Proximity interactome of lymphatic VE-cadherin reveals mechanisms of junctional remodeling and reelin secretion.

The adhesion receptor vascular endothelial (VE)-cadherin transduces an array of signals that modulate crucial lymphatic cell behaviors including permeability and cytoskeletal remodeling. Consequently, VE-cadherin must interact with a multitude of intracellular proteins to exert these functions. Yet, the full protein interactome of VE-cadherin in endothelial cells remains a mystery. Here, we use proximity proteomics to illuminate how the VE-cadherin interactome changes during junctional reorganization from dis-continuous to continuous junctions, triggered by the lymphangiogenic factor adrenomedullin. These analyses identified interactors that reveal roles for ADP ribosylation factor 6 (ARF6) and the exocyst complex in VE-cadherin trafficking and recycling. We also identify a requisite role for VE-cadherin in the in vitro and in vivo control of secretion of reelin-a lymphangiocrine glycoprotein with recently appreciated roles in governing heart development and injury repair. This VE-cadherin protein interactome shines light on mechanisms that control adherens junction remodeling and secretion from lymphatic endothelial cells.

SARS-CoV-2 (COVID-19) Experience at an Academic Medical Examiner's Office.

Introduction: The coronavirus disease of 2019 (COVID-19) pandemic has resulted in a great deal of morbidity and mortality worldwide. Since most deaths related to COVID-19 are currently considered natural, and they tend to occur following a clinically recognized illness, many medical examiner/coroner offices within the United States do not take jurisdiction over the majority of COVID-19 deaths. Methods: In this review, we present the experience of a medium-sized medical examiner's office affiliated with an academic medical school institution, over the first 15 months of the COVID-19 pandemic. Results: Compared to a 15-month period that immediately preceded the pandemic, our office experienced a significant increase in the total number of reported deaths, scene investigations, full autopsies, natural deaths, accidents, homicides, and drug-related deaths, but a decrease in the number of suicides. Overall, our office performed 5 autopsies during the study period where COVID-19 was considered the primary cause of death, 4 cases where COVID-19 was considered a contributory cause of death, and 28 cases where COVID-19 testing was positive, but COVID-19 was not contributory to death. Discussion: The COVID-19 pandemic was accompanied by a sizeable increase in work volume within our academic medical examiner's office. Although this increased workload was not related to a large number of COVID-19-related deaths investigated by the office, there were numerous areas of increased workload that were likely secondarily related to the conditions associated with the pandemic.

Cardiac lymphatics undergo distinct remodeling during hypertrophic and non-hypertrophic pregnancy.

Lymphatic vessels of the heart undergo dynamic remodeling in response to physiological and pathological cardiovascular events such as development, adult cardiac maintenance and injury repair. During pregnancy, the cardiovascular system undergoes physiological changes to meet the increased demand of blood supply to the fetus. These extensive physiologic changes make pregnancy and delivery a high-risk period in a woman's life. However, whether and how cardiac lymphatics change during pregnancy is largely undefined. Therefore, we used whole mount immunofluorescent labeling and quantitative morphometric analysis to characterize the changes in cardiac lymphatic vasculature during pregnancy using two genetically distinct inbred mouse strains, C57BL/6J and BALB/cJ. Compared to age-matched, non-pregnant C57BL/6J control mice, the hearts of C57BL/6J dams in late-pregnancy (gestation day 17.5 (G17.5)) undergo physiologic hypertrophy. However, there were no significant changes in the cardiac lymphatic vasculature. In contrast, BALB/cJ mice do not exhibit pregnancy-induced cardiac hypertrophy at G17.5 compared to age-matched, non-pregnant mice. Yet interestingly, the cardiac lymphatic vasculature of pregnant BALB/cJ dams undergoes extensive morphological changes, including decreased lymphatic length, number of endpoints, and vessel branchpoint junctions on the ventral side of the heart. These findings underscore the complexity of genetic and physiologic factors that contribute to the heterotypic remodeling of cardiac lymphatics during late pregnancy.

Meningeal lymphatic CGRP signaling governs pain via cerebrospinal fluid efflux and neuroinflammation in migraine models.

Recently developed antimigraine therapeutics targeting calcitonin gene-related peptide (CGRP) signaling are effective, though their sites of activity remain elusive. Notably, the lymphatic vasculature is responsive to CGRP signaling, but whether meningeal lymphatic vessels (MLVs) contribute to migraine pathophysiology is unknown. Mice with lymphatic vasculature deficient in the CGRP receptor (CalcrliLEC mice) treated with nitroglycerin-mediated (NTG-mediated) chronic migraine exhibit reduced pain and light avoidance compared with NTG-treated littermate controls. Gene expression profiles of lymphatic endothelial cells (LECs) isolated from the meninges of Rpl22HA/+;Lyve1Cre RiboTag mice treated with NTG revealed increased MLV-immune interactions compared with cells from untreated mice. Interestingly, the relative abundance of mucosal vascular addressin cell adhesion molecule 1-interacting (MAdCAM1-interacting) CD4+ T cells was increased in the deep cervical lymph nodes of NTG-treated control mice but not in NTG-treated CalcrliLEC mice. Treatment of cultured hLECs with CGRP peptide in vitro induced vascular endothelial-cadherin (VE-cadherin) rearrangement and reduced functional permeability. Likewise, intra cisterna magna injection of CGRP caused rearrangement of VE-cadherin, decreased MLV uptake of cerebrospinal fluid (CSF), and impaired CSF drainage in control mice but not in CalcrliLEC mice. Collectively, these findings reveal a previously unrecognized role for lymphatics in chronic migraine, whereby CGRP signaling primes MLV-immune interactions and reduces CSF efflux.

Lethal Complications of Meningiomas: A Case Series.

Background: Meningiomas are the most prevalent type of primary intracranial tumor in adults, comprising nearly one-third of all intracranial tumors. They are typically benign, slow-growing, and asymptomatic but may cause neurological symptoms as they expand due to mass effect. Classification is determined by World Health Organization (WHO) grades 1 to 3 following pathological examination corresponding to benign, atypical, and anaplastic (malignant), respectively, reflecting their rate of growth and risk of recurrence. The vast majority are WHO grade 1 and their slow growth permits timely presentation for elective resection; however, meningiomas in vulnerable locations and coexisting morbidities can result in sudden death. Objectives: We present a series of four adult patients with meningiomas which resulted in death, including a case of fatal seizure, midline hemorrhagic meningioma, postresection meningitis, and compression of the cerebellum. Research design: Retrospective review of the authors' cases was conducted. Available pathology, medical, and autopsy records including gross images were reviewed in each case. The inclusion criteria were adult patients (>18 years old) and that the cause of death had to include meningioma. Subjects: The four patients included a 61-year-old male, an 84-year-old female, a 62-year-old male, and a 37-year-old female. Measures: Qualitative; autopsy reports describing cause of death and pathology report findings including gross and microscopic analysis. Conclusions: Meningiomas are often benign in nature but can rarely result in death. Size and location of the tumor and risk factors are contributory. Autopsy examination can be instrumental in identifying the cause and mechanism of deaths associated with meningiomas.

Double Trouble: Eales Disease in a Background of Paradoxical Embolism.

Eales disease is an idiopathic retinal vasculitis that mainly affects the periphery of the retina. The disease commonly manifests as peripheral retinal perivasculitis, peripheral retinal capillary nonperfusion, neovascularization, and recurrent vitreous hemorrhage. Here, we present the case of a 36-year-old male who was diagnosed with Eales disease after presenting with sudden onset flashes of light, reduced visual acuity, and a black spot in his left eye. Upon examination, his left eye exhibited a superior non-foveal branch retinal artery occlusion (BRAO) with a sludged blood column, an old extramacular branch retinal vein occlusion (BRVO) with hemorrhage, and vascular sheathing. Initial laboratory investigations, including antibody testing for causes of retinal ischemia and stroke workup, were negative. Later, the patient presented with a BRAO in the right eye and a cerebral infarction shortly thereafter, further complicating his clinical picture. A diagnosis of Eales disease was made based on the evolution of retinal findings showing peripheral non-perfusion, vascular sheathing, collateral formation, neovascularization with leakage, absence of additional BRAOs following repair of his patent foramen ovale, and lack of other explanatory conditions. The initiation of systemic corticosteroids resulted in the improvement and stabilization of his vision. This case highlights the challenges in diagnosing Eales disease, underscoring the importance of timely identification for the appropriate management and prevention of vision loss.

No Increase in Symptoms Toward the End of the Ocrelizumab Infusion Cycle in Patients With Multiple Sclerosis: Symptom Burden on Ocrelizumab: A Longitudinal Study (SymBOLS).

Background and Objectives: Some patients with multiple sclerosis (MS) receiving ocrelizumab (OCR) report worsening symptoms toward the end of the 6-month infusion cycle ('wearing off'). The objective of our study was to comprehensively assess changes in symptom burden across 2 consecutive OCR infusion cycles. Methods: SYMptom Burden on Ocrelizumab, a Longitudinal Study (SymBOLS; NCT04855617) was an investigator-initiated, 2-center study of patients with MS starting or receiving OCR. Patients' symptoms were assessed with NeuroQoL short forms, SymptoMScreen, and Work Productivity and Activity Impairment Questionnaire at the start-cycle, mid-cycle, and end-cycle time points in each of the 2 infusion cycles. Symptom scores at the 3 time points within each cycle were compared with repeated-measures ANOVA or the Friedman rank-sum test for non-normal variables. The proportions of patients with a meaningful symptomatic change from the start to the end of each infusion cycle were calculated, and patients whose symptoms improved, worsened, and stayed the same from the start to the end of the cycle were compared with respect to demographic and clinical characteristics. Results: One hundred three patients with MS provided longitudinal data for analyses (mean age [SD]: 46.7 [12.2] years, 68% female, 33% non-White, disease duration: 15.5 [5] years, 41% with the Extended Disability Status Scale score >3). On a group level, NeuroQoL and SymptoMScreen scores mostly remained stable or even improved slightly toward the end of each cycle. On an individual level, symptoms remained unchanged across either cycle for most patients, and meaningful symptom worsening from the start to the end of the cycle was no more common than improvement. Meaningful change in symptoms in both cycles was very rare and generally in the direction of improvement toward the end cycle. Despite the lack of evidence for symptom worsening with a longer time from infusion, 54% of patients endorsed feeling of "wearing off" at least sometimes, most commonly as an increase in fatigue. Discussion: Our prospective study failed to uncover evidence for the worsening of symptoms with a longer time from OCR infusion. These findings cast doubt on the existence of wearing off as a physiologic phenomenon in OCR-treated patients with MS. The perception of wearing off is likely the result of natural fluctuations in MS symptoms and attribution bias.

Coumestrol induces oxidative stress and impairs migration and embryonic growth.

In brief: Healthy development of the placenta is dependent on trophoblast cell migration and reduced oxidative stress presence. This article describes how a phytoestrogen found in spinach and soy causes impaired placental development during pregnancy. Abstract: Although vegetarianism has grown in popularity, especially among pregnant women, the effects of phytoestrogens in placentation lack understanding. Factors such as cellular oxidative stress and hypoxia and external factors including cigarette smoke, phytoestrogens, and dietary supplements can regulate placental development. The isoflavone phytoestrogen coumestrol was identified in spinach and soy and was found to not cross the fetal-placental barrier. Since coumestrol could be a valuable supplement or potent toxin during pregnancy, we sought to examine its role in trophoblast cell function and placentation in murine pregnancy. After treating trophoblast cells (HTR8/SVneo) with coumestrol and performing an RNA microarray, we determined 3079 genes were significantly changed with the top differentially changed pathways related to the oxidative stress response, cell cycle regulation, cell migration, and angiogenesis. Upon treatment with coumestrol, trophoblast cells exhibited reduced migration and proliferation. Additionally, we observed increased reactive oxygen species accumulation with coumestrol administration. We then examined the role of coumestrol within an in vivo pregnancy by treating wildtype pregnant mice with coumestrol or vehicle from day 0 to 12.5 of gestation. Upon euthanasia, fetal and placental weights were significantly decreased in coumestrol-treated animals with the placenta exhibiting a proportional decrease with no obvious changes in morphology. Therefore, we conclude that coumestrol impairs trophoblast cell migration and proliferation, causes accumulation of reactive oxygen species, and reduces fetal and placental weights in murine pregnancy.

Empowering Indigenous Communities Through a Participatory, Culturally Responsive Evaluation of a Federal Program for Older Americans.

This article describes our experience of conducting a 5-year, culturally responsive evaluation of a federal program with Indigenous communities. It describes how we adapted tenets from "participatory evaluation models" to ensure cultural relevance and empowerment. We provide recommendations for evaluators engaged in similar efforts. The evaluation included stakeholder engagement through a Steering Committee and an Evaluation Working Group in designing and implementing the evaluation. That engagement facilitated attention to Indigenous cultural values in developing a program logic model and medicine wheel and in gathering local perspectives through storytelling to facilitate understanding of community traditions. Our ongoing assessment of program grantees' needs shaped our approach to evaluation capacity building and development of a diverse array of experiential learning opportunities and user-friendly tools and resources. We present practical strategies from lessons learned during the evaluation design and implementation phases of our project that might be useful for other evaluators.

Period poverty: The perceptions and experiences of impoverished women living in an inner-city area of Northwest England.

BACKGROUND: The menstrual needs of girls and women are important to health, education, and well-being. Unmet need and harm from poor menstrual health in low-and- middle-income countries have been documented, but with little empirical research undertaken in high income countries. Continuing austerity in the UK suggests menstruators are likely more vulnerable to 'period poverty' than previously, with the COVID-19 pandemic assumed to exacerbate the situation. AIM: To explore the menstrual experiences and perceptions of women in the UK who are living under circumstances of deprivation, alongside views of staff working in organisations supporting these women, to understand whether women's menstrual needs are met. METHODS: A qualitative study was conducted in an inner-city in NW England. Three focus group discussions and 14 in-depth interviews were conducted across three study sites supporting impoverished women. Data was analysed thematically. RESULTS: Themes were: reflections on menstruation; affordability of products; access to public facilities; organisational support; potential solutions. Many women perceived menstruation as a burden in three aspects: physical discomfort and pain; psychological anxiety; and shame and stigma. Managing menstruation was difficult due to cost relative to low incomes, with food, heating and lighting prioritised, leaving women improvising with materials or wearing products for longer than desired. Most suggested that products should be free, often remarking if men required similar items this would happen. Most women were unaware supporting organisations provided free products. Staff felt the small range of products offered did not meet client needs and were ill-prepared to have conversations on products and clients' menstrual needs. CONCLUSION: Impoverished women lack the necessary resources to manage their menses well which negatively impacts their health and brings stress, embarrassment, and shame. Support, including access to free products, is needed at both local and national level to help impoverished women manage their menstrual hygiene.

Death After Poison Ivy Smoke Inhalation.

ABSTRACT: Urushiol, the active antigen in poison ivy ( Toxicodendron radicans ), is frequently associated with type I and type III hypersensitivity reactions. These reactions most often result in cutaneous symptoms that vary in severity and may at times require medical interventions. Injuries involving other body systems associated with urushiol exposure are far less common. Here, we present 2 unrelated cases of urushiol respiratory exposure status after burning of poison ivy that resulted in cardiopulmonary arrest and ultimately death. In both cases, the history, circumstances, and autopsy findings are consistent with urushiol smoke inhalation having either caused or contributed to death. The cases are unique in that they represent the first cases of death related to poison ivy smoke exposure. Clinicians and forensic pathologists should be aware of the fact that urushiol smoke exposure may lead to morbidity and mortality.

Building connection and improving health for Indigenous elders: Findings from the Title VI evaluation.

BACKGROUND: As the older Indigenous population in the United States expands, there is a growing demand for programs to address age-related needs. Although Title VI of the OAA provides culturally responsive strategies to support elders through home- and community-based nutrition services, these programs have not been the subject of a national evaluation; our study is the first. METHODS: We conducted a mixed-methods study to assess the impact of the Title VI programs on elders. We used quantitative data from a national survey of Indigenous elders (n = 1175) and qualitative data collected through interviews (n = 36) and focus groups (18, n = 161) with a subgroup of elders receiving services. We compared outcomes for social and cultural connectedness and physical and mental well-being for different subgroups within our sample of elders based on elders' use of Title VI services and the level of services provided to these elders. Results were adjusted for community characteristics. RESULTS: Elders receiving Title VI services had significantly fewer hospitalizations and falls per year (hospitalizations: 0.9 vs. 1.2, p < 0.05; falls: 1.0 versus 1.1, p < 0.05) and significantly more social and cultural engagements per month (social engagements: 92.6% vs. 75.6%, p < 0.05; cultural practices: 78.8% vs. 64.8%, p < 0.05) compared with elders who did not participate in Title VI services. These findings were confirmed by our qualitative data. CONCLUSIONS: Our findings highlight the vital role that the Title VI program plays in promoting elders' overall health and well-being through decreased hospitalizations and falls and increased connectedness.

A comparison of three decalcification agents for assessments of cranial fracture histomorphology.

The extraction of mineral calcium from bone by decalcification is a critical step in the preparation of histological samples for light microscopy. This study assessed the time required for complete decalcification and the resultant histomorphological preservation of bone histomorphology by three decalcification agents: 7% hydrochloric acid (HCl), 5% nitric acid, and 10% ethylenediaminetetraacetic acid (EDTA). The goal of this study was to identify which decalcification agent provides the optimal combination of expedient processing and quality histological outcomes of cranial fracture samples. HCl provided the most rapid decalcification ( X ¯  = 3.57 days), nitric acid followed closely ( X ¯  = 10.35 days), while EDTA took significantly longer on average ( X ¯  = 78.97 days) but encompassed a broader range of times. Decalcification agent, sample thickness, sample width, and decedent age are significant predictors of decalcification time. Sample visualization quality, measured for tissues, cells, and nuclei on a five-point Likert scale, was highest for samples decalcified in 10% EDTA, second highest using 5% nitric acid, and lowest for 7% HCl. The quality difference between EDTA and nitric acid was not highly significant for any of the three features. For basic assessments of bone histomorphology, the study results indicate 5% nitric acid is suitable for the decalcification of adult specimens and samples thicker than 3 mm. EDTA is a suitable agent for thin samples of the cranial vault (<3 mm) from infants and young children less than three years old, decalcifying samples in a timeframe comparable to nitric acid while providing the best quality and clarity of samples.

Longitudinal Opioid Surveillance Project Involving Toxicologic Analysis of Postmortem Specimens from 9 Counties in Michigan Suggests the Discovery of New High-Intensity Drug Trafficking Areas.

ABSTRACT: Acetyl fentanyl (AF) is a Schedule I fentanyl analog that has been increasingly seen in heroin and fentanyl polydrug toxicity overdoses in Michigan (MI). Drug users are often unaware of the presence of AF in their drugs because it is often sold mixed into or disguised as heroin. High levels of AF in heroin drug products can cause increased incidence of overdose. This article describes data from a longitudinal opioid surveillance program and details 102 decedents in MI who were found to have evidence of heroin in their postmortem blood. A large portion of these decedents were also found to have evidence of fentanyl and AF. Our data further show significant overlap in incidence rates of AF and heroin-related overdose deaths in several MI counties, suggesting that AF is becoming enmeshed in heroin trafficking. Furthermore, we report unprecedented high incidence rates of AF and heroin-related overdose deaths in Calhoun county, and we propose that it is a high-intensity drug trafficking area. Highways US-131 and US-31 are likely used to transport these drugs. More study is needed into the drug trafficking trends in MI to ascertain drug sources and monitor the ever developing and dangerous polydrug heroin combinations.

Keeping the team together: Transformation of an inpatient neurology service at an urban, multi-ethnic, safety net hospital in New York City during COVID-19.

The COVID-19 pandemic dramatically affected the operations of New York City hospitals during March and April of 2020. This article describes the transformation of a neurology division at a 450-bed tertiary care hospital in a multi-ethnic community in Brooklyn during this initial wave of COVID-19. In lieu of a mass redeployment of staff to internal medicine teams, we report a novel method for a neurology division to participate in a hospital's expansion of care for patients with COVID-19 while maintaining existing team structures and their inherent supervisory and interpersonal support mechanisms.

Method to Evaluate the Age of Groundwater Inputs to Surface Waters by Determining the Chirality Change of Metolachlor Ethanesulfonic Acid (MESA) Captured on a Polar Organic Chemical Integrative Sampler (POCIS).

We previously discovered a method to estimate the groundwater mean residence time using the changes in the enantiomeric ratio of metolachlor ethanesulfonic acid (MESA), (2-[(2-ethyl-6-methylphenyl)(2-methoxy-1-methylethyl)amino]-2-oxoethanesulfonic acid), a metabolite of the herbicide metolachlor. However, many grab samples would be needed for each watershed over an extended period, and this is not practical. Thus, we examined the use of a polar organic chemical integrative sampler (POCIS) deployed for 28 days combined with a modified liquid chromatography-mass spectrometry LC-MS/MS method to provide a time-weighted average of the MESA enantiomeric ratio. POCISs equipped with hydrophilic-lipophilic-balanced (HLB) discs were deployed at five sites across the United States where metolachlor was used before and after 1999 and compared the effectiveness of the POCIS to capture MESA versus grab samples. In addition, an in situ POCIS sampling rate (Rs) for MESA was calculated (0.15 L/day), the precision of MESA extraction from stored POCIS discs was determined, and the effectiveness of HLB to extract MESA was examined. Finally, using molecular modeling, the influence of the asymmetric carbon of metolachlor degradation on the MESA enantiomeric ratio was predicted to be negligible. Results of this work will be used in projects to discern the groundwater mean residence times, to evaluate the delivery of nitrate-N from groundwater to surface waters under various soil, agronomic, and land use conditions, and to examine the effectiveness of conservation practices.

Distinct Functional Connectivity Patterns Are Associated With Social and Cognitive Lifestyle Factors: Pathways to Cognitive Reserve.

The importance of diverse lifestyle factors in sustaining cognition during aging and delaying the onset of decline in Alzheimer's disease and related dementias cannot be overstated. We explored the influence of cognitive, social, and physical lifestyle factors on resting-state lagged linear connectivity (LLC) in high-density electroencephalography (EEG) in adults, ages 35-75 years. Diverse lifestyle factors build cognitive reserve (CR), protecting cognition in the presence of physical brain decline. Differences in LLC were examined between high- and low-CR groups formed using cognitive, social, and exercise lifestyle factors. LLC is a measure of lagged coherence that excludes zero phase contributions and limits the effects of volume conduction on connectivity estimates. Significant differences in LLC were identified for cognitive and social factors, but not exercise. Participants high in social CR possessed greater local and long-range connectivity in theta and low alpha for eyes-open and eyes-closed recording conditions. In contrast, participants high in cognitive CR exhibited greater eyes-closed long-range connectivity between the occipital lobe and other cortical regions in low alpha. Greater eyes-closed local LLC in delta was also present in men high in cognitive CR. Cognitive factor scores correlated with sustained attention, whereas social factors scores correlated with spatial working memory. Gender was a significant covariate in our analyses, with women displaying higher local and long-range LLC in low beta. Our findings support distinct relationships between CR and LLC, as well as CR and cognitive function for cognitive and social subcomponents. These patterns reflect the importance of diverse lifestyle factors in building CR.

Improving Thermoregulation for Trauma Patients in the Emergency Department: An Evidence-Based Practice Project.

Extensive evidence exists on the association between hypothermia and increased morbidity and mortality in trauma patients. Gaps in practice related to temperature assessment have been identified in literature, along with limited personnel knowledge regarding management of patients with accidental hypothermia. An interdisciplinary team identified gaps in practice in our institution regarding temperature assessment and documentation of rewarming and initiated an evidence-based practice project to change practice at our institution. The goals were to decrease time to temperature assessment, increase core temperature assessment, and increase implementation of appropriate rewarming methods. This project used the Iowa Model of Evidence-Based Practice to provide a framework for execution and evaluation. We conducted a literature review to address all aspects of hypothermia, including incidence, associated and contributing factors, prevention, recognition, and treatment. This evidence-based knowledge was then applied to clinical practice through staff education and training, equipment availability, and environmental adjustments. More patients with hypothermia and hyperthermia were identified in 2017, as compared with 2016. There was a significant increase in core temperature assessment from 4% in 2016 to 23% in 2017 (p < .001). Blanket use in normothermic patients increased in 2017 (p = .002). This project is an example of how nurses can utilize an evidence-based practice model to translate research into clinical practice. Best practice interventions regarding temperature assessment and rewarming measures for trauma patients can be successfully implemented with negligible cost. Further research should be dedicated to examine barriers to implementation and adherence to evidence-based practice interventions.

Towards onset prevention of cognition decline in adults with Down syndrome (The TOP-COG study): A pilot randomised controlled trial.

BACKGROUND: Dementia is very common in Down syndrome (trisomy 21) adults. Statins may slow brain amyloid ß (Aß, coded on chromosome 21) deposition and, therefore, delay Alzheimer disease onset. One prospective cohort study with Down syndrome adults found participants on statins had reduced risk of incident dementia, but there are no randomised controlled trials (RCTs) on this issue. Evidence is sparse on the best instruments to detect longitudinal cognitive decline in older Down syndrome adults. METHODS: TOP-COG was a feasibility/pilot, double-blind RCT of 12 months simvastatin 40 mg versus placebo for the primary prevention of dementia in Alzheimer disease in Down syndrome adults aged 50 years or older. Group allocation was stratified by age, apolipoprotein E (APOE) ε4 allele status, and cholesterol level. Recruitment was from multiple general community sources over 12 months. Adults with dementia, or simvastatin contraindications, were excluded. Main outcomes were recruitment and retention rates. Cognitive decline was measured with a battery of tests; secondary measures were adaptive behaviour skills, general health, and quality of life. Assessments were conducted pre randomisation and at 12 months post randomisation. Blood Aß40/Aß42 levels were investigated as a putative biomarker. Results were analysed on an intention-to-treat basis. A qualitative sub-study was conducted and analysed using the Framework Approach to determine recruitment motivators/barriers, and participation experience. RESULTS: We identified 181 (78 %) of the likely eligible Down syndrome population, and recruited 21 (11.6 %), from an area with a general population size of 3,135,974. Recruitment was highly labour-intensive. Thirteen (62 %) participants completed the full year. Results favoured the simvastatin group. The most appropriate cognitive instrument (regarding ease of completion and detecting change over time) was the Memory for Objects test from the Neuropsychological Assessment of Dementia in Individuals with Intellectual Disabilities battery. Cognitive testing appeared more sensitive than proxy-rated adaptive behaviour, quality of life, or general health scores. Aß40 levels changed less for the simvastatin group (not statistically significant). People mostly declined to participate because of not wanting to take medication, and not knowing if they would receive simvastatin or placebo. Participants reported enjoying taking part. CONCLUSION: A full-scale RCT is feasible. It will need 37 % UK population coverage to recruit the required 160 participants. Information/education about the importance of RCT participation is needed for this population. TRIAL REGISTRATION: ISRCTN67338640 .

Novel use of dexmedetomidine for the treatment of anticholinergic toxidrome.

INTRODUCTION: We report the case of an adolescent with anticholinergic toxidrome from diphenhydramine overdose, whose symptoms were treated with a novel application of dexmedetomidine. CASE REPORT: A 13-year-old female developed an anticholinergic toxidrome after intentionally ingesting 9.5 mg/kg of diphenhydramine. Despite routine supportive therapies, to include appropriate doses of lorazepam, she continued to have significant agitation, psychosis, and hallucinations. A dexmedetomidine infusion was started to aid in the treatment of her agitation and psychosis with marked improvement of her symptoms. DISCUSSION: Using dexmedetomidine for the treatment of anticholinergic toxidrome has not been previously described in the literature, but there are multiple reports of its use in alcohol withdrawal syndrome. We suggest that adding dexmedetomidine as an adjunctive agent in the therapy of anticholinergic toxidrome may relieve the symptoms of agitation, psychosis, tachycardia, and hypertension, without the attendant risk of respiratory depression associated with high doses of benzodiazepines.