Growing Kalo (Taro) in the Continental United States.

As an increasing number of Native Hawaiian and Pacific Islander adults move to the continental United States, the development and implementation of resources that promote access to cultural foods and support food sovereignty on the continent is crucial to perpetuate cultural practice and connection to the 'aina (land that feeds). Kalo (taro) is an important cultural food central to Native Hawaiian identity. Native Hawaiians connect their genealogy as far back to the cultivation of kalo and the creation of kalo itself. In this practice note, we describe the creation of a mala kalo (cultivated field for taro) in Oregon by the Ka'aha Lahui O 'Olekona Hawaiian Civic Club. An ongoing project over the past 3 years, the creation of a mala kalo exceeded expectations. Not only did the mala allow the cultivation of kalo outside of Hawaii, the mala became a place for the community to unite toward common goals of connecting with the land, promoting mental health, and creating a sense of place in their diaspora. This project indicates that not only is the creation of mala kalo in Oregon feasible, it may also be an important opportunity for the growing number of Native Hawaiians and Pacific Islanders adults living on the continent to improve health outcomes through connections with cultural foods and practices.

Elucidating the Mechanisms of Pulsed Radiofrequency for Pain Treatment.

Pulsed radiofrequency is a well-documented treatment option for multiple painful conditions where pulses of energy are delivered close to neural elements. Since its earliest adoption, this technique has gained increasing acceptance as a minimally invasive procedure, and new applications are evolving. Studies have shown microscopic and biochemical changes that reflect beneficial effects; however, the exact mechanism of action is not yet completely understood. To redress this paucity, 11,476 articles of scientific relevance published between 1980 and November 2022 were mined through a search of the PubMed database, arriving at 49 studies both in animals and humans. In general, the experimental studies examined have shown that pulsed radiofrequency induces multiple changes with antinociceptive and neuromodulatory effects. These modifications include changes in neural and glial cells, synaptic transmission, and perineural space. Studies also reveal that pulsed radiofrequency regulates inflammatory responses, cellular signaling proteins, and the expression of genes related to pain transmission, acting in biological processes in structures such as myelin, mitochondria, axons, glial cells, connective tissue, regulation of proteins, ion channels, and neurotransmitters.

High-throughput gait acquisition system for freely moving mice.

Normal and pathological locomotion can be discriminated by analyzing an animal's gait on a linear walkway. This step is labor intensive and introduces experimental bias due to the handling involved while placing and removing the animal between trials. We designed a system consisting of a runway embedded within a larger arena, which can be traversed ad libitum by unsupervised, freely moving mice, triggering the recording of short clips of locomotor activity. Multiple body parts were tracked using DeepLabCut and fed to an analysis pipeline (GaitGrapher) to extract gait metrics. We compared the results from unsupervised against the standard experimenter-supervised approach and found that gait parameters analyzed via the new approach were similar to a previously validated approach (Visual Gait Lab). These data show the utility of incorporating an unsupervised, automated, approach for collecting kinematic data for gait analysis.NEW & NOTEWORTHY The acquisition and analysis of walkway data is a time-consuming task. Here, we provide an unmonitored approach for collecting gait metrics that reduces the handling and stress of mice and saves time. A detailed pipeline is outlined that provides for the collection and analysis of data using an integrated suite of tools.

Addressing the range anxiety of battery electric vehicles with charging en route.

Battery electric vehicles (BEVs) have emerged as a promising alternative to traditional internal combustion engine (ICE) vehicles due to benefits in improved fuel economy, lower operating cost, and reduced emission. BEVs use electric motors rather than fossil fuels for propulsion and typically store electric energy in lithium-ion cells. With rising concerns over fossil fuel depletion and the impact of ICE vehicles on the climate, electric mobility is widely considered as the future of sustainable transportation. BEVs promise to drastically reduce greenhouse gas emissions as a result of the transportation sector. However, mass adoption of BEVs faces major barriers due to consumer worries over several important battery-related issues, such as limited range, long charging time, lack of charging stations, and high initial cost. Existing solutions to overcome these barriers, such as building more charging stations, increasing battery capacity, and stationary vehicle-to-vehicle (V2V) charging, often suffer from prohibitive investment costs, incompatibility to existing BEVs, or long travel delays. In this paper, we propose Peer-to-Peer Car Charging (P2C2), a scalable approach for charging BEVs that alleviates the need for elaborate charging infrastructure. The central idea is to enable BEVs to share charge among each other while in motion through coordination with a cloud-based control system. To re-vitalize a BEV fleet, which is continuously in motion, we introduce Mobile Charging Stations (MoCS), which are high-battery-capacity vehicles used to replenish the overall charge in a vehicle network. Unlike existing V2V charging solutions, the charge sharing in P2C2 takes place while the BEVs are in-motion, which aims at minimizing travel time loss. To reduce BEV-to-BEV contact time without increasing manufacturing costs, we propose to use multiple batteries of varying sizes and charge transfer rates. The faster but smaller batteries are used for charge transfer between vehicles, while the slower but larger ones are used for prolonged charge storage. We have designed the overall P2C2 framework and formalized the decision-making process of the cloud-based control system. We have evaluated the effectiveness of P2C2 using a well-characterized simulation platform and observed dramatic improvement in BEV mobility. Additionally, through statistical analysis, we show that a significant reduction in carbon emission is also possible if MoCS can be powered by renewable energy sources.

Hypoglossal-Facial Anastomosis for Facial Nerve Reconstruction: Outcomes using the Side-to-End Surgical Technique

Introduction The side-to-end hypoglossal-facial anastomosis (HFA) technique is an excellent alternative technique to the classic end-terminal anastomosis, because itmay decrease the symptoms resulting from hypoglossal-nerve transection. Methods Patients with facial nerve palsy (House-Brackmann [HB] grade VI) requiring facial reconstruction from 2014 to 2017were retrospectively included in the study. Results In total, 12 cases were identified, with a mean follow-up of 3 years. The causes of facial paralysis were due to resection of posterior-fossa tumors and trauma. There was improvement in 91.6% of the patients (11/12) after the HFA. The rate of improvement according to the HB grade was as follows: HB III - 58.3%; HB IV - 16.6%; and HB II - 16.6%. The first signs of improvement were observed in the patients with the shortest time between the paralysis and the anastomosis surgery (3.5months versus 8.5 months; p » 0.011). The patients with HB II and III had a shorter time between the diagnosis and the anastomosis surgery (mean: 5.22 months), while the patients with HB IV and VI had a longer time of paresis (mean: 9.5 months; p » 0.099). We did not observe lingual atrophy or changes in swallowing. Discussion and Conclusion Hypoglossal-facial anastomosis with the terminolateral technique has good results and low morbidity in relation to tongue motility and swallowing problems. The HB grade and recovery appear to be better in patients operated on with a shorter paralysis time.

The Influence of Patient-Provider Language Concordance in Cancer Care: Results of the Hispanic Outcomes by Language Approach (HOLA) Randomized Trial.

PURPOSE: Delivering linguistically competent care is critical to serving patients who have limited English proficiency (LEP) and represents a key national strategy to help reduce health disparities. Current acceptable standards of communication with patients who have LEP include providers communicating through professional interpretive services or bilingual providers speaking the patients' preferred language directly. This randomized clinical trial tests the effect of patient-provider language concordance on patient satisfaction. METHODS AND MATERIALS: Eighty-three adult Spanish-speaking patients with cancer were randomly assigned to receive care from either (1) 1 of 2 bilingual physicians speaking to the patient directly in Spanish or (2) the same physicians speaking English and using a professional interpreter service. Validated questionnaires were administered to assess patient-reported satisfaction with both provider communication and overall care. Transcripts of initial consultations were analyzed for content variations. RESULTS: Compared with patients receiving care through professional interpretive services, patients cared for in direct Spanish reported significantly improved general satisfaction, technical quality of care (mean composite score [MCS], 4.41 vs 4.06; P = .005), care team interpersonal manner (MCS, 4.37 vs 3.88; P = .004), communication (MCS, 4.50 vs 4.25; P = .018), and time spent with patient,(MCS, 4.30 vs 3.92; P = .028). Specific to physician communication, patients rated direct-Spanish care more highly in perceived opportunity to disclose concerns (MCS 4.91 vs 4.62; P = .001), physician empathy (MCS, 4.94 vs 4.59; P <.001), confidence in physician abilities (MCS, 4.84 vs 4.51; P = .001), and general satisfaction with their physician (MCS, 4.88 vs 4.59; P <.001). Analyzing the content of consultation encounters revealed differences between study arms, with the direct-Spanish arm having more physician speech related to patient history verification (mean number of utterances, 13 vs 9; P = .01) and partnering activities (mean utterances, 16 vs 5; P <.001). Additionally, patients in the direct-Spanish arm were more likely to initiate unprompted speech (mean utterances, 11 vs 3; P <.001) and asked their providers more questions (mean utterances, 11 vs 4; P = .007). CONCLUSIONS: This study shows improved patient-reported satisfaction among patients with cancer who had LEP and were cared for in direct Spanish compared with interpreter-based communication. Further research into interventions to mitigate the patient-provider language barrier is necessary to optimize care for this population.

Contributions of h- and Na+/K+ Pump Currents to the Generation of Episodic and Continuous Rhythmic Activities.

Developing spinal motor networks produce a diverse array of outputs, including episodic and continuous patterns of rhythmic activity. Variation in excitability state and neuromodulatory tone can facilitate transitions between episodic and continuous rhythms; however, the intrinsic mechanisms that govern these rhythms and their transitions are poorly understood. Here, we tested the capacity of a single central pattern generator (CPG) circuit with tunable properties to generate multiple outputs. To address this, we deployed a computational model composed of an inhibitory half-center oscillator (HCO). Following predictions of our computational model, we tested the contributions of key properties to the generation of an episodic rhythm produced by isolated spinal cords of the newborn mouse. The model recapitulates the diverse state-dependent rhythms evoked by dopamine. In the model, episodic bursting depended predominantly on the endogenous oscillatory properties of neurons, with Na+/K+ ATPase pump (I Pump) and hyperpolarization-activated currents (I h ) playing key roles. Modulation of either I Pump or I h produced transitions between episodic and continuous rhythms and silence. As maximal activity of I Pump decreased, the interepisode interval and period increased along with a reduction in episode duration. Decreasing maximal conductance of I h decreased episode duration and increased interepisode interval. Pharmacological manipulations of I h with ivabradine, and I Pump with ouabain or monensin in isolated spinal cords produced findings consistent with the model. Our modeling and experimental results highlight key roles of I h and I Pump in producing episodic rhythms and provide insight into mechanisms that permit a single CPG to produce multiple patterns of rhythmicity.

The activation of D2 and D3 receptor subtypes inhibits pathways mediating primary afferent depolarization (PAD) in the mouse spinal cord.

Somatosensory information can be modulated at the spinal cord level by primary afferent depolarization (PAD), known to produce presynaptic inhibition (PSI) by decreasing neurotransmitter release through the activation of presynaptic ionotropic receptors. Descending monoaminergic systems also modulate somatosensory processing. We investigated the role of D1-like and D2-like receptors on pathways mediating PAD in the hemisected spinal cord of neonatal mice. We recorded low-threshold evoked dorsal root potentials (DRPs) and population monosynaptic responses as extracellular field potentials (EFPs). We used a paired-pulse conditioning-test protocol to assess homosynaptic and heterosynaptic depression of evoked EFPs to discriminate between dopaminergic effects on afferent synaptic efficacy and/or on pathways mediating PAD, respectively. DA (10 µM) depressed low-threshold evoked DRPs by 43 %, with no effect on EFPs. These depressant effects on DRPs were mimicked by the D2-like receptor agonist quinpirole (35 %). Moreover, by using selective antagonists at D2-like receptors (encompassing the D2, D3, and D4 subtypes), we found that the D2 and D3 receptor subtypes participate in the quinpirole depressant inhibitory effects of pathways mediating PAD.

Studies in humanized mice and convalescent humans yield a SARS-CoV-2 antibody cocktail.

Neutralizing antibodies have become an important tool in treating infectious diseases. Recently, two separate approaches yielded successful antibody treatments for Ebola-one from genetically humanized mice and the other from a human survivor. Here, we describe parallel efforts using both humanized mice and convalescent patients to generate antibodies against the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein, which yielded a large collection of fully human antibodies that were characterized for binding, neutralization, and three-dimensional structure. On the basis of these criteria, we selected pairs of highly potent individual antibodies that simultaneously bind the receptor binding domain of the spike protein, thereby providing ideal partners for a therapeutic antibody cocktail that aims to decrease the potential for virus escape mutants that might arise in response to selective pressure from a single-antibody treatment.

Activation of α-adrenoceptors depresses synaptic transmission of myelinated afferents and inhibits pathways mediating primary afferent depolarization (PAD) in the in vitro mouse spinal cord.

Somatosensory afferent transmission strength is controlled by several presynaptic mechanisms that reduce transmitter release at the spinal cord level. We focused this investigation on the role of α-adrenoceptors in modulating sensory transmission in low-threshold myelinated afferents and in pathways mediating primary afferent depolarization (PAD) of neonatal mouse spinal cord. We hypothesized that the activation of α-adrenoceptors depresses low threshold-evoked synaptic transmission and inhibits pathways mediating PAD. Extracellular field potentials (EFPs) recorded in the deep dorsal horn assessed adrenergic modulation of population monosynaptic transmission, while dorsal root potentials (DRPs) recorded at root entry zone assessed adrenergic modulation of PAD. We found that noradrenaline (NA) and the α1-adrenoceptor agonists phenylephrine and cirazoline depressed synaptic transmission (by 15, 14 and 22%, respectively). DRPs were also depressed by NA, phenylephrine and cirazoline (by 62, 30, and 64%, respectively), and by the α2-adrenoceptor agonist clonidine, although to a lower extent (20%). We conclude that NA depresses monosynaptic transmission of myelinated afferents onto deep dorsal horn neurons via α1-adrenoceptors and inhibits interneuronal pathways mediating PAD through the activation of α1- and α2-adrenoceptors. The functional significance of these modulatory actions in shaping cutaneous and muscle sensory information during motor behaviors requires further study.

A novel bispecific antibody platform to direct complement activity for efficient lysis of target cells.

Harnessing complement-mediated cytotoxicity by therapeutic antibodies has been limited because of dependency on size and density of antigen, structural constraints resulting from orientation of antibody binding, and blockade of complement activation by inhibitors expressed on target cells. We developed a modular bispecific antibody platform that directs the complement-initiating protein C1q to target cells, increases local complement deposition and induces cytotoxicity against target antigens with a wide-range of expression. The broad utility of this approach to eliminate both prokaryotic and eukaryotic cells was demonstrated by pairing a unique C1q-recruiting arm with multiple targeting arms specific for Staphylococcus aureus, Pseudomonas aeruginosa, B-cells and T-cells, indicating applicability for diverse indications ranging from infectious diseases to cancer. Generation of C1q humanized mice allowed for demonstration of the efficacy of this approach to clear disease-inducing cells in vivo. In summary, we present a novel, broadly applicable, and versatile therapeutic modality for targeted cell depletion.

E-Cadherin gene expression in oral cancer: Clinical and prospective data

Background: Low protein expression of E-cadherin in oral squamous cell carcinoma (OSCC) has been associated with clinical and histopathological traits such as metastases, recurrence, low survival and poor tumor differentiation, and it is considered a high-risk marker of malignancy. However, it is still unknown whether low expression of E-cadherin is also present at the mRNA level in OSCC cases. Objective: The aim of this study was to compare E-cadherin mRNA expression in OSCC patients and controls and to correlate the expression with clinical and prospective characteristics. Material and Methods: Forty patients and 40 controls were enrolled. E-cadherin mRNA expression was evaluated by quantitative real-time polymerase chain reaction using TaqMan probes. Results: E-cadherin mRNA expression was significantly decreased in OSCC patients compared to that of controls (p < 0.001). Whereas no significant association between clinical parameters and E-cadherin expression levels was observed, we noted lower E-cadherin expression levels in patients with positive lymph node metastasis. Conclusions: E-cadherin mRNA expression was markedly diminished in OSCC, in agreement with previous re-sults that examined E-cadherin expression at the protein level. E-cadherin is downregulated in the early clinical stages of OSCC, and its mRNA levels do not change significantly in the advanced stages, suggesting that there is limited usefulness of this parameter for predicting disease progression

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Accurate target identification for Mycobacterium tuberculosis endoribonuclease toxins requires expression in their native host.

The Mycobacterium tuberculosis genome harbors an unusually high number of toxin-antitoxin (TA) systems. These TA systems have been implicated in establishing the nonreplicating persistent state of this pathogen during latent tuberculosis infection. More than half of the M. tuberculosis TA systems belong to the VapBC (virulence associated protein) family. In this work, we first identified the RNA targets for the M. tuberculosis VapC-mt11 (VapC11, Rv1561) toxin in vitro to learn more about the general function of this family of toxins. Recombinant VapC-mt11 cleaved 15 of the 45 M. tuberculosis tRNAs at a single site within their anticodon stem loop (ASL) to generate tRNA halves. Cleavage was dependent on the presence of a GG consensus sequence immediately before the cut site and a structurally intact ASL. However, in striking contrast to the broad enzyme activity exhibited in vitro, we used a specialized RNA-seq method to demonstrate that tRNA cleavage was highly specific in vivo. Expression of VapC-mt11 in M. tuberculosis resulted in cleavage of only two tRNA isoacceptors containing the GG consensus sequence, tRNAGln32-CUG and tRNALeu3-CAG. Therefore, our results indicate that although in vitro studies are useful for identification of the class of RNA cleaved and consensus sequences required for accurate substrate recognition by endoribonuclease toxins, definitive RNA target identification requires toxin expression in their native host. The restricted in vivo specificity of VapC-mt11 suggests that it may be enlisted to surgically manipulate pathogen physiology in response to stress.

Skin to Intramuscular Compartment Thigh Measurement by Ultrasound in Pediatric Population.

INTRODUCTION: Pediatric obesity threatens the efficacy of medications given intramuscularly. In anaphylactic patients, epinephrine auto-injector needle lengths are potentially too short to reach the muscle compartment in patients with elevated body habitus. The objective of the study was to determine needle-length requirements for intramuscular injections in pediatric patients. METHODS: We used ultrasound to measure the distance from skin to muscle compartment of the thigh in 200 pediatric patients of various weight and body mass index who presented to the emergency department. RESULTS: Patients with higher body mass index had an increased distance to muscle and bone. If current recommendations were followed, 5% of patients within the EpiPen adult weight category and 11% of patients within the Centers for Disease Control and Prevention weight category would have potentially used a needle inadequate in length for intramuscular injections. CONCLUSION: With the increase in childhood obesity, needle lengths may be too short to effectively deliver medications to the intramuscular compartment. Needle length should be evaluated to accommodate pediatric patients with increased skin to muscle distance.

Manifestaciones de la cavidad bucal por infección del virus de la inmunodeficiencia humana: reporte de caso clínico / Oral manifestations of the HIV virus: report of a clinical case

Las manifestaciones orales por la infección del virus de la inmunode-ficiencia humana son en ocasiones el primer signo de la enfermedad yen muchos casos un indicador de la progresión de la infección hacia elsíndrome de inmunodeficiencia adquirida. Las ulceraciones indoloras,diferentes tipos de gingivitis agresivas y la leucoplasia vellosa, se desarrollan muy fácilmente en individuos cuyo sistema inmunológico está comprometido, como el de los pacientes que sufren del virus deinmunodeficiencia adquirida.

Oral manifestations caused by the human immunodefi ciency virusare often the fi rst indication that the person is infected and oftenan indicator of its progression into AIDS. Painless ulcers, assortedtypes of aggressive gingivitis, and hairy leukoplakia develop easilyin individuals whose immune system is compromised, such as thoseinfected with HIV.

Emergency Medicine Resident Assessment of the Emergency Ultrasound Milestones and Current Training Recommendations.

OBJECTIVES: Emergency ultrasound (EUS) has been recognized as integral to the training and practice of emergency medicine (EM). The Council of Emergency Medicine Residency-Academy of Emergency Ultrasound (CORD-AEUS) consensus document provides guidelines for resident assessment and progression. The Accredited Council for Graduate Medical Education (ACGME) has adopted the EM Milestones for assessment of residents' progress during their residency training, which includes demonstration of procedural competency in bedside ultrasound. The objective of this study was to assess EM residents' use of ultrasound and perceptions of the proposed ultrasound milestones and guidelines for assessment. METHODS: This study is a prospective stratified cluster sample survey of all U.S. EM residency programs. Programs were stratified based on their geographic location (Northeast, South, Midwest, West), presence/absence of ultrasound fellowship program, and size of residency with programs sampled randomly from each stratum. The survey was reviewed by experts in the field and pilot tested on EM residents. Summary statistics and 95% confidence intervals account for the survey design, with sampling weights equal to the inverse of the probability of selection, and represent national estimates of all EM residents. RESULTS: There were 539 participants from 18 residency programs with an overall survey response rate of 85.1%. EM residents considered several applications to be core applications that were not considered core applications by CORD-AEUS (quantitative bladder volume, diagnosis of joint effusion, interstitial lung fluid, peritonsillar abscess, fetal presentation, and gestational age estimation). Of several core and advanced applications, the Focused Assessment with Sonography in Trauma examination, vascular access, diagnosis of pericardial effusion, and cardiac standstill were considered the most likely to be used in future clinical practice. Residents responded that procedural guidance would be more crucial to their future clinical practice than resuscitative or diagnostic ultrasound. They felt that an average of 325 (301-350) ultrasound examinations would be required to be proficient, but felt that number of examinations poorly represented their competency. They reported high levels of concern about medicolegal liability while using EUS. Eighty-nine percent of residents agreed that EUS is necessary for the practice of EM. CONCLUSIONS: EM resident physicians' opinion of what basic and advanced skills they are likely to utilize in their future clinical practice differs from what has been set forth by various groups of experts. Their opinion of how many ultrasound examinations should be required for competency is higher than what is currently expected during training.

tRNA is a new target for cleavage by a MazF toxin.

Toxin-antitoxin (TA) systems play key roles in bacterial persistence, biofilm formation and stress responses. The MazF toxin from the Escherichia coli mazEF TA system is a sequence- and single-strand-specific endoribonuclease, and many studies have led to the proposal that MazF family members exclusively target mRNA. However, recent data indicate some MazF toxins can cleave specific sites within rRNA in concert with mRNA. In this report, we identified the repertoire of RNAs cleaved by Mycobacterium tuberculosis toxin MazF-mt9 using an RNA-seq-based approach. This analysis revealed that two tRNAs were the principal targets of MazF-mt9, and each was cleaved at a single site in either the tRNA(Pro14) D-loop or within the tRNA(Lys43) anticodon. This highly selective target discrimination occurs through recognition of not only sequence but also structural determinants. Thus, MazF-mt9 represents the only MazF family member known to target tRNA and to require RNA structure for recognition and cleavage. Interestingly, the tRNase activity of MazF-mt9 mirrors basic features of eukaryotic tRNases that also generate stable tRNA-derived fragments that can inhibit translation in response to stress. Our data also suggest a role for tRNA distinct from its canonical adapter function in translation, as cleavage of tRNAs by MazF-mt9 downregulates bacterial growth.

tRNAs taking charge.

Most bacterial toxins derived from chromosomally encoded toxin-antitoxin (TA) systems that have been studied to date appear to protect cells from relatively short pulses of stress by triggering a reversible state of growth arrest. In contrast to many bacterial toxins that are produced as defense mechanisms and secreted from their hosts, TA toxins exert their protective effect from within the cell that produces them. TA toxin-mediated growth arrest is most frequently achieved through their ability to selectively cleave RNA species that participate in protein synthesis. Until very recently, it was thought that the primary conduit for toxin-mediated translation inhibition was cleavage of a single class of RNA, mRNA, thus depleting transcripts and precluding production of essential proteins. This minireview focuses on how the development and implementation of a specialized RNA-seq method to study Mycobacterium tuberculosis TA systems enabled the identification of unexpected RNA targets for toxins, i.e. a handful of tRNAs that are cleaved into tRNA halves. Our result brings to light a new perspective on how these toxins may act in this pathogen and uncovers a striking parallel to signature features of the eukaryotic stress response.

Discovery of novel triazolobenzazepinones as γ-secretase modulators with central Aß42 lowering in rodents and rhesus monkeys.

Synthesis and SAR studies of novel triazolobenzazepinones as gamma secretase modulators (GSMs) are presented in this communication. Starting from our azepinone leads, optimization studies toward improving central lowering of Aß42 led to the discovery of novel benzo-fused azepinones. Several benzazepinones were profiled in vivo and found to lower brain Aß42 levels in Sprague Dawley rats and transgenic APP-YAC mice in a dose-dependent manner after a single oral dose. Compound 34 was further progressed into a pilot study in our cisterna-magna-ported rhesus monkey model, where we observed robust lowering of CSF Aß42 levels.