Publications by authors named "Richard Weiss"

227 Publications

Structural Alterations of Antigens at the Material Interface: An Early Decision Toolbox Facilitating Safe-by-Design Nanovaccine Development.

Int J Mol Sci 2021 Oct 8;22(19). Epub 2021 Oct 8.

Department of Biosciences, University of Salzburg, 5020 Salzburg, Austria.

Nanomaterials have found extensive interest in the development of novel vaccines, as adjuvants and/or carriers in vaccination platforms. Conjugation of protein antigens at the particle surface by non-covalent adsorption is the most widely used approach in licensed particulate vaccines. Hence, it is essential to understand proteins' structural integrity at the material interface in order to develop safe-by-design nanovaccines. In this study, we utilized two model proteins, the wild-type allergen Bet v 1 and its hypoallergenic fold variant (BM4), to compare SiO nanoparticles with Alhydrogel as particulate systems. A set of biophysical and functional assays including circular dichroism spectroscopy and proteolytic degradation was used to examine the antigens' structural integrity at the material interface. Conjugation of both biomolecules to the particulate systems decreased their proteolytic stability. However, we observed qualitative and quantitative differences in antigen processing concomitant with differences in their fold stability. These changes further led to an alteration in IgE epitope recognition. Here, we propose a toolbox of biophysical and functional in vitro assays for the suitability assessment of nanomaterials in the early stages of vaccine development. These tools will aid in safe-by-design innovations and allow fine-tuning the properties of nanoparticle candidates to shape a specific immune response.
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http://dx.doi.org/10.3390/ijms221910895DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8509464PMC
October 2021

Development and validation of a one year predictive model for secondary fractures in osteoporosis.

PLoS One 2021 27;16(9):e0257246. Epub 2021 Sep 27.

Department of Epidemiology, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America.

The number of osteoporosis-related fractures in the United States is no longer declining. Existing risk-based assessment tools focus on long-term risk. Payers and prescribers need additional tools to identify patients at risk for imminent fracture. We developed and validated a predictive model for secondary osteoporosis fractures in the year following an index fracture using administrative medical and pharmacy claims from the Optum Research Database and Symphony Health, PatientSource. Patients ≥50 years with a case-qualifying fracture identified using a validated claims-based algorithm were included. Logistic regression models were created with binary outcome of a second fracture versus no second fracture within a year of index fracture, with the goal of predicting second fracture occurrence. In the Optum Research Database, 197,104 patients were identified with a case-qualifying fracture (43% commercial, 57% Medicare Advantage). Using Symphony data, 1,852,818 met the inclusion/exclusion criteria. Average patient age was 70.09 (SD = 11.09) and 71.28 (SD = 14.24) years in the Optum Research Database and Symphony data, respectively. With the exception of history of falls (41.26% vs 18.74%) and opioid use (62.80% vs 46.78%), which were both higher in the Optum Research Database, the two populations were mostly comparable. A history of falls and steroid use, which were previously associated with increased fracture risk, continue to play an important role in secondary fractures. Conditions associated with bone health (liver disease), or those requiring medications that impact bone health (respiratory disease), and cardiovascular disease and stroke-which may share etiology or risk factors with osteoporosis fractures-were also predictors of imminent fractures. The model highlights the importance of assessment of patient characteristics beyond bone density, including patient comorbidities and concomitant medications associated with increased fall and fracture risk, in alignment with recently issued clinical guidelines for osteoporosis treatment.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0257246PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8475984PMC
September 2021

Benzil Photoperoxidations in Polymer Films and Crosslinking by the Resultant Benzoyl Peroxides in Polystyrene and Other Polymers.

Molecules 2021 Aug 25;26(17). Epub 2021 Aug 25.

Department of Chemistry, Institute for Soft Matter Synthesis and Metrology, Georgetown University, Washington, DC 20057, USA.

Benzil () can be converted almost quantitatively to benzoyl peroxide () in aerated polymer films upon irradiation at >400 nm (i.e., the long-wavelength edge of the → absorption band of , where does not absorb). Here, we summarize results for the photoperoxidation of structures with molecular oxygen, principally in glassy polymer matrices. Some of the polymers are doped directly with or its derivatives, and others, contain covalently attached pendant groups from which groups are derived. While the decomposition of low-molecular-weight doped into polymer films (such as those of polystyrene (PS)) results in a net decrease in polymer molecular weight, thermal decomposition of pendant groups is an efficient method for chain crosslinking. Crosslinking of PS films doped with a molecule containing two covalently linked or groups proceeds in a similar fashion. Free radicals from the covalently attached allow grafting of new monomers, as well. Additionally, the use of radiation filtered through masks has been used to create patterns of polymers on solid surfaces. Crosslinking of photodegradable poly(phenyl vinyl ketone) with structures obtained by photoperoxidation of structures for the preparation of photodegradable polymer networks is described as well. In sum, the use of and and their derivatives offers simple and convenient routes for modifying polymer chains and, especially, for crosslinking them. Specific applications of each use and process are provided. Although applications with PS are featured here, the methodologies described are amenable to a wide variety of other polymers.
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http://dx.doi.org/10.3390/molecules26175154DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8434379PMC
August 2021

Laser facilitated epicutaneous peptide immunization using dry patch technology.

Vaccine 2021 08 4;39(37):5259-5264. Epub 2021 Aug 4.

University of Salzburg, Department of Biosciences, Salzburg, Austria. Electronic address:

The skin has been intensely investigated as a target tissue for immunization because it is populated by multiple types of antigen presenting cells. Directly addressing dendritic cells or Langerhans cells in vivo represents an attractive strategy for inducing T cell responses in cancer immunotherapy. We and others have studied fractional laser ablation as a novel method combining efficient delivery of macromolecules to the skin with an inherent adjuvant effect of laser illumination. In this proof of concept study, we demonstrate the feasibility of peptide delivery to the skin using the P.L.E.A.S.E. professional Erb:YAG fractional infrared laser together with EPIMMUN patches. In an ovalbumin mouse model we demonstrate that a dry patch formulation of SIINFEKL peptide in combination with CpG-ODN1826, but not imiquimod or polyI:C, induces potent cytotoxic T cell responses, which can be further boosted by co-delivery of the pan-helper T cell epitope PADRE.
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http://dx.doi.org/10.1016/j.vaccine.2021.07.083DOI Listing
August 2021

Laser-facilitated epicutaneous immunization of mice with SARS-CoV-2 spike protein induces antibodies inhibiting spike/ACE2 binding.

Vaccine 2021 07 26;39(32):4399-4403. Epub 2021 Jun 26.

University of Salzburg, Department of Biosciences, Salzburg, Austria. Electronic address:

The skin represents an attractive target tissue for vaccination against respiratory viruses such as SARS-CoV-2. Laser-facilitated epicutaneous immunization (EPI) has been established as a novel technology to overcome the skin barrier, which combines efficient delivery via micropores with an inherent adjuvant effect due to the release of danger-associated molecular patterns. Here we delivered the S1 subunit of the Spike protein of SARS-CoV-2 to the skin of BALB/c mice via laser-generated micropores with or without CpG-ODN1826 or the B subunit of heat-labile enterotoxin of E.coli (LT-B). EPI induced serum IgG titers of 1:3200 that could be boosted 5 to 10-fold by co-administration of LT-B and CpG, respectively. Sera were able to inhibit binding of the spike protein to its receptor ACE2. Our data indicate that delivery of recombinant spike protein via the skin may represent an alternative route for vaccines against Covid-19.
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http://dx.doi.org/10.1016/j.vaccine.2021.06.068DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8233963PMC
July 2021

Thiol- and Disulfide-Based Stimulus-Responsive Soft Materials and Self-Assembling Systems.

Molecules 2021 Jun 1;26(11). Epub 2021 Jun 1.

Department of Chemistry, Georgetown University, Washington, DC 20057, USA.

Properties and applications of synthetic thiol- and disulfide-based materials, principally polymers, are reviewed. Emphasis is placed on soft and self-assembling materials in which interconversion of the thiol and disulfide groups initiates stimulus-responses and/or self-healing for biomedical and non-biomedical applications.
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http://dx.doi.org/10.3390/molecules26113332DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8199128PMC
June 2021

Gender Disparities in Osteoporosis Screening and Management Among Older Adults.

Adv Ther 2021 07 30;38(7):3872-3887. Epub 2021 May 30.

Department of Pharmacy Administration, University of Mississippi School of Pharmacy, University, MS, USA.

Introduction: One in two women and one in four men experience an osteoporosis-related fracture in their lifetime. Related morbidity and mortality rates are higher in men versus women. Current guidelines are inconsistent in the screening recommendations for osteoporosis in men. Examination of gender disparities in the management of osteoporosis-related fractures among Medicare enrollees is currently lacking.

Methods: In this retrospective cohort study using 5% National Medicare claims data from January 1, 2012 through December 31, 2016, eligible patients who were at least 65 years of age on the date of a new fracture episode were classified into two mutually exclusive cohorts on the basis of whether they received testing and/or treatment for osteoporosis in the 6-month period after the new fracture episode. The cohorts were defined on the basis of the National Committee for Quality Assurance (NCQA) quality measure "osteoporosis management in women who had a fracture." Patients were followed to identify the occurrence of subsequent fracture, all-cause mortality, and a composite outcome-defined as the first occurrence of either subsequent fracture or mortality. Logistic regression models were carried out to identify predictors of testing and/or treatment and time-varying survival analysis to identify the relationship between the presence of testing and/or treatment and patient outcomes.

Results: Of the 35,774 eligible patients, only 10.2% (12.1% women and 5.7% men) received osteoporosis testing and/or treatment within 6 months after a fracture. The interaction between gender and fragility fracture was significant (P < 0.0001). Fragility fracture had greater adjusted odds of testing and/or treatment among men (adjusted odds ratio [AOR] 3.47; 95% CI 2.94-4.10) than women (AOR 1.65; 95% CI 1.53-1.79). Of patients who were eligible for the outcome assessment, 27.5% experienced a subsequent fracture, 23.2% died, and 44.3% experienced a composite outcome during follow-up. Patients who received testing and/or treatment had a significantly lower hazard of all-cause mortality (hazard ratio [HR] 0.57; 95% CI 0.50-0.65; P < 0.0001) and the composite outcome (HR 0.42; 95% CI 0.39-0.45; P < 0.0001), but no difference in the risk of subsequent fracture (HR 1.02; 95% CI 0.94-1.11; P = 0.6083). Men were found to have a significantly lower hazard of subsequent fracture (HR 0.69; 95% CI 0.64-0.73; P < 0.0001), all-cause mortality (HR 0.67; 95% CI 0.61-0.72; P < 0.0001), and the composite outcome (HR 0.69; 95% CI 0.65-0.73; P < 0.0001).

Conclusion: Testing and/or treatment for osteoporosis among older adults with a fracture is poor in the Medicare fee-for-service population overall and worse for men compared to women. Receiving appropriate testing and/or treatment was associated with reduced mortality and the risk of composite outcome. Improving osteoporosis testing and/or treatment and reducing health disparities are essential for managing the clinical and economic burden of osteoporosis in the USA.
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http://dx.doi.org/10.1007/s12325-021-01792-wDOI Listing
July 2021

Risk Factors for Incident Fracture in Older Adults With Type 2 Diabetes: The Framingham Heart Study.

Diabetes Care 2021 May 17. Epub 2021 May 17.

Hinda and Arthur Marcus Institute for Aging Research, Hebrew SeniorLife, Boston, MA.

Objective: To identify risk factors for fracture in type 2 diabetes.

Research Design And Methods: This prospective study included members of the Framingham Original and Offspring Cohorts. Type 2 diabetes was defined as fasting plasma glucose >125 mg/dL or use of type 2 diabetes therapy. We used repeated-measures Cox proportional hazards regression to calculate hazard ratios (HRs) and 95% CIs for associations between potential predictors and incidence of fragility fracture.

Results: Participants included 793 individuals with type 2 diabetes. Mean ± SD age was 70 ± 10 years; 45% were women. A total of 106 incident fractures occurred over 1,437 observation follow-up intervals. Fracture incidence increased with age (adjusted HRs 1.00, 1.44 [95% CI 0.65, 3.16], and 2.40 [1.14, 5.04] for <60, 60-70, and >70 years, respectively; = 0.02), female sex (2.23 [1.26, 3.95]), HbA (1.00, 2.10 [1.17, 3.75], and 1.29 [0.69, 2.41] for 4.45-6.46% [25-47 mmol/mol], 6.50-7.49% [48-58 mmol/mol], and 7.50-13.86% [58-128 mmol/mol]; =0.03), falls in past year (1.00, 1.87 [0.82, 4.28], and 3.29 [1.34, 8.09] for no falls, one fall, and two or more falls; =0.03), fracture history (2.05 [1.34, 3.12]), and lower grip strength (0.82 [0.69, 0.99] per 5-kg increase). Femoral neck bone mineral density, BMI, smoking, physical function, chronic diseases, medications, and physical function were not associated with fracture incidence.

Conclusions: Prior falls, fractures, low grip strength, and elevated HbA are risk factors for fractures in older adults with type 2 diabetes. Evaluation of these factors may improve opportunities for early intervention and reduce fractures in this high-risk group.
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http://dx.doi.org/10.2337/dc20-3150DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8323187PMC
May 2021

Gold nanoparticles (AuNPs) impair LPS-driven immune responses by promoting a tolerogenic-like dendritic cell phenotype with altered endosomal structures.

Nanoscale 2021 Apr;13(16):7648-7666

Department of Biosciences, Paris-Lodron University Salzburg, Hellbrunner Str. 34, 5020 Salzburg, Austria.

Dendritic cells (DCs) shape immune responses by influencing T-cell activation. Thus, they are considered both an interesting model for studying nano-immune interactions and a promising target for nano-based biomedical applications. However, the accentuated ability of nanoparticles (NPs) to interact with biomolecules may have an impact on DC function that poses an unexpected risk of unbalanced immune reactions. Here, we investigated the potential effects of gold nanoparticles (AuNPs) on DC function and the consequences for effector and memory T-cell responses in the presence of the microbial inflammatory stimulus lipopolysaccharide (LPS). Overall, we found that, in the absence of LPS, none of the tested NPs induced a DC response. However, whereas 4-, 8-, and 11 nm AuNPs did not modulate LPS-dependent immune responses, 26 nm AuNPs shifted the phenotype of LPS-activated DCs toward a tolerogenic state, characterized by downregulation of CD86, IL-12 and IL-27, upregulation of ILT3, and induction of class E compartments. Moreover, this DC phenotype was less proficient in promoting Th1 activation and central memory T-cell proliferation. Taken together, these findings support the perception that AuNPs are safe under homeostatic conditions; however, particular care should be taken in patients experiencing a current infection or disorders of the immune system.
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http://dx.doi.org/10.1039/d0nr09153gDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8087175PMC
April 2021

Abaloparatide Real-World Patient Experience Study.

JBMR Plus 2021 Mar 4;5(3):e10457. Epub 2021 Feb 4.

Health Economics and Outcomes Research Radius Health, Inc. Waltham, MA USA.

Despite the availability of various osteoporosis treatments, adherence remains suboptimal. One contributing factor may be patient experience with therapy. This US, multicenter, combined retrospective chart review and patient questionnaire study included postmenopausal women at high risk for fracture and is the first study to describe real-world patient experience with abaloparatide (ABL) injection. Eight geographically diverse secondary care sites in the United States participated ( = 193). Mean ± SD age was 67.4 ±8.62 years. Most patients (86%) were satisfied with the ABL regimen, especially with ease of preparation (82%), ease of storage (87%), and storage convenience (89%), an attribute 83% of the patients thought was important. The majority of patients reported complete satisfaction with the ABL regimen allowing for their ability to conduct daily activities (85%) and convenience to fit into their daily schedule (84%). All reported taking ABL as directed, by injection in the lower abdomen, and 83% of patients reported medium or high adherence. Patients were satisfied with the needle size (76% completely satisfied), and 93% reported never deliberately missing a dose. Although injecting medication (18%) and higher out-of-pocket costs (17%) were deemed the most bothersome attributes, the majority (69%) noted their healthcare team understands how osteoporosis impacts their lives. In multivariable analyses, ease of preparation (OR = 2.62; 95% CI, 1.01-6.81; = 0.048) and fracture history (OR = 1.72; 95% CI, 1.03-2.86; = 0.037) were significantly associated with overall satisfaction. Ease of preparation was a predictor of higher satisfaction with treatment convenience (coefficient = 13.60; 95% CI, 8.08-19.12; = 0.00). Remembering to take the medication was a significant predictor of self-reported adherence (OR = 16.66; 95% CI, 3.30-84.24; = 0.001). In conclusion, the majority of patients were satisfied with ABL and found it convenient/easy to prepare and store. High self-reported adherence may be associated with positive patient experience including ease of use and adequate support from healthcare providers. © 2020 The Authors. published by Wiley Periodicals LLC. on behalf of American Society for Bone and Mineral Research.
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http://dx.doi.org/10.1002/jbm4.10457DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7990148PMC
March 2021

Luminescent Behavior of Gels and Sols Comprised of Molecular Gelators.

Gels 2021 Feb 17;7(1). Epub 2021 Feb 17.

Department of Chemistry and Institute for Soft Matter Synthesis and Metrology, Georgetown University, Washington, DC 20057, USA.

We present a brief review of some important conceptual and practical aspects for the design and properties of molecular luminescent gelators and their gels. Topics considered include structural and dynamic aspects of the gels, including factors important to their ability to emit radiation from electronically excited states.
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http://dx.doi.org/10.3390/gels7010019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8005951PMC
February 2021

Phase 1b Evaluation of Abaloparatide Solid Microstructured Transdermal System (Abaloparatide-sMTS) in Postmenopausal Women with Low Bone Mineral Density.

Clin Drug Investig 2021 Mar 27;41(3):277-285. Epub 2021 Feb 27.

Radius Health, Inc., (Clinical Development), 22 Boston Wharf Road, Boston, MA, 02210, USA.

Background And Objective: Abaloparatide, an anabolic osteoporosis treatment administered by subcutaneous (SC) injection, increases bone mineral density (BMD) and reduces fracture risk in postmenopausal women with osteoporosis. The abaloparatide-solid Microstructured Transdermal System [abaloparatide-sMTS (Kindeva, St Paul, MN, USA)], which delivers abaloparatide intradermally, is in development to provide an alternative method for abaloparatide delivery. The objective of this study was to evaluate the ability of subjects to self-administer abaloparatide-sMTS, based on pharmacokinetic and pharmacodynamic markers.

Methods: In this single-arm, open-label, Phase 1b study, 22 healthy postmenopausal women aged 50-85 years with low BMD were trained to self-administer abaloparatide-sMTS 300 μg once daily to the thigh for 5 min for 29 days. The primary endpoint was systemic exposure to abaloparatide. Secondary endpoints included percent change from baseline in serum procollagen type I N-terminal propeptide (s-PINP), patient experience, and safety.

Results: All 22 subjects completed the study. At baseline, mean age was 65.2 years, mean total hip T-score was - 1.32, and mean lumbar spine T-score was - 1.98. On Day 1, the median time to reach maximum concentration (T) for abaloparatide-sMTS was 0.33 h and geometric mean (CV %) maximum concentration (C) and area under the concentration-time curve from time 0 to the time of the last quantifiable concentration (AUC) were 447 (38.0) pg/mL and 678 (45.3) pg·h/mL, respectively; the pharmacokinetic profile was similar on Days 15 and 29. Median percentage change in s-PINP was 45.4% and 64.4% at Days 15 and 29, respectively. The most common adverse events (AEs) were application site erythema, pain, and swelling, which were mostly of mild or moderate severity. No AEs led to study drug withdrawal and no serious AEs were reported. The success rate for self-administration at first application was 99.7%, and subject acceptability was high (~ 4.5 on a 5-point Likert Scale).

Conclusions: Subjects successfully self-administered abaloparatide-sMTS, which provided a consistent pharmacokinetic profile over 29 days and produced s-PINP increases from baseline similar to that observed in the pivotal trial with abaloparatide-SC. Observed patient experience along with the clinical data support continued clinical development of abaloparatide-sMTS.

Trial Registration Number: NCT04366726, Date of registration 04/29/2020, retrospectively registered.
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http://dx.doi.org/10.1007/s40261-021-01008-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7946681PMC
March 2021

Triple bubble sign of jejunal atresia.

Abdom Radiol (NY) 2021 07 27;46(7):3512-3514. Epub 2021 Feb 27.

Division of Radiology, Connecticut Children's Medical Center, Hartford, CT, 06106, USA.

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http://dx.doi.org/10.1007/s00261-021-02974-4DOI Listing
July 2021

Features of a rare peripheral primitive neuroectodermal tumour arising from the thoracic spine in a juvenile canine patient.

Vet Med Sci 2021 05 23;7(3):680-685. Epub 2021 Feb 23.

Department of Radiology, Auburn University, College of Veterinary Medicine, Auburn, AL, USA.

Peripheral primitive neuroectodermal tumours are rare tumours in juveniles. The current patient was a paraplegic 8-month-old Scottish deerhound with a suspected pulmonary mass. Radiographically, there was a large extrapleural mass within the mid-left hemithorax. On MRI, the mass was mainly hyperintense on T2-weighted images, isointense on T1-weighted images and was heterogeneously strongly contrast enhancing with a multilobulated appearance, spinal cord compression, paraspinal musculature invasion and intrathoracic extension. Those changes were confirmed on post-mortem, and the mass diagnosed based on immunohistochemistry.
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http://dx.doi.org/10.1002/vms3.449DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8136921PMC
May 2021

NMR spectral fingerprint patterns as diagnostics for the unambiguous configurational analysis of the classic organo-gelator 1,3:2,4-dibenzylidene-d-sorbitol (DBS) and its derivatives.

Magn Reson Chem 2021 06 18;59(6):608-613. Epub 2021 Jan 18.

Departmento de Química Orgánica and Agrupación Estratéxica CITACA, Universidade de Vigo, Vigo, 36310, Spain.

On the basis of experimental data and density functional theory (DFT) chemical shift and scalar coupling predictions, simple spectral nuclear magnetic resonance (NMR) fingerprint patterns have been established for the determination of the configuration in 1,3:2,4-dibenzylidene-d-sorbitol (DBS), a classic low molecular weight gelator, and its derivatives. The results rigorously prove the orientation of the phenyl rings in DBS that had been previously assumed in the literature on the basis of thermodynamic arguments.
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http://dx.doi.org/10.1002/mrc.5124DOI Listing
June 2021

Functionalized multifunctional nanovaccine for targeting dendritic cells and modulation of immune response.

Int J Pharm 2021 Jan 3;593:120123. Epub 2020 Dec 3.

Department of Pharmacy, Biopharmaceutics and Pharmaceutical Technology, Saarland University, Saarbrücken, Germany. Electronic address:

Multifunctional gelatin nanoparticles modified by NIR-emitting gold/silver alloy nanoclusters and loaded with ovalbumin (OVA) as a model antigen were developed. Two different designs of nanoparticles were introduced; positively charged NPs with OVA displayed over the surface (S-NPs) versus OVA encapsulated in the NPs' matrix and the surface is functionalized by dextran (Dex-NPs) for dendritic cell targeting. The nanoparticles showed average particle sizes of 210 and 305 nm and zeta potentials of +25.6 and -23.9 mV, for S-NPs and Dex-NPs, respectively. Both types of NPs succeeded to induce maturation of murine bone marrow-derived dendritic cells (BMDCs) as indicated by the upregulated surface expression of MHC-II and co-stimulatory molecules CD86, CD80 and CD40. Dex-NPs induced no cytotoxicity in BMDCs, in contrast to S-NPs. Functionalization of NPs with dextran increased their uptake by BMDCs, enhanced secretion of immune stimulatory chemokines, and boosted their T cell stimulation capacity. Co-culture of NP loaded BMDCs with OVA-specific CD4 or CD8 T cells, induced enhanced T cell proliferation and release of IL-2 from both CD8 and CD4 cells and IFN-γ from CD8 T cells. This highlights the potential of the developed NPs as vaccines for inducing T helper 1 type CD4 as well as CD8 responses, such as vaccines for cancer or viral infections.
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http://dx.doi.org/10.1016/j.ijpharm.2020.120123DOI Listing
January 2021

Economic Burden of Osteoporosis-Related Fractures in the US Medicare Population.

Ann Pharmacother 2021 07 4;55(7):821-829. Epub 2020 Nov 4.

University of Alabama at Birmingham, Birmingham, AL, USA.

Background: Osteoporosis-related fractures are an important public health burden.

Objective: To examine health care costs in Medicare patients with an osteoporosis-related fracture.

Methods: Medicare fee-for-service members with an osteoporosis-related fracture between January 1, 2010, to September 30, 2014 were included. A nonfracture comparator group was selected by propensity score matching. Generalized linear models using a gamma distribution were used to compare costs between fracture and nonfracture cohorts.

Results: A total of 885 676 Medicare beneficiaries had fracture(s) and met inclusion criteria. Average age was 80.5 (±8.4) years; 91% were White, and 94% female. Mean all-cause costs were greater in the fracture vs nonfracture cohort ($47 163.25 vs $16 034.61) overall and for men ($52 273.79 vs $17 352.68). The highest mean costs were for skilled nursing facility ($29 216), inpatient costs ($24 190.19), and hospice care ($20 996.83). The highest incremental costs versus the nonfracture cohort were for hip ($71 057.83 vs $16 807.74), spine ($37 543.87 vs $16 860.49), and radius/ulna ($24 505.27 vs $14 673.86). Total medical and pharmacy costs for patients who experienced a second fracture were higher compared with those who did not ($78 137.59 vs $44 467.47). Proportionally more patients in the fracture versus nonfracture cohort died (18% vs 9.3%), with higher death rates among men (20% vs 11%).

Conclusion And Relevance: The current findings suggest a significant economic burden associated with fractures. Early identification and treatment of patients at high risk for fractures is of paramount importance for secondary prevention and reduced mortality.
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http://dx.doi.org/10.1177/1060028020970518DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8135238PMC
July 2021

Towards middle-up analysis of polyclonal antibodies: subclass-specific N-glycosylation profiling of murine immunoglobulin G (IgG) by means of HPLC-MS.

Sci Rep 2020 10 22;10(1):18080. Epub 2020 Oct 22.

Department of Biosciences, Bioanalytical Research Labs, University of Salzburg, Hellbrunner Straße 34, 5020, Salzburg, Austria.

In recent years, advanced HPLC-MS strategies based on intact protein ("top-down") or protein subunit ("middle-up/middle-down") analysis have been implemented for the characterization of therapeutic monoclonal antibodies. Here, we assess feasibility of middle-up/middle-down analysis for polyclonal IgGs exhibiting extensive sequence variability. Specifically, we addressed IgGs from mouse, representing an important model system in immunological investigations. To obtain Fc/2 portions as conserved subunits of IgGs, we made use of the bacterial protease SpeB. For this purpose, we initially determined SpeB cleavage sites in murine IgGs. The resulting Fc/2 portions characteristic of different subclasses were subsequently analysed by ion-pair reversed-phase HPLC hyphenated to high-resolution mass spectrometry. This enabled simultaneous relative quantification of IgG subclasses and their N-glycosylation variants, both of which influence IgG effector functions. To assess method capabilities in an immunological context, we applied the analytical workflow to polyclonal antibodies obtained from BALB/c mice immunized with the grass pollen allergen Phl p 6. The study revealed a shift in IgG subclasses and Fc-glycosylation patterns in total and antigen-specific IgGs from different mouse cohorts, respectively. Eventually, Fc/2 characterization may reveal other protein modifications including oxidation, amino acid exchanges, and C-terminal lysine, and may thus be implemented for quality control of functional antibodies.
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http://dx.doi.org/10.1038/s41598-020-75045-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7581757PMC
October 2020

Design of Phl p 6 Variants With Altered Fold-Stability Significantly Impacts Antigen Processing, Immunogenicity and Immune Polarization.

Front Immunol 2020 18;11:1824. Epub 2020 Aug 18.

Department of Biosciences, University of Salzburg, Salzburg, Austria.

Understanding, which factors determine the immunogenicity and immune polarizing properties of proteins, is an important prerequisite for designing better vaccines and immunotherapeutics. While extrinsic immune modulatory factors such as pathogen associated molecular patterns are well-understood, far less is known about the contribution of protein inherent features. Protein fold-stability represents such an intrinsic feature contributing to immunogenicity and immune polarization by influencing the amount of peptide-MHC II complexes (pMHCII). Here, we investigated how modulation of the fold-stability of the grass pollen allergen Phl p 6 affects its ability to stimulate immune responses and T cell polarization. MAESTRO software was used for prediction of stabilizing or destabilizing point mutations. Mutated proteins were expressed in , and their thermal stability and resistance to endolysosomal proteases was determined. Resulting peptides were analyzed by mass spectrometry. The structure of the most stable mutant protein was assessed by X-ray crystallography. We evaluated the capacity of the mutants to stimulate T cell proliferation , as well as antibody responses and T cell polarization in an adjuvant-free BALB/c mouse model. In comparison to wild-type protein, stabilized or destabilized mutants displayed changes in thermal stability ranging from -5 to +14°. While highly stabilized mutants were degraded very slowly, destabilization led to faster proteolytic processing . This was confirmed in BMDCs, which processed and presented the immunodominant epitope from a destabilized mutant more efficiently compared to a highly stable mutant. , stabilization resulted in a shift in immune polarization from TH2 to TH1/TH17 as indicated by higher levels of IgG2a and increased secretion of TNF-α, IFN-γ, IL-17, and IL-21. MAESTRO software was very efficient in detecting single point mutations that increase or reduce fold-stability. Thermal stability correlated well with the speed of proteolytic degradation and presentation of peptides on the surface of dendritic cells . This change in processing kinetics significantly influenced the polarization of T cell responses . Modulating the fold-stability of proteins thus has the potential to optimize and polarize immune responses, which opens the door to more efficient design of molecular vaccines.
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http://dx.doi.org/10.3389/fimmu.2020.01824DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7461793PMC
April 2021

Mechanisms of Particles in Sensitization, Effector Function and Therapy of Allergic Disease.

Front Immunol 2020 30;11:1334. Epub 2020 Jun 30.

Division of Allergy and Immunology, Department of Biosciences, University of Salzburg, Salzburg, Austria.

Humans have always been in contact with natural airborne particles from many sources including biologic particulate matter (PM) which can exhibit allergenic properties. With industrialization, anthropogenic and combustion-derived particles have become a major fraction. Currently, an ever-growing number of diverse and innovative materials containing engineered nanoparticles (NPs) are being developed with great expectations in technology and medicine. Nanomaterials have entered everyday products including cosmetics, textiles, electronics, sports equipment, as well as food, and food packaging. As part of natural evolution humans have adapted to the exposure to particulate matter, aiming to protect the individual's integrity and health. At the respiratory barrier, complications can arise, when allergic sensitization and pulmonary diseases occur in response to particle exposure. Particulate matter in the form of plant pollen, dust mites feces, animal dander, but also aerosols arising from industrial processes in occupational settings including diverse mixtures thereof can exert such effects. This review article gives an overview of the allergic immune response and addresses specifically the mechanisms of particulates in the context of allergic sensitization, effector function and therapy. In regard of the first theme (i), an overview on exposure to particulates and the functionalities of the relevant immune cells involved in allergic sensitization as well as their interactions in innate and adaptive responses are described. As relevant for human disease, we aim to outline (ii) the potential effector mechanisms that lead to the aggravation of an ongoing immune deviation (such as asthma, chronic obstructive pulmonary disease, etc.) by inhaled particulates, including NPs. Even though adverse effects can be exerted by (nano)particles, leading to allergic sensitization, and the exacerbation of allergic symptoms, promising potential has been shown for their use in (iii) therapeutic approaches of allergic disease, for example as adjuvants. Hence, allergen-specific immunotherapy (AIT) is introduced and the role of adjuvants such as alum as well as the current understanding of their mechanisms of action is reviewed. Finally, future prospects of nanomedicines in allergy treatment are described, which involve modern platform technologies combining immunomodulatory effects at several (immuno-)functional levels.
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http://dx.doi.org/10.3389/fimmu.2020.01334DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7344151PMC
April 2021

IL-31 transgenic mice show reduced allergen-induced lung inflammation.

Eur J Immunol 2021 01 21;51(1):191-196. Epub 2020 Jul 21.

Department of Biosciences, University of Salzburg, Salzburg, Austria.

Interleukin-31 (IL-31) is a Th2 cell-derived cytokine that has been closely linked to pruritic skin inflammation. More recently, enhanced IL-31 serum levels have also been observed in patients with allergic rhinitis and allergic asthma. Therefore, the main aim of this study was to unravel the contribution of IL-31 to allergen-induced lung inflammation. We analyzed lung inflammation in response to the timothy grass (Phleum pratense) pollen allergen Phl p 5 in C57BL/6 wild-type (wt) mice, IL-31 transgenic (IL-31tg) mice, and IL-31 receptor alpha-deficient animals (IL-31RA ). IL-31 and IL-31RA levels were monitored by qRT-PCR. Cellular infiltrate in bronchoalveolar lavage fluid (BALF) and lung tissue inflammation, mucus production as well as epithelial thickness were measured by flow cytometry and histomorphology. While allergen challenge induced IL-31RA expression in lung tissue of wt and IL-31tg mice, high IL-31 expression was exclusively observed in lung tissue of IL-31tg mice. Upon Phl p 5 challenge, IL-31tg mice showed reduced numbers of leukocytes and eosinophils in BALF and lung tissue as well as diminished mucin expression and less pronounced epithelial thickening compared to IL-31RA or wt animals. These findings suggest that the IL-31/IL-31RA axis may regulate local, allergen-induced inflammation in the lungs.
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http://dx.doi.org/10.1002/eji.202048547DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7818168PMC
January 2021

Laser-facilitated epicutaneous immunotherapy with hypoallergenic beta-glucan neoglycoconjugates suppresses lung inflammation and avoids local side effects in a mouse model of allergic asthma.

Allergy 2021 01 16;76(1):210-222. Epub 2020 Jul 16.

Department of Biosciences, University of Salzburg, Salzburg, Austria.

Background: Allergen-specific immunotherapy via the skin targets a tissue rich in antigen-presenting cells, but can be associated with local and systemic side effects. Allergen-polysaccharide neoglycogonjugates increase immunization efficacy by targeting and activating dendritic cells via C-type lectin receptors and reduce side effects.

Objective: We investigated the immunogenicity, allergenicity, and therapeutic efficacy of laminarin-ovalbumin neoglycoconjugates (LamOVA).

Methods: The biological activity of LamOVA was characterized in vitro using bone marrow-derived dendritic cells. Immunogenicity and therapeutic efficacy were analyzed in BALB/c mice. Epicutaneous immunotherapy (EPIT) was performed using fractional infrared laser ablation to generate micropores in the skin, and the effects of LamOVA on blocking IgG, IgE, cellular composition of BAL, lung, and spleen, lung function, and T-cell polarization were assessed.

Results: Conjugation of laminarin to ovalbumin reduced its IgE binding capacity fivefold and increased its immunogenicity threefold in terms of IgG generation. EPIT with LamOVA induced significantly higher IgG levels than OVA, matching the levels induced by s.c. injection of OVA/alum (SCIT). EPIT was equally effective as SCIT in terms of blocking IgG induction and suppression of lung inflammation and airway hyperresponsiveness, but SCIT was associated with higher levels of therapy-induced IgE and TH2 cytokines. EPIT with LamOVA induced significantly lower local skin reactions during therapy compared to unconjugated OVA.

Conclusion: Conjugation of ovalbumin to laminarin increased its immunogenicity while at the same time reducing local side effects. LamOVA EPIT via laser-generated micropores is safe and equally effective compared to SCIT with alum, without the need for adjuvant.
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http://dx.doi.org/10.1111/all.14481DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7818228PMC
January 2021

Epidermal activation of Hedgehog signaling establishes an immunosuppressive microenvironment in basal cell carcinoma by modulating skin immunity.

Mol Oncol 2020 09 21;14(9):1930-1946. Epub 2020 Jul 21.

Department of Biosciences, Cancer Cluster Salzburg, Paris-Lodron University Salzburg, Austria.

Genetic activation of hedgehog/glioma-associated oncogene homolog (HH/GLI) signaling causes basal cell carcinoma (BCC), a very frequent nonmelanoma skin cancer. Small molecule targeting of the essential HH effector Smoothened (SMO) has proven an effective therapy of BCC, though the frequent development of drug resistance poses major challenges to anti-HH treatments. In light of recent breakthroughs in cancer immunotherapy, we analyzed the possible immunosuppressive mechanisms in HH/GLI-induced BCC in detail. Using a genetic mouse model of BCC, we identified profound differences in the infiltration of BCC lesions with cells of the adaptive and innate immune system. Epidermal activation of Hh/Gli signaling led to an accumulation of immunosuppressive regulatory T cells, and to an increased expression of immune checkpoint molecules including programmed death (PD)-1/PD-ligand 1. Anti-PD-1 monotherapy, however, did not reduce tumor growth, presumably due to the lack of immunogenic mutations in common BCC mouse models, as shown by whole-exome sequencing. BCC lesions also displayed a marked infiltration with neutrophils, the depletion of which unexpectedly promoted BCC growth. The study provides a comprehensive survey of and novel insights into the immune status of murine BCC and serves as a basis for the design of efficacious rational combination treatments. This study also underlines the need for predictive immunogenic mouse models of BCC to evaluate the efficacy of immunotherapeutic strategies in vivo.
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http://dx.doi.org/10.1002/1878-0261.12758DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7463314PMC
September 2020

Efficacy and Safety of Vandetanib in Progressive and Symptomatic Medullary Thyroid Cancer: Post Hoc Analysis From the ZETA Trial.

J Clin Oncol 2020 08 25;38(24):2773-2781. Epub 2020 Jun 25.

Department of Nuclear Medicine and Endocrine Oncology, Gustave Roussy, Université Paris Saclay, Villejuif, France.

Purpose: We conducted a post hoc analysis of the vandetanib phase III trial involving patients with advanced medullary thyroid cancer (MTC) to assess the efficacy and safety of vandetanib in patients with progressive and symptomatic MTC. The primary objective of the analysis was to determine progression-free survival (PFS) of these patients.

Patients And Methods: Eligible patients from the ZETA trial were divided into 4 disease severity subgroups: progression and symptoms, symptoms only, progression only, and no progression and no symptoms assessed at baseline. PFS, determined from objective tumor measurements performed by the local investigator, overall survival (OS), time to worsening of pain (TWP), and objective response rate (ORR) were evaluated.

Results: Of the 331 patients in this trial, 184 had symptomatic and progressive disease at baseline. In this subgroup, results were similar in magnitude to those observed in the overall trial for PFS (hazard ratio [HR], 0.43; 95% CI, 0.28 to 0.64; < .0001), OS (HR, 1.08; 95% CI, 0.72 to 1.61; = .71), and TWP (HR, 0.67; 95% CI, 0.43 to 1.04; = .07), and the observed adverse events were consistent with the known safety profile of vandetanib. In this subgroup, the ORR was 37% in the treatment arm versus 2% in the placebo arm.

Conclusion: Vandetanib demonstrated clinical benefit-specifically, increased PFS-in patients with symptomatic and progressive MTC.
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http://dx.doi.org/10.1200/JCO.19.02790DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7430220PMC
August 2020

Effect of Abaloparatide on Bone Mineral Density and Fracture Incidence in a Subset of Younger Postmenopausal Women with Osteoporosis at High Risk for Fracture.

Clin Ther 2020 06 6;42(6):1099-1107.e1. Epub 2020 Jun 6.

School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA.

Purpose: Current treatment guidelines recommend treatment for postmenopausal women with a T score <2.5 regardless of age. This subgroup analysis evaluated the efficacy and safety of abaloparatide in younger postmenopausal women considered to be at high risk for fracture.

Methods: Subgroup analysis of women in the Abaloparatide Comparator Trial in Vertebral Endpoints (ACTIVE) trial who were <65 years old and met modified utilization management criteria (baseline T score ≤-2.5 [any site] and ≥1 prevalent vertebral and/or ≥1 prior clinical fracture within 5 years of randomization).

Findings: A total of 296 women (age range, 49-64 years) were included. Significant increases in bone mineral density from baseline were observed for abaloparatide versus placebo at all 3 sites at 6 months (p < 0.01 for total hip and femoral neck; p < 0.0001 for lumbar spine), 12 months (p < 0.0001 at all 3 sites), and 18 months (p < 0.0001 at all 3 sites). Fracture rates were numerically lower for abaloparatide versus placebo, consistent with the overall trial results, although the differences were not statistically significant. The number needed to treat to prevent 1 additional vertebral fracture after 18 months of treatment versus placebo was 18 for abaloparatide and 21 for teriparatide. The number needed to treat had nonsignificant trends toward lower values with abaloparatide versus teriparatide for nonvertebral fractures (23 vs 40) and clinical fractures (16 vs 73) and similar for major osteoporotic fractures (24 vs 27). The safety profile was consistent with the overall ACTIVE population.

Implications: Findings of this subgroup (post hoc) analysis are consistent with the overall ACTIVE population. Abaloparatide appears to be effective and well tolerated in this subgroup of younger postmenopausal women. ClinicalTrials.gov identifier: NCT01343004.
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http://dx.doi.org/10.1016/j.clinthera.2020.04.012DOI Listing
June 2020

Economic burden of osteoporotic fractures in US managed care enrollees.

Am J Manag Care 2020 05 1;26(5):e142-e149. Epub 2020 May 1.

Radius Health, Inc, 550 E Swedesford Rd, Ste 370, Wayne, PA 19087. Email:

Objectives: To examine healthcare resource utilization (HRU) and costs in a population of managed care enrollees who experienced an osteoporotic fracture.

Study Design: Retrospective cohort study using the Optum Research Database (January 2007 to May 2017).

Methods: All-cause and osteoporosis-related HRU and costs were analyzed in patients 50 years and older with a qualifying index fracture and continuous enrollment with medical and pharmacy benefits for 12 months preindex (baseline period).

Results: Of 1,841,263 patients with fractures during the identification period, 302,772 met eligibility criteria. Two-thirds (66.6%) were 65 years and older, 71.6% were women, and 41.2% were commercial (not Medicare Advantage) enrollees. The most common fracture sites were spine (21.9%), radius/ulna (19.5%), and hip (13.7%). Mean (SD) total all-cause healthcare cost was $34,855 ($56,094), with most paid by health plans ($31,863 [$55,025]) versus patients ($2992 [$2935]). Most healthcare costs were for medical ($31,766 [$54,943]) versus pharmacy ($3089 [$6799]) services. Approximately 75% of patients received rehabilitation services (mean [SD] cost = $18,025 [$41,318]). Diagnosis of index fracture during an inpatient stay versus an outpatient visit (cost ratio, 2.16; 95% CI, 2.13-2.19) and fractures at multiple sites (cost ratio, 1.23; 95% CI, 1.21-1.26) were the leading predictors of cost. Kaplan-Meier estimated cumulative second-fracture rates were 6.6% at 1 year, 12.3% at 2 years, 16.9% at 3 years, and 20.9% at 4 years after index fracture.

Conclusions: These findings suggest a significant economic burden associated with fractures, including a high total all-cause cost of care. Early identification and treatment of patients at high risk of fractures are of paramount importance to reduce fracture risk and associated healthcare costs.
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http://dx.doi.org/10.37765/ajmc.2020.43156DOI Listing
May 2020

Effect of structural stability on endolysosomal degradation and T-cell reactivity of major shrimp allergen tropomyosin.

Allergy 2020 11 18;75(11):2909-2919. Epub 2020 Jun 18.

Australian Institute of Tropical Health and Medicine, James Cook University, Townsville, Qld, Australia.

Background: Tropomyosins are highly conserved proteins, an attribute that forms the molecular basis for their IgE antibody cross-reactivity. Despite sequence similarities, their allergenicity varies greatly between ingested and inhaled invertebrate sources. In this study, we investigated the relationship between the structural stability of different tropomyosins, their endolysosomal degradation patterns, and T-cell reactivity.

Methods: We investigated the differences between four tropomyosins-the major shrimp allergen Pen m 1 and the minor allergens Der p 10 (dust mite), Bla g 7 (cockroach), and Ani s 3 (fish parasite)-in terms of IgE binding, structural stability, endolysosomal degradation and subsequent peptide generation, and T-cell cross-reactivity in a BALB/c murine model.

Results: Tropomyosins displayed different melting temperatures, which did not correlate with amino acid sequence similarities. Endolysosomal degradation experiments demonstrated differential proteolytic digestion, as a function of thermal stability, generating different peptide repertoires. Pen m 1 (T 42°C) and Der p 10 (T 44°C) elicited similar patterns of endolysosomal degradation, but not Bla g 7 (T 63°C) or Ani s 3 (T 33°C). Pen m 1-specific T-cell clones, with specificity for regions highly conserved in all four tropomyosins, proliferated weakly to Der p 10, but did not proliferate to Bla g 7 and Ani s 3, indicating lack of T-cell epitope cross-reactivity.

Conclusions: Tropomyosin T-cell cross-reactivity, unlike IgE cross-reactivity, is dependent on structural stability rather than amino acid sequence similarity. These findings contribute to our understanding of cross-sensitization among different invertebrates and design of suitable T-cell peptide-based immunotherapies for shrimp and related allergies.
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http://dx.doi.org/10.1111/all.14410DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7687109PMC
November 2020

Cost-effectiveness of sequential treatment with abaloparatide followed by alendronate vs. alendronate monotherapy in women at increased risk of fracture: A US payer perspective.

Semin Arthritis Rheum 2020 06 13;50(3):394-400. Epub 2020 Feb 13.

Division of Public Health, Epidemiology and Health Economics, University of Liège, Liège, Belgium; Chair for Biomarkers of Chronic Diseases, College of Science, King Saud University, Riyadh, KSA, Saudi Arabia.

Objectives: Emerging evidence supports sequential therapy with anabolic followed by antiresorptive in patients at high-risk of fragility fractures. This study assessed the cost-effectiveness of sequential treatment with abaloparatide (ABL) followed by alendronate (ALN) [(ABL/ALN)] compared to ALN monotherapy and to sequential treatment starting with antiresorptive therapy (ALN/ABL/ALN).

Methods: A previously validated Markov microsimulation model was used to estimate the cost-effectiveness of sequential ABL/ALN compared to ALN monotherapy and to sequential ALN/ABL/ALN from a lifetime US payer perspective. In line with practice guidelines, patients were assumed to receive ABL for 18 months followed by 5 years of ALN, or ALN monotherapy for 5 years, or a sequence of ALN for 2 years followed by 18 months of ABL and then by 3 years ALN. Evaluation was conducted for patients aged 50-80 years old with a BMD T-score ≤-3.5 and without a history of prior fracture, or with a T-score between -2.5 and -3.5 and a history of ≥ 1 osteoporotic fracture.

Results: Sequential ABL/ALN was cost-effective (threshold of US$150,000 per QALY) vs generic ALN monotherapy in women ≥60 years with a BMD T-score ≤-3.5 and in women with BMD T-score between -2.5 and -3.5 and history of osteoporotic fracture. In all simulated populations, sequential ABL/ALN therapy was dominant (lower costs, more QALYs) compared with sequential ALN/ABL/ALN, resulting from limited effect of ABL in patients previously treated with an antiresorptive agent.

Conclusions: Sequential ABL/ALN therapy is cost-effective vs ALN monotherapy for US postmenopausal women aged ≥60 years at increased risk of fractures.
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http://dx.doi.org/10.1016/j.semarthrit.2020.02.004DOI Listing
June 2020
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