Identification of Novel, Selective Ataxia-Telangiectasia Mutated Kinase Inhibitors with the Ability to Penetrate the Blood-Brain Barrier: The Discovery of AZD1390.

The inhibition of ataxia-telangiectasia mutated (ATM) has been shown to chemo- and radio-sensitize human glioma cells in vitro and therefore might provide an exciting new paradigm in the treatment of glioblastoma multiforme (GBM). The effective treatment of GBM will likely require a compound with the potential to efficiently cross the blood-brain barrier (BBB). Starting from clinical candidate AZD0156, 4, we investigated the imidazoquinolin-2-one scaffold with the goal of improving likely CNS exposure in humans. Strategies aimed at reducing hydrogen bonding, basicity, and flexibility of the molecule were explored alongside modulating lipophilicity. These studies identified compound 24 (AZD1390) as an exceptionally potent and selective inhibitor of ATM with a good preclinical pharmacokinetic profile. 24 showed an absence of human transporter efflux in MDCKII-MDR1-BCRP studies (efflux ratio <2), significant BBB penetrance in nonhuman primate PET studies (Kp,uu 0.33) and was deemed suitable for development as a clinical candidate to explore the radiosensitizing effects of ATM in intracranial malignancies.

Measuring categorisation in pre-school children: new toolkit, new insights

Introduction: whilst recent years have witnessed considerable research into infant categorisation, its development during the pre-school period has garnered far less interest and innovation. Objective: this paper documents the development of a valid and reliable new toolkit for measuring categorisation in children, designed to allow fine-grained differentiation through four short tasks. Methods: the paper outlines how a pilot study with 55 children reduced confounding variables, ruled out several explanations for performance variations and enabled procedural refinements. It then documents a study conducted with 190 children aged 30-60 months. Results: this more sophisticated testing mechanism challenges previously accepted developmental norms and suggests both sex and socio-economic status (and their interaction) influence categorisational abilities in pre-schoolers. Conclusion: the results indicate that preschool children's ability to categorise varies markedly, with implications for their capacity to access formal education.

Introdução: embora nos últimos anos tenha havido pesquisas consideráveis sobre a categorização infantil, seu desenvolvimento durante o período pré-escolar atraiu muito menos interesse e inovação. Objetivo: este artigo documenta o desenvolvimento de um novo kit de ferramentas válido e confiável para medir a categorização em crianças, projetado para permitir diferenciação refinada por meio de quatro tarefas curtas. Método: o artigo descreve como um estudo piloto com 55 crianças reduziu variáveis de confusão, descartou várias explicações para variações de desempenho e permitiu refinamentos de procedimentos. Em seguida, documenta um estudo realizado com 190 crianças de 30 a 60 meses. Resultados: este mecanismo de teste mais sofisticado desafia as normas de desenvolvimento previamente aceitas e sugere que o sexo e o status socioeconômico (e sua interação) influenciam as habilidades de categorização em pré-escolares. Conclusão: os resultados indicam que a capacidade de categorização dos pré-escolares varia acentuadamente, com implicações na sua capacidade de acesso à educação forma

Movement of Striacosta albicosta (Smith) (Lepidoptera: Noctuidae) Larvae on Transgenic Bt and Non-Bt Maize.

Exposure of lepidopteran pests to Bacillus thuringiensis (Bt) proteins has been shown to affect the behavior of larvae, including increased movement and avoidance of Bt-expressing plants or diet. Therefore, we hypothesized that the behavior of western bean cutworm, Striacosta albicosta (Smith) (Lepidoptera: Noctuidae), an important pest of maize, could be affected when exposed to Bt plants. To test this hypothesis, we conducted a series of artificial arena and on-plant experiments to determine S. albicosta neonate behavior when exposed to Bt and non-Bt plant tissue. Video tracking experiments presented neonate larvae with the choice of Bt or non-Bt pollen in a Petri dish for 15 min while being video recorded for analysis with EthoVision software. This study showed an increase in mean velocity and total time spent moving for larvae in the presence of Cry1F vs. non-Bt when compared with Vip3A vs. non-Bt or Cry1F vs. Vip3A. However, there was no difference in total distance moved or time spent in the food zone for all scenarios. Maize tissue choice experiments allowed neonatal larvae the choice of feeding on Bt or non-Bt tassel or leaves for 9 h in Petri dish arenas. This experiment showed that larvae preferred tassel tissue over leaves but did not indicate that larvae could distinguish between Bt and non-Bt tissue. In contrast, on-plant experiments (including a whole plant neonate dispersal study under controlled conditions and an in-field silking behavior experiment) indicated that the presence of Cry1F and Vip3A Bt toxins increased plant abandonment, suggesting that larvae are able to detect and avoid Bt toxins. The discrepancy of these results is likely due to the on-plant studies providing more field-realistic environmental conditions and a longer duration of exposure to Bt toxins for the behavioral experiments. Our results represent the first steps in understanding the complex behavior of S. albicosta when exposed to Bt plants. A better understanding of the response of larvae when exposed to Bt traits can aid in the management of this pest, particularly for the design of resistance management strategies and refuge design.

Discovery of a Potent and Orally Bioavailable Zwitterionic Series of Selective Estrogen Receptor Degrader-Antagonists.

Herein, we report the optimization of a meta-substituted series of selective estrogen receptor degrader (SERD) antagonists for the treatment of ER+ breast cancer. Structure-based design together with the use of modeling and NMR to favor the bioactive conformation led to a highly potent series of basic SERDs with promising physicochemical properties. Issues with hERG activity resulted in a strategy of zwitterion formation and ultimately in the identification of 38. This compound was shown to be a highly potent SERD capable of effectively degrading ERα in both MCF-7 and CAMA-1 cell lines. The low lipophilicity and zwitterionic nature led to a SERD with a clean secondary pharmacology profile and no hERG activity. Favorable physicochemical properties resulted in good oral bioavailability in preclinical species and potent in vivo activity in a mouse xenograft model.

Metacarpal Fractures in the National Football League: Injury Characteristics, Management, and Return to Play.

PURPOSE: This study investigated metacarpal fracture occurrences, characteristics, treatments, and return-to-play times for National Football League (NFL) athletes. METHODS: NFL players who sustained metacarpal fractures during the 2012 to 2018 seasons were reviewed. All players on the 32 NFL team active rosters with metacarpal fractures recorded through the NFL Injury Database were included. Player age, time in the league, player position, injury setting, injury mechanism, fractured ray, management, and return-to-play were recorded. RESULTS: There were 208 injury occurrences resulting in 1 or more metacarpal fractures, identified in 205 players. Of these, 81 (39%) injuries were operated. Return-to-play data were available for 173 (83%) injured players. The median return-to-play time for all athletes was 15 days (interquartile range, 1-55 days). Of the injured players, 130 (71%) missed time but returned the same season. Within this 130-player subset, 69 (53%) were treated nonsurgically and 61 (47%) operatively with median return-to-play times of 16 days (interquartile range, 6-30 days) and 20 days (interquartile range, 16-42 days) respectively. Eighteen individuals in this 130-player subgroup sustained a thumb metacarpal fracture. The return-to-play time was slower for patients sustaining thumb metacarpal fractures compared to other metacarpal fractures, and was significantly longer (median, 55 days) following nonsurgical treatment of thumb fractures compared with operative intervention (median, 24 days). A regression analysis revealed no trend or difference in return to football with respect to player age, time in the league, injury setting (practice vs game), injury mechanism, articular involvement, multiple concomitant injuries, or player position. CONCLUSIONS: Most NFL players who sustain metacarpal fractures miss less than 3 weeks and return to play the same season. The only variables that lessen the return-to-play time are involvement of lesser digit metacarpals and operative intervention for treatment of thumb metacarpal fractures. TYPE OF STUDY/LEVEL OF EVIDENCE: Prognostic IV.

B-N/B-H Transborylation: borane-catalysed nitrile hydroboration.

The reduction of nitriles to primary amines is a useful transformation in organic synthesis, however, it often relies upon stoichiometric reagents or transition-metal catalysis. Herein, a borane-catalysed hydroboration of nitriles to give primary amines is reported. Good yields (48-95%) and chemoselectivity (e.g., ester, nitro, sulfone) were observed. DFT calculations and mechanistic studies support the proposal of a double B-N/B-H transborylation mechanism.

Pest population dynamics are related to a continental overwintering gradient.

Overwintering success is an important determinant of arthropod populations that must be considered as climate change continues to influence the spatiotemporal population dynamics of agricultural pests. Using a long-term monitoring database and biologically relevant overwintering zones, we modeled the annual and seasonal population dynamics of a common pest, Helicoverpa zea (Boddie), based on three overwintering suitability zones throughout North America using four decades of soil temperatures: the southern range (able to persist through winter), transitional zone (uncertain overwintering survivorship), and northern limits (unable to survive winter). Our model indicates H. zea population dynamics are hierarchically structured with continental-level effects that are partitioned into three geographic zones. Seasonal populations were initially detected in the southern range, where they experienced multiple large population peaks. All three zones experienced a final peak between late July (southern range) and mid-August to mid-September (transitional zone and northern limits). The southern range expanded by 3% since 1981 and is projected to increase by twofold by 2099 but the areas of other zones are expected to decrease in the future. These changes suggest larger populations may persist at higher latitudes in the future due to reduced low-temperature lethal events during winter. Because H. zea is a highly migratory pest, predicting when populations accumulate in one region can inform synchronous or lagged population development in other regions. We show the value of combining long-term datasets, remotely sensed data, and laboratory findings to inform forecasting of insect pests.

Neuropeptide Y modulates excitatory synaptic transmission and promotes social behavior in the mouse nucleus accumbens.

Social interactions define the human experience, but these integral behaviors are disrupted in many psychiatric disorders. Social behaviors have evolved over millennia, and neuromodulatory systems that promote social behavior in invertebrates are also present in mammalian brains. One such conserved neuromodulator, neuropeptide Y (NPY), acts through several receptors including the Y1r, Y2r, and Y5r. These receptors are present in brain regions that control social behavior, including the nucleus accumbens (NAc). However, whether NPY modulates NAc neurotransmission is unknown. Using whole-cell patch-clamp electrophysiology of NAc neurons, we find that multiple NPY receptors regulate excitatory synaptic transmission in a cell-type specific manner. At excitatory synapses onto D1+ MSNs, Y1r activity enhances transmission while Y2r suppresses transmission. At excitatory synapses onto D1- MSNs, Y5r activity enhances transmission while Y2r suppresses transmission. Directly infusing NPY or the Y1r agonist [Leu31, Pro34]-NPY into the NAc significantly increases social interaction with an unfamiliar conspecific. Inhibition of an enzyme that breaks down NPY, dipeptidyl peptidase IV (DPP-IV), shifts the effect of NPY on D1+ MSNs to a Y1r dominated phenotype. Together, these results increase our understanding of how NPY regulates neurotransmission in the NAc and identify a novel mechanism underlying the control of social behavior. Further, they reveal a potential strategy to shift NPY signaling for therapeutic gain.

Appraisals of previous math experiences play an important role in math anxiety.

Math anxiety affects many people, from young children through to older adults. While there has been debate concerning the developmental trajectory of math anxiety and negative math attitudes, little attention has been given to the role of appraisals of previous math experiences. We surveyed 308 adults (mean age = 27.56 years, SD = 11.25) and assessed self-reported measures of math anxiety, mathematical resilience, math attitudes, and appraisal of previous math experiences. As hypothesized, all variables were found to be interrelated. Math anxiety was significantly negatively related to appraisal of previous math experiences, mathematical resilience, and math attitudes. Moreover, appraisal of previous math experiences was shown to mediate the relations between (1) math anxiety and math attitudes, and (2) mathematical resilience and math attitudes. The findings demonstrate the importance of considering current appraisals of previous math experiences and are consistent with an interpretation account of math anxiety. This may help inform cognitive-based interventions that focus on one's interpretation of past events to support current and future math learning and engagement.

Pharmacokinetics, pharmacodynamics, and safety of verinurad with and without allopurinol in healthy Asian, Chinese, and non-Asian participants.

Verinurad is a selective inhibitor of uric acid transporter 1 (URAT1). Here, we assessed the safety, pharmacokinetics, and pharmacodynamics of verinurad + allopurinol and verinurad monotherapy in healthy participants. Studies 1 (NCT03836599) and 2 (NCT02608710) were randomized Phase 1 studies. In Study 1, 12 healthy Asian participants received 24 mg verinurad + 300 mg allopurinol or placebo, and 9 healthy Chinese participants received 12 mg verinurad + 300 mg allopurinol. In Study 2, 24 healthy non-Asian male participants received 12 mg verinurad. Safety analyses included assessment of adverse events (AEs). Pharmacokinetic parameters included maximum concentration (Cmax ) and area under plasma concentration-time curve (AUC) over 24 h (AUCτ ). Pharmacodynamic parameters included percentage change from baseline (day -1) in serum uric acid (sUA) and urinary uric acid (uUA). There were no serious AEs or deaths in either study. In Study 1, steady-state geometric mean (gCV%) Cmax and AUCτ values of verinurad after 7 days' dosing were 73.6 (29.0) ng/mL and 478 (18.4) ng·h/mL, respectively, in healthy Asian participants, and 42.0 (40.1) ng/mL and 264 (36.1) ng·h/mL, respectively, in healthy Chinese participants; in Study 2, gCV% values were 36.3 (36.5) ng/mL and 271 (31.0) ng·h/mL, respectively. sUA decreased and uUA excretion increased compared with baseline following verinurad + allopurinol (Study 1) or verinurad (Study 2). When accounting for dose, the steady-state pharmacokinetics of verinurad following multiple dosing were comparable between healthy Asian and Chinese participants and healthy non-Asian participants. Verinurad treatments were well tolerated, including at higher verinurad exposures than previously evaluated after repeated dosing.

Building Best Practices for Telehealth Record Documentation in the COVID-19 Pandemic.

Telehealth services for patient visits have substantially surged during the COVID-19 pandemic. Thus, there is increased importance and demand for high-quality telehealth clinical documentation. However, little is known about how clinical data documentation is collected and the quality of data items included. This study aimed to identify the current state of and gaps in documentation and develop a best practice strategy for telehealth record documentation. Data were collected from January to February 2021 via a self-designed questionnaire for administrators and managers from physicians' offices and mental health facilities, resulting in 76 valid responses. Survey items included health organization demographic information, use of telehealth policies and procedures, and clinical documentation for telehealth patient visits. Findings from this study can be used to assist government, policymakers, and healthcare organizations in developing best practices in telehealth usage and clinical documentation improvement strategies.

Patient clinical documentation in telehealth environment: are we collecting appropriate and sufficient information for best practice?

BACKGROUND: During the COVID-19 pandemic, the use of telehealth for patient visits grew rapidly and served an important role as a valuable and necessary resource. Although clinical documentation is critical for telehealth patient visits, there is limited information about how healthcare facilities manage telehealth patient visit documentation, technology used for telehealth visits, and challenges encountered with telehealth patient visit documentation. This study aimed to assess the use of telehealth during the pandemic, the quality of clinical documentation in telehealth practice and to identify challenges and issues encountered with telehealth patient visits in order to develop a strategy for best practices for telehealth documentation and data management. METHODS: Data were collected for this cross-sectional study in January-February 2021 via a self-designed survey of administrators/managers from physicians' offices and mental health facilities. Survey questions included four categories: health organization demographic information; telehealth visits; clinical documentation for telehealth visit; and challenges and barriers related to telehealth documentation technology use. RESULTS: Of 76 respondents, more than half (62%) of the healthcare facilities started using telehealth for patient visits within one year of the onset of the COVID-19 pandemic, with 94% of respondents indicating an increased use of telehealth for patient visits since the pandemic. The most common types of telehealth patient care provided during the pandemic included pediatrics, primary care, cardiology, and women's health. The most consistent data documentation of telehealth visits included: date of service, patient identification number, communication methods, patient informed consent, diagnosis and impression, evaluation results, and recommendations. The telehealth visit data was most commonly used for patient care and clinical practice, billing and reimbursement, quality improvement and patient satisfaction, and administrative planning. The top barriers to telehealth use by the healthcare professionals included patient challenges with telehealth services, such as inequities in quality of technology, lack of patient understanding, and lack of patient satisfaction; this was followed by frustration with constant updates of telehealth guidelines and procedures, understanding required telehealth documentation for reimbursement purposes, payer denial for telehealth visits, and legal and risk issues. CONCLUSIONS: Findings from this study can assist government entities, policymakers, and healthcare organizations in developing and advocating best practices in telehealth usage and clinical documentation improvement strategies.

Preoperative and Postoperative Imaging of Scapholunate Ligament Primary Repair and Modified Brunelli Reconstruction.

Injury of the scapholunate ligament (SLL) complex can lead to scapholunate dissociation, characterized by scapholunate interval widening and volar rotary subluxation of the scaphoid. Loss of the mechanical linkage between the scaphoid and lunate results in carpal instability and eventual scapholunate advanced collapse (SLAC) arthropathy. SLL complex injuries vary from acute and traumatic to chronic and degenerative. A staging system can be used to guide treatment options for these injuries on the basis of the reparability of the SLL dorsal band, carpal alignment and malalignment reducibility, and cartilage damage. Preoperative imaging with radiography and MRI is a component of injury staging and aids in planning surgical procedures. If the SLL dorsal band is reparable, then direct primary ligament repair with dorsal capsulodesis or dorsal intercarpal (DIC) ligament transfer can be performed. If the SLL dorsal band is irreparable with normal alignment or reducible malalignment, then reconstruction can be performed. In the setting of irreducible malalignment or SLAC arthropathy, a salvage procedure can be performed. Knowledge of SLL primary repair and various reconstruction techniques is important not only when evaluating postoperative images but also for accurate description of SLL injuries and aiding the surgeon in treatment planning. The authors present the normal anatomy of the SLL complex, a staging classification of SLL injury with radiographic and MRI findings, and common surgical procedures. Special attention is given to the operative techniques and postoperative imaging appearances of primary SLL repair with DIC ligament transfer and modified Brunelli reconstruction. ©RSNA, 2021.

Resistance of Soybean Genotypes to Anticarsia gemmatalis (Lepidoptera: Erebidae): Antixenosis and Antibiosis Characterization.

Injury by herbivores is a major biotic stress that limits soybean [Glycine max (L.) Merrill] crop production. Among the main soybean insect pests, Anticarsia gemmatalis Hübner is responsible for causing significant economic damage in soybean. The primary management strategy for this insect is chemical control and use of Bt transgenic soybean. Alternative strategies, such as host plant resistance, are considered an efficient and less-aggressive method, especially in association with other strategies as part of an integrated pest management (IPM) approach. In this study, we evaluated 30 soybean genotypes to verify antixenosis expression through oviposition, attractiveness, and food consumption tests. From this, we selected 13 promising genotypes to verify the possible presence of antibiosis. Our results suggest that antixenosis was found in genotypes 'TMG 133' RR, 'TMG 1179' RR, 'IAC 19', 'IAC 17', 'IAC 100', D75-10169, and IAC 78-2318. By influence on behavior and negative impact on larval viability, antixenosis and antibiosis were indicated for the genotypes IAC 74-2832, 'IAC 19', 'IAC 17', 'IAC 100', and PI 274454. 'TMG 7062' IPRO was found to provide antibiosis resistance by negatively affecting larval development and viability. Because of reduced food consumption by larvae, antixenosis was indicated for 'IAC 24'. These genotypes should be considered in soybean breeding programs focusing on soybean resistance to A. gemmatalis.

Medial entorhinal cortex lesions produce delay-dependent disruptions in memory for elapsed time.

Our memory for time is a fundamental ability that we use to judge the duration of events, put our experiences into a temporal context, and decide when to initiate actions. The medial entorhinal cortex (MEC), with its direct projections to the hippocampus, has been proposed to be the key source of temporal information for hippocampal time cells. However, the behavioral relevance of such temporal firing patterns remains unclear, as most of the paradigms used for the study of temporal processing and time cells are either spatial tasks or tasks for which MEC function is not required. In this study, we asked whether the MEC is necessary for rats to perform a time duration discrimination task (TDD), in which rats were trained to discriminate between 10-s and 20-s delay intervals. After reaching a 90% performance criterion, the rats were assigned to receive an excitotoxic MEC-lesion or sham-lesion surgery. We found that after recovering from surgery, rats with MEC lesions were impaired on the TDD task in comparison to rats with sham lesions, failing to return to criterion performance. Their impairment, however, was specific to the longer, 20-s delay trials. These results indicate that time processing is dependent on MEC neural computations only for delays that exceed 10 s, perhaps because long-term memory resources are needed to keep track of longer time intervals.

Results of two Phase 1, Randomized, Double-blind, Placebo-controlled, Studies (Ascending Single-dose and Multiple-dose Studies) to Determine the Safety, Tolerability, and Pharmacokinetics of Orally Administered LX9211 in Healthy Participants.

PURPOSE: For neuropathic pain, current therapies do not provide relief for most patients; less than half achieve a 50% pain reduction. Current analgesics have adverse effects. We present 2 Phase I studies of LX9211, a new small-molecule AP2-associated kinase 1 inhibitor with preclinical effectiveness in pain relief. METHODS: Both randomized, placebo-controlled studies' primary objectives evaluated the tolerability and pharmacokinetic properties of oral LX9211. In the single-ascending dose (SAD) study, single, oral, liquid doses of 5, 10, 15, 20, 30, 40, 80, 120, 160, 200, and 300 mg of LX9211 or placebo were administered in the fasted state and 40 mg in a fed group. In the multiple-ascending dose (MAD) study, a loading dose was administered on day 1 and maintenance doses were administered daily on days 2 to 14. The treatment groups were designated as: 25/2.5, 50/5.0, 100/10, 150/15, and 200/20 mg. The secondary objectives included ECG evaluation. FINDINGS: The SAD study enrolled 96 participants 19 to 61 years of age (86.5% male) in 12 cohorts (2:6 placebo:LX9211), and the MAD study enrolled 50 participants 20 to 63 years of age (78% male) in 5 cohorts (2:8 placebo:LX9211). Both studies had a good LX9211 safety profile. No deaths or serious adverse events occurred. All treatment-emergent adverse events (TEAEs) were mild, except for moderate nausea and vomiting reported in 1 participant in the SAD 300-mg cohort. All TEAEs were considered recovered or resolved, except for blurred vision (n = 1 in the SAD 300-mg group), which was ongoing at the last visit. One participant in the MAD study (50/5 mg group) discontinued participation in the study early because of TEAEs (angioedema, dermatitis allergic, and urticaria). Headache, dizziness, constipation, and nausea were the most common TEAEs. In the SAD study, 4 participants in the 200-mg cohort developed headache approximately 24 hours after dosing, lasting 24 to 48 hours. Only 1 required treatment (acetaminophen). No notable ECG changes from baseline were found in either study. After both single- and multiple-dose administration, plasma exposure of LX9211 was approximately dose proportional. Steady-state LX9211 plasma concentrations were rapidly attained and maintained by a dosing regimen of a loading dose, followed by daily maintenance doses (1/10 the loading dose). No accumulation was as seen after multiple dosing. IMPLICATIONS: These studies found that LX9211 was safe and well tolerated in healthy participants. These findings suggest it is appropriate to take LX9211 forward into Phase II studies of patients with diabetic peripheral neuropathic pain and postherpetic neuralgia. LX9211 has received fast track designation by the US Food and Drug Administration.

A Time Duration Discrimination Task for the Study of Elapsed Time Processing in Rats.

Space and time are both essential features of episodic memory. However, while spatial tasks have been used effectively to study the behavioral relevance of place cells, the behavioral paradigms utilized for the study of time cells have not used time duration as a variable that animals need to be aware of to solve the task. In order to evaluate how time flow is coded into memory, time duration needs to be a variable that animals use to solve the behavioral task. This protocol describes a novel behavioral paradigm, the time duration discrimination (TDD) task, which is designed to directly investigate the neurological mechanisms that underlie temporal processing. During the TDD task, rats navigate around a Figure-8 Maze, which contains a rectangular track with a central arm and a delay box at the end of the central arm. While confined to the delay box, rats experience a 10- or 20-second time delay, during which a tone will play for the duration of the 10- or 20-second delay. When the delay box opens, the rat will choose whether to turn left or right out of the delay box and receive a reward for the correct choice (e.g., 10 seconds = left turn; 20 seconds = right turn). By directly manipulating elapsed time, we can better explore the behavioral relevance of hippocampal time cells and whether the time-dependent activity seen in physiological recordings of hippocampal neurons reflects a neuronal representation of time flow that can be used by the animal for learning and storing memories. Graphic abstract: Elapsed time duration discrimination in rats.

Presence-Absence Sampling Plans for Stink Bugs (Hemiptera: Pentatomidae) in the Midwest Region of the United States.

Stink bugs represent an increasing risk to soybean production in the Midwest region of the United States. The current sampling protocol for stink bugs in this region is tailored for population density estimation and thus is more relevant to research purposes. A practical decision-making framework with more efficient sampling effort for management of herbivorous stink bugs is needed. Therefore, a binomial sequential sampling plan was developed for herbivorous stink bugs in the Midwest region. A total of 146 soybean fields were sampled across 11 states using sweep nets in 2016, 2017, and 2018. The binomial sequential sampling plans were developed using combinations of five tally thresholds at two proportion infested action thresholds to identify those that provided the best sampling outcomes. Final assessment of the operating characteristic curves for each plan indicated that a tally threshold of 3 stink bugs per 25 sweeps, and proportion infested action thresholds of 0.75 and 0.95 corresponding to the action thresholds of 5 and 10 stink bugs per 25 sweeps, provided the optimal balance between highest probability of correct decisions (≥ 99%) and lowest probability of incorrect decisions (≤ 1%). In addition, the average sample size for both plans (18 and 12 sets of 25 sweeps, respectively) was lower than that for the other proposed plans. The binomial sequential sampling plan can reduce the number of sample units required to achieve a management decision, which is important because it can potentially reduce risk/cost of management for stink bugs in soybean in this region.

Comparative bioavailability of inhaled treprostinil administered as LIQ861 and Tyvaso® in healthy subjects.

INTRODUCTION: Treprostinil is a synthetic prostacyclin analogue approved for inhalation administration to patients with pulmonary arterial hypertension (PAH) via nebulized Tyvaso® inhalation solution. LIQ861 is an inhaled, dry-powder formulation of treprostinil produced using Print® (Particle Replication in Nonwetting Templates) technology, a proprietary process for designing and producing highly uniform drug particles. METHODS: We conducted comparative bioavailability analyses of treprostinil exposure from LIQ861 (79.5 µg capsule [approximate delivered dose of 58.1 µg treprostinil]) compared with Tyvaso® (9 breaths [approximate delivered dose of 54 µg treprostinil]). RESULTS: Treprostinil exposure parameters had least squares geometric mean ratios (LIQ861: Tyvaso®) between 0.9 and 1.0 with 90% confidence intervals contained within 0.8 to 1.25. LIQ861 and Tyvaso® were both well tolerated. DISCUSSION: Results showed comparable bioavailability of treprostinil and similar tolerability for LIQ861 and Tyvaso® administered to healthy adults. CONCLUSIONS: Given the comparable treprostinil bioavailability and similar safety profiles of LIQ861 and Tyvaso®, LIQ861 fulfills a significant unmet need for PAH patients by maximizing the therapeutic benefits of treprostinil by safely delivering doses to the lungs in 1 to 2 breaths using a discreet, convenient, easy-to-use inhaler.