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Article ; Online: A Novel Homozygous Germline Mutation in Transferrin Receptor 1 (TfR1) Leads to Combined Immunodeficiency and Provides New Insights into Iron-Immunity Axis.

Aba, Ümran / Maslak, İbrahim Cemal / İpşir, Canberk / Pehlivan, Damla / Warnock, Nicholas I / Tumes, Damon J / Cildir, Gökhan / Erman, Baran

Journal of clinical immunology

2024 Volume 44, Issue 2, Page(s) 55

Abstract: A homozygous missense mutation in the transferrin receptor 1 (TfR1), also known as CD71, leads to a rare inborn error of immunity (IEI) characterized by the impaired lymphocyte activation and proliferation due to defective iron uptake of cells. However, ... ...

Abstract	A homozygous missense mutation in the transferrin receptor 1 (TfR1), also known as CD71, leads to a rare inborn error of immunity (IEI) characterized by the impaired lymphocyte activation and proliferation due to defective iron uptake of cells. However, only one causative mutation (c.58T > C, p.Y20H) in the TFRC gene coding for TfR1 has been reported so far. We herein identified a new disease-causing homozygous germline mutation in the TFRC gene (c.64C > T, p.R22W) (referred to as TfR1
MeSH term(s)	Humans ; Gene Expression Profiling ; Germ-Line Mutation ; Iron ; Primary Immunodeficiency Diseases
Chemical Substances	Iron (E1UOL152H7) ; CD71 antigen
Language	English
Publishing date	2024-01-25
Publishing country	Netherlands
Document type	Journal Article
ZDB-ID	779361-3
ISSN	1573-2592 ; 0271-9142
ISSN (online)	1573-2592
ISSN	0271-9142
DOI	10.1007/s10875-024-01658-0
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Article ; Online: Comparison of Static and Dynamic Baseline Creatinine Surrogates for Defining Acute Kidney Injury.

Warnock, David G / Neyra, Javier A / Macedo, Etienne / Miles, Ayme D / Mehta, Ravindra L / Wanner, Christoph

Nephron

2021 Volume 145, Issue 6, Page(s) 664–674

Abstract: Background: "Dynamic" baseline serum creatinine (sCr), based on a rolling 48-h window, and a static baseline sCr (previous outpatient sCr) were used to define acute kidney injury (AKI).: Methods: Retrospective cohort study of adult admissions to the ... ...

Abstract	Background: "Dynamic" baseline serum creatinine (sCr), based on a rolling 48-h window, and a static baseline sCr (previous outpatient sCr) were used to define acute kidney injury (AKI). Methods: Retrospective cohort study of adult admissions to the University of Alabama (UAB) Health System hospitals for years 2016-2018. Included admissions had >1- and <180-day length of stay, >2 inpatient sCr measurements, and an averaged estimated glomerular filtration rate >15 mL/min/1.73 m2. The final cohort of 62,380 patients included 100,570 admissions, 3,509 inpatient deaths, and 1,916 admissions with inpatient dialysis. AKI was defined by Kidney Disease Improving Global Outcomes (KDIGO) criteria and a static or dynamic baseline sCr. Discrimination was evaluated with area under receiver operator curves (AUC), logistic regression, and net reclassification improvement (NRI). Results: Preadmission outpatient "static" sCr values were available for 43,433 admissions. The lowest sCr value during a rolling 48-h window before each inpatient sCr defined a "dynamic" baseline sCr. Using point-wise comparisons, the dynamic baseline sCr performed better than static baseline sCr for inpatient mortality (AUC [0.819 vs. 0.741; p < 0.001] and NRI ≥0.306 [p < 0.001]) and inpatient dialysis (AUC [0.903 vs. 0.864; p < 0.001] and NRI ≥0.317 [p < 0.001]). Conclusions: The dynamic baseline sCr is available without reference to preadmission sCr values and avoids confounding associated with missing outpatient sCr values. AKI defined with the dynamic baseline sCr significantly improved discrimination of risk for inpatient mortality and dialysis compared to static baseline sCr.
MeSH term(s)	Acute Kidney Injury/blood ; Acute Kidney Injury/physiopathology ; Acute Kidney Injury/therapy ; Adult ; Aged ; Creatinine/blood ; Female ; Glomerular Filtration Rate ; Humans ; Male ; Middle Aged ; Patient Admission ; Renal Replacement Therapy ; Retrospective Studies
Chemical Substances	Creatinine (AYI8EX34EU)
Language	English
Publishing date	2021-08-20
Publishing country	Switzerland
Document type	Comparative Study ; Journal Article
ZDB-ID	207121-6
ISSN	2235-3186 ; 1423-0186 ; 1660-8151 ; 0028-2766
ISSN (online)	2235-3186 ; 1423-0186
ISSN	1660-8151 ; 0028-2766
DOI	10.1159/000516953
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Article ; Online: Risk Factors for Incident CKD in Black and White Americans: The REGARDS Study.

Cheung, Katharine L / Crews, Deidra C / Cushman, Mary / Yuan, Ya / Wilkinson, Katherine / Long, D Leann / Judd, Suzanne E / Shlipak, Michael G / Ix, Joachim H / Bullen, Alexander L / Warnock, David G / Gutiérrez, Orlando M

American journal of kidney diseases : the official journal of the National Kidney Foundation

2023 Volume 82, Issue 1, Page(s) 11–21.e1

Abstract: Rationale & objective: Little information exists on the incidence of and risk factors for chronic kidney disease (CKD) in contemporary US cohorts and whether risk factors differ by race, sex, or region in the United States.: Study design: ... ...

Abstract	Rationale & objective: Little information exists on the incidence of and risk factors for chronic kidney disease (CKD) in contemporary US cohorts and whether risk factors differ by race, sex, or region in the United States. Study design: Observational cohort study. Setting & participants: 4,198 Black and 7,799 White participants aged at least 45 years, recruited from 2003 through 2007 across the continental United States, with baseline estimated glomerular filtration rate (eGFR)>60mL/min/1.73m Exposures: Age, sex, race (Black or White), region ("stroke belt" or other), education, income, systolic blood pressure, body mass index, diabetes, coronary heart disease, hyperlipidemia, smoking, and albuminuria. Outcomes: (1) eGFR change and (2) incident CKD defined as eGFR<60mL/min/1.73m Analytical approach: Linear regression and modified Poisson regression were used to determine the association of risk factors with eGFR change and incident CKD overall and stratified by race, sex, and region. Results: Mean age of participants was 63±8 (SD) years, 54% were female, and 35% were Black. After 9.4±1.0 years of follow-up, CKD developed in 9%. In an age-, sex-, and race-adjusted model, Black race (β =-0.13; P<0.001) was associated with higher risk of eGFR change, but this was attenuated in the fully adjusted model (β=0.02; P=0.5). Stroke belt residence was independently associated with eGFR change (β =-0.10; P<0.001) and incident CKD (relative risk, 1.14 [95% CI, 1.01-1.30]). Albuminuria was more strongly associated with eGFR change (β of-0.26 vs-0.17; P=0.01 for interaction) in Black compared with White participants. Results were similar for incident CKD. Limitations: Persons of Hispanic ethnicity were excluded; unknown duration and/or severity of risk factors. Conclusions: Established CKD risk factors accounted for higher risk of incident CKD in Black versus White individuals. Albuminuria was a stronger risk factor for eGFR decrease and incident CKD in Black compared with White individuals. Living in the US stroke belt is a novel risk factor for CKD.
MeSH term(s)	Humans ; Female ; United States/epidemiology ; Middle Aged ; Aged ; Male ; Albuminuria/epidemiology ; White ; Renal Insufficiency, Chronic ; Risk Factors ; Glomerular Filtration Rate ; Stroke
Language	English
Publishing date	2023-01-06
Publishing country	United States
Document type	Observational Study ; Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	604539-x
ISSN	1523-6838 ; 0272-6386
ISSN (online)	1523-6838
ISSN	0272-6386
DOI	10.1053/j.ajkd.2022.11.015
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Zs.A 1669: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (1.OG) ab Jg. 2022: Lesesaal (EG)
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Article: Kootenay Lake kokanee (Oncorhynchus nerka) collapse into a predator pit

Warnock, Will G. / Thorley, Joseph L. / Arndt, Steven K. / Weir, Tyler J. / Neufeld, Matthew D. / Burrows, Jeff A. / Andrusak, Greg F.

Canadian journal of fisheries and aquatic sciences. 2022, v. 79, no. 2

2022

Abstract: Kootenay Lake is a large, oligotrophic waterbody in southern British Columbia renowned for recreational fisheries for piscivorous rainbow trout (Oncorhynchus mykiss) and bull trout (Salvelinus confluentus). Long-term datasets showed an increase in large- ... ...

Abstract	Kootenay Lake is a large, oligotrophic waterbody in southern British Columbia renowned for recreational fisheries for piscivorous rainbow trout (Oncorhynchus mykiss) and bull trout (Salvelinus confluentus). Long-term datasets showed an increase in large-bodied (>2 kg) piscivore abundance followed by a collapse of the kokanee (Oncorhynchus nerka) prey population in 2013 and subsequent decline of large-bodied piscivores. An unprecedented post-collapse state formed in 2015–2018, characterized by low kokanee spawner abundance and biomass and high catch rates for small-bodied (<2 kg), slow-growing piscivores. Bioenergetics model estimates of average historical (1961–2008) piscivore consumption was 29.3% of the average historical (1993–2008) kokanee prey supply (biomass and production), but increased to 78.7% in 2011, immediately preceding kokanee collapse. From 2015–2018, kokanee did not recover due to persistently poor juvenile survival; estimated piscivore consumption relative to prey supply remained high (73.0%), suggesting that kokanee were trapped in a predator pit. Although the ultimate and interacting causes of the predator build up remain uncertain, overcoming current depensatory dynamics may be aided by kokanee stocking or increasing harvest on still-abundant, unsatiated piscivores.
Keywords	Oncorhynchus mykiss ; Oncorhynchus nerka ; Salvelinus confluentus ; biomass ; data collection ; energy metabolism ; juveniles ; lakes ; piscivores ; surface water ; British Columbia
Language	English
Size	p. 234-248.
Publishing place	NRC Research Press
Document type	Article
ZDB-ID	1473089-3
ISSN	1205-7533 ; 0706-652X
ISSN (online)	1205-7533
ISSN	0706-652X
DOI	10.1139/cjfas-2020-0410
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Article ; Online: Lyso-Gb3 associates with adverse long-term outcome in patients with Fabry disease.

Nowak, Albina / Beuschlein, Felix / Sivasubramaniam, Visnuka / Kasper, David / Warnock, David G

Journal of medical genetics

2021 Volume 59, Issue 3, Page(s) 287–293

Abstract: Background: Fabry disease (FD) is a rare X-linked lysosomal storage disease caused by mutations in the α-galactosidase A gene (: Methods: In a cohort of 66 patients with genetically confirmed FD (26 males and 40 females), we analysed serum Lyso-Gb3 ... ...

Abstract	Background: Fabry disease (FD) is a rare X-linked lysosomal storage disease caused by mutations in the α-galactosidase A gene ( Methods: In a cohort of 66 patients with genetically confirmed FD (26 males and 40 females), we analysed serum Lyso-Gb3 as a factor associated with adverse clinical outcomes in a long-term study. The main outcome was a composite endpoint of incident kidney replacement therapy, atrial fibrillation, pacemaker and/or implantable cardioverter defibrillator, cerebrovascular events or death, whichever occurred first. Results: During the median follow-up time of 68 (40-80) months, events occurred in 19 (29%) of the patients. In a Cox multivariate regression analysis, Lyso-Gb3 levels (HR 4.62 (1.55 to 13.81); p=0.006) and the pretreatment exposure to Lyso-Gb3 (HR 3.41 (1.11 to 10.49); p=0.03) (both per SD increase) were significantly associated with adverse outcomes. If pretreatment Lyso-Gb3 exposure was added to multivariable logistic regression models containing age, sex, phenotype and enzyme replacement therapy as other covariates with the composite outcome as dependent variable, the area under the curve for the composite outcome significantly improved from 0.72 to 0.86 (p comparison=0.04). Conclusion: Lyso-Gb3 is a significant risk factor associated with important clinical events. Whether treatment-related amelioration of Lyso-Gb3 levels will be associated with improved long-term outcome needs to be established in prospective intervention trials.
MeSH term(s)	Fabry Disease/genetics ; Fabry Disease/therapy ; Female ; Glycolipids ; Humans ; Male ; Prospective Studies ; Sphingolipids ; alpha-Galactosidase/genetics
Chemical Substances	Glycolipids ; Sphingolipids ; globotriaosyl lysosphingolipid (126550-86-5) ; alpha-Galactosidase (EC 3.2.1.22)
Language	English
Publishing date	2021-01-25
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	220881-7
ISSN	1468-6244 ; 0022-2593
ISSN (online)	1468-6244
ISSN	0022-2593
DOI	10.1136/jmedgenet-2020-107338
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Article ; Online: Vitamin D receptor activation: implications for daily practice.

Warnock, David G

Contributions to nephrology

2011 Volume 171, Page(s) 172–180

Abstract: ... vitamin D levels, despite the fact that most effects are mediated by vitamin D receptor (VDR) activation ... the most proximate ligand for which is 1,25-OH(2) vitamin D. Evaluation of the separate components ... the effects and consequences of substrate deficiency (25-OH vitamin D), and the direct effects of VDR ...

Abstract	Many clinical studies have focused on the relationship between outcome events and serum 25-OH vitamin D levels, despite the fact that most effects are mediated by vitamin D receptor (VDR) activation, the most proximate ligand for which is 1,25-OH(2) vitamin D. Evaluation of the separate components of this axis are well described, but an integrated view of the components, and the distinctions between the effects and consequences of substrate deficiency (25-OH vitamin D), and the direct effects of VDR activation, is the center of focus and ultimately impacts on the clinical approach to patents with chronic kidney disease (CKD). The focus of this contribution is on the specially defined need for vitamin D treatment in patients with CKD, and the importance of VDR activation in CKD, especially in patients with proteinuria. With the addition of the fibroblast growth factor-23 loop, and the realization that albuminuria represents several critical integrated levels of renal function, there is an emerging emphasis on the proximal tubule, interstitial inflammation and fibrosis. These interacting factors reflect fundamental mechanisms that culminate in progressive loss of kidney function(s), with loss of the glomerular filtration rate the most prominent feature. New therapeutic approaches could potentially intervene along these pathways, but they will have to be rigorously evaluated with defined outcome studies and cost-benefit ratio analyses. The ultimate impact of chronic renal replacement therapy and cardiorenal death are the measures by which all such innovations must be judged.
MeSH term(s)	Chronic Disease ; Clinical Trials as Topic ; Humans ; Kidney Diseases/blood ; Kidney Diseases/drug therapy ; Receptors, Calcitriol/drug effects ; Receptors, Calcitriol/physiology ; Renin-Angiotensin System/physiology ; Vitamin D/administration & dosage ; Vitamin D/analogs & derivatives ; Vitamin D/blood ; Vitamin D Deficiency/epidemiology
Chemical Substances	Receptors, Calcitriol ; Vitamin D (1406-16-2) ; 25-hydroxyvitamin D (A288AR3C9H)
Language	English
Publishing date	2011-05-23
Publishing country	Switzerland
Document type	Journal Article ; Review
ISSN	1662-2782 ; 0302-5144
ISSN (online)	1662-2782
ISSN	0302-5144
DOI	10.1159/000327208
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Article: Understanding and modifying Fabry disease: Rationale and design of a pivotal Phase 3 study and results from a patient-reported outcome validation study.

Wanner, Christoph / Kimonis, Virginia / Politei, Juan / Warnock, David G / Üçeyler, Nurcan / Frey, Aline / Cornelisse, Peter / Hughes, Derralyn

Molecular genetics and metabolism reports

2022 Volume 31, Page(s) 100862

Abstract: The use of available treatments for Fabry disease (FD) (including enzyme replacement therapy [ERT]) may be restricted by their limited symptom improvement and mode of administration. Lucerastat is currently being investigated in the MODIFY study as oral ... ...

Abstract	The use of available treatments for Fabry disease (FD) (including enzyme replacement therapy [ERT]) may be restricted by their limited symptom improvement and mode of administration. Lucerastat is currently being investigated in the MODIFY study as oral substrate reduction therapy for the treatment of FD. By reducing the net globotriaosylceramide (Gb3) load in tissues, lucerastat has disease-modifying potential to improve symptoms and delay disease progression. MODIFY is a multicenter, double-blind, randomized, placebo-controlled, parallel-group Phase 3 study (ClinicalTrial.gov: NCT03425539); here we present the rationale and design of this study. Eligible adults with a genetically confirmed diagnosis of FD and FD-specific neuropathic pain entered screening. Patients were randomized (2:1) to receive either oral lucerastat twice daily or placebo for 6 months; treatment allocation was stratified according to sex and ERT treatment status. The main objectives of MODIFY are to assess the effects of lucerastat on neuropathic pain, gastrointestinal (GI) symptoms, FD biomarkers, and determine its safety and tolerability. Neuropathic pain and GI symptoms are key features of FD that have a significant impact on quality of life. Despite various tools available to assess pain and GI symptoms, there are currently limited tools available to assess neuropathic and GI symptoms in FD, validated according to health authority guidelines. Based on FDA recommendations, we undertook a patient-reported outcome (PRO) validation study, using a novel eDiary-based PRO tool to assess the validity of evaluating neuropathic pain as a primary efficacy endpoint in MODIFY. Results from the PRO validation study are included. To date, MODIFY is the largest Phase 3 clinical study conducted in patients with FD. Enrollment to MODIFY is now complete, with 118 patients randomized. Results will be presented in a separate publication. Long-term effects of lucerastat are being assessed in the ongoing open-label extension study (NCT03737214).
Language	English
Publishing date	2022-03-26
Publishing country	United States
Document type	Journal Article
ZDB-ID	2821908-9
ISSN	2214-4269
ISSN	2214-4269
DOI	10.1016/j.ymgmr.2022.100862
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Article ; Online: Conjunctival lymphangiectasia associated with classic Fabry disease.

Sivley, Melanie D / Wallace, Eric L / Warnock, David G / Benjamin, William J

The British journal of ophthalmology

2017

Abstract: Background: Fabry disease (FD) is a treatable multisystem disease caused by a defect in the alpha-galactosidase gene. Ocular signs of FD, including corneal verticillata, are among the earliest diagnostic findings. Conjunctival lymphangiectasia (CL) has ... ...

Abstract	Background: Fabry disease (FD) is a treatable multisystem disease caused by a defect in the alpha-galactosidase gene. Ocular signs of FD, including corneal verticillata, are among the earliest diagnostic findings. Conjunctival lymphangiectasia (CL) has not previously been associated with FD. Methods: We examined the eyes of a cohort of 13 adult patients, eight men and five women, with documented classic FD, all treated with enzyme replacement therapy (ERT) at the University of Alabama at Birmingham between February 2014 and April 2015. The average age was 48 years with a range of 35-55 years for men and 21-71 years for women. The mean duration of ERT was 8.4 years (men 8.9 years, women 7.6 years) with a range of 4-14 years. Classical Fabry mutations included Q283X, R227X, W236X and W277X. A high resolution Haag-Streit BQ-900 slit lamp with EyeCap imaging system was used to record conjunctival images. Results: CL was observed in 11 of the 13 patients (85%) despite long-term ERT. Clinical presentations included single cysts, beaded dilatations and areas of conjunctival oedema. Lesions were located within 6 mm of the corneal limbus. Ten of the 13 subjects (77%) had Fabry-related cataracts and all 13 demonstrated bilateral corneal verticillata. Twelve of the 13 patients had evidence of dry eye, 9 of whom were symptomatic, and 10 had peripheral lymphoedema. Conclusion: CL represents a common but under-recognised ocular manifestation of FD, which persists despite ERT, and is often accompanied by peripheral lymphoedema and dry eye syndrome.
Language	English
Publishing date	2017-05-12
Publishing country	England
Document type	Journal Article
ZDB-ID	80078-8
ISSN	1468-2079 ; 0007-1161
ISSN (online)	1468-2079
ISSN	0007-1161
DOI	10.1136/bjophthalmol-2016-310088
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Article ; Online: Transcriptional signatures of invasiveness in Meloidogyne incognita populations from sub-Saharan Africa.

Cox, Deborah / Reilly, Brian / Warnock, Neil D / Dyer, Steven / Sturrock, Matthew / Cortada, Laura / Coyne, Danny / Maule, Aaron G / Dalzell, Johnathan J

International journal for parasitology

2019 Volume 49, Issue 11, Page(s) 837–841

Abstract: ... G Protein-Coupled Receptors, cell wall-degrading enzymes and microRNAs. These data demonstrate a surprising diversity ...

Abstract	Meloidogyne incognita is an economically important plant parasitic nematode. Here we demonstrate substantial variation in the invasiveness of four M. incognita populations relative to tomato. Infective (J2) stage transcriptomes reveal significant variation in the expression of protein-coding and non-coding RNAs between populations. We identify 33 gene expression markers that correlate with invasiveness, and which map to genes with predicted roles in host finding and invasion, including neuropeptides, ion channels, G Protein-Coupled Receptors, cell wall-degrading enzymes and microRNAs. These data demonstrate a surprising diversity in microRNA complements between populations, and identify gene expression markers for invasiveness of M. incognita, to our knowledge for the first time.
MeSH term(s)	Animals ; Gene Expression Profiling ; Helminth Proteins/genetics ; Lycopersicon esculentum/parasitology ; MicroRNAs/analysis ; Plant Diseases/parasitology ; Transcriptome ; Tylenchoidea/genetics ; Tylenchoidea/growth & development ; Tylenchoidea/pathogenicity ; Virulence ; Virulence Factors/genetics
Chemical Substances	Helminth Proteins ; MicroRNAs ; Virulence Factors
Language	English
Publishing date	2019-09-13
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	120518-3
ISSN	1879-0135 ; 0020-7519
ISSN (online)	1879-0135
ISSN	0020-7519
DOI	10.1016/j.ijpara.2019.05.013
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Article ; Online: Crisis Response Model Preferences of Mental Health Care Clients With Prior Misdemeanor Arrests and of Their Family and Friends.

Pope, Leah G / Patel, Ashnee / Fu, En / Zingman, Michael / Warnock, Amanda / Ellis, Samantha / Ashekun, Oluwaytoyin / Watson, Amy / Wood, Jennifer / Compton, Michael T

Psychiatric services (Washington, D.C.)

2023 Volume 74, Issue 11, Page(s) 1163–1170

Abstract: The overrepresentation of people with serious mental illnesses in the criminal legal system has spurred the development of crisis response models to improve or reduce police response to a mental health crisis. However, limited research has explored ... ...

Abstract	The overrepresentation of people with serious mental illnesses in the criminal legal system has spurred the development of crisis response models to improve or reduce police response to a mental health crisis. However, limited research has explored preferences for crisis response, and no research in the United States has examined the responses desired by mental health care clients or their family members. This study aimed to understand the experiences of people with serious mental illnesses interacting with police and to learn about their preferences for crisis response models. The authors interviewed 50 clients with serious mental illnesses and a history of arrest who were enrolled in a randomized controlled trial of a police-mental health linkage system, as well as 18 of their family members and friends. Data were coded with deductive and inductive approaches and were grouped into larger themes. Clients and family or friends described needing a calm environment and empathy during a crisis. They selected a nonpolice response as their first choice and response from a crisis intervention team as their last choice among four options, highlighting the importance of trained responders and past negative interactions with police. However, they also noted concerns about safety and the shortcomings of a nonpolice response. These findings build understanding about clients' and family members' preferences for crisis response and highlight concerns that are relevant for policy makers.
MeSH term(s)	Humans ; United States ; Mental Disorders/therapy ; Mental Health ; Friends ; Crisis Intervention ; Mental Health Services ; Police
Language	English
Publishing date	2023-04-18
Publishing country	United States
Document type	Randomized Controlled Trial ; Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	1220173-x
ISSN	1557-9700 ; 1075-2730
ISSN (online)	1557-9700
ISSN	1075-2730
DOI	10.1176/appi.ps.20220363
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