Clinician and staff experiences with frustrated patients during an electronic health record transition: a qualitative case study.

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.

VA Outreach Is an Essential Area for Improving Veterans' Health Care Accessibility.

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.

Refining the Implementation of a Hub-and-Spoke Model for TelePain Through Qualitative Inquiry.

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.

Healthcare providers experiences with shared medical appointments for heart failure.

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.

Implementation of a patient-collected audio recording audit & feedback quality improvement program to prevent contextual error: stakeholder perspective.

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.

A pilot study using telehealth to implement antimicrobial stewardship at two rural Veterans Affairs medical centers.

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.

How the dual process model of human cognition can inform efforts to de-implement ineffective and harmful clinical practices: A preliminary model of unlearning and substitution.

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.

Adaptation of Lean Six Sigma Methodologies for the Evaluation of Veterans Choice Program at 3 Urban Veterans Affairs Medical Centers.

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.

Interaction of (12)C ions with the mouse retinal response to light.

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 (∼ 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 ∼ 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 (∼ 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.

Prior housing conditions and sleep loss may affect recovery from brain injury in rats: a pilot study.

The purpose of this study is to understand the effect of combat-associated conditions such as sleep deprivation (SD) on subsequent traumatic brain injury (TBI). Prior to TBI (or sham surgery) induced by controlled cortical impact (CCI), rats were housed singly in chambers that prevented rapid eye movement sleep or allowed unrestricted sleep (no SD). Sensorimotor function was tested pre-SD and retested on postoperative days (PDs) 4, 7, and 14. Two additional control groups were housed socially prior to either CCI or sham surgery. CCI resulted in immediate performance deficits on sensorimotor tasks. The PD on which performance returned to baseline depended on preinjury conditions. Overall, preinjury SD+CCI resulted in an earlier recovery than no SD+CCI, and the no SD+CCI group (housed singly under conditions comparable with the SD group) recovered slower than all other groups. These data are the first to raise the possibility that recovery of sensorimotor function following TBI is affected by preinjury conditions. The data suggest that preinjury SD 24 h in duration may result in faster recovery and that novel or social isolation conditions may impede recovery. Thus, the combat environment may contribute to complexities associated with TBIs common in U.S. servicemembers.

Distribution of voltage gated calcium channel ß subunits in the mouse retina.

Voltage gated calcium channels (VGCCs) are essential to neuronal excitation and signal transduction. They are multimeric in structure and comprised of an alpha subunit that functions as a calcium pore and two additional subunits: an alpha2delta subunit and a cytoplasmic beta subunit. To better understand the role of VGCCs in the retina we used immunohistochemical methods to determine the distribution of VGCC ß subunits in normal and mutant mice. To verify the specificity of each antibody and to examine the potential for subunit redistribution when beta subunit expression is perturbed, we used 4 mutant mouse lines that each lack a specific ß subunit isoform (ß(1)-ß(4)). We found the ß(1) subunit distributed on cell bodies in the inner nuclear layer (INL) and on processes within both the inner and outer limiting membrane; the ß(2) subunit localized to the outer plexiform layer (OPL) and inner plexiform layer (IPL); the ß(3) subunit was localized to three narrow and distinct bands within the IPL; the ß(4) subunit was localized to three diffuse bands within the IPL. Loss of one ß subunit affected labeling intensity but not general distribution patterns of other ß subunits. It is likely that VGCCs critical for retinal signal transmission are comprised of the ß(2) subunit in the OPL and any of the 4 ß subunits in the IPL. Our results suggest that within the OPL the α(1F) subunit pairs predominantly with the ß(2) subunit while within the IPL it may pair with either any ß subunit.

Retinal ectopias and mechanically weakened basement membrane in a mouse model of muscle-eye-brain (MEB) disease congenital muscular dystrophy.

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.

Interaction between the photoreceptor-specific tubby-like protein 1 and the neuronal-specific GTPase dynamin-1.

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.

Electrophysiological responses of the mouse retina to 12C ions.

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.

Stimulation via a subretinally placed prosthetic elicits central activity and induces a trophic effect on visual responses.

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.

Topical administration of nepafenac inhibits diabetes-induced retinal microvascular disease and underlying abnormalities of retinal metabolism and physiology.

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.

A genetic model for muscle-eye-brain disease in mice lacking protein O-mannose 1,2-N-acetylglucosaminyltransferase (POMGnT1).

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.

Status of the feline retina 5 years after subretinal implantation.

Retinal prosthetics are designed to restore functional vision to patients with photoreceptor degeneration by detecting light and stimulating the retina. Since devices are surgically implanted into the eye, long-term biocompatibility and durability are critical for viable treatment of retinal disease. To extend our previous work, which demonstrated the biocompatibility of a microphotodiode array (MPA) for 10 to 27 months in the normal feline retina, we implanted normal cats with an MPA implant backed with either an iridium oxide or platinum electrode and examined retinal function and biocompatibility for 3 to 5 years. All implants functioned throughout the study period. Retinal function remained steady and normal with a less than 15 percent decrease in electroretinogram response. The retinas had normal laminar structure with no signs of inflammation or rejection in areas adjacent to or distant from the implants. Directly over the implants, a loss of photoreceptor nuclei and remodeling of inner retinal layers existed. These results indicate that the subretinal MPA device is durable and well tolerated by the retina 5 years postimplantation.

Pharmacological studies of the mouse cone electroretinogram.

Electroretinography provides a useful noninvasive approach to evaluate cone pathway activity. Despite wide application of the cone ERG to characterize retinal function in transgenic mice and mouse models of human hereditary retinal disease, the cellular origins of the mouse cone ERG have not been well defined. Here, we address this issue using a pharmacological approach that has been previously applied to other species. Agents that block receptor activation at well-defined retinal loci were dissolved in saline and injected into the vitreous of anesthetized adult BALBc/By J mice; cone ERGs were recorded 1-2 h later. Analysis of the resulting waveforms indicated that the mouse cone ERG includes a cornea-negative component that is derived from the activity of cone photoreceptors and retinal glial (Müller) cells. Similar to other species, activity of cone depolarizing bipolar cells contributes a large amplitude cornea-positive potential to the mouse cone ERG. In contrast to primate but similar to rat, the mouse cone ERG includes only a small contribution from hyperpolarizing bipolar cell activity. The inner retina appears to contribute to both the a- and b-waves of the mouse cone ERG. These results provide a foundation for interpreting changes in the waveform of the mouse cone ERG that may be observed following genetic alteration or other experimental treatment.