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BackgroundEsophagectomy, an esophageal cancer treatment mainstay, is a highly morbid procedure. Prolonged operative time, only partially predetermined by case complexity, may be uniquely harmful to minimally-invasive esophagectomy (MIE) patients for numerous reasons, including anastomotic leak, tenuous conduit perfusion and protracted single-lung ventilation, but the impact is unknown. This multi-center retrospective cohort study sought to characterize the relationship between MIE operative time and post-operative outcomes.MethodsWe abstracted multi-center data on esophageal cancer patients who underwent MIE from 2010 to 2021. Predictor variables included age, sex, comorbidities, body mass index, prior cardiothoracic surgery, stage, and neoadjuvant therapy. Outcomes included complications, readmissions, and mortality. Association analysis evaluated the relationship between predictor variables and operative time. Multivariate logistic regression characterized the influence of potential predictor variables and operative time on post-operative outcomes. Subgroup analysis evaluated the association between MIE >4 h vs. ≤4 h and complications, readmissions and survival.ResultsFor the 297 esophageal cancer patients who underwent MIE between 2010 and 2021, the median operative duration was 4.8 h [IQR: 3.7–6.3]. For patients with anastomotic leak (5.1%) and 1-year mortality, operative duration was elevated above the median at 6.3 h [IQR: 4.8–8.6], p = 0.008) and 5.3 h [IQR: 4.4–6.8], p = 0.04), respectively. In multivariate logistic regression, each additional hour of operative time increased the odds of anastomotic leak and 1-year mortality by 39% and 19%, respectively.ConclusionsEsophageal cancer is a poor prognosis disease, even with optimal treatment. Operative efficiency, a modifiable surgical variable, may be an important target to improve MIE patient outcomes.

Due to their short timescale, stellar flares are a challenging target for the most modern synoptic sky surveys. The upcoming Vera C. Rubin Legacy Survey of Space and Time (LSST), a project designed to collect more data than any precursor survey, is unlikely to detect flares with more than one data point in its main survey. We developed a methodology to enable LSST studies of stellar flares, with a focus on flare temperature and temperature evolution, which remain poorly constrained compared to flare morphology. By leveraging the sensitivity expected from the Rubin system, differential chromatic refraction (DCR) can be used to constrain flare temperature from a single-epoch detection, which will enable statistical studies of flare temperatures and constrain models of the physical processes behind flare emission using the unprecedentedly high volume of data produced by Rubin over the 10 yr LSST. We model the refraction effect as a function of the atmospheric column density, photometric filter, and temperature of the flare, and show that flare temperatures at or above ∼4000 K can be constrained by a single g -band observation at air mass X ≳ 1.2, given the minimum specified requirement on the single-visit relative astrometric accuracy of LSST, and that a surprisingly large number of LSST observations are in fact likely be conducted at X ≳ 1.2, in spite of image quality requirements pushing the survey to preferentially low X . Having failed to measure flare DCR in LSST precursor surveys, we make recommendations on survey design and data products that enable these studies in LSST and other future surveys.

Abstract Gene fusions are known to drive many human cancers. Therefore, the functional characterization of newly discovered fusions is critical to understanding the oncobiology of these tumors and to enable therapeutic development. NPM1–TYK2 is a novel fusion identified in CD30 + lymphoproliferative disorders, and here we present the functional evaluation of this fusion gene as an oncogene. The chimeric protein consists of the amino-terminus of nucleophosmin 1 (NPM1) and the carboxyl-terminus of tyrosine kinase 2 (TYK2), including the kinase domain. Using in vitro lymphoid cell transformation assays and in vivo tumorigenic xenograft models we present direct evidence that the fusion gene is an oncogene. NPM1 fusion partner provides the critical homodimerization needed for the fusion kinase constitutive activation and downstream signaling that are responsible for cell transformation. As a result, our studies identify NPM1–TYK2 as a novel fusion oncogene and suggest that inhibition of fusion homodimerization could be a precision therapeutic approach in cutaneous T-cell lymphoma patients expressing this chimera.

Transcription factor (TF)–promoter pairs have been repurposed from native hosts to provide tools to measure intracellular biochemical production titer and dynamically control gene expression. Most often, native TF–promoter systems require rigorous screening to obtain desirable characteristics optimized for biotechnological applications. High-throughput techniques may provide a rational and less labor-intensive strategy to engineer user-defined TF–promoter pairs using fluorescence-activated cell sorting and deep sequencing methods (sort-seq). Based on the designed promoter library’s distribution characteristics, we elucidate sequence–function interactions between the TF and DNA. In this work, we use the sort-seq method to study the sequence–function relationship of a σ54-dependent, butanol-responsive TF–promoter pair, BmoR-PBMO derived from Thauera butanivorans, at the nucleotide level to improve biosensor characteristics, specifically an improved dynamic range. Activities of promoters from a mutagenized PBMO library were sorted based on gfp expression and subsequently deep sequenced to correlate site-specific sequences with changes in dynamic range. We identified site-specific mutations that increase the sensor output. Double mutant and a single mutant, CA(129,130)TC and G(205)A, in PBMO promoter increased dynamic ranges of 4-fold and 1.65-fold compared with the native system, respectively. In addition, sort-seq identified essential sites required for the proper function of the σ54-dependent promoter biosensor in the context of the host. This work can enable high-throughput screening methods for strain development.

Coumadin (R/S-warfarin) anticoagulant therapy is highly efficacious in preventing the formation of blood clots; however, significant inter-individual variations in response risks over or under dosing resulting in adverse bleeding events or ineffective therapy, respectively. Levels of pharmacologically active forms of the drug and metabolites depend on a diversity of metabolic pathways. Cytochromes P450 play a major role in oxidizing R- and S-warfarin to 6-, 7-, 8-, 10-, and 4′-hydroxywarfarin, and warfarin alcohols form through a minor metabolic pathway involving reduction at the C11 position. We hypothesized that due to structural similarities with warfarin, hydroxywarfarins undergo reduction, possibly impacting their pharmacological activity and elimination. We modeled reduction reactions and carried out experimental steady-state reactions with human liver cytosol for conversion of rac-6-, 7-, 8-, 4′-hydroxywarfarin and 10-hydroxywarfarin isomers to the corresponding alcohols. The modeling correctly predicted the more efficient reduction of 10-hydroxywarfarin over warfarin but not the order of the remaining hydroxywarfarins. Experimental studies did not indicate any clear trends in the reduction for rac-hydroxywarfarins or 10-hydroxywarfarin into alcohol 1 and 2. The collective findings indicated the location of the hydroxyl group significantly impacted reduction selectivity among the hydroxywarfarins, as well as the specificity for the resulting metabolites. Based on studies with R- and S-7-hydroxywarfarin, we predicted that all hydroxywarfarin reductions are enantioselective toward R substrates and enantiospecific for S alcohol metabolites. CBR1 and to a lesser extent AKR1C3 reductases are responsible for those reactions. Due to the inefficiency of reactions, only reduction of 10-hydroxywarfarin is likely to be important in clearance of the metabolite. This pathway for 10-hydroxywarfarin may have clinical relevance as well given its anticoagulant activity and capacity to inhibit S-warfarin metabolism.

Developmental Coordination Disorder (DCD) is one of the least studied and understood developmental disorders. One area that has been minimally investigated in DCD is potential issues with sensory modulation. Further, in other neurodevelopmental disorders (e.g., autism spectrum disorder (ASD)) sensory modulation is related to many other challenges (e.g., social issues, repetitive behaviors, anxiety); however, such potential relationships in children with DCD have been largely unexplored. The purpose of this study is to explore sensory modulation differences in DCD and to understand the relationships between sensory modulation and social emotional measures, behavior, and motor skills in DCD in comparison to ASD and typically developing (TD) peers. Participants (aged 8–17) and their caregivers (DCD, N = 26; ASD, N = 57; and TD, N = 53) completed behavioral and clinical measures. The results indicated that 31% of the DCD group showed sensory modulation difficulties, with the DCD group falling between the ASD and TD groups. In the DCD group, sensory modulation was significantly associated with anxiety, empathic concern, repetitive behaviors, and motor skills. Data are compared to patterns seen in ASD and TD groups and implications for interventions are discussed.

Green synthesis of lead-free Cs2AgBixSb1−xCl6 solid-solution double perovskites and their conversion into bromide and iodide derivatives is reported. Interaction of the single-phase Cs2AgBixSb1−xCl6 double perovskites with sodium iodide in 2-propanol/glycerol yields Cs3Bi2xSb2(1−x)I9 derivatives with varied Bi/Sb ratio, while the similar anion exchange with sodium bromide results in mixtures of Cs3Bi2xSb2(1−x)Cl3Br6 and Cs2AgBixSb1−xCl2Br4. A band-bowing effect is revealed for the starting chloride perovskites and the anion-exchange products, with the indirect band gap of intermediate Bi/Sb mixed compounds being significantly lower than the band gaps of corresponding Bi- and Sb-pure products. Solid-state nuclear magnetic resonance spectroscopy uncovered that the band-bowing originates from the lattice disorder of mixed Bi/Sb halide compounds, thus highlighting a new approach for the bandgap design of halide perovskites. [ABSTRACT FROM AUTHOR]

Abstract We present the Manually Annotated GONG Filaments in H-alpha Observations (MAGFiLO v1.0) dataset. This dataset contains 10,244 annotated filaments from 1,593 observations captured by the Global Oscillation Network Group (GONG), spanning the years 2011 through 2022. Each annotation details one filament’s segmentation, minimum bounding box, spine, and magnetic field chirality. With a total of over one thousand person-hours of annotation, and a double-blind review process, we ensured high-quality ground-truth data. Our inter-annotator agreement reaches a Kappa score of 0.66. We also verified that the hemispheric preference of filaments as annotated in MAGFiLO aligns with the findings from similar datasets of much smaller sample sizes. MAGFiLO is the first dataset of its size, enabling advanced deep learning models to identify filaments and their features with unprecedented precision. It also provides a testbed for solar physicists interested in large-scale analysis of filaments. In this report, we document the details of the annotation and the post-processing phases that were applied.

Abstract There are genetic and environmental risk factors that contribute to the development of cognitive decline in Alzheimer’s disease (AD). Some of these include the genetic predisposition of the apolipoprotein E4 genotype, consuming a high-fat diet (HFD), and the female sex. Brain insulin receptor resistance and deficiency have also been shown to be associated with AD and cognitive impairment. Intranasal (INL) insulin enhances cognition in AD, but the response varies due to genotype, diet, and sex. We investigated here the combination of these risk factors in a humanized mouse model, expressing E3 or E4, following a HFD in males and females on cognitive performance and the brain distribution of insulin following INL delivery. The HFD had a negative effect on survival in male mice only, requiring sex to be collapsed. We found many genotype, diet, and genotype x diet effects in anxiety-related tasks. We further found beneficial effects of INL insulin in our memory tests, with the most important findings showing a beneficial effect of INL insulin in mice on a HFD. We found insulin distribution throughout the brain after INL delivery was largely unaffected by diet and genotype, indicating these susceptible groups can still receive adequate levels of insulin following INL delivery. Our findings support the involvement of brain insulin signaling in cognition and highlight continuing efforts investigating mechanisms resulting from treatment with INL insulin.

Abstract Targeting brain insulin resistance (BIR) has become an attractive alternative to traditional therapeutic treatments for Alzheimer’s disease (AD). Incretin receptor agonists (IRAs), targeting either or both of the glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) receptors, have proven to reverse BIR and improve cognition in mouse models of AD. We previously showed that many, but not all, IRAs can cross the blood-brain barrier (BBB) after intravenous (IV) delivery. Here we determined if widespread brain uptake of IRAs could be achieved by circumventing the BBB using intranasal (IN) delivery, which has the added advantage of minimizing adverse gastrointestinal effects of systemically delivered IRAs. Of the 5 radiolabeled IRAs tested (exenatide, dulaglutide, semaglutide, DA4-JC, and DA5-CH) in CD-1 mice, exenatide, dulaglutide, and DA4-JC were successfully distributed throughout the brain following IN delivery. We observed significant sex differences in uptake for DA4-JC. Dulaglutide and DA4-JC exhibited high uptake by the hippocampus and multiple neocortical areas. We further tested and found the presence of AD-associated Aβ pathology minimally affected uptake of dulaglutide and DA4-JC. Of the 5 tested IRAs, dulaglutide and DA4-JC are best capable of accessing brain regions most vulnerable in AD (neocortex and hippocampus) after IN administration. Future studies will need to be performed to determine if IN IRA delivery can reduce BIR in AD or animal models of that disorder.

Abstract Background Chronic pain affects over 100 million Americans, with a disproportionately high number being Veterans. Chronic pain is often difficult to treat and responds variably to medications, with many providing minimal relief or having adverse side effects that preclude use. Cannabidiol (CBD) has emerged as a potential treatment for chronic pain, yet research in this area remains limited, with few studies examining CBD’s analgesic potential. Because Veterans have a high need for improved pain care, we designed a clinical trial to investigate CBD’s effectiveness in managing chronic pain symptoms among Veterans. We aim to determine whether CBD oral solution compared to placebo study medication is associated with greater improvement in the Patient Global Impression of Change (PGIC). Methods We designed a randomized, double-blind, placebo-controlled, pragmatic clinical trial with 468 participants. Participants will be randomly assigned in a 1:1 ratio to receive either placebo or a CBD oral solution over a 4-week period. The trial is remote via a smartphone app and by shipping study materials, including study medication, to participants. We will compare the difference in PGIC between the CBD and placebo group after four weeks and impacts on secondary outcomes (e.g., pain severity, pain interference, anxiety, suicide ideation, and sleep disturbance). Discussion Once complete, this trial will be among the largest to date investigating the efficacy of CBD for chronic pain. Findings from this clinical trial will contribute to a greater knowledge of CBD’s analgesic potential and guide further research. Given the relative availability of CBD, our findings will help elucidate the potential of an accessible option for helping to manage chronic pain among Veterans. Trial registration This protocol is registered at clinicaltrials.gov under study number NCT06213233.

BackgroundSmoking contributes to 1 in 3 cancer deaths. At the Stanford Cancer Center, tobacco cessation medication management and counseling are provided as a covered benefit. Patients charted as using tobacco are contacted by a tobacco treatment specialist and offered cessation services. As a novel addition, this study examined the acceptability of a virtual reality (VR) mindful exposure therapy app for quitting smoking called MindCotine. ObjectiveThe objective of this study was to determine the feasibility and acceptability of offering 6 weeks of MindCotine treatment as a part of Stanford’s Tobacco Treatment Services for patients seen for cancer care. MethodsAs part of a single-group pilot study, the MindCotine VR program was offered to English- or Spanish-speaking patients interested in quitting smoking. Given the visual interface, epilepsy was a medical exclusion. Viewed from a smartphone with an attachable VR headset, MindCotine provides a digital environment with audiovisual content guiding mindfulness exercises (eg, breathing techniques, body awareness, and thought recognition), text-based coaching, and cognitive behavioral therapy-based self-reflections for quitting smoking. Interested patients providing informed consent were mailed a MindCotine headset and asked to use the app for 10+ minutes a day. At the end of 6 weeks, participants completed a feedback survey. ResultsOf the 357 patients reached by the tobacco treatment specialist, 62 (17.3%) were ineligible, 190 (53.2%) were not interested in tobacco treatment services, and 78 (21.8%) preferred other tobacco treatment services. Among the 105 eligible and interested in assistance with quitting, 27 (25.7%) were interested in MindCotine, of whom 20 completed the informed consent, 9 used the program, and 8 completed their end-of-treatment survey. Participants using MindCotine completed, on average, 13 (SD 20.2) program activities, 19 (SD 26) journal records, and 11 (SD 12.3) coaching engagements. Of the 9 participants who used MindCotine, 4 (44%) reported some dizziness with app use that resolved and 7 (78%) would recommend MindCotine to a friend. In total, 2 participants quit tobacco (22.2% reporting, 10% overall), 2 others reduced their smoking by 50% or more, and 2 quit for 24 hours and then relapsed. ConclusionsIn a feasibility and acceptability pilot study of a novel VR tobacco treatment app offered to patients at a cancer center, 4 of 9 (44%) reporting and 4 of 20 (20%) overall substantially reduced or quit using tobacco after 6 weeks and most would recommend the app to others. Further testing on a larger sample is warranted. Trial RegistrationClinicalTrials.gov NCT05220254; https://clinicaltrials.gov/study/NCT05220254

Abstract Objective A systematic review was conducted to evaluate the use patterns, health perceptions, and cardiopulmonary health effects of cigars. Data sources PubMed and Google Scholar were searched for peer-reviewed articles published between June 2014 and February 2021. Search keywords included cigars, cigarillos, little cigars, and cardiopulmonary health outcomes. Study selection Of 782 papers identified, we excluded non-English articles, review articles, commentaries, and those without empirical data on cigars. Three coders independently reviewed all articles and compared codes to resolve discrepancies. 93 articles met the inclusion criteria and were included. Data synthesis Cigars have evolved from premium cigars to encompass little cigars and cigarillos (LCCs). LCCs are available in an array of flavors and at a price advantage, and as a result, are used by different groups compared to premium cigars. LCCs are more frequently used by youth, young adults, and those who identify as Black/African American. LCCs are often used in combination with other tobacco products, alcohol, and cannabis. Despite limited regulation, cigars generate smoke of a similar composition as cigarettes. Among the studies identified, evidence suggests that cigar use is associated with cardiovascular and pulmonary toxicity. Higher all-cause and cancer-related mortalities are associated with cigar use, particularly with more frequent and deeper inhalation, compared to non-tobacco users. Conclusions LCCs are used more frequently by at-risk groups compared to premium cigars. Recent studies evaluating cigar cardiopulmonary health effects are limited but suggest cigars have similar health risks as conferred by cigarette smoking. With the use of LCCs and targeted marketing on the rise among high-risk groups, there is a critical need for continued research in this area.