Multicentre service evaluation of injectable cabotegravir and rilpivirine delivery and outcomes across 12 UK clinics (SHARE LAI-net).

INTRODUCTION: Long-acting injectable cabotegravir + rilpivirine (CAB + RPV LAI) was approved for use in virally suppressed adults in the England and Wales national health service in November 2021. We describe a service evaluation of delivery processes and outcomes in 12 clinics. METHODS: Centres populated a database using information from local policies and clinical records. Services were asked to describe approval processes, clinic pathways, and adherence to national guidelines. Additional data were collected on reasons for regimen choice, treatment discontinuations, and management of viraemia. RESULTS: In total, 518 adults from 12 clinics were approved for CAB + RPV LAI between February 2022 and December 2023. Of the 518 people approved for CAB + RPV LAI, 423 received at least one injection. Median duration on CAB + RPV was 7.5 months (interquartile range 3.7-11.3). In total, 97% of injections were administered within the ±7-day window. Virological failure occurred in 0.7%, and 6% discontinued CAB + RPV. CONCLUSION: In this large UK-based cohort, robust approval processes and clinic protocols facilitated on-time injections and low rates of both discontinuation and virological failure.

Linking microphytobenthos distribution and mudflat geomorphology under varying sedimentary regimes using unoccupied aerial vehicle (UAV)-acquired multispectral reflectance and photogrammetry.

Microphytobenthic (MPB) biofilms play significant roles in the ecology of coastal mudflats, including provision of essential food resources to shorebird species. In these ecosystems, water-divergence structures like jetties and causeways can drastically alter sedimentation patterns and mudflat topography, yet their effects on MPB biofilm biomass and distribution are poorly understood. Here, we used a combination of unoccupied aerial vehicle (UAV) technologies, photogrammetric processing, and sediment field samples to compare biofilm and mudflat characteristics between areas of the Fraser River Estuary with varying sedimentary regimes and shorebird use. Our aims were to: (1) demonstrate the use of fine spatial resolution UAV-acquired multispectral imagery (cm2) with extensive spatial coverage (>km2) and a co-alignment photogrammetric processing techniques to survey MPB biofilm and mudflat topography at spatial scales and detail relevant to foraging shorebirds; and, (2) investigate the effects of water-divergence structures on mudflat elevation and microtopography, as well as MPB biofilm biomass, distribution, and spatial patterning. From a technical perspective, co-alignment allowed us to analyze aligned and continuous fine-resolution elevation models and orthomosaics for large areas of the estuary, while the normalized difference vegetation index was a good predictor of sediment chlorophyll-a (R2 = 0.9). Using these data products, we found that mudflats in close proximity to water-divergence structures have cross-shore profiles characteristic of low sediment supply as well as decreased microtopographic variability. At disturbed sites, elevation and microtopography had a weaker influence on biofilm biomass compared to intact estuarine ecosystem sites. Analysis of biofilm patch showed that sites either had a relatively small number of large, contiguous patches, or a large number of smaller, isolated patches; however, less disturbed sites did not necessarily have larger biofilm patches than more disturbed sites. We conclude that UAV-acquired multispectral imagery and co-alignment-based workflow are promising new tools for ecologists to map, monitor, and understand MPB biofilm dynamics in ecologically sensitive estuaries.

Culture-dependent identification of rare marine sediment bacteria from the Gulf of Mexico and Antarctica.

Laboratory-viable cultivars of previously uncultured bacteria further taxonomic understanding. Despite many years of modern microbiological investigations, the vast majority of bacterial taxonomy remains uncharacterized. While many attempts have been made to decrease this knowledge gap, culture-based approaches parse away at the unknown and are critical for improvement of both culturing techniques and computational prediction efficacy. To this end of providing culture-based approaches, we present a multi-faceted approach to recovering marine environmental bacteria. We employ combinations of nutritional availability, inoculation techniques, and incubation parameters in our recovery of marine sediment-associated bacteria from the Gulf of Mexico and Antarctica. The recovered biodiversity spans several taxa, with 16S-ITS-23S rRNA gene-based identification of multiple isolates belonging to rarer genera increasingly undergoing phylogenetic rearrangements. Our modifications to traditional culturing techniques have not only recovered rarer taxa, but also resulted in the recovery of biotechnologically promising bacteria. Together, we propose our stepwise combinations of recovery parameters as a viable approach to decreasing the bacterial knowledge gap.

Machine learning designs new GCGR/GLP-1R dual agonists with enhanced biological potency.

Several peptide dual agonists of the human glucagon receptor (GCGR) and the glucagon-like peptide-1 receptor (GLP-1R) are in development for the treatment of type 2 diabetes, obesity and their associated complications. Candidates must have high potency at both receptors, but it is unclear whether the limited experimental data available can be used to train models that accurately predict the activity at both receptors of new peptide variants. Here we use peptide sequence data labelled with in vitro potency at human GCGR and GLP-1R to train several models, including a deep multi-task neural-network model using multiple loss optimization. Model-guided sequence optimization was used to design three groups of peptide variants, with distinct ranges of predicted dual activity. We found that three of the model-designed sequences are potent dual agonists with superior biological activity. With our designs we were able to achieve up to sevenfold potency improvement at both receptors simultaneously compared to the best dual-agonist in the training set.

CCTFv2: Modeling Cyber Competitions.

Cyber competitions are usually team activities, where team performance not only depends on the members' abilities but also on team collaboration. This seems intuitive, especially given that team formation is a well-studied discipline in competitive sports and project management, but unfortunately, team performance and team formation strategies are rarely studied in the context of cybersecurity and cyber competitions. Since cyber competitions are becoming more prevalent and organized, this gap becomes an opportunity to formalize the study of team performance in the context of cyber competitions. This work follows a cross-validating two-approach methodology. The first is the computational modeling of cyber competitions using Agent-Based Modeling. Team members are modeled, in NetLogo, as collaborating agents competing over a network in a red team/blue team match. Members' abilities, team interaction and network properties are parametrized (inputs), and the match score is reported as output. The second approach is grounded in the literature of team performance (not in the context of cyber competitions), where a theoretical framework is built in accordance with the literature. The results of the first approach are used to build a causal inference model using Structural Equation Modeling. Upon comparing the causal inference model to the theoretical model, they showed high resemblance, and this cross-validated both approaches. Two main findings are deduced: first, the body of literature studying teams remains valid and applicable in the context of cyber competitions. Second, coaches and researchers can test new team strategies computationally and achieve precise performance predictions. The targeted gap used methodology and findings which are novel to the study of cyber competitions.

Repurposing a plant peptide cyclase for targeted lysine acylation.

Transpeptidases are powerful tools for protein engineering but are largely restricted to acting at protein backbone termini. Alternative enzymatic approaches for internal protein labelling require bulky recognition motifs or non-proteinogenic reaction partners, potentially restricting which proteins can be modified or the types of modification that can be installed. Here we report a strategy for labelling lysine side chain ε-amines by repurposing an engineered asparaginyl ligase, which naturally catalyses peptide head-to-tail cyclization, for versatile isopeptide ligations that are compatible with peptidic substrates. We find that internal lysines with an adjacent leucine residue mimic the conventional N-terminal glycine-leucine substrate. This dipeptide motif enables efficient intra- or intermolecular ligation through internal lysine side chains, minimally leaving an asparagine C-terminally linked to the lysine side chain via an isopeptide bond. The versatility of this approach is demonstrated by the chemoenzymatic synthesis of peptides with non-native C terminus-to-side chain topology and the conjugation of chemically modified peptides to recombinant proteins.

Exercise increases TCA intermediate concentrations during low-calorie diet independent of insulin resistance among women with obesity.

Tricarboxylic acid cycle intermediates (TCAi) have been proposed to act as myokines that influence energy metabolism. We determined if 2-weeks of low-calorie diet with interval exercise (LCD + INT) would increase TCAi more than a low-calorie diet (LCD). Twenty-three women were randomized to 2-weeks of LCD (n = 12, 48.4 ± 2.5 years, 37.8 ± 1.5 kg/m2, ~1200 kcal/d) or LCD + INT (n = 11, 47.6 ± 4.3 years, 37.9 ± 2.3 kg/m2; 60 min/d supervised INT of 3 min 90% & 50% HRpeak). TCAi and amino acids (AA) were measured at 0 min of a 75 g OGTT, while glucose, insulin, and FFA were obtained at 0, 30, 60, 90, 120, and 180 min to assess total area under the curve (tAUC180min) and insulin resistance (IR; tAUC180min of Glucose × Insulin). Fuel use (indirect calorimetry) was also collected at 0, 60, 120, and 180 min as was fitness (VO2peak) and body composition (BodPod). Treatments reduced weight (p < 0.001), fasting RER (p = 0.01), and IR (p = 0.03), although LCD + INT increased VO2peak (p = 0.02) and maintained RER tAUC180min (p = 0.05) versus LCD. Treatments increased FFA tAUC180min (p = 0.005), cis-aconitate, isocitrate, and succinate (p ≤ 0.02), as well as reduced phenylalanine and tryptophan, cysteine (p ≤ 0.005). However, LCD + INT increased malate, citrate, α-ketoglutarate, and alanine more than LCD (p ≤ 0.04). Thus, INT enhanced LCD effects on some TCAi in women with obesity independent of IR.

Sleep-Deep-Learner is taught sleep-wake scoring by the end-user to complete each record in their style.

Sleep-wake scoring is a time-consuming, tedious but essential component of clinical and preclinical sleep research. Sleep scoring is even more laborious and challenging in rodents due to the smaller EEG amplitude differences between states and the rapid state transitions which necessitate scoring in shorter epochs. Although many automated rodent sleep scoring methods exist, they do not perform as well when scoring new datasets, especially those which involve changes in the EEG/EMG profile. Thus, manual scoring by expert scorers remains the gold standard. Here we take a different approach to this problem by using a neural network to accelerate the scoring of expert scorers. Sleep-Deep-Learner creates a bespoke deep convolution neural network model for individual electroencephalographic or local-field-potential (LFP) records via transfer learning of GoogLeNet, by learning from a small subset of manual scores of each EEG/LFP record as provided by the end-user. Sleep-Deep-Learner then automates scoring of the remainder of the EEG/LFP record. A novel REM sleep scoring correction procedure further enhanced accuracy. Sleep-Deep-Learner reliably scores EEG and LFP data and retains sleep-wake architecture in wild-type mice, in sleep induced by the hypnotic zolpidem, in a mouse model of Alzheimer's disease and in a genetic knock-down study, when compared to manual scoring. Sleep-Deep-Learner reduced manual scoring time to 1/12. Since Sleep-Deep-Learner uses transfer learning on each independent recording, it is not biased by previously scored existing datasets. Thus, we find Sleep-Deep-Learner performs well when used on signals altered by a drug, disease model, or genetic modification.

Distal Biceps Tendon Repair Using a Double Intracortical Button Anatomical Footprint Repair Technique.

INTRODUCTION: Distal biceps tendon repair is usually performed via a double-incision or single-incision bicortical drilling technique. However, these techniques are associated with specific complications and usually do not allow for anatomical footprint restoration. It was the aim of this study to report the clinical results of a double intracortical button anatomical footprint repair technique for distal biceps tendon tears. We hypothesized that this technique would result in supination strength comparable to the uninjured side with a low re-rupture rate and minimal bony or neurological complications. MATERIAL AND METHODS: This was a retrospective, single-surgeon cohort study of a consecutive series of 22 patients with a mean (SD) age of 50.7 (9.4) years and at least 1-year follow-up after distal biceps tendon repair. At final follow-up, complications, range of motion (ROM), the Patient-rated Elbow Evaluation (PREE), Mayo Elbow Performance Score (MEPS), Disabilities of the Arm, Shoulder, and Hand (DASH) questionnaire, visual analog scale (VAS) for pain, patient satisfaction and supination strength in neutral as well as 60° of supination were analyzed. Radiographic evaluation was performed on a CT scan. RESULTS: One patient (4.5%) experienced slight paresthesia in the area of the lateral antebrachial cutaneous nerve. Heterotopic ossification was seen in one patient (4.5%). All patients recovered full ROM except for one who had 10° of loss of flexion and extension. Median PREE score was 4.6 (0-39.6), median MEP was 100 (70-100) and median DASH was 1.4 (0-16.7). All but one patient were very satisfied with the outcome. The affected arm had a mean of 98% (± 13) of neutral supination strength (p=0.633) and 94% (± 12) of supination strength in 60° (p=0.054) compared to the contralateral, unaffected side. There were four cases (18.2%) of cortical thinning due to at least one button and one case of button pull-out (4.5%). CONCLUSIONS: The double intracortical button anatomical footprint repair technique seems to provide reliable restoration of supination strength, excellent patient satisfaction while minimizing complications, particularly nerve damage and heterotopic ossification.

Systematic Review: Strategies for Improving HIV Testing and Detection Rates in European Hospitals.

Undiagnosed HIV infection is a prominent clinical issue throughout Europe that requires the continuous attention of all healthcare professionals and policymakers to prevent missed testing opportunities and late diagnosis. This systematic review aimed to evaluate interventions to increase HIV testing rates and case detection in European hospitals. Out of 4598 articles identified, 29 studies fulfilled the selection criteria. Most of the studies were conducted in single Western European capital cities, and only one study was from Eastern Europe. The main interventions investigated were test-all and indicator-condition-based testing strategies. Overall, the prevalence of undiagnosed HIV was well above 0.1%. The studied interventions increased the HIV testing rate and the case detection rate. The highest prevalence of undiagnosed HIV was found with the indicator-condition-driven testing strategy, whereas the test-all strategy had the most profound impact on the proportion of late diagnoses. Nevertheless, the HIV testing rates and case-finding varied considerably across studies. In conclusion, effective strategies to promote HIV testing in European hospitals are available, but relevant knowledge gaps regarding generalizability and sustainability remain. These gaps require the promotion of adherence to HIV testing guidelines, as well as additional larger studies representing all European regions.

The Impact of Patterns in Linkage Disequilibrium and Sequencing Quality on the Imprint of Balancing Selection.

Regions under balancing selection are characterized by dense polymorphisms and multiple persistent haplotypes, along with other sequence complexities. Successful identification of these patterns depends on both the statistical approach and the quality of sequencing. To address this challenge, at first, a new statistical method called LD-ABF was developed, employing efficient Bayesian techniques to effectively test for balancing selection. LD-ABF demonstrated the most robust detection of selection in a variety of simulation scenarios, compared against a range of existing tests/tools (Tajima's D, HKA, Dng, BetaScan, and BalLerMix). Furthermore, the impact of the quality of sequencing on detection of balancing selection was explored, as well, using: (i) SNP genotyping and exome data, (ii) targeted high-resolution HLA genotyping (IHIW), and (iii) whole-genome long-read sequencing data (Pangenome). In the analysis of SNP genotyping and exome data, we identified known targets and 38 new selection signatures in genes not previously linked to balancing selection. To further investigate the impact of sequencing quality on detection of balancing selection, a detailed investigation of the MHC was performed with high-resolution HLA typing data. Higher quality sequencing revealed the HLA-DQ genes consistently demonstrated strong selection signatures otherwise not observed from the sparser SNP array and exome data. The HLA-DQ selection signature was also replicated in the Pangenome samples using considerably less samples but, with high-quality long-read sequence data. The improved statistical method, coupled with higher quality sequencing, leads to more consistent identification of selection and enhanced localization of variants under selection, particularly in complex regions.

Lateral Opening-Wedge Distal Femoral Osteotomy Made Easy: Tips and Tricks.

A lateral opening-wedge distal femoral osteotomy is useful to offload the lateral tibiofemoral compartment for focal chondral defects or isolated lateral compartment arthritis. Although beneficial for these lateral compartment disorders, a distal femoral osteotomy requires careful forethought to optimize correction accuracy and safety. We recommend the following for effective execution of a distal femoral osteotomy: (1) Plan the desired correction preoperatively while accounting for an individual patient's anatomy and femoral width. (2) Perform an iliotibial band Z-lengthening for large deformity corrections to not overconstrain the lateral structures. (3) Use the plate to help guide the level of the osteotomy, which will facilitate bony contact after the osteotomy and decrease plate prominence. (4) Perform the osteotomy with a saw anteriorly and an osteotome posteriorly for safety and stop the osteotomy approximately 1 cm short of the far cortex. (5) Fashion tricortical wedge grafts at the height of the planned correction to maintain reduction and facilitate plate placement. (6) Control the plate position to lie optimally at the level of the osteotomy, ensuring it is not proud and is parallel with the femoral shaft. With these presurgical and intraoperative steps, a lateral opening-wedge distal femoral osteotomy can be performed effectively.

Extraneous Load, Patient Census, and Patient Acuity Correlate With Cognitive Load During ICU Rounds.

BACKGROUND: Cognitive load theory asserts that learning and performance degrade when cognitive load exceeds working memory capacity. This is particularly relevant in the learning environment of ICU rounds, when multidisciplinary providers integrate complex decision-making and teaching in a noisy, high-stress environment prone to cognitive distractions. RESEARCH QUESTION: What features of ICU rounds correlate with high provider cognitive load? STUDY DESIGN AND METHODS: This was an observational, multisite study of multidisciplinary providers during ICU rounds. Investigators recorded rounding characteristics and hourly extraneous cognitive load events during rounds (defined as distractions, episodes of split-attention or repetition, and deviations from standard communication format). After rounds, investigators measured each provider's cognitive load using the provider task load (PTL), an instrument derived from the National Aeronautics and Space Administration Task Load Index survey that assesses perceived workload associated with complex tasks. Relationships between rounding characteristics, extraneous load, and PTL score were evaluated using mixed-effects modeling. RESULTS: A total of 76 providers were observed during 32 rounds from December 2020 to May 2021. The mean rounding census ± SD was 12.5 ± 2.9 patients. The mean rounding time ± SD was 2 h 17 min ± 49 min. The mean extraneous load ± SD was 20.5 ± 4.5 events per hour, or one event every 2 min 51 s. This included 8.6 ± 3.4 distractions, 8.2 ± 4.2 communication deviations, 1.9 ± 1.4 repetitions, and 1.8 ± 1.3 episodes of split-attention per hour. Controlling for covariates, the hourly extraneous load events, number of new patients, and number of higher acuity patients were each associated with increased PTL score (slope, 2.40; 95% CI, 0.76-4.04; slope, 5.23; 95% CI, 2.02-8.43; slope, 3.35; 95% CI, 1.34-5.35, respectively). INTERPRETATION: Increased extraneous load, new patients, and patient acuity were associated with higher cognitive load during ICU rounds. These results can help direct how the ICU rounding structure may be modified to reduce workload and optimize provider learning and performance.

Win-Paired Cues Modulate the Effect of Dopamine Neuron Sensitization on Decision Making and Cocaine Self-administration: Divergent Effects Across Sex.

BACKGROUND: Both psychostimulant use and engagement with probabilistic schedules of reward sensitize the mesocorticolimbic dopamine (DA) system. Such behaviors may act synergistically to explain the high comorbidity between stimulant use and gambling disorder. The salient audiovisual stimuli of modern electronic gambling may exacerbate the situation. METHODS: To probe these interactions, we sensitized ventral tegmental area DA neurons via chronic chemogenetic stimulation while rats (n = 134) learned a rat gambling task in the presence or absence of casino-like cues. The same rats then learned to self-administer cocaine. In a separate cohort (n = 25), we confirmed that our chemogenetic methods sensitized the locomotor response to cocaine and potentiated phasic excitability of ventral tegmental area DA neurons through in vivo electrophysiological recordings. RESULTS: In the absence of cues, sensitization promoted risk taking in both sexes. When rewards were cued, sensitization expedited the development of a risk-preferring phenotype in males while attenuating cue-induced risk taking in females. CONCLUSIONS: While these results provide further confirmation that ventral tegmental area DA neurons critically modulate risky decision making, they also reveal stark sex differences in the decisional impact that dopaminergic signals exert when winning outcomes are cued. As previously observed, risky decision making on the cued rat gambling task increased as both males and females learned to self-administer cocaine. The combination of DA sensitization and win-paired cues while gambling led to significantly greater cocaine taking, but these rats did not show any increase in risky choice as a result. Therefore, cocaine and heavily cued gambles may partially substitute for each other once the DA system has been rendered labile through sensitization, thereby compounding addiction risk across modalities.

International AIDS society conference 2023 summary.

AIM: This article summarizes key research presented at the International AIDS Society (IAS) Conference in Brisbane, held in July 2023. CO-MORBIDITIES: The REPRIEVE Trial as a conference highlight, demonstrating significantly fewer major cardiovascular events amongst people with HIV who were randomized to pitavastatin compared to placebo. Key data on weight, hypertension and incident diabetes are also summarized. ANTIRETROVIRAL THERAPY: Novel data on doravirine and islatravir are described as are trials demonstrating efficacy dolutegravir/lamivudine first-line in people without baseline resistance testing and in suppressed switch amongst people with historic lamivudine resistance. HIV CURE: The sixth case of HIV cure secondary to stem cell transplantation is summarized, as are new insights into the central nervous system as an HIV reservoir.

Noradrenergic regulation of cue-guided decision making and impulsivity is doubly dissociable across frontal brain regions.

RATIONALE: Win-paired stimuli can promote risk taking in experimental gambling paradigms in both rats and humans. We previously demonstrated that atomoxetine, a noradrenaline reuptake inhibitor, and guanfacine, a selective α2A adrenergic receptor agonist, reduced risk taking on the cued rat gambling task (crGT), a rodent assay of risky choice in which wins are accompanied by salient cues. Both compounds also decreased impulsive premature responding. OBJECTIVE: The key neural loci mediating these effects were unknown. The lateral orbitofrontal cortex (lOFC) and the medial prefrontal cortex (mPFC), which are highly implicated in risk assessment, action selection, and impulse control, receive dense noradrenergic innervation. We therefore infused atomoxetine and guanfacine directly into either the lOFC or prelimbic (PrL) mPFC prior to task performance. RESULTS: When infused into the lOFC, atomoxetine improved decision making score and adaptive lose-shift behaviour in males, but not in females, without altering motor impulsivity. Conversely, intra-PrL atomoxetine improved impulse control in risk preferring animals of both sexes, but did not alter decision making. Guanfacine administered into the PrL, but not lOFC, also altered motor impulsivity in all subjects, though in the opposite direction to atomoxetine. CONCLUSIONS: These data highlight a double dissociation between the behavioural effects of noradrenergic signaling across frontal regions with respect to risky choice and impulsive action. Given that the influence of noradrenergic manipulations on motor impulsivity could depend on baseline risk preference, these data also suggest that the noradrenaline system may function differently in subjects that are susceptible to the risk-promoting lure of win-associated cues.

Massive Hemoptysis Simulation Curriculum Improves Performance.

BACKGROUND: Massive hemoptysis is a rare, high-acuity presentation, which requires the integration of both cognitive and procedural skills. Simulation has been recommended to improve preparation for high-acuity, low-occurrence procedures; however, the effect of a simulation curriculum for massive hemoptysis management has never been investigated. RESEARCH QUESTION: Does simulation for hemoptysis management improve competence? STUDY DESIGN AND METHODS: Kern's six steps for medical education curriculum design were used iteratively to develop a simulation curriculum for the management of massive hemoptysis. Pulmonary and critical care medicine fellows from the University of Colorado participated in a local needs assessment and a massive hemoptysis simulation curriculum. Using a manikin-based massive hemoptysis simulator developed for this curriculum, the simulation session used repetitive practice, clinical variation, a range of difficulties, and directed feedback in a group practice setting. Time to management and performance were assessed for each management attempt; competence was assessed using a combined metric of management-related priorities and global entrustment. RESULTS: During the needs assessment, fellows viewed massive hemoptysis management skills as important, while expressing their current confidence as low. Nineteen fellows participated in a 90-min case-based hemoptysis simulation during which each was exposed to five different cases and acted as the primary manager for two cases. There was significant improvement in performance from the first to final simulation attempts measured by time to successful management (14.24 vs 10.26 min, P = .0067) and entrustment (Global Assessment Scale, 1 [should not perform] to 5 [independent]; 4.11 vs 4.61; P = .015). Fellow self-assessed knowledge and confidence in hemoptysis management and endobronchial blocker placement improved significantly after the simulation. INTERPRETATION: Hemoptysis simulation experience improves fellow confidence and skill for management of this high-acuity, low-occurrence presentation.

Creation and Validation of a Massive Hemoptysis Simulator.

BACKGROUND: Simulation for the management of massive hemoptysis is limited by the absence of a commercially available simulator to practice procedural skills necessary for management. RESEARCH QUESTION: Is it feasible to create and validate a hemoptysis simulator with high functional task alignment? STUDY DESIGN AND METHODS: Pulmonary and critical care medicine (PCCM) attending physicians from four academic institutions in the Denver, Colorado, area and internal medicine residents from the University of Colorado participated in this mixed-methods study. A hemoptysis simulator was constructed by connecting a 3-D-printed airway model to a manikin that may be intubated. Attending PCCM physicians evaluated the simulator through surveys and qualitative interviews. Attendings were surveyed to determine simulation content and appropriate assessment criteria for a hemoptysis simulation. Based on these criteria, expert and novice performance on the simulator was assessed. RESULTS: The manikin-based hemoptysis simulator demonstrated adequate physical resemblance, high functional alignment, and strong affective fidelity. It was universally preferred over a virtual reality simulator by 10 PCCM attendings. Twenty-seven attendings provided input on assessment criteria and established that assessing management priorities (eg, airway protection) was preferred to a skills checklist for hemoptysis management. Three experts outperformed six novices in hemoptysis management on the manikin-based simulator in all management categories assessed, supporting construct validity of the simulation. INTERPRETATION: Creation of a hemoptysis simulator with appropriate content, high functional task alignment, and strong affective fidelity was successful using 3-D-printed airway models and existing manikins. This approach can overcome barriers of cost and availability for simulation of high-acuity, low-occurrence procedures.

OTULIN Haploinsufficiency-Related Fasciitis and Skin Necrosis Treated by TNF Inhibition.

Here, we describe an adult female with severe fasciitis and skin necrosis who carried a private, predicted deleterious missense mutation in OTULIN in heterozygosity. OTULIN is a cellular regulator of deubiquitination that has been shown to play a key role in intrinsic immunity against staphylococcal α-toxin. The patient was treated with broad-spectrum antibiotics, and multiple surgical explorations were conducted without clinical response. Since autoinflammation was the predominant clinical feature, TNF inhibition was started with a good clinical response. We show that excessive inflammation in OTULIN haploinsufficiency can be effectively treated by TNF inhibition.