Genetic predisposition to mosaic Y chromosome loss in blood.

Mosaic loss of chromosome Y (LOY) in circulating white blood cells is the most common form of clonal mosaicism1-5, yet our knowledge of the causes and consequences of this is limited. Here, using a computational approach, we estimate that 20% of the male population represented in the UK Biobank study (n = 205,011) has detectable LOY. We identify 156 autosomal genetic determinants of LOY, which we replicate in 757,114 men of European and Japanese ancestry. These loci highlight genes that are involved in cell-cycle regulation and cancer susceptibility, as well as somatic drivers of tumour growth and targets of cancer therapy. We demonstrate that genetic susceptibility to LOY is associated with non-haematological effects on health in both men and women, which supports the hypothesis that clonal haematopoiesis is a biomarker of genomic instability in other tissues. Single-cell RNA sequencing identifies dysregulated expression of autosomal genes in leukocytes with LOY and provides insights into why clonal expansion of these cells may occur. Collectively, these data highlight the value of studying clonal mosaicism to uncover fundamental mechanisms that underlie cancer and other ageing-related diseases.

Barriers and solutions to the adoption of translational tools for computational psychiatry.

Computational psychiatry is a field aimed at developing formal models of information processing in the human brain, and how alterations in this processing can lead to clinical phenomena. There has been significant progress in the development of tasks and how to model them, presenting an opportunity to incorporate computational psychiatry methodologies into large- scale research projects or into clinical practice. In this viewpoint, we explore some of the barriers to incorporation of computational psychiatry tasks and models into wider mainstream research directions. These barriers include the time required for participants to complete tasks, test-retest reliability, limited ecological validity, as well as practical concerns, such as lack of computational expertise and the expense and large sample sizes traditionally required to validate tasks and models. We then discuss solutions, such as the redesigning of tasks with a view toward feasibility, and the integration of tasks into more ecologically valid and standardized game platforms that can be more easily disseminated. Finally, we provide an example of how one task, the conditioned hallucinations task, might be translated into such a game. It is our hope that interest in the creation of more accessible and feasible computational tasks will help computational methods make more positive impacts on research as well as, eventually, clinical practice.

Assessing the suitability of the Carer Support Needs Assessment Tool (CSNAT-Paediatric) for use with parents of children with a life-limiting condition: A qualitative secondary analysis.

BACKGROUND: The demands of caring for a child with a life-limiting condition can have a profound impact on parents' health and wellbeing. Currently, there is no standard procedure for identifying and addressing the support needs of these parents. AIM: To assess the suitability of the Carer Support Needs Assessment Tool (CSNAT (Paediatric)) for use with parents of children with a life-limiting condition. DESIGN: Secondary qualitative content analysis of two qualitative datasets exploring the health, wellbeing and experiences of support of mothers and fathers of children with a life-limiting condition. SETTING: A total of 30 mothers and 12 fathers were recruited via four UK children's hospices and social media. RESULTS: Parental experiences of support mapped onto the existing domains of the CSNAT (Paediatric). One aspect of their experience, surrounding their child's educational needs, went beyond the existing domains of the CSNAT. An adapted version of the tool CSNAT (Paediatric) should include this domain. CONCLUSION: The CSNAT (Paediatric) is a relevant tool for the assessment of parental support needs. Further research should assess the acceptability and feasibility of implementation of the broader intervention: CSNAT-I (Paediatric).

The educational value of situational judgement tests (SJTs) when used during undergraduate medical training: A systematic review and narrative synthesis.

INTRODUCTION: Situational judgement tests (SJTs) are a recognised assessment method for admission into medical school, selection into postgraduate training programs, and postgraduate competency assessment. More recently, however, SJTs have been used during undergraduate medical training (UMT). This systematic review identifies, describes, and appraises the evidence for SJTs in UMT to determine educational associations and outcomes. METHODS: MEDLINE, EMBASE, ERIC, PsycINFO, SCOPUS, Web of Science, and grey literature were searched for original research studies evaluating SJTs implemented within UMT to 1 November 2022. Studies reporting evaluation outcomes were included. Narrative data syntheses were undertaken. Risk of Bias was appraised using the Quality in Prognosis Studies tool. RESULTS: 24 studies were included. National database-derived SJTs (n = 14) assessed against professionalism, postgraduate attainment, construct of medical degree, medical school admissions scores, personality attributes, and declaration of disability. In-house derived SJTs (n = 10) assessed against professionalism, clinical skills, and personality attributes. Most evidence evaluated and reported inverse SJT associations with professionalism and were moderate risk of bias. CONCLUSION: SJTs may have utility for developing professional behaviours in medical students. However, further research testing SJT robustness, standard setting methodologies, and prospectively evaluating SJTs against objective outcome measures within the context of UMT is warranted.

The health of mothers of children with a life-limiting condition: A qualitative interview study.

BACKGROUND: The number of children with a life-limiting condition is increasing. The mothers of these children commonly provide extensive care at home for their child and are at a higher risk of poor health than other mothers. The impact of this is rarely explored from mothers' perspectives. AIM: To explore mothers' accounts of their physical and mental health, experiences of accessing healthcare and who they think should support their health. DESIGN: Qualitative semi-structured interviews were conducted and analysed using thematic analysis. SETTING/PARTICIPANTS: Thirty mothers of children with a life-limiting condition were recruited via three UK children's hospices and social media. RESULTS: Mothers felt that their health concerns could be misunderstood by professionals, describing untimely and inappropriate support that failed to recognise the nature of caring for a child with a life-limiting condition. This led to mothers' reluctance in addressing these concerns. Mothers felt unable to prioritise their own needs, relative to those of their child and worried about who would look after their child if they did become unwell. They described stress as a result of battles with services rather than as a result of caregiving. Mothers valued feeling recognised as caregivers, which made it easier to look after their health alongside their child's. Hospice support was particularly valuable in this respect. CONCLUSIONS: A more unified system that recognises not only the unique set of challenges presented to mothers caring for a child with a life-limiting condition, but the value of palliative care services in supporting these mothers, is required.

Evidence for Reduced Sensory Precision and Increased Reliance on Priors in Hallucination-Prone Individuals in a General Population Sample.

BACKGROUND: There is increasing evidence that people with hallucinations overweight perceptual beliefs relative to incoming sensory evidence. Past work demonstrating prior overweighting has used simple, nonlinguistic stimuli. However, auditory hallucinations in psychosis are often complex and linguistic. There may be an interaction between the type of auditory information being processed and its perceived quality in engendering hallucinations. STUDY DESIGN: We administered a linguistic version of the conditioned hallucinations (CH) task to an online sample of 88 general population participants. Metrics related to hallucination-proneness, hallucination severity, stimulus thresholds, and stimulus detection rates were collected. Data were used to fit parameters of a Hierarchical Gaussian Filter (HGF) model of perceptual inference to determine how latent perceptual states influenced task behavior. STUDY RESULTS: Replicating past results, higher CH rates were observed both in those with recent hallucinatory experiences as well as participants with high hallucination-proneness; CH rates were positively correlated with increased prior weighting; and increased prior weighting was related to hallucination severity. Unlike past results, participants with recent hallucinatory experiences as well as those with higher hallucination-proneness had higher stimulus thresholds, lower sensitivity to stimuli presented at the highest threshold, and had lower response confidence, consistent with lower precision of sensory evidence. CONCLUSIONS: We replicate the finding that increased CH rates and recent hallucinations correlate with increased prior weighting using a linguistic version of the CH task. Results support a role for reduced sensory precision in the interplay between prior weighting and hallucination-proneness.

The mechanisms underlying conditioning of phantom percepts differ between those with hallucinations and synesthesia.

There are many different kinds of 'phantom' percepts but it is unknown whether they are united by common mechanisms. For example, synaesthesia (e.g., numbers evoking colour) and hallucinations appear conceptually and phenomenologically similar: both result in a percept that does not have an environmental correlate. Here, people with synaesthesia (n = 66) performed a conditioned hallucinations paradigm known to be sensitive to hallucination susceptibility, and we asked whether synaesthetes would show the same behavioural profile as hallucinators in this task. Repeated pairing of checkerboards with tones, and gratings with colours encourages the participant to draw on prior knowledge when asked to report on the presence of the difficult-to-detect target stimulus. Synaesthetes show increased modelled expectancies for the stimulus association across the board, resulting in a higher number of detections at all stimulus intensities. This is in contrast to the pattern observed in hallucinators, who weigh their prior beliefs more strongly than controls, giving rise to more conditioned hallucinations. Results indicate that fundamentally different perceptual processes may be at the core of these seemingly similar experiences.

Psychological well-being of hospice staff: systematic review.

BACKGROUND: Poor psychological well-being among healthcare staff has implications for staff sickness and absence rates, and impacts on the quality, cost and safety of patient care. Although numerous studies have explored the well-being of hospice staff, study findings vary and the evidence has not yet been reviewed and synthesised. Using job demands-resources (JD-R) theory, this review aimed to investigate what factors are associated with the well-being of hospice staff. METHODS: We searched MEDLINE, CINAHL and PsycINFO for peer-reviewed quantitative, qualitative or mixed-methods studies focused on understanding what contributes to the well-being of hospice staff who provide care to patients (adults and children). The date of the last search was 11 March 2022. Studies were published from 2000 onwards in the English language and conducted in Organisation for Economic Co-operation and Development countries. Study quality was assessed using the Mixed Methods Appraisal Tool. Data synthesis was conducted using a result-based convergent design, which involved an iterative, thematic approach of collating data into distinct factors and mapping these to the JD-R theory. RESULTS: A total of 4016 unique records were screened by title and abstract, 115 full-text articles were retrieved and reviewed and 27 articles describing 23 studies were included in the review. The majority of the evidence came from studies of staff working with adult patients. Twenty-seven individual factors were identified in the included studies. There is a strong and moderate evidence that 21 of the 27 identified factors can influence hospice staff well-being. These 21 factors can be grouped into three categories: (1) those that are specific to the hospice environment and role, such as the complexity and diversity of the hospice role; (2) those that have been found to be associated with well-being in other similar settings, such as relationships with patients and their families; and (3) those that affect workers regardless of their role and work environment, that is, that are not unique to working in a healthcare role, such as workload and working relationships. There was strong evidence that neither staff demographic characteristics nor education level can influence well-being. DISCUSSION: The factors identified in this review highlight the importance of assessing both positive and negative domains of experience to determine coping interventions. Hospice organisations should aim to offer a wide range of interventions to ensure their staff have access to something that works for them. These should involve continuing or commencing initiatives to protect the factors that make hospices good environments in which to work, as well as recognising that hospice staff are also subject to many of the same factors that affect psychological well-being in all work environments. Only two studies included in the review were set in children's hospices, suggesting that more research is needed in these settings. PROSPERO REGISTRATION NUMBER: CRD42019136721 (Deviations from the protocol are noted in Table 8, Supplementary material).

Experiences of fathers of children with a life-limiting condition: a systematic review and qualitative synthesis.

BACKGROUND: Children with a life-limiting condition often require extensive and complex care, much of which is provided by their parents at home. There is a growing body of research that aims to understand the experiences of these parents, but the majority of this research is from mothers' perspectives, meaning that fathers' experiences are not well understood. OBJECTIVES: To identify and synthesise findings from existing qualitative studies that have explored the experiences of fathers of children with a life-limiting condition. METHODS: A systematic review of qualitative research was conducted using thematic synthesis. Searches were conducted in MEDLINE, CINAHL, EMBASE, PsycINFO and Social Science Citation Index. RESULTS: Findings from 30 studies were included, representing the experiences of 576 fathers of children with a range of diagnoses including cancer, cystic fibrosis, genetic and neurological conditions. Themes detailed fathers' experiences of uncertainty and shock around the time of their child's diagnosis, their accounts of a 'new normal', difficulties in discussing their emotions, forming relationships with and seeking support from professionals and working fathers' role conflicts. They discussed the life-changing nature of their child's diagnosis, an event that affected all aspects of their lives from everyday activities, to their relationships, spirituality, values and ambitions. CONCLUSIONS: Fathers experience many difficulties in response to their child's diagnosis and ongoing treatment. Findings highlight the need for healthcare professionals to recognise individual family dynamics and the evolving role of the father. Fathers' responses are not widely understood, and research that directly addresses their own well-being is warranted.

A novel computational approach to pain perception modelling within a Bayesian framework using quantitative sensory testing.

Pain perception can be studied as an inferential process in which prior information influences the perception of nociceptive input. To date, there are no suitable psychophysical paradigms to measure this at an individual level. We developed a quantitative sensory testing paradigm allowing for quantification of the influence of prior expectations versus current nociceptive input during perception. Using a Pavlovian-learning task, we investigated the influence of prior expectations on the belief about the varying strength of association between a painful electrical cutaneous stimulus and a visual cue in healthy subjects (N = 70). The belief in cue-pain associations was examined with computational modelling using a Hierarchical Gaussian Filter (HGF). Prior weighting estimates in the HGF model were compared with the established measures of conditioned pain modulation (CPM) and temporal summation of pain (TSP) assessed by cuff algometry. Subsequent HGF-modelling and estimation of the influence of prior beliefs on perception showed that 70% of subjects had a higher reliance on nociceptive input during perception of acute pain stimuli, whereas 30% showed a stronger weighting of prior expectations over sensory evidence. There was no association between prior weighting estimates and CPM or TSP. The data demonstrates relevant individual differences in prior weighting and suggests an importance of top-down cognitive processes on pain perception. Our new psychophysical testing paradigm provides a method to identify individuals with traits suggesting greater reliance on prior expectations in pain perception, which may be a risk factor for developing chronic pain and may be differentially responsive to learning-based interventions.

A computational lens on menopause-associated psychosis.

Psychotic episodes are debilitating disease states that can cause extreme distress and impair functioning. There are sex differences that drive the onset of these episodes. One difference is that, in addition to a risk period in adolescence and early adulthood, women approaching the menopause transition experience a second period of risk for new-onset psychosis. One leading hypothesis explaining this menopause-associated psychosis (MAP) is that estrogen decline in menopause removes a protective factor against processes that contribute to psychotic symptoms. However, the neural mechanisms connecting estrogen decline to these symptoms are still not well understood. Using the tools of computational psychiatry, links have been proposed between symptom presentation and potential algorithmic and biological correlates. These models connect changes in signaling with symptom formation by evaluating changes in information processing that are not easily observable (latent states). In this manuscript, we contextualize the observed effects of estrogen (decline) on neural pathways implicated in psychosis. We then propose how estrogen could drive changes in latent states giving rise to cognitive and psychotic symptoms associated with psychosis. Using computational frameworks to inform research in MAP may provide a systematic method for identifying patient-specific pathways driving symptoms and simultaneously refine models describing the pathogenesis of psychosis across all age groups.

Perceptual pathways to hallucinogenesis.

Recent advances in computational psychiatry have provided unique insights into the neural and cognitive underpinnings of psychotic symptoms. In particular, a host of new data has demonstrated the utility of computational frameworks for understanding how hallucinations might arise from alterations in typical perceptual processing. Of particular promise are models based in Bayesian inference that link hallucinatory perceptual experiences to latent states that may drive them. In this piece, we move beyond these findings to ask: how and why do these latent states arise, and how might we take advantage of heterogeneity in that process to develop precision approaches to the treatment of hallucinations? We leverage specific models of Bayesian inference to discuss components that might lead to the development of hallucinations. Using the unifying power of our model, we attempt to place disparate findings in the study of psychotic symptoms within a common framework. Finally, we suggest directions for future elaboration of these models in the service of a more refined psychiatric nosology based on predictable, testable, and ultimately treatable information processing derangements.

Increases in sensory noise predict attentional disruptions to audiovisual speech perception.

We receive information about the world around us from multiple senses which combine in a process known as multisensory integration. Multisensory integration has been shown to be dependent on attention; however, the neural mechanisms underlying this effect are poorly understood. The current study investigates whether changes in sensory noise explain the effect of attention on multisensory integration and whether attentional modulations to multisensory integration occur via modality-specific mechanisms. A task based on the McGurk Illusion was used to measure multisensory integration while attention was manipulated via a concurrent auditory or visual task. Sensory noise was measured within modality based on variability in unisensory performance and was used to predict attentional changes to McGurk perception. Consistent with previous studies, reports of the McGurk illusion decreased when accompanied with a secondary task; however, this effect was stronger for the secondary visual (as opposed to auditory) task. While auditory noise was not influenced by either secondary task, visual noise increased with the addition of the secondary visual task specifically. Interestingly, visual noise accounted for significant variability in attentional disruptions to the McGurk illusion. Overall, these results strongly suggest that sensory noise may underlie attentional alterations to multisensory integration in a modality-specific manner. Future studies are needed to determine whether this finding generalizes to other types of multisensory integration and attentional manipulations. This line of research may inform future studies of attentional alterations to sensory processing in neurological disorders, such as Schizophrenia, Autism, and ADHD.

Conditioned Hallucinations and Prior Overweighting Are State-Sensitive Markers of Hallucination Susceptibility.

BACKGROUND: Recent advances in computational psychiatry have identified latent cognitive and perceptual states that predispose to psychotic symptoms. Behavioral data fit to Bayesian models have demonstrated an overreliance on priors (i.e., prior overweighting) during perception in select samples of individuals with hallucinations, corresponding to increased precision of prior expectations over incoming sensory evidence. However, the clinical utility of this observation depends on the extent to which it reflects static symptom risk or current symptom state. METHODS: To determine whether task performance and estimated prior weighting relate to specific elements of symptom expression, a large, heterogeneous, and deeply phenotyped sample of hallucinators (n = 249) and nonhallucinators (n = 209) performed the conditioned hallucination (CH) task. RESULTS: We found that CH rates predicted stable measures of hallucination status (i.e., peak frequency). However, CH rates were more sensitive to hallucination state (i.e., recent frequency), significantly correlating with recent hallucination severity and driven by heightened reliance on past experiences (priors). To further test the sensitivity of CH rate and prior weighting to symptom severity, a subset of participants with hallucinations (n = 40) performed a repeated-measures version of the CH task. Changes in both CH frequency and prior weighting varied with changes in auditory hallucination frequency on follow-up. CONCLUSIONS: These results indicate that CH rate and prior overweighting are state markers of hallucination status, potentially useful in tracking disease development and treatment response.

Measuring Voluntary Control Over Hallucinations: The Yale Control Over Perceptual Experiences (COPE) Scales.

Auditory verbal hallucinations (AVH) frequently cause significant distress and dysfunction, and may be unresponsive to conventional treatments. Some voice-hearers report an ability to fully control the onset and offset of their AVH, making them significantly less disruptive. Measuring and understanding these abilities may lead to novel interventions to enhance control over AVH. Fifty-two voice-hearers participated in the pilot study. 318 participants with frequent AVH participated in the validation study. A pool of 59 items was developed by a diverse team including voice-hearers and clinicians. After the pilot study, 35 items were retained. Factorial structure was assessed with exploratory (EFA, n = 148) and confirmatory (CFA, n = 170) factor analyses. Reliability and convergent validity were assessed using a comprehensive battery of validated phenomenological and clinical scales. CFA on the final 18 items supported two factors for a Methods of Control Scale (5 items each, average ω = .87), and one factor for a Degree of Control Scale (8 items, average ω = .95). Correlation with clinical measures supported convergent validity. Degree of control was associated with positive clinical outcomes in voice-hearers both with and without a psychosis-spectrum diagnosis. Degree of control also varied with quality of life independently of symptom severity and AVH content. The Yale control over perceptual experiences (COPE) Scales robustly measure voice-hearers' control over AVH and exhibit sound psychometric properties. Results demonstrate that the capacity to voluntarily control AVH is independently associated with positive clinical outcomes. Reliable measurement of control over AVH will enable future development of interventions meant to bolster that control.

Cardiac autonomic neuropathy in patients with diabetes mellitus: current perspectives.

Cardiac autonomic neuropathy (CAN) is a common and often-underdiagnosed complication of diabetes mellitus (DM). CAN is associated with increased mortality, cardiovascular disease, chronic kidney disease, and morbidity in patients with DM, but despite these significant consequences CAN often remains undiagnosed for a prolonged period. This is commonly due to the disease being asymptomatic until the later stages, as well as a lack of easily available screening strategies. In this article, we review the latest developments in the epidemiology, pathogenesis, diagnosis, consequences, and treatments of CAN in patients with DM.

Incidence of PR3- and MPO-ANCA autoantibody specificity changes in ANCA-associated vasculitis.

BACKGROUND: Monitoring of anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) in remission usually includes indirect immunofluorescence (IIF), proteinase 3 (PR3)-ANCA and myeloperoxidase (MPO)-ANCA. Typically, PR3 and MPO-ANCA are both performed because patients sometimes switch specificity during follow up. Published data are limited to case reports and incidence of change is not reported. The aim of this study was to quantify the incidence of antibody switching. METHODS: Hull and East Yorkshire Hospitals National Health Service Trust serves a population of 720,000 for ANCA testing. We reviewed all ANCA results from January 2000 to August 2012 to quantify incidence of antibody switching. A total of 22,002 IIF screens (14,518 patients) were performed. A total of 9838 (45%) also had PR3- and MPO-ANCA (6439, 44% of patients). Patients that changed specificity from PR3- to MPO-ANCA and vice versa were identified and case notes reviewed. RESULTS: A total of 218 patients with confirmed AAV positive for PR3/MPO-ANCA were followed for a mean of 2.6 years (range <0.1 to 12.4 years; with 113 (52%) patients followed for >1 year). Five patients (2%) changed specificity during follow up (3 GPA, 1 MPA & 1 EGPA). In two patients this was associated with relapse. Incidence of specificity change was 1 per 82 years (including two reversions to presenting specificity) and one per 286 years for changes associated with relapse. Monitoring using only the initial antibody specificity would have resulted in missed relapse in one patient. CONCLUSION: Antibody specificity changes in AAV are rare. Monitoring only the initial antibody specificity would have missed clinical events but rising C-reactive protein presaged relapse in these cases.

Limited evidence that cancer susceptibility regions are preferential targets for somatic mutation.

BACKGROUND: Genome wide-association studies have successfully identified several hundred independent loci harboring common cancer susceptibility alleles that are distinct from the more than 110 cancer predisposition genes. The latter are generally characterized by disruptive mutations in coding genes that have been established as 'drivers' of cancer in large somatic sequencing studies. We set out to determine whether, similarly, common cancer susceptibility loci map to genes that have altered frequencies of mutation. RESULTS: In our analysis of the intervals defined by the cancer susceptibility markers, we observed that cancer susceptibility regions have gene mutation frequencies comparable to background mutation frequencies. Restricting analyses to genes that have been determined to be pleiotropic across cancer types, genes affected by expression quantitative trait loci, or functional genes indicates that most cancer susceptibility genes classified into these subgroups do not display mutation frequencies that deviate from those expected. We observed limited evidence that cancer susceptibility regions that harbor common alleles with small estimated effect sizes are preferential targets for altered somatic mutation frequencies. CONCLUSIONS: Our findings suggest a complex interplay between germline susceptibility and somatic mutation, underscoring the cumulative effect of common variants on redundant pathways as opposed to driver genes. Complex biological pathways and networks likely link these genetic features of carcinogenesis, particularly as they relate to distinct polygenic models for each cancer type.