Water status dynamics and drought tolerance of juvenile European beech, Douglas fir and Norway spruce trees as dependent on neighborhood and nitrogen supply.

To increase the resilience of forests to drought and other hazards, foresters are increasingly planting mixed stands. This requires knowledge about the drought response of tree species in pure and mixed-culture neighborhoods. In addition, drought frequently interacts with continued atmospheric nitrogen (N) deposition. To disentangle these factors for European beech, Norway spruce and Douglas fir, we conducted a replicated 3-factorial sapling growth experiment with three moisture levels, (high, medium, and low), two N levels (high and ambient), and pure and mixed-culture neighborhoods. We measured biomass, stomatal conductance (GS), shoot water potential (at predawn: ΨPD, midday, and turgor loss point: ΨTLP), branch xylem embolism resistance (Ψ50) and minimum epidermal conductance (Gmin). The three species differed most with respect to Gmin (10-fold higher in beech than in the conifers), hydroscape area (larger in beech), and the time elapsed to reach stomatal closure (TΨGS90) and ΨTLP (TTLP; shorter in beech), while Ψ50 and ΨTLP were remarkably similar. Neighborhood (pure vs mixed-culture) influenced biomass production, water status and hydraulic traits, notably GS (higher in Douglas fir, but lower in spruce and beech, in mixtures than pure culture), hydraulic safety margin (smaller for beech in mixtures), and TΨGS90 and TTLP (shorter for spruce in mixture). High N generally increased GS, but no consistent N effects on leaf water status and hydraulic traits were detected, suggesting that neighbor identity had a larger effect on plant water relations than N availability. We conclude that both tree neighborhood and N availability modulate the drought response of beech, spruce, and Douglas fir. Species mixing can alleviate the drought stress of some species, but often by disadvantaging other species. Thus, our study suggests that stabilizing and building resilience of production forests against a drier and warmer climate may depend primarily on the right species choice; species mixing can support the agenda.

Comparison of porcine versus bovine surfactant in preterm respiratory distress syndrome: Evidence from real-world data. A multicentre collaboration from Karnataka.

BACKGROUND & OBJECTIVES: Porcine surfactant (200 mg/kg initial dose) seems to be superior to bovine surfactants (100 mg/kg) in respiratory distress syndrome (RDS). There is limited data on the choice of surfactant from the developing world. Logically, using higher doses of porcine surfactant comes with an additional cost burden. We decided to evaluate the clinical effects of different types of surfactants. METHODS: A retrospective analysis was conducted from August 2019 to December 2022 in six tertiary centers. Neonates 24-34 weeks of gestation with RDS requiring either porcine (200 mg/kg) or bovine surfactant (100 mg/kg) were enrolled. The proportion of BPD, redosing, and other morbidities in either group were analyzed. The outcomes in preterm ≥28 and <28 weeks subgroups were analyzed. RESULTS: Of 1149 eligible babies, 302 (26%) received surfactant after stabilization with CPAP. One hundred fifty-eight received porcine, and 144 received bovine surfactant. There was a higher BPD in porcine compared to the bovine group on univariate analysis [24 (15%) vs. 6 (4%); OR: 4; 95% CI: 1.6-10; p = 0.002]. On logistic regression, the gestational age and PDA requiring treatment were independent predictors of BPD, and the type of surfactant and centres did not influence BPD. Redosing [27 (17%) vs. 18 (12%), OR: 1.4; 95% CI: 0.7-2.7; p = 0.2] was not different between both surfactant types. Other morbidities like mortality, air leaks, invasive ventilation, and CPAP duration were also not different between the groups. CONCLUSION: We could not find a difference in the outcomes of BPD and redosing using porcine surfactant at 200 mg/kg compared to bovine surfactant. Considering the cost burden in the developing world, efficacy needs to be evaluated in randomized clinical trials.

Instability of mixing layers: Momentum and thermal transport in the continuum breakdown regime.

We examine the momentum and thermal transport in the continuum breakdown regime of a mixing layer flow, which exhibits Kelvin-Helmholtz instability under ideal continuum conditions. The Grad 13 moment model is used as it provides an adequate description of the flow physics (second-order accurate in Knudsen number) in the transition regime. Analytical solutions are developed under breakdown conditions for two-dimensional, compressible, parallel shear flows. It is shown that the deviation of viscous stress and heat flux from the Navier-Stokes-Fourier system follows two different scaling regimes depending upon the Mach number. At low Mach numbers, the departure of all stress and heat-flux components depends only upon the Knudsen number. At high Mach number, the scaling of shear stress and transverse heat flux depends on the product of the Knudsen and Mach numbers. The normal stresses depend individually on the Knudsen and Mach number. The scaling results are verified against numerical simulations of compressible mixing layers performed using the unified gas kinetic scheme for various degrees of rarefaction.

Knowledge, Awareness and Practice towards Screening for Prostate Cancer: A Systematic Review and Meta-Analysis.

Background: Globally prostate cancer is one of the most prevalent cancer among men and a leading cause of morbidity and mortality, especially in a developing country, which is mainly due to lack of knowledge and awareness regarding the screening of prostate cancer. The main objective of this review and meta-analysis is to evaluate the knowledge, awareness and practice of adult men about prostate cancer. Method: An extensive literature search was performed on studies published between January 2000 to 2021. The systematic review initially yielded 137 studies, out of which 7 studies were covered on this meta-evaluation. Result: We noted that the pooled estimate of knowledge and awareness were respectively 65% [CI: 29%, 100%], and 74% [CI: 66%, 82%] about prostate cancer. However, there were limited practices noted in screening of prostate cancer. Conclusion: In order to increase the awareness and screening practice rate for prostate cancer, an improved health education is highly recommended.

Radiogenomic Associations Clear Cell Renal Cell Carcinoma: An Exploratory Study.

INTRODUCTION: This study investigates how quantitative texture analysis can be used to non-invasively identify novel radiogenomic correlations with clear cell renal cell carcinoma (ccRCC) biomarkers. METHODS: The Cancer Genome Atlas-Kidney Renal Clear Cell Carcinoma open-source database was used to identify 190 sets of patient genomic data that had corresponding multiphase contrast-enhanced CT images in The Cancer Imaging Archive. 2,824 radiomic features spanning fifteen texture families were extracted from CT images using a custom-built MATLAB software package. Robust radiomic features with strong inter-scanner reproducibility were selected. Random forest, AdaBoost, and elastic net machine learning (ML) algorithms evaluated the ability of the selected radiomic features to predict the presence of 12 clinically relevant molecular biomarkers identified from the literature. ML analysis was repeated with cases stratified by stage (I/II vs. III/IV) and grade (1/2 vs. 3/4). 10-fold cross validation was used to evaluate model performance. RESULTS: Before stratification by tumor grade and stage, radiomics predicted the presence of several biomarkers with weak discrimination (AUC 0.60-0.68). Once stratified, radiomics predicted KDM5C, SETD2, PBRM1, and mTOR mutation status with acceptable to excellent predictive discrimination (AUC ranges from 0.70 to 0.86). CONCLUSIONS: Radiomic texture analysis can potentially identify a variety of clinically relevant biomarkers in patients with ccRCC and may have a prognostic implication.

Oculomotor deficits in attention deficit hyperactivity disorder: a systematic review and meta-analysis.

There is equivocal evidence on the presence of oculomotor deficits among children with attention deficit hyperactivity disorder (ADHD), which can be an additional challenge in this population, especially with reading-related tasks. This study aimed to review the deficits in the oculomotor parameters among children with ADHD compared with age-matched controls. The review was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines. A search of original research articles on various databases was done using key terms, such as "oculomotor deficit," "attention deficit hyperactivity disorder," or related terms. We included case-control studies and excluded studies in which children received medications during the test. Twelve original research studies were considered for this review. Ten studies reported data on various types of saccades, two studies reported data on fixation, and one study reported data on pursuit. Among various oculomotor deficits, the forest-plot analysis of an antisaccade task showed that children with ADHD made more direction errors compared to controls. Although independent studies report that ADHD children have poorer performance compared to control populations during oculomotor tasks, there is a lack of evidence to draw a strong conclusion. Children with ADHD are less precise in performing eye movements and need more time to complete the oculomotor tasks than those without ADHD. The overall results provide minimal evidence regarding the presence of various oculomotor deficits in ADHD.

Revisiting the Conundrum: A Case Report on Trauma Whipple's Pancreaticoduodenectomy.

Despite its rarity, pancreatic trauma is a serious condition because of its retroperitoneal location, association with other organ injuries, and complex bilio-vascular anatomy. Even less common are isolated pancreatic injuries. In grade four injuries, there is a debate over resectional vs. non-resectional management and appropriate treatment is particularly difficult. Here we discuss a patient with grade four pancreatic injury with pancreatic ascites presenting four days after the incident and traumatic pancreatitis. She underwent pylorus-preserving pancreatoduodenectomy and recovered well with acceptable morbidity.

Continuum breakdown in compressible mixing layers.

Gas-kinetic simulations of rarefied and compressible mixing layers are performed to characterize continuum breakdown and the effect on the Kelvin-Helmholtz instability. The unified gas-kinetic scheme (UGKS) is used to perform the simulations at different Mach and Knudsen numbers. The UGKS stress tensor and heat-flux vector fields are compared against those given by the Navier-Stokes-Fourier constitutive equations. The most significant difference is seen in the shear stress and transverse heat flux. The study demonstrates the existence of two distinct continuum breakdown regimes, one at low and the other at high convective Mach numbers. Overall, at low convective Mach numbers, the deviation from continuum stress and heat flux appears to scale exclusively with the micro-macro length scale ratio given by the Knudsen number. On the other hand, at high convective Mach numbers, the deviation depends on the global micro-macro timescale ratio given by the product of Mach and Knudsen numbers. We further demonstrate that, unlike shear stresses and transverse heat flux, the deviations in normal stresses and the streamwise heat flux depend separately on Knudsen and Mach numbers. A local parameter called the gradient Knudsen number is proposed to characterize the rarefaction effects on the local momentum and thermal transport. Noncontinuum aspects of gas-kinetic stress-tensor and heat-flux behavior that Grad's 13-moment equation model reasonably captures are identified.

CT-based radiomics stratification of tumor grade and TNM stage of clear cell renal cell carcinoma.

OBJECTIVES: To evaluate the utility of CT-based radiomics signatures in discriminating low-grade (grades 1-2) clear cell renal cell carcinomas (ccRCC) from high-grade (grades 3-4) and low TNM stage (stages I-II) ccRCC from high TNM stage (stages III-IV). METHODS: A total of 587 subjects (mean age 60.2 years ± 12.2; range 22-88.7 years) with ccRCC were included. A total of 255 tumors were high grade and 153 were high stage. For each subject, one dominant tumor was delineated as the region of interest (ROI). Our institutional radiomics pipeline was then used to extract 2824 radiomics features across 12 texture families from the manually segmented volumes of interest. Separate iterations of the machine learning models using all extracted features (full model) as well as only a subset of previously identified robust metrics (robust model) were developed. Variable of importance (VOI) analysis was performed using the out-of-bag Gini index to identify the top 10 radiomics metrics driving each classifier. Model performance was reported using area under the receiver operating curve (AUC). RESULTS: The highest AUC to distinguish between low- and high-grade ccRCC was 0.70 (95% CI 0.62-0.78) and the highest AUC to distinguish between low- and high-stage ccRCC was 0.80 (95% CI 0.74-0.86). Comparable AUCs of 0.73 (95% CI 0.65-0.8) and 0.77 (95% CI 0.7-0.84) were reported using the robust model for grade and stage classification, respectively. VOI analysis revealed the importance of neighborhood operation-based methods, including GLCM, GLDM, and GLRLM, in driving the performance of the robust models for both grade and stage classification. CONCLUSION: Post-validation, CT-based radiomics signatures may prove to be useful tools to assess ccRCC grade and stage and could potentially add to current prognostic models. Multiphase CT-based radiomics signatures have potential to serve as a non-invasive stratification schema for distinguishing between low- and high-grade as well as low- and high-stage ccRCC. KEY POINTS: • Radiomics signatures derived from clinical multiphase CT images were able to stratify low- from high-grade ccRCC, with an AUC of 0.70 (95% CI 0.62-0.78). • Radiomics signatures derived from multiphase CT images yielded discriminative power to stratify low from high TNM stage in ccRCC, with an AUC of 0.80 (95% CI 0.74-0.86). • Models created using only robust radiomics features achieved comparable AUCs of 0.73 (95% CI 0.65-0.80) and 0.77 (95% CI 0.70-0.84) to the model with all radiomics features in classifying ccRCC grade and stage, respectively.

Virtual Reality vs Dry Laboratory Models: Comparing Automated Performance Metrics and Cognitive Workload During Robotic Simulation Training.

Background: This study compares surgical performance during analogous vesico-urethral anastomosis (VUA) tasks in two robotic training environments, virtual reality (VR) and dry laboratory (DL), to investigate transferability of skill assessment across the two platforms. Utilizing computer-generated performance metrics and pupillary data, we evaluated the two environments to distinguish surgical expertise and ultimately whether performance in the VR simulation correlates with performance in live robotic surgery in the DL. Materials and Methods: Experts (≥300 cases) and trainees (<300 cases) performed analogous VUAs during VR and DL sessions on a da Vinci robotic console following an Institutional Review Board (IRB) approved protocol (HS-16-00318). Twenty-two metrics were generated in each environment (kinematic metrics, tissue metrics, and biometrics). The DL included 18 previously validated automated performance metrics (APMs) (kinematics and event metrics) captured by an Intuitive system data recorder. In both settings, Tobii Pro Glasses 2 recorded the task-evoked pupillary response (reported as Index of Cognitive Activity [ICA]) to indicate cognitive workload, analyzed by EyeTracking cognitive workload software. Pearson correlation, Mann-Whitney, and independent t-tests were used for the comparative analyses. Results: Our study included six experts (median caseload 1300 [interquartile range 400-3000]) and 11 trainees (25 [0-250]). A total of 8/9 metrics directly comparable between VR and DL showed significant positive correlation (r ≥ 0.554, p ≤ 0.032); 5/22 VR metrics distinguished expertise, including task time (p = 0.031), clutch usage (p = 0.040), unnecessary needle piercing (p = 0.026), and suspected injury to the endopelvic fascia (p = 0.040). This contrasts with 14/22 APMs in DL (p ≤ 0.038), including linear velocities of all three instruments (p ≤ 0.038) and dominant-hand instrument wrist articulation (p = 0.013). Trainees experienced higher cognitive workload (ICA) in both environments when compared with experts (p < 0.036). Conclusions: Most performance metrics between VR and DL exhibited moderate to strong correlations, showing transferability of skills across the platforms. Comparing training environments, APMs during DL tasks are better able to distinguish expertise than VR-generated metrics.

Horizontal Transfer of miR-643 from Cisplatin-Resistant Cells Confers Chemoresistance to Recipient Drug-Sensitive Cells by Targeting APOL6.

Acquisition of resistance to cisplatin is a major impediment to the success of cisplatin-based combination therapies for cancer. Recent studies indicate that exosomal miRNAs derived from drug-resistant tumour cells can confer resistance properties to recipient cells by a horizontal transfer mechanism. Although the role of horizontal transfer of a few miRNAs has been described, little is known about the concerted action of horizontal transfer of miRNAs in conferring cisplatin resistance. The present study was designed to identify the role of miR-643, which is one of the most significantly increased miRNA in exosomes released from cisplatin-resistant Heptocarcinoma cells, in altering the cisplatin resistance properties of recipient cells. Drug-sensitivity assays involving miR-643 revealed that ectopic expression of miR-643 can desensitise the cells towards cisplatin. Furthermore, we identified APOL6 as a major target of miR-643. Further mechanistic studies showed that miR-643 can modulate APOL6 mRNA and protein levels, leading to a reversal of APOL6-mediated apoptosis. Altogether, our results suggest an APOL6-dependent mechanism for miR-643 mediated cisplatin resistance upon the horizontal transfer across cell types.

Influence of Knudsen and Mach numbers on Kelvin-Helmholtz instability.

The combined influence of rarefaction and compressibility on classical Kelvin-Helmholtz instability is investigated with numerical simulations employing the unified gas kinetic scheme. Five different regimes in the Reynolds-Mach-Knudsen number parameter space are identified. The flow features in various Mach and Knudsen number regimes are examined. Stabilizing action of compressibility leads to suppression of perturbation kinetic energy and vorticity and/or momentum thickness. The suppression due to rarefaction exhibits a different behavior. At high enough Knudsen numbers, even as the perturbation kinetic energy is suppressed, the vorticity and/or momentum thickness grows. The flow physics underlying the contrasting mechanisms of compressibility and rarefaction is highlighted.

An Objective Assessment of Performance during Robotic Partial Nephrectomy: Validation and Correlation of Automated Performance Metrics with Intraoperative Outcomes.

PURPOSE: Automated performance metrics provide a novel approach to the assessment of surgical performance. Herein, we present a construct validation of automated performance metrics during robotic assisted partial nephrectomy. MATERIALS AND METHODS: Automated performance metrics (instrument motion tracking/system events) and synchronized surgical videos from da Vinci® Si systems during robotic assisted partial nephrectomy were recorded using a system data recorder. Each case was segmented into 7 steps: colon mobilization, ureteral identification/dissection, hilar dissection, exposure of tumor within Gerota's fascia, intraoperative ultrasound/tumor scoring, tumor excision, and renorrhaphy. Automated performance metrics from each step were compared between expert (≥150 cases) and trainee (<150 cases) surgeons by Mann-Whitney U test (continuous variables) and Pearson's chi-squared test (categorical variables). Clinical outcomes were collected prospectively and correlated to automated performance metrics and R.E.N.A.L. (radius, exophytic/endophytic, nearness of tumor to collecting system, anterior/posterior, location relative to polar line) nephrometry score by Spearman's correlation coefficients (r). RESULTS: A total of 50 robotic assisted partial nephrectomy cases were included for analysis, performed by 7 expert and 10 trainee surgeons. Automated performance metric profiles significantly differed between experts and novices in the initial 5 steps (p <0.05). Specifically, experts exhibited faster dominant instrument movement and greater dominant instrument usage (bimanual dexterity) than trainees in select steps (p ≤0.045). Automated performance metrics during tumor excision and renorrhaphy were significantly correlated with R.E.N.A.L. score (r ≥0.364; p ≤0.041). These included metrics related to instrument efficiency, task duration, and dominant instrument use. CONCLUSIONS: Experts are more efficient and directed in their movement during robotic assisted partial nephrectomy. Automated performance metrics during key steps correlate with objective measures of tumor complexity and may serve as predictors of clinical outcomes. These data help establish a standardized metric for surgeon assessment and training during robotic assisted partial nephrectomy.

Revefenacin Absorption, Metabolism, and Excretion in Healthy Subjects and Pharmacological Activity of Its Major Metabolite.

Revefenacin inhalation solution is an anticholinergic indicated for the maintenance treatment of patients with chronic obstructive pulmonary disease. Mass balance, pharmacokinetics, and metabolism of revefenacin were evaluated after intravenous and oral administration of [14C]-revefenacin in healthy subjects. Pharmacological activity of the major revefenacin metabolite was also assessed. Adult males (n = 9) received 20 µg intravenously of approximately 1 µCi [14C]-revefenacin and/or a single 200-µg oral solution of approximately 10 µCi [14C]-revefenacin. Mean recovery of radioactive material was 81.4% after intravenous administration (54.4% in feces; 27.1% in urine) and 92.7% after oral dosing (88.0% in feces, 4.7% in urine). Mean absolute bioavailability of oral revefenacin was low (2.8%). Intact revefenacin accounted for approximately 52.1% and 13.1% of the total radioactivity in plasma after intravenous and oral administration, respectively. Two main circulating metabolites were observed in plasma. After an intravenous dose, a hydrolysis product, THRX-195518 (M2) was observed that circulated in plasma at 14.3% of total radioactivity. After an oral dose, both THRX-195518 and THRX-697795 (M10, N-dealkylation and reduction of the parent compound) were observed at 12.5% of total circulating radioactivity. THRX-195518 was the major metabolite excreted in feces and comprised 18.8% and 9.4% of the administered intravenous and oral dose, respectively. The major metabolic pathway for revefenacin was hydrolysis to THRX-195518. In vitro pharmacological evaluation of THRX-195518 indicated that it had a 10-fold lower binding affinity for the M3 receptor relative to revefenacin. Receptor occupancy analysis suggested that THRX-195518 has minimal contribution to systemic pharmacology relative to revefenacin after inhaled administration. SIGNIFICANCE STATEMENT: The major metabolic pathway for revefenacin was hydrolysis to the metabolite THRX-195518 (M2), and both revefenacin and THRX-195518 underwent hepatic-biliary and fecal elimination after oral or intravenous administration with negligible renal excretion. Pharmacological evaluation of THRX-195518 indicated that it had a 10-fold lower binding affinity for the M3 muscarinic receptor relative to revefenacin and that THRX-195518 has minimal contribution to systemic pharmacology after inhaled administration.

Functional immune mapping with deep-learning enabled phenomics applied to immunomodulatory and COVID-19 drug discovery

Development of accurate disease models and discovery of immune-modulating drugs is challenged by the immune systems highly interconnected and context-dependent nature. Here we apply deep-learning-driven analysis of cellular morphology to develop a scalable "phenomics" platform and demonstrate its ability to identify dose-dependent, high-dimensional relationships among and between immunomodulators, toxins, pathogens, genetic perturbations, and small and large molecules at scale. High-throughput screening on this platform demonstrates rapid identification and triage of hits for TGF-{beta}- and TNF--driven phenotypes. We deploy the platform to develop phenotypic models of active SARS-CoV-2 infection and of COVID-19-associated cytokine storm, surfacing compounds with demonstrated clinical benefit and identifying several new candidates for drug repurposing. The presented library of images, deep learning features, and compound screening data from immune profiling and COVID-19 screens serves as a deep resource for immune biology and cellular-model drug discovery with immediate impact on the COVID-19 pandemic.

Estimation of Effective Radiation Dose to the Eye Lens in Dental Cone Beam Computed Tomography

@#Introduction: Recent advancement in technology, has significantly improved the clinical application of Cone Beam Computed Tomography in the field of dentistry. The main objective of this study is to estimate the effective dose to the eye lens in Cone Bean Computed Tomography. Method: The effective dose to the lens of the eye was estimated using Dose Area Product (DAP) values from i-CAT 17-19 Platinum CBCT scanner during the CBCT examination of either the maxilla or mandible, with an exposure parameters of 120kVp and mAs 37.07. Results: The estimated effective dose for lens of the eye is 8.0±2.49mSv for voxel size 0.2 whereas 6.21±1.55mSv for voxel size 0.25 for CBCT of Mandible and 5.74±1.73mSv for voxel size 0.2 whereas 5.28±1.35mSv for voxel size 0.25 for CBCT of Maxilla. Conclusion: The effective dose to the lens of eyes for a standard protocols 0.2voxel with 26.9 sec and 0.25 voxel with 26.9 sec in CBCT for maxilla and mandible respectively are within the threshold limit of 2.0Gy. Therefore for further reduction of the effective dose to the lens of the eyes we recommend for developing a protocol with lower radiation dose and also implement the application of using an effective protective measures such as bismuth eye shield.

Discovery of TD-0212, an Orally Active Dual Pharmacology AT1 Antagonist and Neprilysin Inhibitor (ARNI).

Dual inhibition of angiotensin-converting enzyme (ACE) and neprilysin (NEP) by drugs such as omapatrilat produces superior antihypertensive efficacy relative to ACE inhibitors but is associated with a higher risk of life-threatening angioedema due to bradykinin elevations. We hypothesized that dual AT1 (angiotensin II type 1 receptor) blockade and NEP inhibition with a single molecule would produce similar antihypertensive efficacy to omapatrilat without the risk of angioedema since ACE (the rate limiting enzyme in bradykinin metabolism) would remain uninhibited. Merging the structures of losartan (an AT1 antagonist) and thiorphan (a NEP inhibitor) led to the discovery of a novel series of orally active, dual AT1 antagonist/NEP inhibitors (ARNIs) exemplified by compound 35 (TD-0212). In models of renin-dependent and -independent hypertension, 35 produced blood pressure reductions similar to omapatrilat and combinations of AT1 receptor antagonists and NEP inhibitors. Upper airway angioedema risk was assessed in a rat tracheal plasma extravasation (TPE) model. Unlike omapatrilat, 35 did not increase TPE at antihypertensive doses. Compound 35 therefore provides the enhanced activity of dual AT1/NEP inhibition with a potentially lower risk of angioedema relative to dual ACE/NEP inhibition.

Pharmacological properties of revefenacin (TD-4208), a novel, nebulized long-acting, and lung selective muscarinic antagonist, at human recombinant muscarinic receptors and in rat, guinea pig, and human isolated airway tissues.

Revefenacin (TD-4208) is a novel, long-acting, and lung-selective muscarinic cholinergic receptor (mAChR) antagonist in development as a nebulized inhalation solution for the treatment of chronic obstructive pulmonary disease (COPD) patients. This study evaluated the pharmacology of revefenacin at human recombinant mAChRs and in airway tissues from rats, guinea pigs, and humans. At human recombinant mAChRs, revefenacin displayed high affinity (pKI = 8.2-9.8) and behaved as a competitive antagonist (pKI, apparent = 9.4-10.9) at the five human recombinant mAChRs. Kinetic studies demonstrated that revefenacin dissociated significantly slower from the hM3 (t1/2 = 82 minutes) compared to the hM 2 (t1/2 = 6.9 minutes) mAChR at 37°C, thereby making it kinetically selective for the former subtype. Similarly, in functional studies, revefenacin-mediated antagonism of acetylcholine (ACh)-evoked calcium mobilization responses were reversed less rapidly at hM3 compared to the hM2 mAChR. In isolated tracheal tissues from rat and guinea pig and isolated bronchial tissues from humans, revefenacin potently antagonized mAChR-mediated contractile responses. Furthermore, the antagonistic effects of revefenacin in rat, guinea pig, and human airway tissues were slowly reversible (t1/2 of 13.3, >16, and >10 hours, respectively). These data demonstrate that revefenacin is a potent, high affinity, and selective functional mAChR antagonist with kinetic selectivity for the hM3 receptor and produces potent and long-lasting antagonism of mAChR-mediated contractile responses in rat, guinea pig, and human airway tissue. These data suggest that revefenacin has the potential to be a potent once-daily dosed inhaled bronchodilator in COPD patients.