Factors Associated with Delays in Initiating Biologic Therapy in Patients with Inflammatory Bowel Disease.

INTRODUCTION: Expeditious initiation of biologic therapy is important in patients with inflammatory bowel disease (IBD). However, initiation of biologics in the outpatient setting may be delayed by various clinical, social, and financial variables. AIM: To evaluate the delay in initiation of an advanced therapy in IBD and to identify factors that contributed to this delay. METHODS: This was a multi-center retrospective study. Outpatients who were initiated on a biologic therapy from 3/1/2019 to 9/30/20 were eligible for the study. Univariate and multivariate linear regression analyses were performed to identify variables associated with a delay in biologic treatment initiation. Delay was defined as the days from decision date (prescription placement) to first infusion or delivery of medication. RESULTS: In total 411 patients (Crohn's disease, n = 276; ulcerative colitis, n = 129) were included in the analysis. The median [interquartile range-(IQR)] delay for all drugs was 20 [12-37] days (infliximab, 19 [13-33] days; adalimumab, 10 [5-26] days; vedolizumab, 21 [14-42] days; and ustekinumab, 21 [14-42] days). Multivariate linear regression analysis identified that the most important variables associated with delays in biologic treatment initiation was self-identification as Black, longer distance from treatment site, and lack of initial insurance coverage approval. CONCLUSION: There may be a significant delay in biologic treatment initiation in patients with IBD. The most important variables associated with this delay included self-identification as Black, longer distance from site, and lack of initial insurance coverage approval.

Opposite perceptual biases in analogous auditory and visual tasks are unique to consonant-vowel strings and are unlikely a consequence of repetition.

Despite wide reporting of a right ear (RE) advantage on dichotic listening tasks and a right visual field (RVF) advantage on visual half-field tasks, we know very little about the relationship between these perceptual biases. Previous studies that have investigated perceptual asymmetries for analogous auditory and visual consonant-vowel tasks have indicated a serendipitous finding: a RE advantage and a left visual field (LVF) advantage with poor cross-modal correlations. In this study, we examined the possibility that this LVF advantage for visual processing of consonant-vowel strings may be a consequence of repetition by examining perceptual biases in analogous auditory and visual tasks for both consonant-vowel strings and words. We replicated opposite perceptual biases for consonant-vowel strings (RE and LVF advantages). This did not extend to word stimuli where we found RE and RVF advantages. Furthermore, these perceptual biases did not differ across the three experimental blocks. Thus, we can firmly conclude that this LVF advantage is unique to consonant-vowel strings and is not a consequence of the repetition of a relatively limited number of stimuli. Finally, a test of covariances indicated no cross-modal relationships between laterality indices suggesting that perceptual biases are dissociable within individuals and cluster on mode of presentation.

Flexible letter-position coding in Chinese-English L2 bilinguals: Evidence from eye movements.

Theories suggest that efficient recognition of English words depends on flexible letter-position coding, demonstrated by the fact that transposed-letter primes (e.g., JUGDE-judge) facilitate written word recognition more than substituted-letter primes (e.g., JUFBE-judge). The multiple route model predicts that reading experience should drive more flexible letter-position coding as readers transition from decoding words letter-by-letter to recognising words as wholes. This study therefore examined whether letter-position is coded flexibly in second-language English sentence reading for native Chinese speakers, and if this is influenced by English proficiency. Eye movements were measured while 54 adult native Chinese speakers read English sentences including either a real word (e.g., cheaply), a transposed-letter nonword (e.g., "chepaly"), or a substituted-letter nonword (e.g., "chegely"). Flexible letter-position coding was observed in initial and later processing stages-reading times were longer for substituted-letter than transposed-letter nonwords. In addition, reading times were longer in both initial and later processing stages for transposed-letter nonwords than real words, indicating that, despite encoding letter-position flexibly, readers processed letter-position. Although pre-registered frequentist analyses suggested that English proficiency did not predict overall reading times, Bayes Factors indicated that there was evidence for such a relationship. It is therefore likely that this proficiency analysis suffered from low power. Finally, neither frequentist nor Bayes Factor analyses suggested that English proficiency influenced the difference in reading times between different target word types, i.e., the nature of letter-position coding. Overall, these results suggest that highly proficient L2 learners code letter-position flexibly.

Communicative capital: a key resource for human-machine shared agency and collaborative capacity.

In this work, we present a perspective on the role machine intelligence can play in supporting human abilities. In particular, we consider research in rehabilitation technologies such as prosthetic devices, as this domain requires tight coupling between human and machine. Taking an agent-based view of such devices, we propose that human-machine collaborations have a capacity to perform tasks which is a result of the combined agency of the human and the machine. We introduce communicative capital as a resource developed by a human and a machine working together in ongoing interactions. Development of this resource enables the partnership to eventually perform tasks at a capacity greater than either individual could achieve alone. We then examine the benefits and challenges of increasing the agency of prostheses by surveying literature which demonstrates that building communicative resources enables more complex, task-directed interactions. The viewpoint developed in this article extends current thinking on how best to support the functional use of increasingly complex prostheses, and establishes insight toward creating more fruitful interactions between humans and supportive, assistive, and augmentative technologies.

Testing the relationship between lateralization on sequence-based motor tasks and language laterality using an online battery.

ABSTRACTStudies have highlighted an association between motor laterality and speech production laterality. It is thought that common demands for sequential processing may underlie this association. However, most studies in this area have relied on relatively small samples and have infrequently explored the reliability of the tools used to assess lateralization. We, therefore, established the validity and reliability of an online battery measuring sequence-based motor laterality and language laterality before exploring the associations between laterality indices on language and motor tasks. The online battery was completed by 621 participants, 52 of whom returned to complete the battery a second time. The three motor tasks included in the battery showed good between-session reliability (r ≥ .78) and were lateralized in concordance with hand preference. The novel measure of speech production laterality was left lateralized at population level as predicted, but reliability was less satisfactory (r = .62). We found no evidence of an association between sequence-based motor laterality and language laterality. Those with a left-hand preference were more strongly lateralized on motor tasks requiring midline crossing; this effect was not observed in right-handers. We conclude that there is little evidence of the co-lateralization of language and sequence-based motor skill on this battery.

Inconsistent language lateralisation - Testing the dissociable language laterality hypothesis using behaviour and lateralised cerebral blood flow.

BACKGROUND: Most people have strong left-brain lateralisation for language, with a minority showing right- or bilateral language representation. On some receptive language tasks, however, lateralisation appears to be reduced or absent. This contrasting pattern raises the question of whether and how language laterality may fractionate within individuals. Building on our prior work, we postulated (a) that there can be dissociations in lateralisation of different components of language, and (b) these would be more common in left-handers. A subsidiary hypothesis was that laterality indices will cluster according to two underlying factors corresponding to whether they involve generation of words or sentences, versus receptive language. METHODS: We tested these predictions in two stages: At Step 1 an online laterality battery (Dichotic listening, Rhyme Decision and Word Comprehension) was given to 621 individuals (56% left-handers); At Step 2, functional transcranial Doppler ultrasound (fTCD) was used with 230 of these individuals (51% left-handers). 108 left-handers and 101 right-handers gave useable data on a battery of three language generation and three receptive language tasks. RESULTS: Neither the online nor fTCD measures supported the notion of a single language laterality factor. In general, for both online and fTCD measures, tests of language generation were left-lateralised. In contrast, the receptive tasks were at best weakly left-lateralised or, in the case of Word Comprehension, slightly right-lateralised. The online measures were only weakly correlated, if at all, with fTCD measures. Most of the fTCD measures had split-half reliabilities of at least .7, and showed a distinctive pattern of intercorrelation, supporting a modified two-factor model in which Phonological Decision (generation) and Sentence Decision (reception) loaded on both factors. The same factor structure fitted data from left- and right-handers, but mean scores on the two factors were lower (less left-lateralised) in left-handers. CONCLUSIONS: There are at least two factors influencing language lateralization in individuals, but they do not correspond neatly to language generation and comprehension. Future fMRI studies could help clarify how far they reflect activity in specific brain regions.

Impedance Planimetry and the Changing Paradigm of Esophageal Dysphagia.

OBJECTIVES: Patients presenting with dysphagia can encounter a pathway to therapy and relief that is expensive and frustrating. High resolution impedance planimetry (HRIP) is a new mechanism for enhancing and possibly hastening that process. A balloon with integrated pressure sensors is utilized to measure luminal geometry and pressure by volume-controlled distention. Esophagogastric junction (EGJ) distensibility and body contractility are assessed at the time of other endoscopic procedures. Here we describe a single-center experience utilizing HRIP in the endoscopic evaluation of patients presenting with dysphagia. METHODS: A prospectively maintained registry of patients undergoing impedance planimetry assessments at an academic medical center was queried for demographics, procedural details, and patient-reported outcomes. RESULTS: Data was reviewed for 122 procedures performed by two providers. HRIP was performed in 63 (52%) patients for initial dysphagia assessment, 36 (30%) for follow-up assessment, and 20 (16%) as a procedural adjunct at the time of other planned procedures. HRIP contractile response was characterized as normal in 36%, absent in 32%, and diminished/disorganized in 14%. These results motivated clinical planning for surgical referral in 7 (5%) patients, 31 (26%) additional testing, and 82 (68%) continued medical management and follow-up. DISCUSSION: HRIP is an emerging endoscopic modality which can streamline diagnostic work-up and therapeutic planning for patients with symptomatic dysphagia. Using functional esophageal assessment at the time of other diagnostic and therapeutic procedures, HRIP may expedite care and lead to improved patient satisfaction and clinical outcomes.

Orthographic neighborhood effects during lateralized lexical decision are abolished with bilateral presentation.

Words presented to the right visual field (RVF) are processed more rapidly than those in the left visual field (LVF), presumably because of more direct links to the language dominant left cerebral hemisphere. This effect is moderated by a word's orthographic neighborhood size (N), with LVF facilitation and RVF inhibition for words with a large N. Across two experiments, we sought to further examine lateralized N effects. Experiment 1 examined how hemispheric dominance for language influenced lateralized N effects, in 140 left-handers using a visual half-field task with bilateral presentation. Neither participants with a right ear advantage on a dichotic listening task nor participants with no right ear advantage showed the expected N effect, making the results ambiguous: it could be that left-handers fail to show N effects, or the effect could be abolished by some procedural aspect. Experiment 2 looked to test these options by testing 56 right-handers who responded to the same stimulus set under the original bilateral presentation condition and under unilateral presentation. N effects were found under unilateral but not bilateral presentation. We had adopted bilateral presentation because it had been recommended as better than unilateral presentation for controlling fixation and visual stimulation; our results indicate that this is not a minor methodological modification: it can dramatically affect lateralized N effects. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Can we shift belief in the 'Law of Small Numbers'?

'Sample size neglect' is a tendency to underestimate how the variability of mean estimates changes with sample size. We studied 100 participants, from science or social science backgrounds, to test whether a training task showing different-sized samples of data points (the 'beeswarm' task) can help overcome this bias. Ability to judge if two samples came from the same population improved with training, and 38% of participants reported that they had learned to wait for larger samples before making a response. Before and after training, participants completed a 12-item estimation quiz, including items testing sample size neglect (S-items). Bonus payments were given for correct responses. The quiz confirmed sample size neglect: 20% of participants scored zero on S-items, and only two participants achieved more than 4/6 items correct. Performance on the quiz did not improve after training, regardless of how much learning had occurred on the beeswarm task. Error patterns on the quiz were generally consistent with expectation, though there were some intriguing exceptions that could not readily be explained by sample size neglect. We suggest that training with simulated data might need to be accompanied by explicit instruction to be effective in counteracting sample size neglect more generally.

Epigenetics: a catalyst of plant immunity against pathogens.

The plant immune system protects against pests and diseases. The recognition of stress-related molecular patterns triggers localised immune responses, which are often followed by longer-lasting systemic priming and/or up-regulation of defences. In some cases, this induced resistance (IR) can be transmitted to following generations. Such transgenerational IR is gradually reversed in the absence of stress at a rate that is proportional to the severity of disease experienced in previous generations. This review outlines the mechanisms by which epigenetic responses to pathogen infection shape the plant immune system across expanding time scales. We review the cis- and trans-acting mechanisms by which stress-inducible epigenetic changes at transposable elements (TEs) regulate genome-wide defence gene expression and draw particular attention to one regulatory model that is supported by recent evidence about the function of AGO1 and H2A.Z in transcriptional control of defence genes. Additionally, we explore how stress-induced mobilisation of epigenetically controlled TEs acts as a catalyst of Darwinian evolution by generating (epi)genetic diversity at environmentally responsive genes. This raises questions about the long-term evolutionary consequences of stress-induced diversification of the plant immune system in relation to the long-held dichotomy between Darwinian and Lamarckian evolution.

A Spy took a bite to get the diagnosis right: the benefit of SpyGlass technology in the diagnosis of autoimmune pancreatitis evading traditional diagnostic methods.

Autoimmune pancreatitis (AIP) is a rare form of chronic pancreatitis that is often overlooked and is usually characterised clinically by frequent presentations with obstructive jaundice. Serum IgG4 testing as a means to 'rule out' IgG4-related disease may not be as helpful as initially thought and may lead to a missed diagnosis if suspicion is low. We present a patient with a years long history of recurrent pancreatitis ultimately found to have AIP after undergoing evaluation with a relatively new technology, SpyGlass, which allows for direct cholangioscopy and enabled us to make the correct diagnosis.

Impaired local intrinsic immunity to SARS-CoV-2 infection in severe COVID-19.

SARS-CoV-2 infection can cause severe respiratory COVID-19. However, many individuals present with isolated upper respiratory symptoms, suggesting potential to constrain viral pathology to the nasopharynx. Which cells SARS-CoV-2 primarily targets and how infection influences the respiratory epithelium remains incompletely understood. We performed scRNA-seq on nasopharyngeal swabs from 58 healthy and COVID-19 participants. During COVID-19, we observe expansion of secretory, loss of ciliated, and epithelial cell repopulation via deuterosomal cell expansion. In mild and moderate COVID-19, epithelial cells express anti-viral/interferon-responsive genes, while cells in severe COVID-19 have muted anti-viral responses despite equivalent viral loads. SARS-CoV-2 RNA+ host-target cells are highly heterogenous, including developing ciliated, interferon-responsive ciliated, AZGP1high goblet, and KRT13+ "hillock"-like cells, and we identify genes associated with susceptibility, resistance, or infection response. Our study defines protective and detrimental responses to SARS-CoV-2, the direct viral targets of infection, and suggests that failed nasal epithelial anti-viral immunity may underlie and precede severe COVID-19.

The gut microbiome of COVID-19 recovered patients returns to uninfected status in a minority-dominated United States cohort.

To investigate the relationship between intestinal microbiota and SARS-CoV-2-mediated pathogenicity in a United States, majority African American cohort. We prospectively collected fecal samples from 50 SARS-CoV-2 infected patients, 9 SARS-CoV-2 recovered patients, and 34 uninfected subjects seen by the hospital with unrelated respiratory medical conditions (controls). 16S rRNA sequencing and qPCR analysis was performed on fecal DNA/RNA. The fecal microbial composition was found to be significantly different between SARS-CoV-2 patients and controls (PERMANOVA FDR-P = .004), independent of antibiotic exposure. Peptoniphilus, Corynebacterium and Campylobacter were identified as the three most significantly enriched genera in COVID-19 patients compared to controls. Actively infected patients were also found to have a different gut microbiota than recovered patients (PERMANOVA FDR-P = .003), and the most enriched genus in infected patients was Campylobacter, with Agathobacter and Faecalibacterium being enriched in the recovered patients. No difference in microbial community structure between recovered patients and uninfected controls was observed, nor a difference in alpha diversity between the three groups. 24 of the 50 COVID-19 patients (48%) tested positive via RT-qPCR for fecal SARS-CoV-2 RNA. A significant difference in gut microbial composition between SARS-CoV-2 positive and negative samples was observed, with Klebsiella and Agathobacter being enriched in the positive cohort. No significant associations between microbiome composition and disease severity was found. The intestinal microbiota is sensitive to the presence of SARS-CoV-2, with increased relative abundance of genera (Campylobacter, Klebsiella) associated with gastrointestinal (GI) disease. Further studies are needed to investigate the functional impact of SARS-CoV-2 on GI health.

Increased ACE2 Levels and Mortality Risk of Patients With COVID-19 on Proton Pump Inhibitor Therapy.

INTRODUCTION: Proton pump inhibitor (PPI) use was recently reported to be associated with increased severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and worse clinical outcomes. The underlying mechanism(s) for this association are unclear. METHODS: We performed a prospective study of hospitalized coronavirus disease 2019 (COVID-19) patients and COVID-negative controls to understand how PPI use may affect angiotensin-converting enzyme 2 (ACE2) expression and stool SARS-CoV-2 RNA. Analysis of a retrospective cohort of hospitalized patients with COVID-19 from March 15, 2020 to August 15, 2020 in 6 hospitals was performed to evaluate the association of PPI use and mortality. Covariates with clinical relevance to COVID-19 outcomes were included to determine predictors of in-hospital mortality. RESULTS: Control PPI users had higher salivary ACE2 mRNA levels than nonusers, 2.39 ± 1.15 vs 1.22 ± 0.92 (P = 0.02), respectively. Salivary ACE2 levels and stool SARS-CoV-2 RNA detection rates were comparable between users and nonusers of PPI. In 694 hospitalized patients with COVID-19 (age = 58 years, 46% men, and 65% black), mortality rate in PPI users and nonusers was 30% (68/227) vs 12.1% (53/439), respectively. Predictors of mortality by logistic regression were PPI use (adjusted odds ratio [aOR] = 2.72, P < 0.001), age (aOR = 1.66 per decade, P < 0.001), race (aOR = 3.03, P = 0.002), cancer (aOR = 2.22, P = 0.008), and diabetes (aOR = 1.95, P = 0.003). The PPI-associated mortality risk was higher in black patients (aOR = 4.16, 95% confidence interval: 2.28-7.59) than others (aOR = 1.62, 95% confidence interval: 0.82-3.19, P = 0.04 for interaction). DISCUSSION: COVID-negative PPI users had higher salivary ACE2 expression. PPI use was associated with increased mortality risk in patients with COVID-19, particularly African Americans.

The role of orthographic neighbourhood effects in lateralized lexical decision: a replication study and meta-analysis.

The effect of orthographic neighbourhood size (N) on lexical decision reaction time differs when words are presented in the left or right visual fields. Evidence suggests a facilitatory N effect (i.e., faster reaction times for words with larger neighbourhoods) in the left visual field. However, the N effect in the right visual field remains controversial: it may have a weaker facilitative role or it may even be inhibitory. In a pre-registered online experiment, we replicated the interaction between N and visual field and provided support for an inhibitory N effect in the right visual field. We subsequently conducted a pre-registered systematic review and meta-analysis to synthesise the available evidence and determine the direction of N effects across visual fields. Based on the evidence, it would seem the effect is inhibitory in the right visual field. Furthermore, the size of the N effect is considerably smaller in the right visual field. Both studies revealed considerable heterogeneity between participants and studies, and we consider the implications of this for future work.

Embodied Cooperation to Promote Forgiving Interactions With Autonomous Machines.

During every waking moment, we must engage with our environments, the people around us, the tools we use, and even our own bodies to perform actions and achieve our intentions. There is a spectrum of control that we have over our surroundings that spans the extremes from full to negligible. When the outcomes of our actions do not align with our goals, we have a tremendous capacity to displace blame and frustration on external factors while forgiving ourselves. This is especially true when we cooperate with machines; they are rarely afforded the level of forgiveness we provide our bodies and often bear much of our blame. Yet, our brain readily engages with autonomous processes in controlling our bodies to coordinate complex patterns of muscle contractions, make postural adjustments, adapt to external perturbations, among many others. This acceptance of biological autonomy may provide avenues to promote more forgiving human-machine partnerships. In this perspectives paper, we argue that striving for machine embodiment is a pathway to achieving effective and forgiving human-machine relationships. We discuss the mechanisms that help us identify ourselves and our bodies as separate from our environments and we describe their roles in achieving embodied cooperation. Using a representative selection of examples in neurally interfaced prosthetic limbs and intelligent mechatronics, we describe techniques to engage these same mechanisms when designing autonomous systems and their potential bidirectional interfaces.

Impaired local intrinsic immunity to SARS-CoV-2 infection in severe COVID-19.

Infection with SARS-CoV-2, the virus that causes COVID-19, can lead to severe lower respiratory illness including pneumonia and acute respiratory distress syndrome, which can result in profound morbidity and mortality. However, many infected individuals are either asymptomatic or have isolated upper respiratory symptoms, which suggests that the upper airways represent the initial site of viral infection, and that some individuals are able to largely constrain viral pathology to the nasal and oropharyngeal tissues. Which cell types in the human nasopharynx are the primary targets of SARS-CoV-2 infection, and how infection influences the cellular organization of the respiratory epithelium remains incompletely understood. Here, we present nasopharyngeal samples from a cohort of 35 individuals with COVID-19, representing a wide spectrum of disease states from ambulatory to critically ill, as well as 23 healthy and intubated patients without COVID-19. Using standard nasopharyngeal swabs, we collected viable cells and performed single-cell RNA-sequencing (scRNA-seq), simultaneously profiling both host and viral RNA. We find that following infection with SARS-CoV-2, the upper respiratory epithelium undergoes massive reorganization: secretory cells diversify and expand, and mature epithelial cells are preferentially lost. Further, we observe evidence for deuterosomal cell and immature ciliated cell expansion, potentially representing active repopulation of lost ciliated cells through coupled secretory cell differentiation. Epithelial cells from participants with mild/moderate COVID-19 show extensive induction of genes associated with anti-viral and type I interferon responses. In contrast, cells from participants with severe lower respiratory symptoms appear globally muted in their anti-viral capacity, despite substantially higher local inflammatory myeloid populations and equivalent nasal viral loads. This suggests an essential role for intrinsic, local epithelial immunity in curbing and constraining viral-induced pathology. Using a custom computational pipeline, we characterized cell-associated SARS-CoV-2 RNA and identified rare cells with RNA intermediates strongly suggestive of active replication. Both within and across individuals, we find remarkable diversity and heterogeneity among SARS-CoV-2 RNA+ host cells, including developing/immature and interferon-responsive ciliated cells, KRT13+ "hillock"-like cells, and unique subsets of secretory, goblet, and squamous cells. Finally, SARS-CoV-2 RNA+ cells, as compared to uninfected bystanders, are enriched for genes involved in susceptibility (e.g., CTSL, TMPRSS2) or response (e.g., MX1, IFITM3, EIF2AK2) to infection. Together, this work defines both protective and detrimental host responses to SARS-CoV-2, determines the direct viral targets of infection, and suggests that failed anti-viral epithelial immunity in the nasal mucosa may underlie the progression to severe COVID-19.

Assessing the reliability of an online behavioural laterality battery: A pre-registered study.

Studies of cerebral lateralization often involve participants completing a series of perceptual tasks under laboratory conditions. This has constrained the number of participants recruited in such studies. Online testing can allow for much larger sample sizes but limits the amount of experimental control that is feasible. Here we considered whether online testing could give valid and reliable results on four tasks: a rhyme decision visual half-field task, a dichotic listening task, a chimeric faces task, and a finger tapping task. We recruited 392 participants, oversampling left-handers, who completed the battery twice. Three of the tasks showed evidence of both validity and reliability, insofar as they showed hemispheric advantages in the expected direction and test-retest reliability of at least r = .75. The reliability of the rhyme decision task was less satisfactory (r = .62). We also confirmed a prediction that extreme left-handers were more likely to depart from typical lateralization. Lateralization across the two language tasks (dichotic listening and rhyme judgement) was weakly correlated, but unrelated to lateralization on the chimeric faces task. We conclude that three of the tasks, dichotic listening, chimeric faces and finger tapping, show considerable promise for online evaluation of cerebral lateralization.