Dynamic CD8+ T cell responses to cancer immunotherapy in human regional lymph nodes are disrupted in metastatic lymph nodes.

CD8+ T cell responses are critical for anti-tumor immunity. While extensively profiled in the tumor microenvironment, recent studies in mice identified responses in lymph nodes (LNs) as essential; however, the role of LNs in human cancer patients remains unknown. We examined CD8+ T cells in human head and neck squamous cell carcinomas, regional LNs, and blood using mass cytometry, single-cell genomics, and multiplexed ion beam imaging. We identified progenitor exhausted CD8+ T cells (Tpex) that were abundant in uninvolved LN and clonally related to terminally exhausted cells in the tumor. After anti-PD-L1 immunotherapy, Tpex in uninvolved LNs reduced in frequency but localized near dendritic cells and proliferating intermediate-exhausted CD8+ T cells (Tex-int), consistent with activation and differentiation. LN responses coincided with increased circulating Tex-int. In metastatic LNs, these response hallmarks were impaired, with immunosuppressive cellular niches. Our results identify important roles for LNs in anti-tumor immune responses in humans.

A Pan-plant Protein Complex Map Reveals Deep Conservation and Novel Assemblies.

Plants are foundational for global ecological and economic systems, but most plant proteins remain uncharacterized. Protein interaction networks often suggest protein functions and open new avenues to characterize genes and proteins. We therefore systematically determined protein complexes from 13 plant species of scientific and agricultural importance, greatly expanding the known repertoire of stable protein complexes in plants. By using co-fractionation mass spectrometry, we recovered known complexes, confirmed complexes predicted to occur in plants, and identified previously unknown interactions conserved over 1.1 billion years of green plant evolution. Several novel complexes are involved in vernalization and pathogen defense, traits critical for agriculture. We also observed plant analogs of animal complexes with distinct molecular assemblies, including a megadalton-scale tRNA multi-synthetase complex. The resulting map offers a cross-species view of conserved, stable protein assemblies shared across plant cells and provides a mechanistic, biochemical framework for interpreting plant genetics and mutant phenotypes.

Determining the three-dimensional atomic structure of an amorphous solid.

Amorphous solids such as glass, plastics and amorphous thin films are ubiquitous in our daily life and have broad applications ranging from telecommunications to electronics and solar cells1-4. However, owing to the lack of long-range order, the three-dimensional (3D) atomic structure of amorphous solids has so far eluded direct experimental determination5-15. Here we develop an atomic electron tomography reconstruction method to experimentally determine the 3D atomic positions of an amorphous solid. Using a multi-component glass-forming alloy as proof of principle, we quantitatively characterize the short- and medium-range order of the 3D atomic arrangement. We observe that, although the 3D atomic packing of the short-range order is geometrically disordered, some short-range-order structures connect with each other to form crystal-like superclusters and give rise to medium-range order. We identify four types of crystal-like medium-range order-face-centred cubic, hexagonal close-packed, body-centred cubic and simple cubic-coexisting in the amorphous sample, showing translational but not orientational order. These observations provide direct experimental evidence to support the general framework of the efficient cluster packing model for metallic glasses10,12-14,16. We expect that this work will pave the way for the determination of the 3D structure of a wide range of amorphous solids, which could transform our fundamental understanding of non-crystalline materials and related phenomena.

Minimizing higher-order aggregation maximizes iron mobilization by small molecules.

The natural product hinokitiol mobilizes iron across lipid bilayers at low concentrations and restores hemoglobinization in iron transporter protein-deficient systems. But hinokitiol fails to similarly mobilize iron at higher concentrations, limiting its uses in chemical biology and medicine. Here we show that at higher concentrations, hinokitiol3:Fe(III) complexes form large, higher-order aggregates, leading to loss of transmembrane iron mobilization. Guided by this understanding and systematic structure-function studies enabled by modular synthesis, we identified FeM-1269, which minimally aggregates and dose-dependently mobilizes iron across lipid bilayers even at very high concentrations. In contrast to hinokitiol, FeM-1269 is also well-tolerated in animals at high doses for extended periods of time. In a mouse model of anemia of inflammation, FeM-1269 increases serum iron, transferrin saturation, hemoglobin and hematocrit. This rationally developed iron-mobilizing small molecule has enhanced potential as a molecular prosthetic for understanding and potentially treating iron transporter deficiencies.

In-context operator learning with data prompts for differential equation problems.

This paper introduces the paradigm of "in-context operator learning" and the corresponding model "In-Context Operator Networks" to simultaneously learn operators from the prompted data and apply it to new questions during the inference stage, without any weight update. Existing methods are limited to using a neural network to approximate a specific equation solution or a specific operator, requiring retraining when switching to a new problem with different equations. By training a single neural network as an operator learner, rather than a solution/operator approximator, we can not only get rid of retraining (even fine-tuning) the neural network for new problems but also leverage the commonalities shared across operators so that only a few examples in the prompt are needed when learning a new operator. Our numerical results show the capability of a single neural network as a few-shot operator learner for a diversified type of differential equation problems, including forward and inverse problems of ordinary differential equations, partial differential equations, and mean-field control problems, and also show that it can generalize its learning capability to operators beyond the training distribution.

The impact of COVID-19 on a college freshman sample reveals genetic and nongenetic forms of susceptibility and resilience to stress.

Using a longitudinal approach, we sought to define the interplay between genetic and nongenetic factors in shaping vulnerability or resilience to COVID-19 pandemic stress, as indexed by the emergence of symptoms of depression and/or anxiety. University of Michigan freshmen were characterized at baseline using multiple psychological instruments. Subjects were genotyped, and a polygenic risk score for depression (MDD-PRS) was calculated. Daily physical activity and sleep were captured. Subjects were sampled at multiple time points throughout the freshman year on clinical rating scales, including GAD-7 and PHQ-9 for anxiety and depression, respectively. Two cohorts (2019 to 2021) were compared to a pre-COVID-19 cohort to assess the impact of the pandemic. Across cohorts, 26 to 40% of freshmen developed symptoms of anxiety or depression (N = 331). Depression symptoms significantly increased in the pandemic years and became more chronic, especially in females. Physical activity was reduced, and sleep was increased by the pandemic, and this correlated with the emergence of mood symptoms. While low MDD-PRS predicted lower risk for depression during a typical freshman year, this genetic advantage vanished during the pandemic. Indeed, females with lower genetic risk accounted for the majority of the pandemic-induced rise in depression. We developed a model that explained approximately half of the variance in follow-up depression scores based on psychological trait and state characteristics at baseline and contributed to resilience in genetically vulnerable subjects. We discuss the concept of multiple types of resilience, and the interplay between genetic, sex, and psychological factors in shaping the affective response to different types of stressors.

Growth regulation by apyrases: Insights from altering their expression level in different organisms.

Apyrase (APY) enzymes are nucleoside triphosphate (NTP) diphosphohydrolases that can remove the terminal phosphate from NTPs and nucleoside diphosphates but not from nucleoside monophosphates. They have conserved structures and functions in yeast, plants, and animals. Among the most studied APYs in plants are those in Arabidopsis (Arabidopsis thaliana; AtAPYs) and pea (Pisum sativum; PsAPYs), both of which have been shown to play major roles in regulating plant growth and development. Valuable insights on their functional roles have been gained by transgenically altering their transcript abundance, either by constitutively expressing or suppressing APY genes. This review focuses on recent studies that have provided insights on the mechanisms by which APY activity promotes growth in different organisms. Most of these studies have used transgenic lines that constitutively expressed APY in multiple different plants and in yeast. As APY enzymatic activity can also be changed post-translationally by chemical blockage, this review also briefly covers studies that used inhibitors to suppress APY activity in plants and fungi. It concludes by summarizing some of the main unanswered questions about how APYs regulate plant growth and proposes approaches to answering them.

Poly-2-methyl-2-oxazoline-modified bioprosthetic heart valve leaflets have enhanced biocompatibility and resist structural degeneration.

Bioprosthetic heart valves (BHV) fabricated from glutaraldehyde-fixed heterograft tissue, such as bovine pericardium (BP), are widely used for treating heart valve disease, a group of disorders that affects millions. Structural valve degeneration (SVD) of BHV due to both calcification and the accumulation of advanced glycation end products (AGE) with associated serum proteins limits durability. We hypothesized that BP modified with poly-2-methyl-2-oxazoline (POZ) to inhibit protein entry would demonstrate reduced accumulation of AGE and serum proteins, mitigating SVD. In vitro studies of POZ-modified BP demonstrated reduced accumulation of serum albumin and AGE. BP-POZ in vitro maintained collagen microarchitecture per two-photon microscopy despite AGE incubation, and in cell culture studies was associated with no change in tumor necrosis factor-α after exposure to AGE and activated macrophages. Comparing POZ and polyethylene glycol (PEG)-modified BP in vitro, BP-POZ was minimally affected by oxidative conditions, whereas BP-PEG was susceptible to oxidative deterioration. In juvenile rat subdermal implants, BP-POZ demonstrated reduced AGE formation and serum albumin infiltration, while calcification was not inhibited. However, BP-POZ rat subdermal implants with ethanol pretreatment demonstrated inhibition of both AGE accumulation and calcification. Ex vivo laminar flow studies with human blood demonstrated BP-POZ enhanced thromboresistance with reduced white blood cell accumulation. We conclude that SVD associated with AGE and serum protein accumulation can be mitigated through POZ functionalization that both enhances biocompatibility and facilitates ethanol pretreatment inhibition of BP calcification.

Leaflet modification before transcatheter aortic valve implantation in patients at risk for coronary obstruction: the ShortCut study.

BACKGROUND AND AIMS: This trial sought to assess the safety and efficacy of ShortCut, the first dedicated leaflet modification device, prior to transcatheter aortic valve implantation (TAVI) in patients at risk for coronary artery obstruction. METHODS: This pivotal prospective study enrolled patients with failed bioprosthetic aortic valves scheduled to undergo TAVI and were at risk for coronary artery obstruction. The primary safety endpoint was procedure-related mortality or stroke at discharge or 7 days, and the primary efficacy endpoint was per-patient leaflet splitting success. Independent angiographic, echocardiographic, and computed tomography core laboratories assessed all images. Safety events were adjudicated by a clinical events committee and data safety monitoring board. RESULTS: Sixty eligible patients were treated (77.0 ± 9.6 years, 70% female, 96.7% failed surgical bioprosthetic valves, 63.3% single splitting and 36.7% dual splitting) at 22 clinical sites. Successful leaflet splitting was achieved in all (100%; 95% confidence interval [CI] 94-100.0%, p<0.001) patients. Procedure time, including imaging confirmation of leaflet splitting, was 30.6 ± 17.9 min. Freedom from the primary safety endpoint was achieved in 59 (98.3%; 95% CI [91.1-100%]) patients, with no mortality and one (1.7%) disabling stroke. At 30 days, freedom from coronary obstruction was 95% (95% CI 86.1-99.0%). Within 90 days, freedom from mortality was 95% (95% CI 86.1-99.0%]), without any cardiovascular deaths. CONCLUSIONS: Modification of failed bioprosthetic aortic valve leaflets using ShortCut was safe, achieved successful leaflet splitting in all patients, and was associated with favorable clinical outcomes in patients at risk for coronary obstruction undergoing TAVI.

Is the assessment of asthma treatment efficacy sufficiently comprehensive?

The goal of asthma guideline therapy is to achieve disease control, by minimizing impairment and decreasing the risk of exacerbations and adverse effects of the disease and its treatment. The primary objective of most clinical trials of biologics for severe asthma is a reduction in exacerbation rate. Recently, studies with patients at the lower guideline steps have also selected exacerbation reduction as a primary objective. These trials in patients with milder disease frequently demonstrate statistically significantly fewer exacerbations, but their power calculations reflect larger sample size and smaller effect size. Exacerbations have a precise consensus definition, although a minimal clinically important difference has not been established. Reduction of exacerbations in severe asthma is commonly 10-fold greater than in mild disease. Further, reduction in exacerbations is not always associated with reduced impairment. If superior control is the objective, both domains should demonstrate consistent and parallel improvement. The disconnect may reflect the need for alternative tools for measurement of impairment or, possibly, different therapeutic mechanisms of action. Determining response to biologics or discussion of disease remission requires assessing symptoms that may occur daily rather than focusing on exacerbations that occur once or twice a year for patients at the highest steps of care according to the guidelines.

Effect of Selective Lesions of Nucleus Accumbens µ-Opioid Receptor-Expressing Cells on Heroin Self-Administration in Male and Female Rats: A Study with Novel Oprm1-Cre Knock-in Rats.

The brain µ-opioid receptor (MOR) is critical for the analgesic, rewarding, and addictive effects of opioid drugs. However, in rat models of opioid-related behaviors, the circuit mechanisms of MOR-expressing cells are less known because of a lack of genetic tools to selectively manipulate them. We introduce a CRISPR-based Oprm1-Cre knock-in transgenic rat that provides cell type-specific genetic access to MOR-expressing cells. After performing anatomic and behavioral validation experiments, we used the Oprm1-Cre knock-in rats to study the involvement of NAc MOR-expressing cells in heroin self-administration in male and female rats. Using RNAscope, autoradiography, and FISH chain reaction (HCR-FISH), we found no differences in Oprm1 expression in NAc, dorsal striatum, and dorsal hippocampus, or MOR receptor density (except dorsal striatum) or function between Oprm1-Cre knock-in rats and wildtype littermates. HCR-FISH assay showed that iCre is highly coexpressed with Oprm1 (95%-98%). There were no genotype differences in pain responses, morphine analgesia and tolerance, heroin self-administration, and relapse-related behaviors. We used the Cre-dependent vector AAV1-EF1a-Flex-taCasp3-TEVP to lesion NAc MOR-expressing cells. We found that the lesions decreased acquisition of heroin self-administration in male Oprm1-Cre rats and had a stronger inhibitory effect on the effort to self-administer heroin in female Oprm1-Cre rats. The validation of an Oprm1-Cre knock-in rat enables new strategies for understanding the role of MOR-expressing cells in rat models of opioid addiction, pain-related behaviors, and other opioid-mediated functions. Our initial mechanistic study indicates that lesioning NAc MOR-expressing cells had different effects on heroin self-administration in male and female rats.SIGNIFICANCE STATEMENT The brain µ-opioid receptor (MOR) is critical for the analgesic, rewarding, and addictive effects of opioid drugs. However, in rat models of opioid-related behaviors, the circuit mechanisms of MOR-expressing cells are less known because of a lack of genetic tools to selectively manipulate them. We introduce a CRISPR-based Oprm1-Cre knock-in transgenic rat that provides cell type-specific genetic access to brain MOR-expressing cells. After performing anatomical and behavioral validation experiments, we used the Oprm1-Cre knock-in rats to show that lesioning NAc MOR-expressing cells had different effects on heroin self-administration in males and females. The new Oprm1-Cre rats can be used to study the role of brain MOR-expressing cells in animal models of opioid addiction, pain-related behaviors, and other opioid-mediated functions.

Methylome-proteome integration after late-life voluntary exercise training reveals regulation and target information for improved skeletal muscle health.

Exercise is a potent stimulus for combatting skeletal muscle ageing. To study the effects of exercise on muscle in a preclinical setting, we developed a combined endurance-resistance training stimulus for mice called progressive weighted wheel running (PoWeR). PoWeR improves molecular, biochemical, cellular and functional characteristics of skeletal muscle and promotes aspects of partial epigenetic reprogramming when performed late in life (22-24 months of age). In this investigation, we leveraged pan-mammalian DNA methylome arrays and tandem mass-spectrometry proteomics in skeletal muscle to provide detailed information on late-life PoWeR adaptations in female mice relative to age-matched sedentary controls (n = 7-10 per group). Differential CpG methylation at conserved promoter sites was related to transcriptional regulation genes as well as Nr4a3, Hes1 and Hox genes after PoWeR. Using a holistic method of -omics integration called binding and expression target analysis (BETA), methylome changes were associated with upregulated proteins related to global and mitochondrial translation after PoWeR (P = 0.03). Specifically, BETA implicated methylation control of ribosomal, mitoribosomal, and mitochondrial complex I protein abundance after training. DNA methylation may also influence LACTB, MIB1 and UBR4 protein induction with exercise - all are mechanistically linked to muscle health. Computational cistrome analysis predicted several transcription factors including MYC as regulators of the exercise trained methylome-proteome landscape, corroborating prior late-life PoWeR transcriptome data. Correlating the proteome to muscle mass and fatigue resistance revealed positive relationships with VPS13A and NPL levels, respectively. Our findings expose differential epigenetic and proteomic adaptations associated with translational regulation after PoWeR that could influence skeletal muscle mass and function in aged mice. KEY POINTS: Late-life combined endurance-resistance exercise training from 22-24 months of age in mice is shown to improve molecular, biochemical, cellular and in vivo functional characteristics of skeletal muscle and promote aspects of partial epigenetic reprogramming and epigenetic age mitigation. Integration of DNA CpG 36k methylation arrays using conserved sites (which also contain methylation ageing clock sites) with exploratory proteomics in skeletal muscle extends our prior work and reveals coordinated and widespread regulation of ribosomal, translation initiation, mitochondrial ribosomal (mitoribosomal) and complex I proteins after combined voluntary exercise training in a sizeable cohort of female mice (n = 7-10 per group and analysis). Multi-omics integration predicted epigenetic regulation of serine ß-lactamase-like protein (LACTB - linked to tumour resistance in muscle), mind bomb 1 (MIB1 - linked to satellite cell and type 2 fibre maintenance) and ubiquitin protein ligase E3 component N-recognin 4 (UBR4 - linked to muscle protein quality control) after training. Computational cistrome analysis identified MYC as a regulator of the late-life training proteome, in agreement with prior transcriptional analyses. Vacuolar protein sorting 13 homolog A (VPS13A) was positively correlated to muscle mass, and the glycoprotein/glycolipid associated sialylation enzyme N-acetylneuraminate pyruvate lyase (NPL) was associated to in vivo muscle fatigue resistance.

The Association of ACGME Milestones With Performance on American Board of Surgery Assessments: A National Investigation of Surgical Trainees.

OBJECTIVE: To determine the relationship between, and predictive utility of, milestone ratings and subsequent American Board of Surgery (ABS) vascular surgery in-training examination (VSITE), vascular qualifying examination (VQE), and vascular certifying examination (VCE) performance in a national cohort of vascular surgery trainees. BACKGROUND: Specialty board certification is an important indicator of physician competence. However, predicting future board certification examination performance during training continues to be challenging. METHODS: This is a national longitudinal cohort study examining relational and predictive associations between Accreditation Council for Graduate Medical Education (ACGME) Milestone ratings and performance on VSITE, VQE, and VCE for all vascular surgery trainees from 2015 to 2021. Predictive associations between milestone ratings and VSITE were conducted using cross-classified random-effects regression. Cross-classified random-effects logistic regression was used to identify predictive associations between milestone ratings and VQE and VCE. RESULTS: Milestone ratings were obtained for all residents and fellows(n=1,118) from 164 programs during the study period (from July 2015 to June 2021), including 145,959 total trainee assessments. Medical knowledge (MK) and patient care (PC) milestone ratings were strongly predictive of VSITE performance across all postgraduate years (PGYs) of training, with MK ratings demonstrating a slightly stronger predictive association overall (MK coefficient 17.26 to 35.76, ß = 0.15 to 0.23). All core competency ratings were predictive of VSITE performance in PGYs 4 and 5. PGY 5 MK was highly predictive of VQE performance [OR 4.73, (95% CI, 3.87-5.78), P <0.001]. PC subcompetencies were also highly predictive of VQE performance in the final year of training [OR 4.14, (95% CI, 3.17-5.41), P <0.001]. All other competencies were also significantly predictive of first-attempt VQE pass with ORs of 1.53 and higher. PGY 4 ICS ratings [OR 4.0, (95% CI, 3.06-5.21), P <0.001] emerged as the strongest predictor of VCE first-attempt pass. Again, all subcompetency ratings remained significant predictors of first-attempt pass on CE with ORs of 1.48 and higher. CONCLUSIONS: ACGME Milestone ratings are highly predictive of future VSITE performance, and first-attempt pass achievement on VQE and VCE in a national cohort of surgical trainees.

Positive modulation of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors differentially alters spatial learning and memory in juvenile rats younger and older than three weeks.

Remarkable performance improvements occur at the end of the third postnatal week in rodents tested in various tasks that require navigation according to spatial context. While alterations in hippocampal function at least partially subserve this cognitive advancement, physiological explanations remain incomplete. Previously, we discovered that developmental modifications to hippocampal glutamatergic α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors in juvenile rats was related to more mature spontaneous alternation behavior in a symmetrical Y-maze. Moreover, a positive allosteric modulator of AMPA receptors enabled immature rats to alternate at rates seen in older animals, suggesting an excitatory synaptic limitation to hippocampal maturation. We then validated the Barnes maze for juvenile rats in order to test the effects of positive AMPA receptor modulation on a goal-directed spatial memory task. Here we report the effects of the AMPA receptor modulator, CX614, on spatial learning and memory in the Barnes maze. Similar to our prior report, animals just over 3 weeks of age display substantial improvements in learning and memory performance parameters compared to animals just under 3 weeks of age. A moderate dose of CX614 enabled immature animals to move more directly to the goal location, but only after 1 day of training. This performance improvement was observed on the second day of training with drug delivery or during a memory probe trial performed without drug delivery after the second day of training. Higher doses created more search errors, especially in more mature animals. Overall, CX614 provided modest performance benefits for immature rats in a goal-directed spatial memory task.

The pudendal syndrome: A photo essay of nerve compression damage visualized at neurolysis in patients with chronic neuropathic pelvic pain.

AIMS: (1) To use intraoperative photographs to visualize and explain pudendal nerve compressions and anatomical variations of compression sites in patients with chronic pelvic pain. (2) To emphasize the diagnostic importance of sensory examination with a safety pin at the six pudendal nerve branches in all patients with chronic pelvic pain; the dorsal nerves (penis or clitoris; the perineal nerves; and the inferior rectal nerves). METHODS: Between 2003 and 2014, "definite" pudendal neuropathy was diagnosed by examination and with two neurophysiologic tests. Neurolysis, via a transgluteal approach, was recommended only after 14 weeks of conservative care failed to adequately improve symptoms and validated symptom scores. Photographs of surgical findings were culled for their educational impact. An illustration of each photo clarifies the surgical anatomy. RESULTS: The transgluteal incision permits access to pudendal anatomy and compression sites from the subpiriformis area through the interligamentary space and the pudendal canal (Alcock canal). Compressions were acquired or congenital and severity varied significantly. Pinprick sensory testing diagnoses pudendal neuropathy in 92% of both genders. Mid-nerve compression occurred commonly between the sacrotuberous and sacrospinous ligaments less frequently in the Alcock canal, but also at aberrant pathways, for example, between layers of the sacrotuberous ligament; a separate inferior rectal nerve passing through the sacrospinous ligament; at an anomalous lateral pathway posterior to the ischial spine. The results of international surgeons are discussed. CONCLUSIONS: Decompression surgery was recommended in approximately 35% of patients in this practice, when pudendal neuropathy (pudendal syndrome), did not respond to two conservative levels of treatment: (1) nerve protection and medications and, (2) a series of three pudendal nerve perineural injections given at 4-week intervals. Significant nerve compression is consistently observed. Pathophysiology includes axonopathy from ischemia and demyelination. Neuropathy is readily diagnosed using a pinprick sensory examination of six pudendal nerve branches. Monitoring with the National Institutes of Health Chronic Prostatitis Symptom Index records cures >13 years.

Medical competence as a multilayered construct.

BACKGROUND: The conceptualisation of medical competence is central to its use in competency-based medical education. Calls for 'fixed standards' with 'flexible pathways', recommended in recent reports, require competence to be well defined. Making competence explicit and measurable has, however, been difficult, in part due to a tension between the need for standardisation and the acknowledgment that medical professionals must also be valued as unique individuals. To address these conflicting demands, a multilayered conceptualisation of competence is proposed, with implications for the definition of standards and approaches to assessment. THE MODEL: Three layers are elaborated. This first is a core layer of canonical knowledge and skill, 'that, which every professional should possess', independent of the context of practice. The second layer is context-dependent knowledge, skill, and attitude, visible through practice in health care. The third layer of personalised competence includes personal skills, interests, habits and convictions, integrated with one's personality. This layer, discussed with reference to Vygotsky's concept of Perezhivanie, cognitive load theory, self-determination theory and Maslow's 'self-actualisation', may be regarded as the art of medicine. We propose that fully matured professional competence requires all three layers, but that the assessment of each layer is different. IMPLICATIONS: The assessment of canonical knowledge and skills (Layer 1) can be approached with classical psychometric conditions, that is, similar tests, circumstances and criteria for all. Context-dependent medical competence (Layer 2) must be assessed differently, because conditions of assessment across candidates cannot be standardised. Here, multiple sources of information must be merged and intersubjective expert agreement should ground decisions about progression and level of clinical autonomy of trainees. Competence as the art of medicine (Layer 3) cannot be standardised and should not be assessed with the purpose of permission to practice. The pursuit of personal excellence in this level, however, can be recognised and rewarded.

Acoustic Activation Imaging With Intravenous Perfluoropropane Nanodroplets Results in Selective Bioactivation of the Risk Area.

BACKGROUND: Acoustically activatable perfluoropropane droplets (PD) can be formulated from commercially available microbubble preparations. Diagnostic transthoracic ultrasound frequencies have resulted in acoustic activation (AA) predominately within myocardial infarct zones (IZ). OBJECTIVE: We hypothesized that the AA area following acute coronary ischemia/reperfusion (I/R) would selectively enhance the developing scar zone, and target bioeffects specifically to this region. METHODS: We administered intravenous PD in 36 rats and 20 pigs at various stages of myocardial scar formation (30 minutes, 1 day, and 7 days post I/R) to determine what effect infarct age had on the AA within the IZ. This was correlated with histology, myeloperoxidase activity, and tissue nitrite activity. RESULTS: The degree of AA within the IZ in rats was not associated with collagen content, neutrophil infiltration, or infarct age. AA within 24 hours of I/R was associated with increased nitric oxide utilization selectively within the IZ (P < .05 compared with remote zone). The spatial extent of AA in pigs correlated with infarct size only when performed before sacrifice at 7 days (r = .74, P < .01). CONCLUSIONS: Acoustic activation of intravenous PD enhances the developing scar zone following I/R, and results in selective tissue nitric oxide utilization.

Alternating the population and control neural networks to solve high-dimensional stochastic mean-field games.

We present APAC-Net, an alternating population and agent control neural network for solving stochastic mean-field games (MFGs). Our algorithm is geared toward high-dimensional instances of MFGs that are not approachable with existing solution methods. We achieve this in two steps. First, we take advantage of the underlying variational primal-dual structure that MFGs exhibit and phrase it as a convex-concave saddle-point problem. Second, we parameterize the value and density functions by two neural networks, respectively. By phrasing the problem in this manner, solving the MFG can be interpreted as a special case of training a generative adversarial network (GAN). We show the potential of our method on up to 100-dimensional MFG problems.

Treating asthma in the time of COVID.

The Precision Interventions for Severe and/or Exacerbation-Prone Asthma clinical trials network is actively assessing novel treatments for severe asthma during the coronavirus disease (COVID-19) pandemic and has needed to adapt to various clinical dilemmas posed by the COVID-19 pandemic. Pharmacologic interactions between established asthma therapies and novel drug interventions for COVID-19 infection, including antivirals, biologics, and vaccines, have emerged as a critical and unanticipated issue in the clinical care of asthma. In particular, impaired metabolism of some long-acting beta-2 agonists by the cytochrome P4503A4 enzyme in the setting of antiviral treatment using ritonavir-boosted nirmatrelvir (NVM/r, brand name Paxlovid) may increase risk for adverse cardiovascular events. Although available data have documented the potential for such interactions, these issues are largely unappreciated by clinicians who treat asthma, or those dispensing COVID-19 interventions in patients who happen to have asthma. Because these drug-drug interactions have not previously been relevant to patient care, clinicians have had no guidance on management strategies to reduce potentially serious interactions between treatments for asthma and COVID-19. The Precision Interventions for Severe and/or Exacerbation-Prone Asthma network considered the available literature and product information, and herein share our considerations and plans for treating asthma within the context of these novel COVID-19-related therapies.