The introduction of orthogonal polarization spectral (OPS) imaging in clinical research has elucidated new perspectives on the role of microcirculatory flow abnormalities in the pathogenesis of ...sepsis. Essential to the process of understanding and reproducing these abnormalities is the method of quantification of flow scores.
In a consensus meeting with collaboraters from six research centres in different fields of experience with microcirculatory OPS imaging, premeditated qualifications for a simple, translucent and reproducible way of flow scoring were defined. Consecutively, a single-centre prospective observational validation study was performed in a group of 12 patients with an abdominal sepsis and a new stoma. Flow images of the microcirculation in vascular beds of the sublingual and stoma region were obtained, processed and analysed in a standardised way. We validated intra-observer and inter-observer reproducibility with kappa cross-tables for both types of microvascular beds.
Agreement and kappa coefficients were >85% and >0.75, respectively, for interrater and intrarater variability in quantification of flow abnormalities during sepsis, in different subsets of microvascular architecture.
Semi-quantitative analysis of microcirculatory flow, as described, provides a reproducible and transparent tool in clinical research to monitor and evaluate the microcirculation during sepsis.
Background
The nutritional problems of patients who are hospitalised for COVID‐19 are becoming increasingly clear. However, a large group of patients have never been hospitalised and also appear to ...experience persistent nutritional problems. The present study describes the nutritional status, risk of sarcopaenia and nutrition‐related complaints of patients recovering from COVID‐19 receiving dietetic treatment in primary care.
Methods
In this retrospective observational study, data were collected during dietetic treatment by a primary care dietitian between April and December 2020. Both patients who had and had not been admitted to the hospital were included at their first visit to a primary care dietitian. Data on nutritional status, risk of sarcopaenia and nutrition‐related complaints were collected longitudinally.
Results
Data from 246 patients with COVID‐19 were collected. Mean ± SD age was 57 ± 16 years and 61% of the patient population was female. At first consultation, two thirds of patients were classified as overweight or obese (body mass index >25 kg m–2). The majority had experienced unintentional weight loss because of COVID‐19. Additionally, 55% of hospitalised and 34% of non‐hospitalised patients had a high risk of sarcopaenia. Most commonly reported nutrition‐related complaints were decreased appetite, shortness of breath, changed or loss of taste and feeling of being full. Nutrition‐related complaints decreased after the first consultation, but remained present over time.
Conclusions
In conclusion, weight changes, risk of sarcopaenia and nutrition‐related complaints were prevalent in patients with COVID‐19, treated by a primary care dietitian. Nutrition‐related complaints improved over time, but remained prevalent until several months after infection.
Key points
Weight changes, risk of sarcopaenia and nutrition‐related complaints were prevalent in patients with COVID‐19 treated by a primary care dietitian.
Most commonly reported nutrition‐related complaints were decreased appetite, shortness of breath, changed or loss of taste and feeling of being full.
Nutrition‐related complaints improved over time, but remained prevalent until several months after infection.
The risk of a poor nutritional status and high risk of sarcopaenia should be considered, especially in combination with persistent nutrition‐related complaints as a result of COVID‐19.
The Fermilab Accelerator Science and Technology facility is currently in operation with its linac based on TESLA-type superconducting rf cavities. Using a 3-MHz micropulse repetition rate with a long ...macropulse composed of up to 3000 micropulses, and with beam energies demonstrated at 300 MeV and projected to reach 800 MeV with two additional cryomodules, the feasibilities for a vacuum ultraviolet (VUV) and an extreme ultraviolet (EUV) free-electron laser oscillator (FELO) with the two energies are evaluated. We have used both the ginger code with an oscillator module and the minerva/opc code to assess FELO saturation prospects at 120 nm with a 5.0-cm-period undulator of 4.5-m length and the minerva/opc code to assess the FELO at 13.4 nm with adjusted parameters. The simulation results support saturation at both of these wavelengths which are much shorter than the demonstrated shortest wavelength record of 168.6 nm from a storage-ring-based FELO. This indicates superconducting rf linac-driven FELOs can be extended into this VUV-EUV wavelength regime previously only reached with single-pass FEL configurations. In addition, emittance-dilution effects due to wakefields in the cavities and the resulting submacropulse centroid slew effects on FELO performance are addressed using minerva/opc simulations for the first time.
To study the potential beneficial role of furosemide in resolving renal failure after hemofiltration in mechanically ventilated critically ill patients.
Single-center randomized, double blind, ...placebo-controlled study.
A 13-bed mixed intensive care unit (ICU) in a teaching hospital.
Patients who had been treated with continuous venovenous hemofiltration were included.
After the end of continuous venovenous hemofiltration, the urine of the first 4 hours was collected for measuring creatinine clearance. Patients were subsequently randomized for furosemide (0.5 mg/kg/hr) or placebo by continuous infusion. To prevent hypovolemia, the rate of fluid infusion was adapted every hour and was set as the urinary production of the previous hour.
End points were renal recovery (creatinine clearance more than 30 mL/min or stable serum creatinine without renal replacement therapy) in the ICU and in the hospital. Seventy-two patients were included and 71 were eligible for the analysis. The 36 furosemide-treated patients had a significantly increased urinary volume compared with the 35 placebo-treated patients (median 247 mL/hr (interquartile range IQR 774 mL/hr) vs. 117 mL/hr (IQR 158 mL/hr), p = 0.003) and greater sodium excretion (median 73 mmol/L (IQR 48) vs. 37 (IQR 48) mmol/L, p = 0.001). In the furosemide group 25 patients and in the placebo group 27 patients showed recovery of renal function at ICU discharge (p = 0.46). Two patients of the furosemide group needed long-term dialysis dependency (p = 0.23).
Furosemide by continuous infusion in the recovery phase of hemofiltration-dependent acute kidney failure did increase urinary volume and sodium excretion but did not lead to a shorter duration of renal failure or more frequent renal recovery.
Antibiotic dosing in critically ill patients is challenging because their pharmacokinetics (PK) are altered and may change rapidly with disease progression. Standard dosing frequently leads to ...inadequate PK exposure. Therapeutic drug monitoring (TDM) offers a potential solution but requires sampling and PK knowledge, which delays decision support. It is our philosophy that antibiotic dosing support should be directly available at the bedside through deep integration into the electronic health record (EHR) system. Therefore we developed AutoKinetics, a clinical decision support system (CDSS) for real time, model informed precision antibiotic dosing.
To provide a detailed description of the design, development, validation, testing, and implementation of AutoKinetics.
We created a development framework and used workflow analysis to facilitate integration into popular EHR systems. We used a development cycle to iteratively adjust and expand AutoKinetics functionalities. Furthermore, we performed a literature review to select and integrate pharmacokinetic models for five frequently prescribed antibiotics for sepsis. Finally, we tackled regulatory challenges, in particular those related to the Medical Device Regulation under the European regulatory framework.
We developed a SQL-based relational database as the backend of AutoKinetics. We developed a data loader to retrieve data in real time. We designed a clinical dosing algorithm to find a dose regimen to maintain antibiotic pharmacokinetic exposure within clinically relevant safety constraints. If needed, a loading dose is calculated to minimize the time until steady state is achieved. Finally, adaptive dosing using Bayesian estimation is applied if plasma levels are available. We implemented support for five extensively used antibiotics following model development, calibration, and validation. We integrated AutoKinetics into two popular EHRs (Metavision, Epic) and developed a user interface that provides textual and visual feedback to the physician.
We successfully developed a CDSS for real time model informed precision antibiotic dosing at the bedside of the critically ill. This holds great promise for improving sepsis outcome. Therefore, we recently started the Right Dose Right Now multi-center randomized control trial to validate this concept in 420 patients with severe sepsis and septic shock.
Altered sphingosine 1-phosphate (S1P) homeostasis and signaling is implicated in various inflammatory diseases including atherosclerosis. As S1P levels are tightly controlled by S1P lyase, we ...investigated the impact of hematopoietic S1P lyase (Sgpl1(-/-)) deficiency on leukocyte subsets relevant to atherosclerosis.
LDL receptor deficient mice that were transplanted with Sgpl1(-/-) bone marrow showed disrupted S1P gradients translating into lymphopenia and abrogated lymphocyte mitogenic and cytokine response as compared to controls. Remarkably however, Sgpl1(-/-) chimeras displayed mild monocytosis, due to impeded stromal retention and myelopoiesis, and plasma cytokine and macrophage expression patterns, that were largely compatible with classical macrophage activation. Collectively these two phenotypic features of Sgpl1 deficiency culminated in diminished atherogenic response.
Here we not only firmly establish the critical role of hematopoietic S1P lyase in controlling S1P levels and T cell trafficking in blood and lymphoid tissue, but also identify leukocyte Sgpl1 as critical factor in monocyte macrophage differentiation and function. Its, partly counterbalancing, pro- and anti-inflammatory activity spectrum imply that intervention in S1P lyase function in inflammatory disorders such as atherosclerosis should be considered with caution.
Introduction Sarcoidosis is a multi-system inflammatory disease of unknown origin with heterogeneous clinical manifestations varying from a single organ non-caseating granuloma site to chronic ...systemic inflammation and fibrosis. Gene expression studies have suggested several genes and pathways implicated in the pathogenesis of sarcoidosis, however, due to differences in study design and variable statistical approaches, results were frequently not reproducible or concordant. Therefore, meta-analysis of sarcoidosis gene-expression datasets is of great importance to robustly establish differentially expressed genes and signalling pathways. Methods We performed meta-analysis on 22 published gene-expression studies on sarcoidosis. Datasets were analysed systematically using same statistical cut-offs. Differentially expressed genes were identified by pooling of p -values using Edgington’s method and analysed for pathways using Ingenuity Pathway Analysis software. Results A consistent and significant signature of novel and well-known genes was identified, those collectively implicated both type I and type II interferon mediated signalling pathways in sarcoidosis. In silico functional analysis showed consistent downregulation of eukaryotic initiation factor 2 signalling, whereas cytokines like interferons and transcription factor STAT1 were upregulated. Furthermore, we analysed affected tissues to detect differentially expressed genes likely to be involved in granuloma biology. This revealed that matrix metallopeptidase 12 was exclusively upregulated in affected tissues, suggesting a crucial role in disease pathogenesis. Discussion Our analysis provides a concise gene signature in sarcoidosis and expands our knowledge about the pathogenesis. Our results are of importance to improve current diagnostic approaches and monitoring strategies as well as in the development of targeted therapeutics.
The birth prevalence of Robin sequence (RS) is frequently cited to be 1 in 8,500 to 14,000 live births (range: 7,1-11,8 per 100.000), which is based on just a few epidemiological studies. The ...objective of this study is to contribute to the limited knowledge of the epidemiology of RS by determining the frequency of RS in a cleft palate (CP) population and the estimated birth prevalence in live births in the Netherlands, using distinct diagnostic criteria. A retrospective population-based analysis of the National Cleft Registry was performed in order to obtain all CP patients registered in the Netherlands from 2000-2010, in addition to a thorough review of the medical records in three Dutch Academic Pediatric Hospitals for the same period. Furthermore, a systematic search of the literature was conducted to allow for comparison of our findings. The Dutch birth prevalence of RS was estimated to be 1:5,600 live births (or 17.7 per 100,000), with a slight female predominance. RS was estimated to occur in a third of the CP population and patients with RS had a more severe cleft grade than the general CP population. The literature search yielded 42 studies reporting the birth prevalence for RS, which varied between 1:3,900 and 1:122,400 (0.8-32.0 per 100,000), with a mean prevalence of 1:24,500 (8.0 per 100,000). The birth prevalence of RS in the Netherlands was higher than reported for most other countries when similar diagnostic criteria were used, with a slight female predominance. A third of the general CP could be classified as RS.
Economic evaluation is an integral component of informed public health decision-making in personalized medicine. However, performing economic evaluation assessments often requires specialized ...knowledge, expertise, and significant resources. To this end, developing generic models can significantly assist towards providing the necessary evidence for the cost-effectiveness of genome-guided therapeutic interventions, compared to the traditional drug treatment modalities. Here, we report a generic cost-utility analysis model, developed in R, which encompasses essential economic evaluation steps. Specifically, critical steps towards a comprehensive deterministic and probabilistic sensitivity analysis were incorporated in our model, while also providing an easy-to-use graphical user interface, which allows even non-experts in the field to produce a fully comprehensive cost-utility analysis report. To further demonstrate the model’s reproducibility, two sets of data were assessed, one stemming from in-house clinical data and one based on previously published data. By implementing the generic model presented herein, we show that the model produces results in complete concordance with the traditionally performed cost-utility analysis for both datasets. Overall, this work demonstrates the potential of generic models to provide useful economic evidence for personalized medicine interventions.
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Contactins in the neurobiology of autism Zuko, Amila; Kleijer, Kristel T.E.; Oguro-Ando, Asami ...
European journal of pharmacology,
11/2013, Letnik:
719, Številka:
1-3
Journal Article
Recenzirano
Autism is a disease of brain plasticity. Inspiring work of Willem Hendrik Gispen on neuronal plasticity has stimulated us to investigate gene defects in autism and the consequences for brain ...development. The central process in the pathogenesis of autism is local dendritic mRNA translation which is dependent on axodendritic communication. Hence, most autism-related gene products (i) are part of the protein synthesis machinery itself, (ii) are components of the mTOR signal transduction pathway, or (iii) shape synaptic activity and plasticity. Accordingly, prototype drugs have been recognized that interfere with these pathways. The contactin (CNTN) family of Ig cell adhesion molecules (IgCAMs) harbours at least three members that have genetically been implicated in autism: CNTN4, CNTN5, and CNTN6. In this chapter we review the genetic and neurobiological data underpinning their role in normal and abnormal development of brain systems, and the consequences for behavior. Although data on each of these CNTNs are far from complete, we tentatively conclude that these three contactins play roles in brain development in a critical phase of establishing brain systems and their plasticity. They modulate neuronal activities, such as neurite outgrowth, synaptogenesis, survival, guidance of projections and terminal branching of axons in forming neural circuits. Current research on these CNTNs concentrate on the neurobiological mechanism of their developmental functions. A future task will be to establish if proposed pharmacological strategies to counteract ASD-related symptomes can also be applied to reversal of phenotypes caused by genetic defects in these CNTN genes.
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