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CMOS oscillators that produce high frequencies with good spectral purity or low jitter are almost always realized as differential LC oscillators. This article gives a comprehensive treatment of this circuit for the practitioner who must make design choices and tradeoffs, and for the newcomer who wants to learn to do so. Phase noise is presented in the form of transfer functions from various noise sources, leading to compact, accurate expressions that guide design. Best practices for IC layout and operation at low voltages are given.

IntroductionThe world’s population is aging at a rapid rate. Nursing homes are needed to care for an increasing number of older adults. Palliative care can improve the quality of life of nursing home residents. Artificial Intelligence can be used to improve palliative care services. The aim of this scoping review is to synthesize research surrounding AI-based palliative care interventions in nursing homes.MethodsA PRISMA-ScR scoping review was carried out using modified guidelines specifically designed for computer science research. A wide range of keywords are considered in searching six databases, including IEEE, ACM, and SpringerLink.ResultsWe screened 3255 articles for inclusion after duplicate removal. 3175 articles were excluded during title and abstract screening. A further 61 articles were excluded during the full-text screening stage. We included 19 articles in our analysis. Studies either focus on intelligent physical systems or decision support systems. There is a clear divide between the two types of technologies. There are key issues to address in future research surrounding palliative definitions, data accessibility, and stakeholder involvement.DiscussionThis paper presents the first review to consolidate research on palliative care interventions in nursing homes. The findings of this review indicate that integrated intelligent physical systems and decision support systems have yet to be explored. A broad range of machine learning solutions remain unused within the context of nursing home palliative care. These findings are of relevance to both nurses and computer scientists, who may use this review to reflect on their own practices when developing such technology.

This article uses a case study of an anti-brand protest that was livestreamed on Twitch to develop a media and cultural studies framework for conceptualizing livestreaming platforms as mechanisms that extract engagement and discoverability value from cultural noise. It begins with a review of several fields of literature: branding, media activism, and culture jamming; livestreaming and affective labor; and social media platforms, affective economies, and noise. Then, it synthesizes this literature into a conceptualization of livestreaming’s cultural product and form, connecting its product to the extraction of engagement metrics from affective economies and its form to the affective labor that livestreamers are performing for the purposes of developing personal brands. Finally, it connects the record-setting viewership numbers the Hogwarts Legacy protest created for Twitch to an affective economy of joy, sadness, anger, and nostalgia, focusing specifically on how this economy became a driver of engagement and discoverability value for a transmedia brand.

Abstract Background Recurrent dehydration causes chronic kidney disease in humans and animal models. The dromedary camel kidney has remarkable capacity to preserve water and solute during long-term dehydration. In this study, we investigated the effects of dehydration and subsequent rehydration in the camel's kidney histology/ultrastructure and changes in aquaporin/solute carrier proteins along with gene expression. Results In light microscopy, dehydration induced few degenerative and necrotic changes in cells of the cortical tubules with unapparent or little effect on medullary cells. The ultrastructural changes encountered in the cortex were infrequent during dehydration and included nuclear chromatin condensation, cytoplasmic vacuolization, mitochondrial swelling, endoplasmic reticulum/ lysosomal degeneration and sometimes cell death. Some mRNA gene expressions involved in cell stability were upregulated by dehydration. Lesions in endothelial capillaries, glomerular membranes and podocyte tertiary processes in dehydrated camels indicated disruption of glomerular filtration barrier which were mostly corrected by rehydration. The changes in proximal tubules brush borders after dehydration, were accompanied by down regulation of ATP1A1 mRNA involved in Na + /K + pump that were corrected by rehydration. The increased serum Na, osmolality and vasopressin were paralleled by modulation in expression level for corresponding SLC genes with net Na retention in cortex which were corrected by rehydration. Medullary collecting ducts and interstitial connective tissue were mostly unaffected during dehydration. CKD, a chronic nephropathy induced by recurrent dehydration in human and animal models and characterized by interstitial fibrosis and glomerular sclerosis, were not observed in the dehydrated/rehydrated camel kidneys. The initiating factors, endogenous fructose, AVP/AVPR2 and uric acid levels were not much affected. TGF-β1 protein and TGF-β1gene expression showed no changes by dehydration in cortex/medulla to mediate fibrosis. KCNN4 gene expression level was hardly detected in the dehydrated camel's kidney; to encode for Ca + + -gated KCa3.1 channel for Ca + + influx to instigate TGF-β1. Modulation of AQP 1, 2, 3, 4, 9 and SLC protein and/or mRNAs expression levels during dehydration/rehydration was reported. Conclusions Long-term dehydration induces reversible or irreversible ultrastructural changes in kidney cortex with minor effects in medulla. Modulation of AQP channels, SLC and their mRNAs expression levels during dehydration/rehydration have a role in water conservation. Cortex and medulla respond differently to dehydration/rehydration.

Abstract Developmental and epileptic encephalopathies (DEEs) feature altered brain development, developmental delay and seizures, with seizures exacerbating developmental delay. Here we identify a cohort with biallelic variants in DENND5A, encoding a membrane trafficking protein, and develop animal models with phenotypes like the human syndrome. We demonstrate that DENND5A interacts with Pals1/MUPP1, components of the Crumbs apical polarity complex required for symmetrical division of neural progenitor cells. Human induced pluripotent stem cells lacking DENND5A fail to undergo symmetric cell division with an inherent propensity to differentiate into neurons. These phenotypes result from misalignment of the mitotic spindle in apical neural progenitors. Cells lacking DENND5A orient away from the proliferative apical domain surrounding the ventricles, biasing daughter cells towards a more fate-committed state, ultimately shortening the period of neurogenesis. This study provides a mechanism for DENND5A-related DEE that may be generalizable to other developmental conditions and provides variant-specific clinical information for physicians and families.

Abstract Glucose regulated protein 78 (GRP78) is a chaperone protein that is a central mediator of the unfolded protein response, a key cellular stress response pathway. GRP78 has been shown to be critically required for infection and replication of a number of flaviviruses, and to interact with both non-structural (NS) and structural flavivirus proteins. However, the nature of the specific interaction between GRP78 and viral proteins remains largely unknown. This study aimed to characterize the binding domain and critical amino acid residues that mediate the interaction of GRP78 to ZIKV E and NS1 proteins. Recombinant EGFP fused GRP78 and individual subdomains (the nucleotide binding domain (NBD) and the substrate binding domain (SBD)) were used as a bait protein and co-expressed with full length or truncated ZIKV E and NS1 proteins in HEK293T/17 cells. Protein–protein interactions were determined by a co-immunoprecipitation assay. From the results, both the NBD and the SBD of GRP78 were crucial for an effective interaction. Single amino acid substitutions in the SBD showed that R492E and T518A mutants significantly reduced the binding affinity of GRP78 to ZIKV E and NS1 proteins. Notably, the interaction of GRP78 with ZIKV E was stably maintained against various single amino acid substitutions on ZIKV E domain III and with all truncated ZIKV E and NS1 proteins. Collectively, the results suggest that the principal binding between GRP78 and viral proteins is mainly a classic canonical chaperone protein-client interaction. The blocking of GRP78 chaperone function effectively inhibited ZIKV infection and replication in neuronal progenitor cells. Our findings reveal that GRP78 is a potential host target for anti-ZIKV therapeutics.

Abstract Background Autism spectrum disorder (hereafter referred to as autism) is characterised by difficulties with (i) social communication, social interaction, and (ii) restricted and repetitive interests and behaviours. Estimates of autism prevalence within the criminal justice system (CJS) vary considerably, but there is evidence to suggest that the condition can be missed or misidentified within this population. Autism has implications for an individual’s journey through the CJS, from police questioning and engagement in court proceedings through to risk assessment, formulation, therapeutic approaches, engagement with support services, and long-term social and legal outcomes. Methods This consensus based on professional opinion with input from lived experience aims to provide general principles for consideration by United Kingdom (UK) CJS personnel when working with autistic individuals, focusing on autistic offenders and those suspected of offences. Principles may be transferable to countries beyond the UK. Multidisciplinary professionals and two service users were approached for their input to address the effective identification and support strategies for autistic individuals within the CJS. Results The authors provide a consensus statement including recommendations on the general principles of effective identification, and support strategies for autistic individuals across different levels of the CJS. Conclusion Greater attention needs to be given to this population as they navigate the CJS.

Abstract Primary familial brain calcification (PFBC) is characterized by calcium deposition in the brain, causing progressive movement disorders, psychiatric symptoms, and cognitive decline. PFBC is a heterogeneous disorder currently linked to variants in six different genes, but most patients remain genetically undiagnosed. Here, we identify biallelic NAA60 variants in ten individuals from seven families with autosomal recessive PFBC. The NAA60 variants lead to loss-of-function with lack of protein N-terminal (Nt)-acetylation activity. We show that the phosphate importer SLC20A2 is a substrate of NAA60 in vitro. In cells, loss of NAA60 caused reduced surface levels of SLC20A2 and a reduction in extracellular phosphate uptake. This study establishes NAA60 as a causal gene for PFBC, provides a possible biochemical explanation of its disease-causing mechanisms and underscores NAA60-mediated Nt-acetylation of transmembrane proteins as a fundamental process for healthy neurobiological functioning.

Background: Central line-associated bloodstream infections (CLABSI) and catheter-associated urinary tract infections (CAUTI) are key healthcare-associated infection (HAI) quality metrics. In this qualitative analysis, we aimed to identify common issues contributing to CLABSIs and CAUTIs occurring during the COVID-19 pandemic. Methods: In an academic healthcare network in Atlanta, GA, four hospitals perform real-time, apparent cause analyses (ACAs) for all CLABSIs and CAUTIs. Contributing factors are entered as free text into an electronic database. We analyzed data from 8/2020–8/2022. We first performed a qualitative open card sort of all reported contributing factors to CLABSI and created a novel framework based on mutually defined critical tasks (e.g., line insertion) and cross-cutting issues (e.g., communication breakdown). Contributing factors could describe ≥1 critical task and/or ≥1 cross-cutting issue. After establishing interrater reliability, a multidisciplinary group applied this framework to classify each contributing factor. For CAUTI, we used the same set of cross-cutting issues but identified new critical tasks via open card sorting. We then used the framework to classify each CAUTI contributing factor. We used descriptive statistics to identify frequent critical tasks and cross-cutting issues. Results: We reviewed 350 CLABSI ACAs with 602 contributing factors and 240 CAUTI ACAs with 405 contributing factors (Figure 1). Our classification framework comprised 11 cross-cutting issues and 9 critical tasks for CLABSI and 7 critical tasks for CAUTI (Figure 2). CLABSI: The critical tasks most often reported were bathing (19%), central line dressing maintenance (15%), and assessing central line indication (8%; Figure 3). Within these tasks, the most frequent issues described for bathing were the task not being performed (20%) and unclear documentation (18%); for dressing maintenance, the task was not performed (15%), not documented (15%), or poorly performed due to lack of competency (15%); and for assessing line indication, there was frequent communication breakdown (33%). CAUTI: The critical tasks most often reported were urinary catheter care (26%) and assessing the indication for urinary catheter (22%; Figure 4). Within these tasks, urinary catheter care was frequently not documented (38%) or not performed (16%); assessing urinary catheter necessity was often not documented (29%) or involved breakdown of communication (19%). Conclusion: We created a novel framework to evaluate common causes of HAIs in an academic healthcare network. This framework can be used to identify and track gaps over time and to develop quality improvement initiatives targeting key tasks and associated factors, such as communication difficulties when assessing device indications.

Abstract Hypertension and its complications are a leading cause of death in the human population. Several factors can contribute to development of hypertension, such as genetic predisposition, high salt intake and environmental stressors, underlying oxidative stress as one of its key trademarks. We studied the effects of increased salt intake and chronic stress on blood pressure parameters and the activity and protein levels of antioxidant enzymes in the heart and aorta of borderline hypertensive rats (BHRs) with genetic susceptibility to hypertension. All animals were randomized into four groups: (1) Wistar rats kept in baseline conditions; (2) BHRs kept in baseline conditions; (3) BHRs drinking 0.9% saline solution; and (4) BHRs drinking 0.9% saline solution and exposed to repeated heterotypic stress. The BHRs exhibited significantly higher blood pressure, mitochondrial superoxide dismutase (SOD2) and catalase (CAT) protein levels and lower glutathione peroxidase (GPx) and glutathione reductase (GR) activities in the aorta, followed by lower CAT and GPx protein levels and higher CAT and GR activities in the heart, compared with normotensive Wistar rats. In the BHR aorta, high salt intake elevated CAT and GPx activities, and when combined with stress it increased GPx and GR activities. In BHR hearts, high salt intake provoked lower CAT activity. Adding repeated stress to salt treatment further decreased CAT activity, in addition to Cu2+–Zn2+ superoxide dismutase (SOD1) and GR activities. The protein level of CAT was lower, whereas SOD2 and GPx increased. Overall, our results suggest that BHR hearts are better adapted to oxidative pressure, compared with the aorta, when exposed to salt and stress.

Gamma-ray bursts (GRBs) are intense and short-lived cosmic explosions. Miniaturised CubeSat-compatible instruments for the study of GRBs are being developed to help bridge the gap in large missions and assist in achieving full sky coverage. CubeSats are small, compact satellites conforming to a design standard and have transformed the space industry. They are relatively low-cost and are developed on fast timescales, which has provided unparalleled access to space. This paper focuses on GMOD, the gamma-ray module, onboard the 2U CubeSat EIRSAT-1, launched on December 1st 2023. GMOD is a scintillation-based instrument with a cerium bromide crystal coupled to an array of sixteen silicon photomultipliers, designed for the detection of GRBs. The characterisation of GMOD in the spacecraft, along with the validation of an updated spacecraft MEGAlib model is presented and this approach can be followed by other CubeSats with similar science goals. The energy resolution of the flight model is 7.07% at 662 keV and the effective area peaks in the tens to hundreds of keV, making it a suitable instrument for the detection of GRBs. An investigation into the instrument’s angular response is also detailed. The results from this characterisation campaign are a benchmark for the instrument’s performance pre-launch and will be used to compare with the detector’s performance in orbit.

Abstract Introduction Testicular cancer is the most common cancer in men aged 15–44 years in many countries. Most men with testicular cancer present with a lump. Testicular symptoms are more likely to occur secondary to benign diseases like epididymo‐orchitis, a common sexually transmitted infection. Gender and sexual minorities are at an increased risk of testicular diseases and health disparities. The aim of this study was to co‐design an inclusive community‐based campaign to promote testicular awareness. Methods This study uses the World Café methodology. Participation was sought from Lesbian, Gay, Bisexual, Transgender and Queer+ friendly organisations, testicular cancer survivors, health policy makers, media and marketing experts and graphic designers. Participants engaged in three rounds of conversations to co‐design the campaign. Data were collected using drawing sheets, artefact cards, sticky notes, coloured markers and a voice recorder. Deductive thematic analysis was conducted. Results Seventeen individuals participated in the study. Six themes emerged from the analysis as follows: (i) online communication; (ii) offline communication; (iii) behavioural targeting and education; (iv) campaign frequency and reach; (v) demographic segmentation; and (vi) campaign identity. The use of social media for campaign delivery featured strongly in all conversations. Participants also recommended offline communication using posters and radio/television advertisements to scale up the campaign and achieve wider reach. Advertisements to overcome embarrassment surrounding testicular health were particularly recommended. Participants emphasised that campaign delivery must be dynamic whilst ensuring that the health‐promoting messages are not diluted or lost. They stressed the importance of being inclusive and tailoring the campaign to different age groups, gender identities and sexual orientations. Conclusions Study recommendations will be used to design and deliver the campaign. Future research will be needed to evaluate the feasibility, acceptability, cost and effect of the campaign on promoting testicular awareness and early detection of testicular diseases. Patient or Public Contribution A participatory research approach was used to co‐design the campaign with members of Lesbian, Gay, Bisexual, Transgender and Queer+ (LGBTQ+) friendly organisations, LGBTQ+ student bodies, LGBTQ+ staff networks, LGBTQ+ sports clubs, men's health organisations, testicular cancer survivors, health policy makers, media and marketing experts and graphic designers.

IntroductionTesticular cancer is among the most common malignancies in men under the age of 50 years. Most testicular symptoms are linked to benign diseases. Men's awareness of testicular diseases and testicular self-examination behaviours are suboptimal. In this pilot feasibility study and process evaluation we examine the feasibility of conducting a future definitive randomised controlled trial (RCT) to test the effect of the Enhancing Men's Awareness of Testicular Diseases using Virtual Reality intervention (E-MATVR) compared to the Enhancing Men's Awareness of Testicular Diseases using Electric information control (E-MATE). The study protocol is registered on ClinicalTrials.gov (NCT05146466).MethodsMale athletes, engaged in Gaelic games, and aged 18 to 50 years were included. Recruitment was via FacebookTM, XTM (formerly TwitterTM), and posters. Participants were individually randomised to either E-MATVR or E-MATE. Data were collected at baseline (T0), immediately post-test (T1), and three months post-test (T2) using surveys. Qualitative interviews were conducted with participants and researchers.ResultsData were collected from 74 participants. Of those, 66 were retained. All E-MATVR participants and most E-MATE participants (n = 33, 89.2%) agreed/strongly agreed that the device was easy to use and that they were engaged to learn by the device. Most E-MATVR participants (n = 34, 91.9%) and all E-MATE participants agreed/strongly agreed that the time it took them to complete the intervention was reasonable. All 74 participants were extremely satisfied/somewhat satisfied with their overall participation in the study. E-MATVR was described as interactive, easy, fun, and close to real life. Initial difficulty using VR equipment, nausea, and technical issues were identified as challenges to engaging with E-MATVR. Recommendations were made to make VR more accessible, shorten the survey, and incorporate more interactivity. Across all participants, mean testicular knowledge scores (range 0-1) increased from 0.4 (SD 0.2) at T0 to 0.8 (SD 0.2) at T1. At T2, overall mean scores for participants were 0.7 (SD 0.2). Mean knowledge scores did not differ by trial arm at any timepoint. At T2, all E-MATVR participants and 29/32 E-MATE participants (90.6%) reported purposefully examining their testes within the past three months.ConclusionFindings are promising, highlighting the feasibility of using VR to promote young athletes' awareness of testicular diseases. Considering the strengths, limitations, and lessons learned from this study, some modifications are required prior to conducing an RCT. These include but are not limited to shortening survey questions, incorporating more interactivity and visual content, and targeting more heterogenous male-dominated environments.

IntroductionNursing home residents often have life limiting illnesses in combination with multiple comorbidities, cognitive deficits, and frailty. Due to these complex characteristics, a high proportion of nursing home residents require palliative care. However, many do not receive palliative care relative to this need resulting in unmet care needs. To the best of our knowledge, there have been no literature reviews to synthesise the evidence on how nursing home staff identify unmet palliative care needs and to determine what guidelines, policies, and frameworks on identifying unmet palliative care needs of nursing home residents are available.AimThe aim of this scoping review is to map and summarise the evidence on identifying unmet palliative care needs of residents in nursing homes.MethodsThis scoping review will be guided by the JBI Manual for Evidence Synthesis. The search will be conducted in CINAHL, MEDLINE, Embase, Web of Science, APA PsycINFO, and APA PsycArticles. A search of grey literature will also be conducted in databases such as CareSearch, Trip, GuidelineCentral, ClinicalTrials.gov, and the National Institute for Health and Care and Excellence website. The search strategy will be developed in conjunction with an academic librarian. Piloting of the screening process will be conducted to ensure agreement among the team on the eligibility criteria. Covidence software will be used to facilitate deduplication, screening, and blind reviewing. Four reviewers will conduct title and abstract screening. Six reviewers will conduct full text screening. Any conflicts will be resolved by a reviewer not involved in the conflict. One reviewer will conduct data extraction using pre-established data extraction tables. Results will be synthesised, and a narrative synthesis will be used to illustrate the findings of this review. Data will be presented visually using tables, figures, and word clouds, as appropriate.

IntroductionDromedary camels robustly withstand dehydration, and the rough desert environment but the adaptation mechanisms are not well understood. One of these mechanisms is that the dromedary camel increases its body temperature to reduce the process of evaporative cooling during the hot weather. Stress in general, has deleterious effects in the body. In this study, we sought to determine the effects of dehydration and rehydration on stress parameters in the dromedary camels and how it pacifies these effects.MethodsNineteen male camels were randomly divided into control, dehydrated and rehydrated groups, and fed alfalfa hay ad-libitum. The dehydrated and rehydrated groups were water-restricted for 20 days after which the rehydrated camels were provided with water for 72 h. The control and dehydrated camels were slaughtered at day 20 from the start of experiment whereas the rehydrated group was killed 72 h later. Many biochemical, hematological histopathological parameters and gene analysis were performed in relevant tissues collected including blood, plasma, and tissues.Results and discussionIt was observed that severely dehydrated camels lost body weight, passed very hard feces, few drops of concentrated urine, and were slightly stressed as reflected behaviorally by loss of appetite. Physiologically, the stress of dehydration elicited modulation of plasma stress hormones for water preservation and energy supply. Our results showed significant increase in cortisol, norepinephrine and dopamine, and significant decrease in epinephrine and serotonin. The significant increase in malondialdehyde was accompanied with significant increase in antioxidants (glutathione, retinol, thiamin, tocopherol) to provide tissue protection from oxidative stress. The physiological blood changes observed during dehydration serve different purposes and were quickly restored to normality by rehydration. The dehydrated/rehydrated camels showed reduced hump size and serous atrophy of perirenal and epicardial fat. The latter changes were accompanied by significantly increased expression of genes encoding proteins for energy production (ANGPTL4, ACSBG1) from fat and significantly decreased expression of genes (THRSP; FADS 1&2) encoding proteins enhancing energy expenditure. This process is vital for camel survival in the desert. Dehydration induced no major effects in the vital organs. Only minor degenerative changes were observed in hepatic and renal cells, physiological cardiomyocyte hypertrophy in heart and follicular hyperplasia in splenic but lipidosis was not depicted in liver hepatocytes. Ketone bodies were not smelled in urine, sweat and breathing of dehydrated animals supporting the previous finding that the ß hydroxybutyrate dehydrogenase, a key enzyme in ketone body formation, is low in the camel liver and rumen. Rehydration restored most of blood and tissues to normal or near normal. In conclusion, camels are adapted to combat dehydration stress and anorexia by increasing anti-stressors and modulating genes involved in fat metabolism.

IntroductionThe days of dusty couches in therapists' offices behind closed doors are long gone. Now, personalized mood tracking, therapy appointments and breathing exercises are just mere clicks (or taps) away: Technologies for self-care (SCTs) that focus on mental health are both a flourishing industry and an academic field of interest. As societal, and cultural artifacts, SCTs for mental health are imbued with values, worldviews, and assumptions about these concepts by their designers and developers. Here, current SCTs tend to lean toward a more medical(ised) approach due to being shaped by dominant views of mental health as an individualized issue. However, this approach is only one of many potential pedagogies and approaches. As an alternative, we explore what SCTs for mental health could be like, from a humanistic, person-centered standpoint: We conceptualize mental health in holistic terms, as an experiential quality of everyday life.MethodsTo this end, we report on two engagements with humanistic practitioners and the person-centered approach as a guiding principle: First, we ran a workshop informed by the Rogerian “encounter group”. This approach is focused on providing the space to meaningfully meet and relate to people. Inspired by this concept, we brought together humanistic practitioners to openly explore what technology for (self-)care means for them. Second, we build on the insights from the aforementioned study by organizing an asynchronous, online whiteboard for humanistic practitioners—counselors, students-in-training, therapists, and researchers—to explore their utopian, realistic and dystopian visions of SCTs.ResultsThrough thematic analysis and affinity-clustering these engagements, we construct an understanding that technology within a person-centered, humanistic context is a constrained, ambiguous undertaking, yet also one full of potential.DiscussionWe conclude the paper by sketching out three design opportunities for how the person-centered approach, and humanistic psychology in general could be integrated into caring technologies.

Introduction Patients diagnosed with coronary artery disease (CAD) are currently treated with medications and lifestyle advice to reduce the likelihood of disease progression and risk of future major adverse cardiovascular events (MACE). Where obstructive disease is diagnosed, revascularisation may be considered to treat refractory symptoms. However, many patients with coexistent cardiovascular risk factors, particularly those with metabolic syndrome (MetS), remain at heightened risk of future MACE despite current management.Cardiac rehabilitation is offered to patients post-revascularisation, however, there is no definitive evidence demonstrating its benefit in a primary prevention setting. We propose that an intensive lifestyle intervention (Super Rehab, SR) incorporating high-intensity exercise, diet and behavioural change techniques may improve symptoms, outcomes, and enable CAD regression.This study aims to examine the feasibility of delivering a multicentre randomised controlled trial (RCT) testing SR for patients with CAD, in a primary prevention setting.Methods and analysis This is a multicentre randomised controlled feasibility study of SR versus usual care in patients with CAD. The study aims to recruit 50 participants aged 18–75 across two centres. Feasibility will be assessed against rates of recruitment, retention and, in the intervention arm, attendance and adherence to SR. Qualitative interviews will explore trial experiences of study participants and practitioners. Variance of change in CAD across both arms of the study (assessed with serial CT coronary angiography) will inform the design and power of a future, multi-centre RCT.Ethics and dissemination Ethics approval was granted by South West—Frenchay Research Ethics Committee (reference: 21/SW/0153, 18 January 2022). Study findings will be disseminated via presentations to relevant stakeholders, national and international conferences and open-access peer-reviewed research publications.Trial registration number ISRCTN14603929.

Abstract The maintenance of glucose homeostasis is obligatory for health and survival. It relies on peripheral glucose sensing and signalling between the brain and peripheral organs via hormonal and neural responses that restore euglycaemia. Failure of these mechanisms causes hyperglycaemia or diabetes. Current anti‐diabetic medications control blood glucose but many patients remain with hyperglycemic condition. Diabetes is often associated with hypertension; the latter is more difficult to control in hyperglycaemic conditions. We ask whether a better understanding of the regulatory mechanisms of glucose control could improve treatment of both diabetes and hypertension when they co‐exist. With the involvement of the carotid body (CB) in glucose sensing, metabolic regulation and control of sympathetic nerve activity, we consider the CB as a potential treatment target for both diabetes and hypertension. We provide an update on the role of the CB in glucose sensing and glucose homeostasis. Physiologically, hypoglycaemia stimulates the release of hormones such as glucagon and adrenaline, which mobilize or synthesize glucose; however, these counter‐regulatory responses were markedly attenuated after denervation of the CBs in animals. Also, CB denervation prevents and reverses insulin resistance and glucose intolerance. We discuss the CB as a metabolic regulator (not just a sensor of blood gases) and consider recent evidence of novel ‘metabolic’ receptors within the CB and putative signalling peptides that may control glucose homeostasis via modulation of the sympathetic nervous system. The evidence presented may inform future clinical strategies in the treatment of patients with both diabetes and hypertension, which may include the CB.

Van Haute et al describe autosomal recessive TEFM variants that impair mitochondrial transcription elongation and reduce the levels of promoter distal mitochondrial RNA transcripts, leading to heterogeneous mitochondrial diseases with a treatable neuromuscular transmission defect.

Background: Testicular cancer (TC) is among the most commonly diagnosed cancers in men aged 15–40 years. The incidence of TC is on the rise. Benign testicular disorders, such as testicular torsion and epididymitis, can lead to testicular ischemia, sepsis, and infertility if left untreated. This updated systematic review aims to evaluate the effectiveness of studies promoting men’s knowledge and awareness of testicular disorders and/or self-examination, behaviours and/or intentions to examine their testes, and help-seeking behaviours and/or intentions for testicular disorder symptoms. Methods: Academic Search Complete, Medline, CINAHL, PsycINFO, ERIC, the Cochrane Library, the World Health Organisation International Clinical Trials Registry Platform, and Clinicaltrials.gov were searched for studies published between April 2018 and August 2023. Methodological quality was assessed and results were synthesised meta-narratively. Results: Five studies were included. The majority of the reviewed interventions were successful in increasing men’s awareness of TC and self-examination, including a PowerPoint presentation, an online educational brochure, video-assisted teaching, a motivational video, and a virtual reality game. Only one study addressed help-seeking for testicular symptoms and promoted men’s awareness of benign as well as malignant testicular diseases. Conclusions: This review highlights the importance of evaluating innovative educational interventions aimed at younger men, whilst raising their awareness of testicular disorders and increasing their help-seeking intentions for testicular disorder symptoms. Given the lack of consensus around scheduled testicular self-examination among younger men, clinicians are encouraged to instruct men to familiarise themselves with the look and feel of their own testes and to seek timely medical attention for abnormalities. Registration: The protocol of the previous version of this review was registered with the International Prospective Register of Systematic Reviews (PROSPERO) under the registration number CRD42018093671.

Summary: Desert animals have evolved systems that enable them to thrive under dry conditions. Focusing on the kidney, we have investigated the transcriptomic adaptations that enable a desert rodent, the Lesser Egyptian Jerboa (Jaculus jaculus), to withstand water deprivation and opportunistic rehydration. Analysis of the whole kidney transcriptome showed many differentially expressed genes in the Jerboa kidney, 6.4% of genes following dehydration and an even greater number (36.2%) following rehydration compared to control. Genes correlated with the rehydration condition included many ribosomal protein coding genes suggesting a concerted effort to accelerate protein synthesis when water is made available. We identify an increase in TGF-beta signaling antagonists in dehydration (e.g., GREM2). We also describe expression of multiple aquaporin and solute carrier transporters mapped to specific nephron segments. The desert adapted renal transcriptome presented here is a valuable resource to expand our understanding of osmoregulation beyond that derived from model organisms.

Background: Testicular cancer (TC) is the most common malignancy in men under 50 years. Athletes are particularly at risk of testicular trauma and diseases. Experiencing negative testicular symptoms does not necessarily imply that men seek help. Men’s awareness of testicular diseases is often lacking and their intention to seek help for testicular symptoms is sub-optimal. The use of virtual reality (VR) may be effective in promoting men’s awareness of testicular diseases. The Enhancing Men's Awareness of Testicular diseases (E-MAT) feasibility trial aims to test the effect of E-MATVR (intervention; interactive experience using virtual reality [VR]) compared to information delivered Electronically E-MATE (control; same information as E-MATVR delivered as plain text and images) on testicular knowledge, and testicular self-examination among male athletes affiliated with a national sports organisation. The overall aim of this mixed method process evaluation will be to describe (i) the experiences of participants and key stakeholders (e.g., researchers); (ii) the perceived effectiveness of intervention components; (iii) acceptability of the feasibility trial and intervention procedures; (iv) the relationship between implementation, mechanisms, and context; and (v) the barriers and facilitators to support effective conduct of a future definitive trial. Methods: This mixed method process evaluation will use a descriptive realist evaluation. Quantitative data will be gathered using a usability and satisfaction survey, in addition to fidelity checks during intervention delivery. Quantitative data will be analysed using descriptive and inferential statistics. Qualitative data will be gathered from semi-structured interviews and focus groups with participants and key stakeholders to investigate their experiences of E-MATVR and E-MATE, and explore areas for improvement. Thematic analysis of transcripts will be conducted. Conclusions: This process evaluation will provide an in-depth understanding of how the interventions worked within this cohort and lessons for a future definitive trial.

Virtual Reality Exposure Therapy is a method of cognitive behavioural therapy that aids in the treatment of anxiety disorders by making therapy practical and cost-efficient. It also allows for the seamless tailoring of the therapy by using objective, continuous feedback. This feedback can be obtained using biosensors to collect physiological information such as heart rate, electrodermal activity and frontal brain activity. As part of developing our objective feedback framework, we developed a Virtual Reality adaptation of the well-established emotional Stroop Colour–Word Task. We used this adaptation to differentiate three distinct levels of anxiety: no anxiety, mild anxiety and severe anxiety. We tested our environment on twenty-nine participants between the ages of eighteen and sixty-five. After analysing and validating this environment, we used it to create a dataset for further machine-learning classification of the assigned anxiety levels. To apply this information in real-time, all of our information was processed within Virtual Reality. Our Convolutional Neural Network was able to differentiate the anxiety levels with a 75% accuracy using leave-one-out cross-validation. This shows that our system can accurately differentiate between different anxiety levels.

Comparative transcriptomic analyses between dromedary camels and rats provide insight into water homeostasis gene responses in animals under water stress conditions.

Abstract Background Stickler syndrome (STL) is a rare, clinically and molecularly heterogeneous connective tissue disorder. Pathogenic variants occurring in a variety of genes cause STL, mainly inherited in an autosomal dominant fashion. Autosomal recessive STL is ultra-rare with only four families with biallelic COL9A3 variants reported to date. Results Here, we report three unrelated families clinically diagnosed with STL carrying different novel biallelic loss of function variants in COL9A3. Further, we have collected COL9A3 genotype–phenotype associations from the literature. Conclusion Our report substantially expands the molecular genetics and clinical basis of autosomal recessive STL and provides an overview about allelic COL9A3 disorders.

Objectives: The excessive release of the antidiuretic hormone vasopressin is implicated in many diseases including cardiovascular disease, diabetes, obesity, and metabolic syndrome. Once thought to be elevated as a consequence of diseases, data now supports a more causative role. We have previously identified CREB3L1 as a transcription factor that co-ordinates vasopressin synthesis and release in the hypothalamus. The objective here was to identify mechanisms orchestrated by CREB3L1 that co-ordinate vasopressin release. Methods: We mined Creb3l1 knockdown SON RNA-seq data to identify downstream target genes. We proceeded to investigate the expression of these genes and associated pathways in the supraoptic nucleus of the hypothalamus in response to physiological and pharmacological stimulation. We used viruses to selectively knockdown gene expression in the supraoptic nucleus and assessed physiological and metabolic parameters. We adopted a phosphoproteomics strategy to investigate mechanisms that facilitate hormone release by the pituitary gland. Results: We discovered glucagon like peptide 1 receptor (Glp1r) as a downstream target gene and found increased expression in stimulated vasopressin neurones. Selective knockdown of supraoptic nucleus Glp1rs resulted in decreased food intake and body weight. Treatment with GLP-1R agonist liraglutide decreased vasopressin synthesis and release. Quantitative phosphoproteomics of the pituitary neurointermediate lobe revealed that liraglutide initiates hyperphosphorylation of presynapse active zone proteins that control vasopressin exocytosis. Conclusion: In summary, we show that GLP-1R signalling inhibits the vasopressin system. Our data advises that hydration status may influence the pharmacodynamics of GLP-1R agonists so should be considered in current therapeutic strategies.

Abstract Background The COVID-19 pandemic brought a new challenge to medical education—health-care students had fewer opportunities to interact with and treat real patients in clinical settings. Interpersonal communication skills are often developed through human interaction and communication in person, and few studies have proposed feasible digital solutions to develop learners’ communication skills. Consequently, understanding how medical teachers facilitate and implement online training programmes, with feasible instruments, to enhance students’ learning effectiveness when in-person training is not possible is critical. Methods By using a convenience sampling method, we recruited 26 health-care students from seven medical schools in Taiwan. Through semistructured interviews and the thematic analysis technique, we analysed the latent learning factors from the experience of implementing the technology-enhanced experiential e-learning tool ‘mPath’. Results Three themes were generated: A) transferring theory into practice, B) increasing authenticity with analytical features, and C) maintaining autonomy with nondirective learning. The features accessibility, flexibility, intractability, and visualisation with the characteristics of remote accessibility and flexibility, repetition and retrospect, feedback requesting, and visualised analytical reports were considered to enhance learning outcomes. Conclusion This study indicated how online training using technology could develop the participants’ person-centred communication skills and what features influenced the learning outcomes of social distancing. mPath may be a feasible online learning approach and has provided inspiration for developing health-care students’ communication skills when in-person training is not possible.

BackgroundAnxiety prediction can be used for enhancing Virtual Reality applications. We aimed to assess the evidence on whether anxiety can be accurately classified in Virtual Reality.MethodsWe conducted a scoping review using Scopus, Web of Science, IEEE Xplore, and ACM Digital Library as data sources. Our search included studies from 2010 to 2022. Our inclusion criteria were peer-reviewed studies which take place in a Virtual Reality environment and assess the user's anxiety using machine learning classification models and biosensors.Results1749 records were identified and out of these, 11 (n = 237) studies were selected. Studies had varying numbers of outputs, from two outputs to eleven. Accuracy of anxiety classification for two-output models ranged from 75% to 96.4%; accuracy for three-output models ranged from 67.5% to 96.3%; accuracy for four-output models ranged from 38.8% to 86.3%. The most commonly used measures were electrodermal activity and heart rate.ConclusionResults show that it is possible to create high-accuracy models to determine anxiety in real time. However, it should be noted that there is a lack of standardisation when it comes to defining ground truth for anxiety, making these results difficult to interpret. Additionally, many of these studies included small samples consisting of mostly students, which may bias the results. Future studies should be very careful in defining anxiety and aim for a more inclusive and larger sample. It is also important to research the application of the classification by conducting longitudinal studies.

Background: The coronavirus disease-2019 (COVID-19) pandemic significantly affected management of cardiovascular disease around the world. The effect of the pandemic on volume of cardiovascular diagnostic procedures is not known. Objectives: This study sought to evaluate the effects of the early phase of the COVID-19 pandemic on cardiovascular diagnostic procedures and safety practices in Asia. Methods: The International Atomic Energy Agency conducted a worldwide survey to assess changes in cardiovascular procedure volume and safety practices caused by COVID-19. Testing volumes were reported for March 2020 and April 2020 and were compared to those from March 2019. Data from 180 centers across 33 Asian countries were grouped into 4 subregions for comparison. Results: Procedure volumes decreased by 47% from March 2019 to March 2020, showing recovery from March 2020 to April 2020 in Eastern Asia, particularly in China. The majority of centers cancelled outpatient activities and increased time per study. Practice changes included implementing physical distancing and restricting visitors. Although COVID testing was not commonly performed, it was conducted in one-third of facilities in Eastern Asia. The most severe reductions in procedure volumes were observed in lower-income countries, where volumes decreased 81% from March 2019 to April 2020. Conclusions: The COVID-19 pandemic in Asia caused significant reductions in cardiovascular diagnostic procedures, particularly in low-income countries. Further studies on effects of COVID-19 on cardiovascular outcomes and changes in care delivery are warranted.

Objectives: Dynamic changes to neuropeptide hormone synthesis and secretion by hypothalamic neuroendocrine cells is essential to ensure metabolic homeostasis. The specialised molecular mechanisms that allow neuroendocrine cells to synthesise and secrete vast quantities of neuropeptides remain ill defined. The objective of this study was to identify novel genes and pathways controlled by transcription factor and endoplasmic reticulum stress sensor Creb3l1 which is robustly activated in hypothalamic magnocellular neurones in response to increased demand for protein synthesis. Methods: We adopted a multiomic strategy to investigate specific roles of Creb3l1 in rat magnocellular neurones. We first performed chromatin immunoprecipitation followed by genome sequencing (ChIP-seq) to identify Creb3l1 genomic targets and then integrated this data with RNA sequencing data from physiologically stimulated and Creb3l1 knockdown magnocellular neurones. Results: The data converged on Creb3l1 targets that code for ribosomal proteins and endoplasmic reticulum proteins crucial for the maintenance of cellular proteostasis. We validated genes that compose the PERK arm of the unfolded protein response pathway including Eif2ak3, Eif2s1, Atf4 and Ddit3 as direct Creb3l1 targets. Importantly, knockdown of Creb3l1 in the hypothalamus led to a dramatic depletion in neuropeptide synthesis and secretion. The physiological outcomes from studies of paraventricular and supraoptic nuclei Creb3l1 knockdown animals were changes to food and water consumption. Conclusion: Collectively, our data identify Creb3l1 as a comprehensive controller of the PERK signalling pathway in magnocellular neurones in response to physiological stimulation. The broad regulation of neuropeptide synthesis and secretion by Creb3l1 presents a new therapeutic strategy for metabolic diseases.

Fernando Alvira-Iraizoz and Benjamin T. Gillard et al. comprehensively catalogue the kidney transcriptome and proteome of dromedary camels in response to chronic dehydration stress and subsequent acute rehydration. Their results suggest that the suppression of the cholesterol biosynthesis may facilitate water retention in the dromedary camel kidney, providing further insight into how these animals survive in arid conditions.

Abstract Background Despite the recommendation of European Working Group on Sarcopenia in Older People 2 (EWGSOP2) consensus statement not to exclude patients younger than 65 years, the prevalence of sarcopenia has not been investigated in younger post‐acute inpatient rehabilitation population. The objectives of this study were to: i) estimate the prevalence of sarcopenia in post‐acute inpatient rehabilitation population; ii) compare the prevalence of sarcopenia in patients above and below 65 years. Methods This cross‐sectional observational study recruited adult patients admitted to an inpatient rehabilitation unit at a metropolitan tertiary referral hospital in Melbourne, Australia. Participants' sarcopenia status was determined using the EWGSOP2 algorithm based on grip strength and muscle mass. Results Between November 2016 and January 2019, 203 participants were enrolled. Participants' broad diagnostic streams included musculoskeletal, neurologic, spinal, cardiac, amputee, and deconditioning. The overall prevalence of sarcopenia was 18% [95% confidence interval (CI) 13% to 24%]. The prevalence of sarcopenia in patients younger than 65 was 14% (95% CI 8% to 22%), and the prevalence in patients 65 and older was 23% (95% CI 15% to 32%), risk difference of 9% (95% CI: −1.2% to 20%; P = 0.1). With incorporation of these results into the most recent meta‐analysis of sarcopenia in inpatient rehabilitation, the mean pooled prevalence of sarcopenia was 47% (95% CI 23% to 71%). Stratified by age, patients with sarcopenia had significantly longer preceding length of stay in the acute hospital (P = 0.015). Conclusions The overall estimated prevalence of sarcopenia in patients admitted to inpatient rehabilitation was 18%, and the estimated prevalence of sarcopenia in patients younger than 65 was 14%.

Abstract Zika virus (ZIKV) is a mosquito-transmitted virus that has caused significant public health concerns around the world, partly because of an association with microcephaly in babies born to mothers who were infected with ZIKV during pregnancy. As a recently emerging virus, little is known as to how the virus interacts with the host cell machinery. A yeast-2-hybrid screen for proteins capable of interacting with the ZIKV E protein domain III, the domain responsible for receptor binding, identified 21 proteins, one of which was the predominantly ER resident chaperone protein GRP78. The interaction of GRP78 and ZIKV E was confirmed by co-immunoprecipitation and reciprocal co-immunoprecipitation, and indirect immunofluorescence staining showed intracellular and extracellular co-localization between GRP78 and ZIKV E. Antibodies directed against the N-terminus of GRP78 were able to inhibit ZIKV entry to host cells, resulting in significant reductions in the levels of ZIKV infection and viral production. Consistently, these reductions were also observed after down-regulation of GRP78 by siRNA. These results indicate that GRP78 can play a role mediating ZIKV binding, internalization and replication in cells. GRP78 is a main regulator of the unfolded protein response (UPR), and the study showed that expression of GRP78 was up-regulated, and the UPR was activated. Increases in CHOP expression, and activation of caspases 7 and 9 were also shown in response to ZIKV infection. Overall these results indicate that the interaction between GRP78 and ZIKV E protein plays an important role in ZIKV infection and replication, and may be a potential therapeutic target.

TMS has become a powerful tool to explore cortical function, and in parallel has proven promising in the development of therapies for various psychiatric and neurological disorders. Unfortunately, much of the inference of the direct effects of TMS has been assumed to be limited to the area a few centimeters beneath the scalp, though clearly more distant regions are likely to be influenced by structurally connected stimulation sites. In this study, we sought to develop a novel paradigm to individualize TMS coil placement to non-invasively achieve activation of specific deep brain targets of relevance to the treatment of psychiatric disorders. In ten subjects, structural diffusion imaging tractography data were used to identify an accessible cortical target in the right frontal pole that demonstrated both anatomic and functional connectivity to right Brodmann area 25 (BA25). Concurrent TMS-fMRI interleaving was used with a series of single, interleaved TMS pulses applied to the right frontal pole at four intensity levels ranging from 80% to 140% of motor threshold. In nine of ten subjects, TMS to the individualized frontal pole sites resulted in significant linear increase in BOLD activation of BA25 with increasing TMS intensity. The reliable activation of BA25 in a dosage-dependent manner suggests the possibility that the careful combination of imaging with TMS can make use of network properties to help overcome depth limitations and allow noninvasive brain stimulation to influence deep brain structures.

The paraventricular nucleus (PVN) is a highly organized structure of the hypothalamus that has a key role in regulating cardiovascular and osmotic homeostasis. Functionally, the PVN is divided into autonomic and neuroendocrine (neurosecretory) compartments, both equally important for maintaining blood pressure (BP) and body fluids in the physiological range. Neurosecretory magnocellular neurons (MCNs) of the PVN are the main source of the hormones vasopressin (VP), responsible for water conservation and hydromineral balance, and oxytocin (OT), involved in parturition and milk ejection during lactation. Further, neurosecretory parvocellular neurons (PCNs) take part in modulation of the hypothalamic–pituitary–adrenal axis and stress responses. Additionally, the PVN takes central place in autonomic adjustment of BP to environmental challenges and contributes to its variability (BPV), underpinning the PVN as an autonomic master controller of cardiovascular function. Autonomic PCNs of the PVN modulate sympathetic outflow toward heart, blood vessels and kidneys. These pre-autonomic neurons send projections to the vasomotor nucleus of rostral ventrolateral medulla and to intermediolateral column of the spinal cord, where postganglionic fibers toward target organs arise. Also, PVN PCNs synapse with NTS neurons which are the end-point of baroreceptor primary afferents, thus, enabling the PVN to modify the function of baroreflex. Neuroendocrine and autonomic parts of the PVN are segregated morphologically but they work in concert when the organism is exposed to environmental challenges via somatodendritically released VP and OT by MCNs. The purpose of this overview is to address both neuroendocrine and autonomic PVN roles in BP and BPV regulation.

Background: Testicular cancer (TC) is the most common malignancy in men under 50 years. Athletes are particularly at risk of testicular trauma and diseases. Experiencing negative testicular symptoms does not necessarily imply that men seek help. Men’s awareness of testicular diseases is often lacking and their intention to seek help for testicular symptoms is sub-optimal. The use of virtual reality (VR) may be effective in promoting men’s awareness of testicular diseases. The Enhancing Men's Awareness of Testicular diseases (E-MAT) feasibility trial aims to test the effect of E-MATVR (intervention; interactive experience using virtual reality [VR]) compared to information delivered Electronically E-MATE (control; same information as E-MATVR delivered as plain text and images) on testicular knowledge, and testicular self-examination among male athletes affiliated with a national sports organisation. The overall aim of this mixed method process evaluation will be to describe (i) the experiences of participants and key stakeholders (e.g., researchers); (ii) the perceived effectiveness of intervention components; (iii) acceptability of the feasibility trial and intervention procedures; (iv) the relationship between implementation, mechanisms, and context; and (v) the barriers and facilitators to support effective conduct of a future definitive trial. Methods: This mixed method process evaluation will use a descriptive realist evaluation. Quantitative data will be gathered using a usability and satisfaction survey, in addition to fidelity checks during intervention delivery. Quantitative data will be analysed using descriptive and inferential statistics. Qualitative data will be gathered from semi-structured interviews and focus groups with participants and key stakeholders to investigate their experiences of E-MATVR and E-MATE, and explore areas for improvement. Thematic analysis of transcripts will be conducted. Conclusions: This process evaluation will provide an in-depth understanding of how the interventions worked within this cohort and lessons for a future definitive trial.

With the rapid expansion of technology and hardware availability within the field of Augmented Reality, building and deploying Augmented Reality learning environments has become more logistically viable than ever before. In this paper, we focus on the development of a new mobile learning experience for a museum by combining multiple technologies to provide additional Human–computer interaction possibilities. This is both to reduce barriers to entry for end-users as well as provide natural interaction methods. Using our method, we implemented a new approach to gesture-based interactions for Augmented Reality interactions by combining two devices, a Leap Motion and a Microsoft HoloLens (1st Generation), via an intermediary device with the use of local-area networking. This was carried out with the intention of comparing this method against alternative forms of Augmented Reality to determine which implementation has the largest impact on adult learners’ ability to retain information. A control group has been used to establish data on memory retention without the use of Augmented Reality technology, along with three focus groups to explore the different methods and locations. Results found that adult learners retain the most overall information when being educated through a traditional lecture, with a statistically significant difference between the methods; however, the use of Augmented Reality resulted in a slower rate of knowledge decay between testing intervals. This contrasts with existing research as adult learners did not respond to the technology in the same way that child and teenage audiences previously have, which suggests that prior research may not be generalisable to all audiences.

Objective: To investigate the association between sarcopenia and functional improvement in patients older and younger than 65 years upon completion of an inpatient rehabilitation program.Design: Prospective cohort study.Participants: Adult consecutive patients who completed the inpatient rehabilitation program at a metropolitan tertiary referral hospital general inpatient rehabilitation unit.Methods: Sarcopenia status was determined using the European Working Group on Sarcopenia in Older People 2 algorithm, using muscle mass measured by BioImpedance Analysis and grip strength. Progress in rehabilitation was measured using change in the Functional Independence Measure and Goal Attainment Scaling score. To investigate the age group by sarcopenia status interaction we used quantile regression models with bootstrapped standard error estimation for functional improvement and linear regression model with robust standard error estimation for GAS score.Results: 257 participants [128 (50%) male, median age 63 years (IQR: 52–72)], 33(13%) with sarcopenia, completed inpatient rehabilitation [median length of stay 16 days (IQR: 11–27.5)]. Participants' median Functional Independence Measure change was 24 (IQR 15–33.5) and mean total Goal Attainment Scaling score was 57.6 (SD 10.2). Adjusting for admission Functional Independence Measure score, the median difference in Functional Independence Measure change between participants with and without sarcopenia was: −4.3 (95% CI: −10.6, 1.9); p = 0.17 in participants 65 years and younger, and 4.6 (95% CI: 1.0, 8.2); p = 0.01 in participants older than 65; age-by-sarcopenia interaction p = 0.02.Conclusions: Unlike younger people, older people with sarcopenia have greater functional improvement in inpatient rehabilitation than those without sarcopenia.

One of the polymer additive manufacturing processes commonly used today is fused deposition modelling (FDM). FDM is the process of manufacturing three-dimensional structure through the use of a layer-by-layer printing of the polymer filament. Due to the anisotropic nature of FDM parts, the orientation of the rasters and the build orientation have an effect on the mechanical properties of a part. This study evaluates the fracture toughness of FDM solid-build specimens manufactured from Ultem 1010. The effects of build orientation and raster orientation were investigated through the use of a full-factorial design of experiments. The fracture toughness was obtained using single-edge notch bend test for a range of build orientations and rasters typically used in the FDM process. The design of experiments uses the results of the single-edge notch bend test to determine the significance the factors, build orientation and raster angle, have on the response variable, conditional critical stress intensity factor. Ultem 1010 parts were also microscopically examined to understand the primary failure mode around the rasters. The primary results of this study include the relationship of the build parameters to each other and to the fracture toughness of Ultem 1010.

There is a crisis in higher education internationally whereby the value of a degree is being called into question. One of the contributing factors to this problem is the growth of the sector internationally. Questions have arisen concerning the quality of provision, especially in the case of courses offered in different contexts as part of transnational partnerships. This research explores the perceptions of staff involved with the delivery of a unique transnational higher education partnership between a Russell Group university in the UK and a new university in Kazakhstan. The research sought to understand whether student development was perceived to be in line with the graduate attributes of the intuitions involved. The research was qualitative, using in depth semi structured interviews with members of faculty involved with the delivery of the foundation course, including administration staff, teachers and managers. Responses from participants indicated that the development of characteristics broadly aligned to those stated in graduate attributes did occur.

Ultradian glucocorticoid rhythms are highly conserved across mammalian species, however, their functional significance is not yet fully understood. Here we demonstrate that pulsatile corticosterone replacement in adrenalectomised rats induces a dynamic pattern of glucocorticoid receptor (GR) binding at ~3,000 genomic sites in liver at the pulse peak, subsequently not found during the pulse nadir. In contrast, constant corticosterone replacement induced prolonged binding at the majority of these sites. Additionally, each pattern further induced markedly different transcriptional responses. During pulsatile treatment, intragenic occupancy by active RNA polymerase II exhibited pulsatile dynamics with transient changes in enrichment, either decreased or increased depending on the gene, which mostly returned to baseline during the inter-pulse interval. In contrast, constant corticosterone exposure induced prolonged effects on RNA polymerase II occupancy at the majority of gene targets, thus acting as a sustained regulatory signal for both transactivation and repression of glucocorticoid target genes. The nett effect of these differences were consequently seen in the liver transcriptome as RNA-seq analysis indicated that despite the same overall amount of corticosterone infused, twice the number of transcripts were regulated by constant corticosterone infusion, when compared to pulsatile. Target genes that were found to be differentially regulated in a pattern-dependent manner were enriched in functional pathways including carbohydrate, cholesterol, glucose and fat metabolism as well as inflammation, suggesting a functional role for dysregulated glucocorticoid rhythms in the development of metabolic dysfunction.

ABSTRACT Background Knowledge of the genetic background of many human diseases is currently lacking from genetically undiscovered regions, including Central Asia. Kazakhstan is the first Central Asian country where the genetic studies of Parkinson's disease (PD) have been emerging since it had become a member of the International Parkinson Disease Genomics Consortium. Here we report on the results of whole‐exome sequencing (WES) in 50 young‐onset PD (YOPD) cases from Kazakhstan. Methodology WES was performed on 50 unrelated individuals with YOPD from Kazakhstan. Exome data were screened for novel/ultra‐rare deleterious variants in known and candidate PD genes. Copy number variants and small indels were also called. Results Only three cases (6%) were found to be positive for known PD genes including two unrelated familial PD cases with LRRK2 p.(Arg1441Cys) and one case with a homozygous pathogenic PRKN p.(Arg84Trp) variant. Four cases had novel and ultra‐rare variants of uncertain significance in LRRK2, DNAJC13, and VPS35. Novel deleterious variants were found in candidate Mendelian PD genes including CSMD1, TNR, EIF4G1, and ATP13A3. Eight cases harbored the East Asian‐specific LRRK2 p.(Ala419Val) variant. Conclusions The low diagnostic yield in our study might imply that a significant proportion of YOPD cases in Central Asia remains unresolved. Therefore, a better understanding of the genetic architecture of PD among populations of Central Asian ancestry and the pathogenicity of numerous rare variants should be further investigated. WES is a valuable technique for large‐scale YOPD genetic studies in Central Asia.

The rapidly expanding biotechnology sector horizon is expected to create a surge in demand for expertise underpinning cell and gene therapies, which are recognized as the next generation of medicines. New and innovative approaches to implement active and performative learning in the Molecular Life Sciences are required to support this and to address limitations associated with traditional “front of class” lectern delivery of challenging, three dimensional molecular concepts. Therefore, an immediate need exists for the development and implementation of immersive learning approaches in Virology, Cellular Sciences and Molecular Biology to underpin sustainable development of graduate students for academic and industrial research careers. The Covid-19 pandemic has led to significant changes in the delivery of education globally, with online engagement and accelerated uptake of novel teaching and assessment modalities into majority practice within institutions. This development has been driven by externally imposed necessity and it remains to be seen what form teaching and learning will take post-Covid. Irrespective of the pandemic, technologies are available which can serve intrinsically motivated, discipline specific shifts toward enhanced learner experiences and learning outcomes. Immersive virtual reality offers one such approach to open new entry points for student learning of abstract molecular concepts, which will be just as relevant upon our return to face-to-face teaching. Key to delivering this will be engagement and collaboration by disciplinary and technical experts. Here, we discuss global advances in the area of VR and Molecular Science education and assess potential paths forward for teaching and learning impact and innovative education.

The chronically increased blood pressure characteristic of essential hypertension represents an insidious and cumulative risk for cardiovascular disease. Essential hypertension is a multifactorial condition, with no known specific aetiology but a strong genetic component. The Spontaneously Hypertensive rat (SHR) shares many characteristics of human essential hypertension, and as such is a commonly used experimental model. The mammalian hypothalamo-neurohypophyseal system (HNS) plays a pivotal role in the regulation of blood pressure, volume and osmolality. In order to better understand the possible role of the HNS in hypertension, we have used microarray analysis to reveal differential regulation of genes in the HNS of the SHR compared to a control normotensive strain, the Wistar Kyoto rat (WKY). These results were validated by quantitative reverse transcription-polymerase chain reaction (qRT-PCR). One of the genes identified and validated as being downregulated in SHR compared to WKY was that encoding the neuropeptide urocortin (Ucn). Immunohistochemical analyses revealed Ucn to be highly expressed within magnocellular neurons of the PVN and SON, with pronounced localisation in dendritic projections containing oxytocin and vasopressin. When Ucn was overexpressed in the PVN of the SHR by in vivo lentiviral mediated gene transfer, blood pressure was unaffected but there were significant, transient reductions in the VLF spectra of systolic blood pressure consistent with an action on autonomic balance. We suggest that Ucn may act, possibly via dendritic release, to subtly regulate neurohumoral aspects of arterial pressure control.

Abstract Introduction We investigated the frequency, neuropathology, and phenotypic characteristics of spastic paraplegia (SP) that precedes dementia in presenilin 1 (PSEN1) related familial Alzheimer's disease (AD). Methods We performed whole exome sequencing (WES) in 60 probands with hereditary spastic paraplegia (HSP) phenotype that was negative for variants in known HSP‐related genes. Where PSEN1 mutation was identified, brain biopsy was performed. We investigated the link between HSP and AD with PSEN1 in silico pathway analysis and measured in vivo the stability of PSEN1 mutant γ‐secretase. Results We identified a PSEN1 variant (p.Thr291Pro) in an individual presenting with pure SP at 30 years of age. Three years later, SP was associated with severe, fast cognitive decline and amyloid deposition with diffuse cortical plaques on brain biopsy. Biochemical analysis of p.Thr291Pro PSEN1 revealed that although the mutation does not alter active γ‐secretase reconstitution, it destabilizes γ‐secretase‐amyloid precursor protein (APP)/amyloid beta (Aβn) interactions during proteolysis, enhancing the production of longer Aβ peptides. We then extended our analysis to all 226 PSEN1 pathogenic variants reported and show that 7.5% were associated with pure SP onset followed by cognitive decline later in the disease. We found that PSEN1 cases manifesting initially as SP have a later age of onset, are associated with mutations located beyond codon 200, and showed larger diffuse, cored plaques, amyloid‐ring arteries, and severe CAA. Discussion We show that pure SP can precede dementia onset in PSEN1‐related familial AD. We recommend PSEN1 genetic testing in patients presenting with SP with no variants in known HSP‐related genes, particularly when associated with a family history of cognitive decline.

Background: Adverse childhood experiences (ACEs) have been identified as an important public health problem with serious implications. Less well understood is how distinct configurations of childhood adversities carry differential risks for mental health, emotional, and social outcomes later in life. Objective: To determine if distinct profiles of childhood adversities exist for males and females and to examine if unique associations exist between the resultant latent profiles of childhood adversities and multiple indicators of mental health and social and emotional wellbeing in adulthood. Method: Participants (N = 1,839) were a nationally representative household sample of adults currently residing in the USA and the data were collected via online self-report questionnaires. Latent class analysis was used to identify the optimal number of classes to explain ACE co-occurrence among males and females, separately. ANOVAs, chi-square tests, and t-tests were used to compare male and female classes across multiple mental health, emotional, and social wellbeing variables in adulthood. Results: Females were significantly more likely than males to report a range of ACEs and mental health, social, and emotional difficulties in adulthood. Two- and four-class models were identified as the best fit for males and females, respectively, indicating more complexity and variation in ACE exposures among females. For males and female, ACEs were strongly associated with poorer mental health, emotional, and social outcomes in adulthood. Among females, growing up in a dysfunctional home environment was a significant risk factor for adverse social outcomes in adulthood. Conclusions: Males and females have distinct patterns of childhood adversities, with females experiencing more complex and varied patterns of childhood adversity. These patterns of ACEs were associated with numerous negative mental, emotional, and social outcomes among both sexes.