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Background:. Unlike in-house call, the Accreditation Council for Graduate Medical Education (ACGME) does not require a postcall day for “home call” shifts. Despite this, we hypothesize that on-call residents are still in the hospital for the majority of their shift despite having the luxury of home call and, thus, are not protected by ACGME postcall duty hour regulations. Methods:. A prospective single center survey study was conducted by surveying junior and senior residents who completed overnight call shifts from January 2023 to April 2023 at one of the busiest level 1 trauma centers in the United States. Data include number of trips into the hospital, hours spent in the hospital, and hours of sleep. Results:. Response rate was 195 of 200 (97.5%) total call shifts from 7 pm to 7 am the next morning. Junior residents reported an average of 3.25, 3.92, and 0.73 hours of sleep when on hand call, face call, and triple call (hand + face + general), respectively. Senior residents reported an average of 4.18 and 4.75 hours of sleep for hand and face call, respectively. Conclusions:. Hours of sleep when taking home call varies widely based on type of call. Junior residents reported significantly decreased sleep and more time in the hospital when taking hand, face, and triple call compared with general call alone. Senior residents reported that both hand and face call result in significantly decreased hours of sleep compared with general call alone. These results highlight the need to discuss ACGME protection for residents taking home call.

Abstract In situ spacecraft observations are critical to our study and understanding of the various phenomena that couple mass, momentum, and energy throughout near‐Earth space and beyond. However, on‐orbit telemetry constraints can severely limit the capability of spacecraft to transmit high‐cadence data, and missions are often only able to telemeter a small percentage of their captured data at full rate. This presents a programmatic need to prioritize intervals with the highest probability of enabling the mission's science goals. Larger missions such as the Magnetospheric Multiscale mission (MMS) aim to solve this problem with a Scientist‐In‐The‐Loop (SITL), where a domain expert flags intervals of time with potentially interesting data for high‐cadence data downlink and subsequent study. Although suitable for some missions, the SITL solution is not always feasible, especially for low‐cost missions such as CubeSats and NanoSats. This manuscript presents a generalizable method for the detection of anomalous data points in spacecraft observations, enabling rapid data prioritization without substantial computational overhead or the need for additional infrastructure on the ground. Specifically, Principal Components Analysis and One‐Class Support Vector Machines are used to generate an alternative representation of the data and provide an indication, for each point, of the data's potential for scientific utility. The technique's performance and generalizability is demonstrated through application to intervals of observations, including magnetic field data and plasma moments, from the CASSIOPE e‐POP/Swarm‐Echo and MMS missions.

Background The mislabeling of seafood, wherein a food product’s marketed name does not match its contents, has the potential to mask species of conservation concern. Less discussed is the role of legally ambiguous market names, wherein a single name could be used to sell multiple species. Here we report the first study in Canada to examine mislabeling and ambiguous market names in both invertebrate (e.g., bivalve, cephalopod, shrimp) and finfish products. Methods A total of 109 invertebrate and 347 finfish products were sampled in Calgary between 2014 and 2020. Market names were documented from the label or equivalent and determined to be precise (the name could apply to only one species) or ambiguous (multiple species could be sold under that name). A region of the cytochrome c oxidase I gene was sequenced and compared to reference sequences from boldsystems.org. Samples were considered mislabeled if the species identified through DNA barcoding did not correspond to the market name, as determined through the Canadian Food Inspection Agency Fish List. Mislabeling was further differentiated between semantic mislabeling, wherein the market name was not found on the Fish List but the barcode identity was in line with what a consumer could reasonably have expected to have purchased; invalid market names, wherein the market name was so unusual that no legitimate inferences as to the product’s identity could be made; and product substitution, wherein the DNA barcode identified the product as a species distinct from that associated with the market name. Invalid market names and product substitutions were used to provide conservative estimates of mislabeling. The global conservation status of the DNA-identified invertebrate or finfish was determined through the International Union for the Conservation of Nature Red List. A logistic regression was used to determine the relationship between precision and accuracy in predicting conservation status of the sampled species. Results There was no significant difference in mislabeling occurrence between invertebrates (33.9% total mislabeling occurrence, 20.2% product substitution) and finfish (32.3% total mislabeling occurrence, 21.3% product substitution/invalid market names). Product substitutions sometimes involved species of conservation concern, such as foods marketed as freshwater eel (Anguilla rostrata) that were determined through DNA barcoding to be European eel (Anguilla anguilla), or cuttlefish balls putatively identified as the Endangered threadfin porgy (Evynnis cardinalis). Product substitutions and ambiguous market names were significantly associated with the sale of species of conservation concern, but ambiguity was a more important predictor. Although preventing the mislabeling of seafoods can and must remain a priority in Canada, our work suggests that moving towards precise names for all seafood products will better support sustainable fisheries goals.

IntroductionSequelae from traumatic brain injuries (TBIs) and post-traumatic stress disorder (PTSD) are major career-limiting factors for combat soldiers. Overlap between TBI and PTSD symptoms alongside other common comorbidities complicate the diagnosis and treatment. Systems-level and high-throughput approaches are key in understanding the underlying biomolecular mechanisms and differentiating these conditions.MethodsThe present study identifies dietary factors and proposes mechanisms behind psychological stress and TBI, using established preclinical animal models and a multi-omics approach. Here, we used microbiome characterizations of rats exposed to simulations of blast-induced TBI and underwater trauma (UWT)-induced psychological stress. We further studied the effect of dietary omega-6 versus omega-3 polyunsaturated fatty acid (n-6, n-3 PUFA) enrichment on the insult responses. The use of excess n-6 PUFA was chosen due to its high prevalence in the Western diet and pro-inflammatory nature. Prior to TBI or UWT, animals were maintained for 6 weeks and continued thereafter on either a standard diet or two customized chows imbalanced and diminished in omega-3 content. Corresponding shams were carried out for all groups. Fecal bacterial microbiome populations were assessed using 16S rRNA gene sequencing.ResultsPhysiologic outcome modeling identified that dietary status affected post-TBI lactate dehydrogenase (LDH) and triglyceride levels, with n-3 PUFA having a large attenuating influence. The UWT model showed similar trends, with diet significantly altering LDH, terminal corticosterone (14 days post-exposure), and a fear behavior susceptibility. Fecal microbiome alpha diversity was significantly reduced by high levels of n-3 PUFA. Likewise, beta diversity of the microbiome was significantly affected by both diet and time but not exposure to TBI or UWT. Compositionally, temporal effects on the microbiome were more likely to be observed with the diets. The most affected features fell within the Proteobacteria phyla, in which n-3 PUFA enrichment significantly reduced Alphaproteobacteria in the TBI model and increased Gammaproteobacteria in the UWT group.DiscussionAll these observations can influence the vulnerability or resilience of the warfighter to blast-induced TBI and acute psychological stress. The microbiome mechanisms facilitate and provide a knowledge-driven unbiased panel of signatures to discriminate between the two insults and is an essential tool for designing precise care management.

Intraocular foreign bodies (IOFBs) remain a severe complication of ocular trauma commonly encountered worldwide. This literature review aimed to discuss current practice patterns, areas of controversy, and advances in the management of IOFBs. Injuries involving IOFBs carry significant ocular morbidity and management can be extremely challenging. A systematic approach to preoperative evaluation and IOFB surgical management is detailed in this article and should be applied in each case. The location and composition of an IOFB have important implications on surgical approach and timing, especially in cases of toxic metals and vegetable matter. The advantages, disadvantages, and previous literature regarding immediate versus delayed foreign body removal are presented. Surgical approaches are described, with an emphasis on posterior chamber IOFB management and removal via pars plana vitrectomy. Final visual acuity is variable, but approaches have been used to prognosticate outcomes including the Ocular Trauma Score. By synthesizing current IOFB literature, the goal is to provide practitioners with guidance that will maximize the chances of surgical success and patient outcomes.

Oxygen is a vital but often overlooked variable in tissue culture experiments. Physiologically relevant oxygen tensions range from partial pressures of 100 mmHg at the alveolar-capillary interface in the lung to less than 7.6 mmHg in the hypoxic regions of solid tumors. These values are markedly lower than the partial oxygen pressure of ambient air, which is standard experimental practice. Physiologically relevant culture environments are needed to better predict cellular and tissue-level responses to drugs or potential toxins. Three commonly used methods to regulate in vitro oxygen tension involve placing cells in 1) a hypoxia chamber, 2) setups that rely on mass transport-limited microenvironments, and 3) microfabricated devices. Hypoxia chambers have the lowest barrier to entry, as they do not require laboratories to change their tissue culture setups. Here, we present a gas-regulation system for a three-zone hypoxia chamber. Each zone can maintain independent environments, with partial pressure compositions of 1–21 % O2 and 1–10 % CO2. The design incorporates small-scale fabrication techniques (e.g., laser cutting and 3D printing) and off-the-shelf electronic components for simple assembly. The hypoxia chambers are significantly lower in cost than the commercial counterparts: $1,400 for the control system or $4,100 for a complete three-zone chamber system.

Background: Total hip (THA) and knee (TKA) discharge disposition is of increasing interest as leaner models are sought, emphasizing the importance of factors affecting discharge disposition. Utilizing the National Surgical and Quality Improvement Program (NSQIP), we hypothesized discharge to home would (1) be more frequent in men, (2) be adversely affected by comorbidities but not by race, and (3) increase in percentage each year. Methods: The NSQIP 2015–2018 database revealed 883,309 orthopedic surgical patients, 413,627 having undergone joint arthroplasty. The primary endpoint was discharge to home. Chi-square tests examined categorical dependent variables, and analysis of variance (ANOVA) assessed continuous variables, with statistical significance accepted for p 0.001) were more likely to be discharged home compared to THA or revision arthroplasty. Race and Ethnicity varied likelihood of going home. Regardless of Ethnicity, Black/African American individuals were least likely to be discharged home. Of patients with reported Ethnicity, Indigenous Non-Hispanics and Indigenous Hispanics had the highest odds of discharge home (OR = 1.94; 1.77, p

Abstract Background and Objectives Despite significant progress in biomedical research, the rate of success in oncology drug development remains inferior to that of other therapeutic fields. Mechanistic models provide comprehensive understanding of the therapeutic effects of drugs, which is crucial for designing effective clinical trials. This study was performed to acquire a better understanding of PI3K–AKT–TOR pathway modulation and preclinical to clinical translational bridging for a specific compound, apitolisib (PI3K/mTOR inhibitor), by developing integrated mechanistic models. Methods Integrated pharmacokinetic (PK)–pharmacodynamic (PD)–efficacy models were developed for xenografts bearing human renal cell adenocarcinoma and for patients with solid tumors (phase 1 studies) to characterize relationships between exposure of apitolisib, modulation of the phosphorylated Akt (pAkt) biomarker triggered by inhibition of the PI3K–AKT–mTOR pathway, and tumor response. Results Both clinical and preclinical integrated models show a steep sigmoid curve linking pAkt inhibition to tumor growth inhibition and quantified that a minimum of 35–45% pAkt modulation is required for tumor shrinkage in patients, based on platelet-rich plasma surrogate matrix and in xenografts based on tumor tissue matrix. Based on this relationship between targeted pAkt modulation and tumor shrinkage rate, it appeared that a constant pAkt inhibition of 61% and 65%, respectively, would be necessary to achieve tumor stasis in xenografts and patients. Conclusions These results help when it comes to evaluating the translatability of the preclinical analysis to the clinical target, and provide information that will enhance the value of future preclinical translational dose-finding and dose-optimization studies to accelerate clinical drug development. Trial Registry ClinicalTrials.gov NCT00854152 and NCT00854126.

Abstract Electrical stimulation can regulate brain activity, producing clear clinical benefits, but focal and effective neuromodulation often requires surgically implanted electrodes. Recent studies argue that temporal interference (TI) stimulation may provide similar outcomes non-invasively. During TI, scalp electrodes generate multiple electrical fields in the brain, modulating neural activity only at their intersection. Despite considerable enthusiasm for this approach, little empirical evidence demonstrates its effectiveness, especially under conditions suitable for human use. Here, using single-neuron recordings in non-human primates, we establish that TI reliably alters the timing, but not the rate, of spiking activity. However, we show that TI requires strategies—high carrier frequencies, multiple electrodes, and amplitude-modulated waveforms—that also limit its effectiveness. Combined, these factors make TI 80 % weaker than other forms of non-invasive brain stimulation. Although unlikely to cause widespread neuronal entrainment, TI may be ideal for disrupting pathological oscillatory activity, a hallmark of many neurological disorders.

Abstract Background Lumbar spinal manipulative therapy (SMT) is a common intervention used to treat low back pain (LBP); however, the exact neurophysiological mechanisms of SMT reducing pain measured through pain pressure threshold (PPT) have not been fully explored beyond an immediate timeframe (e.g., immediately or five-minutes following) referencing a control group. Therefore, the purpose of this study was to investigate the neurophysiological effects of lumbar SMT compared to deactivated ultrasound using PPT immediately following and 30-minutes following SMT. Methods A longitudinal, randomized controlled trial design was conducted between September to October 2023. Fifty-five participants were randomized into a control group of deactivated ultrasound (n = 29) or treatment group of right sidelying lumbar SMT (n = 26). PPT, recorded at the right posterior superior iliac spine (PSIS), was documented for each participant in each group prior to intervention, immediately, and 30-minutes after. A repeated measures ANOVA, with a post-hoc Bonferroni adjustment, was used to assess within-group and between-group differences in PPT. The significance level was set at a

Abstract Mars is a particularly attractive candidate among known astronomical objects to potentially host life. Results from space exploration missions have provided insights into Martian geochemistry that indicate oxychlorine species, particularly perchlorate, are ubiquitous features of the Martian geochemical landscape. Perchlorate presents potential obstacles for known forms of life due to its toxicity. However, it can also provide potential benefits, such as producing brines by deliquescence, like those thought to exist on present-day Mars. Here we show perchlorate brines support folding and catalysis of functional RNAs, while inactivating representative protein enzymes. Additionally, we show perchlorate and other oxychlorine species enable ribozyme functions, including homeostasis-like regulatory behavior and ribozyme-catalyzed chlorination of organic molecules. We suggest nucleic acids are uniquely well-suited to hypersaline Martian environments. Furthermore, Martian near- or subsurface oxychlorine brines, and brines found in potential lifeforms, could provide a unique niche for biomolecular evolution.

Abstract Progressive carcinogenesis of a gastric polyp with transformation to gastric adenocarcinoma and subsequent development of leptomeningeal carcinomatosis is described in an adult male Scottish terrier. Presenting clinical signs consisted of vomiting with intermittent hematemesis. Surgical biopsies over the course of 14 months documented the progression from gastric polyp to minimally invasive gastric carcinoma to invasive gastric adenocarcinoma, a pathogenesis not previously documented in veterinary oncology. The patient ultimately developed neurologic pathology and was euthanized, and necropsy evaluation identified widespread carcinomatosis with accompanying leptomeningeal metastasis. As in humans, gastric polyps in dogs rarely have malignant potential.

Abstract Background Traditional dosing of chemotherapy drugs based on body surface area may overdose small dogs, leading to an increased frequency of adverse events (AEs). Hypothesis/Objectives Evaluate the frequency of hematologic and gastrointestinal AEs in dogs with newly diagnosed lymphoma treated with vincristine weighing ≤15 kg in comparison to dogs weighing >15 kg. We hypothesized that dogs weighing ≤15 kg would experience a higher frequency of AEs. Animals One hundred and thirty‐eight dogs with newly diagnosed lymphoma were treated with vincristine. Methods A multicenter retrospective study reviewing hematologic data and medical record information. Complete blood counts were performed no more than 24 hours before vincristine administration and then between 4 and 8 days post‐administration. Data were evaluated using logistic regression or ordinal logistic regression. Results Thirty‐eight dogs weighing ≤15 kg and 100 dogs weighing >15 kg were included. The median vincristine dose for both groups was 0.6 mg/m2. Seventeen (12.3%) instances of neutropenia occurred with no significant difference in overall frequency or grade between groups. Thirty initially asymptomatic substage A dogs (29.4%) experienced gastrointestinal AEs. Because of the widespread use of gastrointestinal supportive care medications, statistical comparison between groups could not be performed. Seven instances of hospitalization occurred (5.0%) and the risk of hospitalization did not differ significantly between groups (P = .37). Conclusions and Clinical Importance Vincristine dosed at ≤0.6 mg/m2 does not increase the risk of hematologic AEs in dogs weighing ≤15 kg.

Abstract The length of 3′ untranslated regions (3′UTR) is highly regulated during many transitions in cell state, including T cell activation, through the process of alternative polyadenylation (APA). However, the regulatory mechanisms and functional consequences of APA remain largely unexplored. Here we present a detailed analysis of the temporal and condition-specific regulation of APA following activation of primary human CD4+ T cells. We find that global APA changes are regulated temporally and CD28 costimulatory signals enhance a subset of these changes. Most APA changes upon T cell activation involve 3′UTR shortening, although a set of genes enriched for function in the mTOR pathway exhibit 3′UTR lengthening. While upregulation of the core polyadenylation machinery likely induces 3′UTR shortening following prolonged T cell stimulation; a significant program of APA changes occur prior to cellular proliferation or upregulation of the APA machinery. Motif analysis suggests that at least a subset of these early changes in APA are driven by upregulation of RBM3, an RNA-binding protein which competes with the APA machinery for binding. Together this work expands our understanding of the impact and mechanisms of APA in response to T cell activation and suggests new mechanisms by which APA may be regulated.

Abstract Antigenic characterization of circulating influenza A virus (IAV) isolates is routinely assessed by using the hemagglutination inhibition (HI) assays for surveillance purposes. It is also used to determine the need for annual influenza vaccine updates as well as for pandemic preparedness. Performing antigenic characterization of IAV on a global scale is confronted with high costs, animal availability, and other practical challenges. Here we present a machine learning model that accurately predicts (normalized) outputs of HI assays involving circulating human IAV H3N2 viruses, using their hemagglutinin subunit 1 (HA1) sequences and associated metadata. Each season, the model learns an updated nonlinear mapping of genetic to antigenic changes using data from past seasons only. The model accurately distinguishes antigenic variants from non-variants and adaptively characterizes seasonal dynamics of HA1 sites having the strongest influence on antigenic change. Antigenic predictions produced by the model can aid influenza surveillance, public health management, and vaccine strain selection activities.

Abstract Agricultural soils are increasingly undergoing inadvertent and purposeful exposures to engineered CeO2 nanoparticles (NPs), which can impact crops and root-associated microbial communities. However, interactions between NP concentration and exposure duration on plant-mediated responses of root-associated bacterial communities are not well understood. Soybeans seedlings were grown in soil with uncoated NPs added at concentrations of 0, 1 or 100 mg kg−1. Total soil exposure durations were either 190 days, starting 106 days before planting or 84 days with NP amendments coinciding with planting. We assessed plant development, bacterial diversity, differential abundance and inferred functional changes across rhizosphere, rhizoplane, and root tissue compartments. Plant non-monotonic dose responses were mirrored in bacterial communities. Most notably, effects were magnified in the rhizoplane under low-dose, short-exposures. Enriched metabolic pathways were primarily related to biosynthesis and degradation/utilization/assimilation, rather than responses to metals or oxidative stress. Our results indicate that plant-mediated bacterial responses were greater than direct NP impacts. Also, we identify needs for modeling non-monotonic legume stress responses that account for coinfection with mutualistic and parasitic bacteroids. Our findings provide new insights regarding effects of applications of soil amendments such as biosolids containing NPs or nano-enabled formulations used in cultivation of legumes and other crops.

Abstract Extraction of nucleic acids (NAs) is critical for many methods in molecular biology and bioanalytical chemistry. NA extraction has been extensively studied and optimized for a wide range of applications and its importance to society has significantly increased. The COVID-19 pandemic highlighted the importance of early and efficient NA testing, for which NA extraction is a critical analytical step prior to the detection by methods like polymerase chain reaction. This study explores simple, new approaches to extraction using engineered smart nanomaterials, namely NA-binding, intrinsically disordered proteins (IDPs), that undergo triggered liquid–liquid phase separation (LLPS). Two types of NA-binding IDPs are studied, both based on genetically engineered elastin-like polypeptides (ELPs), model IDPs that exhibit a lower critical solution temperature in water and can be designed to exhibit LLPS at desired temperatures in a variety of biological solutions. We show that ELP fusion proteins with natural NA-binding domains can be used to extract DNA and RNA from physiologically relevant solutions. We further show that LLPS of pH responsive ELPs that incorporate histidine in their sequences can be used for both binding, extraction and release of NAs from biological solutions, and can be used to detect SARS-CoV-2 RNA in samples from COVID-positive patients.

While originally intending to explore the venom gland microbiome of the desert hairy scorpion Hadrurus arizonensis Ewing, 1928, nanopore sequencing serendipitously recovered complete mitochondrial genomes for this iconic arachnid. Phylogenetic analysis of these high-quality genomes places Hadrurus as sister to Uroctonus, in agreement with some phylogenomic hypotheses. Additionally, we reveal significant genetic variation among individuals from the same population, highlighting the potential of mitogenomics for population genetics and phylogeography. This study showcases the effectiveness and affordability of nanopore sequencing for research with non-model organisms, opening new avenues for investigating arachnid biodiversity, evolution, and biogeography.

Abstract Background Pulmonary hypertension (PH) is a leading cause of death in patients with systemic sclerosis (SSc). An important component of SSc patient management is early detection and treatment of PH. Recently the threshold for the diagnosis of PH has been lowered to a mean pulmonary artery pressure (mPAP) threshold of > 20 mmHg on right heart catheterization (RHC). However, it is unknown if PH-specific therapy is beneficial in SSc patients with mildly elevated pressure (SSc-MEP, mPAP 21–24 mmHg). Methods The SEPVADIS trial is a randomized, double-blind, placebo-controlled phase 2 trial of sildenafil in SSc-MEP patients with a target enrollment of 30 patients from two academic sites in the United States. The primary outcome is change in six-minute walk distance after 16 weeks of treatment. Secondary endpoints include change in pulmonary arterial compliance by RHC and right ventricular function by cardiac magnetic resonance imaging at 16 weeks. Echocardiography, serum N-terminal probrain natriuretic peptide, and health-related quality of life is being measured at 16 and 52 weeks. Discussion The SEPVADIS trial will be the first randomized study of sildenafil in SSc-MEP patients. The results of this trial will be used to inform a phase 3 study to investigate the efficacy of treating patients with mild elevations in mPAP. Trial registration ClinicalTrials.gov Identifier NCT04797286.

Objective: Open decannulation from femoral venoarterial extracorporeal membrane oxygenation (VA-ECMO) carries high risk of morbidity, including groin wound infection. This study evaluated the impact of percutaneous decannulation on rates of groin wound infection in patients decannulated from femoral VA-ECMO. Methods: Between January 1, 2022, and April 30, 2023, 47 consecutive patients received percutaneous femoral VA-ECMO and survived to decannulation. A percutaneous suture-mediated closure device was used for decannulation in patients with relatively smaller arterial cannulas. Patients with larger arterial cannulas or unsuccessful percutaneous closures underwent surgical cutdown and repair of the femoral artery. The primary outcome was arterial site wound infection following decannulation. Results: Among the 47 patients who survived to decannulation from VA-ECMO, 21 underwent percutaneous decannulation and 27 underwent surgical cutdown. One patient underwent 2 VA-ECMO runs, one with percutaneous decannulation and one with surgical cutdown. Percutaneous decannulation was attempted in 22 patients, with 21 of 22 (95.5%) success rate. Decannulation procedure length was significantly shorter in the percutaneous group (79 minutes vs 148 minutes, P = .0001). The percutaneous group had significantly reduced rates of groin wound complications (0% vs 40.7%, P = .001) and groin wound infections (0% vs 22.2%, P = .03) when compared with the surgical cutdown group. Three patients (14.3%) in the percutaneous group experienced vascular complications, including pseudoaneurysm at the distal perfusion catheter site and nonocclusive thrombus of the common femoral artery. Conclusions: Percutaneous decannulation may reduce decannulation procedure length and rate of groin wound infection in patients who survive to decannulation from VA-ECMO.

Abstract Ultrasound localization microscopy (ULM) enables deep tissue microvascular imaging by localizing and tracking intravenously injected microbubbles circulating in the bloodstream. However, conventional localization techniques require spatially isolated microbubbles, resulting in prolonged imaging time to obtain detailed microvascular maps. Here, we introduce LOcalization with Context Awareness (LOCA)-ULM, a deep learning-based microbubble simulation and localization pipeline designed to enhance localization performance in high microbubble concentrations. In silico, LOCA-ULM enhanced microbubble detection accuracy to 97.8% and reduced the missing rate to 23.8%, outperforming conventional and deep learning-based localization methods up to 17.4% in accuracy and 37.6% in missing rate reduction. In in vivo rat brain imaging, LOCA-ULM revealed dense cerebrovascular networks and spatially adjacent microvessels undetected by conventional ULM. We further demonstrate the superior localization performance of LOCA-ULM in functional ULM (fULM) where LOCA-ULM significantly increased the functional imaging sensitivity of fULM to hemodynamic responses invoked by whisker stimulations in the rat brain.

Abstract Despite regulating overlapping gene enhancers and pathways, CREBBP and KMT2D mutations recurrently co-occur in germinal center (GC) B cell-derived lymphomas, suggesting potential oncogenic cooperation. Herein, we report that combined haploinsufficiency of Crebbp and Kmt2d induces a more severe mouse lymphoma phenotype (vs either allele alone) and unexpectedly confers an immune evasive microenvironment manifesting as CD8+ T-cell exhaustion and reduced infiltration. This is linked to profound repression of immune synapse genes that mediate crosstalk with T-cells, resulting in aberrant GC B cell fate decisions. From the epigenetic perspective, we observe interaction and mutually dependent binding and function of CREBBP and KMT2D on chromatin. Their combined deficiency preferentially impairs activation of immune synapse-responsive super-enhancers, pointing to a particular dependency for both co-activators at these specialized regulatory elements. Together, our data provide an example where chromatin modifier mutations cooperatively shape and induce an immune-evasive microenvironment to facilitate lymphomagenesis.

Abstract Introduction Data on real-world clinical practice and outcomes of patients with pulmonary arterial hypertension associated with connective tissue disease (CTD-PAH) are scarce. The OPUS/OrPHeUS studies enrolled patients newly initiating macitentan, including those with CTD-PAH. This analysis describes patient characteristics, treatment patterns, outcomes, and safety profiles of patients with CTD-PAH newly initiating macitentan in the US using the OPUS/OrPHeUS combined dataset. Methods OPUS was a prospective, US, multicenter, long-term, observational drug registry (April 2014–June 2020). OrPHeUS was a retrospective, US, multicenter medical chart review (October 2013–March 2017). The characteristics, treatment patterns, safety, and outcomes during macitentan treatment of patients with CTD-PAH and its subgroups systemic sclerosis (SSc-PAH), systemic lupus erythematosus (SLE-PAH), and mixed CTD (MCTD-PAH) were descriptively compared to patients with idiopathic/heritable PAH (I/HPAH). Results The combined OPUS/OrPHeUS population included 2498 patients with I/HPAH and 1192 patients with CTD-PAH (708 SSc-PAH; 159 SLE-PAH; 124 MCTD-PAH, and 201 other CTD-PAH etiologies). At macitentan initiation for patients with I/HPAH and CTD-PAH, respectively: 61.2 and 69.3% were in World Health Organization functional class (WHO FC) III/IV; median 6-min walk distance was 289 and 279 m; and 58.1 and 65.2% received macitentan as combination therapy. During follow-up, for patients with I/HPAH and CTD-PAH, respectively: median duration of macitentan exposure observed was 14.0 and 15.8 months; 79.0 and 83.0% experienced an adverse event; Kaplan–Meier estimates (95% confidence limits [CL]) of patients free from all-cause hospitalization at 1 year were 60.3% (58.1, 62.4) and 59.3% (56.1, 62.3); and Kaplan–Meier estimates (95% CL) of survival at 1 year were 90.5% (89.1, 91.7) and 90.6% (88.6, 92.3). Conclusions Macitentan was used in clinical practice in patients with CTD-PAH and its subgroups, including as combination therapy. The safety and tolerability profile of macitentan in patients with CTD-PAH was comparable to that of patients with I/HPAH. Trial Registration OPsumit® Users Registry (OPUS): NCT02126943; Opsumit® Historical Users cohort (OrPHeUS): NCT03197688; www.clinicaltrials.gov Graphical abstract available for this article. Graphical Abstract

Abstract Cystic echinococcosis is caused by the zoonotic tapeworm Echinococcus granulosus. There has been ongoing controversy over whether it causes weight loss in cattle. Recently implemented recording of comorbidities at processors has provided opportunity to investigate this effect. Using prevalence-based observational data from 1,648,049 adult cattle processed in seven states and territories in Australia (2019–2022), we explored associations between carcase weight, hydatid cysts, comorbidities, sex, age, and region. Linear mixed-effect regression models estimated the effect of cystic echinococcosis on carcase weight, guided by directed acyclic graphs to reduce bias. The highest, previously unreported, prevalence was in the southeast Queensland region. The estimated effect of cystic echinococcosis cysts on carcase weight ranged from a gain of 0.32 kg/carcase (standard error [se] 0.58 kg; two-tooth 2022) to a loss of −5.45 kg/carcase (se 0.63 kg; six-tooth 2019) with most point estimates (11/16) between 0 and −2.5 kg across all cattle grouped by year and dentition. This effect size would be practically undetectable in live cattle which is an important finding; cattle producers are unlikely to observe increased productivity through weight gain from cystic echinococcosis prevention in cattle, and awareness to strengthen prevention in domestic dogs around cattle properties to reduce human risk remains a public health focus.

Objective: To develop a deep learning algorithm for the analysis of patch testing. Patients and Methods: A retrospective case series between January 1, 2010, and December 31, 2020, was constructed to develop a deep learning model for the classification of patch test results from photographs. The performance of human expert readers reviewing the same photographs blinded to the original clinical physical examination findings was measured to benchmark model performance. Results: Model performance on the independent test set (n=5070 test site locations from 37 patients) achieved an area under the receiver operating characteristic curve of 0.89 (95% CI, 0.86-0.91) and an F1 score of 37.1. The optimal cutoff had a sensitivity of 70.1% (136/194; 95% CI, 63.1%-76.5%) and a specificity of 91.7% (4472/4876; 95% CI, 90.9%-92.5%). Conclusion: We demonstrated proof-of-concept utility for detecting allergic contact dermatitis using an automated deep learning approach.

Objective: To determine the appropriateness of ophthalmology recommendations from an online chat-based artificial intelligence model to ophthalmology questions. Patients and Methods: Cross-sectional qualitative study from April 1, 2023, to April 30, 2023. A total of 192 questions were generated spanning all ophthalmic subspecialties. Each question was posed to a large language model (LLM) 3 times. The responses were graded by appropriate subspecialists as appropriate, inappropriate, or unreliable in 2 grading contexts. The first grading context was if the information was presented on a patient information site. The second was an LLM-generated draft response to patient queries sent by the electronic medical record (EMR). Appropriate was defined as accurate and specific enough to serve as a surrogate for physician-approved information. Main outcome measure was percentage of appropriate responses per subspecialty. Results: For patient information site-related questions, the LLM provided an overall average of 79% appropriate responses. Variable rates of average appropriateness were observed across ophthalmic subspecialties for patient information site information ranging from 56% to 100%: cataract or refractive (92%), cornea (56%), glaucoma (72%), neuro-ophthalmology (67%), oculoplastic or orbital surgery (80%), ocular oncology (100%), pediatrics (89%), vitreoretinal diseases (86%), and uveitis (65%). For draft responses to patient questions via EMR, the LLM provided an overall average of 74% appropriate responses and varied by subspecialty: cataract or refractive (85%), cornea (54%), glaucoma (77%), neuro-ophthalmology (63%), oculoplastic or orbital surgery (62%), ocular oncology (90%), pediatrics (94%), vitreoretinal diseases (88%), and uveitis (55%). Stratifying grades across health information categories (disease and condition, risk and prevention, surgery-related, and treatment and management) showed notable but insignificant variations, with disease and condition often rated highest (72% and 69%) for appropriateness and surgery-related (55% and 51%) lowest, in both contexts. Conclusion: This LLM reported mostly appropriate responses across multiple ophthalmology subspecialties in the context of both patient information sites and EMR-related responses to patient questions. Current LLM offerings require optimization and improvement before widespread clinical use.

Abstract Background Over one-third of people living with HIV (PLH) in Ukraine are not on treatment. Index testing services, which link potentially exposed partners (named partners) of known PLH (index patients) with testing and treatment services, are being scaled in Ukraine and could potentially close this gap. Methods This retrospective study included patient data from 14,554 adult PLH who initiated antiretroviral treatment (ART) between October 2018 and May 2021 at one of 35 facilities participating in an intervention to strengthen index testing services. Mixed effects modified Poisson models were used to assess differences between named partners and other ART initiators, and an interrupted time series (ITS) analysis was used to assess changes in ART initiation over time. Results Compared to other ART initiators, named partners were significantly less likely to have a confirmed TB diagnosis (aRR = 0.56, 95% CI = 0.40, 0.77, p

Abstract Background There are two major genetic types of Epstein-Barr Virus (EBV): type 1 (EBV-1) and type 2 (EBV-2). EBV functions by manipulating gene expression in host B cells, using virus-encoded gene regulatory proteins including Epstein-Barr Nuclear Antigen 2 (EBNA2). While type 1 EBNA2 is known to interact with human transcription factors (hTFs) such as RBPJ, EBF1, and SPI1 (PU.1), type 2 EBNA2 shares only ~ 50% amino acid identity with type 1 and thus may have distinct binding partners, human genome binding locations, and functions. Results In this study, we examined genome-wide EBNA2 binding in EBV-1 and EBV-2 transformed human B cells to identify shared and unique EBNA2 interactions with the human genome, revealing thousands of type-specific EBNA2 ChIP-seq peaks. Computational predictions based on hTF motifs and subsequent ChIP-seq experiments revealed that both type 1 and 2 EBNA2 co-occupy the genome with SPI1 and AP-1 (BATF and JUNB) hTFs. However, type 1 EBNA2 showed preferential co-occupancy with EBF1, and type 2 EBNA2 preferred RBPJ. These differences in hTF co-occupancy revealed possible mechanisms underlying type-specific gene expression of known EBNA2 human target genes: MYC (shared), CXCR7 (type 1 specific), and CD21 (type 2 specific). Both type 1 and 2 EBNA2 binding events were enriched at systemic lupus erythematosus (SLE) and multiple sclerosis (MS) risk loci, while primary biliary cholangitis (PBC) risk loci were specifically enriched for type 2 peaks. Conclusions This study reveals extensive type-specific EBNA2 interactions with the human genome, possible differences in EBNA2 interaction partners, and a possible new role for type 2 EBNA2 in autoimmune disorders. Our results highlight the importance of considering EBV type in the control of human gene expression and disease-related investigations.

Abstract Histopathologic diagnosis and classification of cancer plays a critical role in guiding treatment. Advances in next-generation sequencing have ushered in new complementary molecular frameworks. However, existing approaches do not independently assess both site-of-origin (e.g. prostate) and lineage (e.g. adenocarcinoma) and have minimal validation in metastatic disease, where classification is more difficult. Utilizing gradient-boosted machine learning, we developed ATLAS, a pair of separate AI Tumor Lineage and Site-of-origin models from RNA expression data on 8249 tumor samples. We assessed performance independently in 10,376 total tumor samples, including 1490 metastatic samples, achieving an accuracy of 91.4% for cancer site-of-origin and 97.1% for cancer lineage. High confidence predictions (encompassing the majority of cases) were accurate 98–99% of the time in both localized and remarkably even in metastatic samples. We also identified emergent properties of our lineage scores for tumor types on which the model was never trained (zero-shot learning). Adenocarcinoma/sarcoma lineage scores differentiated epithelioid from biphasic/sarcomatoid mesothelioma. Also, predicted lineage de-differentiation identified neuroendocrine/small cell tumors and was associated with poor outcomes across tumor types. Our platform-independent single-sample approach can be easily translated to existing RNA-seq platforms. ATLAS can complement and guide traditional histopathologic assessment in challenging situations and tumors of unknown primary.

Biofilms are a highly complex community of microorganisms embedded in a protective extracellular polymeric substance (EPS). Successful biofilm control requires a variety of approaches to better understand the structure-function relationship of the EPS matrix. Magnetic resonance imaging (MRI) is a versatile tool which can measure spatial structure, diffusion, and flow velocities in three dimensions and in situ. It is well-suited to characterize biofilms under natural conditions and at different length scales. MRI contrast is dictated by T1 and T2 relaxation times which vary spatially depending on the local chemical and physical environment of the sample. Previous studies have demonstrated that MRI can provide important insights into the internal structure of biofilms, but the contribution of major biofilm components—such as proteins, polysaccharides, and cells—to MRI contrast is not fully understood. This study explores how these components affect contrast in T1-and T2-weighted MRI by analyzing artificial biofilms with well-defined properties modeled after aerobic granular sludge (AGS), compact spherical biofilm aggregates used in wastewater treatment. MRI of these biofilm models showed that certain gel-forming polysaccharides are a major source of T2 contrast, while other polysaccharides show minimal contrast. Proteins were found to reduce T2 contrast slightly when combined with polysaccharides, while cells had a negligible impact on T2 but showed T1 contrast. Patterns observed in the model biofilms served as a reference for examining T2 and T1-weighted contrast in the void spaces of two distinct AGS granules, allowing for a qualitative evaluation of the EPS components which may be present. Further insights provided by MRI may help improve understanding of the biofilm matrix and guide how to better manage biofilms in wastewater, clinical, and industrial settings.

Northern ungulates contend with Setaria yehi and Rumenfilaria andersoni, filarioid nematodes that are transmitted by ectoparasitic blood-feeding arthropods, which can result in animal and population level impacts. Setaria yehi microfilariae can be detected in fresh blood samples using a modified Knott's test, or by postmortem detection by genetic sampling or through the retrieval of adult specimens in the peritoneal cavity. In this study we validated a novel qPCR for detection of S. yehi DNA in blood samples of moose (Alces alces). Additionally, we compared quantitative values from modified Knott's test to detect both S. yehi and R. andersoni from both fresh and frozen blood samples. Species-specific primers targeting a 121-base pair fragment of the cytochrome oxidase c subunit 1 (cox1) of S. yehi, and a species-specific probe were designed. The qPCR had a detection threshold of 0.157 pg/μL of parasite DNA. We collected 166 blood samples from wild moose captured on the Kenai Peninsula, Alaska from 2019 to 2022. Matching blood aliquots were tested by modified Knott's test and subjected to DNA extraction for subsequent qPCR. Quantitatively, blood samples had an average S. yehi microfilaremia (mf) of 472.2 mf/mL (0–14,490 mf/mL) and R. andersoni of 72.9 mf/mL (0.0–5071.5 mf/mL). Qualitatively, 32.53% (n = 54) of samples tested positive for S. yehi in each of the tests, and 37.35% (n = 62) when both tests were combined, with very good agreement between the results from Knott's test and qPCR (kappa = 0.90). The validation of the qPCR test for S. yehi allows for faster, less labor-intensive diagnosis and epidemiological surveillance of this emerging parasite in moose and other cervid hosts.

ABSTRACTIn higher eukaryotes, the nucleolus harbors at least three sub-phases that facilitate multiple functionalities including ribosome biogenesis. The three prominent coexisting sub-phases are the fibrillar center (FC), the dense fibrillar component (DFC), and the granular component (GC). Here, we review recent efforts in profiling sub-phase compositions that shed light on the types of physicochemical properties that emerge from compositional biases and territorial organization of specific types of macromolecules. We highlight roles played by molecular grammars which refers to protein sequence features including the substrate binding domains, the sequence features of intrinsically disordered regions, and the multivalence of these distinct types of domains / regions. We introduce the concept of a barcode of emergent physicochemical properties of nucleoli. Although our knowledge of the full barcode remains incomplete, we hope that the concept prompts investigations into undiscovered emergent properties and engenders an appreciation for how and why unique microenvironments control biochemical reactions

ABSTRACTWomen are at significantly greater risk of metabolic dysfunction after menopause, which subsequently leads to numerous chronic illnesses. The gut microbiome is associated with obesity and metabolic dysfunction, but its interaction with female sex hormone status and the resulting impact on host metabolism remains unclear. Herein, we characterized inflammatory and metabolic phenotypes as well as the gut microbiome associated with ovariectomy and high-fat diet feeding, compared to gonadal intact and low-fat diet controls. We then performed fecal microbiota transplantation (FMT) using gnotobiotic mice to identify the impact of ovariectomy-associated gut microbiome on inflammatory and metabolic outcomes. We demonstrated that ovariectomy led to greater gastrointestinal permeability and inflammation of the gut and metabolic organs, and that a high-fat diet exacerbated these phenotypes. Ovariectomy also led to alteration of the gut microbiome, including greater fecal β-glucuronidase activity. However, differential changes in the gut microbiome only occurred when fed a low-fat diet, not the high-fat diet. Gnotobiotic mice that received the gut microbiome from ovariectomized mice fed the low-fat diet had greater weight gain and hepatic gene expression related to metabolic dysfunction and inflammation than those that received intact sham control-associated microbiome. These results indicate that the gut microbiome responds to alterations in female sex hormone status and contributes to metabolic dysfunction. Identifying and developing gut microbiome-targeted modulators to regulate sex hormones may be useful therapeutically in remediating menopause-related diseases.

Abstract Lake trophic state is a key ecosystem property that integrates a lake’s physical, chemical, and biological processes. Despite the importance of trophic state as a gauge of lake water quality, standardized and machine-readable observations are uncommon. Remote sensing presents an opportunity to detect and analyze lake trophic state with reproducible, robust methods across time and space. We used Landsat surface reflectance data to create the first compendium of annual lake trophic state for 55,662 lakes of at least 10 ha in area throughout the contiguous United States from 1984 through 2020. The dataset was constructed with FAIR data principles (Findable, Accessible, Interoperable, and Reproducible) in mind, where data are publicly available, relational keys from parent datasets are retained, and all data wrangling and modeling routines are scripted for future reuse. Together, this resource offers critical data to address basic and applied research questions about lake water quality at a suite of spatial and temporal scales.

Introduction: Three-dimensional (3D)-printed custom pelvic implants have become a clinically viable option for patients undergoing pelvic cancer surgery with resection of the hip joint. However, increased clinical utilization has also necessitated improved implant durability, especially with regard to the compression screws used to secure the implant to remaining pelvic bone. This study evaluated six different finite element (FE) screw modeling methods for predicting compression screw pullout and fatigue failure in a custom pelvic implant secured to bone using nine compression screws.Methods: Three modeling methods (tied constraints (TIE), bolt load with constant force (BL-CF), and bolt load with constant length (BL-CL)) generated screw axial forces using functionality built into Abaqus FE software; while the remaining three modeling methods (isotropic pseudo-thermal field (ISO), orthotropic pseudo-thermal field (ORT), and equal-and-opposite force field (FOR)) generated screw axial forces using iterative physics-based relationships that can be implemented in any FE software. The ability of all six modeling methods to match specified screw pretension forces and predict screw pullout and fatigue failure was evaluated using an FE model of a custom pelvic implant with total hip replacement. The applied hip contact forces in the FE model were estimated at two locations in a gait cycle. For each of the nine screws in the custom implant FE model, likelihood of screw pullout failure was predicted using maximum screw axial force, while likelihood of screw fatigue failure was predicted using maximum von Mises stress.Results: The three iterative physics-based modeling methods and the non-iterative Abaqus BL-CL method produced nearly identical predictions for likelihood of screw pullout and fatigue failure, while the other two built-in Abaqus modeling methods yielded vastly different predictions. However, the Abaqus BL-CL method required the least computation time, largely because an iterative process was not needed to induce specified screw pretension forces. Of the three iterative methods, FOR required the fewest iterations and thus the least computation time.Discussion: These findings suggest that the BL-CL screw modeling method is the best option when Abaqus is used for predicting screw pullout and fatigue failure in custom pelvis prostheses, while the iterative physics-based FOR method is the best option if FE software other than Abaqus is used.

The growing interest in the growth and study of thin films of low-dimensional metallic delafossites, with the general formula ABO2, is driven by their potential to exhibit electronic and magnetic characteristics that are not accessible in bulk systems. The layered structure of these compounds introduces unique surface states as well as electronic and structural reconstructions, making the investigation of their surface behavior pivotal to understanding their intrinsic electronic structure. In this work, we study the surface phenomena of epitaxially grown PtCoO2, PdCoO2, and PdCrO2 films, utilizing a combination of molecular-beam epitaxy and angle-resolved photoemission spectroscopy. Through precise control of surface termination and treatment, we discover a pronounced 3×3 surface reconstruction in PtCoO2 films and PdCoO2 films, alongside a 2 × 2 surface reconstruction observed in PdCrO2 films. These reconstructions have not been reported in prior studies of delafossites. Furthermore, our computational investigations demonstrate the BO2 surface’s relative stability compared to the A-terminated surface and the significant reduction in surface energy facilitated by the reconstruction of the A-terminated surface. These experimental and theoretical insights illuminate the complex surface dynamics in metallic delafossites, paving the way for future explorations of their distinctive properties in low-dimensional studies.

Background:. It is increasingly apparent that plastic surgery residency applications with lengthy research publications are the new standard in applicant competitiveness. This study aims to evaluate the research history of plastic surgery program faculty leadership to understand the trends and evolution of research expectations. Methods:. The curriculum vitaes of faculty involved in residency admissions among all US Accreditation Council for Graduate Medical Education-accredited integrated and independent plastic surgery programs were reviewed. Doximity, program websites, and Scopus were used to gather information. H-index and publication count at the time of medical school and residency graduations were collected. Student t test and Pearson product-moment correlation were used for analysis. Results:. Of the 236 plastic surgeons considered, faculty averaged one publication by medical school graduation, two by general surgery residency graduation, and six by plastic surgery residency graduation. Integrated residents held more publications after medical school (1.67 versus 0.56; P = 0.09) and plastic surgery residency (8.48 versus 4.89; P = 0.01) compared with independent residents. Later plastic surgery residency graduation year correlated with more publications (P < 0.001). Chairs had higher h-indices compared with program directors and associate positions (chair: 23.7, program director: 14.7, associate: 12.2; P < 0.001). Conclusions:. The majority of faculty leaders’ research was published after residency. The emerging trend of increased research volume among plastic surgeons-in-training may be a consequence of competitive research requirements to matriculate into residency. Longer-term career follow-up of newer graduates will need to be assessed to determine whether this predicts future postgraduate productivity or if it is just the price of admission to train as a plastic surgeon.

Over the last two decades, there have been numerous initiatives to improve undergraduate student outcomes in STEM. One model for scalable reform is the inclusive Research Education Community (iREC). In an iREC, STEM faculty from colleges and universities across the nation are supported to adopt and sustainably implement course-based research – a form of science pedagogy that enhances student learning and persistence in science. In this study, we used pathway modeling to develop a qualitative description that explicates the HHMI Science Education Alliance (SEA) iREC as a model for facilitating the successful adoption and continued advancement of new curricular content and pedagogy. In particular, outcomes that faculty realize through their participation in the SEA iREC were identified, organized by time, and functionally linked. The resulting pathway model was then revised and refined based on several rounds of feedback from over 100 faculty members in the SEA iREC who participated in the study. Our results show that in an iREC, STEM faculty organized as a long-standing community of practice leverage one another, outside expertise, and data to adopt, implement, and iteratively advance their pedagogy. The opportunity to collaborate in this manner and, additionally, to be recognized for pedagogical contributions sustainably engages STEM faculty in the advancement of their pedagogy. Here, we present a detailed pathway model of SEA that, together with underpinning features of an iREC identified in this study, offers a framework to facilitate transformations in undergraduate science education.

Objective: To assess pathways to parenthood, pregnancy outcomes, future pregnancy desire, and fertility counseling experiences among a cross-sectional sample of transgender men and gender diverse individuals assigned female or intersex at birth in the United States Methods: Participants were recruited from The Population Research in Identity and Disparities for Equality (PRIDE) Study and the general public. Eligible participants for this analysis were able to read and understand English, assigned female or intersex at birth, US residents, 18+ years old, and identified as transgender, nonbinary, or gender diverse. We analyzed responses to close-ended survey questions, overall and stratified by gender identity, race/ethnicity, and testosterone use. We also qualitatively assessed open-text responses on fertility counseling. Results: Among the 1694 participants, median age was 27 years (range: 18–72), 12% had ever been pregnant, and 12% were parents. Carrying a pregnancy where the individual was the egg source (36%) was the most common pathway to parenthood. Individuals with an exclusively binary gender identity (ie, transgender man or man) more often reported becoming parents through adoption than individuals with gender diverse identities (19% vs 12%). A third of individuals did not receive fertility counseling prior to initiating testosterone; individuals who exclusively reported nonbinary identities were recommended to investigate fertility preservation options less often (36%) compared to transgender men (50%). Conclusion: Transgender men and gender diverse individuals who were assigned female or intersex at birth build their families through a variety of pathways, including pregnancy, stepparenting, and adoption. Clinicians should avoid making assumptions about reproductive desires in these populations based on gender identities or testosterone use and should provide consistent fertility counseling prior to and after hormone initiation.

Summary: Eosinophils are involved in host protection against multicellular organisms. However, their recruitment to the mesenteric lymph node (mLN) during type 2 immunity is understudied. Our results demonstrate that eosinophil association with lymphoid stromal niches constructed by fibroblastic reticular cells (FRCs) and lymphatic endothelial cells is diminished in mice selectively lacking interleukin (IL)-4Rα or lymphotoxin-β (LTβ) expression on B cells. Furthermore, eosinophil survival, activation, and enhanced Il1rl1 receptor expression are driven by stromal cell and B cell dialogue. The ligation of lymphotoxin-β receptor (LTβR) on FRCs improves eosinophil survival and significantly augments IL-33 expression and eosinophil homing to the mLN, thus confirming the significance of lymphotoxin signaling for granulocyte recruitment. Eosinophil-deficient ΔdblGATA-1 mice show diminished mLN expansion, reduced interfollicular region (IFR) alarmin expression, and delayed helminth clearance, elucidating their importance in type 2 immunity. These findings provide insight into dialogue between stromal cells and B cells, which govern mLN eosinophilia, and the relevance of these mechanisms during type 2 immunity.

Patients with epilepsy face heightened risk of post-ictal cardiorespiratory suppression and sudden unexpected death in epilepsy (SUDEP). Studies have shown that neuroinflammation, mediated by the activation of microglia and astrocytes, may be a cause or consequence of seizure disorders. Kcnj16 (Kir5.1) knockout rats (SSkcnj16−/−) are susceptible to repeated audiogenic seizures and recapitulate features of human SUDEP, including post-ictal ventilatory suppression, which worsens with repeated seizures and seizure-induced mortality. In this study, we tested the hypothesis that repeated seizures cause neuroinflammation within key brainstem regions that contribute to the control of breathing. Audiogenic seizures were elicited once/day for up to 10 days in groups of adult male SSkcnj16−/− rats, from which frozen brainstem biopsies of the pre-Bötzinger complex/nucleus ambiguus (preBötC/NA), Bötzinger complex (BötC), and raphe magnus (RMg) regions were subjected to a cytokine array. Several cytokines/chemokines, including IL-1α and IL-1ß, were increased selectively in preBötC/NA after 3 or 5 days of seizures with fewer changes in other regions tested. In additional groups of male SSkcnj16−/− rats that underwent repeated seizures, we quantified microglial (IBA-1+) cell counts and morphology, specifically within the preBötC/NA region, and showed increased microglial cell counts, area, and volume consistent with microglial activation. To further test the role of inflammation in physiological responses to seizures and seizure-related mortality, additional groups of SSkcnj16−/− rats were treated with anakinra (IL-1R antagonist), ketoprofen (non-selective COX inhibitor), or saline for 3 days before and up to 10 days of seizures (1/day), and breathing was measured before, during, and after each seizure. Remarkably, IL-1R antagonism mitigated changes in post-ictal ventilatory suppression on days 7–10 but failed to prevent seizure-related mortality, whereas ketoprofen treatment exacerbated post-ictal ventilatory suppression compared to other treatment groups but prevented seizure-related mortality. These data demonstrate neuroinflammation and microglial activation within the key brainstem region of respiratory control following repeated seizures, which may functionally but differentially contribute to the pathophysiological consequences of repeated seizures.

Abstract We perform a set of reactive transport simulations in three‐dimensional fracture networks to characterize the impact of geochemical reactions on flow channelization. Flow channelization, a frequently observed phenomenon in porous and fractured subsurface rock formations, results from the spatially variable hydraulic resistance offered by a geological structure. In addition to geo‐structural features such as network connectivity, geometry, and hydraulic resistance, geochemical reactions, for example, dissolution and precipitation, can dynamically inhibit or enhance flow channelization. These geochemical processes can change the fracture permeability leading to increased flow channelization, which are localized connected regions of high volumetric flow rates that are seemingly ubiquitous in the subsurface. In our simulations, fractures partially filled with quartz are gradually dissolved until quasi‐steady state conditions are obtained. We compare the flow field's initial unreacted and final dissolved states in terms of flow and transport observations. We observe that the dissolved fracture networks provide less resistance to flow and exhibit increased flow channelization when compared to their unreacted counterparts. However, there is substantial variability in the magnitude of these changes which implies that the channelization strongly depends on the network structure. In turn, we identify the interplay between the particular network structure and the impact of geochemical dissolution on flow channelization. The presented results indicate that geological systems that have been weathering or reactive for longer times in older landscapes are likely to have increased flow channelization compared to their equivalent but younger counterparts, which implies a time dependence on flow channelization in fractured media.

Background/objectives Stroke damage to the primary visual cortex induces large, homonymous visual field defects that impair daily living. Here, we asked if vision‐related quality of life (VR‐QoL) is impacted by time since stroke. Subjects/methods We conducted a retrospective meta‐analysis of 95 occipital stroke patients (female/male = 26/69, 27–78 years old, 0.5–373.5 months poststroke) in whom VR‐QoL was estimated using the National Eye Institute Visual Functioning Questionnaire (NEI‐VFQ) and its 10‐item neuro‐ophthalmic supplement (Neuro10). Visual deficit severity was represented by the perimetric mean deviation (PMD) calculated from 24‐2 Humphrey visual fields. Data were compared with published cohorts of visually intact controls. The relationship between VR‐QoL and time poststroke was assessed across participants, adjusting for deficit severity and age with a multiple linear regression analysis. Results Occipital stroke patients had significantly lower NEI‐VFQ and Neuro10 composite scores than controls. All subscale scores describing specific aspects of visual ability and functioning were impaired except for ocular pain and general health, which did not differ significantly from controls. Surprisingly, visual deficit severity was not correlated with either composite score, both of which increased with time poststroke, even when adjusting for PMD and age. Conclusions VR‐QoL appears to improve with time postoccipital stroke, irrespective of visual deficit size or patient age at insult. This may reflect the natural development of compensatory strategies and lifestyle adjustments. Thus, future studies examining the impact of rehabilitation on daily living in this patient population should consider the possibility that their VR‐QoL may change gradually over time, even without therapeutic intervention.

Molecular tension sensors are central tools for mechanobiology studies but have limitations in interpretation. Reporting in Cell Reports Methods, Shoyer et al. discover that fluorescent protein photoswitching in concert with sensor extension may expand the use and interpretation of common force-sensing tools.

Nephroblastoma or Wilms’ tumor (WT) is the most common pediatric renal malignancy but rare in adults. Treatment protocols for adults are typically extrapolated from pediatric guidelines, but there are no standard guidelines for adults due to the rarity of the disease. However, next-generation sequencing has led to new therapeutic options for adult WT patients. We present the first case to our knowledge of a recurrent adult WT treated with dual BRAF/MEK–targeted therapy, which showed initial robust clinical response and was well tolerated.

OBJECTIVES:. Accurate classification of disorders of consciousness (DoC) is key in developing rehabilitation plans after brain injury. The Coma Recovery Scale—Revised (CRS-R) is a sensitive measure of consciousness validated in the rehabilitation phase of care. We tested the feasibility, safety, and impact of CRS-R-guided rehabilitation in the ICU for patients with DoC after acute hemorrhagic stroke. DESIGN:. Retrospective cohort study. SETTING:. This single-center study was conducted in the neurocritical care unit at the University of Maryland Medical Center. PATIENTS:. We analyzed records from consecutive patients with subarachnoid hemorrhage (SAH) or intracerebral hemorrhage (ICH), who underwent serial CRS-R assessments during ICU admission from April 1, 2018, to December 31, 2021, where CRS-R less than 8 is vegetative state/unresponsive wakefulness syndrome (VS/UWS); CRS-R greater than or equal to 8 is a minimally conscious state (MCS). INTERVENTIONS:. None. MEASUREMENTS AND MAIN RESULTS:. Outcomes included adverse events during CRS-R evaluations and associations between CRS-R and discharge disposition, therapy-based function, and mobility. We examined the utility of CRS-R compared with other therapist clinical assessment tools in predicting discharge disposition. Seventy-six patients (22 SAH, 54 ICH, median age = 59, 50% female) underwent 276 CRS-R sessions without adverse events. Discharge to acute rehabilitation occurred in 4.4% versus 41.9% of patients with a final CRS-R less than 8 and CRS-R greater than or equal to 8, respectively (odds ratio [OR] 13.4; 95% CI, 2.7–66.1; p < 0.001). Patients with MCS on final CRS-R completed more therapy sessions during hospitalization and had improved mobility and functional performance. Compared with other therapy assessment tools, the CRS-R had the best performance in predicting discharge disposition (area under the curve: 0.83; 95% CI, 0.72–0.94; p < 0.0001). CONCLUSIONS:. Early neurorehabilitation guided by CRS-R appears to be feasible and safe in the ICU following hemorrhagic stroke complicated by DoC and may enhance access to inpatient rehabilitation, with the potential for lasting benefit on recovery. Further research is needed to assess generalizability and understand the impact on long-term outcomes.

Flexible viscoelastic foams with relative density in the range of 5-50% are widely used to control interaction forces, notably in cushions for impact protection, shoes, mechanical grippers, etc. The design of new foams to improve performance is challenging, due to the lack of efficient models to connect cellular architecture, viscoelasticity of the base resin, and non-linear responses that stem from large deformation of open pores. This paper presents highly efficient solutions for the response of linearly viscoelastic, kinematically non-linear and shear-deformable struts that are loaded at an oblique angle to their axis. The models can be used to predict structure-property relationships for strut-based metamaterials, including non-linear stress-strain response and accompanying hysteresis. To illustrate this, the entire design space of a simple unit cell is mapped in terms of a broad range of strut angles and thicknesses; the unit cell is inspired by features in stochastic foams that dominate their response. An enormous range of stress-strain responses can be obtained from this single foam-like cell, including purely softening, purely stiffening, and non-monotonic stiffness with adjustable tangent moduli. The model is also used to illustrate connections between viscoelastic material parameters, loading rate, and hysteresis for two distinct classifications of non-linear stress-strain response.

Tumor Treating Fields (TTFields) extend the survival of glioblastoma (GBM) patients by interfering with a broad range of tumor cellular processes. Among these, TTFields disrupt primary cilia stability on GBM cells. Here we asked if concomitant treatment of TTFields with other agents that interfere with GBM ciliogenesis further suppress GBM cell proliferation in vitro. Aurora kinase A (AURKA) promotes both cilia disassembly and GBM growth. Inhibitors of AURKA, such as Alisertib, inhibit cilia disassembly and increase ciliary frequency in various cell types. However, we found that Alisertib treatment significantly reduced GBM cilia frequency in gliomaspheres across multiple patient derived cell lines, and in patient biopsies treated ex vivo. This effect appeared glioma cell-specific as it did not reduce normal neuronal or glial cilia frequencies. Alisertib-mediated depletion of glioma cilia appears specific to AURKA and not AURKB inhibition, and attributable in part to autophagy pathway activation. Treatment of two different GBM patient-derived cell lines with TTFields and Alisertib resulted in a significant reduction in cell proliferation compared to either treatment alone. However, this effect was not cilia-dependent as the combined treatment reduced proliferation in cilia-depleted cell lines lacking, ARL13B, or U87MG cells which are naturally devoid of ARL13B+ cilia. Thus, Alisertib-mediated effects on glioma cilia may be a useful biomarker of drug efficacy within tumor tissue. Considering Alisertib can cross the blood brain barrier and inhibit intracranial growth, our data warrant future studies to explore whether concomitant Alisertib and TTFields exposure prolongs survival of brain tumor-bearing animals in vivo.

Tumor vasculature plays a crucial role in tumor progression, affecting nutrition and oxygen transportation as well as the efficiency of drug delivery. While targeting pro-angiogenic growth factors has been a significant focus for treating tumor angiogenesis, recent studies indicate that metabolism also plays a role in regulating endothelial cell behavior. Like cancer cells, tumor endothelial cells undergo metabolic changes that regulate rearrangement for tip cell position during angiogenesis. Our previous studies have shown that altered mechanical properties of the collagen matrix regulate angiogenesis and can promote a tumor vasculature phenotype. Here, we examine the effect of collagen density on endothelial cell tip–stalk cell rearrangement and cellular energetics during angiogenic sprouting. We find that increased collagen density leads to an elevated energy state and an increased rate of tip–stalk cell switching, which is correlated with the energy state of the cells. Tip cells exhibit higher glucose uptake than stalk cells, and inhibition of glucose uptake revealed that invading sprouts rely on glucose to meet elevated energy requirements for invasion in dense matrices. This work helps to elucidate the complex interplay between the mechanical microenvironment and the endothelial cell metabolic status during angiogenesis, which could have important implications for developing new anti-cancer therapies.

Abstract Brexucabtagene autoleucel (brexu‐cel) is an autologous CD19 CAR T‐cell product, approved for relapsed/refractory (r/r) mantle cell lymphoma (MCL). In ZUMA‐2, brexu‐cel demonstrated impressive responses in patients failing ≥2 lines, including a bruton's tyrosine kinase inhibitor, with an overall and complete response rate of 93% and 67%, respectively. Here, we report our real‐world intention‐to‐treat (ITT) outcomes for brexu‐cel in consecutive, prospectively approved patients, from 12 institutions in the United Kingdom between February 2021 and June 2023, with a focus on feasibility, efficacy, and tolerability. Of 119 approved, 104 underwent leukapheresis and 83 received a brexu‐cel infusion. Progressive disease (PD) and/or manufacturing (MF) were the most common reasons for failure to reach harvest and/or infusion. For infused patients, best overall and complete response rates were 87% and 81%, respectively. At a median follow‐up of 13.3 months, median progression‐free survival (PFS) for infused patients was 21 months (10.1–NA) with a 6‐ and 12‐month PFS of 82% (95% confidence interval [CI], 71–89) and 62% (95% CI, 49–73), respectively. ≥Grade 3 cytokine release syndrome and neurotoxicity occurred in 12% and 22%, respectively. On multivariate analysis, inferior PFS was associated with male sex, bulky disease, ECOG PS > 1 and previous MF. Cumulative incidence of non‐relapse mortality (NRM) was 6%, 15%, and 25% at 6, 12, and 24 months, respectively, and mostly attributable to infection. Outcomes for infused patients in the UK are comparable to ZUMA‐2 and other real‐world reports. However, ITT analysis highlights a significant dropout due to PD and/or MF. NRM events warrant further attention.