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  • 1
    Online Resource
    Online Resource
    Immunodeficiency and bone marrow failure with mosaic and germline TLR8 gain of function
    American Society of Hematology ; 2021
    In:  Blood Vol. 137, No. 18 ( 2021-05-6), p. 2450-2462
    Details
    In: Blood, American Society of Hematology, Vol. 137, No. 18 ( 2021-05-6), p. 2450-2462
    Abstract: Inborn errors of immunity (IEI) are a genetically heterogeneous group of disorders with a broad clinical spectrum. Identification of molecular and functional bases of these disorders is important for diagnosis, treatment, and an understanding of the human immune response. We identified 6 unrelated males with neutropenia, infections, lymphoproliferation, humoral immune defects, and in some cases bone marrow failure associated with 3 different variants in the X-linked gene TLR8, encoding the endosomal Toll-like receptor 8 (TLR8). Interestingly, 5 patients had somatic variants in TLR8 with & lt;30% mosaicism, suggesting a dominant mechanism responsible for the clinical phenotype. Mosaicism was also detected in skin-derived fibroblasts in 3 patients, demonstrating that mutations were not limited to the hematopoietic compartment. All patients had refractory chronic neutropenia, and 3 patients underwent allogeneic hematopoietic cell transplantation. All variants conferred gain of function to TLR8 protein, and immune phenotyping demonstrated a proinflammatory phenotype with activated T cells and elevated serum cytokines associated with impaired B-cell maturation. Differentiation of myeloid cells from patient-derived induced pluripotent stem cells demonstrated increased responsiveness to TLR8. Together, these findings demonstrate that gain-of-function variants in TLR8 lead to a novel childhood-onset IEI with lymphoproliferation, neutropenia, infectious susceptibility, B- and T-cell defects, and in some cases, bone marrow failure. Somatic mosaicism is a prominent molecular mechanism of this new disease.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.2020009620
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2021
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  • 2
    Online Resource
    Online Resource
    KCNK3 Mutation Causes Altered Immune Function in Pulmonary Arterial Hypertension Patients and Mouse Models
    MDPI AG ; 2021
    In:  International Journal of Molecular Sciences Vol. 22, No. 9 ( 2021-05-09), p. 5014-
    Details
    In: International Journal of Molecular Sciences, MDPI AG, Vol. 22, No. 9 ( 2021-05-09), p. 5014-
    Abstract: Loss of function KCNK3 mutation is one of the gene variants driving hereditary pulmonary arterial hypertension (PAH). KCNK3 is expressed in several cell and tissue types on both membrane and endoplasmic reticulum and potentially plays a role in multiple pathological process associated with PAH. However, the role of various stressors driving the susceptibility of KCNK3 mutation to PAH is unknown. Hence, we exposed kcnk3fl/fl animals to hypoxia, metabolic diet and low dose lipopolysaccharide (LPS) and performed molecular characterization of their tissue. We also used tissue samples from KCNK3 patients (skin fibroblast derived inducible pluripotent stem cells, blood, lungs, peripheral blood mononuclear cells) and performed microarray, immunohistochemistry (IHC) and mass cytometry time of flight (CyTOF) experiments. Although a hypoxic insult did not alter vascular tone in kcnk3fl/fl mice, RNASeq study of these lungs implied that inflammatory and metabolic factors were altered, and the follow-up diet study demonstrated a dysregulation of bone marrow cells in kcnk3fl/fl mice. Finally, a low dose LPS study clearly showed that inflammation could be a possible second hit driving PAH in kcnk3fl/fl mice. Multiplex, IHC and CyTOF immunophenotyping studies on human samples confirmed the mouse data and strongly indicated that cell mediated, and innate immune responses may drive PAH susceptibility in these patients. In conclusion, loss of function KCNK3 mutation alters various physiological processes from vascular tone to metabolic diet through inflammation. Our data suggests that altered circulating immune cells may drive PAH susceptibility in patients with KCNK3 mutation.
    Type of Medium: Online Resource
    ISSN: 1422-0067
    URL: Article
    DOI: 10.3390/ijms22095014
    Language: English
    Publisher: MDPI AG
    Publication Date: 2021
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  • 3
    Online Resource
    Online Resource
    THU133 Inpatient Hypoglycemia Management: Error Rates In Pediatric Diabetes Care
    The Endocrine Society ; 2023
    In:  Journal of the Endocrine Society Vol. 7, No. Supplement_1 ( 2023-10-05)
    Details
    In: Journal of the Endocrine Society, The Endocrine Society, Vol. 7, No. Supplement_1 ( 2023-10-05)
    Abstract: Disclosure: D.A. Odutayo: None. E.M. Rizzi: None. N. Allen: None. Hypoglycemia is a known side effect of exogenous insulin. During severe hypoglycemia, children with diabetes treated with insulin risk neurodevelopmental sequelae as protective glycolysis and ketogenesis are suppressed. Rapid treatment of hypoglycemia is crucial to prevent deleterious effects on neurocognition. There is a paucity of data elucidating inpatient hypoglycemia incidence and adherence to treatment standards in hospital care. The goal of this study is to assess the rate of hypoglycemia in children and adolescents with diabetes in the inpatient setting, and to assess adherence to American Diabetes Association (ADA) standards of care in treatment of hypoglycemia. Hypoglycemia is defined as blood glucose ≤ 70 mg/dL in children ≥5 years old, and ≤ 80 mg/dL in children & lt;5 years old. ADA guidelines advise treatment with 15 grams of fast acting carbohydrates and glucose recheck in 15 minutes. The study includes a retrospective chart review with patients 18 years of age and under with a diagnosis of either Type 1 or Type 2 diabetes, with inpatient admission to a tertiary care pediatric hospital in a 2-year period beginning January 1, 2020. Point-of-care blood glucose (BG) results were analyzed, as well as appropriate documentation of events and treatment. Time to repeat BG (TTR) was also analyzed and used as a measure of rapid treatment and assurance of resolution; acceptable time to repeat BG is 15 +/-5 minutes. The number of hypoglycemic events was also analyzed. Emergency room visits and venous glucose estimations were excluded. There were 422 hypoglycemic events in children & lt;5 years old, and 482 hypoglycemia events in children ≥5 years old. The median time to recheck was 41 min and 32.50 min with interquartile range of 12 to 65 min and 15 to 62.25 min respectively for children & lt;5 years and children ≥5 years. 4.62% of all reported blood glucose checks showed hypoglycemia. The percentage of rechecks occurring after 20 min were 24% and 65% for children & lt;5 years and children ≥5 years, respectively. Importantly, in the setting of severe hypoglycemia, defined as glucose & lt;55 mg/dL, the median time to recheck was 21 min with interquartile range 7.75 to 34 minutes. Based on the results of the study, ADA guidelines were not met, with the average glucose recheck times being over 15 +/-5 minutes in both groups of children. In the setting of severe hypoglycemia, recheck times were closer to ADA guidelines. Additionally, there was a correlation between increased recheck times and increased rates of hypoglycemia. The next proposed steps are to develop and implement a hypoglycemia algorithm for pediatric diabetes patients during hospitalization. Presentation: Thursday, June 15, 2023
    Type of Medium: Online Resource
    ISSN: 2472-1972
    URL: Article
    DOI: 10.1210/jendso/bvad114.1385
    Language: English
    Publisher: The Endocrine Society
    Publication Date: 2023
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  • 4
    Online Resource
    Online Resource
    NEOTROPICAL FRESHWATER FISHES : A dataset of occurrence and abundance of freshwater fishes in the Neotropics
    Wiley ; 2023
    In:  Ecology Vol. 104, No. 4 ( 2023-04)
    Details
    In: Ecology, Wiley, Vol. 104, No. 4 ( 2023-04)
    Abstract: The Neotropical region hosts 4225 freshwater fish species, ranking first among the world's most diverse regions for freshwater fishes. Our NEOTROPICAL FRESHWATER FISHES data set is the first to produce a large‐scale Neotropical freshwater fish inventory, covering the entire Neotropical region from Mexico and the Caribbean in the north to the southern limits in Argentina, Paraguay, Chile, and Uruguay. We compiled 185,787 distribution records, with unique georeferenced coordinates, for the 4225 species, represented by occurrence and abundance data. The number of species for the most numerous orders are as follows: Characiformes (1289), Siluriformes (1384), Cichliformes (354), Cyprinodontiformes (245), and Gymnotiformes (135). The most recorded species was the characid Astyanax fasciatus (4696 records). We registered 116,802 distribution records for native species, compared to 1802 distribution records for nonnative species. The main aim of the NEOTROPICAL FRESHWATER FISHES data set was to make these occurrence and abundance data accessible for international researchers to develop ecological and macroecological studies, from local to regional scales, with focal fish species, families, or orders. We anticipate that the NEOTROPICAL FRESHWATER FISHES data set will be valuable for studies on a wide range of ecological processes, such as trophic cascades, fishery pressure, the effects of habitat loss and fragmentation, and the impacts of species invasion and climate change. There are no copyright restrictions on the data, and please cite this data paper when using the data in publications.
    Type of Medium: Online Resource
    ISSN: 0012-9658 , 1939-9170
    URL: Issue
    URL: Article
    DOI: 10.1002/ecy.v104.4
    DOI: 10.1002/ecy.3713
    RVK:
    WA 15000
    Language: English
    Publisher: Wiley
    Publication Date: 2023
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    SSG: 12
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  • 5
    Online Resource
    Online Resource
    Influence of Gestational Age at Initiation of Antihypertensive Therapy : Secondary Analysis of CHIPS Trial Data (Control of Hypertension in Pregnancy Study)
    Ovid Technologies (Wolters Kluwer Health) ; 2018
    In:  Hypertension Vol. 71, No. 6 ( 2018-06), p. 1170-1177
    Details
    In: Hypertension, Ovid Technologies (Wolters Kluwer Health), Vol. 71, No. 6 ( 2018-06), p. 1170-1177
    Abstract: For hypertensive women in CHIPS (Control of Hypertension in Pregnancy Study), we assessed whether the maternal benefits of tight control could be achieved, while minimizing any potentially negative effect on fetal growth, by delaying initiation of antihypertensive therapy until later in pregnancy. For the 981 women with nonsevere, chronic or gestational hypertension randomized to less-tight (target diastolic blood pressure, 100 mm Hg), or tight (target, 85 mm Hg) control, we used mixed-effects logistic regression to examine whether the effect of less-tight (versus tight) control on major outcomes was dependent on gestational age at randomization, adjusting for baseline factors as in the primary analysis and including an interaction term between gestational age at randomization and treatment allocation. Gestational age was considered categorically (quartiles) and continuously (linear or quadratic form), and the optimal functional form selected to provide the best fit to the data based on the Akaike information criterion. Randomization before (but not after) 24 weeks to less-tight (versus tight) control was associated with fewer babies with birth weight 〈 10th centile ( P interaction =0.005), but more preterm birth ( P interaction =0.043), and no effect on perinatal death or high-level neonatal care 〉 48 hours ( P interaction =0.354). For the mother, less-tight (versus tight) control was associated with more severe hypertension at all gestational ages but particularly so before 28 weeks ( P interaction =0.076). In women with nonsevere, chronic, or gestational hypertension, there seems to be no gestational age at which less-tight (versus tight) control is the preferred management strategy to optimize maternal or perinatal outcomes. Clinical Trial Registration— URL: https://www.isrctn.com . Unique identifier: ISRCTN71416914.
    Type of Medium: Online Resource
    ISSN: 0194-911X , 1524-4563
    URL: Article
    DOI: 10.1161/HYPERTENSIONAHA.117.10689
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2018
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  • 6
    Online Resource
    Online Resource
    CD19 + CD21lo/neg cells are increased in systemic sclerosis-associated interstitial lung disease
    Springer Science and Business Media LLC ; 2022
    In:  Clinical and Experimental Medicine Vol. 22, No. 2 ( 2022-05), p. 209-220
    Details
    In: Clinical and Experimental Medicine, Springer Science and Business Media LLC, Vol. 22, No. 2 ( 2022-05), p. 209-220
    Abstract: Interstitial lung disease (ILD) represents a significant cause of morbidity and mortality in systemic sclerosis (SSc). The purpose of this study was to examine recirculating lymphocytes from SSc patients for potential biomarkers of interstitial lung disease (ILD). Peripheral blood mononuclear cells (PBMCs) were isolated from patients with SSc and healthy controls enrolled in the Vanderbilt University Myositis and Scleroderma Treatment Initiative Center cohort between 9/2017–6/2019. Clinical phenotyping was performed by chart abstraction. Immunophenotyping was performed using both mass cytometry and fluorescence cytometry combined with t-distributed stochastic neighbor embedding analysis and traditional biaxial gating. This study included 34 patients with SSc-ILD, 14 patients without SSc-ILD, and 25 healthy controls. CD21 lo/neg cells are significantly increased in SSc-ILD but not in SSc without ILD (15.4 ± 13.3% vs. 5.8 ± 0.9%, p  = 0.002) or healthy controls (5.0 ± 0.5%, p   〈  0.0001). While CD21 lo/neg B cells can be identified from a single biaxial gate, tSNE analysis reveals that the biaxial gate is comprised of multiple distinct subsets, all of which are increased in SSc-ILD. CD21 lo/neg cells in both healthy controls and SSc-ILD are predominantly tBET positive and do not have intracellular CD21. Immunohistochemistry staining demonstrated that CD21 lo/neg B cells diffusely infiltrate the lung parenchyma of an SSc-ILD patient. Additional work is needed to validate this biomarker in larger cohorts and longitudinal studies and to understand the role of these cells in SSc-ILD.
    Type of Medium: Online Resource
    ISSN: 1591-9528
    URL: Article
    DOI: 10.1007/s10238-021-00745-5
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2022
    detail.hit.zdb_id: 2054398-0
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  • 7
    Online Resource
    Online Resource
    DataSheet_1.pdf
    Frontiers Media SA ; 2022
    In:  Frontiers in Immunology Vol. 13 ( 2022-12-22)
    Details
    In: Frontiers in Immunology, Frontiers Media SA, Vol. 13 ( 2022-12-22)
    Abstract: Although SARS-CoV-2 vaccines have proven effective in eliciting a protective immune response in healthy individuals, their ability to induce a durable immune response in immunocompromised individuals remains poorly understood. Primary antibody deficiency (PAD) syndromes are among the most common primary immunodeficiency disorders in adults and are characterized by hypogammaglobulinemia and impaired ability to mount robust antibody responses following infection or vaccination. Methods Here, we present an analysis of both the B and T cell response in a prospective cohort of 30 individuals with PAD up to 150 days following initial COVID-19 vaccination and 150 days post mRNA booster vaccination. Results After the primary vaccination series, many of the individuals with PAD syndromes mounted SARS-CoV-2 specific memory B and CD4 + T cell responses that overall were comparable to healthy individuals. Nonetheless, individuals with PAD syndromes had reduced IgG1 + and CD11c + memory B cell responses following the primary vaccination series, with the defect in IgG1 class-switching rescued following mRNA booster doses. Boosting also elicited an increase in the SARS-CoV-2-specific B and T cell response and the development of Omicron-specific memory B cells in COVID-19-naïve PAD patients. Individuals that lacked detectable B cell responses following primary vaccination did not benefit from booster vaccination. Conclusion Together, these data indicate that SARS-CoV-2 vaccines elicit memory B and T cells in most PAD patients and highlights the importance of booster vaccination in immunodeficient individuals.
    Type of Medium: Online Resource
    ISSN: 1664-3224
    URL: Article
    URL: Article
    DOI: 10.3389/fimmu.2022.1033770
    DOI: 10.3389/fimmu.2022.1033770.s001
    Language: Unknown
    Publisher: Frontiers Media SA
    Publication Date: 2022
    detail.hit.zdb_id: 2606827-8
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