Fouling of virus filtration membranes by monoclonal antibody feeds with low aggregate content.

Membrane fouling by monoclonal antibodies (mAbs) is one of the main challenges in virus-filtration processes. Previous publications attributed membrane fouling to the presence of mAb aggregates in the solution, which block the membrane pores. This fouling mechanism can be solved by a prefilter; however, it was shown that there are mAbs that severely foul the membranes (reduce permeability by 90% and more) even after prefiltering the aggregates, while other mAbs foul the membrane weakly (reduce permeability by ~10% and less). Unfortunately, the differences between the fouling- and the nonfouling mAbs have never been convincingly explained. To get a deeper insight on these differences, we measured the fouling of chemically modified Isoprene-Styrene-4-vinylpyridine (ISV) membranes (TeraPore Technologies) by 8 mAbs exhibiting different hydrophobicity and charge. The results show that mAb solutions with low concentration of aggregates foul ISV membranes via an adsorptive mechanism, and the adsorption is driven mainly by hydrophobic forces between the mAb and the membrane. The charge of the mAbs plays a secondary role in fouling. We want to emphasize that the conclusions pertain to ISV membranes; the insights presented in this paper can potentially be used to engineer new surface chemistries to mitigate fouling of other virus-filtration and/or ultrafiltration membranes.

FOCUS may detect wall motion abnormalities in patients with ACS.

BACKGROUND: Chest pain is a common presentation to the Emergency Department (ED) with roughly 6 million visits a year. The primary diagnostic modality for the identification of acute coronary syndrome (ACS) is the electrocardiogram (ECG), which is used to screen for electrocardiographic findings representing acute coronary occlusion. It is known that the ischemia generated by an acutely occluded coronary vessel generates a wall motion abnormality which can be visualized by echocardiogram; however, emergency physician-performed focused cardiac ultrasound (FOCUS) currently does not have a formal role in the diagnosis of OMI within the emergency department. PURPOSE: We sought to define the characteristics of FOCUS performed by emergency physicians of variable training levels in the identification of RWMA in patients presenting to the emergency department with high suspicion for ACS before undergoing cardiac catheterization or formal echocardiography. We also explored whether RWMA was associated with OMI in these patients. METHODS: We performed a structured, retrospective review of adult patients presenting to a large, academic, tertiary care center with suspected ACS from July 1st, 2019, and October 24th, 2020. Patients were included if they underwent FOCUS in the ED during the time-period above for suspected ACS looking for RWMA and FOCUS images were stored and reviewable in our middleware software. The primary outcome was the accuracy, sensitivity, and specificity of FOCUS compared to formal echocardiography for the detection of RWMA. Secondary outcomes were sensitivity of FOCUS compared to formal echocardiography for detection of RWMA in patients with and without cardiac catheterization proven OMI and sensitivity and specificity of FOCUS operators based on training. RESULTS: FOCUS for RWMA performed by emergency physicians had a sensitivity of 94% (95% CI, 82-98), specificity 35% (95% CI, 15-61), and overall accuracy of 78% (95% CI, 66-87). Of all subjects, 82% underwent urgent or emergency coronary angiography, of which 71% had OMI at the time of coronary angiography of the procedure. FOCUS identified RWMA in 87% of patients with coronary angiography proven OMI. Residents (PGY-1 - PGY-3) (n = 31) were able to detect RWMA with a sensitivity of 86% (95% CI, 64-96), a specificity of 56% (95% CI, 23-85%), and an accuracy of 77 (95% CI, 58-90%). Emergency ultrasound fellows and attendings (n = 34) were able to detect RWMA with a sensitivity of 85% (95% CI, 64-95%), a specificity of 75% (95% CI, 36-96%), and an accuracy of 82% (95% CI, 65-93%). CONCLUSIONS: Our retrospective study concludes FOCUS performed by emergency physicians may be used to detect RWMA in patients with high concern for acute coronary syndrome. This may have its greatest utility in patients presenting without STEMI where the ECG is felt to be equivocal, but the clinician has high concern for OMI, in which the presence of RWMA might result in emergent cath lab activation, though this requires further study. The presence of RWMA in such cases may help to rule in OMI as a cause; however, the absence of RWMA should exclude OMI. Further research is necessary to confirm these findings.

Respiratory syncytial virus-A dynamics and the effects of lumicitabine, a nucleoside viral replication inhibitor, in experimentally infected humans.

Background: Respiratory syncytial virus (RSV) causes high morbidity, with mortality rates approaching or exceeding that of influenza in adult and infant patient populations, respectively. Lumicitabine (ALS-008176 or JNJ-64041575) is an oral nucleoside analogue prodrug in clinical development to treat RSV infections. This prodrug converts to plasma-circulating ALS-8112, and then to the 5'-active nucleoside triphosphate (NTP) form within host cells. We conducted an RSV-A challenge study in healthy adults to evaluate lumicitabine's activity during an active RSV infection. Objectives: To develop a semi-mechanistic mathematical model describing RSV kinetics, and the pharmacokinetics (PK) and pharmacodynamics (PD) of lumicitabine during treatment. Methods: Nasopharyngeal viral load and concentrations of ALS-8112 and ALS-8144 (uridine metabolite) were measured frequently over the study duration. Population viral kinetic and PK/PD models were developed using NONMEM. The RSV life-cycle was described using a target-cell-limited model that included a physiological delay. Results: The estimated clearances of ALS-8112 and ALS-8144 were 54.2 and 115 L/h/70 kg, respectively. A semi-physiological model was linked to predict ALS-8112 conversion to active intracellular NTP. Extensive and rapid RSV reduction occurred after lumicitabine treatment (EC50 = 1.79 µM), with >99% viral inhibition at 2 h after loading dose. Simulated NTP exposures and time to EC50 attainment suggested that rapid therapeutic effects and reduced dosing frequency are achievable in adult and paediatric patients. Conclusions: The semi-mechanistic model characterizes RSV kinetics and the antiviral effectiveness of lumicitabine in an adult challenge population. This model is applicable to guide dose selection in adult and paediatric patients.

Short-Duration AL-335, Odalasvir, With or Without Simeprevir, in Patients With HCV GT1 or 3 Infection Without Cirrhosis.

This open-label, phase IIa study assessed the safety, pharmacokinetics, and efficacy of direct-acting antiviral agent (DAA) regimens in patients with chronic hepatitis C virus (HCV) infection. Multiple 6-12-week oral regimens of 400-800 mg once daily (QD) AL-335 + 50 mg QD/every other day odalasvir ± 75-150 mg QD simeprevir were evaluated in treatment-naïve, HCV genotype (GT)1/3-infected patients without cirrhosis. Safety/pharmacokinetic parameters, HCV-RNA, and sequencing data were assessed. Treatment regimens for later study cohorts were adjusted based on emerging data. In total, 112 patients were enrolled. Three serious treatment-emergent adverse events occurred, one of which (a Mobitz type 1 second-degree atrioventricular block [Wenckebach]) was possibly related to high odalasvir exposure and resulted in premature discontinuation of study drugs. No other clinically significant safety findings were identified. GT1-infected patients receiving 3-DAA for 6-8 weeks achieved 100% sustained virologic response 12 weeks and 24 weeks after the end of treatment (sustained virologic response [SVR12/24]). GT1-infected patients receiving 2-DAA or GT3-infected patients receiving 3-DAA had SVR12/24 less than 90%, whether treated for 8 weeks or 12 weeks. Virologic failure was associated with the emergence of generally persistent NS5A and/or transient NS5B resistance-associated substitutions in most patients. Pharmacokinetic characteristics of the three drugs were also elucidated. Conclusions: In treatment-naïve subjects without cirrhosis, AL-335 + odalasvir + simeprevir for 6-8 weeks was generally safe and highly efficacious against HCV GT1. However, inadequate efficacy was observed for the 2-DAA regimen in GT1-infected subjects and the 3-DAA regimen in GT3-infected subjects.

Analysis of a large dataset reveals haplotypes carrying putatively recessive lethal and semi-lethal alleles with pleiotropic effects on economically important traits in beef cattle.

BACKGROUND: In livestock, deleterious recessive alleles can result in reduced economic performance of homozygous individuals in multiple ways, e.g. early embryonic death, death soon after birth, or semi-lethality with incomplete penetrance causing reduced viability. While death is an easy phenotype to score, reduced viability is not as easy to identify. However, it can sometimes be observed as reduced conception rates, longer calving intervals, or lower survival for live born animals. METHODS: In this paper, we searched for haplotypes that carry putatively recessive lethal or semi-lethal alleles in 132,725 genotyped Irish beef cattle from five breeds: Aberdeen Angus, Charolais, Hereford, Limousin, and Simmental. We phased the genotypes in sliding windows along the genome and used five tests to identify haplotypes with absence of or reduced homozygosity. Then, we associated the identified haplotypes with 44,351 insemination records that indicated early embryonic death, and postnatal survival records. Finally, we assessed haplotype pleiotropy by estimating substitution effects on estimates of breeding value for 15 economically important traits in beef production. RESULTS: We found support for one haplotype that carries a putatively recessive lethal (chromosome 16 in Simmental) and two haplotypes that carry semi-lethal alleles (chromosome 14 in Aberdeen Angus and chromosome 19 in Charolais), with population frequencies of 8.8, 15.2, and 14.4%, respectively. These three haplotypes showed pleiotropic effects on economically important traits for beef production. Their allele substitution effects are €2.30, €3.42, and €1.47 for the terminal index and €1.03, - €3.11, and - €0.88 for the replacement index, where the standard deviations for the terminal index are €22.52, €18.65, and €22.70 and for the replacement index they are €31.35, €29.82, and €35.79. We identified ZFAT as the candidate gene for semi-lethality in Aberdeen Angus, several candidate genes for the lethal Simmental haplotype, and no candidate genes for the semi-lethal Charolais haplotype. CONCLUSIONS: We analysed genotype, reproduction, survival, and production data to detect haplotypes that carry putatively recessive lethal or semi-lethal alleles in Irish beef cattle and identified one lethal and two semi-lethal haplotypes, which have pleiotropic effects on economically important traits in beef production.

Activity of Oral ALS-008176 in a Respiratory Syncytial Virus Challenge Study.

BACKGROUND Respiratory syncytial virus (RSV) infection is a cause of substantial morbidity and mortality. There is no known effective therapy. METHODS We conducted a randomized, double-blind, clinical trial in healthy adults inoculated with RSV. Participants received the oral nucleoside analogue ALS-008176 or placebo 12 hours after confirmation of RSV infection or 6 days after inoculation. Treatment was administered every 12 hours for 5 days. Viral load, disease severity, resistance, and safety were measured throughout the 28-day study period, with measurement beginning before inoculation. The primary end point was the area under the curve (AUC) for viral load, which was assessed immediately before administration of the first dose through the 12th day after inoculation in participants infected with RSV. RESULTS A total of 62 participants received placebo or one of three ALS-008176 dosing regimens: 1 loading dose of 750 mg followed by 9 maintenance doses of 500 mg (group 1), 1 loading dose of 750 mg followed by 9 maintenance doses of 150 mg (group 2), or 10 doses of 375 mg (group 3). In the 35 infected participants (23 of whom were treated with ALS-008176), the AUCs for viral load for groups 1, 2, and 3 and the placebo group were 59.9, 73.7, 133.4, and 500.9 log10 plaque-forming-unit equivalents × hours per milliliter, respectively (P≤0.001). The time to nondetectability on polymerase-chain-reaction assay (P<0.001), the peak viral load (P≤0.001), the AUC for symptom score (P<0.05), and the AUC for mucus weight were lower in all groups receiving ALS-008176 than in the placebo group. Antiviral activity was greatest in the two groups that received a loading dose--viral clearance was accelerated (P≤0.05), and the AUC for viral load decreased by 85 to 88% as compared with the placebo group. Within this small trial, no viral rebound or resistance was identified. There were no serious adverse events, and there was no need for premature discontinuation of the study drug. CONCLUSIONS In this RSV challenge study, more rapid RSV clearance and a greater reduction of viral load, with accompanying improvements in the severity of clinical disease, were observed in the groups treated with ALS-008176 than in the placebo group. (Funded by Alios BioPharma; ClinicalTrials.gov number, NCT02094365.).

Cold exposure impacts DNA methylation patterns in cattle sperm.

DNA methylation is influenced by various exogenous factors such as nutrition, temperature, toxicants, and stress. Bulls from the Pacific Northwest region of the United States and other northern areas are exposed to extreme cold temperatures during winter. However, the effects of cold exposure on the methylation patterns of bovine sperm remain unclear. To address, DNA methylation profiles of sperm collected during late spring and winter from the same bulls were analyzed using whole genome bisulfite sequencing (WGBS). Bismark (0.22.3) were used for mapping the WGBS reads and R Bioconductor package DSS was used for differential methylation analysis. Cold exposure induced 3,163 differentially methylated cytosines (DMCs) with methylation difference ≥10% and a q-value < 0.05. We identified 438 differentially methylated regions (DMRs) with q-value < 0.05, which overlapped with 186 unique genes. We also identified eight unique differentially methylated genes (DMGs) (Pax6, Macf1, Mest, Ubqln1, Smg9, Ctnnb1, Lsm4, and Peg10) involved in embryonic development, and nine unique DMGs (Prmt6, Nipal1, C21h15orf40, Slc37a3, Fam210a, Raly, Rgs3, Lmbr1, and Gan) involved in osteogenesis. Peg10 and Mest, two paternally expressed imprinted genes, exhibited >50% higher methylation. The differential methylation patterns of six distinct DMRs: Peg10, Smg9 and Mest related to embryonic development and Lmbr1, C21h15orf40 and Prtm6 related to osteogenesis, were assessed by methylation-specific PCR (MS-PCR), which confirmed the existence of variable methylation patterns in those locations across the two seasons. In summary, cold exposure induces differential DNA methylation patterns in genes that appear to affect embryonic development and osteogenesis in the offspring. Our findings suggest the importance of replicating the results of the current study with a larger sample size and exploring the potential of these changes in affecting offspring development.

High-throughput screening to evaluate optimum coagulation conditions via colloidal stability analysis.

Current methods of optimizing the coagulant dosage in wastewater treatment processes typically rely on the use of labor- and material-intensive jar testers, which are inadequate when coagulation processes require frequent adjustments due to variations in properties of the incoming feed. Analytical centrifuges (ACs) employ an integrated optics system that simultaneously monitors the position of the boundary between two separating phases in multiple samples of fairly low volumes (∼2 mL) - thus it was expected that ACs would be ideally suited to study the stability and settling kinetics of coagulation treatment processes. In this study, wastewater samples from a biogas generation facility (known as centrate) were collected in February 2022 (Batch A) and July 2022 (Batch B). A comprehensive screening of the treatment performance for Batch B was conducted at three pHs (5, 6, and 7) and nine concentrations of ferric chloride (0-500 mg-Fe3+/L) - it was found that the front-tracking profiles measured by the integrated optics system could be used to identify the minimal coagulation conditions needed to transition from slow to rapid settling. While the settling velocity was found to be well correlated with the instability index, a dimensionless number between 0 and 1 (where values closer to 1 indicate better separation), it was determined that the percentage of COD removal from the centrate samples increased up to an instability index of approximately 0.5 and then plateaued. Finally, it was found that the front-tracking profiles could be used to estimate the volume of sludge produced at various coagulation conditions. Thus, the results from this study establish ACs as an important screening tool for rapid evaluation of treatment performance while consuming minimal material and time - in this study, a total of 132 screening experiments were conducted using approximately ∼11 L of centrate and ∼6 hours of operator time.

Lumicitabine, an orally administered nucleoside analog, in infants hospitalized with respiratory syncytial virus (RSV) infection: Safety, efficacy, and pharmacokinetic results.

Respiratory syncytial virus (RSV) infection is the leading cause of infant hospitalizations and mortality. Lumicitabine, an oral nucleoside analog was studied for the treatment of RSV. The phase 1b and phase 2b studies reported here assessed the safety, pharmacokinetics, and pharmacodynamics of lumicitabine in infants/neonates hospitalized with RSV. In the phase 1b study, infants (≥1 to ≤12 months) and neonates (<28 days) received a single-ascending or multiple-ascending doses (single loading dose [LD] then 9 maintenance doses [MD] of lumicitabine, or placebo [3:1]). In the phase 2b study, infants/children (28 days to ≤36 months old) received lumicitabine 40/20 mg/kg, 60/40 mg/kg LD/MD twice-daily or placebo (1:1:1) for 5 days. Safety, pharmacokinetics, and efficacy parameters were assessed over 28 days. Lumicitabine was associated with a dose-related increase in the incidence and severity of reversible neutropenia. Plasma levels of ALS-008112, the active nucleoside analog, were dose-proportional with comparable mean exposure levels at the highest doses in both studies. There were no significant differences between the lumicitabine groups and placebo in reducing viral load, time to viral non-detectability, and symptom resolution. No emergent resistance-associated substitutions were observed at the RSV L-gene positions of interest. In summary, lumicitabine was associated with a dose-related increase in the incidence and severity of reversible neutropenia and failed to demonstrate antiviral activity in RSV-infected hospitalized infants. This contrasts with the findings of the previous RSV-A adult challenge study where significant antiviral activity was noted, without incidence of neutropenia. Trial registration ClinicalTrials.gov Identifier: NCT02202356 (phase 1b); NCT03333317 (phase 2b).

A novel analytical method, Birth Date Selection Mapping, detects response of the Angus (Bos taurus) genome to selection on complex traits.

BACKGROUND: Several methods have recently been developed to identify regions of the genome that have been exposed to strong selection. However, recent theoretical and empirical work suggests that polygenic models are required to identify the genomic regions that are more moderately responding to ongoing selection on complex traits. We examine the effects of multi-trait selection on the genome of a population of US registered Angus beef cattle born over a 50-year period representing approximately 10 generations of selection. We present results from the application of a quantitative genetic model, called Birth Date Selection Mapping, to identify signatures of recent ongoing selection. RESULTS: We show that US Angus cattle have been systematically selected to alter their mean additive genetic merit for most of the 16 production traits routinely recorded by breeders. Using Birth Date Selection Mapping, we estimate the time-dependency of allele frequency for 44,817 SNP loci using genomic best linear unbiased prediction, generalized least squares, and BayesCπ analyses. Finally, we reconstruct the primary phenotypes that have historically been exposed to selection from a genome-wide analysis of the 16 production traits and gene ontology enrichment analysis. CONCLUSIONS: We demonstrate that Birth Date Selection Mapping utilizing mixed models corrects for time-dependent pedigree sampling effects that lead to spurious SNP associations and reveals genomic signatures of ongoing selection on complex traits. Because multiple traits have historically been selected in concert and most quantitative trait loci have small effects, selection has incrementally altered allele frequencies throughout the genome. Two quantitative trait loci of large effect were not the most strongly selected of the loci due to their antagonistic pleiotropic effects on strongly selected phenotypes. Birth Date Selection Mapping may readily be extended to temporally-stratified human or model organism populations.

Resolving the evolution of extant and extinct ruminants with high-throughput phylogenomics.

The Pecorans (higher ruminants) are believed to have rapidly speciated in the Mid-Eocene, resulting in five distinct extant families: Antilocapridae, Giraffidae, Moschidae, Cervidae, and Bovidae. Due to the rapid radiation, the Pecoran phylogeny has proven difficult to resolve, and 11 of the 15 possible rooted phylogenies describing ancestral relationships among the Antilocapridae, Giraffidae, Cervidae, and Bovidae have each been argued as representations of the true phylogeny. Here we demonstrate that a genome-wide single nucleotide polymorphism (SNP) genotyping platform designed for one species can be used to genotype ancient DNA from an extinct species and DNA from species diverged up to 29 million years ago and that the produced genotypes can be used to resolve the phylogeny for this rapidly radiated infraorder. We used a high-throughput assay with 54,693 SNP loci developed for Bos taurus taurus to rapidly genotype 678 individuals representing 61 Pecoran species. We produced a highly resolved phylogeny for this diverse group based upon 40,843 genome-wide SNP, which is five times as many informative characters as have previously been analyzed. We also establish a method to amplify and screen genomic information from extinct species, and place Bison priscus within the Bovidae. The quality of genotype calls and the placement of samples within a well-supported phylogeny may provide an important test for validating the fidelity and integrity of ancient samples. Finally, we constructed a phylogenomic network to accurately describe the relationships between 48 cattle breeds and facilitate inferences concerning the history of domestication and breed formation.

Characterization of microsatellite loci in the SLA class I region.

Microsatellite (MS) markers in the SLA-1 region were characterized via sequencing analysis with BAC clones generated from the National Institute of Health miniature pigs (MIPs). A total of 16 BAC clones were sequenced producing 15,228 shotgun reads, corresponding to 11.2 X sequencing coverage, that were used to construct a contig of 12.18 Mb in length. MS markers were compared with previously deposited GenBank sequences to verify the existence of 423 potential MS candidate markers in the SLA-1 region. Evaluation of these polymorphisms confirmed 59 markers in MIPs, and the combined data including sequences from GenBank revealed 155 polymorphic MS markers. MS markers identified from this analysis can be used to provide an alternative method to direct typing for determining an individual's SLA-1 haplotype.

Point-of-care ultrasound diagnosis of a pyogenic liver abscess in the emergency department.

Pyogenic liver abscess (PLA) is a rarely encountered condition in the emergency department (ED) that necessitates a timely diagnosis by the emergency physician. An early ED diagnosis is challenging as the presenting symptoms of PLA are often variable and nonspecific. The rapid bedside diagnosis of PLA with point-of-care ultrasound (POCUS) performed by emergency physicians has not been investigated thoroughly. This case report describes the expeditious identification and ED management of PLA by implementing emergency physician-performed POCUS as the initial diagnostic modality.

Rationale and design of the randomized, double-blind trial testing INtraveNous and Oral administration of elinogrel, a selective and reversible P2Y(12)-receptor inhibitor, versus clopidogrel to eVAluate Tolerability and Efficacy in nonurgent Percutaneous Coronary Interventions patients (INNOVATE-PCI).

Despite current dual-antiplatelet therapy with aspirin and clopidogrel, adverse clinical events continue to occur during and after percutaneous coronary intervention (PCI). The failure of clopidogrel to provide optimal protection may be related to delayed onset of action, interpatient variability in its effect, and an insufficient level of platelet inhibition. Furthermore, the irreversible binding of clopidogrel to the P2Y(12) receptor for the life span of the platelet is associated with increased bleeding risk especially during urgent or emergency surgery. Novel antiplatelet agents are required to improve management of patients undergoing PCI. Elinogrel is a potent, direct-acting (ie, non-prodrug), selective, competitive, and reversible P2Y(12) inhibitor available in both intravenous and oral formulations. The INNOVATE-PCI study is a phase 2 randomized, double-blind, clopidogrel-controlled trial to evaluate the safety, tolerability, and preliminary efficacy of this novel antiplatelet agent in patients undergoing nonurgent PCI.

Impact of reduced marker set estimation of genomic relationship matrices on genomic selection for feed efficiency in Angus cattle.

BACKGROUND: Molecular estimates of breeding value are expected to increase selection response due to improvements in the accuracy of selection and a reduction in generation interval, particularly for traits that are difficult or expensive to record or are measured late in life. Several statistical methods for incorporating molecular data into breeding value estimation have been proposed, however, most studies have utilized simulated data in which the generated linkage disequilibrium may not represent the targeted livestock population. A genomic relationship matrix was developed for 698 Angus steers and 1,707 Angus sires using 41,028 single nucleotide polymorphisms and breeding values were estimated using feed efficiency phenotypes (average daily feed intake, residual feed intake, and average daily gain) recorded on the steers. The number of SNPs needed to accurately estimate a genomic relationship matrix was evaluated in this population. RESULTS: Results were compared to estimates produced from pedigree-based mixed model analysis of 862 Angus steers with 34,864 identified paternal relatives but no female ancestors. Estimates of additive genetic variance and breeding value accuracies were similar for AFI and RFI using the numerator and genomic relationship matrices despite fewer animals in the genomic analysis. Bootstrap analyses indicated that 2,500-10,000 markers are required for robust estimation of genomic relationship matrices in cattle. CONCLUSIONS: This research shows that breeding values and their accuracies may be estimated for commercially important sires for traits recorded in experimental populations without the need for pedigree data to establish identity by descent between members of the commercial and experimental populations when at least 2,500 SNPs are available for the generation of a genomic relationship matrix.

Fast, Easy, and Good: Assessing Entrustable Professional Activities in Psychiatry Residents With a Mobile App.

PROBLEM: Entrustable professional activities (EPAs) can be used to operationalize competency-based medical education. Mobile apps can efficiently capture feedback based on direct observation. To leverage the benefits of both, the authors developed an assessment tool that combines EPAs with mobile technology. APPROACH: The authors designed an app to collect EPA data based on direct observation using human-technology interface guidelines. Data collected in the app included: name of resident, the 13 end-of-training EPAs for psychiatry, entrustment ratings, and corrective narrative feedback. The app was implemented in an outpatient continuity clinic for second-year psychiatry residents over a 10-month period between September 2017 and June 2018. Ten faculty-resident dyads piloted the app. To assess the feasibility, utility, and validity of this intervention, the authors examined 3 outcomes: (1) utilization (mean time to complete each assessment; percentage of dyads who completed 10 assessments), (2) quality of the comments (proportion of comments that were behaviorally specific and actionable), and (3) correlation between entrustment level and resident experience (defined as days elapsed since the beginning of the experience). OUTCOMES: A total of 99 assessments were completed during the pilot. Mean time to complete an assessment was 76 seconds (standard deviation = 50 seconds, median = 67 seconds). Only 6 of the 10 dyads completed at least 10 assessments. Of all comments, 95% (94) were behaviorally specific and actionable and 91% (90) were corrective. Entrustment scores correlated moderately with resident experience (r = 0.43, P < .001). NEXT STEPS: The authors' EPA mobile app was efficient, generated high-quality feedback, and produced entrustment scores that improved as the residents gained experience. Challenges included uneven adoption. Looking forward, the authors plan to examine the enablers and barriers to adoption from an implementation science perspective.

A mobile app to capture EPA assessment data: Utilizing the consolidated framework for implementation research to identify enablers and barriers to engagement.

INTRODUCTION: Mobile apps that utilize the framework of entrustable professional activities (EPAs) to capture and deliver feedback are being implemented. If EPA apps are to be successfully incorporated into programmatic assessment, a better understanding of how they are experienced by the end-users will be necessary. The authors conducted a qualitative study using the Consolidated Framework for Implementation Research (CFIR) to identify enablers and barriers to engagement with an EPA app. METHODS: Structured interviews of faculty and residents were conducted with an interview guide based on the CFIR. Transcripts were independently coded by two study authors using directed content analysis. Differences were resolved via consensus. The study team then organized codes into themes relevant to the domains of the CFIR. RESULTS: Eight faculty and 10 residents chose to participate in the study. Both faculty and residents found the app easy to use and effective in facilitating feedback immediately after the observed patient encounter. Faculty appreciated how the EPA app forced brief, distilled feedback. Both faculty and residents expressed positive attitudes and perceived the app as aligned with the department's philosophy. Barriers to engagement included faculty not understanding the EPA framework and scale, competing clinical demands, residents preferring more detailed feedback and both faculty and residents noting that the app's feedback should be complemented by a tool that generates more systematic, nuanced, and comprehensive feedback. Residents rarely if ever returned to the feedback after initial receipt. DISCUSSION: This study identified key enablers and barriers to engagement with the EPA app. The findings provide guidance for future research and implementation efforts focused on the use of mobile platforms to capture direct observation feedback.

Serial Point-of-care Echocardiography Performed by an Emergency Physician to Guide Thrombolytic Management of Massive Pulmonary Embolism.

Massive pulmonary embolism (PE) is a life-threatening condition with a high mortality burden. The rapid diagnosis of PE can be supported with focused cardiac ultrasound (FOCUS) by identifying signs of right ventricular dysfunction (RVD). This case report describes a patient with hemodynamically unstable massive PE who received systemic thrombolytic therapy. Emergency physicians performed serial FOCUS examinations to assess the resolution of RVD in guidance of clinical management.