Combined approaches, including long-read sequencing, address the diagnostic challenge of HYDIN in primary ciliary dyskinesia.

Primary ciliary dyskinesia (PCD), a disorder of the motile cilia, is now recognised as an underdiagnosed cause of bronchiectasis. Accurate PCD diagnosis comprises clinical assessment, analysis of cilia and the identification of biallelic variants in one of 50 known PCD-related genes, including HYDIN. HYDIN-related PCD is underdiagnosed due to the presence of a pseudogene, HYDIN2, with 98% sequence homology to HYDIN. This presents a significant challenge for Short-Read Next Generation Sequencing (SR-NGS) and analysis, and many diagnostic PCD gene panels do not include HYDIN. We have used a combined approach of SR-NGS with bioinformatic masking of HYDIN2, and state-of-the-art long-read Nanopore sequencing (LR_NGS), together with analysis of respiratory cilia including transmission electron microscopy and immunofluorescence to address the underdiagnosis of HYDIN as a cause of PCD. Bioinformatic masking of HYDIN2 after SR-NGS facilitated the detection of biallelic HYDIN variants in 15 of 437 families, but compromised the detection of copy number variants. Supplementing testing with LR-NGS detected HYDIN deletions in 2 families, where SR-NGS had detected a single heterozygous HYDIN variant. LR-NGS was also able to confirm true homozygosity in 2 families when parental testing was not possible. Utilising a combined genomic diagnostic approach, biallelic HYDIN variants were detected in 17 families from 242 genetically confirmed PCD cases, comprising 7% of our PCD cohort. This represents the largest reported HYDIN cohort to date and highlights previous underdiagnosis of HYDIN-associated PCD. Moreover this provides further evidence for the utility of LR-NGS in diagnostic testing, particularly for regions of high genomic complexity.

Tracking arboviruses, their transmission vectors and potential hosts by nanopore sequencing of mosquitoes.

The risk to human health from mosquito-borne viruses such as dengue, chikungunya and yellow fever is increasing due to increased human expansion, deforestation and climate change. To anticipate and predict the spread and transmission of mosquito-borne viruses, a better understanding of the transmission cycle in mosquito populations is needed. We present a pathogen-agnostic combined sequencing protocol for identifying vectors, viral pathogens and their hosts or reservoirs using portable Oxford Nanopore sequencing. Using mosquitoes collected in São Paulo, Brazil, we extracted RNA for virus identification and DNA for blood meal and mosquito identification. Mosquitoes and blood meals were identified by comparing cytochrome c oxidase I (COI) sequences against a curated Barcode of Life Data System (BOLD). Viruses were identified using the SMART-9N protocol, which allows amplified DNA to be prepared with native barcoding for nanopore sequencing. Kraken 2 was employed to detect viral pathogens and Minimap2 and BOLD identified the contents of the blood meal. Due to the high similarity of some species, mosquito identification was conducted using blast after generation of consensus COI sequences using RACON polishing. This protocol can simultaneously uncover viral diversity, mosquito species and mosquito feeding habits. It also has the potential to increase understanding of mosquito genetic diversity and transmission dynamics of zoonotic mosquito-borne viruses.

Meaning and role of functional-organic distinction: a study of clinicians in psychiatry and neurology services.

The functional-organic distinction attempts to differentiate disorders with diagnosable biological causes from those without and is a central axis on which diagnoses, medical specialities and services are organised. Previous studies report poor agreement between clinicians regarding the meanings of the terms and the conditions to which they apply, as well as noting value-laden implications of relevant diagnoses. Consequently, we aimed to understand how clinicians working in psychiatry and neurology services navigate the functional-organic distinction in their work. Twenty clinicians (10 physicians, 10 psychologists) working in psychiatry and neurology services participated in semistructured interviews that were analysed applying a constructivist grounded theory approach. The distinction was described as often incongruent with how clinicians conceptualise patients' problems. Organic factors were considered to be objective, unambiguously identifiable and clearly causative, whereas functional causes were invisible and to be hypothesised through thinking and conversation. Contextual factors-including cultural assumptions, service demands, patient needs and colleagues' views-were key in how the distinction was deployed in practice. The distinction was considered theoretically unsatisfactory, eventually to be superseded, but clinical decision making required it to be used strategically. These uses included helping communicate medical problems, navigating services, hiding meaning by making psychological explanations more palatable, tackling stigma, giving hope, and giving access to illness identity. Clinicians cited moral issues at both individual and societal levels as integral to the conceptual basis and deployment of the functional-organic distinction and described actively navigating these as part of their work. There was a considerable distance between the status of the functional-organic distinction as a sound theoretical concept generalisable across conditions and its role as a gatekeeping tool within the structures of healthcare. Ambiguity and contradictions were considered as both obstacles and benefits when deployed in practice and strategic considerations were important in deciding which to lean on.

Co-opting the "neuro" in neurodiversity and the complexities of epistemic injustice.

This article tackles the theoretical thinking behind PPI and inclusion, input from people with neurodiverse conditions. By providing a perspective on how the prefix "Neuro" is positioned in a neutral and authoritative way (exemplified through our brief review of articles within Cortex), we explore how "epistemic injustice" (a concept used frequently in law, politics, philosophy and social science) can potentially arise. Epistemic injustice typically refers to a pernicious power dynamic whereby oppressed groups are silenced (Fricker 2007), either because certain voices are not given weight ("testimonial injustice"), or the ways in which they are allowed to speak (e.g., interpret their own experiences) are limited ("hermeneutical injustice") (Kidd and Carel 2016). We show how, for "neurodiversity", the mainstream "neuro" narratives are often positively felt by those deemed to be neurodiverse, and the lines between oppressor and oppressed break down, as both neuroscientists and people with neurodiverse conditions co-opt and influence each other's positions.

Multiplex MinION sequencing suggests enteric adenovirus F41 genetic diversity comparable to pre-COVID-19 era.

Human adenovirus F41 causes acute gastroenteritis in children, and has recently been associated with an apparent increase in paediatric hepatitis of unknown aetiology in the UK, with further cases reported in multiple countries. Relatively little is known about the genetic diversity of adenovirus F41 in UK children; and it is unclear what, if any, impact the COVID-19 pandemic has had on viral diversity in the UK. Methods that allow F41 to be sequenced from clinical samples without the need for viral culture are required to provide the genomic data to address these questions. Therefore, we evaluated an overlapping-amplicon method of sequencing adenovirus genomes from clinical samples using Oxford Nanopore technology. We applied this method to a small sample of adenovirus-species-F-positive extracts collected as part of standard care in the East of England region in January-May 2022. This method produced genomes with >75 % coverage in 13/22 samples and >50 % coverage in 19/22 samples. We identified two F41 lineages present in paediatric patients in the East of England in 2022. Where F41 genomes from paediatric hepatitis cases were available (n=2), these genomes fell within the diversity of F41 from the UK and continental Europe sequenced before and after the 2020-2021 phase of the COVID-19 pandemic. Our analyses suggest that overlapping amplicon sequencing is an appropriate method for generating F41 genomic data from high-virus-load clinical samples, and currently circulating F41 viral lineages were present in the UK and Europe before the COVID-19 pandemic.

Thinking about hallucinations: why philosophy matters.

Introduction: Hallucinations research is increasingly incorporating philosophy or the work of philosophically trained individuals. We present three different ways in which this is successfully implemented to the enhancement of knowledge and understanding of hallucinations and related phenomena.Method: We review contributions from phenomenology, philosophy of cognitive science, and philosophy of science and psychiatry.Results: We demonstrate that these areas of philosophy make significant contributions to hallucinations research. Phenomenology gives us a sophisticated and critical understanding of the lived experience of hallucinations. Philosophy of cognitive science enables big-picture theorising and synthesis of ideas, as well as a critical engagement with new paradigms. Philosophy of science and psychiatry raises valuable and theoretically informed questions about diagnosis and categorisation.Conclusions: These contributions reflect both the methodological variety within philosophy and its relevance to the hallucinations researcher.

Dealing with floppy iris syndrome.

PURPOSE OF REVIEW: The aim of this study was to review and summarize recent findings and advancements regarding intraoperative floppy iris syndrome (IFIS). Although many improvements have been made for the management of IFIS, it remains a challenging condition for surgeons. An understanding of the syndrome as well as the multitude of tools to mitigate risk of complication is important for surgeons operating on high-risk patients. RECENT FINDINGS: A variety of management approaches have been modified and improved or further supported with new data, such as intracameral compounds, intraoperative devices and surgical techniques. SUMMARY: An understanding of risk factors is important for the identification of at-risk patients. A variety of approaches can greatly reduce incidence of IFIS complications. Multiple management strategies should be utilized to further reduce risk during these difficult surgeries.

Derationalizing Delusions.

Because of the traditional conceptualization of delusion as "irrational belief," cognitive models of delusions largely focus on impairments to domain-general reasoning. Nevertheless, current rationality-impairment models do not account for the fact that (a) equivalently irrational beliefs can be induced through adaptive social cognitive processes, reflecting social integration rather than impairment; (b) delusions are overwhelmingly socially themed; and (c) delusions show a reduced sensitivity to social context both in terms of how they are shaped and how they are communicated. Consequently, we argue that models of delusions need to include alteration to coalitional cognition-processes involved in affiliation, group perception, and the strategic management of relationships. This approach has the advantage of better accounting for both content (social themes) and form (fixity) of delusion. It is also supported by the established role of mesolimbic dopamine in both delusions and social organization and the ongoing reconceptualization of belief as serving a social organizational function.

Losing Ourselves: Active Inference, Depersonalization, and Meditation.

Disruptions in the ordinary sense of selfhood underpin both pathological and "enlightened" states of consciousness. People suffering from depersonalization can experience the loss of a sense of self as devastating, often accompanied by intense feelings of alienation, fear, and hopelessness. However, for meditative contemplatives from various traditions, "selfless" experiences are highly sought after, being associated with enduring peace and joy. Little is understood about how these contrasting dysphoric and euphoric experiences should be conceptualized. In this paper, we propose a unified account of these selfless experiences within the active inference framework. Building on our recent active inference research, we propose an account of the experiences of selfhood as emerging from a temporally deep generative model. We go on to develop a view of the self as playing a central role in structuring ordinary experience by "tuning" agents to the counterfactually rich possibilities for action. Finally, we explore how depersonalization may result from an inferred loss of allostatic control and contrast this phenomenology with selfless experiences reported by meditation practitioners. We will show how, by beginning with a conception of self-modeling within an active inference framework, we have available to us a new way of conceptualizing the striking experiential similarities and important differences between these selfless experiences within a unifying theoretical framework. We will explore the implications for understanding and treating dissociative disorders, as well as elucidate both the therapeutic potential, and possible dangers, of meditation.

Distinguishing volumetric content from perceptual presence within a predictive processing framework.

I argue for an overlooked distinction between perceptual presence and volumetric content, and flesh it out in terms of predictive processing. Within the predictive processing framework we can distinguish between agent-active and object-active expectations. The former expectations account for perceptual presence, while the latter account for volumetric content. I then support this position with reference to how experiences of presence are created by virtual reality technologies, and end by reflecting on what this means for the relationship between sensorimotor enactivism and predictive processing.

What is the functional/organic distinction actually doing in psychiatry and neurology?

The functional-organic distinction aims to distinguish symptoms, signs, and syndromes that can be explained by diagnosable biological changes, from those that cannot. The distinction is central to clinical practice and is a key organising principle in diagnostic systems. Following a pragmatist approach that examines meaning through use, we examine how the functional-organic distinction is deployed and conceptualised in psychiatry and neurology. We note that the conceptual scope of the terms 'functional' and 'organic' varies considerably by context. Techniques for differentially diagnosing 'functional' and 'organic' diverge in the strength of evidence they produce as a necessary function of the syndrome in question. Clinicians do not agree on the meaning of the terms and report using them strategically. The distinction often relies on an implied model of 'zero sum' causality and encourages classification of syndromes into discrete 'functional' and 'organic' versions. Although this clearly applies in some instances, this is often in contrast to our best scientific understanding of neuropsychiatric disorders as arising from a dynamic interaction between personal, social and neuropathological factors. We also note 'functional' and 'organic' have loaded social meanings, creating the potential for social disempowerment. Given this, we argue for a better understanding of how strategic simplification and complex scientific reality limit each other in neuropsychiatric thinking. We also note that the contribution of people who experience the interaction between 'functional' and 'organic' factors has rarely informed the validity of this distinction and the dilemmas arising from it, and we highlight this as a research priority.

Medically Unexplained Symptoms and Antecedent Sexual Abuse: An Observational Study of a Birth Cohort.

OBJECTIVE: Medically unexplained symptoms (MUS) are common and associated with high consumption of health care resources. Cross-sectional studies in selected and clinical populations show consistent linkages between history of childhood sexual abuse (CSA) and presentation with MUS and somatization. However, there are almost no well-controlled prospective studies in population samples. METHODS: Data were gathered in a longitudinal study of a New Zealand birth cohort born in 1977. Hospital e-record data for the period 2008-2015 (age, 30-38 years) were searched for a subsample of 408 study participants who were resident in one District Health Board region, and details of MUS contacts were recorded. Retrospective reports of CSA (<16 years) were obtained at ages 18 and 21 years. Associations between CSA and MUS were sequentially adjusted using logistic regression methods for both childhood confounders assessed before age 16 years and potential mediating mental health/family context up to age 30 years. RESULTS: Twenty (4.9%) participants were classified as having MUS, of whom 11 had a history of CSA. Severe CSA involving attempted/completed sexual penetration was strongly associated with risk of MUS (odds ratio = 11.6, 95% confidence interval = 4.3-31.7, p < .001). A substantial association remained after statistically adjusting for confounding and mediating mental health/family context (adjusted odds ratio = 5.1, 95% confidence interval = 1.2-21.3, p = .024). This strong association was specific to severe CSA (as opposed to childhood physical abuse) and to MUS rather than medically explained symptoms. CONCLUSIONS: CSA involving attempted/completed penetration was strongly associated with attendance at secondary level care for MUS. Implications for prevention and treatment of MUS are discussed.

Influence of covariates on heterogeneity in Hamilton Anxiety Scale ratings in placebo-controlled trials of benzodiazepines in generalized anxiety disorder: Systematic review and meta-analysis.

BACKGROUND: Generalized anxiety disorder is a common psychiatric condition that is associated with decreased quality of life and significant disability. Benzodiazepines are anti-anxiety drugs used widely in the treatment of generalized anxiety disorder. This study examines the influence of several variables on benzodiazepine efficacy in generalized anxiety disorder. METHOD: We performed a systematic review of placebo-controlled randomized controlled trials with benzodiazepines in generalized anxiety disorder. Fifty-eight studies were deemed eligible to include in the meta-analysis. The studies dated from 1977 to 2013 and included over 5400 participants. From each paper, we extracted: benzodiazepine name and dose, dosing regimen, baseline Hamilton Anxiety Scale (HAM-A) score, change in HAM-A score at study endpoint, drop-out rate, year of study publication, diagnostic criteria used, study size, study duration, location, any conflicts of interest and side-effect profile. We then assessed the influence, direct and indirect, of individual variables on the primary outcome (mean difference at endpoint, HAM-A score). RESULTS: Three factors were shown to be associated statistically with change in HAM-A; baseline HAM-A for benzodiazepine arm, baseline HAM-A for the placebo arm, and duration of the study. A higher baseline HAM-A in both arms was associated with a greater mean difference in HAM-A. A shorter study length was also associated with a greater mean difference. DISCUSSION: The major factors determining benzodiazepine response was baseline anxiety level for the benzodiazepine arm and study duration. In any design of further meta-analyses and clinical trials for generalized anxiety disorder we suggest that these should be considered these as confounding factors.

The ice in voices: Understanding negative content in auditory-verbal hallucinations.

Negative voice-content is the best sole predictor of whether the hearer of an auditory-verbal hallucination will experience distress/impairment necessitating contact with mental health services. Yet, what causes negative voice-content and how interventions may reduce it remains poorly understood. This paper offers definitions of negative voice content and considers what may cause negative voice-content. We propose a framework in which adverse life-events may underpin much negative voice-content, a relation which may be mediated by mechanisms including hypervigilance, reduced social rank, shame and self-blame, dissociation, and altered emotional processing. At a neurological level, we note how the involvement of the amygdala and right Broca's area could drive negative voice-content. We observe that negative interactions between hearers and their voices may further drive negative voice-content. Finally, we consider the role of culture in shaping negative voice-content. This framework is intended to deepen and extend cognitive models of voice-hearing and spur further development of psychological interventions for those distressed by such voices. We note that much of the relevant research in this area remains to be performed or replicated. We conclude that more attention needs to be paid to methods for reducing negative voice-content, and urge further research in this important area.

Antidepressant prescribing in New Zealand between 2008 and 2015.

AIM: To examine antidepressant prescribing trends in New Zealand adults from 2008-2015. METHODS: Antidepressant prescribing data was sourced via the Ministry of Health. Data were examined by year, type of drug, ethnicity, gender, age and location of district health board. RESULTS: All individuals dispensed an antidepressant in New Zealand were included. In 2015, 12.6% of all New Zealanders were prescribed an antidepressant (16% of females and 9% of males) an increase of 21% from 2008. The largest increase in drug classes were venlafaxine and tetracyclic antidepressants. The largest class of drugs prescribed were SSRIs, which made up 57% of the total. Europeans were the most likely to receive antidepressants at 15.7%, but increases were seen across all ethnic categories. The highest users were older European females at 22.8%. CONCLUSIONS: Antidepressant prescribing rates continue to increase in New Zealand although this rate of increase is slowing. The highest users were European women, particularly those age 65 and older.

Antipsychotic prescribing in New Zealand between 2008 and 2015.

AIM: To examine antipsychotic prescribing trends in New Zealand adults from 2008-2015. METHODS: Antipsychotic prescribing data was sourced via the Ministry of Health. Data were examined by year, type of drug, ethnicity, gender, age and location of district health board. RESULTS: All individuals dispensed an antipsychotic were included. Rates of antipsychotic prescribing rose from 1.88% to 2.81%, an increase of 49% over the seven years. Most of the increase was in atypical antipsychotics (particularly quetiapine and olanzapine), which accounted for 82% of total antipsychotics in 2015. Maori were prescribed more antipsychotics than non-Maori. Asian people had the lowest rate of prescribing (0.86%). The highest rate of antipsychotic use was in European females aged 65 plus. CONCLUSION: Rates of antipsychotic prescription are increasing. Most of this change is in prescribing atypical antipsychotics. Young Maori males and elderly European females are most likely to receive antipsychotics.

The varieties of inner speech questionnaire - Revised (VISQ-R): Replicating and refining links between inner speech and psychopathology.

Inner speech is a common experience for many but hard to measure empirically. The Varieties of Inner Speech Questionnaire (VISQ) has been used to link everyday phenomenology of inner speech - such as inner dialogue - to various psychopathological traits. However, positive and supportive aspects of inner speech have not always been captured. This study presents a revised version of the scale - the VISQ-R - based on factor analyses in two large samples: respondents to a survey on inner speech and reading (N = 1412) and a sample of university students (N = 377). Exploratory factor analysis indicated a five-factor structure including three previous subscales (dialogic, condensed, and other people in inner speech), an evaluative/critical factor, and a new positive/regulatory factor. Confirmatory factor analysis then replicated this structure in sample 2. Hierarchical regression analyses also replicated a number of relations between inner speech, hallucination-proneness, anxiety, depression, self-esteem, and dissociation.

CardioClassifier: disease- and gene-specific computational decision support for clinical genome interpretation.

PURPOSE: Internationally adopted variant interpretation guidelines from the American College of Medical Genetics and Genomics (ACMG) are generic and require disease-specific refinement. Here we developed CardioClassifier ( http://www.cardioclassifier.org ), a semiautomated decision-support tool for inherited cardiac conditions (ICCs). METHODS: CardioClassifier integrates data retrieved from multiple sources with user-input case-specific information, through an interactive interface, to support variant interpretation. Combining disease- and gene-specific knowledge with variant observations in large cohorts of cases and controls, we refined 14 computational ACMG criteria and created three ICC-specific rules. RESULTS: We benchmarked CardioClassifier on 57 expertly curated variants and show full retrieval of all computational data, concordantly activating 87.3% of rules. A generic annotation tool identified fewer than half as many clinically actionable variants (64/219 vs. 156/219, Fisher's P = 1.1 × 10-18), with important false positives, illustrating the critical importance of disease and gene-specific annotations. CardioClassifier identified putatively disease-causing variants in 33.7% of 327 cardiomyopathy cases, comparable with leading ICC laboratories. Through addition of manually curated data, variants found in over 40% of cardiomyopathy cases are fully annotated, without requiring additional user-input data. CONCLUSION: CardioClassifier is an ICC-specific decision-support tool that integrates expertly curated computational annotations with case-specific data to generate fast, reproducible, and interactive variant pathogenicity reports, according to best practice guidelines.