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BACKGROUND: Electronic health record (EHR) transitions are known to be highly disruptive, can drastically impact clinician and staff experiences, and may influence patients' experiences using the electronic patient portal. Clinicians and staff can gain insights into patient experiences and be influenced by what they see and hear from patients. Through the lens of an emergency preparedness framework, we examined clinician and staff reactions to and perceptions of their patients' experiences with the portal during an EHR transition at the Department of Veterans Affairs (VA). METHODS: This qualitative case study was situated within a larger multi-methods evaluation of the EHR transition. We conducted a total of 122 interviews with 30 clinicians and staff across disciplines at the initial VA EHR transition site before, immediately after, and up to 12 months after go-live (September 2020-November 2021). Interview transcripts were coded using a priori and emergent codes. The coded text segments relevant to patient experience and clinician interactions with patients were extracted and analyzed to identify themes. For each theme, recommendations were defined based on each stage of an emergency preparedness framework (mitigate, prepare, respond, recover). RESULTS: In post-go-live interviews participants expressed concerns about the reliability of communicating with their patients via secure messaging within the new EHR portal. Participants felt ill-equipped to field patients' questions and frustrations navigating the new portal. Participants learned that patients experienced difficulties learning to use and accessing the portal; when unsuccessful, some had difficulties obtaining medication refills via the portal and used the call center as an alternative. However, long telephone wait times provoked patients to walk into the clinic for care, often frustrated and without an appointment. Patients needing increased in-person attention heightened participants' daily workload and their concern for patients' well-being. Recommendations for each theme fit within a stage of the emergency preparedness framework. CONCLUSIONS: Application of an emergency preparedness framework to EHR transitions could help address the concerns raised by the participants, (1) mitigating disruptions by identifying at-risk patients before the transition, (2) preparing end-users by disseminating patient-centered informational resources, (3) responding by building capacity for disrupted services, and (4) recovering by monitoring integrity of the new portal function.
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Registros Eletrônicos de Saúde , Pesquisa Qualitativa , United States Department of Veterans Affairs , Humanos , Estados Unidos , Masculino , Feminino , Entrevistas como Assunto , Pessoa de Meia-Idade , Atitude do Pessoal de Saúde , Portais do Paciente , AdultoRESUMO
BACKGROUND: Using patient audio recordings of medical visits to provide clinicians with feedback on their attention to patient life context in care planning can improve health care delivery and outcomes, and reduce costs. However, such an initiative can raise concerns across stakeholders about surveillance, intrusiveness and merit. This study examined the perspectives of patients, physicians and other clinical staff, and facility leaders over 3 years at six sites during the implementation of a patient-collected audio quality improvement program designed to improve patient-centered care in a non-threatening manner and with minimal effort required of patients and clinicians. METHODS: Patients were invited during the first and third year to complete exit surveys when they returned their audio recorders following visits, and clinicians to complete surveys annually. Clinicians were invited to participate in focus groups in the first and third years. Facility leaders were interviewed individually during the last 6 months of the study. RESULTS: There were a total of 12 focus groups with 89 participants, and 30 leadership interviews. Two hundred fourteen clinicians and 800 patients completed surveys. In a qualitative analysis of focus group data employing NVivo, clinicians initially expressed concerns that the program could be disruptive and/or burdensome, but these diminished with program exposure and were substantially replaced by an appreciation for the value of low stakes constructive feedback. They were also significantly more confident in the value of the intervention in the final year (p = .008), more likely to agree that leadership supports continuous improvement of patient care and gives feedback on outcomes (p = .02), and at a time that is convenient (p = .04). Patients who volunteered sometimes expressed concerns they were "spying" on their doctors, but most saw it as an opportunity to improve care. Leaders were supportive of the program but not yet prepared to commit to funding it exclusively with facility resources. CONCLUSIONS: A patient-collected audio program can be implemented when it is perceived as safe, not disruptive or burdensome, and as contributing to better health care.
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Assistência Centrada no Paciente , Melhoria de Qualidade , Atenção à Saúde , Retroalimentação , Humanos , LiderançaRESUMO
OBJECTIVE: The Veterans Health Administration (VHA) is adapting to meet the changing needs of our Veterans. VHA leaders are promoting quality improvement strategies including Lean Six Sigma (LSS). This study used LSS tools to evaluate the Veterans Choice Program (VCP), a program that aims to improve access to health care services for eligible Veterans by expanding health care options to non-VHA providers. RESEARCH DESIGN: LSS was utilized to assess the current process and efficiency patterns of the VCP at 3 VHA Medical Centers. LSS techniques were used to assess data obtained through semistructured interviews with Veterans, staff, and providers to describe and evaluate the VCP process by identifying wastes and defects. RESULTS: The LSS methodology facilitated the process of targeting priorities for improvement and constructing suggestions to close identified gaps and inefficiencies. Identified key process wastes included inefficient exchange of clinical information between stakeholders in and outside of the VHA; poor dissemination of VCP programmatic information; shortages of VCP-participating providers; duplication of appointments; declines in care coordination; and lack of program adaptability to local processes. Recommendations for improvement were formulated using LSS. CONCLUSIONS: This evaluation illustrates how LSS can be utilized to assess a nationally mandated health care program. By focusing on stakeholder, staff, and Veteran perspectives, process defects in the VCP were identified and improvement recommendations were made. However, the current LSS language used is not intuitive in health care and similar applications of LSS may consider using new language and goals adapted specifically for health care.
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Comportamento de Escolha , Hospitais Urbanos , Hospitais de Veteranos/normas , Melhoria de Qualidade , Gestão da Qualidade Total/métodos , Avaliação de Programas e Projetos de Saúde , Estados Unidos , United States Department of Veterans AffairsRESUMO
BACKGROUND: Shared medical appointments (SMAs) in heart failure (HF) are medical visits where several patients with HF meet with multidisciplinary providers at the same time for efficient and comprehensive care. It is unknown whether HF-SMAs can improve overall and cardiac health status for high-risk patients with HF discharged from acute care. METHODS AND RESULTS: A 3-site, open-label, randomized-controlled-trial was conducted. Participants within 12 weeks of HF acute care (emergency-room/hospitalization) requiring intravenous diuretic therapy were randomized to receive either HF-SMA or usual HF clinical care (usual-care) on a 1:1 ratio. The HF-SMA team, which consisted of a nurse, nutritionist, psychologist, nurse practitioner and/or a clinical pharmacist, provided four 2-hour session HF-SMAs that met every other week for 8 weeks. Primary outcomes were the overall health status measured by European Quality of Life Visual Analog Scale and cardiac health status by Kansas City Cardiomyopathy Questionnaire, 180 days postrandomization. Of the 242 patients enrolled (HF-SMA n=117, usual-care n=125, mean age 69.3±9.4 years, 71.5% White patients, 94.6% male), 84% of participants completed the study (n=8 HF-SMA and n=9 usual-care patients died). After 180 days, both HF-SMA and usual-care participants had significant improvements from baseline in Kansas City Cardiomyopathy Questionnaire that were not statistically different. Only HF-SMA participants had significant improvements in European Quality of Life Visual Analog Scale (mean change = 7.2±15.8 in HF-SMA versus -0.4±19.0 points in usual-care, P < 0.001). CONCLUSIONS: Both HF-SMA and usual-care in participants with HF achieved significant improvements in cardiac health status, but only a team approach through HF-SMA achieved significant improvements in overall health status. Future larger studies are needed to evaluate hospitalization and death outcomes. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02481921.
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Insuficiência Cardíaca , Qualidade de Vida , Consultas Médicas Compartilhadas , Humanos , Insuficiência Cardíaca/terapia , Insuficiência Cardíaca/mortalidade , Masculino , Feminino , Idoso , Pessoa de Meia-Idade , Nível de Saúde , Equipe de Assistência ao Paciente/organização & administração , Resultado do Tratamento , Fatores de Tempo , Diuréticos/uso terapêutico , Alta do PacienteRESUMO
Objectives: The Department of Veterans Affairs (VA) is transitioning from its legacy electronic health record (EHR) to a new commercial EHR in a nationwide, rolling-wave transition. We evaluated clinician and staff experiences to identify strategies to improve future EHR rollouts. Materials and Methods: We completed a convergent mixed-methods formative evaluation collecting survey and interview data to measure and describe clinician and staff experiences. Survey responses were analyzed using descriptive statistics; interview transcripts were coded using a combination of a priori and emergent codes followed by qualitative content analysis. Qualitative and quantitative findings were compared to provide a more comprehensive understanding of participant experience. Employees of specialty and primary care teams at the first nationwide EHR transition site agreed to participate in our study. We distributed surveys at 1-month pre-transition, 2 months post-transition, and 10 months post-transition to each of the 68 identified team members and completed longitudinal interviews with 30 of these individuals totaling 122 semi-structured interviews. Results: Interview participants reported profoundly disruptive experiences during the EHR transition that persisted at 1-year post implementation. Survey responses indicated training difficulties throughout the transition, and sharp declines (P ≤ .05) between pre- and post-go-live measures of EHR usability and increase in EHR burden that were perceived to be due in part to system inefficiencies, discordant positive messaging that initially ignored user challenges, and inadequate support for and attention to ongoing EHR issues. Participants described persistent high levels of stress associated with these disruptions. Discussion: Our findings highlight strategies to improve employee experiences during EHR transitions: (1) working with Oracle Cerner to resolve known issues and improve usability; (2) role-based training with opportunities for self-directed learning; (3) peer-led support systems and timely feedback on issues; (4) messaging that responds to challenges and successes; and (5) continuous efforts to support staff with issues and address clinician and staff stress and burnout. Conclusion: Our findings provide relevant strategies to navigate future EHR transitions while supporting clinical teams.
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INTRODUCTION: The Veterans Health Administration (VHA) is tasked with providing access to health care to veterans of military service. However, many eligible veterans have either not yet enrolled or underutilized VHA services. Further study of barriers to access before veterans enroll in VHA care is necessary to understand how to address this issue. The ChooseVA (née MyVA Access) initiative aims to achieve this mission to improve veterans' health care access. Although veteran outreach was not specifically addressed by the initiative, it is a critical component of improving veterans' access to health care. Findings from this multisite evaluation of ChooseVA implementation describe sites' efforts to improve VHA outreach and veterans' experiences with access. MATERIALS AND METHODS: This quality improvement evaluation employed a multi-method qualitative methodology, including 127 semi-structured interviews and 81 focus groups with VHA providers and staff ("VHA staff") completed during 21 VHA medical center facility site visits between July and November 2017 and 48 telephone interviews with veterans completed between May and October 2018. Interviews and focus groups were transcribed and analyzed using deductive and inductive analysis to capture challenges and strategies to improve VHA health care access (VHA staff data), experiences with access to care (veteran data), barriers and facilitators to care (staff and veteran data), contextual factors, and emerging categories and themes. We developed focused themes describing perceived challenges, descriptions of VHA staff efforts to improve veteran outreach, and veterans' experiences with accessing VHA health care. RESULTS: VHA staff and veteran respondents reported a lack of veteran awareness of eligibility for VHA services. Veterans reported limited understanding of the range of services offered. This awareness gap served as a barrier to veterans' ability to successfully access VHA health care services. Veterans described this awareness gap as contributing to delayed VHA enrollment and delayed or underutilized health care benefits and services. Staff focused on community outreach and engaging veterans for VHA enrollment as part of their efforts to implement the ChooseVA access initiative. Staff and veteran respondents agreed that outreach efforts were helpful for engaging veterans and facilitating access. CONCLUSIONS: Although efforts across VHA programs informed veterans about VHA services, our results suggest that both VHA staff and veterans agreed that missed opportunities exist. Gaps include veterans' lack of awareness or understanding of VHA benefits for which they qualify for. This can result in delayed access to care which may negatively impact veterans, including those separating from the military and vulnerable populations such as veterans who experience pregnancy or homelessness.
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The hub-and-spoke telehealth model leverages centrally located providers who utilize telehealth technology to bring specialized care to medically underserved areas. This model has the potential to promote equitable access to healthcare. However, few studies address how to facilitate the adoption and implementation of hub-and-spoke telehealth. We examined spoke site providers' experiences with TelePain, a national hub-and-spoke model of interdisciplinary chronic pain care, with a focus on improving future implementation. We conducted semi-structured individual interviews (20-45 min) with 27 VA spoke site providers via teleconferencing between August 2020 and February 2021. Interview transcripts were coded in Atlas.ti 8.0 using deductive (identified a priori and used to build the interview guide) and inductive (emerging) codes. Our analysis identified the following themes stressed by the spoke sites: (1) spoke sites needed to envision how TelePain services would work at their site before deciding to adopt; (2) TelePain implementation needed to fit into local existing care processes; (3) hub sites needed to understand spoke sites' context (e.g., via needs assessment) to tailor the services accordingly, and (4) hub-and-spoke sites needed to establish bidirectional communication. Our findings provide a practical guide to improve future rollout of hub-and-spoke telehealth models. Recommendations focus on the role of the hub site in promoting program adoption by (1) developing a clear and detailed marketing plan and (2) considering how the program can be adapted to fit the local spoke site context. To improve implementation, hub-and-spoke sites must establish ongoing and consistent bidirectional communication; this is particularly critical in the everchanging post-peak pandemic healthcare system. An important next step is the development of recommendations and guidelines for implementing hub-and-spoke telehealth, as well as examining pain outcomes for patients touched by this program.
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Shared medical appointments (SMAs) offer a means for providing knowledge and skills needed for chronic disease management to patients. However, SMAs require a time and attention investment from health care providers, who must understand the goals and potential benefits of SMAs from the perspective of patients and providers. To better understand how to gain provider engagement and inform future SMA implementation, qualitative inquiry of provider experience based on a knowledge-attitude-practice model was explored. Semi-structured interviews were conducted with 24 health care providers leading SMAs for heart failure at three Veterans Administration Medical Centers. Rapid matrix analysis process techniques including team-based qualitative inquiry followed by stakeholder validation was employed. The interview guide followed a knowledge-attitude-practice model with a priori domains of knowledge of SMA structure and content (understanding of how SMAs were structured), SMA attitude/beliefs (general expectations about SMA use), attitudes regarding how leading SMAs affected patients, and providers. Data regarding the patient referral process (organizational processes for referring patients to SMAs) and suggested improvements were collected to further inform the development of SMA implementation best practices. Providers from all three sites reported similar knowledge, attitude and beliefs of SMAs. In general, providers reported that the multi-disciplinary structure of SMAs was an effective strategy towards improving clinical outcomes for patients. Emergent themes regarding experiences with SMAs included improved self-efficacy gained from real-time collaboration with providers from multiple disciplines, perceived decrease in patient re-hospitalizations, and promotion of self-management skills for patients with HF. Most providers reported that the SMA-setting facilitated patient learning by providing opportunities for the sharing of experiences and knowledge. This was associated with the perception of increased comradery and support among patients. Future research is needed to test suggested improvements and to develop best practices for training additional sites to implement HF SMA.
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Pessoal de Saúde , Insuficiência Cardíaca/terapia , Consultas Médicas Compartilhadas , Adulto , Agendamento de Consultas , Atitude do Pessoal de Saúde , Feminino , Processos Grupais , Pessoal de Saúde/organização & administração , Pessoal de Saúde/psicologia , Humanos , Entrevistas como Assunto , Satisfação no Emprego , Masculino , Pessoa de Meia-Idade , Percepção , Atenção Primária à Saúde/métodos , Atenção Primária à Saúde/organização & administração , Pesquisa Qualitativa , Inquéritos e Questionários , Estados Unidos , Adulto JovemRESUMO
PURPOSE: Some forms of congenital muscular dystrophy are associated with cortical and retinal dysplasias. Protein O-mannose N-acetylglucosaminyltransferase 1 (POMGnT1) knockout mice, one of the mouse models of muscular dystrophy, exhibit a thinner retina with reduced density of retinal ganglion cells. This study is aimed to further characterize the knockout retina, with special emphasis on the inner limiting membrane, the basement membrane of the retina. METHODS: Immunofluorescence staining and transmission electron microscopy were used to analyze the retinas. Atomic force microscopy was performed on the inner limiting membrane preparations to examine their mechanical properties. RESULTS: The inner limiting membrane of the knockout mice exhibited frequent breaks with protrusions of the Müller glial processes and ectopic placement of retinal ganglion cells into the vitreous humor. Disruptions in inner limiting membrane integrity developmentally precede the cellular abnormalities. Regions of disrupted inner limiting membrane were also associated with molecular abnormalities of Müller glia that included diminished presence of the integral membrane proteins Kir4.1 (an inwardly rectifying potassium channel) and aquaporin-4. When measured with atomic force microscopy, the POMGnT1 knockout mouse inner limiting membrane (ILM) exhibited significantly reduced Young's modulus and is therefore mechanically weaker than the ILM from controls. CONCLUSIONS: Deficiency of POMGnT1-mediated glycosylation of dystroglycan is implicated in reduced stiffness of the ILM. The weakened ILM results in the disruption of the membrane and subsequent reduction in retinal integrity.
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Anormalidades Múltiplas/patologia , Membrana Basal/patologia , Coristoma/patologia , Distrofias Musculares/congênito , Retina/patologia , Estresse Mecânico , Animais , Membrana Basal/ultraestrutura , Forma Celular , Coristoma/complicações , Modelos Animais de Doenças , Módulo de Elasticidade , Camundongos , Camundongos Knockout , Distrofias Musculares/complicações , Distrofias Musculares/patologia , N-Acetilglucosaminiltransferases/metabolismo , Neuroglia/metabolismo , Neuroglia/patologia , Retina/enzimologia , Retina/ultraestrutura , Células Ganglionares da Retina/patologia , Células Ganglionares da Retina/ultraestrutura , Corpo Vítreo/patologia , Corpo Vítreo/ultraestruturaRESUMO
Pharmacologic treatment of diabetic retinopathy via eyedrops could have advantages but has not been successful to date. We explored the effect of topical Nepafenac, an anti-inflammatory drug known to reach the retina when administered via eyedrops, on the development of early stages of diabetic retinopathy and on metabolic and physiologic abnormalities that contribute to the retinal disease. Streptozotocin-induced diabetic rats were assigned to three groups (0.3% Nepafenac eyedrops, vehicle eyedrops, and untreated control) for comparison to age-matched nondiabetic control animals. Eyedrops were administered in both eyes four times per day for 2 and 9 months. At 2 months of diabetes, insulin-deficient diabetic control rats exhibited significant increases in retinal prostaglandin E(2), superoxide, vascular endothelial growth factor (VEGF), nitric oxide (NO), cyclooxygenase-2, and leukostasis within retinal microvessels. All of these abnormalities except NO and VEGF were significantly inhibited by Nepafenac. At 9 months of diabetes, a significant increase in the number of transferase-mediated dUTP nick-end labeling-positive capillary cells, acellular capillaries, and pericyte ghosts were measured in control diabetic rats versus nondiabetic controls, and topical Nepafenac significantly inhibited all of these abnormalities (all P < 0.05). Diabetes-induced activation of caspase-3 and -6 in retina was partially inhibited by Nepafenac (all P < 0.05). Oscillatory potential latency was the only abnormality of retinal function reproducibly detected in these diabetic animals, and Nepafenac significantly inhibited this defect (P < 0.05). Nepafenac did not have a significant effect on diabetes-induced loss of cells in the ganglion cell layer or in corneal protease activity. Topical ocular administration of Nepafenac achieved sufficient drug delivery to the retina and diabetes-induced alterations in retinal vascular metabolism, function, and morphology were inhibited. In contrast, little or no effect was observed on diabetes-induced alterations in retinal ganglion cell survival. Local inhibition of inflammatory pathways in the eye offers a novel therapeutic approach toward inhibiting the development of lesions of diabetic retinopathy.
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Anti-Inflamatórios/uso terapêutico , Benzenoacetamidas/uso terapêutico , Retinopatia Diabética/tratamento farmacológico , Fenilacetatos/uso terapêutico , Retina/efeitos dos fármacos , Administração Tópica , Animais , Anti-Inflamatórios/farmacologia , Benzenoacetamidas/farmacologia , Caspase 3/metabolismo , Caspase 6/metabolismo , Ciclo-Oxigenase 2/metabolismo , Diabetes Mellitus Experimental/complicações , Retinopatia Diabética/metabolismo , Dinoprostona/metabolismo , Potenciais Evocados Visuais/efeitos dos fármacos , Inflamação/tratamento farmacológico , Inflamação/patologia , Masculino , Metaloproteinase 2 da Matriz/efeitos dos fármacos , Óxido Nítrico/metabolismo , Soluções Oftálmicas/uso terapêutico , Fenilacetatos/farmacologia , Distribuição Aleatória , Ratos , Ratos Endogâmicos Lew , Retina/metabolismo , Retina/patologia , Vasos Retinianos/efeitos dos fármacos , Estreptozocina , Superóxidos/metabolismo , Fatores de Crescimento do Endotélio Vascular/metabolismoRESUMO
OBJECTIVE: To test the feasibility of using telehealth to support antimicrobial stewardship at Veterans Affairs medical centers (VAMCs) that have limited access to infectious disease-trained specialists. DESIGN: A prospective quasi-experimental pilot study. SETTING: Two rural VAMCs with acute-care and long-term care units.InterventionAt each intervention site, medical providers, pharmacists, infection preventionists, staff nurses, and off-site infectious disease physicians formed a videoconference antimicrobial stewardship team (VAST) that met weekly to discuss cases and antimicrobial stewardship-related education. METHODS: Descriptive measures included fidelity of implementation, number of cases discussed, infectious syndromes, types of recommendations, and acceptance rate of recommendations made by the VAST. Qualitative results stemmed from semi-structured interviews with VAST participants at the intervention sites. RESULTS: Each site adapted the VAST to suit their local needs. On average, sites A and B discussed 3.5 and 3.1 cases per session, respectively. At site A, 98 of 140 cases (70%) were from the acute-care units; at site B, 59 of 119 cases (50%) were from the acute-care units. The most common clinical syndrome discussed was pneumonia or respiratory syndrome (41% and 35% for sites A and B, respectively). Providers implemented most VAST recommendations, with an acceptance rate of 73% (186 of 256 recommendations) and 65% (99 of 153 recommendations) at sites A and B, respectively. Qualitative results based on 24 interviews revealed that participants valued the multidisciplinary aspects of the VAST sessions and felt that it improved their antimicrobial stewardship efforts and patient care. CONCLUSIONS: This pilot study has successfully demonstrated the feasibility of using telehealth to support antimicrobial stewardship at rural VAMCs with limited access to local infectious disease expertise.
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Gestão de Antimicrobianos/organização & administração , Doenças Transmissíveis/tratamento farmacológico , Pessoal de Saúde/organização & administração , Hospitais de Veteranos/organização & administração , Telemedicina/organização & administração , Hospitais Rurais , Humanos , Entrevistas como Assunto , Cultura Organizacional , Projetos Piloto , Estudos Prospectivos , Pesquisa Qualitativa , Estados UnidosRESUMO
RATIONALE AND OBJECTIVES: One way to understand medical overuse at the clinician level is in terms of clinical decision-making processes that are normally adaptive but become maladaptive. In psychology, dual process models of cognition propose 2 decision-making processes. Reflective cognition is a conscious process of evaluating options based on some combination of utility, risk, capabilities, and/or social influences. Automatic cognition is a largely unconscious process occurring in response to environmental or emotive cues based on previously learned, ingrained heuristics. De-implementation strategies directed at clinicians may be conceptualized as corresponding to cognition: (1) a process of unlearning based on reflective cognition and (2) a process of substitution based on automatic cognition. RESULTS: We define unlearning as a process in which clinicians consciously change their knowledge, beliefs, and intentions about an ineffective practice and alter their behaviour accordingly. Unlearning has been described as "the questioning of established knowledge, habits, beliefs and assumptions as a prerequisite to identifying inappropriate or obsolete knowledge underpinning and/or embedded in existing practices and routines." We hypothesize that as an unintended consequence of unlearning strategies clinicians may experience "reactance," ie, feel their professional prerogative is being violated and, consequently, increase their commitment to the ineffective practice. We define substitution as replacing the ineffective practice with one or more alternatives. A substitute is a specific alternative action or decision that either precludes the ineffective practice or makes it less likely to occur. Both approaches may work independently, eg, a substitute could displace an ineffective practice without changing clinicians' knowledge, and unlearning could occur even if no alternative exists. For some clinical practice, unlearning and substitution strategies may be most effectively used together. CONCLUSIONS: By taking into account the dual process model of cognition, we may be able to design de-implementation strategies matched to clinicians' decision-making processes and avoid unintended consequence.
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Tomada de Decisão Clínica , Cognição , Formação de Conceito , Aprendizagem , Uso Excessivo dos Serviços de Saúde/prevenção & controle , Médicos , Humanos , Modelos Psicológicos , Médicos/psicologia , Médicos/normas , Padrões de Prática Médica , Prática Profissional/normas , Melhoria de QualidadeRESUMO
PURPOSE: Subretinal prosthetics are designed to electrically stimulate second-order cells, replacing dysfunctional photoreceptors in diseases such as retinitis pigmentosa (RP). For functional vision to occur, this signal must also reach central visual structures. In the current study, a subretinally implanted prosthetic was evaluated in the Royal College of Surgeons (RCS) rat model of RP, to determine its capacity to activate the retinotectal pathway. METHODS: Prosthetic implants were placed in RCS and wild-type (WT) rats at 4 weeks of age and evaluated 3 months later. Control rats underwent sham surgery, implantation with inactive prosthetics, or no treatment. Implant- and visible-evoked responses were isolated and evaluated in the superior colliculus (SC). RESULTS: In WT and RCS rats with active prosthetics, implant-driven responses were found in 100% of WT and 64% of RCS rats and were confined to a small SC region that corresponded to the retinal sector containing the implant and differed from visible-evoked responses. In addition, visible-evoked responses were more robust at sites that received implant input compared to sites that did not. These effects were not seen in WT rats or RCS control animals; although a general trophic effect on the number of responsive sites was observed in all RCS rats with surgery compared to untreated RCS rats. CONCLUSIONS: Direct activation of the retina by a subretinal implant induces activity in the SC of RCS rats, suggesting that these implants have some capacity to replace dysfunctional photoreceptors. The data also provide evidence for implant-induced neurotrophic effects as a consequence of both its presence and its activity in the retina.
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Terapia por Estimulação Elétrica/métodos , Eletrodos Implantados , Potenciais Evocados Visuais/fisiologia , Implantação de Prótese , Retina/fisiopatologia , Retinose Pigmentar/fisiopatologia , Vias Visuais/fisiologia , Animais , Microeletrodos , Estimulação Luminosa , Ratos , Ratos Long-Evans , Ratos Mutantes , Retinose Pigmentar/cirurgia , Colículos Superiores/fisiologiaRESUMO
PURPOSE: Tubby-like proteins (TULPs) are a family of four proteins, two of which have been linked to neurosensory disease phenotypes. TULP1 is a photoreceptor-specific protein that is mutated in retinitis pigmentosa, an inherited retinal disease characterized by the degeneration of rod and cone photoreceptor cells. To investigate the function of TULP1 in maintaining the health of photoreceptors, the authors sought the identification of interacting proteins. METHODS: Immunoprecipitation from retinal lysates, followed by liquid chromatography tandem mass spectrometry and in vitro binding assays, were used to identify TULP1 binding partners. RT-PCR was performed on total RNA from wild-type mouse retina to identify the Dynamin-1 isoform expressed in the retina. Immunocytochemistry was used to determine the localization of TULP1 and Dynamin-1 in photoreceptor cells. Electroretinography (ERG) and light microscopy were used to phenotype tulp1-/- mice at a young age. RESULTS: Immunoprecipitation from retinal lysate identified Dynamin-1 as a possible TULP1 binding partner. GST pull-down assays further supported an interaction between TULP1 and Dynamin-1. In photoreceptor cells, Dynamin-1 and TULP1 colocalized primarily to the outer plexiform layer, where photoreceptor terminals synapse on second-order neurons and, to a lesser extent, to the inner segments, where polarized protein translocation occurs. ERG analyses in young tulp1-/- mice indicated a decreased b-wave at ages when the retina retained a full complement of photoreceptor cells. CONCLUSIONS: These data indicated that TULP1 interacts with Dynamin-1 and suggested that TULP1 is involved in the vesicular trafficking of photoreceptor proteins, both at the nerve terminal during synaptic transmission and at the inner segment during protein translocation to the outer segment. These results also raised the possibility that normal synaptic function requires TULP1, and they motivate a closer look at synaptic architecture in the developing tulp1-/- retina.
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Dinamina I/metabolismo , Proteínas do Olho/metabolismo , Neurônios/metabolismo , Células Fotorreceptoras de Vertebrados/metabolismo , Retina/metabolismo , Sequência de Aminoácidos , Animais , Western Blotting , Dinamina I/química , Eletroforese em Gel de Poliacrilamida , Eletrorretinografia , Feminino , Técnica Indireta de Fluorescência para Anticorpo , Imunoprecipitação , Masculino , Camundongos , Camundongos Knockout , Dados de Sequência Molecular , Plasmídeos , Ligação Proteica , Isoformas de Proteínas , RNA Mensageiro/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase ReversaRESUMO
Protein O-mannose beta1,2-N-acetyglucosaminyltransferase 1 (POMGnT1) is an enzyme involved in the synthesis of O-mannosyl glycans. Mutations of POMGnT1 in humans result in the muscle-eye-brain (MEB) disease. In this study, we have characterized a null mutation generated by gene trapping with a retroviral vector inserted into the second exon of the mouse POMGnT1 locus. Expression of POMGnT1 mRNA was abolished in mutant mice. Glycosylation of alpha-dystroglycan was also reduced. POMGnT1 mutant mice were viable with multiple developmental defects in muscle, eye, and brain, similar to the phenotypes observed in human MEB disease. The present study provides the first genetic animal model to further dissect the roles of POMGnT1 in MEB disease.
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Encefalopatias/patologia , Modelos Animais de Doenças , Oftalmopatias/patologia , Fertilidade , Doenças Musculares/patologia , N-Acetilglucosaminiltransferases/genética , Animais , Encéfalo/patologia , Cerebelo/patologia , Distroglicanas/genética , Glicosilação , Homozigoto , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Músculo Esquelético/patologia , Distrofia Muscular Animal/genética , Distrofia Muscular Animal/patologia , Prosencéfalo/patologiaRESUMO
Phosphenes ("light flashes") have been reported by most astronauts on space missions and by healthy subjects whose eyes were exposed to ionizing radiation in early experiments in particle accelerators. The conditions of occurrence suggested retinal effects of heavy ions. To develop an in vivo animal model, we irradiated the eyes of anesthetized wild-type mice with repeated bursts of 12C ions delivered under controlled conditions in accelerator. 12C ions evoked electrophysiological retinal mass responses and activated the visual system as indicated by responses recorded from the visual cortex. No retinal immunohistological damage was detected. Mice proved a suitable animal model to study radiation-induced phosphenes in vivo and our findings are consistent with an origin of phosphenes in radiation activating the retina.
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Carbono , Íons Pesados , Retina/efeitos da radiação , Córtex Visual/fisiologia , Animais , Eletrorretinografia/métodos , Feminino , Camundongos , Camundongos Endogâmicos C57BL , Proteínas do Tecido Nervoso/metabolismo , Fosfenos/efeitos da radiação , Retina/anatomia & histologia , Córtex Visual/efeitos da radiação , Vias Visuais/fisiologia , Vias Visuais/efeitos da radiaçãoRESUMO
PURPOSE: Retinal prosthetics have been designed to interface with the neural retina by electrically stimulating the remaining retinal circuits after photoreceptor degeneration. However, the electrical stimulation provided by the subretinal implant may also stimulate neurotrophic factors that provide neuroprotection to the retina. This study was undertaken to determine whether electrical stimulation from a subretinal photodiode-based implant has a neuroprotective effect on photoreceptors in the RCS rat, a model of photoreceptor degeneration. METHODS: Eyes of RCS rats were implanted with an active or inactive device or underwent sham surgery before photoreceptor degeneration. Outer retinal function was assessed with electroretinogram (ERG) recordings weekly until 8 weeks after surgery, at which time retinal tissue was collected and processed for morphologic assessment, including photoreceptor cell counts and retinal layer thickness. RESULTS: At 4 to 6 weeks after surgery, the ERG responses in the active-implant eyes were 30% to 70% greater in b-wave amplitude than the responses from eyes implanted with inactive devices, those undergoing sham surgery, or the nonsurgical control eyes. At 8 weeks after surgery the ERG responses from active-implant eyes were not significantly different from the control groups. However, the number of photoreceptors in eyes implanted with the active or inactive device was significantly greater in the regions over and around the implant versus sham-surgical and nonsurgical control eyes. CONCLUSIONS: These results suggest that subretinal electrical stimulation provides temporary preservation of retinal function in the RCS rat. In addition, implantation of an active or inactive device into the subretinal space causes morphologic preservation of photoreceptors in the RCS rat until 8 weeks after surgery. Further studies are needed to determine whether the correlation of neuropreservation with subretinal implantation is due to electrical stimulation and/or a mechanical presence of the implant in the subretinal space.
Assuntos
Terapia por Estimulação Elétrica/métodos , Eletrodos Implantados , Próteses e Implantes , Retina/fisiopatologia , Degeneração Retiniana/prevenção & controle , Animais , Contagem de Células , Modelos Animais de Doenças , Eletrorretinografia , Fármacos Neuroprotetores , Células Fotorreceptoras de Vertebrados/patologia , Implantação de Prótese , Ratos , Ratos Mutantes , Retina/cirurgia , Degeneração Retiniana/fisiopatologiaRESUMO
Current retinal prosthetics are designed to stimulate existing neural circuits in diseased retinas to create a visual signal. However, implantation of retinal prosthetics may create a neurotrophic environment that also leads to improvements in visual function. Possible sources of increased neuroprotective effects on the retina may arise from electrical activity generated by the prosthetic, mechanical injury due to surgical implantation, and/or presence of a chronic foreign body. This study evaluates these three neuroprotective sources by implanting Royal College of Surgeons (RCS) rats, a model of retinitis pigmentosa, with a subretinal implant at an early stage of photoreceptor degeneration. Treatment groups included rats implanted with active and inactive devices, as well as sham-operated. These groups were compared to unoperated controls. Evaluation of retinal function throughout an 18 week post-implantation period demonstrated transient functional improvements in eyes implanted with an inactive device at 6, 12 and 14 weeks post-implantation. However, the number of photoreceptors located directly over or around the implant or sham incision was significantly increased in eyes implanted with an active or inactive device or sham-operated. These results indicate that in the RCS rat localized neuroprotection of photoreceptors from mechanical injury or a chronic foreign body may provide similar results to subretinal electrical stimulation at the current output evaluated here.
Assuntos
Estimulação Elétrica/instrumentação , Reação a Corpo Estranho/fisiopatologia , Plasticidade Neuronal/fisiologia , Células Fotorreceptoras de Vertebrados/fisiologia , Próteses e Implantes , Recuperação de Função Fisiológica/fisiologia , Retinose Pigmentar/patologia , Animais , Estimulação Elétrica/métodos , Reação a Corpo Estranho/patologia , Células Fotorreceptoras de Vertebrados/citologia , Ratos , Retinose Pigmentar/fisiopatologia , SilícioRESUMO
Astronauts in orbit reported phosphenes varying in shape and orientation across the visual field; incidence was correlated with the radiation flux. Patients with skull tumors treated by (12)C ions and volunteers whose posterior portion of the eye was exposed to highly ionizing particles in early studies reported comparable percepts. An origin in radiation activating the visual system is suggested. Bursts (â¼ 4 ms) of (12)C ions evoked electrophysiological mass responses comparable to those to light in the retina of anesthetized wild-type mice at threshold flux intensities consistent with the incidence observed in humans. The retinal response amplitude increased in mice with ion intensity to a maximum at â¼ 2000 ions/burst, to decline at higher intensities; the inverted-U relationship suggests complex effects on retinal structures. Here, we show that bursts of (12)C ions presented simultaneously to white light stimuli reduced the presynaptic mass response to light in the mouse retina, while increasing the postsynaptic retinal and cortical responses amplitude and the phase-locking to stimulus of cortical low frequency and gamma (â¼ 25-45 Hz) responses. These findings suggest (12)C ions to interfere with, rather than mimicking the light action on photoreceptors; a parallel action on other retinal structures/mechanisms resulting in cortical activation is conceivable. Electrophysiological visual testing appears applicable to monitor the radiation effects and in designing countermeasures to prevent functional visual impairment during operations in space.
Assuntos
Carbono , Luz , Retina/efeitos da radiação , Animais , Eletrorretinografia , Feminino , Íons , Camundongos Endogâmicos C57BL , Fosfenos/fisiologia , Retina/fisiologiaRESUMO
PURPOSE: In humans, mutations in protocadherin 15 are known to result in Usher Syndrome type 1F (USH1F). Patients with USH1F are born with profound hearing loss and have visual problems that develop in late childhood. Based on the phenotypic hearing loss and an associated mutation in protocadherin 15 (Pcdh15), the Ames waltzer mice have been presented as potential models for USH1F. To determine whether the Ames waltzer is a model for retinopathy in USH1F, retinal structure and function were assessed in all four available alleles of the mouse. METHODS: Activity of both the rod and cone pathways was evaluated by measuring electroretinograms (ERGs) in response to strobe flashes under dark- and light-adapted conditions, respectively. Retinas were processed with standard histochemical procedures, and retinal morphology was examined. The neural retina was dissected from normal pigmented mice at postnatal day (P)0, P5, P7, P20, P40, and P70, and the presence of Pcdh15 was determined by RT-PCR. RESULTS: The amplitude and implicit time of both the rod- and cone-mediated ERG a- and b-waves were comparable between Ames waltzer mutants and heterozygous littermates as old as 13 months. No evidence of retinal degeneration or disorganization was detected in mutant mice. Measures of retinal layer thicknesses were similar in mutant and wild-type control animals. Retinal expression of Pcdh15 was observed at all ages examined between P0 and P70. CONCLUSIONS: Although Pcdh15 is present in neural retina, its role remains unclear. Mutations in the Pcdh15 did not result in retinal abnormalities in the four alleles of Ames waltzer tested in this study. The explanation for the absence of retinal phenotype in the Ames mouse should be helpful in understanding USH1F and developing treatments for this disorder.