Implementation and review of the care ecosystem in an integrated healthcare system.

BACKGROUND AND OBJECTIVES: The University of California, San Francisco Memory and Aging Center (UCSF-MAC) led the development and tested a collaborative care model delivered by lay care team navigators (CTNs) with support from a multidisciplinary team known as the Care Ecosystem (CE). We evaluated outcomes related to the feasibility of the CE in a non-academic healthcare system, including acceptability, adoption, and fidelity to the original UCSF model. RESEARCH DESIGN AND METHODS: The CE team at HealthPartners consisted of two CTNs, a social worker, an RN, a program coordinator, and a behavioral neurologist. Intake forms were developed to collect demographic, baseline, and annual data at one year related to dementia severity and caregiver status. Experience surveys were completed at 6 and 12 months by participating caregivers. All data was entered into REDCap. RESULTS: A total of 570 PWD-caregiver dyads were recruited into the CE: 53% PWDs female, average age 75.2 ± 9.43, 19% living within rural communities. Of the 173 dyads assessed at one year, 30% responded to the annual intake forms and 58% of responded to experience surveys. At one year, PWDs progressed in disease severity and functional impairment, although caregiver burden and mood remained unchanged. We observed a significant reduction in caregiver reported emotional challenges associated with caregiving, sleep problems, and obtaining caregiver help at one year. 86% of caregivers reported feeling supported by their CTN nearly always or quite frequently, and 88% rated the CTN as highly responsive to what was important to them. DISCUSSION AND IMPLICATIONS: The CE was feasible and well-received within a non-academic healthcare system.

Patterns and Predictors of Extra-Corporeal Membrane Oxygenation Related Cerebral Microbleeds.

OBJECTIVES: Recent case-reports have described an atypical cerebral microbleed (CMB) topography after extracorporeal membrane oxygenation (ECMO). The objective of this study was to examine the prevalence, radiographic patterns, and clinical correlates of possibly-ECMO-related (PER) CMB. MATERIALS AND METHODS: We performed a retrospective study of 307 consecutive patients receiving ECMO support at our tertiary-care University Hospital (2013-2018). PER CMB were defined as CMB present in corpus-callosum and/or middle cerebellar peduncle with/without involvement of other lobar/deep structures. Leukoaraiosis was quantified using the Wahlund age-related white matter changes scale. Patient characteristics were compared between cohorts with and without PER CMB. RESULTS: Forty patients (median age 60 years; 33% vv-ECMO and 67% va-ECMO) received at-least one MRI-brain within 3 months of ECMO support. CMB were present in 77.5% (n = 31) patients with 39% (n = 12), 17% (n = 5), and 44% (n = 14) having low (< 10 CMB), moderate (10-30 CMB), and high (> 30 CMB) burden respectively. Among CMB-positive patients, 71% (n = 22) had PER CMB, with 91% of such cases demonstrating involvement of splenium. Leukoaraiosis did not corelate to PER CMB presence (p = 0.267) or burden (ρ = 0.09). Patients with PER CMB had higher rates of ischemic stroke (50 vs. 33%), intracranial hemorrhage (41 vs. 17%), and all-cause mortality (27 vs. 17%); with survivors demonstrating no differences in their discharge disposition or modified Rankin Score. CONCLUSIONS: Post-ECMO cerebral microbleeds have a distinct distribution pattern that commonly involves the splenium of corpus-callosum. Their etiopathogenesis may be independent of microvascular lipohyalinosis. This requires further study in a larger sample-size.

Abnormal clinical presentation and surgical outcome of an intraventricular cavernoma of the third ventricle.

We present a unique case of a man presenting with progressive short-term memory deficits over 10+ years who was found to have a large intraventricular cavernoma in the anterior wall of the third ventricle with invasion of medial limbic structures. Identifying intraventricular cavernomas early is crucial to prevent substantial growth and to increase the chance of successful patient outcomes.

Stroke Characteristics in a Cohort of Hmong American Patients.

Background Prior studies have indicated high rates of vascular risk factors, but little is known about stroke in Hmong. Methods and Results The institutional Get With The Guidelines (GWTG) database was used to identify patients discharged with acute ischemic stroke, intracerebral hemorrhage, or subarachnoid hemorrhage between 2010 and 2019. Hmong patients were identified using clan names and primary language. Univariate analysis was used to compare Hmong and White patients. A subarachnoid hemorrhage comparison was not conducted because of the small sample size. We identified 128 Hmong patients and 3084 White patients. Hmong patients had more prevalent hemorrhagic stroke (31% versus 15%; P<0.0016). In the acute ischemic stroke cohort, compared with White patients, Hmong patients were younger (60±13 versus 71±15 years; P<0.0001), presented to the emergency department almost 4 hours later; and had a lower thrombolysis usage rate (6% versus 14%; P=0.03496), worse lipid profile, higher hemoglobin A1C, similar stroke severity, and less frequent discharge to rehabilitation facilities. The most common ischemic stroke mechanism for Hmong patients was small-vessel disease. In the intracerebral hemorrhage cohort, Hmong patients were younger (55±13 versus 70±15 years; P<0.0001), had higher blood pressure, and had a lower rate of independent ambulation on discharge (9% versus 30%; P=0.0041). Conclusions Hmong patients with stroke were younger and had poorer risk factor control compared with White patients. There was a significant delay in emergency department arrival and low use of acute therapies among the Hmong acute ischemic stroke cohort. Larger studies are needed to confirm these observations, but action is urgently needed to close gaps in primary care and stroke health literacy.

Ethanol-induced microphthalmia is not mediated by changes in retinoic acid or sonic hedgehog signaling during retinal neurogenesis.

BACKGROUND: Microphthalmia (reduced eye size), generally accompanied by vision defects, is a hallmark of fetal alcohol spectrum disorder (FASD) in humans. In zebrafish, embryonic ethanol exposure over the time of retinal neurogenesis also results in microphthalmia. This microphthalmia is in part the consequence of reduced retinal cell differentiation, including photoreceptors. Here we pursue 2 signaling pathways implicated in other aspects of FASD pathogenesis: retinoic acid (RA) and Sonic hedgehog (Shh). METHODS: We evaluated markers for RA and Shh signaling within the eyes of embryos treated with ethanol during the period of retinal neurogenesis. We also performed rescue experiments using administration of exogenous RA and microinjection of cholesterol, which augments Shh signaling. RESULTS: Using sequential or co-treatments, RA did not rescue ethanol-induced microphthalmia at any concentration tested. In addition, RA itself caused microphthalmia, although the underlying mechanisms were distinct from those of ethanol. Interestingly, RA treatment appeared to recover photoreceptor differentiation in a concentration-dependent manner. This may be an independent effect of exogenous RA, as ethanol treatment alone did not alter RA signaling in the eye. Cholesterol injection also did not rescue ethanol-induced microphthalmia at any concentration tested, and ethanol treatments did not alter expression of shh, or of ptc-2, which is normally regulated by Shh signaling. CONCLUSIONS: Together these findings indicate that, during the time of retinal neurogenesis, effects of ethanol on eye development are likely independent of the RA and Shh signaling pathways. These studies suggest that FASD intervention strategies based upon augmentation of RA or Shh signaling may not prevent ethanol-induced microphthalmia.

A Phase II, Single-Center, Randomized, Double-Blind, Placebo-Controlled Study of the Safety and Therapeutic Efficacy of Intranasal Glulisine in Amnestic Mild Cognitive Impairment and Probable Mild Alzheimer's Disease.

BACKGROUND: Intranasal insulin is a potential treatment for neurodegenerative disease shown to increase cerebral glucose uptake, reduce amyloid plaques, and improve verbal memory in cognitively impaired as well as healthy adults. Investigations have suggested rapid-acting insulins such as glulisine may result in superior cognitive benefits compared with regular insulin. OBJECTIVE: The aim of this study was to evaluate the safety and efficacy of rapid-acting intranasal glulisine in subjects with amnestic mild cognitive impairment (MCI) or mild probable Alzheimer's disease (AD). METHODS: We performed a single-center, randomized, double-blind, placebo-controlled study to evaluate the efficacy of intranasal glulisine 20 IU twice daily versus saline placebo in 35 memory-impaired (MCI/AD) subjects using the Impel NeuroPharma I109 Precision Olfactory Delivery (POD®) device. The 13-item Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog13), Clinical Dementia Rating (CDR) global score, and Functional Assessment Questionnaire (FAQ) were measured at baseline and 3 and 6 months. Secondary outcome measures included digit span forward/backwards, Trail Making Test Parts A/B, Controlled Oral Word Association Test (COWAT), and Weschler Memory Scale (WMS)-IV logical memory. Adverse effects (AEs) and serious adverse effects (SAEs) were measured along with blood glucose/insulin levels. RESULTS: No significant difference in ADAS-Cog13, CDR Sum of Boxes (CDR-SOB), or FAQ scores were found between treatment groups at 3 and 6 months. Subjects in the saline group were significantly older than those in the glulisine group (p = 0.022). No significant differences in sex, education, apolipoprotein E4 (ApoE4) status, and Montreal Cognitive Assessment (MoCA) score existed between treatment groups. Overall, the number of adverse events per person was similar between groups (2.32 vs. 2.24; p = 0.824), although subjects receiving intranasal glulisine had higher rates of nasal irritation (25.0% vs. 13.9%) and respiratory symptoms (15.9% vs. 8.3%) compared with placebo. There were no differences in blood sugar or rate of hypoglycemia between the treatment and placebo groups. CONCLUSIONS: Intranasal glulisine was relatively safe and well-tolerated and did not consistently impact peripheral glucose or insulin levels. There were no enhancing effects of intranasal glulisine on cognition, function, or mood, but the ability to detect significance was limited by the number of subjects successfully enrolled and the study duration. CLINICALTRIALS. GOV REGISTRATION: NCT02503501.

Intranasal Insulin: a Treatment Strategy for Addiction.

Addiction to substances such as alcohol, cocaine, opioids, and methamphetamine poses a continuing clinical and public challenge globally. Despite progress in understanding substance use disorders, challenges remain in their treatment. Some of these challenges include limited ability of therapeutics to reach the brain (blood-brain barrier), adverse systemic side effects of current medications, and importantly key aspects of addiction not addressed by currently available treatments (such as cognitive impairment). Inability to sustain abstinence or seek treatment due to cognitive deficits such as poor decision-making and impulsivity is known to cause poor treatment outcomes. In this review, we provide an evidenced-based rationale for intranasal drug delivery as a viable and safe treatment modality to bypass the blood-brain barrier and target insulin to the brain to improve the treatment of addiction. Intranasal insulin with improvement of brain cell energy and glucose metabolism, stress hormone reduction, and improved monoamine transmission may be an ideal approach for treating multiple domains of addiction including memory and impulsivity. This may provide additional benefits to enhance current treatment approaches.

A Successful Quality Improvement Project for Detection and Management of Acute Stroke in Hospitalized Patients.

BACKGROUND: The incidence rate of stroke in hospitalized patients ranges between 2% and 17% of all strokes-a higher rate than in the community. Delays in recognition and management of stroke in hospitalized patients lead to worse outcomes. At our hospital, the existing in-hospital stroke (IHS) code showed low usage and effectiveness. In a quality improvement (QI) project, we aimed to improve the identification of and the quality of care for inpatient strokes. METHODS: A nurse-driven IHS protocol was implemented, which alerted a specialized stroke team and cleared the computed tomography (CT) scanner. The protocol focused on prioritizing staff education, simplifying the process, empowering staff to activate an IHS code, ensuring adequate support and teamwork, identifying well-defined quality metrics (eg, time to CT and documentation tool use), and providing feedback communication. We analyzed 2 years of postimplementation IHS data for impact on stroke detection and outcomes. RESULTS: In the 2 years post QI, there was a more than 10-fold increase in IHS (pre-QI, n = 8; first year post QI, n = 94; second year post QI, n = 123). In the post-QI cohort, after excluding patients with missing information (n = 26), 69 cases had new stroke diagnoses (63 ischemic, 6 hemorrhagic), and 148 were stroke mimics. The mean (SD) time from IHS to CT was 18.7 (7.0) minutes. Of the 63 new ischemic stroke cases, 25 (39.7%) were treated with thrombolytic therapy and/or mechanical thrombectomy. CONCLUSION: The new IHS protocol has led to a marked increase in cases identified, rapid evaluation, and high utilization rate of acute stroke therapies.

Unique Case Report of a Meningeal Sarcoma Arising during Ongoing Treatment for Progressing Intraparenchymal Glioma.

Radiation-induced sarcomas in the brain are extremely rare, usually occur with an average latency of 9 years, and are associated with poor outcomes. Latency periods shorter than 1 year may indicate a genetic predisposition such as Li-Fraumeni syndrome. A 34-year-old man underwent initial tumor resection and radiation therapy for a World Health Organization (WHO) Grade II Astrocytoma. Within 6 months, the tumor recurred as WHO Grade III and was treated with temozolomide and then bevacizumab. Despite the patient's apparent improving condition, MRI revealed new dural-based lesions 10 months after radiation therapy and identified as high-grade sarcoma. The patient resumed bevacizumab, began NovoTTF treatment for progressing glioma, and ifosfamide/doxorubicin for the sarcoma. Genetic testing revealed no pathogenic mutation in the TP53 gene. Ultimately, treatment was unsuccessful and the patient succumbed to glioma and sarcoma within 2 years of initial diagnosis. This case was unique due to the rapidly progressing glioma and sudden appearance of a high-grade sarcoma. It is unusual to have two separate intracranial primary cancers with each requiring a different chemotherapy regimen. We discuss the difficulty of simultaneously treating with separate chemotherapy regimens. It remains unclear whether the sarcoma was induced by the radiation treatment or a genetic predisposition.

Eye-specific gene expression following embryonic ethanol exposure in zebrafish: roles for heat shock factor 1.

The mechanisms through which ethanol exposure results in developmental defects remain unclear. We used the zebrafish model to elucidate eye-specific mechanisms that underlie ethanol-mediated microphthalmia (reduced eye size), through time-series microarray analysis of gene expression within eyes of embryos exposed to 1.5% ethanol. 62 genes were differentially expressed (DE) in ethanol-treated as compared to control eyes sampled during retinal neurogenesis (24-48 h post-fertilization). The EDGE (extraction of differential gene expression) algorithm identified >3000 genes DE over developmental time in ethanol-exposed eyes as compared to controls. The DE lists included several genes indicating a mis-regulated cellular stress response due to ethanol exposure. Combined treatment with sub-threshold levels of ethanol and a morpholino targeting heat shock factor 1 mRNA resulted in microphthalmia, suggesting convergent molecular pathways. Thermal preconditioning partially prevented ethanol-mediated microphthalmia while maintaining Hsf-1 expression. These data suggest roles for reduced Hsf-1 in mediating microphthalmic effects of embryonic ethanol exposure.

Cardiovascular implications in the treatment of obstructive sleep apnea.

Epidemiological studies provide strong evidence that obstructive sleep apnea (OSA) is associated with cardiovascular complications such as systemic hypertension, congestive heart failure, and atrial fibrillation. Successful OSA treatment with continuous positive airway pressure (CPAP) has resulted in coincident reductions in systemic hypertension, improvements in left ventricular systolic function, and reductions in sympathetic nervous activity. These data suggest that successful treatment of OSA may reduce cardiovascular morbidity in such patients. Although CPAP is the more successful treatment for OSA when used properly and consistently, its clinical success is often limited by poor patient and partner acceptance, which leads to suboptimal compliance. Oral appliances or upper airway surgeries are considered a second line of treatment for patients with mild to moderate OSA who do not comply with or refuse long-term CPAP treatment. Oral devices such as mandibular repositioning appliances were recently shown to improve arterial hypertension in OSA patients. Electrical stimulation of the hypoglossal nerve is a new investigational therapy for patients with moderate to severe OSA. This new treatment option, if proven effective, may provide cardiovascular benefits secondary to treating OSA.

Mechanisms for persistent microphthalmia following ethanol exposure during retinal neurogenesis in zebrafish embryos.

The exposure of the developing human embryo to ethanol results in a spectrum of disorders involving multiple organ systems, including the visual system. One common phenotype seen in humans exposed to ethanol in utero is microphthalmia. The objective of this study was to describe the effects of ethanol during retinal neurogenesis in a model organism, the zebrafish, and to pursue the potential mechanisms by which ethanol causes microphthalmia. Zebrafish embryos were exposed to 1% or 1.5% ethanol from 24 to 48 h after fertilization, a period during which the retinal neuroepithelium undergoes rapid proliferation and differentiation to form a laminated structure composed of different retinal cell types. Ethanol exposure resulted in significantly reduced eye size immediately following the treatment, and this microphthalmia persisted through larval development. This reduced eye size could not entirely be accounted for by the accompanying general delay in embryonic development. Retinal cell death was only slightly higher in ethanol-exposed embryos, although cell death in the lens was extensive in some of these embryos, and lenses were significantly reduced in size as compared to those of control embryos. The initiation of retinal neurogenesis was not affected, but the subsequent waves of cell differentiation were markedly reduced. Even cells that were likely generated after ethanol exposure--rod and cone photoreceptors and Müller glia--were delayed in their expression of cell-specific markers by at least 24 h. We conclude that ethanol exposure over the time of retinal neurogenesis resulted in persistent microphthalmia due to a combination of an overall developmental delay, lens abnormalities, and reduced retinal cell differentiation.