Background Trials comparing early and delayed strategies of renal replacement therapy in patients with severe acute kidney injury may have missed differences in survival as a result of mixing together patients at heterogeneous levels of risks. Our aim was to evaluate the heterogeneity of treatment effect on 60-day mortality from an early vs a delayed strategy across levels of risk for renal replacement therapy initiation under a delayed strategy. Methods We used data from the AKIKI, and IDEAL-ICU randomized controlled trials to develop a multivariable logistic regression model for renal replacement therapy initiation within 48 h after allocation to a delayed strategy. We then used an interaction with spline terms in a Cox model to estimate treatment effects across the predicted risks of RRT initiation. Results We analyzed data from 1107 patients (619 and 488 in the AKIKI and IDEAL-ICU trial respectively). In the pooled sample, we found evidence for heterogeneous treatment effects ( P = 0.023). Patients at an intermediate-high risk of renal replacement therapy initiation within 48 h may have benefited from an early strategy (absolute risk difference, − 14%; 95% confidence interval, − 27% to − 1%). For other patients, we found no evidence of benefit from an early strategy of renal replacement therapy initiation but a trend for harm (absolute risk difference, 8%; 95% confidence interval, − 5% to 21% in patients at intermediate-low risk). Conclusions We have identified a clinically sound heterogeneity of treatment effect of an early vs a delayed strategy of renal replacement therapy initiation that may reflect varying degrees of kidney demand-capacity mismatch.
Background: Intermittent hemodialysis (IHD) and continuous renal replacement therapy (CRRT) are the two main RRT modalities in patients with severe acute kidney injury (AKI). Meta-analyses conducted more than 10 years ago did not show survival difference between these two modalities. As the quality of RRT delivery has improved since then, we aimed to reassess whether the choice of IHD or CRRT as first modality affects survival of patients with severe AKI. Methods: This is a secondary analysis of two multicenter randomized controlled trials (AKIKI and IDEAL-ICU) that compared an early RRT initiation strategy with a delayed one. We included patients allocated to the early strategy in order to emulate a trial where patients would have been randomized to receive either IHD or CRRT within twelve hours after the documentation of severe AKI. We determined each patient's modality group as the first RRT modality they received. The primary outcome was 60-day overall survival. We used two propensity score methods to balance the differences in baseline characteristics between groups and the primary analysis relied on inverse probability of treatment weighting. Results: A total of 543 patients were included. Continuous RRT was the first modality in 269 patients and IHD in 274. Patients receiving CRRT had higher cardiovascular and total-SOFA scores. Inverse probability weighting allowed to adequately balance groups on all predefined confounders. The weighted Kaplan-Meier death rate at day 60 was 54·4% in the CRRT group and 46·5% in the IHD group (weighted HR 1·26, 95% CI 1·01-1·60). In a complementary analysis of less severely ill patients (SOFA score: 3-10), receiving IHD was associated with better day 60 survival compared to CRRT (weighted HR 1.82, 95% CI 1·01-3·28; p < 0.01). We found no evidence of a survival difference between the two RRT modalities in more severe patients. Conclusion: Compared to IHD, CRRT as first modality seemed to convey no benefit in terms of survival or of kidney recovery and might even have been associated with less favorable outcome in patients with lesser severity of disease. A prospective randomized non-inferiority trial should be implemented to solve the persistent conundrum of the optimal RRT technique.
In European and many African, Middle Eastern and southern Asian populations, lactase persistence (LP) is the most strongly selected monogenic trait to have evolved over the past 10,000 years1. Although the selection of LP and the consumption of prehistoric milk must be linked, considerable uncertainty remains concerning their spatiotemporal configuration and specific interactions2,3. Here we provide detailed distributions of milk exploitation across Europe over the past 9,000 years using around 7,000 pottery fat residues from more than 550 archaeological sites. European milk use was widespread from the Neolithic period onwards but varied spatially and temporally in intensity. Notably, LP selection varying with levels of prehistoric milk exploitation is no better at explaining LP allele frequency trajectories than uniform selection since the Neolithic period. In the UK Biobank4,5 cohort of 500,000 contemporary Europeans, LP genotype was only weakly associated with milk consumption and did not show consistent associations with improved fitness or health indicators. This suggests that other reasons for the beneficial effects of LP should be considered for its rapid frequency increase. We propose that lactase non-persistent individuals consumed milk when it became available but, under conditions of famine and/or increased pathogen exposure, this was disadvantageous, driving LP selection in prehistoric Europe. Comparison of model likelihoods indicates that population fluctuations, settlement density and wild animal exploitation—proxies for these drivers—provide better explanations of LP selection than the extent of milk exploitation. These findings offer new perspectives on prehistoric milk exploitation and LP evolution. Examination of archaeological pottery residues and modern genes suggest that environmental conditions, subsistence economics and pathogen exposure may explain selection for lactase persistence better than prehistoric consumption of milk.
INTRODUCTION The 3D integrated circuit technology, which smooths out the massive increase in transistors on a chip by stacking numerous silicon layers vertically, is quickly becoming a revolutionary technology. Thermal issues are more relevant for 3D Network-on-Chip (NoC) systems than their 2D counterparts. METHOD This paper presents a novel Vertically-Partially-Connected 3D-Network on-chip architecture that reduces the total length of interconnects and reduces the number of 3D routers. We also present an efficient XYZ routing technique for thermal management. The proposed algorithm distributes traffic based on the number of layers and congestion to achieve chip heat balancing, avoid high peak temperatures, improve average packet latency, and extending chip service life. RESULT Simulation results showed that the routing technique reduces the peak temperature of the chip by an average of 17 C° compared to the exiting routing algorithms, with minimized negative impact on performance CONCLUSION Furthermore, the Vertically-Partially-Connected 3D-Network on-chip implemented in this study using VHDL exhibits improved area occupation by reducing the number of employed LUT in the FPGA compared to previous works.
Five isostructural microporous supramolecular architectures prepared by H‐bonded assembly between the hexa‐anionic complex [Zr 2 (Ox) 7 ] 6‐ (Ox = oxalate, (C 2 O 4 ) 2‐ ) and tripodal cations (H 3 ‐TripCH 2 ‐R) 3+ with R = H, CH 3 , OH and OBn (Bn = CH 2 Ph) are reported. The possibility to obtain the same structure using a mixture of tripodal cations with different R group (R = OH and R = CH 3 ) has also been successfully explored, providing a unique example of three‐component H‐bonded porous framework. The resulting SPA‐1(R) materials feature 1D pores decorated by R groups, with apparent pore diameters ranging from 3.0 to 8.5 Å. Influence of R groups on the sorption properties of these materials is evidenced through CO 2 and H 2 O vapor sorption/desorption experiments, as well as with I 2 capture/release experiments in liquid media. This study is one of the first to demonstrate the possibility of tuning the porosity and exerting precise control over the chemical functionalization of the pores in a given H‐bonded structure, without modifying the topology of the reference structure, and thus finely adjusting the sorption characteristics of the material.
Background: Atherosclerotic cardiovascular disease is the main cause of mortality worldwide and is strongly influenced by circulating low-density lipoprotein (LDL) cholesterol levels. Only a few genes causally related to plasma LDL cholesterol levels have been identified so far, and only 1 gene, ANGPTL3, has been causally related to combined hypocholesterolemia. Here, our aim was to elucidate the genetic origin of an unexplained combined hypocholesterolemia inherited in 4 generations of a French family. Methods: Using next-generation sequencing, we identified a novel dominant rare variant in the LIPC gene, encoding for hepatic lipase, which cosegregates with the phenotype. We characterized the impact of this LIPC-E97G variant on circulating lipid and lipoprotein levels in family members using nuclear magnetic resonance-based lipoprotein profiling and lipidomics. To uncover the mechanisms underlying the combined hypocholesterolemia, we used protein homology modeling, measured triglyceride lipase and phospholipase activities in cell culture, and studied the phenotype of APOE*3.Leiden.CETP mice after LIPC-E97G overexpression. Results: Family members carrying the LIPC-E97G variant had very low circulating levels of LDL cholesterol and high-density lipoprotein cholesterol, LDL particle numbers, and phospholipids. The lysophospholipids/phospholipids ratio was increased in plasma of LIPC-E97G carriers, suggestive of an increased lipolytic activity on phospholipids. In vitro and in vivo studies confirmed that the LIPC-E97G variant specifically increases the phospholipase activity of hepatic lipase through modification of an evolutionarily conserved motif that determines substrate access to the hepatic lipase catalytic site. Mice overexpressing human LIPC-E97G recapitulated the combined hypocholesterolemic phenotype of the family and demonstrated that the increased phospholipase activity promotes catabolism of triglyceride-rich lipoproteins by different extrahepatic tissues but not the liver. Conclusions: We identified and characterized a novel rare variant in the LIPC gene in a family who presents with dominant familial combined hypocholesterolemia. This gain-of-function variant makes LIPC the second identified gene, after ANGPTL3, causally involved in familial combined hypocholesterolemia. Our mechanistic data highlight the critical role of hepatic lipase phospholipase activity in LDL cholesterol homeostasis and suggest a new LDL clearance mechanism.
Background Clinical trials are the cornerstone of drug evaluation but are difficult to perform in children since obtaining written informed consent from both parents is very challenging. We aimed to identify determinants of parents’ decision whether or not to enrol their child in a clinical trial. Methods A Grounded Theory qualitative approach was used, based on semi-structured interviews with parents who had to give their consent to enrol their child some years before in the TOSCANE study, evaluating the occurrence of chorioretinitis. An interview guide based on bibliographic references, expert consultations and work meetings with the TOSCANE investigators was used during video interviews, conducted until saturation was reached. Interviews were audio-recorded, transcribed anonymously into text format, and double coded before analysis. Results Between April 2020 and April 2021, 18 interviews (nine consenting and nine non-consenting parents) were conducted. Saturation was reached after 16 interviews. The important determinants of parents’ decision, already described in the literature and which could result either in consent or refusal, were: investigator perceived to be human and competent, parents’ personality, parents’ working in healthcare, strong preference for one of the treatment groups, good health of the child, opinions regarding research. New determinants, such as mothers’ guilt about toxoplasmosis transmission, were identified and mostly associated with non-consent. Conclusion Parents' decisions depend on a set of determinants related to family history, personality, and perception of the disease and research, none of them predominating. These determinants suggest that a patient-centred approach could be adopted along with the adequate training of investigators, which requires future assessment.
Background : Caveolae are invaginated plasma membrane domains of 50-100 nm in diameter involved in many important physiological functions in cells. They are composed of different proteins, including the membrane-embedded caveolins and the peripheric cavins. Caveolin-1 has already been expressed in various expression systems ( E. coli, insect cells, Toxoplasma gondii, cell-free system), generating intracellular caveolin-enriched vesicles in E. coli , insect cells and T. gondii . These systems helped to understand the protein insertion within the membrane and its oligomerization. There is still need for fundamental insights into the formation of specific domains on membrane, deformation of a biological membrane driven by caveolin-1, the organization of a caveolar coat, and the requirement of specific lipids and proteins during the process. The aim of this study was to test whether the heterologously expressed caveolin-1β was able to induce the formation of intracellular vesicles within a Gram ⁺ bacterium, Lactococcus lactis , since it displays a specific lipid composition different from E. coli and appears to emerge as a good alternative to E. coli for efficient overexpression of various membrane proteins. Results: Recombinant bacteria transformed with the plasmid pNZ-HTC coding for the canine isoform of caveolin-1β has been shown to produce caveolin-1β, under its functional oligomeric form, at a high expression level unexpected for an eukaryotic membrane protein. Electron microscopy revealed several intracellular vesicles from 30 to 60 nm, a size comparable to E. coli h-caveolae, beneath the plasma membrane of the overexpressing bacteria, showing that caveolin-1β is sufficient to induce membrane vesiculation. Immunolabelling studies showed antibodies on such neo-formed intracellular vesicles, but none on plasma membrane. Density gradient fractionation allowed the correlation between detection of oligomers on Western blotting and appearance of vesicles measurable by DLS, showing the requirement of caveolin-1β oligomerization for vesicle formation. Conclusion: These caveolin-1β enriched intracellular neo-formed vesicles might be useful for potential co-expression of membrane proteins of pharmaceutical interest for their simplified functional characterization.
This article focuses on the experiences of social care workers during the first wave of the Covid pandemic. The method involved analyzing diaries kept by 65 professionals in 8 French regions during the first lockdown in France in spring 2020. As a form of non-binding, narrative expression, keeping diaries breaks with traditional models of reporting common in social care structures and allowed professionals to reflect on the experience as it was lived. In the diaries, professionals explored how the crisis disrupted and challenged their personal and professional values but also allowed innovation in care practices for vulnerable populations that will continue beyond the pandemic period. Five care values were put to forefront by professionals: 1) spontaneity/flexibility; 2) respect for persons; 3) team reflexivity; 4) innovation; 5) solidarity. Mobilizing philosopher Paul Ricoeur’s ideas on recognition, Payet and Laforgue’s analysis of weak actors, as well as research on moral distress, we discuss how these values were tested during the crisis and what effect they had on professionals’ and users’ vulnerabilities. We will also elaborate the interest of keeping account of social care work through narrative methods.
Background The use of oxaliplatin in digestive tract cancers could induce severe peripheral neuropathy (OIPN) decreasing the quality of life of patients and survivors. There is currently, no univocal treatment for these peripheral neuropathies. Donepezil, a reversible inhibitor of cholinesterase, used to treat Alzheimer’s disease and dementia, is reported to have a good safety profile in humans, and preclinical data have provided initial evidence of its effectiveness in diminishing neuropathic symptoms and related comorbidities in OIPN animal models. Methods The DONEPEZOX trial will be a proof-of-concept, randomised, triple-blinded, and multicentre study. It will be the first clinical trial evaluating the efficacy and safety of donepezil for the management of OIPN. Adult cancer survivors with OIPN that report sensory neuropathy according to QLQ-CIPN20 sensory score (equivalence of a grade ≥ 2), at least 6 months after the end of an oxaliplatin-based chemotherapy will be included. Eighty patients will be randomly assigned to receive either donepezil or placebo over 16 weeks of treatment. The primary endpoint will be the rate of responders (neuropathic grade decreases according to the QLQ-CIPN20 sensory score) in the donepezil arm. The severity of OIPN will be assessed by the QLQ-CIPN20 sensory scale before and after 16 weeks of treatment. The comparison versus the placebo arm will be a secondary objective. The other secondary endpoints will be tolerance to donepezil, the severity and features of OIPN in each arm before and after treatment, related-comorbidities and quality of life. Fleming’s one-stage design will be used for sample size estimation. This design yields a type I error rate of 0.0417 and power of 91% for a responder rate of at least 30% in donepezil arm. A total of 80 randomized patients is planned. Discussion This study will allow, in the case of positive results, to initiate a phase 3 randomized and placebo-controlled (primary endpoint) clinical study to assess the therapeutic interest of donepezil to treat OIPN. Trial registration NCT05254639, clincialtrials.gov, Registered 24 February 2022.
Brain connectivity-based methods are efficient and reliable for assessing the mental workload during high task demands as the human brain is functionally interconnected during any psychological task. On the other hand, the graph theory approach is a mathematical study that draws the pairwise relationships between objects. This paper covers the deployment of graph theory concepts on the brain connectivity methods to find the complex underlying behaviors of the brain in the simplest way. Furthermore, in this work, mental workload assessments on multimedia animations were performed using a brain connectivity approach based on partial directed coherence (PDC) with graph theory analysis. Electroencephalography (EEG) data were collected from 34 adult participants at baseline and during multimedia learning tasks. The results revealed that the EEG-based connectivity approach with graph theory offers more promising results than the traditional feature extraction techniques. The connectivity approach achieved an accuracy of 85.77% in comparison with the 78.50% accuracy achieved by the existing feature extraction techniques. It is concluded that the proposed PDC method with graph theory network analysis is a better solution for cognitive load assessment during any cognitive task.
Language and thought are intimately related: philosophers have long debated how a given language may condition the oral and written expression of thought. The language chosen to communicate scientific discoveries may facilitate or impede international access to such knowledge. Vector and message may become intertwined in ways not yet fully understood: comparing and contrasting dictionary definitions of key terms, such as the Humboldtian Weltansicht, may provide useful insights into this process. Semantic prosody, a linguistic phenomenon brought to light by corpus linguistics through the analysis of ever vaster corpora, may have unsuspected and even unconscious impacts on the perception of a message. A case study of data from WebsTerre, a diachronic corpus of geological English, explores a twentieth-century Kuhnian paradigm shift in Earth Science, from continental drift to plate tectonics, to demonstrate how interactions between semantic prosody and translation have the potential to alter the history of science.
Bear time records, which are the accumulations of spatial spectrum estimates on the time axis, are often employed for passive sonar information processing. Multi-target jamming is a common difficulty in this approach due to the constraints of Rayleigh limit, and neither the conventional beamforming (CBF) nor minimum variance distortionless response (MVDR) technique can handle it well. This work presents a post-processing tracking framework based on visual pattern recognition algorithms to track weak acoustic targets within jamming environments, which includes target motion analysis, matched filtering, and principal component analysis-based denoising, and we call this ’P-Gabor’ algorithm. The simulations and sea-trial experiments show that the proposed method can track a weak target successfully under −23 dB (signal-to-interference ratio) SIR, which is more effective than the references, especially in terms of using real-world data from sea trials. We further demonstrate that the method also has stable tracking performance at even −25 dB SNR (signal-to-noise ratio) circumstances.
Backgrounds: PLA has limited uses for moist and acidic foods due to its barrier properties which are fairly poor and its sensitivity to moisture. Results: Deposition of thin coatings based on natural biopolymers (gelatin) incorporating bioactive agents allowed to develop active packaging materials while keeping their biodegradability and the food contact allowance. Gelatin coatings containing two phenolic acids (tannic and gallic) have been tested. These coated PLA films displayed a reduction of the moisture permeability and a slight modification of the thermal properties of PLA. Antioxidant properties of films, their release kinetics in a simulant medium have been studied and modelled. Conclusions: Incorporation of the phenolic acids induced interactions with the gelatin that modified the structure of the network which positively affects the retention, diffusivity and transfer rate of the bioactive compounds when coated-PLA films were in contact to the liquid simulant. This article is protected by copyright. All rights reserved.
We report the high capacity of recycling of a technologically simple, easily recoverable, Ru@Fe 3 O 4 magnetic nanocatalyst, efficient in the release of H 2 from ammonia‐borane (AB) solvolysis, using H 2 O or methanol at room temperature (25 °C). The initially oxidized Ru small nanoparticles (2‐4 nm) are well‐dispersed on an iron oxide support ( i. e. super paramagnetic iron oxide of spinel structure, SPIO, as aggregates of 20 nm to a few μm). As nanocatalyst, this composite achieved short‐time (<10 min) AB full hydrolysis (3 equiv H 2 , no NH 3 , [AB] = 0.1 mol L ‐1 ) with a turnover frequency (TOF) of ca 20 min –1 . The post‐catalysis characterization of the composite showed the formation of well‐defined crystalline hcp Ru(0) dispersed on the SPIO. The activity for full H 2 release from AB is conserved over ten cycles, which is among the most effective recycling processes reported to date (a magnetic recycling is achieved in <2 min). Pleasingly, an even superior activity was found in the more challenging AB methanolysis, with a TOF up to ca 30 min –1 for full H 2 release, achieved in a recycling process repeated over 8 cycles.
In mountains, habitat mosaics, such as those found at the upper limit of coniferous forests in temperate regions, host relatively high avian diversity. In European mountains in particular, open habitat bird species are threatened by a decrease in agro-pastoral activities and by global warming. Snow avalanches act as a natural agent of disturbance that maintains open habitats and thus may contribute to habitat heterogeneity at elevations below the treeline. Using the Rock Bunting Emberiza cia as a study species, we assessed the suitability of avalanche tracks as refuges for ecotone and semi-open habitat bird species. We studied habitat associations and other environmental factors that affect the species’ occurrence based on data from point counts and habitat surveys carried out in the Alps. Rock Bunting presence was greater on avalanche tracks than in adjacent habitats at lower elevations. habitats with high Rock Bunting presence were characterised by a shrubby mosaic that was more open than the surrounding forest. There was no difference between avalanche tracks and control points at the treeline. Rock Bunting densities at avalanche tracks in the forest were similar to those in the treeline and the alpine belt, thus showing that avalanches create an ecotone habitat equivalent to the treeline at lower elevations. Rock Buntings used grassy habitats that had an intermediate rock cover, with patches of shrubs inside gullies. This optimal habitat probably provides nest sites that minimise exposure to predators whilst being close to patches of grass that provide foraging habitat. In a context of climate change, where avalanche activity might increase due to later snowfalls in spring, habitat mosaics created by this type of disturbance could play a fundamental role in the conservation of semi-open habitat bird species in the Alps.
Aim: Stratification of colon cancer (CC) of patients with stage II and III for risk of relapse is still needed especially to drive adjuvant therapy administration. Our study evaluates the prognostic performance of two known biomarkers, CDX2 and CD3, standalone or their combined information in stage II and III CC. Patients and methods: CDX2 and CD3 expression was evaluated in Prodige-13 study gathering 443 stage II and 398 stage III primary CC on whole slide colectomy. We developed for this study an H-score to quantify CDX2 expression and used our artificial intelligence (AI)-guided tissue analysis ColoClass to detect CD3 in tumour core and invasive margin. Association between biomarkers and relapse-free survival was investigated. Results: Univariate analysis showed that the combined variable CD3-TC and CD3-IM was associated with prognosis in both stage II and stage III. CDX2, on the contrary, was associated with prognosis only in stage III. We subsequently associated CDX2 and combined immune parameters only in stage III. This multivariate analysis allowed us to distinguish a proportion of stage III CC harbouring a high CDX2 expression and a high immune infiltration with a particularly good prognosis compared to their counterpart. Conclusion: This study validated the prognostic role of CDX2 and CD3 evaluated with immunohistochemistry procedures in stage III but not in stage II. This association would be conceivable in a routine pathology laboratory and could help oncologist to consider chemotherapy de-escalation for a part of stage III patients.
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