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Abstract Restoring motor function after stroke necessitates involvement of numerous cognitive systems. However, the impact of damage to motor and cognitive network organization on recovery is not well understood. To discover correlates of successful recovery, we explored imaging characteristics in chronic stroke subjects by combining noninvasive brain stimulation and fMRI. Twenty stroke survivors (6 months or more after stroke) were randomly assigned to a single session of transcranial direct current stimulation (tDCS) or sham during image acquisition. Twenty healthy subjects were included as controls. tDCS was limited to 10 min at 2 mA to serve as a mode of network modulation rather than therapeutic delivery. Fugl-Meyer Assessments (FMA) revealed significant motor improvement in the chronic stroke group receiving active stimulation (p = 0.0005). Motor changes in this group were correlated in a data-driven fashion with imaging features, including functional connectivity (FC), surface-based morphometry, electric field modeling and network topology, focusing on relevant regions of interest. We observed stimulation-related changes in FC in supplementary motor (p = 0.0029), inferior frontal gyrus (p = 0.0058), and temporo-occipital (p = 0.0095) areas, though these were not directly related to motor improvement. The feature most strongly associated with FMA improvement in the chronic stroke cohort was graph topology of the dorsal attention network (DAN), one of the regions surveyed and one with direct connections to each of the areas with FC changes. Chronic stroke subjects with a greater degree of motor improvement had lower signal transmission cost through the DAN (p = 0.029). While the study was limited by a small stroke cohort with moderate severity and variable lesion location, these results nevertheless suggest a top-down role for higher order areas such as attention in helping to orchestrate the stroke recovery process.

Abstract Permafrost influences 25% of land in the Northern Hemisphere, where it stabilizes the ground beneath communities and infrastructure and sequesters carbon. However, the coevolution of permafrost, river dynamics, and vegetation in Arctic environments remains poorly understood. As rivers meander, they erode the floodplain at cutbanks and build new land through bar deposition, creating sequences of landforms with distinct formation ages. Here we mapped these sequences along the Koyukuk River floodplain, Alaska, analyzing permafrost occurrence, and landform and vegetation types. We used radiocarbon and optically stimulated luminescence (OSL) dating to develop a floodplain age map. Deposit ages ranged from modern to 10 ka, with more younger deposits near the modern channel. Permafrost rapidly reached 50% areal extent in all deposits older than 200 years then gradually increased up to ∼85% extent for deposits greater than 4 Kyr old. Permafrost extent correlated with increases in black spruce and wetland abundance, as well as increases in permafrost extent within wetland, and shrub and scrub vegetation classes. We developed an inverse model to constrain permafrost formation rate as a function of air temperature. Permafrost extent initially increased by ∼25% per century, in pace with vegetation succession, before decelerating to

Introduction: Informal caregivers are essential in supporting end-of-life patients at home but are often ill-prepared for the carer role. There is growing interest in the development of tools to assess caregiver support needs and a recognised need for a greater focus on addressing inequities in end-of-life care. We plan to undertake a scoping review of available literature to (1) identify and describe tools developed to assess the support needs of informal caregivers in end-of-life care; (2) report on any inequities and under-represented groups in tool development and use., Methods and Analysis: The review will conform to best practice methodological guidance (Joanna Briggs Institute) for scoping reviews. The search strategy will target published and unpublished studies using any methodology, which reports on developing or using tools or measures to assess informal carer support needs in end-of-life/palliative care settings. The following databases will be searched: MEDLINE, CINAHL, PsycINFO, Web of Science, ASSIA and Proquest. Both title/abstract screening and full-text assessment will be undertaken to ensure eligibility. Searches will be conducted between May and December 2024. We will extract data relating to (1) tools/measures identified, and outcome measures used to assess these; (2) participant characteristics. Extracted data will be tabulated with accompanying narrative description to address the review objectives. Data will be extracted and write-up will be completed between January and May 2025., Ethics and Dissemination: This scoping review will provide an overview of the tools developed to identify and assess informal caregiver support needs in palliative and end-of-life care. The identification of any inequities will increase awareness of potentially underserved groups and contexts within the current literature, highlighting how future research and resource can be more equitably focused and implemented in a way that does not further embed disparity. Findings will be made publicly available through the Open Science Framework and disseminated through a peer-reviewed publication. As a scoping review of available literature, this work does not require ethical approval., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Long-form audio recordings are increasingly used to study individual variation, group differences, and many other topics in theoretical and applied fields of developmental science, particularly for the description of children's language input (typically speech from adults) and children's language output (ranging from babble to sentences). The proprietary LENA software has been available for over a decade, and with it, users have come to rely on derived metrics like adult word count (AWC) and child vocalization counts (CVC), which have also more recently been derived using an open-source alternative, the ACLEW pipeline. Yet, there is relatively little work assessing the reliability of long-form metrics in terms of the stability of individual differences across time. Filling this gap, we analyzed eight spoken-language datasets: four from North American English-learning infants, and one each from British English-, French-, American English-/Spanish-, and Quechua-/Spanish-learning infants. The audio data were analyzed using two types of processing software: LENA and the ACLEW open-source pipeline. When all corpora were included, we found relatively low to moderate reliability (across multiple recordings, intraclass correlation coefficient attributed to the child identity [Child ICC], was < 50% for most metrics). There were few differences between the two pipelines. Exploratory analyses suggested some differences as a function of child age and corpora. These findings suggest that, while reliability is likely sufficient for various group-level analyses, caution is needed when using either LENA or ACLEW tools to study individual variation. We also encourage improvement of extant tools, specifically targeting accurate measurement of individual variation., (© 2024. The Psychonomic Society, Inc.)

Gender inequalities in health-related quality of life (QoL) are generally few and small, even in large surveys. Many generic measures limit assessment to QoL overall and its physical and psychological dimensions, while overlooking internationally important environmental, social, and spiritual QoL domains. Unique cross-cultural legacy data was collected using four WHOQOL-100 surveys of adults living in 43 cultures world-wide (17,608 adults; ages 15-101). It was first used to examined gender profiles of its five QoL international domains, and their component facets. Few significant gender differences (p < .001) were found. Women reported higher spiritual QoL than men on faith, and spiritual connection facets specifically. Men reported higher physical and psychological QoL domains than women. We aimed to identify those QoL dimensions that contribute to women's overall QoL in health, as this information could inform gender inequalities interventions in health. Environmental QoL explained a substantial 46% of women's overall QoL and health (n = 5,017; 17 cultures) (stepwise multiple regression adjusted for age, education, and marital status covariates). Five environmental QoL facets contributed significantly to this result; home environment offered most explanation. Age band analysis was conducted to understand when interventions might be best timed in the lifespan to improve women's QoL. Younger women (< 45 years) reported the poorest QoL across the lifetime, and on every domain. After 45, all domains except physical QoL increased to very good at about 60, and high levels were sustained beyond 75, especially environmental QoL. Global findings show that assessing environmental, social, and spiritual QoL domains are key to fully understanding women's QoL and health. These assessments should be prioritized in surveys that aim to improve international conservation, and public health policies., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Skevington et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Objectives: ANCA-associated vasculitis (AAV) is associated with significant morbidity, fatigue, pain and poor health-related quality of life (HRQoL). This review aims to assess the comprehensiveness of existing patient reported outcome measures (PROMs) used in AAV and identify associations with poorer HRQoL outcomes., Methods: A literature review of studies using PROMs, including those labelled HRQoL in people with AAV as a primary or secondary study outcome were screened and reviewed up to July 2023. Quality was assessed using the Critical Appraisal Skills Programme., Results: A total of 30 articles were included which utilised 22 different PROM tools, 76.7% (n = 23) used the SF-36 or a variation as a generic measure of health status and or HRQoL. Two studies developed a disease-specific PROM. The AAV-PRO showed good psychometric properties but potential limitations in capturing all relevant aspects of the disease experience for AAV patients. Factors associated with poorer HRQoL included: neurological and sinonasal involvement, women and younger patients. A total of 86.6% of studies showed no meaningful relationships between the SF-36 and BVAS, VDI or disease duration. Depression and anxiety were common and socioeconomic factors such as unemployment were significantly associated with poorer mental health outcomes. Glucocorticoids were found to be independently associated with worse SF-36 scores., Conclusion: Generic PROMs are useful in measuring significant changes but lack sensitivity to specific symptoms and unique AAV-related issues, while existing disease-specific PROMs have some limitations and may not fully capture the AAV patient's perspective on disease and treatment burden., (© The Author(s) 2024. Published by Oxford University Press on behalf of the British Society for Rheumatology.)

Exploring how neurons in the mammalian body interact with the artificial interface of implants can be used to learn about fundamental cell behavior and to refine medical applications. For fundamental and applied research, it is crucial to determine the conditions that encourage neurons to maintain their natural behavior during interactions with non-natural interfaces. Our previous investigations quantified the deterioration of neuronal connectivity when their dendrites deviate from their natural fractal geometry. Fractal resonance proposes that neurons will exhibit enhanced connectivity if an implant's electrode geometry is matched to the fractal geometry of the neurons. Here, we use in vitro imaging to quantify the fractal geometry of mouse retinal neurons and show that they change during interaction with the electrode. Our results demonstrate that it is crucial to understand these changes in the fractal properties of neurons for fractal resonance to be effective in the in vivo mammalian system.

Growing antibiotic resistance is rapidly threatening the efficacy of treatments for Gram-negative infections. Bicycle molecules, constrained bicyclic peptides from diverse libraries generated by bacteriophage display that bind with high affinity to a chosen target are a potential new class of antibiotics. The generally impermeable bacterial outer membrane currently limits the access of peptides to bacteria. The conjugation of membrane active peptides offers an avenue for outer membrane penetration. Here, we investigate which physicochemical properties of a specific membrane active peptide (MAP), derived from ixosin-B, could be tweaked to enhance the penetration of conjugates by generating multiple MAP-Bicycle conjugate variants. We demonstrate that charge and hydrophobicity are important factors, which enhance penetration and, therefore, antimicrobial potency. Interestingly, we show that induction of secondary structure, but not a change in amphipathicity, is vital for effective penetration of the Gram-negative outer membrane. These results offer insights into the ways vectors could be designed to deliver Bicycle molecules (and other cargos) through biological membranes.

Objective . Spinal cord stimulation (SCS) is a well-established treatment for managing certain chronic pain conditions. More recently, it has also garnered attention as a means of modulating neural activity to restore lost autonomic or sensory-motor function. Personalized modeling and treatment planning are critical aspects of safe and effective SCS (Rowald and Amft 2022 Front. Neurorobotics 16 983072, Wagner et al 2018 Nature 563 65-71). However, the generation of spine models at the required level of detail and accuracy requires time and labor intensive manual image segmentation by human experts. This study aims to develop a maximally automated segmentation routine capable of producing high-quality anatomical models, even with limited data, to facilitate safe and effective personalized SCS treatment planning. Approach . We developed an automated image segmentation and model generation pipeline based on a novel convolutional neural network (CNN) architecture trained on feline spinal cord magnetic resonance imaging data. The pipeline includes steps for image preprocessing, data augmentation, transfer learning, and cleanup. To assess the relative importance of each step in the pipeline and our choice of CNN architecture, we systematically dropped steps or substituted architectures, quantifying the downstream effects in terms of tissue segmentation quality (Jaccard index and Hausdorff distance) and predicted nerve recruitment (estimated axonal depolarization). Main results . The leave-one-out analysis demonstrated that each pipeline step contributed a small but measurable increment to mean segmentation quality. Surprisingly, minor differences in segmentation accuracy translated to significant deviations (ranging between 4% and 13% for each pipeline step) in predicted nerve recruitment, highlighting the importance of careful workflow design. Additionally, transfer learning techniques enhanced segmentation metric consistency and allowed generalization to a completely different spine region with minimal additional training data. Significance . To our knowledge, this work is the first to assess the downstream impacts of segmentation quality differences on neurostimulation predictions. It highlights the role of each step in the pipeline and paves the way towards fully automated, personalized SCS treatment planning in clinical settings., (Creative Commons Attribution license.)

Background: The aim was to predict survival of glioblastoma at 8 months after radiotherapy (a period allowing for completing a typical course of adjuvant temozolomide), by applying deep learning to the first brain MRI after radiotherapy completion., Methods: Retrospective and prospective data were collected from 206 consecutive glioblastoma, isocitrate dehydrogenase -wildtype patients diagnosed between March 2014 and February 2022 across 11 UK centers. Models were trained on 158 retrospective patients from 3 centers. Holdout test sets were retrospective (n = 19; internal validation), and prospective (n = 29; external validation from 8 distinct centers). Neural network branches for T2-weighted and contrast-enhanced T1-weighted inputs were concatenated to predict survival. A nonimaging branch (demographics/MGMT/treatment data) was also combined with the imaging model. We investigated the influence of individual MR sequences; nonimaging features; and weighted dense blocks pretrained for abnormality detection., Results: The imaging model outperformed the nonimaging model in all test sets (area under the receiver-operating characteristic curve, AUC P = .038) and performed similarly to a combined imaging/nonimaging model (P > .05). Imaging, nonimaging, and combined models applied to amalgamated test sets gave AUCs of 0.93, 0.79, and 0.91. Initializing the imaging model with pretrained weights from 10 000s of brain MRIs improved performance considerably (amalgamated test sets without pretraining 0.64; P = .003)., Conclusions: A deep learning model using MRI images after radiotherapy reliably and accurately determined survival of glioblastoma. The model serves as a prognostic biomarker identifying patients who will not survive beyond a typical course of adjuvant temozolomide, thereby stratifying patients into those who might require early second-line or clinical trial treatment., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Society for Neuro-Oncology.)

Prediction-based accounts of language acquisition have the potential to explain several different effects in child language acquisition and adult language processing. However, evidence regarding the developmental predictions of such accounts is mixed. Here, we consider several predictions of these accounts in two large-scale developmental studies of syntactic priming of the English dative alternation. Study 1 was a cross-sectional study (N = 140) of children aged 3-9 years, in which we found strong evidence of abstract priming and the lexical boost, but little evidence that either effect was moderated by age. We found weak evidence for a prime surprisal effect; however, exploratory analyses revealed a protracted developmental trajectory for verb-structure biases, providing an explanation as for why prime surprisal effects are more elusive in developmental populations. In a longitudinal study (N = 102) of children in tightly controlled age bands at 42, 48, and 54 months, we found priming effects emerged on trials with verb overlap early but did not observe clear evidence of priming on trials without verb overlap until 54 months. There was no evidence of a prime surprisal effect at any time point and none of the effects were moderated by age. The results relating to the emergence of the abstract priming and lexical boost effects are consistent with prediction-based models, while the absence of age-related effects appears to reflect the structure-specific challenges the dative presents to English-acquiring children. Overall, our complex pattern of findings demonstrates the value of developmental data sets in testing psycholinguistic theory., (© 2024 The Authors. Cognitive Science published by Wiley Periodicals LLC on behalf of Cognitive Science Society (CSS).)

Anti-neutrophil cytoplasmic antibody (ANCA) associated vasculitis (AAV) is a chronic, relapsing-remitting condition associated with increased morbidity. Previous research has shown patients with AAV report high levels of fatigue, pain, depression and anxiety. Over recent years successful work has been carried out to improve clinical outcomes, resulting in reduced mortality and end stage kidney disease (ESKD). Despite this, little work has been done to better understand the role of the patient within this condition. The prevalence of AAV is increasing and to date, there is a shortage of specific tools that assess and measure key features relating to patient reported outcomes (PROs). This protocol details how we can better understand the lived experiences of those with AAV through the development of a disease specific, patient reported outcome measure (PROM), to be used in clinic practice. This will allow us to recognise and validate PROs and the impact the disease and its treatment has on patients' health related quality of life (HRQoL). In addition, we aim to identify potential differences in PRO's between demographics, organ involvement and treatment subgroups in AAV as well as outcomes relating to the patient experience. Patients from a single centre in the UK will be recruited to take part in the exploratory qualitative study which will include focus groups and semi-structured interviews. The inclusion criteria comprise anyone with a diagnosis of AAV and willing to participate, including those who have active or relapsing disease, those are economically active, unemployed, retired and patients receiving renal replacement therapy. The aim of the project is to identify key issues patients experience in relation to their disease and its management and how these can be better assessed in a new PROM developed for use in the clinic setting. This will enable better delivery of individualised care and inform shared decision making, while also serving as a platform for future research looking at PROs in other glomerulonephritides., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Floyd et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Abstract: Many patients with chronic lymphocytic leukemia (CLL) will develop treatment resistance to Bruton tyrosine kinase (BTK) inhibitors. Phosphatidylinositol-3-kinase (PI3K) inhibitors, including umbralisib, have significant clinical activity in relapsed/refractory CLL, but prolonged exposure is associated with potential toxicities. Owing to the synergistic antitumor effects of combined PI3K and BCL-2 inhibition, we sought to explore the feasibility of response-adapted, time-limited therapy to optimize disease control while mitigating the risks of prolonged treatment. We conducted a phase 1/2 clinical trial to determine the safety and efficacy of venetoclax in combination with umbralisib and the anti-CD20 monoclonal antibody, ublituximab, (U2-VeN) in patients with relapsed/refractory CLL (N = 46) and Richter transformation (N = 5). After 12 cycles, treatment was stopped for patients with CLL who achieved undetectable minimal residual disease (uMRD). Adverse events of special interest included diarrhea in 50% of patients (11% grade 3/4), and aspartate aminotransferase and/or alanine aminotransferase elevation in 15 patients (33%), with 3 (7%) grade 3/4. There were no cases of tumor lysis syndrome related to venetoclax, with outpatient initiation in 96% of patients. The intent-to-treat overall response rate for CLL was 98% with best response of 100% in evaluable patients (42% complete responses). The end-of-treatment rate of uMRD at 10-4 in bone marrow was 77% (30/39), including a 71% uMRD rate among 14 patients refractory to prior BTK inhibitor. Time-limited venetoclax and U2 is safe and highly effective combination therapy for patients with relapsed/refractory CLL including those who have been previously treated with covalent BTK inhibitors. This trial was registered on www.clinicaltrials.gov as #NCT03379051., (© 2024 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

This year's cover artists are members of a team of physicists and psy-chologists who create human-centered designs based on psychology experiments that investigate the positive impacts of viewing fractal patterns. These positive impacts include reduced physiological stress levels and enhanced cognitive skills. Here, the team explores the concept of 'fractal iconography' as an approach to employing computers to generate naturalistic art. Adopting this approach, three forms of fractal patterning ('fractal icons') are combined in a variety of ways to generate the rich complexity of nature's scenery. These composite fractals are remarkably effective at conveying nature's aesthetic power.

People are continually exposed to the rich complexity generated by the repetition of fractal patterns at different size scales. Fractals are prevalent in natural scenery and also in patterns generated by artists and mathematicians. In this chapter, we will investigate the powerful significance of fractals for the human senses. In particular, we propose that fractals with mid-range complexity play a unique role in our visual experiences because the visual system has adapted to these prevalent natural patterns. This adaptation is evident at multiple stages of the visual system, ranging from data acquisition by the eye to processing of this data in the higher visual areas of the brain. Based on these results, we will discuss a fluency model in which the visual system processes mid-complexity fractals with relative ease. This fluency optimizes the observer's capabilities (such as enhanced attention and pattern recognition) and generates an aesthetic experience accompanied by a reduction in the observer's physiological stress levels. In addition to reviewing people's responses to viewing fractals, we will compare these responses to recent research focused on fractal sounds and fractal surface textures. We will extend our fractal fluency model to allow for stimuli across multiple senses., (© 2024. The Author(s), under exclusive license to Springer Nature Switzerland AG.)

Imagine a world in which damaged parts of the body - an arm, an eye, and ultimately a region of the brain - can be replaced by artificial implants capable of restoring or even enhancing human performance. The associated improvements in the quality of human life would revolutionize the medical world and produce sweeping changes across society. In this chapter, we discuss several approaches to the fabrication of fractal electronics designed to interface with neural networks. We consider two fundamental functions - stimulating electrical signals in the neural networks and sensing the location of the signals as they pass through the network. Using experiments and simulations, we discuss the favorable electrical performances that arise from adopting fractal rather than traditional Euclidean architectures. We also demonstrate how the fractal architecture induces favorable physical interactions with the cells they interact with, including the ability to direct the growth of neurons and glia to specific regions of the neural-electronic interface., (© 2024. The Author(s), under exclusive license to Springer Nature Switzerland AG.)

Purpose: To report a case of peripapillary subretinal fluid associated with a ridge-shaped morphology surrounding the optic disk, which we termed ridge-shaped peripapilla., Methods: Case report., Results: A 6-year-old girl with mild-to-moderate myopia was referred for an abnormal fundus appearance of the left eye. Fundus examination of the left eye showed a vertical whitish elevation just temporal to the disk with pigment clumping. Spectral domain optical coherence tomography of the left eye showed an elevation of the fundus at the temporal edge of the disk with thinning of the choroid overlying the thickened scleral protrusion and a serous subretinal fluid. Fluorescein angiography of the left eye showed a hyperfluorescent area without leakage at the temporal edge of the disk, indicative of retinal pigment epithelium atrophy. There was no sign of choroidal neovascularization. Based on the fluorescein angiography and optical coherence tomography findings, the protrusion of the sclera seemed to result in overlying choroidal thinning with choroidal blood flow disturbances, and consequent retinal pigment epithelium atrophy, leading to the subretinal fluid., Conclusion: This case highlights an unusual presentation of ridge-shaped peripapilla, characterized by inward convexity of the peripapillary area with a ridge-shaped morphology and localized thickening of the peripapillary sclera, in eyes with myopia.

In parallel to medical applications, exploring how neurons interact with the artificial interface of implants in the human body can be used to learn about their fundamental behavior. For both fundamental and applied research, it is important to determine the conditions that encourage neurons to maintain their natural behavior during these interactions. Whereas previous biocompatibility studies have focused on the material properties of the neuron-implant interface, here we discuss the concept of fractal resonance - the possibility that favorable connectivity properties might emerge by matching the fractal geometry of the implant surface to that of the neurons.To investigate fractal resonance, we first determine the degree to which neurons are fractal and the impact of this fractality on their functionality. By analyzing three-dimensional images of rat hippocampal neurons, we find that the way their dendrites fork and weave through space is important for generating their fractal-like behavior. By modeling variations in neuron connectivity along with the associated energetic and material costs, we highlight how the neurons' fractal dimension optimizes these constraints. To simulate neuron interactions with implant interfaces, we distort the neuron models away from their natural form by modifying the dendrites' fork and weaving patterns. We find that small deviations can induce large changes in fractal dimension, causing the balance between connectivity and cost to deteriorate rapidly. We propose that implant surfaces should be patterned to match the fractal dimension of the neurons, allowing them to maintain their natural functionality as they interact with the implant., (© 2024. The Author(s), under exclusive license to Springer Nature Switzerland AG.)