Top Tips for Designing and Managing a Public Engagement Laboratory.

Public engagement with science is a core facet of the broader science ecosystem, in particular the science research and science education sectors. In this article we demarcate the benefits of dedicated laboratories along with practitioner advice pertaining to the design and running of a public engagement learning environment. A practicing public engagement laboratory and one that is currently being developed are used as illustrative cases to provide real-world insights to public engagement practitioners.

CA9, CYFIP2 and LGALS3BP-A Novel Biomarker Panel to Aid Prognostication in Glioma.

Brain cancer is a devastating and life-changing disease. Biomarkers are becoming increasingly important in addressing clinical issues, including in monitoring tumour progression and assessing survival and treatment response. The goal of this study was to identify prognostic biomarkers associated with glioma progression. Discovery proteomic analysis was performed on a small cohort of astrocytomas that were diagnosed as low-grade and recurred at a higher grade. Six proteins were chosen to be validated further in a larger cohort. Three proteins, CA9, CYFIP2, and LGALS3BP, were found to be associated with glioma progression and, in univariate analysis, could be used as prognostic markers. However, according to the results of multivariate analysis, these did not remain significant. These three proteins were then combined into a three-protein panel. This panel had a specificity and sensitivity of 0.7459 for distinguishing between long and short survival. In silico data confirmed the prognostic significance of this panel.

Localized cardiomyocyte lipid accumulation is associated with slowed epicardial conduction in rats.

Transmural action potential duration differences and transmural conduction gradients aid the synchronization of left ventricular repolarization, reducing vulnerability to transmural reentry and arrhythmias. A high-fat diet and the associated accumulation of pericardial adipose tissue are linked with conduction slowing and greater arrhythmia vulnerability. It is predicted that cardiac adiposity may more readily influence epicardial conduction (versus endocardial) and disrupt normal transmural activation/repolarization gradients. The aim of this investigation was to determine whether transmural conduction gradients are modified in a rat model of pericardial adiposity. Adult Sprague-Dawley rats were fed control/high-fat diets for 15 wk. Left ventricular 300 µm tangential slices were generated from the endocardium to the epicardium, and conduction was mapped using microelectrode arrays. Slices were then histologically processed to assess fibrosis and cardiomyocyte lipid status. Conduction velocity was significantly greater in epicardial versus endocardial slices in control rats, supporting the concept of a transmural conduction gradient. High-fat diet feeding increased pericardial adiposity and abolished the transmural conduction gradient. Slowed epicardial conduction in epicardial slices strongly correlated with an increase in cardiomyocyte lipid content, but not fibrosis. The positive transmural conduction gradient reported here represents a physiological property of the ventricular activation sequence that likely protects against reentry. The absence of this gradient, secondary to conduction slowing and cardiomyocyte lipid accumulation, specifically in the epicardium, indicates a novel mechanism by which pericardial adiposity may exacerbate ventricular arrhythmias.

Weight Gain and Nutritional Improvement After Magnetically Controlled Growing Rod Surgery in Early-Onset Scoliosis: A Single Centre Analysis of 68 Patients.

BACKGROUND: Early-onset scoliosis (EOS) is frequently associated with complex spine and chest wall deformities that may lead to severe cardiopulmonary impairment and malnutrition. The aim of this study is to evaluate the change in the nutritional status of EOS patients after treatment with magnetically controlled growing rod instrumentation (MCGR) in a single center. METHODS: We prospectively collected data of patients treated with MCGR for EOS in a single center. Exclusion criteria were <2 years' follow-up and incomplete weight-for-age Z-scores (WAZ) data. Preoperative and postoperative WAZ, radiographic parameters, including major coronal curve, kyphosis angle, space available for lung ratios, thoracic height, and unplanned returns to the operating room (UPROR), were analyzed. SD and 95% Confidence intervals (CI) are presented with means. RESULTS: Sixty-eight patients (37 males/31 females) were included. The mean age at surgery was 8.2 years (SD 2.8, range 1.8-14.2), and the mean follow-up time was 3.8 years (SD 1.0, range 2.1-6.8). The study population was categorized by the primary diagnosis as follows: 23 neuromuscular, 18 idiopathic, 15 congenital, and 12 syndromic patients. The major coronal curve improved between the preoperative and latest visits by 40% ( P <0.005, SD 27, CI 33-47), while the space available for lung ratios improved by 8% ( P <0.005, SD 13, CI 5-12). Thoracic height increased by 25% ( P <0.005, SD 13, CI 22-28), and kyphosis angle decreased by 25% ( P <0.005, SD 26, CI 9-39). Eighteen patients (27%) required a total of 53 UPRORs. WAZ improved significantly between the preoperative and the latest follow-up ( P =0.005). Regression analysis showed WAZ improvements were most significant in the underweight patients and the Idiopathic or Syndromic EOS patients. UPROR was not associated with deterioration in WAZ. CONCLUSIONS: Treatment of EOS patients with MCGR resulted in an improvement in nutritional status, as evidenced by the significant increase in WAZ. Underweight, Idiopathic and Syndromic EOS patients, and those who required UPROR all had significant improvement in their WAZ with MCGR treatment. LEVEL OF EVIDENCE: Therapeutic Study-Level II.

Using an appetitive operant conditioning paradigm to screen rats for tinnitus induced by intense sound exposure: Experimental considerations and interpretation.

In an effort to help elucidate the neural mechanisms underlying tinnitus in humans, researchers have often relied on animal models; a preclinical approach which ultimately required that behavioral paradigms be designed to reliably screen animals for tinnitus. Previously, we developed a two-alternative forced-choice (2AFC) paradigm for rats that allowed for the simultaneous recording of neural activity at the very moments when they were reporting the presence/absence of tinnitus. Because we first validated our paradigm in rats experiencing transient tinnitus following a high-dose of sodium salicylate, the present study now sought to evaluate its utility to screen for tinnitus caused by intense sound exposure; a common tinnitus-inducer in humans. More specifically, through a series of experimental protocols, we aimed to (1) conduct sham experiments to ensure that the paradigm was able to correctly classify control rats as not having tinnitus, (2) confirm the time course over which the behavioral testing could reliably be performed post-exposure to assess chronic tinnitus, and (3) determine if the paradigm was sensitive to the variable outcomes often observed after intense sound exposure (e.g., hearing loss with our without tinnitus). Ultimately, in accordance with our predictions, the 2AFC paradigm was indeed resistant to false-positive screening of rats for intense sound-induced tinnitus, and it was able to reveal variable tinnitus and hearing loss profiles in individual rats following intense sound exposure. Taken together, the present study documents the utility of our appetitive operant conditioning paradigm to assess acute and chronic sound-induced tinnitus in rats. Finally, based on our findings, we discuss important experimental considerations that will help ensure that our paradigm is able to provide a suitable platform for future investigations into the neural basis of tinnitus.

Design and Evaluation of [18F]CHDI-650 as a Positron Emission Tomography Ligand to Image Mutant Huntingtin Aggregates.

Therapeutic interventions are being developed for Huntington's disease (HD), a hallmark of which is mutant huntingtin protein (mHTT) aggregates. Following the advancement to human testing of two [11C]-PET ligands for aggregated mHTT, attributes for further optimization were identified. We replaced the pyridazinone ring of CHDI-180 with a pyrimidine ring and minimized off-target binding using brain homogenate derived from Alzheimer's disease patients. The major in vivo metabolic pathway via aldehyde oxidase was blocked with a 2-methyl group on the pyrimidine ring. A strategically placed ring-nitrogen on the benzoxazole core ensured high free fraction in the brain without introducing efflux. Replacing a methoxy pendant with a fluoro-ethoxy group and introducing deuterium atoms suppressed oxidative defluorination and accumulation of [18F]-signal in bones. The resulting PET ligand, CHDI-650, shows a rapid brain uptake and washout profile in non-human primates and is now being advanced to human testing.

Understanding Pandemic Solidarity: Mutual Support During the First COVID-19 Lockdown in the United Kingdom.

Throughout the COVID-19 pandemic, the concept of solidarity has been invoked frequently. Much interest has centred around how citizens and communities support one another during times of uncertainty. Yet, empirical research which accounts and understands citizen's views on pandemic solidarity, or their actual practices has remained limited. Drawing upon the analysis of data from 35 qualitative interviews, this article investigates how residents in England and Scotland enacted, understood, or criticised (the lack of) solidarity during the first national lockdown in the United Kingdom in April 2020-at a time when media celebrated solidarity as being at an all-time high. It finds that although solidarity was practiced by some people, the perceived lack of solidarity was just as pronounced. We conclude that despite frequent mobilisations of solidarity by policy makers and other public actors, actual practices of solidarity are poorly understood-despite the importance of solidarity for public health and policy.

Understanding the incidence and timing of rabies cases in domestic animals and wildlife in south-east Tanzania in the presence of widespread domestic dog vaccination campaigns.

The "Zero by 30" strategic plan aims to eliminate human deaths from dog-mediated rabies by 2030 and domestic dog vaccination is a vital component of this strategic plan. In areas where domestic dog vaccination has been implemented, it is important to assess the impact of this intervention. Additionally, understanding temporal and seasonal trends in the incidence of animal rabies cases may assist in optimizing such interventions. Data on the incidence of probable rabies cases in domestic and wild animals were collected between January 2011 and December 2018 in thirteen districts of south-east Tanzania where jackals comprise over 40% of reported rabies cases. Vaccination coverage was estimated over this period, as five domestic dog vaccination campaigns took place in all thirteen districts between 2011 and 2016. Negative binomial generalized linear models were used to explore the impact of domestic dog vaccination on the annual incidence of animal rabies cases, whilst generalized additive models were used to investigate the presence of temporal and/or seasonal trends. Increases in domestic dog vaccination coverage were significantly associated with a decreased incidence of rabies cases in both domestic dogs and jackals. A 35% increase in vaccination coverage was associated with a reduction in the incidence of probable dog rabies cases of between 78.0 and 85.5% (95% confidence intervals ranged from 61.2 to 92.2%) and a reduction in the incidence of probable jackal rabies cases of between 75.3 and 91.2% (95% confidence intervals ranged from 53.0 to 96.1%). A statistically significant common seasonality was identified in the monthly incidence of probable rabies cases in both domestic dogs and jackals with the highest incidence from February to August and lowest incidence from September to January. These results align with evidence supporting the use of domestic dog vaccination as part of control strategies aimed at reducing animal rabies cases in both domestic dogs and jackals in this region. The presence of a common seasonal trend requires further investigation but may have implications for the timing of future vaccination campaigns.

Noise exposure in early adulthood causes age-dependent and brain region-specific impairments in cognitive function.

Hearing loss is a chronic health condition that affects millions of people worldwide. In addition to age-related hearing impairment, excessive noise exposure is a leading cause of hearing loss. Beyond the devastating effects of hearing impairment itself, epidemiological studies have identified hearing loss as a major risk factor for age-related cognitive decline, including dementia. At present, we currently lack a full understanding of the brain regions and underlying molecular changes that are responsible for mediating the link between hearing loss and cognitive impairment across aging. In the present study, we exposed 6-month-old rats to an occupational-like noise (100 dB SPL, 4 h/day × 30 days) or sham exposure and investigated both hippocampal-dependent (i.e., spatial learning and memory, assessed using the Morris water maze) and striatal-dependent (i.e., visuomotor associative learning, assessed using an operant-conditioning task) cognitive function across aging at 7, 10, and 13 months of age. We also investigated brain region-specific changes in microglial expression following noise/sham exposure in order to assess the potential contribution of this cell type to noise-induced cognitive impairments. Consistent with human studies, the occupational-like noise exposure resulted in high-frequency hearing loss, evidenced by a significant increase in hearing thresholds at 20 kHz. Ultimately, our results suggest that not all higher-level cognitive tasks or their associated brain regions appear to be equally susceptible to noise-induced deficits during aging, as the occupational-like noise exposure caused an age-dependent deficit in spatial but not visuomotor associative learning, as well as altered microglial expression in the hippocampus but not the striatum. Interestingly, we found no significant relationships between spatial learning ability and the level of hearing loss or altered microglial density in the hippocampus following noise exposure, suggesting that other changes in the brain likely contribute to hippocampal-dependent cognitive dysfunction following noise exposure. Lastly, we found that a subset of younger animals also showed noise-induced deficits in spatial learning; findings which suggest that noise exposure may represent an increased risk for cognitive impairment in vulnerable subjects. Overall, our findings highlight that even a mild occupational-like noise exposure earlier in adulthood can have long lasting implications for cognitive function later in life.

Democratic research: Setting up a research commons for a qualitative, comparative, longitudinal interview study during the COVID-19 pandemic.

The sudden and dramatic advent of the COVID-19 pandemic led to urgent demands for timely, relevant, yet rigorous research. This paper discusses the origin, design, and execution of the SolPan research commons, a large-scale, international, comparative, qualitative research project that sought to respond to the need for knowledge among researchers and policymakers in times of crisis. The form of organization as a research commons is characterized by an underlying solidaristic attitude of its members and its intrinsic organizational features in which research data and knowledge in the study is shared and jointly owned. As such, the project is peer-governed, rooted in (idealist) social values of academia, and aims at providing tools and benefits for its members. In this paper, we discuss challenges and solutions for qualitative studies that seek to operate as research commons.

The African swine fever modelling challenge: Model comparison and lessons learnt.

Robust epidemiological knowledge and predictive modelling tools are needed to address challenging objectives, such as: understanding epidemic drivers; forecasting epidemics; and prioritising control measures. Often, multiple modelling approaches can be used during an epidemic to support effective decision making in a timely manner. Modelling challenges contribute to understanding the pros and cons of different approaches and to fostering technical dialogue between modellers. In this paper, we present the results of the first modelling challenge in animal health - the ASF Challenge - which focused on a synthetic epidemic of African swine fever (ASF) on an island. The modelling approaches proposed by five independent international teams were compared. We assessed their ability to predict temporal and spatial epidemic expansion at the interface between domestic pigs and wild boar, and to prioritise a limited number of alternative interventions. We also compared their qualitative and quantitative spatio-temporal predictions over the first two one-month projection phases of the challenge. Top-performing models in predicting the ASF epidemic differed according to the challenge phase, host species, and in predicting spatial or temporal dynamics. Ensemble models built using all team-predictions outperformed any individual model in at least one phase. The ASF Challenge demonstrated that accounting for the interface between livestock and wildlife is key to increasing our effectiveness in controlling emerging animal diseases, and contributed to improving the readiness of the scientific community to face future ASF epidemics. Finally, we discuss the lessons learnt from model comparison to guide decision making.

Stochastic modelling of African swine fever in wild boar and domestic pigs: Epidemic forecasting and comparison of disease management strategies.

African swine fever (ASF), caused by the African swine fever virus (ASFV), is highly virulent in domestic pigs and wild boar (Sus scrofa), causing up to 100% mortality. The recent epidemic of ASF in Europe has had a serious economic impact and poses a threat to global food security. Unfortunately, there is no effective treatment or vaccine against ASFV, limiting the available disease management strategies. Mathematical models allow us to further our understanding of infectious disease dynamics and evaluate the efficacy of disease management strategies. The ASF Challenge, organised by the French National Research Institute for Agriculture, Food, and the Environment, aimed to expand the development of ASF transmission models to inform policy makers in a timely manner. Here, we present the model and associated projections produced by our team during the challenge. We developed a stochastic model combining transmission between wild boar and domestic pigs, which was calibrated to synthetic data corresponding to different phases describing the epidemic progression. The model was then used to produce forward projections describing the likely temporal evolution of the epidemic under various disease management scenarios. Despite the interventions implemented, long-term projections forecasted persistence of ASFV in wild boar, and hence repeated outbreaks in domestic pigs. A key finding was that it is important to consider the timescale over which different measures are evaluated: interventions that have only limited effectiveness in the short term may yield substantial long-term benefits. Our model has several limitations, partly because it was developed in real-time. Nonetheless, it can inform understanding of the likely development of ASF epidemics and the efficacy of disease management strategies, should the virus continue its spread in Europe.

COVID-19 Mortality and Therapeutics in Nebraska and Southwest Iowa during Early Pandemic.

Different pharmacotherapeutics have been introduced, and then stopped or continued, for the treatment of SARS-CoV-2. We evaluated the risks associated with mortality from SARS-CoV-2 infection. METHODS: Data was concurrently or retrospectively captured on COVID-19 hospitalized patients from 6 regional hospitals within the health system. Demographic details, the source of SARS-CoV-2 infection, concomitant disease status, as well as the therapeutic agents used for treating SARS-CoV-2 (e.g., antimicrobials, dexamethasone, convalescent plasma, tocilizumab, and remdesivir) were recorded. Discrete and continuous variables were analyzed using SPSS (ver. 27). Logistic regression identified variables significantly correlated with mortality. RESULTS: 471 patients (admitted from 1 March 2020 through 15 July 2020) were reviewed. Mean (±SD) age and body weight (kg) were 62.5 ± 17.7 years and 86.3 ± 27.1 kg, respectively. Patients were Caucasian (50%), Hispanic (34%), African-American (10%), or Asian (5%). Females accounted for 52% of patients. Therapeutic modalities used for COVID-19 illness included remdesivir (16%), dexamethasone (35%), convalescent plasma (17.8%), and tocilizumab (5.8%). The majority of patients returned home (62%) or were transferred to a skilled nursing facility (23%). The overall mortality from SARS-CoV-2 was 14%. Logistic regression identified variables significantly correlated with mortality. Intubation, receipt of dexamethasone, African-American or Asian ethnicity, and being a patient from a nursing home were significantly associated with mortality (x2 = 86.36 (13) p < 0.0005). CONCLUSIONS: SARS-CoV-2 infected hospitalized patients had significant mortality risk if they were intubated, received dexamethasone, were of African-American or Asian ethnicity, or occupied a nursing home bed prior to hospital admission.

Glycogen-autophagy: Molecular machinery and cellular mechanisms of glycophagy.

Autophagy is an essential cellular process involving degradation of superfluous or defective macromolecules and organelles as a form of homeostatic recycling. Initially proposed to be a "bulk" degradation pathway, a more nuanced appreciation of selective autophagy pathways has developed in the literature in recent years. As a glycogen-selective autophagy process, "glycophagy" is emerging as a key metabolic route of transport and delivery of glycolytic fuel substrate. Study of glycophagy is at an early stage. Enhanced understanding of this major noncanonical pathway of glycogen flux will provide important opportunities for new insights into cellular energy metabolism. In addition, glycogen metabolic mishandling is centrally involved in the pathophysiology of several metabolic diseases in a wide range of tissues, including the liver, skeletal muscle, cardiac muscle, and brain. Thus, advances in this exciting new field are of broad multidisciplinary interest relevant to many cell types and metabolic states. Here, we review the current evidence of glycophagy involvement in homeostatic cellular metabolic processes and of molecular mediators participating in glycophagy flux. We integrate information from a variety of settings including cell lines, primary cell culture systems, ex vivo tissue preparations, genetic disease models, and clinical glycogen disease states.

Medicine Maker: An Outreach Activity for Pharmaceutical Manufacturing and Health Literacy.

Public engagement in medicine has become more important in promoting population health management and literacy. Medicine is a topic of great societal importance, and many public engagement activities have been developed to promote this area. However, they often narrowly focus on patient groups, diseases, a singular pharmaceutical drug or analytical technique. Despite the importance of these activities, general audiences are still heavily reliant on doctors and pharmacists for information about their medicine and lack basic knowledge around medication use and personal safety. Given this, a broader engagement approach is warranted to target health literacy among the wider public. "Medicine Maker" is a hands-on public engagement workshop that provides audiences with the opportunity to "manufacture" and inspect the quality of proxy or "dummy" medicine through guided inquiry. Here, we detail the development of the Medicine Maker workshop from its origins in the teaching of Irish third-level pharmacy students, to its initial application with a variety of lay audiences. Formal and informal feedback from participants indicates that the workshop can help foster a more critical understanding of medicine manufacturing, quality control, and personal health.

Tenecteplase use in the management of acute ischemic stroke: Literature review and clinical considerations.

PURPOSE: Several research articles have been published within the last decade comparing the use of tenecteplase to alteplase in ischemic stroke management. Prior reporting on the comparative therapeutic efficacy and safety profiles of tenecteplase and alteplase is reviewed. SUMMARY: Tenecteplase is a variant of native tissue-type plasminogen activator, which rapidly promotes thrombolysis by catalyzing formation of the serine protease plasmin. Tenecteplase has theoretical advantages over alteplase as it has greater fibrin specificity and has a longer half-life than alteplase. This allows the administration of a single bolus over 5 to 10 seconds, as opposed to a bolus followed by a 1-hour infusion with alteplase. While currently approved by the Food and Drug Administration for the treatment of ST-segment elevation myocardial infarction, tenecteplase has also been studied in the treatment of acute ischemic stroke and has extensive data for this off-label indication. The most comprehensive trials to date evaluating the use of tenecteplase in acute ischemic stroke include the TNK-S2B, Australian TNK, ATTEST, Nor-Test, and EXTEND-IA TNK trials. Findings from these randomized controlled studies suggest that tenecteplase is at least as efficacious as alteplase in terms of neurological outcomes. The majority of these studies also reported a trend toward improved safety profiles with the use of tenecteplase. CONCLUSION: Current clinical evidence shows that tenecteplase is not inferior to alteplase for the treatment of ischemic stroke and suggests that tenecteplase may have a superior safety profile. Furthermore, tenecteplase also has practical advantages in terms of its administration. This can potentially lead to a decrease in medication errors and improvement in door to thrombolytic time.

Behavior of potentially toxic elements from stoker-boiler fly ash in Interior Alaska: paired batch leaching and solid-phase characterization.

Despite significant investigation of fly ash spills and mineralogical controls on the release of potentially toxic elements (PTEs) from fly ash, interactions with the surficial environment remain relatively poorly understood. We conducted 90-day batch leaching studies with paired analysis of supernatant and solid-phase mineralogy to assess the elemental release and transformation of fly ash upon reaction with aquatic media (18 MΩ cm-1 water and simulated rainwater). The fly ash in this study, collected from the University of Alaska Fairbanks stoker-boiler power plant, is high in unburned carbon (~20% LOI) and highly enriched in several PTEs relative to the upper continental crust. Supernatant concentrations of oxyanion-forming elements (e.g., As, Se, Mo, Sb) remained relatively low and constant, suggesting equilibrium with the solid phase, possibly ettringite [Ca6Al2(SO4)3(OH)12•26H2O], which is known to incorporate and sorb oxyanion-forming PTEs and was identified by X-ray diffraction. Synthetic precipitation leaching procedure (SPLP) results failed to capture important temporal trends. Lead and Ba supernatant concentrations consistently exceeded drinking water standards, as well as others upon exposure to simulated physiological solutions. Seven-day experiments with dissolved organic matter-isolate solutions indicated that for certain elements, liberation was influenced by carbon concentration and/or the identity of the isolate. Overall, this paired approach can serve as a model for future studies, bridging existing gaps between batch leaching and single-element mineralogical, sorption, or speciation studies.

Elevating CDCA3 Levels Enhances Tyrosine Kinase Inhibitor Sensitivity in TKI-Resistant EGFR Mutant Non-Small-Cell Lung Cancer.

Tyrosine kinase inhibitors (TKIs) are the first-line therapy for non-small-cell lung cancers (NSCLC) that harbour sensitising mutations within the epidermal growth factor receptor (EGFR). However, resistance remains a key issue, with tumour relapse likely to occur. We have previously identified that cell division cycle-associated protein 3 (CDCA3) is elevated in adenocarcinoma (LUAD) and correlates with sensitivity to platinum-based chemotherapy. Herein, we explored whether CDCA3 levels were associated with EGFR mutant LUAD and TKI response. We demonstrate that in a small-cohort tissue microarray and in vitro LUAD cell line panel, CDCA3 protein levels are elevated in EGFR mutant NSCLC as a result of increased protein stability downstream of receptor tyrosine kinase signalling. Here, CDCA3 protein levels correlated with TKI potency, whereby CDCA3high EGFR mutant NSCLC cells were most sensitive. Consistently, ectopic overexpression or inhibition of casein kinase 2 using CX-4945, which pharmacologically prevents CDCA3 degradation, upregulated CDCA3 levels and the response of T790M(+) H1975 cells and two models of acquired resistance to TKIs. Accordingly, it is possible that strategies to upregulate CDCA3 levels, particularly in CDCA3low tumours or upon the emergence of therapy resistance, might improve the response to EGFR TKIs and benefit patients.

[11C]CHDI-626, a PET Tracer Candidate for Imaging Mutant Huntingtin Aggregates with Reduced Binding to AD Pathological Proteins.

The expanded polyglutamine-containing mutant huntingtin (mHTT) protein is implicated in neuronal degeneration of medium spiny neurons in Huntington's disease (HD) for which multiple therapeutic approaches are currently being evaluated to eliminate or reduce mHTT. Development of effective and orthogonal biomarkers will ensure accurate assessment of the safety and efficacy of pharmacologic interventions. We have identified and optimized a class of ligands that bind to oligomerized/aggregated mHTT, which is a hallmark in the HD postmortem brain. These ligands are potentially useful imaging biomarkers for HD therapeutic development in both preclinical and clinical settings. We describe here the optimization of the benzo[4,5]imidazo[1,2-a]pyrimidine series that show selective binding to mHTT aggregates over Aß- and/or tau-aggregates associated with Alzheimer's disease pathology. Compound [11C]-2 was selected as a clinical candidate based on its high free fraction in the brain, specific binding in the HD mouse model, and rapid brain uptake/washout in nonhuman primate positron emission tomography imaging studies.