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  • 1
    Online Resource
    Online Resource
    Demographic history and rare allele sharing among human populations
    Proceedings of the National Academy of Sciences ; 2011
    In:  Proceedings of the National Academy of Sciences Vol. 108, No. 29 ( 2011-07-19), p. 11983-11988
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 108, No. 29 ( 2011-07-19), p. 11983-11988
    Abstract: High-throughput sequencing technology enables population-level surveys of human genomic variation. Here, we examine the joint allele frequency distributions across continental human populations and present an approach for combining complementary aspects of whole-genome, low-coverage data and targeted high-coverage data. We apply this approach to data generated by the pilot phase of the Thousand Genomes Project, including whole-genome 2–4× coverage data for 179 samples from HapMap European, Asian, and African panels as well as high-coverage target sequencing of the exons of 800 genes from 697 individuals in seven populations. We use the site frequency spectra obtained from these data to infer demographic parameters for an Out-of-Africa model for populations of African, European, and Asian descent and to predict, by a jackknife-based approach, the amount of genetic diversity that will be discovered as sample sizes are increased. We predict that the number of discovered nonsynonymous coding variants will reach 100,000 in each population after ∼1,000 sequenced chromosomes per population, whereas ∼2,500 chromosomes will be needed for the same number of synonymous variants. Beyond this point, the number of segregating sites in the European and Asian panel populations is expected to overcome that of the African panel because of faster recent population growth. Overall, we find that the majority of human genomic variable sites are rare and exhibit little sharing among diverged populations. Our results emphasize that replication of disease association for specific rare genetic variants across diverged populations must overcome both reduced statistical power because of rarity and higher population divergence.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.1019276108
    RVK:
    TA 1000
    RVK:
    WA 15000
    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 2011
    detail.hit.zdb_id: 209104-5
    detail.hit.zdb_id: 1461794-8
    SSG: 11
    SSG: 12
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  • 2
    Online Resource
    Online Resource
    Transient Local Bone Remodeling Effects of rhBMP-2 in an Ovine Interbody Spine Fusion Model
    Ovid Technologies (Wolters Kluwer Health) ; 2016
    In:  Journal of Bone and Joint Surgery Vol. 98, No. 24 ( 2016-12-21), p. 2061-2070
    Details
    In: Journal of Bone and Joint Surgery, Ovid Technologies (Wolters Kluwer Health), Vol. 98, No. 24 ( 2016-12-21), p. 2061-2070
    Abstract: Recombinant human bone morphogenetic protein-2 (rhBMP-2) is a powerful osteoinductive morphogen capable of stimulating the migration of mesenchymal stem cells (MSCs) to the site of implantation and inducing the proliferation and differentiation of these MSCs into osteoblasts. Vertebral end-plate and vertebral body resorption has been reported after interbody fusion with high doses of rhBMP-2. In this study, we investigated the effects of 2 rhBMP-2 doses on peri-implant bone resorption and bone remodeling at 7 time points in an end-plate-sparing ovine interbody fusion model. Methods: Twenty-one female sheep underwent an end-plate-sparing discectomy followed by interbody fusion at L2-L3 and L4-L5 using a custom polyetheretherketone (PEEK) interbody fusion device. The PEEK interbody device was filled with 1 of 2 different doses of rhBMP-2 on an absorbable collagen sponge (ACS): 0.13 mg (1×) or 0.90 mg (7×). Bone remodeling and interbody fusion were assessed via high-resolution radiography and histological analyses at 1, 2, 3, 4, 8, 12, and 20 weeks postoperatively. Results: Peri-implant bone resorption peaked between 3 and 8 weeks in both the 1× and the 7× rhBMP-2/ACS-dose group. Osteoclastic activity and corresponding peri-implant bone resorption was dose-dependent, with moderate-to-marked resorption at the 7×-dose level and less resorption at the 1×-dose level. Both dose (p 〈 0.0007) and time (p 〈 0.0025) affected bone resorption significantly. Transient bone-resorption areas were fully healed by 12 weeks. Osseous bridging was seen at all but 1 spinal level at 12 and at 20 weeks. Conclusions: In the ovine end-plate-sparing interbody fusion model, rhBMP-2 dose-dependent osteoclastic resorption is a transient phenomenon that peaks at 4 weeks postoperatively. Clinical Relevance: Using the U.S. Food and Drug Administration (FDA)-approved rhBMP-2 concentration and matching the volume of rhBMP-2/ACS with the volume of desired bone formation within the interbody construct may limit the occurrence of transient bone resorption.
    Type of Medium: Online Resource
    ISSN: 0021-9355 , 1535-1386
    URL: Article
    DOI: 10.2106/JBJS.16.00345
    RVK:
    XA 52200.A
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2016
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  • 3
    Online Resource
    Online Resource
    Empagliflozin in Heart Failure: Regional Nephron Sodium Handling Effects
    Ovid Technologies (Wolters Kluwer Health) ; 2023
    In:  Journal of the American Society of Nephrology ( 2023-12-11)
    Details
    In: Journal of the American Society of Nephrology, Ovid Technologies (Wolters Kluwer Health), ( 2023-12-11)
    Abstract: The effects of sodium-glucose cotransporter-2 inhibitors (SGLT2i) on regional tubular sodium handling is poorly understood in humans but may be important for the cardio-renal benefits. Methods: The study utilized a previously reported randomized, placebo-controlled crossover study of empagliflozin 10 mg daily in patients with diabetes and heart failure. Sodium handling in the proximal tubule (PT), loop of Henle (Loop), and distal nephron were assessed at baseline and day 14 using fractional excretion of lithium (FELi), capturing PT/Loop sodium reabsorption. Assessments were made with and without antagonism of sodium reabsorption through the Loop using bumetanide. Results: Empagliflozin resulted in a large decrease in sodium reabsorption in the PT (increase in FELi=7.5±10.6%, p=0.001, with several observations suggesting inhibition of PT sodium hydrogen exchanger 3. In the absence of renal compensation, this would be expected to result in ∼40 grams of sodium excretion/24 hours with normal kidney function. However, rapid tubular compensation occurred with increased sodium reabsorption both in the Loop (p 〈 0.001) and distal nephron (p 〈 0.001). Inhibition of SGLT2 did not attenuate over 14 days of empagliflozin (p=0.14).) However, there were significant reductions in FELi (p=0.009), FENa (p=0.004), and absolute fractional distal sodium reabsorption (p=0.036), indicating that chronic adaptation to SGLT2i results primarily from increased reabsorption in the Loop and/or PT. Conclusion: Empagliflozin caused substantial redistribution of intra-renal sodium delivery and reabsorption, providing mechanistic substrate to explain some of the benefits of this class. Importantly, the large increase in sodium exit from the PT was balanced by distal compensation, consistent with SGLT2i excellent safety profile.
    Type of Medium: Online Resource
    ISSN: 1046-6673 , 1533-3450
    URL: Article
    DOI: 10.1681/ASN.0000000000000269
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2023
    detail.hit.zdb_id: 2029124-3
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  • 4
    Online Resource
    Online Resource
    In-Hospital Observation on Oral Diuretics After Treatment for Acute Decompensated Heart Failure: Evaluating the Utility
    Ovid Technologies (Wolters Kluwer Health) ; 2023
    In:  Circulation: Heart Failure Vol. 16, No. 4 ( 2023-04)
    Details
    In: Circulation: Heart Failure, Ovid Technologies (Wolters Kluwer Health), Vol. 16, No. 4 ( 2023-04)
    Abstract: Following treatment for acute decompensated heart failure, in-hospital observation on oral diuretics (OOD) is recommended, assuming it provides actionable information on discharge diuretic dosing and thus reduces readmissions. Methods: In the Mechanisms of Diuretic Resistance (MDR) cohort, we analyzed in-hospital measures of diuretic response, provider’s decisions, and diuretic response ≈30 days postdischarge. In a Yale multicenter cohort, we assessed if in-hospital OOD was associated with 30-day readmission risk. The main objective of this study was to evaluate the utility of in-hospital OOD. Results: Of the 468 patients in the MDR cohort, 57% (N=265) underwent in-hospital OOD. During the OOD, weight change and net fluid balance correlated poorly with each other ( r =0.36). Discharge diuretic dosing was similar between patients who had increased, stable, or decreased weight (decreased discharge dose from OOD dose in 77% versus 72% versus 70%, respectively), net fluid status (decreased discharge dose from OOD dose in 100% versus 69% versus 74%, respectively), and urine output (decreased discharge dose from OOD dose in 69% versus 79% versus 72%, respectively) during the 24-hour OOD period ( P 〉 0.27 for all). In participants returning at 30 days for formal quantification of outpatient diuretic response (n=98), outpatient and inpatient OOD natriuresis was poorly correlated ( r =0.26). In the Yale multicenter cohort (n=18 454 hospitalizations), OOD occurred in 55% and was not associated with 30-day hospital readmission (hazard ratio, 0.98 [95% CI, 0.93–1.05]; P =0.51). Conclusions: In-hospital OOD did not provide actionable information on diuretic response, was not associated with outpatient dose selection, did not predict subsequent outpatient diuretic response, and was not associated with lower readmission rate. Additional research is needed to replicate these findings and understand if these resources could be better allocated elsewhere. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT02546583.
    Type of Medium: Online Resource
    ISSN: 1941-3289 , 1941-3297
    URL: Article
    DOI: 10.1161/CIRCHEARTFAILURE.122.010206
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2023
    detail.hit.zdb_id: 2428100-1
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  • 5
    Online Resource
    Online Resource
    Morphometricity as a measure of the neuroanatomical signature of a trait
    Proceedings of the National Academy of Sciences ; 2016
    In:  Proceedings of the National Academy of Sciences Vol. 113, No. 39 ( 2016-09-27)
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 113, No. 39 ( 2016-09-27)
    Abstract: Complex physiological and behavioral traits, including neurological and psychiatric disorders, often associate with distributed anatomical variation. This paper introduces a global metric, called morphometricity, as a measure of the anatomical signature of different traits. Morphometricity is defined as the proportion of phenotypic variation that can be explained by macroscopic brain morphology. We estimate morphometricity via a linear mixed-effects model that uses an anatomical similarity matrix computed based on measurements derived from structural brain MRI scans. We examined over 3,800 unique MRI scans from nine large-scale studies to estimate the morphometricity of a range of phenotypes, including clinical diagnoses such as Alzheimer’s disease, and nonclinical traits such as measures of cognition. Our results demonstrate that morphometricity can provide novel insights about the neuroanatomical correlates of a diverse set of traits, revealing associations that might not be detectable through traditional statistical techniques.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.1604378113
    RVK:
    TA 1000
    RVK:
    WA 15000
    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 2016
    detail.hit.zdb_id: 209104-5
    detail.hit.zdb_id: 1461794-8
    SSG: 11
    SSG: 12
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  • 6
    Online Resource
    Online Resource
    Renal negative pressure treatment as a novel therapy for heart failure-induced renal dysfunction
    American Physiological Society ; 2021
    In:  American Journal of Physiology-Regulatory, Integrative and Comparative Physiology Vol. 321, No. 4 ( 2021-10-01), p. R588-R594
    Details
    In: American Journal of Physiology-Regulatory, Integrative and Comparative Physiology, American Physiological Society, Vol. 321, No. 4 ( 2021-10-01), p. R588-R594
    Abstract: Congestion is the primary pathophysiological lesion in most heart failure (HF) hospitalizations. Renal congestion increases renal tubular pressure, reducing glomerular filtration rate (GFR) and diuresis. Because each nephron is a fluid-filled column, renal negative pressure therapy (rNPT) applied to the urinary collecting system should reduce tubular pressure, potentially improving kidney function. We evaluated the renal response to rNPT in congestive HF. Ten anesthetized ∼80-kg pigs underwent instrumentation with bilateral renal pelvic JuxtaFlow catheters. GFR was determined by iothalamate clearance (mGFR) and renal plasma flow (RPF) by para-aminohippurate clearance. Each animal served as its own control with randomization of left versus right kidney to −30 mmHg rNPT or no rNPT. mGFR and RPF were measured simultaneously from the rNPT and no rNPT kidney. Congestive HF was induced via cardiac tamponade maintaining central venous pressure at 20–22.5 mmHg throughout the experiment. Before HF induction, rNPT increased natriuresis, diuresis, and mGFR compared with the control kidney ( P 〈 0.001 for all). Natriuresis, diuresis, and mGFR decreased following HF ( P 〈 0.001 for all) but were higher in rNPT kidney versus control ( P 〈 0.001 for all). RPF decreased during HF ( P 〈 0.001) without significant differences between rNPT treatments. During HF, the rNPT kidney had similar diuresis and natriuresis ( P 〉 0.5 for both) and higher fractional excretion of sodium ( P = 0.001) compared with the non-rNPT kidney in the no HF period. In conclusion, rNPT resulted in significantly increased diuresis, natriuresis, and mGFR, with or without experimental HF. rNPT improved key renal parameters of the congested cardiorenal phenotype.
    Type of Medium: Online Resource
    ISSN: 0363-6119 , 1522-1490
    URL: Article
    DOI: 10.1152/ajpregu.00115.2021
    Language: English
    Publisher: American Physiological Society
    Publication Date: 2021
    detail.hit.zdb_id: 1477297-8
    SSG: 12
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  • 7
    Online Resource
    Online Resource
    Anatomically interpretable deep learning of brain age captures domain-specific cognitive impairment
    Proceedings of the National Academy of Sciences ; 2023
    In:  Proceedings of the National Academy of Sciences Vol. 120, No. 2 ( 2023-01-10)
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 120, No. 2 ( 2023-01-10)
    Abstract: The gap between chronological age (CA) and biological brain age, as estimated from magnetic resonance images (MRIs), reflects how individual patterns of neuroanatomic aging deviate from their typical trajectories. MRI-derived brain age (BA) estimates are often obtained using deep learning models that may perform relatively poorly on new data or that lack neuroanatomic interpretability. This study introduces a convolutional neural network (CNN) to estimate BA after training on the MRIs of 4,681 cognitively normal (CN) participants and testing on 1,170 CN participants from an independent sample. BA estimation errors are notably lower than those of previous studies. At both individual and cohort levels, the CNN provides detailed anatomic maps of brain aging patterns that reveal sex dimorphisms and neurocognitive trajectories in adults with mild cognitive impairment (MCI, N  = 351) and Alzheimer’s disease (AD, N  = 359). In individuals with MCI (54% of whom were diagnosed with dementia within 10.9 y from MRI acquisition), BA is significantly better than CA in capturing dementia symptom severity, functional disability, and executive function. Profiles of sex dimorphism and lateralization in brain aging also map onto patterns of neuroanatomic change that reflect cognitive decline. Significant associations between BA and neurocognitive measures suggest that the proposed framework can map, systematically, the relationship between aging-related neuroanatomy changes in CN individuals and in participants with MCI or AD. Early identification of such neuroanatomy changes can help to screen individuals according to their AD risk.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.2214634120
    RVK:
    TA 1000
    RVK:
    WA 15000
    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 2023
    detail.hit.zdb_id: 209104-5
    detail.hit.zdb_id: 1461794-8
    SSG: 11
    SSG: 12
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  • 8
    Online Resource
    Online Resource
    FGF-23 (Fibroblast Growth Factor-23) and Cardiorenal Interactions
    Ovid Technologies (Wolters Kluwer Health) ; 2021
    In:  Circulation: Heart Failure Vol. 14, No. 11 ( 2021-11)
    Details
    In: Circulation: Heart Failure, Ovid Technologies (Wolters Kluwer Health), Vol. 14, No. 11 ( 2021-11)
    Abstract: Animal models implicate FGF-23 (fibroblast growth factor-23) as a direct contributor to adverse cardiorenal interactions such as sodium avidity, diuretic resistance, and neurohormonal activation, but this has not been conclusively demonstrated in humans. Therefore, we aimed to evaluate whether FGF-23 is associated with parameters of cardiorenal dysfunction in humans with heart failure, independent of confounding factors. Methods: One hundred ninety-nine outpatients with heart failure undergoing diuretic treatment at the Yale Transitional Care Center were enrolled and underwent blood collection, and urine sampling before and after diuretics. Results: FGF-23 was associated with several metrics of disease severity such as higher home loop diuretic dose and NT-proBNP (N-terminal pro-B-type natriuretic peptide), and lower estimated glomerular filtration rate, serum chloride, and serum albumin. Multivariable analysis demonstrated no statistically significant association between FGF-23 and sodium avidity measured by fractional excretion of sodium, or proximal or distal tubular sodium reabsorption, either before diuretic administration or at peak diuresis ( P ≥0.11 for all). Likewise, FGF-23 was not independently associated with parameters of diuretic resistance (diuretic excretion, cumulative urine and sodium output, and loop diuretic efficiency [ P ≥0.33 for all]) or neurohormonal activation (plasma or urine renin [ P ≥0.36 for all]). Moreover, the upper boundary of the 95% CI of all the partial correlations were ≤0.30, supporting the lack of meaningful correlations. FGF-23 was not associated with mortality in multivariable analysis ( P =0.44). Conclusions: FGF-23 was not meaningfully associated with any cardiorenal parameter in patients with heart failure. While our methods cannot rule out a small effect, FGF-23 is unlikely to be a primary driver of cardiorenal interactions.
    Type of Medium: Online Resource
    ISSN: 1941-3289 , 1941-3297
    URL: Article
    DOI: 10.1161/CIRCHEARTFAILURE.121.008385
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2021
    detail.hit.zdb_id: 2428100-1
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  • 9
    Online Resource
    Online Resource
    First-in-Human Experience With Peritoneal Direct Sodium Removal Using a Zero-Sodium Solution : A New Candidate Therapy for Volume Overload
    Ovid Technologies (Wolters Kluwer Health) ; 2020
    In:  Circulation Vol. 141, No. 13 ( 2020-03-31), p. 1043-1053
    Details
    In: Circulation, Ovid Technologies (Wolters Kluwer Health), Vol. 141, No. 13 ( 2020-03-31), p. 1043-1053
    Abstract: Loop diuretics have well-described toxicities, and loss of response to these agents is common. Alternative strategies are needed for the maintenance of euvolemia in heart failure (HF). Nonrenal removal of sodium directly across the peritoneal membrane (direct sodium removal [DSR]) with a sodium-free osmotic solution should result in extraction of large quantities of sodium with limited off-target solute removal. Methods: This article describes the preclinical development and first-in-human proof of concept for DSR. Sodium-free 10% dextrose was used as the DSR solution. Porcine experiments were conducted to investigate the optimal dwell time, safety, and scalability and to determine the effect of experimental heart failure. In the human study, participants with end-stage renal disease on peritoneal dialysis (PD) underwent randomization and crossover to either a 2-hour dwell with 1 L DSR solution or standard PD solution (Dianeal 4.25% dextrose, Baxter). The primary end point was completion of the 2-hour dwell without significant discomfort or adverse events, and the secondary end point was difference in sodium removal between DSR and standard PD solution. Results: Porcine experiments revealed that 1 L DSR solution removed 4.1±0.4 g sodium in 2 hours with negligible off-target solute removal and overall stable serum electrolytes. Increasing the volume of DSR solution cycled across the peritoneum increased sodium removal and substantially decreased plasma volume ( P =0.005). In the setting of experimental heart failure with elevated right atrial pressure, sodium removal was ≈4 times greater than in healthy animals ( P 〈 0.001). In the human proof-of-concept study, DSR solution was well tolerated and not associated with significant discomfort or adverse events. Plasma electrolyte concentrations were stable, and off-target solute removal was negligible. Sodium removal was substantially higher with DSR (4.5±0.4 g) compared with standard PD solution (1.0±0.3 g; P 〈 0.0001). Conclusions: DSR was well tolerated in both animals and human subjects and produced substantially greater sodium removal than standard PD solution. Additional research evaluating the use of DSR as a method to prevent and treat hypervolemia in heart failure is warranted. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT03801226.
    Type of Medium: Online Resource
    ISSN: 0009-7322 , 1524-4539
    URL: Article
    DOI: 10.1161/CIRCULATIONAHA.119.043062
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2020
    detail.hit.zdb_id: 1466401-X
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  • 10
    Online Resource
    Online Resource
    Natriuretic Equation to Predict Loop Diuretic Response in Patients With Heart Failure
    Elsevier BV ; 2021
    In:  Journal of the American College of Cardiology Vol. 77, No. 6 ( 2021-02), p. 695-708
    Details
    In: Journal of the American College of Cardiology, Elsevier BV, Vol. 77, No. 6 ( 2021-02), p. 695-708
    Type of Medium: Online Resource
    ISSN: 0735-1097
    URL: Article
    DOI: 10.1016/j.jacc.2020.12.022
    RVK:
    XA 17760
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2021
    detail.hit.zdb_id: 1468327-1
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