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1.
Gerontol Geriatr Educ ; : 1-15, 2023 Aug 07.
Artículo en Inglés | MEDLINE | ID: mdl-37548219

RESUMEN

Faculty development programs (FDPs) are an effective, evidence-based method of promoting knowledge, skills and self-efficacy of faculty. However, implementation and sustainability of curricular capstone projects developed by faculty as part of these programs are rarely reported. Challenges to sustaining programmatic implementation of interprofessional FDP curricular content into academic and clinical settings over time were not found in peer-reviewed literature. To better understand the sustained impact of our geriatrics-focused FDP, we explored barriers and facilitators to implementation and sustainability of capstone projects designed by faculty Scholars in our FDP. Thematic analysis of virtual interviews with 17 Scholars revealed several key factors that impacted the implementation and Dynamic sustainability of curricular projects. Three major themes and sub-themes were identified: Project Implementation (Supportive Factors, Hindering Factors and Filling in Gaps in the Field); Pedagogical Development (Enhancement of Skills and Culture Change); and Sustainability Impact (Project Sustainability, Career Development and Passing the Torch). Results suggest it is important to ensure logistical support, dedicated time, and organizational or institutional support. Implementation of geriatrics-focused FDPs provides an evidence-based approach to sustainability. Further study of the ongoing barriers and facilitators to sustainability is encouraged.

2.
Gerontol Geriatr Educ ; 43(3): 429-441, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-33544659

RESUMEN

As the population of older adults continues to grow, the need for health care professionals trained in the delivery of interprofessional care for older adult patients is critical. The purpose of this paper is to detail the outcomes of an interprofessional, geriatrics training program for healthcare professionals with a faculty appointment. Specifically, we gathered outcomes at four levels: reactions/satisfaction, learning, behavioral, and organizational. Our findings suggest that programs structured like the Faculty Development Program (FDP) have the potential to increase the amount of geriatrics content introduced in already existing health professions curricula, as well as to offer faculty needed training in how to provide their students with interprofessional learning experiences.


Asunto(s)
Geriatría , Anciano , Curriculum , Docentes , Geriatría/educación , Empleos en Salud/educación , Humanos , Relaciones Interprofesionales , Aprendizaje
3.
Gerontol Geriatr Educ ; 42(2): 207-223, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33349173

RESUMEN

Fall-related injuries and mortality are increasing in older adults. Evidence suggests a need for a multifactorial, interprofessional approach to reducing falls. The Program for All-Inclusive Care for the Elderly (PACE) utilizes an interprofessional approach to care and serves a high-risk population. The purpose of this study was to investigate the effectiveness of an EBP falls prevention training program conducted at a PACE. The program was a revision of an established program and was led by an interprofessional team. The evaluation used a mixed-methods approach to assess program quality, learning and self-efficacy gains, and intended behavioral changes. Quantitative evaluation demonstrated program satisfaction and qualitative responses identified the depth and interprofessional delivery as favorable. Qualitative data identified opportunities to enhance content and learning design. Overall knowledge gains were statistically significant (mean difference 5%), with the greatest gains related to the evidence base (mean difference 2.67%). Self-efficacy ratings increased significantly after each session. Participants noted changes to team function and a willingness to consider practice changes as a result of the training. The findings support the effectiveness of this interprofessional, EBP training program on falls prevention practices in a PACE and highlight the value of a multifaceted assessment and iterative development.


Asunto(s)
Accidentes por Caídas , Geriatría , Accidentes por Caídas/prevención & control , Anciano , Geriatría/educación , Humanos , Factores de Riesgo
4.
Gerontol Geriatr Educ ; 41(1): 63-84, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-31488030

RESUMEN

With increasing rates of polypharmacy among older adults, preparedness of current and future health care professionals to identify and deprescribe potentially inappropriate medications (PIMs) is critical. Medicine (n = 28), pharmacy (n = 35) and nursing (n = 11) trainees enrolled in an interprofessional course completed a survey assessing preparedness, confidence and attitudes toward deprescribing, and perception of interprofessional roles in the process. Pharmacy (p = .001) and nursing (p = .007) felt that their curriculum prepared them better to identify and deprescribe PIMs compared to medicine trainees. Pharmacy trainees perceived significantly more barriers to deprescribing compared to medicine (p = .003), but not nursing trainees. Physicians and pharmacists were perceived as the main drivers of the deprescribing process. Current curricular content should be modified to address lack of preparedness to deprescribe in clinical practice. Addressing such gaps as part of an interprofessional team may increase interprofessional role recognition and translate into changes in clinical practice as trainees move into the workforce.


Asunto(s)
Actitud del Personal de Salud , Deprescripciones , Relaciones Interprofesionales , Adulto , Estudios Transversales , Curriculum , Femenino , Personal de Salud/psicología , Humanos , Masculino , Grupo de Atención al Paciente , Polifarmacia , Encuestas y Cuestionarios
5.
Ann Pharmacother ; 52(7): 697-699, 2018 07.
Artículo en Inglés | MEDLINE | ID: mdl-29514464

RESUMEN

The scope of practice for pharmacists in the United States increasingly includes elements of prescribing under collaborative practice agreements and statewide protocols. However, as a result of continued health care access concerns, we believe that pharmacists will be called on to serve as independent prescribers in the future. For this anticipated practice expansion to become a successful reality, the assurance of pharmacist preparedness and continuous professional development through profession-wide standards will be imperative.


Asunto(s)
Prescripciones de Medicamentos/normas , Farmacéuticos/normas , Rol Profesional , Actitud del Personal de Salud , Humanos , Estados Unidos
6.
Consult Pharm ; 33(10): 572-608, 2017 Oct 01.
Artículo en Inglés | MEDLINE | ID: mdl-30322434

RESUMEN

Poster abstracts are evaluated based on the following criteria: significance of the problem to healthy aging or medication management; innovativeness of ideas, methods, and/or approach; methodological rigor of methods and approach; presentation of finding; implications identified for future research, practice, and/or policy; and clarity of writing. Submissions are not evaluated through the peer-reviewed process used by The Consultant Pharmacist. Industry support is indicated, where applicable. Presenting author is in italics. The poster abstract presentation is supported by the ASCP Foundation.

7.
Ann Pharmacother ; 50(7): 534-40, 2016 07.
Artículo en Inglés | MEDLINE | ID: mdl-27147704

RESUMEN

BACKGROUND: Medication reconciliation to identify discrepancies is a National Patient Safety Goal. Increasing medication number and complex medication regimens are associated with discrepancies, nonadherence, and adverse events. The Medication Regimen Complexity Index (MRCI) integrates information about dosage form, dosing frequency, and additional directions. OBJECTIVE: This study evaluates the association of MRCI scores and medication number with medication discrepancies and commissions, a discrepancy subtype. METHODS: This was a retrospective cohort study of a convenience sample of 104 ambulatory care patients seen from April 2010 to July 2011 within the Department of Veterans Affairs. Primary outcomes included any medication discrepancy and commissions. Primary exposures included MRCI scores and medication number. Multivariable logistic regression models associated MRCI scores and medication number with discrepancies. Receiver operating characteristic (ROC) curves provided discrepancy thresholds. RESULTS: For the 104 patients analyzed, the median MRCI score was 25 (interquartile range [IQR] = 14-43), and the median medication number was 8 (IQR = 5-13); 60% of patients had any discrepancy, whereas 36% had a commission. In adjusted analyses, patients with MRCI scores ≥25 or medication number ≥8 were more likely to have commissions (odds ratio [OR] = 3.64, 95% CI = 1.41-9.41; OR = 4.51, 95% CI = 1.73-11.73, respectively). The unadjusted ROC threshold for commissions was 36 for MRCI (sensitivity, 59%; specificity, 82%) and 9 for medication number (sensitivity 68%; specificity 67%). CONCLUSION: Patients with either MRCI scores ≥25 or ≥8 medications were more likely to have commissions. Given equal performance in predicting discrepancies, the efficiency and simplicity of medication number supports its use in identifying patients for intensive medication review beyond medication reconciliation.


Asunto(s)
Atención Ambulatoria/estadística & datos numéricos , Prescripciones de Medicamentos/estadística & datos numéricos , Revisión de la Utilización de Medicamentos/métodos , Conciliación de Medicamentos/estadística & datos numéricos , Polifarmacia , Anciano , Atención Ambulatoria/métodos , Protocolos Clínicos , Prescripciones de Medicamentos/clasificación , Prescripciones de Medicamentos/normas , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos , Femenino , Humanos , Modelos Logísticos , Masculino , Persona de Mediana Edad , Análisis Multivariante , Evaluación del Resultado de la Atención al Paciente , Estudios Retrospectivos , Estados Unidos , United States Department of Veterans Affairs , Veteranos
8.
Palliat Med ; 28(4): 335-41, 2014 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-24534725

RESUMEN

BACKGROUND: Delirium may complicate the hospital course and adversely impact remaining quality of life for palliative care inpatients. Medications with anticholinergic properties have been linked to delirium within elderly populations via serum anticholinergic assays. AIM: The aim of this study is to determine whether increasing anticholinergic burden, as measured using a clinical assessment tool, is associated with an increase in delirium among palliative care inpatients. DESIGN: This study was completed as a retrospective, case-control study. SETTING/PARTICIPANTS: Veterans admitted to the Veterans Affairs Boston Healthcare System and consulted to the palliative care service were considered for inclusion. Increase in anticholinergic burden from admission through hospital day 14 was assessed using the Anticholinergic Risk Scale. Presence of delirium was determined by use of a validated chart review instrument. RESULTS: A total of 217 patients were analyzed, with a mean age of 72.9 (±12.8) years. The overall delirium rate was 31% (n = 67). Patients with an increase in Anticholinergic Risk Scale (n = 72 (33%)) were 40% more likely to experience delirium (odds ratio = 1.44, 95% confidence interval = 1.07-1.94) compared to those without increase (n = 145 (67%)). After adjustment for age, brain metastasis, intensive care unit admission, illness severity, opiate use, and admission Anticholinergic Risk Scale using multivariable modeling, delirium risk remained significantly higher in patients with an Anticholinergic Risk Scale increase compared to those without increase (adjusted odds ratio = 1.43, 95% confidence interval = 1.04-1.94). CONCLUSION: An increase in Anticholinergic Risk Scale from admission was associated with delirium in palliative care inpatients. While additional study is needed, anticholinergic burden should be increased cautiously in palliative inpatients, and those with increases should be closely followed for delirium.


Asunto(s)
Antagonistas Colinérgicos/efectos adversos , Delirio/inducido químicamente , Cuidados Paliativos/estadística & datos numéricos , Anciano , Anciano de 80 o más Años , Estudios de Casos y Controles , Femenino , Humanos , Masculino , Massachusetts , Persona de Mediana Edad , Análisis Multivariante , Estudios Retrospectivos , Veteranos
9.
Curr Pharm Teach Learn ; 16(6): 445-452, 2024 06.
Artículo en Inglés | MEDLINE | ID: mdl-38631946

RESUMEN

BACKGROUND AND PURPOSE: Effective communication skills are essential for all pharmacists, regardless of practice setting. An implicit need in pharmacy education is to emphasize direct application of these skills to future healthcare practice prior to experiential rotations. The aim of this article is to describe how we revised a required first professional year (P1) doctor of pharmacy course to achieve two main goals: 1) improve the course relevance by connecting content to real-world skills; and 2) qualify all pharmacy students at our institution as certified National Diabetes Prevention Program (DPP) lifestyle coaches upon course completion. EDUCATIONAL ACTIVITY AND SETTING: Lifestyle coach training approved by the Centers for Disease Control and Prevention (CDC) was integrated into a P1 communications course consisting of 14 modules that include: review of diabetes pathophysiology, group facilitation skills, social determinants of health, food tracking, action planning, participant retention and program administration. This content serves as a direct application of pre-existing course objectives related to knowledge (evidence-based theory) and skills (technical and counseling) required for effective communication with patients, families, and health professionals. FINDINGS: Between 2019 and 2022, the redesigned course was offered to 373 P1 students. Course evaluations during this time were consistently positive. The average evaluation score since DPP activities were integrated into the course was 3.41 (on a 4-point scale). Based upon course evaluations, students appreciated three main benefits of incorporating lifestyle coach certification into the pharmacy curriculum: 1) a certified skill that can differentiate them in the job market; 2) practice of skills on real patients under faculty supervision in the community setting; 3) early exposure to pharmacy patient care topics, thus contributing to professional identity. SUMMARY: Integration of lifestyle coach training into an existing core P1 pharmacy course increased application and assessment of communications skills and allowed wider availability of trained coaches to deliver DPP in the community.


Asunto(s)
Curriculum , Diabetes Mellitus , Promoción de la Salud , Humanos , Promoción de la Salud/métodos , Promoción de la Salud/normas , Diabetes Mellitus/terapia , Curriculum/tendencias , Curriculum/normas , Educación en Farmacia/métodos , Educación en Farmacia/normas , Estilo de Vida , Comunicación , Estudiantes de Farmacia/estadística & datos numéricos
10.
Drugs Aging ; 40(12): 1123-1131, 2023 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-37856064

RESUMEN

BACKGROUND: A growing body of research supports the negative impact of anticholinergic drug burden on physical frailty. However, prior research has been limited to homogeneous white European populations, and few studies have evaluated how anticholinergic burden tools compare in their measurement function and reliability with minority community-dwelling adult populations. This study investigated the association between anticholinergic drug exposure and frailty by conducting a sensitivity analysis using multiple anticholinergic burden tools in a diverse cohort. METHODS: A comprehensive psychometric approach was used to assess the performance of five clinical Anticholinergic Burden Tools: Anticholinergic Cognitive Burden Scale (ACB), Anticholinergic Drug Scale (ADS), average daily dose, total standardized daily doses (TSDD), and Cumulative Anticholinergic Burden scale (CAB). Spearman correlation matrix and intraclass correlation coefficients (ICC) were used to determine the association among the variables. Ordinal logistic regression is used to evaluate the anticholinergic burden measured by each scale to determine the prediction of frailty. Model performance is determined by the area under the curve (AUC). RESULTS: The cohort included 80 individuals (mean age 69 years; 55.7% female, 71% African American). All anticholinergic burden tools were highly correlated (p < 0.001), ICC3 0.66 (p < 0.001, 95% confidence interval (CI) 0.53-0.73). Among individuals prescribed anticholinergics, 33% were robust, 44% were prefrail, and 23% were frail. All five tools predicted prefrail and frail status (p < 0.05) with low model misclassification rates for frail individuals (AUC range 0.78-0.85). CONCLUSION: Anticholinergic burden tools evaluated in this cohort of low-income African American older adults were highly correlated and predicted prefrail and frail status. Findings indicate that clinicians can select the appropriate instrument for the clinic setting and research question while maintaining confidence that all five tools will produce reliable results. Future anticholinergic research is needed to unravel the association between interventions such as deprescribing on incident frailty in longitudinal data.


Asunto(s)
Fragilidad , Humanos , Femenino , Anciano , Masculino , Fragilidad/inducido químicamente , Fragilidad/epidemiología , Reproducibilidad de los Resultados , Antagonistas Colinérgicos/efectos adversos , Vida Independiente
12.
J Bone Miner Res ; 37(9): 1733-1749, 2022 09.
Artículo en Inglés | MEDLINE | ID: mdl-35773783

RESUMEN

Biallelic ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1) deficiency induces vascular/soft tissue calcifications in generalized arterial calcification of infancy (GACI), and low bone mass with phosphate-wasting rickets in GACI survivors (autosomal hypophosphatemic rickets type-2). ENPP1 haploinsufficiency induces early-onset osteoporosis and mild phosphate wasting in adults. Both conditions demonstrate the unusual combination of reduced accrual of skeletal mineral, yet excess and progressive heterotopic mineralization. ENPP1 is the only enzyme that generates extracellular pyrophosphate (PPi), a potent inhibitor of both bone and heterotopic mineralization. Life-threatening vascular calcification in ENPP1 deficiency is due to decreased plasma PPi; however, the mechanism by which osteopenia results is not apparent from an understanding of the enzyme's catalytic activity. To probe for catalysis-independent ENPP1 pathways regulating bone, we developed a murine model uncoupling ENPP1 protein signaling from ENPP1 catalysis, Enpp1T238A mice. In contrast to Enpp1asj mice, which lack ENPP1, Enpp1T238A mice have normal trabecular bone microarchitecture and favorable biomechanical properties. However, both models demonstrate low plasma Pi and PPi, increased fibroblast growth factor 23 (FGF23), and by 23 weeks, osteomalacia demonstrating equivalent phosphate wasting in both models. Reflecting findings in whole bone, calvarial cell cultures from Enpp1asj mice demonstrated markedly decreased calcification, elevated transcription of Sfrp1, and decreased nuclear ß-catenin signaling compared to wild-type (WT) and Enpp1T238A cultures. Finally, the decreased calcification and nuclear ß-catenin signaling observed in Enpp1asj cultures was restored to WT levels by knockout of Sfrp1. Collectively, our findings demonstrate that catalysis-independent ENPP1 signaling pathways regulate bone mass via the expression of soluble Wnt inhibitors such as secreted frizzled-related protein 1 (SFRP1), whereas catalysis dependent pathways regulate phosphate homeostasis through the regulation of plasma FGF23. © 2022 American Society for Bone and Mineral Research (ASBMR).


Asunto(s)
Huesos/fisiología , Hidrolasas Diéster Fosfóricas/metabolismo , Pirofosfatasas/metabolismo , Animales , Catálisis , Raquitismo Hipofosfatémico Familiar , Factores de Crecimiento de Fibroblastos , Mamíferos/metabolismo , Ratones , Fosfatos/metabolismo , Hidrolasas Diéster Fosfóricas/genética , Pirofosfatasas/genética , Calcificación Vascular , beta Catenina
13.
J Parkinsons Dis ; 12(2): 599-606, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-34806617

RESUMEN

BACKGROUND: Individuals with Parkinson's disease (PD) may be especially vulnerable to future cognitive decline from anticholinergic medications. OBJECTIVE: To characterize anticholinergic medication burden, determine the co-occurrence of anticholinergic and cholinesterase inhibitors, and to assess the correlations among anticholinergic burden scales in PD outpatients. METHODS: We studied 670 PD outpatients enrolled in a clinic registry between 2012 and 2020. Anticholinergic burden was measured with the Anticholinergic Cognitive Burden Scale (ACB), Anticholinergic Drug Scale (ADS), Anticholinergic Risk Scale (ARS), and Drug Burden Index-Anticholinergic component (DBI-Ach). Correlations between scales were assessed with weighted kappa coefficients. RESULTS: Between 31.5 to 46.3% of PD patients were taking medications with anticholinergic properties. Among the scales applied, the ACB produced the highest prevalence of medications with anticholinergic properties (46.3%). Considering only medications with definite anticholinergic activity (scores of 2 or 3 on ACB, ADS, or ARS), the most common anticholinergic drug classes were antiparkinsonian (8.2%), antipsychotic (6.4%), and urological (3.3%) medications. Cholinesterase inhibitors and medications with anticholinergic properties were co-prescribed to 5.4% of the total cohort. The most highly correlated scales were ACB and ADS (κ= 0.71), ACB and ARS (κ= 0.67), and ADS and ARS (κ= 0.55). CONCLUSION: A high proportion of PD patients (20%) were either taking antiparkinsonian, urological, or antipsychotic anticholinergic medications or were co-prescribed anticholinergic medications and cholinesterase inhibitors. By virtue of its detection of a high prevalence of anticholinergic medication usage and its high correlation with other scales, our data support use of the ACB scale to assess anticholinergic burden in PD patients.


Asunto(s)
Antipsicóticos , Enfermedad de Parkinson , Antagonistas Colinérgicos/efectos adversos , Inhibidores de la Colinesterasa , Humanos , Pacientes Ambulatorios , Enfermedad de Parkinson/tratamiento farmacológico , Enfermedad de Parkinson/epidemiología
14.
J Am Geriatr Soc ; 69(9): 2619-2624, 2021 09.
Artículo en Inglés | MEDLINE | ID: mdl-33991423

RESUMEN

BACKGROUND/OBJECTIVES: Deprescribing is a strategy intended to reduce harms associated with potentially inappropriate medications. Reflective of the growing interest in deprescribing, there has been an increase in related research to better understand the landscape, opportunities for improvement, how best to develop and implement interventions, and remaining knowledge gaps that can be addressed with additional study. DESIGN: We conducted a narrative review of recent deprescribing literature. SETTING: As part of the US Deprescribing Network's inaugural conference in October 2020, we presented a narrative review of recent deprescribing literature to an audience with a range of clinical and research expertise. PARTICIPANTS: We searched four databases for English-language articles published between January 1, 2019 and August 31, 2020. MEASUREMENTS: We evaluated titles, abstracts, and full-length manuscripts for relevance, novelty, rigor and variety of methods; we also aimed for broad representation of authors, institutions, and nations. RESULTS: The initial search returned 199 citations, from which we reviewed 18 full-length manuscripts, selecting 10 articles to present. Salient themes included missed opportunities to deprescribe in potentially eligible patients, with variable impact of medication- and patient-level factors, along with differing perspectives and behaviors between geriatricians, internists, and cardiologists. Clinical, financial, and economic drivers were also evaluated. Finally, attention was given to issues applicable to deprescribing research, including difficulty recruiting trial participants, perspectives of investigators, and integration of findings into clinical practice. CONCLUSION: This narrative review summarizes key advances in the field while also identifying priority areas for additional research.


Asunto(s)
Investigación Biomédica , Deprescripciones , Anciano , Humanos
15.
IEEE Comput Graph Appl ; 41(1): 87-98, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-32956039

RESUMEN

In response to participant preferences and new ethics guidelines, researchers are increasingly sharing data with health study participants, including data on their own household chemical exposures. Data physicalization may be a useful tool for these communications, because it is thought to be accessible to a general audience and emotionally engaged. However, there are limited studies of data physicalization in the wild with diverse communities. Our application of this method in the Green Housing Study is an early example of using data physicalization in environmental health report-back. We gathered feedback through community meetings, prototype testing, and semistructured interviews, leading to the development of data t-shirts and other garments and person-sized bar charts. We found that participants were enthusiastic about data physicalizations, it connected them to their previous experience, and they had varying desires to share their data. Our findings suggest that researchers can enhance environmental communications by further developing the human experience of physicalizations and engaging diverse communities.


Asunto(s)
Contaminación del Aire Interior , Vestuario , Salud Ambiental , Difusión de la Información , Contaminantes Atmosféricos , Presentación de Datos , Exposiciones como Asunto , Humanos
16.
Bone ; 142: 115656, 2021 01.
Artículo en Inglés | MEDLINE | ID: mdl-32980560

RESUMEN

Ectonucleotide phosphatase/phosphodiesterase 1 (ENPP1) deficiency results in either lethal arterial calcifications ('Generalized Arterial Calcification of Infancy' - GACI), phosphate wasting rickets ('Autosomal Recessive Hypophosphatemic Rickets type 2' - ARHR2), early onset osteoporosis, or progressive spinal rigidity ('Ossification of the Posterior Longitudinal Ligament' - OPLL). As ENPP1 generates a strong endogenous mineralization inhibitor - extracellular pyrophosphate (PPi) - ENPP1 deficiency should not result in reduced bone volume, and therefore the mechanism ENPP1 associated osteoporosis is not apparent given current understanding of the enzyme's function. To investigate genetic pathways driving the skeletal phenotype of ENPP1 deficiency we compared gene expression in Enpp1asj/asj mice and WT sibling pairs by RNAseq and qPCR in whole bones, and in the liver and kidney by qPCR, directly correlating gene expression with measures of bone microarchitectural and biomechanical phenotypes. Unbiased analysis of the differentially expressed genes compared to relevant human disease phenotypes revealed that Enpp1asj/asj mice exhibit strong signatures of osteoporosis, ARHR2 and OPLL. We found that ENPP1 deficient mice exhibited reduced gene transcription of Wnt ligands in whole bone and increased transcription of soluble Wnt inhibitors in the liver and kidney, suggestive of multiorgan inhibition of Wnt activity. Consistent with Wnt suppression in bone, Collagen gene pathways in bone were significantly decreased and Fgf23 was significantly increased, all of which directly correlated with bone microarchitectural defects and fracture risk in Enpp1asj/asj mice. Moreover, the bone findings in 10-week old mice correlated with Enpp1 transcript counts but not plasma [PPi], suggesting that the skeletal phenotype at 10 weeks is driven by catalytically independent ENPP1 function. In contrast, the bone findings in 23-week Enpp1asj/asj mice strongly correlated with plasma PPi, suggesting that chronically low PPi drives the skeletal phenotype in older mice. Finally, correlation between Enpp1 and Fgf23 transcription suggested ENPP1 regulation of Fgf23, which we confirmed by dosing Enpp1asj/asj mice with soluble ENPP1-Fc and observing suppression of intact plasma FGF23 and ALP. In summary, our findings suggest that osteoporosis associated with ENPP1 deficiency involves the suppression of Wnt via catalytically independent Enpp1 pathways, and validates Enpp1asj/asj mice as tools to better understand OPLL and Paradoxical Mineralization Disorders.


Asunto(s)
Osteomalacia , Osteoporosis , Calcificación Vascular , Animales , Factor-23 de Crecimiento de Fibroblastos , Ratones , Osteoporosis/genética , Hidrolasas Diéster Fosfóricas/genética , Monoéster Fosfórico Hidrolasas , Pirofosfatasas/genética
17.
Clin Transl Sci ; 14(1): 362-372, 2021 01.
Artículo en Inglés | MEDLINE | ID: mdl-33064927

RESUMEN

Enzyme replacement with ectonucleotide pyrophosphatase phospodiesterase-1 (ENPP1) eliminates mortality in a murine model of the lethal calcification disorder generalized arterial calcification of infancy. We used protein engineering, glycan optimization, and a novel biomanufacturing platform to enhance potency by using a three-prong strategy. First, we added new N-glycans to ENPP1; second, we optimized pH-dependent cellular recycling by protein engineering of the Fc neonatal receptor; finally, we used a two-step process to improve sialylation by first producing ENPP1-Fc in cells stably transfected with human α-2,6-sialyltransferase (ST6) and further enhanced terminal sialylation by supplementing production with 1,3,4-O-Bu3 ManNAc. These steps sequentially increased the half-life of the parent compound in rodents from 37 hours to ~ 67 hours with an added N-glycan, to ~ 96 hours with optimized pH-dependent Fc recycling, to ~ 204 hours when the therapeutic was produced in ST6-overexpressing cells with 1,3,4-O-Bu3 ManNAc supplementation. The alterations were demonstrated to increase drug potency by maintaining efficacious levels of plasma phosphoanhydride pyrophosphate in ENPP1-deficient mice when the optimized biologic was administered at a 10-fold lower mass dose less frequently than the parent compound-once every 10 days vs. 3 times a week. We believe these improvements represent a general strategy to rationally optimize protein therapeutics.


Asunto(s)
Antígenos de Histocompatibilidad Clase I/uso terapéutico , Hidrolasas Diéster Fosfóricas/farmacología , Ingeniería de Proteínas , Pirofosfatasas/farmacología , Receptores Fc/uso terapéutico , Proteínas Recombinantes de Fusión/farmacología , Calcificación Vascular/tratamiento farmacológico , Animales , Área Bajo la Curva , Modelos Animales de Enfermedad , Terapia de Reemplazo Enzimático/métodos , Glicosilación , Semivida , Antígenos de Histocompatibilidad Clase I/genética , Humanos , Masculino , Ratones Transgénicos , Hidrolasas Diéster Fosfóricas/genética , Hidrolasas Diéster Fosfóricas/aislamiento & purificación , Hidrolasas Diéster Fosfóricas/uso terapéutico , Estructura Terciaria de Proteína/genética , Pirofosfatasas/genética , Pirofosfatasas/aislamiento & purificación , Pirofosfatasas/uso terapéutico , Receptores Fc/genética , Proteínas Recombinantes de Fusión/genética , Proteínas Recombinantes de Fusión/aislamiento & purificación , Proteínas Recombinantes de Fusión/uso terapéutico , Calcificación Vascular/genética
18.
Clin Transl Sci ; 14(2): 437-444, 2021 03.
Artículo en Inglés | MEDLINE | ID: mdl-33026148

RESUMEN

Older adults (i.e., 60 years and older), are the leading consumers of medications, and consequently are suffering the most from medication-related adverse events. Not only are older adults the largest consumers of medications, they are more likely to experience an adverse drug event contributing to increased hospitalization, utilization of emergency medical services, and mortality. Translational Approaches to Personalized Health (TAPH) is a transdisciplinary team of researchers conducting community-engaged participatory research focused on the discovery and translation of pharmacogenomic (PGx) data to improve health outcomes. Underserved and ethnically diverse older adults living in urban settings are significantly under-represented in PGx studies. To address the issue of under-representation, our study enrolls older African American adults into a community-based PGx study. Therefore, we will characterize the frequency of actionable PGx genotypes and identify novel PGx response genes in our cohort of older community dwelling African Americans. The translational component of our work is to use the PGx findings to improve therapeutic outcomes for medication management in older adults. Such findings will serve as a foundation for translational PGx studies aimed at improving medication efficacy and safety for older adults. In this article, we describe the process for launching the TAPH collaborative group, which includes the transdisciplinary team, community-engaged participatory research model, study measures, and the evaluation of PGx genes.


Asunto(s)
Negro o Afroamericano/genética , Investigación Participativa Basada en la Comunidad/organización & administración , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/prevención & control , Colaboración Intersectorial , Investigación Biomédica Traslacional/organización & administración , Factores de Edad , Anciano , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/epidemiología , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/genética , Humanos , Pruebas de Farmacogenómica/estadística & datos numéricos , Variantes Farmacogenómicas , Medicina de Precisión/métodos
19.
J Bone Miner Res ; 36(5): 942-955, 2021 05.
Artículo en Inglés | MEDLINE | ID: mdl-33465815

RESUMEN

Inactivating mutations in human ecto-nucleotide pyrophosphatase/phosphodiesterase-1 (ENPP1) may result in early-onset osteoporosis (EOOP) in haploinsufficiency and autosomal recessive hypophosphatemic rickets (ARHR2) in homozygous deficiency. ARHR2 patients are frequently treated with phosphate supplementation to ameliorate the rachitic phenotype, but elevating plasma phosphorus concentrations in ARHR2 patients may increase the risk of ectopic calcification without increasing bone mass. To assess the risks and efficacy of conventional ARHR2 therapy, we performed comprehensive evaluations of ARHR2 patients at two academic medical centers and compared their skeletal and renal phenotypes with ENPP1-deficient Enpp1asj/asj mice on an acceleration diet containing high phosphate treated with recombinant murine Enpp1-Fc. ARHR2 patients treated with conventional therapy demonstrated improvements in rickets, but all adults and one adolescent analyzed continued to exhibit low bone mineral density (BMD). In addition, conventional therapy was associated with the development of medullary nephrocalcinosis in half of the treated patients. Similar to Enpp1asj/asj mice on normal chow and to patients with mono- and biallelic ENPP1 mutations, 5-week-old Enpp1asj/asj mice on the high-phosphate diet exhibited lower trabecular bone mass, reduced cortical bone mass, and greater bone fragility. Treating the Enpp1asj/asj mice with recombinant Enpp1-Fc protein between weeks 2 and 5 normalized trabecular bone mass, normalized or improved bone biomechanical properties, and prevented the development of nephrocalcinosis and renal failure. The data suggest that conventional ARHR2 therapy does not address low BMD inherent in ENPP1 deficiency, and that ENPP1 enzyme replacement may be effective for correcting low bone mass in ARHR2 patients without increasing the risk of nephrocalcinosis. © 2021 American Society for Bone and Mineral Research (ASBMR).


Asunto(s)
Terapia de Reemplazo Enzimático , Fosfatos , Adolescente , Animales , Suplementos Dietéticos , Humanos , Ratones , Fenotipo , Hidrolasas Diéster Fosfóricas/genética , Pirofosfatasas
20.
Pharmacogenomics ; 21(9): 627-635, 2020 06.
Artículo en Inglés | MEDLINE | ID: mdl-32425117

RESUMEN

Older adults are at high risk for inappropriate prescribing, developing polypharmacy, adverse drug events and poor treatment outcomes due to multimorbidity and geriatric syndromes. Pharmacogenomics could allow healthcare professionals to provide optimal patient care while minimizing the risk of adverse drug events and simplifying complex medication regimens. The implementation of pharmacogenomics in geriatrics medicine requires a broad multilayered bottom-up approach. These include curriculum redesign, rethinking experiential education and patient and provider education. There are barriers associated with adopting pharmacogenomics into clinical practice. These barriers may include economic factors, workflow and informatics support. However, addressing these barriers primarily requires creating a culture of innovative practices in patient care, ongoing interprofessional continuing education and an interdisciplinary approach for patient care.


Asunto(s)
Prescripciones de Medicamentos , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/prevención & control , Prescripción Inadecuada/prevención & control , Educación del Paciente como Asunto/métodos , Farmacogenética/métodos , Polifarmacia , Anciano , Anciano de 80 o más Años , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/epidemiología , Humanos , Prescripción Inadecuada/tendencias , Multimorbilidad/tendencias , Educación del Paciente como Asunto/tendencias , Farmacogenética/tendencias
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