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Gene editing enables non-invasive in vivo PET imaging of human induced pluripotent stem cell-derived liver bud organoids
Get PDFHuman induced pluripotent stem cell (hiPSC)-derived liver cell therapies such as hepatocyte-like cells and liver organoids could provide unlimited therapeutic cells for clinical transplantation, but an inadequate understanding of their in vivo fate impedes translation. Whole body in vivo imaging could enable monitoring of transplanted cell survival and/or expansion non-invasively over time, permitting robust comparisons between emerging therapies to identify those most effective. The human sodium iodide symporter (hNIS) is a radionuclide reporter gene facilitating whole body in vivo cell tracking by positron emission tomography (PET). We gene-edited a clinical Good Manufacturing Practice-compliant hiPSC line at the AAVS1 safe harbor locus enabling constitutive expression of a hNIS-monomeric(m)GFP fusion reporter in hiPSCs and their differentiated progeny. We confirmed reporter integration did not impact pluripotency or differentiation capacity, and radiotracer uptake capacity was retained post-differentiation. In vivo trackable liver bud (LB) organoids were generated from traceable hNIS fused to monomeric GFP (hNIS-mGFP)-hiPSCs and transplanted into healthy and liver-injured mice. LB were imaged quantitatively by 18FBF4−-PET with imaging results confirmed histologically. We report, for the first time, hNIS-mGFP-hiPSC progeny retain differentiated function and PET trackability in vivo using LB. In vivo monitoring could accelerate regenerative cell therapy development by identifying efficacious candidate cells, successful engraftment/survival strategies and addressing safety concerns
Diagnostic Evaluation and Clinical Findings in Children With Persistent Tachypnea of Infancy and Neuroendocrine Cell Hyperplasia of Infancy:A European Multicenter Retrospective Study
Get PDFBackgroundPersistent tachypnea of infancy (PTI)/neuroendocrine cell hyperplasia of infancy (NEHI) is a form of childhood interstitial lung disease (chILD) that predominantly affects young children. Although it is one of the most common chILDs, there is no unified diagnostic approach specific to this condition.Research questionIs there a difference in the clinical presentation and the diagnostic approach in PTI/NEHI patients between the European countries? Study design and methodsThis was a European multicenter, retrospective, observational study. Data on clinical characteristics and diagnostic strategies in PTI/NEHI patients were analyzed and compared across participating countries.ResultsThe study included 378 children with PTI/NEHI from 17 countries (63.5% male, 97.4% Caucasian), diagnosed at the median age of 9 months (IQR: 6-13). The most common baseline symptoms were tachypnea, chest retractions, crackles on auscultation, hypoxemia, and failure to thrive. High-resolution computed tomography (HRCT) was performed on all patients, with most undergoing chest X-rays, echocardiography, and immunology tests. Lung biopsy was done on 23.5% of patients, with a decreasing trend over time and variation by country; its use was associated with longer diagnostic delay. Histopathology showed a hyperplasia of pulmonary neuroendocrine cells in 52.8% of cases. Genetic testing was rare, and its application varied significantly between countries. Additional investigations that do not have an established role, such as assessment for gastroesophageal reflux disease and obstructive sleep apnea, infant pulmonary function tests, and lung ultrasounds were limited to single countries.InterpretationDiagnosis of PTI/NEHI relies on clinical symptoms and HRCT results, with lung biopsies less commonly performed. Differences exist between countries regarding the number and type of investigations. There is a need for guidelines that will uniform the diagnostic approach.Keywords: childhood interstitial lung disease, chILD, neuroendocrine cell hyperplasia of infancy, NEHI, persistent tachypnea of infancy, PTI. <br/
A Developmental Gene Expression Atlas Reveals Novel Biological Basis of Complex Phenotypes in Sheep
Get PDFSheep (Ovis aries) represent one of the most important livestock species for global animal protein and wool production. However, little is known about the genetic and biological basis of ovine phenotypes, particularly those with high economic value and environmental impact. Here, by integrating 1413 RNA sequencing (RNA-seq) samples from 51 distinct tissues across 14 developmental time points, representing early-prenatal, late-prenatal, neonatal, lamb, juvenile, adult, and elderly stages, we constructed a high-resolution Developmental Gene Expression Atlas (dGEA) in sheep. We observed dynamic patterns of gene expression and regulatory networks across tissues and developmental stages. Leveraging this resource to interpret genetic associations for 48 monogenic and 12 complex traits in sheep, we found that genes upregulated at prenatal developmental stages played more important roles in shaping these phenotypes than those upregulated at postnatal stages. For instance, genetic associations of crimp number, mean staple length (MSL), and individual birthweight were significantly enriched in the prenatal rather than postnatal skin and immune tissues. By comprehensively integrating genome-wide association study (GWAS) fine-mapping results with the sheep dGEA, we identified several candidate genes for complex traits in sheep, such as SOX9 for MSL, GNRHR for litter size at birth, and PRKDC for live weight. These results provide novel insights into the developmental and molecular architecture of ovine phenotypes. The dGEA (https://sheepdgea.njau.edu.cn/) will serve as an invaluable resource for sheep developmental biology, genetics, genomics, and selective breeding.</p
Care and vulnerability in Delphine de Vigan and Martin Winckler
No full textIf care studies is sometimes dismissed as maternal and essentialist, Tronto argues that care is political and her concept of ‘caring with’ or solidarity has broadened out care. Some recent critics like Fineman have favoured instead a vulnerability model which Engster applies to care studies to look at ontological vulnerability as part of the human condition and consider the obligations of the state to provide adequate provision. This paper applies a vulnerability studies lens to care in a comparative reading of fictional works by Vigan and Winckler. In an analysis of the undertheorized role of doctors in care studies I argue that literary studies can advance debates which have hitherto mainly taken place in healthcare and the social sciences and expose failings in institutional care. Medical practices are a reflection of society and the texts critique the uncaring face of Neoliberalism, with Winckler proposing an alternative relational model of patient-centred care
Where you place the stakes matter:Examining the relationship between test-based accountability and shadow education
No full textAccountability is a nearly ubiquitous part of education systems around the world. However, often missing is an explicit discussion on who the stakes of accountability are placed and how directing high stakes to one group relative to another can lead to different outcomes. We provide an important contribution to by demonstrating that where you place the stakes matters. We identify the type of test-based accountability in 45 countries or areas, then, using multi-level modeling examine the relationship between type of test-based accountability and shadow education participation. Our findings suggest participation in shadow education is higher in systems where high stakes are placed on students solely, or with educators, compared to when stakes are placed on educators alone. Results have implications for designing accountability policy and suggest that to reduce the prevalence of shadow education in a country, you need to consider where you place the stakes on the national test.</p
MyPath: the roadmap to implementing patient-centred care
No full textGlobally, healthcare systems are grappling with economic and human resource struggles. The ageing of the population and the rising prevalence of cancer are some of the main drivers of healthcare expenditure. If these challenges are not properly managed, the quality of the cancer care provided can deteriorate. Moreover, people with cancer struggle with physical, psychological, and social problems that are not routinely addressed despite overwhelming evidence of the benefits of the systematic assessment and management of symptoms. Based on the evidence that the delivery of patient-centred care (PCC) with active anticancer treatment improves most clinical outcomes and satisfaction with care, international consensus and guidelines revisions recommend the delivery of PCC as an integral part of anticancer treatment. Unfortunately, PCC is not implemented routinely, and patients do not receive the care they need. Funded by the EU, the MyPath project aims to assess whether PCC can be integrated into clinical practice using patient-centred care pathways supported by health information technology. At the core of the project is implementation science. Understanding what is required to successfully implement PCC will facilitate the uptake of evidence-based medicine across the continuum of routine cancer care, from active treatment to palliative care, to ensure that patients receive the care they need, when they need it. The purpose of this article is to present the methodology to be used in the MyPath project to implement PCC routinely. This study will be performed in nine European cancer centres. After its completion, we will assess if the proposed solution is successfully implemented
Sex-specific effects of early-life adversity on adult fitness in a wild mammal
No full textEarly-life adversity influences adult fitness across vertebrate species. In polygynous systems with intense intrasexual competition, males may be more sensitive to conditions experienced during development. However, the importance of different aspects of the early-life environment and how their effects differ between the sexes remains poorly understood. Here, we used a long-Term study of wild Soay sheep to characterize the early-life environment in terms of weather, infection risk, resource competition and maternal investment, and test the hypothesis that males are more vulnerable to early adversity. Birth weight, reflective of maternal investment and conditions during gestation, positively predicted lifetime breeding success in both sexes, suggesting a classic 'silver spoon' effect, though the effects were stronger in males. Males that experienced increased resource competition in their first year had lower lifetime breeding success, suggesting lasting negative consequences of nutritional stress, but there was no association in females. By contrast, challenging weather in the first winter of life was associated with stronger viability selection, with males surviving these harsh conditions having higher adult fitness. Our findings further evidence the important long-Term fitness consequences of early-life adversity in wild vertebrates, demonstrating distinct aspects of the early environment may shape fitness in different and sex-specific ways.</p
Professorships in child and adolescent psychiatry relative to a similarly sized medical specialty in the UK and Ireland:cross-sectional study
No full textBACKGROUND: A youth mental health crisis is considered one of the great challenges of our time, and research and clinical services in child and adolescent psychiatry have become a priority for governments and funders. Academic leadership is needed to drive forward research. It is not clear how many senior academic leadership posts (professorships) there are in child and adolescent psychiatry, nor how this benchmarks against a similarly sized medical specialty.AIMS: This study aimed to determine the number of professorships in child and adolescent psychiatry in the UK and Ireland compared to a similarly sized specialty. A secondary aim was to identify the number of clinical trials registered for mental and behavioural disorders in children.METHOD: We identified registered specialists in child and adolescent psychiatry and a similarly sized specialty who held full professorships in medical schools. We searched the International Standard Randomised Controlled Trial Number (ISRCTN) and ClinicalTrials.gov for trials.RESULTS: As of 23 March 2023, there were 1725 doctors on the General Medical Council's (GMC) specialist register in child and adolescent psychiatry. The closest specialty in terms of number of registered specialists was neurology ( N = 1724). We identified 24 professors in child and adolescent psychiatry across the UK and Ireland, compared to 124 in neurology. For every intervention trial registered for mental and behavioural disorders in children, there were approximately ten trials registered for diseases of the nervous system. CONCLUSIONS: Despite equivalent numbers of medical specialists in child and adolescent psychiatry and neurology, there is a striking disparity in the number of professorship appointments. While young peoples' mental health has, ostensibly, become a priority for policy-makers and funders, this is not reflected in medical professorship appointments. The paucity of senior academic child and adolescent psychiatrists has real-world implications for training, research, innovation and service development in mental health services.</p
Sensitivity of the clinical high-risk and familial high-risk approaches for psychotic disorders - a systematic review and meta-analysis
No full textBACKGROUND: Psychosis prediction has been a key focus of psychiatry research for over 20 years. The two dominant approaches to identifying psychosis risk have been the clinical high-risk (CHR) and the familial high-risk (FHR) approaches. To date, the real-world sensitivity of these approaches - that is, the proportion of all future psychotic disorders in the population that they identify - has not been systematically reviewed.METHODS: We systematically reviewed and meta-analysed studies in MEDLINE, Embase, PsychINFO, and Web of Science (from inception until September 2024) that reported data on the sensitivity of CHR and FHR approaches - i.e., individuals with a psychosis diagnosis preceded by a CHR diagnosis or a history of parental psychosis (PROSPERO: CRD42024542268).RESULTS: We identified four CHR studies and four FHR studies reporting relevant data. The pooled estimate of the sensitivity of the CHR approach was 6.7% (95% CI: 1.5-15.0%) and of the FHR approach was 6.5% (95% CI: 4.4-8.9%). There was a high level of heterogeneity between studies. Most FHR studies had a low risk of bias, but most CHR studies had a high risk of bias.CONCLUSION: Pooled data suggest that CHR and FHR approaches, each, capture only about 6-7% of future psychotic disorders. These findings demonstrate the need for additional approaches to identify risk for psychosis.</p
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