Carcinoma of the uncinate process of the pancreas presenting with deep vein thrombosis: a case report

The uncinate process is a hook-like projection of the inferior aspect of the head of the pancreas. Carcinoma of the uncinate process of the pancreas is considered to be rare, difficult to diagnose and particularly devastating. The current method of detection is computed tomography. We report a case of carcinoma of the uncinate process of the pancreas in a patient who initially presented with deep vein thrombosis. The diagnosis of carcinoma of the uncinate process of the pancreas should be considered in patients who present with primary thromboembolic disease and other nonspecific signs

Letter: liver disease and COVID-19 - not the perfect storm

This article is linked to Garrido et al papers. To view these articles, visit https://doi.org/10.1111/apt.15813 and https://doi.org/10.1111/apt.15886

In Patients With Severe Alcoholic Hepatitis, Prednisolone Increases Susceptibility to Infection and Infection-Related Mortality, and Is Associated With High Circulating Levels of Bacterial DNA

Background & Aims Infections are common in patients with severe alcoholic hepatitis (SAH), but little information is available on how to predict their development or their effects on patients. Prednisolone is advocated for treatment of SAH, but can increase susceptibility to infection. We compared the effects of infection on clinical outcomes of patients treated with and without prednisolone, and identified risk factors for development of infection in SAH. Methods We analyzed data from 1092 patients enrolled in a double-blind placebo-controlled trial to evaluate the efficacy of treatment with prednisolone (40 mg daily) or pentoxifylline (400 mg 3 times each day) in patients with SAH. The 2 × 2 factorial design led to 547 patients receiving prednisolone; 546 were treated with pentoxifylline. The trial was conducted in the United Kingdom from January 2011 through February 2014. Data on development of infection were collected at evaluations performed at screening, baseline, weekly during admission, on discharge, and after 90 days. Patients were diagnosed with infection based on published clinical and microbiologic criteria. Risk factors for development of infection and effects on 90-day mortality were evaluated separately in patients treated with prednisolone (n = 547) and patients not treated with prednisolone (n = 545) using logistic regression. Pretreatment blood levels of bacterial DNA (bDNA) were measured in 731 patients. Results Of the 1092 patients in the study, 135 had an infection at baseline, 251 developed infections during treatment, and 89 patients developed an infection after treatment. There was no association between pentoxifylline therapy and the risk of serious infection (P = .084), infection during treatment (P = .20), or infection after treatment (P = .27). Infections classified as serious were more frequent in patients treated with prednisolone (odds ratio [OR], 1.27; 95% confidence interval [CI], 1.27−2.92; P = .002). There was no association between prednisolone therapy and infection during treatment (OR, 1.04; 95% CI, 0.78−1.37; P = .80). However, a higher proportion (10%) of patients receiving prednisolone developed an infection after treatment than of patients not given prednisolone (6%) (OR, 1.70; 95% CI, 1.07−2.69; P = .024). Development of infection was associated with increased 90-day mortality in patients with SAH treated with prednisolone, independent of model for end-stage liver disease or Lille score (OR, 2.46; 95% CI, 1.41−4.30; P = .002). High circulating bDNA predicted infection that developed within 7 days of prednisolone therapy, independent of Model for End-Stage Liver Disease and white blood cell count (OR, 4.68; 95% CI, 1.80−12.17; P = .001). In patients who did not receive prednisolone, infection was not independently associated with 90-day mortality (OR, 0.94; 95% CI, 0.54−1.62; P = .82) or levels of bDNA (OR, 0.83; 95% CI, 0.39−1.75; P = .62). Conclusions Patients with SAH given prednisolone are at greater risk for developing serious infections and infections after treatment than patients not given prednisolone, which may offset its therapeutic benefit. Level of circulating bDNA before treatment could identify patients at high risk of infection if given prednisolone; these data could be used to select therapies for patients with SAH. EudraCT no: 2009-013897-42; Current Controlled Trials no: ISRCTN88782125

Visualising harms in publications of randomised controlled trials: consensus and recommendations

OBJECTIVE: To improve communication of harm in publications of randomised controlled trials via the development of recommendations for visually presenting harm outcomes. DESIGN: Consensus study. SETTING: 15 clinical trials units registered with the UK Clinical Research Collaboration, an academic population health department, Roche Products, and The BMJ. PARTICIPANTS: Experts in clinical trials: 20 academic statisticians, one industry statistician, one academic health economist, one data graphics designer, and two clinicians. MAIN OUTCOME: measures A methodological review of statistical methods identified visualisations along with those recommended by consensus group members. Consensus on visual recommendations was achieved (at least 60% of the available votes) over a series of three meetings with participants. The participants reviewed and critically appraised candidate visualisations against an agreed framework and voted on whether to endorse each visualisation. Scores marginally below this threshold (50-60%) were revisited for further discussions and votes retaken until consensus was reached. RESULTS: 28 visualisations were considered, of which 10 are recommended for researchers to consider in publications of main research findings. The choice of visualisations to present will depend on outcome type (eg, binary, count, time-to-event, or continuous), and the scenario (eg, summarising multiple emerging events or one event of interest). A decision tree is presented to assist trialists in deciding which visualisations to use. Examples are provided of each endorsed visualisation, along with an example interpretation, potential limitations, and signposting to code for implementation across a range of standard statistical software. Clinician feedback was incorporated into the explanatory information provided in the recommendations to aid understanding and interpretation. CONCLUSIONS: Visualisations provide a powerful tool to communicate harms in clinical trials, offering an alternative perspective to the traditional frequency tables. Increasing the use of visualisations for harm outcomes in clinical trial manuscripts and reports will provide clearer presentation of information and enable more informative interpretations. The limitations of each visualisation are discussed and examples of where their use would be inappropriate are given. Although the decision tree aids the choice of visualisation, the statistician and clinical trial team must ultimately decide the most appropriate visualisations for their data and objectives. Trialists should continue to examine crude numbers alongside visualisations to fully understand harm profiles

Prednisolone or pentoxifylline for alcoholic hepatitis

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

Visualising harms in Randomised Controlled Trial publications: a consensus and recommendations

Objective: To improve communication of harm in RCT publications we identified researchers’ recommendations for visualising harm outcomes. Design: Consensus study evaluating visualisation methods. Setting: 15 UKCRC registered CTUs, an academic population health department, Roche Product Ltd and the BMJ. Participants: Experts in clinical trials: 20 academic statisticians, one industry statistician, one academic health economist, a data graphics designer and two clinicians. Data sources: Visualisations were primarily identified via a methodological review of statistical methods developed specifically to analyse harm outcomes, these were considered alongside visualisations recommended by consensus group members. Interventions: None Main outcomes measured: Consensus for visualisations to recommend achieved over a series of three meetings with participants. Participants reviewed and critically appraised candidate visualisations against an agreed framework. Appraisals were summarised and presented back to participants to inform discussions. After discussions participants voted on whether to endorse each visualisation. Eligibility criteria: Visualisation receiving at least 60% of the available votes were endorsed. Scores marginally below this threshold (50-60%) were revisited for further discussions and votes retaken until a consensus was reached. Results: Twenty-eight visualisations were considered, of which ten are recommended to researchers to consider in publications of main research findings. The choice of visualisations to present will depend on outcome type e.g., binary, count, time-to-event or continuous and the scenario e.g., summarising multiple emerging events or one event of interest. A decision tree to assist trialists decide which visualisations to use is presented. Examples of each endorsed visualisation, along with example interpretation, potential limitations and signposting to code for implementation across a range of standard statistical software are provided. Clinician feedback was incorporated into the explanatory information provided in the recommendations to aid understanding and interpretation. Conclusions: Visualisations provide a powerful tool to communicate harms in clinical trials, offering an alternative perspective to the traditional frequency tables. Increasing the use of visualisations for harm outcomes in clinical trial manuscripts and reports will provide clearer presentation of harm information and thus enable informative interpretation, especially valuable for assessing the profile of harm. Whilst we endorse each of the visualisations presented, we also note their limitations and provide examples of where their use would be inappropriate. Though the decision tree aids the choice of visualisation the statistician and clinical trial team must ultimately decide the most appropriate visualisations for their data and objectives. We recommend trialists continue to examine crude numbers alongside visualisations to fully understand harm profiles

Monocyte dysfunction in alcoholic hepatitis

Severe alcoholic hepatitis (SAH) is the most florid form of alcohol-related liver disease (ALD). It is caused by hepatic inflammation after a prolonged period of heavy alcohol drinking. Causes of death include liver failure and infection. Inflammatory hepatic injury and systemic immunoparesis are therefore key features in disease pathogenesis. This thesis seeks to evaluate this immune dysfunction in detail, focussing on a key component of the innate immune system, the circulating monocyte. A variety of techniques such as flow cytometry, Western blotting and polymerase-chain reaction (PCR) were used to characterise the phenotype and function of monocytes from peripheral blood. Dysfunction was then related to patient outcome and treatments administered by the randomised placebo controlled Steroids and Pentoxyfilline for Alcoholic Hepatitis (STOPAH) clinical trial. Novel findings from this work include the identification of preserved uptake of bacteria by phagocytosis but defective monocyte oxidative burst and bacterial killing of Escherichia coli. Further, I show that the presence of this defect predicts the subsequent development of infection. In addition, this defect is associated with reduced expression of the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase enzyme and may be treatable with N-acetylcysteine (NAC). Secondly, I identify an expanded population of an inflammatory intermediate monocyte subset in SAH that bears high expression of chemokine CC chemokine receptor type 5 (CCR-5), and may be amenable to targeted antibody therapy to reduce hepatic inflammation in SAH patients.Open Acces