Atopic Dermatitis in Early Childhood and Risk of Inflammatory Bowel Disease: A Scandinavian Birth Cohort Study.

OBJECTIVE: To examine the association between early-life atopic manifestations and later risk of inflammatory bowel disease (IBD), for which prospective data are scarce. STUDY DESIGN: The population-based All Babies in Southeast Sweden (ABIS) and Norwegian Mother, Father, and Child (MoBa) cohorts follow children from birth (ABIS 1997-1999; MoBa 2000-2009) to the end of 2021. Based on validated questionnaires, parents prospectively reported information on asthma, food-related allergic symptoms, atopic dermatitis, and allergic rhinitis by age 3. IBD was defined by ≥ 2 diagnostic records in the national health registries. Cox regression estimated hazard ratios adjusted (aHRs) for parental IBD, atopy, education level, smoking habits, and national origin. Cohort-specific estimates were pooled using a random-effects model. RESULTS: We compiled data on 83 311 children (ABIS, n = 9041; MoBa, n = 74 270). In over 1 174 756 person-years of follow-up, 301 participants were diagnosed with IBD. Children with atopic dermatitis at age 3 had an increased risk of IBD (pooled aHR = 1.46 [95% CI = 1.13-1.88]), Crohn's disease (pooled aHR = 1.53 [95%CI = 1.04-2.26]), and ulcerative colitis (pooled aHR = 1.78 [95%CI = 1.15-2.75]). Conversely, any atopic manifestation by age 3 was not associated with IBD (pooled aHR = 1.20 [95%CI = 0.95-1.52]), nor were analyses specifically focused on early-life food-related allergic symptoms, asthma, and allergic rhinitis. CONCLUSION: While atopic manifestations in early childhood were overall not associated with IBD, children with atopic dermatitis specifically were at increased risk of developing IBD, suggesting shared etiologic traits; these findings might be useful in identifying at-risk individuals for IBD.

Tobacco smoke exposure in early childhood and later risk of inflammatory bowel disease: A Scandinavian birth cohort study.

OBJECTIVES: To examine the association between early-life smoking exposure and later risk of inflammatory bowel disease (IBD). METHODS: We followed 115,663 participants from the Norwegian Mother, Father and Child (MoBa) and All Babies in Southeast Sweden (ABIS) cohorts from birth (1997-2009) through 2021. IBD was identified through national patient registers. Validated questionnaire data defined maternal smoking during pregnancy, maternal environmental tobacco smoke (ETS) exposure during pregnancy, and child ETS exposure by age 12 and 36 months. Cox regression was used to estimate adjusted hazard ratios (aHRs) for sex, maternal age, education level, parental IBD and origin. Cohort-specific estimates were pooled using a random-effects model. RESULTS: During 1,987,430 person-years of follow-up, 444 participants developed IBD (ABIS, n=112; MoBa, n=332). Any vs. no maternal smoking during pregnancy yielded a pooled aHR of 1.30 (95%CI=0.97-1.74) for offspring IBD. Higher level of maternal smoking during pregnancy (compared to no smoking, average ≥6 cigarettes/day: pooled aHR=1.60 [95%CI 1.08-2.38]) was associated with offspring IBD, whereas a lower smoking level was not (average 1-5 cigarettes/day: pooled aHR=1.09 [95%CI=0.73-1.64]). Child ETS exposure in the first year of life was associated with later IBD (any vs. no ETS, pooled aHR=1.32 [95%CI=1.03-1.69]). Estimates observed for child ETS exposure by 36 months were similar but not statistically significant. CONCLUSIONS: In this prospective Scandinavian cohort study, children exposed to higher levels of maternal smoking during pregnancy or ETS during the first year of life were at increased risk of later IBD.

Fast estimation of generalized linear latent variable models for performance and process data with ordinal, continuous, and count observed variables.

Different data types often occur in psychological and educational measurement such as computer-based assessments that record performance and process data (e.g., response times and the number of actions). Modelling such data requires specific models for each data type and accommodating complex dependencies between multiple variables. Generalized linear latent variable models are suitable for modelling mixed data simultaneously, but estimation can be computationally demanding. A fast solution is to use Laplace approximations, but existing implementations of joint modelling of mixed data types are limited to ordinal and continuous data. To address this limitation, we derive an efficient estimation method that uses first- or second-order Laplace approximations to simultaneously model ordinal data, continuous data, and count data. We illustrate the approach with an example and conduct simulations to evaluate the performance of the method in terms of estimation efficiency, convergence, and parameter recovery. The results suggest that the second-order Laplace approximation achieves a higher convergence rate and produces accurate yet fast parameter estimates compared to the first-order Laplace approximation, while the time cost increases with higher model complexity. Additionally, models that consider the dependence of variables from the same stimulus fit the empirical data substantially better than models that disregarded the dependence.

MiCId GUI: The Graphical User Interface for MiCId, a Fast Microorganism Classification and Identification Workflow with Accurate Statistics and High Recall.

Although many user-friendly workflows exist for identifications of peptides and proteins in mass-spectrometry-based proteomics, there is a need of easy to use, fast, and accurate workflows for identifications of microorganisms, antimicrobial resistant proteins, and biomass estimation. Identification of microorganisms is a computationally demanding task that requires querying thousands of MS/MS spectra in a database containing thousands to tens of thousands of microorganisms. Existing software can't handle such a task in a time efficient manner, taking hours to process a single MS/MS experiment. Another paramount factor to consider is the necessity of accurate statistical significance to properly control the proportion of false discoveries among the identified microorganisms, and antimicrobial-resistant proteins, and to provide robust biomass estimation. Recently, we have developed Microorganism Classification and Identification (MiCId) workflow that assigns accurate statistical significance to identified microorganisms, antimicrobial-resistant proteins, and biomass estimation. MiCId's workflow is also computationally efficient, taking about 6-17 minutes to process a tandem mass-spectrometry (MS/MS) experiment using computer resources that are available in most laptop and desktop computers, making it a portable workflow. To make data analysis accessible to a broader range of users, beyond users familiar with the Linux environment, we have developed a graphical user interface (GUI) for MiCId's workflow. The GUI brings to users all the functionality of MiCId's workflow in a friendly interface along with tools for data analysis, visualization, and to export results.

Comparative genomics of Leishmania donovani progeny from genetic crosses in two sand fly species and impact on the diversity of diagnostic and vaccine candidates.

Sand fly transmitted Leishmania species are responsible for severe, wide ranging, visceral and cutaneous leishmaniases. Genetic exchange can occur among natural Leishmania populations and hybrids can now be produced experimentally, with limitations. Feeding Phlebotomus orientalis or Phlebotomus argentipes on two strains of Leishmania donovani yielded hybrid progeny, selected using double drug resistance and fluorescence markers. Fluorescence activated cell sorting of cultured clones derived from these hybrids indicated diploid progeny. Multilocus sequence typing of the clones showed hybridisation and nuclear heterozygosity, although with inheritance of single haplotypes in a kinetoplastid target. Comparative genomics showed diversity of clonal progeny between single chromosomes, and extraordinary heterozygosity across all 36 chromosomes. Diversity between progeny was seen for the HASPB antigen, which has been noted previously as having implications for design of a therapeutic vaccine. Genomic diversity seen among Leishmania strains and hybrid progeny is of great importance in understanding the epidemiology and control of leishmaniasis. As an outcome of this study we strongly recommend that wider biological archives of different Leishmania species from endemic regions should be established and made available for comparative genomics. However, in parallel, performance of genetic crosses and genomic comparisons should give fundamental insight into the specificity, diversity and limitations of candidate diagnostics, vaccines and drugs, for targeted control of leishmaniasis.

Evaluating the contribution of historical and contemporary temperature to the oospore production of self-fertile Phytophthora infestans.

Reproductive systems play an important role in the ecological function of species, but little is known about how climate change, such as global warming, may affect the reproductive systems of microbes. In this study, 116 Phytophthora infestans isolates sampled from five different altitudes along a mountain were evaluated under five temperature regimes to determine the effects of historical and experimental temperature on the reproductive system of the pathogen. Both altitude, a proxy for historical pathogen adaptation to temperature, and temperature used in the experiment affected the sexual reproduction of the pathogen, with experimental temperature, that is, contemporary temperature, playing a role several times more important than historical temperature. Furthermore, the potential of sexual reproduction, measured by the number of oospores quantified, increased with the temperature breadth (i.e., difference between the highest and lowest temperature at which sexual reproduction takes place) of the pathogen and reached the maximum at the experimental temperature of 21°C, which is higher than the annual average temperature in many potato-producing areas. The results suggest that rising air temperature associated with global warming may increase the potential of sexual reproduction in P. infestans. Given the importance of sexuality in pathogenicity and ecological adaptation of pathogens, these results suggest that global warming may increase the threat of P. infestans to agricultural production and other ecological services and highlight that new epidemiological strategies may need to be implemented for future food security and ecological resilience.

Metagenomic analysis of Mesolithic chewed pitch reveals poor oral health among stone age individuals.

Prehistoric chewed pitch has proven to be a useful source of ancient DNA, both from humans and their microbiomes. Here we present the metagenomic analysis of three pieces of chewed pitch from Huseby Klev, Sweden, that were dated to 9,890-9,540 before present. The metagenomic profile exposes a Mesolithic oral microbiome that includes opportunistic oral pathogens. We compared the data with healthy and dysbiotic microbiome datasets and we identified increased abundance of periodontitis-associated microbes. In addition, trained machine learning models predicted dysbiosis with 70-80% probability. Moreover, we identified DNA sequences from eukaryotic species such as red fox, hazelnut, red deer and apple. Our results indicate a case of poor oral health during the Scandinavian Mesolithic, and show that pitch pieces have the potential to provide information on material use, diet and oral health.

Proteomic profiling identifies novel inflammation-related plasma proteins associated with ischemic stroke outcome.

BACKGROUND: The inflammatory response to cerebral ischemia is complex; however, most clinical studies of stroke outcome focus on a few selected proteins. We, therefore, aimed to profile a broad range of inflammation-related proteins to: identify proteins associated with ischemic stroke outcome that are independent of established clinical predictors; identify proteins subsets for outcome prediction; and perform sex and etiological subtype stratified analyses. METHODS: Acute-phase plasma levels of 65 inflammation-related proteins were measured in 534 ischemic stroke cases. Logistic regression was used to estimate associations to unfavorable 3-month functional outcome (modified Rankin Scale score > 2) and LASSO regressions to identify proteins with independent effects. RESULTS: Twenty proteins were associated with outcome in univariable models after correction for multiple testing (FDR < 0.05), and for 5 the association was independent of clinical variables, including stroke severity (TNFSF14 [LIGHT], OSM, SIRT2, STAMBP, and 4E-BP1). LASSO identified 9 proteins that could best separate favorable and unfavorable outcome with a predicted diagnostic accuracy (AUC) of 0.81; three associated with favorable (CCL25, TRAIL [TNFSF10], and Flt3L) and 6 with unfavorable outcome (CSF-1, EN-RAGE [S100A12], HGF, IL-6, OSM, and TNFSF14). Finally, we identified sex- and etiologic subtype-specific associations with the best discriminative ability achieved for cardioembolic, followed by cryptogenic stroke. CONCLUSIONS: We identified candidate blood-based protein biomarkers for post-stroke functional outcome involved in, e.g., NLRP3 inflammasome regulation and signaling pathways, such as TNF, JAK/STAT, MAPK, and NF-κB. These proteins warrant further study for stroke outcome prediction as well as investigations into the putative causal role for stroke outcome.

Starvation induces changes in abundance and small RNA cargo of extracellular vesicles released from Plasmodium falciparum infected red blood cells.

The lethal malaria parasite Plasmodium falciparum needs to constantly respond and adapt to changes within the human host in order to survive and transmit. One such change is composed of nutritional limitation, which is augmented with increased parasite loads and intimately linked to severe disease development. Extracellular vesicles released from infected red blood cells have been proposed as important mediators of disease pathogenesis and intercellular communication but whether important for the parasite response to nutritional availability is unknown. Therefore, we investigated the abundance and small RNA cargo of extracellular vesicles released upon short-term nutritional starvation of P. falciparum in vitro cultures. We show that primarily ring-stage parasite cultures respond to glucose and amino acid deprivation with an increased release of extracellular vesicles. Small RNA sequencing of these extracellular vesicles further revealed human miRNAs and parasitic tRNA fragments as the main constituent biotypes. Short-term starvations led to alterations in the transcriptomic profile, most notably in terms of the over-represented biotypes. These data suggest a potential role for extracellular vesicles released from P. falciparum infected red blood cells in the response to nutritional perturbations, their potential as prognostic biomarkers and point towards an evolutionary conserved role among protozoan parasites.

Strain-specific metabarcoding reveals rapid evolution of copper tolerance in populations of the coastal diatom Skeletonema marinoi.

Phytoplankton have short generation times, flexible reproduction strategies, large population sizes and high standing genetic diversity, traits that should facilitate rapid evolution under directional selection. We quantified local adaptation of copper tolerance in a population of the diatom Skeletonema marinoi from a mining-exposed inlet in the Baltic Sea and in a non-exposed population 100 km away. We hypothesized that mining pollution has driven evolution of elevated copper tolerance in the impacted population of S. marinoi. Assays of 58 strains originating from sediment resting stages revealed no difference in the average tolerance to copper between the two populations. However, variation within populations was greater at the mining site, with three strains displaying hyper-tolerant phenotypes. In an artificial evolution experiment, we used a novel intraspecific metabarcoding locus to track selection and quantify fitness of all 58 strains during co-cultivation in one control and one toxic copper treatment. As expected, the hyper-tolerant strains enabled rapid evolution of copper tolerance in the mining-exposed population through selection on available strain diversity. Within 42 days, in each experimental replicate a single strain dominated (30%-99% abundance) but different strains dominated the different treatments. The reference population developed tolerance beyond expectations primarily due to slowly developing plastic response in one strain, suggesting that different modes of copper tolerance are present in the two populations. Our findings provide novel empirical evidence that standing genetic diversity of phytoplankton resting stage allows populations to evolve rapidly (20-50 generations) and flexibly on timescales relevant for seasonal bloom progressions.

Genome wide association analysis of cuticle deposition in laying hens.

The cuticle is an invisible barrier that protects the internal egg contents from microorganisms entering through gas exchange pores. Eggs which have a good cuticle are least likely to be penetrated by microorganisms and improved cuticle cover should reduce vertical transmission of microorganisms and improve biosecurity. The aim was to carry out a genome wide association study for cuticle deposition in 3 independent populations of laying hens using tartrazine and lissamine green staining. Eggs from ∼8,000 hens represented 2 White Leghorn and 1 Rhode Island Red breed. Estimates of heritability using pedigree or genomic relationship matrices were in the 0.2 to 0.3 range. The results were breed specific. Across the populations, genomic regions on chromosomes 1, 2, 4, 5, and 8 were identified as significantly associated with cuticle deposition. No single loci had a large effect. A comparison was made with genes differentially expressed in the shell gland when cuticle deposition was manipulated, however none were obvious candidates for cuticle deposition. The results support the polygenic nature of the trait and the information will help in the future to understand the genetic variance and what might control cuticle deposition and the microbiological safety of the egg.

Investigating Planning and Non-Targeted Exploration in PIAAC 2012: Validating Their Measures Based on Process Data and Investigating Their Relationships with Problem-Solving Competency.

Problem-solving is a critical aspect of intelligence that has become increasingly important in modern society. Mapping out the determinants of success in problem-solving helps understand the underlying cognitive processes involved. This article focuses on two key cognitive processes in problem-solving: non-targeted exploration and planning. We generalize previously defined indicators of planning and non-targeted exploration across tasks in the 2012 Programme for the International Assessment of Adult Competencies and examine the internal construct validity of the indicators using confirmatory factor analysis. We also investigate the relationships between problem-solving competency, planning, and non-targeted exploration, along with the specific dependence between indicators from the same task. The results suggest that (a) the planning indicator across tasks provides evidence of internal construct validity; (b) the non-targeted exploration indicator provides weaker evidence of internal construct validity; (c) overall, non-targeted exploration is strongly related to problem-solving competency, whereas planning and problem-solving competencies are weakly negatively related; and (d) such relationships vary substantially across tasks, emphasizing the importance of accounting for the dependency of measures from the same task. Our findings deepen our understanding of problem-solving processes and can support the use of digital tools in educational practice and validate task design by comparing the task-specific relationships with the desired design.

Historical RNA expression profiles from the extinct Tasmanian tiger.

Paleogenomics continues to yield valuable insights into the evolution, population dynamics, and ecology of our ancestors and other extinct species. However, DNA sequencing cannot reveal tissue-specific gene expression, cellular identity, or gene regulation, which are only attainable at the transcriptional level. Pioneering studies have shown that useful RNA can be extracted from ancient specimens preserved in permafrost and historical skins from extant canids, but no attempts have been made so far on extinct species. We extract, sequence, and analyze historical RNA from muscle and skin tissue of a ∼130-year-old Tasmanian tiger (Thylacinus cynocephalus) preserved in desiccation at room temperature in a museum collection. The transcriptional profiles closely resemble those of extant species, revealing specific anatomical features such as slow muscle fibers or blood infiltration. Metatranscriptomic analysis, RNA damage, tissue-specific RNA profiles, and expression hotspots genome-wide further confirm the thylacine origin of the sequences. RNA sequences are used to improve protein-coding and noncoding annotations, evidencing missing exonic loci and the location of ribosomal RNA genes while increasing the number of annotated thylacine microRNAs from 62 to 325. We discover a thylacine-specific microRNA isoform that could not have been confirmed without RNA evidence. Finally, we detect traces of RNA viruses, suggesting the possibility of profiling viral evolution. Our results represent the first successful attempt to obtain transcriptional profiles from an extinct animal species, providing thought-to-be-lost information on gene expression dynamics. These findings hold promising implications for the study of RNA molecules across the vast collections of natural history museums and from well-preserved permafrost remains.

Partitioning of discrete proton arcs into interlaced subplans can bring proton arc advances to existing proton facilities.

BACKGROUND: Proton arcs have shown potential to reduce the dose to organs at risks (OARs) by delivering the protons from many different directions. While most previous studies have been focused on dynamic arcs (delivery during rotation), an alternative approach is discrete arcs, where step-and-shoot delivery is used over a large number of beam directions. The major advantage of discrete arcs is that they can be delivered at existing proton facilities. However, this advantage comes at the expense of longer treatment times. PURPOSE: To exploit the dosimetric advantages of proton arcs, while achieving reasonable delivery times, we propose a partitioning approach where discrete arc plans are split into subplans to be delivered over different fractions in the treatment course. METHODS: For three oropharyngeal cancer patients, four different arc plans have been created and compared to the corresponding clinical IMPT plan. The treatment plans are all planned to be delivered in 35 fractions, but with different delivery approaches over the fractions. The first arc plan (1×30) has 30 directions to be delivered every fraction, while the others are partitioned into subplans with 10 and 6 beam directions, each to be delivered every third (3×10), fifth fraction (5×6), or seventh fraction (7×10). All plans are assessed with respect to delivery time, target robustness over the treatment course, doses to OARs and NTCP for dysphagia and xerostomia. RESULTS: The delivery time (including an additional delay of 30 s between the discrete directions to simulate manual interaction with the treatment control system) is reduced from on average 25.2 min for the 1×30 plan to 9.2 min for the 3×10 and 7×10 plans and 5.7 min for the 5×6 plans. The delivery time for the IMPT plan is 7.9 min. When accounting for the combination of delivery time, target robustness, OAR sparing, and NTCP reduction, the plans with 10 directions in each fraction are the preferred choice. Both the 3×10 and 7×10 plans show improved target robustness compared to the 1×30 plans, while keeping OAR doses and NTCP values at almost as low levels as for the 1×30 plans. For all patients the NTCP values for dysphagia are lower for the partitioned plans with 10 directions compared to the IMPT plans. NTCP reduction for xerostomia compared to IMPT is seen in two of the three patients. The best results are seen for the first patient, where the NTCP reductions for the 7×10 plan are 1.6 p.p. (grade 2 xerostomia) and 1.5 p.p. (grade 2 dysphagia). The corresponding NTCP reductions for the 1×30 plan are 2.7 p.p. (xerostomia, grade 2) and 2.0 p.p. (dysphagia, grade 2). CONCLUSIONS: Discrete proton arcs can be implemented at any proton facility with reasonable treatment times using a partitioning approach. The technique also makes the proton arc treatments more robust to changes in the patient anatomy.

Genetic markers associated with bone composition in Rhode Island Red laying hens.

BACKGROUND: Bone damage has welfare and economic impacts on modern commercial poultry and is known as one of the major challenges in the poultry industry. Bone damage is particularly common in laying hens and is probably due to the physiological link between bone and the egg laying process. Previous studies identified and validated quantitative trait loci (QTL) for bone strength in White Leghorn laying hens based on several measurements, including bone composition measurements on the cortex and medulla of the tibia bone. In a previous pedigree-based analysis, bone composition measurements showed heritabilities ranging from 0.18 to 0.41 and moderate to strong genetic correlations with tibia strength and density. Bone composition was measured using infrared spectroscopy and thermogravimetry. The aim of this study was to combine these bone composition measurements with genotyping data via a genome-wide association study (GWAS) to investigate genetic markers that contribute to genetic variance in bone composition in Rhode Island Red laying hens. In addition, we investigated the genetic correlations between bone composition and bone strength. RESULTS: We found novel genetic markers that are significantly associated with cortical lipid, cortical mineral scattering, medullary organic matter, and medullary mineralization. Composition of the bone organic matter showed more significant associations than bone mineral composition. We also found interesting overlaps between the GWAS results for tibia composition traits, particularly for cortical lipid and tibia strength. Bone composition measurements by infrared spectroscopy showed more significant associations than thermogravimetry measurements. Based on the results of infrared spectroscopy, cortical lipid showed the highest genetic correlations with tibia density, which was negative (- 0.20 ± 0.04), followed by cortical CO3/PO4 (0.18 ± 0.04). Based on the results of thermogravimetry, medullary organic matter% and mineral% showed the highest genetic correlations with tibia density (- 0.25 ± 0.04 and 0.25 ± 0.04, respectively). CONCLUSIONS: This study detected novel genetic associations for bone composition traits, particularly those involving organic matter, that could be used as a basis for further molecular genetic investigations. Tibia cortical lipids displayed the strongest genetic associations of all the composition measurements, including a significantly high genetic correlation with tibia density and strength. Our results also highlighted that cortical lipid may be a key measurement for further avian bone studies.

A novel precision-serology assay for SARS-CoV-2 infection based on linear B-cell epitopes of Spike protein.

Introduction: The COVID-19 pandemic illustrates the need for serology diagnostics with improved accuracy. While conventional serology based on recognition of entire proteins or subunits thereof has made significant contribution to the antibody assessment space, it often suffers from sub-optimal specificity. Epitope-based, high-precision, serology assays hold potential to capture the high specificity and diversity of the immune system, hence circumventing the cross-reactivity with closely related microbial antigens. Methods: We herein report mapping of linear IgG and IgA antibody epitopes of the SARS-CoV-2 Spike (S) protein in samples from SARS-CoV-2 exposed individuals along with certified SARS-CoV-2 verification plasma samples using peptide arrays. Results: We identified 21 distinct linear epitopes. Importantly, we showed that pre-pandemic serum samples contain IgG antibodies reacting to the majority of protein S epitopes, most likely as a result of prior infection with seasonal coronaviruses. Only 4 of the identified SARS-CoV-2 protein S linear epitopes were specific for SARS-CoV-2 infection. These epitopes are located at positions 278-298 and 550-586, just proximal and distal to the RBD, as well as at position 1134-1156 in the HR2 subdomain and at 1248-1271 in the C-terminal subdomain of protein S. To substantiate the applicability of our findings, we tested three of the high-accuracy protein S epitopes in a Luminex assay, using a certified validation plasma sample set from SARS-CoV-2 infected individuals. The Luminex results were well aligned with the peptide array results, and correlated very well with in-house and commercial immune assays for RBD, S1 and S1/S2 domains of protein S. Conclusion: We present a comprehensive mapping of linear B-cell epitopes of SARS-CoV-2 protein S, that identifies peptides suitable for a precision serology assay devoid of cross-reactivity. These results have implications for development of highly specific serology test for exposure to SARS-CoV-2 and other members of the coronaviridae family, as well as for rapid development of serology tests for future emerging pandemic threats.

Development of a machine learning framework for radiation biomarker discovery and absorbed dose prediction.

Background: Molecular radiation biomarkers are an emerging tool in radiation research with applications for cancer radiotherapy, radiation risk assessment, and even human space travel. However, biomarker screening in genome-wide expression datasets using conventional tools is time-consuming and underlies analyst (human) bias. Machine Learning (ML) methods can improve the sensitivity and specificity of biomarker identification, increase analytical speed, and avoid multicollinearity and human bias. Aim: To develop a resource-efficient ML framework for radiation biomarker discovery using gene expression data from irradiated normal tissues. Further, to identify biomarker panels predicting radiation dose with tissue specificity. Methods: A strategic search in the Gene Expression Omnibus database identified a transcriptomic dataset (GSE44762) for normal tissues radiation responses (murine kidney cortex and medulla) suited for biomarker discovery using an ML approach. The dataset was pre-processed in R and separated into train and test data subsets. High computational cost of Genetic Algorithm/k-Nearest Neighbor (GA/KNN) mandated optimization and 13 ML models were tested using the caret package in R. Biomarker performance was evaluated and visualized via Principal Component Analysis (PCA) and dose regression. The novelty of ML-identified biomarker panels was evaluated by literature search. Results: Caret-based feature selection and ML methods vastly improved processing time over the GA approach. The KNN method yielded overall best performance values on train and test data and was implemented into the framework. The top-ranking genes were Cdkn1a, Gria3, Mdm2 and Plk2 in cortex, and Brf2, Ccng1, Cdkn1a, Ddit4l, and Gria3 in medulla. These candidates successfully categorized dose groups and tissues in PCA. Regression analysis showed that correlation between predicted and true dose was high with R2 of 0.97 and 0.99 for cortex and medulla, respectively. Conclusion: The caret framework is a powerful tool for radiation biomarker discovery optimizing performance with resource-efficiency for broad implementation in the field. The KNN-based approach identified Brf2, Ddit4l, and Gria3 mRNA as novel candidates that have been uncharacterized as radiation biomarkers to date. The biomarker panel showed good performance in dose and tissue separation and dose regression. Further training with larger cohorts is warranted to improve accuracy, especially for lower doses.

Transcriptomics unravels molecular changes associated with cilia and COVID-19 in chronic rhinosinusitis with nasal polyps.

Chronic rhinosinusitis with nasal polyps (CRSwNP) is a common upper respiratory tract complication where the pathogenesis is largely unknown. Herein, we investigated the transcriptome profile in nasal mucosa biopsies of CRSwNP patients and healthy individuals. We further integrated the transcriptomics data with genes located in chromosomal regions containing genome-wide significant gene variants for COVID-19. Among the most significantly upregulated genes in polyp mucosa were CCL18, CLEC4G, CCL13 and SLC9A3. Pathways involving "Ciliated epithelial cells" were the most differentially expressed molecular pathways when polyp mucosa and non-polyp mucosa from the same patient was compared. Natural killer T-cell (NKT) and viral pathways were the most statistically significant pathways in the mucosa of CRSwNP patients compared with those of healthy control individuals. Upregulated genes in polyp mucosa, located within the genome-wide associated regions of COVID-19, included LZTFL1, CCR9, SLC6A20, IFNAR1, IFNAR2 and IL10RB. Interestingly, the second most over-expressed gene in our study, CLEC4G, has been shown to bind directly to SARS-CoV-2 spike's N-terminal domain and mediate its entry and infection. Our results on altered expression of genes related to cilia and viruses point to the de-regulation of viral defenses in CRSwNP patients, and may give clues to future intervention strategies.

Assessing social competence and antisocial behaviors in children: item response theory analysis of the home and community social behavior scales.

BACKGROUND: The Home and Community Social Behavior Scales (HCSBS) is a rating scale that assesses social competence and antisocial behavior among children and youths between ages 5-18. The present study aimed to investigate the psychometric properties of the HCSBS by applying item response theory (IRT). METHODS: The HCSBS was completed by parents of 551 Norwegian children refereed to three independent interventions towards problem behaviors. Data used in this study was collected before the interventions started. IRT was carried out in R version 4.0.0 to investigate HCSBS items, subscales and main scales. RESULTS: The results showed that the two-dimensional IRT models for social competence and antisocial behavior were the most appropriate. The measurement precision of the scales was high for a large range of the latent spectrum, and estimated reliabilities were satisfactory. Model evaluations indicated that the overall model fit for the scales were acceptable, but some misfit existed with respect to specific item pairs. CONCLUSION: The results indicate that the HCSBS is a reliable measurement instrument although there is still a potential for improvement by revising some of the items.

Sex Differences in Treatment and Prognosis of Acute Intracerebral Hemorrhage.

Background: Intracerebral hemorrhage (ICH) accounts for 10%-15% of all stroke cases and is associated with a high risk of death and disability. Prior studies in ischemic stroke have demonstrated a less favorable outcome in women compared with men, but there is a paucity of data regarding differences in outcome by sex in ICH. The aim of the present study was to investigate possible sex differences in acute care and the 3-months follow-up of patients with ICH. Methods: Data were collected from the Swedish National Stroke Registry (Riksstroke). Demographic and baseline characteristics were collected, based on in-hospital data and data from 3-months follow-up. Results: Variables of interest were collected from 1,403 patients. Women (45.1%) were significantly older than men, with a mean age ± standard deviation of 77 ± 13years, versus 71 ± 14 years, p < 0.01. On admission, the ICH severity was similar in men and women. There was no significant association between sex and reception of neuroimaging or neurosurgery. Women were less likely to be treated in a stroke unit (80.8% vs. 85.3%, p = 0.03), or discharged to home (51.5% vs. 63.4%, p < 0.01). At 3-months follow-up, there were no sex-related differences regarding dependence, post-ICH self-reported depression, or case fatality. Conclusions: Women were less likely to be treated in a stroke unit, and were less often discharged to home. However, no significant differences in 3-month functional outcome or survival between men and women with ICH were found in this study.