256 research outputs found
Genomic insights into the overlap between psychiatric disorders: implications for research and clinical practice
Psychiatric disorders such as schizophrenia, bipolar disorder, major depressive disorder, attention-deficit/hyperactivity disorder and autism spectrum disorder are common and result in significant morbidity and mortality. Although currently classified into distinct disorder categories, they show clinical overlap and familial co-aggregation, and share genetic risk factors. Recent advances in psychiatric genomics have provided insight into the potential mechanisms underlying the overlap between these disorders, implicating genes involved in neurodevelopment, synaptic plasticity, learning and memory. Furthermore, evidence from copy number variant, exome sequencing and genome-wide association studies supports a gradient of neurodevelopmental psychopathology indexed by mutational load or mutational severity, and cognitive impairment. These findings have important implications for psychiatric research, highlighting the need for new approaches to stratifying patients for research. They also point the way for work aiming to advance our understanding of the pathways from genotype to clinical phenotype, which will be required in order to inform new classification systems and to develop novel therapeutic strategies
Excitatory-inhibitory balance in children with 22q11.2 deletion syndrome
22q11.2 deletion syndrome (22q11.2DS) is a copy number variant syndrome affecting approximately 1 in 4000 live births. It has a variable phenotype in terms of its physical, cognitive and psychiatric manifestations. People with 22q11.2DS have a range of cognitive difficulties. They also have extremely high rates of psychopathology, particularly attention deficit hyperactivity disorder, autism spectrum disorder, anxiety disorders and psychotic disorders. The mechanisms
underlying the risks of cognitive impairment and psychopathology are not wellunderstood.
The balance between excitation and inhibition in the brain may be affected in 22q11.2DS and could underlie its cognitive and psychiatric features. In this thesis markers of excitatory-inhibitory (E-I) balance were investigated in children with 22q11.2DS (probands) and typically developing children (controls). It was hypothesised that probands would have alterations in E-I balance and that the severity of these alterations would be associated with cognitive and psychiatric features. The phenotypes of children taking part in the brain imaging study was first compared to those of children who did not participate in brain imaging to assess the representativeness of the imaging sample. Resting-state
brain networks and visually-induced gamma oscillations were then investigated using magnetoencephalography (MEG) and gamma-amino-butyric acid (GABA) concentrations were investigated using magnetic resonance spectroscopy (MRS).
Between-group comparisons were performed and the relationships between markers of E-I balance, psychopathology and cognitive impairment were explored
using linear regression.
The phenotypes of children with 22q11.2DS who participated in brain imaging were broadly similar to those who did not participate, suggesting that the imaging sample does not represent a highly-functioning subsample. Compared with controls, probands had alterations in resting-state networks in the delta, alpha
and beta bands which were associated with anxiety, social communication problems and cognitive deficits. In the gamma band, there were reductions in the total induced gamma power in probands, which was similarly associated with social communication and cognitive difficulties. There were no alterations in GABA concentrations in 22q11.2DS, suggesting that further work is needed to
better understand the mechanisms underlying excitatory-inhibitory imbalance in 22q11.2DS
Exploring variation in the use of feedback from national clinical audits : a realist investigation
BACKGROUND: National Clinical Audits (NCAs) are a well-established quality improvement strategy used in healthcare settings. Significant resources, including clinicians' time, are invested in participating in NCAs, yet there is variation in the extent to which the resulting feedback stimulates quality improvement. The aim of this study was to explore the reasons behind this variation. METHODS: We used realist evaluation to interrogate how context shapes the mechanisms through which NCAs work (or not) to stimulate quality improvement. Fifty-four interviews were conducted with doctors, nurses, audit clerks and other staff working with NCAs across five healthcare providers in England. In line with realist principles we scrutinised the data to identify how and why providers responded to NCA feedback (mechanisms), the circumstances that supported or constrained provider responses (context), and what happened as a result of the interactions between mechanisms and context (outcomes). We summarised our findings as Context+Mechanism = Outcome configurations. RESULTS: We identified five mechanisms that explained provider interactions with NCA feedback: reputation, professionalism, competition, incentives, and professional development. Professionalism and incentives underpinned most frequent interaction with feedback, providing opportunities to stimulate quality improvement. Feedback was used routinely in these ways where it was generated from data stored in local databases before upload to NCA suppliers. Local databases enabled staff to access data easily, customise feedback and, importantly, the data were trusted as accurate, due to the skills and experience of staff supporting audit participation. Feedback produced by NCA suppliers, which included national comparator data, was used in a more limited capacity across providers. Challenges accessing supplier data in a timely way and concerns about the quality of data submitted across providers were reported to constrain use of this mode of feedback. CONCLUSION: The findings suggest that there are a number of mechanisms that underpin healthcare providers' interactions with NCA feedback. However, there is variation in the mode, frequency and impact of these interactions. Feedback was used most routinely, providing opportunities to stimulate quality improvement, within clinical services resourced to collect accurate data and to maintain local databases from which feedback could be customised for the needs of the service
Serum N-propeptide of collagen IIA (PIIANP) as a marker of radiographic osteoarthritis burden
Cartilage homeostasis relies on a balance of catabolism and anabolism of cartilage matrix. Our goal was to evaluate the burden of radiographic osteoarthritis and serum levels of type IIA procollagen amino terminal propeptide (sPIIANP), a biomarker representing type II collagen synthesis, in osteoarthritis
Childhood cognitive development in 22q11.2 deletion syndrome: case–control study
Background
22q11.2 deletion syndrome (22q11.2DS) is associated with a high risk of childhood as well as adult psychiatric disorders, in particular schizophrenia. Childhood cognitive deterioration in 22q11.2DS has previously been reported, but only in studies lacking a control sample.
Aims
To compare cognitive trajectories in children with 22q11.2DS and unaffected control siblings.
Method
A longitudinal study of neurocognitive functioning (IQ, executive function, processing speed and attention) was conducted in children with 22q11.2DS (n = 75, mean age time 1 (T1) 9.9, time 2 (T2) 12.5) and control siblings (n = 33, mean age T1 10.6, T2 13.4).
Results
Children with 22q11.2DS exhibited deficits in all cognitive domains. However, mean scores did not indicate deterioration. When individual trajectories were examined, some participants showed significant decline over time, but the prevalence was similar for 22q11.2DS and control siblings. Findings are more likely to reflect normal developmental fluctuation than a 22q11.2DS-specific abnormality.
Conclusions
Childhood cognitive deterioration is not associated with 22q11.2DS. Contrary to previous suggestions, we believe it is premature to recommend repeated monitoring of cognitive function to identifying individual children with 22q11.2DS at high risk of developing schizophrenia
Longitudinal characterization of TK6 cells sequentially adapted to animal product-free, chemically defined culture medium: considerations for genotoxicity studies
© 2023 The Author(s). This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY), https://creativecommons.org/licenses/by/4.0/Introduction: In vitro approaches are an essential tool in screening for toxicity of new chemicals, products and therapeutics. To increase the reproducibility and human relevance of these in vitro assessments, it is advocated to remove animal-derived products such as foetal bovine serum (FBS) from the cell culture system. Currently, FBS is routinely used as a supplement in cell culture medium, but batch-to-batch variability may introduce inconsistency in inter- and intra-lab assessments. Several chemically defined serum replacements (CDSR) have been developed to provide an alternative to FBS, but not every cell line adapts easily and successfully to CDSR-supplemented medium, and the long-term effect on cell characteristics remains uncertain. Aim: The aim of this study was to adapt the TK6 cell line to animal-product free CDSR-supplemented medium and evaluate the long-term effects on cell health, growth, morphology, phenotype, and function. This included a provisional assessment to determine the suitability of the transitioned cell line for standardised genotoxicity testing using the “in vitro mammalian cell micronucleus test” (OECD TG 487). Materials and methods: Gradual adaptation and direct adaptation methodologies were compared by assessing the cell proliferation, size and viability every passage until the cells were fully adapted to animal-free CDSR. The metabolic activity and membrane integrity was assessed every 4-8 passages by PrestoBlue and CytoTox-ONE™ Homogeneous Membrane Integrity Assay respectively. A detailed morphology study by high content imaging was performed and the expression of cell surface markers (CD19 and CD20) was conducted via flow cytometry to assess the potential for phenotypic drift during longer term culture of TK6 in animal-free conditions. Finally, functionality of cells in the OECD TG 487 assay was evaluated. Results: The baseline characteristics of TK6 cells cultured in FBS-supplemented medium were established and variability among passages was used to set up acceptance criteria for CDSR adapted cells. TK6 were adapted to CDSR supplemented medium either via direct or gradual transition reducing from 10% v/v FBS to 0% v/v FBS. The cell growth rate was compromised in the direct adaptation and therefore the gradual adaptation was preferred to investigate the long-term effects of animal-free CDSR on TK6 cells. The new animal cells showed comparable (p > 0.05) viability and cell size as the parent FBS-supplemented cells, with the exception of growth rate. The new animal free cells showed a lag phase double the length of the original cells. Cell morphology (cellular and nuclear area, sphericity) and phenotype (CD19 and CD20 surface markers) were in line (p > 0.05) with the original cells. The new cells cultured in CDSR-supplemented medium performed satisfactory in a pilot OECD TG 487 assay with compounds not requiring metabolic activation. Conclusion: TK6 cells were successfully transitioned to FBS- and animal product-free medium. The new cell cultures were viable and mimicked the characteristics of FBS-cultured cells. The gradual transition methodology utilised in this study can also be applied to other cell lines of interest. Maintaining cells in CDSR-supplemented medium eliminates variability from FBS, which in turn is likely to increase the reproducibility of in vitro experiments. Furthermore, removal of animal derived products from cell culture techniques is likely to increase the human relevance of in vitro methodologies.Peer reviewe
Gaining approvals for mental health research in the NHS
When embarking on mental health research it is often necessary to apply for approvals from one or more review bodies to ensure that the research is ethical and that the safety and well-being of participants are safeguarded. This can be complicated and time consuming, particularly to those unfamiliar with the process. In this article we describe the approvals commonly required for National Health Service-based research involving patients and endeavour to clearly explain what is involved at each stage. We then highlight some of the main considerations, including ethical aspects, which are particularly pertinent to conducting research in the field of mental health, and finish with general advice and considerations for future developments in the area
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