Development of a comprehensive genome-wide cardiovascular disease genetic risk assessment test.

BACKGROUND: Despite monogenic and polygenic contributions to cardiovascular disease (CVD), genetic testing is not widely adopted, and current tests are limited by the breadth of surveyed conditions and interpretation burden. METHODS: We developed a comprehensive clinical genome CVD test with semi-automated interpretation. Monogenic conditions and risk alleles were selected based on systematic assessment of the strength of disease association and evidence for increased disease risk, respectively. Non-CVD secondary finding genes, pharmacogenomic (PGx) variants and CVD polygenic risk scores (PRS) were also assessed for inclusion. Test performance was modeled using 2,594 genomes from the 1000 Genomes Project, and further investigated in 20 previously tested individuals. RESULTS: The CVD genome test is composed of a panel of 215 CVD gene-disease pairs, 35 non-CVD secondary findings genes, 4 risk alleles or genotypes, 10 PGx genes and a PRS for coronary artery disease. Modeling of test performance from samples in the 1000 Genomes Project revealed ~6% of individuals with a monogenic finding in a CVD-associated gene, 6% with a risk allele finding, 0.9% with a non-CVD secondary finding, and 93% with CVD-associated PGx variants. Assessment of blinded clinical samples showed complete concordance with prior testing. An average of 4 variants were reviewed per case, with interpretation and reporting time ranging from 9-96 min. CONCLUSIONS: A genome sequencing based CVD genetic risk assessment can provide comprehensive genetic disease and genetic risk information to patients with CVD. The semi-automated and limited interpretation burden suggest that this testing approach could be scaled to support population-level initiatives.

Impact of Genotype-Phenotype Interactions on Cardiovascular Function in Paediatric Loeys-Dietz Syndrome.

Background: The relationship between genotype and phenotypical vascular and cardiac properties in paediatric Loeys-Dietz syndrome (LDS) patients are not well characterized. This study explores the phenotypical differences in aortic properties and cardiac structural and functional parameters between paediatric LDS patients with TGFBR1 and TGFBR2 mutations. Methods: We included 32 LDS patients with either TGFBR1 (n = 17) or TGFBR2 (n = 15) mutations. Echocardiographic data included aortic dimensions, distensibility, strain, and stiffness at the level of the annulus, sinuses of Valsalva, sinotubular junction, ascending aorta, and descending aorta. Parameters for left ventricular size and function were also recorded. Results: Demographics were similar between the groups. Patients with TGFBR2 were more likely to have undergone aortic surgery (47% vs 12%, P = 0.057) and use angiotensin receptor blockers (93% vs 47%, P = 0.015). Aortic z scores were significantly larger in the TGFBR2 group at the level of the aortic valve annulus (P = 0.007), sinuses of Valsalva (P = 0.001), sinotubular junction (P = 0.001), and ascending aorta (P = 0.054). Patients with TGFBR2 also had significantly lower aortic distensibility and strain coupled with higher stiffness index at the level of the annulus, sinotubular junction, and ascending aorta. Parameters for the descending aorta, cardiac morphology, and cardiac function were similar between the groups. Conclusions: Paediatric LDS patients with TGFBR2 present with more severe cardiovascular phenotypes than patients with TGFBR1 with larger aortic dimensions and increased aortic stiffness. Our findings suggest that genotypes should be taken into consideration in the clinical management of paediatric LDS patients.

Contexte: Les liens entre le génotype des enfants atteints du syndrome de Loeys-Dietz (SLD) et les particularités phénotypiques vasculaires et cardiaques n'ont pas encore été bien caractérisés. La présente étude vise à explorer les différences phénotypiques entre les propriétés de l'aorte et les paramètres cardiaques structuraux et fonctionnels des enfants atteints du SLD qui présentent une mutation du gène TGFBR1 et ceux qui présentent une mutation du gène TGFBR2. Méthodologie: Nous avons inclus dans notre analyse 32 patients atteints du SLD présentant une mutation de TGFBR1 (n = 17) ou de TGFBR2 (n = 15). Les données échocardiographiques colligées incluaient les dimensions de l'aorte, sa distensibilité, sa déformation (strain) et sa rigidité au niveau de l'anneau aortique, des sinus de Valsalva, de la jonction sinotubulaire, de l'aorte ascendante et de l'aorte descendante. Les paramètres ayant trait à la taille et à la fonction du ventricule gauche ont également été consignés. Résultats: Les caractéristiques démographiques étaient comparables dans les deux groupes. Les patients présentant une mutation du gène TGFBR2 étaient plus susceptibles d'avoir subi une intervention chirurgicale de l'aorte (47 % vs 12 %, p = 0,057) et de prendre un antagoniste des récepteurs de l'angiotensine (93 % vs 47 %, p = 0,015). Les scores z aortiques étaient significativement plus élevés chez les patients présentant une mutation de TGFBR2 pour les dimensions de l'anneau de la valve aortique (p = 0,007), des sinus of Valsalva (p = 0,001), de la jonction sinotubulaire (p = 0,001) et de l'aorte ascendante (p = 0,054). Les patients avec une mutation de TGFBR2 présentaient aussi une élasticité et une déformation aortiques significativement plus faibles ainsi qu'une rigidité accrue au niveau de l'anneau aortique, de la jonction sinotubulaire et de l'aorte ascendante. Les paramètres de l'aorte descendante, les caractéristiques morphologiques cardiaques et la fonction cardiaque étaient comparables pour les deux groupes. Conclusions: Chez les enfants atteints du SLD, une mutation du gène TGFBR2 se traduisait par des phénotypes plus défavorables que dans le cas d'une mutation du gène TGFBR1 et se caractérisait par des dimensions et une rigidité aortiques accrues. Nos observations indiquent qu'il convient de prendre le génotype des patients en considération lors de la prise en charge clinique des enfants atteints du SLD.

Mechanistic safety assessment via multi-omic characterisation of systemic pathway perturbations following in vivo MAT2A inhibition.

The tumour suppressor p16/CDKN2A and the metabolic gene, methyl-thio-adenosine phosphorylase (MTAP), are frequently co-deleted in some of the most aggressive and currently untreatable cancers. Cells with MTAP deletion are vulnerable to inhibition of the metabolic enzyme, methionine-adenosyl transferase 2A (MAT2A), and the protein arginine methyl transferase (PRMT5). This synthetic lethality has paved the way for the rapid development of drugs targeting the MAT2A/PRMT5 axis. MAT2A and its liver- and pancreas-specific isoform, MAT1A, generate the universal methyl donor S-adenosylmethionine (SAM) from ATP and methionine. Given the pleiotropic role SAM plays in methylation of diverse substrates, characterising the extent of SAM depletion and downstream perturbations following MAT2A/MAT1A inhibition (MATi) is critical for safety assessment. We have assessed in vivo target engagement and the resultant systemic phenotype using multi-omic tools to characterise response to a MAT2A inhibitor (AZ'9567). We observed significant SAM depletion and extensive methionine accumulation in the plasma, liver, brain and heart of treated rats, providing the first assessment of both global SAM depletion and evidence of hepatic MAT1A target engagement. An integrative analysis of multi-omic data from liver tissue identified broad perturbations in pathways covering one-carbon metabolism, trans-sulfuration and lipid metabolism. We infer that these pathway-wide perturbations represent adaptive responses to SAM depletion and confer a risk of oxidative stress, hepatic steatosis and an associated disturbance in plasma and cellular lipid homeostasis. The alterations also explain the dramatic increase in plasma and tissue methionine, which could be used as a safety and PD biomarker going forward to the clinic.

Deciphering novel TCF4-driven mechanisms underlying a common triplet repeat expansion-mediated disease.

Fuchs endothelial corneal dystrophy (FECD) is an age-related cause of vision loss, and the most common repeat expansion-mediated disease in humans characterised to date. Up to 80% of European FECD cases have been attributed to expansion of a non-coding CTG repeat element (termed CTG18.1) located within the ubiquitously expressed transcription factor encoding gene, TCF4. The non-coding nature of the repeat and the transcriptomic complexity of TCF4 have made it extremely challenging to experimentally decipher the molecular mechanisms underlying this disease. Here we comprehensively describe CTG18.1 expansion-driven molecular components of disease within primary patient-derived corneal endothelial cells (CECs), generated from a large cohort of individuals with CTG18.1-expanded (Exp+) and CTG 18.1-independent (Exp-) FECD. We employ long-read, short-read, and spatial transcriptomic techniques to interrogate expansion-specific transcriptomic biomarkers. Interrogation of long-read sequencing and alternative splicing analysis of short-read transcriptomic data together reveals the global extent of altered splicing occurring within Exp+ FECD, and unique transcripts associated with CTG18.1-expansions. Similarly, differential gene expression analysis highlights the total transcriptomic consequences of Exp+ FECD within CECs. Furthermore, differential exon usage, pathway enrichment and spatial transcriptomics reveal TCF4 isoform ratio skewing solely in Exp+ FECD with potential downstream functional consequences. Lastly, exome data from 134 Exp- FECD cases identified rare (minor allele frequency <0.005) and potentially deleterious (CADD>15) TCF4 variants in 7/134 FECD Exp- cases, suggesting that TCF4 variants independent of CTG18.1 may increase FECD risk. In summary, our study supports the hypothesis that at least two distinct pathogenic mechanisms, RNA toxicity and TCF4 isoform-specific dysregulation, both underpin the pathophysiology of FECD. We anticipate these data will inform and guide the development of translational interventions for this common triplet-repeat mediated disease.

Developing plant functional groups to identify changes in functional composition and diversity in a dryland river experiencing artificially sustained flows.

Land use and climate changes are driving significant shifts in the magnitude and persistence of dryland stream surface flows. The impact of these shifts on ecological functioning is largely unknown, particularly where streams have become wetter rather than drier. This study investigated relationships between hydrologic regime (including surface water persistence, differences in groundwater depth and altered flooding dynamics) with plant traits and riverine vegetation functional composition. Our study system was a previously ephemeral creek in semi-arid northwest Australia that has received groundwater discharge from nearby mining operations for >15 years; surface flows are now persistent for ∼27 km downstream of the discharge point. We aimed to (i) identify plant functional groups (FGs) associated with the creek and adjacent floodplain; and (ii) assess their distribution across hydrological gradients to predict shifts in ecological functioning in response to changing flow regimes. Seven FGs were identified using hierarchical clustering of 40 woody perennial plant species based on morphometric, phenological and physiologic traits. We then investigated how FG abundance (projective foliar cover), functional composition, and functional and taxonomic richness varied along a 14 km gradient from persistent to ephemeral flows, varying groundwater depths, and distances from the stream channel. Dominant FGs were (i) drought avoidant mesic trees that are fluvial stress tolerant, or (ii) drought tolerant xeric tall shrubs that are fluvial stress intolerant. The drought avoidant mesic tree FG was associated with shallow groundwater but exhibited lower cover in riparian areas closer to the discharge (persistent surface flows). However, there were more FGs and higher species richness closer to the discharge point, particularly on the floodplain. Our findings demonstrate that quantifying FG distribution and diversity is a significant step in both assessing the impacts of mine water discharge on riverine ecosystems and for planning for post-mining restoration.

Bulk Free Radical Terpolymerization of Butyl Acrylate, 2-Methylene-1,3-Dioxepane and Vinyl Acetate: Terpolymer Reactivity Ratio Estimation.

This investigation introduces the first estimation of ternary reactivity ratios for a butyl acrylate (BA), 2-methylene-1,3-dioxepane (MDO), and vinyl acetate (VAc) system at 50 °C, with an aim to develop biodegradable pressure-sensitive adhesives (PSAs). In this study, we applied the error-in-variables model (EVM) to estimate reactivity ratios. The ternary reactivity ratios were found to be r12 = 0.417, r21 = 0.071, r13 = 4.459, r31 = 0.198, r23 = 0.260, and r32 = 55.339 (BA/MDO/VAc 1/2/3), contrasting with their binary counterparts, which are significantly different, indicating the critical need for ternary system analysis to accurately model multicomponent polymerization systems. Through the application of a recast Alfrey-Goldfinger model, this investigation predicts the terpolymer's instantaneous and cumulative compositions at various conversion levels, based on the ternary reactivity ratios. These predictions not only provide crucial insights into the incorporation of MDO across different initial feed compositions but also offer estimates of the final terpolymer compositions and distributions, underscoring their potential in designing compostable or degradable polymers.

Health System and Individual Barriers to Supporting Healthy Gestational Weight Gain and Nutrition: A Qualitative Study of the Experiences of Midwives and Obstetricians in Publicly Funded Antenatal Care in Tasmania, Australia.

Individual and health system barriers can impede clinicians from supporting weight-related behaviour change for pregnant women, particularly in publicly funded antenatal care accessed by women from diverse socioeconomic backgrounds. The aim was to understand clinicians' experiences of supporting healthy gestational weight gain for pregnant women in a publicly funded antenatal setting. The work was undertaken to guide the implementation of systems changes, resource development, and workforce capacity building related to nutrition, physical activity, and gestational weight gain in the service. The qualitative descriptive study used purposive sampling and semi-structured interviews conducted between October 2019 and February 2020. Nine midwives and five obstetricians from a publicly funded hospital antenatal service in Tasmania, Australia participated. Interview transcripts were analysed using inductive thematic analysis. The three dominant themes were prioritising immediate needs, continuity of care support weight-related conversations, and limited service capacity for weight- and nutrition-related support. The subthemes were different practices for women according to weight and the need for appropriately tailored resources. Improving access to continuity of care and clinician training, and providing resources that appropriately consider women's socioeconomic circumstances and health literacy would enhance the ability and opportunities for clinicians to better support all women.

Zero Suicide Quality Improvement: Developmental and Pandemic-Related Patterns in Youth at Risk for Suicide Attempts.

The Zero Suicide (ZS) approach to health system quality improvement (QI) aspires to reduce/eliminate suicides through enhancing risk detection and suicide-prevention services. This first report from our randomized trial evaluating a stepped care for suicide prevention intervention within a health system conducting ZS-QI describes 1) our screening and case identification process, 2) variation among adolescents versus young adults; and 3) pandemic-related patterns during the first COVID-19 pandemic year. Between April 2017 and January 2021, youths aged 12-24 with elevated suicide risk were identified through an electronic health record (EHR) case-finding algorithm followed by direct assessment screening to confirm risk. Eligible/enrolled youth were evaluated for suicidality, self-harm, and risk/protective factors. Case finding, screening, and enrollment yielded 301 participants showing suicide risk-indicators: 97% past-year suicidal ideation, 83% past suicidal behavior; 90% past non-suicidal self-injury (NSSI). Compared to young adults, adolescents reported: more past-year suicide attempts (47% vs 21%, p<.001) and NSSI (past 6-months, 64% vs 39%, p<.001); less depression, anxiety, posttraumatic stress, and substance use; and greater social connectedness. Pandemic-onset was associated with lower participation of racial-ethnic minority youths (18% vs 33%, p<.015) and lower past-month suicidal ideation and behavior. Results support the value of EHR case-finding algorithms for identifying youths with potentially elevated risk who could benefit from suicide-prevention services, which merit adaptation for adolescents versus young adults. Lower racial-ethnic minority participation after the COVID-19 pandemic-onset underscores challenges for services to enhance health equity during a period with restricted in-person health care, social distancing, school closures, and diverse stresses.

Emapalumab as salvage therapy for adults with malignancy-associated hemophagocytic lymphohistiocytosis.

Not available.

Improving Conversations about Parkinson's Dementia.

BACKGROUND: People with Parkinson's disease (PD) have an increased risk of dementia, yet patients and clinicians frequently avoid talking about it due to associated stigma, and the perception that "nothing can be done about it". However, open conversations about PD dementia may allow people with the condition to access treatment and support, and may increase participation in research aimed at understanding PD dementia. OBJECTIVES: To co-produce information resources for patients and healthcare professionals to improve conversations about PD dementia. METHODS: We worked with people with PD, engagement experts, artists, and a PD charity to open up these conversations. 34 participants (16 PD; 6 PD dementia; 1 Parkinsonism, 11 caregivers) attended creative workshops to examine fears about PD dementia and develop information resources. 25 PD experts contributed to the resources. RESULTS: While most people with PD (70%) and caregivers (81%) shared worries about cognitive changes prior to the workshops, only 38% and 30%, respectively, had raised these concerns with a healthcare professional. 91% of people with PD and 73% of caregivers agreed that PD clinicians should ask about cognitive changes routinely through direct questions and perform cognitive tests at clinic appointments. We used insights from the creative workshops, and input from a network of PD experts to co-develop two open-access resources: one for people with PD and their families, and one for healthcare professionals. CONCLUSION: Using artistic and creative workshops, co-learning and striving for diverse voices, we co-produced relevant resources for a wider audience to improve conversations about PD dementia.

Towards a standardized framework for AI-assisted, image-based monitoring of nocturnal insects.

Automated sensors have potential to standardize and expand the monitoring of insects across the globe. As one of the most scalable and fastest developing sensor technologies, we describe a framework for automated, image-based monitoring of nocturnal insects-from sensor development and field deployment to workflows for data processing and publishing. Sensors comprise a light to attract insects, a camera for collecting images and a computer for scheduling, data storage and processing. Metadata is important to describe sampling schedules that balance the capture of relevant ecological information against power and data storage limitations. Large data volumes of images from automated systems necessitate scalable and effective data processing. We describe computer vision approaches for the detection, tracking and classification of insects, including models built from existing aggregations of labelled insect images. Data from automated camera systems necessitate approaches that account for inherent biases. We advocate models that explicitly correct for bias in species occurrence or abundance estimates resulting from the imperfect detection of species or individuals present during sampling occasions. We propose ten priorities towards a step-change in automated monitoring of nocturnal insects, a vital task in the face of rapid biodiversity loss from global threats. This article is part of the theme issue 'Towards a toolkit for global insect biodiversity monitoring'.

Endotypes of Exacerbation in Bronchiectasis: An Observational Cohort Study.

RATIONALE: Bronchiectasis is characterised by acute exacerbations but the biological mechanisms underlying these events is poorly characterised. Objectives To investigate the inflammatory and microbial characteristics of exacerbations of bronchiectasis. METHODS: 120 patients with bronchiectasis were enrolled and presented with acute exacerbations within 12 months. Spontaneous sputum samples were obtained during a period of clinical stability and again at exacerbation prior to receipt of antibiotic treatment. A validated rapid PCR assay for bacteria and viruses was used to classify exacerbations as bacterial, viral or both. Sputum inflammatory assessments included label free Liquid chromography/mass spectrometry and measurement of sputum cytokines and neutrophil elastase activity. 16s rRNA sequencing was used to characterise the microbiome. MEASUREMENTS AND MAIN RESULTS: Bronchiectasis exacerbations showed profound molecular heterogeneity. At least one bacteria was identified in 103 samples (86%) and a high bacterial load (total bacterial load >10(7) copies/g) was observed in 81 patients (68%). Respiratory viruses were identified in 55 (46%) patients with rhinovirus being the most common virus (31%). PCR was more sensitive than culture. No consistent change in the microbiome was observed at exacerbation. Exacerbations were associated with increased neutrophil elastase, proteinase-3, Il-1beta and CXCL8. There markers were particularly associated with bacterial and bacterial+viral exacerbations. Distinct inflammatory and microbiome profiles were seen between different exacerbation subtypes, including bacterial, viral and eosinophilic events in both hypothesis led, and hypothesis-free analysis using integrated microbiome and proteomics, demonstrating 4 subtypes of exacerbation. CONCLUSION: Bronchiectasis exacerbations are heterogeneous events with contributions from bacteria, viruses and inflammatory dysregulation.

Rules of engagement for condensins and cohesins guide mitotic chromosome formation.

During mitosis, interphase chromatin is rapidly converted into rod-shaped mitotic chromosomes. Using Hi-C, imaging, proteomics and polymer modeling, we determine how the activity and interplay between loop-extruding SMC motors accomplishes this dramatic transition. Our work reveals rules of engagement for SMC complexes that are critical for allowing cells to refold interphase chromatin into mitotic chromosomes. We find that condensin disassembles interphase chromatin loop organization by evicting or displacing extrusive cohesin. In contrast, condensin bypasses cohesive cohesins, thereby maintaining sister chromatid cohesion while separating the sisters. Studies of mitotic chromosomes formed by cohesin, condensin II and condensin I alone or in combination allow us to develop new models of mitotic chromosome conformation. In these models, loops are consecutive and not overlapping, implying that condensins do not freely pass one another but stall upon encountering each other. The dynamics of Hi-C interactions and chromosome morphology reveal that during prophase loops are extruded in vivo at ~1-3 kb/sec by condensins as they form a disordered discontinuous helical scaffold within individual chromatids.

Prospective evaluation of patients with non-cirrhotic portal hypertension: A single centre study.

BACKGROUND: Non-cirrhotic portal hypertension (NCPH) is a spectrum of liver diseases, including porto-sinusoidal vascular disorder, with portal hypertension (PH) in the absence of cirrhosis. The natural history and diagnostic approach to NCPH are not well understood. AIM: We aimed to evaluate disease progression and outcomes in NCPH. METHODS: Patients with or at risk for NCPH were enrolled in a single centre prospective study; two groups were formed based on the presence of specific features of PH, such as varices, collaterals, portal hypertensive gastropathy or portal hypertensive bleeding. All participants underwent a baseline liver biopsy. Liver stiffness measurement (LSM), and imaging were repeated every 6-12 months. RESULTS: Fifteen patients without specific features of PH (Group I), and 35 patients with specific features (Group II) were enrolled. The median follow-up time was 50 months. Group II had higher hepatic venous pressure gradients, non-invasive measures of PH and a lower platelet count (PLT) when compared to Group I. Rates of survival and decompensation were similar in both groups. Patients with PLT ≤100 K/mcL had lower survival compared to those with PLT >100 K/mcL. Patients with LSM ≥10 kPa had lower survival and survival without decompensation when compared to patients with LSM <10 kPa. CONCLUSIONS: Patients irrespective of specific features of PH had similar survival or survival without decompensation. Patients without specific features are at risk for disease progression and should be monitored closely. Thrombocytopenia and increased LSM are associated with severe forms of liver disease, which are strongly associated with outcomes.

Experiences of mpox illness and case management among cis and trans gay, bisexual and other men who have sex with men in England: a qualitative study.

Background: The 2022-2024 global mpox outbreak, occurring primarily in the sexual networks of gay, bisexual and other men who have sex with men (GBMSM), has not been accompanied by a focus on patient perspectives of illness. We explore the experiences of GBMSM diagnosed with mpox in England to understand needs for social and clinical support. Methods: In-depth interviews (March/July 2023) were conducted with 22 GBMSM diagnosed with mpox in 2022, randomly selected from a national mpox surveillance database, and 4 stakeholders from clinical/community-based organisations. Interviews covered experiences of illness, testing, diagnosis, treatment and contact tracing, and were recorded, transcribed and analysed with a thematic framework. Findings: Media coverage drawing on homophobic stereotypes around sex between men contributed to feelings of stigma and shame. GBMSM living with HIV appeared to cope better with mpox stigma, drawing on their experiences of being diagnosed with HIV for resilience. Younger GBMSM with less experience of stigmatising illness found mpox diagnosis more traumatic and sometimes required support beyond what was provided. Accessing testing could be complicated when healthcare professionals did not recognise mpox symptoms. Men felt information on course of illness, isolation and vaccination after recovery was often inconsistent and contradictory. GBMSM described that care from sexual health and infectious disease units usually better met their emotional and medical needs. This was frequently linked by men to these services having skills in working with the GBMSM community and managing infection risk sensitively. General hospital services and centralised contact tracing could increase feelings and experiences of stigma as some staff were perceived to lack skills in supporting GBMSM and, sometimes, clinical knowledge. Long-term impacts described by men included mental health challenges, urethral/rectal symptoms and life-changing disability. Interpretation: In this study stigma was a central feature of mpox illness among GBMSM and could be exacerbated or lessened depending on the clinical and social support provided. Involving communities affected by outbreaks in co-producing, planning and delivering care (including contact-tracing) may help improve support provided. Funding: TCW, AJR, AS and FMB received support from the National Institute for Health and Care Research (NIHR) under its Programme Grants for Applied Research Programme (Ref: NIHR202038). CS and JS receive support from the National Institute for Health and Care Research Health Protection Research Unit (NIHR HPRU) in Blood Borne and Sexually Transmitted Infections at UCL in partnership with UKHSA; RV receives support from the NIHR HPRU in Emerging and Zoonotic Infections and NIHR HPRU in Gastrointestinal Infections. The views expressed are those of the author(s) and not necessarily those of the NIHR, UK Health Security Agency, World Health Organization or the Department of Health and Social Care.

Factors affecting severity of wildfires in Scottish heathlands and blanket bogs.

Temperate heathlands and blanket bogs are globally rare and face growing wildfire threats. Ecosystem impacts differ between low and high severity fires, where severity reflects immediate fuel consumption. This study assessed factors influencing fire severity in Scottish heathlands and blanket bogs, including the efficacy of the Canadian Fire Weather Index System (CFWIS). Using remote sensing, we measured the differenced Normalised Burn Ratio at 92 wildfire sites from 2015 to 2021. We used Generalised Additive Mixed Models to investigate the impact of topography, habitat wetness, CFWIS components and 30-day weather on severity. Dry heath exhibited higher severity than wet heath and blanket bog, and slope, elevation and south facing aspect were positively correlated to severity. Weather effects were less clear due to data scale differences, yet still indicated weather's significant role in severity. Rainfall had an increasingly negative effect from approximately 15 days before the fire, whilst temperature had an increasingly positive effect. Vapour Pressure Deficit (VPD) was the weather variable with highest explanatory value, and predicted severity better than any CFWIS component. The best-explained fire severity model (R2 = 0.25) incorporated topography, habitat wetness wind and VPD on the day of the fire. The Drought Code (DC), predicting organic matter flammability at ≥10 cm soil depth, was the CFWIS component with the highest predictive effect across habitats. Our findings suggest that wildfires in wet heath and blanket bogs are typically characterised by low severity, but that warmer, drier weather may increase the risk of severe, smouldering fires which threaten peatland carbon stores.

A framework for the evaluation and reporting of incidental findings in clinical genomic testing.

Currently, there are no widely accepted recommendations in the genomics field guiding the return of incidental findings (IFs), defined here as unexpected results that are unrelated to the indication for testing. Consequently, reporting policies for IFs among laboratories offering genomic testing are variable and may lack transparency. Herein we describe a framework developed to guide the evaluation and return of IFs encountered in probands undergoing clinical genome sequencing (cGS). The framework prioritizes clinical significance and actionability of IFs and follows a stepwise approach with stopping points at which IFs may be recommended for return or not. Over 18 months, implementation of the framework in a clinical laboratory facilitated the return of actionable IFs in 37 of 720 (5.1%) individuals referred for cGS, which is reduced to 3.1% if glucose-6-phosphate dehydrogenase (G6PD) deficiency is excluded. This framework can serve as a model to standardize reporting of IFs identified during genomic testing.

Determining the characteristics of genetic disorders that predict inclusion in newborn genomic sequencing programs.

Over 30 international research studies and commercial laboratories are exploring the use of genomic sequencing to screen apparently healthy newborns for genetic disorders. These programs have individualized processes for determining which genes and genetic disorders are queried and reported in newborns. We compared lists of genes from 26 research and commercial newborn screening programs and found substantial heterogeneity among the genes included. A total of 1,750 genes were included in at least one newborn genome sequencing program, but only 74 genes were included on >80% of gene lists, 16 of which are not associated with conditions on the Recommended Uniform Screening Panel. We used a linear regression model to explore factors related to the inclusion of individual genes across programs, finding that a high evidence base as well as treatment efficacy were two of the most important factors for inclusion. We applied a machine learning model to predict how suitable a gene is for newborn sequencing. As knowledge about and treatments for genetic disorders expand, this model provides a dynamic tool to reassess genes for newborn screening implementation. This study highlights the complex landscape of gene list curation among genomic newborn screening programs and proposes an empirical path forward for determining the genes and disorders of highest priority for newborn screening programs.