Rapid emergence of latent knowledge in the sensory cortex drives learning.

Rapid learning confers significant advantages to animals in ecological environments. Despite the need for speed, animals appear to only slowly learn to associate rewarded actions with predictive cues1-4. This slow learning is thought to be supported by a gradual expansion of predictive cue representation in the sensory cortex2,5. However, evidence is growing that animals learn more rapidly than classical performance measures suggest6-8, challenging the prevailing model of sensory cortical plasticity. Here, we investigated the relationship between learning and sensory cortical representations. We trained mice on an auditory go/no-go task that dissociated the rapid acquisition of task contingencies (learning) from its slower expression (performance)7. Optogenetic silencing demonstrated that the auditory cortex (AC) drives both rapid learning and slower performance gains but becomes dispensable at expert. Rather than enhancement or expansion of cue representations9, two-photon calcium imaging of AC excitatory neurons throughout learning revealed two higher-order signals that were causal to learning and performance. First, a reward prediction (RP) signal emerged rapidly within tens of trials, was present after action-related errors only early in training, and faded at expert levels. Strikingly, silencing at the time of the RP signal impaired rapid learning, suggesting it serves an associative and teaching role. Second, a distinct cell ensemble encoded and controlled licking suppression that drove the slower performance improvements. These two ensembles were spatially clustered but uncoupled from underlying sensory representations, indicating a higher-order functional segregation within AC. Our results reveal that the sensory cortex manifests higher-order computations that separably drive rapid learning and slower performance improvements, reshaping our understanding of the fundamental role of the sensory cortex.

Revealing Fermi surface evolution and Berry curvature in an ideal type-II Weyl semimetal.

In type-II Weyl semimetals (WSMs), the tilting of the Weyl cones leads to the coexistence of electron and hole pockets that touch at the Weyl nodes. These electrons and holes experience the Berry curvature generated by the Weyl nodes, leading to an anomalous Hall effect that is highly sensitive to the Fermi level position. Here we have identified field-induced ferromagnetic MnBi2-xSbxTe4 as an ideal type-II WSM with a single pair of Weyl nodes. By employing a combination of quantum oscillations and high-field Hall measurements, we have resolved the evolution of Fermi-surface sections as the Fermi level is tuned across the charge neutrality point, precisely matching the band structure of an ideal type-II WSM. Furthermore, the anomalous Hall conductivity exhibits a heartbeat-like behavior as the Fermi level is tuned across the Weyl nodes, a feature of type-II WSMs that was long predicted by theory. Our work uncovers a large free carrier contribution to the anomalous Hall effect resulting from the unique interplay between the Fermi surface and diverging Berry curvature in magnetic type-II WSMs.

Immunotherapy Efficacy in Advanced Hepatocellular Carcinoma in a Diverse and Underserved Population in the United States.

Background :   Incidence of hepatocellular cancer (HCC) in the Bronx is 61% higher than the rest of New York State. Underserved populations are not well represented in clinical trials of immune checkpoint inhibitors (ICI). Methods: Demographics were tabulated for 194 patients treated with ICI at the Montefiore-Einstein Comprehensive Cancer Center (MECCC) between 2017 and 2022. Categorical variables were analyzed by Chi-squared test, and survival was analyzed using Kaplan-Meier (KM) curves. Results: MECCC patients were 40.7% Hispanic and 20.6% Black, compared with 3% and 2%, respectively, in the landmark IMbrave 150 study. Median overall survival (mOS) on ICI was 9.0 months, 25.0 months for the 100 (51.5%) favorable-prognosis Child Pugh A (CPA) patients included in HCC clinical trials. Disease control rate (DCR) was 58.5% among 123 evaluable patients per mRECIST 1.1. Baseline liver function, as defined by CP and the Model for End-Stage Liver Disease-Sodium (MELD-Na), correlated with survival (p < 0.001). Hepatitis C Virus (HCV) and alcoholism were over-represented relative to National Cancer Institute (NCI) data (56.2% vs 4.7% and 38.7% vs 8.2%, respectively). HCV treatment correlated with prolonged survival in infected patients (p = 0.0017). AFP decline correlated with response (p = 0.001). Hispanic patients lived longer when clinical variables were controlled for (mOS 52 vs 23 months; p = 0.011). Conclusion: In an underserved HCC population, ICI yielded a DCR of 58.5% and low rates of severe toxicity. This work highlights ICI efficacy in minority groups, a need for earlier HCC diagnosis and for studies of genetic and environmental factors in Hispanics with HCC.

Persistent peritonitis in peritoneal dialysis: a comphrenesive review of recurrent, relapsing, refractory, and repeat peritonitis.

Peritonitis is a major cause of morbidity and technique failure in patients receiving peritoneal dialysis. Complicated peritonitis that manifests as multiple or unresolving episodes is classified as refractory, recurrent, relapsing, or repeat peritonitis, and often possesses higher risk of technique failure and mortality as well as lower complete cure rates than primary or uncomplicated episodes. While these peritonitis subtypes affect a considerable portion of PD patients, details regarding their epidemiology, pathogenesis, diagnosis, clinical sequelae, and management have not yet been fully elucidated. Improved clinical awareness and understanding of complicated peritonitis subtypes is crucial to ensure optimal management for these patients; thus, we consolidate and report the pertinent findings of recent literature on these four entities.

Correcting Temporal Inaccuracies in Labeled Training Data for Electromyographic Control Algorithms.

Electromyographic (EMG) control relies on supervised-learning algorithms that correlate EMG to motor intent. The quality of the training dataset is critical to the runtime performance of the algorithm, but labeling motor intent is imprecise and imperfect. Traditional EMG training data is collected while participants mimic predetermined movements of a virtual hand with their own hand. This assumes participants are perfectly synchronized with the predetermined movements, which is unlikely due to reaction time and signal-processing delays. Prior work has used cross-correlation to globally shift and re-align kinematic data and EMG. Here, we quantify the impact of this global re-alignment on both classification algorithms and regression algorithms with and without a human in the loop. We also introduce a novel trial-by-trial re-alignment method to re-align EMG with kinematics on a per-movement basis. We show that EMG and kinematic data are inherently misaligned, and that reaction time is inconsistent throughout data collection. Both global and trial-by-trial re-alignment significantly improved offline performance for classification and regression. Our trial-by-trial re-alignment further improved offline classification performance relative to global realignment. However, online performance, with a human actively in the loop, was no different with or without re-alignment. This work highlights inaccuracies in labeled EMG data and has broad implications for EMG-control applications.

Quality and Agreement With Scientific Consensus of ChatGPT Information Regarding Corneal Transplantation and Fuchs Dystrophy.

PURPOSE: ChatGPT is a commonly used source of information by patients and clinicians. However, it can be prone to error and requires validation. We sought to assess the quality and accuracy of information regarding corneal transplantation and Fuchs dystrophy from 2 iterations of ChatGPT, and whether its answers improve over time. METHODS: A total of 10 corneal specialists collaborated to assess responses of the algorithm to 10 commonly asked questions related to endothelial keratoplasty and Fuchs dystrophy. These questions were asked from both ChatGPT-3.5 and its newer generation, GPT-4. Assessments tested quality, safety, accuracy, and bias of information. Chi-squared, Fisher exact tests, and regression analyses were conducted. RESULTS: We analyzed 180 valid responses. On a 1 (A+) to 5 (F) scale, the average score given by all specialists across questions was 2.5 for ChatGPT-3.5 and 1.4 for GPT-4, a significant improvement (P < 0.0001). Most responses by both ChatGPT-3.5 (61%) and GPT-4 (89%) used correct facts, a proportion that significantly improved across iterations (P < 0.00001). Approximately a third (35%) of responses from ChatGPT-3.5 were considered against the scientific consensus, a notable rate of error that decreased to only 5% of answers from GPT-4 (P < 0.00001). CONCLUSIONS: The quality of responses in ChatGPT significantly improved between versions 3.5 and 4, and the odds of providing information against the scientific consensus decreased. However, the technology is still capable of producing inaccurate statements. Corneal specialists are uniquely positioned to assist users to discern the veracity and application of such information.

Changes in alpha, theta, and gamma oscillations in distinct cortical areas are associated with altered acute pain responses in chronic low back pain patients.

Introduction: Chronic pain negatively impacts a range of sensory and affective behaviors. Previous studies have shown that the presence of chronic pain not only causes hypersensitivity at the site of injury but may also be associated with pain-aversive experiences at anatomically unrelated sites. While animal studies have indicated that the cingulate and prefrontal cortices are involved in this generalized hyperalgesia, the mechanisms distinguishing increased sensitivity at the site of injury from a generalized site-nonspecific enhancement in the aversive response to nociceptive inputs are not well known. Methods: We compared measured pain responses to peripheral mechanical stimuli applied to a site of chronic pain and at a pain-free site in participants suffering from chronic lower back pain (n = 15) versus pain-free control participants (n = 15) by analyzing behavioral and electroencephalographic (EEG) data. Results: As expected, participants with chronic pain endorsed enhanced pain with mechanical stimuli in both back and hand. We further analyzed electroencephalographic (EEG) recordings during these evoked pain episodes. Brain oscillations in theta and alpha bands in the medial orbitofrontal cortex (mOFC) were associated with localized hypersensitivity, while increased gamma oscillations in the anterior cingulate cortex (ACC) and increased theta oscillations in the dorsolateral prefrontal cortex (dlPFC) were associated with generalized hyperalgesia. Discussion: These findings indicate that chronic pain may disrupt multiple cortical circuits to impact nociceptive processing.

Peritoneal dialysis in the setting of acute brain injury: an underappreciated modality.

INTRODUCTION: Dialysis is complicated in the setting of acute brain injury (ABI) due to several factors including acute solute shifts, acid base changes, need for anticoagulation, and changes in intracranial pressure. For these reasons, continuous renal replacement therapy (CRRT) is often the chosen modality for renal replacement needs in these patients. Peritoneal dialysis (PD) is less discussed but shares many of the benefits often attributed to CRRT. We describe, from both nephrology and neurosurgical perspectives, a case successfully managed with PD. CASE: A 25-year-old male with history of end-stage kidney disease (ESKD) secondary to focal segmental glomerulosclerosis on continuous cycling PD for 5 years presented to the hospital with headache and altered mental status. Initial imaging revealed a large intraventricular hemorrhage extending to the fourth ventricle. He underwent an emergent right depressive hemicraniectomy and clot evacuation. Post-operative imaging revealed worsening cerebral edema, intraventricular hemorrhage, and hydrocephalus. The decision was made to continue PD, noting that it retains many of the benefits of CRRT (which it is in fact, a form of) which he tolerated well until the need for a percutaneous gastrostomy tube arose. He was transiently transitioned to hemodialysis but returned to PD once his gastrostomy healed. He continued PD for 1 year without complication and eventually received a kidney transplant. DISCUSSION: In managing patients with ABI undergoing dialysis, a number of considerations must be undertaken including avoidance of hypotension to maintain cerebral perfusion pressure and minimize ischemia reperfusion injury, avoidance of anticoagulants that can precipitate or worsen bleeding, the potential for cerebral edema due to rapid solute clearance and osmotic dissipation of therapeutic hypernatremia, and the mitigation of intracellular acidosis from bicarbonate delivery. Although underutilized, PD may potentially serve as a viable option for dialysis in the setting of ABI as demonstrated by the case presented.

Machine learning prediction of COVID-19 severity levels from salivaomics data.

The clinical spectrum of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the strain of coronavirus that caused the COVID-19 pandemic, is broad, extending from asymptomatic infection to severe immunopulmonary reactions that, if not categorized properly, may be life-threatening. Researchers rate COVID-19 patients on a scale from 1 to 8 according to the severity level of COVID-19, 1 being healthy and 8 being extremely sick, based on a multitude of factors including number of clinic visits, days since the first sign of symptoms, and more. However, there are two issues with the current state of severity level designation. Firstly, there exists variation among researchers in determining these patient scores, which may lead to improper treatment. Secondly, researchers use a variety of metrics to determine patient severity level, including metrics involving plasma collection that require invasive procedures. This project aims to remedy both issues by introducing a machine learning framework that unifies severity level designations based on noninvasive saliva biomarkers. Our results show that we can successfully use machine learning on salivaomics data to predict the severity level of COVID-19 patients, indicating the presence of viral load using saliva biomarkers.

Impact of medical school responses during the COVID-19 pandemic on student satisfaction: a nationwide survey of US medical students.

PURPOSE: Medical schools have faced various challenges in preparing their clinical students for the frontlines of a pandemic. This study investigated medical students' satisfaction with their institutions during the coronavirus disease 2019 (COVID-19) pandemic with the intention of guiding educators in future public health crises. METHODS: In this cross-sectional study surveying students in clinical rotations, the primary outcome was overall satisfaction regarding medical schools' responses to the pandemic, and the four secondary outcomes were school communication, exposure to COVID-19, availability of personal protective equipment, and access to COVID-19 testing. RESULTS: The survey was distributed to ten medical schools, of which 430 students responded for a response rate of 13.0%. While most students were satisfied (61.9%, n=266) with their schools' response, more than one in five (21.9%, n=94) were dissatisfied. Among the four secondary outcomes, communication with students was most predictive of overall satisfaction. CONCLUSION: In future crises, schools can best improve student satisfaction by prioritizing timely communication.

Response of the ENPP1-Deficient Skeletal Phenotype to Oral Phosphate Supplementation and/or Enzyme Replacement Therapy: Comparative Studies in Humans and Mice.

Inactivating mutations in human ecto-nucleotide pyrophosphatase/phosphodiesterase-1 (ENPP1) may result in early-onset osteoporosis (EOOP) in haploinsufficiency and autosomal recessive hypophosphatemic rickets (ARHR2) in homozygous deficiency. ARHR2 patients are frequently treated with phosphate supplementation to ameliorate the rachitic phenotype, but elevating plasma phosphorus concentrations in ARHR2 patients may increase the risk of ectopic calcification without increasing bone mass. To assess the risks and efficacy of conventional ARHR2 therapy, we performed comprehensive evaluations of ARHR2 patients at two academic medical centers and compared their skeletal and renal phenotypes with ENPP1-deficient Enpp1asj/asj mice on an acceleration diet containing high phosphate treated with recombinant murine Enpp1-Fc. ARHR2 patients treated with conventional therapy demonstrated improvements in rickets, but all adults and one adolescent analyzed continued to exhibit low bone mineral density (BMD). In addition, conventional therapy was associated with the development of medullary nephrocalcinosis in half of the treated patients. Similar to Enpp1asj/asj mice on normal chow and to patients with mono- and biallelic ENPP1 mutations, 5-week-old Enpp1asj/asj mice on the high-phosphate diet exhibited lower trabecular bone mass, reduced cortical bone mass, and greater bone fragility. Treating the Enpp1asj/asj mice with recombinant Enpp1-Fc protein between weeks 2 and 5 normalized trabecular bone mass, normalized or improved bone biomechanical properties, and prevented the development of nephrocalcinosis and renal failure. The data suggest that conventional ARHR2 therapy does not address low BMD inherent in ENPP1 deficiency, and that ENPP1 enzyme replacement may be effective for correcting low bone mass in ARHR2 patients without increasing the risk of nephrocalcinosis. © 2021 American Society for Bone and Mineral Research (ASBMR).

Small energy gap revealed in CrBr3 by scanning tunneling spectroscopy.

CrBr3 is a layered van der Waals material with magnetic ordering down to the 2D limit. For decades, based on optical measurements, it is believed that the energy gap of CrBr3 is in the range of 1.68-2.1 eV. However, controversial results have indicated that the band gap of CrBr3 is possibly smaller than that. An unambiguous determination of the energy gap is critical to the correct interpretations of the experimental results of CrBr3. Here, we present the scanning tunneling microscopy and spectroscopy (STM/S) results of CrBr3 thin and thick flakes exfoliated onto highly ordered pyrolytic graphite (HOPG) surfaces and density functional theory (DFT) calculations to reveal the small energy gap (peak-to-peak energy gap to be 0.57 ± 0.04 eV; or the onset signal energy gap to be 0.29 ± 0.05 eV from dI/dV spectra). Atomic resolution topography images show the defect-free crystal structure and the dI/dV spectra exhibit multiple peak features measured at 77 K. The conduction band - valence band peak pairs in the multi-peak dI/dV spectrum agree very well with all reported optical transitions. STM topography images of mono- and bi-layer CrBr3 flakes exhibit edge degradation due to short air exposure (∼15 min) during sample transfer. The unambiguously determined small energy gap settles the controversy and is the key in better understanding CrBr3 and similar materials.

Health research methodology education in Canadian emergency medicine residency programs: A national environmental scan.

OBJECTIVES: Our objective was to describe the variability of research methodology teaching among English-speaking Royal College of Physicians and Surgeons of Canada emergency medicine (RCPSC-EM) residency programs. We also aimed to identify barriers to teaching research methodology curricula. METHODS: An electronic survey was sent by email to program directors and residents of English-speaking RCPSC-EM training programs countrywide. Reminder emails were sent after two, four, and eight weeks. Quantitative, descriptive statistics were prepared, and qualitative data and themes were identified. RESULTS: We received a total of seven responses from the possible 12 program directors (response rate = 58.3%). Out of 354 potential resident respondents, 82 (23.2%) completed the survey. There was disparity between resident and program director responses with respect to the existence of curricula, preparation for Royal College exams, and usefulness for future practice. Barriers to teaching a research methodologies curriculum included lack of time, support, educated faculty, and finances. CONCLUSION: This survey demonstrates that Canadian EM residency programs vary with respect to research methodology curriculum, and discrepancies exist between residents' and program directors' perceptions of the curriculum. Given the lack of a standardized research methodology curriculum for these programs, there is an opportunity to improve training in research methodology.

OBJECTIFS: Notre objectif vise à décrire la variabilité de l'enseignement des méthodologies de la recherche entre les programmes anglophones de résidence en médecine d'urgence du Collège royal des médecins et chirurgiens du Canada (MU - CRMCC). Nous avions également pour but de déterminer les obstacles qui entravent l'enseignement des cursus de méthodologie de la recherche. MÉTHODES: On a transmis par courriel un sondage électronique aux directeurs de programme et résidents des programmes anglophones de formation MU - CRMCC dans tout le pays. Des courriels de rappel ont été envoyés après deux, quatre et huit semaines. On a ensuite préparé des statistiques descriptives quantitatives et identifié des données et thèmes qualitatifs. RÉSULTATS: Nous avons reçu un total de sept réponses des 12 directeurs de programme actuels (taux de réponse = 58,3 %). Quatre-vingt-deux des 354 résidents potentiels, soit 23,2 %, ont répondu au sondage. Nous avons relevé une disparité entre les réponses des résidents et celles des directeurs de programme en ce qui a trait à l'existence du cursus, la préparation en vue des examens du Collège royal et l'utilité dans la pratique future. Parmi les obstacles entravant l'enseignement des cursus de méthodologie de la recherche, on retrouvait le manque de temps, de soutien, de corps professoral qualifié et de fonds. CONCLUSION: Ce sondage démontre que les cursus de méthodologie de la recherche des programmes de résidence en médecine d'urgence varient dans l'ensemble du Canada et que des divergences existent entre le point de vue des résidents et celui des directeurs de programme sur ces cursus. Étant donné l'absence d'un cursus uniforme de méthodologie de la recherche pour ces programmes, ceci nous offre une occasion d'améliorer la formation en méthodologie de la recherche.

Investigation of Incidents and Trends of Antimicrobial Resistance in Foodborne Pathogens in Eight Countries from Historical Sample Data.

Antimicrobial resistance (AMR) causes millions of illnesses every year, threatening the success of lifesaving antibiotic therapy and, thus, public health. To examine the rise and spread of antimicrobial resistance around the world, our study performs a multivariate statistical analysis of antimicrobial resistance gene data from eight different countries: the US, the UK, China, Brazil, Mexico, Canada, Australia, and South Africa. Multi-dimensional data points were projected onto a two-dimensional plane using principal component analysis and organized into a dendrogram utilizing hierarchical clustering to identify significant AMR genes and pathogens. Outlier genes/pathogens were typically involved in high occurrences of antimicrobial resistance, and they were able to indicate the trend of antimicrobial resistance in the future. Statistical analysis of the data identified: (1) tet(A), aph(3'')-Ib, aph(6)-Id, blaEC, blaTEM-1, qacEdelta1, sul1, sul2, and aadA1 as the nine most common AMR genes among the studied countries; (2) Salmonella enterica and E. coli and Shigella as the most common AMR foodborne pathogens; and (3) chicken as the most prevalent meat carrier of antimicrobial resistance. Our study shows that the overall number of reported antimicrobial resistance cases in foodborne pathogens is generally rising. One potential contributing factor for this is the increasing antimicrobial usage in the growing livestock industry.

Validation of a power law model in upper extremity vessels: potential application in ultrasound bleed detection.

Vascular ultrasound can provide quick and reliable diagnosis of arterial bleeding but it requires trained and experienced personnel. Development of automated sonographic bleed detection methods would potentially be valuable for trauma management in the field. We propose a detection method that (1) measures blood flow in a trauma victim, (2) determines the victim's expected normal limb arterial flow using a power law biofluid model where flow is proportional to the vessel diameter taken to a power of k and (3) quantifies the difference between measured and expected flow with a novel metric, flow split deviation (FSD). FSD was devised to give a quantitative value for the likelihood of arterial bleeding and validated in human upper extremities. We used ultrasound to demonstrate that the power law with k = 2.75 appropriately described the normal brachial artery bifurcation geometry and adequately determined the expected normal flows. Our metric was then applied to three-dimensional (3-D) computational models of forearm bleeding and on dialysis patients undergoing surgical construction of wrist arteriovenous fistulas. Computational models showed that larger sized arterial defects produced larger flow deviations. FSD values were statistically higher (paired t-test) for arms with fistulas than those without, with average FSDs of 0.41 ± 0.12 and 0.047 ± 0.021 (mean ± SD), respectively. The average of the differences was 0.36 ± 0.12 (mean ± SD).

Scleral mechanics: comparing whole globe inflation and uniaxial testing.

The purpose of this study was to assess fundamental differences between the mechanics of the posterior sclera in paired eyes using uniaxial and whole globe inflation testing, with an emphasis on the relationship between testing conditions and observed tissue behavior. Twenty porcine eyes, consisting of matched pairs from 10 pigs, were used in this study. Within pairs, one eye was tested with 10 cycles of globe pressurization to 150 mmHg (∼10× normal IOP) while biaxial strains were tracked via an optical system at the posterior sclera. An excised posterior strip from the second eye was subjected to traditional uniaxial testing in which mechanical hysteresis was recorded from 10 cycles to a peak stress of 0.13 MPa (roughly equivalent to the circumferential wall stress produced by an IOP of 150 mmHg under the thin-walled pressure vessel assumption). For approximately equivalent loads, peak strains were more than twice as high in uniaxial tests than in inflation tests. Different trends in the load-deformation plots were seen between the tests, including an extended "toe" region in the uniaxial test, a generally steeper curve in the inflation tests, and reduced variability in the inflation tests. The unique opportunity of being able to mechanically load a whole globe under near physiologic conditions alongside a standard uniaxially tested specimen reveals the effects of testing artifacts relevant to most uniaxially tested soft tissues. Whole globe inflation offers testing conditions that significantly alter load-deformation behavior relative to uniaxial testing; consequently, laboratory studies of interventions or conditions that alter scleral mechanics may greatly benefit from these findings.