Service users' preferences and feasibility - which alternative care pathway for adult ambulance users achieves the optimal balance? Workshops for the COLLABORATE project.

INTRODUCTION: Adults presenting to the ambulance service for diagnosed epilepsy are often transported to emergency departments (EDs) despite no clinical need. An alternative care pathway (CP) could allow paramedics to divert them from ED and instigate ambulatory care improvements. To identify the most promising CP configuration for subsequent testing, the COLLABORATE project surveyed people with epilepsy and family/friends who had recently used the English ambulance service to elicit preferences for 288 CP configurations for different seizures. This allowed CPs to be ranked according to alignment with service users' preferences. However, as well as being acceptable to users, a CP must be feasible. We thus engaged with paramedics, epilepsy specialists and commissioners to identify the optimal configuration. METHODS: Three Knowledge Exchange workshops completed. Participants considered COLLABORATE's evidence on service users' preferences for the different configurations. Nominal group techniques elicited views on the feasibility of users' preferences according to APEASE criteria. Workshop groups specified the configuration/s considered optimum. Qualitative data was analysed thematically. Utility to users of the specified CP configurations estimated using the COLLABORATE preference survey data. RESULTS: Twenty-seven participants found service users' preferences broadly feasible and outlined delivery recommendations. They identified enough commonality in preferences for different seizures to propose a single CP. Its configuration comprised: 1) patients staying where they were; 2) paramedics having access to medical records; 3) care episodes lasting <6 h; 4) paramedics receiving specialist advice on the day; 5) patient's GP being notified; and 6) a follow-up appointment being arranged with an epilepsy specialist. Preference data indicated higher utility for this configuration compared to current care. DISCUSSION: Stakeholders are of the view that the CP configuration favoured by service users could be NHS feasible. It should be developed and evaluated.

Developing an alternative care pathway for emergency ambulance responses for adults with epilepsy: A Discrete Choice Experiment to understand which configuration service users prefer. Part of the COLLABORATE project.

INTRODUCTION: To identify service users' preferences for an alternative care pathway for adults with epilepsy presenting to the ambulance service. METHODS: Extensive formative work (qualitative, survey and knowledge exchange) informed the design of a stated preference discrete choice experiment (DCE). This hypothetical survey was hosted online and consisted of 12 binary choices of alternative care pathways described in terms of: the paramedic's access to medical records/ 'care plan', what happens next (described in terms of conveyance), time, availability of epilepsy specialists today, general practitioner (GP) notification and future contact with epilepsy specialists. DCE scenarios were described as: (i) typical seizure at home. (ii) typical seizure in public, (iii) atypical seizure. Respondents were recruited by a regional English ambulance service and by national public adverts. Participants were randomised to complete 2 of the 3 DCEs. RESULTS: People with epilepsy (PWE; n = 427) and friends/family (n = 167) who completed the survey were representative of the target population. PWE preferred paramedics to have access to medical records, non-conveyance, to avoid lengthy episodes of care, availability of epilepsy specialists today, GP notification, and contact with epilepsy specialists within 2-3 weeks. Significant others (close family members or friends) preferred PWE experiencing an atypical seizure to be conveyed to an Urgent Treatment Centre and preferred shorter times. Optimal configuration of services from service users' perspective far out ranked current practice (rank 230/288 possible configurations). DISCUSSION: Preferences differ to current practice but have minimal variation by seizure type or stakeholder. Further work on feasibility of these pathways in England, and potentially beyond, is required.

The impact of stigma on the management of type 1 diabetes: A systematic review.

AIMS: To systematically review the literature investigating the links between stigma and the management of type 1 diabetes. METHODS: A systematic literature review was conducted in accordance with PRISMA guidelines. Both quantitative and qualitative data were considered. Included papers were subject to quality assessment using the Mixed Methods Appraisal Tool (MMAT), and a narrative synthesis of results was reported. RESULTS: Nineteen articles met the inclusion criteria and were included in the final analysis. Amongst these, one study used mixed methods, nine were qualitative, and nine were quantitative. All studies found a negative relationship between stigma and type 1 diabetes management. Qualitative studies provided a further understanding of the effects observed in the quantitative studies and found that stigma can affect self-care activities, disclosure of diabetes, and the uptake of diabetes technology. Systemic causes of stigma and intersectional stigma were also observed. CONCLUSIONS: This review highlights that people with type 1 diabetes are negatively affected by stigma, irrespective of their age, gender, culture, or use of diabetes technology. Quantitative studies were limited, in that all studies were cross-sectional, and there was a lack of standardisation across outcome measures. There is a need for interventions to target stigma on both an individual and a systemic level, particularly where people experience multiple intersecting stigmas.

"You Forget to Apply It to Staff": A Compassion-Focused Group for Mental Health Inpatient Staff. An Exploration of the Barriers to Attendance.

This study explored the feasibility and acceptability of an experiential compassion-focused group intervention for mental health inpatient staff. Findings demonstrated that although participants found sessions enjoyable, and reported a number of benefits, the group attrition was high. Semi-structured interviews were conducted to explore issues related to group dropout. Thematic analysis highlighted overarching systemic challenges to attendance, and five key themes emerged: The Nature of the Ward; Slowing Down Is Not Allowed; It is Not in Our Nature; Guilt & Threat; We Are Not Important. Clinical implications, limitations and practice recommendations to support group attendance are also addressed.

Psychosocial factors associated with repeat diabetic ketoacidosis in people living with type 1 diabetes: A systematic review.

AIM: To systematically review the literature concerning the psychosocial factors associated with repeat diabetic ketoacidosis for people living with type 1 diabetes. METHODS: PsycInfo, Web of Science, CINAHL, PubMed and ASSIA were searched according to a registered study protocol (PROSPERO CRD42020167381). Data were extracted into a coding spreadsheet, and findings were synthesised narratively. Included papers were also subject to a quality assessment. RESULTS: The search yielded 548 unique articles, of which 22 met inclusion criteria for this review. There was considerable variance across studies with regard to design, quality and outcome measured. Nevertheless, there was relatively consistent evidence to suggest that repeat diabetic ketoacidosis in type 1 diabetes is associated with female gender, adolescent to young adult age range, lower socio-economic status and poor mental health. Some evidence was also observed for the role of ethnicity and, for children and young people at least, family, social and behavioural issues. However, this was limited by issues of methodological rigour and scant investigation. CONCLUSIONS: The review identified four psychosocial factors that appear to play a key role in the cycle of repeat diabetic ketoacidosis. Individuals with these factors present may benefit from targeted support and interventions by specialist healthcare professionals. Knowledge and understanding in this area would be considerably enhanced via increased use of prospective study designs and greater consistency in the operationalisation of variables across studies.

The ethnic density effect in psychosis: a systematic review and multilevel meta-analysis.

BACKGROUND: An 'ethnic' or 'group' density effect in psychosis has been observed, whereby the risk of psychosis in minority group individuals is inversely related to neighbourhood-level proportions of others belonging to the same group. However, there is conflicting evidence over whether this effect differs between minority groups and limited investigation into other moderators. AIMS: To conduct a comprehensive systematic review and meta-analysis of the group density effect in psychosis and examine moderators. METHOD: Four databases were systematically searched. A narrative review was conducted and a three-level meta-analysis was performed. The potential moderating effect of crudely and specifically defined minority groups was assessed. Country, time, area size and whether studies used clinical or non-clinical outcomes were also tested as moderators. RESULTS: Thirty-two studies were included in the narrative review and ten in the meta-analysis. A 10 percentage-point decrease in own-group density was associated with a 20% increase in psychosis risk (OR = 1.20, 95% CI 1.09-1.32, P < 0.001). This was moderated by crudely defined minority groups (F6,68 = 6.86, P < 0.001), with the strongest associations observed in Black populations, followed by a White Other sample. Greater heterogeneity was observed when specific minority groups were assessed (F25,49 = 7.26, P < 0.001). CONCLUSIONS: This is the first review to provide meta-analytic evidence that the risk of psychosis posed by lower own-group density varies across minority groups, with the strongest associations observed in Black individuals. Heterogeneity in effect sizes may reflect distinctive social experiences of specific minority groups. Potential mechanisms are discussed, along with the implications of findings and suggestions for future research.

Need for care, adversity exposure and perceived stress in clinical and healthy voice-hearers.

OBJECTIVES: Psychosis, and in particular auditory verbal hallucinations (AVHs), are associated with adversity exposure. However, AVHs also occur in populations with no need for care or distress. AIMS: This study investigated whether adversity exposure would differentiate clinical and healthy voice-hearers within the context of a 'three-hit' model of vulnerability and stress exposure. METHODS: Samples of 57 clinical and 45 healthy voice-hearers were compared on the three 'hits': familial risk; adversity exposure in childhood and in adolescence/adulthood. RESULTS: Clinical voice-hearers showed greater familial risk than healthy voice-hearers, with more family members with a history of psychosis, but not with other mental disorders. The two groups did not differ in their exposure to adversity in childhood [sexual and non-sexual, victimisation; discrimination and socio-economic status (SES)]. Contrary to expectations, clinical voice-hearers did not differ from healthy voice-hearers in their exposure to victimisation (sexual/non-sexual) and discrimination in adolescence/adulthood, but reported more cannabis and substance misuse, and lower SES. CONCLUSIONS: The current study found no evidence that clinical and healthy voice-hearers differ in lifetime victimisation exposure, suggesting victimisation may be linked to the emergence of AVHs generally, rather than need-for-care. Familial risk, substance misuse and lower SES may be additional risk factors involved in the emergence of need-for-care and distress.

Beliefs about voices in voice-hearers: the role of schema functioning.

BACKGROUND: Evidence is emerging that beliefs about voices are influenced by broader schematic beliefs about the self and others. Similarly, studies indicate that the relationship an individual has with their voice may mirror wider patterns of relating observed in social relationships, which may be influenced by schematic beliefs. AIMS: This study examined associations between beliefs about voices and self and other schemas. Furthermore, associations between schemas and the perceived relationship between the hearer and their predominant voice were explored. METHOD: Forty-four voice-hearing participants were recruited across mental health services. Participants completed self-report measures of beliefs about voices, schema functioning, and relating between the hearer and their voice. Dimensions of voice experience, such as frequency and content, were assessed using a clinician-rated scale. RESULTS: Beliefs about voices correlated with negative voice content and schemas. After controlling for negative voice content, schemas were estimated to predict between 1 and 17% of the variance in the six measured beliefs about voices; three of the associations reached statistical significance. Negative-self schema were the strongest predictors of beliefs about voices, whilst positive-self also showed potential relationships. Schemas also correlated with dimensions of relating between the hearer and their voice. CONCLUSIONS: In line with previous research, this study provides evidence that schemas, particularly self-schema, may be important in the development of beliefs about voices. This study offers preliminary findings to suggest that schemas are also associated with the perceived relationship between the hearer and their voice.

Clinically unnecessary and avoidable emergency health service use for epilepsy: A survey of what English services are doing to reduce it.

PURPOSE: Epilepsy is associated with costly unplanned health service use. The UK's National Audits of Seizure Management in Hospital found use was often clinically unnecessary, avoidable and typically led to little benefit for epilepsy management. We systematically identified how services have responded to reduce such use. METHODS: We invited England's ambulance services, neuroscience and neurology centres and a random sample of Emergency Departments (EDs) to complete a survey. It asked what innovations they (or services they worked with) had made in the past 5 years or were making, the priority afforded to them, user involvement, what comprised usual practice, and barriers to change. RESULTS: 72/87 of invited (82.8 %) services responded. EDs ascribed less priority to reducing emergency hospital use for epilepsy and convulsions, than other service types. Overall, 60 % of services reported a change(s) and/or were planning one. Neurology/neuroscience sites (93.8 %) were most likely to report change; EDs (15.4 %) least likely. Eleven types of change were identified; 5 sought to promote proactive epilepsy care and avert the need for emergency care; 3 focused on the care received from emergency services; and 3 focused on follow-up care ED attendees received. Most were for those with established, rather than new epilepsy and targeted known limitations to current care provision. CONCLUSION: Reducing emergency hospital use by PWE is a high priority for most health services in England and a number of new services have been developed. However, they have not been consistently implemented and innovation is lacking in some areas of care.

The auditory-verbal hallucinations of Welsh-English bilingual people.

OBJECTIVES: Psychological models of voice-hearing propose that auditory-verbal hallucinations occur when inner speech is attributed to a source external to the self. Approximately half of the world's population is multilingual, and the extent to which they use a second language for inner speech depends on their experience and competency in it. Bilingualism therefore provides a natural window into the processes operating in auditory-verbal hallucinations, but no systematic study of voice-hearing in bilinguals has hitherto been conducted. DESIGN: A mixed-methods observational study of psychiatric service users who hear voices and who are Welsh-English bilingual. METHODS: Thirty-seven participants were interviewed about their history and use of Welsh and English and divided into three groups: those who learnt Welsh first (L1 Welsh), those who learnt English first (L1 English), and those who learnt the two languages simultaneously. Detailed phenomenological data were collected using The Mental Health Research Institute Unusual Perceptions Schedule. RESULTS: Both qualitative and quantitative data indicated very considerable variation in the extent to which voices were in Welsh, English, or both, with some voice-hearers reporting that the predominant language of their voices had changed with time. There were modest but statistically significant associations between the predominant language of voices and age of language acquisition (late Welsh learners did not hear voices in Welsh), frequency of language use (more frequent use of Welsh was associated with more Welsh voices), and subjective language proficiency (proficiency in English was associated with a tendency to hear English voices). CONCLUSIONS: Although this was a small study, it was the first of its kind. There is a need for more research on the implications of bilingualism for psychosis in particular and mental illness more generally. The results are broadly consistent with the hypothesis that hallucinated voices are misattributed inner speech. PRACTITIONER POINTS: Assessments of people with mental health difficulties should routinely inquire whether they are multilingual and, if so, which language they prefer to use. People with mental health difficulties may have difficulty expressing complex issues and emotions in a second language, despite apparent fluency. When working with bilingual people who hear voices, mental health professionals should consider the language used by the voices when conducting assessments and proposing formulations.

Clinical and theoretical relevance of responses to analogues of psychotic experiences in people with psychotic experiences with and without a need-for-care: an experimental study.

BACKGROUND: Certain ways of responding to psychotic experiences (PEs) appear more commonly associated with clinical distress (e.g. avoidance) and other ways with benign or positive outcomes (e.g. reappraisal and acceptance). Past research has largely been limited to retrospective self-report. We aimed to compare clinical and non-clinical individuals on experimental analogues of anomalous experiences. METHOD: Response styles of two groups with persistent PEs (clinical n = 84; non-clinical n = 92) and a control group without PEs (n = 83) were compared following experimental analogues of thought interference (Cards Task, Telepath) and hearing voices (Virtual Acoustic Space Paradigm). RESULTS: The non-clinical group with PEs were less likely to endorse unhelpful response styles, such as passive responding or attempts to avoid, suppress, worry about or control mental experiences, compared with the clinical group on all three tasks. The clinical group were more likely to endorse unhelpful response styles compared with controls on two out of three tasks (Cards Task and Telepath). The non-clinical group performed similarly to controls on unhelpful responding across all tasks. There were no group differences for helpful response styles, such as cognitive reappraisal or mindful acceptance of experiences. CONCLUSIONS: In line with cognitive models of psychosis, the findings suggest that the way in which individuals respond to unusual experiences may be an important factor in understanding clinical distress, supporting the therapeutic rationale of targeting potentially unhelpful patterns of response.

Evaluating deciduous tree leaves as biomonitors for ambient particulate matter pollution in Pittsburgh, PA, USA.

Fine particulate matter (PM2.5) air pollution varies spatially and temporally in concentration and composition and has been shown to cause or exacerbate adverse effects on human and ecological health. Biomonitoring using airborne tree leaf deposition as a proxy for particulate matter (PM) pollution has been explored using a variety of study designs, tree species, sampling strategies, and analytical methods. In the USA, relatively few have applied these methods using co-located fine particulate measurements for comparison and relying on one tree species with extensive spatial coverage, to capture spatial variation in ambient air pollution across an urban area. Here, we evaluate the utility of this approach, using a spatial saturation design and pairing tree leaf samples with filter-based PM2.5 across Pittsburgh, Pennsylvania, with the goal of distinguishing mobile and stationary sources using PM2.5 composition. Co-located filter and leaf-based measurements revealed some significant associations with traffic and roadway proximity indicators. We compared filter and leaf samples with differing protection from the elements (e.g., meteorology) and PM collection time, which may account for some variance in PM source and/or particle size capture between samples. To our knowledge, this study is among the first to use deciduous tree leaves from a single tree species as biomonitors for urban PM2.5 pollution in the northeastern USA.

Developing patient-centred, feasible alternative care for adult emergency department users with epilepsy: protocol for the mixed-methods observational 'Collaborate' project.

INTRODUCTION: Emergency department (ED) visits for epilepsy are common, costly, often clinically unnecessary and typically lead to little benefit for epilepsy management. An 'Alternative Care Pathway' (ACP) for epilepsy, which diverts people with epilepsy (PWE) away from ED when '999' is called and leads to care elsewhere, might generate savings and facilitate improved ambulatory care. It is unknown though what features it should incorporate to make it acceptable to persons from this particularly vulnerable target population. It also needs to be National Health Service (NHS) feasible. This project seeks to identify the optimal ACP configuration. METHODS AND ANALYSIS: Mixed-methods project comprising three-linked stages. In Stage 1, NHS bodies will be surveyed on ACPs they are considering and semi-structured interviews with PWE and their carers will explore attributes of care important to them and their concerns and expectations regarding ACPs. In Stage 2, Discrete Choice Experiments (DCE) will be completed with PWE and carers to identify the relative importance placed on different care attributes under common seizure scenarios and the trade-offs people are willing to make. The uptake of different ACP configurations will be estimated. In Stage 3, two Knowledge Exchange workshops using a nominal group technique will be run. NHS managers, health professionals, commissioners and patient and carer representatives will discuss DCE results and form a consensus on which ACP configuration best meets users' needs and is NHS feasible. ETHICS AND DISSEMINATION: Ethical approval: NRES Committee (19/WM/0012) and King's College London ethics Committee (LRS-18/19-10353). Primary output will be identification of optimal ACP configuration which should be prioritised for implementation and evaluation. A pro-active dissemination strategy will make those considering developing or supporting an epilepsy ACP aware of the project and opportunities to take part in it. It will also ensure they are informed of its findings. PROJECT REGISTRATION NUMBER: Researchregistry4723.

Overgeneral autobiographical memory bias in clinical and non-clinical voice hearers.

BACKGROUND: Hearing voices can be a distressing and disabling experience for some, whilst it is a valued experience for others, so-called 'healthy voice-hearers'. Cognitive models of psychosis highlight the role of memory, appraisal and cognitive biases in determining emotional and behavioural responses to voices. A memory bias potentially associated with distressing voices is the overgeneral memory bias (OGM), namely the tendency to recall a summary of events rather than specific occasions. It may limit access to autobiographical information that could be helpful in re-appraising distressing experiences, including voices. METHODS: We investigated the possible links between OGM and distressing voices in psychosis by comparing three groups: (1) clinical voice-hearers (N = 39), (2) non-clinical voice-hearers (N = 35) and (3) controls without voices (N = 77) on a standard version of the autobiographical memory test (AMT). Clinical and non-clinical voice-hearers also completed a newly adapted version of the task, designed to assess voices-related memories (vAMT). RESULTS: As hypothesised, the clinical group displayed an OGM bias by retrieving fewer specific autobiographical memories on the AMT compared with both the non-clinical and control groups, who did not differ from each other. The clinical group also showed an OGM bias in recall of voice-related memories on the vAMT, compared with the non-clinical group. CONCLUSIONS: Clinical voice-hearers display an OGM bias when compared with non-clinical voice-hearers on both general and voices-specific recall tasks. These findings have implications for the refinement and targeting of psychological interventions for psychosis.

Data-Gathering, Belief Flexibility, and Reasoning Across the Psychosis Continuum.

Background: There is evidence for a group of nonclinical individuals with full-blown, persistent psychotic experiences (PEs) but no need-for-care: they are of particular importance in identifying risk and protective factors for clinical psychosis. The aim of this study was to investigate whether reasoning biases are related to PEs or need-for-care. Method: Two groups with persistent PEs (clinical; n = 74; nonclinical; n = 92) and a control group without PEs (n = 83) were compared on jumping-to-conclusions (JTC) and belief flexibility. A randomly selected subset of interviews (n = 104) was analyzed to examine differences in experiential and rational reasoning. Results: As predicted JTC was more common in the clinical than the other 2 groups. Unexpectedly no group differences were observed between clinical and nonclinical groups on measures of belief flexibility. However, the clinical group was less likely to employ rational reasoning, while the nonclinical group was more likely to use experiential reasoning plus a combination of both types of reasoning processes, compared to the other 2 groups. Conclusions: Reasoning biases differ in groups with PEs with and without need-for-care. JTC is associated with need-for-care rather than with PEs. The ability to invoke rational reasoning processes, together with an absence of JTC, may protect against pathological outcomes of persistent PEs. However, marked use of experiential reasoning is associated with the occurrence of PEs in both clinical and nonclinical groups. Implications for theory development, intervention and further research are discussed.

Clinical relevance of appraisals of persistent psychotic experiences in people with and without a need for care: an experimental study.

BACKGROUND: Cognitive models of psychosis propose that appraisals (ie, the interpretation and meaning attributed to experiences) are central to the transition from anomalous experiences to psychotic symptoms. In the Unusual Experiences Enquiry (UNIQUE) study, we investigated the role of appraisals by comparing individuals with persistent psychotic experiences without a need for care with patients and people without psychotic experiences. METHOD: Eligible participants were patients with diagnosed psychotic disorders (clinical group) and adults in the general population with persistent psychotic experiences (non-clinical group) and without psychotic experiences (controls). The appraisals of psychotic experiences among people in the non-clinical and clinical groups were assessed by an in-depth interview, and appraisals of anomalous experiences induced by three experimental tasks were compared between all groups. FINDINGS: We recruited 259 participants, 84 in the clinical group, 92 in the non-clinical group, and 83 controls. The clinical group was more likely than the non-clinical group to display paranoid, personalising interpretations of their psychotic experiences (p<0·008; p values are Sidak adjusted to account for multiple testing) and less likely to have normalising (p<0·008) and supernatural (p=0·039) explanations. The clinical group also appraised their psychotic experiences as being more negative, dangerous, and abnormal and less controllable than the non-clinical group (all p<0·005), but groups did not differ for attributions of general externality (p=0·44). For experimentally induced anomalous experiences, the clinical group endorsed more threatening appraisals on all tasks than the non-clinical group (p<0·003), who did not differ from the control group (p=0·07-0·6). The pattern was similar for ratings of salience, distress, personal relevance, global threat, and incorporation of the induced experiences into participants' own psychotic experiences. INTERPRETATION: We provide robust evidence that the way psychotic experiences are appraised differs between individuals with and without a need for care, supporting cognitive models of psychosis. Specifically, the absence of paranoid and threatening appraisals might protect against persistent psychotic experiences becoming clinically relevant. FUNDING: UK Medical Research Council.

MicroRNA-200b regulates distal airway development by maintaining epithelial integrity.

miR-200b plays a role in epithelial-to-mesenchymal transition (EMT) in cancer. We recently reported abnormal expression of miR-200b in the context of human pulmonary hypoplasia in congenital diaphragmatic hernia (CDH). Smaller lung size, a lower number of airway generations, and a thicker mesenchyme characterize pulmonary hypoplasia in CDH. The aim of this study was to define the role of miR-200b during lung development. Here we show that miR-200b-/- mice have abnormal lung function due to dysfunctional surfactant, increased fibroblast-like cells and thicker mesenchyme in between the alveolar walls. We profiled the lung transcriptome in miR-200b-/- mice, and, using Gene Ontology analysis, we determined that the most affected biological processes include cell cycle, apoptosis and protein transport. Our results demonstrate that miR-200b regulates distal airway development through maintaining an epithelial cell phenotype. The lung abnormalities observed in miR-200b-/- mice recapitulate lung hypoplasia in CDH.

Mutations in HYAL2, Encoding Hyaluronidase 2, Cause a Syndrome of Orofacial Clefting and Cor Triatriatum Sinister in Humans and Mice.

Orofacial clefting is amongst the most common of birth defects, with both genetic and environmental components. Although numerous studies have been undertaken to investigate the complexities of the genetic etiology of this heterogeneous condition, this factor remains incompletely understood. Here, we describe mutations in the HYAL2 gene as a cause of syndromic orofacial clefting. HYAL2, encoding hyaluronidase 2, degrades extracellular hyaluronan, a critical component of the developing heart and palatal shelf matrix. Transfection assays demonstrated that the gene mutations destabilize the molecule, dramatically reducing HYAL2 protein levels. Consistent with the clinical presentation in affected individuals, investigations of Hyal2-/- mice revealed craniofacial abnormalities, including submucosal cleft palate. In addition, cor triatriatum sinister and hearing loss, identified in a proportion of Hyal2-/- mice, were also found as incompletely penetrant features in affected humans. Taken together our findings identify a new genetic cause of orofacial clefting in humans and mice, and define the first molecular cause of human cor triatriatum sinister, illustrating the fundamental importance of HYAL2 and hyaluronan turnover for normal human and mouse development.