The main aim of this paper is to present the feasibility of rigorously designed multiple N-of-1 design in prosthetics research. While research of adequate power and high quality is often lacking in ...rehabilitation, N-of-1 trials can offer a feasible alternative to randomized controlled group trials, both increasing design power at group level and allowing a rigorous, statistically confirmed evaluation of effectiveness at a single patient level. The paper presents a multiple N-of-1 trial protocol, which aim is to evaluate the effectiveness of Unity, a prosthetic add-on suspension system for amputees, on patient-reported comfort during daily activities (main outcome measure), prosthesis wearing time, perception of limb-prosthesis fitting and stump volume and functional walking parameters.
Multicenter, randomized, prospective, double-blind multiple N-of-1 trial using an introduction/withdrawal design alternating Unity connected/disconnected phases of randomized length on twenty patients with unilateral transtibial amputation. The primary outcome measure is the Prosthetic Socket Comfort Score (SCS), a validated measure of comfort, administered daily by an phone app designed for the study. Secondary outcomes measures will be collected during the 50 days period of the N-of-1 trial: (1) by the same app, daily for patient-reported limb-prosthesis fitting, stump volume variation, and daily wearing time of the prosthesis; (2) by a pedometer for the number of steps per day; (3) by blind assessors in the rehabilitation center during adjustment visits for functional walking parameter (L-Test, 6-minute walk test), and by the patient for the QUEST, and ABC-S. Effectiveness of the Unity system regarding SCS and daily secondary outcome measures will be tested by randomization test. The secondary outcome measures assessed during visits in the rehabilitation center will be analyzed by Non Overlap of All pairs. An estimate of the effect on the amputee population will be generated by aggregating each individual clinical trial (N-of-1 trial) by Hierarchical Bayesian methods.
This study protocol was designed to answer the question "which device is best for THIS patient" and to conclude at a group level on the effectiveness of a new devic, using a Multiple N-of-1 trial, which is promising but underused in prosthetics research so far.
N° ID-RCB 2020-A01309-30 Clintrial.gov : NCT04804150 - Retrospectively registered March 20th 2021.
Diagnosing house dust mite (HDM) allergic rhinitis is difficult. The nasal provocation test (NPT) has been shown to be the most pertinent, but several methods are available. According to guidelines, ...the NPT requires a skin end-point titration and an objective measurement of nasal patency. Hence, NPT is time consuming and its use is limited.
To evaluate the sensitivity, specificity, and safety of a new, more rapid, and simple alternative NPT (NPT-R) to HDM.
Eighty-eight patients with from rhinitis (49 allergic to HDM and 39 controls with and without atopy) were included. Allergic rhinitis to HDM was confirmed by a "classic" NPT based on the Lebel score and rhinomanometry. After a period of 4 weeks, NPT-R was performed and only the clinical score was measured.
The study population was young (mean ± SD, 27.7 ± 8.5 years old), composed mostly of women (61 vs 27 men), and 24% reported asthma. The sensitivity and specificity of NPT-R were 83.7% and 100%, respectively. The correlation between the NPTs was statistically significant (0.833, P < .0001, n = 88) and the 2 NPTs were completely safe. Performing NPT-R was more rapid (mean ± SD, 22 ± 8 minutes) than the classic NPT (97 ± 20 minutes).
The NPT-R is safe and easier and faster than the classic NPT. This new method appears to be a very useful tool in the diagnosis of HDM allergic rhinitis when the diagnosis is uncertain or before initiating immunotherapy.
ClinicalTrials.gov, identifier NCT01485523.
Unfractionated heparin (UFH) is used as an anticoagulant during the atrial fibrillation (AF) ablation procedure to prevent the occurrence of thromboembolic events. Guidelines recommend an activated ...clotting time (ACT) greater than 300 s (s) based on studies of patients treated with vitamin K antagonist (VKA) for their AF. However, direct oral anticoagulants (DOACs) have supplanted VKAs in AF and are now used as first-line therapy. It is recommended not to interrupt them during the procedure, which could interfere with the ACT measures.
To assess the real-life relationship between ACT, DOAC concentrations, and UFH anti-Xa activity in patients treated by uninterrupted DOAC therapy.
We conducted a single-center retrospective study. We analyzed consecutive patients with AF who underwent catheter ablation under DOAC therapy.
In total, 40 patients were included, including 15 (37.5%), 20 (50.0%), and 5 (12.5%) on rivaroxaban, apixaban, and dabigatran, respectively. Baseline ACT was significantly lower in the apixaban group. ACT was linearly correlated with the residual concentration of apixaban and dabigatran but not with rivaroxaban. After UFH injection, ACT was linearly correlated with the anti-Xa activity, regardless of DOAC. Patients in the apixaban group received a higher total dose of UFH during the procedure to achieve a target ACT > 300 s, which resulted in significantly higher anti-Xa activity during the procedure.
Our results raise the question of optimal management of intra-procedural heparin therapy and highlight the limitations of the ACT test, particularly in patients on apixaban.
Integration of the HIV-1 cDNA into the human genome is catalyzed by the viral integrase (IN) protein. Several studies have shown the importance of cellular cofactors that interact with integrase and ...affect viral integration and infectivity. In this study, we produced a stable complex between HIV-1 integrase, viral U5 DNA, the cellular cofactor LEDGF/p75 and the integrase binding domain of INI1 (INI1-IBD), a subunit of the SWI/SNF chromatin remodeling factor. The stoichiometry of the IN/LEDGF/INI1-IBD/DNA complex components was found to be 4/2/2/2 by mass spectrometry and Fluorescence Correlation Spectroscopy. Functional assays showed that INI1-IBD inhibits the 3' processing reaction but does not interfere with specific viral DNA binding. Integration assays demonstrate that INI1-IBD decreases the amount of integration events but inhibits by-product formation such as donor/donor or linear full site integration molecules. Cryo-electron microscopy locates INI1-IBD within the cellular DNA binding site of the IN/LEDGF complex, constraining the highly flexible integrase in a stable conformation. Taken together, our results suggest that INI1 could stabilize the PIC in the host cell, by maintaining integrase in a stable constrained conformation which prevents non-specific interactions and auto integration on the route to its integration site within nucleosomes, while LEDGF organizes and stabilizes an active integrase tetramer suitable for specific vDNA integration. Moreover, our results provide the basis for a novel type of integrase inhibitor (conformational inhibitor) representing a potential new strategy for use in human therapy.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The unexpected occurrence of extended stacking faults in silicon nanostructures at high stress and low temperature is discussed. It is shown that those stacking faults result from the operation of ..."composite" dislocation core structures. It is demonstrated that such cores allow for the propagation of partial dislocations in the shuffle set with the benefit of a low Peierls stress. A classical atomistic calculation confirms indeed that shuffle partial dislocations can move under a shear stress of about 3.3 GPa (5.5% shear strain) at room temperature.
Conversion of the genomic RNA of human immunodeficiency virus (HIV) into full-length viral DNA is a complex multistep reaction catalyzed by the reverse transcriptase (RT). Numerous studies have shown ...that the viral nucleocapsid (NC) protein has a vital impact on various steps during reverse transcription, which is crucial for virus infection. However, the exact molecular details are poorly defined. Here, we analyzed the effect of NC on RT-catalyzed single-turnover, single-nucleotide incorporation using different nucleic acid substrates. In the presence of NC, we observed an increase in the amplitude of primer extension of up to 3-fold, whereas the transient rate of nucleotide incorporation (k pol) dropped by up to 50-fold. To unravel the underlying molecular mechanism, we carefully analyzed the effect of NC on RT−nucleic acid substrate dissociation. The studies revealed that NC considerably enhances the stability of RT−substrate complexes by reducing the observed dissociation rate constants, which more than compensates for the observed drop in k pol. In conclusion, our data strongly support the concept that NC not only indirectly assists the reverse transcription process by its nucleic acid chaperoning activity but also positively affects the RT-catalyzed nucleotide incorporation reaction by increasing polymerase processivity presumably via a physical interaction of the two viral proteins.
Spectrally‐resolved single molecule localization microscopy (srSMLM) is a recent technique enriching single molecule localization microscopy with the simultaneous recording of spectra of the single ...emitters. srSMLM resolution is limited by the number of photons collected per emitters. Sharing a photon budget to record the localization and the spectroscopic information results in a loss of spatial and spectral resolution—or forces the sacrifice of one at the expense of the other. Here, srUnet—a deep‐learning Unet‐based image processing routine trained to increase the spectral and spatial signals to compensate for the resolution loss inherent in additionally recording the spectral component is reported. Both localization and spectral precision are improved by srUnet—particularly for the low‐emitting species. srUnet increases the fraction of localization whose signal can be both spatially and spectrally characterized. It preserves spectral shifts and the linearity of the dispersion of light. It strongly facilitates wavelength assignment in multicolor experiments. srUnet is a simple post‐processing add‐on boosting srSMLM performance close to conventional SMLM with the potential to turn srSMLM into the new standard for multicolor single molecule imaging.
srUnet is a postprocessing routine based on a deep‐learning network trained to enhanced spectrally resolved single molecule localization microscopy images. srUnet improves raw images and results in better spatial and spectral precision images. Also, srUnet offsets the cost of spectral data acquisition to bring srSMLM performance close to that of classical SMLM.
Summary
Siderophores are iron‐chelating molecules produced by bacteria to access iron, a key nutrient. These compounds have highly diverse chemical structures, with various chelating groups. They are ...released by bacteria into their environment to scavenge iron and bring it back into the cells. The biosynthesis of siderophores requires complex enzymatic processes and expression of the enzymes involved is very finely regulated by iron availability and diverse transcriptional regulators. Recent data have also highlighted the organization of the enzymes involved in siderophore biosynthesis into siderosomes, multi‐enzymatic complexes involved in siderophore synthesis. An understanding of siderophore biosynthesis is of great importance, as these compounds have many potential biotechnological applications because of their metal‐chelating properties and their key role in bacterial growth and virulence. This review focuses on the biosynthesis of siderophores produced by fluorescent Pseudomonads, bacteria capable of colonizing a large variety of ecological niches. They are characterized by the production of chromopeptide siderophores, called pyoverdines, which give the typical green colour characteristic of fluorescent pseudomonad cultures. Secondary siderophores are also produced by these strains and can have highly diverse structures (such as pyochelins, pseudomonine, yersiniabactin, corrugatin, achromobactin and quinolobactin).
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