Intramedullary brachytherapy for the treatment of long bone metastatic disease: A case report.

Case: A 56-year-old woman with metastatic melanoma and femoral lesions with impending pathologic fracture was indicated for intramedullary brachytherapy (IMBT) and intramedullary nail. Conclusions: IMBT + intramedullary nail is a new technique for the treatment of long bone metastases. IMBT maximizes radiation to the tumor and minimizes radiation to surrounding tissues. It allows the patient to resume systemic treatment expediently. Our cadaver model and patient were both treated for femoral metastases; however, this technique allows for the treatment of any long bone. This is a safe technique that minimizes treatment time compared with other standard radiation regimens.

Amanoacondorensis (Phyllanthaceae), a new shrubby species from the Cordillera del Condor in southern Ecuador.

A new species of Amanoa (Phyllanthaceae) is described from the sandstone Nangaritza Plateau in the Cordillera del Cóndor Region in southern Ecuador. Amanoacondorensis J.L.Clark & D.A.Neill is a small tree, 4 m tall that is only known from the type collection. The new species is distinct by a shrub habit, presence of coriaceous leaves with an acuminate apex, and congested inflorescences. The relatively high elevation of the type locality, presence of an androphore, and the habit as shrub or low tree are an unusual combination for Amanoa. The conservation status of A.condorensis is assessed as Critically Endangered (CR), based on IUCN Criteria.

ResumenSe describe una nueva especie de Amanoa (Phyllanthaceae) de la meseta de arenisca de Nangaritza en la región de la Cordillera del Cóndor en el sur de Ecuador. Amanoacondorensis J.L.Clark & D.A.Neill es un pequeño árbol de 4 metros de altura que sólo se conoce de la colección tipo. La nueva especie se distingue por la presencia de inflorescencias congestionadas, hojas coriáceas con ápice acuminado, y porte arbustivo. La elevación relativamente más alta de la localidad tipo, la presencia de un andróforo, y el hábito de arbusto o árbol pequeño son una combinación inusual para Amanoa. El estado de conservación de A.condorensis se evalúa como En Peligro Crítico (CR) según los Criterios de la UICN.

A risk assessment study of SARS-CoV-2 propagation in the manufacturing of cellular products.

The potential infection of cellular therapies by SARS-CoV-2 present high risks, as the target patients for these treatments are often immunocompromised or have chronic diseases associated with a higher risk of serious illness and death by COVID-19. The multicellular tropism of this virus presents challenges for the manufacturing of cell therapies, whereby the material could potentially become infected at the source or during cell processing. In this review we assess the risk of a SARS-CoV-2 propagation in cell types used to date in cellular therapies. Altogether, the risk of SARS-CoV-2 contamination of cellular products remains low. This risk should be evaluated on an individual basis, considering ACE2 and TMPRSS2 expression, existing literature regarding the susceptibility to infection, and single cell RNA sequencing data of COVID-19 patients. This analysis should ideally be performed for both the cells being manufactured and the cells used to produce the vector to ensure patient safety.

Cell therapies are medicines based on the utilization of different cell types that are manufactured in special facilities. SARS-CoV-2, the virus that causes COVID-19, can infect a wide range of cell types. Patients requiring a cell therapy may be at higher risk of severe COVID-19 due to their underlying medical conditions. In this context, it is of importance to evaluate the risk of a SARS-CoV-2 contamination during the production of cell therapies to avoid possible infections. In this review, the authors assess the risk of an infection for cells being used as therapies to date and propose a systematic way to evaluate this risk.

Percutaneous screw fixation of the pubic symphysis versus plate osteosynthesis: a biomechanical study.

Objectives: To compare the stability of screw fixation with that of plate fixation for symphyseal injuries in a vertically unstable pelvic injury (AO/Tile 61-C1) associated with complete disruption of the sacroiliac joint and the pubic symphysis. Methods: Eight fourth-generation composite pelvis models with sacroiliac and pubic symphyseal disruption (Sawbones, Vashon Island, WA) underwent biomechanical testing simulating static single-leg stance. Four were fixed anteriorly with a symphyseal screw, and 4 with a symphyseal plate. All had single transsacral screw fixation posteriorly. Displacement and rotation were monitored at both sacroiliac joint and pubic symphysis. Results: There was no significant difference between the 2 groups for mean maximum force generated. There was no significant difference in net displacement at both sacroiliac joint and pubic symphysis. There was significantly less rotation but more displacement in the screw group in the Z-axis. The screw group showed increased stiffness compared with the plate group. Conclusions: This is the first biomechanical study to compare screw versus plate symphyseal fixation in a Tile C model. Our biomechanical model using anterior and posterior fixation demonstrates that symphyseal screws may be a viable alternative to classically described symphyseal plating.

Biomechanical Comparison of 4 Transsacral Fixation Constructs in a Type 61C, Zone II Pelvic Fracture Model.

OBJECTIVES: OTA/AO 61C pelvic ring injuries are vertically unstable because of complete sacral fractures combined with anterior ring injury. The objective of this study was to compare the biomechanical characteristics of 4 transsacral screw constructs for posterior pelvic ring fixation, including one that uses a novel fixation method with a pair of locked washers with interdigitating cams. METHODS: Type C pelvic ring disruptions were created on 16 synthetic pelvis models. Each pelvis was fixated with an S2 screw in addition to being allocated to 1 of 4 transsacral constructs through S1: (1) 8.0-mm screw, (2) 8.0-mm bolt, (3) 8.0-mm screw locked with a nut, and (4) 8.00-mm screw locked with a nut with the addition of interdigitating washers between the screw head and ilium on the near cortex, and ilium and nut on the far cortex. The anterior ring fractures were not stabilized. Each pelvis underwent 100,000 cycles at 250 N and was then loaded to failure using a unilateral stance testing model. The anterior and posterior osteotomy sites were instrumented with pairs of infrared (IR) light-emitting markers, and the relative displacement of the markers was monitored using a three-dimensional (3D) motion capture system. Displacement measurements at 25,000; 50,000; 75,000; and 100,000 cycles and failure force were recorded for each pelvis. RESULTS: The novel washer design construct performed better than the screw construct with less posterior ring motion at 75,000 ( P = 0.029) and 100,000 cycles ( P = 0.029). CONCLUSIONS: The novel interdigitating washer design may be superior to using a screw construct alone to achieve rigid, locked posterior ring fixation in a synthetic pelvis model with a Type C pelvic ring disruption.

A Prospective Observational Cohort Comparison of SARS-CoV-2 Seroprevalence Between Paramedics and Matched Blood Donors in Canada During the COVID-19 Pandemic.

STUDY OBJECTIVE: SARS-CoV-2 represents an occupational risk to paramedics, who work in uncontrolled environments. We sought to identify the occupation-specific risk to paramedics by comparing their seroprevalence of SARS-CoV-2 infection-specific antibodies to that of blood donors in Canada. METHODS: In this prospective cohort study, we performed serology testing (Elecsys Anti-SARS-CoV-2 nucleocapsid assay) on samples from paramedics and blood donors (January to July 2021) in Canada. Paramedic samples were compared to blood donor samples through 1:1-matched (based on age, sex, location, date of blood collection, and vaccination status) and raking weighted comparisons. We compared the seroprevalence with a risk difference (and 95% confidence interval [CI]) and performed secondary analyses within subgroups defined by vaccination status. RESULTS: The 1:1 match included 1,627 cases per group; in both groups, 723 (44%) were women, with a median age of 38. The raking weighted comparison included 1,713 paramedic samples and 19,515 blood donor samples, with similar characteristics. In the 1:1 match, the seroprevalence was similar (difference 1.2; 95% CI -0.20 to 2.7) between paramedics (5.2%) and blood donors (3.9%). The raking weighted comparison was consistent (difference 0.97; 95% CI -0.10 to 2.0). The unvaccinated paramedic samples, in comparison to the blood donor samples, demonstrated a higher seroprevalence in the 1:1 (difference 5.9; 95% CI 1.8 to 10) and weighted (difference 6.5; 95% CI 1.8 to 10) comparisons. Among vaccinated cases, the between-group seroprevalence was similar. CONCLUSION: Overall, paramedics demonstrated similar evidence of prior SARS-CoV-2 infection to that of blood donors. However, among unvaccinated individuals, evidence of prior infection was higher among paramedics compared to blood donors.

Pharmacists' views on the impact of the Falsified Medicines Directive on community pharmacies: A cross-sectional survey.

Background: The Falsified Medicines Directive (FMD) was implemented to minimise the circulation of falsified medicines in the legal pharmaceutical supply chain. Whilst pharmacists are involved in the final step of the FMD requirements with the decommissioning of medicines at the point of supply to patients, limited research has been conducted to investigate the impact of fulfilling these requirements on the relevant stakeholders. Objective: To examine community pharmacists' views on how the FMD has affected their practice. Methods: An online survey was disseminated via email in June 2020 to pharmacists in Ireland (n = 4727), who were invited to participate if practising full time or part time in community pharmacies. Quantitative data were captured through multiple option and Likert-scale questions, and analysed using descriptive and inferential statistics. Qualitative data were captured by use of a free-text box, with the open comments analysed thematically. Results: In total, 618 valid responses were received (13.1% response rate). Most perceived that FMD requirements increased waiting times for patients (82%) and reduced time interacting with patients (65%). Only 28% agreed/strongly agreed that the introduction of the FMD legislation improves patient safety. In the open comments, the need for medicine authentication was acknowledged, but it was believed that this should be the wholesalers' responsibility, not pharmacists' responsibility. The additional step of medicines decommissioning was viewed as a time-consuming distraction to clinical checks that increased the risk for error. Pharmacists complained that they were not remunerated for the lost staff productivity or the additional software and equipment costs. Many pharmacists felt that the increased workload was disproportionate to the small risk of patients receiving falsified medicines. Conclusions: Key stakeholder engagement is required to optimise the implementation and integration of the FMD procedures into community pharmacy practice with minimal impact on dispensing and without compromising patient care.

Low Risk of Wound Complications With Sinus Tarsi Approach for Treatment of Calcaneus Fractures.

BACKGROUND: Operative management displaced intra-articular calcaneus fractures is commonly associated with wound complications. Open reduction internal fixation is traditionally performed through the extensile lateral approach has relatively high rates of wound complications. The sinus tarsi approach to displaced intra-articular calcaneus fractures is a less invasive approach to achieve fracture reduction and fixation as well as reduce wound healing complications. The purpose of this study is to report the rates of wound complications associated with the sinus tarsi approach in the treatment of displaced intra-articular calcaneus fractures. METHODS: We retrospectively identified patients treated with a limited sinus tarsi approach for displaced intra-articular calcaneus fractures from January 2009 to December 2018. Demographic and radiographic data were collected including age, gender, mechanism of injury, occupation, presence of diabetes mellitus, smoking status, Sanders classification, Bohler and Gissane angles. Postoperatively, we recorded the presence of complications, return-to-work time, and radiographic measurements. RESULTS: One hundred and five fractures were identified in 100 patients who underwent open reduction internal fixation for displaced intra-articular calcaneus fractures. Using the Sanders computed tomographic classification, we identified 32% Type 2, 48% Type 3, 18% Type 4, and 2% tongue-type variants. For the preoperative Bohler's angle, 38% of fractures displayed a negative angle, 50% had an angle 0° to 20°, and 12% over 20°. Postoperatively, all patients demonstrated an improvement in Bohler's angle with 13% with 0° to 20° and 87% over 20°. Approximately, 72% of patients working prior to the injury had returned to work by 6 months, and 89% by 12 months. The wound complication rate was 11.9% (12/105), with 1.9% (2/105) requiring additional procedures. There was no significant difference in wound complication rates in smokers versus nonsmokers (11.9% vs 12.2%, p = .55). CONCLUSION: Operative management of displaced intra-articular calcaneus fractures through the sinus tarsi approach allows restoration of calcaneal height with a low rate of wound complications, even among active smokers.

Acute-Phase Reactants in Operatively Treated Upper Extremity Infections: A Retrospective Review.

Background: There are limited data on the use of acute-phase markers in the diagnosis of upper extremity infections. The goal of this study was to determine the percentage of patients with elevated white blood cell (WBC) count, erythrocyte sedimentation rate (ESR), and C-reactive protein (CRP) in the setting of an upper extremity infection requiring operative debridement. Methods: In a retrospective review over 12 years, 61 patients who met the inclusion criteria were identified. Results: C-reactive protein was the most sensitive test in the detection of culture-positive infection compared with ESR and WBC (P < .001, P < .0001, respectively). Ninety percent of patients (55 of 61) presented with an abnormal CRP value. The WBC count and ESR were abnormal in 54% and 67% of our cohort, respectively. Conclusions: C-reactive protein is the most sensitive laboratory test when evaluating upper extremity infections that necessitate debridement. The WBC count and ESR should be interpreted with caution and can be normal even in the presence of an infection.

Does Size Matter for Cephalomedullary Nails in Geriatric Intertrochanteric Fractures?

OBJECTIVES: To evaluate the need for reoperation of geriatric intertrochanteric hip fractures treated with 10-mm cephalomedullary nails versus those treated with nails larger than 10 mm. DESIGN: Retrospective review at a single institution. SETTING: Level I trauma center. PATIENTS/PARTICIPANTS: All patients age 60 and over treated with cephalomedullary fixation for an intertrochanteric femur fracture at a single institution. INTERVENTION: Cephalomedullary fixation with variable nail diameters. MAIN OUTCOME MEASUREMENTS: Reoperation rates of geriatric intertrochanteric fractures treated with a size 10-mm diameter cephalomedullary nail compared with patients treated with nails larger than 10 mm. RESULTS: There were no significant differences in reoperation rates when the 10-mm cohort was compared with an aggregate cohort of all nails larger than 10 mm (P = 0.99). This result was true for both all-cause reoperation and noninfectious reoperation. There was no difference between cohorts in regards to age, gender, or fracture pattern. CONCLUSIONS: A 10-mm cephalomedullary nail can be used in lieu of a larger diameter fixation in patients age 60 and older with intertrochanteric femur fractures while still maintaining a comparable rate of reoperation. LEVEL OF EVIDENCE: Prognostic Level III. See Instructions for Authors for a complete description of levels of evidence.

Competition influences tree growth, but not mortality, across environmental gradients in Amazonia and tropical Africa.

Competition among trees is an important driver of community structure and dynamics in tropical forests. Neighboring trees may impact an individual tree's growth rate and probability of mortality, but large-scale geographic and environmental variation in these competitive effects has yet to be evaluated across the tropical forest biome. We quantified effects of competition on tree-level basal area growth and mortality for trees ≥10-cm diameter across 151 ~1-ha plots in mature tropical forests in Amazonia and tropical Africa by developing nonlinear models that accounted for wood density, tree size, and neighborhood crowding. Using these models, we assessed how water availability (i.e., climatic water deficit) and soil fertility influenced the predicted plot-level strength of competition (i.e., the extent to which growth is reduced, or mortality is increased, by competition across all individual trees). On both continents, tree basal area growth decreased with wood density and increased with tree size. Growth decreased with neighborhood crowding, which suggests that competition is important. Tree mortality decreased with wood density and generally increased with tree size, but was apparently unaffected by neighborhood crowding. Across plots, variation in the plot-level strength of competition was most strongly related to plot basal area (i.e., the sum of the basal area of all trees in a plot), with greater reductions in growth occurring in forests with high basal area, but in Amazonia, the strength of competition also varied with plot-level wood density. In Amazonia, the strength of competition increased with water availability because of the greater basal area of wetter forests, but was only weakly related to soil fertility. In Africa, competition was weakly related to soil fertility and invariant across the shorter water availability gradient. Overall, our results suggest that competition influences the structure and dynamics of tropical forests primarily through effects on individual tree growth rather than mortality and that the strength of competition largely depends on environment-mediated variation in basal area.

Evolutionary diversity is associated with wood productivity in Amazonian forests.

Higher levels of taxonomic and evolutionary diversity are expected to maximize ecosystem function, yet their relative importance in driving variation in ecosystem function at large scales in diverse forests is unknown. Using 90 inventory plots across intact, lowland, terra firme, Amazonian forests and a new phylogeny including 526 angiosperm genera, we investigated the association between taxonomic and evolutionary metrics of diversity and two key measures of ecosystem function: aboveground wood productivity and biomass storage. While taxonomic and phylogenetic diversity were not important predictors of variation in biomass, both emerged as independent predictors of wood productivity. Amazon forests that contain greater evolutionary diversity and a higher proportion of rare species have higher productivity. While climatic and edaphic variables are together the strongest predictors of productivity, our results show that the evolutionary diversity of tree species in diverse forest stands also influences productivity. As our models accounted for wood density and tree size, they also suggest that additional, unstudied, evolutionarily correlated traits have significant effects on ecosystem function in tropical forests. Overall, our pan-Amazonian analysis shows that greater phylogenetic diversity translates into higher levels of ecosystem function: tropical forest communities with more distantly related taxa have greater wood productivity.

Trees of Amazonian Ecuador: a taxonomically verified species list with data on abundance and distribution.

We compiled a data set for all tree species collected to date in lowland Amazonian Ecuador in order to determine the number of tree species in the region. This data set has been extensively verified by taxonomists and is the most comprehensive attempt to evaluate the tree diversity in one of the richest species regions of the Amazon. We used four main sources of data: mounted specimens deposited in Ecuadorian herbaria only, specimen records of a large-scale 1-hectare-plot network (60 plots in total), data from the Missouri Botanical Garden Tropicos® database (MO), and literature sources. The list of 2,296 tree species names we provide in this data set is based on 47,486 herbarium records deposited in the following herbaria: Alfredo Paredes Herbarium (QAP), Catholic University Herbarium (QCA), Herbario Nacional del Ecuador (QCNE), Missouri Botanical Garden (MO), and records from an extensive sampling of 29,768 individuals with diameter at breast height (dbh) ≥10 cm recorded in our plot network. We also provide data for the relative abundance of species, geographic coordinates of specimens deposited in major herbaria around the world, whether the species is native or endemic, current hypothesis of geographic distribution, representative collections, and IUCN threat category for every species recorded to date in Amazonian Ecuador. These data are described in Metadata S1 and can be used for macroecological, evolutionary, or taxonomic studies. There are no copyright restrictions; data are freely available for noncommercial scientific use (CC BY 3.0). Please see Metadata S1 (Class III, Section B.1: Proprietary restrictions) for additional information on usage.

Calcaneal Avulsion Fractures: A Multicenter Analysis of Soft-Tissue Compromise and Early Fixation Failure.

OBJECTIVE: To characterize the presentation and outcomes of calcaneal avulsion fractures. DESIGN: Case series. SETTING: Two ACS Level I trauma centers. PATIENTS/PARTICIPANTS: Forty-seven calcaneal avulsion fractures isolated from a cohort of 1365 calcaneus fractures treated over a 17-year period. MAIN OUTCOME MEASUREMENTS: We collected instances of soft-tissue compromise at presentation, evidence of implant failure or fracture displacement after fixation, and reoperation. RESULTS: Forty-one patients were treated operatively, and 6 were treated without surgery. Twenty-one patients (44.7%) had either soft-tissue compromise or an open fracture necessitating urgent treatment at the time of presentation. Of those patients treated operatively with 3-month follow-up (n = 39), 28.2% of patients (11/39) had evidence of implant failure or fracture displacement. Age was the only predictor of catastrophic fixation failure (P = 0.01). The use of washer(s), suture anchor(s), or addition of soft-tissue procedures (eg, Strayer) did not have a significant effect on failure rate. Neither the number of screws used nor size of screw impacted the failure rate. Fourteen patients (35.9%) underwent a secondary operation. DISCUSSION: Avulsion fractures of the calcaneus commonly present with soft-tissue compromise and have a significant rate of treatment failure and reoperation. This injury should be identified early and approached thoughtfully, acknowledging that risks are high. LEVEL OF EVIDENCE: Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence.

Sesenta y cuatro nuevos registros para la flora del Perú a través de inventarios biológicos rápidos en la Amazonía peruana

Durante el período 2000 - 2016, se llevaron a cabo 15 inventarios biológicos en áreas remotas en el pie de monte andino y el llano amazónico del Perú. En estos inventarios, 27 botánicos colectaron un total de 9397 especímenes de plantas vasculares fértiles. Hasta finales del 2017, más de la mitad de estos especímenes se han identificado a nivel de especie, de los cuales 64 especies y 2 géneros (Dicorynia y Monopteryx) representan nuevos registros para la flora del Perú. Si esta tasa de novedades se mantiene, el número de registros nuevos en el material de los inventarios podría aumentar, lo cual nos indica que aún queda mucho por descubrir en la flora andino-amazónica del Perú.

Between 2000 and 2016 we carried out 15 rapid biological inventories in remote areas of the Andean foothills and Amazon basin in Peru. During these inventories, 27 botanists collected 9397 fertile vascular plant specimens. By the end of 2017, more than half of these specimens had been identified to species. Of the 2303 species identified to date, 64 species and 2 genera (Dicorynia and Monopteryx) are new records for the flora of Peru. If this rate of discovery proves typical, the number of new records for Peru in the rapid inventory material could increase, which indicates that there is still much to discover in the Peruvian flora.

Discovery of Small-Molecule Selective mTORC1 Inhibitors via Direct Inhibition of Glucose Transporters.

The mechanistic target of rapamycin (mTOR) is a central regulator of cellular metabolic processes. Dysregulation of this kinase complex can result in a variety of human diseases. Rapamycin and its analogs target mTORC1 directly; however, chronic treatment in certain cell types and in vivo results in the inhibition of both mTORC1 and mTORC2. We have developed a high-throughput cell-based screen for the detection of phosphorylated forms of the mTORC1 (4E-BP1, S6K1) and mTORC2 (Akt) substrates and have identified and characterized a chemical scaffold that demonstrates a profile consistent with the selective inhibition of mTORC1. Stable isotope labeling of amino acids in cell culture-based proteomic target identification revealed that class I glucose transporters were the primary target for these compounds yielding potent inhibition of glucose uptake and, as a result, selective inhibition of mTORC1. The link between the glucose uptake and selective mTORC1 inhibition are discussed in the context of a yet-to-be discovered glucose sensor.

Developing and integrating nursing competence through authentic technology-enhanced clinical simulation education: Pedagogies for reconceptualising the theory-practice gap.

The aim of this review and discussion paper is to advance the debate on competence in nursing, simulation education, and literacy in simulation education pedagogy. Building on our previous patient-safety critical translational research work on drug dosage calculation-competence modelling, and safeMedicate® virtual learning and diagnostic assessment environment design, we introduce three new concepts. First, we re-conceptualise the cognitive and physical modalities of a theory-practice gap, created by the traditional organisation of health professional education practice. Second, that simulated clinical environments occupy the liminal spaces between the ordered, symbolic and abstract world of the classroom, and the situated, messy world of clinical healthcare practice. Third, technology-enhanced boundary objects (TEBOs) function as simulation pedagogy modalities that (a) support students' transition across the liminal space and boundaries between classroom and practice setting, and (b) support competence development and integration in nursing. We use a constructivist-based clinical simulation education model as a guiding pedagogical framework for applying TEBOs and an integrated nursing competence model. The e-version of the paper has embedded animation and illustrative video content to demonstrate these constructivist principles, using technology and computer animation to make complex education ideas accessible to experienced educators and clinicians, early-stage educators, and nursing and healthcare students.

Scaling issues of neutral theory reveal violations of ecological equivalence for dominant Amazonian tree species.

Neutral models are often used as null models, testing the relative importance of niche versus neutral processes in shaping diversity. Most versions, however, focus only on regional scale predictions and neglect local level contributions. Recently, a new formulation of spatial neutral theory was published showing an incompatibility between regional and local scale fits where especially the number of rare species was dramatically under-predicted. Using a forward in time semi-spatially explicit neutral model and a unique large-scale Amazonian tree inventory data set, we show that neutral theory not only underestimates the number of rare species but also fails in predicting the excessive dominance of species on both regional and local levels. We show that although there are clear relationships between species composition, spatial and environmental distances, there is also a clear differentiation between species able to attain dominance with and without restriction to specific habitats. We conclude therefore that the apparent dominance of these species is real, and that their excessive abundance can be attributed to fitness differences in different ways, a clear violation of the ecological equivalence assumption of neutral theory.

Discovery of NV-5138, the first selective Brain mTORC1 activator.

The mechanistic target of rapamycin complex 1 (mTORC1) has been linked to several important chronic medical conditions many of which are associated with advancing age. A variety of inputs including the amino acid leucine are required for full mTORC1 activation. The cytoplasmic proteins Sestrin1 and Sestrin2 specifically bind to the multiprotein complex GATOR2 and communicate leucine sufficiency to the mTORC1 pathway activation complex. Herein, we report NV-5138, a novel orally bioavailable compound that binds to Sestrin2 and activates mTORC1 both in vitro and in vivo. NV-5138 like leucine transiently activates mTORC1 in several peripheral tissues, but in contrast to leucine uniquely activates this complex in the brain due lack of metabolism and utilization in protein synthesis. As such, NV-5138 will permit the exploration in areas of unmet medical need including neuropsychiatric conditions and cognition which have been linked to the activation status of mTORC1.