Morriston Hospital

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: In acute ST-segment elevation myocardial infarction (STEMI), the use of percutaneous coronary intervention (PCI) to treat the artery responsible for the infarct (infarct, or culprit, artery) improves prognosis. The value of PCI in noninfarct coronary arteries with major stenoses (preventive PCI) is unknown. METHODS: From 2008 through 2013, at five centers in the United Kingdom, we enrolled 465 patients with acute STEMI (including 3 patients with left bundle-branch block) who were undergoing infarct-artery PCI and randomly assigned them to either preventive PCI (234 patients) or no preventive PCI (231 patients). Subsequent PCI for angina was recommended only for refractory angina with objective evidence of ischemia. The primary outcome was a composite of death from cardiac causes, nonfatal myocardial infarction, or refractory angina. An intention-to-treat analysis was used. RESULTS: By January 2013, the results were considered conclusive by the data and safety monitoring committee, which recommended that the trial be stopped early. During a mean follow-up of 23 months, the primary outcome occurred in 21 patients assigned to preventive PCI and in 53 patients assigned to no preventive PCI (infarct-artery-only PCI), which translated into rates of 9 events per 100 patients and 23 per 100, respectively (hazard ratio in the preventive-PCI group, 0.35; 95% confidence interval [CI], 0.21 to 0.58; P<0.001). Hazard ratios for the three components of the primary outcome were 0.34 (95% CI, 0.11 to 1.08) for death from cardiac causes, 0.32 (95% CI, 0.13 to 0.75) for nonfatal myocardial infarction, and 0.35 (95% CI, 0.18 to 0.69) for refractory angina. CONCLUSIONS: In patients with STEMI and multivessel coronary artery disease undergoing infarct-artery PCI, preventive PCI in noninfarct coronary arteries with major stenoses significantly reduced the risk of adverse cardiovascular events, as compared with PCI limited to the infarct artery. (Funded by Barts and the London Charity; PRAMI Current Controlled Trials number, ISRCTN73028481.).

The indications for transfusing fresh-frozen plasma (FFP), cryoprecipitate and cryosupernatant plasma are very limited. When transfused they can have unpredictable adverse effects. The risks of transmitting infection are similar to those of other blood components unless a pathogen-reduced plasma (PRP) is used. Of particular concern are allergic reactions and anaphylaxis, transfusion-related acute lung injury, and haemolysis from transfused antibodies to blood group antigens, especially A and B. FFP is not indicated in disseminated intravascular coagulation without bleeding, is only recommended as a plasma exchange medium for thrombotic thrombocytopenic purpura (for which cryosupernatant is a possible alternative), should never be used to reverse warfarin anticoagulation in the absence of severe bleeding, and has only a very limited place in prophylaxis prior to liver biopsy. When used for surgical or traumatic bleeding, FFP and cryoprecipitate doses should be guided by coagulation studies, which may include near-patient testing. FFP is not indicated to reverse vitamin K deficiency for neonates or patients in intensive care units. PRP may be used as an alternative to FFP. In the UK, PRP from countries with a low bovine spongiform encephalopathy incidence is recommended by the Departments of Health for children born after 1 January 1996. Arrangements for limited supplies of single donor PRP of non-UK origin are expected to be completed in 2004. Batched pooled commercially prepared PRP from donors in the USA (Octaplas) is licensed and available in the UK. FFP must be thawed using a technique that avoids risk of bacterial contamination. Plastic packs containing any of these plasma products are brittle in the frozen state and must be handled with care.

Background: Asymptomatic atrial fibrillation (AF) is increasingly common in the aging population and implicated in many ischemic strokes. Earlier identification of AF with appropriate anticoagulation may decrease stroke morbidity and mortality. Methods: We conducted a randomized controlled trial of AF screening using an AliveCor Kardia monitor attached to a WiFi-enabled iPod to obtain ECGs (iECGs) in ambulatory patients. Patients ≥65 years of age with a CHADS-VASc score ≥2 free from AF were randomized to the iECG arm or routine care (RC). iECG participants acquired iECGs twice weekly over 12 months (plus additional iECGs if symptomatic) onto a secure study server with overread by an automated AF detection algorithm and by a cardiac physiologist and/or consultant cardiologist. Time to diagnosis of AF was the primary outcome measure. The overall cost of the devices, ECG interpretation, and patient management were captured and used to generate the cost per AF diagnosis in iECG patients. Clinical events and patient attitudes/experience were also evaluated. Results: We studied 1001 patients (500 iECG, 501 RC) who were 72.6±5.4 years of age; 534 were female. Mean CHADS-VASc score was 3.0 (heart failure, 1.4%; hypertension, 54%; diabetes mellitus, 30%; prior stroke/transient ischemic attack, 6.5%; arterial disease, 15.9%; all CHADS-VASc risk factors were evenly distributed between groups). Nineteen patients in the iECG group were diagnosed with AF over the 12-month study period versus 5 in the RC arm (hazard ratio, 3.9; 95% confidence interval=1.4–10.4; P =0.007) at a cost per AF diagnosis of $10 780 (£8255). There was a similar number of stroke/transient ischemic attack/systemic embolic events (6 versus 10, iECG versus RC; hazard ratio=0.61; 95% confidence interval=0.22–1.69; P =0.34). The majority of iECG patients were satisfied with the device, finding it easy to use without restricting activities or causing anxiety. Conclusions: Screening with twice-weekly single-lead iECG with remote interpretation in ambulatory patients ≥65 years of age at increased risk of stroke is significantly more likely to identify incident AF than RC over a 12-month period. This approach is also highly acceptable to this group of patients, supporting further evaluation in an appropriately powered, event-driven clinical trial. Clinical Trial Registration: URL: https://www.isrctn.com . Unique identifier: ISRCTN10709813.

Introduction: Intravenous(IV) immunoglobulin(Ig) treatment is known to alleviate behavioral deficits in the experimentally induced model of sepsis. To delineate the mechanisms by which IVIg treatment prevents neuronal dysfunction, an array of immunological and apoptosis markers was investigated. Methods: Sepsis was induced by cecal ligation perforation(CLP) in rats. The animals were divided into five groups; sham, control, CLP + saline, CLP + immunoglobulin G IgG(250 mg/kg,iv), and CLP + immunoglobulins enriched with immunoglobulin M-IgGAM(250 mg/kg,iv). Blood and brain samples were taken in two sets of experiments after CLP to see the early(24 hrs) and late(10 days) effects of treatment. Total complement activity, complement 3(C3) and soluble complement C5b-9 levels were measured in sera of rats using ELISA-based methods. Cerebral complement content was analyzed by Western Blot. Immune cell infiltration and gliosis were examined by immunohistochemistry using cluster of differentiation 3, CD4, CD8, CD11b, CD19 and glial fibrillary acidic protein antibodies. Apoptotic neuronal death was investigated by TUNEL staining and Western Blot-based semi-quantitative evaluation of brain homogenates by bax and bcl-2 antibodies. Results: IV IgG and IgGAM administration significantly reduced systemic complement activity but increased serum C3 and soluble C5b-9 levels. Likewise, Western Blot data showed slightly increased C5b-9 expression and significantly reduced C1q expression in brain samples of IgGAM-treated but not IgG-treated septic rats especially in the first day of administration. No cerebral cellular infiltrates were observed in treated and non-treated septic rats. By contrast, IV IgG and IgGAM treatment induced considerable amelioration in glial cell proliferation which was increased in non-treated rats. IgG and IgGAM treated rats exhibited significantly reduced numbers of apoptotic neurons and cerebral expression levels of bax and bcl-2 as compared to nontreated rats. Conclusions: We suggest that IV IgG and IgGAM administration ameliorates neuronal dysfunction and behavioral deficits by reducing apoptotic cell death and glial cell proliferation. IgGAM treatment might be suppressing classical complement pathway by reducing C1q expression.

Regenerative medicine has been highlighted as one of the UK's 8 'Great Technologies' with the potential to revolutionize patient care in the 21st Century. Over the last decade, the concept of '3D bioprinting' has emerged, which allows the precise deposition of cell laden bioinks with the aim of engineering complex, functional tissues. For 3D printing to be used clinically, there is the need to produce advanced functional biomaterials, a new generation of bioinks with suitable cell culture and high shape/print fidelity, to match or exceed the physical, chemical and biological properties of human tissue. With the rapid increase in knowledge associated with biomaterials, cell-scaffold interactions and the ability to biofunctionalize/decorate bioinks with cell recognition sequences, it is important to keep in mind the 'printability' of these novel materials. In this illustrated review, we define and refine the concept of 'printability' and review seminal and contemporary studies to highlight the current 'state of play' in the field with a focus on bioink composition and concentration, manipulation of nozzle parameters and rheological properties.

BACKGROUND: Bleeding and transfusion after percutaneous coronary intervention (PCI) are known predictors of mortality. Transradial arterial access reduces bleeding and transfusion related to femoral access complications, although its association with mortality is unknown. OBJECTIVE: To determine the association of arterial access site (radial or femoral) with transfusion and mortality in unselected PCIs. DESIGN, SETTING AND PATIENTS: By data linkage of three prospectively collated provincial registries, 38,872 procedures in 32,822 patients in British Columbia were analysed. The association between access site, transfusion and outcomes was assessed by logistic regression, propensity score matching and probit regression. MAIN OUTCOME MEASURES: 30-Day and 1-year mortality. RESULTS: 1134 (3.5%) patients had at least one blood transfusion. Transfused patients had a significantly increased 30-day and 1-year mortality, adjusted odds ratio (95% CI) 4.01 (3.08 to 5.22) and 3.58 (2.94 to 4.36), respectively. By probit regression the absolute increase in risk of death at 1 year associated with receiving a transfusion was 6.78%. The number needed to treat was 14.74 (prevention of 15 transfusions required to "avoid" one death). Radial access halved the transfusion rate. After adjustment for all variables, radial access was associated with a significant reduction in 30-day and 1-year mortality, odds ratio = 0.71 (95% CI 0.61 to 0.82) and 0.83 (0.71 to 0.98), respectively (all p<0.001). CONCLUSIONS: In a registry of all comers to PCI, transradial access was associated with a halving of the transfusion rate and a reduction in 30-day and 1-year mortality.

Lamotrigine is a chemically novel antiepileptic drug which has not been adequately assessed for its antineuralgic properties. It was used in a double-blind placebo controlled crossover trial in 14 patients with refractory trigeminal neuralgia. Patients continued to take a steady dose of carbamazepine or phenytoin throughout the trial over a 31-day period. Each arm of the trial lasted 2 weeks with an intervening 3-day washout period. The maintenance dose of lamotrigine was 400 mg. Lamotrigine was superior to placebo (P = 0.011) based on analysis of a composite efficacy index which compared the numbers of patients assigned greater efficacy on lamotrigine with those assigned greater efficacy on placebo. Efficacy for one treatment over another was determined according to a hierarchy of: (i) use of escape medication; (ii) total pain scores; or (iii) global evaluations. Eleven of the 13 patients eligible for inclusion in the composite efficacy index showed better efficacy on lamotrigine compared with placebo. Global evaluations further suggested that patients did better on lamotrigine than placebo (P = 0.025). The adverse reactions with both lamotrigine and placebo were predominantly dose-dependent effects on the central nervous system. A 14th patient withdrew from the study due to severe pain during the placebo arm of the trial. It would appear that lamotrigine has antineuralgic properties.

The guideline group was selected to be representative of UK-based medical experts and included the authors of previous recommendations. Preparation of the guidelines included a review of key literature, including Cochrane Database and MEDLINE and consultation with representatives of relevant specialties. Recommendations are based on appraisal of the relevant literature and expert consensus. The writing group produced the draft guideline, which was subsequently revised by consensus by members of the Transfusion Task Force of the British Committee for Standards in Haematology. The guideline was then reviewed by a sounding board of approximately 100 UK haematologists, the British Committee for Standards in Haematology (BCSH) and the British Society for Haematology Committee and comments incorporated where appropriate. Criteria used to quote levels and grades of evidence are as outlined in appendix 3 of the Procedure for Guidelines Commissioned by the BCSH (http://www.bcshguidelines.com/process1.asp#App3). The objective of this guideline is to provide healthcare professionals with clear guidance on the management of massive blood loss. They do not address the specific problems associated with major obstetric haemorrhage; these are being addressed by the Royal College of Obstetricians. In all cases individual patient circumstances may dictate an alternative approach. These guidelines summarise current opinions regarding the management of massive blood loss and update previous recommendations (Stainsby et al, 2000). These are presented as a template that can be modified to suit local circumstances, and then displayed in clinical areas. The left-hand column outlines the key steps or goals, the centre column adds procedural detail and the right-hand column provides additional advice and information (Table I). Major blood loss jeopardises the survival of patients in many clinical settings and is a challenge for haematological and blood transfusion services. Tensions may arise between those attempting to treat bleeding, those supplying blood and those providing laboratory services. Discord can waste scarce resources, or, worse, result in a bad outcome for the patient. Massive blood loss is arbitrarily defined as the loss of one blood volume within a 24 h period (Mollison et al, 1997), the normal adult blood volume being approximately 7% of ideal body weight in adults and 8–9% in children. Alternative definitions that may be more helpful in the acute situation include a 50% blood volume loss within 3 h or a rate of loss of 150 ml/min (Fakhry & Sheldon, 1994). It is imperative to recognise major blood loss early and institute effective action promptly if shock and its consequences are to be prevented. These are; Maintenance of tissue perfusion and oxygenation by restoration of blood volume and haemoglobin Arrest of bleeding by treating any traumatic, surgical or obstetric source judicious use of blood component therapy to correct coagulopathy A successful outcome requires prompt action and good communication between clinical specialties, diagnostic laboratories, hospital transfusion laboratory staff and the Blood Service. Blood component support takes time to organise and the supplying blood centre may be several hours away from the hospital. Special transfusion requirements for specific indications, e.g. components suitable for neonates, irradiated components for patients at risk of transfusion-associated graft-versus-host disease, (British Committee for Standards in Haematology Blood Transfusion Taskforce, 1996, 2004), should be taken into account if time permits, but it may be necessary to make a pragmatic decision regarding the relative risks of delaying transfusion or giving components that are not of the appropriate specification. Early consultation with senior surgical, anaesthetic and haematology colleagues is essential and the importance of good communication and co-operation in this situation cannot be over-emphasised. Appropriate surgical expertise for the area of bleeding is vital; involvement of vascular surgeons, cardiothoracic surgeons or others with specific interests is crucial to success. Consideration should be given to early referral and if necessary transfer to such expertise. In the more difficult cases, confidence to pack visceral cavities, cross clamp and tie off major vessels may be required. Radiological embolisation or stenting has an established role. An intensive care bed is likely to be required and early warning of this is advisable. A member of the clinical team should be nominated to act as co-ordinator responsible for overall organisation, liaison, communication and documentation. This is a critical role for a designated member of the permanent clinical staff. Accurate documentation of blood components given and the reason for transfusion is necessary in order to enable audit of outcome and satisfy the legal requirement for full traceability (Blood Safety and Quality Regulations, 2005). The hospital transfusion laboratory must be informed of a massive transfusion situation at the earliest possible opportunity. This will provide an opportunity to check stock, reschedule non-urgent work and call in additional staff if required out of hours. Clear local protocols for management of massive blood loss should be accessible in all relevant clinical and laboratory areas and understood by all involved staff. Regular ‘drills’ can improve awareness and confidence and ensure that the blood transfusion chain works efficiently. It is good practice to review such cases after the event, to assess what went well and what did not, and to update protocols accordingly. The Hospital Transfusion Committee (HTC) has a central role in ensuring the optimum and safe use of blood components. The development of protocols for management of massive transfusion is an important part of its remit. The HTC also provides a forum in which a rapid communication cascade can be agreed and massive transfusion episodes critically reviewed. As part of contingency planning for national blood shortage situations, every hospital should have an Emergency Blood Management Plan in place that provides guidance on clinical priorities for the use of large volumes of blood components. In exceptional circumstances it may be necessary to make a decision to cease energetic transfusion support when the chances of the patient's survival are low, determined on a case-by-case basis. The HTC should establish a mechanism for making such difficult decisions on an individual basis, taking into account such factors as co-morbidity, potential for control of bleeding, reversal of the underlying cause and competing demands for available blood components. The over-riding first requirement is maintenance of tissue perfusion and oxygenation, which is critical in preventing the development of hypovolaemic shock and consequent high mortality from multi-organ failure. Restoration of circulating volume is initially achieved by rapid infusion of crystalloid or colloid through large bore (up to 14 gauge) peripheral cannulae (Donaldson et al, 1992). Alternatively, larger bore central access devices can be used dependent on local skills and availability The use of albumin and non-albumin colloids versus crystalloids for volume replacement has been the subject of debate following controversial meta-analyses (Cochrane Injuries Group Albumin Reviewers, 1998; Schierhout & Roberts, 1998). A controlled trial of normal saline versus 4% human albumin for fluid resuscitation involving over 7000 patients in 16 intensive Care Units in Australia and New Zealand (Finfer et al, 2004) found no difference in outcome at 28 d and concluded that they were clinically equivalent (Grade A recommendation, Level 1b evidence). Hypothermia increases the risk of end organ failure and coagulopathy (Iserson & Huestis, 1991; American College of Surgeons, 1997) and may be prevented by pre-warming of resuscitation fluids, patient warming devices such as warm air blankets and the use of temperature controlled blood warmers (Grade C recommendation, Level IV evidence). Blood samples should be sent to the laboratory at the earliest possible opportunity for blood grouping, antibody screening and compatibility testing, as well as for baseline haematology, coagulation screen (including fibrinogen estimation and thrombin time) and biochemistry investigations. Accurate patient identification is of paramount importance in all aspects of healthcare, and particularly in emergency situations. Every patient must wear an identification wristband, and there must be a robust and tested system in place for identification of unknown unconscious patients, including subsequent merging of clinical and laboratory records. When dealing with an evolving process it is important to check parameters frequently, (and after each therapeutic intervention) to monitor the need for and the efficacy of component therapy. Appropriate use of near-patient testing devices, which can include thromboelastography (TEG), can offer rapid data to guide component therapy (Samama & Ozier, 2003) but requires expert interpretation. Advice should be sought from a consultant with transfusion expertise regarding appropriate investigations, their interpretation and optimum corrective therapy. Allogeneic blood from volunteer donors is a limited and valuable resource that must be used carefully, appropriately and safely. There is a lack of good evidence from randomised controlled trials to support recommendations for the use of blood components in massive transfusions, although the design of such trials in the emergency setting is problematic. The target platelet count and the efficacy of fresh frozen plasma are key areas where further research is needed. All blood components supplied by the UK transfusion services are now leucodepleted as a precaution against transfusion transmission of variant Creutzfeldt-Jakob disease (vCJD), in addition to mandatory testing for viral markers (human immunodeficiency virus [HIV], hepatitis B virus [HBV], hepatitis C virus [HCV] and Human T lymphotropic virus type 1 [HTLV 1]). Benefits of leucodepletion also include reduced non-haemolytic febrile transfusion reactions, reduced transmission of leucocyte-associated viruses, such as cytomegalovirus, reduced immunosuppressive effects of transfusion (Blajchman et al, 2001) and reduced cytokine-mediated organ damage. (Erber, 2002) Transfusion giving sets, which should be changed at least 12-hourly during red cell infusion and prior to platelet infusion, include a screen filter. Any additional filter is unnecessary and may impede blood flow. (McClelland, 2001) The function of red cells is oxygen delivery to tissues; they should not be used as a volume expander. In the UK, the blood services will routinely provide leucodepleted red cells in optimal additive solution, which has low viscosity (Hogman et al, 1983) and contains minimal plasma. Red cells also contribute to haemostasis by their effect on platelet margination and function. The optimal haematocrit to prevent coagulopathy is unknown, but experimental evidence suggests that a relatively high haematocrit, possibly 0·35 l/l, may be required to sustain haemostasis in patients with massive blood loss (Reiss, 2000; Hardy et al, 2004). Red cell transfusion is likely to be required when 30–40% blood volume is lost; over 40% blood volume loss is immediately life-threatening (American College of Surgeons, 1997). Blood loss may be underestimated particularly if concealed and in young fit people, such as in the obstetric setting. Blood replacement should be guided by clinical estimation of blood loss in conjunction with the patient's response to volume replacement. Haemoglobin and haematocrit levels should be measured frequently, but in the knowledge that the haemoglobin level is a poor indicator of blood loss in the acute situation. Red cells are rarely indicated when the haemoglobin concentration is >10 g/dl but almost always indicated when it is <6 g/dl. (British Committee for Standards in Haematology Blood Transfusion Task Force, 2001) (Grade C recommendation, Level IV evidence). Decisions on red cell transfusion at intermediate haemoglobin concentrations should be based on the patient's risk factors for complications of inadequate oxygenation, such as rate of blood loss, cardiorespiratory reserve, oxygen consumption and atherosclerotic disease. Measured physiological variables, such as heart rate, arterial pressure, pulmonary capillary wedge pressure and cardiac output may assist the decision-making process, but it should be emphasised that silent tissue or organ ischaemia may occur in the presence of stable vital signs. The clinician who communicates with the transfusion laboratory should indicate the timescale within which blood is needed at the bedside, (i.e. immediately, within 20 min, within an hour) in order that the laboratory scientist knows how much time is available for ABO and D grouping and pre-transfusion testing. In an extreme situation where blood is required immediately and the patient's blood group is unknown, it may be necessary to issue Group O un-crossmatched red cells. Females of reproductive age (i.e. under 50 years) whose blood group is unknown must be given group O Rh D negative red cells in order to avoid sensitisation and the risk of haemolytic disease of the newborn in subsequent pregnancy. It is acceptable to give O Rh D positive cells to males and older females of unknown blood group (Schwab et al, 1986), as group O Rh D negative blood is a scarce resource. ABO group-specific red cells should be given at the earliest possible opportunity. Blood group determination takes less than 10 min and so it should not be necessary to give large volumes of group O blood. In a patient with known red cell antibodies, the risk of a haemolytic transfusion reaction will need to be assessed against the risk of withholding transfusion until compatible blood can be provided. Red cells undergo changes during 4°C storage (the ‘storage lesion’) including increase of extracellular potassium, decrease in ATP and 2,3-diphosphoglycerate (2,3 DPG) content and lowering of pH. Although 2,3 DPG is after d has been within 24 h of transfusion et al, and have not any clinically on oxygen when older components are et al, blood may be of in requirements for blood and can be in where it is in et al, are an alternative to blood but there is no available in the UK 2004). consensus that the platelet count should not be to the critical level of 50 in the bleeding patient (Grade C recommendation, level IV and this is by the BCSH guidelines for the use of platelet (British Committee for Standards in Haematology Blood Transfusion Task Force, 2003) A platelet count of 50 may be when approximately blood volumes have been by fluid or red cell components et al, but there is individual A platelet transfusion of in a patient with bleeding is so as to provide a of to ensure that the level not that critical for A target level of 100 10 has been for those with or central system Task Force of the College of American 1997) (Grade C recommendation, level IV evidence). platelet transfusion may be required when platelet function is as after in patients with or to therapy. In the requirement for are and it may be necessary to from the blood centre at levels the target in order to ensure their availability when needed. can be given an blood giving although a platelet giving it has less Transfusion of through a giving used for red cells is not is the cause of coagulopathy in massive transfusion of of coagulation factors following volume replacement with crystalloid or colloid and transfusion of red cell components. The level of fibrinogen the critical level of is likely to be after blood volume loss, by the of coagulation factors to after blood loss. 1998; 2000). of the time and time to the normal is with an risk of clinical coagulopathy et al, It is essential that laboratory of coagulation are these may need interpretation by a should be the and not from the as this is should have in place to ensure that clinical staff are laboratory should be to issue blood components in the first a agreed It may be necessary to components are on the rate of bleeding and the laboratory Although with fresh plasma is not it may be required in where rapid of coagulation cannot be of should be after one blood volume is 1998). The should be large to coagulation factors well the critical in that the efficacy may be reduced of rapid consumption Task Force of the College of American (Grade C recommendation, level IV evidence). It should be in although is (British Committee for Standards in Haematology Blood Transfusion Taskforce, 2004) and used in of massive blood loss, there is evidence of its clinical efficacy from randomised et al, 2004) frozen plasma if given in will correct fibrinogen and coagulation but large volumes may be required. fibrinogen levels critically low therapy should be Task Force of the College of American (Grade C recommendation, level IV evidence). contains fibrinogen Blood Quality data that contains approximately the is 1 of be to provide an adult therapeutic of provides fibrinogen in a volume of also contains and It should be that transfusion of the patient to fibrinogen is used in but is not in the frozen may be at 4°C for to 24 h (British Committee for Standards in Haematology Blood Transfusion Taskforce, 2004). It is for the laboratory to a therapeutic of as as they of a massive transfusion in order to British Committee for Standards in Haematology Guidelines on as an alternative to when major bleeding (British Committee for Standards in 1998). such as and have been used to established in the setting of massive blood & 2003) concluded that there is evidence from randomised controlled trials of in to support or a clinically important effect et al, et al, 2004) and evidence is et al, This is for use in with to treat bleeding or as for use has been off as a in settings of massive blood transfusion and there are many of its successful The of these is a in blood loss following of the with subsequent patient survival from situations. The is but may effective through transfusion in this setting. The use of as for patients with massive has been to be et al, 2004). A review concluded that the of in patients with bleeding is and relatively safe of evidence from controlled trials is not available so trials are likely to provide more for its use et al, 2005). such evidence available it is to the use of in where there is blood loss of with no evidence of or where surgical control of bleeding is not possible and there has been replacement of coagulation factors with and and of There should be a local in place and the decision should be at consultant coagulation is a in the bleeding patient but is obstetric The clinical of is in vessels can result in damage. A can result from the of the coagulation cascade to tissue in consumption of and coagulation at risk are those with tissue to or and those with massive or et al, 2004). This a high and is difficult to of the and in of that by with and fibrinogen of are of a and estimation of platelet fibrinogen and is of may also be in providing an early evidence of a consumption coagulopathy should be sought bleeding so that appropriate and action can be taken to address the underlying of the coagulation of and given than in but The associated with blood transfusion is the giving of the blood to the which can at result in a haemolytic reaction (Stainsby et al, 2005). of such to the of Transfusion that the risk of may be particularly high in an emergency situation. must be in place for the of blood and blood components (British Committee for Standards in Haematology Blood Transfusion Taskforce, and these must be to the of acute and acute are but occur more following of and than red cells (Stainsby et al, 2005). The Blood now from donors to the risk of changes may occur to and the infusion of large volumes of red cells and blood plasma. The is to & This may occur as a result of large volume plasma infusion, particularly in the presence of where is It should be by infusion of as this requires to A of 10 of has been & to can be given in over 10 min, when the should be and further bleeding and is the of and blood this may to the high extracellular concentration in red cell This may be by and the associated with it should be with with to correct Early is likely to be required after the of bleeding in the of massive on prompt good communication and involvement of senior with the necessary expertise. has to of the associated physiological This has in more with effective blood component therapy guided by testing, and effective warming et al, age and co-morbidity, and of and development of the (Erber, 2002) for audit resuscitation with crystalloids should be by blood for full blood coagulation blood and blood a designated and member of the resuscitation should of a that must type of blood component or replacement time for of the traceability of blood components protocols and must be available and displayed in e.g. and care and blood Regular of emergency management of massive transfusion should be and to Regular audit of management of massive review by Transfusion and Hospital Transfusion Committee against the guidelines with to the advice and information in these guidelines is to be and at the time of to the the British Society for Haematology the any legal for the content of these of the authors has a of Task at time of writing this guideline

The appropriate recording and communication of clinical information between clinicians and patients are of paramount importance. Recently there has been a much-needed drive to improve the information that is shared with patients.1General Medical councilDomain 3: communication partnership and teamwork.https://www.gmc-uk.org/ethical-guidance/ethical-guidance-for-doctors/good-medical-practice/domain-3---communication-partnership-and-teamwork#paragraph-31Date accessed: December 22, 2022Google Scholar However, the preparation of clinical letters can be time consuming. Although there has been an increase in the use of letter templates and voice recognition systems, with the aim of improving efficiency, novel technologies such as natural language processing (NLP) and artificial intelligence (AI) have the power to revolutionise this area of practice. NLP algorithms are designed to recognise and understand the structure and meaning of human language, classify texts according to their content or purpose, and generate responses that are appropriate and coherent.2Jurafsky D Martin JH Speech and language processing.3rd edn. Prentice Hall, 2009Google Scholar OpenAI's ChatGPT chatbot was launched in November, 2022, and uses NLP technology to generate human-like text. The generative pre-trained transformer (GPT) language model is based on a transformer architecture, which allows it to process large amounts of text data and generate coherent text outputs by learning the relationships between input and output sequences. The GPT language model has been trained on large datasets of human language, with several studies demonstrating that it is very good at generating high-quality and coherent text outputs.3Brown T Mann B Ryder N et al.Language models are few-shot learners.arXiv. 2020; (published online July 22.) (preprint).https://doi.org/10.48550/arXiv.2005.14165Google Scholar, 4Radford A Wu J Child R et al.Exploring the limits of transfer learning with a unified text-to-text transformer.arXiv. 2019; (published online July 28.) (preprint).https://doi.org/10.48550/arXiv.1910.10683Google Scholar, 5Vaswani A, Shazeer N, Parmar N, et al. Attention is all you need. NIPS'17: Proceedings of the 31st International Conference on Neural Information Processing Systems. December 2017 (abstr 5998–6008).Google Scholar As a result, AI, like ChatGPT, has the potential to produce high quality clinical letters that are comprehendible by patients while improving efficiency, consistency, accuracy, patient satisfaction, and deliver cost savings to a health-care system. In this Comment we describe the early adoption and evaluation of ChatGPT-generated clinical letters to patients with limited clinical input. The aim was to evaluate the readability, factual correctness, and humanness of ChatGPT-generated clinical letters to patients, using the example of skin cancer as the most common human cancer. We created a series of different clinical communication scenarios that covered the remit of a clinicians' skin cancer practice. To simulate how clinicians might use ChatGPT in the clinical environment we created shorthand instructions to input into the chatbot, which we defined as limited clinical input, because the input is small compared with the relative amount of natural free text a clinician would otherwise be required to write or dictate to generate a clinical letter. In the USA, it is recommended that patient-facing health literature be written at or below a sixth grade level (age 11–12 years).6US Department of Health & Human ServicesNational action plan to improve health literacy.https://health.gov/sites/default/files/2019-09/Health_Literacy_Action_Plan.pdfDate: 2010Date accessed: December 22, 2022Google Scholar There are no specific guidelines on this in the UK. In view of this, all letters were instructed to be written at a reading age of 11–12 years. We sought to evaluate the capabilities of ChatGPT by presenting it with a series of instructions of increasing complexity (appendix p 1). These instructions ranged from simply following specific directions, to using national guidelines and data from these guidelines to provide clinical advice in the letter—eg, the management of anticoagulation peri-operatively. After submitting the instructions, ChatGPT then generated a response in the form of a clinical letter to be issued to the patient. The online tool readable was used to evaluate the readability of letters with commonly used formulae as described in many other studies.7Burke V Greenberg D Determining readability: how to select and apply easy-to-use readability formulas to assess the difficulty of adult literacy materials.Adult Basic Educ Lit. 2010; 4: 34-42Google Scholar, 8Wang L-W Miller MJ Schmitt MR Wen FK Assessing readability formula differences with written health information materials: application, results, and recommendations.Res Social Adm Pharm. 2013; 9: 503-516Crossref PubMed Scopus (181) Google Scholar Factual correctness and humanness of letters were assessed by two independent clinicians using a Likert scale ranging from 0 to 10, with 0 representing completely incorrect or inhuman and 10 representing completely correct and human. Error analysis was performed using linear regression. We used two separate generalised linear models (GLMs) to investigate the effect of the predictor variables of cancer type (basal cell carcinoma [BCC] as reference category), general commands, specific guidelines, and general guidelines on the outcome variables, and median humanness in the first GLM and median correctness in the second GLM. Statistical analysis was done in R (version 4.1.1) p<0·001 was deemed statistically significant. 38 hypothetical clinical scenarios were created, seven of which pertained to BCC, 11 to squamous cell carcinoma (SCC), and 20 to malignant melanoma (MM; appendix p 2). Overall, the readability scores suggest that the text might be suitable for a varying reading ability, and the mean readability age for the generated letters was at a USA ninth grade (aged 14–15 years) and considered by the US Department of Health and Human Services as average difficulty (appendix p 2). Overall median correctness of the clinical information contained in the letter was 7 (range 1–9). Overall median humanness of the writing style was 7 (5–9; appendix pp 3–4). The weighted κ for correctness was 0·80 (p<0·0001) and humanness was 0·77 (p<0·0001). For median correctness, ANOVA howed a statistically significant difference among the groups (F2,35=10·1, p=0·00035). The Tukey honestly significant difference (HSD) test showed that the mean difference between the MM and BCC groups was statistically significant (–2·71 [95% CI –4·32 to –1·11], p<0·0001). There was no statistically significant difference between the SCC and BCC groups (p=0·31) or the SCC and MM groups (p=0·016). For median humanness, ANOVA showed a statistically significant difference among the groups (F2,35=27·76, p<0·0001). The Tukey HSD test showed that there was a statistically significant difference between the MM and BCC groups (–1·63 [–2·17 to –1·09], p<0·0001) and between the SCC and BCC groups (–1·43 [–2·03 to –0·83], p<0·0001). There was no statistically significant difference between the SCC and MM groups (p=0·55). Results of the GLM for median humanness showed that cancer type was a significant predictor, with the MM coefficient being –1·45 (SE 0·30) and the SCC coefficient being –1·32 (0·28; both p<0·0001). The general commands, specific guidelines, and general guidelines variables were not significant predictors of median humanness. The multiple R2 value of 0·622 indicated that the model explained 62·23% of the variance in median humanness, and the F-statistic of 10·55 and corresponding p<0·0001 indicated that the model was significant overall. In the GLM for median correctness, MM was found to be significantly associated with median correctness with a coefficient of –2·64 (SE 0·90; p<0·0001). The other predictors were not significantly associated with median correctness. The multiple R2 value of 0·3729 suggested that the model explained approximately 37·29% of the variance in median correctness. The F-statistic and corresponding p value were used to test the overall significance of the model, and p<0·0001 indicated that the model is significantly different from a model with no predictors. This pilot assessment shows that it is possible to generate clinic letters with a high overall correctness and humanness score with ChatGPT. Furthermore, these letters were written at a reading level that is broadly similar to current real-world human generated letters.9Drury DJ Kaur A Dobbs T Whitaker IS The readability of outpatient plastic surgery clinic letters: are we adhering to plain English writing standards?.Plast Surg Nurs. 2021; 41: 27-33Crossref PubMed Scopus (6) Google Scholar The ability of AI to generate clinical letters as an alternative to those written by clinicians raises important considerations for the quality and effectiveness of health-care communication. It is important that potential risks, such as omissions or errors, which might have serious consequences for patient care, are mitigated. The incorrect reporting of results or interpretation of treatment guidelines could affect patient morbidity and mortality. To mitigate these risks, it is important for the use of AI in health care, including the automated generation of clinical letters, be carefully regulated and monitored. In the early stages of adoption of such new technologies it is necessary to continue with a human-in-the-loop approach, whereby the outputs of such systems are carefully verified by health-care providers. To responsibly incorporate ChatGPT or similar generic AI systems into the clinical workflow, one approach could be to use voice-to-text recognition software with limited human input, followed by rapid clinician editing of the generated letter. This approach could be a feasible starting point for exploring the potential applications of this technology while also addressing any potential risks. Further studies are needed to assess the effectiveness of AI-generated clinical letters in real-world clinical settings and to compare the performance of various AI systems against one another. It is probable that an AI system with a greater medical focus will yield improved results. Additionally, the quality and writing style of input provided to any chatbot should be assessed in a range of settings, including different languages, resource levels, and cultural contexts. Caution must be exercised and potential risks must be proactively addressed to ensure the safety and quality of patient care while introducing such an important technical advancement. We declare no competing interests. SRA and TDD are funded by the Welsh Clinical Academic Training Fellowship. SRA received a Paton Masser grant from the British Association of Plastic, Reconstructive and Aesthetic Surgeons to support this work. ISW is the surgical Specialty Lead for Health and Care Research Wales; the Chief Investigator for the Scar Free Foundation & Health and Care Research Wales Programme of Reconstructive and Regenerative Surgery Research; an associate editor for the Annals of Plastic Surgery; an editorial board member of BMC Medicine and numerous other editorial board roles. Ethical committee approval has been obtained from Swansea University Medical School Research Ethics Subcommittee (2020-0025). The study was performed in accordance with the Declaration of Helsinki. Download .pdf (.43 MB) Help with pdf files Supplementary appendix

BACKGROUND: Antibiotic-associated diarrhoea (AAD) occurs most frequently in older (≥65 years) inpatients exposed to broad-spectrum antibiotics. When caused by Clostridium difficile, AAD can result in life-threatening illness. Although underlying disease mechanisms are not well understood, microbial preparations have been assessed in the prevention of AAD. However, studies have been mostly small single-centre trials with varying quality, providing insufficient data to reliably assess effectiveness. We aimed to do a pragmatic efficacy trial in older inpatients who would be representative of those admitted to National Health Service (NHS) and similar secondary care institutions and to recruit a sufficient number of patients to generate a definitive result. METHODS: We did a multicentre, randomised, double-blind, placebo-controlled, pragmatic, efficacy trial of inpatients aged 65 years and older and exposed to one or more oral or parenteral antibiotics. A computer-generated randomisation scheme was used to allocate participants (in a 1:1 ratio) to receive either a multistrain preparation of lactobacilli and bifidobacteria, with a total of 6 × 10(10) organisms, one per day for 21 days, or an identical placebo. Patients, study staff, and specimen and data analysts were masked to assignment. The primary outcomes were occurrence of AAD within 8 weeks and C difficile diarrhoea (CDD) within 12 weeks of recruitment. Analysis was by modified intention-to-treat. This trial is registered, number ISRCTN70017204. FINDINGS: Of 17,420 patients screened, 1493 were randomly assigned to the microbial preparation group and 1488 to the placebo group. 1470 and 1471, respectively, were included in the analyses of the primary endpoints. AAD (including CDD) occurred in 159 (10·8%) participants in the microbial preparation group and 153 (10·4%) participants in the placebo group (relative risk [RR] 1·04; 95% CI 0·84-1·28; p=0·71). CDD was an uncommon cause of AAD and occurred in 12 (0·8%) participants in the microbial preparation group and 17 (1·2%) participants in the placebo group (RR 0·71; 95% CI 0·34-1·47; p=0·35). 578 (19·7%) participants had one or more serious adverse event; the frequency of serious adverse events was much the same in the two study groups and none was attributed to participation in the trial. INTERPRETATION: We identified no evidence that a multistrain preparation of lactobacilli and bifidobacteria was effective in prevention of AAD or CDD. An improved understanding of the pathophysiology of AAD is needed to guide future studies. FUNDING: Health Technology Assessment programme; National Institute for Health Research, UK.

BACKGROUND: The incidence of incisional hernias (IHs) following midline abdominal incisions is difficult to estimate. Furthermore recent analyses have reported inconsistent findings on the superiority of absorbable versus non-absorbable sutures. OBJECTIVE: To estimate the mean IH rate following midline laparotomy from the published literature, to identify variables that predict IH rates and to analyse whether the type of suture (absorbable versus non-absorbable) affects IH rates. METHODS: We undertook a systematic review according to PRISMA guidelines. We sought randomised trials and observational studies including patients undergoing midline incisions with standard suture closure. Papers describing two or more arms suitable for inclusion had data abstracted independently for each arm. RESULTS: Fifty-six papers, describing 83 separate groups comprising 14,618 patients, met the inclusion criteria. The prevalence of IHs after midline incision was 12.8% (range: 0 to 35.6%) at a weighted mean of 23.7 months. The estimated risk of undergoing IH repair after midline laparotomy was 5.2%. Two meta-regression analyses (A and B) each identified seven characteristics associated with increased IH rate: one patient variable (higher age), two surgical variables (surgery for AAA and either surgery for obesity surgery (model A) or using an upper midline incision (model B)), two inclusion criteria (including patients with previous laparotomies and those with previous IHs), and two circumstantial variables (later year of publication and specifying an exact significance level). There was no significant difference in IH rate between absorbable and non-absorbable sutures either alone or in conjunction with either regression analysis. CONCLUSIONS: The IH rate estimated by pooling the published literature is 12.8% after about two years. Seven factors account for the large variation in IH rates across groups. However there is no evidence that suture type has an intrinsic effect on IH rates.

Worsening fluid balance results in reduced technique and patient survival in peritoneal dialysis. Under these conditions, the glucose polymer icodextrin is known to enhance ultrafiltration in the long dwell. A multicenter, randomized, double-blind, controlled trial was undertaken to compare icodextrin versus 2.27% glucose to establish whether icodextrin improves fluid status. Fifty patients with urine output <750 ml/d, high solute transport, and either treated hypertension or untreated BP >140/90 mmHg, or a requirement for the equivalent of all 2.27% glucose exchanges, were randomized 1:1 and evaluated at 1, 3, and 6 mo. Members of the icodextrin group lost weight, whereas the control group gained weight. Similar differences in total body water were observed, largely explained by reduced extracellular fluid volume in those receiving icodextrin, who also achieved better ultrafiltration and total sodium losses at 3 mo (P < 0.05) and had better maintenance of urine volume at 6 mo (P = 0.039). In patients fulfilling the study's inclusion criteria, the use of icodextrin, when compared with 2.27% glucose, in the long exchange improves fluid removal and status in peritoneal dialysis. This effect is apparent within 1 mo of commencement and was sustained for 6 mo without harmful effects on residual renal function.

after infection with SARS-CoV-2. The GenOMICC (Genetics of Mortality in Critical Care) study enables the comparison of genomes from individuals who are critically ill with those of population controls to find underlying disease mechanisms. Here we use whole-genome sequencing in 7,491 critically ill individuals compared with 48,400 controls to discover and replicate 23 independent variants that significantly predispose to critical COVID-19. We identify 16 new independent associations, including variants within genes that are involved in interferon signalling (IL10RB and PLSCR1), leucocyte differentiation (BCL11A) and blood-type antigen secretor status (FUT2). Using transcriptome-wide association and colocalization to infer the effect of gene expression on disease severity, we find evidence that implicates multiple genes-including reduced expression of a membrane flippase (ATP11A), and increased expression of a mucin (MUC1)-in critical disease. Mendelian randomization provides evidence in support of causal roles for myeloid cell adhesion molecules (SELE, ICAM5 and CD209) and the coagulation factor F8, all of which are potentially druggable targets. Our results are broadly consistent with a multi-component model of COVID-19 pathophysiology, in which at least two distinct mechanisms can predispose to life-threatening disease: failure to control viral replication; or an enhanced tendency towards pulmonary inflammation and intravascular coagulation. We show that comparison between cases of critical illness and population controls is highly efficient for the detection of therapeutically relevant mechanisms of disease.

AIMS: Acute coronary syndromes (ACSs) are driven by inflammation within coronary plaque. Interleukin-1 (IL-1) has an established role in atherogenesis and the vessel-response to injury. ACS patients have raised serum markers of inflammation. We hypothesized that if IL-1 is a driving influence of inflammation in non-ST elevation ACS (NSTE-ACS), IL-1 inhibition would reduce the inflammatory response at the time of ACS. METHODS AND RESULTS: A phase II, double-blinded, randomized, placebo-controlled, study recruited 182 patients with NSTE-ACS, presenting <48 h from onset of chest pain. Treatment was 1:1 allocation to daily, subcutaneous IL-1receptor antagonist (IL-1ra) or placebo for 14 days. Baseline characteristics were well matched. Treatment compliance was 85% at 7 days. The primary endpoint (area-under-the-curve for C-reactive protein over the first 7 days) was: IL-1ra group, 21.98 mg day/L (95%CI 16.31-29.64); placebo group, 43.5 mg day/L (31.15-60.75) (geometric mean ratio = 0.51 mg/L; 95%CI 0.32-0.79; P = 0.0028). In the IL-1ra group, 14-day achieved high-sensitive C-reactive protein (P < 0.0001) and IL-6 levels (P = 0.02) were lower than Day 1. Sixteen days after discontinuation of treatment (Day 30) high-sensitive C-reactive protein levels had risen again in the IL-1ra group [IL-1ra; 3.50 mg/L (2.65-4.62): placebo; 2.21 mg/L (1.67-2.92), P = 0.022]. MACE at Day 30 and 3 months was similar but at 1 year there was a significant excess of events in the IL-1ra group. CONCLUSION: IL-1 drives C-reactive protein elevation at the time of NSTE-ACS. Following 14 days IL-1ra treatment inflammatory markers were reduced. These results show the importance of IL-1 as a target in ACS, but also indicate the need for additional studies with anti-IL-1 therapy in ACS to assess duration and safety. CLINICAL TRIAL REGISTRATION EUCTR: 2006-001767-31-GB: www.clinicaltrialsregister.eu/ctr-search/trial/2006-001767-31/GB.

BACKGROUND: Patients with borderline resectable pancreatic ductal adenocarcinoma have relatively low resection rates and poor survival despite the use of adjuvant chemotherapy. The aim of our study was to establish the feasibility and efficacy of three different types of short-course neoadjuvant therapy compared with immediate surgery. METHODS: twice daily [Monday to Friday] throughout radiotherapy). Patients underwent restaging contrast-enhanced CT at 4-6 weeks after neoadjuvant therapy and underwent surgical exploration if the tumour was still at least borderline resectable. All patients who had their tumour resected received adjuvant therapy at the oncologist's discretion. Primary endpoints were recruitment rate and resection rate. Analyses were done on an intention-to-treat basis. This trial is registered with ISRCTN, 89500674, and is complete. FINDINGS: Between Sept 3, 2014, and Dec 20, 2018, from 478 patients screened, 90 were randomly assigned to a group (33 to immediate surgery, 20 to gemcitabine plus capecitabine, 20 to FOLFIRINOX, and 17 to capecitabine-based chemoradiation); four patients were excluded from the intention-to-treat analysis (one in the capecitabine-based chemoradiotherapy withdrew consent before starting therapy and three [two in the immediate surgery group and one in the gemcitabine plus capecitabine group] were found to be ineligible after randomisation). 44 (80%) of 55 patients completed neoadjuvant therapy. The recruitment rate was 25·92 patients per year from 16 sites; 21 (68%) of 31 patients in the immediate surgery and 30 (55%) of 55 patients in the combined neoadjuvant therapy groups underwent resection (p=0·33). R0 resection was achieved in three (14%) of 21 patients in the immediate surgery group and seven (23%) of 30 in the neoadjuvant therapy groups combined (p=0·49). Surgical complications were observed in 29 (43%) of 68 patients who underwent surgery; no patients died within 30 days. 46 (84%) of 55 patients receiving neoadjuvant therapy were available for restaging. Six (13%) of 46 had a partial response. Median follow-up time was 12·2 months (95% CI 12·0-12·4). 1-year overall survival was 39% (95% CI 24-61) for immediate surgery, 78% (60-100) for gemcitabine plus capecitabine, 84% (70-100) for FOLFIRINOX, and 60% (37-97) for capecitabine-based chemoradiotherapy (p=0·0028). 1-year disease-free survival from surgery was 33% (95% CI 19-58) for immediate surgery and 59% (46-74) for the combined neoadjuvant therapies (hazard ratio 0·53 [95% CI 0·28-0·98], p=0·016). Three patients reported local disease recurrence (two in the immediate surgery group and one in the FOLFIRINOX group). 78 (91%) patients were included in the safety set and assessed for toxicity events. 19 (24%) of 78 patients reported a grade 3 or worse adverse event (two [7%] of 28 patients in the immediate surgery group and 17 [34%] of 50 patients in the neoadjuvant therapy groups combined), the most common of which were neutropenia, infection, and hyperglycaemia. INTERPRETATION: Recruitment was challenging. There was no significant difference in resection rates between patients who underwent immediate surgery and those who underwent neoadjuvant therapy. Short-course (8 week) neoadjuvant therapy had a significant survival benefit compared with immediate surgery. Neoadjuvant chemotherapy with either gemcitabine plus capecitabine or FOLFIRINOX had the best survival compared with immediate surgery. These findings support the use of short-course neoadjuvant chemotherapy in patients with borderline resectable pancreatic ductal adenocarcinoma. FUNDING: Cancer Research UK.

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.

Bladder symptoms in multiple sclerosis (MS) are common and distressing but also highly amenable to treatment. A meeting of stakeholders involved in patients' continence care, including neurologists, urologists, primary care, MS nurses and nursing groups was recently convened to formulate a UK consensus for management. National Institute for Health and Clinical Excellence (NICE) criteria were used for producing recommendations based on a review of the literature and expert opinion. It was agreed that in the majority of cases, successful management could be based on a simple algorithm which includes using reagent sticks to test for urine infection and measurement of the post micturition residual urine volume. This is in contrast with published guidelines from other countries which recommend cystometry. Throughout the course of their disease, patients should be offered appropriate management options for treatment of incontinence, the mainstay of which is antimuscarinic medications, in combination, if necessary, with clean intermittent self-catheterisation. The evidence for other measures, including physiotherapy, alternative strategies aimed at improving bladder emptying, other medications and detrusor injections of botulinum toxin A was reviewed. The management of urinary tract infections as well as the bladder problems as part of severe disability were discussed and recommendations agreed.

Multidrug-resistant, Gram-negative infection is a major global determinant of morbidity, mortality and cost of care. The advent of nanomedicine has enabled tailored engineering of macromolecular constructs, permitting increasingly selective targeting, alteration of volume of distribution and activity/toxicity. Macromolecules tend to passively and preferentially accumulate at sites of enhanced vascular permeability and are then retained. This enhanced permeability and retention (EPR) effect, whilst recognized as a major breakthrough in anti-tumoral targeting, has not yet been fully exploited in infection. Shared pathophysiological pathways in both cancer and infection are evident and a number of novel nanomedicines have shown promise in selective, passive, size-mediated targeting to infection. This review describes the similarities and parallels in pathophysiological pathways at molecular, cellular and circulatory levels between inflammation/infection and cancer therapy, where use of this principle has been established.

Importance: The incidence of early-onset colorectal cancer (younger than 50 years) is rising globally, the reasons for which are unclear. It appears to represent a unique disease process with different clinical, pathological, and molecular characteristics compared with late-onset colorectal cancer. Data on oncological outcomes are limited, and sensitivity to conventional neoadjuvant and adjuvant therapy regimens appear to be unknown. The purpose of this review is to summarize the available literature on early-onset colorectal cancer. Observations: Within the next decade, it is estimated that 1 in 10 colon cancers and 1 in 4 rectal cancers will be diagnosed in adults younger than 50 years. Potential risk factors include a Westernized diet, obesity, antibiotic usage, and alterations in the gut microbiome. Although genetic predisposition plays a role, most cases are sporadic. The full spectrum of germline and somatic sequence variations implicated remains unknown. Younger patients typically present with descending colonic or rectal cancer, advanced disease stage, and unfavorable histopathological features. Despite being more likely to receive neoadjuvant and adjuvant therapy, patients with early-onset disease demonstrate comparable oncological outcomes with their older counterparts. Conclusions and Relevance: The clinicopathological features, underlying molecular profiles, and drivers of early-onset colorectal cancer differ from those of late-onset disease. Standardized, age-specific preventive, screening, diagnostic, and therapeutic strategies are required to optimize outcomes.