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Purpose: In this study, we aimed to determine the effect of a probiotic dietary supplement on physical-anthropometric and biochemical markers in Slovenian patients with metabolic syndrome. Methods: This prospective, randomized, double-blind, placebo-controlled pilot clinical trial involved 16 volunteers who consumed a probiotic dietary supplement over a period of 3 months. The volunteers underwent clinical assessments before and at the end of the period of consuming the dietary supplement or placebo. Results: At a concentration of 1 × 109 colony-forming units per day (N = 8), the Lactobacillus plantarum PCS 26 supplement decreased waist circumference (p = 0.043), lowered serum cholesterol (p = 0.028), and maintained serum adiponectin levels (p = 0.629). In the group that received the placebo (N = 8), no differences were found in the waist circumference (p = 0.750) or serum cholesterol levels (p = 0.225); however, we found a statistically significant reduction of the serum adiponectin levels (p = 0.036). Conclusion: Although the number of patients examined was too low to draw any firm conclusions, dietary supplementation with the probiotic strain Lactobacillus plantarum PCS 26 exerted some favorable effects that could alleviate the symptoms of metabolic syndrome and reduce the clinical manifestations and risks of cardiovascular diseases. These results represent a starting point to carry out an extensive long-term clinical trial that would provide insight into the mechanisms of action of probiotic bacteria in preventing or relieving metabolic syndrome or its components.

BACKGROUND: Uncontrolled pediatric asthma has a large impact on patients and their caregivers. More insight into determinants of uncontrolled asthma is needed. We aim to compare treatment regimens, inhaler techniques, medication adherence and other characteristics of children with controlled and uncontrolled asthma in the: Systems Pharmacology approach to uncontrolled Paediatric Asthma (SysPharmPediA) study. MATERIAL AND METHODS: 145 children with moderate to severe doctor-diagnosed asthma (91 uncontrolled and 54 controlled) aged 6-17 years were enrolled in this multicountry, (Germany, Slovenia, Spain, and the Netherlands) observational, case-control study. The definition of uncontrolled asthma was based on asthma symptoms and/or exacerbations in the past year. Patient-reported adherence and clinician-reported medication use were assessed, as well as lung function and inhalation technique. A logistic regression model was fitted to assess determinants of uncontrolled pediatric asthma. RESULTS: Children in higher asthma treatment steps had a higher risk of uncontrolled asthma (OR (95%CI): 3.30 (1.56-7.19)). The risk of uncontrolled asthma was associated with a larger change in FEV1% predicted post and pre-salbutamol (OR (95%CI): 1.08 (1.02-1.15)). Adherence and inhaler techniques were not associated with risk of uncontrolled asthma in this population. CONCLUSION: This study showed that children with uncontrolled moderate-to-severe asthma were treated in higher treatment steps compared to their controlled peers, but still showed a higher reversibility response to salbutamol. Self-reported adherence and inhaler technique scores did not differ between controlled and uncontrolled asthmatic children. Other determinants, such as environmental factors and differences in biological profiles, may influence the risk of uncontrolled asthma in this moderate to severe asthmatic population. The SysPharmPediA consortium is supported by ZonMW [project number: 9,003,035,001], the Ministry of Education, Science, and Sport of the Republic of Slovenia [contract number C330–16–500,106]; the German Ministry of Education and Research (BMBF) [project number FKZ 031L0088]; Instituto de Salud Carlos III (ISCIII) through Strategic Action for Health Research (AES) and European Community (EC) within the Active and Assisted Living (AAL) Program framework [award numbers AC15/00,015 and AC15/00,058] under the frame of the ERACoSysMed JTC-1 Call.”

Objectives Acute kidney injury (AKI) is associated with higher perioperative mortality and morbidity. Oxidative stress has been proposed as a cause of postoperative AKI. Ascorbic acid (AA) supplementation was suggested as a novel and promising antioxidant. The aim of this study was to evaluate the capability of AA to reduce the incidence of postoperative AKI in cardiac surgery patients. Methods A prospective randomized trial was conducted in patients scheduled for on-pump cardiac surgery. Subjects in the AA group received 2 g of AA intravenously during the induction of anesthesia, 2 g before aortic cross-clamp removal and 1 g every 8 hours for five postoperative days (the JERICA protocol). Postoperatively, the patients were monitored for AKI and other complications. Malondialdehyde levels were monitored in a subpopulation of 100 patients to evaluate the effect of AA on oxidative stress level. Results The AA and control group consisted of 163 and 169 patients, respectively. The groups were well matched for baseline demographics and had similar intraoperative characteristics. The incidence of AKI in the AA and control group was 20.9 and 28.4%, respectively (p = 0.127). The estimated glomerular filtration rate did not differ between the study groups in the entire postoperative period. There was a trend toward higher malondialdehyde values with statistical significance on postoperative day 1 and lower in-hospital mortality in the AA group (0.6 vs. 4.1%, p = 0.067). Conclusion Our results do not support the effectiveness of AA supplementation in reducing the incidence of postoperative AKI in on-pump cardiac surgery patients. Clinical Registration Number This study was registered with the ISRCTN Registry under the trial registration number ISRCTN98572043.

Background: In the last few decades, different coma scoring scales have been proposed. The purpose of this study is to compare two coma scales, the GCS (Glasgow Coma Scale) and the FOUR score (Full Outline of UnResponsiveness score), aiming to examine which scale is better for predicting outcome in traumatic brain injury (TBI) patients in the prehospital setting.Methods: We evaluated the GCS and FOUR scores in the prehospital setting at three different prehospital timepoints, and we reassessed the scores in surviving patients 24 hours, one month and three months after the injury. Then, we compared the outcomes.We used the χ² method, and based on the analysis with the best cut-off point for each model, we calculated the sensitivity, specificity and correct prediction of outcomes with four severity scores. The Youden index, Z score, McNemar's test and ROC curve were also assessed. P < 0.05 was considered statistically significant. Both scales were ranked with gain ratios.Results: We included 200 TBI patients who were treated in a prehospital setting by a prehospital specialized medical unit. In terms of the predictions of positive outcomes, our study showed the following:1. Twenty-four hours after the injury, the best cut-off points obtained were from the FOUR 1 and GCS 1 models.2. One month after the injury, the best cut-off points obtained were from the following models: FOUR 2 and GCS 3 as well as FOUR 3 and GCS 3.3. Three months after the injury, the best cut-off points obtained were from the following models: FOUR 2 and GCS 1, FOUR 3 and GCS 1, and GCS 1 and GCS 2.Conclusions: In our study, the results of our research confirm that there are no practical or clinical differences between the GCS and FOUR scores in terms of predicting morality outcomes 24 hours, one month, and three months after injury. No statistically significant differences were found in the Youden index or the area under the ROC curve 24 hours, one month or three months after the injury.

Although human clinical studies have suggested probiotic effects on blood glucose levels, knowledge about molecular mechanisms is still scarce. To test the hypothesis that selected Lactobacillus probiotic bacteria could regulate the activity of enterocyte glucose transporters, we aimed to measure in vitro effects of selected Lactobacillus probiotic bacteria on transcription and translation of intestinal glucose transporters sodium-dependent glucose cotransporter 1 (SGLT1) and glucose transporter 2 (GLUT2) as well as transepithelial glucose transport. Lactobacillus plantarum strains (PCS20 and PCS26), Lactobacillus rhamnosus GG (LGG) (ATCC 53103) and Lactobacillus acidophilus (L acidophilus) (ATCC 4356) were co-cultivated with noncarcinogenic porcine enterocytes (CLAB) and human epithelial colorectal adenocarcinoma cells (Caco-2) (ATCC HTB-37). Changes in transcription and expression of SGLT1 and GLUT2 were strain and cell line-specific. In CLAB, LGG was the most potent SGLT1 up-regulator, and PCS26 the most potent down-regulator of GLUT2 transcription, which was also reflected on the protein level. In Caco-2, all tested strains tended to downregulate GLUT2 gene expression, while L acidophilus most effectively reduced GLUT2 protein levels. Statistically significant effect of PCS26 and L acidophilus on GLUT2 molecular and protein levels in CLAB and Caco-2 cell lines, respectively, was also followed by a decreased rate of transepithelial glucose transport. Careful selection of specific Lactobacillus probiotic strains could be used to downregulate glucose absorption in intestinal epithelial cells and thereby could be beneficial as a support treatment of pathologies related to glucose homeostasis.

BACKGROUND: Inhaled corticosteroid (ICS) response among patients with asthma is influenced by genetics, but biologically actionable insights based on associations have not been found. Various glucocorticoid response omics datasets are available to interrogate their biological effects. OBJECTIVE: We sought to identify functionally relevant ICS response genetic associations by integrating complementary multiomics datasets. METHODS: Variants with p-values

Familial Progressive Hyper‐ and Hypopigmentation is a pigmentary disorder characterized by a mix of hypo‐ and hyperpigmented lesions, café‐au‐lait spots and hypopigmented ash‐leaf macules. The disorder was previously linked to KITLG and various mutations have been reported to segregate in different families. Furthermore, association between KITLG mutations and malignancies was also suggested. Exome and SANGER sequencing were performed for identification of KITLG mutations. Functional in silico analyses were additionally performed to assess the findings. We identified a de novo mutation in exon 4 of KITLG gene causing NM_000899.4:c.[329A>T] (chr12:88912508A>T) leading to NP_000890.1:p.(Asp110Val) substitution in the 3rd alpha helix. It was predicted as pathogenic, located in a conserved region and causing an increase in hydrophobicity in the KITLG protein. Our findings clearly confirm an additional hot spot of KITLG mutations in the 3rd alpha helix, which very likely increases the risk of malignancies. To our knowledge the present study provides the strongest evidence of association of the KITLG mutation with both Familial Progressive Hyper‐ and Hypopigmentation and malignancy due to its’ location on somatic cancer mutation locus. Additionally we also address difficulties with classification of the unique phenotype and propose a subtype within broader diagnosis.

Background: The polymorphism Arg16 in β2-adrenergic receptor (ADRB2) gene has been associated with an increased risk of exacerbations in asthmatic children treated with long-acting β2-agonists (LABA). However, it remains unclear whether this increased risk is mainly attributed to this single variant or the combined effect of the haplotypes of polymorphisms at codons 16 and 27. Objective: We assessed whether the haplotype analysis could explain the association between the polymorphisms at codons 16 (Arg16Gly) and 27 (Gln27Glu) in ADRB2 and risk of asthma exacerbations in patients treated with inhaled corticosteroids (ICS) plus LABA. Methods: The study was undertaken using data from 10 independent studies (n = 5903) participating in the multi-ethnic Pharmacogenomics in Childhood Asthma (PiCA) consortium. Asthma exacerbations were defined as asthma-related use of oral corticosteroids or hospitalizations/emergency department visits in the past 6 or 12 months prior to the study visit/enrolment. The association between the haplotypes and the risk of asthma exacerbations was performed per study using haplo.stats package adjusted for age and sex. Results were meta-analysed using the inverse variance weighting method assuming random-effects. Results: In subjects treated with ICS and LABA (n = 832, age: 3–21 years), Arg16/Gln27 versus Gly16/Glu27 (OR: 1.40, 95% CI: 1.05–1.87, I2 = 0.0%) and Arg16/Gln27 versus Gly16/Gln27 (OR: 1.43, 95% CI: 1.05–1.94, I2 = 0.0%), but not Gly16/Gln27 versus Gly16/Glu27 (OR: 0.99, 95% CI: 0.71–1.39, I2 = 0.0%), were significantly associated with an increased risk of asthma exacerbations. The sensitivity analyses indicated no significant association between the ADRB2 haplotypes and asthma exacerbations in the other treatment categories, namely as-required short-acting β2-agonists (n = 973), ICS monotherapy (n = 2623), ICS plus leukotriene receptor antagonists (LTRA; n = 338), or ICS plus LABA plus LTRA (n = 686). Conclusion and clinical relevance: The ADRB2 Arg16 haplotype, presumably mainly driven by the Arg16, increased the risk of asthma exacerbations in patients treated with ICS plus LABA. This finding could be beneficial in ADRB2 genotype-guided treatment which might improve clinical outcomes in asthmatic patients.

Background Women with uterine adenomyosis seeking assisted reproduction have been associated with compromised endometrial receptivity to embryo implantation. To understand the mechanisms involved in this process, we aimed to compare endometrial transcriptome profiles during the window of implantation (WOI) between women with and without adenomyosis. Methods We obtained endometrial biopsies LH-timed to the WOI from women with sonographic features of adenomyosis (n=10) and controls (n=10). Isolated RNA samples were subjected to RNA sequencing (RNA-seq) by the Illumina NovaSeq 6000 platform and endometrial receptivity classification with a molecular tool for menstrual cycle phase dating (beREADY®, CCHT). The program language R and Bioconductor packages were applied to analyse RNA-seq data in the setting of the result of accurate endometrial dating. To suggest robust candidate pathways, the identified differentially expressed genes (DEGs) associated with the adenomyosis group in the receptive phase were further integrated with 151, 173 and 42 extracted genes from published studies that were related to endometrial receptivity in healthy uterus, endometriosis and adenomyosis, respectively. Enrichment analyses were performed using Cytoscape ClueGO and CluePedia apps. Results Out of 20 endometrial samples, 2 were dated to the early receptive phase, 13 to the receptive phase and 5 to the late receptive phase. Comparison of the transcriptomics data from all 20 samples provided 909 DEGs (p Conclusions Accurate endometrial dating and RNA-seq analysis resulted in the identification of altered response to IFN signalling as the most promising candidate of impaired uterine receptivity in adenomyosis.

Inhaled corticosteroids (ICS) are the most common asthma controller medication. An important contribution of genetic factors in ICS response has been evidenced. Here, we aimed to identify novel genetic markers involved in ICS response in asthma. A genome-wide association study (GWAS) of the change in lung function after 6 weeks of ICS treatment was performed in 166 asthma patients from the SLOVENIA study. Patients with an improvement in lung function ≥8% were considered as ICS responders. Suggestively associated variants (p-value ≤ 5 × 10−6) were evaluated in an independent study (n = 175). Validation of the association with asthma exacerbations despite ICS use was attempted in European (n = 2681) and admixed (n = 1347) populations. Variants previously associated with ICS response were also assessed for replication. As a result, the SNP rs1166980 from the ROBO2 gene was suggestively associated with the change in lung function (OR for G allele: 7.01, 95% CI: 3.29–14.93, p = 4.61 × 10−7), although this was not validated in CAMP. ROBO2 showed gene-level evidence of replication with asthma exacerbations despite ICS use in Europeans (minimum p-value = 1.44 × 10−5), but not in admixed individuals. The association of PDE10A-T with ICS response described by a previous study was validated. This study suggests that ROBO2 could be a potential novel locus for ICS response in Europeans.

Inhaled corticosteroids (ICS) are the most common asthma controller medication. An important contribution of genetic factors in ICS response has been evidenced. Here, we aimed to identify novel genetic markers involved in ICS response in asthma. A genome-wide association study (GWAS) of the change in lung function after 6 weeks of ICS treatment was performed in 166 asthma patients from the SLOVENIA study. Patients with an improvement in lung function ≥8% were considered as ICS responders. Suggestively associated variants (p-value ≤ 5 × 10−6) were evaluated in an independent study (n = 175). Validation of the association with asthma exacerbations despite ICS use was attempted in European (n = 2681) and admixed (n = 1347) populations. Variants previously associated with ICS response were also assessed for replication. As a result, the SNP rs1166980 from the ROBO2 gene was suggestively associated with the change in lung function (OR for G allele: 7.01, 95% CI: 3.29–14.93, p = 4.61 × 10−7), although this was not validated in CAMP. ROBO2 showed gene-level evidence of replication with asthma exacerbations despite ICS use in Europeans (minimum p-value = 1.44 × 10−5), but not in admixed individuals. The association of PDE10A-T with ICS response described by a previous study was validated. This study suggests that ROBO2 could be a potential novel locus for ICS response in Europeans.

Uterine leiomyomas are tumors, which are hormone driven and originate from the smooth muscle layer of the uterine wall. In addition to known genes in leiomyoma pathogenesis, recent approaches also highlight epigenetic malfunctions as an important mechanism of gene dysregulation. RNA sequencing raw data from pair-matched normal myometrium and fibroid tumors from two independent studies were used as discovery and validation sets and reanalyzed. RNA extracted from normal myometrium and fibroid tumors from 58 Slovenian patients was used as independent confirmation of most significant differentially expressed genes. Subsequently, GWA data from leiomyoma patients were used in order to identify genetic variants at epigenetic marks. Gene Ontology analysis of the overlap of two independent RNA-seq analyses showed that NPTX1, NPTX2, CHRM2, DRD2 and CACNA1A were listed as significant for several enriched GO terms. All five genes were subsequently confirmed in the independent Slovenian cohort. Additional integration and functional analysis showed that genetic variants in these five gene regions are listed at a chromatin structure and state, predicting promoters, enhancers, DNase hypersensitivity and altered transcription factor binding sites. We identified a unique subgroup of dysregulated synaptic signaling genes involved in the biology and pathogenesis of leiomyomas, adding to the complexity of tumor biology.

RationaleSubstantial variability in response to asthma treatment with inhaled corticosteroids (ICS) has been described among individuals and populations, suggesting the contribution of genetic factors. Nonetheless, only a few genes have been identified to date. We aimed to identify genetic variants associated with asthma exacerbations despite ICS use in European children and young adults and to validate the findings in non-Europeans. Moreover, we explored whether a gene-set enrichment analysis could suggest potential novel asthma therapies.MethodsA genome-wide association study (GWAS) of asthma exacerbations was tested in 2681 children of European descent treated with ICS from eight studies. Suggestive association signals were followed up for replication in 538 European asthma patients. Further evaluation was performed in 1773 non-Europeans. Variants revealed by published GWAS were assessed for replication. Additionally, gene-set enrichment analysis focused on drugs was performed.Results10 independent variants were associated with asthma exacerbations despite ICS treatment in the discovery phase (p≤5×10−6). Of those, one variant at theCACNA2D3-WNT5Alocus was nominally replicated in Europeans (rs67026078; p=0.010), but this was not validated in non-European populations. Five other genes associated with ICS response in previous studies were replicated. Additionally, an enrichment of associations in genes regulated by trichostatin A treatment was found.ConclusionsThe intergenic region ofCACNA2D3andWNT5Awas revealed as a novel locus for asthma exacerbations despite ICS treatment in European populations. Genes associated were related to trichostatin A, suggesting that this drug could regulate the molecular mechanisms involved in treatment response.

Objectives Combining of genomic data of different pathologies as a single phenotype has emerged as a useful strategy to identify genetic risk loci shared among immune-mediated diseases. Our study aimed to increase our knowledge of the genetic contribution to Kawasaki disease (KD) and IgA vasculitis (IgAV) by performing the first comprehensive large-scale analysis on the genetic overlap between them. Methods A total of 1190 vasculitis patients and 11 302 healthy controls were analysed. First, in the discovery phase, genome-wide data of 405 KD patients and 6252 controls and 215 IgAV patients and 1324 controls, all of European origin, were combined using an inverse variance meta-analysis. Second, the top associated polymorphisms were selected for replication in additional independent cohorts (570 cases and 3726 controls). Polymorphisms with P-values ≤5 × 10−8 in the global IgAV–KD meta-analysis were considered as shared genetic risk loci. Results A genetic variant, rs3743841, located in an intron of the NAGPA gene, reached genome-wide significance in the cross-disease meta-analysis (P = 8.06 × 10−10). Additionally, when IgAV was individually analysed, a strong association between rs3743841 and this vasculitis was also evident [P = 1.25 × 10−7; odds ratio = 1.47 (95% CI 1.27, 1.69)]. In silico functional annotation showed that this polymorphism acts as a regulatory variant modulating the expression levels of the NAGPA and SEC14L5 genes. Conclusion We identified a new risk locus with pleiotropic effects on the two childhood vasculitides analysed. This locus represents the strongest non-HLA signal described for IgAV to date.

Intestinal transepithelial transport of glucose is mediated by glucose transporters, and affects postprandial blood-glucose levels. This study investigates the effect of wood extracts rich in hydrolyzable tannins (HTs) that originated from sweet chestnut (Castanea sativa Mill.) and oak (Quercus petraea) on the expression of glucose transporter genes and the uptake of glucose and HT constituents in a 3D porcine-small-intestine epithelial-cell model. The viability of epithelial cells CLAB and PSI exposed to different HTs was determined using alamarBlue&reg, qPCR was used to analyze the gene expression of SGLT1, GLUT2, GLUT4, and POLR2A. Glucose uptake was confirmed by assay, and LC&ndash, MS/ MS was used for the analysis of HT bioavailability. HTs at 37 &micro, g/mL were found to adversely affect cell viability and downregulate POLR2A expression. HT from wood extract Tanex at concentrations of 4 &micro, g/mL upregulated the expression of GLUT2, as well as glucose uptake at 1 &micro, g/mL. The time-dependent passage of gallic acid through enterocytes was influenced by all wood extracts compared to gallic acid itself as a control. These results suggest that HTs could modulate glucose uptake and gallic acid passage in the 3D cell model.

Background In some patients securing the peripheral intravenous cannula (PIVC) with a standard adhesive dressing can be difficult because of sweat or other body fluids. The aim of our study was to evaluate the use of tissue adhesives alone as a means to secure PIVCs inserted in the emergency department. Methods We performed a prospective interventional pilot study from November 2019 to May 2020 in a medical emergency department of an urban tertiary hospital. Patients were randomized to two groups: tissue adhesives (TA) or adhesive dressing (AD) group. After randomization we followed them until day 4. Results There were no significant differences between TA and AD groups in the rate of unplanned removal of PIVCs in the first 72 h (57.1% vs. 45.8%, p = 0.29), the rate of unplanned removal of PIVCs in the ED (0% vs. 2.1%, p = 1.00), the rate of unplanned removal of PIVC in the first 24 h (42.8% vs. 35.4%, p = 0.52), as well as in the rate of phlebitis (7.1% vs. 14.6%, p = 0.34) and the rate of any blood-stream infection (0% vs. 0%, p = 1.00). Conclusion We did not observe any significant differences when PIVCs inserted in the emergency department were secured with tissue adhesives alone, compared to standard adhesive dressings. We observed a high rate of unplanned removal of PIVCs, necessitating further research to determine more reliable ways of securing PIVCs.

IntroductionBacterial community-acquired pneumonia (CAP) in children is caused mostly by Streptococcus pneumoniae. The resistance of pneumococci to penicillin is increasing. However, most guidelines still prefer treatment with narrow-spectrum antibiotics. Therefore, we compared the effect of intravenous treatment with penicillin and broad-spectrum β-lactam antibiotics in children with CAP. The objective of our study was to assess the eligibility of treatment of bacterial CAP with intravenous penicillin.Material and methodsWe performed a prospective study and included 136 children hospitalised because of bacterial CAP. Patients were treated intravenously with either penicillin G or broad-spectrum β-lactam antibiotic monotherapy. Lung ultrasound and blood tests were performed at admission and after 2 days of treatment. The time interval from the application of antibiotics to permanent defervescence was recorded.ResultsEighty-seven (64.0%) patients were treated with penicillin G, and 49 (36.0%) were treated with broad-spectrum β-lactam antibiotics. The median time to persistent defervescence was 5 h in the penicillin group and 8 h in the broad-spectrum group (p = 0.18). There were no significant differences between the treatment regimens regarding the effect on the consolidation sizes or C-reactive protein levels. However, the decrease in the white blood cell count was marginally greater in the penicillin treatment group (p = 0.05).ConclusionsWe have shown that penicillin is as effective as broad-spectrum antibiotics in the treatment of bacterial CAP in children. Although the resistance of pneumococci to antibiotics is increasing, clinicians should still use penicillin and other narrow-spectrum β-lactam antibiotics in the treatment of bacterial CAP in children.

Multiple sclerosis is an inflammatory disorder of the central nervous system. Inflammation may create high susceptibility to subclinical atherosclerosis. The purpose of this study was to compare subclinical atherosclerosis and the role of inflammatory cytokines between the group of patients with relapsing-remitting multiple sclerosis (RRMS) and healthy controls matched for age and sex. The study group consisted of 112 non-diabetic and non-hypertensive RRMS patients treated with disease modifying drugs (DMD) and the control group was composed of 51 healthy subjects. The common carotid artery (CCA) intima media thickness (IMT) was investigated. Serum levels of risk factors for atherosclerosis and inflammatory cytokines were also determined. The mean CCA IMT (0.572 ± 0.131 mm vs. 0.571 ± 0.114 mm) did not differ (p > 0.05) between patients and controls. The RRMS patients’ CCA IMT was significantly correlated with serum interleukin 6 (IL-6) (p = 0.027), high-sensitivity C-reactive protein (hs-CRP) (p = 0.027), cystatin C (p

Objectives Previous studies have found evidence for a genetic basis for pelvic organ prolapse (POP), but no genetic studies have differentiated between types of POP. This study investigated whether genetic variants in six previously suggested candidate loci for POP modify the risk of uterine prolapse (UP). Study design One hundred patients, aged 30–55 years, who had undergone surgery due to total UP and 105 healthy controls were included in this study. After extracting the genomic DNA from peripheral blood, six single nucleotide polymorphisms (SNPs) previously identified for POP were genotyped, and association analysis was performed for contributing risk factors. RNA expression was determined from sacrouterine ligaments of patients and controls using quantitative reverse transcription polymerase chain reaction. Results The dominant genotype model for the T allele for SNP rs6051098 at the chromosome 20p13 locus was significant, and this remained significant with the risk factor regression model (p=0.046; odds ratio 1.93, 95 % confidence interval 1.01–3.66). The isocitrate dehydrogenase 3 beta (IDH3B) gene was the only potential candidate gene in the 20p13 locus that was significantly upregulated in sacrouterine biopsies in women with UP compared with controls (p = 0.034). Conclusion To the best of the authors’ knowledge, this is the first study to show that genetic risk factors contribute to UP, and suggested rs6051098 as the best candidate risk factor associated with UP. According to expression data in sacrouterine tissue, this study suggests that the IDH3B gene plays a role in the pathogenesis of UP.

The success rate of percutaneous coronary artery intervention (PCI) of chronic total occlusion (CTO) lesions have increased in the recent years. However, improvement of function is only possible when significant myocardial viability is present. One of the most important factors of maintaining myocardial viability is the opening and development of collaterals. Our hypothesis was that with a higher degree of collaterals more viable myocardium is present. In 38 patients we compared the degree of collaterals, evaluated with a conventional coronary angiogram (CCA) and graded by the Rentrop classification to transmural extent of the scar obtained in a viability study with magnetic resonance (MRI). We found a statistically significant association of the degree of collaterals determined with Rentrop method and transmural extent of the scar as measured by CMR (p = 0.001; Tau = -0.144). Additionally, associations showed an increase in the ratio between viable vs. non-viable myocardium with the degree of collaterals. Our study suggests that it may be beneficial to routinely grade the collaterals at angiography in patients with CTO as an assessment of myocardial viability.

The aetiology of community-acquired pneumonia (CAP) is not easy to establish. As lung ultrasound (LUS) has already proved to be an excellent diagnostic tool for CAP, we analysed its usefulness for discriminating between the aetiologically different types of CAP in children. We included 147 children hospitalized because of CAP. LUS was performed in all patients at admission, and follow-up LUS was performed in most patients. LUS-detected consolidations in viral CAP were significantly smaller, with a median diameter of 15 mm, compared to 20 mm in atypical bacterial CAP (p = 0.05) and 30 mm in bacterial CAP (p

Response to anti-TNF therapy is crucial for life expectancy and life quality in patients with severe Crohn's disease. We investigated if a previously reported gene expression profile predictive for infliximab response could be also applied to adalimumab response in an independent cohort. Forty-seven Slovene Crohn's disease patients indicated for adalimumab therapy were enrolled in the study. Inflamed and non-inflamed colon biopsy samples were obtained during routine colonoscopy prior to adalimumab treatment. Response to adalimumab was measured with IBDQ. Gene expression in inflamed and non-inflamed colon biopsy samples was measured with RT-qPCR. Genotypes were extracted from previously available genotype data. Statistical analysis was performed with SPSS software. The R package e1071 was used to train bootstrap aggregated support vector machines (SVM). SVM prediction model analysis was used to analyze pooled, non-inflamed, and inflamed colon tissue datasets using IBDQ response after 4, 12, 20 and 30 weeks of adalimumab treatment. The bagging approach was used in an endeavor to obtain 100 % accuracy using 10 × 100 or 100 × 100 iterations. Average adalimumab response prediction accuracy is 75.5 % for pooled samples, 90.5 % for inflamed samples, and 100 % for non-inflamed samples. Moreover, models trained on selected SNPs from analyzed genes had an average accuracy of 92.8 %, confirming the involvement of genetic regions mapping the reported genes. Finally, using combined gene expression and SNP data we observed 100 % adalimumab response prediction accuracy for pooled, inflamed, and non-inflamed datasets. Our study supports the reported genetic anti-TNF response profile and extends it for adalimumab prediction. Eine ausreichende Antwort auf Anti-TNF-Behandlung mit Infliximab oder Adalimumab ist entscheidend für Lebenserwartung und Lebensqualität bei Patienten mit schwergradigem Morbus Crohn. Wir untersuchten, ob das zuvor beschriebene Genprofil zur Prognose des Therapieerfolgs mit Infliximab auch zur Prognose des Therapieerfolgs mit Adalimumab in einer unabhängigen Kohorte anwendbar ist. 47 slowenische für Adalimumab-Behandlung indizierte Morbus-Crohn-Patienten wurden in die Studie aufgenommen. Vor der Behandlung mit Adalimumab wurden während der Kolonoskopie entzündete und nicht entzündete Gewebeproben entnommen. Die Reaktion auf Adalimumab wurde mit IBDQ gemessen. Die Genexpression in Gewebeproben wurde mit RT-qPCR gemessen. Genotypen wurden aus zuvor verfügbaren Genotypdaten extrahiert. Die statistische Analyse wurde mit SPSS-Software durchgeführt. Das R-Paket e1071 wurde zum Trainieren von Support Vector Machines benutzt. Die SVM-Vorhersagemodelle wurden verwendet, um die gepoolten, nicht entzündeten und entzündeten Darmproben-Datensätze mit Verwendung von IBDQ-Antwort nach 4, 12, 20 und 30 Wochen Adalimumab-Behandlung zu analysieren. Die Bagging-Methode wurde verwendet, um eine 100-%-Genauigkeit mit Verwendung von 10 × 100 oder 100 × 100 Iterationen zu erreichen. Die Adalimumab-Antwortvorhersage von gepoolten Datensätzen erreichte im Durchschnitt eine Genauigkeit von 75,5 %, von entzündeten Datensätzen 90,5 % und von nicht entzündeten Datensätzen 100 %. Zusätzlich haben die Modelle, die an ausgewählten SNPs in den analysierten Genen trainiert wurden, eine durchschnittliche Genauigkeit von 92,8 % erreicht. Schließlich kombinierten wir Expressions- und Genotypdaten, um den Vorhersagewert weiter zu analysieren. Mithilfe kombinierter Daten konnten wir mit Darmgewebe-Datensätzen eine Adalimumab-Antwortvorhersage mit hundertprozentiger Sicherheit feststellen. Unsere Studie unterstützt das genetische Anti-TNF-Antwortprofil, das für den Adalimumab-Therapieerfolg gleichermaßen relevant ist.

Introduction: Inhaled corticosteroids (ICS) are the most effective medication for control of asthma symptoms. However, a proportion of patients do not respond to this medication and suffer exacerbations, due to a combination of environmental and genetic factors. We performed a meta- genome-wide association study (GWAS) to identify genes associated with ICS response in European children. Methods: A GWAS meta-analysis of asthma exacerbations was performed across eight European studies from the Pharmacogenomics in Childhood Asthma (PiCA) consortium including 2,704 asthmatic children and young adults treated with ICS. Imputation of genetic variants was carried out using the Haplotype Reference Consortium as reference panel and association testing was performed by means of logistic regression models. A total of 8.1 million genetic variants with minor allele frequency ≥1% were meta-analyzed. Results: Nineteen polymorphisms were suggestively associated with asthma exacerbations despite use of ICS (p≤5x10-6). These variants were located at 10 segregating sites (minimum p=6.7x10-7). Novel associations were revealed in biologically plausible genes involved in drug metabolism (AOX1) and previously associated with lung function measurements (WNT5A and CNTNAP5). Moreover, variants located at CNTNAP5 were also nominally associated with a change in FEV1 after ICS treatment in SLOVENIA (minimum p=0.025). Conclusions: We revealed genes suggestively associated with asthma exacerbations in children and young adults despite the use of ICS. Replication will be performed in further independent studies. Study supported by Instituto de Salud Carlos III (AC15/00015) and ERACoSysMed 1st Joint Transnational Call (SysPharmPedia).