Publications by authors named "Andrew Blair"

19 Publications

  • Page 1 of 1

Modeling Human TBX5 Haploinsufficiency Predicts Regulatory Networks for Congenital Heart Disease.

Dev Cell 2021 Feb 14;56(3):292-309.e9. Epub 2020 Dec 14.

Gladstone Institutes, San Francisco, CA 94158, USA; Roddenberry Center for Stem Cell Biology and Medicine at Gladstone, San Francisco, CA 94158, USA; Cardiovascular Research Institute, University of California, San Francisco, CA 94158, USA; Department of Pediatrics, University of California, San Francisco, CA 94158, USA. Electronic address:

Haploinsufficiency of transcriptional regulators causes human congenital heart disease (CHD); however, the underlying CHD gene regulatory network (GRN) imbalances are unknown. Here, we define transcriptional consequences of reduced dosage of the CHD transcription factor, TBX5, in individual cells during cardiomyocyte differentiation from human induced pluripotent stem cells (iPSCs). We discovered highly sensitive dysregulation of TBX5-dependent pathways-including lineage decisions and genes associated with heart development, cardiomyocyte function, and CHD genetics-in discrete subpopulations of cardiomyocytes. Spatial transcriptomic mapping revealed chamber-restricted expression for many TBX5-sensitive transcripts. GRN analysis indicated that cardiac network stability, including vulnerable CHD-linked nodes, is sensitive to TBX5 dosage. A GRN-predicted genetic interaction between Tbx5 and Mef2c, manifesting as ventricular septation defects, was validated in mice. These results demonstrate exquisite and diverse sensitivity to TBX5 dosage in heterogeneous subsets of iPSC-derived cardiomyocytes and predicts candidate GRNs for human CHDs, with implications for quantitative transcriptional regulation in disease.
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http://dx.doi.org/10.1016/j.devcel.2020.11.020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7878434PMC
February 2021

Hydra: A mixture modeling framework for subtyping pediatric cancer cohorts using multimodal gene expression signatures.

PLoS Comput Biol 2020 04 10;16(4):e1007753. Epub 2020 Apr 10.

Genomics Institute, University of California, Santa Cruz, Santa Cruz, California, United States of America.

Precision oncology has primarily relied on coding mutations as biomarkers of response to therapies. While transcriptome analysis can provide valuable information, incorporation into workflows has been difficult. For example, the relative rather than absolute gene expression level needs to be considered, requiring differential expression analysis across samples. However, expression programs related to the cell-of-origin and tumor microenvironment effects confound the search for cancer-specific expression changes. To address these challenges, we developed an unsupervised clustering approach for discovering differential pathway expression within cancer cohorts using gene expression measurements. The hydra approach uses a Dirichlet process mixture model to automatically detect multimodally distributed genes and expression signatures without the need for matched normal tissue. We demonstrate that the hydra approach is more sensitive than widely-used gene set enrichment approaches for detecting multimodal expression signatures. Application of the hydra analysis framework to small blue round cell tumors (including rhabdomyosarcoma, synovial sarcoma, neuroblastoma, Ewing sarcoma, and osteosarcoma) identified expression signatures associated with changes in the tumor microenvironment. The hydra approach also identified an association between ATRX deletions and elevated immune marker expression in high-risk neuroblastoma. Notably, hydra analysis of all small blue round cell tumors revealed similar subtypes, characterized by changes to infiltrating immune and stromal expression signatures.
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http://dx.doi.org/10.1371/journal.pcbi.1007753DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7176284PMC
April 2020

Biological process activity transformation of single cell gene expression for cross-species alignment.

Nat Commun 2019 10 25;10(1):4899. Epub 2019 Oct 25.

Santa Cruz Genomics Institute and Department of Biomolecular Engineering, University of California, Santa Cruz, CA, 95064, USA.

The maintenance and transition of cellular states are controlled by biological processes. Here we present a gene set-based transformation of single cell RNA-Seq data into biological process activities that provides a robust description of cellular states. Moreover, as these activities represent species-independent descriptors, they facilitate the alignment of single cell states across different organisms.
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http://dx.doi.org/10.1038/s41467-019-12924-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6814736PMC
October 2019

Using forum theatre to teach communication skills within an undergraduate pharmacy curriculum: A qualitative evaluation of students' feedback.

Curr Pharm Teach Learn 2019 04 27;11(4):373-381. Epub 2019 Feb 27.

Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, 161 Cathedral St, Glasgow G4 0RE, Scotland, United Kingdom of Great Britain and Northern Ireland. Electronic address:

Background And Purpose: Pharmacists need to learn communication styles which adopt a more consultative model. The objectives of this paper are to describe the use of forum theatre facilitated by actors to teach communication skills to pharmacy students and to highlight perceptions of the workshops.

Educational Activity And Setting: During the actor-led forum theatre, students redirected scenes depicting pharmacist-patient consultations. Students also learned about their own communication styles and role-played consultations and interview situations with actors. Pharmacy undergraduate students enrolled in years 2, 3, and 4 answered open-ended questions online at the end of workshops. All responses were coded to identify themes.

Findings: Five themes emerged from 752 comments: (1) workshops were useful in facilitating communication skills development, (2) workshops encouraged reflection, (3) appreciation of feedback provided, (4) the live, interactive nature of the workshop enhanced learning, and (5) suggestions for improvement. There were requests for more varied scenarios involving different patient groups and more opportunities to participate in the role-plays. Students also requested smaller groups, which would encourage participation from those who were reticent and allow more personal feedback.

Summary: The use of forum theatre employing role-play, small group coaching on consultation and interview skills, and emphasizing feedback was perceived as an effective and engaging method to teach communication skills.
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http://dx.doi.org/10.1016/j.cptl.2019.01.015DOI Listing
April 2019

Ultra-thin and strong formvar-based membranes with controlled porosity for micro- and nano-scale systems.

Nanotechnology 2018 May 7;29(21):215712. Epub 2018 Mar 7.

Center for Integrated Nanotechnologies, Los Alamos National Laboratory, United States of America.

We present a methodology for developing ultra-thin and strong formvar-based membranes with controlled morphologies. Formvar is a thin hydrophilic and oleophilic polymer inert to most chemicals and resistant to radiation. The formvar-based membranes are viable materials as support structures in micro- and macro-scale systems depending on thinness and porosity control. Tunable sub-micron thick porous membranes with 20%-65% porosity were synthesized by controlling the ratios of formvar, glycerol, and chloroform. This synthesis process does not require complex separation or handling methods and allows for the production of strong, thin, and porous formvar-based membranes. An expansive array of these membrane characterizations including chemical compatibility, mechanical responses, wettability, as well as the mathematical simulations as a function of porosity has been presented. The wide range of chemical compatibility allows for membrane applications in various environments, where other polymers would not be suitable. Our formvar-based membranes were found to have an elastic modulus of 7.8 GPa, a surface free energy of 50 mN m and an average thickness of 125 nm. Stochastic model simulations indicate that formvar with the porosity of ∼50% is the optimal membrane formulation, allowing the most material transfer across the membrane while also withstanding the highest simulated pressure loadings before tearing. Development of novel, resilient and versatile membranes with controlled porosity offers a wide range of exciting applications in the fields of nanoscience, microfluidics, and MEMS.
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http://dx.doi.org/10.1088/1361-6528/aab4a4DOI Listing
May 2018

Comparison of postoperative ultrasound criteria to predict unassisted use of arteriovenous fistulas for hemodialysis.

J Vasc Access 2018 Mar 19;19(2):167-171. Epub 2018 Feb 19.

1 Department of Medicine and Division of Nephrology, University of Alabama at Birmingham, Birmingham, Alabama - USA.

Introduction: Arteriovenous fistulas (AVF) frequently fail to mature. Postoperative ultrasounds provide objective measurements to predict unassisted AVF use for hemodialysis (unassisted use) and guide interventions to salvage nonmaturing AVFs. The optimal ultrasound criteria to assess AVF maturation are uncertain. We analyzed data from a multicenter, randomized, controlled, clinical trial to compare 2 published ultrasound maturation criteria used to predict unassisted AVF use for hemodialysis.

Methods: We retrospectively analyzed prospective data on 105 patients undergoing new AVF creation, who underwent standardized postoperative ultrasounds at 6 and 12 weeks to measure AVF diameter and blood flow. Unassisted AVF use was defined as successful cannulation for ≥90 days without requiring prior surgical or percutaneous interventions. Two ultrasound criteria were assessed: (i) National Kidney Foundation (NKF) Kidney Disease Outcome Quality Initiative criteria: AVF outflow vein lumen diameter ≥6 mm and blood flow ≥600 mL/min; and (ii) University of Alabama at Birmingham (UAB) criteria: AVF outflow vein lumen diameter ≥4 mm and blood flow ≥500 mL/min. Performance characteristics were calculated for both criteria.

Results: Compared to the NKF criteria, the UAB criteria had a higher sensitivity (89 vs.68%), but a lower specificity (42 vs. 70%) for unassisted AVF use. For radiocephalic AVFs, the UAB criteria had higher sensitivity (86 vs. 46%) and lower specificity (58 vs. 83%). For brachiocephalic AVFs, both UAB and NKF had high sensitivity (90 and 80%) but low specificity (21 and 53%), respectively.

Conclusions: Using the UAB ultrasound criteria would minimize unnecessary early interventions in AVFs likely to mature without an intervention, but would delay interventions in AVFs that are unlikely to mature. The UAB criteria may be preferred in patients receiving a radiocephalic AVF.
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http://dx.doi.org/10.5301/jva.5000818DOI Listing
March 2018

Tumor-penetrating peptide fused EGFR single-domain antibody enhances cancer drug penetration into 3D multicellular spheroids and facilitates effective gastric cancer therapy.

J Control Release 2015 Feb 30;200:188-200. Epub 2014 Dec 30.

The Comprehensive Cancer Center of Drum-Tower Hospital, Medical School of Nanjing University & Clinical Cancer Institute of Nanjing University, Nanjing, China. Electronic address:

Human tumors, including gastric cancer, frequently express high levels of epidermal growth factor receptors (EGFRs), which are associated with a poor prognosis. Targeted delivery of anticancer drugs to cancerous tissues shows potential in sparing unaffected tissues. However, it has been a major challenge for drug penetration in solid tumor tissues due to the complicated tumor microenvironment. We have constructed a recombinant protein named anti-EGFR-iRGD consisting of an anti-EGFR VHH (the variable domain from the heavy chain of the antibody) fused to iRGD, a tumor-specific binding peptide with high permeability. Anti-EGFR-iRGD, which targets EGFR and αvβ3, spreads extensively throughout both the multicellular spheroids and the tumor mass. The recombinant protein anti-EGFR-iRGD also exhibited antitumor activity in tumor cell lines, multicellular spheroids, and mice. Moreover, anti-EGFR-iRGD could improve anticancer drugs, such as doxorubicin (DOX), bevacizumab, nanoparticle permeability and efficacy in multicellular spheroids. This study draws attention to the importance of iRGD peptide in the therapeutic approach of anti-EGFR-iRGD. As a consequence, anti-EGFR-iRGD could be a drug candidate for cancer treatment and a useful adjunct of other anticancer drugs.
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http://dx.doi.org/10.1016/j.jconrel.2014.12.039DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5008032PMC
February 2015

Application of human type I pancreatic elastase (PRT-201) to the venous anastomosis of arteriovenous grafts in patients with chronic kidney disease.

J Vasc Access 2014 Sep-Oct;15(5):376-84. Epub 2014 May 3.

1 Department of Surgery, University of Louisville, Louisville, KY - USA.

Purpose: To explore the safety and efficacy of PRT-201 applied to the outflow vein of a newly created arteriovenous graft (AVG).

Methods: Randomized, double-blind, placebo-controlled, single-dose escalation study of PRT-201 (0.01 to 9 mg) applied to the graft-vein anastomosis and adjacent outflow vein immediately after AVG placement. The primary outcome measure was safety. The efficacy measures were intraoperative increases in outflow vein diameter and blood flow rate, primary unassisted patency, and secondary patency by dose groups (placebo, low, medium, high and All PRT-201).

Results: A total of 89 patients were treated (28 placebo and 61 PRT-201). There were no significant differences in the proportion of placebo and PRT-201 patients reporting adverse events. Intraoperative outflow vein diameter increased 5% (p=0.14) in the placebo group compared with 13% (p=0.01), 15% (p=0.07) and 12% (p<0.001), in the low, medium and high groups, respectively. The comparison between the high and placebo groups was marginally statistically significant (p=0.06). The intraoperative blood flow did not change in the placebo group, and increased in the low, medium and high groups by 19% (p=0.34), 36% (p=0.09) and 46% (p=0.02), respectively. The low group had the longest primary unassisted and secondary patency and the fewest procedures to restore or maintain patency; however, the differences between groups were not statistically significant.

Conclusions: PRT-201 was well tolerated and increased AVG intraoperative outflow vein diameter and blood flow. Low dose tended to increase secondary patency and decrease the rate of procedures to restore or maintain patency. Larger studies with these doses will be necessary to confirm these results.
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http://dx.doi.org/10.5301/jva.5000235DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6159820PMC
October 2015

A multi-center, dose-escalation study of human type I pancreatic elastase (PRT-201) administered after arteriovenous fistula creation.

J Vasc Access 2013 Apr-Jun;14(2):143-51. Epub 2012 Nov 20.

Department of Cardiovascular Surgery, The Methodist Hospital, Houston, TX, USA.

Purpose: To explore the safety and efficacy of PRT-201.

Methods: Randomized, double-blind, placebo-controlled, single-dose escalation study of PRT-201 (0.0033 to 9 mg) applied after arteriovenous fistula (AVF) creation. Participants were followed for one year. The primary outcome measure was safety. Efficacy measures were the proportion with intra-operative increases in AVF outflow vein diameter or blood flow ≥25% (primary), changes in outflow vein diameter and blood flow, AVF maturation and lumen stenosis by ultrasound criteria and AVF patency.

Results: The adverse events in the PRT-201 group (n=45) were similar to those in the placebo group (n=21). There were no differences in the proportion with ≥25% increase in vein diameter or blood flow, successful maturation or lumen stenosis. There was no statistically significant difference in primary patency between the dose groups (placebo n=21, Low Dose n=16, Medium Dose n=17 and High Dose n=12). In a subgroup analysis that excluded three participants with early surgical failures, the hazard ratio (HR) for primary patency loss of Low Dose compared with placebo was 0.38 (95% CI 0.10-1.41, P=0.15). In a Cox model, Low Dose (HR 0.27, 95% CI 0.04-0.79, P=0.09), white race (HR 0.17, 95% CI 0.03-0.79, P=0.02), and age <65 years (HR 0.25, CI 0.05-1.15, P=0.08) were associated (P<0.10) with a decreased risk of primary patency loss.

Conclusions: PRT-201 was not different from placebo for safety or efficacy measures. There was a suggestion for improved AVF primary patency with Low Dose PRT-201 that is now being studied in a larger clinical trial.
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http://dx.doi.org/10.5301/jva.5000125DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6159815PMC
March 2014

The ability of serum from alpha 1-antitrypsin-deficient patients to inhibit PRT-201, a recombinant human type I pancreatic elastase.

Biotechnol Appl Biochem 2012 Jan-Feb;59(1):22-8. Epub 2012 Jan 2.

Division of Gastroenterology, Hepatology and Endoscopy, Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA.

PRT-201 is a recombinant human pancreatic elastase under development as a treatment for blood vessels to promote hemodialysis access patency. Proteases such as elastase are normally inactivated by antiproteases such as alpha 1-antitrypsin. It is unknown if serum from patients with alpha 1-antitrypsin deficiency will inhibit PRT-201 elastase activity. An assay for PRT-201 elastase activity in the presence of serum was developed and validated. PRT-201 elastase activity inhibition curves were developed using serum and also using purified alpha 1-antitrypsin and alpha 2-macroglobulin. Serum from 15 patients with documented alpha 1-antitrypsin deficiency, some of whom were receiving alpha 1-antitrypsin augmentation therapy, and four normal volunteers was analyzed. Serum from normal volunteers and patients with alpha 1-antitrypsin deficiency completely inactivated PRT-201 elastase activity in vitro. In the alpha 1-antitrypsin-deficient patients, the volume of serum necessary to inhibit elastase activity was related to the serum concentration of alpha 1-antitrypsin and augmentation therapy. Purified alpha 1-antitrypsin and alpha 2-macroglobulin were each alone capable of completely inhibiting PRT-201 elastase activity. It is unlikely that the use of PRT-201 will be associated with negative outcomes in patients with alpha 1-antitrypsin deficiency.
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http://dx.doi.org/10.1002/bab.65DOI Listing
October 2012

Characteristics of Gafchromic XR-RV2 radiochromic film.

Med Phys 2009 Jul;36(7):3050-8

Department of Medical Physics and Bioengineering, Christchurch Hospital, Private Bag 4710, Christchurch 8140, New Zealand.

Gafchromic XR-RV2 is a revised version of the obsolete Gafchromic XR-R-type radiochromic film. This article investigates the dose response, energy response, postexposure growth, and polarizing effects of this film after exposure to ionizing radiation in the diagnostic energy range. The effect of bit depth on scanning was also investigated. Films were scanned using an Epson Expression 10000XL document scanner or an X-Rite model 301 spot densitometer. Color channel analysis was performed. The film showed usable response in the air kerma range of 1-1000 cGy, although by 1500 cGy the film appeared saturated when using the red color channel on a document scanner. The film response varied by 11% between 60 and 96 kVp and 3.5% between 96 and 125 kVp for doses above 1 Gy. Postexposure growth was found to be approximately logarithmic and fairly stable after 24 h. Films stored under office lighting exhibited around twice the density growth compared with film stored in a dark environment. The film showed strong orientation dependence when scanned using a polarized light source. A 48 bit scan provided no increase in sensitivity over 24 bits. Gafchromic XR-RV2 film is a radiochromic film ideally suited for measurement of wide dose ranges at diagnostic energies. The energy dependence of this film limits its accuracy for dosimetry of unknown energy beams. For the document scanners used in this study a 24 bit scan was more than sufficient compared to a 48 bit scan. This is likely to be the case for most document scanners where electrical noise prevents higher bit depths from increasing the sensitivity of measurements.
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http://dx.doi.org/10.1118/1.3147141DOI Listing
July 2009

Sevelamer restores bone volume and improves bone microarchitecture and strength in aged ovariectomized rats.

Endocrinology 2008 Dec 7;149(12):6092-102. Epub 2008 Aug 7.

Genzyme Corporation, Framingham, Massachusetts 01701, USA.

Sevelamer hydrochloride, a noncalcium phosphate binder, has been shown to reduce coronary artery and aortic calcification, and to improve trabecular bone mineral density in hemodialysis patients with chronic kidney disease. Here, we examined whether sevelamer given orally for 12 wk with normal food could restore bone volume (BV) and strength in aged ovariectomized (OVX) rats starting at 4 wk after OVX. Dual-energy x-ray absorptiometry, microcomputerized tomography, and bone histomorphometry analyses showed that OVX animals receiving sevelamer had increased trabecular BV (51%), trabecular number (43%), trabecular thickness (9%), cortical thickness (16%), mineral apposition rate (103%), bone formation rate (25%), and enhanced cortical and trabecular bone mechanical strength as compared with OVX rats. Sevelamer decreased collagen C telopeptide, increased osteocalcin levels, and decreased phosphate and magnesium levels without affecting calcium levels in the blood. Although sevelamer was not absorbed systemically, it stimulated osteoblast differentiation in BM-derived mesenchymal stem cell cultures, as evaluated by alkaline phosphatase positive colony-forming units, and inhibited recombinant human soluble receptor activator of nuclear factor-kappaB ligand-induced osteoclast differentiation, as evaluated by tartrate-resistant acid phosphatase positive cells in bone mineral-hematopoietic stem cell cultures. Surface enhanced laser desorption/ionization time-of-flight mass spectrometry analysis revealed that 69 proteins were differently expressed after OVX, of which 30% (20 of 69) were reversed to sham activity after sevelamer intake. PTH, fibroblast growth factor-23, and cytokine profile in serum were not significantly changed. Together, these results suggest that sevelamer in food increases the BV and improves biomechanical properties of bone in OVX rats.
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http://dx.doi.org/10.1210/en.2008-0205DOI Listing
December 2008

High-resolution infrared studies in slit supersonic discharges: CH2 stretch excitation of jet-cooled CH2Cl radical.

J Chem Phys 2006 Aug;125(5):054303

JILA, National Institute of Standards and Technology and University of Colorado, Boulder, Colorado 80309, USA.

First high-resolution infrared spectra are presented for jet-cooled CH2 35Cl and CH2 37Cl radicals in the symmetric (nu1) CH2 stretching mode. A detailed spectral assignment yields refined lower and upper state rotational constants, as well as fine structure spin-rotation parameters from least-squares fits to the sub-Doppler line shapes for individual transitions. The rotational constants are consistent with a nearly planar structure, but do not exclude substantial large amplitude bending motion over a small barrier to planarity accessible with zero-point excitation. High level coupled cluster (singles/doubles/triples) calculations, extrapolated to the complete basis set limit, predict a slightly nonplanar equilibrium structure (theta approximately 11 degrees), with a vibrationally adiabatic treatment of the bend coordinate yielding a v = 1<--0 anharmonic frequency (393 cm(-1)) in excellent agreement with matrix studies (nu(bend) approximately 400 cm(-1)). The antisymmetric CH2 stretch vibration is not observed despite high sensitivity detection (signal to noise ratio >20:1) in the symmetric stretch band. This is consistent with density functional theory intensity calculations indicating a >35-fold smaller antisymmetric stretch transition moment for CH2Cl, and yet contrasts dramatically with high-resolution infrared studies of CH2F radical, for which both symmetric and antisymmetric CH2 stretches are observed in a nearly 2:1 intensity ratio. A simple physical model is presented based on a competition between bond-dipole and "charge-sloshing" contributions to the transition moment, which nicely explains the trends in CH2X symmetric versus asymmetric stretch intensities as a function of electron withdrawing group (X = D,Br,Cl,F).
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http://dx.doi.org/10.1063/1.2208612DOI Listing
August 2006

Results of a randomized crossover study comparing once-daily and thrice-daily sevelamer dosing.

Am J Kidney Dis 2006 Sep;48(3):437-44

Kidney and Hypertension Center, Cincinnati, OH 45242, USA.

Background: Patients with renal failure require complex regimens of renal replacement therapies and medications, including ingestion of phosphate-binding agents 3 times daily. Previous studies suggested that sevelamer may provide extended phosphate binding and be effective with once-daily dosing, thus simplifying the phosphate-binder regimen.

Methods: Twenty-four patients were enrolled in this study, 21 of whom were randomly assigned to sevelamer administration at their previously prescribed dose, either once daily with the largest meal or thrice daily with meals, with crossover to the other regimen after 4 weeks. Eighteen patients completed both treatment periods. The primary efficacy measure for which the study was powered is comparison of the effect of once-daily versus standard thrice-daily sevelamer dosing on serum phosphorus level control, determined by using equivalence testing. Secondary efficacy measures are the effects of the 2 regimens on serum calcium level corrected for albumin level; calcium x phosphorus product; albumin; intact parathyroid hormone; total, low-density lipoprotein, high-density lipoprotein, and non-high-density lipoprotein cholesterol; and triglyceride levels.

Results: Once-daily sevelamer was as effective as thrice-daily dosing of sevelamer in controlling serum phosphorus, calcium, calcium x phosphorus product, serum albumin, and serum lipid levels. Bioequivalence was not shown for intact parathyroid hormone, likely because of high variability. Mean serum phosphorus levels were 4.6 +/- 0.3 mg/dL (1.49 +/- 0.10 mmol/L) during thrice-daily dosing and 5.0 +/- 0.3 mg/dL (1.61 +/- 0.10 mmol/L) during once-daily dosing. The average prescribed dose of sevelamer during both treatment regimens was 6.7 +/- 2.4 g. Routine laboratory measures were similar in the 2 groups. Both regimens were well-tolerated.

Conclusion: Despite concerted patient-directed educational efforts, phosphorus level control in patients with renal failure is suboptimal and contributes to increased mortality risk. Once-daily sevelamer could simplify these regimens and encourage medication compliance, perhaps improving hyperphosphatemia management.
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http://dx.doi.org/10.1053/j.ajkd.2006.05.026DOI Listing
September 2006

CH stretch/internal rotor dynamics in ethyl radical: high-resolution spectroscopy in the CH3-stretch manifold.

J Chem Phys 2006 Feb;124(5):054316

JILA, University of Colorado, Boulder, Colorado 80309-0440, USA.

High-resolution IR absorption spectra of supersonically cooled ethyl radicals (Trot approximately 20 K) have been obtained in a slit supersonic jet discharge expansion, revealing first rotationally resolved data for CH-stretch excitation of the methyl group. Three different vibrational bands are observed, one parallel (k=0<--0) and two perpendicular (/k/1<--0), which for a nearly decoupled methyl rotor framework would correspond to symmetric and (nearly degenerate) asymmetric CH-stretch excitations. However, the splitting between the two asymmetric CH-stretch excitations is anomalously large (approximately 125 cm(-1)), signaling the presence of interactions between the CH2 radical moiety and the opposing CH bond on the methyl group. This suggests an improved zeroth-order vibrational description as an isolated CH stretch, strongly redshifted by hyperconjugation, with localized vibrations in the remaining CH bonds split into symmetric and asymmetric stretches. Such a dynamical picture highlights a remarkably strong coupling between methyl CH-stretch vibrations and C-C torsional geometry and begins to elucidate discrepancies with previous matrix observations.
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http://dx.doi.org/10.1063/1.2140740DOI Listing
February 2006

Coronary calcification in hemodialysis patients: the contribution of traditional and uremia-related risk factors.

Kidney Int 2005 Apr;67(4):1576-82

Department of Internal Medicine/Division of Nephrology, Federal University of São Paulo, São Paulo, Brazil.

Background: Coronary artery calcification is a common feature of atherosclerosis, occurring in 90% of angiographically significant lesions. There is recent evidence that coronary artery calcification is frequent in hemodialysis patients and it has been suggested that this increased incidence may be associated to uremia-related factors. The development and progression of coronary artery calcification is similar to osteogenesis. The aim of this study was to evaluate the relationship between coronary artery calcification, uremia-related factors, and bone histomorphometry in hemodialysis patients.

Methods: A total of 101 hemodialysis patients were assessed for biochemical markers of inflammation, oxidative stress, and bone metabolism. Subsequently, they were submitted to multislice coronary tomography (MSCT) and transiliac bone biopsy.

Results: The median calcium score was 116.2 (range 0 to 5547). Fifty-two percent of the patients showed moderate and severe coronary artery calcification, 20% had calcium scores greater than 1000. In univariate analysis, age (r= 0.57, P < 0.000001), osteoprotegerin (OPG) (r= 0.44, P= 0.00002), and body mass index (BMI) (r= 0.24, P= 0.01) correlated positively with calcium score. Bone trabecular volume and trabecular thickness correlated negatively with calcium score (r=-0.24, P= 0.02; r=-0.22, P= 0.03). There was a correlation of borderline significance between calcium score and C-reactive protein (CRP) (r= 0.18, P= 0.062). The multiple linear regression analysis identified OPG as the only variable independently associated with coronary artery calcification.

Conclusion: Coronary artery calcification is highly prevalent in the hemodialysis population and is associated with older age, higher BMI, inflammation and reduced trabecular bone volume. Higher OPG is independently associated with coronary artery calcification and may represent an incomplete self-defensive response to the progression of atherosclerosis in hemodialysis patients.
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http://dx.doi.org/10.1111/j.1523-1755.2005.00239.xDOI Listing
April 2005

Effects of sevelamer and calcium-based phosphate binders on uric acid concentrations in patients undergoing hemodialysis: a randomized clinical trial.

Arthritis Rheum 2005 Jan;52(1):290-5

Department of Medicine Research, University of California-San Francisco, UCSF Laurel Heights Suite 430, 3333 California Street, San Francisco, CA 94118-1211, USA.

Objective: Gout affects a large fraction of persons with advanced chronic kidney disease, and hyperuricemia may increase the risk of cardiovascular disease. Several hypouricemic agents are contraindicated in patients with end-stage renal disease. Sevelamer is a nonabsorbed hydrogel that binds phosphorus and bile acids in the intestinal tract. Results of short-term and open-label studies suggest that sevelamer might lower the concentration of uric acid, another organic anion. We undertook this study to test our hypothesis that the reduction in serum uric acid concentration induced by sevelamer would be confirmed in a long-term, randomized, clinical trial comparing sevelamer with calcium-based phosphate binders.

Methods: Two hundred subjects undergoing maintenance hemodialysis were randomly assigned to receive either sevelamer or calcium-based phosphorus binders in an international, multicenter, clinical trial. Data on baseline and end-of-study uric acid concentrations were available in 169 subjects (85%); the change in uric acid concentration from baseline to the end of the study was the outcome of interest.

Results: Baseline clinical characteristics, including mean uric acid concentrations, were similar in subjects randomly assigned to receive sevelamer and calcium-based phosphate binders. The mean change in uric acid concentration (from baseline to the end of the study) was significantly larger in sevelamer-treated subjects (-0.64 mg/dl versus -0.26 mg/dl; P = 0.03). The adjusted mean change in uric acid concentration was more pronounced when the effects of age, sex, diabetes, vintage (time since initiation of dialysis), dialysis dose, and changes in blood urea nitrogen and bicarbonate concentrations were considered (-0.72 mg/dl versus -0.15 mg/dl; P = 0.001). Twenty-three percent of sevelamer-treated subjects experienced a study-related reduction in the concentration of uric acid equal to -1.5 mg/dl or more, compared with 10% of calcium-treated subjects (P = 0.02).

Conclusion: In a randomized clinical trial comparing sevelamer and calcium-based phosphate binders, treatment with sevelamer was associated with a significant reduction in serum uric acid concentrations.
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http://dx.doi.org/10.1002/art.20781DOI Listing
January 2005

Meeting increased demand.

Authors:
Andrew Blair

Jpn Hosp 2004 Jul(23):19-22

New Zealand Private Hospitals Association.

New Zealand is a little country with a little economy but with a population that's rapidly aging. New Zealand's population is only 4.3 million people. It's GDP is only $US58.6 billion (2002). New Zealand's expenditure on health as a percentage of GDP is not out of line with that of other countries. As a nation we have been increasing expenditure on health over recent years. In 1990 we spent 7% of GDP on health. In 1995 that increased to 7.65% and is now 8.3%. However, in per capita terms our expenditure on health does not compare so well with like countries. The size of New Zealand's economy is restricting what our country spends on health. Health is already the second highest demand on the New Zealand tax dollar. The tolerance of New Zealanders would be challenged if a Government attempted to increase taxes further to meet the growing demands for expenditure on health, but at the same time the population's expectations are increasing. This is the challenging situation we face today. What lies ahead? Like all industrialized countries New Zealand is facing an aging population. The population below age 40 is decreasing, but it is increasing significantly over that age. 16% of the population is currently aged over 60. By 2051 this proportion will almost double to just over 31%. Coupled with the aging population is increased awareness and expectations, as access to options for treatment and technology becomes readily accessible to the population through such media as the internet. The extent of the impact of the aging population can be clearly represented by focusing on one specialty such as orthopaedics. The New Zealand Orthopaecic Association undertook a study in July 2003 which concluded (among other things) that as a result of the projected aging of the population, over the next 50 years: Musculo-skeletal operations will increase by over 30%. The number of hip replacements will nearly double. The incidence of osteoporosis will increase by a massive 201%. The number of people affected by arthritis will increase by nearly 50%. A huge increase in numbers affected with musculoskeletal conditions will require significant increases in health care resources, including hospital beds and facilities, orthopaedic surgeons and other health care professionals. New Zealand has been slow to acknowledge and plan for the increased demand for health services which is looming. Growing New Zealand's economy will help, but alone will not be enough. It is more than just finding the financial resources to better meet the demand. The enormous demands on the availability of treatment resources including hospital facilities and trained health care professionals must be addressed. There are major workforce issues to be faced. The change in population distribution between young and old will have an impact and it will be necessary to ensure that there are sufficient numbers of properly trained health care professionals available at all levels. It is hoped that improvements in preventative care programmes and new technologies and treatment techniques may reduce the rate of demand. As the health of our population is improved through targeted programmes dealing with obesity, diabetes, smoking and accident prevention, it may be possible to reallocate or change the focus of resources within the health and hospital sectors. Many countries are developing national strategies for their aging population. Clearly the New Zealand Government needs to move swiftly to develop a plan to manage the increased burden that is developing as a result of the aging population. That plan must create an environment which facilitates, encourages and supports greater private investment in healthcare facilities and healthcare delivery. Incentives must be created to motivate individuals to take greater responsibility for their healthcare needs and the funding of it. The development of a long term strategy to meet the challenges of the aging population is a priority.
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July 2004

Three Cases of Congenital Malformations.

Authors:
Andrew Blair

Trans Edinb Obstet Soc 1875 ;3:136-137

Coupar-Angus.

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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5533346PMC
January 1875