Bioinformatics pipeline for the systematic mining genomic and proteomic variation linked to rare diseases: The example of monogenic diabetes.

Monogenic diabetes is characterized as a group of diseases caused by rare variants in single genes. Like for other rare diseases, multiple genes have been linked to monogenic diabetes with different measures of pathogenicity, but the information on the genes and variants is not unified among different resources, making it challenging to process them informatically. We have developed an automated pipeline for collecting and harmonizing data on genetic variants linked to monogenic diabetes. Furthermore, we have translated variant genetic sequences into protein sequences accounting for all protein isoforms and their variants. This allows researchers to consolidate information on variant genes and proteins linked to monogenic diabetes and facilitates their study using proteomics or structural biology. Our open and flexible implementation using Jupyter notebooks enables tailoring and modifying the pipeline and its application to other rare diseases.

Rare copy number variation in autoimmune Addison's disease.

Autoimmune Addison's disease (AAD) is a rare but life-threatening endocrine disorder caused by an autoimmune destruction of the adrenal cortex. A previous genome-wide association study (GWAS) has shown that common variants near immune-related genes, which mostly encode proteins participating in the immune response, affect the risk of developing this condition. However, little is known about the contribution of copy number variations (CNVs) to AAD susceptibility. We used the genome-wide genotyping data from Norwegian and Swedish individuals (1,182 cases and 3,810 controls) to investigate the putative role of CNVs in the AAD aetiology. Although the frequency of rare CNVs was similar between cases and controls, we observed that larger deletions (>1,000 kb) were more common among patients (OR = 4.23, 95% CI 1.85-9.66, p = 0.0002). Despite this, none of the large case-deletions were conclusively pathogenic, and the clinical presentation and an AAD-polygenic risk score were similar between cases with and without the large CNVs. Among deletions exclusive to individuals with AAD, we highlight two ultra-rare deletions in the genes LRBA and BCL2L11, which we speculate might have contributed to the polygenic risk in these carriers. In conclusion, rare CNVs do not appear to be a major cause of AAD but further studies are needed to ascertain the potential contribution of rare deletions to the polygenic load of AAD susceptibility.

Smoking during pregnancy and its effect on placental weight: a Mendelian randomization study.

BACKGROUND: The causal relationship between maternal smoking in pregnancy and reduced offspring birth weight is well established and is likely due to impaired placental function. However, observational studies have given conflicting results on the association between smoking and placental weight. We aimed to estimate the causal effect of newly pregnant mothers quitting smoking on their placental weight at the time of delivery. METHODS: We used one-sample Mendelian randomization, drawing data from the Avon Longitudinal Study of Parents and Children (ALSPAC) (N = 690 to 804) and the Norwegian Mother, Father and Child Cohort Study (MoBa) (N = 4267 to 4606). The sample size depends on the smoking definition used for different analyses. The analysis was performed in pre-pregnancy smokers only, due to the specific role of the single-nucleotide polymorphism (SNP) rs1051730 (CHRNA5 - CHRNA3 - CHRNB4) in affecting smoking cessation but not initiation. RESULTS: Fixed effect meta-analysis showed a 182 g [95%CI: 29,335] higher placental weight for pre-pregnancy smoking mothers who continued smoking at the beginning of pregnancy, compared with those who stopped smoking. Using the number of cigarettes smoked per day in the first trimester as the exposure, the causal effect on placental weight was 11 g [95%CI: 1,21] per cigarette per day. Similarly, smoking at the end of pregnancy was causally associated with higher placental weight. Using the residuals of birth weight regressed on placental weight as the outcome, we showed evidence of lower offspring birth weight relative to the placental weight, both for continuing smoking at the start of pregnancy as well as continuing smoking throughout pregnancy (change in z-score birth weight adjusted for z-score placental weight: -0.8 [95%CI: -1.6,-0.1]). CONCLUSION: Our results suggest that continued smoking during pregnancy causes higher placental weights.

Acetaminophen Use During Pregnancy and Children's Risk of Autism, ADHD, and Intellectual Disability.

Importance: Several studies suggest that acetaminophen (paracetamol) use during pregnancy may increase risk of neurodevelopmental disorders in children. If true, this would have substantial implications for management of pain and fever during pregnancy. Objective: To examine the associations of acetaminophen use during pregnancy with children's risk of autism, attention-deficit/hyperactivity disorder (ADHD), and intellectual disability. Design, Setting, and Participants: This nationwide cohort study with sibling control analysis included a population-based sample of 2 480 797 children born in 1995 to 2019 in Sweden, with follow-up through December 31, 2021. Exposure: Use of acetaminophen during pregnancy prospectively recorded from antenatal and prescription records. Main Outcomes and Measures: Autism, ADHD, and intellectual disability based on International Classification of Diseases, Ninth Revision and International Classification of Diseases, Tenth Revision codes in health registers. Results: In total, 185 909 children (7.49%) were exposed to acetaminophen during pregnancy. Crude absolute risks at 10 years of age for those not exposed vs those exposed to acetaminophen were 1.33% vs 1.53% for autism, 2.46% vs 2.87% for ADHD, and 0.70% vs 0.82% for intellectual disability. In models without sibling control, ever-use vs no use of acetaminophen during pregnancy was associated with marginally increased risk of autism (hazard ratio [HR], 1.05 [95% CI, 1.02-1.08]; risk difference [RD] at 10 years of age, 0.09% [95% CI, -0.01% to 0.20%]), ADHD (HR, 1.07 [95% CI, 1.05-1.10]; RD, 0.21% [95% CI, 0.08%-0.34%]), and intellectual disability (HR, 1.05 [95% CI, 1.00-1.10]; RD, 0.04% [95% CI, -0.04% to 0.12%]). To address unobserved confounding, matched full sibling pairs were also analyzed. Sibling control analyses found no evidence that acetaminophen use during pregnancy was associated with autism (HR, 0.98 [95% CI, 0.93-1.04]; RD, 0.02% [95% CI, -0.14% to 0.18%]), ADHD (HR, 0.98 [95% CI, 0.94-1.02]; RD, -0.02% [95% CI, -0.21% to 0.15%]), or intellectual disability (HR, 1.01 [95% CI, 0.92-1.10]; RD, 0% [95% CI, -0.10% to 0.13%]). Similarly, there was no evidence of a dose-response pattern in sibling control analyses. For example, for autism, compared with no use of acetaminophen, persons with low (<25th percentile), medium (25th-75th percentile), and high (>75th percentile) mean daily acetaminophen use had HRs of 0.85, 0.96, and 0.88, respectively. Conclusions and Relevance: Acetaminophen use during pregnancy was not associated with children's risk of autism, ADHD, or intellectual disability in sibling control analysis. This suggests that associations observed in other models may have been attributable to familial confounding.

Common single-base insertions in the VNTR of the carboxyl ester lipase (CEL) gene are benign and also likely to arise somatically in the exocrine pancreas.

The CEL gene encodes carboxyl ester lipase, a pancreatic digestive enzyme. CEL is extremely polymorphic due to a variable number tandem repeat (VNTR) located in the last exon. Single-base deletions within this VNTR cause the inherited disorder MODY8, whereas little is known about VNTR single-base insertions in pancreatic disease. We therefore mapped CEL insertion variants (CEL-INS) in 200 Norwegian patients with pancreatic neoplastic disorders. Twenty-eight samples (14.0%) carried CEL-INS alleles. Most common were insertions in repeat 9 (9.5%), which always associated with a VNTR length of 13 repeats. The combined INS allele frequency (0.078) was similar to that observed in a control material of 416 subjects (0.075). We performed functional testing in HEK293T cells of a set of CEL-INS variants, in which the insertion site varied from the first to the 12th VNTR repeat. Lipase activity showed little difference among the variants. However, CEL-INS variants with insertions occurring in the most proximal repeats led to protein aggregation and endoplasmic reticulum stress, which upregulated the unfolded protein response. Moreover, by using a CEL-INS-specific antibody, we observed patchy signals in pancreatic tissue from humans without any CEL-INS variant in the germline. Similar pancreatic staining was seen in knock-in mice expressing the most common human CEL VNTR with 16 repeats. CEL-INS proteins may therefore be constantly produced from somatic events in the normal pancreatic parenchyma. This observation along with the high population frequency of CEL-INS alleles strongly suggests that these variants are benign, with a possible exception for insertions in VNTR repeats 1-4.

Neurological development in children born moderately or late preterm: national cohort study.

OBJECTIVE: To assess long term neurodevelopmental outcomes of children born at different gestational ages, particularly 32-33 weeks (moderately preterm) and 34-36 weeks (late preterm), compared with 39-40 weeks (full term). DESIGN: Nationwide cohort study. SETTING: Sweden. PARTICIPANTS: 1 281 690 liveborn singleton children without congenital malformations born at 32+0 to 41+6 weeks between 1998 and 2012. MAIN OUTCOME MEASURES: The primary outcomes of interest were motor, cognitive, epileptic, hearing, and visual impairments and a composite of any neurodevelopmental impairment, diagnosed up to age 16 years. Hazard ratios and 95% confidence intervals were estimated using Cox regression adjusted for parental and infant characteristics in the study population and in the subset of full siblings. Risk differences were also estimated to assess the absolute risk of neurodevelopmental impairment. RESULTS: During a median follow-up of 13.1 years (interquartile range 9.5-15.9 years), 75 311 (47.8 per 10 000 person years) liveborn singleton infants without congenital malformations had at least one diagnosis of any neurodevelopmental impairment: 5899 (3.6 per 10 000 person years) had motor impairment, 27 371 (17.0 per 10 000 person years) cognitive impairment, 11 870 (7.3 per 10 000 person years) epileptic impairment, 19 700 (12.2 per 10 000 person years) visual impairment, and 20 393 (12.6 per 10 000 person years) hearing impairment. Children born moderately or late preterm, compared with those born full term, showed higher risks for any impairment (hazard ratio 1.73 (95% confidence interval 1.60 to 1.87) and 1.30 (1.26 to 1.35); risk difference 4.75% (95% confidence interval 3.88% to 5.60%) and 2.03% (1.75% to 2.35%), respectively) as well as motor, cognitive, epileptic, visual, and hearing impairments. Risks for neurodevelopmental impairments appeared highest from 32 weeks (the earliest gestational age), gradually declined until 41 weeks, and were also higher at 37-38 weeks (early term) compared with 39-40 weeks. In the sibling comparison analysis (n=349 108), most associations remained stable except for gestational age and epileptic and hearing impairments, where no association was observed; for children born early term the risk was only higher for cognitive impairment compared with those born full term. CONCLUSIONS: The findings of this study suggest that children born moderately or late preterm have higher risks of adverse neurodevelopmental outcomes. The risks should not be underestimated as these children comprise the largest proportion of children born preterm. The findings may help professionals and families achieve a better risk assessment and follow-up.

Maternal Fiber Intake During Pregnancy and Development of Attention-Deficit/Hyperactivity Disorder Symptoms Across Childhood: The Norwegian Mother, Father, and Child Cohort Study.

BACKGROUND: Epidemiological studies suggest that maternal diet quality during pregnancy may influence the risk of neurodevelopmental disorders in offspring. Here, we investigated associations between maternal intake of dietary fiber and attention-deficit/hyperactivity disorder (ADHD) symptoms in early childhood. METHODS: We used longitudinal data of up to 21,852 mother-father-child trios (49.2% female offspring) from MoBa (the Norwegian Mother, Father, and Child Cohort Study). The relationships between maternal fiber intake during pregnancy and offspring ADHD symptoms at ages 3, 5, and 8 years were examined using 1) multivariate regression (overall levels of ADHD symptoms), 2) latent class analysis (subclasses of ADHD symptoms by sex at each age), and 3) latent growth curves (longitudinal change in offspring ADHD symptoms). Covariates were ADHD polygenic scores in child and parents, total energy intake and energy-adjusted sugar intake, parental ages at birth of the child, and sociodemographic factors. RESULTS: Higher maternal prenatal fiber intake was associated with lower offspring ADHD symptom scores at all ages (Bage3 = -0.14 [95% CI, -0.18 to -0.10]; Bage5 = -0.14 [95% CI, -0.19 to -0.09]; Bage8 = -0.14 [95% CI, -0.20 to -0.09]). Of the derived low/middle/high subclasses of ADHD symptoms, fiber was associated with lower risk of belonging to the middle subclass for boys and girls and to the high subclass for girls only (middle: odds ratioboys 0.91 [95% CI, 0.86 to 0.97]/odds ratiogirls 0.86 [95% CI, 0.81 to 0.91]; high: odds ratiogirls 0.82 [95% CI, 0.72 to 0.94]). Maternal fiber intake and rate of change in child ADHD symptoms across ages were not associated. CONCLUSIONS: Low prenatal maternal fiber intake may increase symptom levels of ADHD in offspring during childhood, independently of genetic predisposition to ADHD, unhealthy dietary exposures, and sociodemographic factors.

Direct ink writing of high-resolution cellulose structures.

3D printing is envisioned to play an important role in the production of membranes for e.g., water purification and bio-separation applications due to the prospect of creating new and cleverly designed structures. Among different 3D printing techniques, direct ink writing offers the opportunity to print a wide variety of materials with high-detail resolution. There is a range of parameters that need to be optimized in order to develop robust printing techniques at that scale. In this study, cellulose acetate (CA), which is a biocompatible material, has been used as an ink. In order to examine the printability and the possibility of printing features as small as a few µm, nozzles with different diameters and inks with varying amounts and molecular weights of CA were investigated. Findings in this study indicate that, depending on the wetting on the underlaying structure, the nozzle's internal and external diameter affects the detail resolution of the printed structure. Different inks result in different widths of printed strands and generally a higher amount and higher molecular weights of CA results in higher detail resolution. However, too high amount of CA and molecular weight will increase the clogging risk in the nozzle. In this study, the internal size of the nozzle was 3 µm, and by selecting a  suitable ink, it was possible to print strands down to 1 µm size and 6 µm inter-strand distance in the air, bridging supports with limited sagging. Furthermore, wall structures consisting of 300 layers, corresponding to about 300 µm in total height, were successfully printed.

Small animal PET with spontaneous inhalation of 15O-labelled oxygen gases: Longitudinal assessment of cerebral oxygen metabolism in a rat model of neonatal hypoxic-ischaemic encephalopathy.

Perinatal hypoxic-ischaemic encephalopathy (HIE) is the leading cause of irreversible brain damage resulting in serious neurological dysfunction among neonates. We evaluated the feasibility of positron emission tomography (PET) methodology with 15O-labelled gases without intravenous or tracheal cannulation for assessing temporal changes in cerebral blood flow (CBF) and cerebral metabolic rate for oxygen (CMRO2) in a neonatal HIE rat model. Sequential PET scans with spontaneous inhalation of 15O-gases mixed with isoflurane were performed over 14 days after the hypoxic-ischaemic insult in HIE pups and age-matched controls. CBF and CMRO2 in the injured hemispheres of HIE pups remarkably decreased 2 days after the insult, gradually recovering over 14 days in line with their increase found in healthy controls according to their natural maturation process. The magnitude of hemispheric tissue loss histologically measured after the last PET scan was significantly correlated with the decreases in CBF and CMRO2.This fully non-invasive imaging strategy may be useful for monitoring damage progression in neonatal HIE and for evaluating potential therapeutic outcomes.

A partial form of AIRE deficiency underlies a mild form of autoimmune polyendocrine syndrome type 1.

Autoimmune polyendocrine syndrome type 1 (APS-1) is caused by mutations in the autoimmune regulator (AIRE) gene. Most patients present with severe chronic mucocutaneous candidiasis and organ-specific autoimmunity from early childhood, but the clinical picture is highly variable. AIRE is crucial for negative selection of T cells, and scrutiny of different patient mutations has previously highlighted many of its molecular mechanisms. In patients with a milder adult-onset phenotype sharing a mutation in the canonical donor splice site of intron 7 (c.879+1G>A), both the predicted altered splicing pattern with loss of exon 7 (AireEx7-/-) and normal full-length AIRE mRNA were found, indicating leaky rather than abolished mRNA splicing. Analysis of a corresponding mouse model demonstrated that the AireEx7-/- mutant had dramatically impaired transcriptional capacity of tissue-specific antigens in medullary thymic epithelial cells but still retained some ability to induce gene expression compared with the complete loss-of-function AireC313X-/- mutant. Our data illustrate an association between AIRE activity and the severity of autoimmune disease, with implications for more common autoimmune diseases associated with AIRE variants, such as primary adrenal insufficiency, pernicious anemia, type 1 diabetes, and rheumatoid arthritis.

Characterisation of HNF1A variants in paediatric diabetes in Norway using functional and clinical investigations to unmask phenotype and monogenic diabetes.

AIMS/HYPOTHESIS: Correctly diagnosing MODY is important, as individuals with this diagnosis can discontinue insulin injections; however, many people are misdiagnosed. We aimed to develop a robust approach for determining the pathogenicity of variants of uncertain significance in hepatocyte nuclear factor-1 alpha (HNF1A)-MODY and to obtain an accurate estimate of the prevalence of HNF1A-MODY in paediatric cases of diabetes. METHODS: We extended our previous screening of the Norwegian Childhood Diabetes Registry by 830 additional samples and comprehensively genotyped HNF1A variants in autoantibody-negative participants using next-generation sequencing. Carriers of pathogenic variants were treated by local healthcare providers, and participants with novel likely pathogenic variants and variants of uncertain significance were enrolled in an investigator-initiated, non-randomised, open-label pilot study (ClinicalTrials.gov registration no. NCT04239586). To identify variants associated with HNF1A-MODY, we functionally characterised their pathogenicity and assessed the carriers' phenotype and treatment response to sulfonylurea. RESULTS: In total, 615 autoantibody-negative participants among 4712 cases of paediatric diabetes underwent genetic sequencing, revealing 19 with HNF1A variants. We identified nine carriers with novel variants classified as variants of uncertain significance or likely to be pathogenic, while the remaining ten participants carried five pathogenic variants previously reported. Of the nine carriers with novel variants, six responded favourably to sulfonylurea. Functional investigations revealed their variants to be dysfunctional and demonstrated a correlation with the resulting phenotype, providing evidence for reclassifying these variants as pathogenic. CONCLUSIONS/INTERPRETATION: Based on this robust classification, we estimate that the prevalence of HNF1A-MODY is 0.3% in paediatric diabetes. Clinical phenotyping is challenging and functional investigations provide a strong complementary line of evidence. We demonstrate here that combining clinical phenotyping with functional protein studies provides a powerful tool to obtain a precise diagnosis of HNF1A-MODY.

Two-Photon Polymerization Printing with High Metal Nanoparticle Loading.

Two-photon polymerization (2PP) is an efficient technique to achieve high-resolution, three-dimensional (3D)-printed complex structures. However, it is restricted to photocurable monomer combinations, thus presenting constraints when aiming at attaining functionally active resist formulations and structures. In this context, metal nanoparticle (NP) integration as an additive can enable functionality and pave the way to more dedicated applications. Challenges lay on the maximum NP concentrations that can be incorporated into photocurable resist formulations due to the laser-triggered interactions, which primarily originate from laser scattering and absorption, as well as the limited dispersibility threshold. In this study, we propose an approach to address these two constraints by integrating metallic Rh NPs formed ex situ, purposely designed for this scope. The absence of surface plasmon resonance (SPR) within the visible and near-infrared spectra, coupled with the limited absorption value measured at the laser operating wavelength (780 nm), significantly limits the laser-induced interactions. Moreover, the dispersibility threshold is increased by engineering the NP surface to be compatible with the photocurable resin, permitting us to achieve concentrations of up to 2 wt %, which, to our knowledge, is significantly higher than the previously reported limit (or threshold) for embedded metal NPs. Another distinctive advantage of employing Rh NPs is their role as promising contrast agents for X-ray fluorescence (XRF) bioimaging. We demonstrated the presence of Rh NPs within the whole 2PP-printed structure and emphasized the potential use of NP-loaded 3D-printed nanostructures for medical devices.

Smoking during pregnancy and its effect on placental weight: A Mendelian randomization study.

Background: The causal relationship between maternal smoking in pregnancy and reduced offspring birth weight is well established and is likely due to impaired placental function. However, observational studies have given conflicting results on the association between smoking and placental weight. We aimed to estimate the causal effect of newly pregnant mothers quitting smoking on their placental weight at the time of delivery. Methods: We used one-sample Mendelian randomization, drawing data from the Avon Longitudinal Study of Parents and Children (ALSPAC) (up to N = 805) and the Norwegian Mother, Father and Child Cohort Study (MoBa) (up to N = 4475). The analysis was performed in pre-pregnancy smokers only, due to the specific role of the genetic instrument SNP rs1051730 (CHRNA5 - CHRNA3 - CHRNB4) in affecting smoking cessation but not initiation. Results: Fixed effect meta-analysis showed a 175 g [95%CI: 16, 334] higher placental weight for pre-pregnancy smoking mothers who continued smoking at the beginning of pregnancy, compared with those who stopped smoking. Using the number of cigarettes smoked per day in the first trimester as the exposure, the causal estimate was a 12 g [95%CI: 2,22] higher placental weight per cigarette per day. Results were similar when the smoking exposures were measured at the end of pregnancy. Using the residuals of birth weight regressed on placental weight as the outcome, we showed weak evidence of lower offspring birth weight relative to the placental weight for continuing smoking. Conclusion: Our results suggest that continued smoking during pregnancy causes higher placental weights.

Extending protein interaction networks using proteoforms and small molecules.

MOTIVATION: Biological network analysis for high-throughput biomedical data interpretation relies heavily on topological characteristics. Networks are commonly composed of nodes representing genes or proteins that are connected by edges when interacting. In this study, we use the rich information available in the Reactome pathway database to build biological networks accounting for small molecules and proteoforms modeled using protein isoforms and post-translational modifications to study the topological changes induced by this refinement of the network representation. RESULTS: We find that improving the interactome modeling increases the number of nodes and interactions, but that isoform and post-translational modification annotation is still limited compared to what can be expected biologically. We also note that small molecule information can distort the topology of the network due to the high connectedness of these molecules, which does not necessarily represent the reality of biology. However, by restricting the connections of small molecules to the context of biochemical reactions, we find that these improve the overall connectedness of the network and reduce the prevalence of isolated components and nodes. Overall, changing the representation of the network alters the prevalence of articulation points and bridges globally but also within and across pathways. Hence, some molecules can gain or lose in biological importance depending on the level of detail of the representation of the biological system, which might in turn impact network-based studies of diseases or druggability. AVAILABILITY AND IMPLEMENTATION: Networks are constructed based on data publicly available in the Reactome Pathway knowledgebase: reactome.org.

Development and Evaluation of eHealth Services Regarding Accessibility: Scoping Literature Review.

BACKGROUND: Accessibility is acknowledged as a key to inclusion in the Convention of Rights for People with Disabilities. An inaccessible design can result in exclusion from eHealth and cause disability among people who have impairments. OBJECTIVE: This scoping literature review aimed to investigate how eHealth services have been developed and evaluated regarding accessibility for people with impairments. METHODS: In line with Arksey and O'Malley's framework for scoping studies and using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews (PRISMA-ScR), we conducted a search in 4 databases (PubMed, Scopus, IEEE, and Web of Science) in October 2020 and an update of the search in June 2022. The search strategy was structured according to the PICO model as follows: Population/Problem, digital accessibility for users with impairment; Intervention, health care delivered by any digital solution; Comparison, not applicable; Outcome, use of and adherence to (1) Web Content Accessibility Guidelines (WCAG), (2) other accessibility guidelines, and (3) other means, for designing or evaluating accessibility in eHealth services. A Boolean search was conducted by combining terms related to accessibility and eHealth. All authors participated in screening abstracts according to the eligibility criteria. Each publication, containing a potentially relevant abstract, was read (full text) and assessed for eligibility by 2 authors independently and pairwise. Publications deemed eligible were read by all authors and discussed for consensus. RESULTS: A total of 8643 publications were identified. After abstract screening, 131 publications remained for full-text reading. Of those, 116 publications were excluded as they did not meet the eligibility criteria. Fifteen publications involving studies of 12 eHealth services were included in the study. Of the 15 publications, 2 provided a definition of accessibility, 5 provided an explanation of accessibility, and 8 did not provide any explanation. Five publications used the WCAG to evaluate accessibility when developing eHealth services. One publication used International Organization for Standardization (ISO) 29138, ISO 2941, and ISO/International Electrotechnical Commission (IEC) 30071-1 standards together with the Spanish Association for Standardization (UNE) 139803 standard. Eleven publications used other means to address accessibility, including text-level grading; literature review about accessibility; user tests, focus groups, interviews, and design workshops with target groups of patients, relatives, and health care professionals; and comparative analysis of existing technical solutions to provide information about useful requirements. CONCLUSIONS: Although a clear definition of accessibility can enhance operationalization and thus measurability when evaluating accessibility in eHealth services, accessibility was insufficiently defined in most of the included studies. Further, accessibility guidelines and standards were used to a very limited extent in the development and evaluation of eHealth services. Guidelines for developing complex interventions that include guidance for accessibility are motivated to ensure that accessibility will be considered systematically in eHealth services.

Severity of preterm birth and the risk of pulmonary hypertension in childhood: A population-based cohort study in Sweden.

BACKGROUND: Preterm birth (<37 completed gestational weeks) has been linked to pulmonary hypertension (PH), but the relationship to severity of preterm birth has not been studied. OBJECTIVES: We investigated associations between extremely (<28 weeks), very (28-31 weeks), moderately (32-36 weeks) preterm birth, early-term birth (37-38 weeks) and later PH. Additionally, we explored associations between birthweight for gestational age and PH. METHODS: This registry-based cohort study followed 3.1 million individuals born in Sweden (1987-2016) from 1 up to a maximum of 30 years of age. The outcome was diagnosis or death from PH in national health registers. Adjusted hazard ratios (HR) were estimated using Cox regression analysis. Unadjusted and confounder-adjusted incidence rate differences were also calculated. RESULTS: Of 3,142,812 individuals, there were 543 cases of PH (1.2 per 100,000 person-years), 153 of which in individuals without malformations. Compared with individuals born at 39 weeks, adjusted HRs with 95% confidence interval (CI) for PH for extremely, moderately, and very preterm birth were 68.78 (95% CI 49.49, 95.57), 13.86 (95% CI 9.27, 20.72) and 3.42 (95% CI 2.46, 4.74), respectively, and for early-term birth 1.74 (1.31, 2.32). HRs were higher in subjects without malformations. There were 90 additional cases of PH per 100,000 person-years in the extremely preterm group (50 after excluding malformations). Very small for gestational age (below 2 SD from estimated birthweight for gestational age and sex) was also associated with increased risk of PH (adjusted HR 2.02, 95% CI 1.14, 3.57). CONCLUSIONS: We found an inverse association between gestational age and later PH, but the incidence and absolute risks are low. The severity of preterm birth adds clinically relevant information to the assessment of cardiovascular risks in childhood.

Promoting Healthy Behaviors Among Adolescents and Young Adults With Intellectual Disability: Protocol for Developing a Digital Intervention With Co-Design Workshops.

BACKGROUND: Intellectual disability (ID) is a neurodevelopmental disorder associated with a poorer health profile and higher mortality. Young people with ID have more sedentary lifestyles than their typically developing peers. Consequently, this group is at significant risk of developing lifestyle diseases (ie, noncommunicable diseases) later in life. Increasing physical activity and eating a healthier diet have been argued to be effective ways to improve the health of adolescents and young adults with ID. Digital interventions are a viable option for improving health behaviors. OBJECTIVE: This research protocol describes a co-design approach using workshops to develop a digital intervention that promotes healthy behaviors, including increasing physical activity and eating a healthier diet, among adolescents and young adults with ID. METHODS: A participatory design using a co-design approach will be applied as a strategy to include potential users of the digital intervention and other stakeholders in the research process, comprising research design, data collection, and data analysis. A total of 7 to 10 workshops will be conducted aimed at developing a digital intervention and will include procedures for assessing needs; facilitators and barriers to health promotion; physical, mental, and social well-being; participation; and relationships. The workshops will include 12 to 18 stakeholders with experience of clinical practice and research related to young people with ID, including relatives, as well as adolescents and young adults (aged 16-25 years) with mild to moderate ID. Participants will perform a mixture of individual and group work using whiteboards, sticky notes, felt-tip pens, cards, balls, stickers, and wireframe templates. Data analysis will take place concurrently with data collection as an iterative process. Transcribed data from the audio and video recordings of the groups' discussions will be analyzed following a qualitative methodological procedure. RESULTS: This study protocol provides a systematic record of the scientific methodologies used when developing the digital intervention and provides insights into the potential practical solutions and challenges when following a co-design approach in which relatives and professionals, as well as adolescents and young adults with ID, are included as research partners. Recruitment of participants started in April 2023. Data collection, analysis, and reporting will be completed in December 2023. CONCLUSIONS: This study will explore the effectiveness of workshops at gathering rich, reliable, and valid data in a co-design approach with participants. The results will provide increased knowledge in how to use technology to develop novel, evidence-based, and scalable interventions that adolescents and young adults with ID can and want to use to motivate physical activity and a healthier diet. The project will provide a simple and cognitively accessible digital solution for promoting lifestyle behaviors tailored to the needs of adolescents and young adults with ID. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): PRR1-10.2196/47877.

A polygenic risk score to help discriminate primary adrenal insufficiency of different etiologies.

BACKGROUND: Autoimmune Addison's disease (AAD) is the most common cause of primary adrenal insufficiency (PAI). Despite its exceptionally high heritability, tools to estimate disease susceptibility in individual patients are lacking. We hypothesized that polygenic risk score (PRS) for AAD could help investigate PAI pathogenesis in pediatric patients. METHODS: We here constructed and evaluated a PRS for AAD in 1223 seropositive cases and 4097 controls. To test its clinical utility, we reevaluated 18 pediatric patients, whose whole genome we also sequenced. We next explored the individual PRS in more than 120 seronegative patients with idiopathic PAI. RESULTS: The genetic susceptibility to AAD-quantified using PRS-was on average 1.5 standard deviations (SD) higher in patients compared with healthy controls (p < 2e - 16), and 1.2 SD higher in the young patients compared with the old (p = 3e - 4). Using the novel PRS, we searched for pediatric patients with strikingly low AAD susceptibility and identified cases of monogenic PAI, previously misdiagnosed as AAD. By stratifying seronegative adult patients by autoimmune comorbidities and disease duration we could delineate subgroups of PRS suggesting various disease etiologies. CONCLUSIONS: The PRS performed well for case-control differentiation and susceptibility estimation in individual patients. Remarkably, a PRS for AAD holds promise as a means to detect disease etiologies other than autoimmunity.

Graphene oxide microstructure control of electrosprayed thin films.

The graphene oxide (GO) microstructure, in terms of flake distribution, folding, and crumpling, in thin films affects properties such as electrical conductivity and optical transparency after GO reduction. A thin film can be tailored to the user's application if the microstructure resulting from different deposition methods can be controlled. In this work, we compare the microstructures of GO coatings created through electrospray deposition (ESD) with random deposition processes. The comparisons include both MATLAB simulations and a dip coating process. The microstructure of ESD GO thin films can be altered by changing the distance between the nozzle and the substrate. We developed a semi-automatic image analysis script that analyzes scanning electron microscopy images to find effects of GO stacking or agglomeration, without the risk of human bias. A low nozzle to substrate distance creates structures of flat GO flakes, but solvent flooding the samples causes drying patterns. A high nozzle to substrate distance causes folding and crumpling of the GO flakes due to solvent evaporation, resulting in agglomerated GO on the substrate. For our ESD setup, a nozzle to substrate distance of 2-4 mm produced GO coatings with the lowest combined influence of drying effects and GO flake folding or crumpling.