A qualitative exploration of autistic mothers' experiences I: Pregnancy experiences.

LAY ABSTRACT: Little is known about how autistic people experience pregnancy. We interviewed 24 autistic and 21 non-autistic women during pregnancy to find out about their experiences. Autistic participants had more physical difficulties, such as nausea and pain, during pregnancy than non-autistic participants. They also sometimes felt that healthcare professionals, such as midwives, did not have a good understanding of autism and they did not always feel comfortable telling professionals about their autism diagnosis. Autistic participants told us that they needed professionals to communicate with them clearly and to make changes during appointments such as dimming lights. This research shows that autistic people would benefit from changes to pregnancy appointments and that more training about autism would help maternity care professionals to support autistic people during pregnancy.

A qualitative exploration of autistic mothers' experiences II: Childbirth and postnatal experiences.

LAY ABSTRACT: Very little research has looked at how autistic people experience childbirth and the first few months of parenthood. We interviewed 21 autistic and 25 non-autistic women 2-3 months after their baby was born, to find out how they experienced giving birth and being a parent. Some autistic participants found sensory aspects of giving birth difficult, such as noise and being touched. They also wanted healthcare professionals to give them clear information while giving birth. Participants sometimes thought that healthcare professionals did not know enough about autism. Autistic and non-autistic participants both found parenthood difficult at times and autistic parents sometimes had extra difficulties, such as with planning and organising. Autistic participants also felt good at understanding their baby's needs. This research suggests that autistic people would benefit from changes to childbirth and postnatal healthcare such as being communicated with more clearly. It also indicates that healthcare professionals should receive more training about autism.

Gouty tophus: Unusual case of nasal lump.

Chronic tophaceous gout is a common disease but rarely found in the head and neck region. Here we report a case of a middle aged male who presented with a mass over the right side of the nasal bridge. CT of the paranasal sinuses revealed a tophi lesion in the right nasal bridge with erosion of the underlying nasal bone. The mass was excised and histologically confirmed to be a gouty tophus. This case report illustrates how a common disease presented in an uncommon location could pose a diagnostic challenge.

Variant Intronic Enhancer Controls SCN10A-short Expression and Heart Conduction.

BACKGROUND: Genetic variants in SCN10A, encoding the neuronal voltage-gated sodium channel NaV1.8, are strongly associated with atrial fibrillation, Brugada syndrome, cardiac conduction velocities, and heart rate. The cardiac function of SCN10A has not been resolved, however, and diverging mechanisms have been proposed. Here, we investigated the cardiac expression of SCN10A and the function of a variant-sensitive intronic enhancer previously linked to the regulation of SCN5A, encoding the major essential cardiac sodium channel NaV1.5. METHODS: The expression of SCN10A was investigated in mouse and human hearts. With the use of CRISPR/Cas9 genome editing, the mouse intronic enhancer was disrupted, and mutant mice were characterized by transcriptomic and electrophysiological analyses. The association of genetic variants at SCN5A-SCN10A enhancer regions and gene expression were evaluated by genome-wide association studies single-nucleotide polymorphism mapping and expression quantitative trait loci analysis. RESULTS: We found that cardiomyocytes of the atria, sinoatrial node, and ventricular conduction system express a short transcript comprising the last 7 exons of the gene (Scn10a-short). Transcription occurs from an intronic enhancer-promoter complex, whereas full-length Scn10a transcript was undetectable in the human and mouse heart. Expression quantitative trait loci analysis revealed that the genetic variants in linkage disequilibrium with genetic variant rs6801957 in the intronic enhancer associate with SCN10A transcript levels in the heart. Genetic modification of the enhancer in the mouse genome led to reduced cardiac Scn10a-short expression in atria and ventricles, reduced cardiac sodium current in atrial cardiomyocytes, atrial conduction slowing and arrhythmia, whereas the expression of Scn5a, the presumed enhancer target gene, remained unaffected. In patch-clamp transfection experiments, expression of Scn10a-short-encoded NaV1.8-short increased NaV1.5-mediated sodium current. We propose that noncoding genetic variation modulates transcriptional regulation of Scn10a-short in cardiomyocytes that impacts NaV1.5-mediated sodium current and heart rhythm. CONCLUSIONS: Genetic variants in and around SCN10A modulate enhancer function and expression of a cardiac-specific SCN10A-short transcript. We propose that noncoding genetic variation modulates transcriptional regulation of a functional C-terminal portion of NaV1.8 in cardiomyocytes that impacts on NaV1.5 function, cardiac conduction velocities, and arrhythmia susceptibility.

Factors in Psychiatric Admissions: Before and During the Covid-19 Pandemic.

OBJECTIVE: The COVID-19 pandemic has impacted community mental health, but the effect on psychiatric admissions is unknown. We investigated factors contributing to acute psychiatric admissions, and whether this changed during the first UK lockdown. METHOD: A retrospective case-note review study with an exploratory mixed-methods design to examine factors for psychiatric admissions following the first UK 2020 lockdown compared to the same time periods in 2019 and 2018. RESULTS: Themes of psychopathology, risk, social stressors, community treatment issues, and physical health concerns were generated. The mean number of codes per case was 6.19 (s . d. = 2.43), with a mean number of categories per case of 3.73, (s. d. = 0.98). Changes in routines and isolation were common factors in the study year; accommodation and substance abuse were more prominent in the control year. Relationship stressors featured strongly in both groups. There were significantly more women (χ2(1, N = 98) = 20.80, p < 0.00001) and older adults (χ2(1, N = 98) = 8.61, p = 0.0033) in the study group than the control. Single people, compared to those in a relationship (χ2(1, N = 45) = 4.46, p = 0.035), and people with affective disorders compared to psychotic disorders ((χ2(1, N = 28) = 5.19, p = 0.023), were more likely to have a COVID-19 related admission factor. CONCLUSIONS: Early stages of the COVID-19 pandemic amplified pre-existing psychosocial vulnerabilities with a disproportionate psychiatric admissions impact on the mental health of women, older adults and those with affective disorders.

Genetic Dissection of a Super Enhancer Controlling the Nppa-Nppb Cluster in the Heart.

RATIONALE: ANP (atrial natriuretic peptide) and BNP (B-type natriuretic peptide), encoded by the clustered genes Nppa and Nppb, are important prognostic, diagnostic, and therapeutic proteins in cardiac disease. The spatiotemporal expression pattern and stress-induction of the Nppa and Nppb are tightly regulated, possibly involving their coregulation by an evolutionary conserved enhancer cluster. OBJECTIVE: To explore the physiological functions of the enhancer cluster and elucidate the genomic mechanism underlying Nppa-Nppb coregulation in vivo. METHODS AND RESULTS: By analyzing epigenetic data we uncovered an enhancer cluster with super enhancer characteristics upstream of Nppb. Using CRISPR/Cas9 genome editing, the enhancer cluster or parts thereof, Nppb and flanking regions or the entire genomic block spanning Nppa-Nppb, respectively, were deleted from the mouse genome. The impact on gene regulation and phenotype of the respective mouse lines was investigated by transcriptomic, epigenomic, and phenotypic analyses. The enhancer cluster was essential for prenatal and postnatal ventricular expression of Nppa and Nppb but not of any other gene. Enhancer cluster-deficient mice showed enlarged hearts before and after birth, similar to Nppa-Nppb compound knockout mice we generated. Analysis of the other deletion alleles indicated the enhancer cluster engages the promoters of Nppa and Nppb in a competitive rather than a cooperative mode, resulting in increased Nppa expression when Nppb and flanking sequences were deleted. The enhancer cluster maintained its active epigenetic state and selectivity when its target genes are absent. In enhancer cluster-deficient animals, Nppa was induced but remained low in the postmyocardial infarction border zone and in the hypertrophic ventricle, involving regulatory sequences proximal to Nppa. CONCLUSIONS: Coordinated ventricular expression of Nppa and Nppb is controlled in a competitive manner by a shared super enhancer, which is also required to augment stress-induced expression and to prevent premature hypertrophy.

Best Practice Principles When Working With Individuals With Intellectual Disability and Comorbid Mental Health Concerns.

Working with individuals with dual disabilities can be a complex process in the presence of limited evidence base to guide clinical practice. The aims of this qualitative study were to investigate perceptions of best practices of Australian psychologists who work with this specialist population. Thirty-eight Australian psychologists working in the intellectual disability field participated in eight semistructured focus groups. Perceptions of evidence-based practice for individuals with intellectual disabilities and in relation to mental health assessment were explored. Psychologists demonstrated resourcefulness in adapting to limits in available evidence-based practice and in modifying mainstream practice to suit the needs of individuals with dual disabilities. Findings suggest the necessity of practice-based evidence in contributing to the evidence base, and person-centered approaches in relation to best practice for people with intellectual disabilities. Implications for strengthening psychologists' clinical competency and bridging the research and practice gap are discussed.

An enhancer cluster controls gene activity and topology of the SCN5A-SCN10A locus in vivo.

Mutations and variations in and around SCN5A, encoding the major cardiac sodium channel, influence impulse conduction and are associated with a broad spectrum of arrhythmia disorders. Here, we identify an evolutionary conserved regulatory cluster with super enhancer characteristics downstream of SCN5A, which drives localized cardiac expression and contains conduction velocity-associated variants. We use genome editing to create a series of deletions in the mouse genome and show that the enhancer cluster controls the conformation of a >0.5 Mb genomic region harboring multiple interacting gene promoters and enhancers. We find that this cluster and its individual components are selectively required for cardiac Scn5a expression, normal cardiac conduction and normal embryonic development. Our studies reveal physiological roles of an enhancer cluster in the SCN5A-SCN10A locus, show that it controls the chromatin architecture of the locus and Scn5a expression, and suggest that genetic variants affecting its activity may influence cardiac function.

Conserved NPPB+ Border Zone Switches From MEF2- to AP-1-Driven Gene Program.

BACKGROUND: Surviving cells in the postinfarction border zone are subjected to intense fluctuations of their microenvironment. Recently, border zone cardiomyocytes have been specifically implicated in cardiac regeneration. Here, we defined their unique transcriptional and regulatory properties, and comprehensively validated new molecular markers, including Nppb, encoding B-type natriuretic peptide, after infarction. METHODS: Transgenic reporter mice were used to identify the Nppb-positive border zone after myocardial infarction. Transcriptome analysis of remote, border, and infarct zones and of purified cardiomyocyte nuclei was performed using RNA-sequencing. Top candidate genes displaying border zone spatial specificity were histologically validated in ischemic human hearts. Mice in which Nppb was deleted by genome editing were subjected to myocardial infarction. Chromatin accessibility landscapes of border zone and control cardiomyocyte nuclei were assessed by using assay for transposase-accessible chromatin using sequencing. RESULTS: We identified the border zone as a spatially confined region transcriptionally distinct from the remote myocardium. The transcriptional response of the border zone was much stronger than that of the remote ventricular wall, involving acute downregulation of mitochondrial oxidative phosphorylation, fatty acid metabolism, calcium handling, and sarcomere function, and the activation of a stress-response program. Analysis of infarcted human hearts revealed that the transcriptionally discrete border zone is conserved in humans, and led to the identification of novel conserved border zone markers including NPPB, ANKRD1, DES, UCHL1, JUN, and FOXP1. Homozygous Nppb mutant mice developed acute and lethal heart failure after myocardial infarction, indicating that B-type natriuretic peptide is required to preserve postinfarct heart function. Assay for transposase-accessible chromatin using sequencing revealed thousands of cardiomyocyte lineage-specific MEF2-occupied regulatory elements that lost accessibility in the border zone. Putative injury-responsive enhancers that gained accessibility were highly associated with AP-1 (activator protein 1) binding sites. Nuclear c-Jun, a component of AP-1, was observed specifically in border zone cardiomyocytes. CONCLUSIONS: Cardiomyocytes in a discrete zone bordering the infarct switch from a MEF2-driven homeostatic lineage-specific to an AP-1-driven injury-induced gene expression program. This program is conserved between mouse and human, and includes Nppb expression, which is required to prevent acute heart failure after infarction.

Metal artifact reduction by monoenergetic extrapolation of dual-energy CT in patients with metallic implants.

PURPOSE: The objective of this study is to assess artifact reduction and image quality using dual-energy computed tomography (DECT) and metal artifact reduction techniques in patients with metallic implants. METHODS: Forty patients with metallic implants, who had targeted CT performed by DECT during March to September 2018, were prospectively recruited. Post-processing with monoenergetic extrapolation at 70 and 150 keV was performed. Forty matched controls with metallic implants with single-energy CT (SECT) performed were selected. Attenuation value, noise, and signal-to-noise ratio (SNR) at the site of maximal artifact were measured at muscle and fat areas. Image quality of three sets of images (70 keV, 150 keV, and SECT) was assessed by two independent reviewers using a 5-point Likert-type scale. Statistical analysis of measured values, Likert-type scales, and radiation doses (volume CT dose index (CTDIvol)) of DECT and SECT were performed with Mann-Whitney U test. RESULTS: As compared to SECT, high keV reconstruction of DECT show (1) significantly higher values within muscle and fat surrounding the implant (DECT vs. SECT-muscle: -96 Hounsfield units (HU) vs. -405 HU, fat: -115 HU vs. -301 HU; p < 0.001), (2) significantly lower mean image noise (75 HU vs. 129 HU; p = 0.02), and (3) higher SNR (-0.8 vs. -4.3; p < 0.001). In addition, image quality of high keV reconstruction was rated superior to the other two groups on Likert-type scales ( p < 0.001). The mean radiation doses (CTDIvol) were comparable between DECT and SECT (14.2 mGy vs. 19.3 mGy; p = 0.08). CONCLUSION: For patients with metallic implants, monoenergetic extrapolation of DECT at high keV can reduce metal artifacts, increase SNR, and improve qualitative image quality at comparable radiation dose.

Service satisfaction and helpfulness ratings, mental health literacy and help seeking barriers of carers of individuals with dual disabilities.

BACKGROUND: Carer mental health literacy and help seeking are areas that are not well researched in the intellectual disability field. This study aimed to explore the above including service utilization experiences of Australian parents with an offspring with an intellectual disability and a comorbid psychiatric disorder. METHOD: Forty-one parents took part in an online survey assessing satisfaction and helpfulness ratings of received services. Twenty-six parents also completed items to assess mental health literacy and attitudinal barriers to help seeking. RESULTS: Parents showed good mental health literacy with depression and with challenging behaviour associated with autism and poorer literacy with mixed presentations. Few attitudinal barriers to help seeking were reported. Parents reported varied helpfulness and satisfaction ratings with disability and mental health services. CONCLUSIONS: Parents are capable of recognizing the need to seek professional help for their offspring. Implications for service coordination, provision and carer involvement are discussed.

Structure and function of the Nppa-Nppb cluster locus during heart development and disease.

Atrial natriuretic factor and brain natriuretic peptide are two important biomarkers in clinical cardiology. These two natriuretic peptide hormones are encoded by the paralogous genes Nppa and Nppb, which are evolutionary conserved. Both genes are predominantly expressed by the heart muscle during the embryonic and fetal stages, and in particular Nppa expression is strongly reduced in the ventricles after birth. Upon cardiac stress, Nppa and Nppb are strongly upregulated in the ventricular myocardium. Much is known about the molecular and physiological ques inducing Nppa and Nppb expression; however, the transcriptional regulatory mechanisms of the Nppa-Nppb cluster in vivo has proven to be quite complex and is not well understood. In this review, we will provide recent insights into the dynamic and complex regulation of Nppa and Nppb during heart development and hypertrophy, and the association of this gene cluster with the cardiomyocyte-intrinsic program of heart regeneration.

Inhibiting the clathrin-mediated endocytosis pathway rescues K(IR)2.1 downregulation by pentamidine.

Drug-induced ion channel trafficking disturbance can cause cardiac arrhythmias. We showed that the antiprotozoic pentamidine decreased K(IR)2.x carried I(K1) current and that inhibiting protein degradation in the lysosome increased intracellular K(IR)2.1 levels. In this study, we aim to identify and then inhibit preceding steps in clathrin-mediated endocytosis of K(IR)2.1 to further restore normal levels of functional K(IR)2.1 channels. K(IR)2.1 trafficking in HEK293 cells was studied by live cell imaging, immunofluorescence microscopy, and Western blot following pharmacological intervention with dynasore (Dyn), chlorpromazine (CPZ), bafilomycin A1 (Baf), or chloroquine (CQ). K(IR)2.1 function was determined by patch-clamp electrophysiology. CQ induced lysosomal build-up of full length (3.8 ± 0.8-fold) and N-terminal cleaved K(IR)2.1 protein. Baf induced late endosomal build-up of full length protein only (6.1 ± 1.6-fold). CPZ and Dyn increased plasma membrane-localized channel and protein levels (2.6 ± 0.4- and 4.2 ± 1.1-fold, respectively). Dyn increased I(K1) (at -60 mV) from 31 ± 6 to 55 ± 7 pA/pF (N = 9 and 13 respectively, p < 0.05), while the CPZ effect on current density was not testable due to acute I(K1) block. Baf and CQ did not significantly enhance I(K1) densities. Pentamidine (10 µM, 48 h) reduced K(IR)2.1 levels to 0.6 ± 0.1-fold, which could be rescued by Baf (3.2 ± 0.9), CPZ (1.2 ± 0.3), or Dyn (1.2 ± 0.3). Taken together, the clathrin-mediated endocytosis pathway functions in K(IR)2.1 degradation. Pentamidine-induced downregulation of K(IR)2.1 can be rescued at the level of the plasma membrane, implying that acquired trafficking defects can be rescued.