Measurement network design including traveltime determinations to minimize model prediction uncertainty

Traveltime determinations have found increasing application in the characterization of groundwater systems. No algorithms are available, however, to optimally design sampling strategies including this information type. We propose a first-order methodology to include groundwater age or tracer arrival time determinations in measurement network design and apply the methodology in an illustrative example in which the network design is directed at contaminant breakthrough uncertainty minimization. We calculate linearized covariances between potential measurements and the goal variables of which we want to reduce the uncertainty: the groundwater age at the control plane and the breakthrough locations of the contaminant. We assume the traveltime to be lognormally distributed and therefore logtransform the age determinations in compliance with the adopted Bayesian framework. Accordingly, we derive expressions for the linearized covariances between the transformed age determinations and the parameters and states. In our synthetic numerical example, the derived expressions are shown to provide good first-order predictions of the variance of the natural logarithm of groundwater age if the variance of the natural logarithm of the conductivity is less than 3.0. The calculated covariances can be used to predict the posterior breakthrough variance belonging to a candidate network before samples are taken. A Genetic Algorithm is used to efficiently search, among all candidate networks, for a near-optimal one. We show that, in our numerical example, an age estimation network outperforms (in terms of breakthrough uncertainty reduction) equally sized head measurement networks and conductivity measurement networks even if the age estimations are highly uncertain

Inverse modeling of multimodal conductivity distributions

We present a method for the calibration of multimodal hydraulic conductivity distributions and apply this method to the particular case of confining layers with a complex geological architecture. The basis of our technique is the transformation of the original multimodal conductivity distribution to the standard normal distribution, thus fulfilling the condition of normality which is required by the used representer-based inverse algorithm (Valstar et al., 2004). Using this transformation, a calibration that starts from a homogeneous prior field is shown to radically improve the estimation of the protective properties of the confining layer compared to a unimodal approach to the calibration. The method is also used for the calibration of multimodal heterogeneous prior fields. The inevitable distortion of the original parameter covariances in the posterior fields that results from the transformation process is absorbed by an iterative postprocessing procedure, in which lithologic information obtained from the distorted calibrated fields is used to condition the generation of a new multimodal field that complies again with the original geostatistics. After transformation, this new field can be calibrated again, and this process is repeated until the newly generated field agrees with the measurement information sufficiently well. Then, the lithologic distribution of this new field is fixed, and the intrafacies conductivity distributions are calibrated. This approach is shown to preserve the original geostatistics, both of the lithology field and of the intralithology hydraulic conductivity distributions

The Economics and Politics of Contracting out with the Private Sector: Evidence from the US Transit Industry

The paper studies contracting practices in the US transit industry. It employs the methods of transaction cost economics and public choice theory to develop an empirical model of bus contracting in the US transit industry. The empirical results shed light on why transit services in the US remain largely public, despite many attempts to introduce competition by contracting out services to the private sector. The results show that the decision by transit agencies to contract out with the private sector is constrained by the transaction costs of contracting and the institutional and subsidy arrangements that govern the transit industry in the US. Services that require idiosyncratic investments to provide large densities of passengers are less likely to be contracted out than those services that are provided using standard, small vehicles. Similarly, increases in federal subsidies and dedicated subsidies are found to discourage contracting out with the private sector. On the other hand, increases in state and local subsidies, other things being equal, encourage contracting. Agencies that have high labor costs –– indicating strong labor unions –– are less likely to contract out. In light of these findings, the paper concludes that piecemeal contracting out of services is not likely to increase the role of the private sector in the provision of public transit services. Structures of subsidies and federal arrangements creates intertwined incentives that discourage contracting by transit agencies, thus foiling the attempts to increase efficiencies by establishing competition for transit markets.Institute of Transport and Logistics Studies. Faculty of Economics and Business. The University of Sydne

Imatinib in patients with severe COVID-19: a randomised, double-blind, placebo-controlled, clinical trial

Background The major complication of COVID-19 is hypoxaemic respiratory failure from capillary leak and alveolar oedema. Experimental and early clinical data suggest that the tyrosine-kinase inhibitor imatinib reverses pulmonary capillary leak.Methods This randomised, double-blind, placebo-controlled, clinical trial was done at 13 academic and non-academic teaching hospitals in the Netherlands. Hospitalised patients (aged >= 18 years) with COVID-19, as confirmed by an RT-PCR test for SARS-CoV-2, requiring supplemental oxygen to maintain a peripheral oxygen saturation of greater than 94% were eligible. Patients were excluded if they had severe pre-existing pulmonary disease, had pre-existing heart failure, had undergone active treatment of a haematological or non-haematological malignancy in the previous 12 months, had cytopenia, or were receiving concomitant treatment with medication known to strongly interact with imatinib. Patients were randomly assigned (1:1) to receive either oral imatinib, given as a loading dose of 800 mg on day 0 followed by 400 mg daily on days 1-9, or placebo. Randomisation was done with a computer-based clinical data management platform with variable block sizes (containing two, four, or six patients), stratified by study site. The primary outcome was time to discontinuation of mechanical ventilation and supplemental oxygen for more than 48 consecutive hours, while being alive during a 28-day period. Secondary outcomes included safety, mortality at 28 days, and the need for invasive mechanical ventilation. All efficacy and safety analyses were done in all randomised patients who had received at least one dose of study medication (modified intention-to-treat population). This study is registered with the EU Clinical Trials Register (EudraCT 2020-001236-10).Findings Between March 31, 2020, and Jan 4, 2021, 805 patients were screened, of whom 400 were eligible and randomly assigned to the imatinib group (n=204) or the placebo group (n=196). A total of 385 (96%) patients (median age 64 years [IQR 56-73]) received at least one dose of study medication and were included in the modified intention-to-treat population. Time to discontinuation of ventilation and supplemental oxygen for more than 48 h was not significantly different between the two groups (unadjusted hazard ratio [HR] 0.95 [95% CI 0.76-1.20]). At day 28, 15 (8%) of 197 patients had died in the imatinib group compared with 27 (14%) of 188 patients in the placebo group (unadjusted HR 0.51 [0.27-0.95]). After adjusting for baseline imbalances between the two groups (sex, obesity, diabetes, and cardiovascular disease) the HR for mortality was 0.52 (95% CI 0.26-1.05). The HR for mechanical ventilation in the imatinib group compared with the placebo group was 1.07 (0.63-1.80; p=0.81). The median duration of invasive mechanical ventilation was 7 days (IQR 3-13) in the imatinib group compared with 12 days (6-20) in the placebo group (p=0.0080). 91 (46%) of 197 patients in the imatinib group and 82 (44%) of 188 patients in the placebo group had at least one grade 3 or higher adverse event. The safety evaluation revealed no imatinib-associated adverse events.Interpretation The study failed to meet its primary outcome, as imatinib did not reduce the time to discontinuation of ventilation and supplemental oxygen for more than 48 consecutive hours in patients with COVID-19 requiring supplemental oxygen. The observed effects on survival (although attenuated after adjustment for baseline imbalances) and duration of mechanical ventilation suggest that imatinib might confer clinical benefit in hospitalised patients with COVID-19, but further studies are required to validate these findings. Copyright (C) 2021 Elsevier Ltd. All rights reserved.Pathogenesis and treatment of chronic pulmonary disease

Contribution of plasma cells and B cells to hidradenitis suppurativa pathogenesis

Hidradenitis suppurativa (HS) is a debilitating chronic inflammatory skin disease characterized by chronic abscess formation and development of multiple draining sinus tracts in the groin, axillae, and perineum. Using proteomic and transcriptomic approaches, we characterized the inflammatory responses in HS in depth, revealing immune responses centered on IFN-γ, IL-36, and TNF, with lesser contribution from IL-17A. We further identified B cells and plasma cells, with associated increases in immunoglobulin production and complement activation, as pivotal players in HS pathogenesis, with Bruton’s tyrosine kinase (BTK) and spleen tyrosine kinase (SYK) pathway activation as a central signal transduction network in HS. These data provide preclinical evidence to accelerate the path toward clinical trials targeting BTK and SYK signaling in moderate-to-severe HS

Towards global consensus on core outcomes for hidradenitis suppurativa research: an update from the HISTORIC consensus meetings I and II

Background A core outcomes set (COS) is an agreed minimum set of outcomes that should be measured and reported in all clinical trials for a specific condition. Hidradenitis suppurativa (HS) has no agreed‐upon COS. A central aspect in the COS development process is to identify a set of candidate outcome domains from a long list of items. Our long list had been developed from patient interviews, a systematic review of the literature and a healthcare professional survey, and initial votes had been cast in two e‐Delphi surveys. In this manuscript, we describe two in‐person consensus meetings of Delphi participants designed to ensure an inclusive approach to generation of domains from related items. Objectives To consider which items from a long list of candidate items to exclude and which to cluster into outcome domains. Methods The study used an international and multistakeholder approach, involving patients, dermatologists, surgeons, the pharmaceutical industry and medical regulators. The study format was a combination of formal presentations, small group work based on nominal group theory and a subsequent online confirmation survey. Results Forty‐one individuals from 13 countries and four continents participated. Nine items were excluded and there was consensus to propose seven domains: disease course, physical signs, HS‐specific quality of life, satisfaction, symptoms, pain and global assessments. Conclusions The HISTORIC consensus meetings I and II will be followed by further e‐Delphi rounds to finalize the core domain set, building on the work of the in‐person consensus meetings

What causes hidradenitis suppurativa ?—15 years after

The 14 authors of the first review article on hidradenitis suppurativa (HS) pathogenesis published 2008 in EXPERIMENTAL DERMATOLOGY cumulating from the 1st International Hidradenitis Suppurativa Research Symposium held March 30–April 2, 2006 in Dessau, Germany with 33 participants were prophetic when they wrote “Hopefully, this heralds a welcome new tradition: to get to the molecular heart of HS pathogenesis, which can only be achieved by a renaissance of solid basic HS research, as the key to developing more effective HS therapy.” (Kurzen et al. What causes hidradenitis suppurativa? Exp Dermatol 2008;17:455). Fifteen years later, th

De regulatie van de enzymsynthese en uitscheiding van de pectinolytische hydrolases van Clostridiuin thermosaccharolyticum

De regulatie van de enzymsynthese en uitscheiding van de polygalacturonases van Clostridium thermosaccharolyticum (stam Haren) is onderzocht. Deze stam produceert een methylesterase en twee hydrolases met verschillende activiteitsoptima, respectievelijk bij pH 3 en pH 6. Het organisme groeit op glucose, fructose, galactose, sucrose, maltose, cellobiose, lactose, raffinose en sorbitol. Bij groei op deze suikers en bij groei op glucose met galacturonaat of pectine word geen hydrolyse activiteit waargenomen. Tijdens groei op pectine word wel enzymactiviteit gevonden. De maximale opbrengst van de enzymactiviteit voor het pH3 en het pH6 enzym is respectievelijk 0,04 Units/ml en 0,08 units/ml. Bij groei op pectine in batchculture lijkt de activiteitsproductie groeigebonden. Tijdens groei bij pH 4 gaan de enzymniveau's gelijk lopen. Als de pH van het medium constant op pH 6 word gehouden treedt dit effect niet op. In een pectine gelimiteerde continue culture, bij verschillende dilutiesnelheden, blijken beide hydrolases een verschillend optimum voor de enzymproductie te hebben. Voor het pH3 enzym ligt het optimum tussen 0,07 h-1 en 0,1 h-1 met als maximale opbrengst 0,076 U/ml. Voor het pH6 enzym ligt dit optimum bij 0,2 h-1 met als maximale opbrengst 0,127 U/ml. Het percentage celgebonden activiteit ligt tussen de 20% en 40% voor dilutiesnelheden, variërend tussen 0,001 h-1 en 0,15 h-1. In continue culture wordt het substraat tot di- en trimeer afgebroken, monomeren worden niet gevonden. De gemeten fermentatieproducten zijn methanol, ethanol, acetaat en butyraat.