KU Leuven

The metafor package provides functions for conducting meta-analyses in R. The package includes functions for fitting the meta-analytic fixed- and random-effects models and allows for the inclusion of moderators variables (study-level covariates) in these models. Meta-regression analyses with continuous and categorical moderators can be conducted in this way. Functions for the Mantel-Haenszel and Peto's one-step method for meta-analyses of 2 x 2 table data are also available. Finally, the package provides various plot functions (for example, for forest, funnel, and radial plots) and functions for assessing the model fit, for obtaining case diagnostics, and for tests of publication bias.

The ESH/ESC Guidelines represent the views of the ESH and ESC and were arrived at after careful consideration of the available evidence at the time they were written.Health professionals are encouraged to take them fully into account when exercising their clinical judgement.The guidelines do not, however, override the individual responsibility of health professionals to make appropriate decisions in the circumstances of the individual patients, in consultation with that patient, and where appropriate and necessary the patient's guardian or carer.It is also the health professional's responsibility to verify the rules and regulations applicable to drugs and devices at the time of prescription.

Bayesian inference of phylogeny using Markov chain Monte Carlo (MCMC) plays a central role in understanding evolutionary history from molecular sequence data. Visualizing and analyzing the MCMC-generated samples from the posterior distribution is a key step in any non-trivial Bayesian inference. We present the software package Tracer (version 1.7) for visualizing and analyzing the MCMC trace files generated through Bayesian phylogenetic inference. Tracer provides kernel density estimation, multivariate visualization, demographic trajectory reconstruction, conditional posterior distribution summary, and more. Tracer is open-source and available at http://beast.community/tracer.

The last decade has seen a sharp increase in the number of scientific publications describing physiological and pathological functions of extracellular vesicles (EVs), a collective term covering various subtypes of cell-released, membranous structures, called exosomes, microvesicles, microparticles, ectosomes, oncosomes, apoptotic bodies, and many other names. However, specific issues arise when working with these entities, whose size and amount often make them difficult to obtain as relatively pure preparations, and to characterize properly. The International Society for Extracellular Vesicles (ISEV) proposed Minimal Information for Studies of Extracellular Vesicles ("MISEV") guidelines for the field in 2014. We now update these "MISEV2014" guidelines based on evolution of the collective knowledge in the last four years. An important point to consider is that ascribing a specific function to EVs in general, or to subtypes of EVs, requires reporting of specific information beyond mere description of function in a crude, potentially contaminated, and heterogeneous preparation. For example, claims that exosomes are endowed with exquisite and specific activities remain difficult to support experimentally, given our still limited knowledge of their specific molecular machineries of biogenesis and release, as compared with other biophysically similar EVs. The MISEV2018 guidelines include tables and outlines of suggested protocols and steps to follow to document specific EV-associated functional activities. Finally, a checklist is provided with summaries of key points.

BACKGROUND: Hyperglycemia and insulin resistance are common in critically ill patients, even if they have not previously had diabetes. Whether the normalization of blood glucose levels with insulin therapy improves the prognosis for such patients is not known. METHODS: We performed a prospective, randomized, controlled study involving adults admitted to our surgical intensive care unit who were receiving mechanical ventilation. On admission, patients were randomly assigned to receive intensive insulin therapy (maintenance of blood glucose at a level between 80 and 110 mg per deciliter [4.4 and 6.1 mmol per liter]) or conventional treatment (infusion of insulin only if the blood glucose level exceeded 215 mg per deciliter [11.9 mmol per liter] and maintenance of glucose at a level between 180 and 200 mg per deciliter [10.0 and 11.1 mmol per liter]). RESULTS: At 12 months, with a total of 1548 patients enrolled, intensive insulin therapy reduced mortality during intensive care from 8.0 percent with conventional treatment to 4.6 percent (P<0.04, with adjustment for sequential analyses). The benefit of intensive insulin therapy was attributable to its effect on mortality among patients who remained in the intensive care unit for more than five days (20.2 percent with conventional treatment, as compared with 10.6 percent with intensive insulin therapy, P=0.005). The greatest reduction in mortality involved deaths due to multiple-organ failure with a proven septic focus. Intensive insulin therapy also reduced overall in-hospital mortality by 34 percent, bloodstream infections by 46 percent, acute renal failure requiring dialysis or hemofiltration by 41 percent, the median number of red-cell transfusions by 50 percent, and critical-illness polyneuropathy by 44 percent, and patients receiving intensive therapy were less likely to require prolonged mechanical ventilation and intensive care. CONCLUSIONS: Intensive insulin therapy to maintain blood glucose at or below 110 mg per deciliter reduces morbidity and mortality among critically ill patients in the surgical intensive care unit.

Context. We present the second Gaia data release, Gaia DR2, consisting of astrometry, photometry, radial velocities, and information on astrophysical parameters and variability, for sources brighter than magnitude 21. In addition epoch astrometry and photometry are provided for a modest sample of minor planets in the solar system. Aims. A summary of the contents of Gaia DR2 is presented, accompanied by a discussion on the differences with respect to Gaia DR1 and an overview of the main limitations which are still present in the survey. Recommendations are made on the responsible use of Gaia DR2 results. Methods. The raw data collected with the Gaia instruments during the first 22 months of the mission have been processed by the Gaia Data Processing and Analysis Consortium (DPAC) and turned into this second data release, which represents a major advance with respect to Gaia DR1 in terms of completeness, performance, and richness of the data products. Results. Gaia DR2 contains celestial positions and the apparent brightness in G for approximately 1.7 billion sources. For 1.3 billion of those sources, parallaxes and proper motions are in addition available. The sample of sources for which variability information is provided is expanded to 0.5 million stars. This data release contains four new elements: broad-band colour information in the form of the apparent brightness in the G BP (330–680 nm) and G RP (630–1050 nm) bands is available for 1.4 billion sources; median radial velocities for some 7 million sources are presented; for between 77 and 161 million sources estimates are provided of the stellar effective temperature, extinction, reddening, and radius and luminosity; and for a pre-selected list of 14 000 minor planets in the solar system epoch astrometry and photometry are presented. Finally, Gaia DR2 also represents a new materialisation of the celestial reference frame in the optical, the Gaia -CRF2, which is the first optical reference frame based solely on extragalactic sources. There are notable changes in the photometric system and the catalogue source list with respect to Gaia DR1, and we stress the need to consider the two data releases as independent. Conclusions. Gaia DR2 represents a major achievement for the Gaia mission, delivering on the long standing promise to provide parallaxes and proper motions for over 1 billion stars, and representing a first step in the availability of complementary radial velocity and source astrophysical information for a sample of stars in the Gaia survey which covers a very substantial fraction of the volume of our galaxy.

Gaia is a cornerstone mission in the science programme of the EuropeanSpace Agency (ESA). The spacecraft construction was approved in 2006, following a study in which the original interferometric concept was changed to a direct-imaging approach. Both the spacecraft and the payload were built by European industry. The involvement of the scientific community focusses on data processing for which the international Gaia Data Processing and Analysis Consortium (DPAC) was selected in 2007. Gaia was launched on 19 December 2013 and arrived at its operating point, the second Lagrange point of the Sun-Earth-Moon system, a few weeks later. The commissioning of the spacecraft and payload was completed on 19 July 2014. The nominal five-year mission started with four weeks of special, ecliptic-pole scanning and subsequently transferred into full-sky scanning mode. We recall the scientific goals of Gaia and give a description of the as-built spacecraft that is currently (mid-2016) being operated to achieve these goals. We pay special attention to the payload module, the performance of which is closely related to the scientific performance of the mission. We provide a summary of the commissioning activities and findings, followed by a description of the routine operational mode. We summarise scientific performance estimates on the basis of in-orbit operations. Several intermediate Gaia data releases are planned and the data can be retrieved from the Gaia Archive, which is available through the Gaia home page.

BACKGROUND: In a phase 1-2 trial of albumin-bound paclitaxel (nab-paclitaxel) plus gemcitabine, substantial clinical activity was noted in patients with advanced pancreatic cancer. We conducted a phase 3 study of the efficacy and safety of the combination versus gemcitabine monotherapy in patients with metastatic pancreatic cancer. METHODS: We randomly assigned patients with a Karnofsky performance-status score of 70 or more (on a scale from 0 to 100, with higher scores indicating better performance status) to nab-paclitaxel (125 mg per square meter of body-surface area) followed by gemcitabine (1000 mg per square meter) on days 1, 8, and 15 every 4 weeks or gemcitabine monotherapy (1000 mg per square meter) weekly for 7 of 8 weeks (cycle 1) and then on days 1, 8, and 15 every 4 weeks (cycle 2 and subsequent cycles). Patients received the study treatment until disease progression. The primary end point was overall survival; secondary end points were progression-free survival and overall response rate. RESULTS: A total of 861 patients were randomly assigned to nab-paclitaxel plus gemcitabine (431 patients) or gemcitabine (430). The median overall survival was 8.5 months in the nab-paclitaxel-gemcitabine group as compared with 6.7 months in the gemcitabine group (hazard ratio for death, 0.72; 95% confidence interval [CI], 0.62 to 0.83; P<0.001). The survival rate was 35% in the nab-paclitaxel-gemcitabine group versus 22% in the gemcitabine group at 1 year, and 9% versus 4% at 2 years. The median progression-free survival was 5.5 months in the nab-paclitaxel-gemcitabine group, as compared with 3.7 months in the gemcitabine group (hazard ratio for disease progression or death, 0.69; 95% CI, 0.58 to 0.82; P<0.001); the response rate according to independent review was 23% versus 7% in the two groups (P<0.001). The most common adverse events of grade 3 or higher were neutropenia (38% in the nab-paclitaxel-gemcitabine group vs. 27% in the gemcitabine group), fatigue (17% vs. 7%), and neuropathy (17% vs. 1%). Febrile neutropenia occurred in 3% versus 1% of the patients in the two groups. In the nab-paclitaxel-gemcitabine group, neuropathy of grade 3 or higher improved to grade 1 or lower in a median of 29 days. CONCLUSIONS: In patients with metastatic pancreatic adenocarcinoma, nab-paclitaxel plus gemcitabine significantly improved overall survival, progression-free survival, and response rate, but rates of peripheral neuropathy and myelosuppression were increased. (Funded by Celgene; ClinicalTrials.gov number, NCT00844649.).

Gastric cancer is a leading cause of cancer deaths, but analysis of its molecular and clinical characteristics has been complicated by histological and aetiological heterogeneity. Here we describe a comprehensive molecular evaluation of 295 primary gastric adenocarcinomas as part of The Cancer Genome Atlas (TCGA) project. We propose a molecular classification dividing gastric cancer into four subtypes: tumours positive for Epstein–Barr virus, which display recurrent PIK3CA mutations, extreme DNA hypermethylation, and amplification of JAK2, CD274 (also known as PD-L1) and PDCD1LG2 (also known as PD-L2); microsatellite unstable tumours, which show elevated mutation rates, including mutations of genes encoding targetable oncogenic signalling proteins; genomically stable tumours, which are enriched for the diffuse histological variant and mutations of RHOA or fusions involving RHO-family GTPase-activating proteins; and tumours with chromosomal instability, which show marked aneuploidy and focal amplification of receptor tyrosine kinases. Identification of these subtypes provides a roadmap for patient stratification and trials of targeted therapies. The Cancer Genome Atlas reports on molecular evaluation of 295 primary gastric adenocarcinomas and proposes a new classification of gastric cancers into 4 subtypes, which should help with clinical assessment and trials of targeted therapies. This contribution from The Cancer Genome Atlas (TCGA) project describes the molecular evaluation of 295 primary gastric adenocarcinomas. Based on the results, the authors propose a novel classification separating gastric cancers into four subtypes according to: Epstein–Barr virus positive status, microsatellite instability, chromosomal instability or genomic stability. Given the histologic and etiologic heterogeneity of gastric cancer identification of these subtypes, using a schema that can readily be applied to patient samples should help with patient stratification and trials of targeted therapies.

0

Rhinosinusitis is a significant and increasing health problem which results in a large financial burden on society. This evidence based position paper describes what is known about rhinosinusitis and nasal polyps, offers evidence based recommendations on diagnosis and treatment, and considers how we can make progress with research in this area. Rhinitis and sinusitis usually coexist and are concurrent in most individuals; thus, the correct terminology is now rhinosinusitis. Rhinosinusitis (including nasal polyps) is defined as inflammation of the nose and the paranasal sinuses characterised by two or more symptoms, one of which should be either nasal blockage/obstruction/congestion or nasal discharge (anterior/posterior nasal drip), +/- facial pain/pressure, +/- reduction or loss of smell; and either endoscopic signs of polyps and/or mucopurulent discharge primarily from middle meatus and/or; oedema/mucosal obstruction primarily in middle meatus, and/or CT changes showing mucosal changes within the ostiomeatal complex and/or sinuses. The paper gives different definitions for epidemiology, first line and second line treatment and for research. Furthermore the paper describes the anatomy and (patho)physiology, epidemiology and predisposing factors, inflammatory mechanisms, evidence based diagnosis, medical and surgical treatment in acute and chronic rhinosinusitis and nasal polyposis in adults and children. Evidence based schemes for diagnosis and treatment are given for the first and second line clinicians. Moreover attention is given to complications and socio-economic cost of chronic rhinosinusitis and nasal polyps. Last but not least the relation to the lower airways is discussed.

Table of Contents Introduction Principles New aspects Epidemiological aspects Relationship of blood pressure to cardiovascular and renal damage Definition and classification of hypertension Prevalence of hypertension Hypertension and total cardiovascular risk Assessment of total cardiovascular risk Limitations Summary of recommendations on total cardiovascular risk assessment Diagnostic evaluation Bood pressure measurement Office or clinic blood pressure Out-of-office blood pressure White-coat (or isolated office) hypertension and masked (or isolated ambulatory) hypertension Clinical indications for out-of-office blood pressure Blood pressure during exercise and laboratory stress Central blood pressure Medical history Physical examination Summary of recommendations on blood pressure measurement, history, and physical examination Laboratory investigations Genetics Searching for asymptomatic organ damage Heart Blood vessels Kidney Fundoscopy Brain Clinical value and limitations Summary of recommendations on the search for asymptomatic organ damage, cardiovascular disease, and chronic kidney disease Searching for secondary forms of hypertension Treatment approach Evidence favouring therapeutic reduction of high blood pressure When to initiate antihypertensive drug treatment Recommendations of previous Guidelines Grade 2 and 3 hypertension and high-risk grade 1 hypertension Low-to-moderate risk, grade 1 hypertension Isolated systolic hypertension in youth Grade 1 hypertension in the elderly High normal blood pressure Summary of recommendations on initiation of antihypertensive drug treatment Blood pressure treatment targets Recommendations of previous Guidelines Low-to-moderate risk hypertensive patients Hypertension in the elderly High-risk patients The ‘lower the better’ vs. the J-shaped curve hypothesis Evidence on target blood pressure from organ damage studies Clinic vs. home and ambulatory blood pressure targets Summary of recommendations on blood pressure targets in hypertensive patients Treatment strategies Lifestyle changes Salt restriction Moderation of alcohol consumption Other dietary changes Weight reduction Regular physical exercise Smoking cessation Summary of recommendations on adoption of lifestyle changes Pharmacological therapy Choice of antihypertensive drugs Monotherapy and combination therapy Summary of recommendations on treatment strategies and choice of drugs Treatment strategies in special conditions White-coat hypertension Masked hypertension Summary of recommendations on treatment strategies in white-coat and masked hypertension Elderly Summary of recommendations on antihypertensive treatment strategies in the elderly Young adults Women Oral contraceptives Hormone replacement therapy Pregnancy Long-term cardiovascular consequences in gestational hypertension Summary of recommendations on treatment strategies in hypertensive women Diabetes mellitus Summary of recommendations on treatment strategies in patients with diabetes Metabolic syndrome Summary of recommendations on treatment strategies in hypertensive patients with metabolic syndrome Obstructive sleep apnoea Diabetic and non-diabetic nephropathy Summary of recommendations on therapeutic strategies in hypertensive patients with nephropathy Chronic kidney disease stage 5D Cerebrovascular disease Acute stroke Previous stroke or transient ischaemic attack Cognitive dysfunction and white matter lesions Summary of recommendations on therapeutic strategies in hypertensive patients with cerebrovascular disease Heart disease Coronary heart disease Heart failure Atrial fibrillation Left ventricular hypertrophy Summary of recommendations on therapeutic strategies in hypertensive patients with heart disease Atherosclerosis, arteriosclerosis, and peripheral artery disease Carotid atherosclerosis Increased arterial stiffness Peripheral artery disease Summary of recommendations on therapeutic strategies in hypertensive patients with atherosclerosis, arteriosclerosis, and peripheral artery disease Sexual dysfunction Resistant hypertension Carotid baroreceptor stimulation Renal denervation Other invasive approaches Follow-up in resistant hypertension Summary of recommendations on therapeutic strategies in patients with resistant hypertension Malignant hypertension Hypertensive emergencies and urgencies Perioperative management of hypertension Renovascular hypertension Primary aldosteronism Treatment of associated risk factors Lipid-lowering agents Antiplatelet therapy Treatment of hyperglycaemia Summary of recommendations on treatment of risk factors associated with hypertension Follow-up Follow-up of hypertensive patients Follow-up of subjects with high normal blood pressure and white-coat hypertension Elevated blood pressure at control visits Continued search for asymptomatic organ damage Can antihypertensive medications be reduced or stopped? Improvement of blood pressure control in hypertension Hypertension disease management Team approach in disease management Mode of care delivery The role of information and communication technologies 53 Gaps in evidence and need for future trials Appendix 1 Appendix 2 Acknowledgments References 1. INTRODUCTION 1.1 Principles The 2013 guidelines on hypertension of the European Society of Hypertension (ESH) and the European Society of Cardiology (ESC) follow the guidelines jointly issued by the two societies in 2003 and 2007 [1,2]. Publication of a new document 6 years after the previous one was felt to be timely because, over this period, important studies have been conducted and many new results have been published on both the diagnosis and treatment of individuals with an elevated blood pressure (BP), making refinements, modifications and expansion of the previous recommendations necessary. The 2013 ESH/ESC guidelines continue to adhere to some fundamental principles that inspired the 2003 and 2007 guidelines, namely (i) to base recommendations on properly conducted studies identified from an extensive review of the literature, (ii) to consider, as the highest priority, data from randomized, controlled trials (RCTs) and their meta-analyses, but not to disregard—particularly when dealing with diagnostic aspects—the results of observational and other studies of appropriate scientific calibre, and (iii) to grade the level of scientific evidence and the strength of recommendations on major diagnostic and treatment issues as in European guidelines on other diseases, according to ESC recommendations (Tables 1 and 2). While it was not done in the 2003 and 2007 guidelines, providing the recommendation class and the level of evidence is now regarded as important for providing interested readers with a standard approach, by which to compare the state of knowledge across different fields of medicine. It was also thought that this could more effectively alert physicians on recommendations that are based on the opinions of the experts rather than on evidence. This is not uncommon in medicine because, for a great part of daily medical practice, no good science is available and recommendations must therefore stem from common sense and personal clinical experience, both of which can be fallible. When appropriately recognized, this can avoid guidelines being perceived as prescriptive and favour the performance of studies where opinion prevails and evidence is lacking. A fourth principle, in line with its educational purpose, is to provide a large number of tables and a set of concise recommendations that could be easily and rapidly consulted by physicians in their routine practice.TABLE 1: Classes of recommendationsTABLE 2: Levels of EvidenceThe European members of the Task Force in charge of the 2013 guidelines on hypertension have been appointed by the ESH and ESC, based on their recognized expertise and absence of major conflicts of interest [their declaration of interest forms can be found on the ESC website (www.escardio.org/guidelines) and ESH website (www.eshonline.org)]. Each member was assigned a specific writing task, which was reviewed by three co-ordinators and then by two chairmen, one appointed by ESH and another by ESC. The text was finalized over approximately 18 months, during which the Task Force members met collectively several times and corresponded intensively with one another between meetings. Before publication, the document was also assessed twice by 42 European reviewers, half selected by ESH and half by ESC. It can thus be confidently stated that the recommendations issued by the 2013 ESH/ESC guidelines on hypertension largely reflect the state of the art on hypertension, as viewed by scientists and physicians in Europe. Expenses for meetings and the remaining work have been shared by ESH and ESC. 1.2 New aspects Because of new evidence on several diagnostic and therapeutic aspects of hypertension, the present guidelines differ in many respects from the previous ones [2]. Some of the most important differences are listed below: Epidemiological data on hypertension and control in Europe. of the value of home blood pressure and of its role for diagnosis and management of hypertension, to ambulatory blood pressure of the of white-coat hypertension and masked on of cardiovascular risk asymptomatic organ damage and clinical for total risk of the of asymptomatic blood and of the risk of and target in Hypertension in of antihypertensive and no drug treatment of high normal for and target systolic blood pressure in both and risk approach to for New therapeutic for target on therapeutic strategies in special recommendations on treatment of hypertension in the treatment of to resistant hypertension and new treatment Increased to New approaches to chronic management of hypertensive Relationship of blood pressure to cardiovascular and renal damage The between and and renal been in a large number of observational studies The in in the 2003 and 2007 ESH/ESC guidelines can be as Office an with the of several heart failure and peripheral artery disease as as of renal disease This is at and in The with from high to of for and for to be a of than after the of years and in elderly individuals pressure between and been to have a role This is also by the high risk by patients with an elevated and a normal or systolic hypertension A with is also by out-of-office as by and The between and and is by the of other risk Metabolic risk factors are more common when is high than when it is Definition and classification of hypertension The between and and renal the between and hypertension when based on This is more because, in the and have a practice, are both to the diagnostic approach and to the The classification is from the 2003 and 2007 ESH/ESC guidelines Hypertension is as based on the evidence from that in patients with are and The classification is in and elderly different based on are in and for data from trials are not on classification in and according to their and can be found in the on the evaluation and treatment of high in and and classification of blood pressure Prevalence of hypertension data are available on the of hypertension and the of in different European the of hypertension to be of the with a with also to be differences in the across with no changes in the to the of results and the of a of hypertension been is a good hypertension is by the most important of this A between of hypertension and for stroke been The and of stroke in have been by of European a in to European which a in from stroke Hypertension and total cardiovascular risk a hypertension guidelines on as the or the need the the ESC, ESH and European Society recommendations on of heart disease in clinical and that of be to of total (or This approach is now and been the 2003 and 2007 ESH/ESC guidelines for the management of arterial hypertension [1,2]. The is based on the that a of the hypertensive an of with the risk when and other risk factors to a total risk that is than the of its in high-risk antihypertensive treatment strategies and of of drug and as as other be different from to be in is evidence in high-risk control is more and more the combination of antihypertensive drugs with other as The therapeutic approach total risk in to in to of the management of Assessment of total cardiovascular risk of total risk is in of as with of cardiovascular disease or with elevated risk of the total risk is high or for a large number of patients with hypertension not to of the and the of at high or high risk the of to total risk, as to be to the therapeutic approach have been for total risk and limitations have been reviewed The been based on large European The the risk of from disease over years based on total and The of the for which been done for European the two of are one for high-risk and one for The of as Heart is to also for the of on total The and their can in risk assessment and management but must be in the of the knowledge and experience, with to the that total risk is associated with clinical when with other strategies not been be than in the subjects and with the risk associated with is in subjects than in individuals and from with elevated an not the diagnostic for with and with a history of the of years in and years in total risk is as the risk of from Because of its on in total risk can be in the of high with risk this to a high-risk years treatment be by of risk or by heart and A is available in the European on in Clinical which is when been to of asymptomatic in several in the which the risk that by the of risk A is to for asymptomatic where evidence for the risk of clinical is more than a guidelines for the management of hypertension and 2003 Society of Hypertension Guidelines and the 2003 and 2007 ESH/ESC have risk in different based on risk asymptomatic and of or chronic kidney disease as also done by the ESC guidelines The classification in high and high risk is in the guidelines and to the risk of as by the ESC guidelines The factors on which the is based are in Table 1: of total risk in of high and high risk according to and and of asymptomatic stage or with a high normal but a out-of-office have a risk in the hypertension with a high but normal out-of-office is no or have risk than hypertension for the than for of total risk in Limitations available for risk assessment have limitations that must be The of in of risk is on the damage is based on available limitations also be that the of total risk is to the of to that to grade in to the of risk is by or to a which treatment is It be in that to high total risk is as as the of a value to this and no at is a of on total risk It is that adults are to high-risk when have more than one major risk and a in many elderly a high total risk level being at risk to their The consequences are that most are in is and is to subjects at high risk the in the absence of their to an risk to a high and risk in with of their Summary of recommendations on total cardiovascular risk assessment cardiovascular risk The evaluation of a with hypertension (i) the diagnosis of hypertension, (ii) of secondary hypertension, and (iii) risk, and clinical This for measurement, medical history history, physical laboratory investigations and diagnostic Some of the investigations are in in specific Bood pressure measurement Office or clinic blood pressure can no be a in not or are be according to and their be in a laboratory of at the is and and be to the the of a and between which been to an risk the with the be A is by one a between with measurement, it could be to elderly patients and in other conditions in which be or it is that be 1 and 3 after of the as a reduction in of or in of 3 of been to a for and of in the with the in an isolated providing information be as a to and to by or be associated with measurement of heart heart or in several hypertension for are in Table Office blood pressure Out-of-office blood pressure The major of out-of-office is that it a large number of from the medical which a more assessment of than Out-of-office is assessed by or by A principles and for the two of in to recommendations for measurement The be to the with and in of appropriate medical of the results that the of out-of-office is good for and but for the and for more and and provide different information on the and risk and the two thus be regarded as rather than or The between with and is to Office is than ambulatory and home and the as for the of hypertension for home and ambulatory according to the ESH on are in Table have been and according to and be properly and at 6 The can be on of hypertension by and out-of-office blood pressure blood pressure aspects A number of aspects have been by the ESH on Blood is with the a on the for a period, that it information on during daily and at during the of of the the between the and from measurement by the not be than the of a the be and The is to in normal but to from exercise at the of to and and the with the at heart The is to provide information in a on and that in to the times of drug and and from clinical practice, are at during the and between be the of It be that be at the during the and The are to a and a of can be of during and be or the be The of and the of have been to are is not and be It is that not be when the is and blood pressure to the and are the most in clinical and can be from the on the of the times of and to is to in which the and differ from to It for been that from to and from to 6 with the and but other have been as from to and from 1 to 6 the of different measurement during the and the and to for it is that be for the between or to the of the to avoid of The the between and during the as the of a normal in a it is that the of a of of be as an to subjects as more have been absence of for and women been in a number of but other of an to exercise have also been the of at exercise is to arterial stiffness and and is in women than in and in than in individuals not have that an of during exercise the of hypertension in of at exercise to future hypertension is not of a number of as of of and is no on the of exercise with as after for and other as in as in hypertensive patients the results on the of exercise are not which be to the that the two of in during It is that the is a reduction of during with changes in and or not the arterial is an of at on subjects and in hypertensive patients with of an a the of normal hypertension can be an for of its with masked hypertension the other when hypertension is associated with dysfunction and of the of exercise be a during exercise a as in individuals in patients with disease or with heart failure in a exercise systolic the results the clinical of during exercise for diagnostic and in patients with exercise is as a exercise and data and an A number of stress have been to stress and a of or laboratory stress in not reflect stress and are not have and between to the are results on the of the to with future hypertension are not the is A that to stress an on future risk of elevated hypertension, ventricular atherosclerosis and clinical The results that during stress are not Central blood pressure The measurement of in hypertensive patients interest of both its value for and the of antihypertensive with The arterial pressure is a of the pressure by ventricular and a It be at the in the it the on kidney and large The of can be the as the between the and systolic as a of the for heart to the of and pressure the arterial systolic and be different from the years several and have been to systolic or pressure from pressure have been reviewed in an document studies in the that and by of and in patients with A in several the value of was or not in most studies the guidelines, previous ones the measurement of and is of great interest for in and more is their routine clinical The be in the in some of individuals at the level be to high of the pressure is normal Medical history The medical history the of the diagnosis of arterial hypertension, and and and antihypertensive be to indications of secondary of Women be Hypertension an risk of renal and heart when are a history of be in to assessment of risk, as clinical or a history of heart or heart disease, with an on stroke and transient ischaemic attack A history of the and of kidney and evidence for be A history of hypertension is an important of to hypertension and and on and medical history are in Table and medical Physical examination Physical examination to or the diagnosis of hypertension, for secondary of hypertension and risk be as in and be to the diagnosis of at one to be at both and differences between the two in in investigations of patients of the heart and renal renal on the of the and be with the and and heart be the is at heart an risk of heart the of on physical examination are in Table Physical examination for secondary hypertension, organ damage and Summary of recommendations on blood pressure history, and physical examination pressure history, and physical on Blood pressure history, and physical Laboratory investigations Laboratory investigations are at providing evidence for the of risk for secondary hypertension and for the absence or of from the most to the more on laboratory investigations are in Table Laboratory Genetics A history is a in hypertensive patients with the to between and in the of studies and been for ambulatory forms of hypertension have been as syndrome and where a the of hypertension and the treatment hypertension is a with a studies and their to a total of which are associated with systolic to risk for Searching for asymptomatic organ damage to the of asymptomatic as an stage in the of disease, and as a of risk, of organ be by appropriate It be that a large of evidence is now available on the role of asymptomatic in the risk of individuals with and high The that of of and can of is a in favour of assessment of in daily clinical more data from studies in different be It is also that the risk as the number of Heart A be part of the routine assessment of hypertensive in is by the the or been found in observational studies and clinical trials to be an of the is at in patients over years of can also be to of ventricular or which more risk and is when and ischaemic are Atrial fibrillation is a and common of in hypertensive patients of fibrillation the of by appropriate therapy not from is more than in and is to and renal risk It therefore in a more of risk and in therapy evaluation of the in hypertensive patients of and and While ventricular for or the or of is according to the Society of the between and risk is of for women and for are for of of for in which to the of or been can be in and patients in to to and avoid of It been that the is to by to the and that different for and women be by could in subjects and in ones with with and with normal an of but is the of risk Hypertension is associated with of and as dysfunction is associated with and can of heart when is normal failure with The can and heart failure and but is not to the hypertensive clinical and to recommendations it therefore be with of the of the is of hypertensive heart disease the is reduced more than the and of dysfunction is based on of and and the between and and This is an important of in a large The of and of are on and on The is to an of The value of is recognized in the hypertensive and is associated with risk, of and in hypertensive patients of can provide information and is a for the diagnosis of Left is assessed by its or been to be an of heart fibrillation and ischaemic stroke and for hypertensive heart disease for are in Table The most for in hypertension is to by that the on of and are largely largely from control with the for by the Society of and the European of are in the of for from large in different be available for in the assessment of and in patients with on and systolic can and to systolic dysfunction of hypertensive patients assessment of systolic in hypertensive heart disease not information to at in the of a normal clinical practice, be in hypertensive patients in different clinical and with different in hypertensive patients at total risk, it the risk evaluation by by in hypertensive patients with evidence of it more the hypertrophy and its and in hypertensive patients with it to It is that assessment of and be of diagnostic value in most patients with hypertension and be in hypertensive patients at the a or more on and be for assessment of and when is not and when of have therapeutic consequences are for diagnosis of in hypertensive patients with This is hypertension the of exercise and exercise a normal and an value in patients of When the exercise is or an of as stress or stress is for a of are specific for assessed artery are found with normal associated with disease The of of and on the artery been to from isolated damage A been to have an value in hypertension Blood vessels Carotid examination of the with measurement of the of been to the of both stroke and of risk factors This both for the value at the and for the value at the level of the common artery The between and is a one and a for high risk is rather a been as a of in the 2007 Guidelines the value for high risk was in the elderly patients of the and in the patients of the European on and of a can be identified by an or by a in of or of the value a value for of a and to other for and patients another risk in the A review that the value of be found in asymptomatic individuals at

Worldwide commercial interest in carbon nanotubes (CNTs) is reflected in a production capacity that presently exceeds several thousand tons per year. Currently, bulk CNT powders are incorporated in diverse commercial products ranging from rechargeable batteries, automotive parts, and sporting goods to boat hulls and water filters. Advances in CNT synthesis, purification, and chemical modification are enabling integration of CNTs in thin-film electronics and large-area coatings. Although not yet providing compelling mechanical strength or electrical or thermal conductivities for many applications, CNT yarns and sheets already have promising performance for applications including supercapacitors, actuators, and lightweight electromagnetic shields.

With the continued interest in the role of the gut microbiota in health, attention has now turned to how to harness the microbiota for the benefit of the host. This Consensus Statement outlines the definition and scope of the term 'prebiotic' as determined by an expert panel convened by the International Scientific Association for Probiotics and Prebiotics in December 2016. In December 2016, a panel of experts in microbiology, nutrition and clinical research was convened by the International Scientific Association for Probiotics and Prebiotics to review the definition and scope of prebiotics. Consistent with the original embodiment of prebiotics, but aware of the latest scientific and clinical developments, the panel updated the definition of a prebiotic: a substrate that is selectively utilized by host microorganisms conferring a health benefit. This definition expands the concept of prebiotics to possibly include non-carbohydrate substances, applications to body sites other than the gastrointestinal tract, and diverse categories other than food. The requirement for selective microbiota-mediated mechanisms was retained. Beneficial health effects must be documented for a substance to be considered a prebiotic. The consensus definition applies also to prebiotics for use by animals, in which microbiota-focused strategies to maintain health and prevent disease is as relevant as for humans. Ultimately, the goal of this Consensus Statement is to engender appropriate use of the term 'prebiotic' by relevant stakeholders so that consistency and clarity can be achieved in research reports, product marketing and regulatory oversight of the category. To this end, we have reviewed several aspects of prebiotic science including its development, health benefits and legislation.

BACKGROUND: Osimertinib is an oral, third-generation, irreversible epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) that selectively inhibits both EGFR-TKI-sensitizing and EGFR T790M resistance mutations. We compared osimertinib with standard EGFR-TKIs in patients with previously untreated, EGFR mutation-positive advanced non-small-cell lung cancer (NSCLC). METHODS: In this double-blind, phase 3 trial, we randomly assigned 556 patients with previously untreated, EGFR mutation-positive (exon 19 deletion or L858R) advanced NSCLC in a 1:1 ratio to receive either osimertinib (at a dose of 80 mg once daily) or a standard EGFR-TKI (gefitinib at a dose of 250 mg once daily or erlotinib at a dose of 150 mg once daily). The primary end point was investigator-assessed progression-free survival. RESULTS: The median progression-free survival was significantly longer with osimertinib than with standard EGFR-TKIs (18.9 months vs. 10.2 months; hazard ratio for disease progression or death, 0.46; 95% confidence interval [CI], 0.37 to 0.57; P<0.001). The objective response rate was similar in the two groups: 80% with osimertinib and 76% with standard EGFR-TKIs (odds ratio, 1.27; 95% CI, 0.85 to 1.90; P=0.24). The median duration of response was 17.2 months (95% CI, 13.8 to 22.0) with osimertinib versus 8.5 months (95% CI, 7.3 to 9.8) with standard EGFR-TKIs. Data on overall survival were immature at the interim analysis (25% maturity). The survival rate at 18 months was 83% (95% CI, 78 to 87) with osimertinib and 71% (95% CI, 65 to 76) with standard EGFR-TKIs (hazard ratio for death, 0.63; 95% CI, 0.45 to 0.88; P=0.007 [nonsignificant in the interim analysis]). Adverse events of grade 3 or higher were less frequent with osimertinib than with standard EGFR-TKIs (34% vs. 45%). CONCLUSIONS: Osimertinib showed efficacy superior to that of standard EGFR-TKIs in the first-line treatment of EGFR mutation-positive advanced NSCLC, with a similar safety profile and lower rates of serious adverse events. (Funded by AstraZeneca; FLAURA ClinicalTrials.gov number, NCT02296125 .).

BACKGROUND: Nivolumab combined with ipilimumab resulted in longer progression-free survival and a higher objective response rate than ipilimumab alone in a phase 3 trial involving patients with advanced melanoma. We now report 3-year overall survival outcomes in this trial. METHODS: We randomly assigned, in a 1:1:1 ratio, patients with previously untreated advanced melanoma to receive nivolumab at a dose of 1 mg per kilogram of body weight plus ipilimumab at a dose of 3 mg per kilogram every 3 weeks for four doses, followed by nivolumab at a dose of 3 mg per kilogram every 2 weeks; nivolumab at a dose of 3 mg per kilogram every 2 weeks plus placebo; or ipilimumab at a dose of 3 mg per kilogram every 3 weeks for four doses plus placebo, until progression, the occurrence of unacceptable toxic effects, or withdrawal of consent. Randomization was stratified according to programmed death ligand 1 (PD-L1) status, BRAF mutation status, and metastasis stage. The two primary end points were progression-free survival and overall survival in the nivolumab-plus-ipilimumab group and in the nivolumab group versus the ipilimumab group. RESULTS: At a minimum follow-up of 36 months, the median overall survival had not been reached in the nivolumab-plus-ipilimumab group and was 37.6 months in the nivolumab group, as compared with 19.9 months in the ipilimumab group (hazard ratio for death with nivolumab plus ipilimumab vs. ipilimumab, 0.55 [P<0.001]; hazard ratio for death with nivolumab vs. ipilimumab, 0.65 [P<0.001]). The overall survival rate at 3 years was 58% in the nivolumab-plus-ipilimumab group and 52% in the nivolumab group, as compared with 34% in the ipilimumab group. The safety profile was unchanged from the initial report. Treatment-related adverse events of grade 3 or 4 occurred in 59% of the patients in the nivolumab-plus-ipilimumab group, in 21% of those in the nivolumab group, and in 28% of those in the ipilimumab group. CONCLUSIONS: Among patients with advanced melanoma, significantly longer overall survival occurred with combination therapy with nivolumab plus ipilimumab or with nivolumab alone than with ipilimumab alone. (Funded by Bristol-Myers Squibb and others; CheckMate 067 ClinicalTrials.gov number, NCT01844505 .).

This article provides a classification of primary progressive aphasia (PPA) and its 3 main variants to improve the uniformity of case reporting and the reliability of research results. Criteria for the 3 variants of PPA--nonfluent/agrammatic, semantic, and logopenic--were developed by an international group of PPA investigators who convened on 3 occasions to operationalize earlier published clinical descriptions for PPA subtypes. Patients are first diagnosed with PPA and are then divided into clinical variants based on specific speech and language features characteristic of each subtype. Classification can then be further specified as "imaging-supported" if the expected pattern of atrophy is found and "with definite pathology" if pathologic or genetic data are available. The working recommendations are presented in lists of features, and suggested assessment tasks are also provided. These recommendations have been widely agreed upon by a large group of experts and should be used to ensure consistency of PPA classification in future studies. Future collaborations will collect prospective data to identify relationships between each of these syndromes and specific biomarkers for a more detailed understanding of clinicopathologic correlations.

Photodynamic therapy (PDT) is a clinically approved, minimally invasive therapeutic procedure that can exert a selective cytotoxic activity toward malignant cells. The procedure involves administration of a photosensitizing agent followed by irradiation at a wavelength corresponding to an absorbance band of the sensitizer. In the presence of oxygen, a series of events lead to direct tumor cell death, damage to the microvasculature, and induction of a local inflammatory reaction. Clinical studies revealed that PDT can be curative, particularly in early stage tumors. It can prolong survival in patients with inoperable cancers and significantly improve quality of life. Minimal normal tissue toxicity, negligible systemic effects, greatly reduced long-term morbidity, lack of intrinsic or acquired resistance mechanisms, and excellent cosmetic as well as organ function-sparing effects of this treatment make it a valuable therapeutic option for combination treatments. With a number of recent technological improvements, PDT has the potential to become integrated into the mainstream of cancer treatment.

The synergistic action of cytosolic Ca2+ and inositol 1,4,5-trisphosphate (InsP3) in releasing intracellular Ca2+ stores has been suggested to be responsible for the complex intracellular Ca2 signals observed during hormonal stimulation of many cell types. However, the ability of cytosolic Ca2+ to potentiate Ca2+ release has recently been questioned because of the observed inhibitory effects of Ca2+ chelators used in previous studies. In the present study, EGTA and BAPTA [1,2-bis-(2-amino-phenoxy)ethane- NNN'N'-tetra-acetic acid] poorly inhibited InsP3-induced Ca2+ release from permeabilized A7r5 smooth-muscle cells. Additionally, stimulatory effects of cytosolic and luminal Ca2+ were observed either in the complete absence of Ca2+ chelator or at constant Ca(2+)-free chelator concentration. These data suggest that potentiation of InsP3-induced Ca2+ release by Ca2+ in A7r5 cells reflects an interaction between Ca2+ and InsP3 receptors, rather than a decrease in chelator-dependent inhibition. The EC50 for activation of InsP3-induced Ca2+ release by cytosolic Ca2+ was unaffected by ATP, or by changing InsP3 concentration, although InsP3-induced Ca2+ release became less sensitive to the inhibitory effects of cytosolic Ca2+ as the InsP3 concentration was elevated. Increasing H+ or Mg2+ concentration shifted the Ca(2+)-activation curve towards higher Ca2+ concentrations. These data suggest that, in addition to the InsP3-binding site, the affinity of the Ca(2+)-binding site(s) on InsP3 receptors can be modulated by intracellular cations.

Assessing the applicability of frameworks developed in one country to other countries is an important step in establishing the generalizability of consumer behavior theories. In order for such comparisons to be meaningful, however, the instruments used to measure the theoretical constructs of interest have to exhibit adequate cross-national equivalence. We review the various forms of measurement invariance that have been proposed in the literature, organize them into a coherent conceptual framework that ties different requirements of measure equivalence to the goals of the research, and propose a practical, sequential testing procedure for assessing measurement invariance in cross-national consumer research. The approach is based on multisample confirmatory factor analysis and clarifies under what conditions meaningful comparisons of construct conceptualizations, construct means, and relationships between constructs are possible. An empirical application dealing with the single-factor construct of consumer ethnocentrism in Belgium, Great Britain, and Greece is provided to illustrate the procedure.