Multiomics analysis identifies oxidative phosphorylation as a cancer vulnerability arising from myristoylation inhibition.

BACKGROUND: In humans, two ubiquitously expressed N-myristoyltransferases, NMT1 and NMT2, catalyze myristate transfer to proteins to facilitate membrane targeting and signaling. We investigated the expression of NMTs in numerous cancers and found that NMT2 levels are dysregulated by epigenetic suppression, particularly so in hematologic malignancies. This suggests that pharmacological inhibition of the remaining NMT1 could allow for the selective killing of these cells, sparing normal cells with both NMTs. METHODS AND RESULTS: Transcriptomic analysis of 1200 NMT inhibitor (NMTI)-treated cancer cell lines revealed that NMTI sensitivity relates not only to NMT2 loss or NMT1 dependency, but also correlates with a myristoylation inhibition sensitivity signature comprising 54 genes (MISS-54) enriched in hematologic cancers as well as testis, brain, lung, ovary, and colon cancers. Because non-myristoylated proteins are degraded by a glycine-specific N-degron, differential proteomics revealed the major impact of abrogating NMT1 genetically using CRISPR/Cas9 in cancer cells was surprisingly to reduce mitochondrial respiratory complex I proteins rather than cell signaling proteins, some of which were also reduced, albeit to a lesser extent. Cancer cell treatments with the first-in-class NMTI PCLX-001 (zelenirstat), which is undergoing human phase 1/2a trials in advanced lymphoma and solid tumors, recapitulated these effects. The most downregulated myristoylated mitochondrial protein was NDUFAF4, a complex I assembly factor. Knockout of NDUFAF4 or in vitro cell treatment with zelenirstat resulted in loss of complex I, oxidative phosphorylation and respiration, which impacted metabolomes. CONCLUSIONS: Targeting of both, oxidative phosphorylation and cell signaling partly explains the lethal effects of zelenirstat in select cancer types. While the prognostic value of the sensitivity score MISS-54 remains to be validated in patients, our findings continue to warrant the clinical development of zelenirstat as cancer treatment.

Stress and anxiety during pregnancy and length of gestation: a federated study using data from five Canadian and European birth cohorts.

While its etiology is not fully elucidated, preterm birth represents a major public health concern as it is the leading cause of child mortality and morbidity. Stress is one of the most common perinatal conditions and may increase the risk of preterm birth. In this paper we aimed to investigate the association of maternal perceived stress and anxiety with length of gestation. We used harmonized data from five birth cohorts from Canada, France, and Norway. A total of 5297 pregnancies of singletons were included in the analysis of perceived stress and gestational duration, and 55,775 pregnancies for anxiety. Federated analyses were performed through the DataSHIELD platform using Cox regression models within intervals of gestational age. The models were fit for each cohort separately, and the cohort-specific results were combined using random effects study-level meta-analysis. Moderate and high levels of perceived stress during pregnancy were associated with a shorter length of gestation in the very/moderately preterm interval [moderate: hazard ratio (HR) 1.92 (95%CI 0.83, 4.48); high: 2.04 (95%CI 0.77, 5.37)], albeit not statistically significant. No association was found for the other intervals. Anxiety was associated with gestational duration in the very/moderately preterm interval [1.66 (95%CI 1.32, 2.08)], and in the early term interval [1.15 (95%CI 1.08, 1.23)]. Our findings suggest that perceived stress and anxiety are associated with an increased risk of earlier birth, but only in the earliest gestational ages. We also found an association in the early term period for anxiety, but the result was only driven by the largest cohort, which collected information the latest in pregnancy. This raised a potential issue of reverse causality as anxiety later in pregnancy could be due to concerns about early signs of a possible preterm birth.

Diagnostic yield from symptomatic lower gastrointestinal endoscopy in the UK: A British Society of Gastroenterology analysis using data from the National Endoscopy Database.

BACKGROUND: The value of lower gastrointestinal endoscopy (LGIE; colonoscopy or sigmoidoscopy) relates to its ability to detect clinically relevant findings, predominantly cancers, preneoplastic polyps or inflammatory bowel disease. There are concerns that many LGIEs are performed on low-risk patients with limited benefit. AIMS: To determine the diagnostic outcomes of LGIE for common symptoms. METHODS: We performed a cross-sectional study of diagnostic LGIE between March 2019 and February 2020 using the UK National Endoscopy Database. We used mixed-effects logistic regression models, incorporating random (endoscopist) and fixed (symptoms, patient age, and sex) effects upon two dependent variables (large polyp [≥10 mm] and cancer diagnosis). Adjusted positive predictive values (aPPVs) were calculated. RESULTS: We analysed 384,510 LGIEs; 33.2% were performed on patients aged under 50 and 53.6% on women. Regarding colonoscopies, the unadjusted PPV for cancer was 1.5% (95% CI: 1.4-1.5); higher for men than women (1.9% vs. 1.1%, p < 0.01). The PPV for large polyps was 3.2% (95% CI: 3.1-3.2). The highest colonoscopy cancer aPPVs were in the over 50s (1.9%) and in those with rectal bleeding (2.5%) or anaemia (2.1%). Cancer aPPVs for other symptoms were <1% despite representing 54.3% of activity. In patients under 50, aPPVs were 0.4% for cancer and 1.6% for large polyps. Results were similar for sigmoidoscopy. CONCLUSIONS: Most colonoscopies were performed on patients with low-risk symptoms, where cancer risk was similar to the general population. Cancer and large polyp yield was highest in elderly patients with rectal bleeding or anaemia, although still fell short of FIT-based screening yields.

Visualization and exploration of linked data using virtual reality.

In this report, we analyse the use of virtual reality (VR) as a method to navigate and explore complex knowledge graphs. Over the past few decades, linked data technologies [Resource Description Framework (RDF) and Web Ontology Language (OWL)] have shown to be valuable to encode such graphs and many tools have emerged to interactively visualize RDF. However, as knowledge graphs get larger, most of these tools struggle with the limitations of 2D screens or 3D projections. Therefore, in this paper, we evaluate the use of VR to visually explore SPARQL Protocol and RDF Query Language (SPARQL) (construct) queries, including a series of tutorial videos that demonstrate the power of VR (see Graph2VR tutorial playlist: https://www.youtube.com/playlist?list=PLRQCsKSUyhNIdUzBNRTmE-_JmuiOEZbdH). We first review existing methods for Linked Data visualization and then report the creation of a prototype, Graph2VR. Finally, we report a first evaluation of the use of VR for exploring linked data graphs. Our results show that most participants enjoyed testing Graph2VR and found it to be a useful tool for graph exploration and data discovery. The usability study also provides valuable insights for potential future improvements to Linked Data visualization in VR.

Systematic reanalysis of genomic data by diagnostic laboratories: a scoping review of ethical, economic, legal and (psycho)social implications.

With the introduction of Next Generation Sequencing (NGS) techniques increasing numbers of disease-associated variants are being identified. This ongoing progress might lead to diagnoses in formerly undiagnosed patients and novel insights in already solved cases. Therefore, many studies suggest introducing systematic reanalysis of NGS data in routine diagnostics. Introduction will, however, also have ethical, economic, legal and (psycho)social (ELSI) implications that Genetic Health Professionals (GHPs) from laboratories should consider before possible implementation of systematic reanalysis. To get a first impression we performed a scoping literature review. Our findings show that for the vast majority of included articles ELSI aspects were not mentioned as such. However, often these issues were raised implicitly. In total, we identified nine ELSI aspects, such as (perceived) professional responsibilities, implications for consent and cost-effectiveness. The identified ELSI aspects brought forward necessary trade-offs for GHPs to consciously take into account when considering responsible implementation of systematic reanalysis of NGS data in routine diagnostics, balancing the various strains on their laboratories and personnel while creating optimal results for new and former patients. Some important aspects are not well explored yet. For example, our study shows GHPs see the values of systematic reanalysis but also experience barriers, often mentioned as being practical or financial only, but in fact also being ethical or psychosocial. Engagement of these GHPs in further research on ELSI aspects is important for sustainable implementation.

A morphological basis for path-dependent evolution of visual systems.

Path dependence influences macroevolutionary predictability by constraining potential outcomes after critical evolutionary junctions. Although it has been demonstrated in laboratory experiments, path dependence is difficult to demonstrate in natural systems because of a lack of independent replicates. Here, we show that two types of distributed visual systems recently evolved twice within chitons, demonstrating rapid and path-dependent evolution of a complex trait. The type of visual system that a chiton lineage can evolve is constrained by the number of openings for sensory nerves in its shell plates. Lineages with more openings evolve visual systems with thousands of eyespots, whereas those with fewer openings evolve visual systems with hundreds of shell eyes. These macroevolutionary outcomes shaped by path dependence are both deterministic and stochastic because possibilities are restricted yet not entirely predictable.

Surgical timing and complications, with body image, quality of life, sexual function and genital sensation in patients with congenital adrenal hyperplasia.

INTRODUCTION: The aim of this project was to document the long-term outcomes relating to sexual function, genital sensation, body image and quality of life, in an Australian cohort of adolescent and adult women with congenital adrenal hyperplasia (CAH) who have undergone feminising genitoplasty in infancy, childhood or adolescence. MATERIALS AND METHODS: Identification and follow-up of women with CAH aged 12-40 years who had their first feminising genitoplasty or ongoing management at a single tertiary referral center with multidisciplinary care (n = 80). Medical records were reviewed for Prader stage, and operative outcomes. The prospective component of the study included tracing indivudals aged 12-40 years (n = 69), of whom 34 were contactable. Twenty-one responded to the invitation to participate in the study, completing some or all of a series of validated standardized questionnaires and/or participation in examination of external genital with sensation testing. Results were compared to a control population of similar age distribution (n = 23). RESULTS: The median Prader stage was 3, median age at surgery was four months, median hospital stay of three days with 80 % of surgery undertaken by one surgeon. There was one major and eight minor complications. Re-operation rates were low. There was no difference between participants and controls in terms of sexual function, quality of life, or body image outcomes including genital appearance. Participants had increased sensitivity to soft touch on genital sensation testing compared to controls. Most participants (71 %) reported that early timing of surgery was 'good', four (19 %) felt their surgery was too late, one felt their surgery was too early, and one was unsure. Most were happy with the outcome of their surgery. DISCUSSION: Outcomes after feminising genitoplasty are mixed and influenced not only by the surgery itself, but also the ongoing management of the condition alongside each patient's own cultural and social context. At present there is no comparative data available on the sexual, mental, body image and quality of life outcomes of young females with CAH who have had their operation delayed until adulthood. Our study is limited by low participant response rate, and difficulty recruiting 1:1 control population for all participants, but nevertheless provides some insight into the outcomes of these patients for which limited data is available. CONCLUSION: In the population studied feminising genitoplasty in infancy and childhood had overall positive outcomes. This occurred in a tertiary center with expert multidisciplinary individualised care.

Emotional and behavioral outcomes among youths with mental disorders during the first Covid lockdown and school closures in England: a large clinical population study using health care record integrated surveys.

PURPOSE: Emotional and behavioral problems in children and young people (CYP) have increased over the pandemic. Those with pre-existing mental disorders are more vulnerable but have been understudied. We investigated emotional and behavioral outcomes in this population; differences across diagnostic groups; and social, educational, and clinical determinants. METHODS: We invited 5386 caregivers and CYP (aged 5-17) under child mental health services pre-pandemic to complete an online survey on CYP's emotional/behavioral symptoms and pandemic-related circumstances, and integrated responses with clinicodemographic information extracted from electronic health records. We compared four parent-rated outcomes (total emotional/behavioral scores and emotional/behavioral changes as compared to before the pandemic) across the three most common diagnostic groups in our population (Attention Deficit Hyperactivity Disorder (ADHD), Autism Spectrum Disorder (ASD) and emotional disorders (EmD)). We then estimated the association of clinicodemographic and pandemic-related characteristics with emotional/behavioral outcomes. RESULTS: A total of 1741 parents (32.3%) completed the survey. Parents of CYP with ADHD or ASD reported more behavioral difficulties (t(591) = 5.618 (0.001); t(663) = 6.527 (0.001)); greater emotional deterioration (t(591) = 2.592 (0.009); t(664) = 4.670 (< 0.001); and greater behavioral deterioration (t(594) = 4.529 (< 0.001); t(664) = 5.082 (< 0.001)) as compared to the EmD group. Those with ASD and EmD showed more emotional difficulties than ADHD (t(891) = - 4.431 (< 0.001); t(590) = - 3.254 (0.001)). Across diagnoses, poor parental mental health and challenges with education were most strongly associated with worse outcomes. CONCLUSIONS: Within our clinical population, CYP with ADHD/ASD were the most adversely affected during lockdown. Enhancing clinical service provision that tackles parental stress and supports education may help mitigate the impact of future restrictions.

Gender- and Sexuality-Minoritised Adolescents in DBT: A Reflexive Thematic Analysis of Minority-Specific Treatment Targets and Experience.

Gender- and sexuality-minoritised (GSM) adolescents are at increased risk of self-harm and suicidal behaviours compared to their cisgender and heterosexual peers. This increased risk is thought to be explained in part by exposure to stigma and societal oppression. Dialectical Behaviour Therapy (DBT) is an evidence-based intervention for self-harm and suicidal behaviour that may have advantages for supporting GSM young people in distress. No study has yet sought to understand what GSM-associated difficulties may be important to consider in DBT for adolescents, or the experiences of GSM young people in a standard DBT programme. Therefore, this study aimed to understand the experiences of GSM young people in DBT and what difficulties and dilemmas associated with their gender and sexuality diversity were thought by them to be important to target in DBT. Qualitative interviews were conducted with 14 GSM young people in a comprehensive DBT programme and were analysed using Reflexive Thematic Analysis. The analysis was supported by two further GSM young people who had finished DBT. The findings were split into three overarching themes (Identity, Impact of Others, and Space for Sexual and Gender Identity in DBT), each with themes within. The identity-based theme included "identity confusion and acceptance"; the relationship-based themes included "cis-Heterosexism" and "community connectedness"; and the space within DBT themes included "negotiating focus and targeting in DBT" and "creating safety in DBT". Findings are discussed in relation to implications and recommendations for therapists working with GSM young people within and outside of DBT.

Making ties and social identities: Drawing connections between PPNB communities as based on shell bead typology.

People tend to belong to multiple social circles, which construct and reflect a person's social identity. Group affiliation is embodied and may be expressed by personal adornment. Personal adornment in general has multiple functions in human societies, among them the assimilation and transmission of different aspects of personal and collective, social and cultural identity. Beads in general, including shell beads, often constitute parcels of composite adornment, and as such are used in different configurations to portray these messages. The shared use of similar bead types by different individuals and communities indicates the mutual affiliation of the sharing parties to the same cultural circles and reflects social ties and relationships. The Pre-Pottery Neolithic B (PPNB) period in the Levant is a time of pivotal changes to human lifeways necessitating profound adjustments in all aspects of life, including social relations and networks. Here we use the shell bead assemblage from the cultic-mortuary aggregation site of Kfar HaHoresh, in comparison to shell bead assemblages from multiple other sites in the Levant, as a proxy for the exploration of local and regional networks and connections between PPNB communities. Multivariate analyses of shell bead type distribution patterns across the Levant demonstrate that some types were widely shared among different communities, characterising different geographic regions, while others were rare or unique, highlighting relationships between sites and regions, which are occasionally independent of geographic proximity. Specific occurrences of shared shell bead types between Kfar HaHoresh and compared sites further illuminate the web of connections between PPNB communities in the Levant and the varying breadths of sharing-patterns reflect the hierarchical nature of the underlying social circles. Outlining these widening social affiliations sheds light on the complex structure of Neolithic social identity.

Comments on recent community water fluoridation studies.

Water fluoridation is a public health measure to reduce levels of dental caries in populations. A report of the recently completed CATFISH study has been published. This was the first UK evaluation of fluoridation introduction for many years; it was carefully designed and executed and is welcomed. The purpose of this article is to highlight the 180-page report of the study and comment on some aspects to aid interpretation of the findings. Significant features were that two cohorts, from birth and from five years, were followed for six years in a fluoridated and a non-fluoridated area, and clinical and cost analyses were reported. Areas of the report which deserve comment are: a) interruption of fluoridation for a year for half the children in the intervention area and its effect; b) clinical results were reported as absolute reduction in caries prevalence, with the preventive fraction for caries severity downplayed; c) the power of the study was diminished by an unexpected lower caries increment; and d) control for differences in diet was not possible. Nevertheless, this major UK study showed clinical and cost benefits of water fluoridation. The risk of cessation of water fluoridation is highlighted in examples of three recently published studies.

Ten quick tips for building FAIR workflows.

Research data is accumulating rapidly and with it the challenge of fully reproducible science. As a consequence, implementation of high-quality management of scientific data has become a global priority. The FAIR (Findable, Accesible, Interoperable and Reusable) principles provide practical guidelines for maximizing the value of research data; however, processing data using workflows-systematic executions of a series of computational tools-is equally important for good data management. The FAIR principles have recently been adapted to Research Software (FAIR4RS Principles) to promote the reproducibility and reusability of any type of research software. Here, we propose a set of 10 quick tips, drafted by experienced workflow developers that will help researchers to apply FAIR4RS principles to workflows. The tips have been arranged according to the FAIR acronym, clarifying the purpose of each tip with respect to the FAIR4RS principles. Altogether, these tips can be seen as practical guidelines for workflow developers who aim to contribute to more reproducible and sustainable computational science, aiming to positively impact the open science and FAIR community.

Neuronally enriched microvesicle RNAs are differentially expressed in the serums of Parkinson's patients.

Background: Circulating small RNAs (smRNAs) originate from diverse tissues and organs. Previous studies investigating smRNAs as potential biomarkers for Parkinson's disease (PD) have yielded inconsistent results. We investigated whether smRNA profiles from neuronally-enriched serum exosomes and microvesicles are altered in PD patients and discriminate PD subjects from controls. Methods: Demographic, clinical, and serum samples were obtained from 60 PD subjects and 40 age- and sex-matched controls. Exosomes and microvesicles were extracted and isolated using a validated neuronal membrane marker (CD171). Sequencing and bioinformatics analyses were used to identify differentially expressed smRNAs in PD and control samples. SmRNAs also were tested for association with clinical metrics. Logistic regression and random forest classification models evaluated the discriminative value of the smRNAs. Results: In serum CD171 enriched exosomes and microvesicles, a panel of 29 smRNAs was expressed differentially between PD and controls (false discovery rate (FDR) < 0.05). Among the smRNAs, 23 were upregulated and 6 were downregulated in PD patients. Pathway analysis revealed links to cellular proliferation regulation and signaling. Least absolute shrinkage and selection operator adjusted for the multicollinearity of these smRNAs and association tests to clinical parameters via linear regression did not yield significant results. Univariate logistic regression models showed that four smRNAs achieved an AUC ≥ 0.74 to discriminate PD subjects from controls. The random forest model had an AUC of 0.942 for the 29 smRNA panel. Conclusion: CD171-enriched exosomes and microvesicles contain the differential expression of smRNAs between PD and controls. Future studies are warranted to follow up on the findings and understand the scientific and clinical relevance.

Vertically Aligned One-Dimensional Crystal-Structured Sb2Se3 for High-Efficiency Flexible Solar Cells via Regulating Selenization Kinetics.

Recently, antimony selenide (Sb2Se3) has exhibited an exciting potential for flexible photoelectric applications due to its unique one-dimensional (1D) chain-type crystal structure, low-cost constituents, and superior optoelectronic properties. The 1D structure endows Sb2Se3 with a strong anisotropy in carrier transport and a lasting mechanical deformation tolerance. The control of the crystalline orientation of the Sb2Se3 film is an essential requirement for its device performance optimization. However, the current state-of-the-art Sb2Se3 devices suffer from unsatisfactory orientation control, especially for the (001) orientation, in which the chains stand vertically. Herein, we achieved an unprecedented control of the (001) orientation for the growth of the Sb2Se3 film on a flexible Mo-coated mica substrate by balancing the collision rate and kinetic energy of Se vapor particles with the surface of Sb film by regulating the selenization kinetics. Based on this (001)-oriented Sb2Se3 film, a high efficiency of 8.42% with a record open-circuit voltage (VOC) of 0.47 V is obtained for flexible Sb2Se3 solar cells. The vertical van der Waals gaps in the (001) orientation provide favorable diffusion paths for Se atoms, which results in a Se-rich state at the bottom of the Sb2Se3 film and promotes the in situ formation of the MoSe2 interlayer between Mo and Sb2Se3. These phenomena contribute to a back-surface field enhanced absorber layer and a quasi-Ohmic back contact, improving the device's VOC and the collection of carriers. This method provides an effective strategy for the orientation control of 1D materials for efficient photoelectric devices.

Semi-automatic translation of medicine usage data (in Dutch, free-text) from Lifelines COVID-19 questionnaires to ATC codes.

The mapping of human-entered data to codified data formats that can be analysed is a common problem across medical research and health care. To identify risk and protective factors for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) susceptibility and coronavirus disease 2019 (COVID-19) severity, frequent questionnaires were sent out to participants of the Lifelines Cohort Study starting 30 March 2020. Because specific drugs were suspected COVID-19 risk factors, the questionnaires contained multiple-choice questions about commonly used drugs and open-ended questions to capture all other drugs used. To classify and evaluate the effects of those drugs and group participants taking similar drugs, the free-text answers needed to be translated into standard Anatomical Therapeutic Chemical (ATC) codes. This translation includes handling misspelt drug names, brand names, comments or multiple drugs listed in one line that would prevent a computer from finding these terms in a simple lookup table. In the past, the translation of free-text responses to ATC codes was time-intensive manual labour for experts. To reduce the amount of manual curation required, we developed a method for the semi-automated recoding of the free-text questionnaire responses into ATC codes suitable for further analysis. For this purpose, we built an ontology containing the Dutch drug names linked to their respective ATC code(s). In addition, we designed a semi-automated process that builds upon the Molgenis method SORTA to map the responses to ATC codes. This method can be applied to support the encoding of free-text responses to facilitate the evaluation, categorization and filtering of free-text responses. Our semi-automatic approach to coding of drugs using SORTA turned out to be more than two times faster than current manual approaches to performing this activity. Database URL https://doi.org/10.1093/database/baad019.

The Impact of Mode of Birth, and Episiotomy, on Postpartum Sexual Function in the Medium- and Longer-Term: An Integrative Systematic Review.

(1) Background: Sexual function can be affected up to and beyond 18 months postpartum, with some studies suggesting that spontaneous vaginal birth results in less sexual dysfunction. This review examined the impact of mode of birth on sexual function in the medium- (≥6 months and <12 months postpartum) and longer-term (≥12 months postpartum). (2) Methods: Literature published after January 2000 were identified in PubMed, Embase and CINAHL. Studies that compared at least two modes of birth and used valid sexual function measures were included. Systematic reviews, unpublished articles, protocols and articles not written in English were excluded. Quality was assessed using the Newcastle Ottawa Scale. (3) Results: In the medium-term, assisted vaginal birth and vaginal birth with episiotomy were associated with worse sexual function, compared to caesarean section. In the longer-term, assisted vaginal birth was associated with worse sexual function, compared with spontaneous vaginal birth and caesarean section; and planned caesarean section was associated with worse sexual function in several domains, compared to spontaneous vaginal birth. (4) Conclusions: Sexual function, in the medium- and longer-term, can be affected by mode of birth. Women should be encouraged to seek support should their sexual function be affected after birth.

Identification of genetic variants that impact gene co-expression relationships using large-scale single-cell data.

BACKGROUND: Expression quantitative trait loci (eQTL) studies show how genetic variants affect downstream gene expression. Single-cell data allows reconstruction of personalized co-expression networks and therefore the identification of SNPs altering co-expression patterns (co-expression QTLs, co-eQTLs) and the affected upstream regulatory processes using a limited number of individuals. RESULTS: We conduct a co-eQTL meta-analysis across four scRNA-seq peripheral blood mononuclear cell datasets using a novel filtering strategy followed by a permutation-based multiple testing approach. Before the analysis, we evaluate the co-expression patterns required for co-eQTL identification using different external resources. We identify a robust set of cell-type-specific co-eQTLs for 72 independent SNPs affecting 946 gene pairs. These co-eQTLs are replicated in a large bulk cohort and provide novel insights into how disease-associated variants alter regulatory networks. One co-eQTL SNP, rs1131017, that is associated with several autoimmune diseases, affects the co-expression of RPS26 with other ribosomal genes. Interestingly, specifically in T cells, the SNP additionally affects co-expression of RPS26 and a group of genes associated with T cell activation and autoimmune disease. Among these genes, we identify enrichment for targets of five T-cell-activation-related transcription factors whose binding sites harbor rs1131017. This reveals a previously overlooked process and pinpoints potential regulators that could explain the association of rs1131017 with autoimmune diseases. CONCLUSION: Our co-eQTL results highlight the importance of studying context-specific gene regulation to understand the biological implications of genetic variation. With the expected growth of sc-eQTL datasets, our strategy and technical guidelines will facilitate future co-eQTL identification, further elucidating unknown disease mechanisms.

The Limitations of Frailty Assessment Tools in ANCA-Associated Vasculitis.

Anti-neutrophil cytoplasmic antibody (ANCA) associated vasculitis (AAV) can be associated with a high burden of morbidity and mortality in an ageing population. It is increasingly recognised that individualised management is needed. Few studies have looked specifically at frailty related outcomes in AAV and a gap remains in understanding the application of frailty assessment tools in these patients. We carried out a single centre, cohort study between 2017 to 2022. Forty-one patients who had newly diagnosed or relapsing AAV and aged ≥65 years were included. The Clinical Frailty Scale (CFS) score at presentation was assessed by health care practitioners and interval CFS scores were carried out a minimum of 6 weeks from diagnosis. The aim was to determine if patients living with frailty had worse outcomes or if their perceived frailty improved with immunosuppressive treatment. The median CFS at diagnosis was 4 (vulnerable) and this remained at follow up. There was no significant interval change in CFS (P=0.16) suggesting that the patients did not become frailer and instead there was a tendency towards improved frailty scores at re-assessment. There was no significant difference in end stage kidney disease between those with higher (>5) or lower (≤5) CFS (P=1.0), although crude mortality was higher among those with an initial CFS >5 (P=0.03). Overall, we demonstrated that CFS has limitations in determining patients that may be frail as a result of disease burden with the potential to improve with treatment and clinicians should be mindful of this when making decisions relating to management.

Parent-reported phenotype data on chromosome 6 aberrations collected via an online questionnaire: data consistency and data availability.

BACKGROUND: Even with the introduction of new genetic techniques that enable accurate genomic characterization, knowledge about the phenotypic spectrum of rare chromosomal disorders is still limited, both in literature and existing databases. Yet this clinical information is of utmost importance for health professionals and the parents of children with rare diseases. Since existing databases are often hampered by the limited time and willingness of health professionals to input new data, we collected phenotype data directly from parents of children with a chromosome 6 disorder. These parents were reached via social media, and the information was collected via the online Chromosome 6 Questionnaire, which includes 115 main questions on congenital abnormalities, medical problems, behaviour, growth and development. METHODS: Here, we assess data consistency by comparing parent-reported phenotypes to phenotypes based on copies of medical files for the same individual (n = 20) and data availability by comparing the data available on specific characteristics reported by parents (n = 34) to data available in existing literature (n = 39). RESULTS: The reported answers to the main questions on phenotype characteristics were 85-95% consistent, and the consistency of answers to subsequent more detailed questions was 77-96%. For all but two main questions, significantly more data was collected from parents via the Chromosome 6 Questionnaire than was currently available in literature. For the topics developmental delay and brain abnormalities, no significant difference in the amount of available data was found. The only feature for which significantly more data was available in literature was a sub-question on the type of brain abnormality present. CONCLUSION: This is the first study to compare phenotype data collected directly from parents to data extracted from medical files on the same individuals. We found that the data was highly consistent, and phenotype data collected via the online Chromosome 6 Questionnaire resulted in more available information on most clinical characteristics when compared to phenotypes reported in literature reports thus far. We encourage active patient participation in rare disease research and have shown that parent-reported phenotypes are reliable and contribute to our knowledge of the phenotypic spectrum of rare chromosomal disorders.