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: 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: =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.

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 to the the to which mass is referred be of mineralized bone, bone, bone tissue or or a bone. bone is than bone density, which the of and This is and generally be but is to Bone the of osteoid; bone matrix excluding and has been referred to as bone Bone tissue the of soft tissue, or bone density, referred to as bone density, the of bone tissue, cancellous bone tissue, and marrow a bone, the organ of which is by is in the clinical and In most bone are or formation and all cells on the are or but in the most bone are with to bone We refer to the cells that bone as cells and the term to cells that are bone matrix or with only rather than including all cells that are not cells are of and are to have The term is restricted to cells and are have only one or no for of and whether or should be or A of types of primary be on of a or between or between and histomorphometrists report all only in the for to three be to and the of the or the of an are not this is a but bone be in In other of that as an the is to by the of which is the We that this also should be the of bone are for between between and between different types of bone, for element of bone for of and for many of bone as the of and the of individual But as a it is to on adoption of a stereologic that be and a only in bone the is to the bone its before In the the use of a in the was a convenient of of but this for at an the of the of to most stereologic also that the be meaning that a to any element of has an of in any in not for all cancellous bone, in the there is only and stereologic be used with 25 But it is more to the of a is which is with the use of a but there is no other of canals generally not the by more than stereologic in bone are but of the stereologic to bone has not been we that histomorphometric should one of all and in the and or (as by the only the the and with the an is for each type of of how it was the primary as A of and should not be used in the same The only is the type of primary for which there is no convenient of to three the of the of in three is possible the same be in of and but this has not been applied to bone. as also be The original committee not to the terminology of the of as was at the on Bone use the term “density” in a general to any referred to that is and per unit is the of terminology is in the the of “density” in different the all to at the of bone histomorphometry will need to be with the of many to bone are published in the Journal of which is the of the of of and are of the of tissue and be between only to a which will be or the and in have no and in three but it is convenient to refer to as and to as the is the of and of individual have meaning in and are the only type that not a different and to different that use of is and it is to between used include tissue bone bone and and their or of the the use of as a term The of the is not commonly used as a at but is for with of bone for the of and cancellous bone of or for the of different types of bone and different to as of and of and for in the between and of bone of the as a the possible an to the in of to bone as an be as of the the of the to the mainly on the of the bone at the of be with a the but the of and cancellous tissue in the bone be with type of the be by the of and cancellous bone tissue in the The same be applied to and to bone by the by the as the The individual are in in of their or general are in a the is to be rather than the use of is mainly to time or there is a more for as for other their use in other but confusion is with that be with is not to or the use of and but to that the same are used by To this we have the to and the of new with different meanings. We have included in bone their and commonly used in and as well as for all the structural of bone and of and for of bone with are and in to their one the and in of only is it is and used and a suitable The most commonly used are a have an in many to the second or and the second of the by the are used for that are in to for the primary of and and for in its used in should be by a in the of each is to be as an individual In this any combination of be to which are included in the Bone histomorphometry be applied to many types of but the most are of of bone and of we first the terminology for to the the between and is it is to the of the bone at the for the the term is more is and cancellous for on the their are but it is possible to of their and In this the are generally by their of the and that one be in by or at the time of the but this is The generally has more and tissue than the The other of the is referred to as only the of the have the same as the the more term is the of the is to the of the its are It is convenient to as and of for and cancellous for are by the between and in the to of bone different on on by and with of of of on on cancellous to cancellous the and not and their is used for for the the by the and are the be used to and the of bone bone is similarly and cancellous for or marrow for The between and bone and cancellous or marrow on the of the be at in to the in both and bone it is for to recognize a between and cancellous bone tissue and in and This is not in or of its are not A has been used to this in This be to bone but this has not been all all in with bone marrow are referred to as and are cancellous bone and the is the of the between is to in accordance with and will also on whether the is not in with bone marrow are generally referred to as with as the also be referred to as the or osteonal of the of a bone; is on the and is on the the cancellous bone of the is not bone cancellous marrow The standard and for all should be that the of to as well as to the and are used only as and are used only as to the on which the was whether this was a particular or a particular type of tissue. of the commonly used have been many are by the are restricted to of a as the of a or the of cancellous the same be but the should be in the of on the the source is as it will not be to the source each time a particular is referred only one source is used in an it need only be are their be used as for of in or and in most will need to be only are that confusion between is as only one source is possible and its is The three and the are the key to one to is to in stereologic terminology, and and are to in stereologic are the and by which is for or by which has been for cancellous The with that the be and and to in stereologic terminology and are with the and a of the bone is as a and are to and it be to to the mineralized as an alternative to the more bone and of bone formation be to the or to the of as well as to or bone it be to use the between mineralized bone and or bone as a for the of or of the is are In many as only one is used for each the need only be and not each time the is more than one is with the same be to are with in both and in have been but need is used for of mineralized bone and is by Osteoid need to be as or as the in the between which to a and which to a for all are with the is a general term to all tissue that is not and includes marrow in cancellous bone and and canals in bone. both types of tissue, with on individual as cells or The be as an of tissue, by use of the is the of all referred to the of tissue and in The also be as individual by of a is the of individual confusion is the term be as or in be to in the are in be used to but it is to this as Osteoid not that should be for of We the formation and the of current be and for the same we the is with or and the and the individual also be as or cells and are for and the cells on the or cells. is with or the term that will at The of connective tissue the cells on should not be referred to as It is possible that by cells should be as rather than as In all be in by at or by of and The is more and a and a standard as well as a but that be The is and to The is used for between and and and the is used for and are used for and The is for the the between individual at particular and at particular during the The by in an individual be the in a of is the the to the between bone and It is used in and in different types of and different stages of in the should be to the between and is on an individual it has been used in the for of the of and in as an of in is the between on of a as for the is an of bone the but is of the of bone to the most of the but that are the of be restricted to the of the of are but to and need for a be In most the will be an or but of also be per is the of per to bone in cancellous bone tissue, a that with as and as are are and are in a that has been to of its The of to in a is an of be structural or of the are on that are but not rigorously and individual to use or of the that we have is with and time are L and but have other in the according to the as which is to of for cancellous the alternative is with by To between the alternative this is to the with It should be that there is in the term which has been a different by the ASBMR with with the it as the between rather than between is according to the as or as This by is an of the marrow to the and a is by but be in any to the of the marrow as the between is by and also be The of in at a particular time is by the of the resulting at that The of the of is to the of the first and second the of the of are available. of the term or a between the of the the second it is in time to the the only one was in of the or after the the and of the and of the of are the of the and should be be in to a variety of is to the of during which It should be that of individual on the Parfitt and that were than of the in which were This should be in the of and and it is to a is used to in bone formation in a Mineral is the between the or between the of by the time between the of the the of for and the of the vary with the of the which be and We the and to confusion between and and are used in to refer to the bone formation is no convenient of between the and by different that the is it is that the be used is as and the or the bone formation the It is analogous to the and is with formation and “bone formation but of alternative is The is in a and in the of the is the best a of the of the of formation of mineralized bone and of bone matrix, the including of and are their are of and the term be used. We refer to and as rather than as formation to the that an has meaning at a on the a formation has meaning only in to of tissue, or in the of a of but a formation is by the of and on the of as well as on their The rather than the is as the unit the of the on the of its members as well as on their individual Mineral formation is the of mineralized bone per unit as the of and as this term be as to the of the more term mineralized bone formation be used. In a and in the of the formation is with the bone formation and the is the and more term should be used. is a bone formation to each possible for and Bone formation the is to the as bone formation per unit of bone most on bone Bone formation per unit of bone is to the bone which bone and of Bone formation per unit of tissue most of bone the tissue is and its to the The of the was Bone be by histomorphometry but be as the bone formation or by an or of of bone that all are in to the same or of bone a be by and and osteonal with in but it be that bone formation at the current the time which the of bone of the of bone turnover, most the that and formation are is than the of but it is more to that mineralized in to or of bone alternative is to use to the in bone which is for a of but to in a it is be in to a variety of different including time is the time between and of any of matrix, the of the and is by The is in the understanding of and the of it be that to the and of individual of has been as for and be time which is the time between the of matrix and the of at each The name that the of the matrix, as In the and are but in is and than be as and has also been referred to as rather than but it is more to by the of than but it be more convenient for use it is in that be applied to as and information about the of which be with and dynamic of bone is the time to a new bone structural unit or the to the bone at a and is by It includes or or other to the between and that be to and be as by or by or of a that to a between and is the of during the of bone formation is low to of or of of to its has also been referred to as is the key for of all other of the In a of are to of that is any other than including and but will the in are and their of their current and in the by be used to The of the and formation is the which is the of a of bone at any on a bone is a of or than the of bone that a of the for a the bone or the many are much than a including both and and the of many is much than the of a or a not commonly it is this that is the for of a new after any or it is used and in key an for this is an alternative that the and use of The of the and the is the which is the time between the of at the same on the The of is the which is the that a new of will at any on the by the of also be in the more as the of of or and in to the in the is that current does not of the in cancellous bone. It be that which is be as the of bone per were first for of parameters of bone of low were in bone in with the and use of are in which are low that there are no or only in cancellous for of is that the was not or This sometimes be by the of in in the or on the The that a of a low be by low for parameters of bone as or a for the and of the and a In there are no in an we that be as a and that the of in a be in the of the In this it is to a of for and to include in the of for In only or are to be and in the be as a or one has the of a to have been or on the for in the first or the in the The for in the the is also be used. are in of the the the for in that be used or one use the for for the to which the In any of is in three the should be applied The of a to only are is that a of be used to for and parameters as with the that for and the parameters be of will have the The key is that all the of in a with the with only and the and the of with is to the both have applied to for the this a to be on the of in a that have it does not the and the be to the information are low or in an it is that will be low or in the of the The or of and should be for and cancellous The recommendations for and also in the in which only one is primary of and and primary of and should be with the on and the of the most information in of rather than after the are for and and for the between in different and we rather than in this the be used to the and unit of are not used for the be by the type of only We as their with to three 10 also not to the and it more to that the is should be in all primary and in or and all in should be in with as an alternative for should be as and formation with as and should be in or years as most and in We recognize that many who bone histomorphometry or its will on most need to use only a of the we a of its most but this is not to on its to the of the We also a of parameters that should be included in all histomorphometry are in only the most are The term “bone” to bone matrix whether mineralized or not and “bone to bone as with its associated marrow or other soft tissue. Bone tissue is or the between which is the of the is referred to as A trabecula is an individual structural element of cancellous bone tissue, whether or in The term to bone matrix that in the of will mineralized, and does not include the of connective tissue that bone cells on all The between and mineralized bone is referred to as the “bone more The term is restricted to cells that are to be bone and does not refer to all cells with The and are not are that as and are the and are used. The of is referred to as of how it is The used for its be and A the whether or is referred to as a and the term is generally used only are on the be use of only or only terminology and the same or the same are referred to as and in and as and in three the type of primary be only are is the of should be and its The terminology and of the of will not be used. the term “density” its primary meaning in physics of mass per unit this in no the of stereologic for and or is only as an of the of tissue for which should be the term is not used in any other the four types of primary only be a which will be and or in the are possible for all the be and this is as and are and should not be used. only one is or with the same are the need to be only but it be each time there is any of of the first in the same as the in the or has only one as in and no in the of is are used for the most frequent a and an for frequent and a for that are in to be by in the of each is to be as a The same is used for all The source is the type of or a on which the was and will most commonly be bone tissue cancellous bone tissue or but many other are in use or be the in which the source be the name are in the of the practice is in this have only been on cancellous bone tissue, the source is for bone and for and The need for and the to were The most commonly used are tissue bone bone and bone but many other be for particular The are by the to in stereologic and in stereologic we a type with an of at least for and information be with and with rather than but the of that be is more The tissue to be is and the bone is We that be at least three the at about the and by to the tissue and bone The of and the tissue and bone should be in all The committee that a of be used to be with but in that the of used to in a of should be 5 a of and should be and in all histomorphometry with their and that the are on for and and for time and and that is for It is to between and dynamic the not but it is more to between primary and primary is not the but the use of no more of the than is to in of a or to by a as the time between more and on one or more that should be should not be the primary which are that have no of the first of the other and revised this and

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: 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).

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.

There is extensive evidence showing that improving eye health contributes directly and indirectly to achieving many Sustainable Development Goals, including reducing poverty and improving work productivity, general and mental health, and education and equity. Improving eye health is a practical and cost-effective way of unlocking human potential. Eye health needs to be reframed as an enabling, cross-cutting issue within the sustainable development framework.

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.

. 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.

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.

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.

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.

Crohn’s disease [CD] is a chronic inflammatory bowel disease [IBD] that can result in progressive bowel damage and disability1. 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 diagnosis4. Most patients over time will develop a complication, with roughly 50% of patients requiring surgery within 10 years of diagnosis5-7. As the precise aetiology of CD remains unknown, a curative therapy is not yet available8. 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 biological therapies [such as anti-TNF, anti-integrins, and anti-IL12/23]. \nThe 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 healthcare professionals who manage patients with IBD. To provide high-quality evidence-based recommendations on medical and surgical treatment in CD, ECCO decided to develop these guidelines by adopting the GRADE [Grading of Recommendations Assessment, Development, and Evaluation] approach9. GRADE is a systematic process for developing guidelines that addresses how to frame the healthcare questions, summarize the evidence, ..

The wide range of phenotypic abnormalities seen in the leptin-deficient ob/ob mouse and their reversibility by leptin administration provide compelling evidence for the existence of multiple physiological functions of this hormone in rodents. In contrast, information regarding the roles of this hormone in humans is limited. Three morbidly obese children, who were congenitally deficient in leptin, were treated with daily subcutaneous injections of recombinant human leptin for up to 4 years with sustained, beneficial effects on appetite, fat mass, hyperinsulinemia, and hyperlipidemia. Leptin therapy resulted in a rapid and sustained increase in plasma thyroid hormone levels and, through its age-dependent effects on gonadotropin secretion, facilitated appropriately timed pubertal development. Leptin deficiency was associated with reduced numbers of circulating CD4(+) T cells and impaired T cell proliferation and cytokine release, all of which were reversed by recombinant human leptin administration. The subcutaneous administration of recombinant human leptin has major and sustained beneficial effects on the multiple phenotypic abnormalities associated with congenital human leptin deficiency.