Monitoring day and dark traffic collisions in Toronto neighbourhoods with implications for injury reduction and Vision Zero initiatives: A spatial analysis approach.

The City of Toronto adopted a Vision Zero strategy in 2016 that aims to eliminate deaths and serious injuries from vehicular collisions. The strategy includes policies to improve lighting to reduce collision risks, and past research has suggested lighting as a road safety factor. We apply Bayesian spatial analysis (including Poisson log-normal regression modelling, shared component spatial modelling, and Bayesian spatiotemporal modelling) to publicly available data on traffic collisions where persons are killed or seriously injured (KSI) based on Day/Dark conditions. We assess (1) links between KSI risk and socioeconomic and built environment factors, (2) spatial distributions of relative Day & Dark KSI risk, and (3) area-specific trends in space and time for Day-Dark KSI risk change across Toronto neighbourhoods. Our analysis does not find significant associations between socioeconomic/built environment factors and KSI risk, but we uncover neighbourhoods with heightened Dark KSI risk and pronounced Day-Dark KSI changes compared to Toronto's mean area trend. Findings highlight the need for increased policy attention for impacts of lighting on collisions and provide insight for focus regions for improved Vision Zero policy development.

Multiparametric whole-body MRI of patients with neurofibromatosis type I: spectrum of imaging findings.

Neurofibromatosis (NF) type I is a neuroectodermal and mesodermal dysplasia caused by a mutation of the neurofibromin tumor suppressor gene. Phenotypic features of NF1 vary, and patients develop benign peripheral nerve sheath tumors and malignant neoplasms, such as malignant peripheral nerve sheath tumor, malignant melanoma, and astrocytoma. Multiparametric whole-body MR imaging (WBMRI) plays a critical role in disease surveillance. Multiparametric MRI, typically used in prostate imaging, is a general term for a technique that includes multiple sequences, i.e. anatomic, diffusion, and Dixon-based pre- and post-contrast imaging. This article discusses the value of multiparametric WBMRI and illustrates the spectrum of whole-body lesions of NF1 in a single imaging setting. Examples of lesions include those in the skin (tumors and axillary freckling), soft tissues (benign and malignant peripheral nerve sheath tumors, visceral plexiform, and diffuse lesions), bone and joints (nutrient nerve lesions, non-ossifying fibromas, intra-articular neurofibroma, etc.), spine (acute-angled scoliosis, dural ectasia, intraspinal tumors, etc.), and brain/skull (optic nerve glioma, choroid plexus xanthogranuloma, sphenoid wing dysplasia, cerebral hamartomas, etc.). After reading this article, the reader will gain knowledge of the variety of lesions encountered with NF1 and their WBMRI appearances. Timely identification of such lesions can aid in accurate diagnosis and appropriate patient management.

A Meta-Analysis of Surgical Outcomes in 25727 Patients Undergoing Anterior Cervical Discectomy and Fusion or Anterior Cervical Corpectomy and Fusion for Cervical Deformity.

STUDY DESIGN: Systematic Review. OBJECTIVES: To evaluate which cervical deformity correction technique between anterior cervical discectomy and fusion (ACDF) and anterior cervical corpectomy and fusion (ACCF) produces better clinical, radiographic, and operative outcomes. METHODS: We conducted a meta-analysis comparing studies involving ACDF and ACCF. Adult patients with either original or previously treated cervical spine deformities were included. Two independent reviewers categorized extracted data into clinical, radiographic, and operative outcomes, including complications. Clinical assessments included patient-reported outcomes; radiographic evaluations examined C2-C7 Cobb angle, T1 slope, T1-CL, C2-7 SVA, and graft stability. Surgical measures included surgery duration, blood loss, hospital stay, and complications. RESULTS: 26 studies (25727 patients) met inclusion criteria and were extracted. Of these, 14 studies (19077 patients) with low risk of bias were included in meta-analysis. ACDF and ACCF similarly improve clinical outcomes in terms of JOA and NDI, but ACDF is significantly better at achieving lower VAS neck scores. ACDF is also more advantageous for improving cervical lordosis and minimizing the incidence of graft complications. While there is no significant difference between approaches for most surgical complications, ACDF is favorable for reducing operative time, intraoperative blood loss, and length of hospital stay. CONCLUSIONS: While both techniques benefit cervical deformity patients, when both techniques are feasible, ACDF may be superior with respect to VAS neck scores, cervical lordosis, graft complications and certain perioperative outcomes. Further studies are recommended to address outcome variability and refine surgical approach selection.

Pedicle screw placement in the cervical vertebrae using augmented reality-head mounted displays: a cadaveric proof-of-concept study.

BACKGROUND: The accurate and safe positioning of cervical pedicle screws is crucial. While augmented reality (AR) use in spine surgery has previously demonstrated clinical utility in the thoracolumbar spine, its technical feasibility in the cervical spine remains less explored. PURPOSE: The objective of this study was to assess the precision and safety of AR-assisted pedicle screw placement in the cervical spine. STUDY DESIGN: In this experimental study, five cadaveric cervical spine models were instrumented from C3 to C7 by five different spine surgeons. The navigation accuracy and clinical screw accuracy were evaluated. METHODS: Post-procedural CT scans were evaluated for clinical accuracy by two independent neuroradiologists using the Gertzbein-Robbins scale. Technical precision was assessed by calculating the angular trajectory (°) and linear screw tip (mm) deviations in the axial and sagittal planes from the virtual pedicle screw position as recorded by the AR-guided platform during the procedure compared to the actual pedicle screw position derived from post-procedural imaging. RESULTS: A total of forty-one pedicle screws were placed in five cervical cadavers, with each of the five surgeons navigating at least seven screws. Gertzbein-Robbins grade of A or B was achieved in 100% of cases. The mean values for tip and trajectory errors in the axial and sagittal planes between the virtual versus actual position of the screws was less than 3 mm and 30°, respectively (p<0.05). None of the cervical screws violated the cortex by more than 2 mm or displaced neurovascular structures. CONCLUSIONS: AR-assisted cervical pedicle screw placement in cadavers demonstrated clinical accuracy comparable to existing literature values for image-guided navigation methods for the cervical spine. CLINICAL SIGNIFICANCE: This study provides technical and clinical accuracy data that supports clinical trialing of AR-assisted subaxial cervical pedicle screw placement.

Assessing Sarcoma Awareness Among the General Population in Minnesota: A Cross-Sectional Survey Study from the Minnesota State Fair in 2015 and 2022.

Sarcomas are commonly misdiagnosed, and treatment delays negatively impact patient outcomes. The purpose of this study is to explore patient threshold for and timeline to medical evaluation, to identify providers most likely to be contacted first, and to assess general sarcoma knowledge in Minnesota's general population. Voluntary participants were recruited at the 2015 and 2022 Minnesota State Fair to complete a three-part survey. Part 1 assessed evaluation timeline and provider choice, part 2 evaluated sarcoma knowledge via a ten-question survey, and part 3 documented demographics. Responses were electronically recorded, and results were tabulated. Overall, 2124 participants completed some or all of the survey. Part 1: Participants indicated they would seek more urgent treatment for a painful mass compared to a non-painful mass (p < 0.001). The majority (77%) of participants indicated a family medicine physician would be their first contact for painful and non-painful masses. Part 2: There was no difference in overall score (percent correct) when comparing results from 2015 (mean = 40%) to 2022 (mean = 42%) (p = 0.183). Overall, 16% (349/2117) of participants had no correct responses. Individuals who self-identified as Hispanic or Latino ethnicity and a non-White race performed worse (p < 0.001). In general, scores improved with increased education and those with a graduate or professional degree had an estimated 2.515-point increase in score compared to participants with some high school education or high school diploma/general education diploma (p < 0.001). Participants with a healthcare background scored better (p < 0.001). Pain is a driving factor for patient-initiated evaluation, and primary care providers are the most likely first contact for patients. General sarcoma awareness remains low, even among those with advanced degrees and healthcare experience. Ongoing educational efforts are warranted for both the general public and healthcare communities in Minnesota.

Development of 3'-Deoxy-3',4'-didehydro-nucleoside Prodrug Inhibitors of West Nile and Zika Viruses.

The antiviral enzyme viperin catalyzes the formation of 3'-deoxy-3',4'-didehydro-cytidine-5'-triphosphate (ddhCTP). ddhCTP is incorporated into viral genomes and terminates genomic replication to confer broad-spectrum antiviral effects. We have previously utilized phosphoramidate pronucleotide (ProTide) technology to enable metabolic production of ddhCTP in cells from an exogenously dosed 3'-deoxy-3',4'-didehydro-cytidine ProTide, which confers inhibitory activity against West Nile virus (WNV) and Zika virus (ZIKV). Herein, we synthesized 3'-deoxy-3',4'-didehydro-nucleosides containing all native nucleobases (thymine, uracil, adenine, guanine, and hypoxanthine), elaborated each to a ProTide, and measured their activity for controlling WNV and ZIKV infection. In comparison to the ddhC ProTide, we found that the ProTides of 3'-deoxy-3',4'-didehydro-guanosine and 3'-deoxy-3',4'-didehydro-adenosine possess 2- and 4-fold greater antiviral effects against ZIKV, respectively. Collectively, this work advances the development of 3'-deoxy-3',4'-didehydro nucleosides as promising compounds for further development into broad-spectrum antiviral agents.

A Deep Learning-Derived Transdiagnostic Signature Indexing Hypoarousal and Impulse Control: Implications for Treatment Prediction in Psychiatric Disorders.

BACKGROUND: Psychiatric disorders are traditionally classified within diagnostic categories, but this approach has limitations. Research Domain Criteria (RDoC) constitute a research classification system for psychiatric disorders based on dimensions within domains that cut across these psychiatric diagnoses. The overall aim of RDoC is to better understand mental illness in terms of dysfunction in fundamental neurobiological and behavioral systems, leading to better diagnosis, prevention and treatment. METHODS: A unique electroencephalographic (EEG) feature, referred to as spindling excessive beta (SEB), has been studied in relation to impulse control and sleep, as part of the arousal/regulatory systems RDoC domain. Here, we study EEG frontal beta activity as a potential transdiagnostic biomarker capable of diagnosing and predicting impulse control and sleep problems. RESULTS: We show in the first dataset (n=3279) that the probability of having SEB, classified by a deep learning algorithm, is associated with poor sleep maintenance and low daytime impulse control. Furthermore, in two additional, independent datasets (iSPOT-A, n=336; iSPOT-D, n=1008), we revealed that conventional frontocentral beta power and/or SEB probability, referred to as Brainmarker-III, is associated with a diagnosis of attention deficit hyperactivity disorder (ADHD), with remission to methylphenidate in children with ADHD in a sex-specific manner, and with remission to antidepressant medication in adults with a major depressive disorder in a drug-specific manner. CONCLUSION: Our results demonstrate the value of the RDoC approach in psychiatry research for the discovery of biomarkers with diagnostic and treatment prediction capacities.

Revisiting the Posterior Approach for Cervical Radiculopathy Utilizing Endoscopic Techniques: A Favorable Short-Term Outcome and Cost Comparison With Anterior Cervical Discectomy and Fusion.

BACKGROUND: Cervical radiculopathy is a spine ailment frequently requiring surgical decompression via anterior cervical discectomy and fusion (ACDF) or posterior foraminotomy/discectomy. While endoscopic posterior foraminotomy/discectomy is gaining popularity, its financial impact remains understudied despite equivalent randomized long-term outcomes to ACDF. In a cohort of patients undergoing ACDF vs endoscopic posterior cervical foraminotomy/discectomy, we sought to compare the total cost of the surgical episode while confirming an equivalent safety profile and perioperative outcomes. METHODS: A single-center retrospective cohort study of patients with unilateral cervical radiculopathy undergoing ACDF or endoscopic cervical foraminotomy between 2018 and 2023 was undertaken. Primary outcomes included the total cost of care for the initial surgical episode (not charges or reimbursement). Perioperative variables and neurological recovery were recorded. Multivariable analysis tested age, body mass index, race, gender, insurance type, operative time, and length of stay. RESULTS: A total of 38 ACDF and 17 endoscopic foraminotomy/discectomy operations were performed. All patients underwent single-level surgery except for 2 two-level endoscopic decompressions. No differences were found in baseline characteristics and symptom length except for younger age (46.8 ± 9.4 vs 57.6 ± 10.3, P = 0.002) and more smokers (18.4% vs 11.8%, P = 0.043) in the ACDF group. Actual hospital costs for the episode of surgical care were markedly higher in the ACDF cohort (mean ±95% CI; $27,782 ± $2011 vs $10,103 ± $720, P < 0.001) driven by the ACDF approach (ß = $17,723, P < 0.001) on multivariable analysis. On sensitivity analysis, ACDF was never cost-efficient compared with endoscopic foraminotomy, and endoscopic failure rates of 64% were required for break-even cost. ACDF was associated with significantly longer operative time (167.7 ± 22.0 vs 142.7 ± 27.4 minutes, P < 0.001) and length of stay (1.1 ± 0.5 vs 0.1 ± 0.2 days, P < 0.001). No significant difference was found regarding 90-day neurological improvement, readmission, reoperation, or complications. CONCLUSION: Compared with patients treated with a single-level ACDF for unilateral cervical radiculopathy, endoscopic posterior cervical foraminotomy/discectomy can achieve a similar safety profile, pain relief, and neurological recovery at considerably less cost. These findings may help patients and surgeons revisit offering the posterior cervical foraminotomy/discectomy utilizing endoscopic techniques. CLINICAL RELEVANCE: Endoscopic posterior cervical foraminotomy/discectomy offers comparable safety, pain relief, and neurological recovery to traditional methods but at a significantly lower cost.

Effectiveness and Safety of Extended Treatment Apixaban Versus Low-Molecular-Weight Heparin in Cancer-Associated Venous Thromboembolism.

BACKGROUND: Limited real-world evidence is available comparing the safety and effectiveness of apixaban and low-molecular-weight heparins (LMWHs) for preventing recurrent venous thromboembolism (VTE) in patients with active cancer receiving anticoagulation in an extended treatment setting. This study evaluated the risk of bleeding and recurrent VTE in patients with cancer-associated VTE who were prescribed apixaban or LMWH for ≥3 months. METHODS: A US commercial claims database was used to identify adult patients with VTE and active cancer who initiated apixaban or LMWH 30 days following the first VTE diagnosis and had ≥3 months of continuous enrollment and 3 months of primary anticoagulation treatment. Patients were followed from the day after the end of primary anticoagulation treatment until the earliest of: date of disenrollment, discontinuation of index anticoagulant, switch to another anticoagulant, or end of the study period. Inverse-probability treatment weighting (IPTW) was used to balance treatment cohorts. Incidence rates (IRs) for the outcomes were calculated per 100 person-years (PY). Cox proportional hazard models were used to evaluate the adjusted risk of recurrent VTE, major bleeding (MB), and clinically relevant nonmajor bleeding (CRNMB). RESULTS: A total of 13,564 apixaban- and 2,808 LMWH-treated patients were analyzed. Post-IPTW, the treatment cohorts were balanced. Patients receiving apixaban had lower adjusted IRs for recurrent VTE (4.1 vs 9.6 per 100 PY), MB (6.3 vs 12.6), and CRNMB (26.1 vs 36.0) versus LMWH (P<.0001 for all comparisons) during the follow-up period. Patients on apixaban had a lower adjusted risk of recurrent VTE (hazard ratio [HR], 0.42; 95% CI, 0.34-0.53), MB (HR, 0.50; 95% CI, 0.41-0.61), and CRNMB (HR, 0.76; 95% CI, 0.68-0.85) versus LMWH. CONCLUSIONS: Extended anticoagulation treatment of ≥3 months with apixaban was associated with lower rates of recurrent VTE, MB, and CRNMB compared with LMWH in adults with cancer-associated VTE.

Place-based estimates of cigarette butt litter raise environmental justice concerns in the United States.

Littering of cigarette butts is a major environmental challenge. In 2022, ~124 billion cigarette butts were littered in the United States. This litter may pose an environmental justice concern by disproportionately affecting human and environmental health in communities of color or communities of low socioeconomic status. However, the lack of data on the distribution and magnitude of cigarette butt littering prevents an environmental justice analysis and limits the ability to tackle this environmental challenge. We conducted an environmental justice assessment of tobacco product waste, specifically cigarette butts, through spatially-explicit, place-based estimates across the contiguous U.S. We built a bottom-up model by synthesizing census tract-level population and smoking prevalence, state-level cigarette consumption, and published littering data to assess the spatial pattern of cigarette consumption and littering, and its implications for environmental injustice in >71,600 U.S. census tracts. Further, we compared the model output to urbanicity (rural-urban commuting area) and Social-Environmental Risk (SER; CDC Environmental Justice Index). Cigarette butt density was not uniformly distributed across the U.S. and ranged from 0-45.5 butts/m2, with an area-weighted average of 0.019 ± 0.0005 butts/m2. Cigarette butt density was 96 times higher in metropolitan vs. rural areas. Cigarette butt density increased significantly with SER, with 5.6 times more littered cigarette butts, and a steeper response to population density, in census tracts with the highest SER vs. the lowest SER. These results demonstrate the relative influences of location, smoking prevalence, and population density, and show that cigarette butt littering is a potential environmental justice concern in the U.S. This study provides information that may help devise targeted strategies to reduce cigarette butt pollution and prevent disproportionate impacts. The spatial data layer with place-based cigarette consumption and butt density is a tool that can support municipal, state, and federal level policy work and future studies on associations among cigarette butt pollution and environmental health outcomes.

Applications of artificial intelligence to myeloproliferative neoplasms: a narrative review.

INTRODUCTION: Artificial intelligence (AI) is a rapidly growing field of computational research with the potential to extract nuanced biomarkers for the prediction of outcomes of interest. AI implementations for the prediction for clinical outcomes for myeloproliferative neoplasms (MPNs) are currently under investigation. AREAS COVERED: In this narrative review, we discuss AI investigations for the improvement of MPN clinical care utilizing either clinically available data or experimental laboratory findings. Abstracts and manuscripts were identified upon querying PubMed and the American Society of Hematology conference between 2000 and 2023. Overall, multidisciplinary researchers have developed AI methods in MPNs attempting to improve diagnostic accuracy, risk prediction, therapy selection, or pre-clinical investigations to identify candidate molecules as novel therapeutic agents. EXPERT OPINION: It is our expert opinion that AI methods in MPN care and hematology will continue to grow with increasing clinical utility. We believe that AI models will assist healthcare workers as clinical decision support tools if appropriately developed with AI-specific regulatory guidelines. Though the reported findings in this review are early investigations for AI in MPNs, the collective work developed by the research community provides a promising framework for improving decision-making in the future of MPN clinical care.

Predicting monoclonal antibody binding sequences from a sparse sampling of all possible sequences.

Previous work has shown that binding of target proteins to a sparse, unbiased sample of all possible peptide sequences is sufficient to train a machine learning model that can then predict, with statistically high accuracy, target binding to any possible peptide sequence of similar length. Here, highly sequence-specific molecular recognition is explored by measuring binding of 8 monoclonal antibodies (mAbs) with specific linear cognate epitopes to an array containing 121,715 near-random sequences about 10 residues in length. Network models trained on resulting sequence-binding values are used to predict the binding of each mAb to its cognate sequence and to an in silico generated one million random sequences. The model always ranks the binding of the cognate sequence in the top 100 sequences, and for 6 of the 8 mAbs, the cognate sequence ranks in the top ten. Practically, this approach has potential utility in selecting highly specific mAbs for therapeutics or diagnostics. More fundamentally, this demonstrates that very sparse random sampling of a large amino acid sequence spaces is sufficient to generate comprehensive models predictive of highly specific molecular recognition.

The Effect of a Post-Bronchodilator FEV1/FVC < 0.7 on COPD Diagnosis and Treatment: A Regression Discontinuity Design.

Background: Global Initiative for Chronic Obstructive Lung Disease (GOLD) guidelines recommend the diagnosis of chronic obstructive pulmonary disease (COPD) only in patients with a post-bronchodilator forced expiratory volume in 1 second to forced vital capacity ratio (FEV1/FVC) less than 0.7. However the impact of this recommendation on clinical practice is unknown. Research Question: What is the effect of a documented post-bronchodilator FEV1/FVC < 0.7 on the diagnosis and treatment of COPD? Study Design and Methods: We used a national electronic health record database to identify clinical encounters between 2007 to 2022 with patients 18 years of age and older in which a post-bronchodilator FEV1/FVC value was documented. An encounter was associated with a COPD diagnosis if a diagnostic code for COPD was assigned, and was associated with COPD treatment if a prescription for a medication commonly used to treat COPD was filled within 90 days. We used a regression discontinuity design to measure the effect of a post-bronchodilator FEV1/FVC < 0.7 on COPD diagnosis and treatment. Results: Among 27 817 clinical encounters, involving 18 991 patients, a post-bronchodilator FEV1/FVC < 0.7 was present in 14 876 (53.4%). The presence of a documented post-bronchodilator FEV1/FVC < 0.7 had a small effect on the probability of a COPD diagnosis, increasing by 6.0% (95% confidence interval [CI] 1.1% to 10.9%) from 38.0% just above the 0.7 cutoff to 44.0% just below this cutoff. The presence of a documented post-bronchodilator FEV1/FVC had no effect on the probability of COPD treatment (-2.1%, 95% CI -7.2% to 3.0%). Interpretation: The presence of a documented post-bronchodilator FEV1/FVC < 0.7 has only a small effect on the probability that a clinician will make a guideline-concordant diagnosis of COPD and has no effect on corresponding treatment decisions.

PanIN and CAF transitions in pancreatic carcinogenesis revealed with spatial data integration.

This study introduces a new imaging, spatial transcriptomics (ST), and single-cell RNA-sequencing integration pipeline to characterize neoplastic cell state transitions during tumorigenesis. We applied a semi-supervised analysis pipeline to examine premalignant pancreatic intraepithelial neoplasias (PanINs) that can develop into pancreatic ductal adenocarcinoma (PDAC). Their strict diagnosis on formalin-fixed and paraffin-embedded (FFPE) samples limited the single-cell characterization of human PanINs within their microenvironment. We leverage whole transcriptome FFPE ST to enable the study of a rare cohort of matched low-grade (LG) and high-grade (HG) PanIN lesions to track progression and map cellular phenotypes relative to single-cell PDAC datasets. We demonstrate that cancer-associated fibroblasts (CAFs), including antigen-presenting CAFs, are located close to PanINs. We further observed a transition from CAF-related inflammatory signaling to cellular proliferation during PanIN progression. We validate these findings with single-cell high-dimensional imaging proteomics and transcriptomics technologies. Altogether, our semi-supervised learning framework for spatial multi-omics has broad applicability across cancer types to decipher the spatiotemporal dynamics of carcinogenesis.

The efficacy of cognitive behavioral therapy for mental health and quality of life among individuals diagnosed with cancer: A systematic review and meta-analysis.

OBJECTIVE: It has long been documented that cognitive behavioral therapy (CBT) has positive impacts on improving mental health (MH) and quality of life (QoL) in the general population, but investigations on its effect on cancer survivors remain limited, especially for QoL outcomes. The purpose of this meta-analysis is to investigate the effects of CBT as compared to control on cancer patients' MH and QoL outcomes. Control is defined in this study as standard therapy, waitlist control, and active/alternative therapy. METHODS: In total, 154 clinical trials creating a sample size of 1627 individuals were collected. Analysis focusing on MH and QoL excluded 29 clinical trials resulting in a final analysis of 132 clinical trials (and 1030 effect sizes). R Statistical Software (version 4.2.2) and the robumeta package were utilized to complete analysis, which entailed robust variance estimation (RVE) in intercept-only meta-regression, and univariate meta-regression (for moderator analysis). RESULTS: Across 132 clinical trials and 1030 effect size estimates, we identified that CBT moderately improves MH and QoL in cancer patients d = 0.388, 95% CI 0.294-0.483, p < 0.001. Additionally, age and delivery format can influence the efficacy of CBT in this patient population. CONCLUSIONS: CBT statistically improves the MH and QoL psychosocial parameters in cancer patients with greater efficacy in younger patients. Important clinical and intervention-related factors, that is, age and delivery, should be considered when oncologists consider CBT as a psychotherapeutic intervention for individuals with cancer.

Evaluation of terpenes rich Hura crepitans extract on glucose regulation and diabetic complications in STZ-induced diabetic rats.

The continual increase in global diabetic statistics portends decreased productivity and life spans, thus making it a disease of concern requiring more effective and safe therapeutic options. While several reports on antidiabetic plants, including Hura crepitans, are available, there is still a dearth of information on the holistic antidiabetic properties of H. crepitans and its associated complications. This study evaluated the antidiabetic potential of methanolic extract of Hura crepitans using in vitro, in vivo, and in silico approaches. The extract revealed a dose-dependent in vitro effect, with a 47.97 % and 65.34 % decrease in the fasting blood sugar levels of streptozotocin (STZ) induced diabetic rats at 150 and 300 mg/kg BW, respectively. Likewise, the extract increased serum and pancreatic insulin levels, and significantly ameliorated neuronal oxidative stress and inflammation by reducing the expression levels of cholinesterase, NF-κB, and COX-2 in the brain of hyperglycemic rats. Serum dyslipidemia, liver, and kidney biomarker indices, and hematological alterations in diabetic rats were also significantly attenuated by the extract. Several constituents, mainly terpenes, were identified in the extract. To further predict the drug-likeness, pharmacokinetics, and binding properties of the compounds, in silico analysis was conducted. Ergosta-2,24-dien-26-oicacid,18-(acetyloxy)-5,6-epoxy-4, 22-dihydroxy-1-oxo-,delta.-lactone-4.beta., displayed the highest docking scores for acetylcholinesterase, butyrylcholinesterases, alpha-amylase, and nuclear factor-kB with values of -12.4, -10.9, -10.3, and -9.4 kcal/mol, while ergost-25-ene-6,12-dione,3,5-dihydroxy-, (3.beta.,5.alpha.) topped for cyclooxygenase-2 (-9.0 kcal/mol). The top-ranked compounds also presented significant oral drug-likeness, pharmacokinetics, and safety properties. Altogether, our data provide preclinical evidence of the potential of Hura crepitans in ameliorating diabetes and its associated complications.

Evaluation of large language models as a diagnostic aid for complex medical cases.

Background: The use of large language models (LLM) has recently gained popularity in diverse areas, including answering questions posted by patients as well as medical professionals. Objective: To evaluate the performance and limitations of LLMs in providing the correct diagnosis for a complex clinical case. Design: Seventy-five consecutive clinical cases were selected from the Massachusetts General Hospital Case Records, and differential diagnoses were generated by OpenAI's GPT3.5 and 4 models. Results: The mean number of diagnoses provided by the Massachusetts General Hospital case discussants was 16.77, by GPT3.5 30 and by GPT4 15.45 (p < 0.0001). GPT4 was more frequently able to list the correct diagnosis as first (22% versus 20% with GPT3.5, p = 0.86), provide the correct diagnosis among the top three generated diagnoses (42% versus 24%, p = 0.075). GPT4 was better at providing the correct diagnosis, when the different diagnoses were classified into groups according to the medical specialty and include the correct diagnosis at any point in the differential list (68% versus 48%, p = 0.0063). GPT4 provided a differential list that was more similar to the list provided by the case discussants than GPT3.5 (Jaccard Similarity Index 0.22 versus 0.12, p = 0.001). Inclusion of the correct diagnosis in the generated differential was correlated with PubMed articles matching the diagnosis (OR 1.40, 95% CI 1.25-1.56 for GPT3.5, OR 1.25, 95% CI 1.13-1.40 for GPT4), but not with disease incidence. Conclusions and relevance: The GPT4 model was able to generate a differential diagnosis list with the correct diagnosis in approximately two thirds of cases, but the most likely diagnosis was often incorrect for both models. In its current state, this tool can at most be used as an aid to expand on potential diagnostic considerations for a case, and future LLMs should be trained which account for the discrepancy between disease incidence and availability in the literature.

Trigeminal ganglion neurons are directly activated by influx of CSF solutes in a migraine model.

Classical migraine patients experience aura, which is transient neurological deficits associated with cortical spreading depression (CSD), preceding headache attacks. It is not currently understood how a pathological event in cortex can affect peripheral sensory neurons. In this study, we show that cerebrospinal fluid (CSF) flows into the trigeminal ganglion, establishing nonsynaptic signaling between brain and trigeminal cells. After CSD, ~11% of the CSF proteome is altered, with up-regulation of proteins that directly activate receptors in the trigeminal ganglion. CSF collected from animals exposed to CSD activates trigeminal neurons in naïve mice in part by CSF-borne calcitonin gene-related peptide (CGRP). We identify a communication pathway between the central and peripheral nervous system that might explain the relationship between migrainous aura and headache.