Sheffield Teaching Hospitals NHS Foundation Trust

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.

Preceding the joint meeting of the 19th annual Diabetic Neuropathy Study Group of the European Association for the Study of Diabetes (NEURODIAB) and the 8th International Symposium on Diabetic Neuropathy in Toronto, Canada, 13-18 October 2009, expert panels were convened to provide updates on classification, definitions, diagnostic criteria, and treatments of diabetic peripheral neuropathies (DPNs), autonomic neuropathy, painful DPNs, and structural alterations in DPNs.

Guidelines summarize and evaluate available evidence, with the aim of assisting health professionals in proposing the best management strategies for an individual patient with a given condition. Guidelines and their recommendations should facilitate decision-making of health professionals in their daily practice. However, guidelines are not a substitute for the patient's relationship with their practitioner. The final decisions concerning an individual patient must be made by the responsible health professional(s), based on what they consider to be the most appropriate in the circumstances. These decisions are made in consultation with the patient and caregiver as appropriate. 2022 ESC/ERS pulmonary hypertension guidelines incorporate changes and adaptations focusing on clinical management <https://bit.ly/3QtUvb4>

BACKGROUND: Randomised placebo-controlled trials have shown that daily oral pre-exposure prophylaxis (PrEP) with tenofovir-emtricitabine reduces the risk of HIV infection. However, this benefit could be counteracted by risk compensation in users of PrEP. We did the PROUD study to assess this effect. METHODS: PROUD is an open-label randomised trial done at 13 sexual health clinics in England. We enrolled HIV-negative gay and other men who have sex with men who had had anal intercourse without a condom in the previous 90 days. Participants were randomly assigned (1:1) to receive daily combined tenofovir disoproxil fumarate (245 mg) and emtricitabine (200 mg) either immediately or after a deferral period of 1 year. Randomisation was done via web-based access to a central computer-generated list with variable block sizes (stratified by clinical site). Follow-up was quarterly. The primary outcomes for the pilot phase were time to accrue 500 participants and retention; secondary outcomes included incident HIV infection during the deferral period, safety, adherence, and risk compensation. The trial is registered with ISRCTN (number ISRCTN94465371) and ClinicalTrials.gov (NCT02065986). FINDINGS: We enrolled 544 participants (275 in the immediate group, 269 in the deferred group) between Nov 29, 2012, and April 30, 2014. Based on early evidence of effectiveness, the trial steering committee recommended on Oct 13, 2014, that all deferred participants be offered PrEP. Follow-up for HIV incidence was complete for 243 (94%) of 259 patient-years in the immediate group versus 222 (90%) of 245 patient-years in the deferred group. Three HIV infections occurred in the immediate group (1·2/100 person-years) versus 20 in the deferred group (9·0/100 person-years) despite 174 prescriptions of post-exposure prophylaxis in the deferred group (relative reduction 86%, 90% CI 64-96, p=0·0001; absolute difference 7·8/100 person-years, 90% CI 4·3-11·3). 13 men (90% CI 9-23) in a similar population would need access to 1 year of PrEP to avert one HIV infection. We recorded no serious adverse drug reactions; 28 adverse events, most commonly nausea, headache, and arthralgia, resulted in interruption of PrEp. We detected no difference in the occurrence of sexually transmitted infections, including rectal gonorrhoea and chlamydia, between groups, despite a suggestion of risk compensation among some PrEP recipients. INTERPRETATION: In this high incidence population, daily tenofovir-emtricitabine conferred even higher protection against HIV than in placebo-controlled trials, refuting concerns that effectiveness would be less in a real-world setting. There was no evidence of an increase in other sexually transmitted infections. Our findings strongly support the addition of PrEP to the standard of prevention for men who have sex with men at risk of HIV infection. FUNDING: MRC Clinical Trials Unit at UCL, Public Health England, and Gilead Sciences.

Peer Reviewed

: By definition, an adrenal incidentaloma is an asymptomatic adrenal mass detected on imaging not performed for suspected adrenal disease. In most cases, adrenal incidentalomas are nonfunctioning adrenocortical adenomas, but may also represent conditions requiring therapeutic intervention (e.g. adrenocortical carcinoma, pheochromocytoma, hormone-producing adenoma or metastasis). The purpose of this guideline is to provide clinicians with best possible evidence-based recommendations for clinical management of patients with adrenal incidentalomas based on the GRADE (Grading of Recommendations Assessment, Development and Evaluation) system. We predefined four main clinical questions crucial for the management of adrenal incidentaloma patients, addressing these four with systematic literature searches: (A) How to assess risk of malignancy?; (B) How to define and manage low-level autonomous cortisol secretion, formerly called 'subclinical' Cushing's syndrome?; (C) Who should have surgical treatment and how should it be performed?; (D) What follow-up is indicated if the adrenal incidentaloma is not surgically removed? SELECTED RECOMMENDATIONS: (i) At the time of initial detection of an adrenal mass establishing whether the mass is benign or malignant is an important aim to avoid cumbersome and expensive follow-up imaging in those with benign disease. (ii) To exclude cortisol excess, a 1mg overnight dexamethasone suppression test should be performed (applying a cut-off value of serum cortisol ≤50nmol/L (1.8µg/dL)). (iii) For patients without clinical signs of overt Cushing's syndrome but serum cortisol levels post 1mg dexamethasone >138nmol/L (>5µg/dL), we propose the term 'autonomous cortisol secretion'. (iv) All patients with '(possible) autonomous cortisol' secretion should be screened for hypertension and type 2 diabetes mellitus, to ensure these are appropriately treated. (v) Surgical treatment should be considered in an individualized approach in patients with 'autonomous cortisol secretion' who also have comorbidities that are potentially related to cortisol excess. (vi) In principle, the appropriateness of surgical intervention should be guided by the likelihood of malignancy, the presence and degree of hormone excess, age, general health and patient preference. (vii) Surgery is not usually indicated in patients with an asymptomatic, nonfunctioning unilateral adrenal mass and obvious benign features on imaging studies. We provide guidance on which surgical approach should be considered for adrenal masses with radiological findings suspicious of malignancy. Furthermore, we offer recommendations for the follow-up of patients with adrenal incidentaloma who do not undergo adrenal surgery, for those with bilateral incidentalomas, for patients with extra-adrenal malignancy and adrenal masses and for young and elderly patients with adrenal incidentalomas.

BACKGROUND: Severe hypoglycemia may increase the risk of a poor outcome in patients with type 2 diabetes assigned to an intensive glucose-lowering intervention. We analyzed data from a large study of intensive glucose lowering to explore the relationship between severe hypoglycemia and adverse clinical outcomes. METHODS: We examined the associations between severe hypoglycemia and the risks of macrovascular or microvascular events and death among 11,140 patients with type 2 diabetes, using Cox proportional-hazards models with adjustment for covariates measured at baseline and after randomization. RESULTS: During a median follow-up period of 5 years, 231 patients (2.1%) had at least one severe hypoglycemic episode; 150 had been assigned to intensive glucose control (2.7% of the 5571 patients in that group), and 81 had been assigned to standard glucose control (1.5% of the 5569 patients in that group). The median times from the onset of severe hypoglycemia to the first major macrovascular event, the first major microvascular event, and death were 1.56 years (interquartile range, 0.84 to 2.41), 0.99 years (interquartile range, 0.40 to 2.17), and 1.05 years (interquartile range, 0.34 to 2.41), respectively. During follow-up, severe hypoglycemia was associated with a significant increase in the adjusted risks of major macrovascular events (hazard ratio, 2.88; 95% confidence interval [CI], 2.01 to 4.12), major microvascular events (hazard ratio, 1.81; 95% CI, 1.19 to 2.74), death from a cardiovascular cause (hazard ratio, 2.68; 95% CI, 1.72 to 4.19), and death from any cause (hazard ratio, 2.69; 95% CI, 1.97 to 3.67) (P<0.001 for all comparisons). Similar associations were apparent for a range of nonvascular outcomes, including respiratory, digestive, and skin conditions (P<0.01 for all comparisons). No relationship was found between repeated episodes of severe hypoglycemia and vascular outcomes or death. CONCLUSIONS: Severe hypoglycemia was strongly associated with increased risks of a range of adverse clinical outcomes. It is possible that severe hypoglycemia contributes to adverse outcomes, but these analyses indicate that hypoglycemia is just as likely to be a marker of vulnerability to such events. (Funded by Servier and the National Health and Medical Research Council of Australia; ClinicalTrials.gov number, NCT00145925.).

BACKGROUND: Prostate cancer might have high radiation-fraction sensitivity that would give a therapeutic advantage to hypofractionated treatment. We present a pre-planned analysis of the efficacy and side-effects of a randomised trial comparing conventional and hypofractionated radiotherapy after 5 years follow-up. METHODS: CHHiP is a randomised, phase 3, non-inferiority trial that recruited men with localised prostate cancer (pT1b-T3aN0M0). Patients were randomly assigned (1:1:1) to conventional (74 Gy delivered in 37 fractions over 7·4 weeks) or one of two hypofractionated schedules (60 Gy in 20 fractions over 4 weeks or 57 Gy in 19 fractions over 3·8 weeks) all delivered with intensity-modulated techniques. Most patients were given radiotherapy with 3-6 months of neoadjuvant and concurrent androgen suppression. Randomisation was by computer-generated random permuted blocks, stratified by National Comprehensive Cancer Network (NCCN) risk group and radiotherapy treatment centre, and treatment allocation was not masked. The primary endpoint was time to biochemical or clinical failure; the critical hazard ratio (HR) for non-inferiority was 1·208. Analysis was by intention to treat. Long-term follow-up continues. The CHHiP trial is registered as an International Standard Randomised Controlled Trial, number ISRCTN97182923. FINDINGS: Between Oct 18, 2002, and June 17, 2011, 3216 men were enrolled from 71 centres and randomly assigned (74 Gy group, 1065 patients; 60 Gy group, 1074 patients; 57 Gy group, 1077 patients). Median follow-up was 62·4 months (IQR 53·9-77·0). The proportion of patients who were biochemical or clinical failure free at 5 years was 88·3% (95% CI 86·0-90·2) in the 74 Gy group, 90·6% (88·5-92·3) in the 60 Gy group, and 85·9% (83·4-88·0) in the 57 Gy group. 60 Gy was non-inferior to 74 Gy (HR 0·84 [90% CI 0·68-1·03], pNI=0·0018) but non-inferiority could not be claimed for 57 Gy compared with 74 Gy (HR 1·20 [0·99-1·46], pNI=0·48). Long-term side-effects were similar in the hypofractionated groups compared with the conventional group. There were no significant differences in either the proportion or cumulative incidence of side-effects 5 years after treatment using three clinician-reported as well as patient-reported outcome measures. The estimated cumulative 5 year incidence of Radiation Therapy Oncology Group (RTOG) grade 2 or worse bowel and bladder adverse events was 13·7% (111 events) and 9·1% (66 events) in the 74 Gy group, 11·9% (105 events) and 11·7% (88 events) in the 60 Gy group, 11·3% (95 events) and 6·6% (57 events) in the 57 Gy group, respectively. No treatment-related deaths were reported. INTERPRETATION: Hypofractionated radiotherapy using 60 Gy in 20 fractions is non-inferior to conventional fractionation using 74 Gy in 37 fractions and is recommended as a new standard of care for external-beam radiotherapy of localised prostate cancer. FUNDING: Cancer Research UK, Department of Health, and the National Institute for Health Research Cancer Research Network.

BACKGROUND: Based on previous findings, we hypothesised that radiotherapy to the prostate would improve overall survival in men with metastatic prostate cancer, and that the benefit would be greatest in patients with a low metastatic burden. We aimed to compare standard of care for metastatic prostate cancer, with and without radiotherapy. METHODS: We did a randomised controlled phase 3 trial at 117 hospitals in Switzerland and the UK. Eligible patients had newly diagnosed metastatic prostate cancer. We randomly allocated patients open-label in a 1:1 ratio to standard of care (control group) or standard of care and radiotherapy (radiotherapy group). Randomisation was stratified by hospital, age at randomisation, nodal involvement, WHO performance status, planned androgen deprivation therapy, planned docetaxel use (from December, 2015), and regular aspirin or non-steroidal anti-inflammatory drug use. Standard of care was lifelong androgen deprivation therapy, with up-front docetaxel permitted from December, 2015. Men allocated radiotherapy received either a daily (55 Gy in 20 fractions over 4 weeks) or weekly (36 Gy in six fractions over 6 weeks) schedule that was nominated before randomisation. The primary outcome was overall survival, measured as the number of deaths; this analysis had 90% power with a one-sided α of 2·5% for a hazard ratio (HR) of 0·75. Secondary outcomes were failure-free survival, progression-free survival, metastatic progression-free survival, prostate cancer-specific survival, and symptomatic local event-free survival. Analyses used Cox proportional hazards and flexible parametric models, adjusted for stratification factors. The primary outcome analysis was by intention to treat. Two prespecified subgroup analyses tested the effects of prostate radiotherapy by baseline metastatic burden and radiotherapy schedule. This trial is registered with ClinicalTrials.gov, number NCT00268476. FINDINGS: Between Jan 22, 2013, and Sept 2, 2016, 2061 men underwent randomisation, 1029 were allocated the control and 1032 radiotherapy. Allocated groups were balanced, with a median age of 68 years (IQR 63-73) and median amount of prostate-specific antigen of 97 ng/mL (33-315). 367 (18%) patients received early docetaxel. 1082 (52%) participants nominated the daily radiotherapy schedule before randomisation and 979 (48%) the weekly schedule. 819 (40%) men had a low metastatic burden, 1120 (54%) had a high metastatic burden, and the metastatic burden was unknown for 122 (6%). Radiotherapy improved failure-free survival (HR 0·76, 95% CI 0·68-0·84; p<0·0001) but not overall survival (0·92, 0·80-1·06; p=0·266). Radiotherapy was well tolerated, with 48 (5%) adverse events (Radiation Therapy Oncology Group grade 3-4) reported during radiotherapy and 37 (4%) after radiotherapy. The proportion reporting at least one severe adverse event (Common Terminology Criteria for Adverse Events grade 3 or worse) was similar by treatment group in the safety population (398 [38%] with control and 380 [39%] with radiotherapy). INTERPRETATION: Radiotherapy to the prostate did not improve overall survival for unselected patients with newly diagnosed metastatic prostate cancer. FUNDING: Cancer Research UK, UK Medical Research Council, Swiss Group for Clinical Cancer Research, Astellas, Clovis Oncology, Janssen, Novartis, Pfizer, and Sanofi-Aventis.

BACKGROUND: The ChAdOx1 nCoV-19 (AZD1222) vaccine has been approved for emergency use by the UK regulatory authority, Medicines and Healthcare products Regulatory Agency, with a regimen of two standard doses given with an interval of 4-12 weeks. The planned roll-out in the UK will involve vaccinating people in high-risk categories with their first dose immediately, and delivering the second dose 12 weeks later. Here, we provide both a further prespecified pooled analysis of trials of ChAdOx1 nCoV-19 and exploratory analyses of the impact on immunogenicity and efficacy of extending the interval between priming and booster doses. In addition, we show the immunogenicity and protection afforded by the first dose, before a booster dose has been offered. METHODS: viral particles) of the ChAdOx1 nCoV-19 for the first dose. The primary outcome was virologically confirmed symptomatic COVID-19 disease, defined as a nucleic acid amplification test (NAAT)-positive swab combined with at least one qualifying symptom (fever ≥37·8°C, cough, shortness of breath, or anosmia or ageusia) more than 14 days after the second dose. Secondary efficacy analyses included cases occuring at least 22 days after the first dose. Antibody responses measured by immunoassay and by pseudovirus neutralisation were exploratory outcomes. All cases of COVID-19 with a NAAT-positive swab were adjudicated for inclusion in the analysis by a masked independent endpoint review committee. The primary analysis included all participants who were SARS-CoV-2 N protein seronegative at baseline, had had at least 14 days of follow-up after the second dose, and had no evidence of previous SARS-CoV-2 infection from NAAT swabs. Safety was assessed in all participants who received at least one dose. The four trials are registered at ISRCTN89951424 (COV003) and ClinicalTrials.gov, NCT04324606 (COV001), NCT04400838 (COV002), and NCT04444674 (COV005). FINDINGS: Between April 23 and Dec 6, 2020, 24 422 participants were recruited and vaccinated across the four studies, of whom 17 178 were included in the primary analysis (8597 receiving ChAdOx1 nCoV-19 and 8581 receiving control vaccine). The data cutoff for these analyses was Dec 7, 2020. 332 NAAT-positive infections met the primary endpoint of symptomatic infection more than 14 days after the second dose. Overall vaccine efficacy more than 14 days after the second dose was 66·7% (95% CI 57·4-74·0), with 84 (1·0%) cases in the 8597 participants in the ChAdOx1 nCoV-19 group and 248 (2·9%) in the 8581 participants in the control group. There were no hospital admissions for COVID-19 in the ChAdOx1 nCoV-19 group after the initial 21-day exclusion period, and 15 in the control group. 108 (0·9%) of 12 282 participants in the ChAdOx1 nCoV-19 group and 127 (1·1%) of 11 962 participants in the control group had serious adverse events. There were seven deaths considered unrelated to vaccination (two in the ChAdOx1 nCov-19 group and five in the control group), including one COVID-19-related death in one participant in the control group. Exploratory analyses showed that vaccine efficacy after a single standard dose of vaccine from day 22 to day 90 after vaccination was 76·0% (59·3-85·9). Our modelling analysis indicated that protection did not wane during this initial 3-month period. Similarly, antibody levels were maintained during this period with minimal waning by day 90 (geometric mean ratio [GMR] 0·66 [95% CI 0·59-0·74]). In the participants who received two standard doses, after the second dose, efficacy was higher in those with a longer prime-boost interval (vaccine efficacy 81·3% [95% CI 60·3-91·2] at ≥12 weeks) than in those with a short interval (vaccine efficacy 55·1% [33·0-69·9] at <6 weeks). These observations are supported by immunogenicity data that showed binding antibody responses more than two-fold higher after an interval of 12 or more weeks compared with an interval of less than 6 weeks in those who were aged 18-55 years (GMR 2·32 [2·01-2·68]). INTERPRETATION: The results of this primary analysis of two doses of ChAdOx1 nCoV-19 were consistent with those seen in the interim analysis of the trials and confirm that the vaccine is efficacious, with results varying by dose interval in exploratory analyses. A 3-month dose interval might have advantages over a programme with a short dose interval for roll-out of a pandemic vaccine to protect the largest number of individuals in the population as early as possible when supplies are scarce, while also improving protection after receiving a second dose. FUNDING: UK Research and Innovation, National Institutes of Health Research (NIHR), The Coalition for Epidemic Preparedness Innovations, the Bill & Melinda Gates Foundation, the Lemann Foundation, Rede D'Or, the Brava and Telles Foundation, NIHR Oxford Biomedical Research Centre, Thames Valley and South Midland's NIHR Clinical Research Network, and AstraZeneca.

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.

BACKGROUND: Interprofessional education (IPE) aims to bring together different professionals to learn with, from, and about one another in order to collaborate more effectively in the delivery of safe, high-quality care for patients/clients. Given its potential for improving collaboration and care delivery, there have been repeated calls for the wider-scale implementation of IPE across education and clinical settings. Increasingly, a range of IPE initiatives are being implemented and evaluated which are adding to the growth of evidence for this form of education. AIM: The overall aim of this review is to update a previous BEME review published in 2007. In doing so, this update sought to synthesize the evolving nature of the IPE evidence. METHODS: Medline, CINAHL, BEI, and ASSIA were searched from May 2005 to June 2014. Also, journal hand searches were undertaken. All potential abstracts and papers were screened by pairs of reviewers to determine inclusion. All included papers were assessed for methodological quality and those deemed as "high quality" were included. The presage-process-product (3P) model and a modified Kirkpatrick model were employed to analyze and synthesize the included studies. RESULTS: Twenty-five new IPE studies were included in this update. These studies were added to the 21 studies from the previous review to form a complete data set of 46 high-quality IPE studies. In relation to the 3P model, overall the updated review found that most of the presage and process factors identified from the previous review were further supported in the newer studies. In regard to the products (outcomes) reported, the results from this review continue to show far more positive than neutral or mixed outcomes reported in the included studies. Based on the modified Kirkpatrick model, the included studies suggest that learners respond well to IPE, their attitudes and perceptions of one another improve, and they report increases in collaborative knowledge and skills. There is more limited, but growing, evidence related to changes in behavior, organizational practice, and benefits to patients/clients. CONCLUSIONS: This updated review found that key context (presage) and process factors reported in the previous review continue to have resonance on the delivery of IPE. In addition, the newer studies have provided further evidence for the effects on IPE related to a number of different outcomes. Based on these conclusions, a series of key implications for the development of IPE are offered.

The Cardiovascular Autonomic Neuropathy (CAN) Subcommittee of the Toronto Consensus Panel on Diabetic Neuropathy worked to update CAN guidelines, with regard to epidemiology, clinical impact, diagnosis, usefulness of CAN testing, and management. CAN is the impairment of cardiovascular autonomic control in the setting of diabetes after exclusion of other causes. The prevalence of confirmed CAN is around 20%, and increases up to 65% with age and diabetes duration. Established risk factors for CAN are glycaemic control in type 1 and a combination of hypertension, dyslipidaemia, obesity, and glycaemic control in type 2 diabetes. CAN is a risk marker of mortality and cardiovascular morbidity, and possibly a progression promoter of diabetic nephropathy. Criteria for CAN diagnosis and staging are: (1) one abnormal cardiovagal test result identifies possible or early CAN; (2) at least two abnormal cardiovagal test results are required for definite or confirmed CAN; and (3) the presence of orthostatic hypotension in addition to abnormal heart rate test results identifies severe or advanced CAN. Progressive stages of CAN are associated with increasingly worse prognosis. CAN assessment is relevant in clinical practice for (1) diagnosis of CAN clinical forms, (2) detection and tailored treatment of CAN clinical correlates (e.g. tachycardia, orthostatic hypotension, non-dipping, QT interval prolongation), (3) risk stratification for diabetic complications and cardiovascular morbidity and mortality, and (4) modulation of targets of diabetes therapy. Evidence on the cost-effectiveness of CAN testing is lacking. Apart from the preventive role of intensive glycaemic control in type 1 diabetes, recommendations cannot be made for most therapeutic approaches to CAN.

SMALL-BOWEL CAPSULE ENDOSCOPY (SBCE): 1: ESGE recommends that prior to SBCE patients ingest a purgative (2 L of polyethylene glycol [PEG]) for better visualization.Strong recommendation, high quality evidence.However, the optimal timing for taking purgatives is yet to be established. 2: ESGE recommends that SBCE should be performed as an outpatient procedure if possible, since completion rates are higher in outpatients than in inpatients.Strong recommendation, moderate quality evidence. 3: ESGE recommends that patients with pacemakers can safely undergo SBCE without special precautions.Strong recommendation, low quality evidence. 4: ESGE suggests that SBCE can also be safely performed in patients with implantable cardioverter defibrillators and left ventricular assist devices.Weak recommendation, low quality evidence. 5: ESGE recommends the acceptance of qualified nurses and trained technicians as prereaders of capsule endoscopy studies as their competency in identifying pathology is similar to that of medically qualified readers. The responsibility of establishing a diagnosis must however remain with the attending physician.Strong recommendation, moderate quality evidence. 6: ESGE recommends observation in cases of asymptomatic capsule retention.Strong recommendation, moderate quality evidence.In cases where capsule retrieval is indicated, ESGE recommends the use of device-assisted enteroscopy as the method of choice.Strong recommendation, moderate quality evidence. DEVICE-ASSISTED ENTEROSCOPY (DAE): 1: ESGE recommends performing diagnostic DAE as a day-case procedure in patients without significant underlying co-morbidities; in patients with co-morbidities and/or those undergoing a therapeutic procedure, an inpatient stay is recommended.Strong recommendation, low quality evidenceThe choice between different settings also depends on sedation protocols.Strong recommendation, low quality evidence. 2: ESGE suggests that conscious sedation, deep sedation, and general anesthesia are all acceptable alternatives: the choice between them should be governed by procedure complexity, clinical factors, and local organizational protocols.Weak recommendation, low quality evidence. 3: ESGE recommends that the findings of previous diagnostic investigations should guide the choice of insertion route.Strong recommendation, moderate quality evidence.If the location of the small-bowel lesion is unknown or uncertain, ESGE recommends that the antegrade route should be generally preferred.Strong recommendation, low quality evidence.In the setting of massive overt bleeding, ESGE recommends an initial antegrade approach.Strong recommendation, low quality evidence. 4: ESGE recommends that, for balloon-assisted enteroscopy (i. e., single-balloon enteroscopy [SBE] and double-balloon enteroscopy [DBE]), small-bowel insertion depth should be estimated by counting net advancement of the enteroscope during the insertion phase, with confirmation of this estimate during withdrawal.Strong recommendation, low quality evidence.ESGE recommends that, for spiral enteroscopy, insertion depth should be estimated during withdrawal.Strong recommendation, moderate quality evidence. Since the calculated insertion depth is only a rough estimate, ESGE recommends placing a tattoo to mark the identified lesion and/or the deepest point of insertion.Strong recommendation, low quality evidence. 5: ESGE recommends that all endoscopic therapeutic procedures can be undertaken at the time of DAE.Strong recommendation, moderate quality evidence.Moreover, when therapeutic interventions are performed, additional specific safety measures are needed to prevent complications.Strong recommendation, high quality evidence.

This Guideline is an official statement of the European Society of Gastrointestinal Endoscopy (ESGE). It addresses the diagnosis and management of nonvariceal upper gastrointestinal hemorrhage (NVUGIH). Main Recommendations MR1. ESGE recommends immediate assessment of hemodynamic status in patients who present with acute upper gastrointestinal hemorrhage (UGIH), with prompt intravascular volume replacement initially using crystalloid fluids if hemodynamic instability exists (strong recommendation, moderate quality evidence). MR2. ESGE recommends a restrictive red blood cell transfusion strategy that aims for a target hemoglobin between 7 g/dL and 9 g/dL. A higher target hemoglobin should be considered in patients with significant co-morbidity (e. g., ischemic cardiovascular disease) (strong recommendation, moderate quality evidence). MR3. ESGE recommends the use of the Glasgow-Blatchford Score (GBS) for pre-endoscopy risk stratification. Outpatients determined to be at very low risk, based upon a GBS score of 0 - 1, do not require early endoscopy nor hospital admission. Discharged patients should be informed of the risk of recurrent bleeding and be advised to maintain contact with the discharging hospital (strong recommendation, moderate quality evidence). MR4. ESGE recommends initiating high dose intravenous proton pump inhibitors (PPI), intravenous bolus followed by continuous infusion (80 mg then 8 mg/hour), in patients presenting with acute UGIH awaiting upper endoscopy. However, PPI infusion should not delay the performance of early endoscopy (strong recommendation, high quality evidence). MR5. ESGE does not recommend the routine use of nasogastric or orogastric aspiration/lavage in patients presenting with acute UGIH (strong recommendation, moderate quality evidence). MR6. ESGE recommends intravenous erythromycin (single dose, 250 mg given 30 - 120 minutes prior to upper gastrointestinal [GI] endoscopy) in patients with clinically severe or ongoing active UGIH. In selected patients, pre-endoscopic infusion of erythromycin significantly improves endoscopic visualization, reduces the need for second-look endoscopy, decreases the number of units of blood transfused, and reduces duration of hospital stay (strong recommendation, high quality evidence). MR7. Following hemodynamic resuscitation, ESGE recommends early (≤ 24 hours) upper GI endoscopy. Very early (< 12 hours) upper GI endoscopy may be considered in patients with high risk clinical features, namely: hemodynamic instability (tachycardia, hypotension) that persists despite ongoing attempts at volume resuscitation; in-hospital bloody emesis/nasogastric aspirate; or contraindication to the interruption of anticoagulation (strong recommendation, moderate quality evidence). MR8. ESGE recommends that peptic ulcers with spurting or oozing bleeding (Forrest classification Ia and Ib, respectively) or with a nonbleeding visible vessel (Forrest classification IIa) receive endoscopic hemostasis because these lesions are at high risk for persistent bleeding or rebleeding (strong recommendation, high quality evidence). MR9. ESGE recommends that peptic ulcers with an adherent clot (Forrest classification IIb) be considered for endoscopic clot removal. Once the clot is removed, any identified underlying active bleeding (Forrest classification Ia or Ib) or nonbleeding visible vessel (Forrest classification IIa) should receive endoscopic hemostasis (weak recommendation, moderate quality evidence). MR10. In patients with peptic ulcers having a flat pigmented spot (Forrest classification IIc) or clean base (Forrest classification III), ESGE does not recommend endoscopic hemostasis as these stigmata present a low risk of recurrent bleeding. In selected clinical settings, these patients may be discharged to home on standard PPI therapy, e. g., oral PPI once-daily (strong recommendation, moderate quality evidence). MR11. ESGE recommends that epinephrine injection therapy not be used as endoscopic monotherapy. If used, it should be combined with a second endoscopic hemostasis modality (strong recommendation, high quality evidence). MR12. ESGE recommends PPI therapy for patients who receive endoscopic hemostasis and for patients with adherent clot not receiving endoscopic hemostasis. PPI therapy should be high dose and administered as an intravenous bolus followed by continuous infusion (80 mg then 8 mg/hour) for 72 hours post endoscopy (strong recommendation, high quality evidence). MR13. ESGE does not recommend routine second-look endoscopy as part of the management of nonvariceal upper gastrointestinal hemorrhage (NVUGIH). However, in patients with clinical evidence of rebleeding following successful initial endoscopic hemostasis, ESGE recommends repeat upper endoscopy with hemostasis if indicated. In the case of failure of this second attempt at hemostasis, transcatheter angiographic embolization (TAE) or surgery should be considered (strong recommendation, high quality evidence). MR14. In patients with NVUGIH secondary to peptic ulcer, ESGE recommends investigating for the presence of Helicobacter pylori in the acute setting with initiation of appropriate antibiotic therapy when H. pylori is detected. Re-testing for H. pylori should be performed in those patients with a negative test in the acute setting. Documentation of successful H. pylori eradication is recommended (strong recommendation, high quality evidence). MR15. In patients receiving low dose aspirin for secondary cardiovascular prophylaxis who develop peptic ulcer bleeding, ESGE recommends aspirin be resumed immediately following index endoscopy if the risk of rebleeding is low (e. g., FIIc, FIII). In patients with high risk peptic ulcer (FIa, FIb, FIIa, FIIb), early reintroduction of aspirin by day 3 after index endoscopy is recommended, provided that adequate hemostasis has been established (strong recommendation, moderate quality evidence).

BACKGROUND: Alcoholic hepatitis is a clinical syndrome characterized by jaundice and liver impairment that occurs in patients with a history of heavy and prolonged alcohol use. The short-term mortality among patients with severe disease exceeds 30%. Prednisolone and pentoxifylline are both recommended for the treatment of severe alcoholic hepatitis, but uncertainty about their benefit persists. METHODS: We conducted a multicenter, double-blind, randomized trial with a 2-by-2 factorial design to evaluate the effect of treatment with prednisolone or pentoxifylline. The primary end point was mortality at 28 days. Secondary end points included death or liver transplantation at 90 days and at 1 year. Patients with a clinical diagnosis of alcoholic hepatitis and severe disease were randomly assigned to one of four groups: a group that received a pentoxifylline-matched placebo and a prednisolone-matched placebo, a group that received prednisolone and a pentoxifylline-matched placebo, a group that received pentoxifylline and a prednisolone-matched placebo, or a group that received both prednisolone and pentoxifylline. RESULTS: A total of 1103 patients underwent randomization, and data from 1053 were available for the primary end-point analysis. Mortality at 28 days was 17% (45 of 269 patients) in the placebo-placebo group, 14% (38 of 266 patients) in the prednisolone-placebo group, 19% (50 of 258 patients) in the pentoxifylline-placebo group, and 13% (35 of 260 patients) in the prednisolone-pentoxifylline group. The odds ratio for 28-day mortality with pentoxifylline was 1.07 (95% confidence interval [CI], 0.77 to 1.49; P=0.69), and that with prednisolone was 0.72 (95% CI, 0.52 to 1.01; P=0.06). At 90 days and at 1 year, there were no significant between-group differences. Serious infections occurred in 13% of the patients treated with prednisolone versus 7% of those who did not receive prednisolone (P=0.002). CONCLUSIONS: Pentoxifylline did not improve survival in patients with alcoholic hepatitis. Prednisolone was associated with a reduction in 28-day mortality that did not reach significance and with no improvement in outcomes at 90 days or 1 year. (Funded by the National Institute for Health Research Health Technology Assessment program; STOPAH EudraCT number, 2009-013897-42 , and Current Controlled Trials number, ISRCTN88782125 ).

The guideline group was selected to be representative of UK-based aplastic anaemia (AA) medical experts. Recommendations are based on review of the literature using MEDLINE and PUBMED up to December 2014 under the heading: ‘aplastic anemia’. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) nomenclature was used to evaluate levels of evidence and to assess the strength of recommendations. The GRADE criteria are specified in the BCSH guidance pack http://www.bcshguidelines.com/BCSH_PROCESS/EVIDENCE_LEVELS_AND_GRADES_OF_RECOMMENDATION/43_GRADE.html and the GRADE working group website http://www.gradeworkinggroup.org The objective of this guideline is to provide healthcare professionals with clear guidance on the management of patients with AA. The guidance may not be appropriate to every patient and in all cases individual patient circumstances may dictate an alternative approach. Review of the manuscript was performed by the British Committee for Standards in Haematology (BCSH) Haemato-Oncology Task Force, BCSH Executive Committee and then reviewed by a sounding board of the British Society for Haematology (BSH). This compromises 50 or more members of the BSH who have reviewed this guidance and commented on its content and applicability in the UK setting. It has also been reviewed by the Aplastic Anaemia Trust patient group but they do not necessarily approve or endorse the contents. Aplastic anaemia is a rare and heterogeneous disorder. It is defined as pancytopenia with a hypocellular bone marrow in the absence of an abnormal infiltrate or marrow fibrosis. To diagnose AA there must be at least two of the following (Camitta et al, 1975) haemoglobin concentration (Hb) <100 g/l, platelet count <50 × 109/l, neutrophil count <1·5 × 109/l. The majority (70-80%) of cases are idiopathic (Marsh et al, 2009). The remainder mainly consist of IBMFS. The incidence is 2-3 per million per year in Europe, but higher in East Asia (Montane et al, 2008). There is a biphasic distribution, with peaks at 10-25 years and over 60 years. AA not fulfilling the criteria for SAA or VSAA Patients commonly present with symptoms of anaemia and thrombocytopenia. Serious infection is not a frequent symptom early in the course of the disease. A preceding history of jaundice may suggest a post-hepatitic AA. Whilst the majority of cases are idiopathic, a careful drug, occupational exposure and family history should be obtained. Any putative drugs should be discontinued and the patient should not be re-challenged. If a possible drug association is suspected, this must be reported to the Medicines and MHRA using the Yellow Card Scheme (http://yellowcard.gov.uk). There is usually no hepatosplenomegaly or lymphadenopathy (except in infection). In young adults the presence of short stature, skin hyper/hypo pigmented areas and skeletal abnormalities, particularly affecting the thumb is suggestive of FA (Shimamura & Alter, 2010). The triad of nail dystrophy, reticular skin pigmentation and oral leucoplakia is characteristic of dyskeratosis congenita (DC) (Shimamura & Alter, 2010). The finding of peripheral lymphoedema may indicate a diagnosis of Emberger syndrome due to germline GATA2 mutation. See Table 1 for the summary of investigations for the diagnosis and further evaluation of AA; this table also summarizes the emerging diagnostics incorporating the latest molecular technologies that are likely to feature in the diagnosis and differential diagnosis within the next couple of years. Both a bone marrow aspirate and trephine biopsy are required for the diagnosis of AA, and the key bone marrow findings are summarized in Table 2. Karyotyping may fail in very hypocellular marrows with there being insufficient metaphases. In this situation perform FISH analysis for chromosomes 5, 7, 8 and 13 It was previously assumed that the presence of an abnormal cytogenetic clone indicated a diagnosis of MDS and not AA. However it is now evident that abnormal cytogenetic clones [such as del(13q), trisomy 8 and others], which may be transient, are present in up to 12% of patients with otherwise typical AA at diagnosis (Gupta et al, 2006; Afable et al, 2011b). Although monosomy 7 may indicate the likelihood of MDS in children, in adults monosomy 7 can also be seen in AA. Abnormal cytogenetic clones may arise during the course of the disease and the appearance of a new cytogenetic abnormality may provide evidence of clonal evolution (Maciejewski et al, 2002) The investigations in Table 1 should exclude non-AA causes of pancytopenia with a hypocellular bone marrow, which are listed in Table 3. A MDT meeting approach is recommended to collate relevant results and develop a treatment plan. Consideration should be given for seeking expert advice on the diagnosis and management of patients where there is uncertainty, or when an IBMFS is being considered. A number of inherited/genetic disorders are characterized by BMF/AA, usually in association with one or more somatic abnormality (Alter, 2007). The BMF typically presents in childhood but this can sometimes be in adulthood. The two syndromes frequently associated with generalized BMF/AA are FA and DC (Dokal, 2011; Soulier, 2011), which can sometimes present with AA alone as their initial manifestation. These syndromes are genetically heterogeneous; 16 FA genes and 10 DC genes have been identified. The FA genes are important in DNA repair, the DC genes in telomere maintenance. Based on the DNA repair defect a diagnostic test-‘chromosomal breakage test’ is available for FA. Patients with DC usually have very short telomeres and this measurement [using flow cytometric fluorescence in situ hybridization or multiplex quantitative polymerase chain reaction (PCR)] can be useful in the assessment of DC. Genetic testing for known DC genes (representing c. 60% of cases) is possible in specialized centres. In addition there are other genetic syndromes that are sometimes associated with AA/cytopenias. This includes Shwachman‒Diamond syndrome ‒ SDS (Dror et al, 2011) (mutations in SBDS), congenital amegakaryocytic thrombocytopenia ‒ CAMT (Ballmaier & Germeshausen, 2011) (mutations in MPL) and GATA2 deficiency (Emberger syndrome) (Horwitz, 2014) as well as genetically uncharacterized cases. Some cases of inherited AA first present in adulthood and it is important to recognize these as their management differs from that of idiopathic AA. Where there are sufficient characteristic abnormalities a diagnosis may be straightforward (e.g. mucocutaneous features in DC). Where the presentation is only with AA and with minimal non-haematological abnormalities, inherited BMF should be considered and testing for known BMF syndromes should be undertaken. Investigations for inherited forms of AA should be re-appraised in patients initially classified as “idiopathic AA” and who fail to respond to anti-thymocyte globulin (ATG). For most patients with AA, transfusion with red blood cells (RBC) is essential to maintain a safe blood count, improve symptoms of anaemia and maintain quality of life. The decision to transfuse RBC should be based on clinical symptoms (signs of anaemia), taking into consideration the patient's age and co-morbidities (cardiac, pulmonary or vascular). Although no specific pre-transfusion haemoglobin concentration (Hb) trigger can be recommended, it is important to maintain quality of life and avoid symptoms. A higher trigger may be needed for elderly patients and those with co-morbidities. Optimal use of RBC transfusion involves administration of enough red cells to maximize clinical outcome whilst avoiding unnecessary transfusions (Carson et al, 2012). Alloimmunization against red cell antigens and iron overload are the commonest risks associated with regular transfusion therapy. Provision of phenotype-matched blood (for Rh and Kell) should be considered to reduce the risk of alloimmunization. Regular platelet transfusion support may be required for AA patients. With the exception of one publication (Sagmeister et al, 1999), literature specific to platelet transfusion support in AA is lacking, and evidence is taken from studies addressing the need for platelet transfusion support in patients with reversible thrombocytopenia (Estcourt et al, 2012; Stanworth et al, 2013; Killick et al, 2014). It is recommended that prophylactic platelet transfusions should be given to stable AA patients on active therapy (where the treatment aims to reverse the severe thrombocytopenia) with a platelet count <10 × 109/l. For patients with sepsis, the platelet count should be kept >20 × 109/l. For thrombocytopenic patients requiring invasive procedures, platelet transfusions must be administered, aiming to achieve a platelet count in line with BCSH guidelines for the relevant procedures (British Committee for Standards in Haematology, 2003), and a pre-procedure platelet count should be checked. During treatment with ATG, worsening thrombocytopenia can occur. This is due to increased platelet consumption in the presence of cross-reacting antibodies in ATG binding to platelets. Although there are no studies to support the exact threshold for platelet transfusion support prior to ATG, most authors use a threshold of 20 × 109/l (Scheinberg et al, 2011; Scheinberg & Young, 2012). Regular support with RBC and platelet transfusions increases the risk of HLA and non-HLA (minor histocompatibility) alloimmunization, leading to poor platelet increments and increased risk of graft rejection after HSCT. Leucodepletion of cellular blood components may reduce, but not eliminate, alloimmunization (Killick et al, 1997; Desmarets et al, 2009). The possibility of HLA alloimmunization and provision of HLA-selected platelets should be considered for patients refractory to platelet transfusion, provided other causes of refractoriness have been excluded. In the absence of HLA antibodies and for patients failing to increment with HLA-matched platelets, investigation and matching for human platelet antigen antibodies should be considered. The use of irradiated granulocytes should be considered in patients with life-threatening infection related to severe neutropenia (Quillen et al, 2009), and anecdotally may be life saving. Data about the effectiveness of granulocyte concentrates are limited and usage is linked with a number of adverse events, such as transfusion-related acute lung injury, alloimmunization and febrile reactions. Irradiation of cellular blood components prevents transfusion-associated graft-versus-host disease (TA-GVHD). This is a rare complication of blood transfusion with 100% mortality. Irradiation may also reduce the risk of alloimmunization in AA, as reported from animal data (Bean et al, 1994). Following universal leucodepletion in the UK, the Committee on the of and no the use of blood components they have been for patients with and those should be considered To there has not been a from the British Society of blood and granulocyte components should be provided for Aplastic anaemia patients on regular RBC transfusion support develop iron but there on the clinical of iron In the of a is an adverse of outcome in cell et al, 2007). Although the most for assessment of iron or can and and is a useful its in AA has not been There are data iron therapy in AA. A was the Evaluation of with et al, 2010). This that with can be in patients with AA and can reduce the are required to those who are transfusion is with and the drug should be used with in AA patients who are taking is for use in but only as line therapy when is or is but not recommended in patients et al, For those to or after a is recommended for iron the of in AA (Marsh & In to patients in SAA neutropenia is and in a higher incidence of invasive infection and severe of to ATG in the two has and this has in with and of et al, Aplastic anaemia patients who are should be in when in In the UK it is to prophylactic and regular an as or and of content et al, two (e.g. and or (e.g. may be but the should be to A active or should be used as In the UK, against is not in patients with AA is not with or should be used during and after ATG therapy. During ATG of and is but and not need disease has only very been reported after ATG, most after It is not UK to with and guidelines for the management of febrile the assessment and management of are well and should and for and guidance et al, 2012). as per should be early for patients with as these patients have transfusions may be life in severe sepsis, such as invasive particularly for patients due to to (Quillen et al, 2009). such as and granulocyte are usually in blood in AA patients (Marsh et al, results are reported with the et al, also on of AA in the first line is the of ATG and ATG is no available (Marsh et al, & Scheinberg & Young, 2012). A from the of and a at and and with ATG to ATG for first line (Scheinberg et al, 2011; et al, 2012). There is no for use of with ATG et al, is used with ATG for the of of of There is no age for ATG, but there is increased in patients years with ATG et al, 2011) on of AA in the A course of ATG may be indicated for to respond or after a first course or the patient is for (Marsh et al, & Scheinberg & Young, For a ATG may be A course of ATG is an alternative but this may be associated with more and (Marsh et al, 2012). to ATG, ATG more and in more It is important to that patients prophylactic support when using The of ATG is for It is given as an over to the risk of a must be is to use an of the SAA data the first of the first is given over 1 ATG should be given a or other as it is to peripheral and also for of administration of other drugs and blood of ATG should be with 1 and platelet transfusions aiming to the platelet count × 109/l (Marsh et al, Scheinberg & Young, 2012). to should be given for febrile of the neutrophil commonly during ATG in careful to is is on the after ATG is at a of 1 for by over the should be as the is at a of to achieve blood levels of should be whilst the blood count to A of the drug every can be after at least a further of to reduce the risk of et al, of ATG are early acute pulmonary syndrome and and from the of ATG, most commonly with and is with a and it usually a of platelet transfusions are needed during the of due to platelet There is no for using with ATG as studies have that given for after ATG not improve or et al, to ATG defined in Table is after an of The to a first course of ATG is is 100% for age for for years and for years et al, In the to a first course of ATG is only with (Scheinberg et al, 2011; et al, 2012; Scheinberg & Young, 2012). For ATG results in higher to alone (Marsh et al, after ATG in up to of the risk of clonal evolution to is and in et al, Scheinberg & Young, 2012). previously or or of at least one cell line or of to a course of ATG from most studies is for refractory AA and for AA (Marsh et al, & Scheinberg & Young, 2012). for are summarized in Table It is recommended that expert advice be when the use of other and are not recommended in the treatment of AA Table There is a risk of AA following in those patients who have to The evidence is limited and based on as well as an that a is likely to be an important trigger in the of AA et al, et al, should be following when AA patients should be as recommended for all bone marrow The for are based on the guidelines et al, Patients should be in Society for and centres. from a is indicated for SAA in young and patients who have a data for patients to those years et al, co-morbidities should be to for of for patients years. is indicated for SAA after to respond to one course of There is no age but this should be on an individual patient and to co-morbidities at the The should be or based on HLA for and using a family or a may be other treatment after to respond to and in the absence of a and a et al, 2012; & should be for HLA the presence of which is associated with a very risk of graft There is clear guidance on the exact for alternative as this is or but new to alternative are being using In the rare situation where there is a should be considered in all patients of age as (Marsh & For all AA patients who may be HLA should be performed at of that can as as and the patient not only to HLA but also to and the of is that there is no to a course of ATG and the patient can then to the patient's is of with severe for to is usually at MDT approach is essential for the The aims of the up are to the diagnosis and clonal evolution assess co-morbidities the cell and and the transfusion of the and review of transfusion The of to use on patient age of for of ATG et al, et al, 2011) or (Marsh et al, 2011; et al, 2012). See Table For the is but is the of and 50 years. A analysis has that after are no to in that is not a of et al, 2013; et al, 2014). to AA early management and management of are summarized in Table The treatment of elderly patients with AA is more in patients. In the outcome is due to of the patients should be for co-morbidities and their specific should be as quality of life is an important outcome in this With to it is important to exclude as MDS is more AA in this age group diagnostic age per is not a to treatment in the very is considered the treatment of There is no for as first line therapy in patients can be considered in selected patients with a the least and most treatment should be consideration is a is such that those with life count × or a severe infection requiring should be more those with severe disease. with ATG and results in a more and alone in patients with (Marsh et al, patients and have a higher risk of acute and the risks and of treatment should be up for individual Patients must be as the risk of and with ATG is higher in the patients have an after ATG to patients et al, or Although the of alone is to the of ATG and in is not as patients may respond to line therapy with ATG and (Marsh et al, alone has the of being but patients must be for and may be used as a in AA, but medical very careful assessment in patients prior to this as a possible (Scheinberg et al, 2012). or can be considered in or to et al, et al, has may be a alternative for of is required as it can and blood Patients who are or who should be is a oral In an of an at patients with refractory SAA with et al, 2014). in of patients. The drug was well in most patients. levels may and there are about clonal monosomy 7, which further has been by the and in the for treatment of SAA refractory to It has as of been by the for SAA refractory to or patients who are and for HSCT. It should be used with for clonal or following a clinical It is that a bone marrow is performed prior to treatment to exclude an abnormal cytogenetic clone typical of particularly monosomy Although the or AA and is it a to and with a clinical AA can be for the first during in early or during but the disease may after or or after et al, is during in AA patients who have previously to ATG, those with et al, not trigger of the disease in patients who HSCT. et in previously with for AA. reported a complication in the two cases of and of AA in and a further needed transfusion during blood not from of AA during in particularly in of blood has to in and outcome et al, it is important to with the patient and family the risks to the and et al, It is essential that the patient be frequently initially but more frequently and to disease and with very with the and of a clone should with a The of should be on is the of treatment of AA in and the platelet count be 20 × 109/l with platelet The risk of alloimmunization and platelet refractoriness to be considered. is safe during & and is recommended for those ATG, or for AA during are not should be by flow et al, et al, 2010). of is a and quantitative for the of clones which in up to of AA the on the of the flow cytometric analysis used et al, et al, clones are most in the neutrophil and in AA and be by flow If the patient has a blood transfusion, a of red cells may be by flow in the granulocyte and the clinical of a clone in AA as by flow clones can in or the need for the is important is the presence of a clone associated with clinical or evidence of should be for as this is a feature of when the patient not have of associated with should be with the count, and Patients should be for at the diagnosis of AA. If for years and then to testing If the or for the first years and only reduce the the of the cells has The presence of a clone in the of AA not the of therapy for the There is evidence that the finding of a clone a to but this is not universal in all Patients with a clone ATG, should be for of AA may in patients in the presence of patients should be to one of the two specialized and to be for and for consideration for following MDT Patients be seen in of the two or in one of 10 Data from the to the that cell has an outcome in and to when indicated et al, 2012). the finding of a clone not or on the decision to the advice and in these guidelines is to be and at the of to the the British Committee for Standards in Haematology (BCSH) the for the content of these These guidelines are only to patients with AA. to and for their review of this The authors to the BCSH and the BSH sounding BCSH and the Aplastic Trust for their support in these the guidelines was the authors in and of the authors the of the authors have a of to the BCSH and Task which may be reviewed on In summary the following authors have the following of has from for at and from for at and has from has from for has from for at has from and has from has from and and have from for The of the authors have no of of the group the group new evidence available that the strength of the in this or it The be and from the BCSH guidelines website it If new are an be on the BCSH guidelines website at If are required due to in of evidence or evidence a new of the guidance be on the BCSH

A complete understanding of how exposure to environmental substances promotes cancer formation is lacking. More than 70 years ago, tumorigenesis was proposed to occur in a two-step process: an initiating step that induces mutations in healthy cells, followed by a promoter step that triggers cancer development1. Here we propose that environmental particulate matter measuring ≤2.5 μm (PM2.5), known to be associated with lung cancer risk, promotes lung cancer by acting on cells that harbour pre-existing oncogenic mutations in healthy lung tissue. Focusing on EGFR-driven lung cancer, which is more common in never-smokers or light smokers, we found a significant association between PM2.5 levels and the incidence of lung cancer for 32,957 EGFR-driven lung cancer cases in four within-country cohorts. Functional mouse models revealed that air pollutants cause an influx of macrophages into the lung and release of interleukin-1β. This process results in a progenitor-like cell state within EGFR mutant lung alveolar type II epithelial cells that fuels tumorigenesis. Ultradeep mutational profiling of histologically normal lung tissue from 295 individuals across 3 clinical cohorts revealed oncogenic EGFR and KRAS driver mutations in 18% and 53% of healthy tissue samples, respectively. These findings collectively support a tumour-promoting role for PM2.5 air pollutants and provide impetus for public health policy initiatives to address air pollution to reduce disease burden. Combination of epidemiology, preclinical models and ultradeep DNA profiling of clinical cohorts unpicks the inflammatory mechanism by which air pollution promotes lung cancer

Vaccines based on the spike protein of SARS-CoV-2 are a cornerstone of the public health response to COVID-19. The emergence of hypermutated, increasingly transmissible variants of concern (VOCs) threaten this strategy. Omicron (B.1.1.529), the fifth VOC to be described, harbours multiple amino acid mutations in spike, half of which lie within the receptor-binding domain. Here we demonstrate substantial evasion of neutralization by Omicron BA.1 and BA.2 variants in vitro using sera from individuals vaccinated with ChAdOx1, BNT162b2 and mRNA-1273. These data were mirrored by a substantial reduction in real-world vaccine effectiveness that was partially restored by booster vaccination. The Omicron variants BA.1 and BA.2 did not induce cell syncytia in vitro and favoured a TMPRSS2-independent endosomal entry pathway, these phenotypes mapping to distinct regions of the spike protein. Impaired cell fusion was determined by the receptor-binding domain, while endosomal entry mapped to the S2 domain. Such marked changes in antigenicity and replicative biology may underlie the rapid global spread and altered pathogenicity of the Omicron variant.

BACKGROUND: A new variant of SARS-CoV-2, B.1.1.7, emerged as the dominant cause of COVID-19 disease in the UK from November, 2020. We report a post-hoc analysis of the efficacy of the adenoviral vector vaccine, ChAdOx1 nCoV-19 (AZD1222), against this variant. METHODS: Volunteers (aged ≥18 years) who were enrolled in phase 2/3 vaccine efficacy studies in the UK, and who were randomly assigned (1:1) to receive ChAdOx1 nCoV-19 or a meningococcal conjugate control (MenACWY) vaccine, provided upper airway swabs on a weekly basis and also if they developed symptoms of COVID-19 disease (a cough, a fever of 37·8°C or higher, shortness of breath, anosmia, or ageusia). Swabs were tested by nucleic acid amplification test (NAAT) for SARS-CoV-2 and positive samples were sequenced through the COVID-19 Genomics UK consortium. Neutralising antibody responses were measured using a live-virus microneutralisation assay against the B.1.1.7 lineage and a canonical non-B.1.1.7 lineage (Victoria). The efficacy analysis included symptomatic COVID-19 in seronegative participants with a NAAT positive swab more than 14 days after a second dose of vaccine. Participants were analysed according to vaccine received. Vaccine efficacy was calculated as 1 - relative risk (ChAdOx1 nCoV-19 vs MenACWY groups) derived from a robust Poisson regression model. This study is continuing and is registered with ClinicalTrials.gov, NCT04400838, and ISRCTN, 15281137. FINDINGS: Participants in efficacy cohorts were recruited between May 31 and Nov 13, 2020, and received booster doses between Aug 3 and Dec 30, 2020. Of 8534 participants in the primary efficacy cohort, 6636 (78%) were aged 18-55 years and 5065 (59%) were female. Between Oct 1, 2020, and Jan 14, 2021, 520 participants developed SARS-CoV-2 infection. 1466 NAAT positive nose and throat swabs were collected from these participants during the trial. Of these, 401 swabs from 311 participants were successfully sequenced. Laboratory virus neutralisation activity by vaccine-induced antibodies was lower against the B.1.1.7 variant than against the Victoria lineage (geometric mean ratio 8·9, 95% CI 7·2-11·0). Clinical vaccine efficacy against symptomatic NAAT positive infection was 70·4% (95% CI 43·6-84·5) for B.1.1.7 and 81·5% (67·9-89·4) for non-B.1.1.7 lineages. INTERPRETATION: ChAdOx1 nCoV-19 showed reduced neutralisation activity against the B.1.1.7 variant compared with a non-B.1.1.7 variant in vitro, but the vaccine showed efficacy against the B.1.1.7 variant of SARS-CoV-2. FUNDING: UK Research and Innovation, National Institute for Health Research (NIHR), Coalition for Epidemic Preparedness Innovations, NIHR Oxford Biomedical Research Centre, Thames Valley and South Midlands NIHR Clinical Research Network, and AstraZeneca.