| 2081. |
- Sandvik, R. M., et al.
(author)
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Nationwide lung function monitoring from infancy in newborn-screened children with cystic fibrosis
- 2023
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In: European Respiratory Journal Open Research (ERJ Open Research). - 2312-0541. ; 9:5
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Journal article (peer-reviewed)abstract
- Background Cystic fibrosis (CF) lung disease starts in infancy and can be assessed for structural lung abnormalities using computed tomography or magnetic resonance scans, or for lung function impairment using multiple breath washout (MBW). However, in infancy these two methods are not well correlated. Trajectories of CF lung disease assessed by MBW in infants and toddlers remain poorly described, which is why we aimed to 1) describe the trajectory of lung function, 2) explore risk factors for progression and 3) explore the real-life effect of lumacaftor/ivacaftor. Methods This was a nationwide observational cohort study (2018-2021) using data collected as part of the routine clinical surveillance programme (including MBW and monthly endo-laryngeal suction sampling for bacterial pathogens) in children born after implementation of newborn screening for CF (May 2016). Lumacaftor/ivacaftor commenced from age 2 years in children homozygous for F508del. Ventilation distribution efficiency (VDE), recently described to have advantages over lung clearance index (LCI), was reported as the primary MBW outcome after z-score calculations based on published reference data. Mixed effect linear regression models were the main statistical analyses performed in this study. Results 59 children, aged 2-45 months, contributed with 211 MBW occasions (median (interquartile range (IQR)) 3 (2-5) MBW occasions per child) with a median (IQR) follow-up time of 10.8 (5.222.3) months. An overall mean annual deterioration rate of -0.50 (95% CI -0.78-0.22) z-VDE was observed, starting from an estimated mean z-VDE of -1.68 (95% CI -2.15-1.22) at age 0.0 years (intercept). Pseudomonas aeruginosa "ever" (n=14, MBWs 50) had a significantly worse z-VDE trajectory versus P. aeruginosa "never" (mean difference 0.53 (95% CI 0.16-0.89) per year; p=0.0047) and lumacaftor/ivacaftor treatment (n=22, MBWs 46) significantly improved the trajectory of z-VDE (mean difference 1.72 (95% CI 0.79-2.66) per year; p=0.0004), leading to a stable mean z-VDE trajectory after start of treatment. Conclusions Infants and toddlers with CF demonstrated progressive deterioration in z-VDE over the first years of life. P. aeruginosa isolation "ever" was associated with an accelerated deterioration in lung function, while lumacaftor/ivacaftor therapy significantly improved and stabilised the trajectory.
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| 2082. |
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| 2083. |
- Schartl, Manfred, et al.
(author)
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The Developmental and Genetic Architecture of the Sexually Selected Male Ornament of Swordtails
- 2021
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In: Current Biology. - : Elsevier. - 0960-9822 .- 1879-0445. ; 31:5, s. 911-922.e4
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Journal article (peer-reviewed)abstract
- Sexual selection results in sex-specific characters like the conspicuously pigmented extension of the ventral tip of the caudal fin-the ``sword''-in males of several species of Xiphophorus fishes. To uncover the genetic architecture underlying sword formation and to identify genes that are associated with its development, we characterized the sword transcriptional profile and combined it with genetic mapping approaches. Results showed that the male ornament of swordtails develops from a sexually non-dimorphic prepattern of transcription factors in the caudal fin. Among genes that constitute the exclusive sword transcriptome and are located in the genomic region associated with this trait we identify the potassium channel, Kcnh8, as a sword development gene. In addition to its neural function kcnh8 performs a known role in fin growth. These findings indicate that during evolution of swordtails a brain gene has been co-opted for an additional novel function in establishing a male ornament.
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| 2084. |
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| 2085. |
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| 2086. |
- Schetelig, J, et al.
(author)
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Haplotype Motif-Based Models for KIR-Genotype Informed Selection of Hematopoietic Cell Donors Fail to Predict Outcome of Patients With Myelodysplastic Syndromes or Secondary Acute Myeloid Leukemia
- 2021
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In: Frontiers in immunology. - : Frontiers Media SA. - 1664-3224. ; 11, s. 584520-
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Journal article (peer-reviewed)abstract
- Results from registry studies suggest that harnessing Natural Killer (NK) cell reactivity mediated through Killer cell Immunoglobulin-like Receptors (KIR) could reduce the risk of relapse after allogeneic Hematopoietic Cell Transplantation (HCT). Several competing models have been developed to classify donors as KIR-advantageous or disadvantageous. Basically, these models differ by grouping donors based on distinct KIR–KIR–ligand combinations or by haplotype motif assignment. This study aimed to validate different models for unrelated donor selection for patients with Myelodysplatic Syndromes (MDS) or secondary Acute Myeloid Leukemia (sAML). In a joint retrospective study of the European Society for Blood and Marrow Transplantation (EBMT) and the Center for International Blood and Marrow Transplant Research (CIBMTR) registry data from 1704 patients with secondary AML or MDS were analysed. The cohort consisted mainly of older patients (median age 61 years) with high risk disease who had received chemotherapy-based reduced intensity conditioning and anti-thymocyte globulin prior to allogeneic HCT from well-matched unrelated stem cell donors. The impact of the predictors on Overall Survival (OS) and relapse incidence was tested in Cox regression models adjusted for patient age, a modified disease risk index, performance status, donor age, HLA-match, sex-match, CMV-match, conditioning intensity, type of T-cell depletion and graft type. KIR genes were typed using high-resolution amplicon-based next generation sequencing. In univariable and multivariable analyses none of the models predicted OS and the risk of relapse consistently. Our results do not support the hypothesis that optimizing NK-mediated alloreactivity is possible by KIR-genotype informed selection of HLA-matched unrelated donors. However, in the context of allogeneic transplantation, NK-cell biology is complex and only partly understood. KIR-genes are highly diverse and current assignment of haplotype motifs based on the presence or absence of selected KIR genes is over-simplistic. As a consequence, further research is highly warranted and should integrate cutting edge knowledge on KIR genetics, and NK-cell biology into future studies focused on homogeneous groups of patients and treatment modalities.
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| 2087. |
- Schijven, Dick, et al.
(author)
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Large-scale analysis of structural brain asymmetries in schizophrenia via the ENIGMA consortium
- 2023
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In: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences (PNAS). - 0027-8424 .- 1091-6490. ; 120:14
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Journal article (peer-reviewed)abstract
- Left-right asymmetry is an important organizing feature of the healthy brain that may be altered in schizophrenia, but most studies have used relatively small samples and heterogeneous approaches, resulting in equivocal findings. We carried out the largest case-control study of structural brain asymmetries in schizophrenia, with MRI data from 5,080 affected individuals and 6,015 controls across 46 datasets, using a single image analysis protocol. Asymmetry indexes were calculated for global and regional cortical thickness, surface area, and subcortical volume measures. Differences of asymmetry were calculated between affected individuals and controls per dataset, and effect sizes were meta-analyzed across datasets. Small average case-control differences were observed for thickness asymmetries of the rostral anterior cingulate and the middle temporal gyrus, both driven by thinner left-hemispheric cortices in schizophrenia. Analyses of these asymmetries with respect to the use of antipsychotic medication and other clinical variables did not show any significant associations. Assessment of age- and sex-specific effects revealed a stronger average leftward asymmetry of pallidum volume between older cases and controls. Case-control differences in a multivariate context were assessed in a subset of the data (N = 2,029), which revealed that 7% of the variance across all structural asymmetries was explained by case-control status. Subtle case-control differences of brain macrostructural asymmetry may reflect differences at the molecular, cytoarchitectonic, or circuit levels that have functional relevance for the disorder. Reduced left middle temporal cortical thickness is consistent with altered left-hemisphere language network organization in schizophrenia.
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| 2088. |
- Schirmer, M. D., et al.
(author)
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White matter hyperintensity quantification in large-scale clinical acute ischemic stroke cohorts - The MRI-GENIE study
- 2019
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In: Neuroimage-Clinical. - : Elsevier BV. - 2213-1582. ; 23
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Journal article (peer-reviewed)abstract
- White matter hyperintensity (WMH) burden is a critically important cerebrovascular phenotype linked to prediction of diagnosis and prognosis of diseases, such as acute ischemic stroke (AIS). However, current approaches to its quantification on clinical MRI often rely on time intensive manual delineation of the disease on T2 fluid attenuated inverse recovery (FLAIR), which hinders high-throughput analyses such as genetic discovery. In this work, we present a fully automated pipeline for quantification of WMH in clinical large-scale studies of AIS. The pipeline incorporates automated brain extraction, intensity normalization and WMH segmentation using spatial priors. We first propose a brain extraction algorithm based on a fully convolutional deep learning architecture, specifically designed for clinical FLAIR images. We demonstrate that our method for brain extraction outperforms two commonly used and publicly available methods on clinical quality images in a set of 144 subject scans across 12 acquisition centers, based on dice coefficient (median 0.95; inter-quartile range 0.94-0.95; p < 0.01) and Pearson correlation of total brain volume (r = 0.90). Subsequently, we apply it to the large-scale clinical multi-site MRI-GENIE study (N = 2783) and identify a decrease in total brain volume of -2.4 cc/year. Additionally, we show that the resulting total brain volumes can successfully be used for quality control of image preprocessing. Finally, we obtain WMH volumes by building on an existing automatic WMH segmentation algorithm that delineates and distinguishes between different cerebrovascular pathologies. The learning method mimics expert knowledge of the spatial distribution of the WMH burden using a convolutional auto-encoder. This enables successful computation of WMH volumes of 2533 clinical AIS patients. We utilize these results to demonstrate the increase of WMH burden with age (0.950 cc/year) and show that single site estimates can be biased by the number of subjects recruited.
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| 2089. |
- Schmelz, M., et al.
(author)
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Active "itch fibers" in chronic pruritus
- 2003
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In: Neurology. - : Lippincott Williams & Wilkins. - 0028-3878 .- 1526-632X. ; 61:4, s. 564-566
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Journal article (peer-reviewed)abstract
- An itch-specific neuronal pathway was recently discovered in healthy humans and animals. Here the authors report that activity in this specific pathway coincides with itch under pathophysiologic conditions in a patient with chronic pruritus. Microneurographic recordings from the symptomatic area revealed spontaneous activity in six single C-fiber afferents that had the characteristic features of "itch fibers." Itch may be caused by activity in a specific subpopulation of C-fiber afferents.
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| 2090. |
- Schmelz, M., et al.
(author)
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Chemical response pattern of different classes of C-nociceptors to pruritogens and algogens
- 2003
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In: Journal of Neurophysiology. - Washington : The American Physiological Society. - 0022-3077 .- 1522-1598. ; 89:5, s. 2441-2448
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Journal article (peer-reviewed)abstract
- Vasoneuroactive substances were applied through intradermal microdialysis membranes and characterized as itch- or pain-inducing in psychophysical experiments. Histamine always provoked itching and rarely pain, capsaicin always pain but never itching. Prostaglandin E[2] (PGE[2]) led preferentially to moderate itching. Serotonin, acetylcholine, and bradykinin induced pain more often than itching. Subsequently the same substances were used in microneurography experiments to characterize the sensitivity profile of human cutaneous C-nociceptors. The responses of 89 mechanoresponsive (CMH, polymodal nociceptors), 52 mechanoinsensitive, histamine-negative (CMi[H][i][s][-]), and 24 mechanoinsensitive, histamine-positive (CMi[H][i][s][+]) units were compared. CMi[H][i][s][+] units were most responsive to histamine and to PGE[2] and less to serotonin, ACh, bradykinin, and capsaicin. CMH units (polymodal nociceptors) and CMi[H][i][s] units showed significantly weaker responses to histamine, PGE[2], and acetylcholine. Capsaicin and bradykinin responses were not significantly different in the two classes of mechano-insensitive units. We conclude that CMi[H][i][s][+]units are "selective," but not "specific" for pruritogenic substances and that the pruritic potency of a mediator increases with its ability to activate CMi[H][i][s][+] units but decreases with activation of CMH and CMi[H][i][s] units.
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