Mid Essex Hospital Services NHS Trust

BACKGROUND: Ipilimumab monotherapy (at a dose of 3 mg per kilogram of body weight), as compared with glycoprotein 100, improved overall survival in a phase 3 study involving patients with previously treated metastatic melanoma. We conducted a phase 3 study of ipilimumab (10 mg per kilogram) plus dacarbazine in patients with previously untreated metastatic melanoma. METHODS: We randomly assigned 502 patients with previously untreated metastatic melanoma, in a 1:1 ratio, to ipilimumab (10 mg per kilogram) plus dacarbazine (850 mg per square meter of body-surface area) or dacarbazine (850 mg per square meter) plus placebo, given at weeks 1, 4, 7, and 10, followed by dacarbazine alone every 3 weeks through week 22. Patients with stable disease or an objective response and no dose-limiting toxic effects received ipilimumab or placebo every 12 weeks thereafter as maintenance therapy. The primary end point was overall survival. RESULTS: Overall survival was significantly longer in the group receiving ipilimumab plus dacarbazine than in the group receiving dacarbazine plus placebo (11.2 months vs. 9.1 months, with higher survival rates in the ipilimumab-dacarbazine group at 1 year (47.3% vs. 36.3%), 2 years (28.5% vs. 17.9%), and 3 years (20.8% vs. 12.2%) (hazard ratio for death, 0.72; P<0.001). Grade 3 or 4 adverse events occurred in 56.3% of patients treated with ipilimumab plus dacarbazine, as compared with 27.5% treated with dacarbazine and placebo (P<0.001). No drug-related deaths or gastrointestinal perforations occurred in the ipilimumab-dacarbazine group. CONCLUSIONS: Ipilimumab (at a dose of 10 mg per kilogram) in combination with dacarbazine, as compared with dacarbazine plus placebo, improved overall survival in patients with previously untreated metastatic melanoma. The types of adverse events were consistent with those seen in prior studies of ipilimumab; however, the rates of elevated liver-function values were higher and the rates of gastrointestinal events were lower than expected on the basis of prior studies. (Funded by Bristol-Myers Squibb; ClinicalTrials.gov number, NCT00324155.).

OBJECTIVE: The Surviving Sepsis Campaign (SSC or "the Campaign") developed guidelines for management of severe sepsis and septic shock. A performance improvement initiative targeted changing clinical behavior (process improvement) via bundles based on key SSC guideline recommendations on process improvement and patient outcomes. DESIGN AND SETTING: A multifaceted intervention to facilitate compliance with selected guideline recommendations in the ICU, ED, and wards of individual hospitals and regional hospital networks was implemented voluntarily in the US, Europe, and South America. Elements of the guidelines were "bundled" into two sets of targets to be completed within 6 h and within 24 h. An analysis was conducted on data submitted from January 2005 through March 2008. MAIN RESULTS: Data from 15,022 subjects at 165 sites were analyzed to determine the compliance with bundle targets and association with hospital mortality. Compliance with the entire resuscitation bundle increased linearly from 10.9% in the first site quarter to 31.3% by the end of 2 years (P<0.0001). Compliance with the entire management bundle started at 18.4% in the first quarter and increased to 36.1% by the end of 2 years (P = 0.008). Compliance with all bundle elements increased significantly, except for inspiratory plateau pressure, which was high at baseline. Unadjusted hospital mortality decreased from 37 to 30.8% over 2 years (P = 0.001). The adjusted odds ratio for mortality improved the longer a site was in the Campaign, resulting in an adjusted absolute drop of 0.8% per quarter and 5.4% over 2 years (95% CI, 2.5-8.4%). CONCLUSIONS: The Campaign was associated with sustained, continuous quality improvement in sepsis care. Although not necessarily cause and effect, a reduction in reported hospital mortality rates was associated with participation. The implications of this study may serve as an impetus for similar improvement efforts.

Primary biliary cirrhosis (PBC) is a classical autoimmune liver disease for which effective immunomodulatory therapy is lacking. Here we perform meta-analyses of discovery data sets from genome-wide association studies of European subjects (n=2,764 cases and 10,475 controls) followed by validation genotyping in an independent cohort (n=3,716 cases and 4,261 controls). We discover and validate six previously unknown risk loci for PBC (Pcombined<5 × 10(-8)) and used pathway analysis to identify JAK-STAT/IL12/IL27 signalling and cytokine-cytokine pathways, for which relevant therapies exist.

The overall objective of the guidelines is to provide up‐to‐date, evidence‐based recommendations for the diagnosis and management of the full spectrum of Stevens–Johnson syndrome (SJS), toxic epidermal necrolysis (TEN) and SJS–TEN overlap in adults during the acute phase of the disease. The document aims to: (i) offer an appraisal of all relevant literature up to February 2016, focusing on any key developments; (ii) address important, practical clinical questions relating to the primary guideline objective, i.e. accurate diagnosis and identification of cases and suitable treatment; (iii) provide guideline recommendations; and (iv) discuss areas of uncertainty, potential developments and future directions SJS/TEN is rare and few healthcare professionals are confident in the recognition and management of the disorder. There is widely divergent practice among different specialities and healthcare settings, and limited information on outcomes. These guidelines aim to provide recommendations on the diagnosis and management of SJS/TEN, to inform clinical decision‐making and, when justified by evidence, to standardize practice. The breadth of this document should be sufficient to assist clinicians of all relevant specialities in the management of patients with SJS/TEN. The recommendations will also inform pathways of care to optimize healthcare delivery and highlight key areas of uncertainty for future research. In these guidelines, the term SJS/TEN encompasses the full spectrum of the disease, i.e. SJS, TEN and SJS–TEN overlap (see section section 10 for clinical definition of the separate entities). The guideline is presented as a detailed review with highlighted recommendations for practical use (see section section 64), in addition to the development of a new patient information leaflet [available on the British Association of Dermatologists’ (BAD) website, www.bad.org.uk]. Unless otherwise specified, recommendations apply to all forms of the disease. This guideline does not cover paediatric patients. An addendum to this guideline addressing the needs of paediatric patients with SJS/TEN is planned. The evidence for treatment of children differs from that of adult patients, and will be considered separately. The management of long‐term sequelae of SJS/TEN is not considered in this document. The guideline development group (GDG) consisted of consultant dermatologists (D.C., S.A.W., H.Y.L., J.S., C.B.B., M.R.A.‐J., K.M.T.W., G.A.E.W., C.H.S.), including oral (J.S.) and urogenital specialists (S.A.W., C.B.B.), a histopathologist (M.P.), burns/plastic surgeon specialists (P.D., G.W., M.S.), a burns anaesthestist (R.V.M.), intensive care specialists (A.V., R.V.M.), an ophthalmologist (J.K.G.D.), a dermatological clinical nurse specialist (D.B.) and a patient (P.W.). The draft document went out for consultation to the BAD membership, British Dermatological Nursing Group, Primary Care Dermatological Society, British Burn Association, British Association of Plastic, Reconstructive and Aesthetic Surgeons, Royal College of Ophthalmologists, Association of Anaesthetists of Great Britain and Ireland, Intensive Care Society and SJS Awareness U.K. The comments received were actively considered by the GDG. Following further review, the amended draft was recirculated to the stakeholders for comments and the finalized version peer‐reviewed by the Clinical Standards Unit of the BAD (made up of the Therapy & Guidelines Subcommittee) prior to publication. This set of guidelines has been developed using the BAD's recommended methodology,1 and with reference to the Appraisal of Guidelines Research and Evaluation (AGREE II) instrument (www.agreetrust.org).2 Recommendations were developed for implementation in the National Health Service using a process of considered judgement based on the evidence. A series of specific questions was developed within the scope of the guideline; for each question, PubMed, MEDLINE and Embase, and the Cochrane Library were searched for meta‐analyses, randomized and nonrandomized controlled clinical trials, open studies and case series to February 2016. The literature was searched for evidence to address the questions. The search terms and strategies are detailed online (Data S1; see Supporting Information). Additional relevant references were also isolated from citations in the reviewed literature, as well as specific targeted searches for hypersensitivity testing, causative drugs, diagnostic and prognostic indicators, topical treatments, oral/mouth, growth factors and granulocyte colony‐stimulating factor (G‐CSF), and analgesia. The lead authors screened the identified titles, and those relevant for first‐round inclusion were selected for further scrutiny. All co‐authors then reviewed the abstracts for the shortlisted references and the full papers of relevant material were obtained; disagreements in the final selections were resolved by discussion with the entire GDG. In section section 47, active interventions were assessed only if studies recruited at least eight patients with SJS/TEN into the treatment group. The structure of the guidelines was then discussed, with headings and subheadings decided; different co‐authors were allocated separate subsections. Each co‐author then performed a detailed appraisal of the selected literature, and all subsections were subsequently collated and edited to produce the final guideline. This document has been prepared on behalf of the BAD and is based on the best data available when the document was prepared. It is recognized that under certain conditions it may be necessary to deviate from the guidelines and that the results of future studies may require some of the recommendations herein to be changed. Failure to adhere to these guidelines should not necessarily be considered negligent, nor should adherence to these recommendations constitute a defence against a claim of negligence. The proposed revision date for this set of recommendations is scheduled for 2021; where necessary, important interim changes will be updated on the BAD website. SJS and TEN are severe mucocutaneous reactions, usually to drugs, characterized by blistering and epithelial sloughing.3 The two terms describe phenotypes within a severity spectrum, in which SJS is the less extensive and TEN the more extensive form. The incidence of SJS/TEN is approximately 1–2 cases per million per year.4 5 Although rare, SJS/TEN is a devastating disease; in severe cases the acute phase may be by a of including The for SJS is with the to for overall SJS/TEN is well as an of the acute long‐term SJS/TEN is characterized by epithelial and a process by to of which the factors including factor and may to Although and all been in evidence as the key of in A by the of of in TEN of into SJS/TEN is an severe characterized by epidermal and by A by of patients in a specialist a detailed of the clinical in In a of and the by may also the is a in SJS/TEN, and the of this should the to epidermal Clinical in the series of a in the of and of The are and of are the and to the of the and of the and is areas of in severe cases is to will the to This is by the in which to to the Although not specific for SJS/TEN is also in the is a clinical of epidermal areas and a in which from necrolysis results in the of of areas of and of the of the and is usually an and to an and 10 In the series by of patients with SJS/TEN, developed oral was in of patients, in in and all in epithelial necrolysis in and necrolysis of to to and acute acute may in the phase of SJS/TEN. of is is the of this patient with Stevens–Johnson epidermal necrolysis are are characterized by a by a In some the are This patient with Stevens–Johnson epidermal necrolysis developed on the and a few the to produce areas of in Stevens–Johnson epidermal necrolysis may be widely the and In this the patient developed and blistering on the and also has severe and is a of of and in Stevens–Johnson epidermal necrolysis be and, as at may is the are areas of epidermal on the The within an of on this has developed on the of this Stevens–Johnson epidermal necrolysis In case was epidermal of of necrolysis results in the of of and of areas of This patient with toxic epidermal necrolysis epidermal of in the acute phase of Stevens–Johnson epidermal necrolysis is a and The patient is and of and is may at any within the as in this the of the is with on the and of the In this the also the the clinical of SJS/TEN, a of with blistering of the and the clinical diagnosis and (see diagnosis of Stevens–Johnson epidermal necrolysis diagnosis of Stevens–Johnson epidermal necrolysis In a by a group of in SJS/TEN reviewed the clinical of patients and the cases to of and of epidermal (i) SJS (ii) overlap SJS–TEN of (iii) TEN with (iv) TEN with of epidermal There is that these are not cases with from two more of the may the less severe of the spectrum, of SJS from be In is and blistering with epidermal of in to SJS, the in of on the and from SJS/TEN has is to and to SJS/TEN is usually by a by an SJS is and in some may be characterized by a of with This of SJS has been Although a diagnosis of SJS/TEN is by the of a is necessary to the clinical and blistering (see is epidermal from to epidermal changes are with and as and are the is only a of and with of in some cases of Stevens–Johnson epidermal There are the full of the and a a There is a within the SJS/TEN is any potential The patient should an of the Clinical an appraisal to any as well as specific to SJS/TEN. of an management is necessary as as the patient has been a detailed from the patient with specific reference to the (i) of SJS/TEN, including a of a on the and and of (ii) the date when the and document of the (iii) of the and (iv) and the date of of the by when the patient developed the of the for and a of and all the including and document the date were and the when of document the date when were if has been a any any of including of the of severe characterized by blistering and of (see a full the and with a for and areas of epidermal all for and the of and the of epidermal on a for each the of using the and should as well as it is this the of that has prognostic of in SJS/TEN. of of epidermal of of epidermal The should be (i) full and and (ii) (iii) a from to a for and a from should be for to an (iii) from for (iv) of the to of and of a primary management (i) any potential SJS/TEN (see (ii) where the if (see section section A should be (iii) if the patient and if this is not a and (see section section (iv) a when urogenital is A will also accurate to assist Stevens–Johnson epidermal necrolysis Stevens–Johnson epidermal necrolysis SJS/TEN is a with a in approximately of of the causative may be in cases where a is are by a patient has been to of the is as this the of The should be of specific in SJS/TEN be from which are in a studies the from to cases and the out and consisted of cases and a of that are with the of SJS/TEN has been these are for of all cases (see and an are to be to of SJS/TEN. An of in has been developed to in is as a for of and not for use in the acute phase of the key in be as a for in clinical practice. all by the patient a of prior to the of to a full a for each the date the was and, when to as A the and of SJS/TEN is the is a of a to the in which case the may be the that the was in the at the of the by into of the any and which lead to of in the each by the document any and any of a is more if the patient a of a hypersensitivity with the each by the to SJS/TEN (see a causative be as In severe cases of SJS/TEN the acute sequelae lead to and potential prognostic in SJS/TEN identified factors with including to a specialist patient of and of In a prognostic for SJS/TEN, which clinical to of (see and In is to each of the with A of patients that during with a and the of the by of SJS/TEN case series has to should be in all patients with SJS/TEN within the of epidermal in SJS/TEN is by and sequelae of acute and the the of It is recommended that patients with areas of epidermal are to a specialist intensive care for care management and specialist (see the in SJS/TEN is to a patients are to a that intensive management and and in a burns are well for the management of and extensive studies and a review of TEN cases that to a burns is with is by Stevens–Johnson epidermal necrolysis of intensive care of the specialist necessary for SJS/TEN cases a for The SJS/TEN should be by a specialist in usually and should clinicians from intensive and an the patient should be in a to and to the to be in burns patients at by of with of at by of The in extensive epidermal necrolysis and a is necessary in SJS/TEN patient care to and with SJS/TEN with epidermal should be to a to an with of patients with SJS/TEN and to the of extensive The SJS/TEN should be by a specialist in usually and should clinicians from intensive and specialist Additional clinical to the may be from oral and with SJS/TEN be in a controlled for on a with the to and In SJS/TEN, is to from of the in these patients is In care be to to the when and the patient care is by specialist with are with the of epidermal should be the in SJS/TEN at to of There are to management of with evidence as to which is In the is in to as a for the In cases where are should be and the to the of a to the is during the acute phase of SJS/TEN to and The use of an on will and and the may also active blistering and epidermal may within a few may be and a of to A of to material by using This more be considered of characterized by clinical of epidermal and of into a in SJS/TEN and with The and as a for by and by from the will and may lead to which is the of in SJS/TEN. of may with should only be if are clinical of The SJS/TEN process may be by a which of patients should be for of as and may be by an in The of may also be by a in and a of is on of from which this that of is and the of of in areas that are to in and oral The are to all patients with SJS/TEN and in all (i) to (ii) of the and of will the of epidermal (iii) epidermal by the use of and identification (iv) for and from areas of on the acute phase of if is only if are clinical of of should be by in patients with and are a management to of to and management may a based on the specialist review of the needs of the patient a in all patients as (i) and by using an as (ii) a as with the including using to with topical (iii) a topical to areas The of topical should be by to of use of should be limited if extensive areas are (iv) The may be in to as a should be by and of to Health A should be to & to a in patients with TEN epidermal and evidence of the clinical of epidermal In a may be with a (i) and using a topical under (ii) with (iii) with & in patients with and A of care in SJS/TEN is to and epidermal will in which is by oral to of the In patients with burns the of is to the of the is with in adults at In SJS/TEN, are those by may be with and A by and of patients with TEN with extensive epidermal the of and that be by the epidermal and and if if be by and (see management should be on a necessary, use a to of is in patients, use and based on of may also to oral of should be if SJS/TEN is characterized by a with approximately the epidermal is also with of of and from in SJS/TEN cases with areas of a be to and in intensive care is to to and of in SJS/TEN oral with a should be when of intensive care are and these are in The Society for Clinical and the acute phase of SJS/TEN, by the oral if the is by up to during the phase of SJS/TEN. the the aim should be to provide and SJS/TEN is characterized by which is severe at of epidermal There are studies different in SJS/TEN. In the of evidence, patient should be using the of the Health should to at with the addition of as by of the of the by SJS/TEN may the of the patient to a the patient is in which is by then an using should be of of and is for delivery of Additional is to address with patient changes and be for more limited of and use of these including may an of may of and a to in all patients at least a the is with should be if with oral as a as should be of the potential for and the to severe then by may be in with In patients should be using the on a and prior to any the acute as changes and may require analgesia. may be for this when the of is with areas of epidermal will require for in should this in a as an to patients may require in care patients with SJS/TEN are to and, if at of with a is in the in be with is necessary, and are of the acute phase of SJS/TEN. will the of and of has been to It has also been that the use of in SJS/TEN may be and with SJS/TEN are in should as against the acute phase of SJS/TEN, patients in be may from a to against with SJS/TEN are may from the of in SJS/TEN usually with may the of A by of patients with SJS/TEN that during the acute phase of the of the of the and is by and and epithelial a for SJS/TEN, which the acute (see the patients in the by and in the of patients was acute of acute with TEN more not more acute patients with of those with acute went on to also the to the of patients with SJS/TEN of acute This was in in and severe in patients a of of developed of which the were severe and There was in the severity of acute when patients with SJS and TEN were In the severity of the acute was not a factor for The that be from these studies are that the severity of the nor the of the acute are for the may not the acute clinicians should be of this and management of in the acute of SJS/TEN, in will acute and may the severity of the disease. of acute in Stevens–Johnson epidermal necrolysis of acute in Stevens–Johnson epidermal necrolysis a for has been The is to factors for severe and to of and It to be more the of for acute severity of Stevens–Johnson epidermal necrolysis from for acute severity of Stevens–Johnson epidermal necrolysis from These long‐term which constitute the sequelae of SJS/TEN, and severe to to of the and as well as to and with require management for and of the acute of SJS/TEN the of and the management and of and the identification and management of of and are and and be the acute a patients with SJS/TEN in an a is of is of are for the use of a topical are to A of SJS/TEN cases patients topical during the acute phase with patients with information was the of treatment of topical assessed at an the acute were in the group topical with the The should be by an ophthalmologist as a of the of a patient with SJS/TEN. review is necessary during the acute A to provide and a for is of a should be and the acute to and be out each by an ophthalmologist and be performed using a and may be when are well developed and be with of the with a is not recommended and may The of a topical is necessary prior to the In the of is to the of and a with should be to epithelial be to the care be if is of the All and should in topical is recommended by the authors in the of when has been The of should be by of which widely in different In the U.K. a is as which has a of against and U.K. on and by the which may as in the of an treatment is use of topical to and may be by results when these is in patients with that for and are The use of topical by an may in the acute phase of SJS/TEN. the of and should be with in the of a epithelial to topical are these are available in the U.K. for all the studies to the of on in SJS/TEN. A by patients with acute SJS/TEN by a of oral was group. was at a of SJS/TEN the was was in was evidence of epithelial In a case series from the in eight patients with TEN with were with a group of eight of received oral The patients in the group were all were from A of of patients were and severe All patients received In received oral prior to received a of oral The were and There was in severity of the and A further the of treatment on in patients from with with and care only This that the prognostic for that not from the use of treatment to the in the acute phase of SJS/TEN, is evidence for the of to outcomes. studies are to the of There are a of and during the acute phase of The of of and less case of that may provide from the National Health Service and is available in a 5 as well as The is for the entire may be the usually under The is by a also by the that not require a further for and by a and which to the that may be are to the are in the available case and the is not It to on each and is to out in an under as with it be out under the a may be and are available in the U.K. use and has been performed at the under topical has been in of eight SJS/TEN In these patients, was using a and the into a It is to of in the using The be performed at the A the results of in and in in A from patients with SJS/TEN with patients with performed in the acute phase of the assessed within of treatment in the patients in is and in those with extensive of to the use of should be It may if this is out in cases with severe using a and performed at the is a for this in SJS/TEN is characterized by with blistering and of the of the to with the development of The and are in severe may to the and and are usually by oral in acute SJS/TEN. to be and in usually to be and a (see section section A long‐term of acute oral is and which may and with by to as a in up to of for oral in acute SJS/TEN are and with of the and should be to topical and topical In an series of patients with a of blistering conditions the including SJS/TEN, topical were to oral are widely in oral SJS/TEN, is limited evidence for The should be as a of the of a patient with SJS/TEN. oral review is necessary during the acute to the and then the acute with a a the with an oral the in the and to the of an oral is controlled with then a topical per may be as an be for severe oral an oral to of the available 10 10 by up to will the that this and should be if is should be with oral for oral oral & in the for of the oral may using a topical in 10 as a A more in with be to the during the acute There are controlled of in the management of in are by oral in severe In a series eight cases and cases of SJS, patients were with in a of for during the acute a of in all patients of is evidence to for the treatment of the oral of acute SJS/TEN. There are studies of oral in acute SJS/TEN with of the urogenital in SJS/TEN is characterized by blistering and the acute phase is and is by is a of urogenital may also of the may for the acute phase has with In the in the of and of the in and in with and for urogenital in acute SJS/TEN are and with of the urogenital should be to and topical may be to urogenital the urogenital as a of the of a patient with SJS/TEN. In by a specialist is recommended for of to needs to be with that all be patients should be for urogenital review is necessary during the acute to the urogenital and and the acute Health to areas in the and to and A in should be into the to of a topical to the urogenital all patients to in the There are studies of urogenital in patients with acute SJS/TEN with are an of SJS/TEN, and may be a of severity and does not to with the of epidermal A characterized in SJS/TEN into based on and were and the of the development of during the acute phase and of patients presented with characterized by and an were on with in of these patients, and a of of in the with epithelial by epithelial There was evidence of in this and to at the as in was in of and a was In patients with epithelial may and and A of patients with on to which and The is with a of approximately in of cases and consisted of a group of including and the of epithelial in these was for in this and all patients and on should discussion with an and to the as is should be as to the prognostic of this

BACKGROUND AND AIMS: Approximately 10% of adults experience gastro-oesophageal reflux symptoms with a variable oesophageal response. A total of 60% have no endoscopic abnormality, 30% have oesophagitis, and 10% have Barrett's oesophagus. We investigated whether the inflammatory cell infiltrate and cytokine profiles of these clinical phenotypes merely vary in severity or are fundamentally different. METHODS: Patients with reflux symptoms and a normal oesophagus (n=18), oesophagitis (n=26), and Barrett's oesophagus (n=22 newly diagnosed, n=28 surveillance) were recruited. Endoscopic and histopathological degrees of inflammation were scored. Cytokine expression was determined by competitive reverse transcriptase-polymerase chain reaction and immunohistochemistry. RESULTS: In oesophagitis, endoscopic and histopathological grades of inflammation correlated highly. mRNA expression of proinflammatory interleukin (IL)-1beta, IL-8, and interferon gamma (IFN-gamma) were increased 3-10-fold compared with non-inflamed squamous or Barrett's oesophageal samples. There was a modest increase in anti-inflammatory IL-10 but no increase in IL-4. In Barrett's oesophagus, 29/50 had no endoscopic evidence of inflammation and histopathological inflammation was mild in 17/50 and moderate in 24/50, independent of acid suppressants. Expression of IL-1beta, IL-8, and IFN-gamma was similar to non-inflamed squamous mucosa. IL-10 was increased 1.6-fold similar to oesophagitis. IL-4 was increased fourfold, with 100-fold increase in IL-4/T cell receptor expression, compared with squamous oesophagus or oesophagitis. CONCLUSIONS: Barrett's oesophagus is characterised by a distinct Th-2 predominant cytokine profile compared with the proinflammatory nature of oesophagitis. The specific oesophageal immune responses may influence disease development and progression.

OBJECTIVE: To evaluate the impact of the Cleanyourhands campaign on rates of hospital procurement of alcohol hand rub and soap, report trends in selected healthcare associated infections, and investigate the association between infections and procurement. DESIGN: Prospective, ecological, interrupted time series study from 1 July 2004 to 30 June 2008. SETTING: 187 acute trusts in England and Wales. INTERVENTION: Installation of bedside alcohol hand rub, materials promoting hand hygiene and institutional engagement, regular hand hygiene audits, rolled out nationally from 1 December 2004. MAIN OUTCOME MEASURES: Quarterly (that is, every three months) rates for each trust of hospital procurement of alcohol hand rub and liquid soap; Staphylococcus aureus bacteraemia (meticillin resistant (MRSA) and meticillin sensitive (MSSA)) and Clostridium difficile infection for each trust. Associations between procurement and infection rates assessed by mixed effect Poisson regression model (which also accounted for effect of bed occupancy, hospital type, and timing of other national interventions targeting these infections). RESULTS: Combined procurement of soap and alcohol hand rub tripled from 21.8 to 59.8 mL per patient bed day; procurement rose in association with each phase of the campaign. Rates fell for MRSA bacteraemia (1.88 to 0.91 cases per 10,000 bed days) and C difficile infection (16.75 to 9.49 cases). MSSA bacteraemia rates did not fall. Increased procurement of soap was independently associated with reduced C difficile infection throughout the study (adjusted incidence rate ratio for 1 mL increase per patient bed day 0.993, 95% confidence interval 0.990 to 0.996; P < 0.0001). Increased procurement of alcohol hand rub was independently associated with reduced MRSA bacteraemia, but only in the last four quarters of the study (0.990, 0.985 to 0.995; P < 0.0001). Publication of the Health Act 2006 was strongly associated with reduced MRSA bacteraemia (0.86, 0.75 to 0.98; P = 0.02) and C difficile infection (0.75, 0.67 to 0.84; P < 0.0001). Trust visits by Department of Health improvement teams were also associated with reduced MRSA bacteraemia (0.91, 0.83 to 0.99; P=0.03) and C difficile infection (0.80, 0.71 to 0.90; P=0.01), for at least two quarters after each visit. CONCLUSIONS: The Cleanyourhands campaign was associated with sustained increases in hospital procurement of alcohol rub and soap, which the results suggest has an important role in reducing rates of some healthcare associated infections. National interventions for infection control undertaken in the context of a high profile political drive can reduce selected healthcare associated infections.

INTRODUCTION: Barrett's oesophageal epithelium (BE) is clinically important due to the associated inflammatory and malignant complications which are unevenly distributed throughout the BE segment. As the immunoregulatory environment may influence disease manifestations, we analysed the inflammatory and cytokine responses throughout the BE mucosa. We then investigated whether the inflammatory gradient is related to the distribution of metaplastic cell subtypes, epithelial exposure to the components of refluxate, or squamocolumnar cell interactions. METHODS: Fifty consecutive patients with long segment BE were recruited. The segmental degree of endoscopic and histopathological inflammation was graded, and expression of interleukin (IL)-1 beta, IL-8, IL-4, and IL-10 were determined by ELISA following organ culture with or without addition of acid or bile salts. Mucin staining and IL-10 immunohistochemistry were performed. The effect of squamocolumnar interactions on cytokine expression were analysed using cocultures of squamous (OE-21) and BE (TE7) carcinoma cell lines. RESULTS: There was a histopathological inflammatory gradient in BE. Inflammation was maximal at the new squamocolumnar junction with > or = 2-fold increase in proinflammatory IL-8 and IL-1 beta expression. The proximal proinflammatory response could not be explained by the distribution of metaplastic subtypes. Pulsatile exposure of BE to acid and bile, as well as juxtaposition of BE to squamous epithelial cells in culture, increased expression of IL-1 beta. In contrast, inflammation was minimal distally with a significant increase in anti-inflammatory IL-10 expression and 4/6 cancers occurred distally. CONCLUSIONS: Specific cytokine responses may contribute to the localisation of inflammatory and malignant complications within BE.

The use of biologic therapies has transformed the management of inflammatory arthritis (IA). In contrast to conventional systemic DMARDs (csDMARDs) traditionally used to treat inflammatory disease, these agents offer a targeted approach, and their widespread use has resulted in disease remission becoming an increasingly achievable goal. Biologic therapies are not without potential risk, and hence it is important that clinicians are aware of these risks and ensure that appropriate precautions are taken to minimize them. Information on the safety of biologic therapies continues to be collected through national registries, clinical and cohort studies and case series and reports.<br/><br/>NICE has accredited the process used by the BSR to produce its guidance on the safety of biologic DMARDs in inflammatory arthritis. Accreditation is valid for 5 years from 10 June 2013<br/><br/>This guideline supersedes the previous BSR/BHPR anti-TNF [1], rituximab (RTX) [2] and tocilizumab (TCZ) [3] guidelines and has been developed in line with the BSR Guidelines Protocol.

INTRODUCTION: Achieving a sustained improvement in hand-hygiene compliance is the WHO's first global patient safety challenge. There is no RCT evidence showing how to do this. Systematic reviews suggest feedback is most effective and call for long term well designed RCTs, applying behavioural theory to intervention design to optimise effectiveness. METHODS: Three year stepped wedge cluster RCT of a feedback intervention testing hypothesis that the intervention was more effective than routine practice in 16 English/Welsh Hospitals (16 Intensive Therapy Units [ITU]; 44 Acute Care of the Elderly [ACE] wards) routinely implementing a national cleanyourhands campaign). Intervention-based on Goal & Control theories. Repeating 4 week cycle (20 mins/week) of observation, feedback and personalised action planning, recorded on forms. Computer-generated stepwise entry of all hospitals to intervention. Hospitals aware only of own allocation. PRIMARY OUTCOME: direct blinded hand hygiene compliance (%). RESULTS: All 16 trusts (60 wards) randomised, 33 wards implemented intervention (11 ITU, 22 ACE). Mixed effects regression analysis (all wards) accounting for confounders, temporal trends, ward type and fidelity to intervention (forms/month used). INTENTION TO TREAT ANALYSIS: Estimated odds ratio (OR) for hand hygiene compliance rose post randomisation (1.44; 95% CI 1.18, 1.76;p<0.001) in ITUs but not ACE wards, equivalent to 7-9% absolute increase in compliance. PER-PROTOCOL ANALYSIS FOR IMPLEMENTING WARDS: OR for compliance rose for both ACE (1.67 [1.28-2.22]; p<0.001) & ITUs (2.09 [1.55-2.81]; p<0.001) equating to absolute increases of 10-13% and 13-18% respectively. Fidelity to intervention closely related to compliance on ITUs (OR 1.12 [1.04, 1.20]; p = 0.003 per completed form) but not ACE wards. CONCLUSION: Despite difficulties in implementation, intention-to-treat, per-protocol and fidelity to intervention, analyses showed an intervention coupling feedback to personalised action planning produced moderate but significant sustained improvements in hand-hygiene compliance, in wards implementing a national hand-hygiene campaign. Further implementation studies are needed to maximise the intervention's effect in different settings. TRIAL REGISTRATION: Controlled-Trials.com ISRCTN65246961.

BACKGROUND: Fluorescent angiography (FA) has been useful for assessing blood flow and assessing tissue perfusion in ophthalmology and other surgical disciplines for decades. In plastic surgery, indocyanine green (ICG) dye-based FA is a relatively novel imaging technology with high potential in various applications. We review the various FA detector systems currently available and critically appraise its utility in breast reconstruction. METHODS: A review of the published English literature dating from 1950 to 2015 using databases, such as PubMed, Medline, Web of Science, and EMBASE was undertaken. RESULTS: In comparison to the old fluorescein dye, ICG has a superior side effect profile and can be accurately detected by various commercial devices, such as SPY Elite (Novadaq, Canada), FLARE (Curadel LLC, USA), PDE-Neo (Hamamatsu Photonics, Japan), Fluobeam 800 (Fluoptics, France), and IC-View (Pulsion Medical Systems AG, Germany). In breast reconstruction, ICG has established as a safer, more accurate tracer agent, in lieu of the traditional blue dyes, for detection of sentinel lymph nodes with radioactive isotopes ((99m)-Technetium). In prosthesis-based breast reconstruction, intraoperative assessment of the mastectomy skin flap to guide excision of hypoperfused areas translates to improved clinical outcomes. Similarly, in autologous breast reconstructions, FA can be utilized to detect poorly perfused areas of the free flap, evaluate microvascular anastomosis for patency, and assess SIEA vascular territory for use as an alternative free flap with minimal donor site morbidity. CONCLUSIONS: ICG-based FA is a novel, useful tool for various applications in breast reconstruction. More studies with higher level of evidence are currently lacking to validate this technology.

We performed a systematic review of epidemiological, diagnostic, and therapeutic outcomes of esophageal perforations. A systematic review was performed in PubMed database using the key-phrase 'esophageal perforation'. All studies regarding acute esophageal perforations were reviewed and parameters of epidemiology, diagnosis, and management published in the literature from 2005 up to 2015 were included in the study. Studies of postoperative esophageal leaks were excluded. Two researchers performed individually the research, while quality assessment was performed according to GRADE classification. Main outcomes and exposure were overall mortality, perforation-to-admission interval, anatomical position, cause, prevalent symptom at admission, diagnostic tests used, type of initial management (conservative or surgery), healing rate, and fistula complication. There were 1319 articles retrieved, of which 52 studies including 2,830 cases finally met inclusion criteria. Mean duration of study period was 15.2 years. Mean patient age was 58.4 years. Out of 52 studies included, there were 43 studies of very low or low quality included. The overall mortality rate according to extracted data was 13.3% (n = 214, 1,644 patients, 39 studies). Admission before 24 hours was reported in 58.1% of patients (n = 514). Position was thoracic in 72.6% of patients (n = 813, 1,120 patients, 20 studies). Mean cause of perforation was iatrogenic in 46.5% of patients (n = 899, 1,933 patients, 40 studies). Initial management was conservative in 51.3% of cases (n = 904, 1,762 patients, 41 studies) CT confirmed diagnosis in 38.7% of overall cases in which it was used as imaging diagnostic procedure (n = 266), X-ray in 36.6% (n = 231), and endoscopy in 37.4% (n = 343). Sepsis on admission was observed in 23.3% of cases (209 out of 898 patients, 16 studies). The present systematic review highlighted the significant proportion of cases diagnosed with delay over 24 hours, mortality rates ranging over 10% and no consensus regarding optimal therapeutic approach and optimal diagnostic management. As esophageal perforation represents a high-risk clinical condition without consensus regarding optimal management, there should be large multicenter prospective studies or Randomized Controlled Trial (RCT)s performed in order to advance diagnostic and therapeutic approach of such challenging pathology.

BACKGROUND: We report on the hepatitis C virus (HCV) epidemic among human immunodeficiency virus (HIV)-positive men who have sex with men (MSM) in the United Kingdom and model its trajectory with or without scaled-up HCV direct-acting antivirals (DAAs). METHODS: A dynamic HCV transmission model among HIV-diagnosed MSM in the United Kingdom was calibrated to HCV prevalence (antibody [Ab] or RNA positive), incidence, and treatment from 2004 to 2011 among HIV-diagnosed MSM in the UK Collaborative HIV Cohort (UK CHIC). The epidemic was projected with current or scaled-up HCV treatment, with or without a 20% behavioral risk reduction. RESULTS: HCV prevalence among HIV-positive MSM in UK CHIC increased from 7.3% in 2004 to 9.9% in 2011, whereas primary incidence was flat (1.02-1.38 per 100 person-years). Over the next decade, modeling suggests 94% of infections are attributable to high-risk individuals, comprising 7% of the population. Without treatment, HCV chronic prevalence could have been 38% higher in 2015 (11.9% vs 8.6%). With current treatment and sustained virological response rates (status quo), chronic prevalence is likely to increase to 11% by 2025, but stabilize with DAA introduction in 2015. With DAA scale-up to 80% within 1 year of diagnosis (regardless of disease stage), and 20% per year thereafter, chronic prevalence could decline by 71% (to 3.2%) compared to status quo in 2025. With additional behavioral interventions, chronic prevalence could decline further to <2.5% by 2025. CONCLUSIONS: Epidemiological data and modeling suggest a continuing HCV epidemic among HIV-diagnosed MSM in the United Kingdom driven by high-risk individuals, despite high treatment rates. Substantial reductions in HCV transmission could be achieved through scale-up of DAAs and moderately effective behavioral interventions.

Hospital-acquired infections are on the rise and are a substantial cause of clinical and financial burden for healthcare systems. While infection control plays a major role in curtailing the spread of outbreak organisms, it is not always successful. One organism of particular concern is Acinetobacter baumannii, due to both its persistence in the hospital setting and its ability to acquire antibiotic resistance. A. baumannii has emerged as a nosocomial pathogen that exhibits high levels of resistance to antibiotics, and remains resilient against traditional cleaning measures with resistance to Colistin increasingly reported. Given the magnitude and costs associated with hospital acquired infections, and the increase in multidrug-resistant organisms, it is worth re-evaluating our current approaches and looking for alternatives or adjuncts to traditional antibiotics therapies. The aims of this review are to look at how this organism is spread within the hospital setting, discuss current treatment modalities, and propose alternative methods of outbreak management.

Delays in cancer diagnosis and treatment due to the COVID-19 pandemic is a widespread source of concern, but the scale of the challenge for different tumour sites is not known. Routinely collected NHS England Cancer Waiting Time data were analysed to compare activity for breast cancer in the first 6 months of 2020 compared to the same time period in 2019. The number of referrals for suspected breast cancer was 28% lower (N = 231,765 versus N = 322,994), and the number of patients who received their first treatment for a breast cancer diagnosis was 16% lower (N = 19,965 versus N = 23,881). These data suggest that the number of breast cancers diagnosed during the first half of 2020 is not as low as initially feared, and a substantial proportion of the shortfall can be explained by the suspension of routine screening in March 2020. Further work is needed to examine in detail the impact of measures to manage the COVID-19 pandemic on breast cancer outcomes.

<h3>Objectives</h3> Immigrants with common mental disorders (CMDs) are reported to have a higher risk of disability pension (DP) compared with native residents; however, the reasons for this are not fully understood. This study aimed to investigate (1) differences in morbidity (3 measures) and socioeconomic status in native Swedes, ‘Western’ and ‘non-Western’ immigrants with CMDs and (2) interactions between morbidity and socioeconomic status and immigrant status regarding subsequent DP. <h3>Design</h3> The study was a prospective population-based cohort study using national register data. Crude and multivariate HRs with 95% CIs were calculated using the Cox regression (2007–2010). <h3>Participants</h3> All individuals aged 18–59 with an incident sick-leave spell due to CMDs during 2006 were included in the study (N=66 097). The study population was divided into 3 groups based on country of birth: (1) Sweden, (2) immigrants from ‘Western’ countries (EU25, Norway, Iceland, North America and Oceania) and (3) immigrants from ‘non-Western’ countries (east Europe, Africa, Asia and South America). <h3>Results</h3> Particularly, immigrants born in non-Western countries had higher levels of morbidity and lower socioeconomic status than natives (p&gt;0.001). No significant differences in the associations between specialised psychiatric and somatic care with regard to subsequent DP were found between immigrants and native Swedes. Being prescribed more than 1 type of psychiatric medication was associated with higher HRs for DP in immigrants from Western (HR 3.34; CI 2.3 to 4.9) and non-Western countries (3.6; 1.9 to 6.4) than in native Swedes (2.55; 2.3 to 2.8) (p_interaction=0.003). Low education was a marginally stronger predictor for DP in non-Western immigrants than in native Swedes and Western immigrants (p_interaction=0.03). <h3>Conclusions</h3> Morbidity measured by medication, but not by specialised healthcare, was a stronger predictor for DP in immigrants than in native Swedes, warranting scrutiny of differences in care and treatment in immigrants and native Swedes with CMDs.

[No abstract]

In this study, the authors explored how a group of young people aged 16 to 26 years (who identified themselves as having engaged in deliberate self-harm) made sense of the self by conducting two online focus groups and four e-mail interviews. They analyzed data using interpretive phenomenological analysis. The concept of validation was the primary means of making sense of the self and concerned the desire to be considered legitimate and of worth. This desire was clearly evident across three realms of conflict: (a) the intrinsic or extrinsic self, which marked the distinction between objective fact and subjective opinion; (b) the accepted or denied self; and (c) the notion of normality. It is possible that having one's denied self validated online might lead to an exacerbation of an individual's self-harming behavior. Further work is needed to explore the effects of online discussion forums on such taboo forms of behavior.

OBJECTIVE: Barrett's oesophagus shows appearances described as 'intestinal metaplasia', in structures called 'crypts' but do not typically display crypt architecture. Here, we investigate their relationship to gastric glands. METHODS: Cell proliferation and migration within Barrett's glands was assessed by Ki67 and iododeoxyuridine (IdU) labelling. Expression of mucin core proteins (MUC), trefoil family factor (TFF) peptides and LGR5 mRNA was determined by immunohistochemistry or by in situ hybridisation, and clonality was elucidated using mitochondrial DNA (mtDNA) mutations combined with mucin histochemistry. RESULTS: Proliferation predominantly occurs in the middle of Barrett's glands, diminishing towards the surface and the base: IdU dynamics demonstrate bidirectional migration, similar to gastric glands. Distribution of MUC5AC, TFF1, MUC6 and TFF2 in Barrett's mirrors pyloric glands and is preserved in Barrett's dysplasia. MUC2-positive goblet cells are localised above the neck in Barrett's glands, and TFF3 is concentrated in the same region. LGR5 mRNA is detected in the middle of Barrett's glands suggesting a stem cell niche in this locale, similar to that in the gastric pylorus, and distinct from gastric intestinal metaplasia. Gastric and intestinal cell lineages within Barrett's glands are clonal, indicating derivation from a single stem cell. CONCLUSIONS: Barrett's shows the proliferative and stem cell architecture, and pattern of gene expression of pyloric gastric glands, maintained by stem cells showing gastric and intestinal differentiation: neutral drift may suggest that intestinal differentiation advances with time, a concept critical for the understanding of the origin and development of Barrett's oesophagus.

PURPOSE: The aim of this study is to determine the optimal range of cephalic vein and radial artery diameter following preoperative duplex imaging to enhance maturation and primary patency of Brescia-Cimino radiocephalic arteriovenous fistula. METHODS: A systematic review and meta-aggregation of literature from 1966 to January 2015 in English language and adult subjects in Pubmed, OVID, CINHAL and Cochrane database was conducted. RESULTS: This search produced a total of thirty-six (n = 36) articles. Following the application of recruitment criteria, only twelve articles (n = 12) were found eligible. Their quality was assessed by Oxford Critical Appraisal skills Programme (CASP) and their recommendation for practice was examined through National Institute for Health and Care Excellence (NICE). CONCLUSIONS: The current literature suggests that the optimal range of radial artery for maximum performance (maturation and primary patency) of RCAVF is at least 2 mm (level 2, grade a). The cephalic vein diameter of at least 2 mm (non-augmented) can result in best maturation and primary patency outcomes (level 2, grade a) and threshold below 1.5 mm is not advocated (level 2, grade b).

INTRODUCTION: The benefits and use of low-dose corticosteroids (LDCs) in severe sepsis and septic shock remain controversial. Surviving sepsis campaign guidelines suggest LDC use for septic shock patients poorly responsive to fluid resuscitation and vasopressor therapy. Their use is suspected to be wide-spread, but paucity of data regarding global practice exists. The purpose of this study was to compare baseline characteristics and clinical outcomes of patients treated or not treated with LDC from the international PROGRESS (PROmoting Global Research Excellence in Severe Sepsis) cohort study of severe sepsis. METHODS: Patients enrolled in the PROGRESS registry were evaluated for use of vasopressor and LDC (equivalent or lesser potency to hydrocortisone 50 mg six-hourly plus 50 microg 9-alpha-fludrocortisone) for treatment of severe sepsis at any time in intensive care units (ICUs). Baseline characteristics and hospital mortality were analyzed, and logistic regression techniques used to develop propensity score and outcome models adjusted for baseline imbalances between groups. RESULTS: A total of 8,968 patients with severe sepsis and sufficient data for analysis were studied. A total of 79.8% (7,160/8,968) of patients received vasopressors, and 34.0% (3,051/8,968) of patients received LDC. Regional use of LDC was highest in Europe (51.1%) and lowest in Asia (21.6%). Country use was highest in Brazil (62.9%) and lowest in Malaysia (9.0%). A total of 14.2% of patients on LDC were not receiving any vasopressor therapy. LDC patients were older, had more co-morbidities and higher disease severity scores. Patients receiving LDC spent longer in ICU than patients who did not (median of 12 versus 8 days; P <0.001). Overall hospital mortality rates were greater in the LDC than in the non-LDC group (58.0% versus 43.0%; P <0.001). After adjusting for baseline imbalances, in all mortality models (with vasopressor use), a consistent association remained between LDC and hospital mortality (odds ratios varying from 1.30 to 1.47). CONCLUSIONS: Widespread use of LDC for the treatment of severe sepsis with significant regional and country variation exists. In this study, 14.2% of patients received LDC despite the absence of evidence of shock. Hospital mortality was higher in the LDC group and remained higher after adjustment for key determinates of mortality.