The diagnostic value of CRP, IL-8, PCT, and sTREM-1 in the detection of bacterial infections in pediatric oncology patients with febrile neutropenia

In this study, we evaluated C-reactive protein (CRP), interleukin (IL)-8, procalcitonin (PCT), and soluble triggering receptor expressed on myeloid cells-1 (sTREM-1) as predictors for bacterial infection in febrile neutropenia, plus their usefulness in febrile neutropenia during chemotherapy-induced gastrointestinal mucositis. Plasma was obtained from pediatric oncology patients at presentation with febrile neutropenia (n = 43) and 24-48 h later (n = 17). The patients were classified as having or not having a bacterial infection. Plasma was also obtained of patients in the absence and in the presence of mucositis (n = 26). At presentation with febrile neutropenia, median IL-8 and PCT levels were significantly increased in patients with a bacterial infection, in contrast to CRP and sTREM-1. IL-8 was the most sensitive marker for the early detection of bacterial infection, in combination with clinical parameters or PCT the sensitivity reached 100%. After 24-48 h, only PCT was significantly elevated during bacterial infection. IL-8 levels were significantly increased during mucositis. Mucositis did not cause considerable changes in PCT levels. IL-8 is the most useful marker for the early detection of bacterial infections, compared with CRP, PCT, and sTREM-1. IL-8 in combination with clinical parameters or PCT might be even more useful. Gastrointestinal mucositis alone does not affect PCT levels, in contrast to IL-8 levels, and therefore, PCT might be more useful for the detection of bacterial infections during mucositis than IL-8

Safety, pharmacokinetics and target engagement of novel RIPK1 inhibitor SAR443060 (DNL747) for neurodegenerative disorders:Randomized, placebo-controlled, double-blind phase I/Ib studies in healthy subjects and patients

RIPK1 is a master regulator of inflammatory signaling and cell death and increased RIPK1 activity is observed in human diseases, including Alzheimer's disease (AD) and amyotrophic lateral sclerosis (ALS). RIPK1 inhibition has been shown to protect against cell death in a range of preclinical cellular and animal models of diseases. SAR443060 (previously DNL747) is a selective, orally bioavailable, central nervous system (CNS)-penetrant, small-molecule, reversible inhibitor of RIPK1. In three early-stage clinical trials in healthy subjects and patients with AD or ALS (NCT03757325 and NCT03757351), SAR443060 distributed into the cerebrospinal fluid (CSF) after oral administration and demonstrated robust peripheral target engagement as measured by a reduction in phosphorylation of RIPK1 at serine 166 (pRIPK1) in human peripheral blood mononuclear cells compared to baseline. RIPK1 inhibition was generally safe and well-tolerated in healthy volunteers and patients with AD or ALS. Taken together, the distribution into the CSF after oral administration, the peripheral proof-of-mechanism, and the safety profile of RIPK1 inhibition to date, suggest that therapeutic modulation of RIPK1 in the CNS is possible, conferring potential therapeutic promise for AD and ALS, as well as other neurodegenerative conditions. However, SAR443060 development was discontinued due to long-term nonclinical toxicology findings, although these nonclinical toxicology signals were not observed in the short duration dosing in any of the three early-stage clinical trials. The dose-limiting toxicities observed for SAR443060 preclinically have not been reported for other RIPK1-inhibitors, suggesting that these toxicities are compound-specific (related to SAR443060) rather than RIPK1 pathway-specific

Systematic review and meta-analysis of the value of initial biomarkers in predicting adverse outcome in febrile neutropenic episodes in children and young people with cancer

Background: Febrile neutropenia is a frequently occurring and occasionally life-threatening complication of treatment for childhood cancer. Many biomarkers have been proposed as predictors of adverse events. We aimed to undertake a systematic review and meta-analysis to summarize evidence on the discriminatory ability of initial serum biomarkers of febrile neutropenic episodes in children and young people. Methods: This review was conducted in accordance with the Center for Reviews and Dissemination Methods, using three random effects models to undertake meta-analysis. It was registered with the HTA Registry of systematic reviews, CRD32009100485. Results: We found that 25 studies exploring 14 different biomarkers were assessed in 3,585 episodes of febrile neutropenia. C-reactive protein (CRP), pro-calcitonin (PCT), and interleukin-6 (IL6) were subject to quantitative meta-analysis, and revealed huge inconsistencies and heterogeneity in the studies included in this review. Only CRP has been evaluated in assessing its value over the predictive value of simple clinical decision rules. Conclusions: The limited data available describing the predictive value of biomarkers in the setting of pediatric febrile neutropenia mean firm conclusions cannot yet be reached, although the use of IL6, IL8 and procalcitonin warrant further study

Predicting infectious complications in neutropenic children and young people with cancer (IPD protocol)

<p>Abstract</p> <p>Background</p> <p>A common and potentially life-threatening complication of the treatment of childhood cancer is infection, which frequently presents as fever with neutropenia. The standard management of such episodes is the extensive use of intravenous antibiotics, and though it produces excellent survival rates of over 95%, it greatly inconveniences the three-fourths of patients who do not require such aggressive treatment. There have been a number of studies which have aimed to develop risk prediction models to stratify treatment. Individual participant data (IPD) meta-analysis in therapeutic studies has been developed to improve the precision and reliability of answers to questions of treatment effect and recently have been suggested to be used to answer questions regarding prognosis and diagnosis to gain greater power from the frequently small individual studies.</p> <p>Design</p> <p>In the IPD protocol, we will collect and synthesise IPD from multiple studies and examine the outcomes of episodes of febrile neutropenia as a consequence of their treatment for malignant disease. We will develop and evaluate a risk stratification model using hierarchical regression models to stratify patients by their risk of experiencing adverse outcomes during an episode. We will also explore specific practical and methodological issues regarding adaptation of established techniques of IPD meta-analysis of interventions for use in synthesising evidence derived from IPD from multiple studies for use in predictive modelling contexts.</p> <p>Discussion</p> <p>Our aim in using this model is to define a group of individuals at low risk for febrile neutropenia who might be treated with reduced intensity or duration of antibiotic therapy and so reduce the inconvenience and cost of these episodes, as well as to define a group of patients at very high risk of complications who could be subject to more intensive therapies. The project will also help develop methods of IPD predictive modelling for use in future studies of risk prediction.</p

The Long Road to Collective Skill Formation in the Netherlands

The current vocational education and training (VET) system in the Netherlands originated in the training initiatives undertaken by private actors in the artisan and industrial sectors in the nineteenth and twentieth centuries. Its central features are corporatist administration, significant state involvement, and the dominance of school-based training. Since World War II, the state has played a more active role in VET, and the general education component of VET has increased. The 1980s saw a return to a clearer focus on the needs of the labor market. By the early 1980s, VET was seen as the mutual responsibility of the state, the social partners, and educational institutions. A major reform in 1994 reorganized and streamlined the system of vocational schools and vocational training, increasing cooperation between industry and the VET system

Ultra-fast wind/EDR monitoring algorithms and their performances

Geoscience & Remote SensingCivil Engineering and Geoscience

Prevalence and associated factors of worry for cancer in patients with a Barrett’s esophagus

Abstract Although the risk of cancer progression in a Barrett’s esophagus (BE) is very low, worrying about cancer is known as an important factor affecting HRQoL. The aim of this study was to determine the proportion of BE patients with high levels of worry for cancer, to compare outcomes of patients endoscopically treated for BE neoplasia (DBE), non-dysplastic BE patients (NDBE) and patients with reflux symptoms, and to examine associated factors. We performed a cross sectional, exploratory, self-administered questionnaire study using the cancer worry scale, and the reflux disease questionnaire. A total of 192 DBE patients, 213 NDBE patients and 111 refractory reflux symptom patients were included from October 2019 until July 2021, 76.8% of BE participants were male and aged 66.9 years. High cancer worry was reported in 40.6% of the DBE patients and 36.2% of NDBE patient. Reflux patients scored statistically significant worse with 56.6% stated high cancer worry. Positive correlations were found between reflux symptoms and cancer worry in NDBE patients and reflux patients. In DBE patients’ negative correlations were found between higher cancer worry and younger age as well as a family history of esophageal carcinoma. A clinically significant group of BE patients reported high cancer worry, which was associated with reflux symptoms in NDBE patients and a younger age and a (family) history of esophageal carcinoma diagnosis in BE patients treated for (early) neoplasia. Physicians should communicate about the actual cancer risk, which leads to greater patient understanding and therefore may have a positive impact on health outcomes

First trial postural reactions to unexpected balance disturbances: a comparison with the acoustic startle reaction.

Contains fulltext : 88593.pdf (publisher's version ) (Closed access)Unexpected support-surface movements delivered during stance elicit "first trial" postural reactions, which are larger and cause greater instability compared with habituated responses. The nature of this first trial reaction remains unknown. We hypothesized that first trial postural reactions consist of a generalized startle reaction, with a similar muscle synergy as the acoustic startle response, combined with an automatic postural reaction. Therefore we compared acoustic startle responses to first trial postural reactions. Eight healthy subjects stood on a support surface that unexpectedly rotated backwards 10 times, followed by 10 startling acoustic stimuli, or vice versa. Outcome measures included full body kinematics and surface EMG from muscles involved in startle reactions or postural control. Postural perturbations and startling acoustic stimuli both elicited a clear first trial reaction, as reflected by larger kinematic and EMG responses. The ensuing habituation rate to repeated identical stimuli was comparable for neck and trunk muscles in both conditions. Onset latencies in neck muscles occurred significantly later for first trial perturbations compared with startle responses, but earlier in trunk muscles. Our results show that platform tilting initially induces reactions larger than needed to maintain equilibrium. For neck and trunk muscles, these first trial postural reactions resembled acoustic startle reflexes. First trial postural reactions may be triggered by interaction of afferent volleys formed by somatosensory and vestibular inputs. Acoustic startle reactions may also be partially triggered by vestibular inputs. Similar muscle activation driven by vestibular inputs may be the common element of first trial postural responses and acoustic startle reactions.1 november 201

Endothelial Cells Are Main Producers of Interleukin 8 through Toll-Like Receptor 2 and 4 Signaling during Bacterial Infection in Leukopenic Cancer Patients

Cancer patients who are leukopenic due to chemotherapy are susceptible to bacterial infections. Normally, clinical conditions during bacterial infections are caused by pathogen-associated molecular patterns, which are components that bind to Toll-like receptor (TLR) 2 (TLR-2) and TLR-4 on leukocytes, resulting in the production of inflammatory cytokines. The mechanism of this inflammatory response in cancer patients with diminished numbers of leukocytes is not completely clear. The levels of interleukin 1β (IL-1β) and tumor necrosis factor alpha measured in the circulation of leukopenic cancer patients are lower than those measured in that of nonleukopenic patients during bacterial infections, whereas plasma interleukin 8 (IL-8) levels show distinct identical increases during bacterial infections in both leukopenic and nonleukopenic patients. Normally, these cytokines are mainly secreted by leukocytes. In cancer patients with bacterial infections and a diminished number of leukocytes, other sources of IL-8 production, such as endothelial cells, might be expected. Endothelial cells instead of leukocytes become the most important producers of IL-8 during bacterial infections in patients with chemotherapy-induced leukopenia through TLR-2 and TLR-4 signaling. Whole blood samples from six cancer patients were stimulated with lipopolysaccharide (LPS), and then IL-8 concentrations in supernatants were measured. Further, human umbilical vein endothelial cells (HUVECs) were incubated with sera from leukopenic cancer patients with or without bacterial infections, and then IL-8 concentrations in supernatants were measured (n = 6). In addition, the same HUVEC experiment was performed with the addition of neutralizing antibodies against TLR-2 and TLR-4. During leukopenia (<10(9) cells/liter), LPS stimulation of whole blood did not result in an increase in IL-8 levels. However, when endothelial cells were incubated with sera from leukopenic cancer patients during bacterial infections, a three- to eightfold increase in IL-8 production was found, compared to the IL-8 production found after incubation with sera from patients without signs of infections. This increase did not reflect a higher level of IL-8 already present in the sera. Further, we demonstrated that IL-8 production induced in endothelial cells by sera from patients with documented gram-negative infections could be reduced significantly by up to 40% when the cells were incubated with neutralizing antibodies against TLR-4 (P = 0.028). The addition of TLR-2 antibodies slightly enhanced the reduction of IL-8 production. These results suggest that during bacterial infections in cancer patients with markedly diminished numbers of leukocytes, endothelial cells become important producers of IL-8 through TLR-4 signaling and, to a lesser extent, TLR-2 signaling