patients ≥ 75 years treated with oral anticoagulants ≥ 3 months attended in Internal Medicine Departments in Spain. Results A total of 837 patients （83.0 ± 5.0 years; CHA2DS2-VASc： 5.0 ± 1.4; HAS-BLED： 2.1 ± 0.9） were included. 44.4% of patients had some degree of dependency, 43.3% were fragile, and 32.3% had cognitive impairment. Patients with any of these conditions were older, had a worse clinical profile, with more comorbidities and higher risks of thromboembolic and bleeding events. All these conditions were independently associated among them. Overall, 70.8% of patients were taking vitamin K antagonists, the remaining 29.2% direct oral anticoagulants and 9.7% oral antiplatelets. This distribution was independent of the presence of dependency or fragility, but there was a trend to a higher prescription of vitamin K antagonists in those patients with cognitive impairment （75.2% vs. 68.8%; P = 0.05）. Conclusions Approximately 32%-44% of elderly anticoagulated AF patients attended have some degree of dependency, fragility and/or cognitive impairment. Patients with any of these conditions are older and have a worse clinical profile. Ap？proximately 71% of patients are taking vitamin K antagonists, regardless dependency or frailty, but with a trend to higher prescription in patients with cognitive impairment.

Ocular trauma in an urban Spanish population:epidemiology and visual outcome

AIM:To describe epidemiological aspects,clinical findings,and visual results in eye trauma patients requiring urgent surgery at a tertiary hospital.METHODS:Retrospective review of adult patients requiring urgent surgery for trauma to the eyeball from January 2010 and April 2020.Data was collected relative to age,gender,mechanism of the injury,type of wound,initial and final visual acuity,number and type of surgeries carried out.Injuries were classed according to the Birmingham Eye Trauma Terminology(BETT)and the Ocular Trauma Score(OTS)categories.RESULTS:The survey included 92 eyes.Mean age was 54.76±22.18 y.The most frequent cause was domestic accidents(44.6%),followed by aggression(22.80%)and occupational accidents(17.4%).Trauma from aggression was more frequent in men(P=0.006)and accidents in the home more common in women(P=0.011).Patients over 65 y presented an odds ratio(OR)of 10.71 for suffering a domestic accident.Patients between 15-45 and 46-65 y were at higher risk of trauma from aggression(OR=17.52 and OR=10.94,respectively).As for the type of injury,63.04%were open-globe lesions,Zone II being the most frequently affected(27.2%).In Logistic regression analysis,old age(P=0.05)and retinal involvement(P=0.001)were found to be associated with higher rate of unfavourable visual outcome.CONCLUSION:The epidemiological aspects of eye trauma are highly dependent on the area of population studied.Domestic accidents are more relevant than workplace accidents in older urban areas with high socioeconomic status.A better knowledge of the epidemiological characteristics is useful for implementing specific prevention measures and appropriate treatment strategies.

Common misconceptions about 5-aminosalicylates and thiopurines in inflammatory bowel disease

Misconceptions are common in the care of patients with inflammatory bowel disease(IBD).In this paper,we state the most commonly found misconceptions in clinical practice and deal with the use of 5-aminosalicylates and thiopurines,to review the related scientificevidence,and make appropriate recommendations.Prevention of errors needs knowledge to avoid making such errors through ignorance.However,the amount of knowledge is increasing so quickly that one new danger is an overabundance of information.IBD is a model of a very complex disease and our goal with this review is to summarize the key evidence for the most common daily clinical problems.With regard to the use of 5-aminosalicylates,the best practice may to be consider abandoning the use of these drugs in patients withsmall bowel Crohn's disease.The combined approach with oral plus topical 5-aminosalicylates should be the first-line therapy in patients with active ulcerative colitis;once-daily treatment should be offered as a first choice regimen due to its better compliance and higher efficacy.With regard to thiopurines,they seem to be as effective in ulcerative colitis as in Crohn's disease.Underdosing of thiopurines is a form of undertreatment.Thiopurines should probably be continued indefinitely because their withdrawal is associated with a high risk of relapse.Mercaptopurine is a safe alternative in patients with digestive intolerance or hepatotoxicity due to azathioprine.Finally,thiopurine methyltransferase(TPMT)screening cannot substitute for regular monitoring because the majority of cases of myelotoxicity are not TPMT-related.

Optimizing clarithromycin-containing therapy for Helicobacter pylori in the era of antibiotic resistance

The efficacy of triple therapy for Helicobacter pylori infection has dramatically declined over the last decade,largely related to increasing clarithromycin resistance rates.From a microbiological standpoint,bismuth quadruple therapy is the ideal replacement since it combines drugs for which resistance does not impair its efficacy.Nonetheless,several obstacles such as availability,complexity or tolerance prevent a general implementation of bismuth quadruple therapy,so nonbismuth quadruple regimens remain the best firstline treatment in clinical practice in many geographical areas.We review the rationale and efficacy of several optimization tools(increasing the length of duration,high-dose acid suppression,probiotics),which have been largely evaluated over the last 5 years to increase the effectiveness of standard triple therapy.Then,we update available evidence on the effectiveness of several non-bismuth quadruple therapies(sequential,concomitant,hybrid,miscellaneous therapy),which have gained interest lately.We also revise evidence on the efficacy of the aforementioned optimization tools for non-bismuth quadruples schemes and,finally we provide a novel regionalized therapeutic algorithm,based on novel formulas recently developed for predicting the outcome of non-bismuth quadruple regimens,upon local antibiotic resistance rates.

Heart failure in the elderly

Heart failure （HF） is a major public health problem worldwide entailing high morbidity and mortality as well as high costs. This chronic syndrome associates with a low functional status and quality of life. Most patients with HF are elderly, constituting up to 80% of patients suffering from this disease with both incidence and prevalence of the condition increasing with age. This is due to the progressive aging of the population as well as improved and better survival after cardiac insults, such as myocardial infarction,

Noninvasive diagnosis of vulnerable coronary plaque

Myocardial infarction and sudden cardiac death are frequently the first manifestation of coronary artery disease.For this reason,screening of asymptomatic coronary atherosclerosis has become an attractive field of research in cardiovascular medicine.Necropsy studies have described histopathological changes associated with the development of acute coronary events.In this regard,thin-cap fibroatheroma has been identified as the main vulnerable coronary plaque feature.Hence,many imaging techniques,such as coronary computed tomography,cardiac magnetic resonance or positron emission tomography,have tried to detect noninvasively these histomorphological characteristics with different approaches.In this article,we review the role of these diagnostic tools in the detection of vulnerable coronary plaque with particular interest in their advantages and limitations as well as the clinical implications of the derived findings.

Severe ulcerative colitis: At what point should we define resistance to steroids?

Corticoesteroids are still the first-line treatment for active ulcerative colitis more than 50 years after the publication of trials assessing their beneficial effect, with about a 50% remission rate in cases of severe disease. The mortality related to severe attacks of ulcerative colitis has decreased dramatically, to less than 1%, in experienced centers, due to the appropriate use of intensive therapeutic measures (intravenous steroids, fluids and electrolytes, artificial nutritional support, antibiotics, etc), along with timely decision-making about second-line medical therapy and early identification of patients requiring colectomy. One of the most difficult decisions in the management of severe ulcerative colitis is knowing for how long corticosteroids should be administered before deciding that a patient is a non-responder. Studies assessing the outcome of acute attacks after steroid initiation have demonstrated that, in steroid-sensitive patients, the response generally occurs early on, in the first days of treatment. Different indexes to predict treatment failure, when applied on the third day of treatment, have demonstrated a high positive predictive value for colectomy. In contrast to this resolute approach, which is the most widely accepted, other authors have suggested that in some patients a completeand prolonged response to steroids may take longer. Either way, physicians taking care of these patients need to recognize that severe ulcerative colitis may be life-threatening, and they need to be careful with excessively prolonged medical treatment and delayed surgery.

Usefulness of applying lidocaine in esophagogastroduodenoscopy performed under sedation with propofol

AIM:To determine whether topical lidocaine benefits esophagogastroduoduenoscopy(EGD) by decreasing propofol dose necessary for sedation or procedurerelated complications.METHODS:The study was designed as a prospective,single centre,double blind,randomised clinical trial and was conducted in 2012 between January and May(NCT01489891).Consecutive patients undergoing EGD were randomly assigned to receive supplemental topical lidocaine(L;50 mg in an excipient solution which was applied as a spray to the oropharynx) or placebo(P;taste excipients solution without active substance,similarly delivered) prior to the standard propofol sedation procedure.The propofol was administered as a bolus intravenous(iv) dose,with patients in the L and P groups receiving initial doses based on the patient’s American Society of Anaesthesiologists(ASA) classification(ASAⅠ-Ⅱ:0.50-0.60 mg/kg;ASA Ⅲ-Ⅳ:0.25-0.35 mg/kg),followed by 10-20 mg iv dose every 30-60 s at the anaesthetist’s discretion.Vital signs,anthropometric measurements,amount of propofol administered,sedation level reached,examination time,and the subjective assessments of the endoscopist’s and anaesthetist’s satisfaction(based upon a four point Likert scale) were recorded.All statistical tests were performed by the Stata statistical software suite(Release 11,2009;StataCorp,LP,College Station,TX,United States).RESULTS:No significant differences were found between the groups treated with lidocaine or placebo in terms of total propofol dose(310.7 ± 139.2 mg/kg per minute vs 280.1 ± 87.7 mg/kg per minute,P = 0.15) or intraprocedural propofol dose(135.3 ± 151.7 mg/kg per minute vs 122.7 ± 96.5 mg/kg per minute,P = 0.58).Only when the L and P groups were analysed with the particular subgroups of female,【 65-year-old,and lower anaesthetic risk level(ASA Ⅰ-Ⅱ) was a statistically significant difference found(L:336.5 ± 141.2 mg/kg per minute vs P:284.6 ± 91.2 mg/kg per minute,P = 0.03) for greater total propofol requirements).The total incidence of complications was also similar between the two groups,with the L group showing a complication rate of 32.2%(95%CI:21.6-45.0) and the P group showing a complication rate of 26.7%(95%CI:17.0-39.0).In addition,the use of lidocaine had no effect on the anaesthetist’s or endoscopist’s satisfaction with the procedure.Thus,the endoscopist’s satisfaction Likert assessments were equally distributed among the L and P groups:unsatisfactory,[L:6.8%(95%CI:2.2-15.5) vs P:0%(95%CI:0-4.8);neutral,L:10.1%(95%CI:4.2-19.9) vs P:15%(95%CI:7.6-25.7)];satisfactory,[L:25.4%(95%CI:10-29.6) vs P:18.3%(95%CI:15.5-37.6);and very satisfactory,L:57.6%(95%CI:54-77.7) vs P:66.6%(95%CI:44.8-69.7)].Likewise,the anaesthetist’s satisfaction Likert assessments regarding the ease of maintaining a patient at an optimum sedation level without agitation or modification of the projected sedation protocol were not affected by the application of lidocaine,as evidenced by the lack of significant differences between the scores for the placebo group:unsatisfactory,L:5.8%(95%CI:1.3-13.2) vs P:0%(95%CI:0-4.8);neutral,L:16.9%(95%CI:8.9-28.4) vs P:16.7%(95%CI:8.8-27.7);satisfactory,L:15.2%(95%CI:7.7-26.1) vs P:20.3%(95%CI:11.3-31.6);and very satisfactory,L:62.7%(95%CI:49.9-74.3) vs P:63.3%(95%CI:50.6-74.7).CONCLUSION:Topical pharyngeal anaesthesia is safe in EGD but does not reduce the necessary dose of propofol or improve the anaesthetist’s or endoscopist’s satisfaction with the procedure.

Desperately seeking hepatitis C virus

Spanish investigators described recently the so-called occult hepatitis C virus (HCV) infection, emphasizing the detection of genomic and antigenomic HCV RNA strands in liver and peripheral blood mononuclear cells. Therefore, the persistence of viral replication in occult HCV infection should be considered as a putative source of infection among family members and patients undergoing invasive procedures, transfusion or transplantation. Additionally, the most worrisome finding is that an occult HCV infection may persist in patients with sustained virological response.

Immunogenicity and mechanisms impairing the response to vaccines in inflammatory bowel disease

Inflammatory bowel disease(IBD) is an immunological disorder that is usually treated with immunosuppressive therapy,potentially leading to increases in vulnerability to infections. Although many infections can be pre-vented by vaccination,vaccination coverage in these patients in clinical practice is insufficient. Therefore,the seroprotection condition should be verified,even for routine vaccines,such as hepatitis B or pneu-mococcus. Response to vaccines in IBD patients is thought to be impaired due to the immunological alterations generated by the disease and to the immunomodulatory treatments. The immunogenicity of hepatitis B,influenza,and pneumococcal vaccines is impaired in IBD patients,whereas the response to papillomavirus vaccine seems similar to that observed in the healthy population. On the other hand,data on the immunogenicity of tetanus vaccine in IBD patients are conflicting. Studies assessing the response to measles-mumps-rubella,varicella,and herpes zoster vaccines in IBD patients are scarce. The cellular and molecular mechanisms responsible for the impairment of the response to vaccination in IBD patients are poorly understood. Studies aiming to assess the response to vaccines in IBD patients and to identify the mechanisms involved in their immunogenicity are warranted. A better understanding of the immune response,specifically to vaccines,in patients with immune-mediated diseases(such as IBD),is crucial when developing vaccines that trigger more potent immunologic responses.

Cutaneous perivascular epithelioid cell tumors:A review on an infrequent neoplasm

"Perivascular epithelioid cutaneous" cell tumors(PEComa) are a family of mesenchymal tumors with shared microscopic and immunohistochemical properties: They exhibit both smooth muscle cell and melanocytic differentiation. Non-neoplastic counterpart of PEComa's cells are unknown, as well as the relationship between extracutaneous PEComa and primary cutaneous ones. We will review the clinical setting, histopathologic features, chromosomal abnormalities, differential diagnosis and treatment options for cutaneous PEComa.

Management of incidentally discovered appendiceal neuroendocrine tumors after an appendicectomy

Appendiceal neuroendocrine tumors(aNETs)are an uncommon neoplasm that is relatively indolent in most cases.They are typically diagnosed in younger patients than other neuroendocrine tumors and are often an incidental finding after an appendectomy.Although there are numerous clinical practice guidelines on management of a NETs,there is continues to be a dearth of evidence on optimal treatment.Management of these tumors is stratified according to risk of locoregional and distant metastasis.However,there is a lack of consensus regarding tumors that measure 1-2 cm.In these cases,some histopathological features such as size,tumor grade,presence of lymphovascular invasion,or mesoappendix infiltration must also be considered.Computed tomography or magnetic resonance imaging scans are recommended for evaluating the presence of additional disease,except in the case of tumors smaller than 1 cm without additional risk factors.Somatostatin receptor scintigraphy or positron emission tomography with computed tomography should be considered in cases with suspected residual or distant disease.The main point of controversy is the indication for performing a completion right hemicolectomy after an initial appendectomy,based on the risk of lymph node metastases.The main factor considered is tumor size and 2 cm is the most common threshold for indicating a colectomy.Other factors such as mesoappendix infiltration,lymphovascular invasion,or tumor grade may also be considered.On the other hand,potential complications,and decreased quality of life after a hemicolectomy as well as the lack of evidence on benefits in terms of survival must be taken into consideration.In this review,we present data regarding the current indications,outcomes,and benefits of a colectomy.

Molecular analysis of pancreatic cystic neoplasm in routine clinical practice

BACKGROUND Cystic pancreatic lesions consist of a wide variety of lesions that are becoming increasingly diagnosed with the growing use of imaging techniques.Of these,mucinous cysts are especially relevant due to their risk of malignancy.However,morphological findings are often suboptimal for their differentiation.Endoscopic ultrasound fine-needle aspiration(EUS-FNA)with molecular analysis has been suggested to improve the diagnosis of pancreatic cysts.AIM To determine the impact of molecular analysis on the detection of mucinous cysts and malignancy.METHODS An 18-month prospective observational study of consecutive patients with pancreatic cystic lesions and an indication for EUS-FNA following European clinical practice guidelines was conducted.These cysts included those>15 mm with unclear diagnosis,and a change in follow-up or with concerning features in which results might change clinical management.EUS-FNA with cytological,biochemical and glucose and molecular analyses with next-generation sequencing were performed in 36 pancreatic cysts.The cysts were classified as mucinous and non-mucinous by the combination of morphological,cytological and biochemical analyses when surgery was not performed.Malignancy was defined as cytology positive for malignancy,high-grade dysplasia or invasive carcinoma on surgical specimen,clinical or morphological progression,metastasis or death related to neoplastic complications during the 6-mo follow-up period.Next-generation sequencing results were compared for cyst type and malignancy.RESULTS Of the 36 lesions included,28(82.4%)were classified as mucinous and 6(17.6%)as non-mucinous.Furthermore,5(13.9%)lesions were classified as malignant.The amount of deoxyribonucleic acid obtained was sufficient for molecular analysis in 25(69.4%)pancreatic cysts.The amount of intracystic deoxyribonucleic acid was not statistically related to the cyst fluid volume obtained from the lesions.Analysis of KRAS and/or GNAS showed 83.33%[95%confidence interval(CI):63.34-100]sensitivity,60%(95%CI:7.06-100)specificity,88.24%(95%CI:69.98-100)positive predictive value and 50%(95%CI:1.66-98.34)negative predictive value(P=0.086)for the diagnosis of mucinous cystic lesions.Mutations in KRAS and GNAS were found in 2/5(40%)of the lesions classified as non-mucinous,thus recategorizing those lesions as mucinous neoplasms,which would have led to a modification of the follow-up plan in 8%of the cysts in which molecular analysis was successfully performed.All 4(100%)malignant cysts in which molecular analysis could be performed had mutations in KRAS and/or GNAS,although they were not related to malignancy(P>0.05).None of the other mutations analyzed could detect mucinous or malignant cysts with statistical significance(P>0.05).CONCLUSION Molecular analysis can improve the classification of pancreatic cysts as mucinous or non-mucinous.Mutations were not able to detect malignant lesions.

End-of-life care in a cardiology department： have we improved？

Background End-of-life care is not usually a priority in cardiology departments. We sought to evaluate the changes in end-of-life care after the introduction of a do-not-resuscitate （DNR） order protocol. Methods ＆ Results Retrospective analysis of all deaths in a cardiology department in two periods, before and after the introduction of the protocol. Comparison of demographic characteristics, use of DNR orders, and end-of-life care issues between both periods, according to the presence in the second period of the new DNR sheet （Group A）, a conven- tional DNR order （Group B） or the absence of any DNR order （Group C）. The number of deaths was similar in both periods （n = 198 vs. n = 197）. The rate of patients dying with a DNR order increased significantly （57.1% vs. 68.5%; P = 0.02）. Only 4% of patients in both periods were aware of the decision taken about cardiopulmonary resuscitation. Patients in Group A received the DNR order one day earlier, and 24.5% received it within the first 24 h of admission （vs. 2.6% in the first period; P 〈 0.001）. All patients in Group A with an implantable cardioverter defibrillator （ICD） had shock therapies deactivated （vs. 25.0% in the first period; P = 0.02）. Conclusions The introduction of a DNR order protocol may improve end-of-life care in cardiac patients by increasing the use and shortening the time of registration of DNR orders. It may also contribute to increase ICD deactivation in patients with these orders in place. However, the introduction of the sheet in late stages of the disease failed to improve patient participation.

Scientific evidence in the COVID-19 treatment: A comprehensive review

In December 2019,cases of unknown origin pneumonia appeared in Wuhan,China;the causal agent of this pneumonia was a new virus of the coronaviridae family called severe acute respiratory syndrome coronavirus-2(SARS-CoV-2).According to the clinical severity,symptoms and response to the different treatments,the evolution of the disease is divided in three phases.We analysed the most used treatments for coronavirus disease 2019 and the phase in which they are supposed to be effective.In the viral phase,remdesivir has demonstrated reduction in recovery time but no mortality reduction.Other drugs proposed for viral phase such as convalescent plasma and lopinavir/ritonavir did not demonstrate to be effective.In the inflammatory phase,corticosteroids demonstrated reduction of 28-d mortality in patients who needed oxygen,establishing that a corticosteroid regimen should be part of the standard treatment of critically ill patients.There are other immunosuppressive and immunomodulatory treatments such as anakinra,sarilumab,tocilizumab,colchicine or baricitinib that are being studied.Other treatments that were proposed at the beginning,like hydroxichloroquine or azithromycin,demonstrated no efficacy and increased mortality when combined.

Interplay among cellular polarization,lipoprotein metabolism and hepatitis C virus entry

Hepatitis C virus (HCV) infects more than three million new individuals worldwide each year. In a high percent age of patients, acute infections become chronic, eventually progressing to fibrosis, cirrhosis, and hepatocellular carcinoma. Given the lack of effective prophylactic or therapeutic vaccines, and the limited sustained virological response rates to current therapies, new approaches are needed to prevent, control, and clear HCV infection.Entry into the host cell, being the first step of the viral cycle, is a potential target for the design of new antiviral compounds. Despite the recent discovery of the tight junction-associated proteins claudin-1 and occludin as HCV co-receptors, which is an important step towards the understanding of HCV entry, the precise mechanisms are still largely unknown. In addition, increasing evidence indicates that tools that are broadly employed to study HCV infection do not accurately reflect the real process in terms of viral particle composition and host cell phenotype. Thus, systems that more closely mimic natural infection are urgently required to elucidate the mechanisms of HCV entry, which will in turn help to design antiviral strategies against this part of the infection process.

Crohnology: A tale of time and times and inflammatory bowel diseases

Time, times and timing are key words in inflammatory bowel diseases （IBD）. The leifmotif of this issue or World Journal of Gastroenterology is time. We have asked experts to review on the epidemiology of these diseases over time, the changes in innate immunity that could be present in the first time, and then the timing of key treatments. The correct time of using azathioprine, mercaptopurine, infliximab, cyclosporine and surgery are reviewed. We have chosen experts with not only great clinical expertise but also personal interest in clinical and basic investigation. Our goal in this monograph is to get an idea not only of the present but of the immediate future in some of the key management issues in IBD. To this end, we think that the authors are the most adequate.

“Rescue” regimens after Helicobacter pylori treatment failure

Helicobacter pylori (H pylori) infection is the main cause of gastritis, gastroduodenal ulcer disease, and gastric cancer. After more than 20 years of experience in H pylori treatment, in my opinion, the ideal regimen to treat this infection is still to be found. Currently, apart from having to know first-line eradication regimens well, we must also be prepared to face treatment failures. Therefore, in designing a treatment strategy we should not focus on the results of primary therapy alone, but also on the final (overall) eradication rate. The choice of a "rescue" treatment depends on which treatment is used initially. If a clarithromycin- based regimen was used initially, a subsequent metronidazole-based treatment (quadruple therapy) may be used afterwards, and then a levofloxacin- based combination would be a third "rescue" option. Alternatively, it has recently been suggested that levofloxacin-based rescue therapy constitutes an encouraging second-line strategy, representing an alternative to quadruple therapy in patients with previous PPI-clarithromycin-amoxicillin failure, with the advantage of efficacy, simplicity and safety. In this case, a quadruple regimen may be reserved as a third-line rescue option. Finally, rifabutin-based rescue therapy constitutes an encouraging empirical fourth- line strategy after multiple previous eradication failures with key antibiotics such as amoxicillin, clarithromycin, metronidazole, tetracycline, and levofloxacin. Even after two consecutive failures, several studies have demonstrated that H pylori eradication can finally be achieved in almost all patients if several rescue therapies are consecutively given. Therefore, the attitude in H pylori eradication therapy failure, evenafter two or more unsuccessful attempts, should be to fight and not to surrender.