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.

Correction: Attention promotes the neural encoding of prediction errors.

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

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.

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.

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.

Stochastic resonance enhances the rate of evidence accumulation during combined brain stimulation and perceptual decision-making.

Perceptual decision-making relies on the gradual accumulation of noisy sensory evidence. It is often assumed that such decisions are degraded by adding noise to a stimulus, or to the neural systems involved in the decision making process itself. But it has been suggested that adding an optimal amount of noise can, under appropriate conditions, enhance the quality of subthreshold signals in nonlinear systems, a phenomenon known as stochastic resonance. Here we asked whether perceptual decisions made by human observers obey these stochastic resonance principles, by adding noise directly to the visual cortex using transcranial random noise stimulation (tRNS) while participants judged the direction of coherent motion in random-dot kinematograms presented at the fovea. We found that adding tRNS bilaterally to visual cortex enhanced decision-making when stimuli were just below perceptual threshold, but not when they were well below or above threshold. We modelled the data under a drift diffusion framework, and showed that bilateral tRNS selectively increased the drift rate parameter, which indexes the rate of evidence accumulation. Our study is the first to provide causal evidence that perceptual decision-making is susceptible to a stochastic resonance effect induced by tRNS, and to show that this effect arises from selective enhancement of the rate of evidence accumulation for sub-threshold sensory events.

USP8 regulates mitophagy by removing K6-linked ubiquitin conjugates from parkin.

Mutations in the Park2 gene, encoding the E3 ubiquitin-ligase parkin, are responsible for a familial form of Parkinson's disease (PD). Parkin-mediated ubiquitination is critical for the efficient elimination of depolarized dysfunctional mitochondria by autophagy (mitophagy). As damaged mitochondria are a major source of toxic reactive oxygen species within the cell, this pathway is believed to be highly relevant to the pathogenesis of PD. Little is known about how parkin-mediated ubiquitination is regulated during mitophagy or about the nature of the ubiquitin conjugates involved. We report here that USP8/UBPY, a deubiquitinating enzyme not previously implicated in mitochondrial quality control, is critical for parkin-mediated mitophagy. USP8 preferentially removes non-canonical K6-linked ubiquitin chains from parkin, a process required for the efficient recruitment of parkin to depolarized mitochondria and for their subsequent elimination by mitophagy. This work uncovers a novel role for USP8-mediated deubiquitination of K6-linked ubiquitin conjugates from parkin in mitochondrial quality control.

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.

Patient-specific mental rehearsal with interactive visual aids: a path worth exploring?

BACKGROUND: Surgeons of today are faced with unprecedented challenges; necessitating a novel approach to pre-operative preparation which takes into account the specific tests each case poses. In this study, we examine patient-specific mental rehearsal for pre-surgical practice and assess whether this method has an additional effect when compared to generic mental rehearsal. METHODS: Sixteen medical students were trained how to perform a simulated laparoscopic cholecystectomy (SLC). After baseline assessments, they were randomised to two equal groups and asked to complete three SLCs involving different anatomical variants. Prior to each procedure, Group A practiced mental rehearsal with the use of a pre-prepared checklist and Group B mental rehearsal with the checklist combined with virtual models matching the anatomical variations of the SLCs. The performance of the two groups was compared using simulator provided metrics and competency assessment tool (CAT) scoring by two blinded assessors. RESULTS: The participants performed equally well when presented with a "straight-forward" anatomy [Group A vs. Group B-time sec: 445.5 vs. 496 p = 0.64-NOM: 437 vs. 413 p = 0.88-PL cm: 1317 vs. 1059 p = 0.32-per: 0.5 vs. 0 p = 0.22-NCB: 0 vs. 0 p = 0.71-DVS: 0 vs. 0 p = 0.2]; however, Group B performed significantly better [Group A vs. B Total CAT score-Short Cystic Duct (SCD): 20.5 vs. 26.31 p = 0.02 η 2 = 0.32-Double cystic Artery (DA): 24.75 vs. 30.5 p = 0.03 η 2 = 0.28] and committed less errors (Damage to Vital Structures-DVS, SCD: 4 vs. 0 p = 0.03 η 2=0.34, DA: 0 vs. 1 p = 0.02 η 2 = 0.22). in the cases with more challenging anatomies. CONCLUSION: These results suggest that patient-specific preparation with the combination of anatomical models and mental rehearsal may increase operative quality of complex procedures.

Separate banks of information channels encode size and aspect ratio.

Size and aspect ratio are ecologically important visual attributes. Relative size confers depth, and aspect ratio is a size-invariant cue to object identity. The mechanisms of their analyses by the visual system are uncertain. In a series of three psychophysical experiments we show that adaptation causes perceptual repulsion in these properties. Experiment 1 shows that adaptation to a square causes a subsequently viewed smaller (larger) test square to appear smaller (larger) still. Experiment 2 reveals that a test rectangle with an aspect ratio (height/width) of two appears more slender after adaptation to rectangles with aspect ratios less than two, while the same test stimulus appears more squat after adaptation to a rectangle with an aspect ratio greater than two. Significantly, aftereffect magnitudes peak and then decline as the sizes or aspect ratios of adaptor and test diverge. Experiment 3 uses the results of Experiments 1 and 2 to show that the changes in perceived aspect ratio are due to adaptation to aspect ratio rather than adaptation to the height and width of the stimuli. The results are consistent with the operation of distinct banks of information channels tuned for different values of each property. The necessary channels have log-Gaussian sensitivity profiles, have equal widths when expressed as ratios, are labeled with their preferred magnitudes, and are distributed at exponentially increasing intervals. If an adapting stimulus reduces each channel's sensitivity in proportion to its activation then the displacement of the centroid of activity due to a subsequently experienced test stimulus predicts the measured size or aspect ratio aftereffect.

The broad orientation dependence of the motion streak aftereffect reveals interactions between form and motion neurons.

The extended integration time of visual neurons can lead to the production of the neural equivalent of an orientation cue along the axis of motion in response to fast-moving objects. The dominant model argues that these motion streaks resolve the inherent directional uncertainty arising from the small size of receptive fields in V1, by combining spatial orientation with motion signals in V1. This model was tested in humans using visual aftereffects, in which adapting to a static grating causes the perceived direction of a subsequently presented motion stimulus to be tilted away from the adapting orientation. We found that a much broader range of orientations produced aftereffects than predicted by the current model, suggesting that these orientation cues influence motion perception at a later stage than V1. We also found that varying the spatial frequency of the adaptor changed the aftereffect from repulsive to attractive for motion-test but not form-test stimuli. Finally, manipulations of V1 excitability, using transcranial stimulation, reduced the aftereffect, suggesting that the orientation cue is dependent on V1. These results can be accounted for if the orientation information from the motion streak, gathered in V1, enters the motion system at a later stage of motion processing, most likely V5. A computational model of motion direction is presented incorporating gain modifications of broadly tuned motion-selective neurons by narrowly tuned orientation-selective cells in V1, which successfully accounts for the extant data. These results reinforce the suggestion that orientation places strong constraints on motion processing but in a previously undescribed manner.

Role of form information in motion pooling and segmentation.

Traditional theories of visual perception have focused on either form or motion processing, implying a functional separation. However, increasing evidence indicates that these features interact at early stages of visual processing. The current study examined a well-known form-motion interaction, where a shape translates along a circular path behind opaque apertures, giving the impression of either independently translating lines (segmentation) or a globally coherent, translating shape. The purpose was to systemically examine how low-level motion information and form information interact to determine which percept is reported. To this end, we used a stimulus with boundaries comprising multiple, spatially-separated Gabor patches with three to eight sides. Results showed that shapes with four or fewer sides appeared to move in a segmented manner, whereas those with more sides were integrated as a solid shape. The separation between directions, rather than the total number of sides, causes this switch between integrated or segmented percepts. We conclude that the change between integration and segmentation depends on whether local motion directions can be independently resolved. We also reconcile previous results on the influence of shape closure on motion integration: Shapes that form open contours cause segmentation, but with no corresponding enhanced sensitivity for shapes forming closed contours. Overall, our results suggest that the resolution of the local motion signal determines whether motion segmentation or integration is perceived with only a small overall influence of form.

Anodal transcranial direct current stimulation over auditory cortex degrades frequency discrimination by affecting temporal, but not place, coding.

We report three studies of the effects of anodal transcranial direct current stimulation (tDCS) over auditory cortex on audition in humans. Experiment 1 examined whether tDCS enhances rapid frequency discrimination learning. Human subjects were trained on a frequency discrimination task for 2 days with anodal tDCS applied during the first day with the second day used to assess effects of stimulation on retention. This revealed that tDCS did not affect learning but did degrade frequency discrimination during both days. Follow-up testing 2-3 months after stimulation showed no long-term effects. Following the unexpected results, two additional experiments examined the effects of tDCS on the underlying mechanisms of frequency discrimination, place and temporal coding. Place coding underlies frequency selectivity and was measured using psychophysical tuning curves with broader curves indicating poorer frequency selectivity. Temporal coding is determined by measuring the ability to discriminate sounds with different fine temporal structure. We found that tDCS does not broaden frequency selectivity but instead degraded the ability to discriminate tones with different fine temporal structure. The overall results suggest anodal tDCS applied over auditory cortex degrades frequency discrimination by affecting temporal, but not place, coding mechanisms.

The shape of motion perception: global pooling of transformational apparent motion.

Transformational apparent motion (TAM) is a visual phenomenon highlighting the utility of form information in motion processing. In TAM, smooth apparent motion is perceived when shapes in certain spatiotemporal arrangements change. It has been argued that TAM relies on a separate high-level form-motion system. Few studies have, however, systematically examined how TAM relates to conventional low-level motion-energy systems. To this end, we report a series of experiments showing that, like conventional motion stimuli, multiple TAM signals can combine into a global motion percept. We show that, contrary to previous claims, TAM does not require selective attention, and instead, multiple TAM signals can be simultaneously combined with coherence thresholds reflecting integration across the entire stimulus area. This system is relatively weak, less tolerant to noise, and easily overridden when motion energy cues are sufficiently strong. We conclude that TAM arises from high-level form-motion information that enters the motion system by, at least, the stage of global motion pooling.

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.

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.

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.

Experimental and computational analysis of polyglutamine-mediated cytotoxicity.

Expanded polyglutamine (polyQ) proteins are known to be the causative agents of a number of human neurodegenerative diseases but the molecular basis of their cytoxicity is still poorly understood. PolyQ tracts may impede the activity of the proteasome, and evidence from single cell imaging suggests that the sequestration of polyQ into inclusion bodies can reduce the proteasomal burden and promote cell survival, at least in the short term. The presence of misfolded protein also leads to activation of stress kinases such as p38MAPK, which can be cytotoxic. The relationships of these systems are not well understood. We have used fluorescent reporter systems imaged in living cells, and stochastic computer modeling to explore the relationships of polyQ, p38MAPK activation, generation of reactive oxygen species (ROS), proteasome inhibition, and inclusion body formation. In cells expressing a polyQ protein inclusion, body formation was preceded by proteasome inhibition but cytotoxicity was greatly reduced by administration of a p38MAPK inhibitor. Computer simulations suggested that without the generation of ROS, the proteasome inhibition and activation of p38MAPK would have significantly reduced toxicity. Our data suggest a vicious cycle of stress kinase activation and proteasome inhibition that is ultimately lethal to cells. There was close agreement between experimental data and the predictions of a stochastic computer model, supporting a central role for proteasome inhibition and p38MAPK activation in inclusion body formation and ROS-mediated cell death.

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.