Gastroschisis prevalence patterns in 27 surveillance programs from 24 countries, International Clearinghouse for Birth Defects Surveillance and Research, 1980-2017.

BACKGROUND: Gastroschisis is a serious birth defect with midgut prolapse into the amniotic cavity. The objectives of this study were to evaluate the prevalence and time trends of gastroschisis among programs in the International Clearinghouse for Birth Defects Surveillance and Research (ICBDSR), focusing on regional variations and maternal age changes in the population. METHODS: We analyzed data on births from 1980 to 2017 from 27 ICBDSR member programs, representing 24 countries and three regions (Europe+ (includes Iran) , Latin America, North America). Cases were identified using diagnostic codes (i.e., 756.7, 756.71, or Q79.3). We excluded cases of amniotic band syndrome, limb-body wall defect, and ruptured omphalocele. Programs provided annual counts for gastroschisis cases (live births, stillbirths, and legally permitted pregnancy terminations for fetal anomalies) and source population (live births, stillbirths), by maternal age. RESULTS: Overall, gastroschisis occurred in 1 of every 3268 births (3.06 per 10,000 births; 95% confidence intervals [CI]: 3.01, 3.11), with marked regional variation. European+ prevalence was 1.49 (95%CI: 1.44, 1.55), Latin American 3.80 (95%CI: 3.69, 3.92) and North American 4.32 (95%CI: 4.22, 4.42). A statistically significant increasing time trend was observed among six European+ , four Latin American, and four North American programs. Women <20 years of age had the highest prevalence in all programs except the Slovak Republic. CONCLUSIONS: Gastroschisis prevalence increased over time in 61% of participating programs, and the highest increase in prevalence was observed among the youngest women. Additional inquiry will help to assess the impact of the changing maternal age proportions in the birth population on gastroschisis prevalence.

Novel molecular mechanism in Malan syndrome uncovered through genome sequencing reanalysis, exon-level Array, and RNA sequencing.

The NFIX gene encodes a DNA-binding protein belonging to the nuclear factor one (NFI) family of transcription factors. Pathogenic variants of NFIX are associated with two autosomal dominant Mendelian disorders, Malan syndrome (MIM 614753) and Marshall-Smith syndrome (MIM 602535), which are clinically distinct due to different disease-causing mechanisms. NFIX variants associated with Malan syndrome are missense variants mostly located in exon 2 encoding the N-terminal DNA binding and dimerization domain or are protein-truncating variants that trigger nonsense-mediated mRNA decay (NMD) resulting in NFIX haploinsufficiency. NFIX variants associated with Marshall-Smith syndrome are protein-truncating and are clustered between exons 6 and 10, including a recurrent Alu-mediated deletion of exons 6 and 7, which can escape NMD. The more severe phenotype of Marshall-Smith syndrome is likely due to a dominant-negative effect of these protein-truncating variants that escape NMD. Here, we report a child with clinical features of Malan syndrome who has a de novo NFIX intragenic duplication. Using genome sequencing, exon-level microarray analysis, and RNA sequencing, we show that this duplication encompasses exons 6 and 7 and leads to NFIX haploinsufficiency. To our knowledge, this is the first reported case of Malan Syndrome caused by an intragenic NFIX duplication.

Dating Violence and Mental Health in Emerging Adulthood.

Dating violence constitutes a serious social and health problem. This study aims to increase knowledge on dating violence in emerging adulthood by analysing the relevance of gender and of having or not having a current partner in the victimization and perpetration of such violence. It also analyses the association between dating violence and mental health, as well as the relevance of traditional gender role attitudes and the internalization of feminine/expressive and masculine/instrumental traits in the victimization and perpetration of such types of violence. The participants were 930 Spanish emerging adults who were assessed by six self-report questionnaires and scales. Men reported more psychological and physical violence victimization and physical violence perpetration than women, and women and men without a current partner reported more psychological and sexual violence than women and men with a current partner. Dating violence victimization was associated with more mental symptomatology, less life satisfaction, and lower self-esteem in men with a current partner and in women without a current partner. The main predictor of dating violence victimization was dating violence perpetration, and the main predictor of dating violence perpetration was victimization by such violence. More traditional gender role attitudes also predicted greater victimization and perpetration of dating violence, except among women without a current partner.

International Undiagnosed Diseases Programs (UDPs): components and outcomes.

Over the last 15 years, Undiagnosed Diseases Programs have emerged to address the significant number of individuals with suspected but undiagnosed rare genetic diseases, integrating research and clinical care to optimize diagnostic outcomes. This narrative review summarizes the published literature surrounding Undiagnosed Diseases Programs worldwide, including thirteen studies that evaluate outcomes and two commentary papers. Commonalities in the diagnostic and research process of Undiagnosed Diseases Programs are explored through an appraisal of available literature. This exploration allowed for an assessment of the strengths and limitations of each of the six common steps, namely enrollment, comprehensive clinical phenotyping, research diagnostics, data sharing and matchmaking, results, and follow-up. Current literature highlights the potential utility of Undiagnosed Diseases Programs in research diagnostics. Since participants have often had extensive previous genetic studies, research pipelines allow for diagnostic approaches beyond exome or whole genome sequencing, through reanalysis using research-grade bioinformatics tools and multi-omics technologies. The overall diagnostic yield is presented by study, since different selection criteria at enrollment and reporting processes make comparisons challenging and not particularly informative. Nonetheless, diagnostic yield in an undiagnosed cohort reflects the potential of an Undiagnosed Diseases Program. Further comparisons and exploration of the outcomes of Undiagnosed Diseases Programs worldwide will allow for the development and improvement of the diagnostic and research process and in turn improve the value and utility of an Undiagnosed Diseases Program.

Experiences of living without a sense of smell: Like "Being Behind Glass".

This study addresses the paucity of research concerning the subjective experiences of those affected by anosmia. In the study, we interviewed individuals(n = 11) recruited via the charity (Fifth Sense) and used Interpretative Phenomenological Analysis (IPA) to analyse the data. Findings revealed three main themes and seven sub themes. The main themes are Living with Anosmia; Remembrance of things old and new and Resilience. The study reveals the process of becoming aware of being anosmic and the relationships with others in this process including potentially unhelpful minimisations of the impact by professionals. In addition to a sense of isolation and insecurity, living with anosmia for some participants brought with it an identification of being 'anosmic' and feeling part of a community. This was in contrast to a general lack of public knowledge and understanding of anosmia. The findings of the study demonstrated the importance of smell to time, place and relationship and the recalling of smells as bringing a sense of connectivity to loved ones, of times past and also a sense of loss of ability. Participants also described the ways in which they coped and adapted to a life with anosmia and focused on positive aspects of life. These findings provide a rich qualitative account of the experience of anosmia. The findings point towards future research which could inform us about the lives of those who are anosmic and currently unaware and of those recently diagnosed, which will create a richer understanding of the experiences of anosmia.

The burden, prevention and care of infants and children with congenital anomalies in sub-Saharan Africa: A scoping review.

The aim of this scoping review was to determine the scope, objectives and methodology of contemporary published research on congenital anomalies (CAs) in sub-Saharan Africa (SSA), to inform activities of the newly established sub-Saharan African Congenital Anomaly Network (sSCAN). MEDLINE was searched for CA-related articles published between January 2016 and June 2021. Articles were classified into four main areas (public health burden, surveillance, prevention, care) and their objectives and methodologies summarized. Of the 532 articles identified, 255 were included. The articles originated from 22 of the 49 SSA countries, with four countries contributing 60% of the articles: Nigeria (22.0%), Ethiopia (14.1%), Uganda (11.7%) and South Africa (11.7%). Only 5.5% of studies involved multiple countries within the region. Most articles included CA as their primary focus (85%), investigated a single CA (88%), focused on CA burden (56.9%) and care (54.1%), with less coverage of surveillance (3.5%) and prevention (13.3%). The most common study designs were case studies/case series (26.6%), followed by cross-sectional surveys (17.6%), retrospective record reviews (17.3%), and cohort studies (17.2%). Studies were mainly derived from single hospitals (60.4%), with only 9% being population-based studies. Most data were obtained from retrospective review of clinical records (56.1%) or via caregiver interviews (34.9%). Few papers included stillbirths (7.5%), prenatally diagnosed CAs (3.5%) or terminations of pregnancy for CA (2.4%).This first-of-a-kind-scoping review on CA in SSA demonstrated an increasing level of awareness and recognition among researchers in SSA of the contribution of CAs to under-5 mortality and morbidity in the region. The review also highlighted the need to address diagnosis, prevention, surveillance and care to meet Sustainable Development Goals 3.2 and 3.8. The SSA sub-region faces unique challenges, including fragmentation of efforts that we hope to surmount through sSCAN via a multidisciplinary and multi-stakeholder approach.

Using a health observance event to raise awareness: An assessment of World Birth Defects Day.

World Birth Defects Day (WorldBDDay), observed annually on March 3, was launched in 2015 to advocate for public health surveillance, research, and prevention of birth defects, along with improved care and treatment for affected individuals. Following its fifth observance in 2019, we assessed WorldBDDay by analyzing: (a) engagement and content of over 2000 WorldBDDay posts on Facebook, Twitter, and Instagram; (b) interview responses from 9 WorldBDDay charter (founding) organizations on their perceptions of strengths and areas for improvement for WorldBDDay; (c) survey responses from 61 WorldBDDay 2019 partner (participating) organizations on their WorldBDDay 2019 activities; and (d) post-2019 social media engagement. Most social media posts (60%) occurred from organizations using Twitter (80% vs. 14% for Instagram and 6% for Facebook), although posts from individuals had higher levels of engagement (e.g., likes and comments). The highest engagement occurred for posts focused on general awareness, prevention, or events. Charter organizations reported the need for existing and new partner engagement, including a designated WorldBDDay contact for regular communication and coordination of activities and prepared prevention-focused messaging. Partner organizations reported using the WorldBDDay toolkit, especially key messages and social media tips, and suggested expanding the toolkit with relevant resources. Post-2019 Twitter engagement was lower than 2019 WorldBDDay (peak event) but showed similar reach to WorldBDDay events prior to 2019. Our assessment identified WorldBDDay health observance events as an important tool to support knowledge dissemination and global community engagement around birth defects. Moving forward, engagement with more individuals and organizations may improve the reach of WorldBDDay.

Mediated and moderated associations between cumulative lifetime stressor exposure, emotional dysregulation, impulsivity, and lifetime alcohol use: A cross-sectional scoping study of UK drinkers.

Stress, trait impulsivity, and emotional dysregulation are independent predictors of alcohol use and misuse, but little is known about the potential mechanisms that link these risk factors together. To address this issue, we carried out an exploratory cross-sectional study, on UK-based participants. Our preregistered, hypothesised theoretical framework was that emotional dysregulation mediates the association between cumulative lifetime stressor exposure and lifetime alcohol use. We also hypothesised that heightened impulsivity would strengthen these relations. As hypothesised, emotional dysregulation fully mediated the relation between cumulative lifetime stressor exposure and lifetime alcohol use. Several facets of impulsivity moderated these associations. For example, as levels of negative urgency increased, the associations between cumulative lifetime stressor exposure and emotional dysregulation, emotional dysregulation and lifetime alcohol use, and lifetime stress exposure and lifetime alcohol use, via emotional dysregulation, strengthened. These preliminary findings propose a theoretically framed model which integrates several prominent risk-factors for alcohol misuse, extending prior research and generating interesting and novel lines of enquiry for longitudinal and cross-cultural analyses. The findings also highlight the potential clinical utility of screening for lifetime stress exposure while tailoring personalised treatment interventions.

Estrés relacionado con el trabajo y sintomatología mental en personas trabajadoras: Un análisis de género / Work-related stress and mental symptoms in working people: A gender analysis

El objetivo fue analizar el estrés laboral de mujeres y hombres con empleo y categorías laborales y demográficas similares, estudiando su asociación con la sintomatología mental. Estudio exploratoriodescriptivo y transversal con una muestra de conveniencia formada por 2643 personas con empleo y edades entre 18 y 64 años de las cuales el 54.3% son hombres y el 45.7% mujeres. Todas fueron evaluadas mediante cinco autoinformes y una hoja de recogida de datos sociodemográficos y de usos del tiempo. Resultados: El 67.5% de los hombres y el 66.5% de las mujeres tuvo algún tipo de estrés relacionado con el trabajo, no existiendo diferencias entre mujeres y hombres en ninguna de las medidas de estrés laboral, en insatisfacción con el rol laboral, ni en la asociación entre el estrés laboral y la sintomatología mental, asociación que era muy baja en mujeres y en hombres. Las mujeres tenían más estrés crónico no laboral y mayores contrariedades diarias que los hombres, además de mayor sintomatología mental de ansiedad, depresión grave, somática y de disfunción social. Asimismo, dedicaban más tiempo a las tareas domésticas y de cuidado y menos al ocio y a las actividades físico-deportivas que los hombres. Conclusiones: los resultados evidenciaron que el rol laboral no supone amenazas específicas para la salud mental de las mujeres con empleo, aunque sí parecen suponerlas su mayor dedicación a las tareas domésticas y de cuidado. Los resultados del presente trabajo son relevantes para el diseño de políticas y programas destinados a fomentar la salud de la ciudadanía y al logro de mayor igualdad de género(AU)

The objective was to analyze work stress in women and men with similar occupation and demographic categories, studying its association with mental symptomatology. Exploratory-descriptive and cross-sectional study with a convenience sample of 2643 employed persons aged 18 to 64 years, 54.3% of whom were men and 45.7% women. All were assessed by five self-reports and a sociodemographic and time-use data collection sheet. Results: 67.5% of the men and 66.5% of the women had some type of work-related stress. There were no differences between women and men in any of the measures of work stress, in dissatisfaction with the work role, or in the association between work stress and mental symptomatology, association that was very low in both women and men. Women had more chronic non-work stress and greater daily hassles than men, as well as greater symptomatology of anxiety, severe depression, somatic and social dysfunction. In addition, they spent more time on housework and caregiving and less time on leisure and physical-sports activities than men. Conclusions: the results show that the work role does not pose specific threats to the mental health of working women, although their greater dedication to domestic and caregiving tasks does seem to do so. The results of this study are relevant for the design of policies and programs aimed at promoting the health of citizens and achieving greater gender equality(AU)

Gender, life events, and mental well-being in emerging adulthood.

BACKGROUND: Emerging adulthood is a critical period of life involving many life transitions that may generate stress and compromise health and mental well-being. AIMS: To know the most frequent life events of women and men in emerging adulthood, analyzing also the relevance that such stressors have on their psychological well-being and life satisfaction. A second aim is to determine the relevance of age, educational level, most frequent life events, coping styles, and perceived social support as risk and protective factors for well-being. METHOD: The sample consisted of 2,000 individuals from the general Spanish population (55% women), aged between 18 and 29, who were assessed using five questionnaires and scales measuring life events, coping styles, life satisfaction, psychological well-being, and social support. RESULTS: The findings showed that 90% of the sample had experienced one or more life events during the previous year and that a higher number of life events experienced over the past year was associated with lower mental well-being. Multiple regression analyses made clear that, although some events experienced in the previous year (namely, family conflicts and change in the relationship with parents) were associated with lower women's and men's well-being, the most important determinants of well-being in either gender were coping styles; however, some predictors of women's well-being proved different from those of men. In the case of women, family and intimate partner conflicts predicted lower life satisfaction and psychological well-being was lower in the case of family conflicts. As for men, work or academic life events predicted lower life satisfaction. CONCLUSION: These research findings are relevant for the design of programs and strategies to improve mental well-being in emerging adulthood.

Venous outflow obstruction in pediatric left lateral segment split liver transplantation.

BACKGROUND: Venous outflow obstruction (VOO) is a known cause of graft and patient loss after pediatric liver transplantation (LT). We analyzed the incidence, risk factors, diagnosis, management, and outcome of VOO in a large, consecutive series of left lateral segment (LLS) split LT with end-to-side triangular venous anastomosis. METHODS: We evaluated data collected in our prospective databases relative to all consecutive pediatric liver transplants performed from January 2006 to December 2021. We included in this study children undergoing LLS split liver transplant with end-to-side triangular anastomosis. Diagnosis of VOO was based on clinical suspicion and radiological confirmation. RESULTS: VOO occurred in 24/279 transplants (8.6%), and it was associated with lower graft weight (p = .04), re-transplantation (p = .008), and presence of two hepatic veins (p < .0001). In presence of two segmental veins' orifices, the type of reconstruction (single anastomosis after venoplasty or double anastomosis) was not significantly related to VOO (p = .87). Multivariable analysis indicated VOO as a risk factor for graft lost (hazard ratio 3.21, 95% confidence interval 1.22-8.46; p = .01). Percutaneous Transluminal Angioplasty (PTA) was effective in 17/22 (77%) transplants. Surgical anastomosis was redone in one case. Overall six grafts (25%) were lost. CONCLUSION: VOO after LLS split LT with end-to-side triangular anastomosis is an unusual but critical complication leading to graft loss in a quarter of cases. The occurrence of VOO was associated with lower graft weight, re-transplantation, and presence of two hepatic veins. PTA was safe and effective to restore proper venous outflow in most cases.

SON-Related Zhu-Tokita-Takenouchi-Kim Syndrome With Recurrent Hemiplegic Migraine: Putative Role of PRRT2.

Background and Objectives: Zhu-Tokita-Takenouchi-Kim (ZTTK) syndrome (OMIM 617140) is a recently identified neurodevelopmental disorder caused by heterozygous loss-of-function (LoF) variants in SON. Because the SON protein functions as an RNA-splicing regulator, it has been shown that some clinical features of ZTTK syndrome can be attributed to abnormal RNA splicing. Several neurologic features have been observed in patients with ZTTK syndrome, including seizure/epilepsy and other EEG abnormalities. However, a relationship between SON LoF in ZTTK syndrome and hemiplegic migraine remains unknown. Methods: We identified a patient with a pathogenic variant in SON who shows typical clinical features of ZTTK syndrome and experienced recurrent episodes of hemiplegic migraine. To define clinical features, brain MRI and EEG during and after episodes of hemiplegic migraine were characterized. To identify molecular mechanisms for this clinical presentation, we investigated the impact of small interfering RNA (siRNA)-mediated SON knockdown on mRNA expression of the CACNA1A, ATP1A2, SCN1A, and PRRT2 genes, known to be associated with hemiplegic migraine, by quantitative RT-PCR. Pre-mRNA splicing of PRRT2 on SON knockdown was further examined by RT-PCR using primers targeting specific exons. Results: Recurrent episodes of hemiplegic migraine in our patient typically followed modest closed head injuries, and recurrent seizures occurred during the most severe of these episodes. Transient hemispheric cortical interstitial edema and asymmetric EEG slowing were identified during episodes. Our siRNA experiments revealed that SON knockdown significantly reduces PRRT2 mRNA levels in U87MG and SH-SY5Y cell lines, although a reduction in CACNA1A, ATP1A2, and SCN1A mRNA expression was not observed. We further identified that SON knockdown leads to failure in intron 2 removal from PRRT2 pre-mRNA, resulting in a premature termination codon that blocks the generation of functionally intact full-length PRRT2. Discussion: This report identifies recurrent hemiplegic migraine as a novel clinical manifestation of ZTTK syndrome, further characterizes this clinical feature, and provides evidence for downregulation of PRRT2 caused by SON LoF as a mechanism causing hemiplegic migraine. Examination of the SON gene may be indicated in individuals with recurrent hemiplegic migraine.

A novel RAD51 variant resulting in Fanconi anemia identified in an infant with multiple congenital anomalies.

Fanconi anemia, FA, is a rare, multi-system disease caused by pathogenic variants in DNA repair genes. We report a novel RAD51 variant in an infant with FA whose tracheobronchomalacia has not been described in FA. His severe presentation expands the phenotype of RAD51-associated FA, reported only in three patients previously.

The management of endoscopic retrograde cholangio- pancreatography-related infections risk: results of an italian survey at regional level.

Background and aim: Among the Endoscopic retrograde cholangiopancreatography (ERCP) adverse events, an increasingly arising problem is the transmission of Multi Drug Resistant (MDR) Bacteria through duodenoscopes. The aim of this survey was to evaluate the current clinical practice of management of ERCP associated infections in Emilia-Romagna, Italy. Methods: An online survey was developed including 12 questions on management of ERCP associated infections risk. The survey was proposed to all 12 endoscopy centers in Emilia Romagna that perform at least > 200 ERCPs per year. Results: 11 centers completed the survey (92%). Among all risk factors of ERCP infections, hospitalization in intensive care units, immunosuppressant therapies, and previous MDR infections have achieved a 80 % minimum of concurrence by our respondents. The majority of them did not have a formalized document in their hospital describing categories and risk factors helpful in the detection of patients undergoing ERCP with an high-level infective risk (9/11, 82%). Most centers (8/11, 72%) do not perform screening in patients at risk of ERCP infections. Post procedural monitoring is performed by 6 of 11 centers (55%). Conclusion: Our survey showed that, at least at regional level, there is a lack of procedures and protocols related to the management of patients at risk of ERCP infections.

Patterns of multiple congenital anomalies in the National Birth Defect Prevention Study: Challenges and insights.

BACKGROUND: About 20%-30% of children with birth defects have multiple major birth defects in more than one organ system, often referred to as multiple congenital anomalies (MCAs). Evaluating the patterns of MCAs can provide clues to the underlying causes, pathogenic mechanisms, and developmental pathways. We sought to explore selected patterns of MCAs within the National Birth Defects Prevention Study (NBDPS), a population-based, case-control study that excluded cases attributed to known chromosomal or single-gene abnormalities. METHODS: We defined MCAs as having two or more NBDPS-eligible birth defects and calculated the adjusted observed-to-expected ratio for all observed MCA patterns using co-occurring defect analysis. RESULTS: Of the 50,186 case infants eligible for NBDPS, 2,734 (3.7%) had at least two eligible birth defects. We observed 209 distinct 2-way combinations of birth defects, 297 distinct 3-way combinations, 179 distinct 4-way combinations, and 69 distinct 5-way combinations. Sacral agenesis had the largest proportion of cases with MCAs (70%), whereas gastroschisis had the lowest (3%). Among the cases with MCAs, 63% had a heart defect, 23% had an oral cleft, and 21% had anorectal atresia/stenosis. Of the patterns with adjusted observed-to-expected ratios in the top 20%, most were consistent with the known associations or syndromes, including VATER/VACTERL association and CHARGE syndrome. CONCLUSIONS: Most but not all patterns that had the highest adjusted observed-to-expected ratios were instances of known syndromes or associations. These findings highlight the importance of considering birth defect combinations that suggest syndromic patterns in the absence of a formal syndromic diagnosis. New approaches for screening for sequences and associations, and VATER/VACTERL in particular, in surveillance systems with limited resources for manual review may be valuable for improving surveillance system quality. The observed MCA patterns within NBDPS may help focus future genetic studies by generating case groups of higher yield.

Associations Between Self-reported Inhibitory Control, Stress, and Alcohol (Mis)use During the First Wave of the COVID-19 Pandemic in the UK: a National Cross-sectional Study Utilising Data From Four Birth Cohorts.

We explored (1) self-reported changes in alcohol use during the pandemic in the UK and (2) the extent to which self-reported inhibitory control and/or stress were associated with any change in drinking behaviour. We used a UK-based cross-sectional online survey administered to four nationally representative birth cohorts (N = 13,453). A significant minority of 30- (29.08%) and 50-year-olds (26.67%) reported drinking more, and between 32.23 and 45.02% of respondents reported feeling more stressed depending on the cohort. Stress was associated with hazardous drinking among 30-year-olds (OR = 3.77, 95% CI 1.15 to 12.28). Impatience was associated with both increased alcohol use (1.14, 95% CI 1.06, 1.24) and hazardous drinking (1.20, 95% CI 1.05, 1.38) among 19-year-olds. Risk-taking was associated with hazardous drinking for 30-year-olds (OR = 1.18, 95% CI 1.05, 1.32). These data highlight concerns for those at risk of alcohol misuse and alcohol-related harm during COVID-19 lockdowns. Supplementary Information: The online version contains supplementary material available at 10.1007/s11469-021-00599-8.

Establishing UK research priorities in smell and taste disorders: A James Lind alliance priority setting partnership.

OBJECTIVES: To determine the top 10 research priorities in Smell and Taste Disorders (SATD). DESIGN: After steering group was established, an electronic survey was disseminated to determine the list of questions. After removing out-of-scope responses, the remainder were consolidated to create summary questions. A literature search was conducted to remove already answered questions. A second survey was used to determine the top questions that formed the subject of final debate at a workshop attended by clinicians and patients to determine the top 10 priorities. SETTING: A James Lind Alliance Priority Setting Partnership (JLAPSP) was established by FifthSense to identify the top 10 research questions in SATDs in the United Kingdom. PARTICIPANT: All stakeholders in SATDs (patients, healthcare professionals, family, carers, researchers). MAIN OUTCOME MEASURES: Final 10 research priorities. RESULTS: The 665 respondents to the initial survey provided 1698 research questions. Thirteen were out-of-scope and removed; remaining 1685 were then consolidated to form 147 summary questions. Following literature search and discussion with the steering group, 37 questions remained for the second survey, which 235 people responded. The top ten priorities agreed upon in the workshop covered themes of improved understanding of pathophysiologlogy, improving health services, and managing long-term effects of smell/taste disorders. The most important research question agreed was "How can we further our understanding of the mechanism of disease in the nerve pathways that affect smell and taste disorders, including where parosmia and phantosmia exist." CONCLUSION: We report the top 10 research priorities in smell and taste disorders. These priorities will now empower researchers to secure research funding and provide the basis of the FifthSense research hub.

ATP6V0C variants impair V-ATPase function causing a neurodevelopmental disorder often associated with epilepsy.

The vacuolar H+-ATPase is an enzymatic complex that functions in an ATP-dependent manner to pump protons across membranes and acidify organelles, thereby creating the proton/pH gradient required for membrane trafficking by several different types of transporters. We describe heterozygous point variants in ATP6V0C, encoding the c-subunit in the membrane bound integral domain of the vacuolar H+-ATPase, in 27 patients with neurodevelopmental abnormalities with or without epilepsy. Corpus callosum hypoplasia and cardiac abnormalities were also present in some patients. In silico modelling suggested that the patient variants interfere with the interactions between the ATP6V0C and ATP6V0A subunits during ATP hydrolysis. Consistent with decreased vacuolar H+-ATPase activity, functional analyses conducted in Saccharomyces cerevisiae revealed reduced LysoSensor fluorescence and reduced growth in media containing varying concentrations of CaCl2. Knockdown of ATP6V0C in Drosophila resulted in increased duration of seizure-like behaviour, and the expression of selected patient variants in Caenorhabditis elegans led to reduced growth, motor dysfunction and reduced lifespan. In summary, this study establishes ATP6V0C as an important disease gene, describes the clinical features of the associated neurodevelopmental disorder and provides insight into disease mechanisms.

Novel SLC13A3 Variants and Cases of Acute Reversible Leukoencephalopathy and α-Ketoglutarate Accumulation and Literature Review.

Objectives: Acute reversible leukoencephalopathy with increased urinary alpha-ketoglutarate (ARLIAK) is a recently described autosomal recessive leukoencephalopathy caused by pathogenic variants in the SLC13A3 gene. ARLIAK is characterized by acute neurologic involvement, often precipitated by febrile illness, with largely reversible clinical symptoms and imaging findings. Three patients have been reported in the literature to date. Our objective is to report newly identified patients and their genetic variants and phenotypes and review published literature on ARLIAK. Methods: This report contributes 4 additional patients to the literature; describes novel variants in SLC13A3; and reviews genetic, biochemical, clinical, and radiologic features of all published patients with ARLIAK. Results: We provide additional genetic, imaging, and laboratory insights into ARLIAK, an atypical leukodystrophy with clinical and radiologic findings that can normalize. Discussion: Our case series highlights the importance of reanalysis of next-generation sequencing in the diagnostic workup.