Plasma lipid profiles discriminate bacterial from viral infection in febrile children

Fever is the most common reason that children present to Emergency Departments. Clinical signs and symptoms suggestive of bacterial infection are often non-specific, and there is no definitive test for the accurate diagnosis of infection. The 'omics' approaches to identifying biomarkers from the host-response to bacterial infection are promising. In this study, lipidomic analysis was carried out with plasma samples obtained from febrile children with confirmed bacterial infection (n = 20) and confirmed viral infection (n = 20). We show for the first time that bacterial and viral infection produces distinct profile in the host lipidome. Some species of glycerophosphoinositol, sphingomyelin, lysophosphatidylcholine and cholesterol sulfate were higher in the confirmed virus infected group, while some species of fatty acids, glycerophosphocholine, glycerophosphoserine, lactosylceramide and bilirubin were lower in the confirmed virus infected group when compared with confirmed bacterial infected group. A combination of three lipids achieved an area under the receiver operating characteristic (ROC) curve of 0.911 (95% CI 0.81 to 0.98). This pilot study demonstrates the potential of metabolic biomarkers to assist clinicians in distinguishing bacterial from viral infection in febrile children, to facilitate effective clinical management and to the limit inappropriate use of antibiotics

Performance of non-invasive tests and histology for the prediction of clinical outcomes in patients with non-alcoholic fatty liver disease: an individual participant data meta-analysis

BackgroundHistologically assessed liver fibrosis stage has prognostic significance in patients with non-alcoholic fatty liver disease (NAFLD) and is accepted as a surrogate endpoint in clinical trials for non-cirrhotic NAFLD. Our aim was to compare the prognostic performance of non-invasive tests with liver histology in patients with NAFLD.MethodsThis was an individual participant data meta-analysis of the prognostic performance of histologically assessed fibrosis stage (F0–4), liver stiffness measured by vibration-controlled transient elastography (LSM-VCTE), fibrosis-4 index (FIB-4), and NAFLD fibrosis score (NFS) in patients with NAFLD. The literature was searched for a previously published systematic review on the diagnostic accuracy of imaging and simple non-invasive tests and updated to Jan 12, 2022 for this study. Studies were identified through PubMed/MEDLINE, EMBASE, and CENTRAL, and authors were contacted for individual participant data, including outcome data, with a minimum of 12 months of follow-up. The primary outcome was a composite endpoint of all-cause mortality, hepatocellular carcinoma, liver transplantation, or cirrhosis complications (ie, ascites, variceal bleeding, hepatic encephalopathy, or progression to a MELD score ≥15). We calculated aggregated survival curves for trichotomised groups and compared them using stratified log-rank tests (histology: F0–2 vs F3 vs F4; LSM: 2·67; NFS: 0·676), calculated areas under the time-dependent receiver operating characteristic curves (tAUC), and performed Cox proportional-hazards regression to adjust for confounding. This study was registered with PROSPERO, CRD42022312226.FindingsOf 65 eligible studies, we included data on 2518 patients with biopsy-proven NAFLD from 25 studies (1126 [44·7%] were female, median age was 54 years [IQR 44–63), and 1161 [46·1%] had type 2 diabetes). After a median follow-up of 57 months [IQR 33–91], the composite endpoint was observed in 145 (5·8%) patients. Stratified log-rank tests showed significant differences between the trichotomised patient groups (p<0·0001 for all comparisons). The tAUC at 5 years were 0·72 (95% CI 0·62–0·81) for histology, 0·76 (0·70–0·83) for LSM-VCTE, 0·74 (0·64–0·82) for FIB-4, and 0·70 (0·63–0·80) for NFS. All index tests were significant predictors of the primary outcome after adjustment for confounders in the Cox regression.InterpretationSimple non-invasive tests performed as well as histologically assessed fibrosis in predicting clinical outcomes in patients with NAFLD and could be considered as alternatives to liver biopsy in some cases

Arginine 357 of SecY is needed for SecA-dependent initiation of preprotein translocation

The Escherichia coli SecYEG complex forms a transmembrane channel for both protein export and membrane protein insertion. Secretory proteins and large periplasmic domains of membrane proteins require for translocation in addition the SecA ATPase. The conserved arginine 357 of SecY is essential for a yet unidentified step in the SecA catalytic cycle. To further dissect its role, we have analysed the requirement for R357 in membrane protein insertion. Although R357 substitutions abolish post-translational translocation, they allow the translocation of periplasmic domains targeted co-translationally by an N-terminal transmembrane segment. We propose that R357 is essential for the initiation of SecA-dependent translocation only.

LOFIT (Lifestyle front Office For Integrating lifestyle medicine in the Treatment of patients): a novel care model towards community-based options for lifestyle change—study protocol

Background: A healthy lifestyle is indispensable for the prevention of noncommunicable diseases. However, lifestyle medicine is hampered by time constraints and competing priorities of treating physicians. A dedicated lifestyle front office (LFO) in secondary/tertiary care may provide an important contribution to optimize patient-centred lifestyle care and connect to lifestyle initiatives from the community. The LOFIT study aims to gain insight into the (cost-)effectiveness of the LFO. Methods: Two parallel pragmatic randomized controlled trials will be conducted for (cardio)vascular disorders (i.e. (at risk of) (cardio)vascular disease, diabetes) and musculoskeletal disorders (i.e. osteoarthritis, hip or knee prosthesis). Patients from three outpatient clinics in the Netherlands will be invited to participate in the study. Inclusion criteria are body mass index (BMI) ≥25 (kg/m2) and/or smoking. Participants will be randomly allocated to either the intervention group or a usual care control group. In total, we aim to include 552 patients, 276 in each trial divided over both treatment arms. Patients allocated to the intervention group will participate in a face-to-face motivational interviewing (MI) coaching session with a so-called lifestyle broker. The patient will be supported and guided towards suitable community-based lifestyle initiatives. A network communication platform will be used to communicate between the lifestyle broker, patient, referred community-based lifestyle initiative and/or other relevant stakeholders (e.g. general practitioner). The primary outcome measure is the adapted Fuster-BEWAT, a composite health risk and lifestyle score consisting of resting systolic and diastolic blood pressure, objectively measured physical activity and sitting time, BMI, fruit and vegetable consumption and smoking behaviour. Secondary outcomes include cardiometabolic markers, anthropometrics, health behaviours, psychological factors, patient-reported outcome measures (PROMs), cost-effectiveness measures and a mixed-method process evaluation. Data collection will be conducted at baseline, 3, 6, 9 and 12 months follow-up. Discussion: This study will gain insight into the (cost-)effectiveness of a novel care model in which patients under treatment in secondary or tertiary care are referred to community-based lifestyle initiatives to change their lifestyle. Trial registration: ISRCTN ISRCTN13046877. Registered 21 April 2022

LOFIT (Lifestyle front Office For Integrating lifestyle medicine in the Treatment of patients): a novel care model towards community-based options for lifestyle change-study protocol

BACKGROUND: A healthy lifestyle is indispensable for the prevention of noncommunicable diseases. However, lifestyle medicine is hampered by time constraints and competing priorities of treating physicians. A dedicated lifestyle front office (LFO) in secondary/tertiary care may provide an important contribution to optimize patient-centred lifestyle care and connect to lifestyle initiatives from the community. The LOFIT study aims to gain insight into the (cost-)effectiveness of the LFO. METHODS: Two parallel pragmatic randomized controlled trials will be conducted for (cardio)vascular disorders (i.e. (at risk of) (cardio)vascular disease, diabetes) and musculoskeletal disorders (i.e. osteoarthritis, hip or knee prosthesis). Patients from three outpatient clinics in the Netherlands will be invited to participate in the study. Inclusion criteria are body mass index (BMI) ≥25 (kg/m 2) and/or smoking. Participants will be randomly allocated to either the intervention group or a usual care control group. In total, we aim to include 552 patients, 276 in each trial divided over both treatment arms. Patients allocated to the intervention group will participate in a face-to-face motivational interviewing (MI) coaching session with a so-called lifestyle broker. The patient will be supported and guided towards suitable community-based lifestyle initiatives. A network communication platform will be used to communicate between the lifestyle broker, patient, referred community-based lifestyle initiative and/or other relevant stakeholders (e.g. general practitioner). The primary outcome measure is the adapted Fuster-BEWAT, a composite health risk and lifestyle score consisting of resting systolic and diastolic blood pressure, objectively measured physical activity and sitting time, BMI, fruit and vegetable consumption and smoking behaviour. Secondary outcomes include cardiometabolic markers, anthropometrics, health behaviours, psychological factors, patient-reported outcome measures (PROMs), cost-effectiveness measures and a mixed-method process evaluation. Data collection will be conducted at baseline, 3, 6, 9 and 12 months follow-up. DISCUSSION: This study will gain insight into the (cost-)effectiveness of a novel care model in which patients under treatment in secondary or tertiary care are referred to community-based lifestyle initiatives to change their lifestyle. TRIAL REGISTRATION: ISRCTN ISRCTN13046877 . Registered 21 April 2022

LOFIT (Lifestyle front Office For Integrating lifestyle medicine in the Treatment of patients): a novel care model towards community-based options for lifestyle change—study protocol

A healthy lifestyle is indispensable for the prevention of noncommunicable diseases. However, lifestyle medicine is hampered by time constraints and competing priorities of treating physicians. A dedicated lifestyle front office (LFO) in secondary/tertiary care may provide an important contribution to optimize patient-centred lifestyle care and connect to lifestyle initiatives from the community. The LOFIT study aims to gain insight into the (cost-)effectiveness of the LFO

An unbiased ranking of murine dietary models based on their proximity to human metabolic dysfunction-associated steatotic liver disease (MASLD).

Metabolic dysfunction-associated steatotic liver disease (MASLD), previously known as non-alcoholic fatty liver disease, encompasses steatosis and metabolic dysfunction-associated steatohepatitis (MASH), leading to cirrhosis and hepatocellular carcinoma. Preclinical MASLD research is mainly performed in rodents; however, the model that best recapitulates human disease is yet to be defined. We conducted a wide-ranging retrospective review (metabolic phenotype, liver histopathology, transcriptome benchmarked against humans) of murine models (mostly male) and ranked them using an unbiased MASLD 'human proximity score' to define their metabolic relevance and ability to induce MASH-fibrosis. Here, we show that Western diets align closely with human MASH; high cholesterol content, extended study duration and/or genetic manipulation of disease-promoting pathways are required to intensify liver damage and accelerate significant (F2+) fibrosis development. Choline-deficient models rapidly induce MASH-fibrosis while showing relatively poor translatability. Our ranking of commonly used MASLD models, based on their proximity to human MASLD, helps with the selection of appropriate in vivo models to accelerate preclinical research.This study has been conducted as part of the Preclinical work package of the LITMUS (Liver Investigation: Testing Marker Utility in Steatohepatitis) project. The LITMUS study is a large multi-centre study aiming to evaluate Non-Alcoholic Fatty Liver Disease biomarkers. The Innovative Medicines Initiative 2 (IMI2) Joint Undertaking under Grant Agreement 777377, funded the LITMUS study. This Joint Undertaking receives support from the European Union's Horizon 2020 research and innovation program and EFPIA. EMBL-EBI Core funding supported EP and IK through funding and computing resources from EMBL-EBI. Funding from the MRC (Medical Research Council) supported IK. M.V. is supported by the University of Bari (Horizon Europe Seed cod. id. S06-miRNASH), the Foundation for Liver Research (Intramural Funding), Associazione Italiana Ricerca sul Cancro (IG2022 Grant n. 27521) and Ministry of University and Research on Next Generation EU Funds [COD: P202222FCC, CUP: H53D23009960001, D.D. MUR 1366 (01-09-2023), Title: “System Biology” approaches in HCV Patients with Residual Hepatic Steatosis after Viral Eradication; Cod PE00000003, CUP: H93C22000630001, DD MUR 1550, Title: “ON Foods - Research and innovation network on food and nutrition Sustainability, Safety and Security – Working ON Foods”; Cod: CN00000041, CUP: H93C22000430007, Title PNRR “National Center for Gene Therapy and Drugs based on RNA Technology”, M4C2-Investment 1.4; Code: CN00000013, CUP: H93C22000450007, Title PNNR: “National Centre for HPC, Big Data and Quantum Computing”). A.V-P. is funded by MRC MDU, MRC Metabolic Diseases Unit (MC_UU_00014/5): Disease Model Core, Biochemistry Assay Lab, Histology Core and British Heart Foundation. F.O. is funded by UK Medical Research Council Program Grants MR/K0019494/1 and MR/R023026/1. C.M.P.R. is supported by Fundação para a Ciência e Tecnologia (PTDC/MED-FAR/3492/2021) and La Caixa Foundation (LCF/PR/HR21/52410028). Q.M.A. is supported by the Newcastle NIHR Biomedical Research Centre. S.L.F. and W.S. are supported by the NIH (NIH R01 DK128289; NCI 5P30CA196521-08 to S.L.F.; NIH R01 DK136016 to W.S.). The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript

Long-term complications in patients with poor immunological recovery despite virological successful HAART in Dutch ATHENA cohort.

Contains fulltext : 108543.pdf (publisher's version ) (Closed access)OBJECTIVE: We investigated the risk of AIDS and serious non-AIDS-defining diseases (non-ADDs) according to the degree of immunological recovery after 2 years of virological successful antiretroviral therapy (HAART). DESIGN: Retrospective observational cohort study including HIV-infected patients treated with HAART resulting in viral suppression (<500 copies/ml). METHODS: Patients were grouped according to their CD4 cell count after 2 years of HAART: CD4 cell count less than 200 cells/mul (group A), 200-350 cells/mul (group B), 351-500 cells/mul (group C) or more than 500 cells/mul (group D). Analysis was done to assess predictors for poor immunological recovery and the occurrence of a composite endpoint [death, AIDS, malignancies, liver cirrhosis and cardiovascular events (CVEs)], non-ADDs, CVEs and non-AIDS-defining malignancies (non-ADMs). RESULTS: Three thousand and sixty-eight patients were included. Older age, lower CD4 cell nadir and lower plasma HIV-RNA at the start of HAART were independent predictors for a poor immunological recovery. The composite endpoint, non-ADDs and CVE were observed most frequently in group A (overall log rank, P < 0.0001, P = 0.002 and P = 0.01). In adjusted analyses, age was a strong independent predictor for all endpoints. Compared with group A, patients in group D had a lower risk for the composite endpoint [hazard ratio 0.54 (95% confidence interval [CI] 0.33-0.87]; patients in group B had a lower risk for CVEs [hazard ratio 0.34 (95% CI 0.14-0.86)]. CONCLUSION: Poor immunological recovery despite virological successful HAART is associated with a higher risk for overall morbidity and mortality and CVEs in particular. This study underlines the importance of starting HAART at higher CD4 cell counts, particularly in older patients