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1.
Eye (Lond) ; 2024 Apr 02.
Artigo em Inglês | MEDLINE | ID: mdl-38565599

RESUMO

School eye health (SEH) has been on the global agenda for many years, and there is mounting evidence available to support that school-based visual screenings are one of the most effective and cost-efficient interventions to reach children over five years old. A scoping review was conducted in MEDLINE, Web of Science, PubMed, and CINHAL between February and June 2023 to identify current priorities in recent literature on school eye health in low- and middle-income countries (LMICs). Selection of relevant publications was performed with Covidence, and the main findings were classified according to the WHO Health Promoting Schools framework (HPS). A total of 95 articles were included: cross-sectional studies (n = 55), randomised controlled trials (n = 7), qualitative research (n = 7) and others. Results demonstrate that multi-level action is required to implement sustainable and integrated school eye health programmes in low and middle-income countries. The main priorities identified in this review are: standardised and rigorous protocols; cost-effective workforce; provision of suitable spectacles; compliance to spectacle wear; efficient health promotion interventions; parents and community engagement; integration of programmes in school health; inter-sectoral, government-owned programmes with long-term financing schemes. Even though many challenges remain, the continuous production of quality data such as the ones presented in this review will help governments and other stakeholders to build evidence-based, comprehensive, integrated, and context-adapted programmes and deliver quality eye care services to children all over the world.

2.
RNA ; 29(12): 1928-1938, 2023 12.
Artigo em Inglês | MEDLINE | ID: mdl-37783489

RESUMO

Ribosomal pauses are a critical part of cotranslational events including protein folding and localization. However, extended ribosome pauses can lead to ribosome collisions, resulting in the activation of ribosome rescue pathways and turnover of protein and mRNA. While this relationship has been known, there has been little exploration of how ribosomal stalls impact translation duration at a quantitative level. We have taken a method used to measure elongation time and adapted it for use in Saccharomyces cerevisiae to quantify the impact of elongation stalls. We find, in transcripts containing Arg CGA codon repeat-induced stalls, a Hel2-mediated dose-dependent decrease in protein expression and mRNA level and an elongation delay on the order of minutes. In transcripts that contain synonymous substitutions to nonoptimal Leu codons, there is a decrease in protein and mRNA levels, as well as similar elongation delay, but this occurs through a non-Hel2-mediated mechanism. Finally, we find that Dhh1 selectively increases protein expression, mRNA level, and elongation rate. This indicates that distinct poorly translated mRNAs will activate different rescue pathways despite similar elongation stall durations. Taken together, these results provide new quantitative mechanistic insight into the surveillance of translation and the roles of Hel2 and Dhh1 in mediating ribosome pausing events.


Assuntos
Proteínas de Saccharomyces cerevisiae , Saccharomyces cerevisiae , Saccharomyces cerevisiae/genética , Saccharomyces cerevisiae/metabolismo , Biossíntese de Proteínas , Ribossomos/genética , Ribossomos/metabolismo , Códon/genética , Códon/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Elongação Traducional da Cadeia Peptídica , Proteínas de Saccharomyces cerevisiae/genética , Proteínas de Saccharomyces cerevisiae/metabolismo , Ubiquitina-Proteína Ligases/genética
3.
Front Neurosci ; 17: 1210175, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37588516

RESUMO

Traumatic Brain Injury (TBI) is a major cause of disability and mortality, particularly among the elderly, yet our mechanistic understanding of how age renders the post-traumatic brain vulnerable to poor clinical outcomes and susceptible to neurological disease remains poorly understood. It is well established that dysregulated and sustained immune responses contribute to negative outcomes after TBI, however our understanding of the interactions between central and peripheral immune reservoirs is still unclear. The meninges serve as the interface between the brain and the immune system, facilitating important bi-directional roles in healthy and disease settings. It has been previously shown that disruption of this system exacerbates inflammation in age related neurodegenerative disorders such as Alzheimer's disease, however we have an incomplete understanding of how the meningeal compartment influences immune responses after TBI. Here, we examine the meningeal tissue and its response to brain injury in young (3-months) and aged (18-months) mice. Utilizing a bioinformatic approach, high-throughput RNA sequencing demonstrates alterations in the meningeal transcriptome at sub-acute (7-days) and chronic (1 month) timepoints after injury. We find that age alone chronically exacerbates immunoglobulin production and B cell responses. After TBI, adaptive immune response genes are up-regulated in a temporal manner, with genes involved in T cell responses elevated sub-acutely, followed by increases in B cell related genes at chronic time points after injury. Pro-inflammatory cytokines are also implicated as contributing to the immune response in the meninges, with ingenuity pathway analysis identifying interferons as master regulators in aged mice compared to young mice following TBI. Collectively these data demonstrate the temporal series of meningeal specific signatures, providing insights into how age leads to worse neuroinflammatory outcomes in TBI.

4.
PLoS One ; 18(7): e0288363, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37440485

RESUMO

The pathophysiological changes that occur after traumatic brain injury (TBI) can lead to the development of post-traumatic epilepsy, a life-long complication of brain trauma. The etiology of post-traumatic epilepsy remains unknown, but TBI brains exhibit an abnormal excitatory / inhibitory balance. In this study, we examine how brain injury alters susceptibility to chemically-induced seizures in C57Bl/6J mice, and if pharmacological enhancement of glutamate transporters can reduce chronic post-traumatic seizures. We found that controlled cortical impact (CCI) mice display delayed susceptibility to pentylenetetrazol (PTZ)-induced seizures. While CCI mice have no change in seizure susceptibility at 7d post-injury (dpi), at 70dpi they have reduced latency to PTZ-induced seizure onset, higher seizure frequency and longer seizure duration. Quantification of glutamate transporter mRNA showed that levels of Scl1a2 and Scl1a3 mRNA were increased at 7dpi, but significantly decreased at 70dpi. To test if increased levels of glutamate transporters can ameliorate delayed-onset seizure susceptibility in TBI mice, we exposed a new cohort of mice to CCI and administered ceftriaxone (200mg/kg/day) for 14d from 55-70dpi. We found that ceftriaxone significantly increased Scl1a2 and Scl1a3 in CCI mouse brain at 70dpi, and prevented the susceptibility of CCI mice to PTZ-induced seizures. This study demonstrates cortical impact can induce a delayed-onset seizure phenotype in mice. Delayed (55dpi) ceftriaxone treatment enhances glutamate transporter mRNA in the CCI brain, and reduces PTZ-induced seizures in CCI mice.


Assuntos
Lesões Encefálicas Traumáticas , Epilepsia Pós-Traumática , Humanos , Camundongos , Animais , Ceftriaxona/farmacologia , Ceftriaxona/uso terapêutico , Tempo para o Tratamento , Lesões Encefálicas Traumáticas/complicações , Lesões Encefálicas Traumáticas/tratamento farmacológico , Convulsões/induzido quimicamente , Convulsões/tratamento farmacológico , Convulsões/complicações , Pentilenotetrazol/toxicidade , Camundongos Endogâmicos C57BL , Glutamatos , Modelos Animais de Doenças
5.
Cochrane Database Syst Rev ; 7: CD013610, 2023 07 18.
Artigo em Inglês | MEDLINE | ID: mdl-37462324

RESUMO

BACKGROUND: Cystic fibrosis (CF) is a life-limiting genetic disorder predominantly affecting the lungs and pancreas. Airway clearance techniques (ACTs) and exercise therapy are key components of physiotherapy, which is considered integral in managing CF; however, low adherence is well-documented. Poor physiotherapy adherence may lead to repeated respiratory infections, reduced exercise tolerance, breathlessness, reduced quality of life, malaise and reduced life expectancy, as well as increased use of pharmacology, healthcare access and hospital admission. Therefore, evidence-based strategies to inform clinical practice and improve adherence to physiotherapy may improve quality of life and reduce treatment burden. OBJECTIVES: To assess the effects of interventions to enhance adherence to airway clearance treatment and exercise therapy in people with CF and their effects on health outcomes, such as pulmonary exacerbations, exercise capacity and health-related quality of life. SEARCH METHODS: We searched the Cochrane Cystic Fibrosis Trials Register, compiled from electronic database searches and handsearching of journals and conference abstract books. Date of last search: 1 March 2023. We also searched online trials registries and the reference lists of relevant articles and reviews. Date of last search: 28 March 2023. SELECTION CRITERIA: We included randomised controlled trials (RCTs) and quasi-RCTs of parallel design assessing any intervention aimed at enhancing adherence to physiotherapy in people with CF versus no intervention, another intervention or usual care. DATA COLLECTION AND ANALYSIS: Two review authors independently checked search results for eligible studies and independently extracted data. We used standard procedures recommended by Cochrane and assessed the certainty of evidence using the GRADE system. MAIN RESULTS: Two RCTs (77 participants with CF; age range 2 to 20 years; 44 (57%) males) met the inclusion criteria of this review. One study employed an intervention to improve adherence to exercise and the second an intervention to improve adherence to ACT. Both studies measured outcomes at baseline and at three months, but neither study formally assessed our primary outcome of adherence in terms of our planned outcome measures, and results were dependent on self-reported data. Adherence to ACTs One RCT (43 participants) assessed using specifically-composed music alongside ACTs compared to self-selected or no music (usual care). The ACT process consisted of nebuliser inhalation treatment, ACTs and relaxation or antibiotic nebuliser treatment. We graded all evidence as very low certainty. This study reported adherence to ACTs using the Morisky-Green questionnaire and also participants' perception of treatment time and enjoyment, which may influence adherence (outcome not reported specifically in this review). We are uncertain whether participants who received specifically-composed music may be more likely to adhere at six and 12 weeks compared to those who received usual care, risk ratio (RR) 1.75 (95% confidence interval (CI) 1.07 to 2.86) and RR 1.56 (95% CI 1.01 to 2.40) respectively. There may not be any difference in adherence when comparing specifically-composed music to self-selected music at six weeks, RR 1.21 (95% CI 0.87 to 1.68) or 12 weeks, RR 1.52 (95% CI 0.97 to 2.38); or self-selected music to usual care at six weeks, RR 1.44 (95% CI 0.82 to 2.52) or 12 weeks, RR 1.03 (95% CI 0.57 to 1.86). The music study also reported the number of respiratory infections requiring hospitalisation at 12 weeks, with no difference seen in the risk of hospitalisation between all groups. Adherence to exercise One RCT (24 participants) compared the provision of a manual of aerobic exercises, recommended exercise prescription plus two-weekly follow-up phone calls to reinforce exercise practice over a period of three months to verbal instructions for aerobic exercise according to the CF centre's protocol. We graded all evidence as very low certainty. We are uncertain whether an educational intervention leads to more participants in the intervention group undertaking increased regular physical activity at three months (self-report), RR 3.67 (95% CI 1.24 to 10.85), and there was no reported difference between groups in the number undertaking physical activity three times per week or undertaking at least 40 minutes of physical activity. No effect was seen on secondary outcome measures of spirometry, exercise capacity or any CF quality of life domains. This study did not report on the frequency of respiratory infections (hospitalised or not) or adverse events. AUTHORS' CONCLUSIONS: We are uncertain whether a music-based motivational intervention may increase adherence to ACTs or affect the risk of hospitalisation for a respiratory infection. We are also uncertain whether an educational intervention increases adherence to exercise or reduces the frequency of respiratory infection-related hospital admission. However, these results are largely based on self-reported data and the impact of strategies to improve adherence to ACT and exercise in children and adolescents with stable CF remains inconclusive. Given that adherence to ACT and exercise therapy are fundamental to the clinical management of people with CF, there is an urgent need for well-designed, large-scale clinical trials in this area, which should conform to the CONSORT statement for standards of reporting and use appropriate, validated outcome measures. Studies should also ensure full disclosure of data for all important clinical outcomes.


Assuntos
Fibrose Cística , Masculino , Adolescente , Criança , Humanos , Pré-Escolar , Adulto Jovem , Adulto , Feminino , Fibrose Cística/complicações , Exercício Físico , Terapia Respiratória , Qualidade de Vida , Modalidades de Fisioterapia
6.
bioRxiv ; 2023 Mar 20.
Artigo em Inglês | MEDLINE | ID: mdl-36993688

RESUMO

Ribosomal pauses are a critical part of co-translational events including protein folding and localization. However, extended ribosome pauses can lead to ribosome collisions, resulting in the activation of ribosome rescue pathways and turnover of protein and mRNA. While this relationship has been known, the specific threshold between permissible pausing versus activation of rescue pathways has not been quantified. We have taken a method used to measure elongation time and adapted it for use in S. cerevisiae to quantify the impact of elongation stalls. We find, in transcripts containing Arg CGA codon repeat-induced stalls, a Hel2-mediated dose-dependent decrease in protein expression and mRNA level and an elongation delay on the order of minutes. In transcripts that contain synonymous substitutions to non-optimal Leu codons, there is a decrease in protein and mRNA levels, as well as similar elongation delay, but this occurs through a non-Hel2-mediated mechanism. Finally, we find that Dhh1 selectively increases protein expression, mRNA level, and elongation rate. This indicates that distinct poorly translated codons in an mRNA will activate different rescue pathways despite similar elongation stall durations. Taken together, these results provide new quantitative mechanistic insight into the surveillance of translation and the roles of Hel2 and Dhh1 in mediating ribosome pausing events.

7.
Methods Protoc ; 5(5)2022 Sep 27.
Artigo em Inglês | MEDLINE | ID: mdl-36287049

RESUMO

In aging, the brain is more vulnerable to injury and neurodegenerative disease, but the mechanisms responsible are largely unknown. Evidence now suggests that neuroinflammation, mediated by resident brain astrocyte and microglia populations, are key players in the generation of inflammatory responses and may influence both age related processes and the initiation/progression of neurodegeneration. Consequently, targeting these cell types individually and collectively may aid in the development of novel disease-modifying therapies. We have optimized and characterized a protocol for the effective sequential isolation of both microglia and astrocytes from the adult mouse brain in young and aged mice. We demonstrate a technique for the sequential isolation of these immune cells by using magnetic beads technology, optimized to increase yield and limit potential artifacts in downstream transcriptomic applications, including RNA-sequencing pipelines. This technique is versatile, cost-effective, and reliable for the study of responses within the same biological context, simultaneously being advantageous in reducing mice numbers required to assess cellular responses in normal and age-related pathological conditions.

8.
Elife ; 112022 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-36107469

RESUMO

During times of unpredictable stress, organisms must adapt their gene expression to maximize survival. Along with changes in transcription, one conserved means of gene regulation during conditions that quickly repress translation is the formation of cytoplasmic phase-separated mRNP granules such as P-bodies and stress granules. Previously, we identified that distinct steps in gene expression can be coupled during glucose starvation as promoter sequences in the nucleus are able to direct the subcellular localization and translatability of mRNAs in the cytosol. Here, we report that Rvb1 and Rvb2, conserved ATPase proteins implicated as protein assembly chaperones and chromatin remodelers, were enriched at the promoters and mRNAs of genes involved in alternative glucose metabolism pathways that we previously found to be transcriptionally upregulated but translationally downregulated during glucose starvation in yeast. Engineered Rvb1/Rvb2-binding on mRNAs was sufficient to sequester mRNAs into mRNP granules and repress their translation. Additionally, this Rvb tethering to the mRNA drove further transcriptional upregulation of the target genes. Further, we found that depletion of Rvb2 caused decreased alternative glucose metabolism gene mRNA induction, but upregulation of protein synthesis during glucose starvation. Overall, our results point to Rvb1/Rvb2 coupling transcription, mRNA granular localization, and translatability of mRNAs during glucose starvation. This Rvb-mediated rapid gene regulation could potentially serve as an efficient recovery plan for cells after stress removal.


Assuntos
Adenosina Trifosfatases/metabolismo , Glucose , Proteínas de Saccharomyces cerevisiae/metabolismo , Fatores de Transcrição/metabolismo , Cromatina/metabolismo , DNA Helicases/metabolismo , Glucose/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Saccharomyces cerevisiae/genética , Saccharomyces cerevisiae/metabolismo , Proteínas de Saccharomyces cerevisiae/genética
9.
Biology (Basel) ; 11(7)2022 Jul 08.
Artigo em Inglês | MEDLINE | ID: mdl-36101412

RESUMO

Traumatic brain injury (TBI) is a significant risk factor for the development of sleep and circadian rhythm impairments. In this study we compare the circadian rhythms and sleep patterns in the high-frequency head impact (HFHI) and controlled cortical impact (CCI) mouse models of TBI. These mouse models have different injury mechanisms key differences of pathology in brain regions controlling circadian rhythms and EEG wave generation. We found that both HFHI and CCI caused dysregulation in the diurnal expression of core circadian genes (Bmal1, Clock, Per1,2, Cry1,2) at 24 h post-TBI. CCI mice had reduced locomotor activity on running wheels in the first 7 d post-TBI; however, both CCI and HFHI mice were able to maintain circadian behavior cycles even in the absence of light cues. We used implantable EEG to measure sleep cycles and brain activity and found that there were no differences in the time spent awake, in NREM or REM sleep in either TBI model. However, in the sleep states, CCI mice have reduced delta power in NREM sleep and reduced theta power in REM sleep at 7 d post-TBI. Our data reveal that different types of brain trauma can result in distinct patterns of circadian and sleep disruptions and can be used to better understand the etiology of sleep disorders after TBI.

10.
J Intensive Care Soc ; 23(2): 183-190, 2022 May.
Artigo em Inglês | MEDLINE | ID: mdl-35615241

RESUMO

Background: The unprecedented increase in critically ill patients due to the COVID-19 pandemic mandated rapid training in critical care for redeployed staff to work safely in intensive care units (ICU). Methods: The COVID-19 ICU Remote-Learning Course (CIRLC) is a remote delivery course developed in response to the pandemic. This was a one-day course focused on the fundamentals of Intensive Care. The course used blended learning with recorded lectures and interactive tutorials delivered by shielding and frontline ICU trained professionals. The course was developed within one week and piloted at three NHS Trusts. It was then made publicly available free of charge to redeployed healthcare professionals across the UK and Ireland. An iterative cycle of improvement was used to update the course content weekly. A course confidence questionnaire with quantitative and qualitative questions was used to evaluate effectiveness. Data is reported as n (%), means (SD) and thematic analysis was used for the open questions. Results: 1,269 candidates from 171 organisations completed the course, with 99 volunteer trainers. 96% of respondents rated the course as very or extremely useful. 86% rated the online platform as excellent. Overall confidence improved from 2.7/5 to 3.9/5. Qualitative data showed that the course was pitched at the appropriate level, accessible and built clinicians confidence to work in intensive care. Conclusion: This model of educational delivery with a rapid iteration cycle was a pragmatic, effective solution to knowledge-based training under social distancing measures. Whilst full course evaluation was not possible, we believe that this work demonstrates practical guidance on educational response in a pandemic as well as highlighting the altruistic nature of the critical care community.

11.
RNA Biol ; 19(1): 636-649, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35491906

RESUMO

Protein synthesis is energetically expensive and its rate is influenced by factors such as cell type and environment. Suppression of translation is a canonical response to stressful changes in the cellular environment. In particular, inhibition of the initiation step of translation has been highlighted as the key control step in stress-induced translational suppression as mechanisms that quickly suppress initiation are well-conserved. However, cells have evolved complex regulatory means to control translation apart from initiation. Here, we examine the role of the elongation step of translation in yeast subjected to acute glucose deprivation. The use of ribosome profiling and in vivo reporter assays demonstrated elongation rates slow progressively following glucose removal. We observed that ribosome distribution broadly shifts towards the downstream ends of transcripts after both acute and gradual glucose deprivation but not in response to other stressors. Additionally, on assessed mRNAs, a correlation existed between ribosome occupancy and protein production pre-stress but was lost after stress. These results indicate that stress-induced elongation regulation causes ribosomes to slow down and build up on a considerable proportion of the transcriptome in response to glucose withdrawal. Finally, we report ribosomes that built up along transcripts are competent to resume elongation and complete protein synthesis after readdition of glucose to starved cells. This suggests that yeast has evolved mechanisms to slow translation elongation in response to glucose starvation which do not preclude continuation of protein production from those ribosomes, thereby averting a need for new initiation events to take place to synthesize proteins.Abbreviations: AUG: start codon, bp: base pair(s), CDS: coding sequence, CHX: cycloheximide, eEF2: eukaryotic elongation factor 2, LTM: lactimidomycin, nt: nucleotide, PGK1: 3-phosphoglycerate kinase, ribosomal biogenesis: ribi, RO: ribosome occupancy, RPF: ribosome protected fragment, TE: translational efficiency.


Assuntos
Proteínas de Saccharomyces cerevisiae , Saccharomyces cerevisiae , Glucose , Elongação Traducional da Cadeia Peptídica , Ribossomos/genética , Ribossomos/metabolismo , Saccharomyces cerevisiae/genética , Saccharomyces cerevisiae/metabolismo , Proteínas de Saccharomyces cerevisiae/genética , Proteínas de Saccharomyces cerevisiae/metabolismo
12.
J Intensive Care Soc ; 23(4): 485-491, 2022 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-36751346

RESUMO

Background: Optimising outcomes for critically ill patients with COVID-19 patients requires early interdisciplinary rehabilitation. As admission numbers soared through the pandemic, the redeployed workforce needed rapid, effective training to deliver these rehabilitation interventions. Methods: The COVID-19 ICU Remote-Learning Rehab Course (CIRLC-rehab) is a one-day interdisciplinary course developed after the success of CIRLC-acute. The aim of CIRLC-rehab was to rapidly train healthcare professionals to deliver physical, nutritional and psychological rehabilitation strategies in the ICU/acute setting. The course used blended learning with interactive tutorials delivered by shielding critical care professionals. CIRLC-rehab was evaluated through a mixed-methods approach, including questionnaires, and follow-up semi-structured interviews to evaluate perceived impact on clinical practice. Quantitative data are reported as n (%) and means (SD). Inductive descriptive thematic analysis with methodological triangulation was used to analyse the qualitative data from the questionnaires and interviews. Results: 805 candidates completed CIRLC-rehab. 627 (78.8%) completed the post-course questionnaire. 95% (n = 596) found CIRLC-rehab extremely or very useful and 96.0% (n = 602) said they were very likely to recommend the course to colleagues. Overall confidence rose from 2.78/5 to 4.14/5. The course promoted holistic and humanised care, facilitated informal networks, promoted interdisciplinary working and equipped the candidates with practical rehabilitation strategies that they implemented into clinical practice. Conclusion: This pragmatic solution to educating redeployed staff during a pandemic increased candidates' confidence in the rehabilitation of critically ill patients. There was also evidence of modifications to clinical care utilising learning from the course that subjectively facilitated holistic and humanised rehabilitation, combined with the importance of recognising the humanity, of those working in ICU settings themselves. Whilst these data are self-reported, we believe that this work demonstrates the real-term benefits of remote, scalable and rapid educational delivery.

13.
J Biomol Tech ; 33(2)2022 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-36756538

RESUMO

A current method to locate sites of N-linked glycosylation on a protein involves the identification of deamidated sites after releasing the glycans with peptide-N-glycosidase F (PNGase F). PNGase F deglycosylation converts glycosylated Asn residues into Asp. The 1-Da mass tag created by this process is observable by liquid chromatography-tandem mass spectrometry analysis. A potential interference to this method of N-glycosylation site mapping is the chemical deamidation of Asn residues, which occurs spontaneously and can result in false positives. Deamidation is a pH-dependent process that results in the formation of iso-Asp (i-Asp) and native Asp (n-Asp) by a succinimide intermediate, whereas PNGase F deglycosylation results in the conversion of the glycosylation Asn residue into n-Asp. N-linked glycosylation sites can thus be identified by the presence of a single chromatographic peak corresponding to an n-Asp residue within the consensus sequence Asn-X-Ser/Thr, whereas sites of deamidation led to 2 chromatographic peaks resulting from the presence of n-Asp and i-Asp. The intent of this study is to alert investigators in the field to the potential and unexpected errors resulting from this phenomenon and to suggest a strategy to overcome this pitfall and limit the number of false-positive identifications.


Assuntos
Asparagina , Glicosilação , Peptídeo-N4-(N-acetil-beta-glucosaminil) Asparagina Amidase/química , Asparagina/química , Asparagina/metabolismo , Espectrometria de Massas , Cromatografia Líquida
14.
Nat Commun ; 12(1): 2613, 2021 05 10.
Artigo em Inglês | MEDLINE | ID: mdl-33972519

RESUMO

Repeated head impact exposure can cause memory and behavioral impairments. Here, we report that exposure to non-damaging, but high frequency, head impacts can alter brain function in mice through synaptic adaptation. High frequency head impact mice develop chronic cognitive impairments in the absence of traditional brain trauma pathology, and transcriptomic profiling of mouse and human chronic traumatic encephalopathy brain reveal that synapses are strongly affected by head impact. Electrophysiological analysis shows that high frequency head impacts cause chronic modification of the AMPA/NMDA ratio in neurons that underlie the changes to cognition. To demonstrate that synaptic adaptation is caused by head impact-induced glutamate release, we pretreated mice with memantine prior to head impact. Memantine prevents the development of the key transcriptomic and electrophysiological signatures of high frequency head impact, and averts cognitive dysfunction. These data reveal synapses as a target of high frequency head impact in human and mouse brain, and that this physiological adaptation in response to head impact is sufficient to induce chronic cognitive impairment in mice.


Assuntos
Lesões Encefálicas Traumáticas/metabolismo , Cognição , Neurônios/patologia , Sinapses/metabolismo , Sinapses/patologia , Transcriptoma/genética , Peptídeos beta-Amiloides/metabolismo , Animais , Escala de Avaliação Comportamental , Lesões Encefálicas Traumáticas/genética , Cognição/efeitos dos fármacos , Disfunção Cognitiva/patologia , Eletrofisiologia , Ontologia Genética , Ácido Glutâmico/metabolismo , Memantina/administração & dosagem , Camundongos , Microglia/metabolismo , Família Multigênica , Plasticidade Neuronal/genética , Neurônios/citologia , Receptores de N-Metil-D-Aspartato/metabolismo , Sinapses/genética , Proteínas tau/metabolismo
15.
Suicide Life Threat Behav ; 51(3): 606-615, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33634908

RESUMO

OBJECTIVE: This study examined the relationship between explicit and implicit measures of hopelessness and self-injurious behavior (defined here as self-harming or suicidal actions and thoughts). METHOD: A community sample of 267 participants completed explicit measures of hopelessness (Beck's Hopelessness Scale and a Feeling Thermometer), an implicit measure of hopelessness (Hopelessness Implicit Association Test), and a self-report measure of their history of self-injurious behavior. RESULTS: The results showed that high levels of hopelessness, measured both explicitly or implicitly, were associated with a past and recent history of self-injury. However, there was also an interaction between the implicit and explicit measures such that explicit hopelessness was more strongly predictive of self-injury in people with high levels of implicit hopelessness. CONCLUSION: The findings show that the implicit measurement of hopelessness can help predict past and recent self-injury beyond what explicit measures of hopelessness currently achieve and could be used in the assessment of risk of both self-harming and suicidal behaviors.


Assuntos
Comportamento Autodestrutivo , Emoções , Humanos , Autoimagem , Autorrelato , Ideação Suicida
16.
Sci Rep ; 11(1): 2485, 2021 Jan 28.
Artigo em Inglês | MEDLINE | ID: mdl-33510363

RESUMO

We present a new methodology for measuring few-femtosecond electronic and nuclear dynamics in both atoms and polyatomic molecules using multidimensional high harmonic generation (HHG) spectroscopy measurements, in which the spectra are recorded as a function of the laser intensity to form a two-dimensional data set. The method is applied to xenon atoms and to benzene molecules, the latter exhibiting significant fast nuclear dynamics following ionization. We uncover the signature of the sub-cycle evolution of the returning electron flux in strong-field ionized xenon atoms, implicit in the strong field approximation but not previously observed directly. We furthermore extract the nuclear autocorrelation function in strong field ionized benzene cations, which is determined to have a decay of [Formula: see text] fs, in good agreement with the [Formula: see text] fs obtained from direct dynamics variational multi-configuration Gaussian calculations. Our method requires minimal assumptions about the system, and is applicable even to un-aligned polyatomic molecules.

17.
BMJ Simul Technol Enhanc Learn ; 6(4): 199-205, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32832100

RESUMO

INTRODUCTION: Physiotherapists working on-call to provide emergency respiratory services report stress and lack of confidence in on-call scenarios. Simulation-based education (SBE) is a potential solution to improve confidence and reduce stress of on-call physiotherapists. In physiotherapy, use of SBE is sporadic. The aim of this study was to evaluate the addition of SBE to an on-call training programme on non-respiratory physiotherapists' self-evaluated confidence. Additionally, the study aimed to evaluate if SBE facilitates identification of learning needs. METHODS: This cohort study took a mixed methods approach. Participants were recruited from staff providing on-call respiratory physiotherapy services at a UK hospital. Participants received traditional on-call training over 1 year, with SBE added the subsequent year, in a pre-post analysis design. Self-evaluated confidence was assessed with the Association of Chartered Physiotherapists in Respiratory Care Acute Respiratory/On-call Physiotherapy Self-evaluation of Competence (ACPRC) questionnaire. Two focus groups were conducted post-SBE. RESULTS: There were 10 participants. Thematic analysis of focus groups indicated participants found SBE provided coping strategies for on-call working. Using coping strategies taught in SBE reduced stress levels and increased confidence of non-specialist on-call physiotherapists. ACPRC questionnaire scores significantly improved following the addition of SBE (median change 5.5%, p=0.034, r=0.57). SBE assisted in identification of learning needs through recognition of unconscious incompetence and reinforcement of conscious and unconscious competence. CONCLUSIONS: SBE may improve self-evaluated confidence of non-specialist on-call physiotherapists. SBE assists in learning needs identification. SBE could enhance training of physiotherapists providing on-call respiratory services. Further larger trials investigating optimal methods of on-call physiotherapy postgraduate education are warranted.

18.
NPJ Prim Care Respir Med ; 29(1): 24, 2019 06 27.
Artigo em Inglês | MEDLINE | ID: mdl-31249313

RESUMO

The British Thoracic Society (BTS) Guidelines for Bronchiectasis in adults were published in January 2019, and comprise recommendations for treatment from primary to tertiary care. Here, we outline the practical implications of these guidelines for primary care practitioners. A diagnosis of bronchiectasis should be considered when a patient presents with a recurrent or persistent (>8 weeks) productive cough. A definitive diagnosis is made by using thin-section chest computed tomography (CT). Once diagnosed, patients should be initially assessed by a specialist respiratory team and a shared management plan formulated with the patient, the specialist and primary care teams. The cornerstone of primary care management is physiotherapy to improve airway sputum clearance and maximise exercise capacity, with prompt treatment of acute exacerbations with antibiotics.


Assuntos
Bronquiectasia/terapia , Modalidades de Fisioterapia/normas , Guias de Prática Clínica como Assunto , Atenção Primária à Saúde/normas , Sociedades Médicas , Cirurgia Torácica , Progressão da Doença , Humanos , Qualidade de Vida , Reino Unido , Adulto Jovem
19.
Phys Chem Chem Phys ; 21(19): 10038-10051, 2019 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-31046039

RESUMO

Time-resolving and controlling coupled electronic and nuclear dynamics at conical intersections on the sub-femtosecond to few-femtosecond time scale is among the challenging goals of attosecond physics. Here we present numerical simulations of time-resolved photoelectron spectroscopy of such dynamics in NO2, where the coupled electron-nuclear motion at the 2A1/2B2 conical intersection is steered on the sub-laser-cycle time scale by a nearly single-cycle, waveform controlled mid-infrared laser pulse. For a rigorous description of the photoionization dynamics, we employ ab initio energy- and geometry-resolved photoionization matrix elements obtained with the multichannel R-matrix method, using a multiconfigurational description of the molecule and a newly developed algorithm to generate photoionization dipoles that are phase consistent on the level of both the neutral and the ionic states. We find that for sufficient molecular alignment, the time- and energy-resolved anisotropy parameters of the photoelectron angular distributions provide a particularly clear picture of both the ultrafast natural molecular dynamics at the conical intersection and its modifications by the control pulse. In particular, changes in the electronic and nuclear configurations induced by the control pulse lead to the appearance of non-vanishing odd anisotropy parameters in the photoelectron spectra. These are absent in the spectra obtained without the control pulse and therefore provide sensitive, background-free diagnostic of the control.

20.
J Bras Pneumol ; 45(1): e20170347, 2019 Feb 11.
Artigo em Inglês, Português | MEDLINE | ID: mdl-30758427

RESUMO

Dysfunctional breathing (DB) is a respiratory condition characterized by irregular breathing patterns that occur either in the absence of concurrent diseases or secondary to cardiopulmonary diseases. Although the primary symptom is often dyspnea or "air hunger", DB is also associated with nonrespiratory symptoms such as dizziness and palpitations. DB has been identified across all ages. Its prevalence among adults in primary care in the United Kingdom is approximately 9.5%. In addition, among individuals with asthma, a positive diagnosis of DB is found in a third of women and a fifth of men. Although DB has been investigated for decades, it remains poorly understood because of a paucity of high-quality clinical trials and validated outcome measures specific to this population. Accordingly, DB is often underdiagnosed or misdiagnosed, given the similarity of its associated symptoms (dyspnea, tachycardia, and dizziness) to those of other common cardiopulmonary diseases such as COPD and asthma. The high rates of misdiagnosis of DB suggest that health care professionals do not fully understand this condition and may therefore fail to provide patients with an appropriate treatment. Given the multifarious, psychophysiological nature of DB, a holistic, multidimensional assessment would seem the most appropriate way to enhance understanding and diagnostic accuracy. The present narrative review was developed as a means of summarizing the available evidence about DB, as well as improving understanding of the condition by researchers and practitioners.


Assuntos
Transtornos Respiratórios/fisiopatologia , Tolerância ao Exercício/fisiologia , Coração/fisiopatologia , Humanos , Hiperventilação/fisiopatologia , Pulmão/fisiopatologia , Transtornos Respiratórios/líquido cefalorraquidiano , Transtornos Respiratórios/psicologia , Músculos Respiratórios/fisiopatologia
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