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2.
EBioMedicine ; 75: 103778, 2022 Jan 07.
Artigo em Inglês | MEDLINE | ID: mdl-35007819

RESUMO

BACKGROUND: Treatment of degenerating tendons still presents a major challenge, since the aetiology of tendinopathies remains poorly understood. Besides mechanical overuse, further known predisposing factors include rheumatoid arthritis, diabetes, obesity or smoking all of which combine with a systemic inflammation. METHODS: To determine whether the systemic inflammation accompanying these conditions contributes to the onset of tendinopathy, we studied the effect of a systemic inflammation induced by an allergic episode on tendon properties. To this end, we induced an allergic response in mice by exposing them to a timothy grass pollen allergen and subsequently analysed both their flexor and Achilles tendons. Additionally, we analysed data from a health survey comprising data from more than 10.000 persons for an association between the occurrence of an allergy and tendinopathy. FINDINGS: Biomechanical testing and histological analysis revealed that tendons from allergic mice not only showed a significant reduction of both elastic modulus and tensile stress, but also alterations of the tendon matrix. Moreover, treatment of 3D tendon-like constructs with sera from allergic mice resulted in a matrix-remodelling expression profile and the expression of macrophage-associated markers and matrix metalloproteinase 2 (MMP2) was increased in allergic Achilles tendons. Data from the human health study revealed that persons suffering from an allergy have an increased propensity to develop a tendinopathy. INTERPRETATION: Our study demonstrates that the presence of a systemic inflammation accompanying an allergic condition negatively impacts on tendon structure and function. FUNDING: This study was financially supported by the Fund for the Advancement of Scientific Research at Paracelsus Medical University (PMU-FFF E-15/22/115-LEK), by the Land Salzburg, the Salzburger Landeskliniken (SALK, the Health Care Provider of the University Hospitals Landeskrankenhaus and Christian Doppler Klinik), the Paracelsus Medical University, Salzburg and by unrestricted grants from Bayer, AstraZeneca, Sanofi-Aventis, Boehringer-Ingelheim.

3.
J Pediatr Surg ; 2021 Nov 06.
Artigo em Inglês | MEDLINE | ID: mdl-34865831

RESUMO

BACKGROUND: One of the most competitive surgical sub-specialty fellowships remains Pediatric Surgery (PS), which requires candidates to develop a strong and research-oriented curriculum vitae. Although some objective factors of matriculation are known, factors for the interview selection and ranking per the program directors (PDs) have not been reviewed in over a decade. METHODS: A web-based survey of US and Canadian PS program directors (PDs) (n = 58) was used to evaluate a comprehensive list of factors in the selection criteria for PS fellowships. A mix of dichotomous, ranking, five-point Likert scale, and open-ended questions evaluated applicant characteristics, ABSITE scores, research productivity, interview day, and rank order criteria. RESULTS: Fifty-five programs responded to the survey for a 95% participation rate. PDs desired an average of two years in dedicated research and weighted first authorship and total number of publications heavily. Only 38% of programs used an ABSITE score cutoff for offering interviews; however, the majority agreed that an overall upward trend was important. Quality letters of recommendation, especially from known colleagues, carried weight when deciding to offer interviews. Interview performance, being a team player, observed interpersonal interactions, perceived operative skills and patient care, and leadership were some of the notable factors when finalizing rank lists. CONCLUSIONS: A multitude of factors define a successful matriculant, including quality of letters of recommendation, quality and quantity of publications, supportive phone calls, observed interactions, interview performance, perceptions of being team player with leadership skills as well as perceptions of good operative skills and patient care. LEVEL OF EVIDENCE: Type II. TYPE OF STUDY: Prognostic (retrospective).

4.
Front Cell Dev Biol ; 9: 774985, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34869375

RESUMO

Besides their role as a storage for neutral lipids and sterols, there is increasing evidence that lipid droplets (LDs) are involved in cellular detoxification. LDs are in close contact to a broad variety of organelles where protein- and lipid exchange is mediated. Mitochondria as a main driver of the aging process produce reactive oxygen species (ROS), which damage several cellular components. LDs as highly dynamic organelles mediate a potent detoxification mechanism by taking up toxic lipids and proteins. A stimulation of LDs induced by the simultaneously overexpression of Lro1p and Dga1p (both encoding acyltransferases) prolongs the chronological as well as the replicative lifespan of yeast cells. The increased number of LDs reduces mitochondrial fragmentation as well as mitochondrial ROS production, both phenotypes that are signs of aging. Strains with an altered LD content or morphology as in the sei1∆ or lro1∆ mutant lead to a reduced replicative lifespan. In a yeast strain defective for the LON protease Pim1p, which showed an enhanced ROS production, increased doubling time and an altered mitochondrial morphology, a LRO1 overexpression resulted in a partially reversion of this "premature aging" phenotype.

5.
J Pediatr Surg ; 2021 Oct 29.
Artigo em Inglês | MEDLINE | ID: mdl-34857373

RESUMO

BACKGROUND: The 2020 Pediatric Surgery (PS) fellowship selection process was heavily impacted by the COVID-19 pandemic. A review of lessons learned can help determine best practices for the future. The purpose of the study was to analyze the virtual interview experience and assess opportunities to improve the post-pandemic fellowship recruitment process. STUDY DESIGN: Using a 28-question survey of Program Directors (PDs) of PS fellowships as well as a 44-question survey of applicants to PS fellowships in the US and Canada, we gathered information on the recruitment process during the COVID-19 pandemic (2020). Dichotomous, multiple choice and open-ended questions about the changes in process, platforms used, format, comparison to on-site interviews and overall satisfaction were used for objective and subjective feedback. RESULTS: A 95% participation rate was recorded for the PD survey. 24 out of 55 programs (44%) changed their on-site interviews to virtual format due to the pandemic. Most PDs described their overall impression of virtual interviews as satisfactory (66%, 16/24) and did not have an impact on the applicant's success in the match (35/54; 65%). About 50% of PDs preferred to have on-site interviews with virtual screening in the future. While the participation rate from applicants was much less (26 of 70), responses confirmed our survey results. Majority preferred on-site interviews (17/26), 6 of which preferred virtual screening followed by on-site interviews. CONCLUSION: Components of virtual screening and interviews were found to have benefits financially and from both time and stress perspectives, and thus might survive past the pandemic. LEVELS OF EVIDENCE LEVEL IV: .

7.
Int J Mol Sci ; 22(19)2021 Oct 08.
Artigo em Inglês | MEDLINE | ID: mdl-34639235

RESUMO

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 SiO2 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.


Assuntos
Alérgenos/imunologia , Antígenos de Plantas/imunologia , Epitopos/imunologia , Ativação Linfocitária/imunologia , Nanopartículas/química , Dióxido de Silício/química , Vacinas/imunologia , Alérgenos/química , Humanos , Hidrogéis , Imunoglobulina E/imunologia , Hipersensibilidade Respiratória/imunologia , Linfócitos T/imunologia
8.
Osteoporos Int ; 2021 Oct 23.
Artigo em Inglês | MEDLINE | ID: mdl-34686906

RESUMO

This study highlights an unmet need in osteoporosis management, suggesting that beyond bone mineral density and fracture history, gender, fracture type, and age should be considered for fracture risk assessment. Following fragility fracture, men, patients with a spine or hip fracture, and those aged ≥ 65 have a higher disease burden. INTRODUCTION: The objective of this study was to characterize osteoporosis-related fracture incidence and identify predictors of subsequent fractures and mortality. METHODS: This retrospective cohort study, conducted within Kaiser Permanente Southern California, included patients aged ≥ 50 years with qualifying fractures from 1/1/2007 to 12/31/2016, identified from diagnosis/procedure codes. Rates for fracture incidence, mortality, and resource utilization in the year post-fracture are reported. Associations between index fracture types and demographic/clinical characteristics, and mortality, subsequent fracture, and rehospitalization outcomes were estimated. RESULTS: Of 63,755 eligible patients, 66.7% were ≥ 65 years and 69.1% female. Index fractures included nonhip/nonspine (64.4%), hip (25.3%), and spine (10.3%). Age-adjusted subsequent fracture rate/100 person-years was higher for those with an index spine (14.5) versus hip fracture (6.3). Hospitalization rate/100 person-years was highest for patients ≥ 65 (31.8) and for spine fractures (43.5). Men (vs women) had higher age-adjusted rates of hospitalization (19.4; 17.7), emergency room visits (73.8; 66.3), and use of rehabilitation services (31.7; 27.2). The 30-day age-adjusted mortality rate/100 person-years was 46.7, 32.4, and 15.5 for spine, hip, and nonspine/nonhip fractures. The 1-year age-adjusted mortality rate/100 person-years was 14.7 for spine and 15.6 for hip fractures. In multivariable analyses, spine and hip fractures (vs nonhip/nonspine fractures) were significant predictors of 1-year mortality, all-cause and osteoporosis-related hospitalization, and nursing home use (all P-values < 0.0001). CONCLUSION: Morbidity is high in the year following a fragility fracture and men, patients with a spine or hip fracture, and those aged ≥ 65 have a greater disease burden.

9.
PLoS One ; 16(9): e0257246, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34570793

RESUMO

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.

10.
Molecules ; 26(17)2021 Aug 25.
Artigo em Inglês | MEDLINE | ID: mdl-34500588

RESUMO

Benzil (BZ) can be converted almost quantitatively to benzoyl peroxide (BP) in aerated polymer films upon irradiation at >400 nm (i.e., the long-wavelength edge of the n→π* absorption band of BZ, where BP does not absorb). Here, we summarize results for the photoperoxidation of BZ structures with molecular oxygen, principally in glassy polymer matrices. Some of the polymers are doped directly with BZ or its derivatives, and others, contain covalently attached BZ pendant groups from which BP groups are derived. While the decomposition of low-molecular-weight BP doped into polymer films (such as those of polystyrene (PS)) results in a net decrease in polymer molecular weight, thermal decomposition of pendant BP groups is an efficient method for chain crosslinking. Crosslinking of PS films doped with a molecule containing two covalently linked BZ or BP groups proceeds in a similar fashion. Free radicals from the covalently attached BP 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 BP structures obtained by photoperoxidation of BZ structures for the preparation of photodegradable polymer networks is described as well. In sum, the use of BZ and BP 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.

11.
Vaccine ; 39(37): 5259-5264, 2021 08 31.
Artigo em Inglês | MEDLINE | ID: mdl-34364720

RESUMO

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.


Assuntos
Lasers , Pele , Animais , Imunização , Células de Langerhans , Camundongos , Tecnologia
12.
Molecules ; 26(11)2021 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-34206043

RESUMO

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.

13.
Vaccine ; 39(32): 4399-4403, 2021 07 22.
Artigo em Inglês | MEDLINE | ID: mdl-34226102

RESUMO

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.


Assuntos
COVID-19 , Glicoproteína da Espícula de Coronavírus , Animais , Anticorpos Antivirais , Vacinas contra COVID-19 , Humanos , Imunização , Lasers , Camundongos , Camundongos Endogâmicos BALB C , Peptidil Dipeptidase A , Ligação Proteica , SARS-CoV-2 , Vacinação
14.
Adv Ther ; 38(7): 3872-3887, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34053012

RESUMO

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.


Assuntos
Osteoporose , Fraturas por Osteoporose , Idoso , Feminino , Humanos , Masculino , Programas de Rastreamento , Medicare , Osteoporose/diagnóstico , Osteoporose/epidemiologia , Fraturas por Osteoporose/epidemiologia , Fraturas por Osteoporose/prevenção & controle , Estudos Retrospectivos , Estados Unidos/epidemiologia
15.
Diabetes Care ; 44(7): 1547-1555, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34001536

RESUMO

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; P trend = 0.02), female sex (2.23 [1.26, 3.95]), HbA1c (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]; P trend =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; P trend =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 HbA1c 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.

16.
Nanoscale ; 13(16): 7648-7666, 2021 Apr 30.
Artigo em Inglês | MEDLINE | ID: mdl-33928963

RESUMO

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.


Assuntos
Ouro , Nanopartículas Metálicas , Células Dendríticas , Humanos , Lipopolissacarídeos , Nanopartículas Metálicas/toxicidade , Fenótipo
17.
Gels ; 7(1)2021 Feb 17.
Artigo em Inglês | MEDLINE | ID: mdl-33671130

RESUMO

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.

18.
JBMR Plus ; 5(3): e10457, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33778325

RESUMO

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 (n = 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; p = 0.048) and fracture history (OR = 1.72; 95% CI, 1.03-2.86; p = 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; p = 0.00). Remembering to take the medication was a significant predictor of self-reported adherence (OR = 16.66; 95% CI, 3.30-84.24; p = 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. JBMR Plus published by Wiley Periodicals LLC. on behalf of American Society for Bone and Mineral Research.

20.
Clin Drug Investig ; 41(3): 277-285, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33638863

RESUMO

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 (Tmax) for abaloparatide-sMTS was 0.33 h and geometric mean (CV %) maximum concentration (Cmax) and area under the concentration-time curve from time 0 to the time of the last quantifiable concentration (AUC0-t) 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.


Assuntos
Conservadores da Densidade Óssea/uso terapêutico , Densidade Óssea/efeitos dos fármacos , Osteoporose Pós-Menopausa/tratamento farmacológico , Proteína Relacionada ao Hormônio Paratireóideo/administração & dosagem , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Injeções Subcutâneas , Vértebras Lombares/efeitos dos fármacos , Pessoa de Meia-Idade , Fragmentos de Peptídeos/sangue , Pró-Colágeno/sangue
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