Summary
Background
MicroRNA‐122 (miR‐122) is an important host factor for hepatitis C virus replication. Administration of miravirsen, an anti‐miR‐122 oligonucleotide, resulted in a dose dependent ...and prolonged decrease in HCV RNA levels in chronic hepatitis C patients.
Aim
To assess the plasma level of various miRNAs in patients dosed with miravirsen.
Methods
We included 16 of 36 chronic hepatitis C patients who received five injections of either 3 mg/kg (n = 4), 5 mg/kg (n = 4), 7 mg/kg (n = 4) miravirsen or placebo (n = 4) over a 4‐week period in a double‐blind, randomised phase 2a study. Plasma levels of 179 miRNAs were determined by qPCR and compared between patients dosed with miravirsen or placebo.
Results
Median plasma miR‐122 level at baseline in patients receiving miravirsen was 3.9 × 103 compared to 1.3 × 104 copies/4 μL in placebo‐dosed patients (P = 0.68). At week 1, 4, 6 and 10/12, patients dosed with miravirsen had respectively a median 72‐fold, 174‐fold, 1109‐fold and 552‐fold lower expression of miR‐122 than at baseline (P = 0.001, as compared to patients receiving placebo). At week 4 of dosing, miRNA‐profiling demonstrated a significant lower expression of miR‐210 and miR‐532‐5p compared to baseline (3.0 and 4.7‐fold lower respectively). However, subsequent longitudinal analysis showed no significant differences in miR‐210 and miR‐532‐5p plasma levels throughout the study period.
Conclusions
We demonstrated a substantial and prolonged decrease in plasma miR‐122 levels in patients dosed with miravirsen. Plasma levels of other miRNAs were not significantly affected by antagonising miR‐122.
Background.Diabetes mellitus (DM) is a known risk factor for tuberculosis (TB), and with the increasing prevalence of type 2 DM in less developed regions, many patients with TB will have concomitant ...DM. Presently, little is known about the effect of DM on the clinical presentation and treatment outcome of TB. Methods.In an urban setting in Indonesia, 737 patients with pulmonary TB were screened for DM and were followed up prospectively during TB treatment. Clinical characteristics and outcome were compared between patients with TB who had DM and patients with TB who did not have DM. Results.DM was diagnosed in 14.8% of patients with TB and was associated with older age and a greater body weight. On presentation, diabetic patients with TB had more symptoms but had no evidence of more-severe TB. After 2 months, results of sputum microscopic examination was more often positive in diabetic patients (18.1% vs. 10.0%). After 6 months, 22.2% of cultured sputum specimens from diabetic patients were positive for Mycobacterium tuberculosis (adjusted odds ratio, 7.65; P = .004). Conclusion.DM seems to have a negative effect on the outcome of TB treatment. The underlying mechanisms for the different response to treatment in diabetic patients with TB must be explored. Screening for DM and subsequent glycemic control may improve the outcome of TB treatment.
Biofilm accumulation in nanofiltration and reverse osmosis membrane elements results in a relative increase of normalised pressure drop (ΔNPD). However, an increase in ΔNPD is not exclusively linked ...to biofouling. In order to quantify biofouling, the biomass parameters adenosine triphosphate (ATP), total cell count and heterotrophic plate count in membrane elements were investigated during membrane autopsies and compared with ΔNPD in test rigs and 15 full scale investigations with different types of feed water. The combination of biomass related parameters ATP and total cell count in membrane elements seem to be suitable parameters for diagnosis of biofouling, whereas plate counts were not appropriate to assess biofouling. The applied ΔNPD measurement was too insensitive for early detection of fouling. Measurements of biological parameters in the water were shown to be not appropriate in quantifying biofouling. Evidently, there is a need for a practical tool, sensitive pressure drop data and systematic research.
Worldwide, more than 1.2 million adolescents and young adults (AYAs; those aged 15–39 years) are diagnosed with cancer each year. Although considerable variability exists according to cancer site and ...stage of disease, the 5-year relative survival at the time of diagnosis has been estimated at >80% for all AYA patients with cancer combined. Extensive survivorship research in recent decades has focused on patients diagnosed with cancer as children (<15 years) and older adults (>39 years), yet few studies to date have reported outcomes specifically for patients diagnosed as AYAs. With increasing incidence and improving survival for many tumor types, leading to the majority of AYA patients with cancer becoming long-term survivors, there is a critical need for research efforts to inform the survivorship care of this growing population. This article describes the population of AYA cancer survivors according to their epidemiology and late and long-term effects, the challenges and models of AYA survivorship care, as well as future opportunities for research and healthcare.
We recently reported a high cumulative incidence of thrombotic complications in critically ill patients with COVID-19 admitted to the intensive care units (ICUs) of three Dutch hospitals. In ...answering questions raised regarding our study, we updated our database and repeated all analyses.
We re-evaluated the incidence of the composite outcome of symptomatic acute pulmonary embolism (PE), deep-vein thrombosis, ischemic stroke, myocardial infarction and/or systemic arterial embolism in all COVID-19 patients admitted to the ICUs of 2 Dutch university hospitals and 1 Dutch teaching hospital from ICU admission to death, ICU discharge or April 22nd 2020, whichever came first.
We studied the same 184 ICU patients as reported on previously, of whom a total of 41 died (22%) and 78 were discharged alive (43%). The median follow-up duration increased from 7 to 14 days. All patients received pharmacological thromboprophylaxis. The cumulative incidence of the composite outcome, adjusted for competing risk of death, was 49% (95% confidence interval CI 41–57%). The majority of thrombotic events were PE (65/75; 87%). In the competing risk model, chronic anticoagulation therapy at admission was associated with a lower risk of the composite outcome (Hazard Ratio HR 0.29, 95%CI 0.091–0.92). Patients diagnosed with thrombotic complications were at higher risk of all-cause death (HR 5.4; 95%CI 2.4–12). Use of therapeutic anticoagulation was not associated with all-cause death (HR 0.79, 95%CI 0.35–1.8).
In this updated analysis, we confirm the very high cumulative incidence of thrombotic complications in critically ill patients with COVID-19 pneumonia.
COVID-19 may predispose to both venous and arterial thromboembolism due to excessive inflammation, hypoxia, immobilisation and diffuse intravascular coagulation. Reports on the incidence of ...thrombotic complications are however not available.
We evaluated the incidence of the composite outcome of symptomatic acute pulmonary embolism (PE), deep-vein thrombosis, ischemic stroke, myocardial infarction or systemic arterial embolism in all COVID-19 patients admitted to the ICU of 2 Dutch university hospitals and 1 Dutch teaching hospital.
We studied 184 ICU patients with proven COVID-19 pneumonia of whom 23 died (13%), 22 were discharged alive (12%) and 139 (76%) were still on the ICU on April 5th 2020. All patients received at least standard doses thromboprophylaxis. The cumulative incidence of the composite outcome was 31% (95%CI 20-41), of which CTPA and/or ultrasonography confirmed VTE in 27% (95%CI 17-37%) and arterial thrombotic events in 3.7% (95%CI 0-8.2%). PE was the most frequent thrombotic complication (n = 25, 81%). Age (adjusted hazard ratio (aHR) 1.05/per year, 95%CI 1.004-1.01) and coagulopathy, defined as spontaneous prolongation of the prothrombin time > 3 s or activated partial thromboplastin time > 5 s (aHR 4.1, 95%CI 1.9-9.1), were independent predictors of thrombotic complications.
The 31% incidence of thrombotic complications in ICU patients with COVID-19 infections is remarkably high. Our findings reinforce the recommendation to strictly apply pharmacological thrombosis prophylaxis in all COVID-19 patients admitted to the ICU, and are strongly suggestive of increasing the prophylaxis towards high-prophylactic doses, even in the absence of randomized evidence.
The Na+‐taurocholate cotransporting polypeptide (NTCP/SLC10A1) is believed to be pivotal for hepatic uptake of conjugated bile acids. However, plasma bile acid levels are normal in a subset of NTCP ...knockout mice and in mice treated with myrcludex B, a specific NTCP inhibitor. Here, we elucidated which transport proteins mediate the hepatic uptake of conjugated bile acids and demonstrated intestinal sensing of elevated bile acid levels in plasma in mice. Mice or healthy volunteers were treated with myrcludex B. Hepatic bile acid uptake kinetics were determined in wild‐type (WT), organic anion transporting polypeptide (OATP) knockout mice (lacking Slco1a/1b isoforms), and human OATP1B1‐transgenic mice. Effects of fibroblast growth factor 19 (FGF19) on hepatic transporter mRNA levels were assessed in rat hepatoma cells and in mice by peptide injection or adeno‐associated virus–mediated overexpression. NTCP inhibition using myrcludex B had only moderate effects on bile acid kinetics in WT mice, but completely inhibited active transport of conjugated bile acid species in OATP knockout mice. Cholesterol 7α‐hydroxylase Cyp7a1 expression was strongly down‐regulated upon prolonged inhibition of hepatic uptake of conjugated bile acids. Fgf15 (mouse counterpart of FGF19) expression was induced in hypercholanemic OATP and NTCP knockout mice, as well as in myrcludex B–treated cholestatic mice, whereas plasma FGF19 was not induced in humans treated with myrcludex B. Fgf15/FGF19 expression was induced in polarized human enterocyte‐models and mouse organoids by basolateral incubation with a high concentration (1 mM) of conjugated bile acids. Conclusion: NTCP and OATPs contribute to hepatic uptake of conjugated bile acids in mice, whereas the predominant uptake in humans is NTCP mediated. Enterocytes sense highly elevated levels of (conjugated) bile acids in the systemic circulation to induce FGF15/19, which modulates hepatic bile acid synthesis and uptake. (Hepatology 2017;66:1631–1643).
Variations in the reporting of potentially confounding variables in studies investigating systemic treatments for unresectable pancreatic cancer pose challenges in drawing accurate comparisons ...between findings. In this Review, we establish the first international consensus on mandatory baseline and prognostic characteristics in future trials for the treatment of unresectable pancreatic cancer. We did a systematic literature search to find phase 3 trials investigating first-line systemic treatment for locally advanced or metastatic pancreatic cancer to identify baseline characteristics and prognostic variables. We created a structured overview showing the reporting frequencies of baseline characteristics and the prognostic relevance of identified variables. We used a modified Delphi panel of two rounds involving an international panel of 23 leading medical oncologists in the field of pancreatic cancer to develop a consensus on the various variables identified. In total, 39 randomised controlled trials that had data on 15 863 patients were included, of which 32 baseline characteristics and 26 prognostic characteristics were identified. After two consensus rounds, 23 baseline characteristics and 12 prognostic characteristics were designated as mandatory for future pancreatic cancer trials. The COnsensus statement on Mandatory Measurements in unresectable PAncreatic Cancer Trials (COMM-PACT) identifies a mandatory set of baseline and prognostic characteristics to allow adequate comparison of outcomes between pancreatic cancer studies.
ESSENTIALS: Targeting of factor VIII values is a challenge during perioperative replacement therapy in hemophilia. This study aims to identify the extent and predictors of factor VIII underdosing and ...overdosing. Blood group O predicts underdosing and is associated with perioperative bleeding. To increase quality of care and cost-effectiveness of treatment, refining of dosing is obligatory.
Perioperative administration of factor VIII (FVIII) concentrate in hemophilia A may result in both underdosing and overdosing, leading to respectively a risk of bleeding complications and unnecessary costs.
This retrospective observational study aims to identify the extent and predictors of underdosing and overdosing in perioperative hemophilia A patients (FVIII levels < 0.05 IU mL(-1)).
One hundred nineteen patients undergoing 198 elective, minor, or major surgical procedures were included (median age 40 years, median body weight 75 kg). Perioperative management was evaluated by quantification of perioperative infusion of FVIII concentrate and achieved FVIII levels. Predictors of underdosing and (excessive) overdosing were analyzed by logistic regression analysis. Excessive overdosing was defined as upper target level plus ≥ 0.20 IU mL(-1).
Depending on postoperative day, 7-45% of achieved FVIII levels were under and 33-75% were above predefined target ranges as stated by national guidelines. A potential reduction of FVIII consumption of 44% would have been attained if FVIII levels had been maintained within target ranges. Blood group O and major surgery were predictive of underdosing (odds ratio OR 6.3, 95% confidence interval CI 2.7-14.9; OR 3.3, 95% CI 1.4-7.9). Blood group O patients had more bleeding complications in comparison to patients with blood group non-O (OR 2.02, 95% CI 1.00-4.09). Patients with blood group non-O were at higher risk of overdosing (OR 1.5, 95% CI 1.1-1.9). Additionally, patients treated with bolus infusions were at higher risk of excessive overdosing (OR 1.8, 95% CI 1.3-2.4).
Quality of care and cost-effectiveness can be improved by refining of dosing strategies based on individual patient characteristics such as blood group and mode of infusion.
The processing of pro-interleukin-1β depends on activation of caspase-1. Controversy has arisen whether Toll-like receptor (TLR) ligands alone can activate caspase-1 for release of interleukin-1β ...(IL-1β). Here we demonstrate that human blood monocytes release processed IL-1β after a one-time stimulation with either TLR2 or TLR4 ligands, resulting from constitutively activated caspase-1 and release of endogenous adenosine triphosphate. The constitutive activation of caspase-1 depends on the inflammasome components, apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC), and NALP3, but in monocytes caspase-1 activation is uncoupled from pathogen-associated molecular pattern recognition. In contrast, macrophages are unable to process and release IL-1β solely by TLR ligands and require a second adenosine triphosphate stimulation. We conclude that IL-1β production is differentially regulated in monocytes and macrophages, and this reflects their separate functions in host defense and inflammation.
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