University Hospitals Coventry and Warwickshire NHS Trust

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.

Importance: Application of deep learning algorithms to whole-slide pathology images can potentially improve diagnostic accuracy and efficiency. Objective: Assess the performance of automated deep learning algorithms at detecting metastases in hematoxylin and eosin-stained tissue sections of lymph nodes of women with breast cancer and compare it with pathologists' diagnoses in a diagnostic setting. Design, Setting, and Participants: Researcher challenge competition (CAMELYON16) to develop automated solutions for detecting lymph node metastases (November 2015-November 2016). A training data set of whole-slide images from 2 centers in the Netherlands with (n = 110) and without (n = 160) nodal metastases verified by immunohistochemical staining were provided to challenge participants to build algorithms. Algorithm performance was evaluated in an independent test set of 129 whole-slide images (49 with and 80 without metastases). The same test set of corresponding glass slides was also evaluated by a panel of 11 pathologists with time constraint (WTC) from the Netherlands to ascertain likelihood of nodal metastases for each slide in a flexible 2-hour session, simulating routine pathology workflow, and by 1 pathologist without time constraint (WOTC). Exposures: Deep learning algorithms submitted as part of a challenge competition or pathologist interpretation. Main Outcomes and Measures: The presence of specific metastatic foci and the absence vs presence of lymph node metastasis in a slide or image using receiver operating characteristic curve analysis. The 11 pathologists participating in the simulation exercise rated their diagnostic confidence as definitely normal, probably normal, equivocal, probably tumor, or definitely tumor. Results: The area under the receiver operating characteristic curve (AUC) for the algorithms ranged from 0.556 to 0.994. The top-performing algorithm achieved a lesion-level, true-positive fraction comparable with that of the pathologist WOTC (72.4% [95% CI, 64.3%-80.4%]) at a mean of 0.0125 false-positives per normal whole-slide image. For the whole-slide image classification task, the best algorithm (AUC, 0.994 [95% CI, 0.983-0.999]) performed significantly better than the pathologists WTC in a diagnostic simulation (mean AUC, 0.810 [range, 0.738-0.884]; P < .001). The top 5 algorithms had a mean AUC that was comparable with the pathologist interpreting the slides in the absence of time constraints (mean AUC, 0.960 [range, 0.923-0.994] for the top 5 algorithms vs 0.966 [95% CI, 0.927-0.998] for the pathologist WOTC). Conclusions and Relevance: In the setting of a challenge competition, some deep learning algorithms achieved better diagnostic performance than a panel of 11 pathologists participating in a simulation exercise designed to mimic routine pathology workflow; algorithm performance was comparable with an expert pathologist interpreting whole-slide images without time constraints. Whether this approach has clinical utility will require evaluation in a clinical setting.

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 .

BACKGROUND: People of Sub Saharan Africa (SSA) and South Asians(SA) ethnic minorities living in Europe have higher risk of stroke than native Europeans(EU). Study objective is to provide an assessment of gender specific absolute differences in office systolic(SBP) and diastolic(DBP) blood pressure(BP) levels between SSA, SA, and EU. METHODS AND FINDINGS: We performed a systematic review and meta-analysis of observational studies conducted in Europe that examined BP in non-selected adult SSA, SA and EU subjects. Medline, PubMed, Embase, Web of Science, and Scopus were searched from their inception through January 31st 2015, for relevant articles. Outcome measures were mean SBP and DBP differences between minorities and EU, using a random effects model and tested for heterogeneity. Twenty-one studies involving 9,070 SSA, 18,421 SA, and 130,380 EU were included. Compared with EU, SSA had higher values of both SBP (3.38 mmHg, 95% CI 1.28 to 5.48 mmHg; and 6.00 mmHg, 95% CI 2.22 to 9.78 in men and women respectively) and DBP (3.29 mmHg, 95% CI 1.80 to 4.78; 5.35 mmHg, 95% CI 3.04 to 7.66). SA had lower SBP than EU(-4.57 mmHg, 95% CI -6.20 to -2.93; -2.97 mmHg, 95% CI -5.45 to -0.49) but similar DBP values. Meta-analysis by subgroup showed that SA originating from countries where Islam is the main religion had lower SBP and DBP values than EU. In multivariate meta-regression analyses, SBP difference between minorities and EU populations, was influenced by panethnicity and diabetes prevalence. CONCLUSIONS: 1) The higher BP in SSA is maintained over decades, suggesting limited efficacy of prevention strategies in such group in Europe;2) The lower BP in Muslim populations suggests that yet untapped lifestyle and behavioral habits may reveal advantages towards the development of hypertension;3) The additive effect of diabetes, emphasizes the need of new strategies for the control of hypertension in groups at high prevalence of diabetes.

Detection and classification of cell nuclei in histopathology images of cancerous tissue stained with the standard hematoxylin and eosin stain is a challenging task due to cellular heterogeneity. Deep learning approaches have been shown to produce encouraging results on histopathology images in various studies. In this paper, we propose a Spatially Constrained Convolutional Neural Network (SC-CNN) to perform nucleus detection. SC-CNN regresses the likelihood of a pixel being the center of a nucleus, where high probability values are spatially constrained to locate in the vicinity of the centers of nuclei. For classification of nuclei, we propose a novel Neighboring Ensemble Predictor (NEP) coupled with CNN to more accurately predict the class label of detected cell nuclei. The proposed approaches for detection and classification do not require segmentation of nuclei. We have evaluated them on a large dataset of colorectal adenocarcinoma images, consisting of more than 20,000 annotated nuclei belonging to four different classes. Our results show that the joint detection and classification of the proposed SC-CNN and NEP produces the highest average F1 score as compared to other recently published approaches. Prospectively, the proposed methods could offer benefit to pathology practice in terms of quantitative analysis of tissue constituents in whole-slide images, and potentially lead to a better understanding of cancer.

Abstract Cancer develops through a process of somatic evolution 1,2 . Sequencing data from a single biopsy represent a snapshot of this process that can reveal the timing of specific genomic aberrations and the changing influence of mutational processes 3 . Here, by whole-genome sequencing analysis of 2,658 cancers as part of the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA) 4 , we reconstruct the life history and evolution of mutational processes and driver mutation sequences of 38 types of cancer. Early oncogenesis is characterized by mutations in a constrained set of driver genes, and specific copy number gains, such as trisomy 7 in glioblastoma and isochromosome 17q in medulloblastoma. The mutational spectrum changes significantly throughout tumour evolution in 40% of samples. A nearly fourfold diversification of driver genes and increased genomic instability are features of later stages. Copy number alterations often occur in mitotic crises, and lead to simultaneous gains of chromosomal segments. Timing analyses suggest that driver mutations often precede diagnosis by many years, if not decades. Together, these results determine the evolutionary trajectories of cancer, and highlight opportunities for early cancer detection.

Abstract The genetic make-up of an individual contributes to the susceptibility and response to viral infection. Although environmental, clinical and social factors have a role in the chance of exposure to SARS-CoV-2 and the severity of COVID-19 1,2 , host genetics may also be important. Identifying host-specific genetic factors may reveal biological mechanisms of therapeutic relevance and clarify causal relationships of modifiable environmental risk factors for SARS-CoV-2 infection and outcomes. We formed a global network of researchers to investigate the role of human genetics in SARS-CoV-2 infection and COVID-19 severity. Here we describe the results of three genome-wide association meta-analyses that consist of up to 49,562 patients with COVID-19 from 46 studies across 19 countries. We report 13 genome-wide significant loci that are associated with SARS-CoV-2 infection or severe manifestations of COVID-19. Several of these loci correspond to previously documented associations to lung or autoimmune and inflammatory diseases 3–7 . They also represent potentially actionable mechanisms in response to infection. Mendelian randomization analyses support a causal role for smoking and body-mass index for severe COVID-19 although not for type II diabetes. The identification of novel host genetic factors associated with COVID-19 was made possible by the community of human genetics researchers coming together to prioritize the sharing of data, results, resources and analytical frameworks. This working model of international collaboration underscores what is possible for future genetic discoveries in emerging pandemics, or indeed for any complex human disease.

STUDY QUESTION: What is the recommended management of women with recurrent pregnancy loss (RPL) based on the best available evidence in the literature? SUMMARY ANSWER: The guideline development group formulated 77 recommendations answering 18 key questions on investigations and treatments for RPL, and on how care should be organized. WHAT IS KNOWN ALREADY: A previous guideline for the investigation and medical treatment of recurrent miscarriage was published in 2006 and is in need of an update. STUDY DESIGN SIZE DURATION: The guideline was developed according to the structured methodology for development of ESHRE guidelines. After formulation of key questions by a group of experts, literature searches and assessments were performed. Papers published up to 31 March 2017 and written in English were included. Cumulative live birth rate, live birth rate and pregnancy loss rate (or miscarriage rate) were considered the critical outcomes. PARTICIPANTS/MATERIALS SETTING METHODS: Based on the collected evidence, recommendations were formulated and discussed until consensus was reached within the guideline group. A stakeholder review was organized after finalization of the draft. The final version was approved by the guideline group and the ESHRE Executive Committee. MAIN RESULTS AND THE ROLE OF CHANCE: The guideline provides 38 recommendations on risk factors, prevention and investigations in couples with RPL, and 39 recommendations on treatments. These include 60 evidence-based recommendations - of which 31 were formulated as strong recommendations and 29 as conditional - and 17 good practice points. The evidence supporting investigations and treatment of couples with RPL is limited and of moderate quality. Of the evidence-based recommendations, only 10 (16.3%) were supported by moderate quality evidence. The remaining recommendations were supported by low (35 recommendations: 57.4%), or very low quality evidence (16 recommendations: 26.2%). There were no recommendations based on high quality evidence. Owing to the lack of evidence-based investigations and treatments in RPL care, the guideline also clearly mentions investigations and treatments that should not be used for couples with RPL. LIMITATIONS REASONS FOR CAUTION: Several investigations and treatments are offered to couples with RPL, but most of them are not well studied. For most of these investigations and treatments, a recommendation against the intervention or treatment was formulated based on insufficient evidence. Future studies may require these recommendations to be revised. WIDER IMPLICATIONS OF THE FINDINGS: The guideline provides clinicians with clear advice on best practice in RPL, based on the best evidence available. In addition, a list of research recommendations is provided to stimulate further studies in RPL. One of the most important consequences of the limited evidence is the absence of evidence for a definition of RPL. STUDY FUNDING/COMPETING INTERESTS: The guideline was developed and funded by ESHRE, covering expenses associated with the guideline meetings, with the literature searches and with the dissemination of the guideline. The guideline group members did not receive payment. J.E. reports position funding from CARE Fertility. S.L. reports position funding from SpermComet Ltd. S.M. reports research grants, consulting and speaker's fees from GSK, BMS/Pfizer, Sanquin, Aspen, Bayer and Daiichi Sankyo. S.Q. reports speaker's fees from Ferring. The other authors report no conflicts of interest.ESHRE Pages are not externally peer reviewed. This article has been approved by the Executive Committee of ESHRE.

The 2016 Warwick Agreement on femoroacetabular impingement (FAI) syndrome was convened to build an international, multidisciplinary consensus on the diagnosis and management of patients with FAI syndrome. 22 panel members and 1 patient from 9 countries and 5 different specialties participated in a 1-day consensus meeting on 29 June 2016. Prior to the meeting, 6 questions were agreed on, and recent relevant systematic reviews and seminal literature were circulated. Panel members gave presentations on the topics of the agreed questions at Sports Hip 2016, an open meeting held in the UK on 27-29 June. Presentations were followed by open discussion. At the 1-day consensus meeting, panel members developed statements in response to each question through open discussion; members then scored their level of agreement with each response on a scale of 0-10. Substantial agreement (range 9.5-10) was reached for each of the 6 consensus questions, and the associated terminology was agreed on. The term 'femoroacetabular impingement syndrome' was introduced to reflect the central role of patients' symptoms in the disorder. To reach a diagnosis, patients should have appropriate symptoms, positive clinical signs and imaging findings. Suitable treatments are conservative care, rehabilitation, and arthroscopic or open surgery. Current understanding of prognosis and topics for future research were discussed. The 2016 Warwick Agreement on FAI syndrome is an international multidisciplinary agreement on the diagnosis, treatment principles and key terminology relating to FAI syndrome.Author note The Warwick Agreement on femoroacetabular impingement syndrome has been endorsed by the following 25 clinical societies: American Medical Society for Sports Medicine (AMSSM), Association of Chartered Physiotherapists in Sports and Exercise Medicine (ACPSEM), Australasian College of Sports and Exercise Physicians (ACSEP), Austian Sports Physiotherapists, British Association of Sports and Exercise Medicine (BASEM), British Association of Sport Rehabilitators and Trainers (BASRaT), Canadian Academy of Sport and Exercise Medicine (CASEM), Danish Society of Sports Physical Therapy (DSSF), European College of Sports and Exercise Physicians (ECOSEP), European Society of Sports Traumatology, Knee Surgery and Arthroscopy (ESSKA), Finnish Sports Physiotherapist Association (SUFT), German-Austrian-Swiss Society for Orthopaedic Traumatologic Sports Medicine (GOTS), International Federation of Sports Physical Therapy (IFSPT), International Society for Hip Arthroscopy (ISHA), Groupo di Interesse Specialistico dell'A.I.F.I., Norwegian Association of Sports Medicine and Physical Activity (NIMF), Norwegian Sports Physiotherapy Association (FFI), Society of Sports Therapists (SST), South African Sports Medicine Association (SASMA), Sports Medicine Australia (SMA), Sports Doctors Australia (SDrA), Sports Physiotherapy New Zealand (SPNZ), Swedish Society of Exercise and Sports Medicine (SFAIM), Swiss Society of Sports Medicine (SGMS/SGSM), Swiss Sports Physiotherapy Association (SSPA).

Abstract A key mutational process in cancer is structural variation, in which rearrangements delete, amplify or reorder genomic segments that range in size from kilobases to whole chromosomes 1–7 . Here we develop methods to group, classify and describe somatic structural variants, using data from the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA), which aggregated whole-genome sequencing data from 2,658 cancers across 38 tumour types 8 . Sixteen signatures of structural variation emerged. Deletions have a multimodal size distribution, assort unevenly across tumour types and patients, are enriched in late-replicating regions and correlate with inversions. Tandem duplications also have a multimodal size distribution, but are enriched in early-replicating regions—as are unbalanced translocations. Replication-based mechanisms of rearrangement generate varied chromosomal structures with low-level copy-number gains and frequent inverted rearrangements. One prominent structure consists of 2–7 templates copied from distinct regions of the genome strung together within one locus. Such cycles of templated insertions correlate with tandem duplications, and—in liver cancer—frequently activate the telomerase gene TERT . A wide variety of rearrangement processes are active in cancer, which generate complex configurations of the genome upon which selection can act.

BACKGROUND: Little information has been reported on regional and time trends of human papillomavirus (HPV) prevalence rates of oropharyngeal cancer (OPC) and non-OPC. METHODS: The study consisted of a systematic review and meta-analysis using random effects logistic regression models. RESULTS: Overall HPV prevalence in OPC (47.7%; 95% confidence interval [CI], 42.9-52.5%) increased significantly over time: from 40.5% (95% CI, 35.1-46.1) before 2000, to 64.3% (95% CI, 56.7-71.3) between 2000 and 2004, and 72.2% (95% CI, 52.9-85.7) between 2005 and 2009 (p < .001). Prevalence increased significantly in North America and Europe, and the significant gap between them that existed before 2000 (50.7% vs 35.3%, respectively, p = .008) has now disappeared (69.7% vs 73.1%, respectively, p = .8). Prevalence in non-OPC (21.8%; 95% CI, 18.9-25.1%) has not increased over time (p = .97). CONCLUSIONS: The sharp increase in the proportion of HPV-positive OPC over the last decade has occurred at a faster rate in Europe compared with that in North America. In contrast, the relatively low prevalence of HPV in non-OPC remains unchanged.

The guideline group was selected to be representative of UK-based medical experts. MEDLINE and EMBASE were searched systematically for publications in English, using the keywords: thrombotic thrombocytopenia purpura (TTP), ADAMTS13, plasma exchange (PEX) and relevant key words related to the subsections of this guideline. The writing group produced the draft guideline, which was subsequently revised by consensus by members of the Haemostasis and Thrombosis Task Force of the BCSH. The guideline was then reviewed by a sounding board of British haematologists, the BCSH and the British Society for Haematology Committee and comments incorporated where appropriate. The ‘GRADE’ system was used to quote levels and grades of evidence, details of which can be found at http://www.bcshguidelines.com. The objective of this guideline is to provide healthcare professionals with clear, up-to-date, and practical guidance on the management of TTP and related thrombotic microangiopathies, defined by thrombocytopenia, microangiopathic haemolytic anaemia (MAHA) and small vessel thrombosis. Thrombotic thrombocytopenic purpura (TTP) is rare, with a reported incidence of six cases per million per year in the UK (Scully et al, 2008). It is an important diagnosis to make because the untreated mortality is 90%, which can be reduced with the prompt delivery of plasma exchange (PEX). Early death still occurs: approximately half of the deaths in the regional UK registry occurred within 24 h of presentation, primarily in women (Scully et al, 2008). In the last 15 years there has been a marked increase in the understanding of the pathogenesis of TTP. It is now recognized that congenital and acute acquired TTP are due to a deficiency of von Willebrand factor (VWF) cleaving protein, also known as ADAMTS1, (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13 – von Willebrand factor cleaving protein) (Fujikawa et al, 2001; Levy et al, 2001). In the absence of ADAMTS13, ultra large multimers of VWF (ULVWF) released from endothelium are not cleaved appropriately, and cause spontaneous platelet aggregates in conditions of high shear, such as in the microvasculature of the brain, heart and kidneys. Congenital TTP is due to an inherited deficiency of ADAMTS13, but acquired immune TTP is due to the reduction of ADAMTS13 by autoantibodies directed against ADAMTS13 (Furlan et al, 1998a; Tsai & Lian, 1998). Other clinical forms of thrombotic microangiopathy (TMA) occur in the absence of severe deficiency. Diagnosis can be difficult, as there is clinical overlap with haemolytic uraemic syndrome (HUS), autoimmune disease and a spectrum of pregnancy-related problems. Thrombotic thrombocytopenic purpura was originally characterized by a pentad of thrombocytopenia, MAHA, fluctuating neurological signs, renal impairment and fever, often with insidious onset. However, TTP can present without the full pentad; up to 35% of patients do not have neurological signs at presentation and renal abnormalities and fever are not prominent features. The revised diagnostic criteria state that TTP must be considered in the presence of thrombocytopenia and MAHA alone (Galbusera et al, 2006). This can result in an increased referral of other TMAs (Table 1). TTP remains a diagnosis based on clinical history, examination of the patient and the blood film. ADAMTS 13 assays help to confirm the diagnosis and monitor the course of the disease and possible need for additional treatments. Presenting symptoms and signs are summarized in Table 2 and reflect widespread multi organ thromboses. Neurological impairment has multiple presentations including headache, altered personality, reduced cognition, transient ischaemic attacks, fits and fluctuating levels of consciousness including coma; the latter is a poor prognostic sign. Acute renal failure requiring haemodialysis is rare in TTP and more indicative of HUS (Coppo et al, 2006; Scully et al, 2008). Additional ischaemic complications may be seen, such as abdominal pain due to intestinal ischaemia. Consumption of platelets in platelet-rich thrombi results in thrombocytopenia. The median platelet count is typically 10–30 × 109/l at presentation (Dervenoulas et al, 2000; Vesely et al, 2003; Coppo et al, 2006; Tuncer et al, 2007; Scully et al, 2008). Mechanical fragmentation of erythrocytes during flow through partially occluded, high shear small vessels causes a MAHA. Median haemoglobin levels on admission are typically 80–100 g/l, with schistocytes in the film, low haptoglobin levels and raised reticulocyte counts due to haemolysis. The direct Coombs test is negative. The combination of haemolysis and tissue ischaemia produces elevated lactate dehydrogenase (LDH) values. The clotting screen (prothrombin time, activated partial thromboplastin time and fibrinogen) is usually normal. A virology screen pre-treatment is necessary to exclude human immunodeficency virus (HIV) and other viral-associated TTP, and as a baseline prior to plasma exposure. Troponin T levels are raised in 50% of acute idiopathic TTP cases (Hughes et al, 2009), highlighting that cardiac involvement is common. Raised troponin levels are a sinister finding, for coronary artery occlusion is a common mode of early death. The incidence of symptomatic heart failure is increased in patients who have been given a recent platelet transfusion (Gami et al, 2005) (Table 3). Blood must be taken prior to treatment to assess baseline ADAMTS13 activity. Severely reduced ADAMTS13 activity (<5%) ± the presence of an inhibitor or IgG antibodies, confirms the diagnosis (Peyvandi et al, 2004; Coppo et al, 2006; Ferrari et al, 2007; Scully et al, 2007a). Decreased ADAMTS13 activity (<40% but >5%) has been reported in a wide variety of non-TTP conditions such as uraemia, inflammatory states, post-operatively and during pregnancy (Loof et al, 2001; Mannucci et al, 2001; Moore et al, 2001). The specificity of severe ADAMTS13 deficiency (<5%) in distinguishing acute TTP from HUS is 90% (Bianchi et al, 2002; Zheng et al, 2004) ADAMTS13 assays currently available include assays of activity, antigen and neutralizing or non-neutralizing anti-ADAMTS13 autoantibodies. Functional assays measuring ADAMTS13 activity are based on the failure of the patient plasma to degrade VWF multimers or synthetic VWF peptides. Inhibitory autoantibodies can be titrated in vitro using classical mixing studies and non-neutralizing antibodies can be detected by Western blotting or enzyme-linked immunosorbent assays (Peyvandi et al, 2010). 1 The diagnosis of TTP should be treated as a medical emergency (1A). 2 The initial diagnosis of TTP should be made on clinical history, examination and routine laboratory parameters of the patient, including blood film review (1A). 3 In view of the high risk of preventable, early deaths in TTP, treatment with PEX should be initiated as soon as possible, preferably within 4–8 h, regardless of the time of day at presentation, if a patient presents with a MAHA and thrombocytopenia in the absence of any other identifiable clinical cause (1B). 4 Serological tests for HIV, hepatitis B virus and hepatitis C virus, autoantibody screen and when appropriate, a pregnancy test, should be performed at presentation (1A). 5 Pre-treatment samples should be obtained to measure ADAMTS13 activity levels and to detect anti-ADAMTS13 antibodies. Measurement of ADAMTS 13 antigen levels is also useful in congenital TTP cases (1B). Congenital TTP is a rare disorder, with over 100 patients described worldwide, but this is likely to be an underestimate. It has a varied phenotype and can present at any age. As a general rule, those with more severe phenotypes present early: 1 Neonates typically have severe neonatal jaundice. Blood film examination may show schistocytes together with red cell anisocytosis. (Scully et al, 2006a). 2 More frequently, the diagnosis is made later in infancy or childhood (Schiff et al, 2004), typically with thrombocytopenia, MAHA, jaundice and elevated LDH, although some children may only have an isolated thrombocytopenia. Neurological symptoms, such as hemiparesis, hemiplegia or seizures, occur in 35% of cases (Loirat et al, 2006). 3 Patients may present in adulthood. In women, pregnancy is a common precipitant and is associated with a significant neonatal morbidity and mortality (Fujimura et al, 2009). Rarely ‘late-onset phenotype’ cases may not develop symptoms until their 50s and 60s with isolated cerebral events or renal disease ((Fujimura et al, 2011). Asymptomatic male cases have been reported, usually detected because they have affected siblings. Patients with congenital TTP have persistently low levels of ADAMTS13, but they can be asymptomatic until a further precipitating event results in a frank TTP episode. Events include febrile episodes, infections, vaccinations, excess alcohol intake and pregnancy (Furlan et al, 1997, 1998b; Schneppenheim et al, 2003). Congenital TTP has been missed in the past, because the diagnosis has not been considered, or diagnosed as idiopathic thrombocytopenic purpura or ‘atypical’ HUS (Veyradier et al, 2003), illustrating the importance of consideration of the diagnosis, review of the blood film and measurement of ADAMTS13 . The diagnosis of congenital TTP is dependent on detecting ADAMTS13 activity <5%, in the absence of antibodies to ADAMTS13. In the last few years molecular diagnosis has been used to confirm the diagnosis, and either a homozygous or compound heterozygote defect in ADAMTS13 is found. Testing of siblings and other first-degree relatives at risk should be considered. 1 Congenital TTP should be considered in neonates presenting with severe jaundice. Presentation may also occur in childhood or as an adult (1A). 2 The diagnosis of congenital TTP should be considered in children and adults with unexplained thrombocytopenia (1B). 3 The diagnosis of congenital TTP is confirmed by ADAMTS13 activity <5%, absence of antibody and confirmation of homozygous or compound heterozygous defects of the ADAMTS13 gene (1A). Acute idiopathic TTP is the most common form of TTP. It is an autoimmune disease characterized by antibodies, usually IgG, directed against ADAMTS13. The incidence is four to six cases per million of the population per year in the United States (Miller et al, 2004; Terrell et al, 2005) and six cases per million per year in the UK (Scully et al, 2008). Thrombotic thrombocytopenia purpura may be the initial presenting feature of HIV disease or in those with low CD4 counts following non- compliance with antiviral treatment (Ucar et al, 1994; Gervasoni et al, 2002). Remission is dependent upon improving the immune status of the patient, for stopping highly active anti retroviral therapy (HAART) can result in acute TTP relapse (Miller et al, 2005), but continued use of HAART usually prevents further relapses. TTP in HIV-positive individuals may be associated with the presence of severe ADAMTS13 deficiency and anti-ADAMTS13 antibodies. Those with severe ADAMTS13 deficiency (<5%) have fewer acquired immunodeficiency syndrome-related complications and higher CD4+ T cell counts, compared to HIV-TTP with ADAMTS13 levels >5%, who have an increased mortality (Malak et al, 2008). Pregnancy can be the initiating event for approximately 5–25% of TTP cases (Ridolfi & Bell, 1981; Vesely et al, 2004; Scully et al, 2008), which are late onset adult congenital TTP or acute idiopathic TTP. Differentiating TTP from the more common pregnancy-related TMAs, such as pre-eclampsia, syndrome elevated low and HUS is difficult, if TTP presents (Table Thrombosis in the in untreated TTP and results in death and is a continued risk of relapse during with levels of ADAMTS13 have a risk of relapse et al, 2003; Scully et al, to be for of TTP cases et al, 2003; Scully et al, 2008). can cause an disorder, typically in TTP is recognized in with with an incidence of per patients but has been described with and there is there is a et al, 2009). et al, Vesely et al, 2003; et al, 2004; Scully et al, 2008), et al, and used to hepatitis C et al, 2007; et al, 2007; et al, have been associated with TTP. are of acquired TTP associated with such as the and therapy (Scully et al, 2008). such as and can cause HUS but not TTP. 1 associated with of TTP include and which should be to relapse in patients with a of TTP 2 with TTP should be microangiopathy is a MAHA and thrombocytopenia that It may reflect associated with infections, such as A and disease has important from TTP, absence of ADAMTS13 rare neurological a poor to PEX and of of et al, Thrombotic microangiopathy in with a variety of & 2001). Presentation may be either at an early of or associated with ADAMTS13 activity is not reduced in patients et al, 2001). haemolytic anaemia has been reported in with acute a of of ADAMTS13 activity was only reduced and not with the of TTP or patients were treated with PEX and et al, 2009). associated typically with is treated with which in some cases renal not typically associated with but may be associated with symptoms, to TTP, should be treated with PEX et al, 2011). The factor HUS and TTP is the presence of renal in the of defects in HUS is defined & and use of the in cases et al, et al, but may also have a in severe et al, 2011). A of the treatment is in preferably with is the of treatment and has reduced mortality from over 90% to It of and ADAMTS13. in of PEX to early mortality et al, PEX remains the treatment of large plasma are if there is to be a in PEX has been to be to plasma at the of the treatment and at and and et al, The of PEX and the of to is highly but is in TTP (Coppo et al, 2006). has not been In the plasma exchange was performed on the 3 by exchange et al, More such as may be in cases if there is such as neurological or cardiac The of an PEX has been to as other are often initiated or et al, 2008). should for a of 2 defined as platelet count of has not been to relapse & 1998). is at as as plasma et al, et al, The UK of the use of plasma in TTP patients to the risk of and immune (Scully et al, plasma reduced levels of but an increased thrombotic has not been reported in cases where with low molecular and low was used the platelet count was × 109/l (Scully et al, ADAMTS13 activity is present in in and et al, In the is the plasma for use in in those to the risk of et al, has been associated with increased of PEX and in TTP et al, 2001; et al, 2008). A using compared to and et al, 2006). such as and to be more prior to the use of plasma (Scully et al, 1 PEX should be with using plasma in and (1B). 2 The of exchange can be reduced to when the clinical and laboratory test results are 3 in and or of PEX should be considered in cases 4 PEX should for a of 2 platelet count has been × and then or of ADAMTS13 are not treatment of plasma or the use of a factor ADAMTS13, such as et al, which has a small and can be given in the or of has been used with reported although there is of ADAMTS13 in such to ADAMTS 13 have not been detected following the use of that ADAMTS13 has a of only (Furlan et al, et al, 2004), the clinical of of plasma or are such that are only to a platelet and haemoglobin the of treatment on the therapy to the platelet count and at of and other The who have a platelet count most of the time, only 1 plasma or should be used to congenital TTP 2 for congenital TTP should be to the phenotype (1A). Diagnosis of TTP is if In any with a and as to the diagnosis that and can present in the PEX should be considered. TTP in the PEX may of pregnancy with delivery of a et al, et al, et al, Scully et al, is the treatment of for although delivery not of TTP. Pre-treatment ADAMTS13 assays congenital and acquired TTP from other In and syndrome ADAMTS13 activity is reduced but antibodies to ADAMTS13 are not found. with an with in and is with artery should be used to assess if there is and to assess blood alone may be in with congenital TTP. However, at delivery PEX may be to levels of ADAMTS13. The of plasma during pregnancy is In acquired TTP, is to relapse in A reduction in ADAMTS13 activity at the of pregnancy may therapy to during has been used in pregnancy in autoimmune and et al, 2011). 1 a be by a non-TTP pregnancy-related then the diagnosis of TTP must be considered and PEX should be 2 with congenital TTP should a and ADAMTS13 pregnancy and the (1A). 3 with an with a in is in with TTP (1A). 4 In with acquired TTP, ADAMTS13 activity should be pregnancy to help the need for therapy and (1B). 5 is for and women of should be of pregnancy and In those with severe ADAMTS13 there is in ADAMTS13 activity, as the CD4 count and HIV treatment with HAART and further therapy is for with or which do not cause a significant increase in complications et al, 2011). HAART should be given PEX to for time for 1 a patient with TTP is found to have HIV then should be and an HIV should be in management (1A). 2 TTP should be considered in an HIV-positive with a MAHA and thrombocytopenia (1A). 3 PEX in with HAART or should be as soon as the diagnosis of TTP is made (1B). 3 HAART should be given PEX therapy to time for (1A). 4 HAART should be continued to further relapse (1B). 5 In TTP, be considered is difficult, as stopping or to such as may has been with in a review was associated with an increased mortality et al, is of use of et al, et al, exchange has et al, The treatment of the is the of 1 PEX is not in the management of and (1A). 2 In associated further treatment for the should be considered (1A). are used in combination with PEX in the initial treatment of acute immune TTP. have to be associated with an patient and usually have et al, 2010). there is a combination of PEX and is to PEX 1 for – adult or high 1 should be considered (1B). studies have that is and in immune TTP, when patients to to PEX and and in acute idiopathic TTP et al, Scully et al, 2007a). has been used for 4 Patients in anti-ADAMTS13 IgG antibody levels and increased ADAMTS13 activity (Scully et al, 2007a). The risk of relapse to be reduced with use et al, 2007; Scully et al, 2011). PEX should be for at 4 h a & 2006; Scully et al, 2007a). more may during PEX et al, 2010). is of increased risk with in TTP A recent UK has in using as a therapy at presentation of TTP (Scully et al, 2011). 1 In acute idiopathic TTP with which are associated with a high should be considered on in with PEX and (1B). 2 Patients with or TTP should be (1B). A was used in patient with TTP et al, but further occurred of In a clinical of PEX with either or initial occurred in subsequently on and there was a relapse stopping of of the patients a relapse in the compared with of the patients a with an increase in ADAMTS13 activity and in antibodies to ADAMTS13 et al, In patients with renal is an but may and may be considered as therapy in patients with acute or acquired TTP the and of other used for and such as and use is associated with severe and has been in small of patients et al, et al, 2005), are not as of a clinical The mortality of in acute TTP was reported to be approximately In a of patients for acute and the was et al, et al, may be considered in the of TTP but has The TTP patients to PEX and with and without and et al, was in or and a of early death in the 15 in the group et al, 1 The clinical of in TTP is but they are (1B). 2 may be given during platelet count × cell transfusion and are during active haemolysis. It has been that transfusion in the is using a transfusion of this was not to those with cardiac disease et al, as cardiac is a feature of TTP, a higher haemoglobin may be in those with of cardiac involvement and acute haemolysis. to the risk of precipitating further thrombotic platelet are there is The risk of has been in acute TTP but is likely to be increased due to and acute routine should be given the platelet count has to × 109/l et al, 2003). B should be considered in TTP, a platelet of × 109/l has been but studies of are in the of continued PEX with 1 cell transfusion should be to clinical need if there is cardiac involvement (1A). 2 is during active haemolysis (1A). 3 are in TTP there is (1A). 4 with is platelet count has × (1B). is a of patients who present with TTP who subsequently show a or to PEX ± disease was defined as thrombocytopenia or a of PEX is not a of disease activity. have disease as of clinical symptoms or thrombocytopenia of PEX with the of or and the of further have some et al, et al, & & 2004; et al, 2008). is the of in disease (Scully et al, 2007a). of PEX and of can be considered in TTP (1B). is defined as an of acute TTP more and in of cases et al, & & The that over a of patients relapse et al, Patients with ADAMTS13 activity or an anti-ADAMTS13 antibody in a increase in relapse over 1 year (Peyvandi et al, 2008). In a further if ADAMTS13 was in relapse occurred in but if ADAMTS13 activity was only et al, The use of in an acute and the incidence of relapse (Scully et al, 2011). to patients should be the risk and the symptoms and signs of In patients who have TTP and where a reduction of ADAMTS 13 activity from levels to is therapy has been with of ADAMTS 13 activity (Scully et al, et al, 2009). Patients up with ADAMTS 13 1 PEX therapy are the of in disease (1B). 2 Patients should be symptoms, signs and risk of relapse with and (1A). 3 In patients with a reduction of ADAMTS 13 activity to <5%, therapy with can be considered (1B). uraemic syndrome is characterized by MAHA, thrombocytopenia and acute renal It associated with and cardiac and diagnostic overlap with TTP can It is important to HUS and TTP because the and management are (Table The is to et al, and et al, for further guidance in children and TTP and other TMAs The is to that haematologists, and are of the need to acute TTP as a medical emergency to early The of and in the should to in the the and in is to be and at the time of to the the British Society for Haematology the any for the of . In the British Society for Haematology the for the diagnosis and management of thrombotic et al, 2003). have revised based on available and for syndrome et al, and HUS et al, are now have been UK for review of 1 and for review of Table The Haemostasis has an from

BACKGROUND: Dietary fibre consists of non-digestible forms of carbohydrate, usually as polysaccharides that originate from plant-based foods. Over recent decades, our diet within Westernised societies has changed radically from that of our hominid ancestors, with implications for our co-evolved gut microbiota. This includes increased ingestion of ultra-processed foods that are typically impoverished of dietary fibre, and associated reduction in the intake of fibre-replete plant-based foods. Over recent decades, there has been a transformation in our understanding of the health benefits of dietary fibre. OBJECTIVE: To explore the current medical literature on the health benefits of dietary fibre, with a focus on overall metabolic health. DATA SOURCES: We performed a narrative review, based on relevant articles written in English from a PubMed search, using the terms 'dietary fibre and metabolic health'. RESULTS: In the Western world, our diets are impoverished of fibre. Dietary fibre intake associates with overall metabolic health (through key pathways that include insulin sensitivity) and a variety of other pathologies that include cardiovascular disease, colonic health, gut motility and risk for colorectal carcinoma. Dietary fibre intake also correlates with mortality. The gut microflora functions as an important mediator of the beneficial effects of dietary fibre, including the regulation of appetite, metabolic processes and chronic inflammatory pathways. CONCLUSIONS: Multiple factors contribute to our fibre-impoverished modern diet. Given the plethora of scientific evidence that corroborate the multiple and varied health benefits of dietary fibre, and the risks associated with a diet that lacks fibre, the optimization of fibre within our diets represents an important public health strategy to improve both metabolic and overall health. If implemented successfully, this strategy would likely result in substantial future health benefits for the population.

BACKGROUND: Concern about the use of epinephrine as a treatment for out-of-hospital cardiac arrest led the International Liaison Committee on Resuscitation to call for a placebo-controlled trial to determine whether the use of epinephrine is safe and effective in such patients. METHODS: In a randomized, double-blind trial involving 8014 patients with out-of-hospital cardiac arrest in the United Kingdom, paramedics at five National Health Service ambulance services administered either parenteral epinephrine (4015 patients) or saline placebo (3999 patients), along with standard care. The primary outcome was the rate of survival at 30 days. Secondary outcomes included the rate of survival until hospital discharge with a favorable neurologic outcome, as indicated by a score of 3 or less on the modified Rankin scale (which ranges from 0 [no symptoms] to 6 [death]). RESULTS: At 30 days, 130 patients (3.2%) in the epinephrine group and 94 (2.4%) in the placebo group were alive (unadjusted odds ratio for survival, 1.39; 95% confidence interval [CI], 1.06 to 1.82; P=0.02). There was no evidence of a significant difference in the proportion of patients who survived until hospital discharge with a favorable neurologic outcome (87 of 4007 patients [2.2%] vs. 74 of 3994 patients [1.9%]; unadjusted odds ratio, 1.18; 95% CI, 0.86 to 1.61). At the time of hospital discharge, severe neurologic impairment (a score of 4 or 5 on the modified Rankin scale) had occurred in more of the survivors in the epinephrine group than in the placebo group (39 of 126 patients [31.0%] vs. 16 of 90 patients [17.8%]). CONCLUSIONS: In adults with out-of-hospital cardiac arrest, the use of epinephrine resulted in a significantly higher rate of 30-day survival than the use of placebo, but there was no significant between-group difference in the rate of a favorable neurologic outcome because more survivors had severe neurologic impairment in the epinephrine group. (Funded by the U.K. National Institute for Health Research and others; Current Controlled Trials number, ISRCTN73485024 .).

OBJECTIVE: Recurrent digital ulcers are a manifestation of vascular disease in patients with systemic sclerosis (SSc; scleroderma) and lead to pain, impaired function, and tissue loss. We investigated whether treatment with the endothelin receptor antagonist, bosentan, decreased the development of new digital ulcers in patients with SSc. METHODS: This was a randomized, prospective, placebo-controlled, double-blind study of 122 patients at 17 centers in Europe and North America, evaluating the effect of treatment on prevention of digital ulcers. The primary outcome variable was the number of new digital ulcers developing during the 16-week study period. Secondary assessments included healing of existing digital ulcers and evaluation of hand function using the Scleroderma Health Assessment Questionnaire. RESULTS: Patients receiving bosentan had a 48% reduction in the mean number of new ulcers during the treatment period (1.4 versus 2.7 new ulcers; P = 0.0083). Patients who had digital ulcers at the time of entry in the study were at higher risk for the development of new ulcers; in this subgroup the mean number of new ulcers was reduced from 3.6 to 1.8 (P = 0.0075). In patients receiving bosentan, a statistically significant improvement in hand function was observed. There was no difference between treatment groups in the healing of existing ulcers. Serum transaminase levels were elevated to >3-fold the upper limit of normal in bosentan-treated patients; this elevation is comparable with that observed in previous studies of this agent. Other side effects were similar in the 2 treatment groups. CONCLUSION: Endothelins may play an important role in the pathogenesis of vascular disease in patients with SSc. Treatment with the endothelin receptor antagonist bosentan may be effective in preventing new digital ulcers and improving hand function in patients with SSc.

Current guidelines recommend that "overweight" and "obese" individuals lose weight through engaging in lifestyle modification involving diet, exercise and other behavior change. This approach reliably induces short term weight loss, but the majority of individuals are unable to maintain weight loss over the long term and do not achieve the putative benefits of improved morbidity and mortality. Concern has arisen that this weight focus is not only ineffective at producing thinner, healthier bodies, but may also have unintended consequences, contributing to food and body preoccupation, repeated cycles of weight loss and regain, distraction from other personal health goals and wider health determinants, reduced self-esteem, eating disorders, other health decrement, and weight stigmatization and discrimination. This concern has drawn increased attention to the ethical implications of recommending treatment that may be ineffective or damaging. A growing trans-disciplinary movement called Health at Every Size (HAES) challenges the value of promoting weight loss and dieting behavior and argues for a shift in focus to weight-neutral outcomes. Randomized controlled clinical trials indicate that a HAES approach is associated with statistically and clinically relevant improvements in physiological measures (e.g., blood pressure, blood lipids), health behaviors (e.g., eating and activity habits, dietary quality), and psychosocial outcomes (such as self-esteem and body image), and that HAES achieves these health outcomes more successfully than weight loss treatment and without the contraindications associated with a weight focus. This paper evaluates the evidence and rationale that justifies shifting the health care paradigm from a conventional weight focus to HAES.

Abstract The discovery of drivers of cancer has traditionally focused on protein-coding genes 1–4 . Here we present analyses of driver point mutations and structural variants in non-coding regions across 2,658 genomes from the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium 5 of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA). For point mutations, we developed a statistically rigorous strategy for combining significance levels from multiple methods of driver discovery that overcomes the limitations of individual methods. For structural variants, we present two methods of driver discovery, and identify regions that are significantly affected by recurrent breakpoints and recurrent somatic juxtapositions. Our analyses confirm previously reported drivers 6,7 , raise doubts about others and identify novel candidates, including point mutations in the 5′ region of TP53 , in the 3′ untranslated regions of NFKBIZ and TOB1 , focal deletions in BRD4 and rearrangements in the loci of AKR1C genes. We show that although point mutations and structural variants that drive cancer are less frequent in non-coding genes and regulatory sequences than in protein-coding genes, additional examples of these drivers will be found as more cancer genomes become available.

Aicardi-Goutières syndrome is an inflammatory disease occurring due to mutations in any of TREX1, RNASEH2A, RNASEH2B, RNASEH2C, SAMHD1, ADAR or IFIH1. We report on 374 patients from 299 families with mutations in these seven genes. Most patients conformed to one of two fairly stereotyped clinical profiles; either exhibiting an in utero disease-onset (74 patients; 22.8% of all patients where data were available), or a post-natal presentation, usually within the first year of life (223 patients; 68.6%), characterized by a sub-acute encephalopathy and a loss of previously acquired skills. Other clinically distinct phenotypes were also observed; particularly, bilateral striatal necrosis (13 patients; 3.6%) and non-syndromic spastic paraparesis (12 patients; 3.4%). We recorded 69 deaths (19.3% of patients with follow-up data). Of 285 patients for whom data were available, 210 (73.7%) were profoundly disabled, with no useful motor, speech and intellectual function. Chilblains, glaucoma, hypothyroidism, cardiomyopathy, intracerebral vasculitis, peripheral neuropathy, bowel inflammation and systemic lupus erythematosus were seen frequently enough to be confirmed as real associations with the Aicardi-Goutieres syndrome phenotype. We observed a robust relationship between mutations in all seven genes with increased type I interferon activity in cerebrospinal fluid and serum, and the increased expression of interferon-stimulated gene transcripts in peripheral blood. We recorded a positive correlation between the level of cerebrospinal fluid interferon activity assayed within one year of disease presentation and the degree of subsequent disability. Interferon-stimulated gene transcripts remained high in most patients, indicating an ongoing disease process. On the basis of substantial morbidity and mortality, our data highlight the urgent need to define coherent treatment strategies for the phenotypes associated with mutations in the Aicardi-Goutières syndrome-related genes. Our findings also make it clear that a window of therapeutic opportunity exists relevant to the majority of affected patients and indicate that the assessment of type I interferon activity might serve as a useful biomarker in future clinical trials.

BACKGROUND: Two clinical trials, one British and one American, have shown that early, prophylactic elective surgery does not improve five-year survival among patients with small abdominal aortic aneurysms. We report long-term outcomes in the United Kingdom Small Aneurysm Trial. METHODS: We randomly assigned 1090 patients, 60 to 76 years of age, with small abdominal aortic aneurysms (diameter, 4.0 to 5.5 cm) to one of two groups: 563 were assigned to undergo early elective surgery, and 527 were assigned to undergo surveillance by ultrasonography. Patients were followed in the trial until June 1998 and thereafter until August 2001; the mean duration of follow-up was 8 years (range, 6 to 10). RESULTS: The mean duration of survival was 6.5 years among patients in the surveillance group, as compared with 6.7 years among patients in the early-surgery group (P=0.29). The adjusted hazard ratio for death from any cause in the early-surgery group as compared with the surveillance group was 0.83 (95 percent confidence interval, 0.69 to 1.00; P=0.05). The 30-day operative mortality in the early-surgery group (5.5 percent) led to an early disadvantage in terms of survival. The survival curves crossed at three years, and at eight years, mortality in the early-surgery group was 7.2 percentage points lower than that in the surveillance group (P=0.03). There was no evidence that age, sex, or the initial size of the aneurysm modified the hazard ratio or that delayed surgery in the surveillance group increased 30-day postoperative mortality. Death was attributable to a ruptured aneurysm in 19 of the 411 men who died (5 percent) and in 12 of the 85 women who died (14 percent) (P=0.001). The rate of early cessation of smoking was higher in the early-surgery group than in the surveillance group. CONCLUSIONS: Among patients with a small abdominal aortic aneurysm, we found no long-term difference in mean survival between the early-surgery and surveillance groups, although after eight years, total mortality was lower in the early-surgery group. This difference may be attributed in part to beneficial changes in lifestyle adopted by members of the early-surgery group.

BACKGROUND: Localised prostate cancer is commonly treated with external-beam radiotherapy. Moderate hypofractionation has been shown to be non-inferior to conventional fractionation. Ultra-hypofractionated stereotactic body radiotherapy would allow shorter treatment courses but could increase acute toxicity compared with conventionally fractionated or moderately hypofractionated radiotherapy. We report the acute toxicity findings from a randomised trial of standard-of-care conventionally fractionated or moderately hypofractionated radiotherapy versus five-fraction stereotactic body radiotherapy for low-risk to intermediate-risk localised prostate cancer. METHODS: PACE is an international, phase 3, open-label, randomised, non-inferiority trial. In PACE-B, eligible men aged 18 years and older, with WHO performance status 0-2, low-risk or intermediate-risk prostate adenocarcinoma (Gleason 4 + 3 excluded), and scheduled to receive radiotherapy were recruited from 37 centres in three countries (UK, Ireland, and Canada). Participants were randomly allocated (1:1) by computerised central randomisation with permuted blocks (size four and six), stratified by centre and risk group, to conventionally fractionated or moderately hypofractionated radiotherapy (78 Gy in 39 fractions over 7·8 weeks or 62 Gy in 20 fractions over 4 weeks, respectively) or stereotactic body radiotherapy (36·25 Gy in five fractions over 1-2 weeks). Neither participants nor investigators were masked to allocation. Androgen deprivation was not permitted. The primary endpoint of PACE-B is freedom from biochemical or clinical failure. The coprimary outcomes for this acute toxicity substudy were worst grade 2 or more severe Radiation Therapy Oncology Group (RTOG) gastrointestinal or genitourinary toxic effects score up to 12 weeks after radiotherapy. Analysis was per protocol. This study is registered with ClinicalTrials.gov, NCT01584258. PACE-B recruitment is complete and follow-up is ongoing. FINDINGS: Between Aug 7, 2012, and Jan 4, 2018, we randomly assigned 874 men to conventionally fractionated or moderately hypofractionated radiotherapy (n=441) or stereotactic body radiotherapy (n=433). 432 (98%) of 441 patients allocated to conventionally fractionated or moderately hypofractionated radiotherapy and 415 (96%) of 433 patients allocated to stereotactic body radiotherapy received at least one fraction of allocated treatment. Worst acute RTOG gastrointestinal toxic effect proportions were as follows: grade 2 or more severe toxic events in 53 (12%) of 432 patients in the conventionally fractionated or moderately hypofractionated radiotherapy group versus 43 (10%) of 415 patients in the stereotactic body radiotherapy group (difference -1·9 percentage points, 95% CI -6·2 to 2·4; p=0·38). Worst acute RTOG genitourinary toxicity proportions were as follows: grade 2 or worse toxicity in 118 (27%) of 432 patients in the conventionally fractionated or moderately hypofractionated radiotherapy group versus 96 (23%) of 415 patients in the stereotactic body radiotherapy group (difference -4·2 percentage points, 95% CI -10·0 to 1·7; p=0·16). No treatment-related deaths occurred. INTERPRETATION: Previous evidence (from the HYPO-RT-PC trial) suggested higher patient-reported toxicity with ultrahypofractionation. By contrast, our results suggest that substantially shortening treatment courses with stereotactic body radiotherapy does not increase either gastrointestinal or genitourinary acute toxicity. FUNDING: Accuray and National Institute of Health Research.