“SQiD, the Single Question in Delirium; can a single question help clinicians to detect delirium in hospitalised cancer patients?” running heading Single Question in Delirium” (Bcan-D-20-01665)

AimA serious syndrome for cancer in-patients, delirium risk increases with age and medical acuity. Screening tools exist but detection is frequently delayed or missed. We test the 'Single Question in Delirium' (SQiD), in comparison to psychiatrist clinical interview.MethodsInpatients in two comprehensive cancer centres were prospectively screened. Clinical staff asked informants to respond to the SQiD: "Do you feel that [patient's name] has been more confused lately?". The primary endpoint was negative predictive value (NPV) of the SQiD versus psychiatrist diagnosis (Diagnostic and Statistics Manual criteria). Secondary endpoints included: NPV of the Confusion Assessment Method (CAM), sensitivity, specificity and Cohen's Kappa coefficient.ResultsBetween May 2012 and July 2015, the SQiD plus CAM was applied to 122 patients; 73 had the SQiD and psychiatrist interview. Median age was 65 yrs. (interquartile range 54-74), 46% were female; median length of hospital stay was 12 days (5-18 days). Major cancer types were lung (19%), gastric or other upper GI (15%) and breast (14%). 70% of participants had stage 4 cancer. Diagnostic values were similar between the SQiD (NPV = 74, 95% CI 67-81; kappa = 0.32) and CAM (NPV = 72, 95% CI 67-77, kappa = 0.32), compared with psychiatrist interview. Overall the CAM identified only a small number of delirious cases but all were true positives. The specificity of the SQiD was 87% (74-95) The SQiD had higher sensitivity than CAM (44% [95% CI 41-80] vs 26% [10-48]).ConclusionThe SQiD, administered by bedside clinical staff, was feasible and its psychometric properties are now better understood. The SQiD can contribute to delirium detection and clinical care for hospitalised cancer patients

Global metabolic changes induced by plant-derived pyrrolizidine alkaloids following a human poisoning outbreak and in a mouse model

Several hundred cases of Hirmi Valley Liver Disease (HVLD), an often fatal liver injury, occurred from 2001 to 2011 in a cluster of rural villages in Tigray, Ethiopia. HVLD is principally caused by contamination of the food supply with plant derived pyrrolizidine alkaloids (PAs), with high exposure to the pesticide DDT among villagers increasing their susceptibility. In an untargeted global approach we aimed to identify metabolic changes induced by PA exposure through 1H NMR spectroscopic based metabolic profiling. We analysed spectra acquired from urine collected from HVLD cases and controls and a murine model of PA exposure and PA/DDT co-exposure, using multivariate partial least squares discriminant analysis. In the human models we identified changes in urinary concentrations of tyrosine, pyruvate, bile acids, N-acetylglycoproteins, N-methylnicotinamide and formate, hippurate, p-cresol sulphate, p-hydroxybenzoate and 3-(3-hydroxyphenyl) propionic acid. Tyrosine and p-cresol sulphate were associated with both exposure and disease. Similar changes to tyrosine, one-carbon intermediates and microbial associated metabolites were observed in the mouse model, with tyrosine correlated with the extent of liver damage. These results provide mechanistic insight and implicate the gut microflora in the human response to challenge with toxins. Pathways identified here may be useful in translational research and as “exposome” signals

Quality of Life as an outcome in Alzheimer's disease and other dementias- obstacles and goals

<p>Abstract</p> <p>Background</p> <p>The number of individuals at risk for dementia will probably increase in ageing societies as will the array of preventive and therapeutic options, both however within limited economic resources. For economic and medical purposes valid instruments are required to assess disease processes and the efficacy of therapeutic interventions for different forms and stages of illness. In principal, the impact of illness and success of an intervention can be assessed with biomedical variables, e.g. severity of symptoms or frequency of complications of a disease. However, this does not allow clear judgement on clinical relevance or comparison across different diseases.</p> <p>Discussion</p> <p>Outcome model variables such as quality of life (QoL) or health care resource utilization require the patient to appraise their own well-being or third parties to set preferences. In Alzheimer's disease and other dementias the evaluation process performed by the patient is subject to the disease process itself because over progress of the disease neuroanatomical structures are affected that mediate evaluation processes.</p> <p>Summary</p> <p>Published research and methodological considerations thus lead to the conclusion that current QoL-instruments, which have been useful in other contexts, are ill-suited and insufficiently validated to play a major role in dementia research, decision making and resource allocation. New models integrating biomedical and outcome variables need to be developed in order to meet the upcoming medical and economic challenges.</p

A Rapid and Sensitive Method for Measuring NAcetylglucosaminidase Activity in Cultured Cells

A rapid and sensitive method to quantitatively assess N-acetylglucosaminidase (NAG) activity in cultured cells is highly desirable for both basic research and clinical studies. NAG activity is deficient in cells from patients with Mucopolysaccharidosis type IIIB (MPS IIIB) due to mutations in NAGLU, the gene that encodes NAG. Currently available techniques for measuring NAG activity in patient-derived cell lines include chromogenic and fluorogenic assays and provide a biochemical method for the diagnosis of MPS IIIB. However, standard protocols require large amounts of cells, cell disruption by sonication or freeze-thawing, and normalization to the cellular protein content, resulting in an error-prone procedure that is material- and time-consuming and that produces highly variable results. Here we report a new procedure for measuring NAG activity in cultured cells. This procedure is based on the use of the fluorogenic NAG substrate, 4- Methylumbelliferyl-2-acetamido-2-deoxy-alpha-D-glucopyranoside (MUG), in a one-step cell assay that does not require cell disruption or post-assay normalization and that employs a low number of cells in 96-well plate format. We show that the NAG one-step cell assay greatly discriminates between wild-type and MPS IIIB patient-derived fibroblasts, thus providing a rapid method for the detection of deficiencies in NAG activity. We also show that the assay is sensitive to changes in NAG activity due to increases in NAGLU expression achieved by either overexpressing the transcription factor EB (TFEB), a master regulator of lysosomal function, or by inducing TFEB activation chemically. Because of its small format, rapidity, sensitivity and reproducibility, the NAG one-step cell assay is suitable for multiple procedures, including the high-throughput screening of chemical libraries to identify modulators of NAG expression, folding and activity, and the investigation of candidate molecules and constructs for applications in enzyme replacement therapy, gene therapy, and combination therapies

Basin-scale transport of hydrothermal dissolved metals across the South Pacific Ocean

Hydrothermal venting along mid-ocean ridges exerts an important control on the chemical composition of sea water by serving as a major source or sink for a number of trace elements in the ocean(1-3). Of these, iron has received considerable attention because of its role as an essential and often limiting nutrient for primary production in regions of the ocean that are of critical importance for the global carbon cycle(4). It has been thought that most of the dissolved iron discharged by hydrothermal vents is lost from solution close to ridge-axis sources(2,5) and is thus of limited importance for ocean biogeochemistry(6). This long-standing view is challenged by recent studies which suggest that stabilization of hydrothermal dissolved iron may facilitate its longrange oceanic transport(7-10). Such transport has been subsequently inferred from spatially limited oceanographic observations(11-13). Here we report data from the US GEOTRACES Eastern Pacific Zonal Transect (EPZT) that demonstrate lateral transport of hydrothermal dissolved iron, manganese, and aluminium from the southern East Pacific Rise (SEPR) several thousand kilometres westward across the South Pacific Ocean. Dissolved iron exhibits nearly conservative (that is, no loss from solution during transport and mixing) behaviour in this hydrothermal plume, implying a greater longevity in the deep ocean than previously assumed(6,14). Based on our observations, we estimate a global hydrothermal dissolved iron input of three to four gigamoles per year to the ocean interior, which is more than fourfold higher than previous estimates(7,11,14). Complementary simulations with a global-scale ocean biogeochemical model suggest that the observed transport of hydrothermal dissolved iron requires some means of physicochemical stabilization and indicate that hydrothermally derived iron sustains a large fraction of Southern Ocean export productio

Use of electronic personal health record systems to encourage HIV screening: an exploratory study of patient and provider perspectives

<p>Abstract</p> <p>Background</p> <p>When detected, HIV can be effectively treated with antiretroviral therapy. Nevertheless in the U.S. approximately 25% of those who are HIV-infected do not know it. Much remains unknown about how to increase HIV testing rates. New Internet outreach methods have the potential to increase disease awareness and screening among patients, especially as electronic personal health records (PHRs) become more widely available. In the US Department of Veterans' Affairs medical care system, 900,000 veterans have indicated an interest in receiving electronic health-related communications through the PHR. Therefore we sought to evaluate the optimal circumstances and conditions for outreach about HIV screening. In an exploratory, qualitative research study we examined patient and provider perceptions of Internet-based outreach to increase HIV screening among veterans who use the Veterans Health Administration (VHA) health care system.</p> <p>Findings</p> <p>We conducted two rounds of focus groups with veterans and healthcare providers at VHA medical centers. The study's first phase elicited general perceptions of an electronic outreach program to increase screening for HIV, diabetes, and high cholesterol. Using phase 1 results, outreach message texts were drafted and then presented to participants in the second phase. Analysis followed modified grounded theory.</p> <p>Patients and providers indicated that electronic outreach through a PHR would provide useful information and would motivate patients to be screened for HIV. Patients believed that electronic information would be more convenient and understandable than information provided verbally. Patients saw little difference between messages about HIV versus about diabetes and cholesterol. Providers, however, felt patients would disapprove of HIV-related messages due to stigma. Providers expected increased workload from the electronic outreach, and thus suggested adding primary care resources and devising methods to smooth the flow of patients getting screened. When provided a choice between unsecured emails versus PHRs as the delivery mechanism for disease screening messages, both patients and providers preferred PHRs.</p> <p>Conclusions</p> <p>There is considerable potential to use PHR systems for electronic outreach and social marketing to communicate to patients about, and increase rates of, disease screening, including for HIV. Planning for direct-to-patient communications through PHRs should include providers and address provider reservations, especially about workload increases.</p

The management of patients with primary chronic anal fissure: a position paper

Anal fissure is one of the most common and painful proctologic diseases. Its treatment has long been discussed and several different therapeutic options have been proposed. In the last decades, the understanding of its pathophysiology has led to a progressive reduction of invasive and potentially invalidating treatments in favor of conservative treatment based on anal sphincter muscle relaxation. Despite some systematic reviews and an American position statement, there is ongoing debate about the best treatment for anal fissure. This review is aimed at identifying the best treatment option drawing on evidence-based medicine and on the expert advice of 6 colorectal surgeons with extensive experience in this field in order to produce an Italian position statement for anal fissures. While there is little chance of a cure with conservative behavioral therapy, medical treatment with calcium channel blockers, diltiazem and nifepidine or glyceryl trinitrate, had a considerable success rate ranging from 50 to 90%. Use of 0.4% glyceryl trinitrate in standardized fashion seems to have the best results despite a higher percentage of headache, while the use of botulinum toxin had inconsistent results. Nonresponding patients should undergo lateral internal sphincterotomy. The risk of incontinence after this procedure seems to have been overemphasized in the past. Only a carefully selected group of patients, without anal hypertonia, could benefit from anoplasty

Variation in antibiotic prescription rates in febrile children presenting to emergency departments across Europe (MOFICHE) : A multicentre observational study

Funding Information: This project has received funding from the European Union?s Horizon 2020 research and innovation programme under grant agreement No. 668303. The Research was supported by the National Institute for Health Research Biomedical Research Centres at Imperial College London, Newcastle Hospitals NHS Foundation Trust and Newcastle University. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health. For the remaining authors no sources of funding were declared. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. We acknowledge all research nurses for their help in collecting data, and Anda Nagle (Riga) and the Institute of Microbiology at University Medical Centre Ljubljana for their help in collecting data on antimicrobial resistance. Members of the PERFORM consortium are listed in S11 Text. Publisher Copyright: Copyright: © 2020 Hagedoorn et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Copyright: Copyright 2020 Elsevier B.V., All rights reserved.Background The prescription rate of antibiotics is high for febrile children visiting the emergency department (ED), contributing to antimicrobial resistance. Large studies at European EDs covering diversity in antibiotic and broad-spectrum prescriptions in all febrile children are lacking. A better understanding of variability in antibiotic prescriptions in EDs and its relation with viral or bacterial disease is essential for the development and implementation of interventions to optimise antibiotic use. As part of the PERFORM (Personalised Risk assessment in Febrile illness to Optimise Real-life Management across the European Union) project, the MOFICHE (Management and Outcome of Fever in Children in Europe) study aims to investigate variation and appropriateness of antibiotic prescription in febrile children visiting EDs in Europe. Methods and findings Between January 2017 and April 2018, data were prospectively collected on febrile children aged 0–18 years presenting to 12 EDs in 8 European countries (Austria, Germany, Greece, Latvia, the Netherlands [n = 3], Spain, Slovenia, United Kingdom [n = 3]). These EDs were based in university hospitals (n = 9) or large teaching hospitals (n = 3). Main outcomes were (1) antibiotic prescription rate; (2) the proportion of antibiotics that were broad-spectrum antibiotics; (3) the proportion of antibiotics of appropriate indication (presumed bacterial), inappropriate indication (presumed viral), or inconclusive indication (unknown bacterial/viral or other); (4) the proportion of oral antibiotics of inappropriate duration; and (5) the proportion of antibiotics that were guideline-concordant in uncomplicated urinary and upper and lower respiratory tract infections (RTIs). We determined variation of antibiotic prescription and broad-spectrum prescription by calculating standardised prescription rates using multilevel logistic regression and adjusted for general characteristics (e.g., age, sex, comorbidity, referral), disease severity (e.g., triage level, fever duration, presence of alarming signs), use and result of diagnostics, and focus and cause of infection. In this analysis of 35,650 children (median age 2.8 years, 55% male), overall antibiotic prescription rate was 31.9% (range across EDs: 22.4%–41.6%), and among those prescriptions, the broad-spectrum antibiotic prescription rate was 52.1% (range across EDs: 33.0%–90.3%). After standardisation, differences in antibiotic prescriptions ranged from 0.8 to 1.4, and the ratio between broad-spectrum and narrow-spectrum prescriptions ranged from 0.7 to 1.8 across EDs. Standardised antibiotic prescription rates varied for presumed bacterial infections (0.9 to 1.1), presumed viral infections (0.1 to 3.3), and infections of unknown cause (0.1 to 1.8). In all febrile children, antibiotic prescriptions were appropriate in 65.0% of prescriptions, inappropriate in 12.5% (range across EDs: 0.6%–29.3%), and inconclusive in 22.5% (range across EDs: 0.4%–60.8%). Prescriptions were of inappropriate duration in 20% of oral prescriptions (range across EDs: 4.4%–59.0%). Oral prescriptions were not concordant with the local guideline in 22.3% (range across EDs: 11.8%–47.3%) of prescriptions in uncomplicated RTIs and in 45.1% (range across EDs: 11.1%–100%) of prescriptions in uncomplicated urinary tract infections. A limitation of our study is that the included EDs are not representative of all febrile children attending EDs in that country. Conclusions In this study, we observed wide variation between European EDs in prescriptions of antibiotics and broad-spectrum antibiotics in febrile children. Overall, one-third of prescriptions were inappropriate or inconclusive, with marked variation between EDs. Until better diagnostics are available to accurately differentiate between bacterial and viral aetiologies, implementation of antimicrobial stewardship guidelines across Europe is necessary to limit antimicrobial resistance.publishersversionPeer reviewe