Publications by authors named "R Darrell Nelson"

5,019 Publications

  • Page 1 of 1

Comprehensive Search for Novel Circulating miRNAs and Axon Guidance Pathway Proteins Associated with Risk of End Stage Kidney Disease in Diabetes.

J Am Soc Nephrol 2021 Jun 17. Epub 2021 Jun 17.

A Krolewski, Research Division, Joslin Diabetes Center, Boston, United States.

Mechanisms underlying the progression of diabetic kidney disease to end-stage kidney disease (ESKD) are not fully understood. We performed global micro-RNA (miRNA) analysis in plasma in two cohorts encompassing 375 individuals with type 1 and type 2 diabetes with late diabetic kidney disease and targeted proteomics analysis in plasma in four cohorts encompassing 746 individuals with late and early diabetic kidney disease. We examined structural lesions in kidney biopsies from the 105 individuals with early diabetic kidney disease. Human umbilical vein endothelial cells were used to assess the effects of miRNA mimics or inhibitors on regulation of candidate proteins. In the late diabetic kidney disease cohorts, we identified 17 circulating miRNAs represented by four exemplars (miR-1287-5p, miR-197-5p, miR-339-5p, miR-328-3p), which were strongly associated with 10-year risk of ESKD. These miRNAs targeted proteins in the axon guidance pathway. Circulating levels of six of these proteins-most notably EFNA4 and EPHA2-were strongly associated with 10-year risk of ESKD in all cohorts. Furthermore, circulating levels of these proteins correlated with severity of structural lesions in kidney biopsies. In contrast, expression levels of genes encoding these proteins had no apparent effects on the lesions. In in vitro experiments, mimics of miR-1287-5p and miR-197-5p and inhibitors of miR-339-5p and miR328-3p upregulated concentrations of EPHA2 in either cell lysate, supernatant, or both. This study reveals novel mechanisms involved in progression to ESKD and points to the importance of systemic factors in the development of diabetic kidney disease. Some circulating miRNAs and axon guidance pathway proteins represent potential targets for new therapies to prevent and treat this condition.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1681/ASN.2021010105DOI Listing
June 2021

Increased Hemoglobin A Time in Range Reduces Adverse Health Outcomes in Older Adults With Diabetes.

Diabetes Care 2021 Jun 14. Epub 2021 Jun 14.

VA Boston Healthcare System, Boston, MA.

Objective: Short- and long-term glycemic variability are risk factors for diabetes complications. However, there are no validated A1C target ranges or measures of A1C stability in older adults. We evaluated the association of a patient-specific A1C variability measure, A1C time in range (A1C TIR), on major adverse outcomes.

Research Design And Methods: We conducted a retrospective observational study using administrative data from the Department of Veterans Affairs and Medicare from 2004 to 2016. Patients were ≥65 years old, had diabetes, and had at least four A1C tests during a 3-year baseline period. A1C TIR was the percentage of days during the baseline in which A1C was in an individualized target range (6.0-7.0% up to 8.0-9.0%) on the basis of clinical characteristics and predicted life expectancy. Increasing A1C TIR was divided into categories of 20% increments and linked to mortality and cardiovascular disease (CVD) (i.e., myocardial infarction, stroke).

Results: The study included 402,043 veterans (mean [SD] age 76.9 [5.7] years, 98.8% male). During an average of 5.5 years of follow-up, A1C TIR had a graded relationship with mortality and CVD. Cox proportional hazards models showed that lower A1C TIR was associated with increased mortality (A1C TIR 0 to <20%: hazard ratio [HR] 1.22 [95% CI 1.20-1.25]) and CVD (A1C TIR 0 to <20%: HR 1.14 [95% CI 1.11-1.19]) compared with A1C TIR 80-100%. Competing risk models and shorter follow-up (e.g., 24 months) showed similar results.

Conclusions: In older adults with diabetes, maintaining A1C levels within individualized target ranges is associated with lower risk of mortality and CVD.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2337/dc21-0292DOI Listing
June 2021

Skeletal diversity in Pt- and Au-catalyzed annulations of allenedienes: dissecting unconventional mechanistic pathways.

Chem Sci 2020 Mar 27;11(16):4209-4220. Epub 2020 Mar 27.

Centro Singular de Investigación en Química Biolóxica e Materiais Moleculares (CiQUS), Departamento de Química Orgánica, Universidade de Santiago de Compostela 15782 Santiago de Compostela Spain

We describe the discovery of unprecedented annulation processes of 1,7-allenedienes, promoted by Pt or Au catalysts. These transformations revealed mechanistic pathways that had not been previously observed in reactions involving carbophilic catalysis. In particular, we have found that allenedienes bearing a silyl ether in the carbon tether connecting the diene and the allene divergently afford cyclopropane-embedded tricyclic derivatives, 6,6-fused bicarbocyclic products or 5,6-fused bicarbocyclic systems, depending on the type of Au or Pt catalyst used. We have carried out experimental and computational studies that shed light on the mechanistic reasons behind this rich and unusual skeletal divergence, and provide new lessons on the drastic influence of platinum ancillary ligands on the reaction outcome.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1039/d0sc00650eDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8152626PMC
March 2020

Cerebrospinal Fluid Leaks from the Lateral Ventricle: A Case Series.

Otol Neurotol 2021 Jun 11. Epub 2021 Jun 11.

Department of Otolaryngology-Head and Neck Surgery Indiana University School of Medicine Department of Radiology - Section of Neuroradiology and Imaging Sciences Department of Neurosurgery, Indiana University School of Medicine, Indianapolis, Indiana.

Objectives: Describe the diagnosis and management of lateral skull base (LSB) cerebrospinal fluid (CSF) leaks originating from the lateral ventricle.

Study Design: Retrospective case review.

Setting: Tertiary referral academic center.

Patients: Patients with CSF leaks with direct communication to the lateral ventricle on preoperative imaging.

Intervention: Surgical repair via the middle cranial fossa (MCF) approach.

Main Outcome Measures: CSF leak patient characteristics (age, sex, body mass index [BMI]) and postoperative course (complications and CSF leak resolution) were collected.

Results: Three patients had CSF leaks from the lateral ventricle and all patients demonstrated encephalomalacia of the temporal lobe on preoperative imaging. Encephalomalacia resulted from trauma in one case (age 5) and neurodegeneration in two cases (age 77 and 84). BMI ranged from 16.3 to 26.6 mg/kg2 and follow-up ranged from 4 to 21 months. Two patients presented with preoperative meningitis and all patients had resolution of CSF leaks after MCF repair. With the exception of the higher rate of meningitis, patient presentations did not differ from other spontaneous CSF leaks through middle fossa defects. There were no minor or major postoperative complications.

Conclusions: CSF leaks from the lateral ventricle represent a rare subset of LSB CSF leaks and can occur in non-obese patients secondary to temporal lobe encephalomalacia. The MCF approach allows for repair of the dura and skull base in this cohort of patients with high-flow CSF leaks and loss of brain parenchyma.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/MAO.0000000000003211DOI Listing
June 2021

Nonventilator hospital-acquired pneumonia: A call to action.

Infect Control Hosp Epidemiol 2021 Jun 9:1-6. Epub 2021 Jun 9.

Department of Population Medicine, Harvard Medical School and Harvard Pilgrim Health Care Institute, Boston.

In 2020 a group of U.S. healthcare leaders formed the National Organization to Prevent Hospital-Acquired Pneumonia (NOHAP) to issue a call to action to address non-ventilator-associated hospital-acquired pneumonia (NVHAP). NVHAP is one of the most common and morbid healthcare-associated infections, but it is not tracked, reported, or actively prevented by most hospitals. This national call to action includes (1) launching a national healthcare conversation about NVHAP prevention; (2) adding NVHAP prevention measures to education for patients, healthcare professionals, and students; (3) challenging healthcare systems and insurers to implement and support NVHAP prevention; and (4) encouraging researchers to develop new strategies for NVHAP surveillance and prevention. The purpose of this document is to outline research needs to support the NVHAP call to action. Primary needs include the development of better models to estimate the economic cost of NVHAP, to elucidate the pathophysiology of NVHAP and identify the most promising pathways for prevention, to develop objective and efficient surveillance methods to track NVHAP, to rigorously test the impact of prevention strategies proposed to prevent NVHAP, and to identify the policy levers that will best engage hospitals in NVHAP surveillance and prevention. A joint task force developed this document including stakeholders from the Veterans' Health Administration (VHA), the U.S. Centers for Disease Control and Prevention (CDC), The Joint Commission, the American Dental Association, the Patient Safety Movement Foundation, Oral Health Nursing Education and Practice (OHNEP), Teaching Oral-Systemic Health (TOSH), industry partners and academia.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1017/ice.2021.239DOI Listing
June 2021