Hospital de São João

BACKGROUND: Toxic epidermal necrolysis and Stevens-Johnson syndrome are rare, life-threatening, drug-induced cutaneous reactions. We conducted a case-control study to quantify the risks associated with the use of specific drugs. METHODS: Data were obtained through surveillance networks in France, Germany, Italy, and Portugal. Drug use before the onset of disease was compared in 245 people who were hospitalized because of toxic epidermal necrolysis or Stevens-Johnson syndrome and 1147 patients hospitalized for other reasons (controls). Crude relative risks were calculated and adjusted for confounding by multivariate methods when numbers were large enough. RESULTS: Among drugs usually used for short periods, the risks were increased for trimethoprim-sulfamethoxazole and other sulfonamide antibiotics (crude relative risk, 172; 95 percent confidence interval, 75 to 396), chlormezanone (crude relative risk, 62; 21 to 188), aminopenicillins (multivariate relative risk, 6.7; 2.5 to 18), quinolones (multivariate relative risk, 10; 2.6 to 38), and cephalosporins (multivariate relative risk, 14; 3.2 to 59). For acetaminophen, the multivariate relative risk was 0.6 (95 percent confidence interval, 0.2 to 1.3) in France but 9.3 (3.9 to 22) in the other countries. Among drugs usually used for months or years, the increased risk was confined largely to the first two months of treatment, when crude relative risks were as follows: carbamazepine, 90 (95 percent confidence interval, 19 to infinity); phenobarbital, 45 (19 to 108); phenytoin, 53 (11 to infinity); valproic acid, 25 (4.3 to infinity); oxicam nonsteroidal antiinflammatory drugs (NSAIDs), 72 (25 to 209); allopurinol, 52 (16 to 167); and corticosteroids, 54 (23 to 124). For many drugs, including thiazide diuretics and oral hypoglycemic agents, there was no significant increase in risk. CONCLUSIONS: The use of antibacterial sulfonamides, anticonvulsant agents, oxicam NSAIDs, allopurinol, chlormezanone, and corticosteroids is associated with large increases in the risk of Stevens-Johnson syndrome or toxic epidermal necrolysis. But for none of the drugs does the excess risk exceed five cases per million users per week.

OBJECTIVE: Behçet's disease (BD) is a chronic, relapsing, inflammatory vascular disease with no pathognomonic test. Low sensitivity of the currently applied International Study Group (ISG) clinical diagnostic criteria led to their reassessment. METHODS: An International Team for the Revision of the International Criteria for BD (from 27 countries) submitted data from 2556 clinically diagnosed BD patients and 1163 controls with BD-mimicking diseases or presenting at least one major BD sign. These were randomly divided into training and validation sets. Logistic regression, 'leave-one-country-out' cross-validation and clinical judgement were employed to develop new International Criteria for BD (ICBD) with the training data. Existing and new criteria were tested for their performance in the validation set. RESULTS: For the ICBD, ocular lesions, oral aphthosis and genital aphthosis are each assigned 2 points, while skin lesions, central nervous system involvement and vascular manifestations 1 point each. The pathergy test, when used, was assigned 1 point. A patient scoring ≥4 points is classified as having BD. In the training set, 93.9% sensitivity and 92.1% specificity were assessed compared with 81.2% sensitivity and 95.9% specificity for the ISG criteria. In the validation set, ICBD demonstrated an unbiased estimate of sensitivity of 94.8% (95% CI: 93.4-95.9%), considerably higher than that of the ISG criteria (85.0%). Specificity (90.5%, 95% CI: 87.9-92.8%) was lower than that of the ISG-criteria (96.0%), yet still reasonably high. For countries with at least 90%-of-cases and controls having a pathergy test, adding 1 point for pathergy test increased the estimate of sensitivity from 95.5% to 98.5%, while barely reducing specificity from 92.1% to 91.6%. CONCLUSION: The new proposed criteria derived from multinational data exhibits much improved sensitivity over the ISG criteria while maintaining reasonable specificity. It is proposed that the ICBD criteria to be adopted both as a guide for diagnosis and classification of BD.

The most recent European guidelines and task force reports on hospital-acquired pneumonia (HAP) and ventilator-associated pneumonia (VAP) were published almost 10 years ago. Since then, further randomised clinical trials of HAP and VAP have been conducted and new information has become available. Studies of epidemiology, diagnosis, empiric treatment, response to treatment, new antibiotics or new forms of antibiotic administration and disease prevention have changed old paradigms. In addition, important differences between approaches in Europe and the USA have become apparent.The European Respiratory Society launched a project to develop new international guidelines for HAP and VAP. Other European societies, including the European Society of Intensive Care Medicine and the European Society of Clinical Microbiology and Infectious Diseases, were invited to participate and appointed their representatives. The Latin American Thoracic Association was also invited.A total of 15 experts and two methodologists made up the panel. Three experts from the USA were also invited (Michael S. Niederman, Marin Kollef and Richard Wunderink).Applying the GRADE (Grading of Recommendations, Assessment, Development and Evaluation) methodology, the panel selected seven PICO (population-intervention-comparison-outcome) questions that generated a series of recommendations for HAP/VAP diagnosis, treatment and prevention.

BACKGROUND: The diagnosis of pediatric-onset inflammatory bowel disease (PIBD) can be challenging in choosing the most informative diagnostic tests and correctly classifying PIBD into its different subtypes. Recent advances in our understanding of the natural history and phenotype of PIBD, increasing availability of serological and fecal biomarkers, and the emergence of novel endoscopic and imaging technologies taken together have made the previous Porto criteria for the diagnosis of PIBD obsolete. METHODS: We aimed to revise the original Porto criteria using an evidence-based approach and consensus process to yield specific practice recommendations for the diagnosis of PIBD. These revised criteria are based on the Paris classification of PIBD and the original Porto criteria while incorporating novel data, such as for serum and fecal biomarkers. A consensus of at least 80% of participants was achieved for all recommendations and the summary algorithm. RESULTS: The revised criteria depart from existing criteria by defining 2 categories of ulcerative colitis (UC, typical and atypical); atypical phenotypes of UC should be treated as UC. A novel approach based on multiple criteria for diagnosing IBD-unclassified (IBD-U) is proposed. Specifically, these revised criteria recommend upper gastrointestinal endoscopy and ileocolonscopy for all suspected patients with PIBD, with small bowel imaging (unless typical UC after endoscopy and histology) by magnetic resonance enterography or wireless capsule endoscopy. CONCLUSIONS: These revised Porto criteria for the diagnosis of PIBD have been developed to meet present challenges and developments in PIBD and provide up-to-date guidelines for the definition and diagnosis of the IBD spectrum.

Children and adolescents with Crohn's disease (CD) present often with a more complicated disease course compared to adult patients. In addition, the potential impact of CD on growth, pubertal and emotional development of patients underlines the need for a specific management strategy of pediatric-onset CD. To develop the first evidenced based and consensus driven guidelines for pediatric-onset CD an expert panel of 33 IBD specialists was formed after an open call within the European Crohn's and Colitis Organisation and the European Society of Pediatric Gastroenterolog, Hepatology and Nutrition. The aim was to base on a thorough review of existing evidence a state of the art guidance on the medical treatment and long term management of children and adolescents with CD, with individualized treatment algorithms based on a benefit-risk analysis according to different clinical scenarios. In children and adolescents who did not have finished their growth, exclusive enteral nutrition (EEN) is the induction therapy of first choice due to its excellent safety profile, preferable over corticosteroids, which are equipotential to induce remission. The majority of patients with pediatric-onset CD require immunomodulator based maintenance therapy. The experts discuss several factors potentially predictive for poor disease outcome (such as severe perianal fistulizing disease, severe stricturing/penetrating disease, severe growth retardation, panenteric disease, persistent severe disease despite adequate induction therapy), which may incite to an anti-TNF-based top down approach. These guidelines are intended to give practical (whenever possible evidence-based) answers to (pediatric) gastroenterologists who take care of children and adolescents with CD; they are not meant to be a rule or legal standard, since many different clinical scenario exist requiring treatment strategies not covered by or different from these guidelines.

INTRODUCTION: Eosinophilic esophagitis (EoE) is one of the most prevalent esophageal diseases and the leading cause of dysphagia and food impaction in children and young adults. This underlines the importance of optimizing diagnosys and treatment of the condition, especially after the increasing amount of knowledge on EoE recently published. Therefore, the UEG, EAACI ESPGHAN, and EUREOS deemed it necessary to update the current guidelines regarding conceptual and epidemiological aspects, diagnosis, and treatment of EoE. METHODS: General methodology according to the Appraisal of Guidelines for Research and Evaluation (AGREE) II and the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) system was used in order to comply with current standards of evidence assessment in formulation of recommendations. An extensive literature search was conducted up to August 2015 and periodically updated. The working group consisted of gastroenterologists, allergists, pediatricians, otolaryngologists, pathologists, and epidemiologists. Systematic evidence-based reviews were performed based upon relevant clinical questions with respect to patient-important outcomes. RESULTS: The guidelines include updated concept of EoE, evaluated information on disease epidemiology, risk factors, associated conditions, and natural history of EoE in children and adults. Diagnostic conditions and criteria, the yield of diagnostic and disease monitoring procedures, and evidence-based statements and recommendation on the utility of the several treatment options for patients EoE are provided. Recommendations on how to choose and implement treatment and long-term management are provided based on expert opinion and best clinical practice. CONCLUSION: Evidence-based recommendations for EoE diagnosis, treatment modalities, and patients' follow up are proposed in the guideline.

Main Recommendations Patients with chronic atrophic gastritis or intestinal metaplasia (IM) are at risk for gastric adenocarcinoma. This underscores the importance of diagnosis and risk stratification for these patients. High definition endoscopy with chromoendoscopy (CE) is better than high definition white-light endoscopy alone for this purpose. Virtual CE can guide biopsies for staging atrophic and metaplastic changes and can target neoplastic lesions. Biopsies should be taken from at least two topographic sites (antrum and corpus) and labelled in two separate vials. For patients with mild to moderate atrophy restricted to the antrum there is no evidence to recommend surveillance. In patients with IM at a single location but with a family history of gastric cancer, incomplete IM, or persistent Helicobacter pylori gastritis, endoscopic surveillance with CE and guided biopsies may be considered in 3 years. Patients with advanced stages of atrophic gastritis should be followed up with a high quality endoscopy every 3 years. In patients with dysplasia, in the absence of an endoscopically defined lesion, immediate high quality endoscopic reassessment with CE is recommended. Patients with an endoscopically visible lesion harboring low or high grade dysplasia or carcinoma should undergo staging and treatment. H. pylori eradication heals nonatrophic chronic gastritis, may lead to regression of atrophic gastritis, and reduces the risk of gastric cancer in patients with these conditions, and it is recommended. H. pylori eradication is also recommended for patients with neoplasia after endoscopic therapy. In intermediate to high risk regions, identification and surveillance of patients with precancerous gastric conditions is cost-effective.

BACKGROUND: There is no consensus method for determining progression of disability in patients with multiple sclerosis (MS) when each patient has had only a single assessment in the course of the disease. METHODS: Using data from two large longitudinal databases, the authors tested whether cross-sectional disability assessments are representative of disease severity as a whole. An algorithm, the Multiple Sclerosis Severity Score (MSSS), which relates scores on the Expanded Disability Status Scale (EDSS) to the distribution of disability in patients with comparable disease durations, was devised and then applied to a collection of 9,892 patients from 11 countries to create the Global MSSS. In order to compare different methods of detecting such effects the authors simulated the effects of a genetic factor on disability. RESULTS: Cross-sectional EDSS measurements made after the first year were representative of overall disease severity. The MSSS was more powerful than the other methods the authors tested for detecting different rates of disease progression. CONCLUSION: The Multiple Sclerosis Severity Score (MSSS) is a powerful method for comparing disease progression using single assessment data. The Global MSSS can be used as a reference table for future disability comparisons. While useful for comparing groups of patients, disease fluctuation precludes its use as a predictor of future disability in an individual.

The treatment of inflammatory bowel disease (IBD) has been revolutionised over the past decade by the increasing use of immunomodulators. With such immunomodulation, the potential for opportunistic infection is a key safety concern for patients with IBD. Opportunistic infections pose particular problems for the clinician: they are often difficult to recognise and are associated with appreciable morbidity or mortality, because they are potentially serious and hard to treat effectively. This led the European Crohn's and Colitis Organisation (ECCO) to update the previous Consensus meeting on opportunistic infections in IBD. To organise the work, infections were classified into six major topics. Guideline statements of 2009 were analysed systematically by the chairs and the working parties. In parallel, the working parties performed a systematic literature search of their topic with the appropriate key words using Medline/Pubmed and the Cochrane database, as well as their own files. The evidence level (EL) was graded according to the 2011 Oxford Centre for Evidence-Based Medicine (http://www.cebm.net/index.aspx?o=5653). Provisional update guideline statements were then posted on a weblog. Discussions and exchange of the literature evidence among the working party members was then performed on the weblog. The working parties then met in Lille on the 15th–16th of November 2012 to agree on the statements. Consensus was defined as agreement by > 80% of participants, termed a Consensus Statement and numbered for convenience in the document. This paper is the product of work by gastroenterologists, infectious disease experts and pediatricians. It provides guidance on the prevention, detection and management of opportunistic infections in patients of all age categories with IBD. After a section on definitions and risk factors for developing opportunistic infection, there are five sections on different infectious agents, followed by a section on information and guidance for patients with IBD travelling frequently or to less economically developed countries. In the final section, a systematic work up and vaccination programme is proposed for consideration in patients exposed to immunomodulator therapies. The final document on each topic was written by the workgroup leader and their working party. Statements are intended to be read in context with qualifying comments and not read in isolation. The final text was edited for consistency of style by JF Rahier, F Magro, R Eliakim and JF Colombel before being circulated and approved by the participants. In some areas the level of evidence is generally low, which reflects the paucity of randomised controlled trials. Consequently expert opinion is included where appropriate. An immunocompromised host has an alteration in phagocytic, cellular, or humoral immunity that increases the risk of an infectious complication or an opportunistic process. Patients may also be immunocompromised if they have a breach of their skin or mucosal defense barriers that permits microorganisms to cause either local or systemic infection.1 There is no clearcut definition of an immunocompromised state. Three categories are recognised by the Centers for Disease Control,2 depending on the severity of immunosuppression: Persons who are severely immunocompromised not as a result of HIV infection: Severe immunosuppression can be the result of congenital immunodeficiency, leukemia, lymphoma, generalised malignancy or therapy with alkylating agents, antimetabolites, radiation, or high doses of corticosteroids (2 mg/kg body weight, or > 20 mg/day of prednisolone, Section 2.4.1) Persons with HIV infection Persons with conditions that cause limited immune deficits (e.g. hyposplenism and renal failure) An opportunistic infection may be defined as a usually progressive infection by a microorganism that has limited (or no) pathogenic capacity under ordinary circumstances, but which is able to cause serious disease as a result of the predisposing effect of another disease or of its treatment.3 Patients with IBD should not be routinely considered to have altered immunocompetence [EL5] per se, despite evidence of impaired innate mucosal immunity. Different immunomodulators may alter immune responsiveness by different mechanisms and to varying degrees, but there is currently no single method of evaluating the effects of immunosuppression on the immune system [EL5] From genome wide association studies there is increasing evidence of an aberrant immune response in IBD.4 Susceptibility loci involve both the innate and adaptive immune response towards a diminished diversity of commensal microbiota.5 Description of the numerous mechanisms contributing to this dysimmunity is beyond the scope of this article. Despite evidence of defective mucosal immunity, there is no proof of a systemic immune defect in patients with IBD in the absence of concomitant immunomodulator therapy. Patients with IBD are therefore rendered immunocompromised through their treatment. 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be on an in with on the of infection in patients with IBD. the of not in IBD patients immunosuppression is generally considered to the risk of vaccination is the method for infection and is therefore for patients on immunomodulators in the for Disease of are should be used for age and is not for patients on immunomodulators. In the may be used for on IBD patients on immunomodulators are considered to be risk and vaccination has been with and proof of is There is to that vaccination may be less in patients with IBD The use of may also response to the immune response to vaccination in patients with IBD and is not associated with a

Reactivation of telomerase has been implicated in human tumorigenesis, but the underlying mechanisms remain poorly understood. Here we report the presence of recurrent somatic mutations in the TERT promoter in cancers of the central nervous system (43%), bladder (59%), thyroid (follicular cell-derived, 10%) and skin (melanoma, 29%). In thyroid cancers, the presence of TERT promoter mutations (when occurring together with BRAF mutations) is significantly associated with higher TERT mRNA expression, and in glioblastoma we find a trend for increased telomerase expression in cases harbouring TERT promoter mutations. Both in thyroid cancers and glioblastoma, TERT promoter mutations are significantly associated with older age of the patients. Our results show that TERT promoter mutations are relatively frequent in specific types of human cancers, where they lead to enhanced expression of telomerase. Reactivation of telomerase has been implicated in human tumorigenesis. Here, somatic mutations in the TERT promoter are reported in cancers of the central nervous system, bladder, follicular cell-derived thyroid and melanoma, thus demonstrating that TERTpromoter mutations are a frequent event in human cancer.

The purpose of this chapter is to assist in the use and interpretation of intrapartum cardiotocography (CTG), as well as in the clinical management of specific CTG patterns. In the preparation of these guidelines, it has been assumed that all necessary resources, both human and material, required for intrapartum monitoring and clinical management are readily available. Unexpected complications may occur during labor, even in patients without prior evidence of risk, so maternity hospitals need to ensure the presence of trained staff, as well as appropriate facilities and equipment for an expedite delivery (in particular emergency cesarean delivery). CTG monitoring should never be regarded as a substitute for good clinical observation and judgement, or as an excuse for leaving the mother unattended during labor. The evidence for the benefits of continuous CTG monitoring, as compared with intermittent auscultation, in both low- and high-risk labors is scientifically inconclusive [1,2]. When compared with intermittent auscultation, continuous CTG has been shown to decrease the occurrence of neonatal seizures, but no effect has been demonstrated on the incidence of overall perinatal mortality or cerebral palsy. However, these studies were carried out in the 1970s, 1980s, and early 1990s where equipment, clinical experience, and interpretation criteria were very different from current practice, and they were clearly underpowered to evaluate differences in major outcomes [3]. These issues are discussed in more detail in Section 8 of this chapter. In spite of these limitations, most experts believe that continuous CTG monitoring should be considered in all situations where there is a high risk of fetal hypoxia/acidosis, whether due to maternal health conditions (such as vaginal hemorrhage and maternal pyrexia), abnormal fetal growth during pregnancy, epidural analgesia, meconium stained liquor, or the possibility of excessive uterine activity, as occurs with induced or augmented labor. Continuous CTG is also recommended when abnormalities are detected during intermittent fetal auscultation. The use of continuous intrapartum CTG in low-risk women is more controversial, although it has become standard of care in many countries. An alternative approach is to provide intermittent CTG monitoring alternating with fetal heart rate (FHR) auscultation. There is some evidence to support that this is associated with similar neonatal outcomes in low-risk pregnancies [4]. Intermittent monitoring should be carried out long enough to allow adequate evaluation of the basic CTG features (see below). The routine use of admission CTG for low-risk women on entrance to the labor ward has been associated with an increase in cesarean delivery rates and no improvement in perinatal outcomes [5], but studies were also underpowered to show such differences. In spite of the lack of evidence regarding benefit, this procedure has also become standard of care in many countries. Maternal supine recumbent position can result in aortocaval compression by the pregnant uterus, affecting placental perfusion and fetal oxygenation. Prolonged monitoring in this position should therefore be avoided. The lateral recumbent, half-sitting, and upright positions are preferable alternatives [6]. CTG acquisition can be performed by portable sensors that transmit signals wirelessly to a remote fetal monitor (telemetry). This solution has the advantage of allowing the mother to move freely during signal acquisition, rather than be restrained to bed or a sofa, and should therefore be the preferred option when available. Telemetry systems differ in the maximum distance allowed between patient and monitor for adequate signal transmission [7]. The horizontal scale for CTG registration and viewing is commonly called “paper speed” and available options are usually 1, 2, or 3 cm/min. In many countries throughout the world 1 cm/min is selected, while in the Netherlands it is usually 2 cm/min, and in North America and Japan it is almost exclusively 3 cm/min. Some experts feel that 1 cm/min provides records of sufficient detail for clinical analysis, and this has the advantage of reducing tracing length. Other experts feel that the small details of CTG tracings are better evaluated using higher papers speeds. The vertical scale used for registration and viewing may also be different, and available alternatives are 20 or 30 bpm/cm. The paper scales used in each center should be the ones with which healthcare professionals are most familiar, because tracing interpretation depends on pattern recognition and these patterns may appear very different. Inadvertent use of paper scales to which the staff is unaccustomed may lead to erroneous interpretations of CTG features. For example, at 3 cm/min variability appears reduced to a clinician familiar with the 1 cm/min scale, while it may appear exaggerated in the opposite situation (see examples below). External FHR monitoring uses a Doppler ultrasound transducer to detect the movement of cardiac structures. The resulting signal requires signal modulation and autocorrelation to provide adequate quality recordings [8]. This process results in an approximation of the true heart rate intervals, but this is considered to be sufficiently accurate for analysis. External FHR monitoring is more prone to signal loss, to inadvertent monitoring of the maternal heart rate (Fig. 1) [9], and to signal artefacts such as double-counting (Fig. 2) and half-counting [8], particularly during the second stage of labor. It may also not record fetal cardiac arrhythmias accurately. Maternal heart rate monitoring in the last 9 minutes of the tracing. External fetal heart rate monitoring at 1 cm/min (top graph), 2 cm/min (middle graph), and 3 cm/min (bottom graph). Double-counting of the fetal heart rate during decelerations (arrows). External fetal heart rate monitoring at 1 cm/min (top graph), 2 cm/min (middle graph), and 3 cm/min (bottom graph). Internal FHR monitoring using a fetal electrode (usually known as scalp electrode, but it can also be applied to the breech) evaluates the time intervals between successive heart beats by identifying R waves on the fetal electrocardiogram QRS complex, and therefore measures ventricular depolarization cycles. This method provides a more accurate evaluation of intervals between cardiac cycles, but it is more expensive because it requires a disposable electrode. It is very important that the fetal electrode is only applied after a clear identification of the presenting part and that delicate fetal structures such as the sutures and fontanels are avoided. Internal FHR monitoring requires ruptured membranes and has established contraindications, mainly related to the increased risk of vertical transmission of infections. It should not be used in patients with active genital herpes infection, those who are seropositive to hepatitis B, C, D, E, or to HIV [10,11], in suspected fetal blood disorders, when there is uncertainty about the presenting part, or when artificial rupture of membranes is inappropriate (i.e. an unengaged presentation). Fetal electrode placement should also preferably be avoided in very preterm fetuses (under 32 weeks of gestation). External FHR monitoring is the recommended initial method for routine intrapartum monitoring, provided that a recording of acceptable quality is obtained, i.e. that the basic CTG features can be identified. Minimum requirements for using this method are that careful repositioning of the probe is carried out during the second stage of labor, that in all atypical FHR tracings maternal heart rate monitoring is ruled out (see below), and if any doubt remains, fetal auscultation, ultrasound evaluation, or internal FHR monitoring are performed. If an acceptable record cannot be obtained with external monitoring or if a cardiac arrhythmia is suspected, then internal monitoring should be used, in the absence of the previously mentioned contraindications. External monitoring of uterine contractions using a tocodynamometer (toco) evaluates increased myometrial tension measured through the abdominal wall. Incorrect placement, reduced tension applied to the supporting elastic band, or abdominal adiposity may result in failed or inadequate registration of contractions. In addition, this technology only provides accurate information on the frequency of contractions. It is not possible to extract reliable information regarding the intensity and duration of contractions, nor on basal uterine tone. Internal monitoring of uterine contractions using an intrauterine catheter provides quantitative information on the intensity and duration of contractions, as well as on basal uterine tone, but it is more expensive as the catheter is disposable, and requires ruptured membranes. Contraindications include uterine hemorrhage of unknown cause and placenta previa. It may also be associated with a small risk of fetal injury, placental hemorrhage, uterine perforation, and infection [12]. The routine use of intrauterine pressure catheters has not been shown to be associated with improved outcomes in induced and augmented labor [13], and so it is not recommended for routine clinical use. Simultaneous monitoring of the maternal heart rate (MHR) can be useful in specific maternal health conditions and in cases where it is difficult to distinguish between maternal and fetal heart rates (for example complete fetal heart block) [9]. Some CTG monitors provide the possibility of continuous MHR monitoring, either by electrocardiography or pulse oximetry. In some recent models, the latter technology has been incorporated in the tocodynamometer, allowing continuous MHR monitoring without the use of additional equipment. Providing that the technology is available and does not cause discomfort to the mother, simultaneous MHR monitoring should be considered when performing continuous CTG, especially during the second stage of labor, when tracings show accelerations coinciding with contractions and expulsive efforts [9], or when the MHR is elevated. Continuous external FHR monitoring of twin gestations during labor should preferably be performed with dual channel monitors that allow simultaneous monitoring of both FHRs, as duplicate monitoring of the same twin may occur and this can be picked up by observing almost identical tracings. Some monitors have embedded algorithms to alarm when this situation is suspected. During the second stage of labor, external FHR monitoring of twins is particularly affected by signal loss, and for this reason some experts believe that the presenting twin should preferably be monitored internally for better signal quality [14], if no contraindications to fetal electrode placement are present. Other experts believe that external monitoring of both twins is acceptable, provided that distinct and good quality FHR signals can be obtained. All CTG tracings need to be identified with the patient name, place of recording, “paper speed,” and date and time when acquisition started and ended. In hospitals where paper CTG recordings are used, the latter should be considered as part of the patient record and preserved as such. In hospitals using digital CTG archives [15], a secure file backup system needs to be in place, and all tracings should be readily available for review by the clinical staff. CTG analysis starts with the evaluation of basic CTG features (baseline, variability, accelerations, decelerations, and contractions) followed by overall CTG classification. This is the mean level of the most horizontal and less oscillatory FHR segments. It is estimated in time periods of 10 minutes and expressed in beats per minute (bpm). The baseline value may vary between subsequent 10-minute sections. Normal baseline: a value between 110 and 160 bpm. Fetal behavioral state of active wakefulness. This pattern may lead to erroneously high baseline estimation if it is identified at the top of accelerations. External fetal heart rate monitoring at 1 cm/min (top graph), 2 cm/min (middle graph), and 3 cm/min (bottom graph). Preterm fetuses tend to have values toward the upper end of this range and post-term fetuses towards the lower end. Some experts consider the normal baseline values at term to be between 110-150 bpm. Tachycardia: a baseline value above 160 bpm lasting more than 10 minutes. Maternal pyrexia is the most frequent cause of fetal tachycardia, and it may be of extrauterine origin or associated with intrauterine infection. Epidural analgesia may also cause a rise in maternal temperature resulting in fetal tachycardia [17]. In the initial stages of a nonacute fetal hypoxemia, catecholamine secretion may also result in tachycardia. Other less frequent causes are the administration of beta-agonist drugs [18] (salbutamol, terbutaline, ritodrine, fenoterol), parasympathetic blockers (atropine, scopolamine), and fetal arrhythmias such as supraventricular tachycardia and atrial flutter. Bradycardia: a baseline value below 110 bpm lasting more than 10 minutes. Values between 100 and 110 bpm may occur in normal fetuses, especially in postdate pregnancies. Maternal hypothermia [19], administration of beta-blockers [20], and fetal arrhythmias such as atrioventricular block are other possible causes. Normal variability: a bandwidth amplitude of 5−25 bpm. Reduced variability: a bandwidth amplitude below 5 bpm for more than 50 minutes in baseline segments [21] (4, 5), or for more than 3 minutes during decelerations [22] (see 8, 9). Reduced variability. External fetal heart rate monitoring at 1 cm/min (top graph), 2 cm/min (middle graph), and 3 cm/min (bottom graph). Reduced variability. The baseline is affected by contractions causing decreases in fetal heart rate that are close to fulfilling the criteria for decelerations, but the bandwidth remains reduced. Internal fetal heart rate monitoring at 1 cm/min (top graph), 2 cm/min (middle graph), and 3 cm/min (bottom graph). Reduced variability can occur due to central nervous system hypoxia/acidosis and resulting decreased sympathetic and parasympathetic activity, but it can also be due to previous cerebral injury [23], infection, administration of central nervous system depressants or parasympathetic blockers. During deep sleep, variability is usually in the lower range of normality, but the bandwidth amplitude is seldom under 5 bpm. There is a high degree of subjectivity in the visual evaluation of this and therefore careful is recommended in an normal CTG, reduced variability due to is very to occur during labor without or decelerations and a rise in the variability a bandwidth value bpm lasting more than 30 minutes (Fig. variability: Internal fetal heart rate monitoring at 1 cm/min (top graph), 2 cm/min (middle graph), and 3 cm/min (bottom graph). The of this pattern is but it may be with decelerations, when hypoxia/acidosis very It is to be by fetal system to in less than 30 in FHR above the of more than bpm in and lasting more than but less than 10 minutes. accelerations with fetal and are a of a that does not have 32 weeks of amplitude and frequency may be lower and 10 bpm of with the of fetal behavioral accelerations occur during periods of deep sleep, which can last up to 50 minutes The absence of accelerations in an normal intrapartum CTG is of but it is to coinciding with uterine contractions, especially in the second stage of labor, possible erroneous recording of the maternal heart the FHR more with a while the maternal heart rate [9]. decelerations that are with normal variability the and are with contractions. are to be by fetal compression and not fetal decelerations decelerations that a to in less than 30 good variability the to the and to uterine contractions (Fig. Internal fetal heart rate monitoring at 1 cm/min (top graph), 2 cm/min (middle graph), and 3 cm/min (bottom graph). decelerations the of decelerations during labor, and they a to increased as occurs with compression are seldom associated with an important degree of fetal hypoxia/acidosis, they to a reduced variability the (see decelerations below), duration 3 minutes (see decelerations below). decelerations with reduced decelerations with a a to the baseline reduced variability the (Fig. and occurs when more than 30 between the of a and When contractions are decelerations more than 20 after the of a have a after the and a to the baseline after the end of the decelerations in the second of the tracing. External fetal heart rate monitoring at 1 cm/min (top graph), 2 cm/min (middle graph), and 3 cm/min (bottom graph). These decelerations are of a to fetal In the presence of a tracing with no accelerations and reduced variability, the of decelerations also those with an amplitude of bpm. Prolonged lasting more than 3 minutes. These are to include a and to 5 with FHR at less than bpm and reduced variability the (Fig. are associated with fetal hypoxia/acidosis and Prolonged External fetal heart rate monitoring at 1 cm/min (top graph), 2 cm/min (middle graph), and 3 cm/min (bottom graph). a with an amplitude of and a frequency of per This pattern more than 30 and with accelerations (Fig. External fetal heart rate monitoring at 1 cm/min (top graph), 2 cm/min (middle graph), and 3 cm/min (bottom graph). The of the pattern is but it occurs in with fetal as is in hemorrhage, and ruptured previa. It has also been in cases of fetal infection, cardiac and pattern the but with a more rather than the (Fig. duration seldom 30 minutes and it is by normal patterns and External fetal heart rate monitoring at 1 cm/min (top graph), 2 cm/min (middle graph), and 3 cm/min (bottom graph). This pattern has been after administration to the mother, and during periods of fetal and other It is difficult to distinguish the pattern from the true leaving the duration of the as the most important to between the This to periods of fetal deep alternating with periods of active and The occurrence of different behavioral is a of fetal and absence of can last up to 50 minutes [21] and is associated with a very accelerations, and variability. is the most frequent behavioral and is by a of accelerations and normal variability. is and by a of accelerations and normal variability (Fig. In the latter accelerations may be so frequent as to cause in baseline estimation (see between the different patterns become after weeks of to fetal nervous system These are in the uterine signal followed by with in This an excessive frequency of contractions and is as the occurrence of more than contractions in 10 in successive 10-minute or a requires a previous evaluation of basic CTG features (see should be of or to the criteria in Other systems a of are recommended by some experts to the of CTG signals during labor, of the tracing should be carried out at 30 minutes. and to the mother, can FHR features (see so CTG analysis needs to be with other clinical information for a interpretation and adequate a if the to a baseline and a variability, the risk of to the central is very However, the that should clinical management are in When fetal hypoxia/acidosis is or suspected and and is required to neonatal this does not mean an cesarean delivery or vaginal The cause for the of the pattern can be identified and the situation with subsequent of adequate fetal and the to a normal tracing. uterine is the most frequent cause of fetal hypoxia/acidosis and it can be detected by in the CTG tracing the uterine It can usually be by reducing or if with (salbutamol, terbutaline, or During the second stage of labor, maternal efforts can also to fetal hypoxia/acidosis and the mother can be to the situation is compression can occur in the supine position and lead to reduced placental uterine may also be associated with the supine position due to the of the by the uterine In these the mother to is followed by of the CTG compression is cause of CTG and these can be by the maternal position or by performing maternal can also occur during labor, usually after epidural or analgesia and it is usually by administration an Other less frequent complications affecting the maternal maternal or the fetal can also result in fetal hypoxia/acidosis and management is the of this administration to the mother is used with the of fetal and CTG but there is no evidence from clinical that this when performed in is when maternal is adequate are also commonly used for the purpose of CTG but there is no evidence from clinical to that this is in women clinical is required to the cause for a or CTG, to the of the conditions with which it is and to the of with the of fetal hypoxia/acidosis, as well as may be used to evaluate fetal When a or CTG pattern is the cause should be a tracing If the situation does not and the pattern to needs to be for evaluation or delivery if a pattern During the second stage of labor, due to the additional effect of maternal hypoxia/acidosis may more should be to the of maternal and if there is no delivery should be has limitations, and it is necessary to be of these for use of the It has been well demonstrated that CTG analysis is to and even when use The that are prone to are the identification and of decelerations, the evaluation of variability and the of tracings as and The subjectivity of analysis has also been demonstrated in of where CTG features are to be more abnormal in cases with known neonatal studies have evaluated the of and to the occurrence of CTG interpretation different intervals between tracing and and different criteria to have been used, resulting in However, it is that hypoxia/acidosis has not been after a normal CTG tracing. the other and tracings have a to and i.e. a of cases with and tracings not have these outcomes there is a between FHR patterns and hypoxia/acidosis, to between with or without is they are but have a and However, it should not be that the of intrapartum fetal monitoring is to situations that so as to fetal The subjectivity of CTG interpretation and the that is a that may not the of or injury are important to these of have been continuous CTG monitoring with intermittent as for fetal hypoxia/acidosis during labor, in both low- and high-risk women [1,2]. However, these place in the 1970s, 1980s, and early and used different CTG interpretation so it is difficult to results to current clinical these in they a of continuous CTG for fetal monitoring in all women during labor, as the only improvement a in neonatal not evaluated in most and no differences were in the of overall perinatal mortality and cerebral palsy. However, it is that the were underpowered to detect differences in these outcomes [3]. a small of perinatal and cerebral are by intrapartum hypoxia/acidosis, so a of cases are to show any the other continuous CTG associated with a increase in cesarean delivery and a increase in vaginal additional for the mother and and the may result from CTG of the of fetal and inadequate clinical It is for clinical need to be as and as to allow even in and In addition, and of the labor ward staff is to ensure use of this The have no of to

The conserved serine/threonine kinase mTOR (the mammalian target of rapamycin), a downstream effector of the PI3K/AKT pathway, forms two distinct multiprotein complexes: mTORC1 and mTORC2. mTORC1 is sensitive to rapamycin, activates S6K1 and 4EBP1, which are involved in mRNA translation. It is activated by diverse stimuli, such as growth factors, nutrients, energy and stress signals, and essential signalling pathways, such as PI3K, MAPK and AMPK, in order to control cell growth, proliferation and survival. mTORC2 is considered resistant to rapamycin and is generally insensitive to nutrients and energy signals. It activates PKC-α and AKT and regulates the actin cytoskeleton. Deregulation of multiple elements of the mTOR pathway (PI3K amplification/mutation, PTEN loss of function, AKT overexpression, and S6K1, 4EBP1 and eIF4E overexpression) has been reported in many types of cancers, particularly in melanoma, where alterations in major components of the mTOR pathway were reported to have significant effects on tumour progression. Therefore, mTOR is an appealing therapeutic target and mTOR inhibitors, including the rapamycin analogues deforolimus, everolimus and temsirolimus, are submitted to clinical trials for treating multiple cancers, alone or in combination with inhibitors of other pathways. Importantly, temsirolimus and everolimus were recently approved by the FDA for the treatment of renal cell carcinoma, PNET and giant cell astrocytoma. Small molecules that inhibit mTOR kinase activity and dual PI3K-mTOR inhibitors are also being developed. In this review, we aim to survey relevant research, the molecular mechanisms of signalling, including upstream activation and downstream effectors, and the role of mTOR in cancer, mainly in melanoma.

Skin tests are of paramount importance for the evaluation of drug hypersensitivity reactions. Drug skin tests are often not carried out because of lack of concise information on specific test concentrations. The diagnosis of drug allergy is often based on history alone, which is an unreliable indicator of true hypersensitivity.To promote and standardize reproducible skin testing with safe and nonirritant drug concentrations in the clinical practice, the European Network and European Academy of Allergy and Clinical Immunology (EAACI) Interest Group on Drug Allergy has performed a literature search on skin test drug concentration in MEDLINE and EMBASE, reviewed and evaluated the literature in five languages using the GRADE system for quality of evidence and strength of recommendation. Where the literature is poor, we have taken into consideration the collective experience of the group.We recommend drug concentration for skin testing aiming to achieve a specificity of at least 95%. It has been possible to recommend specific drug concentration for betalactam antibiotics, perioperative drugs, heparins, platinum salts and radiocontrast media. For many other drugs, there is insufficient evidence to recommend appropriate drug concentration. There is urgent need for multicentre studies designed to establish and validate drug skin test concentration using standard protocols. For most drugs, sensitivity of skin testing is higher in immediate hypersensitivity compared to nonimmediate hypersensitivity.

AIMS: The aim of this study was to investigate the clinical picture and outcome of cardiogenic shock and to develop a risk prediction score for short-term mortality. METHODS AND RESULTS: The CardShock study was a multicentre, prospective, observational study conducted between 2010 and 2012. Patients with either acute coronary syndrome (ACS) or non-ACS aetiologies were enrolled within 6 h from detection of cardiogenic shock defined as severe hypotension with clinical signs of hypoperfusion and/or serum lactate >2 mmol/L despite fluid resuscitation (n = 219, mean age 67, 74% men). Data on clinical presentation, management, and biochemical variables were compared between different aetiologies of shock. Systolic blood pressure was on average 78 mmHg (standard deviation 14 mmHg) and mean arterial pressure 57 (11) mmHg. The most common cause (81%) was ACS (68% ST-elevation myocardial infarction and 8% mechanical complications); 94% underwent coronary angiography, of which 89% PCI. Main non-ACS aetiologies were severe chronic heart failure and valvular causes. In-hospital mortality was 37% (n = 80). ACS aetiology, age, previous myocardial infarction, prior coronary artery bypass, confusion, low LVEF, and blood lactate levels were independently associated with increased mortality. The CardShock risk Score including these variables and estimated glomerular filtration rate predicted in-hospital mortality well (area under the curve 0.85). CONCLUSION: Although most commonly due to ACS, other causes account for one-fifth of cases with shock. ACS is independently associated with in-hospital mortality. The CardShock risk Score, consisting of seven common variables, easily stratifies risk of short-term mortality. It might facilitate early decision-making in intensive care or guide patient selection in clinical trials. TRIAL REGISTRATION: NCT01374867.

OBJECTIVES: This guideline provides recommendations for the diagnosis and management of suspected cow's-milk protein allergy (CMPA) in Europe. It presents a practical approach with a diagnostic algorithm and is based on recently published evidence-based guidelines on CMPA. DIAGNOSIS: If CMPA is suspected by history and examination, then strict allergen avoidance is initiated. In certain circumstances (eg, a clear history of immediate symptoms, a life-threatening reaction with a positive test for CMP-specific IgE), the diagnosis can be made without a milk challenge. In all other circumstances, a controlled oral food challenge (open or blind) under medical supervision is required to confirm or exclude the diagnosis of CMPA. TREATMENT: In breast-fed infants, the mother should start a strict CMP-free diet. Non-breast-fed infants with confirmed CMPA should receive an extensively hydrolyzed protein-based formula with proven efficacy in appropriate clinical trials; amino acids-based formulae are reserved for certain situations. Soy protein formula, if tolerated, is an option beyond 6 months of age. Nutritional counseling and regular monitoring of growth are mandatory in all age groups requiring CMP exclusion. REEVALUATION: Patients should be reevaluated every 6 to 12 months to assess whether they have developed tolerance to CMP. This is achieved in >75% by 3 years of age and >90% by 6 years of age. Inappropriate or overly long dietary eliminations should be avoided. Such restrictions may impair the quality of life of both child and family, induce improper growth, and incur unnecessary health care costs.

BACKGROUND: Heart failure (HF) is responsible for a huge burden in hospital care. Our goal was to evaluate the value of N-terminal-pro-brain natriuretic peptide (NT-proBNP) in predicting death or hospital readmission after discharge of HF patients. METHODS AND RESULTS: We included 182 patients consecutively admitted to hospital because of decompensated HF. Patients were followed up for 6 months. The primary end point was death or readmission. Twenty-six patients died in hospital. The median admission NT-proBNP level was 6778.5 pg/mL, and the median level at discharge was 4137.0 pg/mL (P<0.001). Patients were classified into 3 groups: (1) decreasing NT-proBNP levels by at least 30% (n=82), (2) no significant modifications on NT-proBNP levels (n=49), and (3) increasing NT-proBNP levels by at least 30% (n=25). The primary end point was observed in 42.9% patients. Variables associated with an increased hazard of death and/or hospital readmission in univariate analysis were length of hospitalization, heart rate, signs of volume overload, no use of ACE inhibitors, higher NYHA class at discharge, admission and discharge NT-proBNP, and the change in NT-proBNP levels. The variation in NT-proBNP was the strongest predictor of an adverse outcome. Independent variables associated with an increased risk of readmission or death were signs of volume overload and the change in NT-proBNP levels. CONCLUSIONS: Variations in NT-proBNP levels are related to hospital readmission and death within 6 months. NT-proBNP levels are potentially useful in the evaluation of treatment efficacy and might help clinicians in planning discharge of HF patients. Whether therapeutic strategies aimed to lower NT-proBNP levels modify prognosis warrants future investigation.

The histologic examination of endoscopic biopsies or resection specimens remains a key step in the work-up of affected inflammatory bowel disease (IBD) patients and can be used for diagnosis and differential diagnosis, particularly in the differentiation of UC from CD and other non-IBD related colitides. The introduction of new treatment strategies in inflammatory bowel disease (IBD) interfering with the patients' immune system may result in mucosal healing, making the pathologists aware of the impact of treatment upon diagnostic features. The European Crohn's and Colitis Organisation (ECCO) and the European Society of Pathology (ESP) jointly elaborated a consensus to establish standards for histopathology diagnosis in IBD. The consensus endeavors to address: (i) procedures required for a proper diagnosis, (ii) features which can be used for the analysis of endoscopic biopsies, (iii) features which can be used for the analysis of surgical samples, (iv) criteria for diagnosis and differential diagnosis, and (v) special situations including those inherent to therapy. Questions that were addressed include: how many features should be present for a firm diagnosis? What is the role of histology in patient management, including search for dysplasia? Which features if any, can be used for assessment of disease activity? The statements and general recommendations of this consensus are based on the highest level of evidence available, but significant gaps remain in certain areas.

Melanoma represents the most aggressive and the deadliest form of skin cancer. Current therapeutic approaches include surgical resection, chemotherapy, photodynamic therapy, immunotherapy, biochemotherapy, and targeted therapy. The therapeutic strategy can include single agents or combined therapies, depending on the patient's health, stage, and location of the tumor. The efficiency of these treatments can be decreased due to the development of diverse resistance mechanisms. New therapeutic targets have emerged from studies of the genetic profile of melanocytes and from the identification of molecular factors involved in the pathogenesis of the malignant transformation. In this review, we aim to survey therapies approved and under evaluation for melanoma treatment and relevant research on the molecular mechanisms underlying melanomagenesis.

Polycystic ovary syndrome (PCOS) is the most common ovarian disorder associated with androgen excess in women, which justifies the growing interest of endocrinologists. Great efforts have been made in the last 2 decades to define the syndrome. The presence of three different definitions for the diagnosis of PCOS reflects the phenotypic heterogeneity of the syndrome. Major criteria are required for the diagnosis, which in turn identifies different phenotypes according to the combination of different criteria. In addition, the relevant impact of metabolic issues, specifically insulin resistance and obesity, on the pathogenesis of PCOS, and the susceptibility to develop earlier than expected glucose intolerance states, including type 2 diabetes, has supported the notion that these aspects should be considered when defining the PCOS phenotype and planning potential therapeutic strategies in an affected subject. This paper offers a critical endocrine and European perspective on the debate on the definition of PCOS and summarises all major aspects related to aetiological factors, including early life events, potentially involved in the development of the disorder. Diagnostic tools of PCOS are also discussed, with emphasis on the laboratory evaluation of androgens and other potential biomarkers of ovarian and metabolic dysfunctions. We have also paid specific attention to the role of obesity, sleep disorders and neuropsychological aspects of PCOS and on the relevant pathogenetic aspects of cardiovascular risk factors. In addition, we have discussed how to target treatment choices based according to the phenotype and individual patient's needs. Finally, we have suggested potential areas of translational and clinical research for the future with specific emphasis on hormonal and metabolic aspects of PCOS.

Atrophic gastritis, intestinal metaplasia, and epithelial dysplasia of the stomach are common and are associated with an increased risk for gastric cancer. In the absence of guidelines, there is wide disparity in the management of patients with these premalignant conditions. The European Society of Gastrointestinal Endoscopy (ESGE), the European Helicobacter Study Group (EHSG), the European Society of Pathology (ESP) and the Sociedade Portuguesa de Endoscopia Digestiva (SPED) have therefore combined efforts to develop evidence-based guidelines on the management of patients with precancerous conditions and lesions of the stomach (termed MAPS). A multidisciplinary group of 63 experts from 24 countries developed these recommendations by means of repeat online voting and a meeting in June 2011 in Porto, Portugal. The recommendations emphasize the increased cancer risk in patients with gastric atrophy and metaplasia, and the need for adequate staging in the case of high grade dysplasia, and they focus on treatment and surveillance indications and methods.