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1.
J Clin Invest ; 134(1)2024 Jan 02.
Artigo em Inglês | MEDLINE | ID: mdl-38165037

RESUMO

Myotonic dystrophy type 1 (DM1) is an autosomal dominant disorder caused by an unstable expanded CTG repeat located in the 3'-UTR of the DM1 protein kinase (DMPK) gene. The pathogenic mechanism results in misregulated alternative splicing of hundreds of genes, creating the dilemma of establishing which genes contribute to the mechanism of DM1 skeletal muscle pathology. In this issue of the JCI, Cisco and colleagues systematically tested the combinatorial effects of DM1-relevant mis-splicing patterns in vivo and identified the synergistic effects of mis-spliced calcium and chloride channels as a major contributor to DM1 skeletal muscle impairment. The authors further demonstrated the therapeutic potential for calcium channel modulation to block the synergistic effects and rescue myopathy.


Assuntos
Distrofia Miotônica , Humanos , Distrofia Miotônica/metabolismo , Splicing de RNA , Músculo Esquelético/metabolismo , Processamento Alternativo , Canais Iônicos/metabolismo , Miotonina Proteína Quinase/genética , Miotonina Proteína Quinase/metabolismo , Expansão das Repetições de Trinucleotídeos
2.
J Oral Maxillofac Surg ; 81(9): 1116-1123, 2023 09.
Artigo em Inglês | MEDLINE | ID: mdl-37336493

RESUMO

BACKGROUND: Magnetic resonance imaging (MRI) is being increasingly considered as an alternative for the evaluation and reconstruction of orbital fractures. No previous research has compared the orbital volume of an MRI-imaged, three-dimensional (3D), reconstructed, and virtually restored bony orbit to the gold standard of computed tomography (CT). PURPOSE: To measure the orbital volumes generated from MRI-based 3D models of fractured bony orbits with virtually positioned prebent fan plates in situ and compare them to the volumes of CT-based virtually reconstructed orbital models. STUDY DESIGN: This retrospective in-vitro study used CT and MRI data from adult patients with orbital trauma assessed at the Royal Brisbane and Women's Hospital Outpatient Maxillofacial Clinic from 2011 to 2012. Only those with orbital blowout fractures were included in the study. PREDICTOR VARIABLE: The primary predictor variable was imaging modality, with CT- and MRI-based 3D models used for plate bending and placement. MAIN OUTCOME VARIABLE: The primary outcome variable was the orbital volume of the enclosed 3D models. COVARIATES: Additional data collected was age, sex, and side of fractured orbit. The effect of operator variability on plate contouring and orbital volume was quantified. ANALYSES: The Wilcoxon signed rank test was used to assess differences between orbital volumes with a significance level P < .05. RESULTS: Of 11 eligible participants, six patients (four male and two female; mean age 31 ± 8.6 years) were enrolled. Two sets of six CT-based virtually restored orbits were smaller than the intact contralateral CT models by an average of 1.02 cm3 (95% CI -0.07 to 2.11 cm3; P = .028) and 0.99 cm3 (95% CI 0.07 to 1.91 cm3; P = .028), respectively. The average volume difference between the MRI-based virtually restored orbit and the intact contralateral MRI model was 0.97 cm3 (95% CI -1.08 to 1.94 cm3; P = .75). Imaging modality did affect orbital volume difference for 1 set of CT and MRI models (0.63 cm3; 95% CI -0.11 to 1.29 cm3; P = .046) but not the other (0.69 cm3; 95% CI -0.11 to 1.23 cm3; P = .075). Single operator variability in plate bending did not result in significant (P = .75) volume differences. CONCLUSIONS: MRI can be used to reconstruct orbital volume with a clinically acceptable level of accuracy.


Assuntos
Fraturas Orbitárias , Adulto , Humanos , Masculino , Feminino , Adulto Jovem , Estudos Retrospectivos , Fraturas Orbitárias/diagnóstico por imagem , Fraturas Orbitárias/cirurgia , Tomografia Computadorizada por Raios X/métodos , Órbita/diagnóstico por imagem , Órbita/cirurgia , Imageamento por Ressonância Magnética
3.
Life Sci Alliance ; 6(6)2023 06.
Artigo em Inglês | MEDLINE | ID: mdl-36977593

RESUMO

Postnatal skeletal muscle development is a highly dynamic period associated with widespread alternative splicing changes required to adapt tissues to adult function. These splicing events have significant implications because the reversion of adult mRNA isoforms to fetal isoforms is observed in forms of muscular dystrophy. LIMCH1 is a stress fiber-associated protein that is alternatively spliced to generate uLIMCH1, a ubiquitously expressed isoform, and mLIMCH1, a skeletal muscle-specific isoform containing six additional exons simultaneously included after birth in the mouse. CRISPR/Cas9 was used to delete the six alternatively spliced exons of LIMCH1 in mice, thereby forcing the constitutive expression of the predominantly fetal isoform, uLIMCH1. mLIMCH1 knockout mice had significant grip strength weakness in vivo, and maximum force generated was decreased ex vivo. Calcium-handling deficits were observed during myofiber stimulation that could explain the mechanism by which mLIMCH1 knockout leads to muscle weakness. In addition, LIMCH1 is mis-spliced in myotonic dystrophy type 1, with the muscleblind-like (MBNL) family of proteins acting as the likely major regulator of Limch1 alternative splicing in skeletal muscle.


Assuntos
Processamento Alternativo , Distrofia Miotônica , Animais , Camundongos , Processamento Alternativo/genética , Camundongos Knockout , Músculo Esquelético/metabolismo , Distrofia Miotônica/genética , Distrofia Miotônica/metabolismo , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , Splicing de RNA
4.
Int J Mol Sci ; 24(3)2023 Feb 02.
Artigo em Inglês | MEDLINE | ID: mdl-36769228

RESUMO

The contractile cells of skeletal muscles, called myofibers, are elongated multinucleated syncytia formed and maintained by the fusion of proliferative myoblasts. Human myofibers can be hundreds of microns in diameter and millimeters in length. Myofibers are non-mitotic, obviating the need for microtubules in cell division. However, microtubules have been adapted to the unique needs of these cells and are critical for myofiber development and function. Microtubules in mature myofibers are highly dynamic, and studies in several experimental systems have demonstrated the requirements for microtubules in the unique features of muscle biology including myoblast fusion, peripheral localization of nuclei, assembly of the sarcomere, transport and signaling. Microtubule-binding proteins have also been adapted to the needs of the skeletal muscle including the expression of skeletal muscle-specific protein isoforms generated by alternative splicing. Here, we will outline the different roles microtubules play in skeletal muscle cells, describe how microtubule abnormalities can lead to muscle disease and discuss the broader implications for microtubule function.


Assuntos
Fibras Musculares Esqueléticas , Músculo Esquelético , Humanos , Músculo Esquelético/metabolismo , Fibras Musculares Esqueléticas/metabolismo , Microtúbulos , Diferenciação Celular , Desenvolvimento Muscular , Homeostase
5.
Nucleic Acids Res ; 51(3): 1245-1259, 2023 02 22.
Artigo em Inglês | MEDLINE | ID: mdl-36617982

RESUMO

Loss of gene function can be compensated by paralogs with redundant functions. An example of such compensation are the paralogs of the Muscleblind-Like (MBNL) family of RNA-binding proteins that are sequestered and lose their function in Myotonic Dystrophy Type 1 (DM1). Loss of MBNL1 increases the levels of its paralog MBNL2 in tissues where Mbnl2 expression is low, allowing MBNL2 to functionally compensate for MBNL1 loss. Here, we show that loss of MBNL1 increases the inclusion of Mbnl2 exon 6 and exon 9. We find that inclusion of Mbnl2 exon 6 increases the translocation of MBNL2 to the nucleus, while the inclusion of Mbnl2 exon 9 shifts the reading frame to an alternative C-terminus. We show that the C-terminus lacking exon 9 contains a PEST domain which causes proteasomal degradation. Loss of MBNL1 increases the inclusion of exon 9, resulting in an alternative C-terminus lacking the PEST domain and the increase of MBNL2. We further find that the compensatory mechanism is active in a mouse DM1 model. Together, this study uncovers the compensatory mechanism by which loss of MBNL1 upregulates its paralog MBNL2 and highlights a potential role of the compensatory mechanism in DM1.


Assuntos
Processamento Alternativo , Distrofia Miotônica , Proteínas de Ligação a RNA , Animais , Camundongos , Proteínas de Ligação a DNA/genética , Éxons , Distrofia Miotônica/genética , Proteínas de Ligação a RNA/metabolismo , Ativação Transcricional , Regulação para Cima
6.
Opt Express ; 30(25): 44556-44568, 2022 Dec 05.
Artigo em Inglês | MEDLINE | ID: mdl-36522878

RESUMO

We present near-ideal axisymmetric numerically optimized spline concentrators (OSCs) which outperform the compound parabolic concentrator (CPC). By perturbing the profile of the revolved CPC by a variable-offset spline defined in tangent-normal space, we show that ray rejection can be reduced to nearly half of that of the CPC, without increasing concentrator length. The resulting OSCs achieve acceptance efficiencies as high as 99.3% for an acceptance angle of 45°, the highest reported for any finite-length CPC-like light concentrator. A set of design curves is presented which can be used to generate near "best-form" OSCs for any acceptance angle in the range 10° to 45°.

7.
Int J Mol Sci ; 23(23)2022 Nov 26.
Artigo em Inglês | MEDLINE | ID: mdl-36499107

RESUMO

Myotonic dystrophy (DM) is a highly variable, multisystemic disorder that clinically affects one in 8000 individuals. While research has predominantly focused on the symptoms and pathological mechanisms affecting striated muscle and brain, DM patient surveys have identified a high prevalence for gastrointestinal (GI) symptoms amongst affected individuals. Clinical studies have identified chronic and progressive dysfunction of the esophagus, stomach, liver and gallbladder, small and large intestine, and rectum and anal sphincters. Despite the high incidence of GI dysmotility in DM, little is known regarding the pathological mechanisms leading to GI dysfunction. In this review, we summarize results from clinical and molecular analyses of GI dysfunction in both genetic forms of DM, DM type 1 (DM1) and DM type 2 (DM2). Based on current knowledge of DM primary pathological mechanisms in other affected tissues and GI tissue studies, we suggest that misregulation of alternative splicing in smooth muscle resulting from the dysregulation of RNA binding proteins muscleblind-like and CUGBP-elav-like is likely to contribute to GI dysfunction in DM. We propose that a combinatorial approach using clinical and molecular analysis of DM GI tissues and model organisms that recapitulate DM GI manifestations will provide important insight into defects impacting DM GI motility.


Assuntos
Distrofia Miotônica , Humanos , Distrofia Miotônica/complicações , Distrofia Miotônica/genética , Processamento Alternativo , Músculo Esquelético/metabolismo , Proteínas de Ligação a RNA/metabolismo
8.
Langmuir ; 38(13): 4077-4089, 2022 Apr 05.
Artigo em Inglês | MEDLINE | ID: mdl-35316062

RESUMO

We report on the optoelectronic properties of a series of unsymmetrical π-conjugated phenyleneethynylene macromolecules bearing ferrocene (Fc) as the electron-donor group (D), (benzyl) benzoate (Bz) or benzoic acid (Ac) as the electron attractor group (A) and connected through 2,5-di(alcoxy) phenyleneethynylene(s) (nPE) with n = 1, 2, 3 as π-conjugated bridges. In the series, by increasing the distance between the electron-attracting and electron-donor groups, the push-pull effect decreases. The intramolecular charge transfer (D → π → A) was evaluated by static and dynamic spectroscopy, electrochemistry, and density functional theory (DFT) theoretical calculations. The longest oligomer Fc3PEBz formed the best optical quality films. A study at the atomic level by scanning tunneling microscopy (STM) revealed that the molecules self-assemble on highly ordered pyrolytic graphite (HOPG) in domains with a short-range order. Films are mesoporous and the molecules arrange in a lamellar-like pattern, with an edge-on conformation with respect to HOPG, where the conjugated backbones lie parallel to the surface. Two different assemblies were identified in the monoatomic film, which depends on the ferrocene-ferrocene or benzyl-benzyl interactions.

9.
N Z Vet J ; 70(6): 304-312, 2022 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34586965

RESUMO

AIMS: To explore practising veterinarians' expectations of an 8-week mindfulness training programme, their perceived barriers to participating in the programme, their experiences of the programme and the extent to which they continued to engage in mindfulness practices following training. METHODS: Participants were 10 companion animal veterinarians practising in Auckland, New Zealand. All took part in an 8-week mindfulness-based training programme. A longitudinal qualitative design was used: data were collected by structured interviews prior to the programme, upon completion of the programme and 3 months after completion. Data were analysed using thematic analysis to identify recurring themes, or patterns, within the data. RESULTS: Before commencing the programme, participants generally thought mindfulness training would provide some benefits for wellbeing but were otherwise not clear on what to expect. The main concerns about taking part were time constraints and apprehensions about potentially having to share personal information, and consequently how they might be perceived by other participants. On completion of the training programme, the opportunity to share experiences within the group with the support of a trained facilitator was reported as the most valuable aspect of the programme, rather than the mindfulness practices themselves. At the 3-month follow-up, participants reported they had learnt some useful techniques for managing stressful thoughts and situations, but despite the perceived benefits, few were still practicing mindfulness techniques. CONCLUSIONS AND CLINICAL RELEVANCE: Training in mindfulness practices may have some value for helping practicing veterinarians manage their wellbeing, but it is not a complete solution in itself. Participants reported that the greatest benefits came from facilitated peer support.


Assuntos
Atenção Plena , Médicos Veterinários , Animais , Humanos , Atenção Plena/métodos , Motivação , Nova Zelândia , Pesquisa Qualitativa
11.
Inorg Chem ; 60(21): 16570-16583, 2021 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-34662517

RESUMO

The optical properties of coordination complexes with ligands containing nitrogen heterocycles have been extensively studied for decades. One subclass of these materials, metal complexes utilizing substituted pyrazines and quinoxalines as ligands, has been employed in a variety of photochemical applications ranging from photodynamic therapy to organic light-emitting diodes. A vast majority of this work focuses on characterization of the metal-to-ligand charge-transfer states in these metal complexes; however, literature reports rarely investigate the photophysics of the parent pyrazine or quinoxaline ligand or perform control experiments utilizing metal complexes that lack low-lying charge-transfer (CT) states in order to determine how metal-atom coordination influences the photophysical properties of the ligand. With this in mind, we examined the steady-state and time-resolved photophysics of 2,3-di(pyridin-2-yl)benzo[g]quinoxaline (dpb) and explored how the coordination of ZnX2 (X = Cl-, Br-, I-) affects the photophysical properties of dpb. In dpb, we find that the dominant mode of deactivation from the singlet excited state is intersystem crossing (ISC). Coordination of ZnX2 perturbs the relative energies of the ππ* and nπ* excited states of dpb, leading to drastically different rates of ISC as well as radiative and nonradiative decay in the [Zn(dpb)X2] complexes compared to dpb. These differences in the rates change the dominant singlet-excited-state decay pathway from ISC in dpb to a mixture of ISC and fluorescence in [Zn(dpb)Cl2] and [Zn(dpb)Br2] and to nonradiative decay in [Zn(dpb)I2]. Coordination of ZnX2 and the choice of the halide ligand also have profound effects on the rate constants for excited-state bimolecular reactions, including triplet-triplet annihilation and oxygen quenching. These results demonstrate that metal coordination, even in complexes lacking low-lying CT states, and the choice of the ancillary ligand can dramatically alter the photophysical properties of chromophores containing nitrogen heterocycles.

12.
BMJ Case Rep ; 14(9)2021 Sep 20.
Artigo em Inglês | MEDLINE | ID: mdl-34544699

RESUMO

Granular cell tumour (GCT) is a rare soft tissue lesion which many consider to have malignant potential of yet unknown aetiopathogenesis. Oral GCT lesions may occur in an area of leucoplakia and are predominantly present on the tongue. This case study highlights an uncommon presentation of this condition located on the buccal mucosa and illustrates the need for meticulous evaluation of suspicious lesions. Due to the malignant risk associated with GCT lesions, it is important to make the correct diagnosis and ensure complete surgical excision for these cases. Ongoing long-term follow-up is also indicated to monitor for recurrence or malignancy.


Assuntos
Tumor de Células Granulares , Neoplasias da Língua , Tumor de Células Granulares/diagnóstico por imagem , Tumor de Células Granulares/cirurgia , Humanos , Mucosa Bucal , Recidiva Local de Neoplasia , Língua
13.
Phys Chem Chem Phys ; 23(21): 12033-12044, 2021 Jun 02.
Artigo em Inglês | MEDLINE | ID: mdl-33942042

RESUMO

Four core and six distyryl-extended methylated-meso-phenyl-BODIPY dyes with varying iodine content were synthesized. The influence of iodine loading and substitution position on the photophysical properties of these chromophores was evaluated. Selective iodine insertion at the 2- and 6-positions of the methylated-meso-phenyl-BODIPY core, rather than maximum iodine content, resulted in the highest intersystem crossing efficiency. Iodination of the distyryl-extended BODIPY core afforded intersystem crossing quantum yields comparable to 2,6-diiodo-BODIPY. Inclusion of an iodine at the para-meso-phenyl position generally enhanced non-radiative decay in the BODIPY excited-state, leading to lower fluorescence and intersystem crossing quantum yield values. Iodine substitution at the styryl-positions resulted in negligible changes to the excited-state dynamics. This study highlights: (1) the rate of radiative decay is similar in all ten derivatives (on the order of 1 × 108 s-1), (2) iodination of the 2,6-positions results in the greatest enhancement of intersystem crossing efficiency, (3) care must be taken when modifying the para-meso-phenyl position as it could have detrimental effects on the excited-state dynamics, (4) the excited-state is negligibly affected by iodination of the styryl groups, potentially enabling orthogonal functionalization without modifying the molecular photophysics, (5) distyryl extension of the chromophore core diminishes rates of non-radiative decay and intersystem crossing, resulting in higher fluorescence quantum yields and lower intersystem crossing yields in the π-extended derivatives compared to the core BDP derivatives, and (6) DFT calculations provide insight into the electronic and structural factors regulating intersystem crossing and vibrational relaxation in these molecules.

14.
JCI Insight ; 6(5)2021 03 08.
Artigo em Inglês | MEDLINE | ID: mdl-33497365

RESUMO

Myotonic dystrophy type 1 (DM1) is caused by a CTG repeat expansion in the DMPK gene. Expression of pathogenic expanded CUG repeat (CUGexp) RNA causes multisystemic disease by perturbing the functions of RNA-binding proteins, resulting in expression of fetal protein isoforms in adult tissues. Cardiac involvement affects 50% of individuals with DM1 and causes 25% of disease-related deaths. We developed a transgenic mouse model for tetracycline-inducible and heart-specific expression of human DMPK mRNA containing 960 CUG repeats. CUGexp RNA is expressed in atria and ventricles and induced mice exhibit electrophysiological and molecular features of DM1 disease, including cardiac conduction delays, supraventricular arrhythmias, nuclear RNA foci with Muscleblind protein colocalization, and alternative splicing defects. Importantly, these phenotypes were rescued upon loss of CUGexp RNA expression. Transcriptome analysis revealed gene expression and alternative splicing changes in ion transport genes that are associated with inherited cardiac conduction diseases, including a subset of genes involved in calcium handling. Consistent with RNA-Seq results, calcium-handling defects were identified in atrial cardiomyocytes isolated from mice expressing CUGexp RNA. These results identify potential tissue-specific mechanisms contributing to cardiac pathogenesis in DM1 and demonstrate the utility of reversible phenotypes in our model to facilitate development of targeted therapeutic approaches.


Assuntos
Miócitos Cardíacos , Distrofia Miotônica/genética , Miotonina Proteína Quinase/genética , Processamento Alternativo , Animais , Células Cultivadas , Humanos , Camundongos , Camundongos Transgênicos , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , Isoformas de Proteínas/metabolismo , Expansão das Repetições de Trinucleotídeos
15.
J Psychiatr Res ; 134: 192-199, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33388702

RESUMO

Pro-inflammatory status has been implicated in depression and suicidal behaviors. Polyunsaturated fatty acids (PUFAs) and cytokines, two types of inflammatory biomarkers, have been associated with suicide, independent of depression severity. How these biomarkers relate to each other is less clear. We measured plasma phospholipid levels of arachidonic acid (AA%), docosahexaenoic acid (DHA%), and eicosapentaenoic acid (EPA%) as a percentage of total phospholipids, as well as serum interleukin-6 (IL-6), interleukin-1ß (IL-1ß) and tumor necrosis factor α (TNF-α), in 80 patients with major depressive disorder (MDD) and 24 healthy controls (HC). Individual PUFA and cytokine species were compared using ANOVA across four suicide risk-stratified groups: 1) highest-risk, recent (within 5 years) suicide attempters (n = 20); 2) high-risk, severe current suicidal ideators (having intent or plan) with no recent attempt history (n = 22); 3) low-risk, current non-ideators who were also lifetime non-attempters (n = 38); and 4) HC (n = 24). None of the participants were enrolled following an acute suicide attempt. Of biomarkers studied, only DHA% (p = 0.012) and IL-1ß (p = 0.002) differed between groups. In post-hoc testing, DHA% was lower in attempters than ideators (p = 0.018) or MDD non-ideators (trend level, p = 0.073). IL-1ß was lowest in attempters, differentiating them from ideators (p = 0.009) and HC (p = 0.004). Recent suicide attempt, one of the most powerful predictors of suicide risk, was also most closely tied to inflammatory indices in this study. Low DHA% as an indicator of suicide risk is consistent with previous reports; however, lower IL-1ß was unexpected and may relate to acuity/chronicity of inflammation. There is a need for prospective studies of immune status with respect to suicidal behaviors.


Assuntos
Transtorno Depressivo Maior , Biomarcadores , Depressão , Humanos , Estudos Prospectivos , Tentativa de Suicídio
16.
Wiley Interdiscip Rev RNA ; 12(1): e1634, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33191580

RESUMO

RNA has major regulatory roles in a wide range of biological processes and a surge of RNA research has led to the classification of numerous functional RNA species. One example is long noncoding RNAs (lncRNAs) that are structurally complex transcripts >200 nucleotides (nt) in length and lacking a canonical open reading frame (ORF). Despite a general lack of sequence conservation and low expression levels, many lncRNAs have been shown to have functionality in diverse biological processes as well as in mechanisms of disease. In parallel with the growing understanding of lncRNA functions, there is a growing subset of microsatellite expansion disorders in which the primary mechanism of pathogenesis is an RNA gain of function arising from RNA transcripts from the mutant allele. Microsatellite expansion disorders are caused by an expansion of short (3-10 nt) repeats located within coding genes. Expanded repeat-containing RNA mediates toxicity through multiple mechanisms, the details of which remain only partially understood. The purpose of this review is to highlight the links between functional mechanisms of lncRNAs and the potential pathogenic mechanisms of expanded microsatellite RNA. These shared mechanisms include protein sequestration, peptide translation, micro-RNA (miRNA) processing, and miRNA sequestration. Recognizing the parallels between the normal functions of lncRNAs and the negative impact of expanded microsatellite RNA on biological processes can provide reciprocal understanding to the roles of both RNA species. This article is categorized under: RNA Interactions with Proteins and Other Molecules > Protein-RNA Interactions: Functional Implications RNA in Disease and Development > RNA in Disease.


Assuntos
MicroRNAs , RNA Longo não Codificante , Repetições de Microssatélites , Proteínas , RNA Longo não Codificante/genética
18.
J Health Organ Manag ; 31(2): 709-724, 2020 Sep 08.
Artigo em Inglês | MEDLINE | ID: mdl-32979045

RESUMO

PURPOSE: Highly-experienced allied health professionals have the opportunity to perform at the expert-level by sharing knowledge and skills with more junior staff, with the aim of upskilling the workforce. The study explored the current motivators, aspirations and the role of work in the life of highly-experienced practitioners, revealing factors that hinder or support them to further develop their own expertise and be inspiring role-models and mentors for less experienced staff. DESIGN/METHODOLOGY/APPROACH: Taking a grounded theoretical research design, we report on interviews with 45 allied health practitioners with at least seven years of professional experience from different professions and across organisational sectors. Transcripts were coded iteratively in conjunction with reviewing the literature, and cases were categorised to form a conceptual typology of work orientation. FINDINGS: Four work orientations are characterised capturing the diversity of the allied health workforce, particularly in relation to two dimensions of personal fulfilment and future ambition. The relationship between the types and expert-level performance is discussed, leading to recommendations for support that can be implemented to develop and sustain expert-level performance within a community. ORIGINALITY/VALUE: A new view of work orientation is introduced that relates expert-level performance with meaningful work. The findings highlight a diversity of work orientation for highly-experienced allied health professionals, that all require managerial awareness. Once recognised, the four types would benefit from different supports that could develop and maintain expert-level performance in those that seek it. Alternatives are also available for those that do not. Implications for workforce policy are discussed.


Assuntos
Pessoal Técnico de Saúde , Competência Clínica , Satisfação no Emprego , Adulto , Idoso , Pessoal Técnico de Saúde/psicologia , Feminino , Humanos , Entrevistas como Assunto , Masculino , Pessoa de Meia-Idade , Nova Zelândia , Pesquisa Qualitativa , Adulto Jovem
19.
JAMA Netw Open ; 3(8): e2013211, 2020 08 03.
Artigo em Inglês | MEDLINE | ID: mdl-32785636

RESUMO

Importance: A single subanesthetic dose of ketamine produces an antidepressant response in patients with major depressive disorder (MDD) within hours, but the mechanism of antidepressant effect is uncertain. Objective: To evaluate whether ketamine dose and brain glutamate and glutamine (Glx) and γ-aminobutyric acid (GABA) level responses to ketamine are related to antidepressant benefit and adverse effects. Design, Setting, and Participants: This randomized, parallel-group, triple-masked clinical trial included 38 physically healthy, psychotropic medication-free adult outpatients who were in a major depressive episode of MDD but not actively suicidal. The trial was conducted at Columbia University Medical Center. Data were collected from February 2012 to May 2015. Data analysis was conducted from January to March 2020. Intervention: Participants received 1 dose of placebo or ketamine (0.1, 0.2, 0.3, 0.4, or 0.5 mg/kg) intravenously during 40 minutes of a proton magnetic resonance spectroscopy scan that measured ventro-medial prefrontal cortex Glx and GABA levels in 13-minute data frames. Main Outcomes and Measures: Clinical improvement was measured using a 22-item version of the Hamilton Depression Rating Scale (HDRS-22) 24 hours after ketamine was administered. Ketamine and metabolite blood levels were measured after the scan. Results: A total of 38 individuals participated in the study, with a mean (SD) age of 38.6 (11.2) years, 23 (60.5%) women, and 25 (65.8%) White patients. Improvement in HDRS-22 score at 24 hours correlated positively with ketamine dose (t36 = 2.81; P = .008; slope estimate, 19.80 [95% CI, 5.49 to 34.11]) and blood level (t36 = 2.25; P = .03; slope estimate, 0.070 [95% CI, 0.007 to 0.133]). The lower the Glx response, the better the antidepressant response (t33 = -2.400; P = .02; slope estimate, -9.85 [95% CI, -18.2 to -1.50]). Although GABA levels correlated with Glx (t33 = 8.117; P < .001; slope estimate, 0.510 [95% CI, 0.382 to 0.638]), GABA response did not correlate with antidepressant effect. When both ketamine dose and Glx response were included in a mediation analysis model, ketamine dose was no longer associated with antidepressant effect, indicating that Glx response mediated the relationship. Adverse effects were related to blood levels in men only (t5 = 2.606; P = .048; estimated slope, 0.093 [95% CI, 0.001 to 0.186]), but Glx and GABA response were not related to adverse effects. Conclusions and Relevance: In this study, intravenous ketamine dose and blood levels correlated positively with antidepressant response. The Glx response correlated inversely with ketamine dose and with antidepressant effect. Future studies are needed to determine whether the relationship between Glx level and antidepressant effect is due to glutamate or glutamine. Trial Registration: ClinicalTrials.gov Identifier: NCT01558063.


Assuntos
Antidepressivos/administração & dosagem , Transtorno Depressivo Maior , Ácido Glutâmico/metabolismo , Ketamina/administração & dosagem , Ácido gama-Aminobutírico/metabolismo , Adulto , Antidepressivos/efeitos adversos , Antidepressivos/farmacocinética , Antidepressivos/uso terapêutico , Transtorno Depressivo Maior/diagnóstico por imagem , Transtorno Depressivo Maior/tratamento farmacológico , Transtorno Depressivo Maior/metabolismo , Feminino , Humanos , Ketamina/efeitos adversos , Ketamina/farmacocinética , Ketamina/uso terapêutico , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Córtex Pré-Frontal/diagnóstico por imagem , Córtex Pré-Frontal/metabolismo
20.
Adv Funct Mater ; 30(28): 1910562, 2020 Jul 09.
Artigo em Inglês | MEDLINE | ID: mdl-32684903

RESUMO

The fabrication, molecular structure, and spectroscopy of a stable cholesteric liquid crystal platinum acetylide glass obtained from trans-Pt(PEt3)2(C≡C-C6H5-C≡N)(C≡C-C6H5-COO-Cholesterol), are described and designated as PE1-CN-Chol. Polarized optical microscopy, differential scanning calorimetry, and wide-angle X-ray scattering experiments show room temperature glassy/crystalline texture with crystal formation upon heating to 165 °C. Further heating results in conversion to cholesteric phase. Cooling to room temperature leads to the formation of a cholesteric liquid crystal glass. Scanning tunneling microscopy of a PE1-CN-Chol monolayer reveals self-assembly at the solid-liquid interface with an array of two molecules arranged in pairs, oriented head-to-head through the CN groups, giving rise to a lamella arrangement. The lamella structure obtained from molecular dynamics calculations shows a clear phase separation between the conjugated platinum acetylide and the hydrophobic cholesterol moiety with the lamellae separation distance being 4.0 nm. Ultrafast transient absorption and flash photolysis spectra of the glass show intersystem crossing to the triplet state occurring within 100 ps following excitation. The triplet decay time of the film compared to aerated and deoxygenated solutions is consistent with oxygen quenching at the film surface but not within the film. The high chromophore concentration, high glass thermal stability, and long triplet lifetime in air show that these materials have potential as nonlinear absorbing materials.

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