PHASE 2 STUDY OF THE SAFETY AND EFFICACY OF BRIMONIDINE DRUG DELIVERY SYSTEM (BRIMO DDS) GENERATION 1 IN PATIENTS WITH GEOGRAPHIC ATROPHY SECONDARY TO AGE-RELATED MACULAR DEGENERATION.

PURPOSE: To evaluate the safety and efficacy of Brimonidine Drug Delivery System (Brimo DDS), a biodegradable intravitreal implant, in the treatment of geographic atrophy (GA) secondary to age-related macular degeneration. METHODS: Phase 2, randomized, multicenter, double-masked, 24-month study. Study eyes were treated (Day 1; Month 6 retreatment) with Brimo DDS 132 µg (n = 49), Brimo DDS 264 µg (n = 41), or sham procedure (n = 23). The primary timepoint for efficacy analysis was Month 12. RESULTS: Mean GA area growth at Month 12 was 1.78 mm2, 1.59 mm2, and 2.19 mm2 in the Brimo DDS 132 µg, 264 µg, and sham groups, respectively. Geographic atrophy area growth was consistently smaller with Brimo DDS 132 and 264 µg than sham; between-group differences were significant (P ≤ 0.032) at Month 3. In patients with baseline lesion area ≥6 mm2 (two-thirds of patients), GA lesion area and effective radius growth was reduced with Brimo DDS 132 and 264 µg at Month 12 (P ≤ 0.050 vs. sham). Treatment-related adverse events were usually injection procedure-related. CONCLUSION: Brimo DDS demonstrated a favorable safety profile and reduced GA lesion area growth at Month 3. Lesion growth at Month 12 was reduced in patients with baseline GA lesion area ≥6 mm2. The results support Phase 3 development.

Intravitreal administration of small molecule read-through agents demonstrate functional activity in a nonsense mutation mouse model.

The prevalence of nonsense mutations as a class within genetic diseases such as inherited retinal disorders (IRDs) presents an opportunity to develop a singular, common therapeutic agent for patients whose treatment options are otherwise limited. We propose a novel approach to addressing IRDs utilizing Eukaryotic Ribosome Selective Glycosides, ELX-01 and ELX-06, delivered to the eye by intravitreal (IVT) injection. We assessed read-through activity in vitro using a plasmid-based dual luciferase assay and in vivo in a mouse model of oculocutaneous albinism type 2. These models interrogate a naturally occurring R262X nonsense mutation in the OCA2 gene. ELX-01 and ELX-06 both produced a concentration-dependent increase in read-through of the OCA2 R262X mutation in the dual luciferase assay, with an effect at the top concentration which is superior to both gentamicin and G418. When testing both compounds in vivo, a single IVT injection produced a dose-dependent increase in melanin, consistent with compound read-through activity and functional restoration of the Oca2 protein. These results establish that ELX-01 and ELX-06 produce read-through of a premature stop codon in the OCA2 gene both in vitro and in vivo. The in vivo results suggest that these compounds can be dosed IVT to achieve read-through at the back of the eye. These data also suggest that ELX-01 or ELX-06 could serve as a common therapeutic agent across nonsense mutation-mediated IRDs and help to establish a target exposure range for development of a sustained release IVT formulation.

Preoperative Carbohydrate Loading in Patients Undergoing Thoracic Surgery: A Quality-Improvement Project.

PURPOSE: The purpose of this project was to implement carbohydrate loading in patients undergoing thoracic surgery in an effort to decrease postoperative pain, nausea, and length of stay as a part of an enhanced recovery after surgery protocol. DESIGN: This quality-improvement project used a preintervention and postintervention design. METHODS: Carbohydrate loading was given to 50 patients before undergoing thoracic surgery. Chart review was performed for 47 patients who received standard preoperative instructions in the preintervention group as historical control. FINDINGS: Patients who received carbohydrate loading had a decreased use of opioids in the first 4 hours after surgery (P = .028) and decreased use of antiemetic medication in the first 24 hours after surgery compared with the preintervention group (P = .066). Patients who were instructed to consume carbohydrate loading complied 87% of the time. CONCLUSIONS: Carbohydrate loading can decrease postoperative nausea and pain in patients undergoing thoracic surgery.

Oral Memantine for the Treatment of Glaucoma: Design and Results of 2 Randomized, Placebo-Controlled, Phase 3 Studies.

PURPOSE: To evaluate the effectiveness and safety of oral memantine as a potential neuroprotective agent in open-angle glaucoma (OAG) at risk for progression. DESIGN: Two randomized, double-masked, placebo-controlled, parallel-group, multicenter, 48-month studies identically designed, initiated 1 year apart, and completed in 2006. Protocol amendments included a 1-year extension (first study) and change in primary endpoint and analysis (second study). PARTICIPANTS: Patients (2298 total) with bilateral OAG; glaucomatous optic disc damage and visual field loss in 1 eye; glaucomatous optic disc damage and/or visual field loss in the contralateral eye (at screening), topically treated or untreated intraocular pressure (IOP) of 21 mmHg or less (at baseline); and at risk of glaucomatous progression (per prespecified criteria). METHODS: Patients were randomized 3:2:2 to receive memantine 20 mg, memantine 10 mg, or placebo tablets daily. Glaucomatous progression was assessed in the intent-to-treat population by full-threshold standard automated perimetry (SAP), frequency doubling technology (FDT), and stereoscopic optic disc photographs, standardized by quality control assessment at centralized reading centers. Safety evaluations included adverse events (AEs), best-corrected visual acuity, biomicroscopy, IOP, and ophthalmoscopy. Efficacy data from each study were analyzed per protocol. Pooled analyses of efficacy and safety data were also performed. MAIN OUTCOME MEASURES: The predefined primary efficacy measure was glaucomatous visual field progression, as measured by SAP. Additional efficacy measures included glaucomatous progression of visual field (FDT) and optic nerve damage (stereoscopic optic disc photographs). RESULTS: The proportion of patients who completed the studies was similar among groups (80%-83%). Compared with placebo, daily treatment with memantine 10 mg or 20 mg for 48 months did not delay glaucomatous progression significantly in the individual studies and pooled analyses. The pooled risk reduction ratio (95% confidence interval) assessed by SAP was -0.13 (-0.40, 0.09) and -0.17 (-0.46, 0.07) for memantine 10 mg and 20 mg, respectively. Results were similar per FDT and stereoscopic optic disc photographs. The most common AEs leading to treatment discontinuations were dizziness, headache, fatigue, and nausea. CONCLUSIONS: With technologies available when the studies were conducted, daily treatment with memantine over 48 months was not shown to prevent glaucomatous progression in this patient population.

The Effects of a Take-Home Educational Video on Patient Knowledge Retention, Anxiety, Satisfaction, and Provider Time.

Patient anxiety related to prostate cancer surgery may lead to reduced patient satisfaction. Repeated reinforcement of pre-operative education to reduce anxiety greatly impacts provider time. Improved knowledge retention of what to expect postoperatively may reduce patient anxiety. This quality improvement project demonstrated that a take-home educational video supports patient knowledge retention, reduces patient anxiety, increases patient satisfaction, and saves postoperative provider time

Adherence to antiemetic guidelines in patients with malignant glioma: a quality improvement project to translate evidence into practice.

PURPOSE: A quality improvement project was implemented to improve adherence to evidence-based antiemetic guidelines for malignant glioma patients treated with moderately emetic chemotherapy (MEC). Poorly controlled chemotherapy-induced nausea and vomiting (CINV) reduce cancer treatment efficacy and significantly impair cancer patients' quality of life (QOL). A review of Duke University Preston Robert Tisch Brain Tumor Center (PRTBTC)'s usual practice demonstrates a high incidence (45%) of CINV, despite premedication with short-acting 5-HT3-serotonin-receptor antagonists (5-HT3-RAs). National Comprehensive Cancer Network (NCCN)'s evidence-based guidelines recommend the combination of the long-acting 5-HT3-RA palonosetron (PAL) and dexamethasone (DEX) for the prevention of acute and delayed CINV with MEC. Low adherence (58%) to antiemetic guidelines may have explained our high CINV incidence. METHODS: One-sample binomial test, quasi-experimental design, evaluated a combination intervention that included a provider education session; implementation of risk-assessment tool with computerized, standardized antiemetic guideline order sets; and a monthly audit-feedback strategy. Post-implementation adherence to evidence-based antiemetic order sets and patient outcomes were measured and compared to baseline and historical data. Primary outcome was the guideline order set adherence rate. Secondary outcomes included nausea/vomiting rates and QOL. RESULTS: Adherence to ordering MEC guideline antiemetics increased significantly, from 58% to a sustained 90%, with associated improvement in nausea/vomiting. In acute and delayed phases, 75 and 84% of patients, respectively, did not experience CINV. There was no significant change in QOL. CONCLUSION: Combination intervention and audit-feedback strategy to translate evidence into oncology practice improved and sustained adherence to antiemetic guidelines. Adherence corresponded with effective nausea/vomiting control and preserved QOL in patients with malignant gliomas.

The experience and self-management of fatigue in patients on hemodialysis.

Fatigue is a common and debilitating symptom for adult patients with end stage renal disease on hemodialysis, and has been associated with decreased survival and quality of life. Patients on hemodialysis must find ways to manage their fatigue and mitigate its effects on their lives. The purpose of this qualitative descriptive work was to describe the experience and self-management of fatigue in patients on incenter hemodialysis. Several themes were identified which included the nature of fatigue, management of fatigue, consequences of fatigue, and factors associated with fatigue. This information will be valuable to nephrology nurses as they continue to care for and educate patients on hemodialysis.

The Development and Integration of a Safety Officer Role to Facilitate Prevention of COVID-19 Virus Transmission in an Adult Inpatient Rehabilitation Setting Using Collaborative Change Leadership Methodology.

BACKGROUND: With the onset of the COVID-19 pandemic, a large urban academic hospital responded by creating the temporary role of a "Safety Officer (SO)." The key task of the SO role was to supervise staff donning and doffing personal protective equipment (PPE) and provide real-time feedback on their performance. The support for safe donning and doffing would contribute to staff well-being by reducing their fear of infection transmission. METHODS: A Collaborative Change Leadership (CCL) approach was used to facilitate the development, implementation, and evaluation of the role. This included an iterative feedback process with clinicians and safety officers to continually refine the role. FINDINGS: Feedback indicated value in the initiative as increasing staff confidence about preventing virus transmission, as well as their sense of safety at work. Areas for future improvement included additional communication strategies for interprofessional teams and external partners, as well as planning around logistics to better support the safety officers in performing this new, temporary role. CONCLUSIONS/APPLICATION TO PRACTICE: The Safety Officer role was able to help alleviate concerns regarding potential infection transmission and contribute positively to staff well-being.

Leveraging conscious and nonconscious learning for efficient AI.

Various interpretations of the literature detailing the neural basis of learning have in part led to disagreements concerning how consciousness arises. Further, artificial learning model design has suffered in replicating intelligence as it occurs in the human brain. Here, we present a novel learning model, which we term the "Recommendation Architecture (RA) Model" from prior theoretical works proposed by Coward, using a dual-learning approach featuring both consequence feedback and non-consequence feedback. The RA model is tested on a categorical learning task where no two inputs are the same throughout training and/or testing. We compare this to three consequence feedback only models based on backpropagation and reinforcement learning. Results indicate that the RA model learns novelty more efficiently and can accurately return to prior learning after new learning with less computational resources expenditure. The final results of the study show that consequence feedback as interpretation, not creation, of cortical activity creates a learning style more similar to human learning in terms of resource efficiency. Stable information meanings underlie conscious experiences. The work provided here attempts to link the neural basis of nonconscious and conscious learning while providing early results for a learning protocol more similar to human brains than is currently available.

Consciousness beyond the human case.

There is growing interest in the relationship been AI and consciousness. Joseph LeDoux and Jonathan Birch thought it would be a good moment to put some of the big questions in this area to some leading experts. The challenge of addressing the questions they raised was taken up by Kristin Andrews, Nicky Clayton, Nathaniel Daw, Chris Frith, Hakwan Lau, Megan Peters, Susan Schneider, Anil Seth, Thomas Suddendorf, and Marie Vanderkerckhoeve.

Genomic epidemiology reveals the dominance of Hennepin County in transmission of SARS-CoV-2 in Minnesota from 2020-2022.

SARS-CoV-2 has had an unprecedented impact on human health and highlights the need for genomic epidemiology studies to increase our understanding of virus evolution and spread, and to inform policy decisions. We sequenced viral genomes from over 22,000 patient samples tested at Mayo Clinic Laboratories between 2020-2022 and use Bayesian phylodynamics to describe county and regional spread in Minnesota. The earliest introduction into Minnesota was to Hennepin County from a domestic source around January 22, 2020; six weeks before the first confirmed case in the state. This led to the virus spreading to Northern Minnesota, and eventually, the rest of the state. International introductions were most abundant in Hennepin (home to the Minneapolis/St. Paul International (MSP) airport) totaling 45 (out of 107) over the two-year period. Southern Minnesota counties were most common for domestic introductions with 19 (out of 64), potentially driven by bordering states such as Iowa and Wisconsin as well as Illinois which is nearby. Hennepin also was, by far, the most dominant source of in-state transmissions to other Minnesota locations (n=772) over the two-year period. We also analyzed the diversity of the location source of SARS-CoV-2 viruses in each county and noted the timing of state-wide policies as well as trends in clinical cases. Neither the number of clinical cases or major policy decisions, such as the end of the lockdown period in 2020 or the end of all restrictions in 2021, appeared to have impact on virus diversity across each individual county.

Genomic epidemiology reveals the dominance of Hennepin County in the transmission of SARS-CoV-2 in Minnesota from 2020 to 2022.

IMPORTANCE: We analyzed over 22,000 severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) genomes of patient samples tested at Mayo Clinic Laboratories during a 2-year period in the COVID-19 pandemic, which included Alpha, Delta, and Omicron variants of concern to examine the roles and relationships of Minnesota virus transmission. We found that Hennepin County, the most populous county, drove the transmission of SARS-CoV-2 viruses in the state after including the formation of earlier clades including 20A, 20C, and 20G, as well as variants of concern Alpha and Delta. We also found that Hennepin County was the source for most of the county-to-county introductions after an initial predicted introduction with the virus in early 2020 from an international source, while other counties acted as transmission "sinks." In addition, major policies, such as the end of the lockdown period in 2020 or the end of all restrictions in 2021, did not appear to have an impact on virus diversity across individual counties.

Implementing the Condensed Memorial Symptom Assessment Scale on an Inpatient Oncology Unit.

BACKGROUND: Symptom distress places a burden on patients and their families, but it is often not captured in nursing documentation. Using a symptom management tool, such as the Condensed Memorial Symptom Assessment Scale (CMSAS), can assist in this capture and link patients to resources. OBJECTIVES: The purpose of this quality improvement (QI) project was to implement the CMSAS and capture symptom burden to create a streamlined method of documentation. METHODS: A QI pilot was conducted on an inpatient oncology unit implementing the CMSAS. Then, surveys were provided to the patients to complete at admission and discharge. The most distressing symptoms patients reported were added into the electronic health record nursing care plan that automatically uploaded interventions based on ONS Guidelines™. FINDINGS: Patient (N = 73) symptom distress was quickly tracked, and there were no statistically significant changes in patient distress from admission to discharge, except for two symptoms.

Two (or more) for one: Identifying classes of household energy- and water-saving measures to understand the potential for positive spillover.

A key component of behavior-based energy conservation programs is the identification of target behaviors. A common approach is to target behaviors with the greatest energy-saving potential. The concept of behavioral spillover introduces further considerations, namely that adoption of one energy-saving behavior may increase (or decrease) the likelihood of other energy-saving behaviors. This research aimed to identify and describe household energy- and water-saving measure classes within which positive spillover is likely to occur (e.g., adoption of energy-efficient appliances may correlate with adoption of water-efficient appliances), and explore demographic and psychographic predictors of each. Nearly 1,000 households in a California city were surveyed and asked to report whether they had adopted 75 different energy- and/or water-saving measures. Principal Component Analysis and Network Analysis based on correlations between adoption of these diverse measures revealed and characterized eight water-energy-saving measure classes: Water Conservation, Energy Conservation, Maintenance and Management, Efficient Appliance, Advanced Efficiency, Efficient Irrigation, Green Gardening, and Green Landscaping. Understanding these measure classes can help guide behavior-based energy program developers in selecting target behaviors and designing interventions.

Use of a fluorescence imaging device to detect elevated bacterial loads, enhance antimicrobial stewardship, and increase communication across inpatient complex wound care teams.

INTRODUCTION: Wounds are increasing in number and complexity within the hospital inpatient system, and coordinated and dedicated wound care along with the use of emerging technologies can result in improved patient outcomes. OBJECTIVE: This prospective implementation study at 2 hospital inpatient sites examines the effect of bedside fluorescence imaging of wounds in the detection of elevated bacterial loads and its location in/around the wound on the inpatient wound population. MATERIALS AND METHODS: Clinical assessment and fluorescence imaging assessments were performed on 26 wounds in 21 patients. Treatment plans were recorded after the clinical assessment and again after fluorescence imaging, and any alterations made to the treatment plans after imaging were noted. RESULTS: Prior to fluorescence imaging, antimicrobial use in this patient population was common. An antimicrobial dressing, a topical antibiotic, or an oral antibiotic was prescribed in 23 wounds (88% of assessments), with antimicrobial dressings prescribed 73% of the time. Based on clinical assessment, more than half of the treated wounds were deemed negative for suspected infection. In 12 of 26 wounds, the fluorescence imaging information on bacterial presence had the potential to prompt a change in whether an antimicrobial dressing was prescribed. Five of these 12 wounds were fluorescence imaging-positive and an antimicrobial drug was not prescribed, whereas 7 of the 12 wounds were negative upon fluorescence imaging and clinical assessment but antimicrobial dressing was prescribed. Overall, fluorescence imaging detected 70% more wounds, with bacterial fluorescence indicating elevated bacterial loads, compared with clinical assessment alone, and use of imaging resulted in altered treatment plans in 35% of cases. CONCLUSIONS: Fluorescence imaging can aid in antimicrobial stewardship goals by supporting evidence-based decision-making at the point of care. In addition, use of such imaging resulted in increased communication, enhanced efficiency, and improved continuity of care between wound care providers and hospital sites.

ONS Guidelines™ to Support Patient Adherence to Oral Anticancer Medications.

PURPOSE: This evidence-based guideline intends to support patients, clinicians, and others regarding interventions and processes to support patient adherence to oral anticancer medications (OAMs). METHODOLOGIC APPROACH: A panel of healthcare professionals and patient representatives developed a clinical practice guideline to support patients taking OAMs. GRADE (Grading of Recommendations Assessment, Development, and Evaluation) methodology and criteria for trustworthy guidelines were followed. Risk of bias was assessed using the Cochrane Risk of Bias 2 tool. A quantitative or narrative synthesis of the evidence was completed. Certainty of the evidence was assessed using GRADE. FINDINGS: The panel agreed on recommendations and suggested an adherence risk assessment, education addressing adherence, ongoing assessment, proactive follow-up, coaching, and motivational interviewing in addition to usual care. The panel suggested the implementation of a structured OAM program. IMPLICATIONS FOR NURSING: As cancer treatment shifts from clinic to home settings, interventions and programs to support patients on OAMs are needed.

CD8alpha+ dendritic cells prime TCR-peptide-reactive regulatory CD4+FOXP3- T cells.

CD4(+) T cells with immune regulatory function can be either FOXP3(+) or FOXP3(-). We have previously shown that priming of naturally occurring TCR-peptide-reactive CD4(+)FOXP3(-) Treg specifically controls Vbeta8.2(+)CD4(+) T cells mediating EAE. However, the mechanism by which these Treg are primed to recognize their cognate antigenic determinant, which is derived from the TCRVbeta8.2-chain, is not known. In this study we show that APC derived from splenocytes of naïve mice are able to stimulate cloned CD4(+) Treg in the absence of exogenous antigen, and their stimulation capacity is augmented during EAE. Among the APC populations, DC were the most efficient in stimulating the Treg. Stimulation of CD4(+) Treg was dependent upon processing and presentation of TCR peptides from ingested Vbeta8.2TCR(+)CD4(+) T cells. Additionally, DC pulsed with TCR peptide or apoptotic Vbeta8.2(+) T cells were able to prime Treg in vivo and mediate protection from disease in a CD8-dependent fashion. These data highlight a novel mechanism for the priming of CD4(+) Treg by CD8alpha(+) DC and suggest a pathway that can be exploited to prime antigen-specific regulation of T-cell-mediated inflammatory disease.

Suspended and localized single nanostructure growth across a nanogap by an electric field.

Direct growth of a suspended single nanostructure (SSN) at a specific location is presented. The SSN is grown across a metallic nanoscale gap by migration in air at room temperature. The nanogap is fabricated by industrial standard optical lithography and anisotropic wet chemical silicon etching. A DC current bias, 1 nA, is applied across the metallic gap to induce nanoscale migration of Zn or ZnO. The history of the voltage drop across the gap as a function of time clearly indicates the moment when migration begins. The shape of SSNs grown across the nanogap by the migration is asymmetric at each electrode due to the asymmetric electric field distribution within the nanogap. An SSN can be used as the platform for two-terminal active or passive nanoscale electronics in optoelectronics, radio frequency (RF) resonators, and chemical/biological sensors.

Effect of virtual reality on time perception in patients receiving chemotherapy.

PURPOSE: Virtual reality (VR) during chemotherapy has resulted in an elapsed time compression effect, validating the attention diversion capabilities of VR. Using the framework of the pacemaker-accumulator cognitive model of time perception, this study explored the influence of age, gender, state anxiety, fatigue, and cancer diagnosis in predicting the difference between actual time elapsed during receipt of intravenous chemotherapy while immersed in a VR environment versus patient's retrospective estimates of time elapsed during this treatment. MATERIALS AND METHODS: This secondary analysis from three studies yielded a pooled sample of N = 137 participants with breast, lung, or colon cancer. Each study employed a crossover design requiring two matched intravenous chemotherapy treatments, with participants randomly assigned to receive VR during one treatment. Regressions modeled the effect of demographic variables, diagnosis, and Piper Fatigue Scale and State Anxiety Inventory scores on the difference between actual and estimated time elapsed during chemotherapy with VR. RESULTS: In a forward regression model, three predictors (diagnosis, gender, and anxiety) explained a significant portion of the variability for altered time perception (F=5.06, p = 0.0008). Diagnosis was the strongest predictor; individuals with breast and colon cancer perceived time passed more quickly. CONCLUSIONS: VR is a noninvasive intervention that can make chemotherapy treatments more tolerable. Women with breast cancer are more likely and lung cancer patients less likely to experience altered time perception during VR (a possible indicator of effectiveness for this distraction intervention). Understanding factors that predict responses to interventions can help clinicians tailor coping strategies to meet each patient's needs.

Effectiveness of a combined home visiting and group intervention for low income African American mothers: the pride in parenting program.

Intervention strategies are needed to improve maternal and infant outcomes in minority populations living in poverty. Home visiting by nurses has improved outcomes for mothers and young children, but use of professional staff makes these programs expensive. Pride in Parenting was a randomized controlled trial of paraprofessional home visitation to provide health and developmental intervention for high-risk African American mothers in Washington, DC. This study proposed to test whether paraprofessional visitors drawn from the community could effectively influence health and mothers' parenting behaviors and attitudes. African American mothers with inadequate prenatal care were recruited at delivery and randomized to intervention or usual care groups. The intervention curriculum was delivered through both home visitation and parent-infant groups for 1 year. The intervention curriculum was designed to improve knowledge, influence attitudes, and promote life skills that would assist low-income mothers in offering better health oversight and development for their infants. Both intervention and usual care groups received monthly social work contact over the one-year study period to provide referrals for identified needs. The intervention participants improved their home environments, a characteristic important for promoting good child development. Mothers' perceptions of available social support improved and child-rearing attitudes associated with child maltreatment were reduced. Paraprofessional home visitors can be successful in improving the child-rearing environments and parenting attitudes for infants at risk, perhaps offering a less costly option to professional home visitors.