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Abstract Background Pulmonary intravascular thrombus formation has been widely observed in patients with respiratory failure, for example, in patients with SARS-CoV-2 infection (COVID-19). The aim of this study was to evaluate the efficacy/safety of alteplase thrombolysis in COVID-19 severe hypoxemic respiratory failure. In this multicenter, open-label study, patients were randomized to receive alteplase (low- or high-dose) over 5 days plus standard of care (SOC), or SOC alone. The primary endpoint was time to clinical improvement (≥ 2-point decrease on WHO Clinical Progression Scale, or hospital discharge) up to Day 28. Secondary endpoints included all-cause mortality at Day 28, treatment failure at Day 28 and change in arterial oxygen partial pressure/fractional inspired oxygen (PaO2/FiO2) ratio at Day 6 versus baseline. Results Sixty-nine patients were randomized to alteplase (low- or high-dose) and 35 to SOC; 65% were on high-flow oxygen or non-invasive ventilation at baseline. Median time to clinical improvement was 25 days in the alteplase group and > 28 days (median not reached) in the SOC group. All-cause mortality was 8/69 (12%) versus 10/35 (29%) in the alteplase versus SOC groups, respectively (unadjusted risk difference [RD], − 17% [95% confidence interval (CI) − 34 to 0], p = 0.047; adjusted RD, − 16% [95% CI − 31 to 1], p = 0.058). The PaO2/FiO2 ratio (mean [standard deviation]) increased by + 30 (84) mmHg in the alteplase group and decreased by − 12 (59) mmHg in the SOC group (adjusted mean difference vs. SOC, p = 0.052). Differences were greater in patients receiving high-dose alteplase, and in those not receiving invasive ventilation. Eighteen patients (26.1%) in the alteplase group discontinued treatment due to adverse events. Major bleeding was more frequent with alteplase than with SOC (9 vs. 0 patients); no bleeding was fatal. The study closed early due to insufficient patient recruitment. Conclusion Alteplase was not associated with faster clinical recovery from COVID-19 severe hypoxemic respiratory failure. A numerical difference in survival and PaO2/FiO2 ratio was observed, particularly in patients not receiving invasive ventilation. These exploratory findings merit further investigation in larger patient cohorts that are adequately powered to confirm the hypotheses generated in this study regarding the impact of alteplase on treatment outcomes. Trial registration ClinicalTrials.gov: NCT04640194 (November 23, 2020); https://clinicaltrials.gov/study/NCT04640194 (early discontinuation due to insufficient patient recruitment).

Abstract Background Convalescent plasma (CP) reduced the mortality in COVID-19 induced ARDS (C-ARDS) patients treated in the CONFIDENT trial. As patients are immunologically heterogeneous, we hypothesized that clusters may differ in their treatment responses to CP. Methods We measured 20 cytokines, chemokines and cell adhesion markers using a multiplex technique at the time of inclusion in the CONFIDENT trial in patients of centers having accepted to participate in this secondary study. We performed descriptive statistics, unsupervised hierarchical cluster analysis, and examined the association between the clusters and CP effect on day-28 mortality. Results Of the 475 patients included in CONFIDENT, 391 (82%) were sampled, and 196/391 (50.1%) had been assigned to CP. We identified four sub-phenotypes representing 89 (22.8%), 178 (45.5%), 38 (9.7%), and 86 (22.0%) patients. The most contributing biomarkers in the principal component analysis were IL-1β, IL-12p70, IL-6, IFN-α, IL-17A, IFN-γ, IL-13, TFN-α, total IgG, and CXCL10. Sub-phenotype-1 displayed a lower immune response, sub-phenotype-2 a higher adaptive response, sub-phenotype-3 the highest innate antiviral, pro and anti-inflammatory response, and adhesion molecule activation, and sub-phenotype-4 a higher pro and anti-inflammatory response, migration protein and adhesion molecule activation. Sub-phenotype-2 and sub-phenotype-4 had higher severity at the time of inclusion. The effect of CP treatment on mortality appeared higher than standard care in each sub-phenotype, without heterogeneity between sub-phenotypes (p = 0.97). Conclusion In patients with C-ARDS, we identified 4 sub-phenotypes based on their immune response. These sub-phenotypes were associated with different clinical profiles. The response to CP was similar across the 4 sub-phenotypes. Trial registration: Ethics Committee of the University Hospital of Liège CE 2020/239. Clinicaltrials.gov NCT04558476. Registered 2020-09-11, https://www.clinicaltrials.gov/study/NCT04558476 .

This technical letter gives a concise overview of the state-of-the-art in concrete pumping. It outlines the different pump systems, briefly describes the general flow behavior of concrete in pipes, and addresses the main challenges of pumping. It also elaborates upon factors influencing the pumping behavior and how to control the pumping process.

Introduction Lymphoedema is a chronic condition caused by lymphatic insufficiency. It leads to swelling of the limb/midline region and an increased risk of infection. Lymphoedema is often associated with mental and physical problems limiting quality of life. The first choice of treatment is a conservative treatment, consisting of exercises, skin care, lymph drainage and compression. Reconstructive lymphatic surgery is also often performed, that is, lymphovenous anastomoses, lymph node transfer or a combination. However, robust evidence on the effectiveness of reconstructive lymphatic surgery is missing. Therefore, the objective of this trial is to investigate the added value of reconstructive lymphatic surgery to the conservative treatment in patients with lymphoedema.Methods and analysis A multicentre randomised controlled and pragmatic trial was started in March 2022 in three Belgian university hospitals. 90 patients with arm lymphoedema and 90 patients with leg lymphoedema will be included. All patients are randomised between conservative treatment alone (control group) or conservative treatment with reconstructive lymphatic surgery (intervention group). Assessments are performed at baseline and at 1, 3, 6, 12, 18, 24 and 36 months. The primary outcome is lymphoedema-specific quality of life at 18 months. Key secondary outcomes are limb volume and duration of wearing the compression garment at 18 months. The approach of reconstructive lymphatic surgery is based on presurgical investigations including clinical examination, lymphofluoroscopy, lymphoscintigraphy, lymph MRI or CT angiography (if needed). All patients receive conservative treatment during 36 months, which is applied by the patient’s own physical therapist and by the patient self. From months 7 to 12, the hours a day of wearing the compression garment are gradually decreased.Ethics and dissemination The study has been approved by the ethical committees of University Hospitals Leuven, Ghent University Hospital and CHU UCL Namur. Results will be disseminated via peer-reviewed journals and presentations.Trial registration number NCT05064176

Exportcontroleregelgeving laat zich niet meer wegdenken uit de wereld van internationale handel. Het verplicht zakenpartners om na te gaan met wie en hoe men zakendoet. Bij internationale toeleveringsketens zijn de compliance-uitdagingen veel groter dan voor een individuele exporteur, vanwege de steeds uitdijende relaties die in een keten worden aangegaan. Omdat ketenpartners vaak uiteenlopende en tegenstrijdige belangen nastreven, zijn extra prikkels nodig om alle ketenpartijen te overtuigen van het naleven van de regelgeving. Deze prikkels, die theoretisch geduid kunnen worden als “Contract-Boundary Spanning Governance mechanismen’’ (CBSGM) vullen de bestaande regelgeving aan en bieden een houvast om ketenpartijen te prikkelen tot meer compliance-inspanningen. Dit wordt geïllustreerd aan de hand van de complexe toeleveringsketen van de F-35, waar de prikkels de weg voor de Amerikaanse overheid hebben voorbereid om noodzakelijk preventieve en detectieve compliancecontroles uit te voeren.

Perineural anesthesia of the tibial nerve can be performed ultrasound-guided or blindly, with the latter still being commonly used in equine practice due to practical constraints, despite its lower accuracy and hence, common failure to achieve desensitization. This may be associated with anatomical variations or inadequate landmarks for injection. To examine the course of the tibial nerve, document potential anatomical variations, and determine optimal landmarks for perineural injection, dissection was conducted along the medial aspect of the tibia in 10 paired cadaver hindlimbs. No anatomical variations of the tibial nerve were observed. Mean tibial nerve thickness was 6 ± 1 mm. The junction with the plantar nerves was located at a maximum of 85 mm and the junction with the medial cutaneous branch was at a maximum of 150 mm proximal to the proximal aspect of the calcaneal tubercle. The mean distance of the tibial nerve to the cranial border of the superficial digital flexor was 11 ± 6 mm. In conclusion, problems with perineural anesthesia of the tibial nerve cannot simply be attributed to anatomical variations. The thickness of the nerve and the amount of perineural tissue may present specific challenges for achieving adequate desensitization. Our results support the generally recommended site for tibial nerve perineural injection at 100 mm proximal to the calcaneal tubercle and 11 mm cranial to the superficial digital flexor.

In skill acquisition, instructing individuals the stimulus-response mappings indicating how to perform and act, yields better performance. Additionally, performance is helped by repeated practice. Whether providing instructions and repeated practice interact to achieve optimal performance remains debated. This paper addresses that question by analyzing the learning curves of individuals learning stimulus-response mappings of varying complexity. We particularly focus on the question whether instructions lead to improved performance in the longer run. Via evidence accumulation modeling, we find no evidence for this assertion. Instructions seem to provide individuals with a head start, leading to better initial performance in the early stages of learning, without long-lasting effects on behavior. We discuss the results in light of related studies that do report long-lasting effects of instructions, and propose that the complexity of a skill determines whether long-lasting benefits of initial instructions exist.

Abstract Background Ventilator-associated pneumonia caused by Pseudomonas aeruginosa (PA) in hospitalised patients is associated with high mortality. The effectiveness of the bivalent, bispecific mAb MEDI3902 (gremubamab) in preventing PA nosocomial pneumonia was assessed in PA-colonised mechanically ventilated subjects. Methods EVADE (NCT02696902) was a phase 2, randomised, parallel-group, double-blind, placebo-controlled study in Europe, Turkey, Israel, and the USA. Subjects ≥ 18 years old, mechanically ventilated, tracheally colonised with PA, and without new-onset pneumonia, were randomised (1:1:1) to MEDI3902 500, 1500 mg (single intravenous dose), or placebo. The primary efficacy endpoint was the incidence of nosocomial PA pneumonia through 21 days post-dose in MEDI3902 1500 mg versus placebo, determined by an independent adjudication committee. Results Even if the initial sample size was not reached because of low recruitment, 188 subjects were randomised (MEDI3902 500/1500 mg: n = 16/87; placebo: n = 85) between 13 April 2016 and 17 October 2019. Out of these, 184 were dosed (MEDI3902 500/1500 mg: n = 16/85; placebo: n = 83), comprising the modified intent-to-treat set. Enrolment in the 500 mg arm was discontinued due to pharmacokinetic data demonstrating low MEDI3902 serum concentrations. Subsequently, enrolled subjects were randomised (1:1) to MEDI3902 1500 mg or placebo. PA pneumonia was confirmed in 22.4% (n = 19/85) of MEDI3902 1500 mg recipients and in 18.1% (n = 15/83) of placebo recipients (relative risk reduction [RRR]: − 23.7%; 80% confidence interval [CI] − 83.8%, 16.8%; p = 0.49). At 21 days post-1500 mg dose, the mean (standard deviation) serum MEDI3902 concentration was 9.46 (7.91) μg/mL, with 80.6% (n = 58/72) subjects achieving concentrations > 1.7 μg/mL, a level associated with improved outcome in animal models. Treatment-emergent adverse event incidence was similar between groups. Conclusions The bivalent, bispecific monoclonal antibody MEDI3902 (gremubamab) did not reduce PA nosocomial pneumonia incidence in PA-colonised mechanically ventilated subjects. Trial registration Registered on Clinicaltrials.gov ( NCT02696902 ) on 11th February 2016 and on EudraCT ( 2015-001706-34 ) on 7th March 2016.

Abstract The microbial rearing quality influences the survival of marine larvae. Microbially matured water treatment systems (MMS) provide a more favourable rearing water microbiome than flow-through systems (FTS). It has previously been hypothesised, but not investigated, that initial rearing in MMS leaves a protective legacy effect in Atlantic cod larvae (Gadus morhua). We tested this hypothesis through a crossover 2 × 2 factorial experiment varying the rearing water treatment system (MMS vs FTS) and the microbial carrying capacity (+ /− added organic matter). At 9 days post-hatching, we switched the rearing water treatment system. By comparing switched and unswitched rearing tanks, we evaluated if legacy effects had been established in the larvae or their surrounding rearing water bacterial community. We analysed the bacterial communities with flow cytometry and 16S rRNA gene sequencing. We found no evidence that the initial rearing condition left a legacy effect in the communities by evaluating the bacterial community diversity and structure. Instead, the present rearing condition was the most important driver for differences in the rearing water microbiota. Furthermore, we found that MMS with high microbial carrying capacity appeared to seed a stable bacterial community to the rearing tanks. This finding highlights the importance of keeping a similar carrying capacity between the inlet and rearing water. Moreover, we reject the hypothesis that the initial rearing condition leaves a protective legacy effect in larvae, as the larval survival and robustness were linked to the present rearing condition. In conclusion, our results highlight the importance of maintaining a beneficial microbial rearing environment from hatching and throughout the larval rearing period.

Bibliotherapy is the use of reading supplements as a form of therapy and children with autism are a population that could benefit significantly from the implementation of such treatment. Board-Certified Behavior Analysts (BCBA) are instrumental in creating a curriculum to shape the behavior of those with autism. This study surveyed BCBAs throughout the United States on their use and knowledge of bibliotherapy, as well as different practices related to its utilization. Overall, 89 BCBAs responded to the survey. Results revealed that BCBAs who used bibliotherapy did not have previous knowledge of the practice. BCBAs who did implement bibliotherapy did not have formal training. Further research is necessary to better understand bibliotherapy as a potential resource for children with autism.

Recent findings have shown an inverse association between circulating C15:0/C17:0 fatty acids with disease risk, therefore, their origin needs to be determined to understanding their role in these pathologies. Through combinations of both animal and human intervention studies, we comprehensively investigated all possible contributions of these fatty acids from the gut-microbiota, the diet, and novel endogenous biosynthesis. Investigations included an intestinal germ-free study and a C15:0/C17:0 diet dose response study. Endogenous production was assessed through: a stearic acid infusion, phytol supplementation, and a Hacl1-/- mouse model. Two human dietary intervention studies were used to translate the results. Finally, a study comparing baseline C15:0/C17:0 with the prognosis of glucose intolerance. We found that circulating C15:0/C17:0 levels were not influenced by the gut-microbiota. The dose response study showed C15:0 had a linear response, however C17:0 was not directly correlated. The phytol supplementation only decreased C17:0. Stearic acid infusion only increased C17:0. Hacl1-/- only decreased C17:0. The glucose intolerance study showed only C17:0 correlated with prognosis. To summarise, circulating C15:0 and C17:0 are independently derived; C15:0 correlates directly with dietary intake, while C17:0 is substantially biosynthesized, therefore, they are not homologous in the aetiology of metabolic disease. Our findings emphasize the importance of the biosynthesis of C17:0 and recognizing its link with metabolic disease.

Simple Summary: Perineural anesthesia of the tibial nerve can be performed ultrasound-guided or blindly, with the latter still being commonly used in equine practice due to practical constraints, despite its lower accuracy and hence, its common failure to achieve desensitization. This may be associated with anatomical variations or inadequate landmarks for injection. In this anatomical study on the course of the tibial nerve on paired cadaveric limbs, we found that problems with perineural anesthesia cannot simply be attributed to anatomical variations. The large diameter of the tibial nerve (6 ± 1 mm) and the substantial amount of perineural tissue may present specific challenges for achieving adequate desensitization. Regarding landmarks, this study confirms that perineural injection should be performed 10 cm proximal to the proximocranial aspect of the calcaneal tubercle and 11 mm cranial to the superficial digital flexor. Perineural anesthesia of the tibial nerve can be performed ultrasound-guided or blindly, with the latter still being commonly used in equine practice due to practical constraints, despite its lower accuracy and hence, common failure to achieve desensitization. This may be associated with anatomical variations or inadequate landmarks for injection. To examine the course of the tibial nerve, document potential anatomical variations, and determine optimal landmarks for perineural injection, dissection was conducted along the medial aspect of the tibia in 10 paired cadaver hindlimbs. No anatomical variations of the tibial nerve were observed. Mean tibial nerve thickness was 6 ± 1 mm. The junction with the plantar nerves was located at a maximum of 85 mm and the junction with the medial cutaneous branch was at a maximum of 150 mm proximal to the proximal aspect of the calcaneal tubercle. The mean distance of the tibial nerve to the cranial border of the superficial digital flexor was 11 ± 6 mm. In conclusion, problems with perineural anesthesia of the tibial nerve cannot simply be attributed to anatomical variations. The thickness of the nerve and the amount of perineural tissue may present specific challenges for achieving adequate desensitization. Our results support the generally recommended site for tibial nerve perineural injection at 100 mm proximal to the calcaneal tubercle and 11 mm cranial to the superficial digital flexor. [ABSTRACT FROM AUTHOR]

Background: COVID-19 restrictive measures have had a considerable impact on daily life routines, which may be especially challenging for families of children with autism. In pre-schoolers with autism, it is likely that the disruption of routines mainly impacts the presence of restrictive and repetitive behaviours (RRBs). Furthermore, influence of comorbid conditions, secondary behavioural difficulties and home environment characteristics on RRBs was explored. Method: A cross-sectional online survey design was used to collect parent-report data on 254 children with autism (2.5–6 years) during lockdown in the early months of the pandemic. RRBs were assessed using the Repetitive Behaviour Scale-Revised (RBS-R). Results: Parents reported a significant increase in stereotypic, self-injurious, compulsive and ritualistic behaviour, and restricted interests after implementation of COVID-19 restrictions. The presence of a co-occurring condition, such as language impairments or intellectual disability, was associated with more self-injurious and stereotypic behaviour. However, there was no effect of home environment on RRBs. Further, most children showed increases in internalising and/or externalising behaviour. Increased inattentive behaviour was associated with more ritualistic and stereotypic behaviour, and restricted interests. Decreases in hyperactivity were related to more restricted interests. Importantly, in a subset of children, parents reported less behavioural difficulties during the lockdown. Conclusions: Findings highlight the importance of flexible implementation and continuity of care for pre-schoolers with autism and support for parents. Further follow-up of children with autism and RRBs, and co-occurring behavioural difficulties is needed and could enhance our understanding of the long-term effects associated with sudden restrictive measures to daily routines.