Background & Aims The diagnostic accuracy of non-invasive liver fibrosis tests that may replace liver biopsy in patients with chronic hepatitis remains controversial. We assessed and compared the ...accuracy of FibroScan® and that of the main biomarkers used for predicting cirrhosis and significant fibrosis (METAVIR ⩾ F2) in patients with chronic viral hepatitis. Methods A multicenter prospective cross-sectional diagnostic accuracy study was conducted in the Hepatology departments of 23 French university hospitals. Index tests and reference standard (METAVIR fibrosis score on liver biopsy) were measured on the same day and interpreted blindly. Consecutive patients with chronic viral hepatitis (hepatitis B or C virus, including possible Human Immunodeficiency Virus co-infection) requiring liver biopsy were recruited in the study. Results The analysis was first conducted on the total population (1839 patients), and after excluding 532 protocol deviations, on 1307 patients (non-compliant FibroScan® examinations). The overall accuracy of FibroScan® was high (AUROC 0.89 and 0.90, respectively) and significantly higher than that of biomarkers in predicting cirrhosis (AUROC 0.77–0.86). All non-invasive methods had a moderate accuracy in predicting significant fibrosis (AUROC 0.72–0.78). Based on multilevel likelihood ratios, non-invasive tests provided a relevant gain in the likelihood of diagnosis in 0–60% of patients (cirrhosis) and 9–30% of patients (significant fibrosis). Conclusions The diagnostic accuracy of non-invasive tests was high for cirrhosis, but poor for significant fibrosis. A clinically relevant gain in the likelihood of diagnosis was achieved in a low proportion of patients. Although the diagnosis of cirrhosis may rely on non-invasive tests, liver biopsy is warranted to diagnose intermediate stages of fibrosis.
Despite the proven therapeutic role of capsaicin in human health, its usage is still hampered by its high pungency. In this sense, nonpungent capsaicin analogues as olvanil are a feasible alternative ...to the unpleasant sensations produced by capsaicin while maintaining a similar pharmacological profile. Olvanil can be obtained by a lipase‐catalyzed chemoenzymatic process. In the present work, recombinant Candida antarctica lipase B (CALB) was expressed in Pichia pastoris and subsequently immobilized by cross‐linked enzyme aggregate (CLEA) methodology for the synthesis of olvanil. The CALB‐CLEAs were obtained directly from the fermentation broth of P. pastoris without any purification step in order to assess the role of the contaminant proteins of the crude extract as co‐feeders. The CALB‐CLEAs were also bioimprinted to enhance the catalytic performance in olvanil synthesis. When CALB was precipitated with isopropanol, the obtained CALB‐CLEAs exhibited the highest activity in the synthesis of olvanil, regardless of the glutaraldehyde concentration. The maximum product synthesis was found at 72 hr obtaining 6.8 g L−1 of olvanil with a reaction yield of 16%. When CALB was bioimprinted with olvanil, the synthesis was enhanced 1.3 times, reaching 10.7 g L−1 of olvanil at 72 hr of reaction with a reaction yield of 25%. Scanning electron microscopy images indicated different morphologies of the CLEAs depending on the precipitating agent and the template used for bioimprinting. Recombinant CALB‐CLEAs obtained directly from the fermentation broth are a suitable alternative to commercial enzymatic preparations for the synthesis of olvanil in organic medium.
Injury occurring in the neonatal period in mammals is known to induce plasticity in pain pathways that may lead to pain dysfunction in later life. Whether these effects are unique to the mammalian ...nervous system is not well understood. Here, we investigate whether similar effects of early-life injury are found in a large-brained comparative model, the cephalopod
. We show that the peripheral nervous system of
undergoes profound and permanent plasticity after injury of peripheral tissue in the early post-hatching period, but not after the same injury given in the later juvenile period. Additionally, both innate defensive behaviour and learning are impaired by injury in early life. We suggest that these similar patterns of nervous system and behavioural remodelling that occur in squid and in mammals indicate an adaptive value for long-lasting plasticity arising from early-life injury, and suggest that injuries inflicted in very early life may signal to the nervous system that the environment is highly dangerous. Thus, neonatal pain plasticity may be a conserved pattern whose purpose is to set the developing nervous system's baseline responsiveness to threat. This article is part of the Theo Murphy meeting issue 'Evolution of mechanisms and behaviour important for pain'.
OBJECTIVE:To determine whether the total small vessel disease (SVD) score adds information to the prediction of stroke outcome compared to validated predictors, we tested different predictive models ...of outcome in stroke patients.
METHODS:White matter hyperintensity, lacunes, perivascular spaces, microbleeds, and atrophy were quantified in two prospective datasets of 428 and 197 first-ever stroke patients, using MRI collected 24-to-72 hours after stroke onset. Functional, cognitive, and psychological status were assessed at the 3–6 month follow-up. The predictive accuracy (in terms of calibration and discrimination) of age, baseline NIHSS, and infarct volume was quantified (model-1) on dataset-1, the total SVD score was added (model-2), and the improvement in predictive accuracy was evaluated. These two models were also developed in dataset-2 for replication. Finally, in model-3, the MRI features of cerebral SVD were included rather than the total SVD score.
RESULTS:Model-1 showed excellent performance for discriminating poor vs. good functional outcomes (AUC=0.915), and fair performance for identifying cognitively impaired and depressed patients (AUCs, 0.750 and 0.688 respectively). A higher SVD score was associated with a poorer outcome (odds ratio=1.30 1.07, 1.58, p=0.0090 at best for functional outcome). However, adding the total SVD score (model-2) or individual MRI features (model-3) did not improve the prediction over model-1. Results for dataset-2 were similar.
CONCLUSIONS:Cerebral SVD was independently associated with functional, cognitive, and psychological outcomes, but had no clinically relevant added value to predict the individual outcomes of patients when compared to the usual predictors, such as age and baseline NIHSS.
The high time needed to reconfigure cloud resources in Network Function Virtualization network environments has led to the proposal of solutions in which a prediction based-resource allocation is ...performed. All of them are based on traffic or needed resource prediction with the minimization of symmetric loss functions like Mean Squared Error. When inevitable prediction errors are made, the prediction methodologies are not able to differently weigh positive and negative prediction errors that could impact the total network cost. In fact if the predicted traffic is higher than the real one then an over allocation cost, referred to as over-provisioning cost, will be paid by the network operator; conversely, in the opposite case, Quality of Service degradation cost, referred to as under-provisioning cost, will be due to compensate the users because of the resource under allocation. In this paper we propose and investigate a resource allocation strategy based on a Long Short Term Memory algorithm in which the training operation is based on the minimization of an asymmetric cost function that differently weighs the positive and negative prediction errors and the corresponding over-provisioning and under-provisioning costs. In a typical traffic and network scenario, the proposed solution allows for a cost saving by 30% with respect to the case of solution with symmetric cost function.
Celotno besedilo
Dostopno za:
CEKLJ, DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Subgroups of capillaroscopic scleroderma landscape have been correlated with stages of SSc: two groups for Maricq's classification (slow and active), and three for Cutolo's classification (early, ...active and late). We report inter- and intra-observer agreement for these classifications as a preliminary step in the multicentre prospective SCLEROCAP study, which aims to assess the classification and single capillaroscopic items as prognostic tools for SSc.
SCLEROCAP included 385 patients. Agreement was studied in the first 100 patients, who were independently rated twice by two observers, blind to patients' characteristics; 30 of the patients were rated once by six observers. After consensus meetings, these ratings were held again. Kappa and intraclass correlation coefficients were used to assess agreement.
Interobserver agreement on 100 patients was moderate for Maricq and Cutolo classifications κ 0.47 (0.28, 0.66) and 0.49 (0.33, 0.65), respectively, and became substantial after consensus meetings 0.64 (0.50, 0.77) and 0.69 (0.56, 0.81). Intra-observer agreement between two observers was moderate to substantial: κ 0.54 (0.33, 0.75) and 0.70 (0.57, 0.83) for Maricq's classification; 0.57 (0.38, 0.77) and 0.76 (0.65, 0.87) for Cutolo's. Thirty patients were rated once by each of six observers, and agreement was moderate to substantial: κ 0.57 ± 0.10 (Maricq) and 0.61 ± 0.12 (Cutolo). Agreement was substantial for bushy, giant capillaries and microhaemorrhages, moderate for capillary density and low for oedema, disorganization and avascular areas.
The moderate reproducibility of Maricq and Cutolo classifications might hamper their prognostic value in SSc patients. Consensus meetings improve reliability, a prerequisite for better prognostic performances. A focus on giant capillaries, haemorrhages and capillary density might be more reliable.
Therapeutic options are limited in secondary progressive multiple sclerosis (SPMS). Open-label studies suggested efficacy of monthly IV cyclophosphamide (CPM) without induction for delaying ...progression but no randomized trial was conducted so far.
To compare CPM to methylprednisolone (MP) in SPMS.
Randomized, double-blind clinical trial on two parallel groups. Patient with SPMS, with a documented worsening of the Expanded Disability Status Scale (EDSS) score during the last year and an EDSS score between 4·0 and 6·5 were recruited and received one intravenous infusion of treatment (CPM: 750 mg /m2 body surface area-MP: 1g) every four weeks for one year, and every eight weeks for the second year. The primary endpoint was the time to EDSS deterioration, when confirmed sixteen weeks later, analyzed using a Cox model.
Due to recruitment difficulties, the study was terminated prematurely after 138 patients were included (CPM, n = 72; MP, n = 66). In the CPM group, 33 patients stopped treatment prematurely, mainly due to tolerability, compared with 22 in the MP group. Primary endpoint: the hazard ratio for EDSS deterioration in the CPM in comparison with the MP group was 0.61 95% CI: 0·31-1·22(p = 0·16). According to the secondary multistate model analysis, patients in the CPM group were 2.2 times more likely (1·14-4.29; p = 0.02) to discontinue treatment than those in the MP group and 2.7 times less likely (HR = 0.37, 95% CI: 0.17-0.84; p = 0.02) to experience disability progression when they did not stop treatment prematurely. Safety profile was as expected.
Although the primary end-point was negative, secondary analysis suggested that CPM decreases the risk of progression in SPMS, but its use may be limited by low tolerability.
Clinicaltrials.gov NCT00241254.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Summary
Objective
The performance of late‐night salivary cortisol (LNSC) to accurately screen for postoperative recurrence of Cushing's disease (CD) at an early stage is unknown. The aim of this ...study was to compare the accuracy of multiple sampling strategies to suggest the optimal number of LNSC samples needed for diagnosing post‐surgical recurrences of CD at an early stage.
Design
Retrospective analysis in a single centre.
Patients and measurements
Thirty‐six patients in surgical remission of CD had successive measurements of LNSC, defined as ‘sequences’, using a locally modified RIA assay as part of long‐term follow‐up (69·2 ± 10·6 months). Patients underwent an extensive biochemical evaluation within 3 months before or after a sequence of saliva sampling and were classified as being in remission or in early‐stage recurrence. The accuracy of three diagnostic strategies combining two, three or four LNSC results from a sequence was estimated using areas under the ROC curves (AUC), sensitivity, specificity and predictive values.
Results
Forty‐four sequences of LNSC measurements were available. Fifty‐two percent of sequences were performed during early‐stage recurrence. The intrasequence variability of LNSC was higher during recurrence than during remission (medians of SDs: 2·1 vs 0·5 nm; P < 0·0001). AUCs from ROC curves ranged from 0·93 to 0·96 depending on the strategy. For 90% sensitivities, the best specificities (92·9% and 90·9%) were achieved by strategies taking into account three or four measurements summarized either by their mean or their maximum value.
Conclusions
Increase in LNSC concentration is an early abnormality during post‐surgical recurrence of CD. However, due to a major within‐patient variability of LNSC from 1 day to another, a screening strategy using three or four samples collected on successive days may be recommended to detect early‐stage recurrence of CD with a high accuracy.
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