Cambridge University Hospitals NHS Foundation Trust

In this paper we report the set-up and results of the Multimodal Brain Tumor Image Segmentation Benchmark (BRATS) organized in conjunction with the MICCAI 2012 and 2013 conferences. Twenty state-of-the-art tumor segmentation algorithms were applied to a set of 65 multi-contrast MR scans of low- and high-grade glioma patients-manually annotated by up to four raters-and to 65 comparable scans generated using tumor image simulation software. Quantitative evaluations revealed considerable disagreement between the human raters in segmenting various tumor sub-regions (Dice scores in the range 74%-85%), illustrating the difficulty of this task. We found that different algorithms worked best for different sub-regions (reaching performance comparable to human inter-rater variability), but that no single algorithm ranked in the top for all sub-regions simultaneously. Fusing several good algorithms using a hierarchical majority vote yielded segmentations that consistently ranked above all individual algorithms, indicating remaining opportunities for further methodological improvements. The BRATS image data and manual annotations continue to be publicly available through an online evaluation system as an ongoing benchmarking resource.

Background A safe and efficacious vaccine against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), if deployed with high coverage, could contribute to the control of the COVID-19 pandemic. We evaluated the safety and efficacy of the ChAdOx1 nCoV-19 vaccine in a pooled interim analysis of four trials. Methods This analysis includes data from four ongoing blinded, randomised, controlled trials done across the UK, Brazil, and South Africa. Participants aged 18 years and older were randomly assigned (1:1) to ChAdOx1 nCoV-19 vaccine or control (meningococcal group A, C, W, and Y conjugate vaccine or saline). Participants in the ChAdOx1 nCoV-19 group received two doses containing 5 × 10 10 viral particles (standard dose; SD/SD cohort); a subset in the UK trial received a half dose as their first dose (low dose) and a standard dose as their second dose (LD/SD cohort). The primary efficacy analysis included symptomatic COVID-19 in seronegative participants with a nucleic acid amplification test-positive swab more than 14 days after a second dose of vaccine. Participants were analysed according to treatment received, with data cutoff on Nov 4, 2020. Vaccine efficacy was calculated as 1 - relative risk derived from a robust Poisson regression model adjusted for age. Studies are registered at ISRCTN89951424 and ClinicalTrials.gov, NCT04324606, NCT04400838, and NCT04444674. Findings Between April 23 and Nov 4, 2020, 23 848 participants were enrolled and 11 636 participants (7548 in the UK, 4088 in Brazil) were included in the interim primary efficacy analysis. In participants who received two standard doses, vaccine efficacy was 62·1% (95% CI 41·0–75·7; 27 [0·6%] of 4440 in the ChAdOx1 nCoV-19 group vs 71 [1·6%] of 4455 in the control group) and in participants who received a low dose followed by a standard dose, efficacy was 90·0% (67·4–97·0; three [0·2%] of 1367 vs 30 [2·2%] of 1374; p interaction =0·010). Overall vaccine efficacy across both groups was 70·4% (95·8% CI 54·8–80·6; 30 [0·5%] of 5807 vs 101 [1·7%] of 5829). From 21 days after the first dose, there were ten cases hospitalised for COVID-19, all in the control arm; two were classified as severe COVID-19, including one death. There were 74 341 person-months of safety follow-up (median 3·4 months, IQR 1·3–4·8): 175 severe adverse events occurred in 168 participants, 84 events in the ChAdOx1 nCoV-19 group and 91 in the control group. Three events were classified as possibly related to a vaccine: one in the ChAdOx1 nCoV-19 group, one in the control group, and one in a participant who remains masked to group allocation. Interpretation ChAdOx1 nCoV-19 has an acceptable safety profile and has been found to be efficacious against symptomatic COVID-19 in this interim analysis of ongoing clinical trials. Funding UK Research and Innovation, National Institutes for Health Research (NIHR), Coalition for Epidemic Preparedness Innovations, Bill & Melinda Gates Foundation, Lemann Foundation, Rede D'Or, Brava and Telles Foundation, NIHR Oxford Biomedical Research Centre, Thames Valley and South Midland's NIHR Clinical Research Network, and AstraZeneca.

Abstract Somatic mutations in cancer genomes are caused by multiple mutational processes, each of which generates a characteristic mutational signature 1 . Here, as part of the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium 2 of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA), we characterized mutational signatures using 84,729,690 somatic mutations from 4,645 whole-genome and 19,184 exome sequences that encompass most types of cancer. We identified 49 single-base-substitution, 11 doublet-base-substitution, 4 clustered-base-substitution and 17 small insertion-and-deletion signatures. The substantial size of our dataset, compared with previous analyses 3–15 , enabled the discovery of new signatures, the separation of overlapping signatures and the decomposition of signatures into components that may represent associated—but distinct—DNA damage, repair and/or replication mechanisms. By estimating the contribution of each signature to the mutational catalogues of individual cancer genomes, we revealed associations of signatures to exogenous or endogenous exposures, as well as to defective DNA-maintenance processes. However, many signatures are of unknown cause. This analysis provides a systematic perspective on the repertoire of mutational processes that contribute to the development of human cancer.

Abstract Cancer is driven by genetic change, and the advent of massively parallel sequencing has enabled systematic documentation of this variation at the whole-genome scale 1–3 . Here we report the integrative analysis of 2,658 whole-cancer genomes and their matching normal tissues across 38 tumour types from the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA). We describe the generation of the PCAWG resource, facilitated by international data sharing using compute clouds. On average, cancer genomes contained 4–5 driver mutations when combining coding and non-coding genomic elements; however, in around 5% of cases no drivers were identified, suggesting that cancer driver discovery is not yet complete. Chromothripsis, in which many clustered structural variants arise in a single catastrophic event, is frequently an early event in tumour evolution; in acral melanoma, for example, these events precede most somatic point mutations and affect several cancer-associated genes simultaneously. Cancers with abnormal telomere maintenance often originate from tissues with low replicative activity and show several mechanisms of preventing telomere attrition to critical levels. Common and rare germline variants affect patterns of somatic mutation, including point mutations, structural variants and somatic retrotransposition. A collection of papers from the PCAWG Consortium describes non-coding mutations that drive cancer beyond those in the TERT promoter 4 ; identifies new signatures of mutational processes that cause base substitutions, small insertions and deletions and structural variation 5,6 ; analyses timings and patterns of tumour evolution 7 ; describes the diverse transcriptional consequences of somatic mutation on splicing, expression levels, fusion genes and promoter activity 8,9 ; and evaluates a range of more-specialized features of cancer genomes 8,10–18 .

Pancreatic ductal adenocarcinoma (PDA) is among the most lethal human cancers in part because it is insensitive to many chemotherapeutic drugs. Studying a mouse model of PDA that is refractory to the clinically used drug gemcitabine, we found that the tumors in this model were poorly perfused and poorly vascularized, properties that are shared with human PDA. We tested whether the delivery and efficacy of gemcitabine in the mice could be improved by coadministration of IPI-926, a drug that depletes tumor-associated stromal tissue by inhibition of the Hedgehog cellular signaling pathway. The combination therapy produced a transient increase in intratumoral vascular density and intratumoral concentration of gemcitabine, leading to transient stabilization of disease. Thus, inefficient drug delivery may be an important contributor to chemoresistance in pancreatic cancer.

We investigated SARS-CoV-2 potential tropism by surveying expression of viral entry-associated genes in single-cell RNA-sequencing data from multiple tissues from healthy human donors. We co-detected these transcripts in specific respiratory, corneal and intestinal epithelial cells, potentially explaining the high efficiency of SARS-CoV-2 transmission. These genes are co-expressed in nasal epithelial cells with genes involved in innate immunity, highlighting the cells’ potential role in initial viral infection, spread and clearance. The study offers a useful resource for further lines of inquiry with valuable clinical samples from COVID-19 patients and we provide our data in a comprehensive, open and user-friendly fashion at www.covid19cellatlas.org . An analysis of single-cell transcriptomics datasets from different tissues shows that ACE2 and TMPRSS2 are co-expressed in respiratory, corneal and intestinal epithelial cell populations, and that respiratory expression of ACE2 is associated with genes involved in innate immunity.

Before publication of the original version of this report in 1987, practitioners of bone histomorphometry communicated with each other in a variety of arcane languages, which in general were unintelligible to those outside the field. The need for standardization of nomenclature had been recognized for many years,1 during which there had been much talk but no action. To satisfy this need, B Lawrence Riggs (ASBMR President, 1985 to 1986) asked A Michael Parfitt to convene an ASBMR committee to develop a new and unified system of terminology, suitable for adoption by the Journal of Bone and Mineral Research (JBMR) as part of its Instructions to Authors. The resulting recommendations were published in 19872 and were quickly adopted not only by JBMR but also by all respected journals in the bone field. The recommendations improved markedly the ability of histomorphometrists to communicate with each other and with nonhistomorphometrists, leading to a broader understanding and appreciation of histomorphometric data. In 2012, 25 years after the development of the standardized nomenclature system, Thomas L Clemens (Editor in Chief of JBMR) felt that it was time to revise and update the recommendations. The original committee was reconvened by David W Dempster, who appointed one new member, Juliet E Compston. The original document was circulated to the committee members and was extensively revised according to their current recommendations. The key revisions include omission of terminology used before 1987, recommendations regarding the parameters and technical information that should be included in all histomorphometry articles, recommendations on how to handle dynamic parameters of bone formation in settings of low bone turnover, and updating of references. It is generally agreed that a bone is an individual organ of the skeletal system, but the term "bone" has at least three meanings. The first is mineralized bone matrix excluding osteoid; this usage conforms rigorously to the definition of bone as a hard tissue. Osteoid is bone matrix that will be (but is not yet) mineralized, and is sometimes referred to as pre-bone. The second meaning of "bone," and the one we have adopted, is bone matrix, whether mineralized or not, ie, including both mineralized bone and osteoid. The third meaning of "bone" is a tissue including bone marrow and other soft tissue, as well as bone as just defined. We refer to the combination of bone and associated soft tissue or marrow as "bone tissue." "Tissue" is defined3 as "an aggregation of similarly specialized cells united in the performance of a particular function." In this sense, bone, bone marrow, and the contents of osteonal canals are certainly not the same tissue, but in a more general sense, most textbooks of histology recognize only four fundamental tissues—epithelium, nerve, muscle, and connective tissue4—of which the last-named includes bone and all its accompanying nonmineralized tissue. In current clinical and radiologic parlance, "trabecular" and "cortical" refer to contrasting structural types of bone. But "trabecular" does not appear in any standard textbook of anatomy or histology as a name for a type of bone; rather, "spongy" or "cancellous" is used. "Spongiosa" (primary or secondary) is best restricted to the stages of endochondral ossification; "cancellous" is most commonly used in textbooks4, 5 and is the term we have chosen. We retain the noun "trabecula" and its associated adjective "trabecular" to refer to an individual structural element of cancellous bone, in accordance with current practice in histology,4 pathology,6 and biomechanics.7 Etymologically, a trabecula is a beam or rod, and in young people plates rather than rods are the predominant structural elements, both in the spine8 and in the ilium,9 but no convenient alternative is available. The size, shape, and orientation of trabeculae (as just defined) vary considerably between different types of cancellous bone.9, 10 "Density" is a frequent source of confusion in discussions about bone. We propose that the term should be restricted as far as possible to its primary meaning in physics of mass per unit volume,11, 12 with a subsidiary meaning analogous to population density, which is applied mainly to cells. This precludes the use of "density" in its stereologic sense, as will be discussed later. Corresponding to the definitions given earlier, the volume to which mass is referred can be of mineralized bone, bone, bone tissue (cortical or cancellous), or a whole bone. Mineralized bone density is slightly less than true bone density, which excludes the volume of osteocyte lacunae and canaliculi.11 This volume is small and generally ignored; lacunar volume can be readily measured,13 but canalicular volume is inaccessible to light microscopy. Bone density reflects the volumetric proportion of osteoid; bone matrix volume, excluding lacunar and canalicular volume, has been referred to as absolute bone volume.14 Bone tissue density reflects the volumetric proportion of soft tissue, or porosity. Whole bone density, often referred to as apparent bone density, reflects the volumetric proportions of cortical bone tissue, cancellous bone tissue, and diaphyseal marrow within a bone, the organ volume of which is usually measured by Archimedes' principle.15 "Osteoblast" is defined differently in the clinical and experimental literature. In young, rapidly growing small animals, most bone surfaces are undergoing either resorption or formation and virtually all cells on the surface are either osteoclasts or osteoblasts,16 but in the adult human, most bone surfaces are quiescent with respect to bone remodeling. We refer to the flat cells that cover quiescent internal (nonperiosteal) bone surfaces as lining cells and restrict the term "osteoblast" to cells that are making bone matrix currently or with only temporary interruption, rather than including all surface cells that are not osteoclasts.16 Lining cells are of osteoblast lineage and are thought to have osteogenic potential.17 The term "osteoclast" is restricted to bone-resorbing cells containing lysosomes and tartrate-resistant acid phosphatase; they are usually multinucleated, although some osteoclast profiles may have only one or no nucleus. Criteria for identification of osteoblasts and osteoclasts, whether morphologic or histochemical,18, 19 should always be stated or referenced. A two-dimensional histological section displays profiles of three-dimensional structures. Four types of primary measurement can be made on these profiles—area, length (usually of a perimeter or boundary), distance between points or between lines, and number.20 Some histomorphometrists report all results only in these two-dimensional terms because the assumptions needed for extrapolation to three dimensions may be difficult to justify and because the diagnostic significance of the measurements or the statistical significance of an experimental result are not affected. For these limited objectives, this is a reasonable view, but bone cannot be fully understood unless conceived in three-dimensional terms. In every other branch of science that uses microscopy as an investigative tool, the ultimate goal is to understand three-dimensional reality by the application of stereology, which is the relevant mathematical discipline.20-22 We believe that this also should be the goal of bone histomorphometry. Accurate three-dimensional data are necessary for proper comparison between species, between bones, and between different types of bone, for input into finite element models of bone strength, for realistic estimation of radiation burdens, and for many aspects of bone physiology, such as the calculation of diffusion distances and the measurement of individual cell work. But as a practical matter, it is unrealistic to insist on universal adoption of a three-dimensional format. All stereologic theorems require that sampling be random and unbiased, a condition only rarely fulfilled in bone histomorphometry; the closest feasible approach is to rotate the cylindrical bone sample randomly around its longitudinal axis before embedding.20, 23 In the past, the use of a hemispherical grid20-22 in the ocular lens was a convenient way of ensuring randomness of test line orientation, but even this cannot compensate for sampling bias introduced at an earlier stage. With the exception of the conversion of area fractions to volume fractions, most stereologic theorems also require that the structure be isotropic, meaning that a perpendicular to any element of surface has an equal likelihood of pointing in any direction in space.20, 24 Although not true for all cancellous bone, in the ilium there is only moderate deviation from isotropy, and stereologic theorems may be used with acceptable error.24, 25 But it is more accurate to apply the theory of vertical sections; a cycloid test grid is required, which is incompatible with the use of a digitizer,23, 26 but there is no other way of obtaining truly unbiased estimates. Because Haversian canals generally do not deviate from the long axis by more than 10°, stereologic problems in diaphyseal cortical bone are minimal, but investigation of the correct stereologic approach to iliac cortical bone has not been done. Accordingly, we recommend that everyone reporting histomorphometric data should select one of two options: either present all results strictly and consistently in two dimensions, using the terms perimeter (for length), area, and width (for distance), or (as favored by the committee) present only the corresponding three-dimensional results using the terms surface, volume, and thickness; with the latter option, an explanation is needed for each type of measurement of exactly how it was derived from the primary two-dimensional measurement, as described later. A mixture of two- and three-dimensional terms should not be used in the same article. The only exception is number, the fourth type of primary measurement, for which there is no convenient way of extrapolating to three dimensions without making assumptions concerning the three-dimensional shape of the objects counted.21, 22 Direct enumeration of number in three dimensions is possible if the same object can be identified in serial sections of known thickness and separation,27 but this method has not yet been applied to bone. Topological properties such as connectivity also cannot be determined from two-dimensional sections.28 The original committee chose not to adopt the terminology of the International Society of Stereology, as was suggested at the First International Workshop on Bone Morphometry.29 Stereologists use the term "density" in a very general sense to identify any measurement referred to some defined containing volume,21, 22 so that fractional volume is "volume density" (Vv) and surface area per unit volume is "surface density" (Sv). Although the unification of scientific terminology is desirable in the long term, the practical disadvantage of using "density" in two different senses outweighs the theoretical advantage. Nevertheless, all investigators wishing to remain at the cutting edge of bone histomorphometry will need to be thoroughly familiar with the terminologic conventions of stereology because many important methodologic articles applicable to bone are published in the Journal of Microscopy, which is the official journal of the International Society of Stereology.26-28 Primary two-dimensional measurements of perimeter, area, and number are indices of the amount of tissue examined and can be compared between subjects only when related to a common referent, which will be some clearly defined area or perimeter within the section. Absolute perimeter length and absolute area in two dimensions have no corresponding absolute surface area and absolute volume in three dimensions, but it is convenient to refer to perimeters as surfaces and to areas as volumes if the appropriate referent is clear from the context. Primary two-dimensional measurements of width (and corresponding three-dimensional thicknesses) and mean profile areas of individual structures have meaning in isolation and are the only type that do not require a referent. Different referents serve different purposes and lead to different interpretations, so that use of multiple referents is unavoidable, and it is important to clearly distinguish between them.30 Commonly used referents include tissue volume (TV), bone volume (BV), bone surface (BS), and osteoid surface (OS) and their corresponding two-dimensional areas or perimeters. With explicit identification of the referent, the use of "relative" as a qualifying term becomes redundant. The volume of the cylindrical biopsy core is not commonly used as a referent at present but is needed for comparison with physical methods of measuring bone density,31 for comparing the absolute amounts of cortical and cancellous bone lost because of aging or disease,31 for determining the contributions of different types of bone and different surfaces to various histological indices, such as amount of osteoid and surface extent of osteoblasts,32 and for examining in detail the relationships between histological and biochemical indices of whole-body bone remodeling.32 Use of the core volume (CV) as a referent provides the closest approach possible from an iliac biopsy to the in vivo level of organization corresponding to bone as an organ. An intact, full-thickness transiliac biopsy can be regarded as representative of the entire bone18, 33 because the length of the cylindrical biopsy core perpendicular to the external surface depends mainly on the width of the iliac bone at the site of sampling. Cortical thickness can be measured with a vertical biopsy through the iliac crest,5 but the proportions of cortical and cancellous tissue in the bone cannot be measured. However, with either type of biopsy, the results can be weighted by the proportions of cortical and cancellous bone tissue in the entire skeleton.34 The same principle can be applied to rib biopsies and to long bone cross sections by using the whole area enclosed by the periosteum as the referent. The recommended individual terms are listed in Table 1 in alphabetical order of their abbreviations or symbols. Several general comments are in order. First, like a dictionary, the lexicon is intended to be consulted, rather than memorized. Second, the use of abbreviations is always discretionary, never compulsory. Although designed mainly to save time or space, there is a more subtle reason for abbreviations, as for other symbols. Words frequently carry unwanted implications from their use in other contexts, but confusion is less likely with symbols that can be approached with fewer preconceptions.1 Nevertheless, our purpose is not to encourage or discourage the use of abbreviations and symbols but to ensure that the same ones are used by everybody. To this end, we have made the lexicon comprehensive to anticipate future needs and forestall the introduction of new abbreviations with different meanings. We have included metals frequently identified in bone (with their usual elemental abbreviations) and terms commonly used in quantitative microscopy and stereology, as well as terms for all the major structural features of bone and of bones and for some important concepts of bone physiology. Terms with unfamiliar meanings are explained and defined in relation to their use. With one exception, the abbreviations and symbols in Table 1 consist of only two letters; "BMU" (basic multicellular unit) is retained because it is important and widely used and lacks a suitable alternative. The most commonly used descriptive terms are given a single capital letter. Other terms have an additional lowercase letter, chosen in many cases to emphasize the second or later syllable and usually avoiding the second letter of the word abbreviated by the single capital letter. Single lowercase letters are used for terms that are in some sense related to time, for the primary data of classical grid counting (hit and intersection), and for n in its usual statistical sense. When used in combination, double-letter abbreviations should be demarcated by a period; in the absence of periods, each letter is to be construed as an individual abbreviation. In this way, any combination of abbreviations can be unambiguously deciphered without having to determine which terms are included in the lexicon. Bone histomorphometry can be applied to many types of material, but the most common are sections of cylindrical biopsy samples of iliac bone obtained from human subjects and sections of long bones obtained from experimental animals. For orientation, we first present the terminology for describing these sections. "Core" (C) refers to the entire biopsy specimen (Fig. 1). For transiliac biopsies, the distance between external (Ex) and internal (In) periosteum is termed "width" (Wi) because it is related to the thickness of the iliac bone at the biopsy site; for vertical biopsies through the iliac crest, the term "length" (Le) is more appropriate. Core width is subdivided into cortical (Ct) widths and cancellous (Cn) width; for transiliac biopsies, measurements on the two cortices (including their width) are usually pooled, but it is possible to keep track of their identity and examine them separately. In this case, the two cortices are generally distinguished by their width (thick versus thin). Identification of the inner and outer cortex would require that one be marked in some way (eg, by ink or cotton thread) at the time of the biopsy, but this is seldom done. The outer cortex generally has more attached fibrous and muscle tissue than the inner cortex. The other dimension of the core is referred to as "diameter" (Dm), although only sections through the central axis of the cylinder have the same diameter as the trephine; the more accurate term "chord length" is too cumbersome. If the axis of the transiliac core is oblique to the plane of the ilium, its dimensions are apparently changed (Fig. It is convenient to core diameter as mean length" and of because true for cortical and cancellous width for are given by the relationships between length and area in the to of representative bone biopsies from different transiliac cortex on vertical on by transiliac biopsy from and with of sections through cylindrical biopsy core of of perpendicular on oblique on core width; core cortical width; cancellous to core area cortical area cancellous area the inner and outer periosteum do not from and their mean length is used for these relationships remain true for the oblique section because the areas enclosed by the and are the relationships can be used to and without measuring the of For long bone cross sections (Fig. bone diameter is similarly subdivided into two cortical widths and either cancellous diameter for cross or marrow diameter for diaphyseal cross sections. The relationships between these and bone area, cortical area, and cancellous or marrow area depends on the of the cross section. For such measurements may be needed at multiple in relation to the in vivo For both iliac and long bone it is necessary for purposes to recognize a between cortical and cancellous bone tissue and in and This is not in or because methods of its are not yet fully A has been used to this in quantitative This may be applicable to iliac bone biopsy but this has not yet been For all bones, all surfaces in with bone marrow are referred to as and are subdivided into cancellous bone surface and the latter is the inner of the cortex. between these is to unless made in accordance with some and will also on whether the is measured separately. surfaces not in with bone marrow are generally referred to as cortical with as the cortical surface can also be referred to as the Haversian or osteonal of cross sections through the of a long bone; is on the and diaphyseal is on the For the cancellous bone of the is not bone cortical width; cancellous marrow The standard and applicable method for reporting all data should be that the of to as well as to the and are used only as and are used only as described refers to the structure on which the measurement was whether this was a particular surface or a particular type of tissue. of the commonly used have been defined many are by using the lexicon 1). If measurements are restricted to some of a such as the outer of a or the central of cancellous the same can be but the appropriate should be made in the of For measurements made on the entire the source is identified as it will not be necessary to the source each time a particular is referred only one source is used in an it need only be If are their can be used as for of results in or and in most cases will need to be only if measurements from are discussed such that confusion between them is For some such as only one source is possible and its is redundant. The three and the two are the key needed to from one referent to is to in stereologic terminology, and and are to in stereologic are derived from the corresponding two-dimensional and either by which is correct for or by which has been determined for human iliac cancellous The with so that the always be stated and and to in stereologic terminology and are with the corresponding and For some a of the bone surface is needed as a referent surface and surface are often related to osteoid surface usually and it can be to osteoclasts to the mineralized surface as an alternative to the more usual referents bone surface and surface indices of bone formation can be related to the osteoblast surface or to the number of osteoblast profiles as well as to osteoid surface or bone it may be appropriate to use the between mineralized bone and or bone as a referent for the length of or of because the is these features are In many as when only one referent is used for each measurement, the referent need only be and not each time the measurement is If more than one referent is measurements with the same referent can be to are listed with abbreviations in both and in Table have been defined but some need additional is used for of mineralized bone volume and is given by volume osteoid Osteoid may need to be as or as the in the lexicon between which refers to a and which refers to a for all measurements are with the indices discussed is a general term applicable to all tissue that is not and includes marrow in cancellous bone and Haversian and canals in cortical bone. For both types of tissue, can with area measurements on individual such as cells or cortical The profiles can be as an of tissue, by use of the appropriate referent. For is the area of all cell profiles referred to the area of tissue and in terms. The profiles can also be as individual by absence of a is the mean area of individual If confusion is the term be as or mean areas in cannot be to mean volumes in unless the structures are in cylindrical mean area can be used to but it is to this as described later. Osteoid do not so that some width should be for measurement of osteoid surface We the terms formation surface and resorption surface because the implications of current may be and for the same reason we the surface is with or lacunar surface and the osteoclast surface and the surface individual can also be as osteoclast or osteoclast Some cells and methods are needed for and the cells on the surface or cells. surface is with or the term that will at some future The of connective tissue the flat lining cells on quiescent surfaces should not be referred to as It is possible that some surface by flat lining cells should be as quiescent surface rather than as In all distance measurements can be obtained in two by measurement at multiple or by calculation from measurements of area and The method is more and can a and a standard deviation as well as a mean but that measurement be randomly The method is less and less to sampling The method is usually used for distance between and cell and dimensions, and the method is usually used for thickness diameter and methods are widely used for osteoid thickness and cortical The method is for the from the relationships between individual measurement at particular and at particular during the The mean determined by either method in an individual be distinguished from the mean in a of Mineralized thickness is the distance from the line to the between bone and It is used in and in different types of osteoid and different stages of in the mean should be to the between thickness and osteoid thickness is measured on an individual it has been used in the for calculation of the of and in human subjects as an of in thickness is the mean distance between on of a usually as for the is an of bone from the cortical surface, but too is known of the internal of iliac cortical bone to

Ulcerative colitis and Crohn's disease are the principal forms of inflammatory bowel disease. Both represent chronic inflammation of the gastrointestinal tract, which displays heterogeneity in inflammatory and symptomatic burden between patients and within individuals over time. Optimal management relies on understanding and tailoring evidence-based interventions by clinicians in partnership with patients. This guideline for management of inflammatory bowel disease in adults over 16 years of age was developed by Stakeholders representing UK physicians (British Society of Gastroenterology), surgeons (Association of Coloproctology of Great Britain and Ireland), specialist nurses (Royal College of Nursing), paediatricians (British Society of Paediatric Gastroenterology, Hepatology and Nutrition), dietitians (British Dietetic Association), radiologists (British Society of Gastrointestinal and Abdominal Radiology), general practitioners (Primary Care Society for Gastroenterology) and patients (Crohn's and Colitis UK). A systematic review of 88 247 publications and a Delphi consensus process involving 81 multidisciplinary clinicians and patients was undertaken to develop 168 evidence- and expert opinion-based recommendations for pharmacological, non-pharmacological and surgical interventions, as well as optimal service delivery in the management of both ulcerative colitis and Crohn's disease. Comprehensive up-to-date guidance is provided regarding indications for, initiation and monitoring of immunosuppressive therapies, nutrition interventions, pre-, peri- and postoperative management, as well as structure and function of the multidisciplinary team and integration between primary and secondary care. Twenty research priorities to inform future clinical management are presented, alongside objective measurement of priority importance, determined by 2379 electronic survey responses from individuals living with ulcerative colitis and Crohn's disease, including patients, their families and friends.

BACKGROUND: The management of metastatic breast cancer requires monitoring of the tumor burden to determine the response to treatment, and improved biomarkers are needed. Biomarkers such as cancer antigen 15-3 (CA 15-3) and circulating tumor cells have been widely studied. However, circulating cell-free DNA carrying tumor-specific alterations (circulating tumor DNA) has not been extensively investigated or compared with other circulating biomarkers in breast cancer. METHODS: We compared the radiographic imaging of tumors with the assay of circulating tumor DNA, CA 15-3, and circulating tumor cells in 30 women with metastatic breast cancer who were receiving systemic therapy. We used targeted or whole-genome sequencing to identify somatic genomic alterations and designed personalized assays to quantify circulating tumor DNA in serially collected plasma specimens. CA 15-3 levels and numbers of circulating tumor cells were measured at identical time points. RESULTS: Circulating tumor DNA was successfully detected in 29 of the 30 women (97%) in whom somatic genomic alterations were identified; CA 15-3 and circulating tumor cells were detected in 21 of 27 women (78%) and 26 of 30 women (87%), respectively. Circulating tumor DNA levels showed a greater dynamic range, and greater correlation with changes in tumor burden, than did CA 15-3 or circulating tumor cells. Among the measures tested, circulating tumor DNA provided the earliest measure of treatment response in 10 of 19 women (53%). CONCLUSIONS: This proof-of-concept analysis showed that circulating tumor DNA is an informative, inherently specific, and highly sensitive biomarker of metastatic breast cancer. (Funded by Cancer Research UK and others.).

BACKGROUND: Angiogenesis plays a role in the biology of ovarian cancer. We examined the effect of bevacizumab, the vascular endothelial growth factor inhibitor, on survival in women with this disease. METHODS: We randomly assigned women with ovarian cancer to carboplatin (area under the curve, 5 or 6) and paclitaxel (175 mg per square meter of body-surface area), given every 3 weeks for 6 cycles, or to this regimen plus bevacizumab (7.5 mg per kilogram of body weight), given concurrently every 3 weeks for 5 or 6 cycles and continued for 12 additional cycles or until progression of disease. Outcome measures included progression-free survival, first analyzed per protocol and then updated, and interim overall survival. RESULTS: A total of 1528 women from 11 countries were randomly assigned to one of the two treatment regimens. Their median age was 57 years; 90% had epithelial ovarian cancer, 69% had a serous histologic type, 9% had high-risk early-stage disease, 30% were at high risk for progression, and 70% had stage IIIC or IV ovarian cancer. Progression-free survival (restricted mean) at 36 months was 20.3 months with standard therapy, as compared with 21.8 months with standard therapy plus bevacizumab (hazard ratio for progression or death with bevacizumab added, 0.81; 95% confidence interval, 0.70 to 0.94; P=0.004 by the log-rank test). Nonproportional hazards were detected (i.e., the treatment effect was not consistent over time on the hazard function scale) (P<0.001), with a maximum effect at 12 months, coinciding with the end of planned bevacizumab treatment and diminishing by 24 months. Bevacizumab was associated with more toxic effects (most often hypertension of grade 2 or higher) (18%, vs. 2% with chemotherapy alone). In the updated analyses, progression-free survival (restricted mean) at 42 months was 22.4 months without bevacizumab versus 24.1 months with bevacizumab (P=0.04 by log-rank test); in patients at high risk for progression, the benefit was greater with bevacizumab than without it, with progression-free survival (restricted mean) at 42 months of 14.5 months with standard therapy alone and 18.1 months with bevacizumab added, with respective median overall survival of 28.8 and 36.6 months. CONCLUSIONS: Bevacizumab improved progression-free survival in women with ovarian cancer. The benefits with respect to both progression-free and overall survival were greater among those at high risk for disease progression. (Funded by Roche and others; ICON7 Controlled-Trials.com number, ISRCTN91273375.).

The genomic landscape of breast cancer is complex, and inter- and intra-tumour heterogeneity are important challenges in treating the disease. In this study, we sequence 173 genes in 2,433 primary breast tumours that have copy number aberration (CNA), gene expression and long-term clinical follow-up data. We identify 40 mutation-driver (Mut-driver) genes, and determine associations between mutations, driver CNA profiles, clinical-pathological parameters and survival. We assess the clonal states of Mut-driver mutations, and estimate levels of intra-tumour heterogeneity using mutant-allele fractions. Associations between PIK3CA mutations and reduced survival are identified in three subgroups of ER-positive cancer (defined by amplification of 17q23, 11q13-14 or 8q24). High levels of intra-tumour heterogeneity are in general associated with a worse outcome, but highly aggressive tumours with 11q13-14 amplification have low levels of intra-tumour heterogeneity. These results emphasize the importance of genome-based stratification of breast cancer, and have important implications for designing therapeutic strategies.

BACKGROUND: Droplet-based single-cell RNA sequence analyses assume that all acquired RNAs are endogenous to cells. However, any cell-free RNAs contained within the input solution are also captured by these assays. This sequencing of cell-free RNA constitutes a background contamination that confounds the biological interpretation of single-cell transcriptomic data. RESULTS: We demonstrate that contamination from this "soup" of cell-free RNAs is ubiquitous, with experiment-specific variations in composition and magnitude. We present a method, SoupX, for quantifying the extent of the contamination and estimating "background-corrected" cell expression profiles that seamlessly integrate with existing downstream analysis tools. Applying this method to several datasets using multiple droplet sequencing technologies, we demonstrate that its application improves biological interpretation of otherwise misleading data, as well as improving quality control metrics. CONCLUSIONS: We present SoupX, a tool for removing ambient RNA contamination from droplet-based single-cell RNA sequencing experiments. This tool has broad applicability, and its application can improve the biological utility of existing and future datasets.

BACKGROUND: Xerostomia is the most common late side-effect of radiotherapy to the head and neck. Compared with conventional radiotherapy, intensity-modulated radiotherapy (IMRT) can reduce irradiation of the parotid glands. We assessed the hypothesis that parotid-sparing IMRT reduces the incidence of severe xerostomia. METHODS: We undertook a randomised controlled trial between Jan 21, 2003, and Dec 7, 2007, that compared conventional radiotherapy (control) with parotid-sparing IMRT. We randomly assigned patients with histologically confirmed pharyngeal squamous-cell carcinoma (T1-4, N0-3, M0) at six UK radiotherapy centres between the two radiotherapy techniques (1:1 ratio). A dose of 60 or 65 Gy was prescribed in 30 daily fractions given Monday to Friday. Treatment was not masked. Randomisation was by computer-generated permuted blocks and was stratified by centre and tumour site. Our primary endpoint was the proportion of patients with grade 2 or worse xerostomia at 12 months, as assessed by the Late Effects of Normal Tissue (LENT SOMA) scale. Analyses were done on an intention-to-treat basis, with all patients who had assessments included. Long-term follow-up of patients is ongoing. This study is registered with the International Standard Randomised Controlled Trial register, number ISRCTN48243537. FINDINGS: 47 patients were assigned to each treatment arm. Median follow-up was 44·0 months (IQR 30·0-59·7). Six patients from each group died before 12 months and seven patients from the conventional radiotherapy and two from the IMRT group were not assessed at 12 months. At 12 months xerostomia side-effects were reported in 73 of 82 alive patients; grade 2 or worse xerostomia at 12 months was significantly lower in the IMRT group than in the conventional radiotherapy group (25 [74%; 95% CI 56-87] of 34 patients given conventional radiotherapy vs 15 [38%; 23-55] of 39 given IMRT, p=0·0027). The only recorded acute adverse event of grade 2 or worse that differed significantly between the treatment groups was fatigue, which was more prevalent in the IMRT group (18 [41%; 99% CI 23-61] of 44 patients given conventional radiotherapy vs 35 [74%; 55-89] of 47 given IMRT, p=0·0015). At 24 months, grade 2 or worse xerostomia was significantly less common with IMRT than with conventional radiotherapy (20 [83%; 95% CI 63-95] of 24 patients given conventional radiotherapy vs nine [29%; 14-48] of 31 given IMRT; p<0·0001). At 12 and 24 months, significant benefits were seen in recovery of saliva secretion with IMRT compared with conventional radiotherapy, as were clinically significant improvements in dry-mouth-specific and global quality of life scores. At 24 months, no significant differences were seen between randomised groups in non-xerostomia late toxicities, locoregional control, or overall survival. INTERPRETATION: Sparing the parotid glands with IMRT significantly reduces the incidence of xerostomia and leads to recovery of saliva secretion and improvements in associated quality of life, and thus strongly supports a role for IMRT in squamous-cell carcinoma of the head and neck. FUNDING: Cancer Research UK (CRUK/03/005).

Eye health and vision have widespread and profound implications for many aspects of life, health, sustainable development, and the economy.Yet nowadays, many people, families, and populations continue to suffer the consequences of poor access to high-quality, affordable eye care, leading to vision impairment and blindness.In 2020, an estimated 596 million people had distance vision impairment worldwide, of whom 43 million were blind.Another 510 million people had uncorrected near vision impairment, simply because of not having reading spectacles.A large proportion of those affected (90%), live in low-income and middle-income countries (LMICs).However, encouragingly, more than 90% of people with vision impairment have a preventable or treatable cause with existing highly cost-effective interventions.Eye conditions affect all stages of life, with young children and older people being particularly affected.Crucially, women, rural populations, and ethnic minority groups are more likely to have vision impairment, and this pervasive inequality needs to be addressed.By 2050, population ageing, growth, and urbanisation might lead to an estimated 895 million people with distance vision impairment, of whom 61 million will be blind.Action to prioritise eye health is needed now.This Commission defines eye health as maximised vision, ocular health, and functional ability, thereby contributing to overall health and wellbeing, social inclusion, and quality of life.Eye health is essential to achieve many of the Sustainable Development Goals (SDGs).Poor eye health and impaired vision have a negative effect on quality of life and restrict equitable access to and achievement in education and the workplace.Vision loss has substantial financial implications for affected individuals, families, and communities.Although high-quality data for global economic estimates are scarce, particularly for LMICs, conservative assessments based on the latest prevalence figures for 2020 suggest that annual global productivity loss from vision impairment is approximately US$410•7 billion purchasing power parity.Vision impairment reduces mobility, affects mental wellbeing, exacerbates risk of dementia, increases likelihood of falls and road traffic crashes, increases the need for social care, and ultimately leads to higher mortality rates.By contrast, vision facilitates many daily life activities, enables better educational outcomes, and increases work productivity, reducing inequality.An increasing amount of evidence shows the potential for vision to advance the SDGs, by contributing towards poverty reduction, zero hunger, good health and wellbeing, quality education, gender equality, and decent work.Eye health is a global public priority, transforming lives in both poor and wealthy communities.Therefore, eye health needs to be reframed as a development as well as a health issue and given greater prominence within the global development and health agendas.Vision loss has many causes that require promotional, preventive, treatment, and rehabilitative interventions.Cataract, uncorrected refractive error, glaucoma, agerelated macular degeneration, and diabetic retinopathy www.thelancet.

BACKGROUND: Reaching the therapeutic target of remission or low-disease activity has improved outcomes in patients with rheumatoid arthritis (RA) significantly. The treat-to-target recommendations, formulated in 2010, have provided a basis for implementation of a strategic approach towards this therapeutic goal in routine clinical practice, but these recommendations need to be re-evaluated for appropriateness and practicability in the light of new insights. OBJECTIVE: To update the 2010 treat-to-target recommendations based on systematic literature reviews (SLR) and expert opinion. METHODS: A task force of rheumatologists, patients and a nurse specialist assessed the SLR results and evaluated the individual items of the 2010 recommendations accordingly, reformulating many of the items. These were subsequently discussed, amended and voted upon by >40 experts, including 5 patients, from various regions of the world. Levels of evidence, strengths of recommendations and levels of agreement were derived. RESULTS: The update resulted in 4 overarching principles and 10 recommendations. The previous recommendations were partly adapted and their order changed as deemed appropriate in terms of importance in the view of the experts. The SLR had now provided also data for the effectiveness of targeting low-disease activity or remission in established rather than only early disease. The role of comorbidities, including their potential to preclude treatment intensification, was highlighted more strongly than before. The treatment aim was again defined as remission with low-disease activity being an alternative goal especially in patients with long-standing disease. Regular follow-up (every 1-3 months during active disease) with according therapeutic adaptations to reach the desired state was recommended. Follow-up examinations ought to employ composite measures of disease activity that include joint counts. Additional items provide further details for particular aspects of the disease, especially comorbidity and shared decision-making with the patient. Levels of evidence had increased for many items compared with the 2010 recommendations, and levels of agreement were very high for most of the individual recommendations (≥9/10). CONCLUSIONS: The 4 overarching principles and 10 recommendations are based on stronger evidence than before and are supposed to inform patients, rheumatologists and other stakeholders about strategies to reach optimal outcomes of RA.

BACKGROUND AND AIMS: Acute appendicitis (AA) is among the most common causes of acute abdominal pain. Diagnosis of AA is still challenging and some controversies on its management are still present among different settings and practice patterns worldwide. In July 2015, the World Society of Emergency Surgery (WSES) organized in Jerusalem the first consensus conference on the diagnosis and treatment of AA in adult patients with the intention of producing evidence-based guidelines. An updated consensus conference took place in Nijemegen in June 2019 and the guidelines have now been updated in order to provide evidence-based statements and recommendations in keeping with varying clinical practice: use of clinical scores and imaging in diagnosing AA, indications and timing for surgery, use of non-operative management and antibiotics, laparoscopy and surgical techniques, intra-operative scoring, and peri-operative antibiotic therapy. METHODS: This executive manuscript summarizes the WSES guidelines for the diagnosis and treatment of AA. Literature search has been updated up to 2019 and statements and recommendations have been developed according to the GRADE methodology. The statements were voted, eventually modified, and finally approved by the participants to the consensus conference and by the board of co-authors, using a Delphi methodology for voting whenever there was controversy on a statement or a recommendation. Several tables highlighting the research topics and questions, search syntaxes, and the statements and the WSES evidence-based recommendations are provided. Finally, two different practical clinical algorithms are provided in the form of a flow chart for both adults and pediatric (< 16 years old) patients. CONCLUSIONS: The 2020 WSES guidelines on AA aim to provide updated evidence-based statements and recommendations on each of the following topics: (1) diagnosis, (2) non-operative management for uncomplicated AA, (3) timing of appendectomy and in-hospital delay, (4) surgical treatment, (5) intra-operative grading of AA, (6) ,management of perforated AA with phlegmon or abscess, and (7) peri-operative antibiotic therapy.

Many common variants have been associated with hematological traits, but identification of causal genes and pathways has proven challenging. We performed a genome-wide association analysis in the UK Biobank and INTERVAL studies, testing 29.5 million genetic variants for association with 36 red cell, white cell, and platelet properties in 173,480 European-ancestry participants. This effort yielded hundreds of low frequency (<5%) and rare (<1%) variants with a strong impact on blood cell phenotypes. Our data highlight general properties of the allelic architecture of complex traits, including the proportion of the heritable component of each blood trait explained by the polygenic signal across different genome regulatory domains. Finally, through Mendelian randomization, we provide evidence of shared genetic pathways linking blood cell indices with complex pathologies, including autoimmune diseases, schizophrenia, and coronary heart disease and evidence suggesting previously reported population associations between blood cell indices and cardiovascular disease may be non-causal.

. In vitro, B.1.617.2 is sixfold less sensitive to serum neutralizing antibodies from recovered individuals, and eightfold less sensitive to vaccine-elicited antibodies, compared with wild-type Wuhan-1 bearing D614G. Serum neutralizing titres against B.1.617.2 were lower in ChAdOx1 vaccinees than in BNT162b2 vaccinees. B.1.617.2 spike pseudotyped viruses exhibited compromised sensitivity to monoclonal antibodies to the receptor-binding domain and the amino-terminal domain. B.1.617.2 demonstrated higher replication efficiency than B.1.1.7 in both airway organoid and human airway epithelial systems, associated with B.1.617.2 spike being in a predominantly cleaved state compared with B.1.1.7 spike. The B.1.617.2 spike protein was able to mediate highly efficient syncytium formation that was less sensitive to inhibition by neutralizing antibody, compared with that of wild-type spike. We also observed that B.1.617.2 had higher replication and spike-mediated entry than B.1.617.1, potentially explaining the B.1.617.2 dominance. In an analysis of more than 130 SARS-CoV-2-infected health care workers across three centres in India during a period of mixed lineage circulation, we observed reduced ChAdOx1 vaccine effectiveness against B.1.617.2 relative to non-B.1.617.2, with the caveat of possible residual confounding. Compromised vaccine efficacy against the highly fit and immune-evasive B.1.617.2 Delta variant warrants continued infection control measures in the post-vaccination era.

Crohn’s disease [CD] is a chronic inflammatory bowel disease [IBD] that can result in progressive bowel damage and disability.1 CD can affect individuals of any age, from children to the elderly,2,3 and may cause significant morbidity and impact on quality of life. Up to one-third of patients present with complicated behaviour [strictures, fistula, or abscesses] at diagnosis.4 Most patients over time will develop a complication, with roughly 50% of patients requiring surgery within 10 years of diagnosis.5–7 As the precise aetiology of CD remains unknown, a curative therapy is not yet available.8 Several agents are available for the medical treatment of CD. Medical agents include mesalazine [5-ASA], locally active steroids [such as budesonide], systemic steroids, thiopurines such as azathioprine [AZA] and mercaptopurine [MP], methotrexate [MTX], and biologic therapies (such as anti-tumour necrosis factor [TNF], anti-integrins, and anti-interleukin [IL] 12/23]. The European Crohn’s and Colitis Organisation [ECCO] produces and regularly updates several guidelines aimed at providing evidence-based guidance on critical aspects of IBD care to all health care professionals who manage patients with IBD. To provide high-quality evidence-based recommendations on medical treatment in CD, ECCO decided to develop these guidelines by adopting the GRADE [Grading of Recommendations Assessment, Development, and Evaluation] approach.9 GRADE is a systematic process for developing guidelines which addresses how to frame the health care questions, summarise the evidence, formulate the recommendations, and grade their strength and the quality of the associated evidence. GRADE increases transparency at all levels of this process and makes explicit the three considerations that lead to a particular recommendation: the quality of the evidence, the balance of benefits and harms, and the patients’ values and preferences. Therefore ECCO reviewed the available high-quality evidence on the medical management of CD and developed evidence-based recommendations on the medical treatment of adult patients with CD. These guidelines do not cover specific situations, such as postoperative management of adult patients with CD, which was already covered in the latest ECCO Guidelines on Crohn’s disease.10 Based on the GRADE workflow, the Guidelines Committee of ECCO [GuiCom] selected a panel of 48 experts supported by a team of methodologists and librarians. Selection was based on IBD expertise, scientific background, and knowledge of the GRADE methodology. All panellists received adequate training in GRADE before starting the process. Additionally, four patients with CD representing the European Federation of Crohn’s and Colitis Associations [EFCCA] were invited to participate in all face-to-face meetings and to provide their experiences and state their preferences. Three domains for medical treatment of CD were identified: 1] induction therapy; 2] maintenance therapy; 3] therapy of fistulising perianal disease. All panellists were assigned to one of three working groups coordinated by one to two working group leaders under the supervision of two Guideline coordinators. The panellists first formulated a series of specific questions using the PICO format [Population, Intervention, Comparator, Outcomes] which were deemed to be clinically important for the medical treatment of CD. The outcomes of all PICO questions were subsequently graded as ‘not important’, ‘important’, or ‘critical’ during a face-to-face kick-off meeting in Vienna, using a Delphi consensus process. A team of professional librarians performed a comprehensive literature search on EMBASE, PubMed/Medline, and Cochrane Central databases using specific search strings for each PICO question [Supplementary Files 1, 2, and 3, available as Supplementary data at ECCO-JCC online]. Two independent working group members [one assigned to the PICO and another one from the same group as a second reviewer] assessed the relevance of each abstract to PICO and included or excluded all the relevant papers for the final data extraction and analysis. Subsequently, the working group members assigned to each PICO question systematically reviewed and summarised the evidence on every outcome, to compile a Summary of Findings [SoF] table for each question. The GRADE method follows a hierarchical approach to synthesise evidence; recent high-quality systematic reviews and meta-analyses of clinical trials were preferentially used to create the recommendations. When these were not available, individual randomised clinical trials [RCTs] followed by observational studies were reviewed; results of individual studies were pooled using random-effects meta-analysis as appropriate and when needed. To define disease activity and severity [mild-to-moderate and moderate-to-severe], we accepted the definitions used by the investigators of the studies selected as an evidence basis for our work. The quality of evidence was classified into the following four categories in accordance with the GRADE approach: ‘high’ [meaning that further research is unlikely to change our in the research may change our in the research to change our in the and [meaning that any of is each PICO the quality of evidence was to the quality of evidence outcomes graded as The strength of each was graded as [meaning the of an the or or as [meaning the balance is the quality of evidence, values or and the outcomes were not in the clinical this was in the To the recommendations, we from the systematic reviews or our group of methodologists performed the All recommendations were to by the panel the ECCO for each with and from a of ECCO members who to the were not selected to be of the The final of all was panel members during a final consensus meeting in and to a final recommendations were at of the panellists with the and associated strength The of the and and the of the were reviewed by two Guideline Committee members and by the ECCO who the final of these The literature search the relevant definitions of and a of the and the the evidence can be in the Supplementary available as Supplementary data at ECCO-JCC As CD is a therapy to in the and in the The that chronic and results in to a recent in medical treatment and disease is that and may patients to their and therapy are to high-quality evidence is not available to this affect the of medical These include disease disease activity and to and of perianal or fistulising the individual for and the individual and the and of each be As is a clinical and is of to disease and therapy at based on and approach will provide the with the to therapy the of of the disease and which is to be to disease to the management of CD a series of health care maintenance be to be and be and appropriate guidance or for and be as in ECCO or the of for induction of of Crohn’s disease performed a meta-analysis of that the of or with in patients with active CD [Supplementary 1, available as Supplementary data at ECCO-JCC online]. The of from to patients with disease with or disease were was significant for induction of clinical [Supplementary 1, available as Supplementary data at ECCO-JCC online]. A recent Cochrane significant and to be in our as was significant in to when with [Supplementary 2, available as Supplementary data at ECCO-JCC online]. the trials of was over for clinical [Supplementary 3, available as Supplementary data at ECCO-JCC online]. significant in to was in trials that [Supplementary available as Supplementary data at ECCO-JCC online]. meta-analysis a significant on clinical the that at of another meta-analysis was to any such A pooled of three trials of a of a in the Crohn’s with the in and was not clinically Two trials with for induction of clinical A pooled a of [Supplementary available as Supplementary data at ECCO-JCC online]. was not by any significant in for [Supplementary available as Supplementary data at ECCO-JCC online]. in trials that the of was to patients with The of or for the treatment of CD not in using for the induction of clinical in patients with active Crohn’s disease to the A Cochrane systematic and included three that at a of with [Supplementary 2, available as Supplementary data at ECCO-JCC online]. Two of these clinical as in or at at was in all three was to for clinical and clinical in patients with active CD in the to the As with steroids which are associated with systemic activity and systemic and and a was to be in the reviewed A Cochrane systematic and meta-analysis from reviewed two that at a of with mesalazine to a mesalazine in patients with active CD [Supplementary 3, available as Supplementary data at ECCO-JCC online]. All trials clinical in or and clinical at was not to mesalazine for clinical in patients with active CD in the [Supplementary available as Supplementary data at ECCO-JCC online]. clinical was in patients in patients mesalazine [Supplementary available as Supplementary data at ECCO-JCC online]. The of was with and in groups [Supplementary and available as Supplementary data at ECCO-JCC online]. studies the of treatment on CD. and to clinical or with the of these the European on the of to or Therefore a was not on to CD, for the treatment of patients with Crohn’s we the of systemic for the induction of clinical and Two on the of systemic or with for the treatment of active available as Supplementary data at ECCO-JCC online]. was at a of 48 and on a basis to and of from to with a of is at over an from these studies in a Cochrane systematic patients on induction of clinical was in patients as with were to be as in clinical in the two studies patients on the of patients from the of systemic was available from one patients with The of was in patients with included of and in patients with and in was for the outcomes to which a quality of evidence the of thiopurines as for the induction of of Crohn’s disease Several studies on the of thiopurines with for induction of and in [Supplementary available as Supplementary data at ECCO-JCC online]. trials the of thiopurines for induction of clinical in with or patients were The active was in four of these and the active was in the The trials were in of of active and of for of the trials for the of The pooled was performed on an basis and for induction of thiopurines and in the active with in the group Three trials on clinical not with of disease these of of disease were of the patients as with of clinical The of clinical was was and to data and the quality of evidence was for this [Supplementary available as Supplementary data at ECCO-JCC online]. one on during The pooled of any was not and thiopurines were in two of of developed The quality of evidence was deemed to a of and on a quality of The groups was at for and for of the trials on at the of the induction data were available that for a pooled trials in of such as or in thiopurines as with a of at and at and for the thiopurines and a of in the group and a significant in in and one relevant was this patients with active CD were randomised to of or for with a of at that was over a [Supplementary available as Supplementary data at ECCO-JCC online]. a of patients with were in clinical The of treatment for and was in with this is by and such as the of studies were that for the induction of of CD. was in the the of for CD and the decided to Three and studies the of and thiopurines for induction of in [Supplementary available as Supplementary data at ECCO-JCC online]. These studies used and of Two studies used at of and and one used at All patients were and received systemic steroids at of the individual studies or the pooled a significant in the to [Supplementary available as Supplementary data at ECCO-JCC online]. the of is with the data are and the quality of evidence is for can be Based on the evidence, on a for the of for clinical in patients with CD not be may be as an for patients with disease when be The to therapy in patients a be the of and to in patients with Crohn’s disease who not to therapy are and therapies for the treatment of CD include and is not in the European for CD, is available in and is a at a of at 2, and during induction and every is a at a of and followed by every is a at a of at 2, and followed by every on agents and from several meta-analyses of their for induction of clinical and clinical [Supplementary available as Supplementary data at ECCO-JCC in patients who not adequate or were to data were available for the induction two studies a the evidence was to on clinical were and data on were by to the of patients included in the meta-analysis on outcomes and and and quality of are was in of The of on and in a that with and were to for induction of The of of biologic agents is a of that patients with fistulising perianal complicated from the of to a of or of agents be the first in disease these results are based on from clinical the of and thiopurines over to clinical and one the of therapy of with as with for the induction of clinical in patients to therapies [Supplementary available as Supplementary data at ECCO-JCC online]. this therapy was not to for clinical therapy was associated with at this was at the of was in to associated with therapy the of used in this was the used in CD patients of therapy with a when starting to in patients with Crohn’s who an to therapy The and Crohn’s the of with over in patients to who to to steroids or [Supplementary available as Supplementary data at ECCO-JCC online]. therapy in of clinical at as with therapy was to result in at this was in for were of in therapy A in clinical is patients who or an to thiopurines and in therapy is in such maintenance in with the benefits in of A of of the of therapy starting therapy in this be in the of evidence, an approach be for induction of in patients with Crohn’s disease with to therapy to therapy high-quality is an that to the by the and CD, induction be using a of systematic and meta-analysis pooled the results from in which was with for induction of in patients with active available as Supplementary data at ECCO-JCC online]. patients with or induction of clinical and induction of clinical at were and a meta-analysis was an of clinical of [Supplementary available as Supplementary data at ECCO-JCC online]. The quality of evidence was The of clinical was [Supplementary available as Supplementary data at ECCO-JCC online]. The quality of evidence was CD patients that of patients at as with of The quality of evidence was on or The pooled of any was not and [Supplementary available as Supplementary data at ECCO-JCC online]. the pooled of any was not and [Supplementary available as Supplementary data at ECCO-JCC the quality of evidence was The of to be for induction of and in patients with Crohn’s disease with to therapy to therapy is a that by the in is at a of at 2, and for and every who do not at can from an at Three randomised trials patients with or on induction of clinical induction of clinical and in adult patients with active available as Supplementary data at ECCO-JCC online]. in these studies were followed for to 10 was in patients with [Supplementary available as Supplementary data at ECCO-JCC online]. clinical was in patients with [Supplementary available as Supplementary data at ECCO-JCC online]. The quality of evidence for these outcomes was of with were not with [Supplementary available as Supplementary data at ECCO-JCC online]. The quality of evidence for this was to from the of or for the treatment of active Crohn’s disease in patients who therapy systematic and meta-analysis performed an of and for induction of in patients with active CD who were or to a of patients with or on induction of clinical and clinical [Supplementary available as Supplementary data at ECCO-JCC online]. The pooled of clinical and clinical were not and the quality of evidence was for a of patients with or on or The pooled of any was not and the pooled of any was not and the quality of evidence was surgery be as an in is for the induction of in patients with CD, as a and of at or a or a Crohn’s of with and is a knowledge on how to CD in of the the and or in patients with disease. Therefore the is to the who the individual and of systemic steroids are in in CD, are by important Additionally, of not disease Therefore we that the of or to steroids the of 10 or within of starting steroids, a within of steroids, or the for a of in all a are not in thiopurines a of and are for in CD patients are with steroids at the of patients with a of steroids and in at and is associated with a of this may be medical and surgery are not or are associated with individual patients with CD as a or with or to therapy we the of These include agents [such as and or All these agents are in and CD The on and and the induction of in the of with thiopurines is for of therapy over was in the performed to The the of or the of and over or in with this be and in The for the of Crohn’s that the of with in patients at of as with a was associated with of and for surgery in patients with A that is associated with to clinical the and of therapy to be a in in the therapy not to be associated with at in the a that therapy is associated with for and as with Therefore the is to the who and to be as specific such as the at for or and at for specific such as patients who or are is evidence on the and in patients with or as a first assessed the and of these agents when used in therapy as with to be in the in was in patients with in patients with CD with disease or to at one surgery be as an the of a for induction of and for using of clinical the or of therapy not on on the disease severity impact of disease in the individual the and for the inflammatory of and disease appropriate studies that the of over a on the of and and that for disease be studies were by this as important research the of for maintenance of in patients with Crohn’s disease for the maintenance of of CD [Supplementary available as Supplementary data at ECCO-JCC online]. significant [Supplementary available as Supplementary data at ECCO-JCC online]. trials that assessed and were from to with trials a of were significant in the of patients an or to or The data were and this [Supplementary available as Supplementary data at ECCO-JCC online]. are for the maintenance of in patients with Crohn’s disease The of maintenance treatment with or to patients with CD who are in one [Supplementary available as Supplementary data at ECCO-JCC online]. meta-analysis included data from trials and A of patients with to were included and followed for to was to in disease activity in was to for the maintenance of in patients outcomes were in four trials and a of patients followed for to The of during maintenance treatment with thiopurines was with The of in patients with thiopurines was and were the the of therapy in patients with Crohn’s disease for that the of thiopurines disease Two studies the of of the for of Crohn’s disease in and the trials [Supplementary available as Supplementary data at ECCO-JCC online]. The excluded from our table was not or the adult patients with a recent of CD were randomised to or to were to active disease in this The results were not significant for any of the critical outcomes of clinical not the two groups patients with and were in The of as and were in patients in the group and in the group methotrexate for the maintenance of in patients with Crohn’s disease on the of are from one patients were of or of for [Supplementary available as Supplementary data at ECCO-JCC online]. with active CD, who to of treatment with were assigned to at a of or for for CD were the of patients who in was in the group in the group 50% of the patients in the group by the of the were in in the group as with the group over the observational [one and the a and patients in the group in the of the was one treatment of these of severity to treatment or from the The of was in patients with Crohn’s disease who with maintenance treatment using the same treatment is Two systematic reviews the of maintenance treatment with and to patients with CD who disease with the same [Supplementary available as Supplementary data at ECCO-JCC online]. trials and were pooled in the meta-analysis from one was on two on and two on A of patients were included and followed for to of the studies included and one included all was as a The of with was The following values were with with and with A significant the three are pooled data available on of all as a performed in the of a Cochrane the for for and were and with is as with for the maintenance of in CD the and of do not the of that may in and observational for clinical in patients with Crohn’s disease who with at every was to in clinical in patients with CD who with [Supplementary available as Supplementary data at ECCO-JCC online]. patients every and patients every were in clinical as with patients and was at clinical and a of with data are to the the of to clinical in patients with Crohn’s disease who with outcomes for the maintenance of with in CD patients [Supplementary available as Supplementary data at ECCO-JCC to in the induction were to every or or a of the patients were in clinical as with of A that at clinical was by of patients every and by of patients every as with in the The treatment every and was and was treatment every and Therefore was every or was in of patients of patients The pooled of any was not patients who were and are data on as this was assessed in a of patients at was significant in patients in the group as with patients in the treatment were during the of were and with significant in the and was an of in the maintenance groups patients in and data are to the are randomised trials or with agents for the maintenance of clinical in patients with CD who or with the same A included trials used the to define clinical with The a time of All were the the the quality of evidence was specific was the in the maintenance Based on is evidence to to or in patients who to induction treatment with any or is a to that and to trials that for the of who from a biologic over the Crohn’s disease patients in clinical under is evidence to for or the of to clinical outcomes as to care from two with a of patients with CD were used to this [Supplementary available as Supplementary data at ECCO-JCC online]. These two of over clinically based for any of our critical clinical [one clinical [one [one [one or [one the a of IBD patients with to maintenance therapy were randomised to or groups were or to a and of the that in patients in clinical a or was in and of in clinical or at were and based the group who received during the patients with CD, with an induction therapy with and were randomised to the following three based on clinical and levels of with of or of or based on clinical The was to a was in clinical with from to in the three in in in studies important in their which the strength of our The outcomes in studies were clinical important such as and to be The in Crohn’s that is on and and that during the induction may outcomes and treatment the that with adequate of patients are Crohn’s disease patients who to an is evidence to for or the of to clinical outcomes to the of in patients on therapy with active to the of of and to clinical was with on clinical in one in a of patients with CD with were randomised to every or based on and levels using the was in clinical the group and the group [Supplementary available as Supplementary data at ECCO-JCC online]. studies a adequate and clinical outcomes from clinical to Based on these observational recent clinical guidelines and a group of experts supported the of the quality of evidence from observational a of patients with active IBD with who and clinical were for and at a of was in of patients in the as with in the clinical was in and in the group another a of the using a of was to a at was this group and a group in which were of was significant in clinical the approach was in the evidence not an a and clinical outcomes a of thiopurines in Crohn’s disease patients in on maintenance as the of is when the treatment is our meta-analysis to the two of in CD patients in on maintenance therapy [Supplementary available as Supplementary data at ECCO-JCC online]. from four trials were included received from to before randomised to or or to or All studies a time of to results that the of clinical is [Supplementary available as Supplementary data at ECCO-JCC online]. meta-analysis for was the data a with of the results were not significant [Supplementary available as Supplementary data at ECCO-JCC online]. for the be performed the data from the To the evidence for the of clinical is in of of as when the treatment was the of was not and from studies that patients treatment for are and this an important research from observational studies and for the of and in patients to treatment with The time and the of patients included in the studies of the meta-analysis are to and that may in the reviewed the literature to the approach of using thiopurines an literature we not evidence the two treatment one was of thiopurines was with thiopurines in the of therapy in patients with IBD. The was as was not to data from and CD specific was patients with Crohn’s disease who with the of and we with A Cochrane based on two the same patients who therapy with or [Supplementary available as Supplementary data at ECCO-JCC online]. The same the of for therapy or These results are to an of in the therapy studies included and studies are to the A of when agents are with the and were as 10 in one meta-analysis of patients included in the patients with Crohn’s disease who with the of and we with the basis of a meta-analysis of studies on by the data included were the and groups to be to the relevant PICO question. The result of this not any in maintenance of clinical therapy and [Supplementary and Supplementary available as Supplementary data at ECCO-JCC online]. this meta-analysis was to of in the studies with a are quality data available for clinical in the which is an that follows the of patients in the on the of were in patients with or at years of The meta-analysis by which was not any in with and therapy [Supplementary available as Supplementary data at ECCO-JCC online]. is evidence to or of therapy in Crohn’s disease patients the to therapy be and and be with the randomised

These guidelines provide a practical and evidence-based resource for the management of patients with Barrett's oesophagus and related early neoplasia. The Appraisal of Guidelines for Research and Evaluation (AGREE II) instrument was followed to provide a methodological strategy for the guideline development. A systematic review of the literature was performed for English language articles published up until December 2012 in order to address controversial issues in Barrett's oesophagus including definition, screening and diagnosis, surveillance, pathological grading for dysplasia, management of dysplasia, and early cancer including training requirements. The rigour and quality of the studies was evaluated using the SIGN checklist system. Recommendations on each topic were scored by each author using a five-tier system (A+, strong agreement, to D+, strongly disagree). Statements that failed to reach substantial agreement among authors, defined as >80% agreement (A or A+), were revisited and modified until substantial agreement (>80%) was reached. In formulating these guidelines, we took into consideration benefits and risks for the population and national health system, as well as patient perspectives. For the first time, we have suggested stratification of patients according to their estimated cancer risk based on clinical and histopathological criteria. In order to improve communication between clinicians, we recommend the use of minimum datasets for reporting endoscopic and pathological findings. We advocate endoscopic therapy for high-grade dysplasia and early cancer, which should be performed in high-volume centres. We hope that these guidelines will standardise and improve management for patients with Barrett's oesophagus and related neoplasia.