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OBJECTIVE: The COVID-19 pandemic required mental health clinicians globally to transition to the delivery of care via telehealth. This study aimed to gain an understanding of clients' satisfaction with and attitudes towards telehealth mental health services. METHOD: Seventy adults who had attended a clinic for mood and anxiety disorders, and participated in at least one telehealth consultation with a psychologist or psychiatrist, completed an anonymous online survey. RESULTS: The majority of participants (81.5%) reported satisfaction with telehealth mental health care provided during the COVID-19 pandemic. However, satisfaction overall was significantly higher amongst participants who had received both telehealth and face-to-face mental health care, compared to participants who received care via telehealth only. Advantages of telehealth care reported included convenience and increased access to mental health clinicians. However, disadvantages of telehealth care included greater difficulty developing a rapport with a clinician and expressing oneself via telehealth. CONCLUSIONS: Whilst client satisfaction with telehealth mental health care for mood and anxiety disorders is generally high, clinicians should consider the limitations of telehealth from clients' perspectives. In particular, strategies to enhance therapeutic connection during telehealth sessions may be needed, and client preferences for mode of delivery should be taken into consideration when possible.
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Perioperative immune checkpoint inhibitor (ICI) trials for intermediate high-risk clear cell renal cell carcinoma (ccRCC) have failed to consistently demonstrate improved patient outcomes. These unsuccessful ICI trials suggest that the tumour infiltrating immunophenotypes, termed here as the immune cell types, states and their spatial location within the tumour microenvironment (TME), were unfavourable for ICI treatment. Defining the tumour infiltrating immune cells may assist with the identification of predictive immunophenotypes within the TME that are favourable for ICI treatment. To define the immunophenotypes within the ccRCC TME, fresh para-tumour (pTME, n = 2), low-grade (LG, n = 4, G1-G2) and high-grade (HG, n = 4, G3-G4) tissue samples from six patients with ccRCC presenting at a tertiary referral hospital underwent spatial transcriptomics sequencing (ST-seq). Within the generated ST-seq datasets, immune cell types and states, termed here as exhausted/pro-tumour state or non-exhausted/anti-tumour state, were identified using multiple publicly available single-cell RNA and T-cell receptor sequencing datasets as references. HG TMEs revealed abundant exhausted/pro-tumour immune cells with no consistent increase in expression of PD-1, PD-L1 and CTLA4 checkpoints and angiogenic genes. Additional HG TME immunophenotype characteristics included: pro-tumour tissue-resident monocytes with consistently increased expression of HAVCR2 and LAG3 checkpoints; an exhausted CD8+ T cells sub-population with stem-like progenitor gene expression; and pro-tumour tumour-associated macrophages and monocytes within the recurrent TME with the expression of TREM2. Whilst limited by a modest sample size, this study represents the largest ST-seq dataset on human ccRCC. Our study reveals that high-risk ccRCC TMEs are infiltrated by exhausted/pro-tumour immunophenotypes lacking specific checkpoint gene expression confirming that HG ccRCC TME are immunogenic but not ICI favourable.
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Unlike bulk and single-cell/single-nuclei RNA sequencing methods, spatial transcriptome sequencing (ST-seq) resolves transcriptome expression within the spatial context of intact tissue. This is achieved by integrating histology with RNA sequencing. These methodologies are completed sequentially on the same tissue section placed on a glass slide with printed oligo-dT spots, termed ST-spots. Transcriptomes within the tissue section are captured by the underlying ST-spots and receive a spatial barcode in the process. The sequenced ST-spot transcriptomes are subsequently aligned with the hematoxylin and eosin (H&E) image, giving morphological context to the gene expression signatures within intact tissue. We have successfully employed ST-seq to characterize mouse and human kidney tissue. Here, we describe in detail the application of Visium Spatial Tissue Optimization (TO) and Visium Spatial Gene Expression (GEx) protocols for ST-seq in fresh frozen kidney tissue.
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Perfilação da Expressão Gênica , Rim , Transcriptoma , Animais , Humanos , Perfilação da Expressão Gênica/métodos , Rim/metabolismo , Transcriptoma/genética , Hematoxilina , Amarelo de Eosina-(YS) , Camundongos , Criopreservação , Coloração e Rotulagem , Permeabilidade , Fluorescência , CrioultramicrotomiaRESUMO
Identifying tissue-specific molecular signatures of active regulatory elements is critical to understanding gene regulatory mechanisms. In this study, transcription start sites (TSS) and enhancers were identified using Cap analysis of gene expression (CAGE) across endometrial stromal cell (ESC) samples obtained from women with (n = 4) and without endometriosis (n = 4). ESC TSSs and enhancers were compared to those reported in other tissue and cell types in FANTOM5 and were integrated with RNA-seq and ATAC-seq data from the same samples for regulatory activity and network analyses. CAGE tag count differences between women with and without endometriosis were statistically tested and tags within close proximity to genetic variants associated with endometriosis risk were identified. Over 90% of tag clusters mapping to promoters were observed in cells and tissues in FANTOM5. However, some potential cell-type-specific promoters and enhancers were also observed. Regions of open chromatin identified using ATAC-seq provided further evidence of the active transcriptional regions identified by CAGE. Despite the small sample number, there was evidence of differences associated with endometriosis at 210 consensus clusters, including IGFBP5, CALD1 and OXTR. ESC TSSs were also located within loci associated with endometriosis risk from genome-wide association studies. This study provides novel evidence of transcriptional differences in endometrial stromal cells associated with endometriosis and provides a valuable cell-type specific resource of active TSSs and enhancers in endometrial stromal cells.
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Endometriose , Estudo de Associação Genômica Ampla , Humanos , Feminino , Sítio de Iniciação de Transcrição , Endometriose/genética , Regiões Promotoras Genéticas/genética , Regulação da Expressão GênicaRESUMO
BACKGROUND: Medulloblastoma (MB) is a malignant tumour of the cerebellum which can be classified into four major subgroups based on gene expression and genomic features. Single-cell transcriptome studies have defined the cellular states underlying each MB subgroup; however, the spatial organisation of these diverse cell states and how this impacts response to therapy remains to be determined. METHODS: Here, we used spatially resolved transcriptomics to define the cellular diversity within a sonic hedgehog (SHH) patient-derived model of MB and show that cells specific to a transcriptional state or spatial location are pivotal for CDK4/6 inhibitor, Palbociclib, treatment response. We integrated spatial gene expression with histological annotation and single-cell gene expression data from MB, developing an analysis strategy to spatially map cell type responses within the hybrid system of human and mouse cells and their interface within an intact brain tumour section. RESULTS: We distinguish neoplastic and non-neoplastic cells within tumours and from the surrounding cerebellar tissue, further refining pathological annotation. We identify a regional response to Palbociclib, with reduced proliferation and induced neuronal differentiation in both treated tumours. Additionally, we resolve at a cellular resolution a distinct tumour interface where the tumour contacts neighbouring mouse brain tissue consisting of abundant astrocytes and microglia and continues to proliferate despite Palbociclib treatment. CONCLUSIONS: Our data highlight the power of using spatial transcriptomics to characterise the response of a tumour to a targeted therapy and provide further insights into the molecular and cellular basis underlying the response and resistance to CDK4/6 inhibitors in SHH MB.
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Neoplasias Cerebelares , Meduloblastoma , Animais , Humanos , Camundongos , Diferenciação Celular , Neoplasias Cerebelares/metabolismo , Quinase 4 Dependente de Ciclina/genética , Quinase 4 Dependente de Ciclina/metabolismo , Proteínas Hedgehog/genética , Proteínas Hedgehog/metabolismo , Meduloblastoma/metabolismo , Transcriptoma , Quinase 6 Dependente de Ciclina/antagonistas & inibidoresRESUMO
Workplace sickness absence is a major public health and economic problem, and common mental disorders (CMDs) such as anxiety and depression are associated with particularly high rates of long-term sickness absence. Effective return-to-work (RTW) interventions are required. This pilot study investigates the feasibility, acceptability, and potential effectiveness of a new therapist-assisted Web-based RTW intervention (Workable) for injured workers on sick leave for a psychological or physical injury. A single-group open pilot trial design was used, with assessments at pre-treatment and post-treatment. The intervention consisted of 6 weeks of online modules and 6 coaching calls from a psychologist. A total of 13 participants were recruited and 9 completed all questionnaires. Program adherence was high, with 92% of participants completing the 6-week intervention. Participants reported high levels of intervention satisfaction and ease of use. There were large and significant reductions between pre- and post-treatment on measures of depression, anxiety, stress, and workdays missed over the past four weeks, along with a significant increase in self-reported work ability. These results suggest that Workable is a feasible and acceptable intervention for injured workers, with the potential to improve mental health and RTW outcomes. A randomized controlled trial is required to determine the efficacy of the intervention.
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Transtornos Mentais , Humanos , Projetos Piloto , Transtornos Mentais/psicologia , Saúde Mental , Emprego , Ansiedade/terapia , Transtornos de Ansiedade , Licença MédicaRESUMO
Available transcriptomes of the mammalian kidney provide limited information on the spatial interplay between different functional nephron structures due to the required dissociation of tissue with traditional transcriptome-based methodologies. A deeper understanding of the complexity of functional nephron structures requires a non-dissociative transcriptomics approach, such as spatial transcriptomics sequencing (ST-seq). We hypothesize that the application of ST-seq in normal mammalian kidneys will give transcriptomic insights within and across species of physiology at the functional structure level and cellular communication at the cell level. Here, we applied ST-seq in six mice and four human kidneys that were histologically absent of any overt pathology. We defined the location of specific nephron structures in the captured ST-seq datasets using three lines of evidence: pathologist's annotation, marker gene expression, and integration with public single-cell and/or single-nucleus RNA-sequencing datasets. We compared the mouse and human cortical kidney regions. In the human ST-seq datasets, we further investigated the cellular communication within glomeruli and regions of proximal tubules-peritubular capillaries by screening for co-expression of ligand-receptor gene pairs. Gene expression signatures of distinct nephron structures and microvascular regions were spatially resolved within the mouse and human ST-seq datasets. We identified 7,370 differentially expressed genes (p adj < 0.05) distinguishing species, suggesting changes in energy production and metabolism in mouse cortical regions relative to human kidneys. Hundreds of potential ligand-receptor interactions were identified within glomeruli and regions of proximal tubules-peritubular capillaries, including known and novel interactions relevant to kidney physiology. Our application of ST-seq to normal human and murine kidneys confirms current knowledge and localization of transcripts within the kidney. Furthermore, the generated ST-seq datasets provide a valuable resource for the kidney community that can be used to inform future research into this complex organ.
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Cellular development is tightly regulated as mature cells with aberrant functions may initiate pathogenic processes. The endometrium is a highly regenerative tissue, shedding and regenerating each month. Endometrial stromal fibroblasts are regenerated each cycle from mesenchymal stem cells and play a pivotal role in endometriosis, a disease characterised by endometrial cells that grow outside the uterus. Why the cells of some women are more capable of developing into endometriosis lesions is not clear. Using isolated, purified and cultured endometrial cells of mesenchymal origin from 19 women with (n = 10) and without (n = 9) endometriosis we analysed the transcriptome of 33,758 individual cells and compared these to clinical characteristics and in vitro growth profiles. We show purified mesenchymal cell cultures include a mix of mesenchymal stem cells and two endometrial stromal fibroblast subtypes with distinct transcriptomic signatures indicative of varied progression through the differentiation processes. The fibroblast subgroup characterised by incomplete differentiation was predominantly (81%) derived from women with endometriosis and exhibited an altered in vitro growth profile. These results uncover an inherent difference in endometrial cells of women with endometriosis and highlight the relevance of cellular differentiation and its potential to contribute to disease susceptibility.
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Endometriose , Células-Tronco Mesenquimais , Diferenciação Celular , Endometriose/genética , Endométrio , Feminino , Fibroblastos/patologia , HumanosRESUMO
BACKGROUND: Junior physicians report higher levels of psychological distress than senior doctors and report several barriers to seeking professional mental health support, including concerns about confidentiality and career progression. Mobile health (mHealth) apps may be utilized to help overcome these barriers to assist the emotional well-being of this population and encourage help-seeking. OBJECTIVE: This study describes the development and pilot trial of the Shift mHealth app to provide an unobtrusive avenue for junior physicians to seek information about, and help for, well-being and mental health concerns, which is sensitive to workplace settings. METHODS: A 4-phase iterative development process was undertaken to create the content and features of Shift involving junior physicians using the principles of user-centered design. These 4 phases were-needs assessment, on the basis of interviews with 12 junior physicians; prototype development with user experience feedback from 2 junior physicians; evaluation, consisting of a pilot trial with 22 junior physicians to assess the usability and acceptability of the initial prototype; and redesign, including user experience workshops with 51 junior physicians. RESULTS: Qualitative results informed the content and design of Shift to ensure that the app was tailored to junior physicians' needs. The Shift app prototype contained cognitive behavioral, mindfulness, value-based actions, and psychoeducational modules, as well as a tracking function that visualized patterns of daily variations in mood and health behaviors. Pilot-testing revealed possible issues with the organization of the app content, which were addressed through a thorough restructuring and redesign of Shift with the help of junior physicians across 3 user experience workshops. CONCLUSIONS: This study demonstrates the importance of ongoing end user involvement in the creation of a specialized mHealth app for a unique working population experiencing profession-specific stressors and barriers to help-seeking. The development and pilot trial of this novel Shift mHealth app are the first steps in addressing the mental health and support-seeking needs of junior physicians, although further research is required to validate its effectiveness and appropriateness on a larger scale.
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BACKGROUND: Medical practitioners can experience considerable stress and poor mental health during their careers, with doctors in training known to be particularly vulnerable. Previous research has documented work-related factors that may play a role in the mental health status of junior doctors. However, these and additional factors, need to be explored further by considering theory-driven, social, structural and contextual issues. This qualitative study aimed to explore the experiences of junior doctors working in Australian hospitals to identify factors that impact their mental health during medical training. METHOD: Semi-structured interviews were conducted with 12 junior medical officers (JMOs) employed across six hospitals in Australia. Transcribed de-identified interviews were analysed thematically using a data-driven inductive approach. RESULTS: Four interrelated main themes were identified: i) professional hierarchies; ii) occupational stress; iii) emotional labour, and iv) taking distress home; which detail the complex affective, relational and professional experiences of JMOs. The accounts demonstrate how the social, professional and organisational dimensions of these experiences impact upon trainee's well-being and mental health, both positively and negatively. Together, the findings document the dynamic, nuanced aspects of junior doctors' experiences of medical training and practice and highlights the importance of relational connections and the workplace environment in shaping JMOs' social and emotional well-being. CONCLUSION: The current study adds to the understanding of how junior doctors navigate medical training in Australian hospitals and highlights the complexities of this experience, particularly the ways in which mental health and well-being are shaped by different elements. These findings have important implications to inform new strategies to improve JMO mental health and to leverage work and non-work contexts to better support JMOs during medical training.
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Saúde Mental , Médicos , Atitude do Pessoal de Saúde , Austrália , Humanos , Corpo Clínico Hospitalar , Pesquisa QualitativaRESUMO
Phosphatidylinositol 4-kinase IIIα (PI4KIIIα/PI4KA/OMIM:600286) is a lipid kinase generating phosphatidylinositol 4-phosphate (PI4P), a membrane phospholipid with critical roles in the physiology of multiple cell types. PI4KIIIα's role in PI4P generation requires its assembly into a heterotetrameric complex with EFR3, TTC7 and FAM126. Sequence alterations in two of these molecular partners, TTC7 (encoded by TTC7A or TCC7B) and FAM126, have been associated with a heterogeneous group of either neurological (FAM126A) or intestinal and immunological (TTC7A) conditions. Here we show that biallelic PI4KA sequence alterations in humans are associated with neurological disease, in particular hypomyelinating leukodystrophy. In addition, affected individuals may present with inflammatory bowel disease, multiple intestinal atresia and combined immunodeficiency. Our cellular, biochemical and structural modelling studies indicate that PI4KA-associated phenotypical outcomes probably stem from impairment of PI4KIIIα-TTC7-FAM126's organ-specific functions, due to defective catalytic activity or altered intra-complex functional interactions. Together, these data define PI4KA gene alteration as a cause of a variable phenotypical spectrum and provide fundamental new insight into the combinatorial biology of the PI4KIIIα-FAM126-TTC7-EFR3 molecular complex.
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Doenças Desmielinizantes Hereditárias do Sistema Nervoso Central/genética , Atresia Intestinal/genética , Antígenos de Histocompatibilidade Menor/genética , Fosfotransferases (Aceptor do Grupo Álcool)/genética , Doenças da Imunodeficiência Primária/genética , Feminino , Humanos , Masculino , Linhagem , Polimorfismo de Nucleotídeo ÚnicoRESUMO
OBJECTIVE: This study aimed to examine the relationship between shared decision-making (SDM) and the implementation of treatment recommendations amongst outpatients at a specialist Depression Clinic. METHODS: A total of 110 adult outpatients in a specialist Depression Clinic in Sydney, Australia, completed an online survey examining their experiences of shared decision-making (SDM) during their psychiatrist consultation and the extent to which they later implemented Depression Clinic treatment recommendations. RESULTS: The odds of implementing treatment recommendations were over four times higher in patients who reported a high level of SDM in their consultation, compared to those who reported a low level of SDM. Further, three elements of patient-rated SDM were significantly associated with an increased likelihood of implementing depression treatment recommendations. These three elements were: i) being given the opportunity to ask questions or voice concerns; ii) being asked about any problems or side effects from previous treatments; and iii) being involved in deciding their treatment plan. CONCLUSIONS: SDM was significantly associated with an increased likelihood of implementing psychiatrists' treatment recommendations at a specialist Depression Clinic. PRACTICE IMPLICATIONS: We recommend that clinicians be informed of the potential benefits of SDM and adopt SDM when developing treatment plans with patients living with depression.
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Depressão , Participação do Paciente , Adulto , Austrália , Tomada de Decisões , Tomada de Decisão Compartilhada , Depressão/terapia , HumanosRESUMO
OBJECTIVES: To examine the perceptions of health professionals regarding the gaps in mental health service provision in Australia and their need for assistance in managing patients with mental illness. METHOD: A total of 570 health professionals participated in an anonymous online survey in January 2018 that assessed: i) health professionals' current levels of need for assistance in the management of patients with mental health conditions; and ii) perceived gaps in the mental health care system, and how these can be addressed. Data were analysed using a mixed-methods approach. RESULTS: Of those surveyed, 71.2% of health professionals and 77.3% of general practitioners reported that they required assistance in managing their patients with at least one stage of care for at least one type of mental disorder. Qualitative analyses revealed eight major themes in health professionals' perceptions of gaps in mental health service provision, including affordability and accessibility, the problems with crisis-driven care and the 'missing middle'. CONCLUSION: Overall, the results of this study provide a concerning insight into the substantial gaps in mental health care within the Australian system. Implications for public health: The results of this study add weight to ongoing calls for reform of and increased investment in the Australian mental health care system.
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Competência Clínica , Serviços Comunitários de Saúde Mental/organização & administração , Pessoal de Saúde/psicologia , Saúde Mental/estatística & dados numéricos , Atenção Primária à Saúde/organização & administração , Adulto , Idoso , Austrália , Estudos Transversais , Feminino , Conhecimentos, Atitudes e Prática em Saúde , Acessibilidade aos Serviços de Saúde , Humanos , Masculino , Transtornos Mentais , Serviços de Saúde Mental , Pessoa de Meia-Idade , Inquéritos e QuestionáriosRESUMO
BACKGROUND: Doctors-in-training report elevated rates of mental disorders and high levels of stress. Whilst a number of work-related sources of stress have been identified in the medical profession, it remains unclear as to the relative importance of workplace stressors for mental ill-health in junior doctors. AIMS: To examine workplace stressors reported by junior doctors and identify variables associated with adverse mental health outcomes. METHODS: Cross-sectional analysis of national 2013 survey of Australian doctors focussing on junior medical officers (N = 3053; 24.9% of total sample). Primary outcomes were caseness of common mental disorder (CMD) and suicidal ideation in the past year. RESULTS: Perceived level of conflict between study/career and family/personal responsibility (OR = 3.76, 95% CI: 2.61-5.43; P < 0.01) and sleep deprivation (OR = 2.19, 95% CI: 1.46-3.28; P < 0.01) were significantly associated with CMD, while perceived level of conflict between study/career and family/personal responsibility (OR = 3.13, 95% CI: 1.78-5.50; P < 0.01) and bullying (OR = 2.92, 95% CI: 1.42-6.03; P < 0.01) were most strongly associated with suicidal ideation in adjusted models. CONCLUSION: This study identifies modifiable workplace variables that are influential in junior doctors' mental health, and in doing so, provides meaningful evidence-informed targets for future interventions to prevent suicide and mental disorder in this population.
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Transtornos Mentais , Estresse Ocupacional , Austrália/epidemiologia , Estudos Transversais , Humanos , Transtornos Mentais/epidemiologia , Estresse Ocupacional/epidemiologia , Fatores de Risco , Ideação Suicida , Local de TrabalhoRESUMO
BACKGROUND: Depression is common among doctors. However, concerns remain that doctors are unlikely to ask for help when symptoms of depression arise. AIMS: To determine rates and patterns of help-seeking for depression among doctors and to identify predictors of and barriers to such behaviour. METHODS: A secondary analysis was conducted on a nation-wide survey of 12 252 Australian doctors. The study sample consisted of doctors who reported having ever felt seriously depressed (n = 4154; 33.9% of total sample). Rates of help-seeking, professional help-seeking behaviours and self-reported barriers were explored. Logistic regression was used to examine the association between professional help-seeking and predetermined predictive factors. RESULTS: Sixty percent (95% confidence interval (CI): 58.5-61.5) of doctors who have ever felt seriously depressed reported some form of professional help-seeking for depression. The most common barrier to help-seeking was 'privacy/confidentiality'. Females (odds ratio (OR) = 1.74; 95% CI: 1.50-2.01; P < 0.001), locally trained doctors (OR = 1.34; 95% CI: 1.12-1.59; P = 0.001) and senior doctors (OR = 1.35; 95% CI: 1.14-1.61; P = 0.001) were more likely to seek professional help than their counterparts. Compared with general practitioners, psychiatrists (OR = 1.565; 95% CI: 1.15-2.13; P = 0.004) were more likely to seek professional help while surgeons (OR = 0.518; 95% CI: 0.37-0.72; P < 0.001) and pathologists/radiologists (OR = 0.695; 95% CI: 0.49-0.99; P = 0.043) were less likely. CONCLUSION: While it is reassuring that the majority of depressed doctors were able to seek professional help, many were not. Major barriers to professional help-seeking, particularly concerns about confidentiality and impact on career, remain a problem. Male, overseas-trained, junior doctors, surgeons and pathologists/radiologists were less likely to seek help for depression. Targeted interventions are required to increase appropriate help-seeking for depression in doctors.
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Depressão , Médicos , Austrália/epidemiologia , Depressão/diagnóstico , Depressão/epidemiologia , Depressão/terapia , Feminino , Humanos , Modelos Logísticos , Masculino , Aceitação pelo Paciente de Cuidados de SaúdeRESUMO
Genetic white matter disorders have heterogeneous etiologies and overlapping clinical presentations. We performed a study of the diagnostic efficacy of genome sequencing in 41 unsolved cases with prior exome sequencing, resolving an additional 14 from an historical cohort (n = 191). Reanalysis in the context of novel disease-associated genes and improved variant curation and annotation resolved 64% of cases. The remaining diagnoses were directly attributable to genome sequencing, including cases with small and large copy number variants (CNVs) and variants in deep intronic and technically difficult regions. Genome sequencing, in combination with other methodologies, achieved a diagnostic yield of 85% in this retrospective cohort.
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Leucoencefalopatias/diagnóstico , Leucoencefalopatias/genética , Sistema de Registros , Sequenciamento Completo do Genoma , Adolescente , Criança , Pré-Escolar , Feminino , Humanos , Leucoencefalopatias/patologia , Masculino , LinhagemRESUMO
OBJECTIVE: Despite concern regarding high rates of mental illness and suicide amongst the medical profession, the link between working hours and doctors' mental health remains unclear. This study examines the relationship between average weekly working hours and junior doctors' (JDs') mental health in Australia. DESIGN AND PARTICIPANTS: A randomly selected sample of 42 942 Australian doctors were invited to take part in an anonymous Beyondblue National Mental Health Survey in 2013, of whom 12 252 doctors provided valid data (response rate approximately 27%). The sample of interest comprised 2706 full-time graduate medical trainees in various specialties, at either intern, prevocational or vocational training stage. Consultants and retired doctors were excluded. OUTCOME MEASURES: Main outcomes of interest were caseness of common mental disorder (CMD) (assessed using a cut-off of 4 as a threshold on total General Health Questionnaire-28 score), presence of suicidal ideation (SI) (assessed with a single item) and average weekly working hours. Logistic regression modelling was used to account for the impact of age, gender, stage of training, location of work, specialty, marital status and whether JDs had trained outside Australia. RESULTS: JDs reported working an average of 50.1 hours per week (SD=13.4). JDs who worked over 55 hours a week were more than twice as likely to report CMD (adjusted OR=2.05; 95% CI 1.62 to 2.59, p<0.001) and SI (adjusted OR=2.00; 95% CI 1.42 to 2.81, p<0.001) compared to those working 40-44 hours per week. CONCLUSIONS: Our results show that around one in four JDs are currently working hours that are associated with a doubling of their risk of common mental health problems and SI. These findings suggest that management of working hours represents an important focus for workplaces to improve the mental health of medical trainees.
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Atitude do Pessoal de Saúde , Corpo Clínico Hospitalar/psicologia , Saúde Mental , Transtornos Psicóticos/epidemiologia , Ideação Suicida , Carga de Trabalho/psicologia , Adulto , Austrália/epidemiologia , Estudos Transversais , Feminino , Humanos , Incidência , Masculino , Transtornos Psicóticos/psicologia , Estudos Retrospectivos , Inquéritos e QuestionáriosRESUMO
There is increasing appreciation of nephronophthisis (NPHP) as an autosomal recessive cause of kidney failure and earlier stages of chronic kidney disease among adults. We identified 2 families with presumed adult-diagnosed nonsyndromic NPHP and negative diagnostic genetic testing results from our Renal Genetics Clinic. Both had 2 affected siblings without extrarenal phenotypes. After informed consent, research whole-genome sequencing was undertaken. Biallelic NPHP4 variants were identified in trans and clinically confirmed in all 4 affected individuals, confirming a genetic diagnosis. Participant 1 of the first family (F1P1) had kidney failure diagnosed at 19 years of age. An affected younger sibling (F1P2) reached kidney failure at age 15 years after kidney biopsy suggested NPHP. Pathogenic variants detected in NPHP4 in this family were NM_015102.4:c.3766C>T (p.Gln1256*) and a 31-kb deletion affecting exons 12 to 16. In the second family, F2P3 reached kidney failure at age 27 years having undergone kidney biopsy suggesting NPHP. An affected younger sibling (F2P4) has chronic kidney disease stage 4 at age 39 years. The NPHP4 variants detected were NM_015102.4:c.1998_1999del (p.Tyr667Phefs*23) and c.3646G>T (p.Asp1216Tyr). The latter variant was initially missed in diagnostic sequencing due to inadequate NPHP4 coverage (94.3% exonic coverage). With these reports, we identify NPHP4 as an appreciable genetic cause for adult-diagnosed nonsyndromic NPHP that should be considered by adult nephrologists.
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Doenças Renais Císticas/genética , Rim/patologia , Proteínas/genética , Insuficiência Renal Crônica/genética , Adolescente , Adulto , Austrália , Códon sem Sentido , Feminino , Mutação da Fase de Leitura , Heterozigoto , Humanos , Doenças Renais Císticas/metabolismo , Doenças Renais Císticas/patologia , Falência Renal Crônica/genética , Falência Renal Crônica/metabolismo , Falência Renal Crônica/patologia , Masculino , Linhagem , Polimorfismo de Nucleotídeo Único , Insuficiência Renal Crônica/metabolismo , Insuficiência Renal Crônica/patologia , Adulto JovemRESUMO
A variety of methods have been developed to demultiplex pooled samples in a single cell RNA sequencing (scRNA-seq) experiment which either require hashtag barcodes or sample genotypes prior to pooling. We introduce scSplit which utilizes genetic differences inferred from scRNA-seq data alone to demultiplex pooled samples. scSplit also enables mapping clusters to original samples. Using simulated, merged, and pooled multi-individual datasets, we show that scSplit prediction is highly concordant with demuxlet predictions and is highly consistent with the known truth in cell-hashing dataset. scSplit is ideally suited to samples without external genotype information and is available at: https://github.com/jon-xu/scSplit.
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Análise de Sequência de RNA , Análise de Célula Única , Software , HumanosRESUMO
Mechanically activated (MA) ion channels convert physical forces into electrical signals. Despite the importance of this function, the involvement of mechanosensitive ion channels in human disease is poorly understood. Here we report heterozygous missense mutations in the gene encoding the MA ion channel TMEM63A that result in an infantile disorder resembling a hypomyelinating leukodystrophy. Four unrelated individuals presented with congenital nystagmus, motor delay, and deficient myelination on serial scans in infancy, prompting the diagnosis of Pelizaeus-Merzbacher (like) disease. Genomic sequencing revealed that all four individuals carry heterozygous missense variants in the pore-forming domain of TMEM63A. These variants were confirmed to have arisen de novo in three of the four individuals. While the physiological role of TMEM63A is incompletely understood, it is highly expressed in oligodendrocytes and it has recently been shown to be a MA ion channel. Using patch clamp electrophysiology, we demonstrated that each of the modeled variants result in strongly attenuated stretch-activated currents when expressed in naive cells. Unexpectedly, the clinical evolution of all four individuals has been surprisingly favorable, with substantial improvements in neurological signs and developmental progression. In the three individuals with follow-up scans after 4 years of age, the myelin deficit had almost completely resolved. Our results suggest a previously unappreciated role for mechanosensitive ion channels in myelin development.