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Circulating inflammatory markers are essential to human health and disease, and they are often dysregulated or malfunctioning in cancers as well as in cardiovascular, metabolic, immunologic and neuropsychiatric disorders. However, the genetic contribution to the physiological variation of levels of circulating inflammatory markers is largely unknown. Here we report the results of a genome-wide genetic study of blood concentration of ten cytokines, including the hitherto unexplored calcium-binding protein (S100B). The study leverages a unique sample of neonatal blood spots from 9,459 Danish subjects from the iPSYCH initiative. We estimate the SNP-heritability of marker levels as ranging from essentially zero for Erythropoietin (EPO) up to 73% for S100B. We identify and replicate 16 associated genomic regions (p < 5 x 10-9), of which four are novel. We show that the associated variants map to enhancer elements, suggesting a possible transcriptional effect of genomic variants on the cytokine levels. The identification of the genetic architecture underlying the basic levels of cytokines is likely to prompt studies investigating the relationship between cytokines and complex disease. Our results also suggest that the genetic architecture of cytokines is stable from neonatal to adult life.

Background: Sever’s disease, or calcaneal apophysitis, stands as the most prevalent cause of heel pain in children, often linked to sports like soccer, Australian football, and basketball. While various therapies are documented in the scientific literature, the standard choice is conservative treatment. Thus, the objective of this research was to assess the effectiveness of diverse conservative methods and techniques in alleviating Sever’s disease symptoms. Methods: Systematic searches were conducted in October 2023 in PubMed, Web of Science, Scopus, SportDiscus, and PEDro, using terms like Osteochondritis, Osteochondrosis, Apophysitis, Sever’s disease, Calcaneus, Adolescent, Child, and Childhood. The PEDro scale gauged methodological quality, and the Cochrane Risk of Bias tool evaluated the risk of bias. Results: Eight randomized controlled studies were included, featuring commonly used treatments such as insoles, therapeutic exercises, Kinesio taping, and foot orthoses. The methodological quality was generally good, with an average PEDro score of 6.75 points. Regarding bias, four articles had low risk, three had high risk, and one had some concern. Conclusions: Conservative treatment emerges as an effective option for alleviating symptoms associated with Sever’s disease.

The present work aimed to establish the influence of self-reported trait anxiety on computerized and self-reported measures of executive control, and speed of processing in young adults using latent variable modeling. One hundred and six participants completed the State-trait anxiety questionnaire (STAI-t), the Attentional Control Scale (ACS), and a set of computerized tasks of executive control, tapping into the updating, inhibition, and shifting components. Higher scores in the latent variable of trait anxiety were negatively associated with the self-reported latent variable of attentional control. Notably, self-reported and performance-based indicators of executive control showed no associations at the latent level. Contrary to our hypotheses, higher trait anxiety did not affect any performance-based executive component but was associated with an increase in response times. We show that self-reported trait anxiety is related to a lower self-perceived sense of attentional control and does not affect executive functioning in non-clinical samples. In turn, trait anxiety is mainly associated with a slowed speed of processing. In conclusion, the tendency to experience a negative mood is related with cognitive processing by reducing its speed even in the absence of threatening stimuli.

Gastrointestinal infections can be life threatening, but not much is known about the host's genetic contribution to susceptibility to gastrointestinal infections or the latter's association with psychiatric disorders. We utilized iPSYCH, a genotyped population-based sample of individuals born between 1981 and 2005 comprising 65,534 unrelated Danish individuals (45,889 diagnosed with mental disorders and 19,645 controls from a random population sample) in which all individuals were linked utilizing nationwide population-based registers to estimate the genetic contribution to susceptibility to gastrointestinal infections, identify genetic variants associated with gastrointestinal infections, and examine the link between gastrointestinal infections and psychiatric and neurodevelopmental disorders. The SNP heritability of susceptibility to gastrointestinal infections ranged from 3.7% to 6.4% on the liability scale. Significant correlations were found between gastrointestinal infections and the combined group of mental disorders (OR = 2.09; 95% CI: 1.82-2.4, P = 1.87 × 10-25). Correlations with autism spectrum disorder, attention deficit hyperactivity disorder, and depression were also significant. We identified a genome-wide significant locus associated with susceptibility to gastrointestinal infections (OR = 1.13; 95% CI: 1.08-1.18, P = 2.9 × 10-8), where the top SNP was an eQTL for the ABO gene. The risk allele was associated with reduced ABO expression, providing, for the first time, genetic evidence to support previous studies linking the O blood group to gastrointestinal infections. This study also highlights the importance of integrative work in genetics, psychiatry, infection, and epidemiology on the road to translational medicine.

Infections and mental disorders are two of the major global disease burdens. While correlations between mental disorders and infections have been reported, the possible genetic links between them have not been assessed in large-scale studies. Moreover, the genetic basis of susceptibility to infection is largely unknown, as large-scale genome-wide association studies of susceptibility to infection have been lacking. We utilized a large Danish population-based sample (N = 65,534) linked to nationwide population-based registers to investigate the genetic architecture of susceptibility to infection (heritability estimation, polygenic risk analysis, and a genome-wide association study (GWAS)) and examined its association with mental disorders (comorbidity analysis and genetic correlation). We found strong links between having at least one psychiatric diagnosis and the occurrence of infection (P = 2.16 × 10-208, OR = 1.72). The SNP heritability of susceptibility to infection ranged from ~2 to ~7% in samples of differing psychiatric diagnosis statuses (suggesting the environment as a major contributor to susceptibility), and polygenic risk scores moderately but significantly explained infection status in an independent sample. We observed a genetic correlation of 0.496 (P = 2.17 × 10-17) between a diagnosis of infection and a psychiatric diagnosis. While our GWAS did not identify genome-wide significant associations, we found 90 suggestive (P ≤ 10-5) associations for susceptibility to infection. Our findings suggest a genetic component in susceptibility to infection and indicate that the occurrence of infections in individuals with mental illness may be in part genetically driven.

Studies on parent-of-origin effects have been limited in terms of sample size due to lack of parental genomes or known genealogies. Here, the authors develop a method to infer the parent-of-origin of an individual alleles in biobank-scale datasets, without requiring parental genomes or prior knowledge of genealogy, allowing discovery of parent-of-origin effects with an unprecedented sample size.

ABSTRACT The detection and accurate identification of bacterial species in clinical samples are crucial for diagnosis and appropriate antibiotic treatment. To date, sequencing of the 16S rRNA gene has been widely used as a complementary molecular approach when identification by culture fails. The accuracy and sensitivity of this method are highly affected by the selection of the 16S rRNA gene region targeted. In this study, we assessed the clinical utility of 16S rRNA reverse complement PCR (16S RC-PCR), a novel method based on next-generation sequencing (NGS), for the identification of bacterial species. We investigated the performance of 16S RC-PCR on 11 bacterial isolates, 2 polymicrobial community samples, and 59 clinical samples from patients suspected of having a bacterial infection. The results were compared to culture results, if available, and to the results of Sanger sequencing of the 16S rRNA gene (16S Sanger sequencing). By 16S RC-PCR, all bacterial isolates were accurately identified to the species level. Furthermore, in culture-negative clinical samples, the rate of identification increased from 17.1% (7/41) to 46.3% (19/41) when comparing 16S Sanger sequencing to 16S RC-PCR. We conclude that the use of 16S RC-PCR in the clinical setting leads to an increased sensitivity of detection of bacterial pathogens, resulting in a higher number of diagnosed bacterial infections, and thereby can improve patient care. IMPORTANCE The identification of the causative infectious pathogen in patients suspected of having a bacterial infection is essential for diagnosis and the start of appropriate treatment. Over the past 2 decades, molecular diagnostics have improved the ability to detect and identify bacteria. However, novel techniques that can accurately detect and identify bacteria in clinical samples and that can be implemented in clinical diagnostics are needed. Here, we demonstrate the clinical utility of bacterial identification in clinical samples by a novel method called 16S RC-PCR. Using 16S RC-PCR, we reveal a significant increase in the number of clinical samples in which a potentially clinically relevant pathogen is identified compared to the commonly used 16S Sanger method. Moreover, RC-PCR allows automation and is well suited for implementation in a diagnostic laboratory. In conclusion, the implementation of this method as a diagnostic tool is expected to result in an increased number of diagnosed bacterial infections, and in combination with adequate treatment, this could improve clinical outcomes for patients.

The increase in microbial sequenced genomes from pure cultures and metagenomic samples reflects the current attainability of whole-genome and shotgun sequencing methods. However, software for genome visualization still lacks automation, integration of different analyses, and customizable options for non-experienced users. In this study, we introduce GenoVi, a Python command-line tool able to create custom circular genome representations for the analysis and visualization of microbial genomes and sequence elements. It is designed to work with complete or draft genomes, featuring customizable options including 25 different built-in color palettes (including 5 color-blind safe palettes), text formatting options, and automatic scaling for complete genomes or sequence elements with more than one replicon/sequence. Using a Genbank format file as the input file or multiple files within a directory, GenoVi (i) visualizes genomic features from the GenBank annotation file, (ii) integrates a Cluster of Orthologs Group (COG) categories analysis using DeepNOG, (iii) automatically scales the visualization of each replicon of complete genomes or multiple sequence elements, (iv) and generates COG histograms, COG frequency heatmaps and output tables including general stats of each replicon or contig processed. GenoVi's potential was assessed by analyzing single and multiple genomes of Bacteria and Archaea. Paraburkholderia genomes were analyzed to obtain a fast classification of replicons in large multipartite genomes. GenoVi works as an easy-to-use command-line tool and provides customizable options to automatically generate genomic maps for scientific publications, educational resources, and outreach activities. GenoVi is freely available and can be downloaded from https://github.com/robotoD/GenoVi.

Autism spectrum disorder (ASD) and attention deficit hyperactivity disorder (ADHD) are highly heritable neurodevelopmental disorders that frequently co-occur. Both rare and common genetic variants are important for ASD and ADHD risk but their combined contribution to clinical heterogeneity is unclear. In a sample of 39 ASD and/or ADHD families we estimated the overall variance explained by known rare copy number variants (CNVs) and polygenic risk score (PRS) from common variants to be 10% in comorbid ASD/ADHD, 4% in ASD and 2% in ADHD. We show that burden of large, rare CNVs and PRS is significantly higher in adult ASD and/or ADHD patients with sustained need for specialist care compared to their unaffected relatives, while affected relatives fall in-between the two.

The duration of pregnancy is influenced by fetal and maternal genetic and non-genetic factors. Here we report a fetal genome-wide association meta-analysis of gestational duration, and early preterm, preterm, and postterm birth in 84,689 infants. One locus on chromosome 2q13 is associated with gestational duration; the association is replicated in 9,291 additional infants (combined P = 3.96 × 10-14). Analysis of 15,588 mother-child pairs shows that the association is driven by fetal rather than maternal genotype. Functional experiments show that the lead SNP, rs7594852, alters the binding of the HIC1 transcriptional repressor. Genes at the locus include several interleukin 1 family members with roles in pro-inflammatory pathways that are central to the process of parturition. Further understanding of the underlying mechanisms will be of great public health importance, since giving birth either before or after the window of term gestation is associated with increased morbidity and mortality.

Human leukocyte antigen (HLA) genes encode proteins with important roles in the regulation of the immune system. Many studies have also implicated HLA genes in psychiatric and neurodevelopmental disorders. However, these studies usually focus on one disorder and/or on one HLA candidate gene, often with small samples. Here, we access a large dataset of 65,534 genotyped individuals consisting of controls (N = 19,645) and cases having one or more of autism spectrum disorder (N = 12,331), attention deficit hyperactivity disorder (N = 14,397), schizophrenia (N = 2401), bipolar disorder (N = 1391), depression (N = 18,511), anorexia (N = 2551) or intellectual disability (N = 3175). We imputed participants' HLA alleles to investigate the involvement of HLA genes in these disorders using regression models. We found a pronounced protective effect of DPB1*1501 on susceptibility to autism (p = 0.0094, OR = 0.72) and intellectual disability (p = 0.00099, OR = 0.41), with an increased protective effect on a comorbid diagnosis of both disorders (p = 0.003, OR = 0.29). We also identified a risk allele for intellectual disability, B*5701 (p = 0.00016, OR = 1.33). Associations with both alleles survived FDR correction and a permutation procedure. We did not find significant evidence for replication of previously-reported associations for autism or schizophrenia. Our results support an implication of HLA genes in autism and intellectual disability, which requires replication by other studies. Our study also highlights the importance of large sample sizes in HLA association studies.

Identifying the causes of similarities and differences in genetic disease prevalence among humans is central to understanding disease etiology. While present-day humans are not strongly differentiated, vast amounts of genomic data now make it possible to study subtle patterns of genetic variation. This allows us to trace our genomic history thousands of years into the past and its implications for the distribution of disease-associated variants today. Genomic analyses have shown that demographic processes shaped the distribution and frequency of disease-associated variants over time. Furthermore, local adaptation to new environmental conditions-including pathogens-has generated strong patterns of differentiation at particular loci. Researchers are also beginning to uncover the genetic architecture of complex diseases, affected by many variants of small effect. The field of population genomics thus holds great potential for providing further insights into the evolution of human disease.

There is mounting evidence that seemingly diverse psychiatric disorders share genetic etiology, but the biological substrates mediating this overlap are not well characterized. Here we leverage the unique Integrative Psychiatric Research Consortium (iPSYCH) study, a nationally representative cohort ascertained through clinical psychiatric diagnoses indicated in Danish national health registers. We confirm previous reports of individual and cross-disorder single-nucleotide polymorphism heritability for major psychiatric disorders and perform a cross-disorder genome-wide association study. We identify four novel genome-wide significant loci encompassing variants predicted to regulate genes expressed in radial glia and interneurons in the developing neocortex during mid-gestation. This epoch is supported by partitioning cross-disorder single-nucleotide polymorphism heritability, which is enriched at regulatory chromatin active during fetal neurodevelopment. These findings suggest that dysregulation of genes that direct neurodevelopment by common genetic variants may result in general liability for many later psychiatric outcomes.

Chimeric antigen receptor (CAR-) T cell therapy is a relatively new form of immunotherapy for hematological malignancies. Although patients are at increased risk of infection following CAR-T cell therapy, reports of fungal infections are scarce. We report a case of Scedosporium apiospermum infection causing bursitis of the elbow in a lymphoma patient after treatment with CAR-T cells. The fungal bursitis relapsed under posaconazole treatment, but was cured after surgical extirpation of the bursa.

Context: The antagonistic capacity of Trichoderma harzianum Rifai against fungal pathogen Sclerotium oryzae (Catt.) strain A-34, and the action mechanisms against the fungal pathogen of Sclerotium oryzae (Catt.), which caused crop losses. Aim: To evaluate the antagonistic capacity of Trichoderma harzianum Rifai against the fungal pathogen Sclerotium oryzae (Catt.). Methods: The concentration of spores/ml-1, the viability and mycelia growth inhibition of the pathogen, and the antagonistic capacity of Trichoderma harzianum, through the action mechanisms. The results were processed using SPSS, version 22.0, for Windows, and Tukey’s test results had a 0.05% probability. A completely randomized experimental design was used for each pathogenic fungus. Results: No antibiosis was observed at 24 hours because the antagonistic did not inhibit pathogen growth; at 72 hours, there was hyphal interaction between S. oryzae and T. harzianum, and there was no mycoparasitism by the antagonist. S. oryzae grew more than the antagonistic at 96 hours, and at 120 hours, the antagonistic grew more than S. oryzae; therefore, no antagonistic or hyper-parasitic activity were observed in the pathogen. Conclusions: The antagonist did not affect the mycelial growth of S. oryzae during the dual challenge. Likewise, T. harzianum (strain A-34) showed no antagonistic activity against Sclerotium oryzae, with a negative inhibition percent of Radial Growth, seen through antibiosis and the action mechanisms.

Contexto: En el país se desconoce la capacidad antagónica de Trichoderma harzianum Rifai cepa A-34 y la acción de los mecanismos frente al fitopatógeno fúngico del arroz Sclerotium oryzae (Catt.) donde ocasionó pérdidas en el cultivo. Objetivo: Evaluar la capacidad antagónica de Trichoderma harzianum Rifai cepa A-34 frente al fitopatógeno fúngico del arroz Sclerotium oryzae (Catt.). Métodos: Se midió concentración de esporas/ ml-1, viabilidad e inhibición del crecimiento micelial del patógeno y la capacidad antagónica de Trichoderma harzianum mediante los mecanismos de acción. Los resultados se procesaron en el paquete estadístico SPSS versión 22,0 para Windows, realizando el Test de Tukey con el 0,05% de probabilidad. Se utilizó un diseño completamente aleatorizado para cada hongo fitopatógeno. Resultados: Se evidencia que no hubo antibiosis a las 24 horas debido a que el antagonista no inhibió el crecimiento del patógeno; a las 72 horas se observó interacción hifal entre S. oryzae y T. harzianum donde no existió micoparasitismo por el antagonista ya que S. oryzae creció más que este a las 96 horas y no fue hasta las 120 horas que el antagonista creció sobre S. oryzae, por tanto, no hubo actividad antagónica ni hiperparasítica sobre el patógeno. Conclusiones: El antagonista no afectó el crecimiento micelial del agente fitopatógeno S. oryzae en el enfrentamiento dual; así mismo T. harzianum (cepa A-34) no manifestó capacidad antagónica, frente a Sclerotium oryzae donde se obtuvo un Porciento de Inhibición del Crecimiento Radial (PICR) negativo, evidenciado a través de la antibiosis y los mecanismos de acción.

Spatial mapping is a promising strategy to investigate the mechanisms underlying the incidence of psychosis. We analyzed a case-cohort study (n = 24,028), drawn from the 1.47 million Danish persons born between 1981 and 2005, using a novel framework for decomposing the geospatial risk for schizophrenia based on locale of upbringing and polygenic scores. Upbringing in a high environmental risk locale increases the risk for schizophrenia by 122%. Individuals living in a high gene-by-environmental risk locale have a 78% increased risk compared to those who have the same genetic liability but live in a low-risk locale. Effects of specific locales vary substantially within the most densely populated city of Denmark, with hazard ratios ranging from 0.26 to 9.26 for environment and from 0.20 to 5.95 for gene-by-environment. These findings indicate the critical synergism of gene and environment on the etiology of schizophrenia and demonstrate the potential of incorporating geolocation in genetic studies.

We studied the developmental course of the spreading of phonological activation in individuals with and without dyslexia by means of a phonological version of the Deese/Roediger-McDermott false memory task. The false memory effect is assumed to reflect the spreading of activation from the presented stimuli to similar words in the lexicon. We assessed 35 volunteers with dyslexia and a group of matched controls with ages ranging from 6 to 58 years. They were first presented with six lists of ten two-syllable words each, all of which shared one syllable with a reference unpresented word. Then, they answered a recognition questionnaire including 24 presented words, 18 phonologically related unpresented words, and 12 unrelated unpresented words. False recognition of phonologically related words increased with age in the control group but stayed at very low levels in the dyslexia group. Our study indicates the existence of a deficit in the spreading of phonological activation in individuals with dyslexia throughout life.

BackgroundThe COVID-19 pandemic has affected the implementation of most ongoing clinical trials worldwide including the PREDIMED-Plus study. The PREDIMED-Plus is an ongoing, multicenter, controlled intervention trial, aimed at weight-loss and cardiovascular disease prevention, in which participants were randomized (1:1 ratio) to an intervention group (energy-reduced Mediterranean diet, promotion of physical activity, and behavioral support) or to a control group (Mediterranean diet with usual care advice). When the pandemic began, the trial was in the midst of the planned intervention. The objective of this report was to examine the effects of the pandemic on the delivery of the intervention and to describe the strategies established to mitigate the possible adverse effects of the pandemic lockdown on data collection and adiposity.MethodsWe assessed the integrity of the PREDIMED-Plus trial during 5 identified periods of the COVID-19 pandemic determined according to restrictions dictated by the Spanish government authorities. A standardized questionnaire was delivered to each of the 23 PREDIMED-Plus recruiting centers to collected data regarding the trial integrity. The effect of the restrictions on intervention components (diet, physical activity) was evaluated with data obtained in the three identified lockdown phases: pre lockdown, lockdown proper, and post lockdown.ResultsDuring the lockdown (March/2020-June/2021), 4,612 participants (48% women, mean age 65y) attended pre-specified yearly follow-up visits to receive lifestyle recommendations and obtain adiposity measures. The overall mean (SD) of the proportions reported by each center showed that 40.4% (25.4) participants had in-person visits, 39.8% (18.2) participants were contacted by telephone and 35% (26.3) by electronic means. Participants’ follow-up and data collection rates increased across lockdown periods (from ≈10% at onset to ≈80% at the end). Compared to pre-lockdown, waist circumference increased during (0.75 cm [95% CI: 0.60–0.91]) and after (0.72 cm [95% CI: 0.56–0.89]) lockdown. Body weight did not change during lockdown (0.01 kg [95% CI: –0.10 to 0.13) and decreased after lockdown (-0.17 kg [95% CI: –0.30 to –0.04]).ConclusionMitigating strategies to enforce the intervention and patient’s follow-up during lockdown have been successful in preserving the integrity of the trial and ensuring its continuation, with minor effects on adiposity.Clinical trial registrationhttps://doi.org/10.1186/ISRCTN89898870, identifier ISRCTN89898870.