Resident-as-Teacher: Can It Be Done With an E-Learning Module?

Background Resident-as-teacher initiatives are traditionally specialty-specific and performed in-person, limiting ability to disseminate essential teaching skills to all residents. Objective The aim of this study was to develop, implement, and evaluate a resident-as-teacher interactive e-learning module on growth mindset and coaching. Methods The module was designed and implemented between August 2022 and March 2023. It was distributed to postgraduate year (PGY) 1 residents in all specialties at a large academic institution. Completion rates, Likert ratings, and answers to 2 open-ended questions were used for assessment. Descriptive statistics and 1-way analysis of variance with Sîdák correction for multiple comparisons were performed on Likert ratings. Responses to open-ended questions were evaluated using content analysis. Results The module was completed by all 277 PGY-1 residents (100%), with the evaluation completed by 276 of 277 (99.6%) residents. Mean rating of the module's relevance to the role of resident teacher was 4.06±0.90 (5-point Likert scale), with general surgery residents rating the module less favorably compared to all specialties (3.28±1.06; P<.01; 95% CI 0.26-1.30). Open-ended comments revealed that residents most liked the delivery of relevant teaching strategies and the interactive design of the module. The most common area for suggested improvement was the addition of content such as teaching in challenging situations. Time needed for design, implementation, and evaluation was 80 hours total. Conclusions An e-learning module offers an interactive platform for teaching skills and was found to be an acceptable method of instruction for residents.

Minocycline-Induced Black Bone Disease in Foot and Ankle Surgery: A Case Report.

BACKGROUND: Bone and periarticular tissue discoloration can be an unexpected finding that is often disconcerting for surgeons and may alter surgical plans and overall patient management. Common causes of bone discoloration include infection, avascular necrosis, and bone inflammation. Minocycline-induced black bone disease is a rare and relatively benign abnormality encountered in foot and ankle surgery that can cause significant black, blue, and gray discoloration of bone. METHODS: Unanticipated intraoperative findings of diffuse black, blue, and gray bone discoloration during an elective forefoot operation raised concern for a metabolically malignant process and prompted the conversion of plans for a first metatarsophalangeal joint implant arthroplasty to a Keller arthroplasty. The plan for proximal interphalangeal joint arthroplasties of the lesser digits were continued as planned. Bone specimens were sent for pathologic analysis. RESULTS: Postoperative analysis identified chronic use of a minocycline for acne vulgaris. Pathologic analysis of the specimens ruled out malignant processes. Altogether, the data available led to the diagnosis of minocycline-induced black bone disease. Since the last follow-up, the patient has healed well without complications. CONCLUSIONS: Our case report underscores the importance of including the chronic use of tetracyclines in medical history intake during preoperative visits to assist the surgeon in intraoperative decision-making.

Function-Oriented Synthesis of Pentacyclic Triterpenoids and Discovery of an ent-Estrane as a Natural Product-Inspired Androgen Receptor Antagonist.

While pentacyclic triterpenoids have a rich history in chemistry and biology, the challenges associated with their asymmetric synthesis contribute to the current reality that medicinal exploration in the area is largely constrained to natural product derivatization. To address this deficiency, a function-oriented synthesis of pentacyclic triterpenoids was pursued. Overall, we report a divergent synthesis of 26-norgermanicol and 26-norlupeol and we have identified a new class of androgen receptor antagonist that is ∼6× more potent than lupeol.

From Functional Fatty Acids to Potent and Selective Natural-Product-Inspired Mimetics via Conformational Profiling.

Fatty acids play important signaling roles in biology, albeit typically lacking potency or selectivity, due to their substantial conformational flexibility. While being recognized as having properties of potentially great value as therapeutics, it is often the case that the functionally relevant conformation of the natural fatty acid is not known, thereby complicating efforts to develop natural-product-inspired ligands that have similar functional properties along with enhanced potency and selectivity profiles. In other words, without structural information associated with a particular functional relationship and the hopelessly unbiased conformational preferences of the endogenous ligand, one is molecularly ill-informed regarding the precise ligand-receptor interactions that play a role in driving the biological activity of interest. To address this problem, a molecular strategy to query the relevance of distinct subpopulations of fatty acid conformers has been established through "conformational profiling", a process whereby a unique collection of chiral and conformationally constrained fatty acids is employed to deconvolute beneficial structural features that impart natural-product-inspired function. Using oleic acid as an example because it is known to engage a variety of receptors, including GPR40, GPR120, and TLX, a 24-membered collection of mimetics was designed and synthesized. It was then demonstrated that this collection contained members that have enhanced potency and selectivity profiles, with some being clearly biased for engagement of the GPCRs GPR40 and GPR120 while others were identified as potent and selective modulators of the nuclear receptor TLX. A chemical synthesis strategy that exploited the power of modern technology for stereoselective synthesis was critical to achieving success, establishing a common sequence of bond-forming reactions to access a disparate collection of chiral mimetics, whose conformational preferences are impacted by the nature of stereodefined moieties differentially positioned about the C18 skeleton of the parent fatty acid. Overall, this study establishes a foundation to fuel future programs aimed at developing natural-product-inspired fatty acid mimetics as valuable tools in chemical biology and potential therapeutic leads.

Physics-driven structural docking and protein language models accelerate antibody screening and design for broad-spectrum antiviral therapy.

Therapeutic antibodies have become one of the most influential therapeutics in modern medicine to fight against infectious pathogens, cancer, and many other diseases. However, experimental screening for highly efficacious targeting antibodies is labor-intensive and of high cost, which is exacerbated by evolving antigen targets under selective pressure such as fast-mutating viral variants. As a proof-of-concept, we developed a machine learning-assisted antibody generation pipeline that greatly accelerates the screening and re-design of immunoglobulins G (IgGs) against a broad spectrum of SARS-CoV-2 coronavirus variant strains. These viruses infect human host cells via the viral spike protein binding to the host cell receptor angiotensin-converting enzyme 2 (ACE2). Using over 1300 IgG sequences derived from convalescent patient B cells that bind with spike's receptor binding domain (RBD), we first established protein structural docking models in assessing the RBD-IgG-ACE2 interaction interfaces and predicting the virus-neutralizing activity of each IgG with a confidence score. Additionally, employing Gaussian process regression (also known as Kriging) in a latent space of an antibody language model, we predicted the landscape of IgGs' activity profiles against individual coronaviral variants of concern. With functional analyses and experimental validations, we efficiently prioritized IgG candidates for neutralizing a broad spectrum of viral variants (wildtype, Delta, and Omicron) to prevent the infection of host cells in vitro and hACE2 transgenic mice in vivo. Furthermore, the computational analyses enabled rational redesigns of selective IgG clones with single amino acid substitutions at the RBD-binding interface to improve the IgG blockade efficacy for one of the severe, therapy-resistant strains - Delta (B.1.617). Our work expedites applications of artificial intelligence in antibody screening and re-design even in low-data regimes combining protein language models and Kriging for antibody sequence analysis, activity prediction, and efficacy improvement, in synergy with physics-driven protein docking models for antibody-antigen interface structure analyses and functional optimization.

SUPRACHOROIDAL SPACE INJECTION TECHNIQUE: Expert Panel Guidance.

PURPOSE: To develop professional guidelines for best practices for suprachoroidal space (SCS) injection, an innovative technique for retinal therapeutic delivery, based on current published evidence and clinical experience. METHODS: A panel of expert ophthalmologists reviewed current published evidence and clinical experience during a live working group meeting to define points of consensus and key clinical considerations to inform the development of guidelines for in-office SCS injection. RESULTS: Core consensus guidelines for in-office SCS injection were reached and reported by the expert panel. Current clinical evidence and physician experience supported SCS injection as a safe and effective method for delivering retinal and choroidal therapeutics. The panel established consensus on the rationale for SCS injection, including potential benefits relative to other intraocular delivery methods and current best practices in patient preparation, pre- and peri-injection management, SCS-specific injection techniques, and postinjection management and follow-up. CONCLUSION: These expert panel guidelines may support and promote standardization of SCS injection technique, with the goal of optimizing patient safety and outcomes. Some aspects of the procedure may reasonably be modified based on the clinical setting and physician judgment, as well as additional study.

Influence of Grazing on Canola Grain, Canola Forage Yield, and Beef Cattle Performance.

Interest is increasing in grazing winter canola (Brassica napus) as an alternative crop in winter wheat (Triticum aestivum) rotations in the Southern High Plains (SHP) of the USA and similar environments. In this stidy, winter cereal rye (Secale cereale) and winter canola pastures (forage) were compared for two winter growing seasons at New Mexico State University's Rex E. Kirksey Agricultural Science Center at Tucumcari, NM, USA, to determine the relative effect of pasture type on late-gestation beef cows and growing yearling cattle, along with the effect of grazing on canola grain production. Canola grain yields were reduced by 25% when canola was grazed until removal approximately one month after grazing was initiated, but before the onset of rapid regrowth after winter (641 vs. 486 kg grain ha-1 for never grazed or grazed canola, respectively, p < 0.0256). No differences existed for forage mass, nutritive value, or animal performance, although forage mineral composition of canola could be a concern. Grazing winter canola as a dual-purpose crop in the SHP and similar environments is feasible when proper grazing management is applied; producers should anticipate a 20-25% reduction in grain yield, but expect animal gains to offset that loss.

METformin for the MINimization of Geographic Atrophy Progression (METforMIN): A Randomized Trial.

Purpose: Metformin use has been associated with a decreased risk of age-related macular degeneration (AMD) progression in observational studies. We aimed to evaluate the efficacy of oral metformin for slowing geographic atrophy (GA) progression. Design: Parallel-group, multicenter, randomized phase II clinical trial. Participants: Participants aged ≥ 55 years without diabetes who had GA from atrophic AMD in ≥ 1 eye. Methods: We enrolled participants across 12 clinical centers and randomized participants in a 1:1 ratio to receive oral metformin (2000 mg daily) or observation for 18 months. Fundus autofluorescence imaging was obtained at baseline and every 6 months. Main Outcome Measures: The primary efficacy endpoint was the annualized enlargement rate of the square root-transformed GA area. Secondary endpoints included best-corrected visual acuity (BCVA) and low luminance visual acuity (LLVA) at each visit. Results: Of 66 enrolled participants, 34 (57 eyes) were randomized to the observation group and 32 (53 eyes) were randomized to the treatment group. The median follow-up duration was 13.9 and 12.6 months in the observation and metformin groups, respectively. The mean ± standard error annualized enlargement rate of square root transformed GA area was 0.35 ± 0.04 mm/year in the observation group and 0.42 ± 0.04 mm/year in the treatment group (risk difference = 0.07 mm/year, 95% confidence interval = -0.05 to 0.18 mm/year; P = 0.26). The mean ± standard error decline in BCVA was 4.8 ± 1.7 letters/year in the observation group and 3.4 ± 1.1 letters/year in the treatment group (P = 0.56). The mean ± standard error decline in LLVA was 7.3 ± 2.5 letters/year in the observation group and 0.8 ± 2.2 letters/year in the treatment group (P = 0.06). Fourteen participants in the metformin group experienced nonserious adverse events related to metformin, with gastrointestinal side effects as the most common. No serious adverse events were attributed to metformin. Conclusions: The results of this trial as conducted do not support oral metformin having effects on reducing the progression of GA. Additional placebo-controlled trials are needed to explore the role of metformin for AMD, especially for earlier stages of the disease. Financial Disclosures: Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Progress Toward the Asymmetric De Novo Synthesis of Limonoids.

Asymmetric de novo construction of limonoids remains a challenging problem in stereoselective synthesis due to the diverse and complex structures associated with this class of natural products. Here, a unique synthetic pathway to an "intact" limonoid system is described. The synthetic route is based on exploiting an oxidative rearrangement reaction of a densely functionalized late-stage intermediate to simultaneously establish the stereodefined C10 quaternary center and an allylic acetate at C12. This is a unique example of a complex rearrangement reaction that proceeds on a system whose presumed intermediate allyl cation is highly hindered and lacks neighboring protons that are otherwise required for cation termination.

CasPEDIA Database: a functional classification system for class 2 CRISPR-Cas enzymes.

CRISPR-Cas enzymes enable RNA-guided bacterial immunity and are widely used for biotechnological applications including genome editing. In particular, the Class 2 CRISPR-associated enzymes (Cas9, Cas12 and Cas13 families), have been deployed for numerous research, clinical and agricultural applications. However, the immense genetic and biochemical diversity of these proteins in the public domain poses a barrier for researchers seeking to leverage their activities. We present CasPEDIA (http://caspedia.org), the Cas Protein Effector Database of Information and Assessment, a curated encyclopedia that integrates enzymatic classification for hundreds of different Cas enzymes across 27 phylogenetic groups spanning the Cas9, Cas12 and Cas13 families, as well as evolutionarily related IscB and TnpB proteins. All enzymes in CasPEDIA were annotated with a standard workflow based on their primary nuclease activity, target requirements and guide-RNA design constraints. Our functional classification scheme, CasID, is described alongside current phylogenetic classification, allowing users to search related orthologs by enzymatic function and sequence similarity. CasPEDIA is a comprehensive data portal that summarizes and contextualizes enzymatic properties of widely used Cas enzymes, equipping users with valuable resources to foster biotechnological development. CasPEDIA complements phylogenetic Cas nomenclature and enables researchers to leverage the multi-faceted nucleic-acid targeting rules of diverse Class 2 Cas enzymes.

Composition of indoor organic surface films in residences: simulating the influence of sources, partitioning, particle deposition, and air exchange.

Indoor surfaces are coated with organic films that modulate thermodynamic interactions between the surfaces and room air. Recently published models can simulate film formation and growth via gas-surface partitioning, but none have statistically investigated film composition. The Indoor Model of Aerosols, Gases, Emissions, and Surfaces (IMAGES) was used here to simulate ten years of nonreactive film growth upon impervious indoor surfaces within a Monte Carlo procedure representing a sub-set of North American residential buildings. Film composition was resolved into categories reflecting indoor aerosol (gas + particle phases) factors from three sources: outdoor-originating, indoor-emitted, and indoor-generated secondary organic material. In addition to gas-to-film partitioning, particle deposition was modeled as a vector for organics to enter films, and it was responsible for a majority of the film mass after ∼1000 days of growth for the median simulation and is likely the main source of LVOCs within films. Therefore, the organic aerosol factor possessing the most SVOCs contributes most strongly to the composition of early films, but as the film ages, films become more dominated by the factor with the highest particle concentration. Indoor-emitted organics (e.g. from cooking) often constituted at least a plurality of the simulated mass in developed films, but indoor environments are diverse enough that any major organic material source could be the majority contributor to film mass, depending on building characteristics and indoor activities. A sensitivity analysis suggests that rapid film growth is most likely in both newer, more air-tight homes and older homes near primary pollution sources.

Reducing Transdermal Uptake of Semivolatile Plasticizers from Indoor Environments: A Clothing Intervention.

Models and laboratory studies suggest that everyday clothing influences the transdermal uptake of semivolatile organic compounds, including phthalate plasticizers, from indoor environments. However, this effect has not been documented in environmental exposure settings. In this pilot study, we quantified daily excretion of 17 urinary metabolites (µg/day) for phthalates and phthalate alternatives in nine participants during 5 days. On Day 0, baseline daily excretion was determined in participants' urine. Starting on Day 1, participants refrained from eating phthalate-heavy foods and using personal care products. On Days 3 and 4, participants wore precleaned clothing as an exposure intervention. We observed a reduction in the daily excretion of phthalates during the intervention; mono-n-butyl phthalate, monoisobutyl phthalate (MiBP), and monobenzyl phthalate were significantly reduced by 35, 38, and 56%, respectively. Summed metabolites of di(2-ethylhexyl)phthalate (DEHP) were also reduced (27%; not statistically significant). A similar reduction among phthalate alternatives was not observed. The daily excretion of MiBP during the nonintervention period strongly correlated with indoor air concentrations of diisobutyl phthalate (DiBP), suggesting that inhalation and transdermal uptake of DiBP from the air in homes are dominant exposure pathways. The results indicate that precleaned clothing can significantly reduce environmental exposure to phthalates and phthalate alternatives.

Effects of stochastic coding on olfactory discrimination in flies and mice.

Sparse coding can improve discrimination of sensory stimuli by reducing overlap between their representations. Two factors, however, can offset sparse coding's benefits: similar sensory stimuli have significant overlap and responses vary across trials. To elucidate the effects of these 2 factors, we analyzed odor responses in the fly and mouse olfactory regions implicated in learning and discrimination-the mushroom body (MB) and the piriform cortex (PCx). We found that neuronal responses fall along a continuum from extremely reliable across trials to extremely variable or stochastic. Computationally, we show that the observed variability arises from noise within central circuits rather than sensory noise. We propose this coding scheme to be advantageous for coarse- and fine-odor discrimination. More reliable cells enable quick discrimination between dissimilar odors. For similar odors, however, these cells overlap and do not provide distinguishing information. By contrast, more unreliable cells are decorrelated for similar odors, providing distinguishing information, though these benefits only accrue with extended training with more trials. Overall, we have uncovered a conserved, stochastic coding scheme in vertebrates and invertebrates, and we identify a candidate mechanism, based on variability in a winner-take-all (WTA) inhibitory circuit, that improves discrimination with training.

The persistence of smoke VOCs indoors: Partitioning, surface cleaning, and air cleaning in a smoke-contaminated house.

Wildfires are increasing in frequency, raising concerns that smoke can permeate indoor environments and expose people to chemical air contaminants. To study smoke transformations in indoor environments and evaluate mitigation strategies, we added smoke to a test house. Many volatile organic compounds (VOCs) persisted days following the smoke injection, providing a longer-term exposure pathway for humans. Two time scales control smoke VOC partitioning: a faster one (1.0 to 5.2 hours) that describes the time to reach equilibrium between adsorption and desorption processes and a slower one (4.8 to 21.2 hours) that describes the time for indoor ventilation to overtake adsorption-desorption equilibria in controlling the air concentration. These rates imply that vapor pressure controls partitioning behavior and that house ventilation plays a minor role in removing smoke VOCs. However, surface cleaning activities (vacuuming, mopping, and dusting) physically removed surface reservoirs and thus reduced indoor smoke VOC concentrations more effectively than portable air cleaners and more persistently than window opening.

Understanding the key features of the spontaneous formation of bona fide prions through a novel methodology that enables their swift and consistent generation.

Among transmissible spongiform encephalopathies or prion diseases affecting humans, sporadic forms such as sporadic Creutzfeldt-Jakob disease are the vast majority. Unlike genetic or acquired forms of the disease, these idiopathic forms occur seemingly due to a random event of spontaneous misfolding of the cellular PrP (PrPC) into the pathogenic isoform (PrPSc). Currently, the molecular mechanisms that trigger and drive this event, which occurs in approximately one individual per million each year, remain completely unknown. Modelling this phenomenon in experimental settings is highly challenging due to its sporadic and rare occurrence. Previous attempts to model spontaneous prion misfolding in vitro have not been fully successful, as the spontaneous formation of prions is infrequent and stochastic, hindering the systematic study of the phenomenon. In this study, we present the first method that consistently induces spontaneous misfolding of recombinant PrP into bona fide prions within hours, providing unprecedented possibilities to investigate the mechanisms underlying sporadic prionopathies. By fine-tuning the Protein Misfolding Shaking Amplification method, which was initially developed to propagate recombinant prions, we have created a methodology that consistently produces spontaneously misfolded recombinant prions in 100% of the cases. Furthermore, this method gives rise to distinct strains and reveals the critical influence of charged surfaces in this process.

Reward expectations direct learning and drive operant matching in Drosophila.

Foraging animals must use decision-making strategies that dynamically adapt to the changing availability of rewards in the environment. A wide diversity of animals do this by distributing their choices in proportion to the rewards received from each option, Herrnstein's operant matching law. Theoretical work suggests an elegant mechanistic explanation for this ubiquitous behavior, as operant matching follows automatically from simple synaptic plasticity rules acting within behaviorally relevant neural circuits. However, no past work has mapped operant matching onto plasticity mechanisms in the brain, leaving the biological relevance of the theory unclear. Here, we discovered operant matching in Drosophila and showed that it requires synaptic plasticity that acts in the mushroom body and incorporates the expectation of reward. We began by developing a dynamic foraging paradigm to measure choices from individual flies as they learn to associate odor cues with probabilistic rewards. We then built a model of the fly mushroom body to explain each fly's sequential choice behavior using a family of biologically realistic synaptic plasticity rules. As predicted by past theoretical work, we found that synaptic plasticity rules could explain fly matching behavior by incorporating stimulus expectations, reward expectations, or both. However, by optogenetically bypassing the representation of reward expectation, we abolished matching behavior and showed that the plasticity rule must specifically incorporate reward expectations. Altogether, these results reveal the first synapse-level mechanisms of operant matching and provide compelling evidence for the role of reward expectation signals in the fly brain.

Cloth-Air Partitioning of Neutral Per- and Polyfluoroalkyl Substances (PFAS) in North Carolina Homes during the Indoor PFAS Assessment (IPA) Campaign.

Partitioning of per- and polyfluoroalkyl substances (PFAS) to indoor materials, including clothing, may prolong the residence time of PFAS indoors and contribute to exposure. During the Indoor PFAS Assessment (IPA) Campaign, we measured concentrations of nine neutral PFAS in air and cotton cloth in 11 homes in North Carolina, for up to 9 months. Fluorotelomer alcohols (i.e., 6:2 FTOH, 8:2 FTOH, and 10:2 FTOH) are the dominant target species in indoor air, with concentrations ranging from 1.8 to 49 ng m-3, 1.2 to 53 ng m-3, and 0.21 to 5.7 ng m-3, respectively. In cloth, perfluorooctane sulfonamidoethanols (i.e., MeFOSE and EtFOSE) accumulated most significantly over time, reaching concentrations of up to 0.26 ng cm-2 and 0.24 ng cm-2, respectively. From paired measurements of neutral PFAS in air and suspended cloth, we derived cloth-air partition coefficients (Kca) for 6:2, 8:2, and 10:2 FTOH; ethylperfluorooctane sulfonamide (EtFOSA); MeFOSE; and EtFOSE. Mean log(Kca) values range from 4.7 to 6.6 and are positively correlated with the octanol-air partition coefficient. We investigated the effect of the cloth storage method on PFAS accumulation and the influence of home characteristics on air concentrations. Temperature had the overall greatest effect. This study provides valuable insights into PFAS distribution, fate, and exposure indoors.

Progress Toward the Asymmetric de Novo Synthesis of Lanostanes: A Counter Biomimetic Cucurbitane-to-Lanostane Type Transformation.

An oxidative rearrangement has been established that enables a cucurbitane-to-lanostane type rearrangement that is counter to known biomimetic transformations that proceed in an opposite direction by way of a lanostane-to-cucurbitane transformation. Here, an oxidative dearomatization/Wagner-Meerwein rearrangement with a substrate bearing the characteristic cucurbitane triad of quaternary centers at C9, C13 and C14, and possessing an alkene at C11-C12, proceeds in a manner that selectively shifts the methyl group at C9 to C10 in concert with the establishment of a sterically hindered allylic cation. The major product isolated from this transformation is formed by trapping of the allylic cation by addition of acetate to C12, rather than termination of the cascade by loss of a proton at C8. While proceeding by way of a unique sequence of bond-forming reactions that begins by oxidative dearomatization, this process achieves what we believe is an unprecedented cucurbitane-to-lanostane transformation, generating a product that contains the characteristic lantostane triad of quaternary centers at C10, C13 and C14 while also delivering a functionalized C-ring.

Characterization of adverse joint outcomes in patients with osteoarthritis treated with subcutaneous tanezumab.

OBJECTIVE: Due to the risk of rapidly progressive osteoarthritis (RPOA), the phase III studies of subcutaneous (SC) tanezumab in patients with moderate to severe hip or knee osteoarthritis (OA) included comprehensive joint safety surveillance. This pooled analysis summarizes these findings. METHOD: Joint safety events in the phase III studies of SC tanezumab (2 placebo- and 1- nonsteroidal anti-inflammatory drug [NSAID]-controlled) were adjudicated by a blinded external committee. Outcomes of RPOA1 and RPOA2, primary osteonecrosis, subchondral insufficiency fracture, and pathological fracture comprised the composite joint safety endpoint (CJSE). Potential patient- and joint-level risk factors for CJSE, RPOA, and total joint replacement (TJR) were explored. RESULTS: Overall, 145/4541 patients (3.2%) had an adjudicated CJSE (0% placebo; 3.2% tanezumab 2.5 mg; 6.2% tanezumab 5 mg; 1.5% NSAID). There was a dose-dependent risk of adjudicated CJSE, RPOA1, and TJR with tanezumab vs NSAID. Patient-level cross-tabulation found associations between adjudicated RPOA with more severe radiographic/symptomatic (joint pain, swelling, and physical limitation) OA. Risk of adjudicated RPOA1 was highest in patients with Kellgren-Lawrence (KL) grade 2 or 3 OA at baseline. Risk of adjudicated RPOA2 or TJR was highest in patients with KL grade 4 joints at baseline. A higher proportion of joints with adjudicated RPOA2 had a TJR (14/26) than those with adjudicated RPOA1 (16/106). CONCLUSION: In placebo- and NSAID controlled studies of SC tanezumab for OA, adjudicated CJSE, RPOA, and TJR most commonly occurred in patients treated with tanezumab and with more severe radiographic or symptomatic OA. NCT02697773; NCT02709486; NCT02528188.

Effective mass accommodation for partitioning of organic compounds into surface films with different viscosities.

Indoor surfaces can act as reservoirs and reaction media influencing the concentrations and type of species that people are exposed to indoors. Mass accommodation and partitioning are impacted by the phase state and viscosity of indoor surface films. We developed the kinetic multi-layer model KM-FILM to simulate organic film formation and growth, but it is computationally expensive to couple such comprehensive models with indoor air box models. Recently, a novel effective mass accommodation coefficient (αeff) was introduced for efficient and effective treatments of gas-particle partitioning. In this study, we extended this approach to a film geometry with αeff as a function of penetration depth into the film, partitioning coefficient, bulk diffusivity, and condensed-phase reaction rate constant. Comparisons between KM-FILM and the αeff method show excellent agreement under most conditions, but with deviations before the establishment of quasi-equilibrium within the penetration depth. We found that the deposition velocity of species and overall film growth are impacted by bulk diffusivity in highly viscous films (Db ∼<10-15 cm2 s-1). Reactions that lead to non-volatile products can increase film thicknesses significantly, with the extent of film growth being dependent on the gas-phase concentration, rate coefficient, partitioning coefficient and diffusivity. Amorphous semisolid films with Db > ∼10-17-10-19 cm2 s-1 can be efficient SVOC reservoirs for compounds with higher partitioning coefficients as they can be released back to the gas phase over extended periods of time, while glassy solid films would not be able to act as reservoirs as gas-film partitioning is impeded.