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Objective: Computer-assisted child-focused interventions are expected to improve efficiency and personalization of therapist-led treatments for children and adolescents. However, therapist-led, outpatient interventions using computer assistance are lacking for children with oppositional defiant disorder (ODD) or conduct disorder (CD). The present randomized controlled trial examined the efficacy of individualized computer-assisted social skills training for children with aggressive behavior compared to a resource activation intervention., Method: A total of 100 children aged 6-12 years with a diagnosis of ODD/CD and peer-related aggression were randomly (1:1) assigned to either individually delivered computer-assisted social skills training (ScouT) or an individually delivered supportive resource activation treatment (STARK). The primary outcome was parent-rated peer-related aggression, assessed with the respective scale of the Questionnaire for Aggressive Behavior of Children (FAVK) and measured at pre-assessment and after the 16-week intervention (post-assessment). Further parent-, self-, teacher- and/or clinician-rated outcomes included ODD and CD symptoms, a wide range of behavioral and emotional symptoms, callous-unemotional traits, functional impairment, and quality of life., Results: After correcting for multiple testing, analyses of covariance comparing the efficacy of ScouT to the efficacy of STARK yielded small to moderate treatment effects in favor of the ScouT condition regarding parent-rated peer-related aggression (primary outcome; d = -0.64, 95% CI = -1.05, -0.24), parent-rated callous and uncaring traits, and parent-rated quality of life. However, the analyses did not reveal any significant effects for self- or teacher-rated peer-related aggression assessed with the respective scale of the FAVK (self-report: d = -0.21, 95% CI = -0.69, 0.29; teacher rating: d = -0.17, 95% CI = -0.56, 0.22). Moreover, after controlling for multiple comparisons, no significant effects emerged for the following: parent-, self-, and teacher-rated adult-related aggression; parent-, self-, teacher-, and clinician-rated ODD and CD symptoms; parent-, self-, and teacher-rated emotional and behavioral symptoms; and parent-rated functional impairment., Conclusion: According to parent ratings, school-age children with disruptive behavior disorders and peer-related aggression seem to benefit more from individualized, computer-assisted social skills training than from resource activation treatment. However, this conclusion is limited by the missing effects on the clinician-, self-, and teacher-rated measures., Clinical Trial Registration Information: Treatment of Children With Peer Related Aggressive Behavior (ScouT); https://clinicaltrials.gov/; NCT02143427., (Copyright © 2022 American Academy of Child and Adolescent Psychiatry. Published by Elsevier Inc. All rights reserved.)

Trichinellosis is a potentially deadly parasitic zoonosis that is contracted by consuming undercooked infected meat. Reliable detection of infectious Trichinella spp. larvae in meat is therefore pivotal to ensure consumer's safety. The recently authorised PrioCHECK™ Trichinella Alternative Artificial Digestion (AAD) test kit appears promising when used with the standard magnetic stirrer method, but evaluation with other apparatus types is lacking. In this study, the performance of the AAD kit in an adapted Trichomatic-35 (TM35) instrument was evaluated, first, at the Swiss National Reference Laboratory for trichinellosis (NRL); second, in a ring trial involving four Swiss official laboratories. Proficiency pork samples spiked with larvae of Trichinella spiralis, T. britovi, or T. pseudospiralis were tested with the AAD kit and with the reference pepsin-HCl digestion method in TM35 instruments. At the NRL, both methods yielded identical qualitative and similar quantitative results independently of the Trichinella species. In the ring trial, satisfactory results were obtained for 47/50 (94.0%) (AAD) and 62/67 (92.5%) (reference method) of the analysed samples. Technical problems impairing analysis were more frequently observed with the AAD kit (n = 22) than with the reference method (n = 5) and were mainly (16/22) reported by one of the external labs. When no technical issues were recorded, the performance of both methods was comparable, in agreement with the observations at the NRL; however, these results suggest a need for further training with the kit and standardisation of the adapted TM35 instruments., (Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.)

Protease-activated receptor 4 (PAR4) mediates sustained thrombin signaling in platelets and is required for a stable thrombus. PAR4 is activated by proteolysis of the N terminus to expose a tethered ligand. The structural basis for PAR4 activation and the location of its ligand binding site (LBS) are unknown. Using hydrogen/deuterium exchange (H/D exchange), computational modeling, and signaling studies, we determined the molecular mechanism for tethered ligand-mediated PAR4 activation. H/D exchange identified that the LBS is composed of transmembrane 3 (TM3) domain and TM7. Unbiased computational modeling further predicted an interaction between Gly48 from the tethered ligand and Thr153 from the LBS. Mutating Thr153 significantly decreased PAR4 signaling. H/D exchange and modeling also showed that extracellular loop 3 (ECL3) serves as a gatekeeper for the interaction between the tethered ligand and LBS. A naturally occurring sequence variant (P310L, rs2227376) and 2 experimental mutations (S311A and P312L) determined that the rigidity conferred by prolines in ECL3 are essential for PAR4 activation. Finally, we examined the role of the polymorphism at position 310 in venous thromboembolism (VTE) using the International Network Against Venous Thrombosis (INVENT) consortium multi-ancestry genome-wide association study (GWAS) meta-analysis. Individuals with the PAR4 Leu310 allele had a 15% reduction in relative risk for VTE (odds ratio, 0.85; 95% confidence interval, 0.77-0.94) compared with the Pro310 allele. These data are consistent with our H/D exchange, molecular modeling, and signaling studies. In conclusion, we have uncovered the structural basis for PAR4 activation and identified a previously unrecognized role for PAR4 in VTE., (© 2020 by The American Society of Hematology.)

Introduction: The use of oxygen is a key component of acute burn resuscitation, particularly when there is concern for carbon monoxide toxicity or inhalation injury. Prior studies of critically-ill patients have shown an association between early hyperoxia and increased mortality. There are no studies to date evaluating outcomes related to excessive oxygen administration in burn patients., Methods: We conducted a retrospective analysis of 219 severely burned patients to quantify the average amount of oxygen given during initial resuscitation, the level of carbon monoxide exposure, and to determine if early exposure to supratherapeutic oxygen was associated with increased hospital mortality or ventilator-associated pneumonia (VAP). The models were adjusted for inhalation injury and total body surface area (TBSA) burned., Results: Early hyperoxia in severely burn patients is common and possibly associated with increased overall mortality, although the results were inconclusive and after adjusting for burn-specific scoring systems, we found a negative correlation between hyperoxia and mortality. Confirmed carbon monoxide poisoning was relatively uncommon, but also associated with increased mortality. Patients with elevated carboxyhemoglobin did not receive more oxygen compared to others within the cohort., Conclusions: Burn patients are exposed to higher concentrations of pure oxygen compared to other critically-ill patients, presumably for empiric treatment of carbon monoxide poisoning. Our data showed a liberal use of oxygen therapy across all patients. Considering the potentially negative effects of hyperoxia, this study exposes either a gap in clinical research or need for clearer indications., (Published by Elsevier Ltd.)

Background: Single ventricle (SV) patients with a Fontan circulation are at risk for functional deterioration. The aim of this study was to assess longitudinal Fontan hemodynamics using serial cardiovascular magnetic resonance (CMR) data and to study the impact of aortopulmonary collateral (APC) flow and type of SV morphology., Methods: Forty-one Fontan patients (age at first CMR 13.4 ± 6.0 years) with two CMR examinations within a time interval of at least 4 years (follow-up 5.3 ± 0.9 years) were included. The protocol consisted of short-axis cine volumetry and 2-dimensional blood flow measurements in the inferior vena cava (IVC), superior vena cava (SVC) and ascending aorta (Ao). APC flow was calculated as Ao - (SVC + IVC). Myocardial strain/strain rate was assessed using feature tracking technique., Results: SV end-diastolic volume (p = 0.14) and ejection fraction (p = 0.70) remained constant. No significant changes in CMR derived myocardial strain/strain rate values were observed. Ao flow decreased (p = 0.01), IVC flow remained unchanged (p = 0.52), while SVC flow (p = 0.003) and APC flow (p = 0.006) decreased significantly. Patients with a systemic right ventricle (RV) showed unchanged APC flow and a further increase in SV size over time compared to patients with a systemic left ventricle., Conclusions: Longitudinal CMR data in a cohort of clinically stable Fontan patients revealed no significant changes in SV dimensions and myocardial performance while APC flow decreased spontaneously. Patients with a systemic RV seem to be at risk for permanent SV volume overload through APCs and might therefore benefit from consequent interventional APC embolization., Competing Interests: Declaration of competing interest The authors declare that they have no conflict of interest., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Transient receptor potential (TRP) channels are cation channels which participate in a wide variety of physiological processes in organisms ranging from fungi to humans. They fulfill roles in body homeostasis, are sensors for noxious chemicals and temperature in the mammalian somatosensory system and are activated by light stimulated phospholipase C activity in Drosophila or by hypertonicity in yeast. The transmembrane topology of TRP channels is similar to that of voltage-gated cation channels. TRP proteins assemble as tetramers with each subunit containing six transmembrane helices (S1-S6) and intracellular N- and C-termini. Here we focus on the emerging functions of the cytosolic S4-S5 linker on TRP channel gating. Most of this knowledge comes from pathogenic mutations within the S4-S5 linker that alter TRP channel activities. This knowledge has stimulated forward genetic approaches to identify additional residues around this region which are essential for channel gating and is supported, in part, by recent structures obtained for TRPV1, TRPV2, TRPV6, TRPA1, and TRPP2., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

The Ca 2+ -selective tetrameric Transient Receptor Potential Vanilloid 6 (TRPV6) channel is an inwardly rectifying ion channel. The constitutive current endures Ca 2+ -induced inactivation as a result of the activation of phospholipase C followed depletion of phosphatidylinositol 4,5-bisphosphate, and calmodulin binding. Replacing a glycine residue within the cytosolic S4-S5 linker of the human TRPV6 protein, glycine 516, which is conserved in all TRP channel proteins, by a serine residue forces the channels into an open conformation thereby enhancing constitutive Ca 2+ entry and preventing inactivation. Introduction of a second mutation (T621A) into TRPV6 G516S reduces constitutive activity and partially rescues the TRPV6 function. According to the recently revealed crystal structure of the rat TRPV6 the T621 is adjacent to the distal end of the transmembrane segment 6 (S6) within a short linker between S6 and the helix formed by the TRP domain. These results indicate that the S4-S5 linker and the S6-TRP-domain linker are critical constituents of TRPV6 channel gating and that disturbance of their sequences foster constitutive Ca 2+ entry., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Cows on an alpine pasture were presented with severe signs of vaginitis. To rule out infection with Tritrichomonas foetus, vaginal swabs were taken and real-time PCR based on detection via fluorescence resonance energy transfer (FRET) probes and targeting the first internal transcribed spacer (ITS-1) of nuclear ribosomal DNA (rDNA) was performed. PCR was positive in 25 of totally 34 assessed cows. However, the melting profiles of the probes targeting the diagnostic PCR products differed from the T. foetus positive control. Subsequent sequencing of the amplicons revealed 91% identity to Simplicimonas sp. sequences deposited in GenBank™. Furthermore, there was no clear association between positive PCR result and presence of vaginitis. To investigate the distribution of this Simplicimonas-like organism in cows, more herds grazing on the same alpine pastures as well as unrelated cows were tested. In total, 133 cows and 16 heifers were sampled, 53 cows and 6 heifers even twice. Vaginitis was evident in 43 cows and 4 heifers. All-over-positivity of PCR was 44%, including nine tests performed on heifers. Melting peak analysis indicated Simplicimonas-like organisms in all positive samples. Culture attempts in bovine InPouch ™ TF failed. No association between a positive PCR result and the presence of vaginitis was found. This is, to the best of our knowledge, the first report on Simplicimonas-like DNA in vaginal swabs of female cattle. Our data suggest that when testing vaginal swabs of cattle by means of T. foetus PCR, false positive reactions due to Simplicimonas-like organisms may occur., (Copyright © 2017 Elsevier B.V. All rights reserved.)

This paper presents the design and evaluation of a minimal order Generalized Minimum Variance controller with long-range prediction horizon and how it affects the controller and plant output variances. This study investigates how the increased prediction horizon can contribute to mitigate stochastic disturbances and attenuate oscillations. In order to design high order prediction minimum variance filters, a design procedure independent of the Diophantine Equation solution is used. The evaluation is conducted through simulations and practical essays with two different plants: a first order water flow rate problem and a second order under-damped electronic circuit. Both problems are assessed under an incremental control scheme and based on identified stochastic models. Also, two optimal tuning procedures for the algorithm are proposed., (Copyright © 2016 ISA. Published by Elsevier Ltd. All rights reserved.)

Differential scanning fluorimetry (DSF) is used to assess protein stability, transition states, or the Kd values of various ligands, drug molecules, and antibodies. All fluorescent probes published to date either are incompatible with hydrophobic proteins/ligands, precluding analyses of transmembrane or membrane-associated proteins, or have excitation and detection wavelengths outside the range of real-time polymerase chain reaction (RT-PCR) machines, necessitating the use of dedicated devices. Here, we describe a thiol-reactive probe, BODIPY FL L-cystine (BFC), to overcome both of these shortcomings. The probe supports an inexpensive application of DSF measurements suitable for detection with standard RT-PCR machines in a hydrophilic or hydrophobic environment., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Osteoporotic proximal femur fractures are caused by low energy trauma, typically when falling on the hip from standing height. Finite element simulations, widely used to predict the fracture load of femora in fall, usually include neither mass-related inertial effects, nor the viscous part of bone׳s material behavior. The aim of this study was to elucidate if quasi-static non-linear homogenized finite element analyses can predict in vitro mechanical properties of proximal femora assessed in dynamic drop tower experiments. The case-specific numerical models of 13 femora predicted the strength (R(2)=0.84, SEE=540N, 16.2%), stiffness (R(2)=0.82, SEE=233N/mm, 18.0%) and fracture energy (R(2)=0.72, SEE=3.85J, 39.6%); and provided fair qualitative matches with the fracture patterns. The influence of material anisotropy was negligible for all predictions. These results suggest that quasi-static homogenized finite element analysis may be used to predict mechanical properties of proximal femora in the dynamic sideways fall situation., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Objectives: To assess inter-observer variability of renal blood oxygenation level-dependent MRI (BOLD-MRI) using a new method of analysis, called the concentric objects (CO) technique, in comparison with the classical ROI (region of interest)-based technique., Methods: MR imaging (3T) was performed before and after furosemide in 10 chronic kidney disease (CKD) patients (mean eGFR 43±24ml/min/1.73m(2)) and 10 healthy volunteers (eGFR 101±28ml/min1.73m(2)), and R2* maps were determined on four coronal slices. In the CO-technique, R2* values were based on a semi-automatic procedure that divided each kidney in six equal layers, whereas in the ROI-technique, all circles (ROIs) were placed manually in the cortex and medulla. The mean R2*values as assessed by two independent investigators were compared., Results: With the CO-technique, inter-observer variability was 0.7%-1.9% across all layers in non-CKD, versus 1.6%-3.8% in CKD. With the ROI-technique, median variability for cortical and medullary R2* values was 3.6 and 6.8% in non-CKD, versus 4.7 and 12.5% in CKD; similar results were observed after furosemide., Conclusion: The CO-technique offers a new, investigator-independent, highly reproducible alternative to the ROI-based technique to estimate renal tissue oxygenation in CKD., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Only 16 XPG-defective patients with 20 different mutations have been described. The current hypothesis is that missense mutations impair repair (xeroderma pigmentosum (XP) symptoms), whereas truncating mutations impair both repair and transcription (XP and Cockayne syndrome (CS) symptoms). We identified three cell lines of XPG-defective patients (XP40GO, XP72MA, and XP165MA). Patients' fibroblasts showed a reduced post-UVC cell survival. The reduced repair capability, assessed by host cell reactivation, could be complemented by XPG cDNA. XPG mRNA expression of XP165MA, XP72MA, and XP40GO was 83%, 97%, and 82.5%, respectively, compared with normal fibroblasts. XP165MA was homozygous for a p.G805R mutation; XP72MA and XP40GO were both compound heterozygous (p.W814S and p.E727X, and p.L778P and p.Q150X, respectively). Allele-specific complementation analysis of these five mutations revealed that p.L778P and p.W814S retained considerable residual repair activity. In line with the severe XP/CS phenotypes of XP72MA and XP165MA, even the missense mutations failed to interact with the transcription factor IIH subunits XPD and to some extent cdk7 in coimmunoprecipitation assays. Immunofluorescence techniques revealed that the mutations destabilized early recruitment of XP proteins to localized photodamage and delayed their redistribution in vivo. Thus, we identified three XPG missense mutations in the I-region of XPG that impaired repair and transcription and resulted in severe XP/CS.

Anthropogenically induced changes to estuaries, including shifts from seagrass to macroalgae-dominated habitats, have led to concerns about the ability of estuaries to support fish and invertebrates. To assess differences in habitat quality of seagrass and macroalgae, we examined faunal community structure and consumer carbon assimilation in adjacent areas of seagrass, macroalgae, and bare sediments in Sage Lot Pond, Waquoit Bay, MA. Vegetation was an important factor controlling abundances, and both seagrass and macroalgae provided suitable habitat for a range of benthic fauna. Differences in consumption and assimilation of carbon of seagrass and macroalgal origin were demonstrated by shifts in δ(13)C values of consumers between the seagrass meadow and adjacent macroalgal mats. Overall, consumers generally reflected incorporation of carbon from the dominant producers in the habitat where they were collected although macroalgae was an important carbon source for organisms in this study. These results revealed differences in carbon flow from producers to consumers across very small spatial scales (<10 m) within an estuary., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Hypoxia of renal medulla is a key factor implicated in the development of drug-induced renal failure. Drugs are known to influence renal hemodynamics and, subsequently, affect renal tissue oxygenation. Changes in renal oxygenation can be assessed non-invasively in humans using blood oxygenation level-dependent magnetic resonance imaging (BOLD-MRI). This study was designed to test the acute effects of administration of specific drugs in healthy human kidney oxygenation using BOLD-MRI. Acute changes in renal tissue oxygenation induced by the non-steroidal anti-inflammatory drug indomethacin, the iodinated radio-contrast media (RCM) iopromidum, and the calcineurin inhibitors cyclosporine micro-emulsion (CsA-ME) and tracrolimus were studied in 30 healthy volunteers. A modified Multi Echo Data Image Combination sequence was used to acquire 12 T(2)(*)-weighted images. Four coronal slices were selected to cover both kidneys. The mean R(2)(*) (1/T(2)(*)) values determined in medulla and cortex showed no significant changes induced by indomethacin and tacrolimus administration. CsA-ME decreased medullary (P=0.008) and cortical (P=0.004) R(2)(*) values 2 h after ingestion. Iopromidum caused a significant increase in medullary R(2)(*) within the first 20 min after injection (P<0.001), whereas no relevant changes were observed in renal cortex. None of the measurements showed left-right kidney differences. Significant differences in renal medullary oxygenation were evidenced between female and male subjects (P=0.013). BOLD-MRI was efficient to show effects of specific drugs in healthy renal tissue. Cyclosporine increased renal medullary oxygenation 2 h after ingestion of a single dose, whereas indomethacin and tacrolimus showed no effect on renal oxygenation. Injection of iodinated RCM decreased renal medullary oxygenation.

The lipophilicity and plasma binding of 16 spirolactones and 4 hydroxy acid analogs were determined. Mathematical expressions were derived to correlate quantitatively the extent of plasma binding to the lipophilicity of the drugs. The nonspecific binding of these spirolactones and their hydroxy acid analogs was also analyzed using purified serum albumin. A computer program was developed to examine the mechanism of drug-serum protein interactions. One class of binding sites was observed for the range of concentrations used. The number of binding sites and the equilibrium binding constant were computed and were sensitive to substitution at the C-6 and C7 positions. Hydrolysis of the C-17 lactone ring in spirolactones to form hydroxy acid analogs resulted in a decrease in the lipophilicity and, hence, the equilibrium constant for binding.