Publications by authors named "Mark Donovan"

36 Publications

Author Correction: Reconstructed Skin Models Revealed Unexpected Differences in Epidermal African and Caucasian Skin.

Sci Rep 2020 Oct 21;10(1):18371. Epub 2020 Oct 21.

L'Oréal Research and Innovation, 1 avenue E. Schueller, 93600, Aulnay-sous-Bois, France.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.
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http://dx.doi.org/10.1038/s41598-020-74970-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7577967PMC
October 2020

Filaggrin and filaggrin 2 processing are linked together through skin aspartic acid protease activation.

PLoS One 2020 21;15(5):e0232679. Epub 2020 May 21.

L'Oréal Research & Innovation, Aulnay-sous-Bois, France.

Skin aspartic acid protease (SASPase) is believed to be a key enzyme involved in filaggrin processing during epidermal terminal differentiation. Since little is known about the regulation of SASPase function, the aim of this study was to identify involved protein partners in the process. Yeast two hybrid analyses using SASPase as bait against a human reconstructed skin library identified that the N-terminal domain of filaggrin 2 binds to the N-terminal fragment of SASPase. This interaction was confirmed in reciprocal yeast two hybrid screens and by Surface Plasmon Resonance analyses. Immunohistochemical studies in human skin, using specific antibodies to SASPase and the N-terminal domain of filaggrin 2, showed that the two proteins partially co-localized to the stratum granulosum. In vitro enzymatic assays showed that the N-terminal domain of filaggrin 2 enhanced the autoactivation of SASPase to its 14 kDa active form. Taken together, the data suggest that the N-terminal domain of filaggrin 2 regulates the activation of SASPase that may be a key event upstream of filaggrin processing to natural moisturizing factors in the human epidermis.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0232679PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7241785PMC
August 2020

Hyaluronic-Acid-Presenting Self-Assembled Nanoparticles Transform a Hyaluronidase HYAL1 Substrate into an Efficient and Selective Inhibitor.

Angew Chem Int Ed Engl 2020 08 3;59(32):13591-13596. Epub 2020 Jun 3.

Univ. Bordeaux, CNRS, Bordeaux INP, LCPO, UMR 5629, 33600, Pessac, France.

In this study, an original method of macromolecular design was used to develop a hyaluronidase-1 (HYAL1) inhibitor from its principal substrate, hyaluronic acid (HA). HA-based nanoparticles (HA-NP) were obtained by copolymer self-assembly and their effects on HYAL1 activity were investigated by combining different analytical tools. Compared to HA, HA-NP exhibited an enhanced stability against HYAL1 degradation while maintaining its interaction with the HA receptors CD44 and aggrecan. HA-NP displayed a strong and selective inhibition of HYAL1 activity and retarded the hydrolysis of higher-molar-mass HA in solution. A co-nanoprecipitation process was used to formulate a range of hybrid nanoparticle samples, which demonstrated the specificity and efficiency of HA-NP in HYAL1 inhibition.
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http://dx.doi.org/10.1002/anie.202005212DOI Listing
August 2020

Reconstructed Skin Models Revealed Unexpected Differences in Epidermal African and Caucasian Skin.

Sci Rep 2019 05 15;9(1):7456. Epub 2019 May 15.

L'Oréal Research and Innovation, 1 avenue E. Schueller, 93600, Aulnay-sous-Bois, France.

Clinical observations of both normal and pathological skin have shown that there is a heterogeneity based on the skin origin type. Beside external factors, intrinsic differences in skin cells could be a central element to determine skin types. This study aimed to understand the in vitro behaviour of epidermal cells of African and Caucasian skin types in the context of 3D reconstructed skin. Full-thickness skin models were constructed with site matched human keratinocytes and papillary fibroblasts to investigate potential skin type related differences. We report that reconstructed skin epidermis exhibited remarkable differences regarding stratification and differentiation according to skin types, as demonstrated by histological appearance, gene expression analysed by DNA microarray and quantitative proteomic analysis. Signalling pathways and processes related to terminal differentiation and lipid/ceramide metabolism were up-regulated in epidermis constructed with keratinocytes from Caucasian skin type when compared to that of keratinocytes from African skin type. Specifically, the expression of proteins involved in the processing of filaggrins was found different between skin models. Overall, we show unexpected differences in epidermal morphogenesis and differentiation between keratinocytes of Caucasian and African skin types in in vitro reconstructed skin containing papillary fibroblasts that could explain the differences in ethnic related skin behaviour.
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http://dx.doi.org/10.1038/s41598-019-43128-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6520399PMC
May 2019

Anisotropic cellular forces support mechanical integrity of the Stratum Corneum barrier.

J Mech Behav Biomed Mater 2019 04 27;92:11-23. Epub 2018 Dec 27.

L'Oréal Research and Innovation, Aulnay-sous-Bois, France. Electronic address:

The protective function of biological surfaces that are exposed to the exterior of living organisms is the result of a complex arrangement and interaction of cellular components. This is the case for the most external cornified layer of skin, the stratum corneum (SC). This layer is made of corneocytes, the elementary 'flat bricks' that are held together through adhesive junctions. Despite the well-known protective role of the SC under high mechanical stresses and rapid cell turnover, the subtleties regarding the adhesion and mechanical interaction among the individual corneocytes are still poorly known. Here, we explore the adhesion of single corneocytes at different depths of the SC, by pulling them using glass microcantilevers, and measuring their detachment forces. We measured their interplanar adhesion between SC layers, and their peripheral adhesion among cells within a SC layer. Both adhesions increased considerably with depth. At the SC surface, with respect to adhesion, the corneocyte population exhibited a strong heterogeneity, where detachment forces differed by more than one order of magnitude for corneocytes located side by side. The measured detachment forces indicated that in the upper-middle layers of SC, the peripheral adhesion was stronger than the interplanar one. We conclude that the stronger peripheral adhesion of corneocytes in the SC favors an efficient barrier which would be able to resist strong stresses.
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http://dx.doi.org/10.1016/j.jmbbm.2018.12.027DOI Listing
April 2019

Multivalent and multifunctional polysaccharide-based particles for controlled receptor recognition.

Sci Rep 2018 10 3;8(1):14730. Epub 2018 Oct 3.

Laboratoire de Chimie des Polymères Organiques, CNRS, Université de Bordeaux INP/ENSCBP, 16 avenue Pey Berland, 33600, Pessac, France.

Polysaccharides represent a versatile class of building blocks that are used in macromolecular design. By choosing the appropriate saccharide block, various physico-chemical and biological properties can be introduced both at the level of the polymer chains and the resulting self-assembled nanostructures. Here, we synthetized amphiphilic diblock copolymers combining a hydrophobic and helical poly(γ-benzyl-L-glutamate) PBLG and two polysaccharides, namely hyaluronic acid (HA) and laminarin (LAM). The copolymers could self-assemble to form particles in water by nanoprecipitation. In addition, hybrid particles containing both HA and LAM in different ratios were obtained by co-nanoprecipitation of the two copolymers. By controlling the self-assembly process, five particle samples with different morphologies and compositions were developed. The interaction between the particles and biologically relevant proteins for HA and LAM, namely CD44 and Dectin-1 respectively, was evaluated by surface plasmon resonance (SPR). We demonstrated that the particle-protein interaction could be modulated by the particle structure and composition. It is therefore suggested that this method based on nanoprecipitation is a practical and versatile way to obtain particles with controllable interactions with proteins, hence with the appropriate biological properties for biomedical applications such as drug delivery.
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http://dx.doi.org/10.1038/s41598-018-32994-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6170371PMC
October 2018

Reassessing Phase II Heart Failure Clinical Trials: Consensus Recommendations.

Circ Heart Fail 2017 Apr;10(4)

From the Department of Medicine, Stony Brook University, NY (J.B., C.E.H.); Division of Cardiology and the CardioVascular Center, Tufts Medical Center, Boston, MA (J.E.U.); Division of Cardiology, Inova Heart & Vascular Institute, Falls Church, VA (C.O'C.); Department of Medicine, Division of Cardiovascular Medicine, Henry Ford Hospital, Detroit, MI (H.N.S.); Division of Cardiology, University of Brescia and Civil Hospital, Italy (M.M.); Division of Cardiology, Northwestern University Feinberg School of Medicine, Chicago, IL (S.J.S., C.Y.); Section on Cardiovascular Medicine, Wake Forest School of Medicine, Winston-Salem, NC (D.W.K.); Division of Cardiology, University of California San Francisco (J.R.T.); Merck & Co., Kenilworth, NJ (H.S.B., J.K.); Gilead Sciences, Foster City, CA (G.B., J.H., C.S.); Amgen Inc., Thousand Oaks, CA (C.D., M.K.); Bristol-Myers Squibb, Princeton, NJ (M.M.D., M.D., R.J.F., P.M., S.M., C.R.); Bayer, Wuppertal, Germany (W.D., M.v.d.L.); Department of Cardiology, HELIOS Clinic Wuppertal, University Hospital Witten/Herdecke, Germany (W.D.); AstraZeneca, Gaithersburg, MD (R.F.-D., J.H., L.-M.G.); AstraZeneca, Gothenburg, Sweden (R.F.-D., J.H., L.-M.G.); Relypsa Inc., Redwood City, CA (D.G., M.M.); Vifor Pharma, Opfikon, Switzerland (U.-M.G.); Department of Cardiology, Nippon Medical School Musashi-Kosugi Hospital, Kawasaki, Japan (S.I.); Novartis Pharmaceuticals Inc., East Hanover, NJ (P.K.-M., V.S.); Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA (C.J.L.); Bayer Pharma AG, Wuppertal, Germany (L.R.); Cardiology Division, Columbia University Medical Center, New York, NY (C.R.); Boehringer Ingelheim Pharmaceuticals Inc, Ridgefield, CT (A.S.); Moderna Therapeutics, Cambridge, MA (B.T.); Division of Cardiovascular and Renal Products, United States Food and Drug Administration, Silver Spring, MD (N.S.); Center for Cardiovascular Innovation, Feinberg School of Medicine, Northwestern University, Chicago, IL (M.G.).

The increasing burden and the continued suboptimal outcomes for patients with heart failure underlines the importance of continued research to develop novel therapeutics for this disorder. This can only be accomplished with successful translation of basic science discoveries into direct human application through effective clinical trial design and execution that results in a substantially improved clinical course and outcomes. In this respect, phase II clinical trials play a pivotal role in determining which of the multitude of potential basic science discoveries should move to the large and expansive registration trials in humans. A critical examination of the phase II trials in heart failure reveals multiple shortcomings in their concept, design, execution, and interpretation. To further a dialogue on the challenges and potential for improvement and the role of phase II trials in patients with heart failure, the Food and Drug Administration facilitated a meeting on October 17, 2016, represented by clinicians, researchers, industry members, and regulators. This document summarizes the discussion from this meeting and provides key recommendations for future directions.
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http://dx.doi.org/10.1161/CIRCHEARTFAILURE.116.003800DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5400283PMC
April 2017

iTRAQ-based quantitative proteomics of stratum corneum of dandruff scalp reveals new insights into its aetiology and similarities with atopic dermatitis.

Arch Dermatol Res 2016 Nov 6;308(9):631-642. Epub 2016 Sep 6.

L'Oreal Research and Innovation, 1 Avenue Eugène Schueller, 93600, Aulnay-Sous-Bois, France.

The study aimed at detecting differentially expressed proteins in the stratum corneum of dandruff versus non-dandruff scalps to better understand dandruff aetiology. iTRAQ-based quantitative proteomic analysis revealed a total of 68 differentially expressed biomarkers. A detailed analysis of their known physiological functions provided new insights into the affected metabolic pathways of a dandruff scalp. Dandruff scalp showed (1) profound changes in the expression and maturation of structural and epidermal differentiation related proteins, that are responsible for the integrity of the skin, (2) altered relevant factors that regulate skin hydration, and (3) an imbalanced physiological protease-protease inhibitor ratio. Stratum corneum proteins with antimicrobial activity, mainly those derived from sweat and sebaceous glands were also found modified. Comparing our data with those reported for atopic dermatitis revealed that about 50 % of the differentially expressed proteins in the superficial layers of the stratum corneum from dandruff and atopic dermatitis are identical.
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http://dx.doi.org/10.1007/s00403-016-1681-4DOI Listing
November 2016

The case for wireless temperature monitoring.

Authors:
Mark Donovan

MLO Med Lab Obs 2016 09;48(9):41

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September 2016

Perforated Stercoral Ulcer: A 10-Year Experience.

J Am Geriatr Soc 2016 Apr;64(4):912-4

Department of Surgery, Santa Barbara Cottage Hospital, Santa Barbara, California.

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http://dx.doi.org/10.1111/jgs.14057DOI Listing
April 2016

Wireless temperature monitoring systems: things to consider.

Authors:
Mark Donovan

MLO Med Lab Obs 2014 Aug;46(8):20

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August 2014

Assessment of the cardiovascular safety of saxagliptin in patients with type 2 diabetes mellitus: pooled analysis of 20 clinical trials.

Cardiovasc Diabetol 2014 Feb 4;13:33. Epub 2014 Feb 4.

Bristol-Myers Squibb, Route 206 & Providence Line Rd, Princeton, NJ 08543, USA.

Background: It is important to establish the cardiovascular (CV) safety profile of novel antidiabetic drugs.

Methods: Pooled analyses were performed of 20 randomized controlled studies (N = 9156) of saxagliptin as monotherapy or add-on therapy in patients with type 2 diabetes mellitus (T2DM) as well as a subset of 11 saxagliptin + metformin studies. Adjudicated major adverse CV events (MACE; CV death, myocardial infarction [MI], and stroke) and investigator-reported heart failure were assessed, and incidence rates (IRs; events/100 patient-years) and IR ratios (IRRs; saxagliptin/control) were calculated (Mantel-Haenszel method).

Results: In pooled datasets, the IR point estimates for MACE and individual components of CV death, MI, and stroke favored saxagliptin, but the 95% CI included 1. IRR (95% CI) for MACE in the 20-study pool was 0.74 (0.45, 1.25). The Cox proportional hazard ratio (95% CI) was 0.75 (0.46, 1.21), suggesting no increased risk of MACE in the 20-study pool. In the 11-study saxagliptin + metformin pool, the IRR for MACE was 0.93 (0.44, 1.99). In the 20-study pool, the IRR for heart failure was 0.55 (0.27, 1.12).

Conclusions: Analysis of pooled data from 20 clinical trials in patients with T2DM suggests that saxagliptin is not associated with an increased CV risk.
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http://dx.doi.org/10.1186/1475-2840-13-33DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3918110PMC
February 2014

Safety of saxagliptin: events of special interest in 9156 patients with type 2 diabetes mellitus.

Diabetes Metab Res Rev 2014 Oct;30(7):556-69

AstraZeneca, Wilmington, DE, USA.

Background: A post hoc pooled analysis was undertaken to evaluate the safety of saxagliptin in patients with type 2 diabetes mellitus, with attention to events of special interest for dipeptidyl peptidase-4 inhibitors.

Methods: Pooled analyses were performed for 20 randomized controlled studies (N = 9156) of saxagliptin as monotherapy or add-on therapy, and a subset of 11 saxagliptin + metformin studies. Adverse events and events of special interest (gastrointestinal adverse events, infections, hypersensitivity, pancreatitis, skin lesions, lymphopenia, thrombocytopenia, hypoglycaemia, bone fracture, severe cutaneous adverse reactions, opportunistic infection, angioedema, malignancy, worsening renal function, and specific laboratory events) were assessed; incidence rates (events/100 person-years) and incidence rates ratios (saxagliptin/control) were calculated (Mantel-Haenszel method).

Results: In both pooled datasets, the incidence rates for deaths, serious adverse events, discontinuations due to adverse events, pancreatitis, malignancy, and most other events of special interest, excepting bone fractures and hypersensitivity, were similar between treatments, with 95% confidence intervals (CIs) for incidence rates ratios including 1. In the 20-study pool, the incidence rates per 100 person-years was higher with saxagliptin versus control for bone fractures [1.1 vs 0.6; incidence rates ratio (95% CI), 1.81 (1.04-3.28)] and hypersensitivity adverse events [1.3 vs 0.8; 1.67 (1.01-2.87)].

Conclusions: Pooled data from 20 studies confirm that saxagliptin has a favourable safety and benefit-risk profile.
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http://dx.doi.org/10.1002/dmrr.2502DOI Listing
October 2014

Calmodulin-like skin protein level increases in the differentiated epidermal layers in atopic dermatitis.

Exp Dermatol 2013 Dec;22(12):836-7

L'Oréal R & I, Aulnay sous Bois, France.

In atopic dermatitis (AD), the skin barrier is disturbed, and the expression of calcium-dependent S100 proteins and the calcium gradient is also altered in the epidermis. The calmodulin-like skin protein (CLSP), which is expressed in the differentiated epidermis, is believed to modulate the function of calcium-dependent proteins involved in barrier formation and is significantly increased in the epidermis of psoriatic patients. We, therefore, investigated the CLSP level in skin biopsies taken from patients with acute exacerbated and non-exacerbated AD as well as from healthy control subjects. Immunohistochemical, Western blot and ELISA analyses showed significant increases (P < 0.03) in CLSP level in the epidermis from patients with acute exacerbated AD as compared to that from patients with non-exacerbated AD and from control subjects. Such increased expression of CLSP may help re-establish a functional epidermal barrier in acute AD.
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http://dx.doi.org/10.1111/exd.12274DOI Listing
December 2013

Saxagliptin add-on therapy to insulin with or without metformin for type 2 diabetes mellitus: 52-week safety and efficacy.

Clin Drug Investig 2013 Oct;33(10):707-17

Diabetes Centre, Heart of England National Health Service Foundation Trust and University of Birmingham, Birmingham, UK.

Background: Achievement of glycemic control is an important objective in the management of type 2 diabetes mellitus (T2DM).

Objective: The objective of this study was to evaluate the safety and efficacy of the dipeptidyl peptidase-4 inhibitor saxagliptin versus placebo as add-on therapy in patients with T2DM inadequately controlled with insulin alone or insulin plus metformin.

Methods: This was a long-term (28-week) extension of a short-term (24-week), randomized, double-blind, parallel-group trial of saxagliptin 5 mg once daily versus placebo as add-on therapy to open-label insulin or insulin plus metformin therapy totaling 52 weeks of treatment. In contrast with the goal of maintaining a stable insulin dosage during the short-term phase, during the extension phase the insulin dosage was flexible and adjusted as deemed appropriate by the investigator. The study was conducted in a clinical practice setting, including family practice and hospital sites. Patients with T2DM aged 18-78 years with glycated hemoglobin (HbA1c) 7.5-11 % on a stable insulin regimen (30-150 U/day with or without metformin) for ≥8 weeks at screening were included in the study. Patients were stratified by metformin use and randomly assigned 2:1 to oral saxagliptin 5 mg (n = 304) or placebo (n = 151) once daily. All patients who completed the initial 24 weeks of treatment were eligible to participate in the 28-week extension, regardless of whether they had required rescue treatment. The main outcome measure was change in HbA1c from baseline to week 52.

Results: In general, the outcomes achieved at week 24 were sustained to week 52. Adjusted mean change from baseline HbA1c at week 52 was greater with saxagliptin (-0.75 %) versus placebo (-0.38 %); the adjusted between-group difference was -0.37 % (95 % CI -0.55 to -0.19); between-group differences were similar in patients treated with metformin (-0.37 % [95 % CI -0.59 to -0.15]) and without metformin (-0.37 % [95 % CI -0.69 to -0.04]). At week 52, a greater proportion of patients receiving saxagliptin achieved HbA1c <7 % than those receiving placebo (21.3 vs. 8.7 %; between-group difference 12.6 % [95 % CI 6.1-19.1]). The increase from baseline in mean total daily insulin dose at week 52 was numerically smaller with saxagliptin (5.67 vs 6.67 U with placebo; difference, -1.01 U [95 % CI -3.24 to 1.22]). During the 52-week study period, the proportion of patients reporting ≥1 adverse event (AE) was 66.4 % with saxagliptin and 71.5 % with placebo, the majority being mild or moderate in intensity. The most common AEs (≥5 % with saxagliptin or placebo) were urinary tract infection, nasopharyngitis, upper respiratory tract infection, headache, influenza, and pain in extremity; the incidence of each AE was similar between treatment groups. In the saxagliptin and placebo groups, the incidence of reported hypoglycemia was 22.7 and 26.5 %, respectively; the incidence of confirmed hypoglycemia (fingerstick glucose ≤50 mg/dL [≤2.77 mmol/L] with characteristic symptoms) was 7.6 and 6.6 %, respectively. Adjusted mean change from baseline body weight was +0.8 kg with saxagliptin and +0.5 kg with placebo.

Conclusion: Saxagliptin 5 mg once daily as add-on to insulin, with or without concomitant metformin, produced a durable improvement in glycemic control and was well tolerated over 52 weeks of treatment.
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http://dx.doi.org/10.1007/s40261-013-0107-8DOI Listing
October 2013

Proteomic analysis identifies new biomarkers for postmenopausal and dry skin.

Exp Dermatol 2012 Mar;21(3):205-10

L'Oréal Research and Innovation, Clichy, France.

A proteomic analysis of stratum corneum (SC) samples of normal healthy skin revealed the presence of more than 70 proteins by 2D electrophoresis. The majority of these proteins to our knowledge have not yet been described in normal SC. We analysed by Western blot the levels of 25 proteins in the SC taken from postmenopausal and dry skin compared with young and normal skin, respectively. In postmenopausal skin, there was a significantly increased amount of heat shock protein 27, plakoglobin and desmoglein 1, whereas transglutaminase 3, apolipoprotein D and acid ceramidase levels were significantly reduced compared with the SC of young skin. We confirmed corneodesmosin as a marker of dry skin. In addition, we showed for the first time that the levels of both phosphatidylethanolamine-binding protein 1 and annexin A2 were significantly increased in the SC of dry skin compared with the SC of normal skin. These results suggest that a proteomic analysis of the SC obtained using a non-invasive varnish stripping method is an attractive alternative to invasive methods to better characterize changes in the physiology of ageing and dry skin.
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http://dx.doi.org/10.1111/j.1600-0625.2011.01434.xDOI Listing
March 2012

Effect of saxagliptin as add-on therapy in patients with poorly controlled type 2 diabetes on insulin alone or insulin combined with metformin.

Curr Med Res Opin 2012 Apr 1;28(4):513-23. Epub 2012 Mar 1.

University of Birmingham and BioMedical Research Centre, Heart of England National Health Service Foundation Trust, Birmingham, UK.

Objective: To evaluate efficacy and safety of saxagliptin as add-on therapy in patients with type 2 diabetes (T2D) with inadequate glycemic control on insulin alone or combined with metformin.

Methods: Adults (n = 455) with HbA(1c) 7.5-11% on stable insulin therapy (30-150 U/day ± metformin) for at least 8 weeks were stratified by metformin use and randomly assigned 2:1 to receive saxagliptin 5 mg or placebo once daily for 24 weeks. Patients were to maintain stable insulin doses but these could be decreased to reduce risk of hypoglycemia. Patients with hyperglycemia or substantially increased insulin use were rescued with a flexible insulin regimen and remained in the study. Metformin doses were kept stable. The primary efficacy endpoint was change in HbA(1c) from baseline to week 24 (or rescue).

Results: Patients treated with saxagliptin versus placebo had significantly greater reductions in adjusted mean HbA(1c) (difference: -0.41%, p < 0.0001), postprandial glucose (PPG) 180-minute area under the curve (-3829.8 mg·min/dL, p = 0.0011), and 120-minute PPG (-23.0 mg/dL, p = 0.0016) at 24 weeks. Treatment with saxagliptin resulted in similar reductions in HBA(1c) relative to placebo, irrespective of metformin treatment. At 24 weeks, difference in adjusted mean fasting plasma glucose for saxagliptin versus placebo was -4.02 mg/dL (p = 0.3958); 17.3% and 6.7% of patients in the saxagliptin and placebo groups, respectively, achieved HbA(1c) < 7%. Mean change from baseline in body weight at week 24 was 0.39 kg for saxagliptin and 0.18 kg for placebo. Hypoglycemia was reported in 18.4% and 19.9% of patients in the saxagliptin and placebo groups, respectively (confirmed hypoglycemia: 5.3%, 3.3%). Other adverse events reported in at least 5% of patients were urinary tract infection (saxagliptin, placebo: 5.9%, 6.0%), influenza (3.0%, 6.6%), and pain in extremity (1.6%, 6.0%).

Conclusions: Saxagliptin 5-mg once-daily add-on therapy improves glycemic control in T2D patients on insulin alone or combined with metformin and is generally well-tolerated. NCT00757588.
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http://dx.doi.org/10.1185/03007995.2012.665046DOI Listing
April 2012

Efficacy and safety of saxagliptin combination therapy in US patients with type 2 diabetes.

Postgrad Med 2011 Jul;123(4):63-70

Global Clinical Research, Bristol-Myers Squibb, Princeton, NJ 08543, USA.

Background: The mechanism of action of dipeptidyl peptidase-4 inhibitors, such as saxagliptin, makes them suitable for combination therapy in type 2 diabetes mellitus (T2DM). Genetic, cultural, and environmental differences in individuals from different regions of the world may result in differences in treatment response to oral antidiabetic drugs (OADs). This post-hoc subanalysis assessed the efficacy and safety of saxagliptin as add-on therapy to metformin, glyburide, or a thiazolidinedione in patients with inadequately controlled T2DM in the United States.

Methods: In 3 phase 3 studies of patients with T2DM uncontrolled on monotherapy, 547 adult US patients were randomized to receive saxagliptin (2.5 or 5 mg/d) or placebo as add-on to metformin, glyburide, or a thiazolidinedione (pioglitazone or rosiglitazone). Efficacy was assessed as the change from baseline to week 24 in glycated hemoglobin (HbA1c), fasting plasma glucose (FPG), and postprandial glucose area under the curve (PPG-AUC) and the proportion of patients achieving HbA1c<7.0%. Pooled safety and tolerability data across trials were also analyzed.

Results: Reductions from baseline to week 24 in HbA1c were observed in all saxagliptin treatment groups versus placebo: saxagliptin 2.5 or 5 mg plus metformin (mean difference from placebo, -0.87% and -0.89%, respectively), glyburide (-0.51% and -0.52%), or thiazolidinedione (-0.45% and -0.60%). Improvement was also observed in FPG and PPG-AUC. Adverse events for the US cohort were consistent with previously reported data from the 3 trials. The pooled incidence of reported hypoglycemia was 5.3% and 11.4% with saxagliptin 2.5 and 5 mg/d add-on, respectively, versus 6.8% with placebo add-on.

Conclusions: This post-hoc analysis in a cohort of US patients with T2DM uncontrolled on monotherapy suggests that saxagliptin 2.5 or 5 mg as add-on therapy to OADs results in improvement across key glycemic parameters compared with placebo add-on and was generally safe and well tolerated.
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http://dx.doi.org/10.3810/pgm.2011.07.2305DOI Listing
July 2011

Detection of corneodesmosin on the surface of stratum corneum using atomic force microscopy.

Exp Dermatol 2010 Nov;19(11):1014-9

Institute for Biophysics, University of Linz, Linz, Austria.

Corneodesmosin, a protein known to be present in the stratum corneum (SC), plays an important role in its physical integrity. Here, a specific antibody to corneodesmosin was tethered via a flexible linker to an atomic force microscopy tip, and the interaction forces between this tip and the surface of the SC were successfully measured. Using the recently developed technique of simultaneous topography and recognition imaging, we were able to map the distribution of corneodesmosin on the surface of the SC at the nanoscale.
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http://dx.doi.org/10.1111/j.1600-0625.2010.01179.xDOI Listing
November 2010

Surgonomics of unruptured intracranial aneurysms.

J Neurointerv Surg 2010 Jun;2(2):168-70

Department of Neurosurgery, Cedars-Sinai Medical Center, Los Angeles, CA, USA.

Background/aims: A comparison of reimbursement for endovascular coil embolization and surgical clipping of unruptured aneurysms has not been previously reported. The aim of this study is to assess the reimbursement to physicians and hospitals for each of these two unruptured aneurysm treatments with long-term follow-up.

Methods: Hospital and physician payents were determined for 14 patients treated with coil embolization or surgical clipping of a single unruptured aneurysm per patient from 2004 to 2005, retrospectively. For this analysis, each considered hospital and physician payment encompassed one clipping or coiling procedure plus all pre- and post-operative diagnostic angiograms performed through 2007 to evaluate the treated aneurysm. Reimbursements were analyzed in three categories: physician payments, hospital payments and total payments.

Results: Average physician payments were significantly lower for coil embolization ($3422) than surgical clipping ($5645). Average length of stay after coil embolization was 2.6 days (range: 1-7) and after surgical clipping was 4.7 days (range: 2-11). The length of hospital stay directly affected hospital and total payments only, but was not significantly altered by which procedure was performed.

Conclusion: This study suggests that physician payment for an unruptured aneurysm coil embolization treatment was statistically lower than for a surgical clip treatment. Although physicians were compensated at a lower rate for performing a coil embolization, there was no significant difference in the hospital or total payments between coil or clip treatment modalities.
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http://dx.doi.org/10.1136/jnis.2009.001065DOI Listing
June 2010

A systematic assessment of cardiovascular outcomes in the saxagliptin drug development program for type 2 diabetes.

Postgrad Med 2010 May;122(3):16-27

Bristol-Myers Squibb, Princeton, NJ 08543, USA.

Objective: The objective was to assess the relative risk (RR) for cardiovascular (CV) events across all 8 randomized phase 2/3 trials evaluating saxagliptin in patients with type 2 diabetes mellitus.

Methods: Cardiovascular events (death, myocardial infarction [MI], stroke, revascularization procedures, and cardiac ischemia) were reported by investigators through standard adverse event reporting procedures and were systematically identified. Post hoc blinded adjudication of all deaths, MIs, and strokes was performed using prespecified endpoint definitions by an independent clinical events committee (CEC).

Results: A total of 4607 randomized and treated patients (n = 3356 treated with saxagliptin [2.5-100 mg/d]; n = 1251, comparator [n = 656, placebo; n = 328, metformin; n = 267, uptitrated glyburide]) were included. The median ages were 54 years (saxagliptin) and 55 years (comparator) (interquartile range, 47-61 each); 51% were female, 73% were white, 52% were hypertensive, 44% had hypercholesterolemia, 39% had a smoking history, 20% had a first-degree family member with premature coronary heart disease, and 12% had prior CV disease. Cardiovascular events were experienced by 61 patients (38 [1.1%], saxagliptin; 23 [1.8%], comparator), and CV death/MI/stroke events were reported by investigators in 41 patients: 23 (0.7%), saxagliptin; 18 (1.4%), comparator (relative risk, 95% confidence interval [CI], 0.44 [0.24-0.82]). The CEC reviewed 147 patients with potential CV events and identified a total of 40 patients with CV death/MI/stroke: 22 (0.7%), saxagliptin; 18 (1.4%), comparator (RR, 0.43 [0.23-0.80]). Component proportions for CV death, MI, and stroke were (saxagliptin vs comparator): 7 (0.2%) vs 10 (0.8%), 8 (0.2%) vs 8 (0.6%), and 11 (0.3%) vs 5 (0.4%), respectively.

Conclusion: No increased risk of CV death/MI/stroke was observed in patients randomly assigned saxagliptin across a broad drug development program. Although this systematic overview has inherent and important limitations, the data support a potential reduction in CV events with saxagliptin. The hypothesis of CV protection with saxagliptin will be tested prospectively in a large randomized clinical outcome trial evaluating saxagliptin compared with standard of care in patients with type 2 diabetes at increased risk for CV events.
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http://dx.doi.org/10.3810/pgm.2010.05.2138DOI Listing
May 2010

Baseline plasma NT-proBNP and clinical characteristics: results from the irbesartan in heart failure with preserved ejection fraction trial.

J Card Fail 2010 Feb 4;16(2):128-34. Epub 2009 Nov 4.

McMaster University and Hamilton Health Sciences, Hamilton, ON, Canada.

Background: N-terminal B type natriuretic peptide (NT-proBNP) is usually elevated in heart failure (HF) patients with reduced ejection fraction (EF). Less is known about NT-proBNP in HF with preserved EF (HF-PEF). We measured baseline NT-proBNP in 3562 HF-PEF enrolled patients in the Irbesartan in Heart Failure with Preserved Ejection Fraction trial.

Methods And Results: Patients with EF >or=45%, age >or=60 years, and either New York Heart Association (NYHA) II-IV symptoms with HF hospitalization (HFH) within 6 months or NYHA III-IV symptoms with corroborative evidence of HF or structural changes associated with HF-PEF. NT-proBNP (pg/mL) measured centrally using the Elecsys proBNP assay (Roche). Mean age 72 +/- 7 years, 60% were women, the investigator indicated HF etiology was hypertension in 64%; the majority were in NYHA III. Medications included diuretics in 82%, angiotensin-converting enzyme inhibitor in 26%, beta-blocker in 59%, and spironolactone in 15%. Median NT-proBNP was 341 pg/mL (interquartile range 135 to 974 pg/mL) and geometric mean was 354 pg/mL. In multivariate analysis, the baseline characteristics most strongly associated with higher NT-proBNP levels were atrial fibrillation (ratio of geometric mean 2.59, P < .001), NYHA IV symptoms (1.52, P < .001), lower estimated glomerular filtration rate (1.44, P < .001), and HFH hospitalization within 6 months (1.37, P < .001).

Conclusions: Most HF-PEF patients have elevated NT-proBNP levels. The NT-proBNP concentrations were related to baseline characteristics generally associated with worse outcomes for HF patients.
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http://dx.doi.org/10.1016/j.cardfail.2009.09.007DOI Listing
February 2010

Clinical and immunohistochemical features associated with a response to bortezomib in patients with multiple myeloma.

Clin Cancer Res 2009 Jan;15(2):714-22

Clinical Haematology/Bone Marrow Transplant Department, The Alfred Hospital, Commercial Road, Prahran, Melbourne, Victoria, Australia 3181.

Purpose: Multiple myeloma is an incurable disease with heterogeneous clinical behavior. Bortezomib has offered some patients with relapsed and refractory disease an opportunity for prolonged survival. However, there remains a paucity of data in patients treated with bortezomib that accurately delineates and identifies such patients. This information is crucial to guide management.

Experimental Design: In this study, we aimed to identify the patients most likely to respond to bortezomib salvage therapy. We analyzed the baseline clinical variables and profiled the baseline expression of a broad range of immunohistochemical markers of cell cycle activity, apoptosis, and angiogenesis in a large cohort of multiply relapsed myeloma patients recruited to one of two prospective multicentre trials assessing the efficacy of bortezomib salvage therapy.

Results: Using the European Group for Bone Marrow Transplantation criteria, response (complete or partial) to bortezomib salvage therapy was associated with a previous history of complete response to alternative antimyeloma treatment. Patients who expressed cyclin D1 were more likely to achieve a response. In contrast, patients who expressed p16(INK4A), cytoplasmic p53, and the highest intensity of Bcl-2 staining had a poor response. Patients who achieved a response to bortezomib and those patients who expressed cyclin D1 at baseline showed a significant survival advantage. Patients who expressed FGFR3, a poor prognostic marker, responded equally well and had similar outcomes with bortezomib compared with FGFR3-negative patients.

Conclusions: Baseline clinical variables and selective immunohistochemical markers expressed by patients may be used effectively to identify patients that are most likely to achieve a meaningful clinical response to bortezomib salvage therapy.
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http://dx.doi.org/10.1158/1078-0432.CCR-08-1022DOI Listing
January 2009

Irbesartan in patients with heart failure and preserved ejection fraction.

N Engl J Med 2008 Dec 11;359(23):2456-67. Epub 2008 Nov 11.

University of California, San Francisco, and San Francisco Veterans Affairs Medical Center, San Francisco 94121, USA.

Background: Approximately 50% of patients with heart failure have a left ventricular ejection fraction of at least 45%, but no therapies have been shown to improve the outcome of these patients. Therefore, we studied the effects of irbesartan in patients with this syndrome.

Methods: We enrolled 4128 patients who were at least 60 years of age and had New York Heart Association class II, III, or IV heart failure and an ejection fraction of at least 45% and randomly assigned them to receive 300 mg of irbesartan or placebo per day. The primary composite outcome was death from any cause or hospitalization for a cardiovascular cause (heart failure, myocardial infarction, unstable angina, arrhythmia, or stroke). Secondary outcomes included death from heart failure or hospitalization for heart failure, death from any cause and from cardiovascular causes, and quality of life.

Results: During a mean follow-up of 49.5 months, the primary outcome occurred in 742 patients in the irbesartan group and 763 in the placebo group. Primary event rates in the irbesartan and placebo groups were 100.4 and 105.4 per 1000 patient-years, respectively (hazard ratio, 0.95; 95% confidence interval [CI], 0.86 to 1.05; P=0.35). Overall rates of death were 52.6 and 52.3 per 1000 patient-years, respectively (hazard ratio, 1.00; 95% CI, 0.88 to 1.14; P=0.98). Rates of hospitalization for cardiovascular causes that contributed to the primary outcome were 70.6 and 74.3 per 1000 patient-years, respectively (hazard ratio, 0.95; 95% CI, 0.85 to 1.08; P=0.44). There were no significant differences in the other prespecified outcomes.

Conclusions: Irbesartan did not improve the outcomes of patients with heart failure and a preserved left ventricular ejection fraction. (ClinicalTrials.gov number, NCT00095238.)
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http://dx.doi.org/10.1056/NEJMoa0805450DOI Listing
December 2008

Use of simulation to compare the performance of minimization with stratified blocked randomization.

Pharm Stat 2009 Oct-Dec;8(4):264-78

Covance, Statistical Sciences, Maidenhead, Berkshire, UK.

Minimization is an alternative method to stratified permuted block randomization, which may be more effective at balancing treatments when there are many strata. However, its use in the regulatory setting for industry trials remains controversial, primarily due to the difficulty in interpreting conventional asymptotic statistical tests under restricted methods of treatment allocation. We argue that the use of minimization should be critically evaluated when designing the study for which it is proposed. We demonstrate by example how simulation can be used to investigate whether minimization improves treatment balance compared with stratified randomization, and how much randomness can be incorporated into the minimization before any balance advantage is no longer retained. We also illustrate by example how the performance of the traditional model-based analysis can be assessed, by comparing the nominal test size with the observed test size over a large number of simulations. We recommend that the assignment probability for the minimization be selected using such simulations.
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http://dx.doi.org/10.1002/pst.346DOI Listing
February 2010

Heparanase 1: a key participant of inner root sheath differentiation program and hair follicle homeostasis.

Exp Dermatol 2008 Dec 14;17(12):1017-23. Epub 2008 Jun 14.

L'Oréal Recherche, Clichy, France.

Heparanase is a heparan sulphate endo-glycosidase which was previously detected in the outer root sheath of murine hair follicles. Heparanase overexpression was reported to improve mouse hair (re)growth. In this study, we investigated its involvement in human hair biology. Immunofluorescence detection was used to explore heparanase distribution in both anagen and catagen hair follicles. Heparanase functionality was assessed in in vitro cultured hair follicles, in the presence of a heparanase activity inhibitor. Our results showed that heparanase expression was (i) primarily located in the inner root sheath (IRS) of human hair follicle, and there (ii) restricted to anagen phase. Furthermore, inhibition of heparanase in in vitro cultured hair follicles induced a catagen-like process. Hair shaft retreat upward was accompanied by a decrease in Ki67-positive cells, the formation of an epithelial strand as evidenced by K14 keratin expression, and the loss of IRS as assessed by transglutaminase 1 and desmoglein labelling. IRS distribution of heparanase and the induction of catagen-like involution of hair follicles when a potent heparanase inhibitor is added suggest that heparanase is a key actor of IRS differentiation and hair homeostasis.
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http://dx.doi.org/10.1111/j.1600-0625.2008.00739.xDOI Listing
December 2008

Heart failure with preserved ejection fraction: clinical characteristics of 4133 patients enrolled in the I-PRESERVE trial.

Eur J Heart Fail 2008 Feb;10(2):149-56

Department of Cardiology, Western Infirmary, Glasgow, and Faculty of Medicine, University of Glasgow, Scotland, UK.

Background: We describe the baseline characteristics of subjects randomised in the largest placebo-controlled, morbidity-mortality trial to date in patients with heart failure and preserved ejection fraction - the irbesartan in heart failure with preserved systolic function trial (I-PRESERVE).

Methods And Results: 4133 patients with a mean age of 72 years (a third were 75 years or older) were randomised and 60% were women. The mean (SD) LVEF was 59 (9)% and almost 80% of patients were in NYHA Class III or IV. Approximately 80% of patients were also overweight or obese. Heart failure was reported by investigators to have a hypertensive aetiology in 64% of patients. Prior myocardial infarction was relatively uncommon (24%), as was coronary revascularisation (13%). Atrial fibrillation and diabetes each occurred in between a quarter and a third of patients. The following treatments were used at baseline: diuretic 83%, beta-blocker 59%, calcium channel blocker 40%, ACE inhibitor 25%, spironolactone 15% and digoxin 14%.

Conclusions: Patients in I-PRESERVE are broadly representative of those seen in epidemiological studies and, because of this, the results of this trial should be generally applicable to "real world" patients with heart failure and preserved ejection fraction.
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http://dx.doi.org/10.1016/j.ejheart.2007.12.010DOI Listing
February 2008

Initial combination therapy with irbesartan/hydrochlorothiazide for hypertension: an analysis of the relationship between baseline blood pressure and the need for combination therapy.

J Clin Hypertens (Greenwich) 2007 Dec;9(12 Suppl 5):15-22

University of California-Irvine, 155 Barlock Avenue, Los Angeles, CA 90049, USA.

Hypertension treatment guidelines recommend initiating 2-drug therapy whenever blood pressure (BP) is > or =20 mm Hg systolic or > or =10 mm Hg diastolic above goal. This post hoc pooled analysis of 2 multicenter, randomized, double-blind, active-controlled forced-titration studies in 1235 patients with moderate and severe hypertension examined how baseline BP levels relate to the need for combination therapy by comparing the antihypertensive efficacy and tolerability of once-daily fixed-dose irbesartan/hydrochlorothiazide (HCTZ) 300/25 mg compared with irbesartan 300-mg or HCTZ 25-mg monotherapies. In study 1, patients with severe hypertension (seated diastolic BP [SeDBP] > or =110 mm Hg) were treated for 7 weeks with irbesartan or irbesartan/HCTZ combination therapy, with forced-titration after week 1. In study 2, patients with moderate hypertension (seated systolic BP [SeSBP] 160-180 mm Hg or SeDBP 100-110 mm Hg) were treated for 12 weeks with irbesartan/HCTZ, irbesartan monotherapy, or HCTZ monotherapy, with forced-titration after week 2. The relationship between baseline BP and the likelihood of achieving BP goals (SeSBP <140 mm Hg or SeDBP <90 mm Hg; SeSBP <130 mm Hg or SeDBP <80 mm Hg) as well as the antihypertensive response was evaluated at week 7/8. The need for combination therapy increased with increasing baseline BP and lower BP goals across the range of BP levels studied, with a comparable adverse effect profile to monotherapy. These results suggest that the likelihood of achieving an early BP goal for a given BP severity should be considered when choosing initial combination therapy vs monotherapy.
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http://dx.doi.org/10.1111/j.1524-6175.2007.07808.xDOI Listing
December 2007

Predicting event times in clinical trials when randomization is masked and blocked.

Clin Trials 2007 ;4(5):481-90

Pharmaceutical Research Institute, Bristol-Myers Squibb Company, Pennington, NJ 08534, USA.

Background: Timing for interim or final analysis of data in an event-based trial is often determined by the accrual of events during the study. Existing Bayesian methods may be used to predict the date of the landmark event using observed enrollment, event, and loss times when treatment arm information is masked.

Purpose: For event-based trials with a blocked randomization, knowledge of blocks in which patients are enrolled can provide additional information to improve predictions versus models that only assume a known treatment allocation proportion. We therefore propose to incorporate blocking information into existing methods for prediction.

Methods: We derive a latent variable (LV) extension of a mixture model used in Donovan JM, Elliott MR, Heitjan DF. Predicting Event Times in Clinical Trials When Treatment Arm is Masked. J Biopharmaceut Stat 2006; 16:343-56 to incorporate block randomization (constrained LV) for predicting the landmark event and compare this model with (a) methods where blocking information is ignored (unconstrained LV), and (b) methods assuming a single population (SP).

Results: Comparison of the constrained and unconstrained LV models in our application shows that the constrained LV model has narrower prediction intervals. Simulation studies show that the constrained LV model can have better coverage probabilities for the prediction intervals than SP models if a treatment effect is present, and prediction intervals from the constrained LV model are narrower than those for the unconstrained LV model. These differences varied by block size and prediction time.

Limitations: We have limited focus to the exponential model for events. Coverage for the LV models may be somewhat reduced if no treatment effect is present.

Conclusions: Extra information provided by knowledge of blocking can be used to decrease prediction interval width versus the unconstrained LV model, while providing better coverage properties than the SP model if a treatment effect is present.
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http://dx.doi.org/10.1177/1740774507083390DOI Listing
February 2008

Predicting event times in clinical trials when treatment arm is masked.

J Biopharm Stat 2006 May;16(3):343-56

Center for Clinical Epidemiology and Biostatistics, Department of Biostatistics and Epidemiology, University of Pennsylvania School of Medicine, Philadelphia 19104-6021, USA.

Because power is primarily determined by the number of events in event-based clinical trials, the timing for interim or final analysis of data is often determined based on the accrual of events during the course of the study. Thus, it is of interest to predict early and accurately the time of a landmark interim or terminating event. Existing Bayesian methods may be used to predict the date of the landmark event, based on current enrollment, event, and loss to follow-up, if treatment arms are known. This work extends these methods to the case where the treatment arms are masked by using a parametric mixture model with a known mixture proportion. Posterior simulation using the mixture model is compared with methods assuming a single population. Comparison of the mixture model with the single-population approach shows that with few events, these approaches produce substantially different results and that these results converge as the prediction time is closer to the landmark event. Simulations show that the mixture model with diffuse priors can have better coverage probabilities for the prediction interval than the nonmixture models if a treatment effect is present.
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http://dx.doi.org/10.1080/10543400600609445DOI Listing
May 2006