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The ubiquitin-proteasome system mediates the degradation of a wide variety of proteins. Proteasome dysfunction is associated with neurodegenerative diseases and neurodevelopmental disorders in humans. Here we identified mutations in PSMC5, an AAA ATPase subunit of the proteasome 19S regulatory particle, in individuals with neurodevelopmental disorders, which were initially considered as variants of unknown significance. We have now found heterozygotes with the following mutations: P320R (6 individuals), R325W, Q160A, and one nonsense mutation at Q69. We focused on understanding the functional consequence of PSMC5 insufficiency and the P320R mutation in cells and found that both impair proteasome function and activate apoptosis. Interestingly, the P320R mutation impairs proteasome function by weakening the association between the 19S regulatory particle and the 20S core particle. Our study supports that proteasome dysfunction is the pathogenic cause of neurodevelopmental disorders in individuals carrying PSMC5 variants.
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Introduction: There is growing evidence suggesting that dual-task training benefits people with Parkinson's disease (PD) on both physical and cognitive outcomes. However, there is no known data regarding professionals' educational needs and barriers to its implementation. This study aimed to explore the barriers and educational needs of healthcare and exercise professionals to integrate dual-task training into their practice with people with PD. Methods: We conducted a study based on a web survey. Social media channels were used to recruit a convenience sample of exercise and healthcare professionals working with people with PD. Results: Of the 185 eligible responses, the majority were physiotherapists (68.1%) followed by occupational therapists (10.8%). Most participants attended Parkinson specific training (88.6%) and employed the treatments set up in individual one on-one sessions (58.9%). We identified several barriers to dual-task training implementation, with lack of time (to prepare materials), staying creative and/ or accessing new ideas, unreliable tools for measuring gains, and insufficient expertise as the most referred by participants. The educational needs most referred included accessing examples of interventions in general, knowing what strategies to apply and their application for people with different symptoms. Discussion: Our results highlight that professionals remain challenged to integrate dualtask training into PD clinical care mainly due to knowledge gaps, difficulties in accessing new ideas, and lack of time.
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Evidence suggests that tart cherry (TC) supplementation has beneficial effects on health indices and recovery following strenuous exercise. However, little is known about the mechanisms and how TC might modulate the human metabolome. The aim of this study was to evaluate the influence of an acute high- and low-dose of Vistula TC supplementation on the metabolomic profile in humans. In a randomised, double-blind, placebo controlled, cross-over design, 12 healthy participants (nine male and three female; mean ± SD age, stature, and mass were 29 ± 7 years old, 1.75 ± 0.1 m, and 77.3 ± 10.5 kg, respectively) visited the laboratory on three separate occasions (high dose; HI, low dose; LO, or placebo), separated by at least seven days. After an overnight fast, a baseline venous blood sample was taken, followed by consumption of a standardised breakfast and dose conditions (HI, LO, or placebo). Subsequent blood draws were taken 1, 2, 3, 5, and 8 h post consumption. Following sample preparation, an untargeted metabolomics approach was adopted, and the extracts analysed by LCMS/MS. When all time points were collated, a principal component analysis showed a significant difference between the conditions (p < 0.05), such that the placebo trial had homogeneity, and HI showed greater heterogeneity. In a sub-group analysis, cyanidine-3-O-glucoside (C3G), cyanidine-3-O-rutinoside (C3R), and vanillic acid (VA) were detected in plasma and showed significant differences (p < 0.05) following acute consumption of Vistula TC, compared to the placebo group. These results provide evidence that phenolics are bioavailable in plasma and induce shifts in the metabolome following acute Vistula TC consumption. These data could be used to inform future intervention studies where changes in physiological outcomes could be influenced by metabolomic shifts following acute supplementation.
Subject(s)
Prunus avium , Humans , Female , Male , Young Adult , Adult , Metabolome , Metabolomics , Body Height , BreakfastABSTRACT
Medical simulation has become an integral aspect of modern healthcare education and practice. It has evolved to become an essential aspect of teaching core concepts and skills, common and rare presentations, algorithms and protocols, communication, interpersonal and teamworking skills and testing new equipment and systems. Simulation-based learning (SBL) is useful for the novice to the senior clinician. Healthcare is a complex adaptive system built from very large numbers of mutually interacting subunits (e.g., different professions, departments, equipment). These subunits generate multiple repeated interactions that have the potential to result in rich, collective behaviour that feeds back into the organisation. There is a unique opportunity in New Zealand with the formation of Te Whatu Ora - Health New Zealand and Te Aka Whai Ora - Maori Health Authority and the reorganisation of the healthcare system. This viewpoint is a white paper for the integration of SBL into our healthcare system. We describe our concerns in the current system and list our current capabilities. The way SBL could be implemented in pre- and post-registration phases of practice are explored as well as the integration of communication and culture. Interprofessional education has been shown to improve outcomes and is best done with an interprofessional simulation curriculum. We describe ways that simulation is currently used in our system and describe other uses such as quality improvement, safety and systems engineering and integration. The aim of this viewpoint is to alert Te Whatu Ora and Te Aka Whai Ora of the existing infrastructure of the simulation community in New Zealand and encourage them to invest in its future.
Subject(s)
Delivery of Health Care , Simulation Training , Curriculum , New ZealandABSTRACT
PURPOSE: Fem1 homolog B (FEM1B) acts as a substrate recognition subunit for ubiquitin ligase complexes belonging to the CULLIN 2-based E3 family. Several biological functions have been proposed for FEM1B, including a structurally resolved function as a sensor for redox cell status by controlling mitochondrial activity, but its implication in human disease remains elusive. METHODS: To understand the involvement of FEM1B in human disease, we made use of Matchmaker exchange platforms to identify individuals with de novo variants in FEM1B and performed their clinical evaluation. We performed functional validation using primary neuronal cultures and in utero electroporation assays, as well as experiments on patient's cells. RESULTS: Five individuals with a recurrent de novo missense variant in FEM1B were identified: NM_015322.5:c.377G>A NP_056137.1:p.(Arg126Gln) (FEM1BR126Q). Affected individuals shared a severe neurodevelopmental disorder with behavioral phenotypes and a variable set of malformations, including brain anomalies, clubfeet, skeletal abnormalities, and facial dysmorphism. Overexpression of the FEM1BR126Q variant but not FEM1B wild-type protein, during mouse brain development, resulted in delayed neuronal migration of the target cells. In addition, the individuals' cells exhibited signs of oxidative stress and induction of type I interferon signaling. CONCLUSION: Overall, our data indicate that p.(Arg126Gln) induces aberrant FEM1B activation, resulting in a gain-of-function mechanism associated with a severe syndromic developmental disorder in humans.
Subject(s)
Mutation, Missense , Neurodevelopmental Disorders , Ubiquitin-Protein Ligases , Humans , Mutation, Missense/genetics , Female , Mice , Male , Animals , Neurodevelopmental Disorders/genetics , Neurodevelopmental Disorders/pathology , Ubiquitin-Protein Ligases/genetics , Child , Child, Preschool , Phenotype , Cell Cycle Proteins/genetics , Cell Cycle Proteins/metabolism , Neurons/metabolism , Neurons/pathology , InfantABSTRACT
Smokeless powders (SLPs) are composed of a combination of thermolabile and non-thermolabile compounds. When analysed by GC-MS, injection conditions may therefore play a fundamental role on the characterisation of forensic samples. However, no systematic investigations have ever been carried out. This casts doubt on the optimal conditions that should be adopted in advanced profiling applications (e.g. class attribution and source association), especially when a traditional split/splitless (S/SL) injector is used. Herein, a study is reported that specifically focused on the evaluation of the liner type (Ltype) and inlet temperature (Tinj). Results showed that both could affect the exhaustiveness and repeatability of the observed chemical profiles, with Ltype being particularly sensitive despite typically not being clarified in published works. Perhaps as expected, degradation effects were observed for the most thermolabile compounds (e.g. nitroglycerin) at conditions maximising the heat transfer rates (Ltype = packed and Tinj ≥ 200 °C). However, these did not seem to be as influential as, perhaps, suggested in previous studies. Indeed, the harshest injection conditions in terms of heat transfer rate (Ltype = packed and Tinj = 260 °C) were found to lead to better performances (including better overall %RSDs and LODs) compared to the mildest ones. This suggested that implementing conditions minimising heat-induced breakdowns during injection was not necessarily a good strategy for comparison purposes. The reported findings represent a concrete step forward in the field, providing a robust body of data for the development of the next generation of SLP profiling methods.
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We report, for the first time, a multimodal investigation of current crude oil reprocessing and storage sites to assess their impact on the environment after 50 years of continuous operation. We have adopted a dual approach to investigate potential soil contamination. The first approach uses conventional analytical techniques i.e. energy dispersive X-ray fluorescence (ED-XRF) for metal analysis, and a complementary metabolomic investigation using hydrophilic liquid interaction chromatography hi-resolution mass spectrometry (HILIC-MS) for organic contaminants. Secondly, the deployment of an unmanned aerial vehicle (UAV) with a multispectral image (MSI) camera, for the remote sensing of vegetation stress, as a proxy for sub-surface soil contamination. The results identified high concentrations of barium (mean 21 017 ± 5950 µg g-1, n = 36) as well as metabolites derived from crude oil (polycyclic aromatic hydrocarbons), cleaning processes (surfactants) and other organic pollutants (e.g. pesticides, plasticizers and pharmaceuticals) in the reprocessing site. This data has then been correlated, with post-flight data analysis derived vegetation indices (NDVI, GNDVI, SAVI and Cl green VI), to assess the potential to identify soil contamination because of vegetation stress. It was found that strong correlations exist (an average R2 of >0.68) between the level of soil contamination and the ground cover vegetation. The potential to deploy aerial remote sensing techniques to provide an initial survey, to inform decision-making, on suspected contaminated land sites can have global implications.
Subject(s)
Petroleum , Remote Sensing Technology , SoilABSTRACT
The flowering stage of oilseed rape (Brassica napus L.) is of vital interest in precision agriculture. It has been shown that data describing the flower production of oilseed rape (OSR), at stage 3, in spring can be used to predict seed yield at harvest. Traditional field-based techniques for assessing OSR flowers are based on a visual assessment which is subjective and time consuming. However, a high throughput phenotyping technique, using an unmanned aerial vehicle (UAV) with multispectral image (MSI) camera, was used to investigate the growth stages of OSR (in terms of crop height) and to quantify its flower production. A simplified approach using a normalised difference yellowness index (NDYI) was coupled with an iso-cluster classification method to quantify the number of OSR flower pixels and incorporate the data into an OSR seed yield estimation. The estimated OSR seed yield showed strong correlation with the actual OSR seed yield (R2 = 0.86), as determined using in-situ sensors mounted on the combine harvester. Also, using our approach allowed the variation in crop height to be assessed across all growing stages; the maximum crop height of 1.35 m OSR was observed at the flowering stage. This methodology is proposed for effectively predicting seed yield 3 months prior to harvesting.
Subject(s)
Brassica napus , Unmanned Aerial Devices , Agriculture , Flowers , SeedsABSTRACT
Introduction: The purpose of VIKING II is to create an observational cohort of volunteers with ancestry from the Northern Isles of Scotland, primarily for identifying genetic variants influencing disease. The new online protocol is separate to, but follows on from, earlier genetic epidemiological clinic-based studies in the isolated populations of Orkney and Shetland. These populations are favourable for the study of rarer genetic variants due to genetic drift, the large number of relatives, and availability of pedigree information. They are known to be genetically distinct from mainland British populations. Methods and analysis: Online methods are being used to recruit ~4,000 people who have Northern Isles ancestry, living anywhere in the world. The option for participants to have actionable genetic results returned is offered. Consent will be taken electronically. Data will be collected at baseline through an online questionnaire and longitudinally through linkage to NHS data in the electronic health record. The questionnaire collects a variety of phenotypes including personal and family health. DNA will be extracted from saliva samples then genome-wide genotyped and exome sequenced. VIKING II aims to capitalise on the special features of the Northern Isles populations to create a research cohort that will facilitate the analysis of genetic variants associated with a broad range of traits and disease endpoints, including otherwise rare variants that have drifted to high frequency in these populations. Ethics and dissemination: The South East Scotland Research Ethics Committee gave the study a favourable opinion. VIKING II is sponsored by the University of Edinburgh and NHS Lothian. Summary research findings will be disseminated to participants and funding bodies, presented at conferences and reported in peer-reviewed publications. Article summary: Strengths and limitations of this studyDetailed data and biological sample collection of research volunteers with unique ancestry.Consent for access to routinely collected clinical EHR data and for future re-contact, providing a longitudinal component.Optional consent for return of actionable genetic results.~4,000 participants is a relatively small number for certain types of genetic analyses, so the cohort is underpowered on its own, in some study designs.Resources to maintain the cohort, and to store data and DNA samples, are significant, with sustainability dependent on infrastructure support and funding.
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Ambulatory Care Facilities , Electronic Health Records , Ethics Committees, Research , Exome , Family Health , HumansABSTRACT
Laundering of textiles is a significant source of waterborne microfiber pollution, and solutions are now being sought to mitigate this issue including improvements in clothing technology and integration of filtration systems into washing machines. Vented tumble dryers are a potential source of airborne microfiber pollution, as their built-in lint filtration systems have been found to be inefficient with significant quantities of textile microfibers being released to the external environment through their exhaust air ducts. The present study is the first to evaluate the impact of condenser dryers, finding that they are significant contributors to waterborne microfiber pollution from the lint filter (if users clean this with water), the condenser and the condensed water. Microfiber release from drying of real consumer loads in condenser and vented tumble dryers was compared, finding that real loads release surprisingly high levels of microfibers (total 341.5 ± 126.0 ppm for those dried in a condenser dryer and 256.0 ± 74.2 ppm for those dried in a vented dryer), similar in quantity to microfibers produced during the first highly-shedding drying cycle of a new T-shirt load (total 321.4 ± 11.2 ppm) in a condenser dryer. Vented dryers were found to be significant contributors to waterborne microfiber pollution if consumers clean the lint filter with water in accordance with some published appliance usage instructions, as most (86.1 ± 5.5% for the real consumer loads tested) of the microfibers generated during vented tumble drying were collected on the lint filter. Therefore, tumble dryers are a significant source of waterborne and (for vented dryers) airborne microfiber pollution. While reducing the pore size of tumble dryer lint filters and instructing consumers to dispose of fibers collected on lint filters as municipal solid waste could help reduce the issue, more sophisticated engineering solutions will likely be required to achieve a more comprehensive solution.
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Desiccation , Environmental Pollution , Engineering , Solid Waste , WaterABSTRACT
Background: Utilization of sacubitril/valsartan is increasing as a component of guideline-directed medical therapy in patients with heart failure with reduced ejection fraction (HFrEF). Common adverse effects associated with the medication such as hypotension and hyperkalaemia have been described; however, hyponatraemia is very rarely reported to have a potential association with use of the medication. In this report, we describe what we believe to be the first reported case of acute hyponatraemia likely attributable to inpatient initiation of sacubitril/valsartan. Case Summary: A 71-year-old female presented with 2 weeks of progressively worsening dyspnoea and orthopnoea. Bedside echocardiography identified a dilated cardiomyopathy with an estimated left ventricular ejection fraction <30% and diffuse hypokinesis, and given the associated clinical syndrome, she was diagnosed with heart failure with reduced ejection fraction. In conjunction with diuresis, guideline-directed medical therapy was initiated. She developed acute worsening of her previously mild hyponatraemia shortly after starting sacubitril/valsartan, and this improved following discontinuation of the medication. She was subsequently able to tolerate losartan while maintaining eunatraemia, and her ejection fraction improved to 46% on repeat imaging. Discussion: Angiotensin receptor-neprilysin inhibitors are an integral component of guideline-directed medical therapy with proven benefits for patients with heart failure with reduced ejection fraction. Although the association between use of these medications and hyponatraemia appears to be exceedingly rare, clinicians should maintain awareness of this potential adverse effect.
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Peer review supports the integrity and quality of scientific publishing. However, although it is a fundamental part of the publishing process, peer review can also be challenging for reviewers, editors, and other stakeholders. The present study aims to explore the nurses' motivations, barriers, and facilitators in engaging in a peer review process. This qualitative, descriptive exploratory study will be developed in partnerships with three research centers. Researchers followed the consolidated criteria for reporting qualitative research (COREQ) checklist to ensure the quality of this study protocol. According to the selection criteria, the purposive sampling will be used to recruit nurse researchers that act as peer reviewers for several scientific journals in various fields of knowledge. Interviews will be conducted until data have been sufficiently consistent with meeting the initial objectives. Researchers will develop a guide comprising a set of open-ended questions to collect participants' characteristics, descriptive review behavior, and perceptions regarding their motivations, barriers, and facilitators. Researchers will analyze data using an inductive process of content analysis with the help of the QDA Miner Lite database. Findings from this study will generate knowledge that may help stakeholders identify facilitating factors and barriers and guide the development of strategies to remove or minimize these barriers.
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BACKGROUND: Falling and gait difficulties in people with Parkinson's disease (PD) are associated with impaired reactive postural adjustments and impairments in attentional resources. Combined intensive balance motor and cognitive exercise can be beneficial. However, uncertainties persist regarding the true effects and safety when applying such training. Using trampoline beds may be a favorable safe environment for a highly intensive, cognitive, and balancing training approach. The primary goal of this randomized controlled trial is to assess the effects of an intensive cognitive-motor training program in a safe trampoline environment in addition to usual care on balance impairment, gait, physical capacity, fear of falling, falls frequency and severity, cognition, and clinical impairments in people with mild or moderate PD. METHODS: Sixty participants diagnosed with idiopathic PD, in stage 2-4 Hoehn and Yahr, with a clinical history of gait deficits and a fall history (at least one fall in the last 6 months) will be recruited and randomly allocated to an intervention group receiving cognitive-motor trampoline training or a control group undergoing their usual care. The intervention will consist of 8-week individual training sessions (1-h training, 3 days per week) led by specialized physiotherapists that will provide progressive, challenging training, and guarantee safety. Assessment will be conducted prior to and immediately after the 8-week intervention and at 3 months follow-up after participating in the study. Primary outcome measures will be balance performance (assessed using the Mini-BEST Test and nonlinear analysis) and change in gait parameters (Motor and Cognitive Timed-Up-Go and nonlinear analysis). Secondary outcomes will be change in clinical improvement (Movement Disorder Society Unified Parkinson's Disease Rating Scale), falls (falls weekly registry), fear of falling (assessed using the Falls Efficacy Scale), physical capacity (6-min walk test), and cognition (Montreal Cognitive Assessment). DISCUSSION: This study will provide new evidence on the benefits of intensive cognitive-motor balance training on a trampoline for people living with PD. Better guidance on how professionals can apply safer dual-task balance and gait training in rehabilitation is needed. TRIAL REGISTRATION: ISRCTN Registry ISRCTN13160409 . Retrospectively registered on February 23, 2022.
Subject(s)
Parkinson Disease , Humans , Parkinson Disease/psychology , Fear , Exercise Therapy/adverse effects , Exercise Therapy/methods , Gait , Postural Balance , Randomized Controlled Trials as TopicABSTRACT
Drug-responsive T-cells are activated with the parent compound or metabolites, often via different pathways (pharmacological interaction and hapten). An obstacle to the investigation of drug hypersensitivity is the scarcity of reactive metabolites for functional studies and the absence of coculture systems to generate metabolites in situ. Thus, the aim of this study was to utilize dapsone metabolite-responsive T-cells from hypersensitive patients, alongside primary human hepatocytes to drive metabolite formation, and subsequent drug-specific T-cell responses. Nitroso dapsone-responsive T-cell clones were generated from hypersensitive patients and characterized in terms of cross-reactivity and pathways of T-cell activation. Primary human hepatocytes, antigen-presenting cells, and T-cell cocultures were established in various formats with the liver and immune cells separated to avoid cell contact. Cultures were exposed to dapsone, and metabolite formation and T-cell activation were measured by LC-MS and proliferation assessment, respectively. Nitroso dapsone-responsive CD4+ T-cell clones from hypersensitive patients were found to proliferate and secrete cytokines in a dose-dependent manner when exposed to the drug metabolite. Clones were activated with nitroso dapsone-pulsed antigen-presenting cells, while fixation of antigen-presenting cells or omission of antigen-presenting cells from the assay abrogated the nitroso dapsone-specific T-cell response. Importantly, clones displayed no cross-reactivity with the parent drug. Nitroso dapsone glutathione conjugates were detected in the supernatant of hepatocyte immune cell cocultures, indicating that hepatocyte-derived metabolites are formed and transferred to the immune cell compartment. Similarly, nitroso dapsone-responsive clones were stimulated to proliferate with dapsone, when hepatocytes were added to the coculture system. Collectively, our study demonstrates the use of hepatocyte immune cell coculture systems to detect in situ metabolite formation and metabolite-specific T-cell responses. Similar systems should be used in future diagnostic and predictive assays to detect metabolite-specific T-cell responses when synthetic metabolites are not available.
Subject(s)
Drug Hypersensitivity , Humans , Coculture Techniques , Dapsone/pharmacology , Liver , Hepatocytes , Lymphocyte ActivationABSTRACT
Background: Access to specialised early intervention mental health services for children, including group counselling for parents/carers, is still a challenge in non-metropolitan areas of Australia. Aim: To gain understanding of the acceptability of a school-based targeted parenting group program delivered via telehealth by exploring the experiences of parents/carers, clinicians and school staff, and asking what works, how, why and in what circumstances. Methods: Caregivers, clinicians and school staff involved in the delivery of a mental health program via telehealth into primary schools in two rural Local Health Districts (LHDs) in southern New South Wales (NSW) were invited to participate in interviews and/or focus group discussions. Thematic analysis of the data was conducted with reference to realist theory. Findings: We conducted semi-structured interviews with 12 caregivers, five semi-structured interviews and two focus group discussions with school staff from six participating schools, and three focus groups with seven clinicians who delivered the intervention. We found that the intervention and micro contexts interacted to influence acceptability by initiating or enhancing cohesion among caregivers, establishing channels of communication between caregivers and teachers, and connection between caregivers and clinicians despite geographic distance. Several adaptations were made to strengthen the therapeutic alliance between caregivers and clinicians. Conclusion: Relationships crucial to the success of delivering psychological group counselling were established. Regional community contexts can facilitate acceptability of parenting group counselling delivered into schools via telehealth. Implementation of the program was flexible enough to allow clinicians to adjust their approach and materials to better suit the telehealth modality.