In-person and online mixed method non-randomised studies exploring feasibility and acceptability of HEADS: UP, an adapted Mindfulness-Based Stress Reduction programme for stroke survivors experiencing symptoms of anxiety and depression.

BACKGROUND: Depression and anxiety are prevalent after stroke and associated with poor outcomes. We previously co-developed a stroke-specific self-management intervention, HEADS: UP (Helping Ease Anxiety and Depression after Stroke). The two studies reported here aimed to test the feasibility and acceptability of the HEADS: UP course and supporting materials, and research processes ahead of a definitive trial. METHODS: We recruited community-dwelling stroke survivors (SS) ≥ 3 months post-stroke, with symptoms of mood disorder (Hospital Anxiety and Depression Scale ≥ 8). Participants could 'enrol' a family member/ 'other' to take part with them, if desired. Study 1 tested HEADS: UP delivered in-person, and informed optimisation of research processes and intervention delivery and materials. In a pragmatic response to Covid-related socialising restrictions, HEADS: UP was then adapted for online delivery, tested in Study 2. The primary outcome (both studies) was the feasibility (acceptability, fidelity) of the intervention and of research processes. Quantitative data (including patient-reported outcome measures (PROMs) assessing mood and quality of life) and qualitative data were collected pre-/post-intervention. Descriptive statistics were used to analyse quantitative data; a thematic framework approach was used to analyse qualitative data. Both studies received ethical approval prior to commencement. RESULTS: Study 1 Feasibility: 13 (59.1%) of 22 potentially eligible stroke survivors consented; aged 66 (median, interquartile range (IQR) 14); male (n = 9; 69%); 28 (IQR 34) months post-stroke. Of these, n = 10 (76.9%) completed PROMS pre-intervention; n = 6 (46.2%) post-intervention. Acceptability: Nine (69.2%) of the 13 participants attended ≥ 4 core intervention sessions. Aspects of screening and data collection were found to be burdensome. Study 2 Feasibility: SS n = 9 (41%) of 22 potentially eligible stroke survivors consented; aged 58 years (median; IQR 12); male (n = 4; 44.4%); 23 (IQR 34) months post-stroke. Of these, n = 5 (55.6%) completed PROMS pre-intervention; n = 5 (55.6%) post-intervention. Acceptability: Five (55.6%) of the 9 participants attended ≥ 4 core sessions. They found online screening and data collection processes straightforward.

Remotely Modulating the Optical Properties of Organic Charge-Transfer Crystallites via Molecular Packing.

Organic charge-transfer complex (CTC) formation has emerged as an effective molecular engineering strategy for achieving the desired optical properties via intermolecular interactions. By synthesizing organic CTCs with carbazole-based electron donors and a 7,7,8,8-tetracyanoquinodimethane acceptor and adopting a molecular linker located remotely from the charge-transfer interface within the donors, we were able to modulate near-infrared absorptive and short-wavelength infrared emissive properties. Structural characterizations performed by using single-crystal X-ray diffraction confirmed that the unique molecular arrangements induced by the steric hindrance from the remotely located linker significantly influence the electronic interactions between the donor and acceptor molecules, resulting in different photophysical properties. Our findings offer an improved understanding of the interplay between molecular packing and optoelectronic properties, providing a foundation for designing advanced materials for optoelectronic applications.

A Quality Initiative to Improve Appropriate Medication Dosing in Pediatric Patients with Obesity.

Introduction: Emerging evidence supports the use of alternative dosing weights for medications in patients with obesity. Pediatric obesity presents a particular challenge because most medications are dosed based on patient weight. Additionally, building system-wide pediatric obesity safeguards is difficult due to pediatric obesity definitions of body mass index-percentile-for-age via the Center for Disease Control growth charts. We describe a quality initiative to increase appropriate medication dosing in inpatients with obesity. The specific aim was to increase appropriate dosing for 7 high-risk medications in inpatients with obesity ≥2 years old from 37% to >74% and to sustain for 1 year. Methods: The Institute for Healthcare Improvement model for improvement was used to plan interventions and track outcomes progress. Interventions included a literature review to establish internal dosing guidance, electronic health record (EHR) functionality to identify pediatric patients with obesity, a default selection for medication weight with an opt-out, and obtaining patient heights in the emergency department. Results: Appropriate dosing weight use in medication ordered for patients with obesity increased from 37% to 83.4% and was sustained above the goal of 74% for 12 months. Conclusions: Implementation of EHR-based clinical decision support has increased appropriate evidence-based dosing of medications in pediatric and adult inpatients with obesity. Future studies should investigate the clinical and safety implications of using alternative dosing weights in pediatric patients.

Improving digital partner notification for sexually transmitted infections and HIV through a systematic review and application of the Behaviour Change Wheel approach.

BACKGROUND: Partner notification (PN) is key to controlling sexually transmitted infections (STIs) and human immunodeficiency virus (HIV). Digital PN options (e.g. social media, short message service (SMS), emails) are promising in increasing PN behaviour. However, their implementation is often challenging and studies report varied levels of acceptability and uptake of PN, highlighting the need to optimise digital PN interventions. METHODS: A systematic review of barriers and facilitators to digital PN interventions for STIs, including HIV, across eight research databases (from 2010 to 2023) identified eight relevant studies, two of which addressed HIV. Data extraction identified 98 barriers and 54 facilitators to the use of digital PN interventions. These were synthesised into 18 key barriers and 17 key facilitators that were each deemed amenable to change. We then used the Behaviour Change Wheel approach, the Acceptability, Practicability, Effectiveness, Affordability, Side-effects and Equity criteria, and multidisciplinary expert input, to systematically develop practical recommendations to optimise digital PN. RESULTS: Thirty-two specific recommendations clustered around three themes. Digital PN interventions should: (1) empower and support the index patient by providing a range of notification options, accompanied by clear instructions; (2) integrate into users' existing habits and the digital landscape, meeting contemporary standards and expectations of usability; and (3) address the social context of PN both online and offline through normalising the act of PN, combating STI-related stigma and stressing the altruistic aspects of PN through consistent messaging to service users and the public. CONCLUSIONS: Our evidence-based recommendations should be used to optimise existing digital PN interventions and inform the co-production of new ones.

Characterizing Delirium and Associated Risk Factors Using the Cornell Assessment of Pediatric Delirium Score in Pediatric Burn Patients.

Delirium is a syndrome of acute brain dysfunction with disturbance in consciousness and cognition that is increasingly recognized in critically ill pediatric patients. The Cornell Assessment of Pediatric Delirium (CAPD) tool is used to detect delirium in children of all ages and developmental stages in various hospital settings. To date, the incidence of delirium in the pediatric burn population has been poorly defined. In order to describe the incidence as well as risk factors for delirium in this patient population, we retrospectively reviewed patients <18 years of age admitted to our American Burn Association-verified pediatric burn center from March 2018 to May 2021 who underwent delirium screening using the CAPD tool. Patient demographics, burn characteristics, hospitalization details, and date of first positive delirium screening were collected, and χ2, Fisher's exact test, univariate, and multivariate analyses were performed. Delirium was identified in 42 (10.8%) of 389 patients meeting inclusion criteria. Patients screening positive for delirium were older (4 years [IQR: 2, 11] vs 2 years [IQR: 1, 6], P < .0005) and had larger TBSA burns (21.63% [IQR: 9, 42] vs 3.5% [IQR: 1.75, 6], P < .0001) than delirium-negative patients. Delirium-positive patients required a longer duration of mechanical ventilation (OR 4.23; 95% CI [1.16-15.39], P = .0289) and had higher TBSA burns (OR 1.12; 95% CI [1.06-1.17], P < .0001). Delirium-positive patients had 1.6 day longer length-of-stay adjusted for TBSA burned (95% CI [0.81-2.41], P < .0001). Compared to delirium-negative patients, delirium-positive patients had a 5.4-day longer PICU admission (95% CI [2.93-10.3]; P < .0001). Screening pediatric burn patients with risk factors known to be associated with delirium by using the CAPD score could improve delirium prevention and allow for early intervention.

Noninvasive Neuromonitoring Modalities in Children Part I: Pupillometry, Near-Infrared Spectroscopy, and Transcranial Doppler Ultrasonography.

BACKGROUND: Noninvasive neuromonitoring in critically ill children includes multiple modalities that all intend to improve our understanding of acute and ongoing brain injury. METHODS: In this article, we review basic methods and devices, applications in clinical care and research, and explore potential future directions for three noninvasive neuromonitoring modalities in the pediatric intensive care unit: automated pupillometry, near-infrared spectroscopy, and transcranial Doppler ultrasonography. RESULTS: All three technologies are noninvasive, portable, and easily repeatable to allow for serial measurements and trending of data over time. However, a paucity of high-quality data supporting the clinical utility of any of these technologies in critically ill children is currently a major limitation to their widespread application in the pediatric intensive care unit. CONCLUSIONS: Future prospective multicenter work addressing major knowledge gaps is necessary to advance the field of pediatric noninvasive neuromonitoring.

Improving HIV pre-exposure prophylaxis (PrEP) adherence and retention in care: Process evaluation and recommendation development from a nationally implemented PrEP programme.

INTRODUCTION: HIV pre-exposure prophylaxis (PrEP), in which people take HIV medication to prevent HIV acquisition, underpins global HIV transmission elimination strategies. Effective prevention needs people to adhere to PrEP and remain in care during periods of risk, but this is difficult to achieve. We undertook a process evaluation of Scotland's PrEP programme to explore barriers and facilitators to PrEP adherence and retention in care and to systematically develop evidence-based, theoretically-informed recommendations to address them. METHODS: We conducted semi-structured interviews and focus groups (09/2018-07/2019) with patients who identified as gay or bisexual men and were either using PrEP, had declined the offer of PrEP, had stopped PrEP, or had been assessed as ineligible for PrEP (n = 39 of whom n = 5 (13%) identified as trans, median age 31 years and interquartile range 14 years), healthcare professionals involved in PrEP provision (n = 54 including specialist sexual health doctors and nurses of various grades, PrEP prescribing general practitioners, health promotion officers, midwifes, and a PrEP clinical secretary), and clients (n = 9) and staff (n = 15) of non-governmental organisations with an HIV prevention remit across Scotland. We used thematic analysis to map key barriers and facilitators to priority areas that could enhance adherence and retention in care. We used implementation science analytic tools (Theoretical Domains Framework, Intervention Functions, Behaviour Change Technique Taxonomy, APEASE criteria) and expert opinion to systematically generate recommendations. RESULTS: Barriers included perceived complexity of on-demand dosing, tendency for users to stop PrEP before seeking professional support, troublesome side-effects, limited flexibility in the settings/timings/nature of review appointments, PrEP-related stigma and emerging stigmas around not using PrEP. Facilitators included flexible appointment scheduling, reminders, and processes to follow up non-attenders. Examples of the 25 recommendations include: emphasising benefits of PrEP reviews and providing appointments flexibly within individualised PrEP care; using clinic systems to remind/recall PrEP users; supporting PrEP conversations among sexual partners; clear on-demand dosing guidance; encouraging good PrEP citizenship; detailed discussion on managing side-effects and care/coping planning activities. CONCLUSIONS: PrEP adherence and retention in care is challenging, reducing the effectiveness of PrEP at individual and population levels. We identify and provide solutions to where and how collaborative interventions across public health, clinical, and community practice could address these challenges.

Cryo-EM structures of tau filaments from the brains of mice transgenic for human mutant P301S Tau.

Mice transgenic for human mutant P301S tau are widely used as models for human tauopathies. They develop neurodegeneration and abundant filamentous inclusions made of human mutant four-repeat tau. Here we used electron cryo-microscopy (cryo-EM) to determine the structures of tau filaments from the brains of Tg2541 and PS19 mice. Both lines express human P301S tau (0N4R for Tg2541 and 1N4R for PS19) on mixed genetic backgrounds and downstream of different promoters (murine Thy1 for Tg2541 and murine Prnp for PS19). The structures of tau filaments from Tg2541 and PS19 mice differ from each other and those of wild-type tau filaments from human brains. The structures of tau filaments from the brains of humans with mutations P301L, P301S or P301T in MAPT are not known. Filaments from the brains of Tg2541 and PS19 mice share a substructure at the junction of repeats 2 and 3, which comprises residues I297-V312 of tau and includes the P301S mutation. The filament core from the brainstem of Tg2541 mice consists of residues K274-H329 of tau and two disconnected protein densities. Two non-proteinaceous densities are also in evidence. The filament core from the cerebral cortex of line PS19 extends from residues G271-P364 of tau. One strong non-proteinaceous density is also present. Unlike the tau filaments from human brains, the sequences following repeat 4 are missing from the cores of tau filaments from the brains of Tg2541 and PS19 mice.

Improving HIV pre-exposure prophylaxis (PrEP) uptake and initiation: process evaluation and recommendation development from a national PrEP program†.

BACKGROUND: HIV pre-exposure prophylaxis (PrEP) is key to HIV transmission elimination but implementation is challenging and under-researched. We undertook a process evaluation of the first 2years of a national PrEP program to explore barriers and facilitators to implementation and to develop recommendations to improve implementation, focusing on PrEP uptake and initiation. METHODS: Stage 1 involved semi-structured telephone interviews and focus groups (September 2018-July 2019) with geographically and demographically diverse patients seeking/using/declining/stopping PrEP (n =39), sexual healthcare professionals (n =54), community-based organisation service users (n =9) and staff (n =15) across Scotland. We used deductive thematic analysis, to derive and then map key barriers and facilitators to priority areas that experts agreed would enhance uptake and initiation. In Stage 2, we used analytic tools from implementation science to systematically generate evidence-based, theoretically-informed recommendations to enhance uptake and initiation of PrEP. RESULTS: Barriers and facilitators were multi-levelled and interdependent. Barriers included the rapid pace of implementation without additional resource, and a lack of familiarity with PrEP prescribing. Facilitators included opportunities for acquisition of practice-based knowledge and normalisation of initiation activities. We refined our 68 'long-list' recommendations to 41 using expert input and the APEASE (Acceptability, Practicability, Effectiveness, Affordability, Side-effects, and Equity) criteria. Examples include: provision of PrEP in diverse settings to reach all in need; co-produced, culturally sensitive training resources for healthcare professionals, with focused content on non-daily dosing; meaningful collaborative working across all stakeholders. CONCLUSIONS: These evidence-based, theory informed recommendations provide a robust framework for optimising PrEP uptake and initiation in diverse settings to ensure PrEP reaches all who may benefit.

Tyrosine kinase inhibitor toxicities: A society of gynecologic oncology review and recommendations.

OBJECTIVE: Oral tyrosine kinase inhibitors (TKIs) have new indications for treatment in gynecologic malignancies. These targeted drugs have both unique and overlapping toxicities, which require careful attention and management. New combination therapies with immune-oncology agents have demonstrated promise in endometrial cancer. This review examines common adverse events associated with TKIs and provides readers with an evidence-based review on current uses and strategies for the management of these medications. METHODS: A comprehensive review of the medical literature on TKI use in gynecologic cancer was undertaken by a committee approach. Details of each drug, its molecular target, and relevant data on both clinical efficacy and side effects were compiled and organized for clinical use. Information on drug-related secondary effects and management strategies for specific toxicities, including dose reduction and concomitant medications, were gathered. RESULTS: TKIs can potentially offer improved response rates and durable responses for a group of patients who were previously without an effective standard second-line therapy. The combination of lenvatinib and pembrolizumab represents a more targeted approach to the drivers of endometrial cancer; however, there remains significant drug-related toxicity, and thus dose reduction and dose delay are frequently required. Toxicity management requires frequent check-ins and management strategies to help patients find the highest tolerable dose. TKIs are expensive and patient financial toxicity is as critical a measure of a drug's utility as any drug side effect. Many of these drugs have patient assistance programs, which should be fully utilized to minimize cost. CONCLUSIONS: Future studies are needed to expand the role of TKIs into new molecularly driven groups. Attention to cost, durability of response, and long-term toxicity management is needed to ensure all eligible patients have access to treatment.

Understanding Intersectional Ageism and Stigma of Dementia: Protocol for a Scoping Review.

BACKGROUND: Ageism and stigma reduce the quality of life of older adults living with dementia. However, there is a paucity of literature addressing the intersection and combined effects of ageism and stigma of dementia. This intersectionality, rooted in the social determinants of health (ie, social support and access to health care), compounds health disparities and is, therefore, an important area of inquiry. OBJECTIVE: This scoping review protocol outlines a methodology that will be used to examine ageism and stigma confronting older adults living with dementia. The aim of this scoping review will be to identify the definitional components, indicators, and measures used to track and evaluate the impact of ageism and stigma of dementia. More specifically, this review will focus on examining the commonalities and differences in definitions and measures to develop a better understanding of intersectional ageism and stigma of dementia as well as the current state of the literature. METHODS: Guided by Arksey and O'Malley's 5-stage framework, our scoping review will be conducted by searching 6 electronic databases (PsycINFO, MEDLINE, Web of Science, CINAHL, Scopus, and Embase) and a web-based search engine (ie, Google Scholar). Reference lists of relevant journal articles will be hand-searched to identify additional articles. The results from our scoping review will be presented using the PRISMA-ScR (Preferred Reporting Items for Systematic Reviews and Meta-Analyses for Scoping Reviews) checklist. RESULTS: This scoping review protocol was registered with the Open Science Framework on January 17, 2023. Data collection and analysis and manuscript writing will occur from March to September 2023. The target date for manuscript submission will be October 2023. Findings from our scoping review will be disseminated through various means, such as journal articles, webinars, national networks, and conference presentations. CONCLUSIONS: Our scoping review will summarize and compare the core definitions and measures used to understand ageism and stigma toward older adults with dementia. This is significant because there is limited research addressing the intersectionality of ageism and stigma of dementia. Accordingly, findings from our study may provide critical knowledge and insight to help inform future research, programs, and policies to address intersectional ageism and stigma of dementia. TRIAL REGISTRATION: Open Science Framework; https://osf.io/yt49k. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): PRR1-10.2196/46093.

Cryo-EM structures of amyloid-ß filaments with the Arctic mutation (E22G) from human and mouse brains.

The Arctic mutation, encoding E693G in the amyloid precursor protein (APP) gene [E22G in amyloid-ß (Aß)], causes dominantly inherited Alzheimer's disease. Here, we report the high-resolution cryo-EM structures of Aß filaments from the frontal cortex of a previously described case (AßPParc1) with the Arctic mutation. Most filaments consist of two pairs of non-identical protofilaments that comprise residues V12-V40 (human Arctic fold A) and E11-G37 (human Arctic fold B). They have a substructure (residues F20-G37) in common with the folds of type I and type II Aß42. When compared to the structures of wild-type Aß42 filaments, there are subtle conformational changes in the human Arctic folds, because of the lack of a side chain at G22, which may strengthen hydrogen bonding between mutant Aß molecules and promote filament formation. A minority of Aß42 filaments of type II was also present, as were tau paired helical filaments. In addition, we report the cryo-EM structures of Aß filaments with the Arctic mutation from mouse knock-in line AppNL-G-F. Most filaments are made of two identical mutant protofilaments that extend from D1 to G37 (AppNL-G-F murine Arctic fold). In a minority of filaments, two dimeric folds pack against each other in an anti-parallel fashion. The AppNL-G-F murine Arctic fold differs from the human Arctic folds, but shares some substructure.

Catheter-associated deep vein thrombosis in children with severe traumatic brain injury: A single-center experience.

BACKGROUND: This study was performed to describe the single-center experience of deep vein thrombosis (DVT) in children with severe traumatic brain injury (sTBI) who were mechanically ventilated with a central line, and to identify potentially modifiable risk factors. It was hypothesized that children with DVT would have a longer duration of central venous line (CVL) and a higher use of hypertonic saline (HTS) compared to those without DVT. PROCEDURE/METHODS: This was a retrospective study of children (0-18 years) with sTBI, who were intubated, had a CVL, and a minimum intensive care unit (ICU) stay of 3 days. Children were analyzed by the presence or absence of DVT. HTS use was evaluated using milliliter per kilogram (ml/kg) of 3% equivalents. Univariable and multivariable logistic regression models were used to determine which factors were associated with DVT. RESULTS: Seventy-seven children met inclusion criteria, 23 (29.9%) had a DVT detected in an extremity. On univariable analysis, children with DVT identified in an extremity had prolonged CVL use (14 vs. 8.5 days, p = .021) and longer duration of mechanical ventilation (15 vs. 10 days, p = .013). HTS 3% equivalent ml/kg was not different between groups. On multivariable analysis, mechanical ventilation duration was associated with DVT detection in an extremity, whereas neither CVL duration nor HTS use had an association. CONCLUSIONS: There was a high incidence of extremity DVT detected in children with sTBI who received invasive mechanical ventilation and had a CVL. HTS administration was not associated with DVT detection in an extremity.

Ketamine for Management of Neonatal and Pediatric Refractory Status Epilepticus.

BACKGROUND AND OBJECTIVES: Few data are available regarding the use of anesthetic infusions for refractory status epilepticus (RSE) in children and neonates, and ketamine use is increasing despite limited data. We aimed to describe the impact of ketamine for RSE in children and neonates. METHODS: Retrospective single-center cohort study of consecutive patients admitted to the intensive care units of a quaternary care children's hospital treated with ketamine infusion for RSE. RESULTS: Sixty-nine patients were treated with a ketamine infusion for RSE. The median age at onset of RSE was 0.7 years (interquartile range 0.15-7.2), and the cohort included 13 (19%) neonates. Three patients (4%) had adverse events requiring intervention during or within 12 hours of ketamine administration, including hypertension in 2 patients and delirium in 1 patient. Ketamine infusion was followed by seizure termination in 32 patients (46%), seizure reduction in 19 patients (28%), and no change in 18 patients (26%). DISCUSSION: Ketamine administration was associated with few adverse events, and seizures often terminated or improved after ketamine administration. Further data are needed comparing first-line and subsequent anesthetic medications for treatment of pediatric and neonatal RSE. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence on the therapeutic utility of ketamine for treatment of RSE in children and neonates.

Cryo-EM structures of amyloid-ß 42 filaments from human brains.

Filament assembly of amyloid-ß peptides ending at residue 42 (Aß42) is a central event in Alzheimer's disease. Here, we report the cryo­electron microscopy (cryo-EM) structures of Aß42 filaments from human brains. Two structurally related S-shaped protofilament folds give rise to two types of filaments. Type I filaments were found mostly in the brains of individuals with sporadic Alzheimer's disease, and type II filaments were found in individuals with familial Alzheimer's disease and other conditions. The structures of Aß42 filaments from the brain differ from those of filaments assembled in vitro. By contrast, in AppNL-F knock-in mice, Aß42 deposits were made of type II filaments. Knowledge of Aß42 filament structures from human brains may lead to the development of inhibitors of assembly and improved imaging agents.

Increase in Tau Pathology in P290S Mapt Knock-In Mice Crossed with App NL-G-F Mice.

Alzheimer's Disease (AD) is characterized by the pathologic assembly of amyloid ß (Aß) peptide, which deposits into extracellular plaques, and tau, which accumulates in intraneuronal inclusions. To investigate the link between Aß and tau pathologies, experimental models featuring both pathologies are needed. We developed a mouse model featuring both tau and Aß pathologies by knocking the P290S mutation into murine Mapt and crossing these Mapt P290S knock-in (KI) mice with the App NL-G-F KI line. Mapt P290S KI mice developed a small number of tau inclusions, which increased with age. The amount of tau pathology was significantly larger in App NL-G-F xMapt P290S KI mice from 18 months of age onward. Tau pathology was higher in limbic areas, including hippocampus, amygdala, and piriform/entorhinal cortex. We also observed AT100-positive and Gallyas-Braak-silver-positive dystrophic neurites containing assembled filamentous tau, as visualized by in situ electron microscopy. Using a cell-based tau seeding assay, we showed that Sarkosyl-insoluble brain extracts from both 18-month-old Mapt P290S KI and App NL-G-F xMapt P290S KI mice were seed competent, with brain extracts from double-KI mice seeding significantly more than those from the Mapt P290S KI mice. Finally, we showed that App NL-G-F xMapt P290S KI mice had neurodegeneration in the piriform cortex from 18 months of age. We suggest that App NL-G-F xMapt P290S KI mice provide a good model for studying the interactions of aggregation-prone tau, Aß, neuritic plaques, neurodegeneration, and aging.

Assembly of α-synuclein and neurodegeneration in the central nervous system of heterozygous M83 mice following the peripheral administration of α-synuclein seeds.

Peripheral administration (oral, intranasal, intraperitoneal, intravenous) of assembled A53T α-synuclein induced synucleinopathy in heterozygous mice transgenic for human mutant A53T α-synuclein (line M83). The same was the case when cerebellar extracts from a case of multiple system atrophy with type II α-synuclein filaments were administered intraperitoneally, intravenously or intramuscularly. We observed abundant immunoreactivity for pS129 α-synuclein in nerve cells and severe motor impairment, resulting in hindlimb paralysis and shortened lifespan. Filaments immunoreactive for pS129 α-synuclein were in evidence. A 70% loss of motor neurons was present five months after an intraperitoneal injection of assembled A53T α-synuclein or cerebellar extract with type II α-synuclein filaments from an individual with a neuropathologically confirmed diagnosis of multiple system atrophy. Microglial cells changed from a predominantly ramified to a dystrophic appearance. Taken together, these findings establish a close relationship between the formation of α-synuclein inclusions in nerve cells and neurodegeneration, accompanied by a shift in microglial cell morphology. Propagation of α-synuclein inclusions depended on the characteristics of both seeds and transgenically expressed protein.

Variability in Pediatric Brain Death Determination Protocols in the United States.

OBJECTIVE: To determine the variability in pediatric death by neurologic criteria (DNC) protocols between US pediatric institutions and compared to the 2011 DNC guidelines. METHODS: Cross-sectional study of DNC protocols obtained from pediatric institutions in the United States (US) via regional organ procurement organizations. Protocols were evaluated across five domains: general DNC procedures, prerequisites, neurologic examination, apnea testing and ancillary testing. Descriptive statistics compared protocols to each other and the 2011 guidelines. RESULTS: One hundred and thirty protocols were analyzed with 118 dated after publication of the 2011 guidelines. Of those 118 protocols, identification of a mechanism of irreversible brain injury was required in 97%, while 67% required an observation period after acute brain injury before DNC evaluation. Most protocols required guideline-based prerequisites such as exclusion of hypotension (94%), hypothermia (97%), and metabolic derangements (92%). On neurologic examination, 91% required a lack of responsiveness, 93% no response to noxious stimuli, and 99% loss of brainstem reflexes. 84% of protocols required the guideline-recommened two apnea tests. CO2 targets were consistent with guidelines in 64%. Contrary to guidelines, fifteen percent required ancillary testing for all patients and 15% permitted ancillary studies that are not validated in pediatrics. CONCLUSIONS: and Relevance: Variability exists between pediatric institutional DNC protocols in all domains of DNC determination, especially with respect to apnea and ancillary testing. Better alignment of DNC protocols with national guidelines may improve the consistency and accuracy of DNC determination.