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Abstract Background and aims Despite that 93% of people indicate that a mattress plays a pivotal role in achieving high‐quality sleep, there is a scarcity of research investigating the influence of mattresses on sleep quality, pain, and mood in nonclinical poor sleepers. The purpose was to examine the effectiveness of a pressure‐releasing medium‐firm grid mattress on sleep and health outcomes (e.g., mood, pain, daytime fatigue) of adults with nonclinical insomnia symptoms using a quasi‐experimental design. Methods Participants were 39 adults (mean age = 45.29) with nonclinical insomnia (i.e., occasional sleeplessness). Following 1 week of baseline assessments on their current mattress, they slept on a pressure‐relieving grid mattress for 8 weeks. Participants completed self‐report assessments of the Pittsburgh Sleep Quality Index, Berlin Questionnaire, Insomnia Severity Index, Restorative Sleep Questionnaire, Perceived Stress Scale, Profile of Mood States, Daytime Fatigue Scale, Pain and Sleep Questionnaire, and Brief Pain Inventory at Baseline and Weeks 1, 2, 3, 4, and 8. Participants continually wore an Oura Ring to objectively assess sleep and daytime activity. The data were collected from January 2022 to April 2022 and were stored electronically. Repeated‐measures analyses of variance were used to analyze mean time differences. Results Self‐reported sleep quality, perceived pain, perceived stress, mood, and daytime fatigue improved significantly from Baseline to Week 8, p's

IntroductionRecent evidence indicates that respiratory distress (RD) in near-term infants is caused by elevated airway liquid (EL) volume at the beginning of air-breathing after birth. While the adverse effects EL volumes on newborn lung function are known, the effects on respiratory control and breathing patterns shortly after birth (

Bordered by the Swartberg mountain range to the north and the Cape Fold Mountains to the south, the semi-desert region and its people inspired Pauline Smith’s eponymous collection of stories, The Little Karoo (1925). Earlier critics have argued that, in Smith’s stories, the region’s geographical boundaries (as well as her use of Afrikaans-inflected language) ‘confine’ and ‘restrict’ the world of its characters. Informed by the precepts of ecocriticism, this paper provides a fresh take on Smith’s stories of the Karoo, close to a century after their first publication. Our intention is to ‘read for water’ after Isabel Hoffman, Sarah Nuttall and Charne Lavery, as the motility of the streams and rivers that flow in and through this arid landscape challenges the fixity and enclosure the earlier critics read into her work. Drawing on Hubert Zapf’s conception of literature as ‘cultural ecology’, we are interested in the ‘energetic processes’ of water in the stories, and the ‘ecological space’ in which it makes its impact. Rather than reading water as being at the behest of humans, we seek to recognise the valency it is given in the stories, and in this light to explore the impacts of its presence, its actions, and its absence. Contribution: This article adds to the emerging field of ecocriticism in South Africa by exploring the literary valency given to water in Pauline Smith’s stories of the Karoo.

Forced copulation is common, presumably because it can increase male reproductive success. Forced extra-pair copulation (FEPC) occurs in birds, even though most species lack a penis and are widely thought to require female cooperation for fertilization. How FEPC persists, despite a presumed lack of siring success and likely non-negligible costs to the male, is unknown. Using the jackdaw (Corvus monedula) as a case study, we use SNPs to quantify the extra-pair paternity rate through FEPC and evaluate explanations for the persistence of FEPC in species without a penis. We then collate evidence for FEPC across penis-lacking birds. Combining genetic and behavioural analyses, our study suggests that the most likely explanations for the maintenance of FEPC in jackdaws are that it provides a selective advantage to males or it is a relic. Our literature review shows that across birds lacking a penis, FEPC is taxonomically widespread, and yet, little is known about its evolution. A broader implementation of the approach used here, combining both genetic and behavioural data, may shed light on why this widespread sexual behaviour persists. Additional work is necessary to understand whether a penis is needed for paternity through forced copulation and to quantify the costs of FEPC.

Background:. Delay in surgical treatment for carpal tunnel syndrome (CTS) may result in long-term decreased functional outcomes. Few investigators have examined the relationship between type of health insurance plan and time to definitive treatment of CTS following diagnosis. We investigated the relationship between insurance type, treatment decision, and the time between diagnosis and surgery across groups. Methods:. This was a retrospective cohort study using the MarketScan Commercial Claims and Encounters Database 2011–2020. We used χ2 tests, linear regression, and logistic regression models to analyze demographic data and the time lag interval between CTS diagnosis and treatment. Results:. Overall, 28% of high-deductible health plan (HDHP) patients underwent carpal tunnel release, compared with 20% of traditional insurance patients (P < 0.001). HDHPs are defined by the internal revenue service as a deductible of $1400 for an individual or $2800 for a family per year. The odds of undergoing surgery versus no treatment for HDHP patients were 47% higher than traditional patients (P < 0.001). Among the patients who underwent surgery, HDHP patients underwent surgery 65 days earlier on average following diagnosis compared with traditional patients (P < 0.001). Conclusions:. Patients with HDHPs who receive a diagnosis of CTS are more likely to undergo surgery, with a shorter time lag between diagnosis and surgery. The results from this study call attention to differences in surgical decision-making between patients enrolled in different insurance plans.

Resumo: Ao longo da história, os surdos foram privados do acesso às áreas das ciências da natureza, seja pelo tardio consenso quanto à forma como deveriam se comunicar, seja pela crença limitante de que não estavam aptos para tais habilidades. O objetivo deste artigo é discutir a importância da criação de novos sinais e termos científicos para a área das ciências. Realizamos uma pesquisa exploratória e qualitativa, na qual buscamos sinais e termos de modo a manter a fidelidade dos conceitos abordados na exposição de um centro de ciências itinerante. Como resultado, encontramos uma escassez de sinais de parte considerável dos conceitos tratados e a falta de padronização entre os que estão disponíveis e em uso. Concluímos que é necessário maior unidade entre grupos de pesquisa para o desenvolvimento de glossários de ciências em Língua Brasileira de Sinais para que os surdos possam abstrair o conhecimento mais facilmente.

Tissue electrical impedance (or bioimpedance) is a quantity related to the passive, frequency-dependent electrical properties of a biological tissue and is a promising modality for continuous monitoring of relative bladder volume and bladder activity. In this study, the impact of body position [specifically 6° head-down tilt (HDT)] intended to induce fluid redistribution and, therefore, result in a change in the electrical resistance of the abdomen is evaluated. The abdomen resistance (10 kHz–100 kHz) of nine healthy young adults was measured before and after 240 min in a 6° HDT position. Over this period, the resistance increase was not statistically significant even though the average bladder volume increased by 506 mL. It was expected that the abdomen resistance would decrease with an increase in bladder volume over this period. The masking of the expected resistance decrease is attributed to the shift in the fluid from the legs/abdomen to the neck/chest caused by the HDT body position over this period. Overall, this suggests that methods to differentiate bladder volume changes from other types of fluid shifts in the body are needed for resistance-based monitoring under free-living conditions.

# Background Fatigue is common in sports, impairing performance and increasing injury risk, yet little is known regarding fatigue and concussion. Impaired neck neuromuscular function may contribute to concussion at baseline, where central fatigue may further impair neck function resulting in increased concussion risk. These effects may be magnified in athletes with a history of concussion. # Purpose To determine the effect of exercise induced central fatigue on neck joint position error, strength, and endurance in healthy subjects and those with a history of concussion. The investigators hypothesized that EICF would have a negative effect on all variables. # Study Design Healthy subjects were examined using a single factor, within-subjects repeated measures design. Concussion history subjects were examined using a single-subject design. # Methods Nineteen healthy subjects and five subjects with a history of concussion were recruited for the study. Cervical joint position error, muscle strength, and neck flexor endurance were tested before and after exercise induced fatigue. # Results There was a significant increase in constant (p = 0.0027) and absolute joint position error (JPE) (p \< 0.001); decrease in neck flexor endurance (p \< 0.001); and decrease neck strength into cervical flexion (p = 0.01) in healthy subjects following fatigue. Among concussion history subjects, five demonstrated a significant increase in absolute and constant JPE (p \< 0.05); four demonstrated a significant decrease in neck flexor endurance (p \< 0.05); one in neck flexion muscle strength (p \< 0.05); and three in neck extension and rotation muscle strength (p \< 0.05) following fatigue. # Conclusions Cervical neuromuscular function deteriorated following fatigue in healthy subjects. Resulting impairments may affect force alterations in cervical control, potentially increasing concussion risk. Concussion history subjects descriptively demonstrated similar results, however further research should examine formal comparisons involving subjects with and without concussion history. # Level of Evidence 3b

Abstract Unrest began in July 2021 at Askja volcano in the Northern Volcanic Zone (NVZ) of Iceland. Its most recent eruption, in 1961, was predominantly effusive and produced ∼0.1 km3 lava field. The last plinian eruption at Askja occurred in 1875. Geodetic measurements between 1983 and 2021 detail subsidence of Askja, decaying in an exponential manner. At the end of July 2021, inflation was detected at Askja volcano, from GNSS observations and Sentinel‐1 interferograms. The inflationary episode can be divided into two periods from the onset of inflation until September 2023. An initial period until 20 September 2021 when geodetic models suggest transfer of magma (or magmatic fluids) from within the shallowest part of the magmatic system (comprising an inflating and deflating source), potentially involving silicic magma. A following period when one source of pressure increase at shallow depth can explain the observations.

OBJECTIVES:. Inhaled volatile anesthetics support management of status asthmaticus (SA), status epilepticus (SE), and difficult sedation (DS). This study aimed to evaluate the effectiveness, safety, and feasibility of using inhaled anesthetics for SA, SE, and DS in adult ICU and PICU patients. DATA SOURCES:. MEDLINE, Cochrane Central Register of Controlled Trials, and Embase. STUDY SELECTION:. Primary literature search that reported the use of inhaled anesthetics in ventilated patients with SA, SE, and DS from 1970 to 2021. DATA EXTRACTION:. Study data points were extracted by two authors independently. Quality assessment was performed using the Joanna Briggs Institute appraisal tool for case studies/series, Newcastle criteria for cohort/case–control studies, and risk-of-bias framework for clinical trials. DATA SYNTHESIS:. Primary outcome was volatile efficacy in improving predefined clinical or physiologic endpoints. Secondary outcomes were adverse events and delivery logistics. From 4281 screened studies, the number of included studies/patients across diagnoses and patient groups were: SA (adult: 38/121, pediatric: 28/142), SE (adult: 18/37, pediatric: 5/10), and DS (adult: 21/355, pediatric: 10/90). Quality of evidence was low, consisting mainly of case reports and series. Clinical and physiologic improvement was seen within 1–2 hours of initiating volatiles, with variable efficacy across diagnoses and patient groups: SA (adult: 89–95%, pediatric: 80–97%), SE (adults: 54–100%, pediatric: 60–100%), and DS (adults: 60–90%, pediatric: 62–90%). Most common adverse events were cardiovascular, that is, hypotension and arrhythmias. Inhaled sedatives were commonly delivered using anesthesia machines for SA/SE and miniature vaporizers for DS. Few (10%) of studies reported required non-ICU personnel, and only 16% had ICU volatile delivery protocol. CONCLUSIONS:. Volatile anesthetics may provide effective treatment in patients with SA, SE, and DS scenarios but the quality of evidence is low. Higher-quality powered prospective studies of the efficacy and safety of using volatile anesthetics to manage SA, SE, and DS patients are required. Education regarding inhaled anesthetics and the protocolization of their use is needed.

This article considers an arts-based project, Learning Returns (2023), that seeks to capture the experiences of adults who have returned to arts study after some time away from formal education. The aims of the project are twofold: firstly, to evaluate the combination of narrative inquiry and digital film-making hosted on YouTube as a method of investigating adult learning and secondly, through an analysis of the Learning Returns content, to discover what themes the participants considered important to communicate to an imagined, virtual audience. The findings suggested that the aesthetics of the videos/films interconnect with the lived experiences of the participants. The participants were able to give an account of their experiences spontaneously, and at the same time communicate messages of hope to prospective adult returners. It was also discovered that the editing process offers a means of analysing the content of the films that is analogous to the approaches associated with qualitative research.

The intricate nature of native cartilage, characterized by zonal variations in oxygen levels and ECM composition, poses a challenge for existing hydrogel-based tissue models. Consequently, these 3D models often present simplified renditions of the native tissue, failing to fully capture its heterogenous nature. The combined effects of hydrogel components, network properties, and structural designs on cellular responses are often overlooked. In this work, we aim to establish more physiological cartilage models through biofabrication of photopolymerizable allylated-gelatin (GelAGE) and Thiolated Heparin (HepSH) constructs with tailorable matrix stiffness and customized architectures. This involves systematically studying how the native glycosaminoglycan Heparin together with hydrogel stiffness, and oxygen availability within 3D structures influence chondrogenic differentiation and regional heterogeneity. A comprehensive library of 3D hydrogel constructs was successfully developed, encompassing GelAGE-HepSH hydrogels with three distinct stiffness levels: 12, 55 and 121 kPa, and three unique geometries: spheres, discs, and square lattices. In soft GelAGE-HepSH hydrogels, the localization of differentiating cells was observed to be irregular, while stiff hydrogels restricted the overall secretion of ECM components. The medium-stiff hydrogels were found to be most applicable, supporting both uniform tissue formation and maintained shape fidelity. Three different 3D architectures were explored, where biofabrication of smaller GelAGE-HepSH spheres without oxygen gradients induced homogenous, hyaline cartilage tissue formation. Conversely, fabrication of larger constructs (discs and lattices) with oxygen gradients could be utilized to design heterogenous cartilage tissue models. Similarly, temporal oxygen gradients were observed to drive interconnected deposition of glycosaminoglycans (GAGs). Control samples of GelAGE without HepSH did not exhibit any notable changes in chondrogenesis as a function of stiffness, architectures, or oxygen concentrations. Overall, the incorporation of HepSH within GelAGE hydrogels was observed to serve as an amplifier for the biological effects from both stiffness and oxygen cues. In conclusion, fabrication of GelAGE-HepSH constructs designed to impose limitations on oxygen availability induce more zone-specific cartilage tissue alignment. This systematic study of matrix components, network stiffness, and oxygen levels in 3D biofabricated structures contributes to the development of more physiologically relevant cartilage models while further enhancing our overall understanding of cartilage tissue engineering.

PurposeThis review is focused on radium and radionuclides in its decay chain in honor of Marie Curie, who discovered this element.Materials and methodsWe conglomerated current knowledge regarding radium and its history predating our present understanding of this radionuclide.ResultsAn overview of the properties of radium and its dose assessment is shown followed by discussions about both the negative detrimental and positive therapeutic applications of radium with this history and its evolution reflecting current innovations in medical science.ConclusionsWe hope to remind all those who are interested in the progress of science about the vagaries of the process of scientific discovery. In addition, we raise the interesting question of whether Marie Curie's initial success was in part possible due to her tight alignment with her husband Pierre Curie who pushed the work along.

The Genome Empowerment Scale (GEmS), developed as a research tool, assesses perspectives of parents of children with undiagnosed disorders about to undergo exome or genome sequencing related to the process of empowerment. We defined genomic healthcare empowerment as follows: perceived ability to understand and seek new information related to the genomic sequencing, manage emotions related to the diagnostic process and outcomes, and utilize genomic sequencing information to the betterment of the individual/child and family. The GEmS consists of four scales, two are primarily emotion-focused (Meaning of a Diagnosis, and Emotional Management of the Process) and two are action-oriented (Seeking Information and Support, and Implications and Planning). The purpose of this research was to provide a strategy for interpreting results from the GEmS and present illustrative cases. These illustrations should serve to facilitate use of the GEmS in the clinical and research arena, particularly with respect to guiding genetic counseling processes for parents of children with undiagnosed conditions.

In this narrative article, I document my implementation of action logs as a tool for reflective practice and teacher development as I transitioned from working in a small "eikaiwa" (English conversation) school to working in a private international university. After providing a brief description of my contextual background and how I came to start action logging, I give examples of student feedback I received and their relevance to my reflective teaching. Finally, I explain the varied ways in which I feel using action logs aided me in improving the efficacy of my classroom practice and influenced my evolving teacher identity during a stressful transition between two markedly different professional worlds.

Signing on to take part in Bush Blitz TeachLive (BBTL) is an easy decision for many teacher applicants. The opportunity to be a scientist's field-assistant and to beam the experience back to students in the classroom is an enticing one. Yet the reality of an expedition often far exceeds the initial expectation. This article describes the experiences of five Western Australian teachers, alongside the Bush Blitz scientific team, on a research expedition to Wilinggin Country, a vast swathe of rugged bushland and gorges that is home to some of Australia's most diverse flora and fauna.

Set within the context of a longitudinal project that seeks to engage physical education teachers from the four countries of the UK in cross-border curriculum analysis, dialogue and learning, the current study lays the foundation by mapping and comparing curriculum discourses that currently shape how physical education is conceptualised in England, Northern Ireland, Scotland and Wales. As a team of researchers with affiliations to each of the four nations of the UK, we identified those curriculum documents from each context that were written to directly inform physical education teachers' curriculum planning and enactment. We firstly identified those discourses evident in each document to understand how physical education is conceptualised within each curriculum, before engaging in a dialogical process that converged around how physical education is constructed similarly or differently within and across curricula. We found some variation in relation to how the concept of health is articulated. With the exception of the curriculum in Wales, we also found that performance discourses related to developing motor competencies for sports continue to dominate as the main purpose of physical education. Finally, there are several points of divergence in relation to how much agency or guidance teachers are afforded within each curriculum. The intention of this research is to initiate dialogue across each of the four nations, creating opportunities for learning so that, collectively, teachers can build capacity to contribute to future curricula and pedagogies in physical education.

Abstract Background Epithelial ovarian cancer (EOC) is a global health burden, with the poorest five-year survival rate of the gynecological malignancies due to diagnosis at advanced stage and high recurrence rate. Recurrence in EOC is driven by the survival of chemoresistant, stem-like tumor-initiating cells (TICs) that are supported by a complex extracellular matrix and immunosuppressive microenvironment. To target TICs to prevent recurrence, we identified genes critical for TIC viability from a whole genome siRNA screen. A top hit was the cancer-associated, proteoglycan subunit synthesis enzyme UDP-glucose dehydrogenase (UGDH). Methods Immunohistochemistry was used to characterize UGDH expression in histological and molecular subtypes of EOC. EOC cell lines were subtyped according to the molecular subtypes and the functional effects of modulating UGDH expression in vitro and in vivo in C1/Mesenchymal and C4/Differentiated subtype cell lines was examined. Results High UGDH expression was observed in high-grade serous ovarian cancers and a distinctive survival prognostic for UGDH expression was revealed when serous cancers were stratified by molecular subtype. High UGDH was associated with a poor prognosis in the C1/Mesenchymal subtype and low UGDH was associated with poor prognosis in the C4/Differentiated subtype. Knockdown of UGDH in the C1/mesenchymal molecular subtype reduced spheroid formation and viability and reduced the CD133 + /ALDH high TIC population. Conversely, overexpression of UGDH in the C4/Differentiated subtype reduced the TIC population. In co-culture models, UGDH expression in spheroids affected the gene expression of mesothelial cells causing changes to matrix remodeling proteins, and fibroblast collagen production. Inflammatory cytokine expression of spheroids was altered by UGDH expression. The effect of UGDH knockdown or overexpression in the C1/ Mesenchymal and C4/Differentiated subtypes respectively was tested on mouse intrabursal xenografts and showed dynamic changes to the tumor stroma. Knockdown of UGDH improved survival and reduced tumor burden in C1/Mesenchymal compared to controls. Conclusions These data show that modulation of UGDH expression in ovarian cancer reveals distinct roles for UGDH in the C1/Mesenchymal and C4/Differentiated molecular subtypes of EOC, influencing the tumor microenvironmental composition. UGDH is a strong potential therapeutic target in TICs, for the treatment of EOC, particularly in patients with the mesenchymal molecular subtype.

Abstract Tacrolimus, the most common immunosuppressant for organ transplant, has a narrow therapeutic range and is metabolized by CYP3A4/5. Trough concentration monitoring and dosing adjustments are used to reach a therapeutic range. CYP3A5 intermediate and normal metabolizers (*1 allele carriers; IM/NM) demonstrate faster tacrolimus metabolism than poor metabolizers (PM). We analyzed the electronic health records of 93 patients aged 150% of the required daily dose compared with PM. The concentration/dose ratio was influenced by age and concomitant fluconazole (p = 0.0003, p = 0.034, respectively) and the average daily dose decreases with age in CYP3A5 PM (p = 0.001). Tremors were more common in patients who ever had a trough concentration >15 ng/mL compared with those who never had a trough concentration >15 ng/mL (OR 3.31, 95% CI 1.03–8.98, p = 0.038). Using standard dosing, CYP3A5 IM/NM took longer to reach the goal range and require more dose adjustments and higher doses than PM. Preemptive genotyping could decrease the number of dose changes necessary to reach a therapeutic dose. We have implemented pre‐transplant CYP3A5 testing at our institution.

Abstract Intracranial metastases in prostate cancer are uncommon but clinically aggressive. A detailed molecular characterization of prostate cancer intracranial metastases would improve our understanding of their pathogenesis and the search for new treatment strategies. We evaluated the clinical and molecular characteristics of 36 patients with metastatic prostate cancer to either the dura or brain parenchyma. We performed whole genome sequencing (WGS) of 10 intracranial prostate cancer metastases, as well as WGS of primary prostate tumors from men who later developed metastatic disease (n = 6) and nonbrain prostate cancer metastases (n = 36). This first study focused on WGS of prostate intracranial metastases led to several new insights. First, there was a higher diversity of complex structural alterations in prostate cancer intracranial metastases compared to primary tumor tissues. Chromothripsis and chromoplexy events seemed to dominate, yet there were few enrichments of specific categories of structural variants compared with non-brain metastases. Second, aberrations involving the AR gene, including AR enhancer gain were observed in 7/10 (70%) of intracranial metastases, as well as recurrent loss of function aberrations involving TP53 in 8/10 (80%), RB1 in 2/10 (20%), BRCA2 in 2/10 (20%), and activation of the PI3K/AKT/PTEN pathway in 8/10 (80%). These alterations were frequently present in tumor tissues from other sites of disease obtained concurrently or sequentially from the same individuals. Third, clonality analysis points to genomic factors and evolutionary bottlenecks that contribute to metastatic spread in patients with prostate cancer. These results describe the aggressive molecular features underlying intracranial metastasis that may inform future diagnostic and treatment approaches.

ABSTRACT: Objectives: To determine whether weekly oral supplementation with 10,000 IU vitamin D3 for 3 years reduces the risk of sensitization to M. tuberculosis in South African schoolchildren aged 6-11 years with negative QuantiFERON-tuberculosis (TB) Gold Plus (QFT-Plus) assay results at baseline. Methods: We conducted a phase 3 randomized placebo-controlled trial in 1682 children attending 23 primary schools in Cape Town. The primary outcome was a positive end-trial QFT-Plus result, analyzed using a mixed effects logistic regression model with the school of attendance included as a random effect. Results: 829 vs. 853 QFT-Plus-negative children were randomized to receive vitamin D3 vs. placebo, respectively. Mean end-study 25(OH)D concentrations in participants randomized to vitamin D vs. placebo were 104.3 vs 64.7 nmol/l, respectively (95% confidence interval for difference, 37.6 to 41.9 nmol/l). A total of 76/667 (11.4%) participants allocated to vitamin D vs. 89/687 (13.0%) participants allocated to placebo tested QFT-Plus positive at 3-year follow-up (adjusted odds ratio 0.86, 95% confidence interval 0.62-1.19, P = 0.35). Conclusion: Weekly oral supplementation with 10,000 IU vitamin D3 for 3 years elevated serum 25(OH)D concentrations among QFT-Plus-negative Cape Town schoolchildren but did not reduce their risk of QFT-Plus conversion.

Abstract The Laser Interferometer Space Antenna (LISA) has two scientific objectives of cosmological focus: to probe the expansion rate of the universe, and to understand stochastic gravitational-wave backgrounds and their implications for early universe and particle physics, from the MeV to the Planck scale. However, the range of potential cosmological applications of gravitational-wave observations extends well beyond these two objectives. This publication presents a summary of the state of the art in LISA cosmology, theory and methods, and identifies new opportunities to use gravitational-wave observations by LISA to probe the universe.

Abstract Background Arts therapies are widely but inconsistently provided in community mental health. Whilst they are appealing to patients, evidence for their effectiveness is mixed. Trials to date have been limited to one art-form or diagnosis. Patients may hold strong preferences for or against an art-form whilst group therapies rely on heterogeneity to provide a range of learning experiences. This study will test whether manualised group arts therapies (art therapy, dance movement therapy and music therapy) are effective in reducing psychological distress for diagnostically heterogeneous patients in community mental health compared to active group counselling control. Methods A pragmatic multi-centre 2-arm randomised controlled superiority trial with health economic evaluation and nested process evaluation. Adults aged ≥ 18, living in the community with a primary diagnosis of psychosis, mood, or anxiety disorder will be invited to participate and provide written informed consent. Participants are eligible if they score ≥ 1.65 on the Global Severity Index of the Brief Symptom Inventory. Those eligible will view videos of arts therapies and be asked for their preference. Participants are randomised to either their preferred type of group arts therapy or counselling. Groups will run twice per week in a community venue for 20 weeks. Our primary outcome is symptom distress at the end of intervention. Secondary outcomes include observer-rated symptoms, social situation and quality of life. Data will be collected at baseline, post-intervention and 6 and 12 months post-intervention. Outcome assessors and trial statisticians will be blinded. Analysis will be intention-to-treat. Economic evaluation will assess the cost-effectiveness of group arts therapies. A nested process evaluation will consist of treatment fidelity analysis, exploratory analysis of group process measures and qualitative interviews with participants and therapists. Discussion This will be the first trial to account for patient preferences and diagnostic heterogeneity in group arts therapies. As with all group therapies, there are a number of logistical challenges to which we have had to further adapt due to the COVID-19 pandemic. Overall, the study will provide evidence as to whether there is an additive benefit or not to the use of the arts in group therapy in community mental health care. Trial registration ISRCTN, ISRCTN88805048 . Registered on 12 September 2018.

Abstract Th17 cells that produce Interleukin IL-17 are pathogenic in many human diseases, including inflammatory bowel disease, but are, paradoxically, essential for maintaining the integrity of the intestinal barrier in a non-inflammatory state. However, the intracellular mechanisms that regulate distinct transcriptional profiles and functional diversity of Th17 cells remain unclear. Here we show Raftlin1, a lipid raft protein, specifically upregulates and forms a complex with RORγt in pathogenic Th17 cells. Disruption of the RORγt-Raftlin1 complex results in the reduction of pathogenic Th17 cells in response to Citrobacter rodentium; however, there is no effect on nonpathogenic Th17 cells in response to commensal segmented filamentous bacteria. Mechanistically, we show that Raftlin1 recruits distinct phospholipids to RORγt and promotes the pathogenicity of Th17 cells. Thus, we have identified a mechanism that drives the pathogenic function of Th17 cells, which could provide a platform for advanced therapeutic strategies to dampen Th17-mediated inflammatory diseases.

Abstract Severe, protracted symptoms are associated with poor outcomes in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. In a placebo-controlled study of casirivimab and imdevimab (CAS + IMD) in persons at high risk of severe coronavirus disease 2019 (COVID-19; n = 3816), evolution of individual symptoms was assessed for resolution patterns across risk factors, and baseline SARS-CoV-2-specific antibody responses against S1 and N domains. CAS + IMD versus placebo provided statistically significant resolution for 17/23 symptoms, with greater response linked to absence of endogenous anti–SARS-CoV-2 immunoglobulin (Ig)G, IgA, or specific neutralizing antibodies at baseline, or high baseline viral load. Resolution of five key symptoms (onset days 3–5)—dyspnea, cough, feeling feverish, fatigue, and loss of appetite—independently correlated with reduced hospitalization and death (hazard ratio range: 0.31–0.56; P

Abstract Pyridoxal 5’-phosphate (PLP)-dependent enzymes utilize a vitamin B6-derived cofactor to perform a myriad of chemical transformations on amino acids and other small molecules. Some PLP-dependent enzymes, such as serine hydroxymethyltransferase (SHMT), are promising drug targets for the design of small-molecule antimicrobials and anticancer therapeutics, while others have been used to synthesize pharmaceutical building blocks. Understanding PLP-dependent catalysis and the reaction specificity is crucial to advance structure-assisted drug design and enzyme engineering. Here we report the direct determination of the protonation states in the active site of Thermus thermophilus SHMT (TthSHMT) in the internal aldimine state using room-temperature joint X-ray/neutron crystallography. Conserved active site architecture of the model enzyme TthSHMT and of human mitochondrial SHMT (hSHMT2) were compared by obtaining a room-temperature X-ray structure of hSHMT2, suggesting identical protonation states in the human enzyme. The amino acid substrate serine pathway through the TthSHMT active site cavity was tracked, revealing the peripheral and cationic binding sites that correspond to the pre-Michaelis and pseudo-Michaelis complexes, respectively. At the peripheral binding site, the substrate is bound in the zwitterionic form. By analyzing the observed protonation states, Glu53, but not His residues, is proposed as the general base catalyst, orchestrating the retro-aldol transformation of L-serine into glycine.

BACKGROUND: Financial mismanagement and abuse in dementia have serious consequences for patients and their families. Vulnerability to these outcomes reflects both patient and contextual factors. OBJECTIVE: Our study aimed to assess how multidisciplinary care coordination programs assist families in addressing psychosocial vulnerabilities and accessing needed resources. METHODS: Our study was embedded in a clinical trial of the Care Ecosystem, a telephone- and internet-based supportive care intervention for patients with dementia and caregivers. This program is built around the role of the Care Team Navigator (CTN), an unlicensed dementia care guide who serves as the patient and caregivers primary point of contact, screening for common problems and providing support. We conducted a qualitative analysis of case summaries from a subset of 19 patient/caregiver dyads identified as having increased risk for financial mismanagement and abuse, to examine how Care Ecosystem staff identified vulnerabilities and provided support to patients and families. RESULTS: CTNs elicited patient and caregiver needs using templated conversations to address common financial and legal planning issues in dementia. Sources of financial vulnerability included changes in patients behavior, caregiver burden, intrafamily tension, and confusion about resources to facilitate end-of-life planning. The Care Ecosystem staffs rapport with their dyads helped them address these issues by providing emotional support, information on how to access financial, medical, and legal resources, and improving intra-familial communication. CONCLUSION: The Care Ecosystem offers a scalable way to address vulnerabilities to financial mismanagement and abuse in patients and caregivers through coordinated care by unlicensed care guides supported by a multidisciplinary team.

Animal models are an integral part of the drug development and evaluation process. However, they are unsurprisingly imperfect reflections of humans, and the extent and nature of many immunological differences are unknown. With the rise of targeted and biological therapeutics, it is increasingly important that we understand the molecular differences in the immunological behavior of humans and model organisms. However, very few antibodies are raised against non-human primate antigens, and databases of cross-reactivity between species are incomplete. Thus, we screened 332 antibodies in five immune cell populations in blood from humans and four non-human primate species generating a comprehensive cross-reactivity catalog that includes cell type-specificity. We used this catalog to create large mass cytometry universal cross-species phenotyping and signaling panels for humans, along with three of the model organisms most similar to humans: rhesus and cynomolgus macaques and African green monkeys; and one of the mammalian models most widely used in drug development: C57BL/6 mice. As a proof-of-principle, we measured immune cell signaling responses across all five species to an array of 15 stimuli using mass cytometry. We found numerous instances of different cellular phenotypes and immune signaling events occurring within and between species, and detailed three examples (double-positive T cell frequency and signaling; granulocyte response to Bacillus anthracis antigen; and B cell subsets). We also explore the correlation of herpes simian B virus serostatus on the immune profile. Antibody panels and the full dataset generated are available online as a resource to enable future studies comparing immune responses across species during the evaluation of therapeutics.

Assessing the health and competence of the immune system is central to evaluating vaccination responses, autoimmune conditions, cancer prognosis, and treatment. With an increasing number of studies examining immune dysregulation, there is a growing need for a curated reference of variation in immune parameters in healthy individuals. We used mass cytometry (CyTOF) to profile blood from 86 humans in response to 15 ex vivo immune stimuli. We present reference ranges for cell-specific immune markers and highlight differences that appear across sex and age. We identified modules of immune features that suggest there exists an underlying structure to the immune system based on signaling pathway responses across cell types. We observed increased MAPK signaling in inflammatory pathways in innate immune cells and greater overall coordination of immune cell responses in females. In contrast, males exhibited stronger pSTAT1 and pTBK1 responses. These reference data are publicly available as a resource for immune profiling studies.

The nomenclature used to describe animals working in roles supporting people can be confusing. The same term may be used to describe different roles, or two terms may mean the same thing. This confusion is evident among researchers, practitioners, and end users. Because certain animal roles are provided with legal protections and/or government-funding support in some jurisdictions, it is necessary to clearly define the existing terms to avoid confusion. The aim of this paper is to provide operationalized definitions for nine terms, which would be useful in many world regions: "assistance animal", "companion animal", "educational/school support animal", "emotional support animal", "facility animal", "service animal", "skilled companion animal", "therapy animal", and "visiting/visitation animal". At the International Society for Anthrozoology (ISAZ) conferences in 2018 and 2020, over 100 delegates participated in workshops to define these terms, many of whom co-authored this paper. Through an iterative process, we have defined the nine terms and explained how they differ from each other. We recommend phasing out two terms (i.e., "skilled companion animal" and "service animal") due to overlap with other terms that could potentially exacerbate confusion. The implications for several regions of the world are discussed.