Aspirin as Venous Thromboembolism Prophylaxis in Arthroplasty Patients: An Analysis of Clinical Practice Guidelines Recommendations.

BACKGROUND: Venous thromboembolism (VTE) is a recognized postoperative complication of hip or knee arthroplasty and incurs major morbidity and mortality. While anticoagulants are the mainstay of chemoprophylaxis, aspirin has recently emerged as a popular prophylactic agent. However, there is a lack of high-quality evidence comparing aspirin to anticoagulants as a method of VTE prophylaxis, and current guidelines are conflicting regarding using aspirin as first-line chemoprophylaxis. We aimed to investigate guideline characteristics that are associated with the recommendation for or against aspirin as a first-line agent. METHODS: MEDLINE, Embase, Cumulative Index to Nursing and Allied Health Literature, and PubMed databases were searched from 1966 to January 2024 to identify clinical practice guidelines for VTE prophylaxis in adult hip or knee arthroplasty inpatients of average risk. The characteristics of the guideline were collected by 2 independent reviewers. Logistic regression was used to test the association between the recommendation for or against aspirin and guideline characteristics. RESULTS: There were 26 guidelines published from February 2003 to September 2023 and included in this study. There were 5 guidelines that recommended aspirin and 11 guidelines that recommended against aspirin as first-line therapy. With a more recent year of publication, aspirin was more likely to be recommended (odds ratio 1.72, 95% confidence interval: 1.05 to 2.84) and less likely to be recommended against (odds ratio 0.61, 95% confidence interval: 0.41 to 0.90). No other variables, including the level of evidence used, the composition of the guideline working group, or the objective of the guideline, were associated with the recommendation for or against aspirin. CONCLUSIONS: Guidelines were inconsistent in their recommendations regarding aspirin as first-line therapy as VTE prophylaxis in arthroplasty patients. Adequately powered randomized controlled trials using modern practices, such as early postoperative mobilization, are needed to better inform clinical practice guidelines.

Expectation violations enhance neuronal encoding of sensory information in mouse primary visual cortex.

The response of cortical neurons to sensory stimuli is shaped both by past events (adaptation) and the expectation of future events (prediction). Here we employed a visual stimulus paradigm with different levels of predictability to characterise how expectation influences orientation selectivity in the primary visual cortex (V1) of male mice. We recorded neuronal activity using two-photon calcium imaging (GCaMP6f) while animals viewed sequences of grating stimuli which either varied randomly in their orientations or rotated predictably with occasional transitions to an unexpected orientation. For single neurons and the population, there was significant enhancement in the gain of orientation-selective responses to unexpected gratings. This gain-enhancement for unexpected stimuli was prominent in both awake and anaesthetised mice. We implemented a computational model to demonstrate how trial-to-trial variability in neuronal responses were best characterised when adaptation and expectation effects were combined.

Mapping two decades of multiple sclerosis rehabilitation trials: A systematic scoping review and call to action to advance the study of race and ethnicity in rehabilitation research.

BACKGROUND: Multiple sclerosis (MS), is prevalent across many racial and ethnic groups, and disproportionately impacts racially minoritized populations. Rehabilitation interventions are an important component of comprehensive MS care. Yet, we do not know the extent to which MS rehabilitation trials consider race and ethnicity in defining eligibility criteria, planning recruitment strategies, selecting outcome measures, supporting intervention delivery, and designing approaches to promote adherence and retention. METHODS: We conducted a scoping review of five databases (MEDLINE, CINAHL, Cochrane Central, EMBASE, and Web of Science) to locate randomized controlled rehabilitation trials published from January 2002 to March 2022. We extracted data from relevant studies, assessed their methodological quality, and narratively summarized results. Reporting of this review is in line with the Preferred Reporting Items for Systematic reviews and Meta-Analyses extension for Scoping Reviews (PRISMA-ScR). RESULTS: Fifty-six studies of neurorehabilitation (n = 3), cognitive rehabilitation (n = 6), exercise training (n = 9) and self-management (n = 38) interventions were included in this review. The studies were predominantly from North America (n = 44; 73%) or Europe (n = 12; 20%) and included 4280 participants. Most participants (n = 3669; 86%) were Caucasians. Less than 10% of participants were Black (n = 282), Latinx/Hispanic (n = 60), Asian (n = 46), Indigenous (n = 7), or Arab (n = 2). Few studies discussed how race and/or ethnicity were considered in trial planning or execution. CONCLUSIONS: Without consistent and systematic attention to race and ethnicity, both in terms of trial design and reporting, it is impossible to know how MS rehabilitation interventions will translate into real-world applications. This call to action - to the MS rehabilitation research community to ensure trial and intervention processes that accommodate the needs of diverse racial and ethnic groups - is an important first step in addressing inequities in rehabilitation care for persons with MS.

Structure and dynamics of Toll immunoreceptor activation in the mosquito Aedes aegypti.

Aedes aegypti has evolved to become an efficient vector for arboviruses but the mechanisms of host-pathogen tolerance are unknown. Immunoreceptor Toll and its ligand Spaetzle have undergone duplication which may allow neofunctionalization and adaptation. Here we present cryo-EM structures and biophysical characterisation of low affinity Toll5A complexes that display transient but specific interactions with Spaetzle1C, forming asymmetric complexes, with only one ligand clearly resolved. Loop structures of Spaetzle1C and Toll5A intercalate, temporarily bridging the receptor C-termini to promote signalling. By contrast unbound receptors form head-to-head homodimers that keep the juxtamembrane regions far apart in an inactive conformation. Interestingly the transcriptional signature of Spaetzle1C differs from other Spaetzle cytokines and controls genes involved in innate immunity, metabolism and tissue regeneration. Taken together our results explain how upregulation of Spaetzle1C in the midgut and Toll5A in the salivary gland shape the concomitant immune response.

Temporal order judgment of multisensory stimuli in rat and human.

We do not fully understand the resolution at which temporal information is processed by different species. Here we employed a temporal order judgment (TOJ) task in rats and humans to test the temporal precision with which these species can detect the order of presentation of simple stimuli across two modalities of vision and audition. Both species reported the order of audiovisual stimuli when they were presented from a central location at a range of stimulus onset asynchronies (SOA)s. While both species could reliably distinguish the temporal order of stimuli based on their sensory content (i.e., the modality label), rats outperformed humans at short SOAs (less than 100 ms) whereas humans outperformed rats at long SOAs (greater than 100 ms). Moreover, rats produced faster responses compared to humans. The reaction time data further revealed key differences in decision process across the two species: at longer SOAs, reaction times increased in rats but decreased in humans. Finally, drift-diffusion modeling allowed us to isolate the contribution of various parameters including evidence accumulation rates, lapse and bias to the sensory decision. Consistent with the psychophysical findings, the model revealed higher temporal sensitivity and a higher lapse rate in rats compared to humans. These findings suggest that these species applied different strategies for making perceptual decisions in the context of a multimodal TOJ task.

Contemporary evaluation of adverse outcome risks associated with 'did not wait' emergency department presentations.

OBJECTIVE: Did not wait (DNW) is a frequently cited ED key performance indicator. We conducted a network-based observational study of consecutive DNW presentations. METHODS: Prospective cohort study of Western Sydney Local Health District with a primary outcome measure of reported 30-day all-cause mortality and secondary outcomes of demographic characteristics and representation risk. For re-presenting patients who were subsequently admitted, a manual review of electronic records and incident report systems based on a priori plan assessed each case for the length of stay and adverse outcomes. RESULTS: During the study window, there were 1114 DNW presentations with 172 (15.4%) re-presentation within 72 h. The analysis of re-presented patients did not reveal adverse outcomes or prolonged length of stay. A review of available outcomes data revealed one DNW patient died within 30 days but had a previous palliative plan for terminal illness. CONCLUSION: While a proportion of DNW patients re-presented within 72 h, an excess prevalence of poor outcomes were not observed.

Enhanced Sensory Coding in Mouse Vibrissal and Visual Cortex through TRPA1.

Transient receptor potential ankyrin 1 (TRPA1) is a non-selective cation channel, broadly expressed throughout the body. Despite its expression in the mammalian brain, little is known about the contribution of TRPA1 to cortical function. Here, we characterize how TRPA1 affects sensory information processing in two cortical areas in mice: the primary vibrissal (whisker) somatosensory cortex (vS1) and the primary visual cortex (V1). In vS1, local activation of TRPA1 by allyl isothiocyanate (AITC) increases the ongoing activity of neurons and their evoked response to vibrissal stimulation, producing a positive gain modulation. The gain modulation is reversed by TRPA1 inhibitor HC-030031 and is absent in TRPA1 knockout mice. Similarly, in V1, TRPA1 activation increases the gain of direction and orientation selectivity. Linear decoding of V1 population activity confirms faster and more reliable encoding of visual signals under TRPA1 activation. Overall, our findings reveal a physiological role for TRPA1 in enhancing sensory signals in the mammalian cortex.

Viral Delivery of CAR Targets to Solid Tumors Enables Effective Cell Therapy.

Chimeric antigen receptor (CAR) T cell therapy has had limited efficacy for solid tumors, largely due to a lack of selectively and highly expressed surface antigens. To avoid reliance on a tumor's endogenous antigens, here we describe a method of tumor-selective delivery of surface antigens using an oncolytic virus to enable a generalizable CAR T cell therapy. Using CD19 as our proof of concept, we engineered a thymidine kinase-disrupted vaccinia virus to selectively deliver CD19 to malignant cells, and thus demonstrated potentiation of CD19 CAR T cell activity against two tumor types in vitro. In an immunocompetent model of B16 melanoma, this combination markedly delayed tumor growth and improved median survival compared with antigen-mismatched combinations. We also found that CD19 delivery could improve CAR T cell activity against tumor cells that express low levels of cognate antigen, suggesting a potential application in counteracting antigen-low escape. This approach highlights the potential of engineering tumors for effective adoptive cell therapy.

Divergence of Many-Body Perturbation Theory for Noncovalent Interactions of Large Molecules.

Prompted by recent reports of large errors in noncovalent interaction (NI) energies obtained from many-body perturbation theory (MBPT), we compare the performance of second-order MoÌ·ller-Plesset MBPT (MP2), spin-scaled MP2, dispersion-corrected semilocal density functional approximations (DFAs), and post-Kohn-Sham random phase approximation (RPA) for predicting binding energies of supramolecular complexes contained in the S66, L7, and S30L benchmarks. All binding energies are extrapolated to the basis set limit, corrected for basis set superposition errors, and compared to reference results of the domain-based local pair-natural orbital coupled-cluster (DLPNO-CCSD(T)) or better quality. Our results confirm that MP2 severely overestimates binding energies of large complexes, producing relative errors of over 100% for several benchmark compounds. RPA relative errors consistently range between 5 and 10%, significantly less than reported previously using smaller basis sets, whereas spin-scaled MP2 methods show limitations similar to MP2, albeit less pronounced, and empirically dispersion-corrected DFAs perform almost as well as RPA. Regression analysis reveals a systematic increase of relative MP2 binding energy errors with the system size at a rate of approximately 0.1% per valence electron, whereas the RPA and dispersion-corrected DFA relative errors are virtually independent of the system size. These observations are corroborated by a comparison of computed rotational constants of organic molecules to gas-phase spectroscopy data contained in the ROT34 benchmark. To analyze these results, an asymptotic adiabatic connection symmetry-adapted perturbation theory (AC-SAPT) is developed, which uses monomers at full coupling, whose ground-state density is constrained to the ground-state density of the complex. Using the fluctuation-dissipation theorem, we obtain a nonperturbative "screened second-order" expression for the dispersion energy in terms of monomer quantities, which is exact for non-overlapping subsystems and free of induction terms; a first-order RPA-like approximation to the Hartree, exchange, and correlation kernel recovers the macroscopic Lifshitz limit. The AC-SAPT expansion of the interaction energy is obtained from Taylor expansion of the coupling strength integrand. Explicit expressions for the convergence radius of the AC-SAPT series are derived within RPA and MBPT and numerically evaluated. While the AC-SAPT expansion is always convergent for nondegenerate monomers when RPA is used, it is found to spuriously diverge for second-order MBPT, except for the smallest and least polarizable monomers. The divergence of the AC-SAPT series for MBPT is numerically confirmed within RPA; prior numerical results on the convergence of the SAPT expansion for MBPT methods are revisited and support this conclusion once sufficiently high orders are included. The cause of the failure of MBPT methods for NIs of large systems is missing or incomplete "electrodynamic" screening of the Coulomb interaction due to induced particle-hole pairs between electrons in different monomers, leaving the effective interaction too strong for AC-SAPT to converge. Hence, MBPT cannot be considered reliable for quantitative predictions of NIs, even in moderately polarizable molecules with a few tens of atoms. The failure to accurately account for electrodynamic polarization makes MBPT qualitatively unsuitable for applications such as NIs of nanostructures, macromolecules, and soft materials; more robust nonperturbative approaches such as RPA or coupled cluster methods should be used instead whenever possible.

Neural dynamics of the attentional blink revealed by encoding orientation selectivity during rapid visual presentation.

The human brain is inherently limited in the information it can make consciously accessible. When people monitor a rapid stream of visual items for two targets, they typically fail to see the second target if it occurs within 200-500 ms of the first, a phenomenon called the attentional blink (AB). The neural basis for the AB is poorly understood, partly because conventional neuroimaging techniques cannot resolve visual events displayed close together in time. Here we introduce an approach that characterises the precise effect of the AB on behaviour and neural activity. We employ multivariate encoding analyses to extract feature-selective information carried by randomly-oriented gratings. We show that feature selectivity is enhanced for correctly reported targets and suppressed when the same items are missed, whereas irrelevant distractor items are unaffected. The findings suggest that the AB involves both short- and long-range neural interactions between visual representations competing for access to consciousness.

Attention Mechanism with BERT for Content Annotation and Categorization of Pregnancy-Related Questions on a Community Q&A Site.

In recent years, the social web has been increasingly used for health information seeking, sharing, and subsequent health-related research. Women often use the Internet or social networking sites to seek information related to pregnancy in different stages. They may ask questions about birth control, trying to conceive, labor, or taking care of a newborn or baby. Classifying different types of questions about pregnancy information (e.g., before, during, and after pregnancy) can inform the design of social media and professional websites for pregnancy education and support. This research aims to investigate the attention mechanism built-in or added on top of the BERT model in classifying and annotating the pregnancy-related questions posted on a community Q&A site. We evaluated two BERT-based models and compared them against the traditional machine learning models for question classification. Most importantly, we investigated two attention mechanisms: the built-in self-attention mechanism of BERT and the additional attention layer on top of BERT for relevant term annotation. The classification performance showed that the BERT-based models worked better than the traditional models, and BERT with an additional attention layer can achieve higher overall precision than the basic BERT model. The results also showed that both attention mechanisms work differently on annotating relevant content, and they could serve as feature selection methods for text mining in general.

On-Demand Droplet Collection for Capturing Single Cells.

Droplet-based microfluidic techniques are extensively used in efficient manipulation and genome-wide analysis of individual cells, probing the heterogeneity among populations of individuals. However, the extraction and isolation of single cells from individual droplets remains difficult due to the inevitable sample loss during processing. Herein, an automated system for accurate collection of defined numbers of droplets containing single cells is presented. Based on alternate sorting and dispensing in three branch channels, the droplet number can be precisely controlled down to single-droplet resolution. While encapsulating single cells and reserving one branch as a waste channel, sorting can be seamlessly integrated to enable on-demand collection of single cells. Combined with a lossless recovery strategy, this technique achieves capture and culture of individual cells with a harvest rate of over 95%. The on-demand droplet collection technique has great potential to realize quantitative processing and analysis of single cells for elucidating the role of cell-to-cell variations.

Bcl-2-associated athanogene 5 (BAG5) regulates Parkin-dependent mitophagy and cell death.

As pathogenic Parkin mutations result in the defective clearance of damaged mitochondria, Parkin-dependent mitophagy is thought to be protective against the dopaminergic neurodegeneration observed in Parkinson's disease. Recent studies, however, have demonstrated that Parkin can promote cell death in the context of severe mitochondrial damage by degrading the pro-survival Bcl-2 family member, Mcl-1. Therefore, Parkin may act as a 'switch' that can shift the balance between protective or pro-death pathways depending on the degree of mitochondrial damage. Here, we report that the Parkin interacting protein, Bcl-2-associated athanogene 5 (BAG5), impairs mitophagy by suppressing Parkin recruitment to damaged mitochondria and reducing the movement of damaged mitochondria into the lysosomes. BAG5 also enhanced Parkin-mediated Mcl-1 degradation and cell death following severe mitochondrial insult. These results suggest that BAG5 may regulate the bi-modal activity of Parkin, promoting cell death by suppressing Parkin-dependent mitophagy and enhancing Parkin-mediated Mcl-1 degradation.

A new visual illusion of aspect-ratio context.

Perception of local properties of the visual field is influenced by aftereffects of adaptation. The tilt aftereffect describes repulsion of the perceived orientation of a line from the orientation of an adapting line. Analogous effects of spatial context are often called illusions. Repulsion of the perceived orientation of a grating from the orientation of a surrounding grating is referred to as the tilt illusion. In the same manner, the size aftereffect and Ebbinghaus illusion form a complementary pair of temporal and spatial context effects of size. Here we report psychophysical evidence for a previously unknown aspect-ratio illusion which causes the perceived aspect-ratio of a rectangle to be repelled from the aspect-ratio of rectangles surrounding it. This illusion provides a spatial analogue to the aspect-ratio aftereffect.

Correction: Attention promotes the neural encoding of prediction errors.

[This corrects the article DOI: 10.1371/journal.pbio.2006812.].

Sialyl Lewisx-P-selectin cascade mediates tumor-mesothelial adhesion in ascitic fluid shear flow.

Organ-specific colonization suggests that specific cell-cell recognition is essential. Yet, very little is known about this particular interaction. Moreover, tumor cell lodgement requires binding under shear stress, but not static, conditions. Here, we successfully isolate the metastatic populations of cancer stem/tumor-initiating cells (M-CSCs). We show that the M-CSCs tether more and roll slower than the non-metastatic (NM)-CSCs, thus resulting in the preferential binding to the peritoneal mesothelium under ascitic fluid shear stress. Mechanistically, this interaction is mediated by P-selectin expressed by the peritoneal mesothelium. Insulin-like growth factor receptor-1 carrying an uncommon non-sulfated sialyl-Lewisx (sLex) epitope serves as a distinct P-selectin binding determinant. Several glycosyltransferases, particularly α1,3-fucosyltransferase with rate-limiting activity for sLex synthesis, are highly expressed in M-CSCs. Tumor xenografts and clinical samples corroborate the relevance of these findings. These data advance our understanding on the molecular regulation of peritoneal metastasis and support the therapeutic potential of targeting the sLex-P-selectin cascade.

The landscape of Parkin variants reveals pathogenic mechanisms and therapeutic targets in Parkinson's disease.

Mutations in Parkin (PARK2), which encodes an E3 ubiquitin ligase implicated in mitophagy, are the most common cause of early-onset Parkinson's disease (EOPD). Hundreds of naturally occurring Parkin variants have been reported, both in Parkinson's disease (PD) patient and population databases. However, the effects of the majority of these variants on the function of Parkin and in PD pathogenesis remain unknown. Here we develop a framework for classification of the pathogenicity of Parkin variants based on the integration of clinical and functional evidence-including measures of mitophagy and protein stability and predictive structural modeling-and assess 51 naturally occurring Parkin variants accordingly. Surprisingly, only a minority of Parkin variants, even among those previously associated with PD, disrupted Parkin function. Moreover, a few of these naturally occurring Parkin variants actually enhanced mitophagy. Interestingly, impaired mitophagy in several of the most common pathogenic Parkin variants could be rescued both by naturally occurring (p.V224A) and structure-guided designer (p.W403A; p.F146A) hyperactive Parkin variants. Together, the findings provide a coherent framework to classify Parkin variants based on pathogenicity and suggest that several pathogenic Parkin variants represent promising targets to stratify patients for genotype-specific drug design.

Attention promotes the neural encoding of prediction errors.

The encoding of sensory information in the human brain is thought to be optimised by two principal processes: 'prediction' uses stored information to guide the interpretation of forthcoming sensory events, and 'attention' prioritizes these events according to their behavioural relevance. Despite the ubiquitous contributions of attention and prediction to various aspects of perception and cognition, it remains unknown how they interact to modulate information processing in the brain. A recent extension of predictive coding theory suggests that attention optimises the expected precision of predictions by modulating the synaptic gain of prediction error units. Because prediction errors code for the difference between predictions and sensory signals, this model would suggest that attention increases the selectivity for mismatch information in the neural response to a surprising stimulus. Alternative predictive coding models propose that attention increases the activity of prediction (or 'representation') neurons and would therefore suggest that attention and prediction synergistically modulate selectivity for 'feature information' in the brain. Here, we applied forward encoding models to neural activity recorded via electroencephalography (EEG) as human observers performed a simple visual task to test for the effect of attention on both mismatch and feature information in the neural response to surprising stimuli. Participants attended or ignored a periodic stream of gratings, the orientations of which could be either predictable, surprising, or unpredictable. We found that surprising stimuli evoked neural responses that were encoded according to the difference between predicted and observed stimulus features, and that attention facilitated the encoding of this type of information in the brain. These findings advance our understanding of how attention and prediction modulate information processing in the brain, as well as support the theory that attention optimises precision expectations during hierarchical inference by increasing the gain of prediction errors.

Prediction error and repetition suppression have distinct effects on neural representations of visual information.

Predictive coding theories argue that recent experience establishes expectations in the brain that generate prediction errors when violated. Prediction errors provide a possible explanation for repetition suppression, where evoked neural activity is attenuated across repeated presentations of the same stimulus. The predictive coding account argues repetition suppression arises because repeated stimuli are expected, whereas non-repeated stimuli are unexpected and thus elicit larger neural responses. Here, we employed electroencephalography in humans to test the predictive coding account of repetition suppression by presenting sequences of visual gratings with orientations that were expected either to repeat or change in separate blocks of trials. We applied multivariate forward modelling to determine how orientation selectivity was affected by repetition and prediction. Unexpected stimuli were associated with significantly enhanced orientation selectivity, whereas selectivity was unaffected for repeated stimuli. Our results suggest that repetition suppression and expectation have separable effects on neural representations of visual feature information.

Picoinjection-Enabled Multitarget Loop-Mediated Isothermal Amplification for Detection of Foodborne Pathogens.

In this study, we develop a method to detect multiple DNAs of foodborne pathogens by encapsulating emulsion droplets for loop-mediated isothermal amplification (LAMP). In contrast to the traditional bulk-phase LAMP, which involves a labor-intensive mixing process, with our method, different primers are automatically mixed with DNA samples and LAMP buffers after picoinjection. By directly observing and analyzing the fluorescence intensity of the resultant droplets, one can detect DNA from different pathogens, with a detection limit 500 times lower than that obtained by bulk-phase LAMP. We further demonstrate the ability to quantify bacteria concentration by detecting bacterial DNA in practical samples, showing great potential in monitoring water resources and their contamination by pathogenic bacteria.