RESUMO
BACKGROUND: We aimed to synthesize the qualitative evidence on the impacts of COVID-19-related restricted family presence policies from the perspective of patients, families, and healthcare professionals from neonatal (NICU), pediatric (PICU), or adult ICUs. METHODS: We searched MEDLINE, EMBASE, Cochrane Databases of Reviews and Clinical Trials, CINAHL, Scopus, PsycINFO, and Web of Science. Two researchers independently reviewed titles/abstracts and full-text articles for inclusion. Thematic analysis was completed following appraising article quality and assessing confidence in the individual review findings using standardized tools. RESULTS: We synthesized 54 findings from 184 studies, revealing the impacts of these policies in children and adults on: (1) Family integrated care and patient and family-centered care (e.g., disruption to breastfeeding/kangaroo care, dehumanizing of patients); (2) Patients, families, and healthcare professionals (e.g., negative mental health consequences, moral distress); (3) Support systems (e.g., loss of support from friends/families); and (4) Relationships (e.g., loss of essential bonding with infant, struggle to develop trust). Strategies to mitigate these impacts are reported. CONCLUSION: This review highlights the multifaceted impacts of restricted visitation policies across distinct care settings and strategies to mitigate the harmful effects of these policies and guide the creation of compassionate family presence policies in future health crises. REGISTRATION: https://www.crd.york.ac.uk/PROSPERO/display_record.php?RecordID=290263 .
Assuntos
COVID-19 , Estado Terminal , Família , Pesquisa Qualitativa , Humanos , COVID-19/epidemiologia , COVID-19/psicologia , Família/psicologia , Estado Terminal/psicologia , Cuidados Críticos/psicologia , SARS-CoV-2 , Visitas a Pacientes/psicologia , Pandemias , Pessoal de Saúde/psicologia , Adulto , Unidades de Terapia IntensivaRESUMO
BACKGROUND: Lung ultrasound (LUS) is a non-invasive point of care diagnostic tool used to assess the presence and severity of various lung disorders for more than two decades. Within the healthcare professionals are the respiratory therapists (RTs) who play a vital role in managing ventilated and other patients requiring respiratory support, but the incorporation of LUS into their scope of practice has not been well highlighted. This international cross-sectional survey was specifically designed to evaluate the knowledge, attitude, and practice of RTs with respect to LUS. METHODS: This observational cross-sectional study was conducted among RTs from different parts of the world using a questionnaire-based study tool. 514 RTs responded to all the questions and were considered for statistical analysis. Descriptive statistics, Analysis of variance, Fisher's exact, Chi-square, Bonferroni post-hoc analysis, and Binomial logistic regression analyses were performed to identify the significance of the data. RESULTS: From 22 countries, 514 RTs responded to the survey, with the major share from the middle eastern countries. Out of the 514 responders, 44.9% of the responders were in the age group of 23-30 years; 67.1% were bachelor's degree holders; and 40.9% of participants had more than 10 years of experience. The knowledge-based questions revealed that RTs with higher experience and academic qualification provided more positive responses. While in the attitude-related domain it is observed that standardized training in LUS helps them to enhance the current practice and to add LUS to the academic curriculum of respiratory therapy schools; however there remains barriers to practice LUS based on their responses. The practice-based questions revealed that RTs expect some additional seminars/workshops/webinars to be done on LUS frequently. More than half of the participants are found to be knowledgeable with a positive attitude and working towards the inclusion of LUS in respiratory therapy profession. CONCLUSION: It is concluded that respiratory therapists have a positive attribute towards the inclusion of lung ultrasound in their clinical practice. Providing more structured training for professional respiratory therapists and including lung ultrasound modules in the respiratory therapy school curriculum may facilitate mastering their diagnostic skills, thereby expanding the scope of practice.
RESUMO
BACKGROUND: LRRK2-targeting therapeutics that inhibit LRRK2 kinase activity have advanced to clinical trials in idiopathic Parkinson's disease (iPD). LRRK2 phosphorylates Rab10 on endolysosomes in phagocytic cells to promote some types of immunological responses. The identification of factors that regulate LRRK2-mediated Rab10 phosphorylation in iPD, and whether phosphorylated-Rab10 levels change in different disease states, or with disease progression, may provide insights into the role of Rab10 phosphorylation in iPD and help guide therapeutic strategies targeting this pathway. METHODS: Capitalizing on past work demonstrating LRRK2 and phosphorylated-Rab10 interact on vesicles that can shed into biofluids, we developed and validated a high-throughput single-molecule array assay to measure extracellular pT73-Rab10. Ratios of pT73-Rab10 to total Rab10 measured in biobanked serum samples were compared between informative groups of transgenic mice, rats, and a deeply phenotyped cohort of iPD cases and controls. Multivariable and weighted correlation network analyses were used to identify genetic, transcriptomic, clinical, and demographic variables that predict the extracellular pT73-Rab10 to total Rab10 ratio. RESULTS: pT73-Rab10 is absent in serum from Lrrk2 knockout mice but elevated by LRRK2 and VPS35 mutations, as well as SNCA expression. Bone-marrow transplantation experiments in mice show that serum pT73-Rab10 levels derive primarily from circulating immune cells. The extracellular ratio of pT73-Rab10 to total Rab10 is dynamic, increasing with inflammation and rapidly decreasing with LRRK2 kinase inhibition. The ratio of pT73-Rab10 to total Rab10 is elevated in iPD patients with greater motor dysfunction, irrespective of disease duration, age, sex, or the usage of PD-related or anti-inflammatory medications. pT73-Rab10 to total Rab10 ratios are associated with neutrophil degranulation, antigenic responses, and suppressed platelet activation. CONCLUSIONS: The extracellular serum ratio of pT73-Rab10 to total Rab10 is a novel pharmacodynamic biomarker for LRRK2-linked innate immune activation associated with disease severity in iPD. We propose that those iPD patients with higher serum pT73-Rab10 levels may benefit from LRRK2-targeting therapeutics that mitigate associated deleterious immunological responses.
Assuntos
Serina-Treonina Proteína Quinase-2 com Repetições Ricas em Leucina , Doença de Parkinson , Serina-Treonina Proteína Quinase-2 com Repetições Ricas em Leucina/genética , Serina-Treonina Proteína Quinase-2 com Repetições Ricas em Leucina/metabolismo , Doença de Parkinson/sangue , Doença de Parkinson/metabolismo , Animais , Humanos , Camundongos , Ratos , Proteínas rab de Ligação ao GTP/metabolismo , Inflamação/metabolismo , Feminino , Fosforilação , Camundongos Transgênicos , Masculino , Pessoa de Meia-Idade , Idoso , Índice de Gravidade de DoençaRESUMO
Background: LRRK2-targeting therapeutics that inhibit LRRK2 kinase activity have advanced to clinical trials in idiopathic Parkinson's disease (iPD). LRRK2 phosphorylates Rab10 on endolysosomes in phagocytic cells to promote some types of immunological responses. The identification of factors that regulate LRRK2-mediated Rab10 phosphorylation in iPD, and whether phosphorylated-Rab10 levels change in different disease states, or with disease progression, may provide insights into the role of Rab10 phosphorylation in iPD and help guide therapeutic strategies targeting this pathway. Methods: Capitalizing on past work demonstrating LRRK2 and phosphorylated-Rab10 interact on vesicles that can shed into biofluids, we developed and validated a high-throughput single-molecule array assay to measure extracellular pT73-Rab10. Ratios of pT73-Rab10 to total Rab10 measured in biobanked serum samples were compared between informative groups of transgenic mice, rats, and a deeply phenotyped cohort of iPD cases and controls. Multivariable and weighted correlation network analyses were used to identify genetic, transcriptomic, clinical, and demographic variables that predict the extracellular pT73-Rab10 to total Rab10 ratio. Results: pT73-Rab10 is absent in serum from Lrrk2 knockout mice but elevated by LRRK2 and VPS35 mutations, as well as SNCA expression. Bone-marrow transplantation experiments in mice show that serum pT73-Rab10 levels derive primarily from circulating immune cells. The extracellular ratio of pT73-Rab10 to total Rab10 is dynamic, increasing with inflammation and rapidly decreasing with LRRK2 kinase inhibition. The ratio of pT73-Rab10 to total Rab10 is elevated in iPD patients with greater motor dysfunction, irrespective of disease duration, age, sex, or the usage of PD-related or anti-inflammatory medications. pT73-Rab10 to total Rab10 ratios are associated with neutrophil activation, antigenic responses, and the suppression of platelet activation. Conclusions: The extracellular ratio of pT73-Rab10 to total Rab10 in serum is a novel pharmacodynamic biomarker for LRRK2-linked innate immune activation associated with disease severity in iPD. We propose that those iPD patients with higher serum pT73-Rab10 levels may benefit from LRRK2-targeting therapeutics to mitigate associated deleterious immunological responses.
RESUMO
Four weeks before competition in the 2023 Marathon des Sables, a 6-stage, ~250 km running event in the Sahara Desert, we examined the effects of a 7-day intake of New Zealand blackcurrant extract (210 mg anthocyanins per day) on 1 h treadmill running-induced physiological and metabolic responses in the heat (~34 °C, relative humidity: ~30%) in non-acclimatized amateur female and male athletes (age: 23, 38 yrs, BMI: 24.2, 28.4 kg·m-2, body fat%: 29.2, 18.8%, VËO2max: 50.1, 52.1 mL·kg-1·min-1). During the 1 h run at 50%VËO2max (speed female: 7.3, male: 7.5 km·h-1), indirect calorimetry was used, and heart rate was recorded at 15 min intervals with core temperature monitoring (0.05 Hz). The 1 h runs took place 3 h after a light breakfast and 2 h after intake of the final dose of New Zealand blackcurrant extract with water allowed ad libitum during the run. The New Zealand blackcurrant extract had no effects on the female athlete. The respiratory exchange ratio (RER) of the female athlete in the non-supplement control condition was 0.77 ± 0.01, indicating an existing ~77% contribution of fat oxidation to the energy requirements. In the male athlete, during 1 h of running, fat oxidation was higher by 21% (p < 0.01), carbohydrate oxidation was 31% lower (p = 0.05), RER was 0.03 units lower (p = 0.04), and core temperature was 0.4 °C lower (p < 0.01) with no differences for heart rate, minute ventilation, oxygen uptake, and carbon dioxide production for the New Zealand blackcurrant condition compared to the non-supplement control condition. Seven-day intake of New Zealand blackcurrant extract (210 mg anthocyanins per day) provided beneficial physiological and metabolic responses during exertional heat stress by 1 h of indoor (~34 °C) treadmill running in a male Marathon des Sables athlete 4 weeks before competition. Future work is required to address whether New Zealand blackcurrant provides a nutritional ergogenic effect for Marathon des Sables athletes during long-duration running in the heat combined with personalized nutrition.
RESUMO
BACKGROUND: Parkinson's disease is a progressive neurodegenerative disorder with multifactorial causes, among which genetic risk factors play a part. The RAB GTPases are regulators and substrates of LRRK2, and variants in the LRRK2 gene are important risk factors for Parkinson's disease. We aimed to explore genetic variability in RAB GTPases within cases of familial Parkinson's disease. METHODS: We did whole-exome sequencing in probands from families in Canada and Tunisia with Parkinson's disease without a genetic cause, who were recruited from the Centre for Applied Neurogenetics (Vancouver, BC, Canada), an international consortium that includes people with Parkinson's disease from 36 sites in 24 countries. 61 RAB GTPases were genetically screened, and candidate variants were genotyped in relatives of the probands to assess disease segregation by linkage analysis. Genotyping was also done to assess variant frequencies in individuals with idiopathic Parkinson's disease and controls, matched for age and sex, who were also from the Centre for Applied Neurogenetics but unrelated to the probands or each other. All participants were aged 18 years or older. The sequencing and genotyping findings were validated by case-control association analyses using bioinformatic data obtained from publicly available clinicogenomic databases (AMP-PD, GP2, and 100 000 Genomes Project) and a private German clinical diagnostic database (University of Tübingen). Clinical and pathological findings were summarised and haplotypes were determined. In-vitro studies were done to investigate protein interactions and enzyme activities. FINDINGS: Between June 1, 2010, and May 31, 2017, 130 probands from Canada and Tunisia (47 [36%] female and 83 [64%] male; mean age 72·7 years [SD 11·7; range 38-96]; 109 White European ancestry, 18 north African, two east Asian, and one Hispanic] underwent whole-exome sequencing. 15 variants in RAB GTPase genes were identified, of which the RAB32 variant c.213C>G (Ser71Arg) cosegregated with autosomal dominant Parkinson's disease in three families (nine affected individuals; non-parametric linkage Z score=1·95; p=0·03). 2604 unrelated individuals with Parkinson's disease and 344 matched controls were additionally genotyped, and five more people originating from five countries (Canada, Italy, Poland, Turkey, and Tunisia) were identified with the RAB32 variant. From the database searches, in which 6043 individuals with Parkinson's disease and 62 549 controls were included, another eight individuals were identified with the RAB32 variant from four countries (Canada, Germany, UK, and USA). Overall, the association of RAB32 c.213C>G (Ser71Arg) with Parkinson's disease was significant (odds ratio [OR] 13·17, 95% CI 2·15-87·23; p=0·0055; I2=99·96%). In the people who had the variant, Parkinson's disease presented at age 54·6 years (SD 12·75, range 31-81, n=16), and two-thirds had a family history of parkinsonism. RAB32 Ser71Arg heterozygotes shared a common haplotype, although penetrance was incomplete. Findings in one individual at autopsy showed sparse neurofibrillary tangle pathology in the midbrain and thalamus, without Lewy body pathology. In functional studies, RAB32 Arg71 activated LRRK2 kinase to a level greater than RAB32 Ser71. INTERPRETATION: RAB32 Ser71Arg is a novel genetic risk factor for Parkinson's disease, with reduced penetrance. The variant was found in individuals with Parkinson's disease from multiple ethnic groups, with the same haplotype. In-vitro assays show that RAB32 Arg71 activates LRRK2 kinase, which indicates that genetically distinct causes of familial parkinsonism share the same mechanism. The discovery of RAB32 Ser71Arg also suggests several genetically inherited causes of Parkinson's disease originated to control intracellular immunity. This shared aetiology should be considered in future translational research, while the global epidemiology of RAB32 Ser71Arg needs to be assessed to inform genetic counselling. FUNDING: National Institutes of Health, the Canada Excellence Research Chairs program, Aligning Science Across Parkinson's, the Michael J Fox Foundation for Parkinson's Research, and the UK Medical Research Council.
Assuntos
Doença de Parkinson , Proteínas rab de Ligação ao GTP , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Canadá/epidemiologia , Estudos de Casos e Controles , Sequenciamento do Exoma , Ligação Genética/genética , Predisposição Genética para Doença/genética , Genótipo , Serina-Treonina Proteína Quinase-2 com Repetições Ricas em Leucina/genética , Doença de Parkinson/genética , Proteínas rab de Ligação ao GTP/genética , TunísiaRESUMO
Background: Parkinson's disease (PD) is a progressive neurodegenerative disorder. Mendelian forms have revealed multiple genes, with a notable emphasis on membrane trafficking; RAB GTPases play an important role in PD as a subset are both regulators and substrates of LRRK2 protein kinase. To explore the role of RAB GTPases in PD, we undertook a comprehensive examination of their genetic variability in familial PD. Methods: Affected probands from 130 multi-incident PD families underwent whole-exome sequencing and genotyping, Potential pathogenic variants in 61 RAB GTPases were genotyped in relatives to assess disease segregation. These variants were also genotyped in a larger case-control series, totaling 3,078 individuals (2,734 with PD). The single most significant finding was subsequently validated within genetic data (6,043 with PD). Clinical and pathologic findings were summarized for gene-identified patients, and haplotypes were constructed. In parallel, wild-type and mutant RAB GTPase structural variation, protein interactions, and resultant enzyme activities were assessed. Findings: We found RAB32 c.213C>G (Ser71Arg) to co-segregate with autosomal dominant parkinsonism in three multi-incident families. RAB32 Ser71Arg was also significantly associated with PD in case-control samples: genotyping and database searches identified thirteen more patients with the same variant that was absent in unaffected controls. Notably, RAB32 Ser71Arg heterozygotes share a common haplotype. At autopsy, one patient had sparse neurofibrillary tangle pathology in the midbrain and thalamus, without Lewy body pathology. In transfected cells the RAB32 Arg71 was twice as potent as Ser71 wild type to activate LRRK2 kinase. Interpretation: Our study provides unequivocal evidence to implicate RAB32 Ser71Arg in PD. Functional analysis demonstrates LRRK2 kinase activation. We provide a mechanistic explanation to expand and unify the etiopathogenesis of monogenic PD. Funding: National Institutes of Health, the Canada Excellence Research Chairs program, Aligning Science Across Parkinson's, the Michael J. Fox Foundation for Parkinson's Research, and the UK Medical Research Council.
RESUMO
Background: Respiratory therapists (RTs) are expected to stay updated on technology, treatments, research, and best practices to provide high-quality patient care. They must possess the skills to interpret, evaluate, and contribute to evidence-based practices. However, RTs often rely on research from other professions that may not fully address their specific needs, leading to insufficient guidance for their practice. Additionally, there has been no exploration of knowledge gaps and research needs from RTs' perspectives to enhance their practice and patient outcomes. The research questions guiding this study were: (i) what are the perceived practice-oriented knowledge gaps? and (ii) what are the necessary research priorities across the respiratory therapy profession according to experts in respiratory therapy? Methods: A qualitative description study was conducted using semi-structured focus groups with 40 expert RTs from seven areas of practice across Canada. Data was analyzed using qualitative content analysis. Results: We identified four major themes relating to what these experts perceive as the practice-oriented gaps and necessary research priorities across the respiratory therapy profession: 1) system-level impact of RTs, 2) optimizing respiratory therapy practices, 3) scholarship on the respiratory therapy profession and 4) respiratory therapy education. Discussion: The findings establish a fundamental understanding of the current gaps and the specific needs of RTs that require further investigation. Participants strongly emphasized the significance of research priorities that consider the breadth and depth of the respiratory therapy profession, which underscores the complex nature of respiratory therapy and its application in practice. Conclusion: The unique insights garnered from this study highlight the knowledge gaps and research needs specific to RTs. These findings pave the way for further exploration, discourse, and research aimed at understanding the specific contributions and requirements of RTs.
RESUMO
Epidemiological and histopathological findings have raised the possibility that misfolded α-synuclein protein might spread from the gut to the brain and increase the risk of Parkinson's disease. Although past experimental studies in mouse models have relied on gut injections of exogenous recombinant α-synuclein fibrils to study gut-to-brain α-synuclein transfer, the possible origins of misfolded α-synuclein within the gut have remained elusive. We recently demonstrated that sensory cells of intestinal mucosa express α-synuclein. Here, we employed mouse intestinal organoids expressing human α-synuclein to observe the transfer of α-synuclein protein from epithelial cells in organoids to cocultured nodose neurons devoid of α-synuclein. In mice expressing human α-synuclein, but no mouse α-synuclein, α-synuclein fibril-templating activity emerged in α-synuclein-seeded fibril aggregation assays in intestine, vagus nerve, and dorsal motor nucleus. In newly engineered transgenic mice that restrict pathological human α-synuclein expression to intestinal epithelial cells, α-synuclein fibril-templating activity transfered to the vagus nerve and dorsal motor nucleus. Subdiaphragmatic vagotomy prior to induction of α-synuclein expression in intestinal epithelial cells effectively protected the hindbrain from emergence of α-synuclein fibril-templating activity. Overall, these findings highlight a potential non-neuronal source of fibrillar α-synuclein protein that might arise in gut mucosal cells.
Assuntos
Doença de Parkinson , Nervo Vago , alfa-Sinucleína , Animais , Humanos , Camundongos , alfa-Sinucleína/metabolismo , Encéfalo/metabolismo , Neurônios/metabolismo , Doença de Parkinson/metabolismo , Nervo Vago/metabolismo , Mucosa Gástrica/metabolismoRESUMO
Recent studies have identified increasing levels of nanoplastic pollution in the environment. Here, we find that anionic nanoplastic contaminants potently precipitate the formation and propagation of α-synuclein protein fibrils through a high-affinity interaction with the amphipathic and non-amyloid component (NAC) domains in α-synuclein. Nanoplastics can internalize in neurons through clathrin-dependent endocytosis, causing a mild lysosomal impairment that slows the degradation of aggregated α-synuclein. In mice, nanoplastics combine with α-synuclein fibrils to exacerbate the spread of α-synuclein pathology across interconnected vulnerable brain regions, including the strong induction of α-synuclein inclusions in dopaminergic neurons in the substantia nigra. These results highlight a potential link for further exploration between nanoplastic pollution and α-synuclein aggregation associated with Parkinson's disease and related dementias.
Assuntos
Doença de Parkinson , alfa-Sinucleína , Camundongos , Animais , alfa-Sinucleína/metabolismo , Doença de Parkinson/metabolismo , Microplásticos , Corpos de Inclusão/metabolismo , Neurônios Dopaminérgicos/metabolismoRESUMO
Recent studies have identified increasing levels of nanoplastic pollution in the environment. Here we find that anionic nanoplastic contaminants potently precipitate the formation and propagation of α-synuclein protein fibrils through a high-affinity interaction with the amphipathic and non-amyloid component (NAC) domains in α-synuclein. Nanoplastics can internalize in neurons through clathrin-dependent endocytosis, causing a mild lysosomal impairment that slows the degradation of aggregated α-synuclein. In mice, nanoplastics combine with α-synuclein fibrils to exacerbate the spread of α-synuclein pathology across interconnected vulnerable brain regions, including the strong induction of α-synuclein inclusions in dopaminergic neurons in the substantia nigra. These results highlight a potential link for further exploration between nanoplastic pollution and α-synuclein aggregation associated with Parkinson's disease and related dementias.
RESUMO
We examined the effects of substitution time (i.e., recovery time) in a simulated field hockey test on physical, technical and perceptual/cognitive performance. Nine sub-elite male field hockey players (age: 20 ± 2 yrs, height: 1.81 ± 0.06 m, body mass: 71 ± 10 kg, body fat: 10.3 ± 3.7%, VÌO2max: 67 ± 3 mL·kg-1·min-1) completed four 8-min 40-s bouts of high-intensity intermittent exercise with 2-min and 5.5-min substitution time replicating the demands of a 4-quarter field hockey match. After each bout, a 15-m maximal sprint, agility/dribbling test, passing accuracy test, and a cognitive task were completed. Heart rate (p < .001) and rating of perceived exertion (RPE) (p < .001) increased with every bout. RPE was higher for the 5.5-min condition during the 2nd and 4th bout. No differences were observed between the substitution times and the number of bouts on 15-m maximal sprint time (2-min: 2.03 ± 0.14 s, 5.5-min: 2.07 ± 0.12 s), average reaction time (2-min: 347.19 ± 30.78 ms, 5.5-min: 346.69 ± 38.73 ms), cognitive error rate (2-min: 0.86 ± 0.77; 5.5-min: 0.44 ± 0.37), passing accuracy (2-min: 6 ± 1, 5.5-min: 6 ± 1) and agility/dribbling time (2-min: 7.06 ± 0.41 s, 5.5-min: 7.23 ± 0.55 s). It was concluded that a longer recovery time (i.e., substitution time 5.5-min) did not provide better physical and technical performance than 2-min during a simulated 4-quarter field hockey test. Further research with a larger sample size should address whether the shorter 2-min substitution time seemed to result in lower cognitive performance.
RESUMO
RATIONALE: Engagement in scholarly practice has been associated with professional empowerment, role satisfaction and improvements in care delivery and patient outcomes across many healthcare professions. However, in evolving professions like respiratory therapy, scholarly practice is excluded from competency frameworks, resulting in a gap in education and subsequent application of this competency in practice. An exploration of scholarly practice in respiratory therapy may provide insights into evolving professions that face tensions between meeting competency requirements as outlined in frameworks and providing quality healthcare to the populations they serve. AIMS AND OBJECTIVES: The aim of the study was to explore what scholarly practice means, and how it manifests in practice from respiratory therapists' (RTs) perspectives. METHODS: We used interpretive description methodology. We purposively sampled participants to obtain varied perspectives of scholarly practice in respiratory therapy. We conducted 26 semistructured interviews with RTs in different roles (clinicians, educators, researchers, leaders and managers) across Canada and analysed the data using inductive analysis. Data collection and analysis proceeded concurrently. RESULTS: We developed five main themes: (i) the identity of a scholarly practitioner in RTs; (ii) factors influencing scholarly practice; (iii) one's impression of their professional self-image; (iv) scholarly practice as a vehicle for changing practice and (v) the complex interconnections between knowledges and practices. CONCLUSION: Scholarly practice appears to be a multifaceted phenomenon encompassing a wide range of activities and skills including conducting research, reflective practice, application of research to practice, and contributing to the advancement of the profession and healthcare. Scholarly practice is influenced by organisational context and culture, available resources, intrinsic motivation and external political context. We identified similarities between professional identity and the description of the scholarly practitioner, suggesting that these two phenomena may be interconnected. Furthermore, participants believed that scholarly practice could enhance the image, credibility, legitimacy and professionalisation of the profession.
Assuntos
Pessoal Técnico de Saúde , Atenção à Saúde , Humanos , Canadá , AutoimagemRESUMO
Epidemiological and histopathological findings have raised the possibility that misfolded α-synuclein protein might spread from the gut to the brain and increase the risk of Parkinson's disease (PD). While past experimental studies in mouse models have relied on gut injections of exogenous recombinant α-synuclein fibrils to study gut to brain α-synuclein transfer, the possible origins of misfolded α-synuclein within the gut have remained elusive. We recently demonstrated that sensory cells of the gut mucosa express α-synuclein. In this study, we employed mouse intestinal organoids expressing human α-synuclein to observe the transfer of α-synuclein protein from gut epithelial cells in organoids co-cultured with vagal nodose neurons that are otherwise devoid of α-synuclein expression. In intact mice that express pathological human α-synuclein, but no mouse α-synuclein, α-synuclein fibril templating activity emerges in α-synuclein seeded fibril aggregation assays in tissues from the gut, vagus nerve, and dorsal motor nucleus. In newly engineered transgenic mice that restrict pathological human α-synuclein expression to intestinal epithelial cells, α-synuclein fibril-templating activity transfers to the vagus nerve and to the dorsal motor nucleus. Subdiaphragmatic vagotomy prior to the induction of α-synuclein expression in the gut epithelial cells effectively protects the hindbrain from the emergence of α-synuclein fibril templating activity. Overall, these findings highlight a novel potential non-neuronal source of fibrillar α-synuclein protein that might arise in gut mucosal cells.
RESUMO
Parkinson's disease (PD) is the most common neurodegenerative movement disorder, and neuroprotective or disease-modifying interventions remain elusive. High-throughput markers aimed at stratifying patients on the basis of shared etiology are required to ensure the success of disease-modifying therapies in clinical trials. Mitochondrial dysfunction plays a prominent role in the pathogenesis of PD. Previously, we found brain region-specific accumulation of mitochondrial DNA (mtDNA) damage in PD neuronal culture and animal models, as well as in human PD postmortem brain tissue. To investigate mtDNA damage as a potential blood-based marker for PD, we describe herein a PCR-based assay (Mito DNADX) that allows for the accurate real-time quantification of mtDNA damage in a scalable platform. We found that mtDNA damage was increased in peripheral blood mononuclear cells derived from patients with idiopathic PD and those harboring the PD-associated leucine-rich repeat kinase 2 (LRRK2) G2019S mutation in comparison with age-matched controls. In addition, mtDNA damage was elevated in non-disease-manifesting LRRK2 mutation carriers, demonstrating that mtDNA damage can occur irrespective of a PD diagnosis. We further established that Lrrk2 G2019S knock-in mice displayed increased mtDNA damage, whereas Lrrk2 knockout mice showed fewer mtDNA lesions in the ventral midbrain, compared with wild-type control mice. Furthermore, a small-molecule kinase inhibitor of LRRK2 mitigated mtDNA damage in a rotenone PD rat midbrain neuron model and in idiopathic PD patient-derived lymphoblastoid cell lines. Quantifying mtDNA damage using the Mito DNADX assay may have utility as a candidate marker of PD and for measuring the pharmacodynamic response to LRRK2 kinase inhibitors.
Assuntos
DNA Mitocondrial , Doença de Parkinson , Humanos , Animais , Camundongos , Ratos , DNA Mitocondrial/genética , Doença de Parkinson/genética , Leucócitos Mononucleares , Mitocôndrias , Dano ao DNARESUMO
[This corrects the article DOI: 10.3389/frobt.2023.1137750.].
RESUMO
Crystallographic and computational studies suggest the occurrence of favourable interactions between polarizable arenes and halogen atoms. However, the systematic experimental quantification of halogenâ â â arene interactions in solution has been hindered by the large variance in the steric demands of the halogens. Here we have synthesized molecular balances to quantify halogenâ â â arene contacts in 17 solvents and solvent mixtures using 1 H NMR spectroscopy. Calculations indicate that favourable halogenâ â â arene interactions arise from London dispersion in the gas phase. In contrast, comparison of our experimental measurements with partitioned SAPT0 energies indicate that dispersion is sufficiently attenuated by the solvent that the halogenâ â â arene interaction trend was instead aligned with increasing exchange repulsion as the halogen increased in size (ΔGX â â â Ph =0 to +1.5â kJ mol-1 ). Halogenâ â â arene contacts were slightly less disfavoured in solvents with higher solvophobicities and lower polarizabilities, but strikingly, were always less favoured than CH3 â â â arene contacts (ΔGMe â â â Ph =0 to -1.4â kJ mol-1 ).
RESUMO
BACKGROUND: Cancer patients often experience treatment-related symptoms which, if uncontrolled, may require emergency department admission. We developed models identifying breast or genitourinary cancer patients at the risk of attending emergency department (ED) within 30-days and demonstrated the development, validation, and proactive approach to in-production monitoring of an artificial intelligence-based predictive model during a 3-month simulated deployment at a cancer hospital in the United States. METHODS: We used routinely-collected electronic health record data to develop our predictive models. We evaluated models including a variational autoencoder k-nearest neighbors algorithm (VAE-kNN) and model behaviors with a sample containing 84,138 observations from 28,369 patients. We assessed the model during a 77-day production period exposure to live data using a proactively monitoring process with predefined metrics. RESULTS: Performance of the VAE-kNN algorithm is exceptional (Area under the receiver-operating characteristics, AUC = 0.80) and remains stable across demographic and disease groups over the production period (AUC 0.74-0.82). We can detect issues in data feeds using our monitoring process to create immediate insights into future model performance. CONCLUSIONS: Our algorithm demonstrates exceptional performance at predicting risk of 30-day ED visits. We confirm that model outputs are equitable and stable over time using a proactive monitoring approach.
Patients with cancer often need to visit the hospital emergency department (ED), for example due to treatment side effects. Predicting these visits might help us to better manage the treatment of patients who are at risk. Here, we develop a computer-based tool to identify patients with cancer who are at risk of an unplanned ED visit within 30 days. We use health record data from over 28,000 patients who had visited a single cancer hospital in the US to create and test the model. The model performed well and was consistent across different demographic and disease groups. We monitor model behavior over time and show that it is stable. The approach we take to monitoring model performance may be a particularly useful contribution toward implementing similar predictive models in the clinic and checking that they are performing as intended.
RESUMO
The recognition that cytosolic mitochondrial DNA (mtDNA) activates cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) innate immune signaling has unlocked novel disease mechanisms. Here, an uncharacterized variant predicted to affect TOP1MT function, P193L, was discovered in a family with multiple early onset autoimmune diseases, including Systemic Lupus Erythematosus (SLE). Although there was no previous genetic association between TOP1MT and autoimmune disease, the role of TOP1MT as a regulator of mtDNA led us to investigate whether TOP1MT could mediate the release of mtDNA to the cytosol, where it could then activate the cGAS-STING innate immune pathway known to be activated in SLE and other autoimmune diseases. Through analysis of cells with reduced TOP1MT expression, we show that loss of TOP1MT results in release of mtDNA to the cytosol, which activates the cGAS-STING pathway. We also characterized the P193L variant for its ability to rescue several TOP1MT functions when expressed in TOP1MT knockout cells. We show that the P193L variant is not fully functional, as its re-expression at high levels was unable to rescue mitochondrial respiration deficits, and only showed partial rescue for other functions, including repletion of mtDNA replication following depletion, nucleoid size, steady state mtDNA transcripts levels and mitochondrial morphology. Additionally, expression of P193L at endogenous levels was unable to rescue mtDNA release-mediated cGAS-STING signaling. Overall, we report a link between TOP1MT and mtDNA release leading to cGAS-STING activation. Moreover, we show that the P193L variant has partial loss of function that may contribute to autoimmune disease susceptibility via cGAS-STING mediated activation of the innate immune system.
Assuntos
Doenças Autoimunes , Lúpus Eritematoso Sistêmico , Humanos , DNA Mitocondrial/genética , Imunidade Inata/genética , Interferons , Nucleotidiltransferases/genética , Nucleotidiltransferases/metabolismoRESUMO
Surveying active nuclear facilities for spread of alpha and beta contamination is currently performed by human operators. However, a skills gap of qualified workers is emerging and is set to worsen in the near future due to under recruitment, retirement and increased demand. This paper presents an autonomous ground vehicle that can survey nuclear facilities for alpha, beta and gamma radiation and generate radiation heatmaps. New methods for preventing the robot from spreading radioactive contamination using a state-machine and radiation costmaps are introduced. This is the first robot that can detect alpha and beta contamination and autonomously re-plan around the contamination without the wheels passing over the contaminated area. Radiation avoidance functionality is proven experimentally to reduce alpha and beta contamination spread as well as gamma radiation dose to the robot. The robot's survey area is defined using a custom designed, graphically controlled area coverage planner. It was concluded that the robot is highly suited to certain monotonous room scale radiation surveying tasks and therefore provides the opportunity for financial savings, to mitigate a future skills gap, and provision of radiation surveys that are more granular, accurate and repeatable than those currently performed by human operators.