Mouth Closure and Airflow in Patients With Obstructive Sleep Apnea: A Nonrandomized Clinical Trial.

Importance: Mouth breathing is associated with increased airway resistance, pharyngeal collapsibility, and obstructive sleep apnea (OSA) severity. The common belief is that closing the mouth can mitigate the negative effects of mouth breathing during sleep. However, mouth breathing may serve as an essential route to bypassing obstruction along the nasal route (eg, the velopharynx). Objective: To investigate the role of mouth breathing as an essential route in some patients with OSA and its association with upper airway anatomical factors. Design, Setting, and Participants: This nonrandomized clinical trial included participants diagnosed with OSA who underwent drug-induced sleep endoscopy. Patients were stratified into 3 quantiles based on oral-breathing level (quantile 1: oral airflow < 0.05 L/min; quantile 2: oral airflow 0.05-2.2 L/min; quantile 3: oral airflow > 2.2 L/min). Interventions: Closing the mouth during sleep during alternating breaths by applying pressure to the mentum until teeth are in occlusion. Main Outcomes and Measures: The primary outcome was total inspiratory flow defined as the change in airflow in the transition from mouth relaxed to mouth closed, analyzed overall and by 3 oral-breathing quantiles. The association of velopharyngeal obstruction on the change in total inspiratory airflow was also investigated. Results: Of 66 enrolled patients with OSA, 12 were excluded due to insufficient baseline airflow. The analytic cohort consisted of 54 patients (39 [72%] male; median [IQR] age, 55 [46-64] years; apnea-hypopnea index, 26.9 [17.6-39.9] events/h; and body mass index calculated as weight in kilograms divided by height in meters squared, 28.9 [27.1-31.6]). Mouth closure increased total inspiratory flow by 27.8 percentage points overall (ß, 1.0 [95% CI, 0.4-1.9] L/min). However, outcomes varied based on the degree of baseline oral breathing. No association was found for 10 patients with near-zero mouth breathing (0.9 [95% CI, -0.2 to 2.1] L/min). Airflow improved with mouth closure in 32 patients with moderate levels of mouth breathing (2.0 [95% CI, 1.3-2.7] L/min), whereas it worsened in patients with high levels of mouth breathing (-1.9 [95% CI, -3.1 to -0.6] L/min). Velopharyngeal obstruction was associated with increased mouth breathing (0.6 [95% CI, 0.1-3.0] L/min) and reduced airflow with mouth closure (-1.9 [95% CI, -3.1 to -0.7] L/min). Conclusion and Relevance: Although mouth closure increased inspiratory airflow in the overall cohort of this nonrandomized clinical trial, the outcomes were heterogeneous. In patients who breathe primarily through their mouth during sleep and have velopharyngeal obstruction, airflow worsens with mouth closure. Hence, personalized approaches to treating mouth breathing should be considered. Trial Registration: ClinicalTrials.gov Identifier: NCT06547658.

Endoscopic and Open Treatment Techniques for Posterior Glottic Stenosis in Children: A Systematic Review and Meta-Analysis.

OBJECTIVES: To evaluate the outcomes of open and endoscopic posterior cricoid split grafting and mucosal flaps for the treatment of pediatric posterior glottic stenosis (PGS). DATA SOURCES: COCHRANE Library, CINAHL, PubMed, and Scopus databases. METHODS: Studies were grouped by treatment method. Outcomes included decannulation rate, improvement in airway obstruction, remaining vocal symptoms, and subsequent airway procedures. A meta-analysis of continuous measures and proportions (%) with 95% confidence interval (CI) was conducted. RESULTS: Nineteen studies with 223 patients were included, with 72 patients having isolated PGS. Twelve studies (n = 23) reported endoscopic repair (group 1), while seven studies (n = 49) reported open techniques (group 2). Most patients in group 1 and group 2 had grade IV PGS (55.9% [26.1%-83.5%] and 56.9% [30.5%-80.8%], respectively). Post-operatively, 70.8% [43.5%-91.7%] of group 1 patients had tracheostomies with 83.4% [62.1%-95.5%] subsequently being decannulated, whereas 97.3% [89.1%-99.8%] of group 2 patients had tracheostomies post-operatively with 90.2% [79.2%-96.5%] subsequently being decannulated. Group 1 and group 2 had 87.1% [70.5%-96.3%] and 84.4% [64.9%-95.5%] improvement in airway obstruction, respectively. CONCLUSION: There are multiple open and endoscopic surgical options for pediatric PGS. Posterior cricoid split with cartilage graft and mucosal advancement flaps can be performed for high PGS grades. Endoscopic and open techniques are efficacious with high decannulation rates and improvement in airway obstruction, with endoscopic surgeries offering a less invasive approach. Laryngoscope, 2024.

A sequential binding mechanism for 5' splice site recognition and modulation for the human U1 snRNP.

Splice site recognition is essential for defining the transcriptome. Drugs like risdiplam and branaplam change how human U1 snRNP recognizes particular 5' splice sites (5'SS) and promote U1 snRNP binding and splicing at these locations. Despite the therapeutic potential of 5'SS modulators, the complexity of their interactions and snRNP substrates have precluded defining a mechanism for 5'SS modulation. We have determined a sequential binding mechanism for modulation of -1A bulged 5'SS by branaplam using a combination of ensemble kinetic measurements and colocalization single molecule spectroscopy (CoSMoS). Our mechanism establishes that U1-C protein binds reversibly to U1 snRNP, and branaplam binds to the U1 snRNP/U1-C complex only after it has engaged with a -1A bulged 5'SS. Obligate orders of binding and unbinding explain how reversible branaplam interactions cause formation of long-lived U1 snRNP/5'SS complexes. Branaplam targets a ribonucleoprotein, not only an RNA duplex, and its action depends on fundamental properties of 5'SS recognition.

Kairos positive airway pressure (KPAP) equals continuous PAP in effectiveness, and offers superior comfort for obstructive sleep apnea treatment.

STUDY OBJECTIVES: A recent study challenged the prevailing clinical view that maintaining inspiratory positive airway pressure (IPAP) is necessary for upper airway patency, demonstrating no differences in apnea hypopnea index (AHI) between continuous PAP (CPAP) with and without a resistor to reduce IPAP. In this study, we assessed the effect of Kairos PAP (KPAP), a new algorithm which features multiple drops in IPAP, only returning to therapeutic pressure near the end expiration, on sleep apnea severity and subjective comfort. METHODS: Two randomized clinical trials were conducted. In the Efficacy trial, the effect of KPAP vs. CPAP on AHI in PAP-treated OSA patients was examined using a split-night design, adjusting for period, sequence and fraction of supine sleep (mixed models). Unintentional leak differences between treatments were also examined. Exploratory analyses assessed the effect of KPAP vs. CPAP on key polysomnography outcomes. In the Comfort trial, we tested subjective preference for KPAP vs. CPAP at 9 and 13 cmH2O in PAP-naïve OSA patients. RESULTS: In the Efficacy trial (N = 48), KPAP reduced AHI more than CPAP (mean difference [95%CI]: -0.5 [-0.8, -0.2] events/h, P = 0.007). Unintentional leak was also reduced by over 50 % (-2.5 [-3.2, -1.7] L/min, P < 0.001). No significant change was observed in the exploratory variables assessed. In the Comfort trial (N = 150), 69 [61, 77] % and 84 [77, 89] % of participants preferred KPAP over CPAP at 9 and 13 cmH2O, respectively (P < 0.001). CONCLUSIONS: KPAP is as effective as CPAP in reducing respiratory events, but is more comfortable and potentially better tolerated.

Flexible use of facial features supports face identity processing.

People prioritize diagnostic features in classification tasks. However, it is not clear whether this priority is fixed or is flexibly applied depending on the specific classification decision, or how feature use behavior contributes to individual differences in performance. Here we examined whether flexibility in features used in a face identification task supports face recognition ability. In Experiment 1, we show that the facial features most useful for identification vary-to a surprising degree-depending on the specific face identity comparison at hand. While the ears and eyes were the most diagnostic for face identification in general, they were the most diagnostic feature for just 22% and 14% of identity decisions, respectively. In three subsequent experiments, we find that flexibility in feature use contributes to an individual's face identity matching ability. Higher face identification accuracy was associated with being aware of (Experiments 2 and 4) and attending to (Experiments 3 and 4) the most diagnostic features for a specific facial comparison. This conferred an enhanced benefit relative to focusing on features that were diagnostic of face identity decisions in general (Experiment 4). We conclude that adaptability in information sampling supports face recognition ability and discuss theoretical and applied implications. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Obstructive sleep apnea and obesity: A review of epidemiology, pathophysiology and the effect of weight-loss treatments.

Despite the commonly-accepted paradigm that patients with obstructive sleep apnea (OSA) also invariably have obesity, OSA prevalence extends beyond obesity. This necessitates a reevaluation of screening strategies, biomarkers of increased OSA risk, and heightened awareness among healthcare providers about the array of OSA treatments for diverse adult populations. While obesity contributes importantly to OSA pathogenesis, there is substantial evidence that non-anatomical factors also play a crucial role, especially in patients who do not have obesity. In recent years, notwithstanding the recognition of diverse contributors to OSA pathogenesis, research has frequently focused on weight reduction to address OSA. Insights from past experiences with bariatric surgery in OSA serve as a lens to anticipate potential outcomes of emerging anti-obesity pharmacotherapies. Pharmacological alternatives, particularly incretin agonists, exhibit promise in weight reduction and OSA improvement, but encounter obstacles such as potential side effects and high costs. With this comprehensive narrative review, we delve into the complex epidemiological and pathophysiological connections between OSA and obesity. Additionally, we emphasize the importance of a multifaceted approach to OSA treatment, recognizing that while weight management is crucial, there is a need for comprehensive strategies that go beyond traditional weight-centric perspectives.

Exploring the Intersection Between Neural Architecture Search and Continual Learning.

Despite the significant advances achieved in deep learning, the deep neural networks' (DNNs) design approach remains notoriously tedious, depending primarily on intuition, experience, and trial and error. This human-dependent process is often time-consuming and prone to errors. Furthermore, the models are generally bound to their training contexts, with no considerations to their surrounding environments. Continual adaptiveness and automation of neural networks is of paramount importance to several domains where model accessibility is limited after deployment (e.g., IoT devices, self-driving vehicles, etc.). Additionally, even accessible models require frequent maintenance postdeployment to overcome issues such as data/concept drift, which can be cumbersome and restrictive. By leveraging and combining approaches from neural architecture search (NAS) and continual learning (CL), more robust and adaptive agents can be developed. This study conducts the first extensive review on the intersection between NAS and CL, formalizing the prospective paradigm and outlining research directions for lifelong autonomous DNNs.

Information sampling differences supporting superior face identity processing ability.

Face recognition in humans is often cited as a model example of perceptual expertise that is characterized by an increased tendency to process faces as holistic percepts. However emerging evidence across different domains of expertise points to a critical role of feature-based processing strategies during the initial encoding of information. Here, we examined the eye-movement patterns of super-recognisers-individuals with extremely high face identification ability compared with the average person-using gaze-contingent "spotlight" apertures that restrict visual face information in real time around their point of fixation. As an additional contrast, we also compared their performance with that of facial examiners-highly trained individuals whose superiority has been shown to rely heavily on featural processing. Super-recognisers and facial examiners showed equivalent face matching accuracy in both spotlight aperture and natural viewing conditions, suggesting that they were equally adept at using featural information for face identity processing. Further, both groups sampled more information across the face than controls. Together, these results show that the active exploration of facial features is an important determinant of face recognition ability that generalizes across different types of experts.

Pediatric Necrotizing Otitis Externa: A Scoping Review.

OBJECTIVE: This review sought to answer the following research question: What are the characteristics of pediatric necrotizing otitis externa (NOE)? Moreover, we wanted to highlight the clinical importance of the current limitations in the literature. METHODS: A scoping review was performed to determine what is known about NOE in the pediatric population. Four databases (COCHRANE Library, CINAHL, PubMed, and Scopus) were queried for articles published in English between 1976 to 2022. Variables extracted included comorbidities, demographics, outcomes, and treatment. RESULTS: A total of 20 studies (N = 439) reported sufficient measures to be included in the review. Patients with NOE had a mean age of 10.0 years (range 2 months to 14 years) with a male-to-female gender ratio of 1.1:1. Mean length of hospital stay was 2.9 days (95%CI: 2.7-3.0). Demographics included 45.4% Caucasian, 6.0% African American, and 2.7% Asian/Pacific Islander. Less than 5% of patients had diabetes, while other reported comorbidities included neutropenia (n = 6), anemia (n = 5), dehydration/malnutrition (n = 4), Stevens Johnson Syndrome (n = 2), some form of immunosuppression/organ transplantation (n = 2), thrombocytopenia (n = 2), and leukopenia (n = 2). There have been no reported deaths from NOE in children. CONCLUSIONS: In the adult population NOE most commonly affects patients with diabetes, but our review reveals that diabetes does not appear to play as big a role in children. The disease seems to commonly affect patients with immunosuppression or severe health conditions. Complications such as cranial nerve palsies appear to be more common in the pediatric population. Specifically, the role of biopsy and culture in the treatment of pediatric NOE is stressed as they are important in treatment decisions.

Top-down and bottom-up oscillatory dynamics regulate implicit visuomotor sequence learning.

Implicit visuomotor sequence learning is crucial for acquiring skills that result in automated behaviors. The oscillatory dynamics underpinning this learning process are not well understood. To address this gap, the current study employed electroencephalography with a medium-density array (64 electrodes) to investigate oscillatory activity associated with implicit visuomotor sequence learning in the Serial Reaction Time task. In the task, participants unknowingly learn a series of finger movements. Eighty-five healthy adults participated in the study. Analyses revealed that theta activity at the vertex and alpha/beta activity over the motor areas decreased over the course of learning. No associations between alpha/beta and theta power were observed. These findings are interpreted within a dual-process framework: midline theta activity is posited to regulate top-down attentional processes, whereas beta activity from motor areas underlies the bottom-up encoding of sensory information from movement. From this model, we suggest that during implicit visuomotor sequence learning, top-down processes become disengaged (indicated by a reduction in theta activity), and modality specific bottom-up processes encode the motor sequence (indicated by a reduction in alpha/beta activity).

An Individual vs Parent Supported Physical Activity Intervention in Adolescents with Intellectual Disabilities.

INTRODUCTION: Moderate-to-vigorous physical activity (MVPA) is inadequate in adolescents with intellectual and developmental disabilities (IDD). This report describes the results of an 18-mo. clinical trial in adolescents with IDD which compared changes in accelerometer assessed daily MVPA, gross motor quotient and leg press strength between participants randomized to an exercise intervention delivered to adolescents only (AO) or to the adolescent and a parent (A + P). METHODS: The 18-mo. trial included a 6-mo. active intervention, 6-mo. maintenance interventions, and a 6-mo. no-contact follow-up. Adolescents in both arms were asked to attend 40 min. remotely delivered group video exercise sessions (0-6 mos. =3 sessions·wk-1., 7-12 mos. =1 session·wk-1). In the A + P arm, one parent/guardian was asked to attend all group remote video exercise sessions and a monthly remotely delivered 30-min. educations/support session with their adolescent across the 12-mo. intervention. RESULTS: Adolescents (n = 116) with IDD (age ~ 16 yrs., 52% female) were randomized to the AO (n = 59) or A + P (n = 57) arms. Mixed modeling, controlling for baseline MVPA and season, indicated minimal but statistically significant changes in MVPA across 6 (p = 0.006), 12 (p < 0.001), and 18 mos. (p < 0.001). However, the change in MVPA in the two intervention arms did not differ significantly at any time point (all p > 0.05). Similarly, gross motor quotient and leg press strength improved significantly over time (p < 0.001) and these changes did not differ between intervention arms (all p > 0.05). CONCLUSIONS: Parental involvement had no impact on changes in daily MVPA, gross motor quotient or leg press strength in response to a remotely delivered exercise intervention in adolescents with IDD.

A large-scale CRISPR screen reveals context-specific genetic regulation of retinal ganglion cell regeneration.

Many genes are known to regulate retinal regeneration after widespread tissue damage. Conversely, genes controlling regeneration after limited cell loss, as per degenerative diseases, are undefined. As stem/progenitor cell responses scale to injury levels, understanding how the extent and specificity of cell loss impact regenerative processes is important. Here, transgenic zebrafish enabling selective retinal ganglion cell (RGC) ablation were used to identify genes that regulate RGC regeneration. A single cell multiomics-informed screen of 100 genes identified seven knockouts that inhibited and 11 that promoted RGC regeneration. Surprisingly, 35 out of 36 genes known and/or implicated as being required for regeneration after widespread retinal damage were not required for RGC regeneration. The loss of seven even enhanced regeneration kinetics, including the proneural factors neurog1, olig2 and ascl1a. Mechanistic analyses revealed that ascl1a disruption increased the propensity of progenitor cells to produce RGCs, i.e. increased 'fate bias'. These data demonstrate plasticity in the mechanism through which Müller glia convert to a stem-like state and context specificity in how genes function during regeneration. Increased understanding of how the regeneration of disease-relevant cell types is specifically controlled will support the development of disease-tailored regenerative therapeutics.

Resting Energy Expenditure Equations Have Lower Accuracy for Adolescents with Overweight/Obesity Versus Healthy-Weight Adolescents.

Objective: The objectives of the study were (1) to assess whether resting energy expenditure (REE) equations have comparable validity for adolescents with overweight/obesity vs. adolescents with healthy weight and (2) to examine determinants of measured REE in adolescents with overweight/obesity vs. adolescents with healthy weight. Methods: Ten equations were used to predict REE for 109 adolescents (70% males; 36.7% with overweight/obesity); 95% equivalence testing was used to assess how well each equation agreed with the criterion measure of indirect calorimetry. Linear regression models were fitted to examine how much REE variance was accounted for by age, sex, race, fat-free mass (FFM), and fat mass. Results: For adolescents with healthy weight, all ten equations were significantly equivalent to the criterion measure within ±8.4% (p < 0.05), whereas for participants with overweight/obesity, only three equations were equivalent within the same range (p < 0.05). Controlling for age, sex, race, fat mass, and FFM accounted for 74% of REE variance. FFM explained the greatest amount (26%) of variance in REE, while weight status itself explained an additional 22%. Conclusions: Prediction equations tend to be more accurate for adolescents with healthy weight than adolescents with overweight/obesity unless the original sample specifically included participants with overweight/obesity. Determinants of REE are similar regardless of weight status.

Effectiveness of a symptom-clinic intervention delivered by general practitioners with an extended role for people with multiple and persistent physical symptoms in England: the Multiple Symptoms Study 3 pragmatic, multicentre, parallel-group, individually randomised controlled trial.

BACKGROUND: People with multiple and persistent physical symptoms have impaired quality of life and poor experiences of health care. We aimed to evaluate the effectiveness of a community-based symptom-clinic intervention in people with multiple and persistent physical symptoms, hypothesising that this symptoms clinic plus usual care would be superior to usual care only. METHODS: The Multiple Symptoms Study 3 was a pragmatic, multicentre, parallel-group, individually randomised controlled trial conducted in 108 general practices in the UK National Health Service in four regions of England between Dec 6, 2018, and June 30, 2023. Participants were individually randomised (1:1) to the symptom-clinic intervention plus usual care or to usual care only via a computer-generated, pseudo-random list stratified by trial centre. Allocation was done by the trial statistician and concealed with a centralised, web-based randomisation system; masking participants was not possible due to the nature of the intervention. The symptom-clinic intervention was a sequence of up to four medical consultations that aimed to elicit a detailed clinical history, fully hear and validate the participant, offer rational explanations for symptoms, and assist the participant to develop ways of managing their symptoms; it was delivered by general practitioners with an extended role. The primary outcome was Patient Health Questionnaire-15 (PHQ-15) score 52 weeks after randomisation, analysed by intention to treat. The trial is registered on the ISRCTN registry (ISRCTN57050216). FINDINGS: 354 participants were randomly assigned; 178 (50%) were assigned to receive the community-based symptoms clinic plus usual care and 176 (50%) were assigned to receive usual care only. At the primary-outcome point of 52 weeks, PHQ-15 scores were 14·1 (SD 3·7) in the group receiving usual care and 12·2 (4·5) in the group receiving the intervention. The adjusted between-group difference of -1·82 (95% CI -2·67 to -0·97) was statistically significantly in favour of the intervention group (p<0·0001). There were 39 adverse events in the group receiving usual care and 36 adverse events in the group receiving the intervention. There were no statistically significant between-group differences in the proportion of participants who had non-serious adverse events (-0·03, 95% CI -0·11 to 0·05) or serious adverse events (0·02, -0·02 to 0·07). No serious adverse event was deemed to be related to the trial intervention. INTERPRETATION: Our symptom-clinic intervention, which focused on explaining persistent symptoms to participants in order to support self-management, led to sustained improvement in multiple and persistent physical symptoms. FUNDING: UK National Institute for Health and Care Research.

Acceptance and Commitment Therapy plus usual care for improving quality of life in people with motor neuron disease (COMMEND): a multicentre, parallel, randomised controlled trial in the UK.

BACKGROUND: Motor neuron disease is a progressive, fatal neurodegenerative disease for which there is no cure. Acceptance and Commitment Therapy (ACT) is a psychological therapy incorporating acceptance, mindfulness, and behaviour change techniques. We aimed to evaluate the effectiveness of ACT plus usual care, compared with usual care alone, for improving quality of life in people with motor neuron disease. METHODS: We conducted a parallel, multicentre, two-arm randomised controlled trial in 16 UK motor neuron disease care centres or clinics. Eligible participants were aged 18 years or older with a diagnosis of definite or laboratory-supported probable, clinically probable, or possible familial or sporadic amyotrophic lateral sclerosis; progressive muscular atrophy; or primary lateral sclerosis; which met the World Federation of Neurology's El Escorial diagnostic criteria. Participants were randomly assigned (1:1) to receive up to eight sessions of ACT adapted for people with motor neuron disease plus usual care or usual care alone by a web-based system, stratified by site. Participants were followed up at 6 months and 9 months post-randomisation. Outcome assessors and trial statisticians were masked to treatment allocation. The primary outcome was quality of life using the McGill Quality of Life Questionnaire-Revised (MQOL-R) at 6 months post-randomisation. Primary analyses were multi-level modelling and modified intention to treat among participants with available data. This trial was pre-registered with the ISRCTN Registry (ISRCTN12655391). FINDINGS: Between Sept 18, 2019, and Aug 31, 2022, 435 people with motor neuron disease were approached for the study, of whom 206 (47%) were assessed for eligibility, and 191 were recruited. 97 (51%) participants were randomly assigned to ACT plus usual care and 94 (49%) were assigned to usual care alone. 80 (42%) of 191 participants were female and 111 (58%) were male, and the mean age was 63·1 years (SD 11·0). 155 (81%) participants had primary outcome data at 6 months post-randomisation. After controlling for baseline scores, age, sex, and therapist clustering, ACT plus usual care was superior to usual care alone for quality of life at 6 months (adjusted mean difference on the MQOL-R of 0·66 [95% CI 0·22-1·10]; d=0·46 [0·16-0·77]; p=0·0031). Moderate effect sizes were clinically meaningful. 75 adverse events were reported, 38 of which were serious, but no adverse events were deemed to be associated with the intervention. INTERPRETATION: ACT plus usual care is clinically effective for maintaining or improving quality of life in people with motor neuron disease. As further evidence emerges confirming these findings, health-care providers should consider how access to ACT, adapted for the specific needs of people with motor neuron disease, could be provided within motor neuron disease clinical services. FUNDING: National Institute for Health and Care Research Health Technology Assessment and Motor Neurone Disease Association.

The statistical and dynamic modeling of the first part of the 2013-2014 Euromaidan protests in Ukraine: The Revolution of Dignity and preceding times.

Ukraine's tug-of-war between Russia and the West has had significant and lasting consequences for the country. In 2013, Viktor Yanukovych, the Ukrainian president aligned with Russia, opted against signing an association agreement with the European Union. This agreement aimed to facilitate trade and travel between the EU and Ukraine. This decision sparked widespread protests that coalesced in Kyiv's Maidan Square, eventually becoming known as the Euromaidan protests. In this study, we analyze the protest data from 2013, sourced from Ukraine's Center for Social and Labor Research. Despite the dataset's limitations and occasional inconsistencies, we demonstrate the extraction of valuable insights and the construction of a descriptive model from such data. Our investigation reveals a pre-existing state of self-excitation within the system even before the onset of the Euromaidan protests. This self-excitation intensified during the Euromaidan protests. A statistical analysis indicates that the government's utilization of force correlates with increased future protests, exacerbating rather than quelling the protest movement. Furthermore, we introduce the implementation of Hawkes process models to comprehend the spatiotemporal dynamics of the protest activity. Our findings highlight that, while protest activities spread across the entire country, the driving force behind the dynamics of these protests was the level of activity in Kyiv. Furthermore, in contrast to prior research that emphasized geographical proximity as a key predictor of event propagation, our study illustrates that the political alignment among oblasts, which are the distinct municipalities comprising Ukraine, had a more profound impact than mere geographic distance. This underscores the significance of social and cultural factors in molding the trajectory of political movements.

A Hypothesis Test for Detecting Spatial Patterns in Categorical Areal Data.

The vast growth of spatial datasets in recent decades has fueled the development of many statistical methods for detecting spatial patterns. Two of the most commonly studied spatial patterns are clustering, loosely defined as datapoints with similar attributes existing close together, and dispersion, loosely defined as the semi-regular placement of datapoints with similar attributes. In this work, we develop a hypothesis test to detect spatial clustering or dispersion at specific distances in categorical areal data. Such data consists of a set of spatial regions whose boundaries are fixed and known (e.g., counties) associated with a categorical random variable (e.g. whether the county is rural, micropolitan, or metropolitan). We propose a method to extend the positive area proportion function (developed for detecting spatial clustering in binary areal data) to the categorical case. This proposal, referred to as the categorical positive areal proportion function test, can detect various spatial patterns, including homogeneous clusters, heterogeneous clusters, and dispersion. Our approach is the first method capable of distinguishing between different types of clustering in categorical areal data. After validating our method using an extensive simulation study, we use the categorical positive area proportion function test to detect spatial patterns in Boulder County, Colorado USA biological, agricultural, built and open conservation easements.

A Sequential Binding Mechanism for 5' Splice Site Recognition and Modulation for the Human U1 snRNP.

Splice site recognition is essential for defining the transcriptome. Drugs like risdiplam and branaplam change how U1 snRNP recognizes particular 5' splice sites (5'SS) and promote U1 snRNP binding and splicing at these locations. Despite the therapeutic potential of 5'SS modulators, the complexity of their interactions and snRNP substrates have precluded defining a mechanism for 5'SS modulation. We have determined a sequential binding mechanism for modulation of -1A bulged 5'SS by branaplam using a combination of ensemble kinetic measurements and colocalization single molecule spectroscopy (CoSMoS). Our mechanism establishes that U1-C protein binds reversibly to U1 snRNP, and branaplam binds to the U1 snRNP/U1-C complex only after it has engaged a -1A bulged 5'SS. Obligate orders of binding and unbinding explain how reversible branaplam interactions cause formation of long-lived U1 snRNP/5'SS complexes. Branaplam is a ribonucleoprotein, not RNA duplex alone, targeting drug whose action depends on fundamental properties of 5'SS recognition.

Cost-effectiveness of acceptance and commitment therapy for people living with motor neuron disease, and their health-related quality of life.

BACKGROUND: Given the degenerative nature of the condition, people living with motor neuron disease (MND) experience high levels of psychological distress. The purpose of this research was to investigate the cost-effectiveness of acceptance and commitment therapy (ACT), adapted for the specific needs of this population, for improving quality of life. METHODS: A trial-based cost-utility analysis over a 9-month period was conducted comparing ACT plus usual care (n = 97) versus usual care alone (n = 94) from the perspective of the National Health Service. In the primary analysis, quality-adjusted life years (QALYs) were computed using health utilities generated from the EQ-5D-5L questionnaire. Sensitivity analyses and subgroup analyses were also carried out. RESULTS: Difference in costs was statistically significant between the two arms, driven mainly by the intervention costs. Effects measured by EQ-5D-5L were not statistically significantly different between the two arms. The incremental cost-effectiveness was above the £20,000 to £30,000 per QALY gained threshold used in the UK. However, the difference in effects was statistically significant when measured by the McGill Quality of Life-Revised (MQOL-R) questionnaire. The intervention was cost-effective in a subgroup experiencing medium deterioration in motor neuron symptoms. CONCLUSIONS: Despite the intervention being cost-ineffective in the primary analysis, the significant difference in the effects measured by MQOL-R, the low costs of the intervention, the results in the subgroup analysis, and the fact that ACT was shown to improve the quality of life for people living with MND, suggest that ACT could be incorporated into MND clinical services.

Pilot Study Investigating Effects of Changing Process Variables on Elastic and Energy-Absorbing Characteristics in Polyurethane/Agglomerated Cork Mix for Use in Micro-Transport Helmet.

This pilot investigation identifies the influence that changing the process variables of curing pressure, curing temperature, and mix ratio of a polyurethane/agglomerated cork matrix has on the mechanical properties of energy absorption, Young's modulus of elasticity, and spring stiffness in safety helmets intended for micro-transport riders. The results are compared to expanded polystyrene, a material commonly used in micro-transport helmets. Mechanical testing of the various samples found that, over the range tested, curing pressure had no effect on any of the mechanical properties, while increasing amounts of resin caused a stiffer structure, and increasing curing temperature led to increased energy absorption. Consistent with the elastic modulus findings, all polyurethane/agglomerated cork test samples demonstrated higher median levels of spring stiffness, ranging from 7.1% to 61.9% greater than those found for expanded polystyrene. The sample mixed at a 1.5:1 binder/cork ratio and cured at 40 °C displayed the closest spring stiffness to EPS. While the mechanical properties of the eco-friendly polyurethane/agglomerated cork matrix did not match those of expanded polystyrene, the difference in performance found in this study is promising. Further investigation into process variables could characterise this more ecologically based matrix with equivalent energy-absorbing and structural characteristics, making it equivalent to currently used expanded polystyrene and suitable for use in micro-transport helmets.