Publications by authors named "Jasmin Divers"

178 Publications

The Impact of Racial and Ethnic Health Disparities in Diabetes Management on Clinical Outcomes: A Reinforcement Learning Analysis of Health Inequity Among Youth and Young Adults in the SEARCH for Diabetes in Youth Study.

Diabetes Care 2021 Nov 2. Epub 2021 Nov 2.

Department of Nutrition, University of North Carolina at Chapel Hill, Chapel Hill, NC.

Objective: To estimate difference in population-level glycemic control and the emergence of diabetes complications given a theoretical scenario in which non-White youth and young adults (YYA) with type 1 diabetes (T1D) receive and follow an equivalent distribution of diabetes treatment regimens as non-Hispanic White YYA.

Research Design And Methods: Longitudinal data from YYA diagnosed 2002-2005 in the SEARCH for Diabetes in Youth Study were analyzed. Based on self-reported race/ethnicity, YYA were classified as non-White race or Hispanic ethnicity (non-White subgroup) versus non-Hispanic White race (White subgroup). In the White versus non-White subgroups, the propensity score models estimated treatment regimens, including patterns of insulin modality, self-monitored glucose frequency, and continuous glucose monitoring use. An analysis based on policy evaluation techniques in reinforcement learning estimated the effect of each treatment regimen on mean hemoglobin A (HbA) and the prevalence of diabetes complications for non-White YYA.

Results: The study included 978 YYA. The sample was 47.5% female and 77.5% non-Hispanic White, with a mean age of 12.8 ± 2.4 years at diagnosis. The estimated population mean of longitudinal average HbA over visits was 9.2% and 8.2% for the non-White and White subgroup, respectively (difference of 0.9%). Within the non-White subgroup, mean HbA across visits was estimated to decrease by 0.33% (95% CI -0.45, -0.21) if these YYA received the distribution of diabetes treatment regimens of the White subgroup, explaining ∼35% of the estimated difference between the two subgroups. The non-White subgroup was also estimated to have a lower risk of developing diabetic retinopathy, diabetic kidney disease, and peripheral neuropathy with the White youth treatment regimen distribution ( < 0.05), although the low proportion of YYA who developed complications limited statistical power for risk estimations.

Conclusions: Mathematically modeling an equalized distribution of T1D self-management tools and technology accounted for part of but not all disparities in glycemic control between non-White and White YYA, underscoring the complexity of race and ethnicity-based health inequity.
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http://dx.doi.org/10.2337/dc21-0496DOI Listing
November 2021

Absence of COVID-19 Disease Among Chronically Ventilated Nursing Home Patients.

J Am Med Dir Assoc 2021 12 29;22(12):2500-2503. Epub 2021 Sep 29.

NYU Long Island School of Medicine, Mineola, NY, USA; Department of Medicine, NYU Langone Hospital-Long Island, Mineola, NY, USA.

Objective: To describe the experience of COVID-19 disease among chronically ventilated and nonventilated nursing home patients living in 3 separate nursing homes.

Design: Observational study of death, respiratory illness and COVID-19 polymerase chain reaction (PCR) results among residents and staff during nursing home outbreaks in 2020.

Setting And Participants: 93 chronically ventilated nursing home patients and 1151 nonventilated patients living among 3 separate nursing homes on Long Island, New York, as of March 15, 2020. Illness, PCR results, and antibody studies among staff are also reported.

Measurements: Data were collected on death rate among chronically ventilated and nonventilated patients between March 15 and May 15, 2020, compared to the same time in 2019; prevalence of PCR positivity among ventilated and nonventilated patients in 2020; reported illness, PCR positivity, and antibody among staff.

Results: Total numbers of deaths among chronically ventilated nursing home patients during this time frame were similar to the analogous period 1 year earlier (9 of 93 in 2020 vs 8 of 100 in 2019, P = .8), whereas deaths among nonventilated patients were greatly increased (214 of 1151 in 2020 vs 55 of 1189 in 2019, P < .001). No ventilated patient deaths were clinically judged to be COVID-19 related. No clusters of COVID-19 illness could be demonstrated among ventilated patients. Surveillance PCR testing of ventilator patients failed to reveal COVID-19 positivity (none of 84 ventilator patients vs 81 of 971 nonventilator patients, P < .002). Illness and evidence of COVID-19 infection was demonstrated among staff working both in nonventilator and in ventilator units.

Conclusions And Implications: COVID-19 infection resulted in illness and death among nonventilated nursing home residents as well as among staff. This was not observed among chronically ventilated patients. The mechanics of chronic ventilation appears to protect chronically ventilated patients from COVID-19 disease.
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http://dx.doi.org/10.1016/j.jamda.2021.09.019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8479505PMC
December 2021

Determining diagnosis date of diabetes using structured electronic health record (EHR) data: the SEARCH for diabetes in youth study.

BMC Med Res Methodol 2021 10 10;21(1):210. Epub 2021 Oct 10.

Department of Biostatistics and Data Science, Division of Public Health Sciences, Wake Forest School of Medicine, Winston-Salem, NC, USA.

Background: Disease surveillance of diabetes among youth has relied mainly upon manual chart review. However, increasingly available structured electronic health record (EHR) data have been shown to yield accurate determinations of diabetes status and type. Validated algorithms to determine date of diabetes diagnosis are lacking. The objective of this work is to validate two EHR-based algorithms to determine date of diagnosis of diabetes.

Methods: A rule-based ICD-10 algorithm identified youth with diabetes from structured EHR data over the period of 2009 through 2017 within three children's hospitals that participate in the SEARCH for Diabetes in Youth Study: Cincinnati Children's Hospital, Cincinnati, OH, Seattle Children's Hospital, Seattle, WA, and Children's Hospital Colorado, Denver, CO. Previous research and a multidisciplinary team informed the creation of two algorithms based upon structured EHR data to determine date of diagnosis among diabetes cases. An ICD-code algorithm was defined by the year of occurrence of a second ICD-9 or ICD-10 diabetes code. A multiple-criteria algorithm consisted of the year of first occurrence of any of the following: diabetes-related ICD code, elevated glucose, elevated HbA1c, or diabetes medication. We assessed algorithm performance by percent agreement with a gold standard date of diagnosis determined by chart review.

Results: Among 3777 cases, both algorithms demonstrated high agreement with true diagnosis year and differed in classification (p = 0.006): 86.5% agreement for the ICD code algorithm and 85.9% agreement for the multiple-criteria algorithm. Agreement was high for both type 1 and type 2 cases for the ICD code algorithm. Performance improved over time.

Conclusions: Year of occurrence of the second ICD diabetes-related code in the EHR yields an accurate diagnosis date within these pediatric hospital systems. This may lead to increased efficiency and sustainability of surveillance methods for incidence of diabetes among youth.
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http://dx.doi.org/10.1186/s12874-021-01394-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8502379PMC
October 2021

Demographic Correlates of Short-Term Mortality Among Youth and Young Adults With Youth-Onset Diabetes Diagnosed From 2002 to 2015: The SEARCH for Diabetes in Youth Study.

Diabetes Care 2021 Oct 4. Epub 2021 Oct 4.

Division of Health Services Research, Department of Foundations of Medicine, New York University Long Island School of Medicine, Mineola, NY.

Objective: To examine short-term mortality and cause of death among youth and young adults (YYAs) with youth-onset diabetes.

Research Design And Methods: We included 19,717 YYAs newly diagnosed with diabetes before 20 years of age from 1 January 2002 to 31 December 2015 enrolled in the SEARCH for Diabetes in Youth Study. Of these, 14,721 had type 1; 4,141 type 2; and 551 secondary and 304 other/unknown diabetes type. Cases were linked with the National Death Index through 31 December 2017. We calculated standardized mortality ratios (SMRs) and 95% CIs based on age, sex, and race/ethnicity for state and county population areas and examined underlying causes of death.

Results: During 170,148 person-years (PY) (median follow-up 8.5 years), 283 individuals died: 133 with type 1 (103.0/100,000 PY), 55 with type 2 (161.5/100,000 PY), 87 with secondary (1,952/100,000 PY), and 8 with other/unknown diabetes type (312.3/100,000 PY). SMRs (95% CI) for the first three groups were 1.5 (1.2-1.8), 2.3 (1.7-3.0), and 28.0 (22.4-34.6), respectively. Diabetes was the underlying cause of death for 42.1%, 9.1%, and 4.6% of deaths, respectively. The SMR was greater for type 2 than for type 1 diabetes ( < 0.001). SMRs were significantly higher for individuals with type 1 diabetes who were <20 years of age, non-Hispanic White and Hispanic, and female and for individuals with type 2 diabetes who were <25 years of age, from all race/ethnic minority groups, and from both sexes.

Conclusion: Excess mortality was observed among YYAs for each type of diabetes with differences in risk associated with diabetes type, age, race/ethnicity, and sex. The root causes of excess mortality among YYAs with diabetes merit further study.
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http://dx.doi.org/10.2337/dc21-0728DOI Listing
October 2021

Genome-wide Association Study of Lipid Traits in Youth With Type 2 Diabetes.

J Endocr Soc 2021 Nov 18;5(11):bvab139. Epub 2021 Aug 18.

Division of Pediatric Endocrinology, University of California at San Francisco, San Francisco, CA, USA.

Context: Dyslipidemia is highly prevalent in youth with type 2 diabetes (T2D), yet the pathogenic components of dyslipidemia in youth with T2D are poorly understood.

Objective: To evaluate the genetic determinants of lipid traits in youth with T2D through a genome-wide association study.

Design Participants And Main Outcome Measures: We genotyped 206 928 variants and imputed 17 642 824 variants in 1076 youth (mean age 15.0 ± 2.48 years) with T2D from the Treatment Options for Type 2 Diabetes in Adolescents and Youth (TODAY) and SEARCH for Diabetes in Youth (SEARCH) studies as part of the Progress in Diabetes Genetics in Youth (ProDiGY) consortium. We performed association testing for triglyceride and low-density lipoprotein cholesterol and high-density lipoprotein cholesterol (HDL-c) concentrations adjusted for the genetic relationship matrix within each substudy followed by meta-analyses for each trait.

Results: We identified a novel association between a deletion on chromosome 3 (3:67817380_AT/A_Deletion:RP11-81N13.1) and triglyceride levels at genome-wide level of significance ( = 2.3 × 10) with each risk allele increasing triglycerides by 20%. We also identified a genome-wide significant signal at rs247617 ( = 5.1 × 10) between and associated with HDL-c, with carriers of 1 copy of the risk allele having twice higher HDL-c.

Conclusions: Our genetic analyses of lipid traits in youth with T2D have identified 1 novel and 1 previously known locus. Additional studies are needed to further characterize the genetic architecture of dyslipidemia in youth with T2D.
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http://dx.doi.org/10.1210/jendso/bvab139DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8459445PMC
November 2021

Trends in Prevalence of Type 1 and Type 2 Diabetes in Children and Adolescents in the US, 2001-2017.

JAMA 2021 08;326(8):717-727

Department of Epidemiology and Biostatistics, University of South Carolina Arnold School of Public Health, Columbia.

Importance: Changes in the prevalence of youth-onset diabetes have previously been observed.

Objective: To estimate changes in prevalence of type 1 and type 2 diabetes in youths in the US from 2001 to 2017.

Design, Setting, And Participants: In this cross-sectional observational study, individuals younger than 20 years with physician-diagnosed diabetes were enumerated from 6 areas in the US (4 geographic areas, 1 health plan, and select American Indian reservations) for 2001, 2009, and 2017.

Exposures: Calendar year.

Main Outcomes And Measures: Estimated prevalence of physician-diagnosed type 1 and type 2 diabetes overall and by race and ethnicity, age, and sex.

Results: Among youths 19 years or younger, 4958 of 3.35 million had type 1 diabetes in 2001, 6672 of 3.46 million had type 1 diabetes in 2009, and 7759 of 3.61 million had type 1 diabetes in 2017; among those aged 10 to 19 years, 588 of 1.73 million had type 2 diabetes in 2001, 814 of 1.85 million had type 2 diabetes in 2009, and 1230 of 1.85 million had type 2 diabetes in 2017. The estimated type 1 diabetes prevalence per 1000 youths for those 19 years or younger increased significantly from 1.48 (95% CI, 1.44-1.52) in 2001 to 1.93 (95% CI, 1.88-1.98) in 2009 to 2.15 (95% CI, 2.10-2.20) in 2017, an absolute increase of 0.67 per 1000 youths (95%, CI, 0.64-0.70) and a 45.1% (95% CI, 40.0%-50.4%) relative increase over 16 years. The greatest absolute increases were observed among non-Hispanic White (0.93 per 1000 youths [95% CI, 0.88-0.98]) and non-Hispanic Black (0.89 per 1000 youths [95% CI, 0.88-0.98]) youths. The estimated type 2 diabetes prevalence per 1000 youths aged 10 to 19 years increased significantly from 0.34 (95% CI, 0.31-0.37) in 2001 to 0.46 (95% CI, 0.43-0.49) in 2009 to 0.67 (95% CI, 0.63-0.70) in 2017, an absolute increase of 0.32 per 1000 youths (95% CI, 0.30-0.35) and a 95.3% (95% CI, 77.0%-115.4%) relative increase over 16 years. The greatest absolute increases were observed among non-Hispanic Black (0.85 per 1000 youths [95% CI, 0.74-0.97]) and Hispanic (0.57 per 1000 youths [95% CI, 0.51-0.64]) youths.

Conclusions And Relevance: In 6 areas of the US from 2001 to 2017, the estimated prevalence of diabetes among children and adolescents increased for both type 1 and type 2 diabetes.
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http://dx.doi.org/10.1001/jama.2021.11165DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8385600PMC
August 2021

Monogenic Diabetes in Youth With Presumed Type 2 Diabetes: Results From the Progress in Diabetes Genetics in Youth (ProDiGY) Collaboration.

Diabetes Care 2021 Aug 6. Epub 2021 Aug 6.

Division of Endocrinology, Diabetes, and Nutrition, Department of Medicine, University of Maryland School of Medicine, Baltimore, MD

Objective: Maturity-onset diabetes of the young (MODY) is frequently misdiagnosed as type 1 or type 2 diabetes. Correct diagnosis may result in a change in clinical treatment and impacts prediction of complications and familial risk. In this study, we aimed to assess the prevalence of MODY in multiethnic youth under age 20 years with a clinical diagnosis of type 2 diabetes.

Research Design And Methods: We evaluated whole-exome sequence data of youth with a clinical diagnosis of type 2 diabetes. We considered participants to have MODY if they carried a MODY gene variant classified as likely pathogenic (LP) or pathogenic (P) according to current guidelines.

Results: Of 3,333 participants, 93 (2.8%) carried an LP/P variant in (16 participants), (23), (44), (5), (4), and (1). Compared with those with no LP/P variants, youth with MODY had a younger age at diagnosis (12.9 ± 2.5 vs. 13.6 ± 2.3 years, = 0.002) and lower fasting C-peptide levels (3.0 ± 1.7 vs. 4.7 ± 3.5 ng/mL, < 0.0001). Youth with MODY were less likely to have hypertension (6.9% vs. 19.5%, = 0.007) and had higher HDL cholesterol (43.8 vs. 39.7 mg/dL, = 0.006).

Conclusions: By comprehensively sequencing the coding regions of all MODY genes, we identified MODY in 2.8% of youth with clinically diagnosed type 2 diabetes; importantly, in 89% ( = 83) the specific diagnosis would have changed clinical management. No clinical criterion reliably separated the two groups. New tools are needed to find ideal criteria for selection of individuals for genetic testing.
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http://dx.doi.org/10.2337/dc21-0491DOI Listing
August 2021

Low-Dose Tocilizumab With High-Dose Corticosteroids in Patients Hospitalized for COVID-19 Hypoxic Respiratory Failure Improves Mortality Without Increased Infection Risk.

Ann Pharmacother 2021 Jun 28:10600280211028882. Epub 2021 Jun 28.

New York University Langone Health, NY, USA.

Background: Severe hypoxic respiratory failure from COVID-19 pneumonia carries a high mortality risk. There is uncertainty surrounding which patients benefit from corticosteroids in combination with tocilizumab and the dosage and timing of these agents. The balance of controlling inflammation without increasing the risk of secondary infection is difficult. At present, dexamethasone 6 mg is the standard of care in COVID-19 hypoxia; whether this is the ideal choice of steroid or dosage remains to be proven.

Objectives: The primary objective was to assess the impact on mortality of tocilizumab only, corticosteroids only, and combination therapy in patients with COVID-19 respiratory failure.

Methods: A multihospital, retrospective study of adult patients with severe respiratory failure from COVID-19 who received supportive therapy, corticosteroids, tocilizumab, or combination therapy were assessed for 28-day mortality, biomarker improvement, and relative risk of infection. Propensity-matched analysis was performed between corticosteroid alone and combination therapies to further assess mortality benefit.

Results: The steroid-only, tocilizumab-only, and combination groups showed hazard reduction in mortality at 28 days when compared with supportive therapy. In a propensity-matched analysis, the combination group (daily equivalent dexamethasone 10 mg and tocilizumab 400 mg) had an improved 28-day mortality compared with the steroid-only group (daily equivalent dexamethasone 10 mg; hazard ratio (95% CI) = 0.56 (0.38-0.84), = 0.005] without increasing the risk of infection.

Conclusion And Relevance: Combination of tocilizumab and corticosteroids was associated with improved 28-day survival when compared with corticosteroids alone. Modification of steroid dosing strategy as well as steroid type may further optimize therapeutic effect of the COVID-19 treatment.
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http://dx.doi.org/10.1177/10600280211028882DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8250585PMC
June 2021

Fine-mapping, trans-ancestral and genomic analyses identify causal variants, cells, genes and drug targets for type 1 diabetes.

Nat Genet 2021 07 14;53(7):962-971. Epub 2021 Jun 14.

Department of Pathology, Immunology, and Laboratory Medicine, University of Florida, Gainesville, FL, USA.

We report the largest and most diverse genetic study of type 1 diabetes (T1D) to date (61,427 participants), yielding 78 genome-wide-significant (P < 5 × 10) regions, including 36 that are new. We define credible sets of T1D-associated variants and show that they are enriched in immune-cell accessible chromatin, particularly CD4 effector T cells. Using chromatin-accessibility profiling of CD4 T cells from 115 individuals, we map chromatin-accessibility quantitative trait loci and identify five regions where T1D risk variants co-localize with chromatin-accessibility quantitative trait loci. We highlight rs72928038 in BACH2 as a candidate causal T1D variant leading to decreased enhancer accessibility and BACH2 expression in T cells. Finally, we prioritize potential drug targets by integrating genetic evidence, functional genomic maps and immune protein-protein interactions, identifying 12 genes implicated in T1D that have been targeted in clinical trials for autoimmune diseases. These findings provide an expanded genomic landscape for T1D.
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http://dx.doi.org/10.1038/s41588-021-00880-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8273124PMC
July 2021

Genome-wide association study of vitamin D concentrations and bone mineral density in the African American-Diabetes Heart Study.

PLoS One 2021 20;16(5):e0251423. Epub 2021 May 20.

Department of Biostatistical Sciences, Wake Forest School of Medicine, Winston-Salem, NC, United States of America.

Relative to European Americans, African Americans have lower 25-hydroxyvitamin D (25OHD) and vitamin D binding protein (VDBP) concentrations, higher 1,25-dihydroxyvitamin D (1,25(OH)2D3) concentrations and bone mineral density (BMD), and paradoxically reduced burdens of calcified atherosclerotic plaque (subclinical atherosclerosis). To identify genetic factors contributing to vitamin D and BMD measures, association analysis of >14M variants was conducted in a maximum of 697 African American-Diabetes Heart Study participants with type 2 diabetes (T2D). The most significant association signals were detected for VDBP on chromosome 4; variants rs7041 (β = 0.44, SE = 0.019, P = 9.4x10-86) and rs4588 (β = 0.17, SE = 0.021, P = 3.5x10-08) in the group-specific component (vitamin D binding protein) gene (GC). These variants were found to be independently associated. In addition, rs7041 was also associated with bioavailable vitamin D (BAVD; β = 0.16, SE = 0.02, P = 3.3x10-19). Six rare variants were significantly associated with 25OHD, including a non-synonymous variant in HSPG2 (rs116788687; β = -1.07, SE = 0.17, P = 2.2x10-10) and an intronic variant in TNIK (rs143555701; β = -1.01, SE = 0.18, P = 9.0x10-10), both biologically related to bone development. Variants associated with 25OHD failed to replicate in African Americans from the Insulin Resistance Atherosclerosis Family Study (IRASFS). Evaluation of vitamin D metabolism and bone mineral density phenotypes in an African American population enriched for T2D could provide insight into ethnic specific differences in vitamin D metabolism and bone mineral density.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0251423PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8136717PMC
October 2021

Genetic landscape of Gullah African Americans.

Am J Phys Anthropol 2021 08 19;175(4):905-919. Epub 2021 May 19.

Department of Medicine, Medical University of South Carolina, Charleston, South Carolina, USA.

Objectives: Gullah African Americans are descendants of formerly enslaved Africans living in the Sea Islands along the coast of the southeastern U.S., from North Carolina to Florida. Their relatively high numbers and geographic isolation were conducive to the development and preservation of a unique culture that retains deep African features. Although historical evidence supports a West-Central African ancestry for the Gullah, linguistic and cultural evidence of a connection to Sierra Leone has led to the suggestion of this country/region as their ancestral home. This study sought to elucidate the genetic structure and ancestry of the Gullah.

Materials And Methods: We leveraged whole-genome genotype data from Gullah, African Americans from Jackson, Mississippi, African populations from Sierra Leone, and population reference panels from Africa and Europe to infer population structure, ancestry proportions, and global estimates of admixture.

Results: Relative to non-Gullah African Americans from the Southeast US, the Gullah exhibited higher mean African ancestry, lower European admixture, a similarly small Native American contribution, and increased male-biased European admixture. A slightly tighter bottleneck in the Gullah 13 generations ago suggests a largely shared demographic history with non-Gullah African Americans. Despite a slightly higher relatedness to populations from Sierra Leone, our data demonstrate that the Gullah are genetically related to many West African populations.

Discussion: This study confirms that subtle differences in African American population structure exist at finer regional levels. Such observations can help to inform medical genetics research in African Americans, and guide the interpretation of genetic data used by African Americans seeking to explore ancestral identities.
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http://dx.doi.org/10.1002/ajpa.24333DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8286328PMC
August 2021

Predictors of preference for cognitive-behavioral therapy (CBT) and yoga interventions among older adults.

J Psychiatr Res 2021 06 30;138:311-318. Epub 2021 Mar 30.

Department of Social Sciences and Health Policy, Wake Forest School of Medicine, United States. Electronic address:

The purpose of this study was to examine factors that influence a person's choice of cognitive-behavioral therapy (CBT) or yoga, the stability of these preferences, and the impact of preference on engagement and process measures. We conducted a randomized preference trial of CBT and yoga in 500 adults ≥60 years with symptoms of worry. Participants reported their intervention preference, strength of preference, and factors impacting preference. Engagement in the intervention (session completion and dropout rates) was assessed. Process measures included satisfaction with the intervention, therapeutic alliance, and intervention expectancy. Neither intervention preference (48% and 52% chose CBT and yoga, respectively) nor strength of preference differed significantly between the two preference trial groups. Intervention expectancies at baseline among those in the preference trial were approximately 4.5 units (40-point scale) higher for their preferred intervention (p < .0001 within each group). A principal component analysis of factors influencing preference identified three constructs. Using logistic regression, components focused on attitudes about CBT or yoga were predictive of ultimate preference (odds ratio = 11.5, 95% C.I.6.3-21.0 per 1SD difference in component 1 for choosing CBT; odds ratio = 7.8, 95% CI4.3-13.9 per 1SD difference in component 2 for choosing yoga). There were no significant differences between the randomized and preference trials on intervention adherence, completion of assessments, intervention satisfaction, or working alliance. Receiving a preferred treatment had no significant effects on intervention outcomes through participant engagement or process measures. When options are limited, providers may have confidence in offering the most readily available non-pharmacological treatments.
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http://dx.doi.org/10.1016/j.jpsychires.2021.03.055DOI Listing
June 2021

Diagnosis, Education, and Care of Patients with -Associated Nephropathy: A Delphi Consensus and Systematic Review.

J Am Soc Nephrol 2021 Apr 14. Epub 2021 Apr 14.

Department of Bioethics and Humanities, University of Washington, Seattle, Washington.

Background: variants contribute to the markedly higher incidence of ESKD in Blacks compared with Whites. Genetic testing for these variants in patients with African ancestry who have nephropathy is uncommon, and no specific treatment or management protocol for -associated nephropathy currently exists.

Methods: A multidisciplinary, racially diverse group of 14 experts and patient advocates participated in a Delphi consensus process to establish practical guidance for clinicians caring for patients who may have -associated nephropathy. Consensus group members took part in three anonymous voting rounds to develop consensus statements relating to the following: () counseling, genotyping, and diagnosis; () disease awareness and education; and () a vision for management of -associated nephropathy in a future when treatment is available. A systematic literature search of the MEDLINE and Embase databases was conducted to identify relevant evidence published from January 1, 2009 to July 14, 2020.

Results: The consensus group agreed on 55 consensus statements covering such topics as demographic and clinical factors that suggest a patient has -associated nephropathy, as well as key considerations for counseling, testing, and diagnosis in current clinical practice. They achieved consensus on the need to increase awareness among key stakeholders of racial health disparities in kidney disease and of -associated nephropathy and on features of a successful education program to raise awareness among the patient community. The group also highlighted the unmet need for a specific treatment and agreed on best practice for management of these patients should a treatment become available.

Conclusions: A multidisciplinary group of experts and patient advocates defined consensus-based guidance on the care of patients who may have -associated nephropathy.
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http://dx.doi.org/10.1681/ASN.2020101399DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8425659PMC
April 2021

The First Genome-Wide Association Study for Type 2 Diabetes in Youth: The Progress in Diabetes Genetics in Youth (ProDiGY) Consortium.

Diabetes 2021 04 21;70(4):996-1005. Epub 2021 Jan 21.

Department of Epidemiology, University of Colorado School of Public Health, Aurora, CO.

The prevalence of type 2 diabetes in youth has increased substantially, yet the genetic underpinnings remain largely unexplored. To identify genetic variants predisposing to youth-onset type 2 diabetes, we formed ProDiGY, a multiethnic collaboration of three studies (TODAY, SEARCH, and T2D-GENES) with 3,006 youth case subjects with type 2 diabetes (mean age 15.1 ± 2.9 years) and 6,061 diabetes-free adult control subjects (mean age 54.2 ± 12.4 years). After stratifying by principal component-clustered ethnicity, we performed association analyses on ∼10 million imputed variants using a generalized linear mixed model incorporating a genetic relationship matrix to account for population structure and adjusting for sex. We identified seven genome-wide significant loci, including the novel locus rs10992863 in ( = 3.2 × 10; odds ratio [OR] = 1.23). Known loci identified in our analysis include rs7903146 in ( = 8.0 × 10; OR 1.58), rs72982988 near ( = 4.4 × 10; OR 1.53), rs200893788 in ( = 1.1 × 10; OR 1.32), rs2237892 in ( = 4.8 × 10; OR 1.59), rs937589119 in ( = 3.1 × 10; OR 1.34), and rs113748381 in ( = 4.1 × 10; OR 1.04). Secondary analysis with 856 diabetes-free youth control subjects uncovered an additional locus in ( = 3.2 × 10; OR 2.1) and consistent direction of effect for diabetes risk. In conclusion, we identified both known and novel loci in the first genome-wide association study of youth-onset type 2 diabetes.
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http://dx.doi.org/10.2337/db20-0443DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7980197PMC
April 2021

Apolipoprotein L1 risk genotypes in Ghanaian patients with systemic lupus erythematosus: a prospective cohort study.

Lupus Sci Med 2021 01;8(1)

Department of Biostatistics, Division of Health Sciences Research, NYU Winthrop Hospital, Mineola, New York, USA.

Objective: Two apolipoprotein L1 () risk variants (RV) are enriched in sub-Saharan African populations due to conferred resistance to . These variants associate with adverse renal outcomes by multiple causes including SLE. Despite emerging reports that SLE is common in Ghana, where variant allelic frequencies are high, the regional contribution to SLE outcomes has not been described. Accordingly, this prospective longitudinal cohort study tested the associations between high-risk genotypes and kidney outcomes, organ damage accrual and death in 100 Ghanaian patients with SLE.

Methods: This was a prospective cohort study of 100 SLE outpatients who sought care at Korle bu Teaching Hospital in Accra, Ghana. Adult patients who met 4 American College of Rheumatology criteria for SLE were genotyped for APOL1 and followed longitudinally for SLE activity as measured by the Safety of Estrogens in Lupus National Assessment-Systemic Lupus Erythematosus Disease Activity Index (SELENA-SLEDAI) hybrid and organ injury as measured by the Systemic Lupus International Collaborating Clinics Damage Index (SDI) at baseline and every 6 months for 1 year. Outcomes of interest were kidney function, SDI and case fatality.

Results: Assuming a recessive inheritance, the high-risk genotype (2RV) associated with end-stage renal disease (ESRD) at an OR of 14 (p=0.008). These patients accrued more SDI points particularly in renal and neurological domains. The SDI was 81.3% higher in 2RV patients compared with 0RV or 1RV patients despite no difference in SLE activity (p=0.01). After a 12-month period of observation, 3/12 (25%) of the 2RV patients died compared with 2/88 (2.3%) of the 0RV or 1RV carriers (OR=13.6, p=0.01). Deaths were due to end-stage kidney disease and heart failure.

Conclusion: RVs were heritable risk factors for morbidity and mortality in this Ghanaian SLE cohort. Despite no appreciable differences in SLE activity, high-risk patients exhibited progressive renal disease, organ damage accrual and a 13-fold higher case fatality.
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http://dx.doi.org/10.1136/lupus-2020-000460DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7816898PMC
January 2021

Corrigendum to 'A randomized preference trial of cognitive-behavioral therapy and yoga for the treatment of worry in anxious older adults' [Contemp. Clin. Trials Commun. 10 (2018) 169-176].

Contemp Clin Trials Commun 2020 Sep 3;19:100517. Epub 2020 Jan 3.

Department of Social Sciences and Health Policy, Wake Forest School of Medicine, 1 Medical Center Blvd., Winston-Salem, NC, 27157, USA.

[This corrects the article DOI: 10.1016/j.conctc.2018.05.002.].
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http://dx.doi.org/10.1016/j.conctc.2020.100517DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7691668PMC
September 2020

Trajectories in estimated glomerular filtration rate in youth-onset type 1 and type 2 diabetes: The SEARCH for Diabetes in Youth Study.

J Diabetes Complications 2021 02 23;35(2):107768. Epub 2020 Oct 23.

University of North Carolina Kidney Center, UNC School of Medicine, Chapel Hill, NC, United States of America. Electronic address:

Aims: We sought to characterize the direction and associated factors of eGFR change following diagnosis of youth-onset type 1 and type 2 diabetes.

Methods: We assessed the direction of eGFR change at two visits (mean 6.6 years apart) in SEARCH, a longitudinal cohort study of youth-onset type 1 and type 2 diabetes. We used the CKiD equation to estimate GFR and categorized 'rising' and 'declining' eGFR as an annual change of ≥3 ml/min/1.73 m in either direction. Multivariable logistic regression evaluated factors associated with directional change in eGFR.

Results: Estimated GFR declined in 23.8% and rose in 2.8% of participants with type 1 diabetes (N = 1225; baseline age 11.4 years), and declined in 18.1% and rose in 15.6% of participants with type 2 diabetes (N = 160; baseline age 15.0 years). Factors associated with rising and declining eGFR (versus stable) in both type 1 and type 2 diabetes included sex, age at diagnosis, baseline eGFR and difference in fasting glucose between study visits. Additional factors in type 1 diabetes included time from baseline visit, HbA1c and body mass index.

Conclusions: Over the first decade of diabetes, eGFR decline is more common in type 1 diabetes whereas eGFR rise is more common in type 2 diabetes.
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http://dx.doi.org/10.1016/j.jdiacomp.2020.107768DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7855388PMC
February 2021

Comparison of cognitive-behavioral therapy and yoga for the treatment of late-life worry: A randomized preference trial.

Depress Anxiety 2020 12 27;37(12):1194-1207. Epub 2020 Oct 27.

Department of Social Sciences and Health Policy, Wake Forest School of Medicine, Winston-Salem, North Carolina, USA.

Background: The purpose of this study was to compare the effects of cognitive-behavioral therapy (CBT) and yoga on late-life worry, anxiety, and sleep; and examine preference and selection effects on these outcomes.

Methods: A randomized preference trial of CBT and yoga was conducted in community-dwelling adults 60 years or older, who scored 26 or above on the Penn State Worry Questionnaire-Abbreviated (PSWQ-A). CBT consisted of 10 weekly telephone sessions. Yoga consisted of 20 biweekly group yoga classes. The primary outcome was worry (PSWQ-A); the secondary outcomes were anxiety (PROMIS-Anxiety) and sleep (Insomnia Severity Index [ISI]). We examined both preference effects (average effect for those who received their preferred intervention [regardless of whether it was CBT or yoga] minus the average for those who did not receive their preferred intervention [regardless of the intervention]) and selection effect (which addresses the question of whether there is a benefit to getting to select one intervention over the other, and measures the effect on outcomes of self-selection to a specific intervention).

Results: Five hundred older adults were randomized to the randomized trial (125 each in CBT and yoga) or the preference trial (120 chose CBT; 130 chose yoga). In the randomized trial, the intervention effect of yoga compared with CBT adjusted for baseline psychotropic medication use, gender, and race was 1.6 (-0.2, 3.3), p = .08 for the PSWQ-A. Similar results were observed with PROMIS-Anxiety (adjusted intervention effect: 0.3 [-1.5, 2.2], p = .71). Participants randomized to CBT experienced a greater reduction in the ISI compared with yoga (adjusted intervention effect: 2.4 [1.2, 3.7], p < .01]). Estimated in the combined data set (N = 500), the preference and selection effects were not significant for the PSWQ-A, PROMIS-Anxiety, and ISI. Of the 52 adverse events, only two were possibly related to the intervention. None of the 26 serious adverse events were related to the study interventions.

Conclusions: CBT and yoga were both effective at reducing late-life worry and anxiety. However, a greater impact was seen for CBT compared with yoga for improving sleep. Neither preference nor selection effects was found.
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http://dx.doi.org/10.1002/da.23107DOI Listing
December 2020

The accuracy of provider diagnosed diabetes type in youth compared to an etiologic criteria in the SEARCH for Diabetes in Youth Study.

Pediatr Diabetes 2020 12 6;21(8):1403-1411. Epub 2020 Oct 6.

Department of Epidemiology, Colorado School of Public Health, University of Colorado, Lifecourse Epidemiology of Adiposity and Diabetes (LEAD Center) Anschutz Medical Campus, Denver, Colorado, USA.

Background: Although surveillance for diabetes in youth relies on provider-assigned diabetes type from medical records, its accuracy compared to an etiologic definition is unknown.

Methods: Using the SEARCH for Diabetes in Youth Registry, we evaluated the validity and accuracy of provider-assigned diabetes type abstracted from medical records against etiologic criteria that included the presence of diabetes autoantibodies (DAA) and insulin sensitivity. Youth who were incident for diabetes in 2002-2006, 2008, or 2012 and had complete data on key analysis variables were included (n = 4001, 85% provider diagnosed type 1). The etiologic definition for type 1 diabetes was ≥1 positive DAA titer(s) or negative DAA titers in the presence of insulin sensitivity and for type 2 diabetes was negative DAA titers in the presence of insulin resistance.

Results: Provider diagnosed diabetes type correctly agreed with the etiologic definition of type for 89.9% of cases. Provider diagnosed type 1 diabetes was 96.9% sensitive, 82.8% specific, had a positive predictive value (PPV) of 97.0% and a negative predictive value (NPV) of 82.7%. Provider diagnosed type 2 diabetes was 82.8% sensitive, 96.9% specific, had a PPV and NPV of 82.7% and 97.0%, respectively.

Conclusion: Provider diagnosis of diabetes type agreed with etiologic criteria for 90% of the cases. While the sensitivity and PPV were high for youth with type 1 diabetes, the lower sensitivity and PPV for type 2 diabetes highlights the value of DAA testing and assessment of insulin sensitivity status to ensure estimates are not biased by misclassification.
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http://dx.doi.org/10.1111/pedi.13126DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7819667PMC
December 2020

Genetic and Clinical Predictors of Age of ESKD in Individuals With Autosomal Dominant Tubulointerstitial Kidney Disease Due to Mutations.

Kidney Int Rep 2020 Sep 3;5(9):1472-1485. Epub 2020 Jul 3.

Nephrology Department, Beaumont Hospital, Dublin, Ireland.

Introduction: Autosomal dominant tubulo-interstitial kidney disease due to mutations (ADTKD-) is a rare condition associated with high variability in the age of end-stage kidney disease (ESKD). The minor allele of rs4293393, located in the promoter of the gene, is present in 19% of the population and downregulates uromodulin production by approximately 50% and might affect the age of ESKD. The goal of this study was to better understand the genetic and clinical characteristics of ADTKD- and to perform a Mendelian randomization study to determine if the minor allele of rs4293393 was associated with better kidney survival.

Methods: An international group of collaborators collected clinical and genetic data on 722 affected individuals from 249 families with 125 mutations, including 28 new mutations. The median age of ESKD was 47 years. Men were at a much higher risk of progression to ESKD (hazard ratio 1.78,  < 0.001).

Results: The allele frequency of the minor rs4293393 allele was only 11.6% versus the 19% expected ( < 0.01), resulting in Hardy-Weinberg disequilibrium and precluding a Mendelian randomization experiment. An score reflecting the severity of the trafficking defect of uromodulin mutants was found to be a promising predictor of the age of ESKD.

Conclusion: We report the clinical characteristics associated with 125 mutations. Male gender and a new score predict age of ESKD.
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http://dx.doi.org/10.1016/j.ekir.2020.06.029DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7486199PMC
September 2020

An Acidic Environment Induces APOL1-Associated Mitochondrial Fragmentation.

Am J Nephrol 2020 31;51(9):695-704. Epub 2020 Aug 31.

Department of Internal Medicine, Section on Nephrology, Wake Forest School of Medicine, Winston-Salem, North Carolina, USA.

Background: Apolipoprotein L1 gene (APOL1) G1 and G2 kidney-risk variants (KRVs) cause CKD in African Americans, inducing mitochondrial dysfunction. Modifying factors are required, because a minority of individuals with APOL1 high-risk genotypes develop nephropathy. Given that APOL1 function is pH-sensitive and the pH of the kidney interstitium is <7, we hypothesized the acidic kidney interstitium may facilitate APOL1 KRV-induced mitochondrial dysfunction.

Methods: Human embryonic kidney (HEK293) cells conditionally expressing empty vector (EV), APOL1-reference G0, and G1 or G2 KRVs were incubated in media pH 6.8 or 7.4 for 4, 6, or 8 h. Genotype-specific pH effects on mitochondrial length (µm) were assessed using confocal microscopy in live cells and Fiji derivative of ImageJ software with MiNA plug-in. Lower mitochondrial length indicated fragmentation and early dysfunction.

Results: After 6 h doxycycline (Dox) induction in pH 6.8 media, G2-expressing cells had shorter mitochondria (6.54 ± 0.40) than cells expressing EV (7.65 ± 0.72, p = 0.02) or G0 (7.46 ± 0.31, p = 0.003). After 8 h Dox induction in pH 6.8 media, both G1- (6.21 ± 0.26) and G2-expressing cells had shorter mitochondria (6.46 ± 0.34) than cells expressing EV (7.13 ± 0.32, p = 0.002 and p = 0.008, respectively) or G0 (7.22 ± 0.45, p = 0.003 and p = 0.01, respectively). Mitochondrial length in cells incubated in pH 7.4 media were comparable after 8 h Dox induction regardless of genotype. APOL1 mRNA expression and cell viability were comparable regardless of pH or genotype after 8 h Dox induction.

Conclusion: Acidic pH facilitates early mitochondrial dysfunction induced by APOL1 G1 and G2 KRVs in HEK293 cells. We propose that the acidic kidney interstitium may play a role in APOL1-mediated mitochondrial pathophysiology and nephropathy.
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http://dx.doi.org/10.1159/000509989DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7511450PMC
July 2021

Detection of Diabetes Status and Type in Youth Using Electronic Health Records: The SEARCH for Diabetes in Youth Study.

Diabetes Care 2020 10 31;43(10):2418-2425. Epub 2020 Jul 31.

Division of Health Services Research, NYU Winthrop Research Institute, NYU Long Island School of Medicine, Mineola, NY.

Objective: Diabetes surveillance often requires manual medical chart reviews to confirm status and type. This project aimed to create an electronic health record (EHR)-based procedure for improving surveillance efficiency through automation of case identification.

Research Design And Methods: Youth (<20 years old) with potential evidence of diabetes ( = 8,682) were identified from EHRs at three children's hospitals participating in the SEARCH for Diabetes in Youth Study. True diabetes status/type was determined by manual chart reviews. Multinomial regression was compared with an ICD-10 rule-based algorithm in the ability to correctly identify diabetes status and type. Subsequently, the investigators evaluated a scenario of combining the rule-based algorithm with targeted chart reviews where the algorithm performed poorly.

Results: The sample included 5,308 true cases (89.2% type 1 diabetes). The rule-based algorithm outperformed regression for overall accuracy (0.955 vs. 0.936). Type 1 diabetes was classified well by both methods: sensitivity () (>0.95), specificity () (>0.96), and positive predictive value (PPV) (>0.97). In contrast, the PPVs for type 2 diabetes were 0.642 and 0.778 for the rule-based algorithm and the multinomial regression, respectively. Combination of the rule-based method with chart reviews ( = 695, 7.9%) of persons predicted to have non-type 1 diabetes resulted in perfect PPV for the cases reviewed while increasing overall accuracy (0.983). The , , and PPV for type 2 diabetes using the combined method were ≥0.91.

Conclusions: An ICD-10 algorithm combined with targeted chart reviews accurately identified diabetes status/type and could be an attractive option for diabetes surveillance in youth.
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http://dx.doi.org/10.2337/dc20-0063DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7510036PMC
October 2020

Cardiovascular risk and heart rate variability in young adults with type 2 diabetes and arterial stiffness: The SEARCH for Diabetes in Youth Study.

J Diabetes Complications 2020 10 16;34(10):107676. Epub 2020 Jul 16.

Cincinnati Children's Hospital Medical Center and the University of Cincinnati, United States of America.

Aims: To evaluate cardiovascular risk factors and heart rate variability (HRV) in young adults with type 2 diabetes and arterial stiffness and to explore the relationship between HRV and arterial stiffness.

Methods: We studied 185 young adults with youth-onset T2D enrolled in the SEARCH for Diabetes in Youth Study. Cardiovascular risk factors and HRV were compared between individuals with and without type 2 diabetes and arterial stiffness (defined as a pulse wave velocity greater than the 90th percentile of healthy controls, >6.767 m/s). Semiparametric regression evaluated the independent relationship between HRV and PWV.

Results: Participants with T2D and arterial stiffness were more likely to be older, non-Hispanic Black, have higher systolic and diastolic blood pressure, greater adiposity and obesity-related dyslipidemia (higher triglycerides and lower HDLC). Participants with T2D and arterial stiffness also had lower overall HRV (lower SDNN) with parasympathetic loss (lower RMSSD and PNN50), p < 0.05. Lower HRV tended to be but was not significantly associated with arterial stiffness after adjustment for age, race/ethnicity, sex and cardiovascular risk factors (beta coefficient = -1.11, p = 0.08).

Conclusions: Youth with T2D and arterial stiffness have a worse cardiovascular risk profile, specifically risk factors related to the metabolic syndrome and lower HRV.
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http://dx.doi.org/10.1016/j.jdiacomp.2020.107676DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7502460PMC
October 2020

A randomized pilot study to evaluate graft versus fistula vascular access strategy in older patients with advanced kidney disease: results of a feasibility study.

Pilot Feasibility Stud 2020 17;6:86. Epub 2020 Jun 17.

Division of Health Services Research, Department of Foundations of Medicine, NYU Long Island School of Medicine, Long Island, NY USA.

Background: Although older adults encompass almost half of patients with advanced chronic kidney disease, it remains unclear which long-term hemodialysis vascular access type, arteriovenous fistula or arteriovenous graft, is optimal with respect to effectiveness and patient satisfaction. Clinical outcomes based on the initial AV access type have not been evaluated in randomized controlled trials. This pilot study tested the feasibility of randomizing older adults with advanced kidney disease to initial arteriovenous fistula versus graft vascular access surgery.

Methods: Patients 65 years or older with pre-dialysis chronic kidney disease or incident end-stage kidney disease and no prior arteriovenous vascular access intervention were randomized in a 1:1 ratio to undergo surgical placement of a fistula or a graft after providing informed consent. Trial feasibility was evaluated as (i) recruitment of ≥ 70% of eligible participants, (ii) ≥ 50 to 70% of participants undergo placement of index arteriovenous access within 90 to 180 days of enrollment, respectively, (iii) ≥ 80% adherence to study-related assessments, and (iv) ≥ 70% of participants who underwent index arteriovenous access placement will have a follow-up duration of ≥ 12 months after index surgery date.

Results: Between September 2018 and October 2019, 81% (44/54) of eligible participants consented and were enrolled in the study; 11 had pre-dialysis chronic kidney disease, and 33 had incident or prevalent end-stage kidney disease. After randomization, 100% (21/21) assigned to arteriovenous fistula surgery and 78% (18/23) assigned to arteriovenous graft surgery underwent index arteriovenous access placement within a median (1st, 3rd quartile) of 5.0 (1.0, 14.0) days and 13.0 (5.0, 44.3) days, respectively, after referral to vascular surgery. The completion rates for study-specific assessments ranged between 40.0 and 88.6%. At median follow-up of 215.0 days, 5 participants expired, 7 completed 12 months of follow-up, and 29 are actively being followed. Assessments of grip strength, functional independence, and vascular access satisfaction were completed by > 85% of patients who reached pre-specified post-operative assessment time point.

Conclusions: Results from this study reveal it is feasible to enroll and randomize older adults with advanced kidney disease to one of two different arteriovenous vascular access placement surgeries. The study can progress with minor protocol adjustments to a multisite clinical trial.

Trial Registration: Clinical Trials ID, NCT03545113.
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http://dx.doi.org/10.1186/s40814-020-00619-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7298797PMC
June 2020

Kidney-Risk Variants Induce Mitochondrial Fission.

Kidney Int Rep 2020 Jun 30;5(6):891-904. Epub 2020 Mar 30.

Department of Internal Medicine, Section on Nephrology, Wake Forest School of Medicine, Winston-Salem, North Carolina, USA.

Introduction: G1 and G2 nephropathy-risk variants cause mitochondrial dysfunction and contribute to kidney disease. Analyses were performed to determine the genetic regulation of and elucidate potential mechanisms in -nephropathy.

Methods: A global gene expression analysis was performed in human primary renal tubule cell lines derived from 50 African American individuals. Follow-up gene knock out, cell-based rescue, and microscopy experiments were performed.

Results: genotypes did not alter expression levels in the global gene expression analysis. Expression quantitative trait locus (eQTL) analysis in polyinosinic-polycytidylic acid (poly IC)-stimulated renal tubule cells revealed that single nucleotide polymorphism (SNP) rs513349 adjacent to was a eQTL for and a eQTL for ; and were co-expressed in cells. knockout in a human podocyte cell line resulted in diminished APOL1 protein, supporting a pivotal effect for BAK1 on expression. Because BAK1 is involved in mitochondrial dynamics, mitochondrial morphology was examined in primary renal tubule cells and HEK293 Tet-on cells of various genotypes. Mitochondria in wild-type (G0G0) tubule cells maintained elongated morphology when stimulated by low-dose poly IC, whereas those with G1G1, G2G2, and G1G2 genotypes appeared to fragment. HEK293 Tet-on cells overexpressing G0, G1, and G2 were created; G0 cells appeared to promote mitochondrial fusion, whereas G1 and G2 induced mitochondrial fission. The mitochondrial dynamic regulator Mdivi-1 significantly preserved cell viability and mitochondrial cristae structure and reversed mitochondrial fission induced by overexpression of G1 and G2.

Conclusion: Results suggest the mitochondrial fusion/fission pathway may be a therapeutic target in -nephropathy.
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http://dx.doi.org/10.1016/j.ekir.2020.03.020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7271005PMC
June 2020

Gene-educational attainment interactions in a multi-ancestry genome-wide meta-analysis identify novel blood pressure loci.

Mol Psychiatry 2021 06 5;26(6):2111-2125. Epub 2020 May 5.

Health Disparities Research Section, Laboratory of Epidemiology and Population Sciences, National Institute on Aging, National Institutes of Health, Baltimore, MD, 21224, USA.

Educational attainment is widely used as a surrogate for socioeconomic status (SES). Low SES is a risk factor for hypertension and high blood pressure (BP). To identify novel BP loci, we performed multi-ancestry meta-analyses accounting for gene-educational attainment interactions using two variables, "Some College" (yes/no) and "Graduated College" (yes/no). Interactions were evaluated using both a 1 degree of freedom (DF) interaction term and a 2DF joint test of genetic and interaction effects. Analyses were performed for systolic BP, diastolic BP, mean arterial pressure, and pulse pressure. We pursued genome-wide interrogation in Stage 1 studies (N = 117 438) and follow-up on promising variants in Stage 2 studies (N = 293 787) in five ancestry groups. Through combined meta-analyses of Stages 1 and 2, we identified 84 known and 18 novel BP loci at genome-wide significance level (P < 5 × 10). Two novel loci were identified based on the 1DF test of interaction with educational attainment, while the remaining 16 loci were identified through the 2DF joint test of genetic and interaction effects. Ten novel loci were identified in individuals of African ancestry. Several novel loci show strong biological plausibility since they involve physiologic systems implicated in BP regulation. They include genes involved in the central nervous system-adrenal signaling axis (ZDHHC17, CADPS, PIK3C2G), vascular structure and function (GNB3, CDON), and renal function (HAS2 and HAS2-AS1, SLIT3). Collectively, these findings suggest a role of educational attainment or SES in further dissection of the genetic architecture of BP.
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http://dx.doi.org/10.1038/s41380-020-0719-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7641978PMC
June 2021

Long-term Kidney Transplantation Outcomes Network (APOLLO): Design and Rationale.

Kidney Int Rep 2020 Mar 13;5(3):278-288. Epub 2019 Dec 13.

Division of Nephrology, Department of Medicine, Vagelos College of Physicians & Surgeons, Columbia University, New York, New York, USA.

Introduction: Much of the higher risk for end-stage kidney disease (ESKD) in African American individuals relates to ancestry-specific variation in the apolipoprotein L1 gene (). Relative to kidneys from European American deceased-donors, kidneys from African American deceased-donors have shorter allograft survival and African American living-kidney donors more often develop ESKD. The National Institutes of Health (NIH)-sponsored Long-term Kidney Transplantation Outcomes Network (APOLLO) is prospectively assessing kidney allograft survival from donors with recent African ancestry based on donor and recipient genotypes.

Methods: APOLLO will evaluate outcomes from 2614 deceased kidney donor-recipient pairs, as well as additional living-kidney donor-recipient pairs and unpaired deceased-donor kidneys.

Results: The United Network for Organ Sharing (UNOS), Association of Organ Procurement Organizations, American Society of Transplantation, American Society for Histocompatibility and Immunogenetics, and nearly all U.S. kidney transplant programs, organ procurement organizations (OPOs), and histocompatibility laboratories are participating in this observational study. APOLLO employs a central institutional review board (cIRB) and maintains voluntary partnerships with OPOs and histocompatibility laboratories. A Community Advisory Council composed of African American individuals with a personal or family history of kidney disease has advised the NIH Project Office and Steering Committee since inception. UNOS is providing data for outcome analyses.

Conclusion: This article describes unique aspects of the protocol, design, and performance of APOLLO. Results will guide use of genotypic data to improve the assessment of quality in deceased-donor kidneys and could increase numbers of transplanted kidneys, reduce rates of discard, and improve the safety of living-kidney donation.
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http://dx.doi.org/10.1016/j.ekir.2019.11.022DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7056919PMC
March 2020

Genome-wide association study for time to failure of kidney transplants from African American deceased donors.

Clin Transplant 2020 06 25;34(6):e13827. Epub 2020 Apr 25.

Department of Internal Medicine, Section on Nephrology, Wake Forest School of Medicine, Winston-Salem, NC, USA.

Two renal-risk variants in the apolipoprotein L1 gene (APOL1) in African American (AA) deceased donors (DD) are associated with shorter renal allograft survival after transplantation. To identify additional genes contributing to allograft survival, a genome-wide association study was performed in 532 AA DDs. Phenotypic data were obtained from the Scientific Registry of Transplant Recipients. Association and single-nucleotide polymorphism (SNP)-by-APOL1 interaction tests were conducted using death-censored renal allograft survival accounting for relevant covariates. Replication and inverse-variance-weighted meta-analysis were performed using data from 250 AA DD in the Genomics of Transplantation study. Accounting for APOL1, multiple SNPs near the Nudix Hydrolase 7 gene (NUDT7) showed strong independent effects (P = 1.6 × 10 -2.2 × 10 ). Several SNPs in the Translocation protein SEC63 homolog (SEC63; P = 2 × 10 -3.7 × 10 ) and plasmacytoma variant translocation 1 (PVT1) genes (P = 4.0 × 10 -7 × 10 ) modified the effect of APOL1 on allograft survival. SEC63 is expressed in human renal tubule cells and glomeruli, and PVT1 is associated with diabetic kidney disease. Overall, associations were detected for 41 SNPs (P = 2 × 10 -5 × 10 ) contributing independently or interacting with APOL1 to impact renal allograft survival after transplantation from AA DD. Given the small sample size of the discovery and replication sets, independent validations and functional genomic efforts are needed to validate these results.
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http://dx.doi.org/10.1111/ctr.13827DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7694574PMC
June 2020

Trends in Incidence of Type 1 and Type 2 Diabetes Among Youths - Selected Counties and Indian Reservations, United States, 2002-2015.

MMWR Morb Mortal Wkly Rep 2020 Feb 14;69(6):161-165. Epub 2020 Feb 14.

Diabetes is one of the most common chronic diseases among persons aged <20 years (1). Onset of diabetes in childhood and adolescence is associated with numerous complications, including diabetic kidney disease, retinopathy, and peripheral neuropathy, and has a substantial impact on public health resources (2,3). From 2002 to 2012, type 1 and type 2 diabetes incidence increased 1.4% and 7.1%, respectively, among U.S. youths (4). To assess recent trends in incidence of diabetes in youths (defined for this report as persons aged <20 years), researchers analyzed 2002-2015 data from the SEARCH for Diabetes in Youth Study (SEARCH), a U.S. population-based registry study with clinical sites located in five states. The incidence of both type 1 and type 2 diabetes in U.S. youths continued to rise at constant rates throughout this period. Among all youths, the incidence of type 1 diabetes increased from 19.5 per 100,000 in 2002-2003 to 22.3 in 2014-2015 (annual percent change [APC] = 1.9%). Among persons aged 10-19 years, type 2 diabetes incidence increased from 9.0 per 100,000 in 2002-2003 to 13.8 in 2014-2015 (APC = 4.8%). For both type 1 and type 2 diabetes, the rates of increase were generally higher among racial/ethnic minority populations than those among whites. These findings highlight the need for continued surveillance for diabetes among youths to monitor overall and group-specific trends, identify factors driving these trends, and inform health care planning.
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http://dx.doi.org/10.15585/mmwr.mm6906a3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7017961PMC
February 2020
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