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  • 1
    In: Journal of the American Society of Nephrology, Ovid Technologies (Wolters Kluwer Health), Vol. 32, No. 12 ( 2021-12), p. 3114-3129
    Kurzfassung: Autosomal dominant polycystic kidney disease (ADPKD) is caused by mutations in PKD1 and PKD2 ( PKD1/2 ) in renal tubular epithelium. PKD1/2 somatic mutations were previously implicated in cyst formation, but studies of this second-hit model in ADPKD had significant technical limitations. Comprehensive analysis of renal cyst epithelium by whole-genome sequencing identified pathogenic inactivating somatic mutations of PKD1/2 in all 24 patients and in 93% of their 90 cysts. Short variant mutations occurred in 77% of cysts, and another 18% acquired chromosomal loss of heterozygosity encompassing PKD1/2, frequently at chromosomal fragile sites or in regions comprising chromosome microdeletion diseases/syndromes. These findings support a cellular recessive mechanism for renal cystogenesis in ADPKD caused by inactivating germline and somatic variants of PKD1/2 . Background Autosomal dominant polycystic kidney disease (ADPKD) is a genetic disorder characterized by the development of multiple cysts in the kidneys. It is often caused by pathogenic mutations in PKD1 and PKD2 genes that encode polycystin proteins. Although the molecular mechanisms for cystogenesis are not established, concurrent inactivating germline and somatic mutations in PKD1 and PKD2 have been previously observed in renal tubular epithelium (RTE). Methods To further investigate the cellular recessive mechanism of cystogenesis in RTE, we conducted whole-genome DNA sequencing analysis to identify germline variants and somatic alterations in RTE of 90 unique kidney cysts obtained during nephrectomy from 24 unrelated participants. Results Kidney cysts were overall genomically stable, with low burdens of somatic short mutations or large-scale structural alterations. Pathogenic somatic “second hit” alterations disrupting PKD1 or PKD2 were identified in 93% of the cysts. Of these, 77% of cysts acquired short mutations in PKD1 or PKD2 ; specifically, 60% resulted in protein truncations (nonsense, frameshift, or splice site) and 17% caused non-truncating mutations (missense, in-frame insertions, or deletions). Another 18% of cysts acquired somatic chromosomal loss of heterozygosity (LOH) events encompassing PKD1 or PKD2 ranging from 2.6 to 81.3 Mb. 14% of these cysts harbored copy number neutral LOH events, while the other 3% had hemizygous chromosomal deletions. LOH events frequently occurred at chromosomal fragile sites, or in regions comprising chromosome microdeletion diseases/syndromes. Almost all somatic “second hit” alterations occurred at the same germline mutated PKD1/2 gene. Conclusions These findings further support a cellular recessive mechanism for cystogenesis in ADPKD primarily caused by inactivating germline and somatic variants of PKD1 or PKD2 genes in kidney cyst epithelium.
    Materialart: Online-Ressource
    ISSN: 1046-6673 , 1533-3450
    Sprache: Englisch
    Verlag: Ovid Technologies (Wolters Kluwer Health)
    Publikationsdatum: 2021
    ZDB Id: 2029124-3
    Standort Signatur Einschränkungen Verfügbarkeit
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  • 2
    In: Journal of the American Society of Nephrology, Ovid Technologies (Wolters Kluwer Health), Vol. 29, No. 8 ( 2018-8), p. 2139-2156
    Kurzfassung: Autosomal dominant polycystic kidney disease (ADPKD) is a ciliopathy caused by mutations in PKD1 and PKD2 that is characterized by renal tubular epithelial cell proliferation and progressive CKD. Although the molecular mechanisms involved in cystogenesis are not established, concurrent inactivating constitutional and somatic mutations in ADPKD genes in cyst epithelium have been proposed as a cellular recessive mechanism. Methods We characterized, by whole-exome sequencing (WES) and long-range PCR techniques, the somatic mutations in PKD1 and PKD2 genes in renal epithelial cells from 83 kidney cysts obtained from nine patients with ADPKD, for whom a constitutional mutation in PKD1 or PKD2 was identified. Results Complete sequencing data by long-range PCR and WES was available for 63 and 65 cysts, respectively. Private somatic mutations of PKD1 or PKD2 were identified in all patients and in 90% of the cysts analyzed; 90% of these mutations were truncating, splice site, or in-frame variations predicted to be pathogenic mutations. No trans -heterozygous mutations of PKD1 or PKD2 genes were identified. Copy number changes of PKD1 ranging from 151 bp to 28 kb were observed in 12% of the cysts. WES also identified significant mutations in 53 non- PKD1/2 genes, including other ciliopathy genes and cancer-related genes. Conclusions These findings support a cellular recessive mechanism for cyst formation in ADPKD caused primarily by inactivating constitutional and somatic mutations of PKD1 or PKD2 in kidney cyst epithelium. The potential interactions of these genes with other ciliopathy- and cancer-related genes to influence ADPKD severity merits further evaluation.
    Materialart: Online-Ressource
    ISSN: 1046-6673 , 1533-3450
    Sprache: Englisch
    Verlag: Ovid Technologies (Wolters Kluwer Health)
    Publikationsdatum: 2018
    ZDB Id: 2029124-3
    Standort Signatur Einschränkungen Verfügbarkeit
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  • 3
    Online-Ressource
    Online-Ressource
    Wiley ; 2022
    In:  Biometrics Vol. 78, No. 2 ( 2022-06), p. 460-473
    In: Biometrics, Wiley, Vol. 78, No. 2 ( 2022-06), p. 460-473
    Kurzfassung: Truncation is a statistical phenomenon that occurs in many time‐to‐event studies. For example, autopsy‐confirmed studies of neurodegenerative diseases are subject to an inherent left and right truncation, also known as double truncation. When the goal is to study the effect of risk factors on survival, the standard Cox regression model cannot be used when the survival time is subject to truncation. Existing methods that adjust for both left and right truncation in the Cox regression model require independence between the survival times and truncation times, which may not be a reasonable assumption in practice. We propose an expectation‐maximization algorithm to relax the independence assumption in the Cox regression model under left, right, or double truncation to an assumption of conditional independence on the observed covariates. The resulting regression coefficient estimators are consistent and asymptotically normal. We demonstrate through extensive simulations that the proposed estimator has little bias and has a similar or lower mean‐squared error compared to existing estimators. We implement our approach to assess the effect of occupation on survival in subjects with autopsy‐confirmed Alzheimer's disease.
    Materialart: Online-Ressource
    ISSN: 0006-341X , 1541-0420
    URL: Issue
    RVK:
    Sprache: Englisch
    Verlag: Wiley
    Publikationsdatum: 2022
    ZDB Id: 2054197-1
    SSG: 12
    Standort Signatur Einschränkungen Verfügbarkeit
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  • 4
    In: BMC Medical Research Methodology, Springer Science and Business Media LLC, Vol. 21, No. 1 ( 2021-12)
    Kurzfassung: Beginning in 2019, stepped-wedge designs (SWDs) were being used in the investigation of interventions to reduce opioid-related deaths in communities across the United States. However, these interventions are competing with external factors such as newly initiated public policies limiting opioid prescriptions, media awareness campaigns, and the COVID-19 pandemic. Furthermore, control communities may prematurely adopt components of the intervention as they become available. The presence of time-varying external factors that impact study outcomes is a well-known limitation of SWDs; common approaches to adjusting for them make use of a mixed effects modeling framework. However, these models have several shortcomings when external factors differentially impact intervention and control clusters. Methods We discuss limitations of commonly used mixed effects models in the context of proposed SWDs to investigate interventions intended to reduce opioid-related mortality, and propose extensions of these models to address these limitations. We conduct an extensive simulation study of anticipated data from SWD trials targeting the current opioid epidemic in order to examine the performance of these models in the presence of external factors. We consider confounding by time, premature adoption of intervention components, and time-varying effect modification— in which external factors differentially impact intervention and control clusters. Results In the presence of confounding by time, commonly used mixed effects models yield unbiased intervention effect estimates, but can have inflated Type 1 error and result in under coverage of confidence intervals. These models yield biased intervention effect estimates when premature intervention adoption or effect modification are present. In such scenarios, models incorporating fixed intervention-by-time interactions with an unstructured covariance for intervention-by-cluster-by-time random effects result in unbiased intervention effect estimates, reach nominal confidence interval coverage, and preserve Type 1 error. Conclusions Mixed effects models can adjust for different combinations of external factors through correct specification of fixed and random time effects. Since model choice has considerable impact on validity of results and study power, careful consideration must be given to how these external factors impact study endpoints and what estimands are most appropriate in the presence of such factors.
    Materialart: Online-Ressource
    ISSN: 1471-2288
    Sprache: Englisch
    Verlag: Springer Science and Business Media LLC
    Publikationsdatum: 2021
    ZDB Id: 2041362-2
    Standort Signatur Einschränkungen Verfügbarkeit
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  • 5
    In: Cancer Treatment and Research Communications, Elsevier BV, Vol. 24 ( 2020), p. 100198-
    Materialart: Online-Ressource
    ISSN: 2468-2942
    Sprache: Englisch
    Verlag: Elsevier BV
    Publikationsdatum: 2020
    ZDB Id: 2866646-X
    Standort Signatur Einschränkungen Verfügbarkeit
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  • 6
    In: Brain, Oxford University Press (OUP), Vol. 141, No. 7 ( 2018-07-01), p. 2181-2193
    Materialart: Online-Ressource
    ISSN: 0006-8950 , 1460-2156
    RVK:
    Sprache: Englisch
    Verlag: Oxford University Press (OUP)
    Publikationsdatum: 2018
    ZDB Id: 1474117-9
    SSG: 12
    Standort Signatur Einschränkungen Verfügbarkeit
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  • 7
    In: Journal of Medical Internet Research, JMIR Publications Inc., Vol. 22, No. 5 ( 2020-5-26), p. e17968-
    Kurzfassung: Past mobile health (mHealth) efforts to empower type 2 diabetes (T2D) self-management include portals, text messaging, collection of biometric data, electronic coaching, email, and collection of lifestyle information. Objective The primary objective was to enhance patient activation and self-management of T2D using the US Department of Defense’s Mobile Health Care Environment (MHCE) in a patient-centered medical home setting. Methods A multisite study, including a user-centered design and a controlled trial, was conducted within the US Military Health System. Phase I assessed preferences regarding the enhancement of the enabling technology. Phase II was a single-blinded 12-month feasibility study that randomly assigned 240 patients to either the intervention (n=123, received mHealth technology and behavioral messages tailored to Patient Activation Measure [PAM] level at baseline) or the control group (n=117, received equipment but not messaging. The primary outcome measure was PAM scores. Secondary outcome measures included Summary of Diabetes Self-Care Activities (SDSCA) scores and cardiometabolic outcomes. We used generalized estimating equations to estimate changes in outcomes. Results The final sample consisted of 229 patients. Participants were 61.6% (141/229) male, had a mean age of 62.9 years, mean glycated hemoglobin (HbA1c) of 7.5%, mean BMI of 32.7, and a mean duration of T2D diagnosis of 9.8 years. At month 12, the control group showed significantly greater improvements compared with the intervention group in PAM scores (control mean 7.49, intervention mean 1.77; P=.007), HbA1c (control mean −0.53, intervention mean −0.11; P=.006), and low-density lipoprotein cholesterol (control mean −7.14, intervention mean 4.38; P=.01). Both groups showed significant improvement in SDSCA, BMI, waist size, and diastolic blood pressure; between-group differences were not statistically significant. Except for patients with the highest level of activation (PAM level 4), intervention group patients exhibited significant improvements in PAM scores. For patients with the lowest level of activation (PAM level 1), the intervention group showed significantly greater improvement compared with the control group in HbA1c (control mean −0.09, intervention mean −0.52; P=.04), BMI (control mean 0.58, intervention mean −1.22; P=.01), and high-density lipoprotein cholesterol levels (control mean −4.86, intervention mean 3.56; P 〈 .001). Significant improvements were seen in AM scores, SDSCA, and waist size for both groups and in diastolic and systolic blood pressure for the control group; the between-group differences were not statistically significant. The percentage of participants who were engaged with MHCE for ≥50% of days period was 60.7% (68/112; months 0-3), 57.4% (62/108; months 3-6), 49.5% (51/103; months 6-9), and 43% (42/98; months 9-12). Conclusions Our study produced mixed results with improvement in PAM scores and outcomes in both the intervention and control groups. Structural design issues may have hampered the influence of tailored behavioral messaging within the intervention group. Trial Registration ClinicalTrials.gov NCT02949037; https://clinicaltrials.gov/ct2/show/NCT02949037 International Registered Report Identifier (IRRID) RR2-10.2196/resprot.6993
    Materialart: Online-Ressource
    ISSN: 1438-8871
    Sprache: Englisch
    Verlag: JMIR Publications Inc.
    Publikationsdatum: 2020
    ZDB Id: 2028830-X
    Standort Signatur Einschränkungen Verfügbarkeit
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  • 8
    In: JAMA Pediatrics, American Medical Association (AMA), Vol. 176, No. 12 ( 2022-12-01), p. 1208-
    Kurzfassung: There is limited evidence for therapeutic options for pediatric COVID-19 outside of multisystem inflammatory syndrome in children (MIS-C). Objective To determine whether the use of steroids within 2 days of admission for non–MIS-C COVID-19 in children is associated with hospital length of stay (LOS). The secondary objective was to determine their association with intensive care unit (ICU) LOS, inflammation, and fever defervescence. Design, Setting, and Participants This cohort study analyzed data retrospectively for children ( & amp;lt;18 years) who required hospitalization for non–MIS-C COVID-19. Data from March 2020 through September 2021 were provided by 58 hospitals in 7 countries who participate in the Society of Critical Care Medicine Discovery Viral Infection and Respiratory Illness Universal Study (VIRUS) COVID-19 registry. Exposure Administration of steroids within 2 days of admission. Main Outcomes and Measures Length of stay in the hospital and ICU. Adjustment for confounders was done by mixed linear regression and propensity score matching. Results A total of 1163 patients met inclusion criteria and had a median (IQR) age of 7 years (0.9-14.3). Almost half of all patients (601/1163, 51.7%) were male, 33.8% (392/1163) were non-Hispanic White, and 27.9% (324/1163) were Hispanic. Of the study population, 184 patients (15.8%) received steroids within 2 days of admission, and 979 (84.2%) did not receive steroids within the first 2 days. Among 1163 patients, 658 (56.5%) required respiratory support during hospitalization. Overall, patients in the steroids group were older and had greater severity of illness, and a larger proportion required respiratory and vasoactive support. On multivariable linear regression, after controlling for treatment with remdesivir within 2 days, country, race and ethnicity, obesity and comorbidity, number of abnormal inflammatory mediators, age, bacterial or viral coinfection, and disease severity according to ICU admission within first 2 days or World Health Organization ordinal scale of 4 or higher on admission, with a random intercept for the site, early steroid treatment was not significantly associated with hospital LOS (exponentiated coefficient, 0.94; 95% CI, 0.81-1.09; P  = .42). Separate analyses for patients with an LOS of 2 days or longer (n = 729), those receiving respiratory support at admission (n = 286), and propensity score–matched patients also showed no significant association between steroids and LOS. Early steroid treatment was not associated with ICU LOS, fever defervescence by day 3, or normalization of inflammatory mediators. Conclusions and Relevance Steroid treatment within 2 days of hospital admission in a heterogeneous cohort of pediatric patients hospitalized for COVID-19 without MIS-C did not have a statistically significant association with hospital LOS.
    Materialart: Online-Ressource
    ISSN: 2168-6203
    Sprache: Englisch
    Verlag: American Medical Association (AMA)
    Publikationsdatum: 2022
    Standort Signatur Einschränkungen Verfügbarkeit
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  • 9
    In: BMJ Open Diabetes Research & Care, BMJ, Vol. 8, No. 1 ( 2020-07), p. e001333-
    Kurzfassung: Several adipokines are implicated in the pathophysiology of gestational diabetes mellitus (GDM), however, longitudinal data in early pregnancy on many adipokines are lacking. We prospectively investigated the association of a panel of adipokines in early and mid-pregnancy with GDM risk. Research design and methods Within the National Institute of Child Health and Human Development (NICHD) Fetal Growth Studies-Singletons cohort (n=2802), a panel of 10 adipokines (plasma fatty acid binding protein-4 (FABP4), chemerin, interleukin-6 (IL-6), leptin, soluble leptin receptor (sOB-R), adiponectin, omentin-1, vaspin, and retinol binding protein-4) were measured at gestational weeks (GWs) 10–14, 15–26, 23–31, and 33–39 among 107 GDM cases (ascertained on average at GW 27) and 214 non-GDM controls. Conditional logistic regression was used to estimate ORs of each adipokine and GDM, controlling for known GDM risk factors including pre-pregnancy body mass index. Results Throughout pregnancy changes in chemerin, sOB-R, adiponectin, and high-molecular-weight adiponectin (HMW-adiponectin) concentrations from 10–14 to 15–26 GWs were significantly different among GDM cases compared with non-GDM controls. In early and mid-pregnancy, FABP4, chemerin, IL-6 and leptin were positively associated with increased GDM risk. For instance, at 10–14 GWs, the OR comparing the highest versus lowest quartile (ORQ4–Q1) of FABP4 was 3.79 (95% CI 1.63 to 8.85). In contrast, in both early and mid-pregnancy adiponectin (eg, ORQ4–Q1 0.14 (0.05, 0.34) during 10–14 GWs) and sOB-R (ORQ4–Q1 0.23 (0.11, 0.50) during 10–14 GWs) were inversely related to GDM risk. At 10–14 GWs a model that included conventional GDM risk factors and FABP4, chemerin, sOB-R, and HMW-adiponectin improved the estimated prediction (area under the curve) from 0.71 (95% CI 0.66 to 0.77) to 0.77 (95% CI 0.72 to 0.82). Conclusions A panel of understudied adipokines including FABP4, chemerin, and sOB-R may be implicated in the pathogenesis of GDM with significant associations detected approximately 10–18 weeks before typical GDM screening.
    Materialart: Online-Ressource
    ISSN: 2052-4897
    Sprache: Englisch
    Verlag: BMJ
    Publikationsdatum: 2020
    ZDB Id: 2732918-5
    Standort Signatur Einschränkungen Verfügbarkeit
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  • 10
    In: ACS ES&T Water, American Chemical Society (ACS), Vol. 2, No. 11 ( 2022-11-11), p. 2225-2232
    Materialart: Online-Ressource
    ISSN: 2690-0637 , 2690-0637
    Sprache: Englisch
    Verlag: American Chemical Society (ACS)
    Publikationsdatum: 2022
    ZDB Id: 3049563-5
    Standort Signatur Einschränkungen Verfügbarkeit
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