Search

IntroductionThe “silent” antimicrobial resistance (AMR) pandemic is responsible for nearly five million deaths annually, with a group of seven biofilm-forming pathogens, known as the ESKAPEE pathogens, responsible for 70% of these fatalities. Biofilm-resident bacteria, as they exist within the disease site, are canonically highly resistant to antibiotics. One strategy to counter AMR and improve disease resolution involves developing methods to disrupt biofilms. These methods aim to release bacteria from the protective biofilm matrix to facilitate their killing by antibiotics or immune effectors. Several laboratories working on such strategies have demonstrated that bacteria newly released from a biofilm display a transient phenotype of significantly increased susceptibility to antibiotics. Similarly, we developed an antibody-based approach for biofilm disruption directed against the two-membered DNABII family of bacterial DNA-binding proteins, which serve as linchpins to stabilize the biofilm matrix. The incubation of biofilms with α-DNABII antibodies rapidly collapses them to induce a population of newly released bacteria (NRel).MethodsIn this study, we used a humanized monoclonal antibody (HuTipMab) directed against protective epitopes of a DNABII protein to determine if we could disrupt biofilms formed by the high-priority ESKAPEE pathogens as visualized by confocal laser scanning microscopy (CLSM) and COMSTAT2 analysis. Then, we demonstrated the potentiated killing of the induced NRel by seven diverse classes of traditional antibiotics by comparative plate count.ResultsTo this end, ESKAPEE biofilms were disrupted by 50%−79% using a single tested dose and treatment period with HuTipMab. The NRel of each biofilm were significantly more sensitive to killing than their planktonically grown counterparts (heretofore, considered to be the most sensitive to antibiotic-mediated killing), even when tested at a fraction of the MIC (1/250–1/2 MIC). Moreover, the bacteria that remained within the biofilms of two representative ESKAPEE pathogens after HuTipMab disruption were also significantly more susceptible to killing by antibiotics.DiscussionNew data presented in this study support our continued development of a combinatorial therapy wherein HuTipMab is delivered to a patient with recalcitrant disease due to an ESKAPEE pathogen to disrupt a pathogenic biofilm, along with a co-delivered dose of an antibiotic whose ability to rapidly kill the induced NRel has been demonstrated. This novel regimen could provide a more successful clinical outcome to those with chronic, recurrent, or recalcitrant diseases, while limiting further contribution to AMR.

To evaluate a potentially valuable tool to study cancer progression and metastasis, we characterized a novel murine model composed of a parental oncogene-transformed embryonic fibroblast line and five cell lines isolated from progressively advanced tumors. Lines derived from distant metastases displayed significantly greater rates of motility, invasiveness, and extracellular acidification than lines derived from a primary tumor or local metastases. A comprehensive proteomic analysis of these cells showed numerous oncogenes to be upregulated and tumor suppressors to be downregulated in the advanced lines, and provided novel targets for future examination. The first cell line capable of extravasation displayed particularly high proteomic variation, which could provide insight into its epithelial to mesenchymal transition. The proteomic variation was less than that of an established human breast cancer model, indicating that the observed differences are more likely contributive to tumorigenesis. In total, we validated a novel cell model for the study of tumorigenesis, while providing a robust proteomic data set to guide future research.

OBJECTIVES Improved knowledge of hepatitis C virus (HCV) screening, linkage to care, and treatment is needed among nonspecialist medical professionals to combat the HCV epidemic. The authors sought to implement and analyze the impact of an HCV curriculum for primary care professionals (PCPs) across the state of Vermont, USA. METHODS This investigation was a retrospective analysis of uptake of a Vermont HCV educational curriculum and its impact on HCV direct-acting antiviral (DAA) prescribing rates within the state before and after the study period. The curriculum was delivered online and in-person over 2 years from 2019 to 2020. The primary outcome was health care professional performance on a pre- and post-curriculum short-term knowledge assessment exam. The secondary outcome was assessing the number of unique healthcare professionals within a single payor database prescribing DAA treatment for HCV in Vermont before and after the study intervention, from January 1, 2017 until December 1, 2021. RESULTS There were 31 unique respondents on the pre- and post-intervention examinations, which represented 9% of known participants. Respondents included physicians (n = 15), nurse practitioners (n = 8), and nurses (n = 8). Pre- and post-intervention knowledge scores increased significantly across all provider groups, from 3.2 (SD 0.6) to 4.5 (SD 0.4) 1 to 5 scale ( P = .01). The total number of unique HCV DAA therapy prescribers decreased over the study period, from 17 in 2017 to 9 in 2021. CONCLUSIONS A Vermont statewide HCV curriculum for PCPs was successful at increasing short-term HCV-related knowledge. However, this did not obviously translate to an increase in new professionals treating HCV.

BackgroundVeterans with psychiatric disorders want additional career development services to support their recovery and pursuit of meaningful employment. However, no career counseling programs have been designed for this specific population. We developed the Purposeful Pathways intervention to fill this need. ObjectiveThis study protocol aims to (1) evaluate the feasibility and acceptability of the Purposeful Pathways intervention for veterans living with psychiatric disorders and (2) explore preliminary clinical outcome data. MethodsA total of 50 veterans who are participating in transitional work vocational rehabilitation services at a Veterans Affairs hospital will be randomized to either treatment as usual or the augmented treatment condition (treatment as usual plus Purposeful Pathways). Feasibility will be assessed via recruitment rates, clinician fidelity to treatment, retention rates, and acceptability of randomization procedures. Acceptability will be assessed via client satisfaction at treatment termination using quantitative and qualitative data collection. Preliminary clinical and vocational outcomes will be assessed at baseline, 6 weeks, 12 weeks (treatment termination), and a 3-month follow-up via quantitative measures assessing vocational functioning, vocational process, and mental and physical functioning. ResultsThis pilot randomized controlled trial is beginning recruitment in June 2023 and is expected to continue through November 2025. Data collection is expected to be completed by February 2026, with full data analysis completed by March 2026. ConclusionsFindings from this study will provide information on the feasibility and acceptability of the Purposeful Pathways intervention, as well as secondary outcomes related to vocational functioning, vocational process, and mental and physical functioning. Trial RegistrationClinicalTrials.gov NCT04698967; https://clinicaltrials.gov/ct2/show/NCT04698967 International Registered Report Identifier (IRRID)PRR1-10.2196/47986

Despite over 20 years of effort in academic research centers, start-up companies, and established pharmaceutical companies, there are no FDA-approved inner ear therapeutics for treatment of sensorineural hearing loss. There are a number of systemic barriers to creation of this new field of inner ear therapeutics. These include insufficient understanding of the particularity of different causes of hearing loss at the cellular and molecular level, lack of diagnostics of adequate sensitivity and specificity to discern these differences in vivo, a tendency for start-up biotech/pharma companies to prioritize competition over collaboration, and a drug development ecosystem that is really in the “pre-competitive” phase and a lack of infrastructure to develop, validate, gain regulatory approval, and successfully market an inner ear therapeutic. These issues will be discussed in this perspective article and a proposed remedy in the form of an inner ear therapeutics “moon shot” will be offered.

Voluntary wheel running (VWR) is widely used to study how exercise impacts a variety of physiologies and pathologies in rodents. The primary activity readout of VWR is aggregated wheel turns over a given time interval (most often, days). Given the typical running frequency of mice (∼4 Hz) and the intermittency of voluntary running, aggregate wheel turn counts, therefore, provide minimal insight into the heterogeneity of voluntary activity. To overcome this limitation, we developed a six-layer convolutional neural network (CNN) to determine the hindlimb foot strike frequency of mice exposed to VWR. Aged female C57BL/6 mice (22 months, n = 6) were first exposed to wireless angled running wheels for 2 h/d, 5 days/wk for 3 weeks with all VWR activities recorded at 30 frames/s. To validate the CNN, we manually classified foot strikes within 4800 1-s videos (800 randomly chosen for each mouse) and converted those values to frequency. Upon iterative optimization of model architecture and training on a subset of classified videos (4400), the CNN model achieved an overall training set accuracy of 94%. Once trained, the CNN was validated on the remaining 400 videos (accuracy: 81%). We then applied transfer learning to the CNN to predict the foot strike frequency of young adult female C57BL6 mice (4 months, n = 6) whose activity and gait differed from old mice during VWR (accuracy: 68%). In summary, we have developed a novel quantitative tool that non-invasively characterizes VWR activity at a much greater resolution than was previously accessible. This enhanced resolution holds potential to overcome a primary barrier to relating intermittent and heterogeneous VWR activity to induced physiological responses.

The novel mechanisms of action (MOA) derived from some recently introduced molecular targets have led to regulatory approvals for rapid acting antidepressants (RAADs) that can generate responses within hours or days, rather than weeks or months. These novel targets include the N-methyl-D-glutamate receptor antagonist ketamine, along with its enantiomers and various derivatives, and the allosteric modulators of gamma-aminobutyric acid (GABA) receptors. There has also been a strong resurgence in interest in psychedelic compounds that impact a range of receptor sites including D1, 5-HT7, KOR, 5-HT5A, Sigma-1, NMDA, and BDNF. The RAADs developed from these novel targets have enabled successful treatment for difficult to treat depressed individuals and has generated a new wave of innovation in research and treatment. Despite the advances in the neurobiology and clinical treatment of mood disorders, we are still using rating instruments that were created decades ago for drugs from a different era (e.g., The Hamilton and Montgomery-Åsberg depression rating scales, HDRS, and MADRS) continue to be used. These rating instruments were designed to assess mood symptoms over a 7-day time frame. Consequently, the use of these rating instruments often requires modifications to address items that cannot be assessed in short time frames, such as the sleep and appetite items. This review describes the adaptative approaches that have been made with the existing scales to meet this need and examines additional domains such as daily activities, side effects, suicidal ideation and behavior, and role functioning. Recommendations for future studies are described, including the challenges related to implementation of these adapted measures and approaches to mitigation.

Background: Patients with a pseudarthrosis after anterior cervical discectomy and fusion (ACDF) may have concurrent adjacent segment disease (ASD). Although prior studies have shown posterior cervical decompression and fusion (PCDF) is effective in repairing pseudarthrosis, improvement in patient reported outcomes (PROs) has been marginal. The aim of this study is to evaluate the effectiveness of PCDF in achieving symptom relief in patients with pseudarthrosis after ACDF and whether that is altered by the additional treatment of ASD. Methods: Thirty-two patients with pseudarthrosis were compared with 31 patients with pseudarthrosis and concurrent ASD after ACDF who underwent revision PCDF with a minimum 1-year follow-up. Primary outcomes measures included the neck disability index (NDI), and numerical rating scale (NRS) scores for neck and arm pain. Secondary measures included estimated blood loss (EBL), operating room (OR) time, and length of stay. Results: Demographics between cohorts were similar, however there was a significantly higher mean body mass index (BMI) in the group with concurrent ASD (32.23 vs. 27.76, p=.007). Patients with concurrent ASD had more levels fused during PCDF (3.7 vs. 1.9, p

Background: Novel methods of bone density assessment using computed tomography (CT) and magnetic resonance imaging (MRI) have been increasingly reported in the spine surgery literature. Correlations between these newer measurements and traditional Dual-Energy X-ray Absorptiometry (DEXA) is not well known. The purpose of this study is to perform an updated systematic review of correlations between bone mineral density (BMD) from CT or MRI and DEXA. Methods: Articles published between 2011 and 2021 that reported correlations between the CT-HU or MRI measurements to DEXA t-scores or BMD of lumbar spine or hip were included in this systematic review. Results: A total of 25 studies (15 CT, 10 MRI) met the inclusion criteria with a total number of 2,745 patients. The pooled correlation coefficient of spine CT-HU versus spine DEXA, spine CT-HU versus hip DEXA and spine CT-HU versus lowest t-score were 0.60, 0.50 and 0.60 respectively. Regarding spine DEXA parameters, the pooled r2 for spine CT-HU versus spine t-score was 0.684 and spine CT-HU versus spine BMD was 0.598. Furthermore, in patients undergoing spine surgery in four studies, the pooled correlation between spine CT and spine DEXA was (r2: 0.64). In MRI studies, the pooled r2 of spine MRI versus spine DEXA and spine MRI versus hip DEXA were -0.41 and -0.44 respectively. Conclusions: CT-HU has stronger correlations with DEXA than MRI measurements. Lumbar CT-HU has the highest pooled correlation (r2 = 0.6) with both spine DEXA and lowest skeletal t-score followed by lumbar CT-HU with hip DEXA (r2 = 0.5) and lumbar MRI with hip (r2 = 0.44) and spine (r2 = 0.41) DEXA. Both imaging modalities achieved only a moderate correlation with DEXA. Few studies in both modalities have investigated the correlation in spine surgery populations and the available data shows that the correlations are worse in the degenerative spine population. A careful interruption of CT HU and MRI measurement when evaluation of BMD as they only moderately correlated with DEXA scores. At this time, it is unclear which modality is a better predictor of mechanical complications and clinical outcomes in spine surgery patients.

Undifferentiated round cell sarcomas (URCS) are an extremely rare form of cancer, comprising a heterogeneous group of bone and soft tissue tumors occurring primarily in young adults (but distributed across all ages; range 2mo-81 years) and displaying a slight male predominance. URCS are primarily identified by their genetic abnormalities, with three recurrent oncogenic fusion rearrangements associated in the literature and recently added to the WHO classifications: EWSR1-non-ETS, BCOR-CCNB3, and CIC-DUX4. We present/describe a rare case of an URCS diagnosed in a 27-year-old female following six years of non-specific symptoms including pain and swelling of the third proximal phalanx. This case is only the third reported in a digit and, based on FoundationOne genotyping, was uniquely treated with tamoxifen. This patient also received radiation therapy, surgical resection, and palliative chemotherapy. Metastases were noted in the lungs and mediastinum, and the patient died of disease 89 months after the first treatment. While diagnosis of these tumors is becoming increasingly dependent on molecular profiles, treatment remains mostly unchanged and does not largely reflect the use of genetic results in treatment plans. A comprehensive review of the literature was completed to examine URCS and assist in the development of a diagnostic/treatment algorithm.

Improving geo-information decision evaluation is an important part of geospatial decision support research, particularly when considering vulnerability, risk, resilience, and sustainability (V-R-R-S) of urban land–water systems (ULWSs). Previous research enumerated a collection of V-R-R-S conceptual component commonalties and differences resulting in a synthesis concept called VRRSability. As a single concept, VRRSability enhances our understanding of the relationships within and among V-R-R-S. This paper reports research that extends and deepens the VRRSability synthesis by elucidating relationships among the V-R-R-S concepts, and organizes them into a VRRSability conceptual framework meant to guide operationalization within decision support systems. The core relationship within the VRRSability framework is ‘functional performance’, which couples land and water concerns within complex ULWS. Using functional performance, we elucidate other significant conceptual relationships, e.g., scale, scenarios and social knowledge, among others. A narrative about the functional performance of green stormwater infrastructure as part of a ULWS offers a practical application of the conceptual framework. VRRSability decision evaluation trade-offs among land and water emerge through the narrative, particularly how land cover influences water flow, which in turn influences water quality. The discussion includes trade-offs along risk–resilience and vulnerability–sustainability dimensions as key aspects of functional performance. Conclusions include knowledge contributions about a VRRSability conceptual framework and the next steps for operationalization within decision support systems using artificial intelligence.

Among carbapenem-resistant Enterobacterales (CRE) are diverse mechanisms, including those that are resistant to meropenem but susceptible to ertapenem, adding further complexity to the clinical landscape. This study investigates the emergence of ertapenem-resistant, meropenem-susceptible (ErMs) Escherichia coli and Klebsiella pneumoniae CRE across five hospitals in San Antonio, Texas, USA, from 2012 to 2018. The majority of the CRE isolates were non-carbapenemase producers (NCP; 54%; 41/76); 56% of all NCP isolates had an ErMs phenotype. Among ErMs strains, E. coli comprised the majority (72%). ErMs strains carrying blaCTX-M had, on average, 9-fold higher copies of blaCTX-M than CP-ErMs strains as well as approximately 4-fold more copies than blaCTX-M-positive but ertapenem- and meropenem-susceptible (EsMs) strains (3.7 vs. 0.9, p < 0.001). Notably, carbapenem hydrolysis was observed to be mediated by strains harboring blaCTX-M with and without a carbapenemase(s). ErMs also carried more mobile genetic elements, particularly IS26 composite transposons, than EsMs (37 vs. 0.2, p < 0.0001). MGE- ISVsa5 was uniquely more abundant in ErMs than either EsMs or ErMr strains, with over 30 more average ISVsa5 counts than both phenotype groups (p < 0.0001). Immunoblot analysis demonstrated the absence of OmpC expression in NCP-ErMs E. coli, with 92% of strains lacking full contig coverage of ompC. Overall, our findings characterize both collaborative and independent efforts between blaCTX-M and OmpC in ErMs strains, indicating the need to reappraise the term “non-carbapenemase (NCP)”, particularly for strains highly expressing blaCTX-M. To improve outcomes for CRE-infected patients, future efforts should focus on mechanisms underlying the emerging ErMs subphenotype of CRE strains to develop technologies for its rapid detection and provide targeted therapeutic strategies.

One of the main obstacles to therapeutic success in colorectal cancer (CRC) is the development of acquired resistance to treatment with drugs such as 5-fluorouracil (5-FU). Whilst some resistance mechanisms are well known, it is clear from the stasis in therapy success rate that much is still unknown. Here, a proteomics approach is taken towards identification of candidate proteins using 5-FU-resistant sublines of human CRC cell lines generated in house. Using a multiplexed stable isotope labelling with amino acids in cell culture (SILAC) strategy, 5-FU-resistant and equivalently passaged sensitive cell lines were compared to parent cell lines by growing in Heavy medium with 2D liquid chromatography and Orbitrap Fusion™ Tribrid™ Mass Spectrometry analysis. Among 3003 commonly quantified proteins, six (CD44, APP, NAGLU, CORO7, AGR2, PLSCR1) were found up-regulated, and six (VPS45, RBMS2, RIOK1, RAP1GDS1, POLR3D, CD55) down-regulated. A total of 11 of the 12 proteins have a known association with drug resistance mechanisms or role in CRC oncogenesis. Validation through immunodetection techniques confirmed high expression of CD44 and CD63, two known drug resistance mediators with elevated proteomics expression results. The information revealed by the sensitivity of this method warrants it as an important tool for elaborating the complexity of acquired drug resistance in CRC.

After decades of brown dwarf discovery and follow-up, we can now infer the functional form of the mass distribution within 20 pc, which serves as a constraint on star formation theory at the lowest masses. Unlike objects on the main sequence that have a clear luminosity-to-mass correlation, brown dwarfs lack a correlation between an observable parameter (luminosity, spectral type, or color) and mass. A measurement of the brown dwarf mass function must therefore be procured through proxy measurements and theoretical models. We utilize various assumed forms of the mass function, together with a variety of birthrate functions, low-mass cutoffs, and theoretical evolutionary models, to build predicted forms of the effective temperature distribution. We then determine the best fit of the observed effective temperature distribution to these predictions, which in turn reveals the most likely mass function. We find that a simple power law ( ${dN}/{dM}\propto {M}^{-\alpha }$ ) with α ≈ 0.5 is optimal. Additionally, we conclude that the low-mass cutoff for star formation is ≲0.005 M _⊙ . We corroborate the findings of Burgasser, which state that the birthrate has a far lesser impact than the mass function on the form of the temperature distribution, but we note that our alternate birthrates tend to favor slightly smaller values of α than the constant birthrate. Our code for simulating these distributions is publicly available. As another use case for this code, we present findings on the width and location of the subdwarf temperature gap by simulating distributions of very old (8–10 Gyr) brown dwarfs.

Titan’s impact craters are hundreds of meters shallower than expected, compared to similar-sized craters on Ganymede. Only 90 crater candidates have been identified, the majority of which have low certainty of an impact origin. Many processes have been suggested to shallow, modify, and remove Titan’s craters, including fluvial erosion by liquid from rainfall, aeolian sand infill, and topographic relaxation induced by insulating sand infill. Here we propose an additional mechanism: topographic relaxation due to an insulating methane clathrate crustal layer in Titan’s upper ice shell. We use finite element modeling to test whether a clathrate crust 5, 10, 15, or 20 km thick could warm the ice shell and relax craters to their currently observed depths or remove them completely. We model the viscoelastic evolution of crater diameters 120, 100, 85, and 40 km, with two initial depths based on depth−diameter trends of Ganymede’s craters. We find that all clathrate crustal thicknesses result in rapid topographic relaxation, despite Titan’s cold surface temperature. The 5 km thick clathrate crust can reproduce nearly all of the observed shallow depths, many in under 1000 yr. A 10 km thick crust can reproduce the observed depths of the larger craters over geologic timescales. If relaxation is the primary cause of the shallow craters, then the clathrate thickness is likely 5–10 km thick. Topographic relaxation alone cannot remove craters; crater rims and flexural moats remain. To completely remove craters and reproduce the observed biased crater distribution, multiple modification processes must act together.

Evidence for the beneficial role of impacts in the creation of urable or habitable environments on Earth prompts the question of whether meteorite impacts could play a similar role at other potentially urable/habitable worlds like Enceladus, Europa, and Titan. In this work, we demonstrate that to first order, impact conditions on these worlds are likely to have been consistent with the survival of organic compounds and/or sufficient for promoting synthesis in impact melt. We also calculate melt production and freezing times for crater sizes found at Enceladus, Europa, and Titan and find that even the smallest craters at these worlds offer the potential to study the evolution of chemical pathways within impact melt. These first-order calculations point to a critical need to investigate these processes at higher fidelity with lab experiments, sophisticated thermodynamic and chemical modeling, and, eventually, in situ investigations by missions.

Seismology is a powerful tool for probing the deep interiors of planetary bodies. Just as deep moonquakes triggered by Earth’s tides occur on the Moon, as observed by the Apollo seismometers, icy moons of the giant planets may also have seismically active deep interiors, opening up future prospects for in situ seismic investigations at their surfaces. Of notable interest is Jupiter’s moon Europa, with its dynamic ice shell and potentially habitable subsurface ocean. In this work, we use different interior models of the Moon and model the tidal stress inside them to determine the most likely times and locations for the triggering of tidal moonquakes. Using the Mohr–Coulomb failure criterion, we derive cohesion and friction values for the lunar interior to match the observations of deep moonquakes by Apollo at a depth between 700 and 1200 km. By extending the same approach to different interior models of Europa, we show that Europa quakes triggered by the tides of Jupiter are 10 times more likely to occur than tidal moonquakes. The strength and depth of these tidal Europa quakes (euroquakes) strongly depend on the interior structure, with stronger events at the core–mantle boundary for liquid core models, while solid core models can be more prone to failure at the bottom of the ocean floor. Models without a metallic core favor failure in the upper third of the mantle with event strength similar to that in the solid core models.

A complete accounting of nearby objects—from the highest-mass white dwarf progenitors down to low-mass brown dwarfs—is now possible, thanks to an almost complete set of trigonometric parallax determinations from Gaia, ground-based surveys, and Spitzer follow-up. We create a census of objects within a Sun-centered sphere of 20 pc radius and check published literature to decompose each binary or higher-order system into its separate components. The result is a volume-limited census of ∼3600 individual star formation products useful in measuring the initial mass function across the stellar (

Recent work has suggested exceptional species-level diversity in the lichen-forming Lecanora polytropa complex (Lecanoraceae, Ascomycota). However, biogeographic patterns and the spatial structuring of this diversity remains poorly known. To investigate diversity across multiple spatial scales, we sampled members of this species complex from two distinct regions—the Pacific Coast Ranges in southern Alaska, USA, and montane habitats in Spain. We also included sequence data from several species within this complex that were recently described from populations in France. Using the standard DNA barcoding marker and a sequence-based species delimitation approach (ASAP), we inferred a total of 123 candidate species (SHs) within the Lecanora polytropa complex, 32 of which were sampled for the first time here. Of 123 SHs, 21 had documented intercontinental distributions, while the vast majority were found at much smaller spatial scales. From our samples collected from Alaska, USA, and Spain, representing 36 SHs, we found high genetic diversity occurring within each sampled site, but limited overlap among all sites. Mountain ranges in both regions had high proportions of endemic lineages, with the highest diversity and endemism occurring in mountain ranges in Spain. Our sequence data generally support the recent taxonomic proposals, and an integrative taxonomy may help partly resolve the taxonomic conundrums within this hyper-diverse lineage.

Particle acceleration is a fundamental process arising in many astrophysical objects, including active galactic nuclei, black holes, neutron stars, gamma-ray bursts, accretion disks, solar and stellar coronae, and planetary magnetospheres. Its ubiquity means energetic particles permeate the Universe and influence the conditions for the emergence and continuation of life. In our solar system, the Sun is the most energetic particle accelerator, and its proximity makes it a unique laboratory in which to explore astrophysical particle acceleration. However, despite its importance, the physics underlying solar particle acceleration remain poorly understood. The SPARK mission will reveal new discoveries about particle acceleration through a uniquely powerful and complete combination of γ-ray, X-ray, and EUV imaging and spectroscopy at high spectral, spatial, and temporal resolutions. SPARK’s instruments will provide a step change in observational capability, enabling fundamental breakthroughs in our understanding of solar particle acceleration and the phenomena associated with it, such as the evolution of solar eruptive events. By providing essential diagnostics of the processes that drive the onset and evolution of solar flares and coronal mass ejections, SPARK will elucidate the underlying physics of space weather events that can damage satellites and power grids, disrupt telecommunications and GPS navigation, and endanger astronauts in space. The prediction of such events and the mitigation of their potential impacts are crucial in protecting our terrestrial and space-based infrastructure.

The study aimed to differentiate experts from novices in laparoscopic surgery tasks using electroencephalogram (EEG) topographic features. A microstate-based common spatial pattern (CSP) analysis with linear discriminant analysis (LDA) was compared to a topography-preserving convolutional neural network (CNN) approach. Expert surgeons (N = 10) and novice medical residents (N = 13) performed laparoscopic suturing tasks, and EEG data from 8 experts and 13 novices were analysed. Microstate-based CSP with LDA revealed distinct spatial patterns in the frontal and parietal cortices for experts, while novices showed frontal cortex involvement. The 3D CNN model (ESNet) demonstrated a superior classification performance (accuracy > 98%, sensitivity 99.30%, specificity 99.70%, F1 score 98.51%, MCC 97.56%) compared to the microstate based CSP analysis with LDA (accuracy ~90%). Combining spatial and temporal information in the 3D CNN model enhanced classifier accuracy and highlighted the importance of the parietal–temporal–occipital association region in differentiating experts and novices.

Recently, a Y727C variant in the dual-specific 3′,5′-cyclic nucleotide phosphodiesterase 11A (PDE11A-Y727C) was linked to increased sleep quality and reduced myopia risk in humans. Given the well-established role that the PDE11 substrates cAMP and cGMP play in eye physiology and sleep, we determined if (1) PDE11A protein is expressed in the retina or other eye segments in mice, (2) PDE11A-Y7272C affects catalytic activity and/or subcellular compartmentalization more so than the nearby suicide-associated PDE11A-M878V variant, and (3) Pde11a deletion alters eye growth or sleep quality in male and female mice. Western blots show distinct protein expression of PDE11A4, but not PDE11A1-3, in eyes of Pde11a WT, but not KO mice, that vary by eye segment and age. In HT22 and COS-1 cells, PDE11A4-Y727C reduces PDE11A4 catalytic activity far more than PDE11A4-M878V, with both variants reducing PDE11A4-cAMP more so than PDE11A4-cGMP activity. Despite this, Pde11a deletion does not alter age-related changes in retinal or lens thickness or axial length, nor vitreous or anterior chamber depth. Further, Pde11a deletion only minimally changes refractive error and sleep quality. That said, both variants also dramatically alter the subcellular compartmentalization of human and mouse PDE11A4, an effect occurring independently of dephosphorylating PDE11A4-S117/S124 or phosphorylating PDE11A4-S162. Rather, re-compartmentalization of PDE11A4-Y727C is due to the loss of the tyrosine changing how PDE11A4 is packaged/repackaged via the trans-Golgi network. Therefore, the protective impact of the Y727C variant may reflect a gain-of-function (e.g., PDE11A4 displacing another PDE) that warrants further investigation in the context of reversing/preventing sleep disturbances or myopia.

A dragonfly visual neuron independently facilitates responses to rival targets within the same visual field, mediating selective attention.

Abstract Merkel cell carcinoma (MCC) is a rare neuroendocrine cutaneous cancer, with incidence of less than 1/100,000, low survival rates and variable response to chemotherapy or immunotherapy. Herein we explore the application of patient tumor organoids (PTOs) in modeling personalized research in this rare malignancy. Unsorted and non-expanded MCC tumor cells were isolated from surgical specimens and suspended in an ECM based hydrogel, along with patient matched blood and lymph node tissue to generate immune enhanced organoids (iPTOs). Organoids were treated with chemotherapy or immunotherapy agents and efficacy was determined by post-treatment viability. Nine specimens from seven patients were recruited from December 2018-January 2022. Establishment rate was 88.8% (8/9) for PTOs and 77.8% (7/9) for iPTOs. Histology on matched patient tissues and PTOs demonstrated expression of MCC markers. Chemotherapy response was exhibited in 4/6 (66.6%) specimens with cisplatin and doxorubicin as the most effective agents (4/6 PTO sets) while immunotherapy was not effective in tested iPTO sets. Four specimens from two patients demonstrated resistance to pembrolizumab, correlating with the corresponding patient’s treatment response. Routine establishment and immune enhancement of MCC PTOs is feasible directly from resected surgical specimens allowing for personalized research and exploration of treatment regimens in the preclinical setting.

14,000 year old DNA reveals the evolutionary dynamics and adaptations of South American vultures.

Abstract Virtual reality (VR) simulator has emerged as a laparoscopic surgical skill training tool that needs validation using brain–behavior analysis. Therefore, brain network and skilled behavior relationship were evaluated using functional near-infrared spectroscopy (fNIRS) from seven experienced right-handed surgeons and six right-handed medical students during the performance of Fundamentals of Laparoscopic Surgery (FLS) pattern of cutting tasks in a physical and a VR simulator. Multiple regression and path analysis (MRPA) found that the FLS performance score was statistically significantly related to the interregional directed functional connectivity from the right prefrontal cortex to the supplementary motor area with F (2, 114) = 9, p

The aim of this study is to elucidate the character of the earliest phases of Jurassic rifting in North-East Greenland. To achieve this, detailed sedimentological analysis and geological mapping were undertaken on the outcrops of central Kuhn Ø (74°53’55’’N,20°20’56”W). In this region the basement is overlain by the fluvial Bastians Dal Formation (Middle Jurassic) which is, in turn, overlain by the coal-bearing Muslingebjerg Formation. A maximum thickness of 140 m is calculated for the Bastians Dal Formation and mapping of stratal geometries demonstrates thinning to both the north and south, confirming that these deposits infill a palaeovalley. Predominantly south-westward palaeocurrent orientations are observed and likely reflect the orientation of the palaeovalley (NE–SW). The overlying Muslingebjerg Formation displays significant lateral variations in thickness as well as facies, thickening from a 5-m-thick coal seam in the north to 50 m in the south. Southern outcrops include two intervals of fine-grained sandstones displaying low-angle and trough cross-bedding some of which contain suggestions of tidal bundling. The arrangement of facies suggests that coal formation occurred in both fluvial- and shallow-marine (tidal?) environments. Coals are similar to those described elsewhere from the Muslingebjerg Formation and display subtle differences consistent with variable degrees of marine influence. Mapping demonstrates the presence of an NE–SW-oriented bounding fault in the south of the region into which the Muslingebjerg Formation thickens. This likely also controlled the orientation of the underlying NE–SW-aligned palaeovalley and is oblique to the proposed overall N–S orientation of faulting related to rifting through the Mid to Late Jurassic. Instead, these alignments resemble those that define pre-Jurassic phases of rifting and may therefore indicate a transitional phase of tectonism. Faulting on a similar alignment can be traced SW, cutting Lindeman Fjord and following the valleys east of the A. P. Olsen Land plateau.

Abstract Concussion diagnosis is complicated by a lack of objective measures. Ubiquitin carboxyl-terminal esterase L1 (UCHL1) is a biomarker that has been shown to increase following traumatic brain injury but has not been investigated in concussed athletes on the sideline of athletic events. Therefore, this study was conducted to determine if UCHL1 can be used to aid in sideline concussion diagnosis. Blood was taken via standard venipuncture from a recreationally active control group, a group of rugby players prior to match play (pre-match), rugby players following match-play (match-control), and rugby players after suffering a sport-related concussion (SRC). UCHL1 was not significantly different among groups (p > 0.05) and was unable to distinguish between SRC and controls (AUROC 0.05). However, when sex-matched data were used, it was found that the female match-control group had a significantly higher serum UCHL1 concentration than the pre-match group (p = 0.041). Differences were also found in serum UCHL1 concentrations between male and female athletes in the match-control group (p = 0.007). This study does not provide evidence supporting the use of UCHL1 in sideline concussion diagnosis when blood is collected soon after concussion but does show differences in serum UCHL1 accumulation between males and females.

Background: As the proportion of visceral (VAT) to subcutaneous adipose tissue (SAT) may contribute to type 2 diabetes (T2D) development, we examined this relation in a cross-sectional design within the Multiethnic Cohort that includes Japanese Americans known to have high VAT. The aim was to understand how ectopic fat accumulation differs by glycemic status across ethnic groups with disparate rates of obesity, T2D, and propensity to accumulate VAT. Methods: In 2013–2016, 1,746 participants aged 69.2 (standard deviation, 2.7) years from five ethnic groups completed questionnaires, blood collections, and whole-body dual X-ray absorptiometry and abdominal magnetic resonance imaging scans. Participants with self-reported T2D and/or medication were classified as T2D, those with fasting glucose >125 and 100–125 mg/dL as undiagnosed cases (UT2D) and prediabetes (PT2D), respectively. Using linear regression, we estimated adjusted means of adiposity measures by T2D status. Results: Overall, 315 (18%) participants were classified as T2D, 158 (9%) as UT2D, 518 (30%) as PT2D, and 755 (43%) as normoglycemic (NG), with significant ethnic differences (P < 0.0001). In fully adjusted models, VAT, VAT/SAT, and percent liver fat increased significantly from NG, PT2D, UT2D, to T2D (P < 0.001). Across ethnic groups, the VAT/SAT ratio was lowest for NG participants and highest for T2D cases. Positive trends were observed in all groups except African Americans, with highest VAT/SAT in Japanese Americans. Conclusion: These findings indicate that VAT plays an important role in T2D etiology, in particular among Japanese Americans with high levels of ectopic adipose tissue, which drives the development of T2D to a greater degree than in other ethnic groups.

EGFR regulates cellular processes across the animal kingdom. Here, the authors show that transmembrane conformational coupling is the first step in EGFR signaling, providing evidence for the existence of transmembrane intramolecular conformational changes in a single pass membrane protein.

Abstract Plant growth under spectrally-enriched low light conditions leads to adjustment in the relative abundance of the two photosystems in an acclimatory response known as photosystem stoichiometry adjustment. Adjustment of photosystem stoichiometry improves the quantum efficiency of photosynthesis but how this process perceives light quality changes and how photosystem amount is regulated remain largely unknown. By using a label-free quantitative mass spectrometry approach in Arabidopsis here we show that photosystem stoichiometry adjustment is primarily driven by the regulation of photosystem I content and that this forms the major thylakoid proteomic response under light quality. Using light and redox signaling mutants, we further show that the light quality-responsive accumulation of photosystem I gene transcripts and proteins requires phytochrome B photoreceptor but not plastoquinone redox signaling as previously suggested. In far-red light, the increased acceptor side limitation might deplete active photosystem I pool, further contributing to the adjustment of photosystem stoichiometry.

Abstract Activity-induced neurogenesis has been extensively studied in rodents but the lack of ante mortem accessibility to human brain at the cellular and molecular levels limits studies of the process in humans. Using cerebral spheroids derived from human induced pluripotent stem cells (iPSCs), we investigated the effects of 4-aminopyridine (4AP) on neuronal activity and associated neurogenesis. Our studies demonstrate that 4AP increases neuronal activity in 3-month-old cerebral spheroids while increasing numbers of new neurons and decreasing the population of new glial cells. We also observed a significant decrease in the expression of miR-135a, which has previously been shown to be decreased in exercise-induced neurogenesis. Predicted targets of miR-135a include key participants in the SMAD2/3 and BDNF pathways. Together, our results suggest that iPSC-derived cerebral spheroids are an attractive model to study several aspects of activity-induced neurogenesis.

An attractive route for carbon-negative synthesis of biochemical products is the reverse β-oxidation pathway coupled to the Wood-Ljungdahl pathway. Here the authors use a high-throughput in vitro prototyping workflow to screen 762 unique pathway combinations using cell-free extracts tailored for r-BOX to identify enzyme sets for enhanced product selectivity.

Abstract The excavations undertaken at the Campo de Hockey site in 2008 led to the identification of a major Neolithic necropolis in the former Island of San Fernando (Bay of Cádiz). This work presents the results of the latest studies, which indicate that the site stands as one of the oldest megalithic necropolises in the Iberian Peninsula. The main aim of this work is to present with precision the chronology of this necropolis through a Bayesian statistical model that confirms that the necropolis was in use from c. 4300 to 3800 cal BC. The presence of prestige grave goods in the earliest and most monumental graves suggest that the Megalithism phenomenon emerged in relation to maritime routes linked to the distribution of exotic products. We also aim to examine funerary practices in these early megalithic communities, and especially their way of life and the social reproduction system. As such, in addition to the chronological information and the Bayesian statistics, we provide the results of a comprehensive interdisciplinary study, including anthropological, archaeometric and genetic data.

Background The Distance-Oxygen-Gender-Age-Physiology (DO-GAP) index has been shown to improve prognostication in idiopathic pulmonary fibrosis (IPF) compared to the Gender-Age-Physiology (GAP) score. We sought to externally validate the DO-GAP index compared to the GAP index for baseline risk assessment in patients with IPF. Additionally, we evaluated the utility of serial change in the DO-GAP index in predicting survival. Methods We performed an analysis of patients with IPF from the Pulmonary Fibrosis Foundation-Patient Registry (PFF-PR). Discrimination and calibration of the two models were assessed to predict transplant-free survival and IPF-related mortality. Joint longitudinal time-to-event modelling was utilised to individualise survival prediction based on DO-GAP index trajectory. Results There were 516 patients with IPF from the PFF-PR with available demographics, pulmonary function tests, 6-min walk test data and outcomes included in this analysis. The DO-GAP index (C-statistic: 0.73) demonstrated improved discrimination in discerning transplant-free survival compared to the GAP index (C-statistic: 0.67). DO-GAP index calibration was adequate, and the model retained predictive accuracy to identify IPF-related mortality (C-statistic: 0.74). The DO-GAP index was similarly accurate in the subset of patients taking antifibrotic medications. Serial change in the DO-GAP index improved model discrimination (cross-validated area under the curve: 0.83) enabling the personalised prediction of disease trajectory in individual patients. Conclusion The DO-GAP index is a simple, validated, multidimensional score that accurately predicts transplant-free survival in patients with IPF and can be adapted longitudinally in individual patients. The DO-GAP may also find use in studies of IPF to risk stratify patients and possibly as a clinical trial end-point.

BackgroundChronic pain and problematic substance use are commonly co-occurring and highly detrimental issues that are especially prevalent in U.S. veteran populations. Although COVID-19 made clinical management of these conditions potentially difficult, some research suggests that certain veterans with these conditions did not experience this period as negatively as others. It is thus important to consider whether resilience factors, such as the increasingly-studied process of psychological flexibility, might have led to better outcomes for veterans managing pain and problematic substance use during this time of global crisis.MethodsThis planned sub-analysis of a larger cross-sectional, anonymous, and nationally-distributed survey (N = 409) was collected during the first year of the COVID-19 pandemic. Veteran participants completed a short screener and battery of online surveys assessing pain severity and interference, substance use, psychological flexibility, mental health functioning, and pandemic-related quality of life.ResultsFor veterans with chronic pain and problematic substance use, the pandemic resulted in a significant lowering of their quality of life related to meeting basic needs, emotional health, and physical health compared to veterans with problematic substance use but no chronic pain diagnosis. However, moderation analyses revealed that veterans with these comorbid conditions experienced less negative impacts from the pandemic on quality of life and mental health when they reported greater psychological flexibility. For veterans with problematic substance use only, psychological flexibility was also related to better mental health functioning, but did not significantly correlate with their quality of life.ConclusionResults highlight how COVID-19 differentially impacted veterans with both problematic substance use and chronic pain, such that this group reported particularly negative impacts of the pandemic on multiple areas of quality of life. However, our findings further emphasize that psychological flexibility, a modifiable resiliency process, also buffered against some of the negative impacts of the pandemic on mental health and quality of life. Given this, future research into the impact of natural crises and healthcare management should investigate how psychological flexibility can be targeted to help increase resiliency for veterans with chronic pain and problematic substance use.

Abstract COVID‐19 related lung disease (CRLD) has emerged as an indication for lung transplantation (LT) in highly select patients. The prevalence and prognostic implication of coexisting pulmonary hypertension (PH) in patients with CRLD listed for LT is not known. Adult patients in the United Network for Organ Sharing database listed for LT for COVID‐19 related acute respiratory distress syndrome or fibrosis through March 2022 were identified. The prevalence and impact of precapillary PH on pre‐ and posttransplantation survival was determined. Time‐to‐event analysis was used to compare outcomes between those with and without precapillary PH. We identified 245 patients listed for LT for CRLD who had right heart catheterization data available at the time of registry listing. Median age of the cohort was 54 years (interquartile range [IQR]: 46, 60), 56 (22.9%) were female, and the median lung allocation score was 81.3 (IQR: 53.3, 89.4). The prevalence of precapillary PH at the time of transplant listing was 27.9%. There was no significant difference in pretransplant mortality in patients with and without precapillary PH (sHR: 0.5; 95% confidence interval [CI]: 0.1–1.7, p = 0.261). A total of 187 patients ultimately underwent LT; of those, 60 (31.0%) were identified as having precapillary PH during the waitlist period. Posttransplantation survival was similar between patients with and without pretransplant precapillary PH (hazard ratio: 0.96; 95% CI: 0.2–3.7, p = 0.953). We observed a high rate of concomitant precapillary PH in patients listed for LT for CRLD. Though common, coexisting precapillary PH was not associated with a significant difference in either pre‐ or post‐transplantation outcomes.

Abstract Pulmonary hypertension (PH) is a frequent complication of interstitial lung disease (ILD). Although PH has mostly been described in idiopathic pulmonary fibrosis, it can manifest in association with many other forms of ILD. Associated pathogenetic mechanisms are complex and incompletely understood but there is evidence of disruption of molecular and genetic pathways, with panvascular histopathologic changes, multiple pathophysiologic sequelae, and profound clinical ramifications. While there are some recognized clinical phenotypes such as combined pulmonary fibrosis and emphysema and some possible phenotypes such as connective tissue disease associated with ILD and PH, the identification of further phenotypes of PH in ILD has thus far proven elusive. This statement reviews the current evidence on the pathogenesis, recognized patterns, and useful diagnostic tools to detect phenotypes of PH in ILD. Distinct phenotypes warrant recognition if they are characterized through either a distinct presentation, clinical course, or treatment response. Furthermore, we propose a set of recommendations for future studies that might enable the recognition of new phenotypes.

ABSTRACT Mycobacterium tuberculosis (Mtb) is transmitted through aerosols and primarily colonizes within the lung. The World Health Organization estimates that Mtb kills ~1.4 million people every year. A key aspect that makes Mtb such a successful pathogen is its ability to overcome iron limitation mounted by the host immune response. In our previous studies, we have shown that Mtb can utilize iron from heme, the largest source of iron in the human host, and that it uses two redundant heme utilization pathways. In this study, we show that the ESX-4 type VII secretion system (T7SS) is necessary for extracellular heme uptake into the Mtb cell through both heme utilization pathways. ESX-4 influences the secretion of the culture filtrate proteins Rv0125 and Rv1085c, which are also necessary for efficient heme utilization. We also discovered that deletion of the alternative sigma factor SigM significantly reduced Mtb heme utilization through both pathways and predict that SigM is a global positive regulator of core heme utilization genes of both pathways. Finally, we present the first direct evidence that some mycobacterial PPE (proline-proline-glutamate motif) proteins of the PPE protein family are pore-forming membrane proteins. Altogether, we identified core components of both Mtb Heme utilization pathways that were previously unknown and identified a novel channel-forming membrane protein of Mtb. IMPORTANCE M. tuberculosis (Mtb) is completely dependent on iron acquisition in the host to cause disease. The largest source of iron for Mtb in the human host is heme. Here, we show that the ancestral ESX-4 type VII secretion system is required for the efficient utilization of heme as a source of iron, which is an essential nutrient. This is another biological function identified for ESX-4 in Mtb, whose contribution to Mtb physiology is poorly understood. A most exciting finding is that some mycobacterial PPE (proline-proline-glutamate motif) proteins that have been implicated in the nutrient acquisition are membrane proteins that can form channels in a lipid bilayer. These observations have far-reaching implications because they support an emerging theme that PPE proteins can function as channel proteins in the outer mycomembrane for nutrient acquisition. Mtb has evolved a heme uptake system that is drastically different from all other known bacterial heme acquisition systems.

IntroductionNecrotizing enterocolitis (NEC) is a complex inflammatory disorder of the human intestine that most often occurs in premature newborns. Animal models of NEC typically use mice or rats; however, pigs have emerged as a viable alternative given their similar size, intestinal development, and physiology compared to humans. While most piglet NEC models initially administer total parenteral nutrition prior to enteral feeds, here we describe an enteral-feed only piglet model of NEC that recapitulates the microbiome abnormalities present in neonates that develop NEC and introduce a novel multifactorial definitive NEC (D-NEC) scoring system to assess disease severity.MethodsPremature piglets were delivered via Caesarean section. Piglets in the colostrum-fed group received bovine colostrum feeds only throughout the experiment. Piglets in the formula-fed group received colostrum for the first 24 h of life, followed by Neocate Junior to induce intestinal injury. The presence of at least 3 of the following 4 criteria were required to diagnose D-NEC: (1) gross injury score ≥4 of 6; (2) histologic injury score ≥3 of 5; (3) a newly developed clinical sickness score ≥5 of 8 within the last 12 h of life; and (4) bacterial translocation to ≥2 internal organs. Quantitative reverse transcription polymerase chain reaction was performed to confirm intestinal inflammation in the small intestine and colon. 16S rRNA sequencing was performed to evaluate the intestinal microbiome.ResultsCompared to the colostrum-fed group, the formula-fed group had lower survival, higher clinical sickness scores, and more severe gross and histologic intestinal injury. There was significantly increased bacterial translocation, D-NEC, and expression of IL-1α and IL-10 in the colon of formula-fed compared to colostrum-fed piglets. Intestinal microbiome analysis of piglets with D-NEC demonstrated lower microbial diversity and increased Gammaproteobacteria and Enterobacteriaceae.ConclusionsWe have developed a clinical sickness score and a new multifactorial D-NEC scoring system to accurately evaluate an enteral feed-only piglet model of NEC. Piglets with D-NEC had microbiome changes consistent with those seen in preterm infants with NEC. This model can be used to test future novel therapies to treat and prevent this devastating disease.

Whether microbes show habitat preferences is a fundamental question in microbial ecology. If different microbial lineages have distinct traits, those lineages may occur more frequently in habitats where their traits are advantageous. Sphingomonas is an ideal bacterial clade in which to investigate how habitat preference relates to traits because these bacteria inhabit diverse environments and hosts. Here we downloaded 440 publicly available Sphingomonas genomes, assigned them to habitats based on isolation source, and examined their phylogenetic relationships. We sought to address whether: (1) there is a relationship between Sphingomonas habitat and phylogeny, and (2) whether there is a phylogenetic correlation between key, genome-based traits and habitat preference. We hypothesized that Sphingomonas strains from similar habitats would cluster together in phylogenetic clades, and key traits that improve fitness in specific environments should correlate with habitat. Genome-based traits were categorized into the Y-A-S trait-based framework for high growth yield, resource acquisition, and stress tolerance. We selected 252 high quality genomes and constructed a phylogenetic tree with 12 well-defined clades based on an alignment of 404 core genes. Sphingomonas strains from the same habitat clustered together within the same clades, and strains within clades shared similar clusters of accessory genes. Additionally, key genome-based trait frequencies varied across habitats. We conclude that Sphingomonas gene content reflects habitat preference. This knowledge of how environment and host relate to phylogeny may also help with future functional predictions about Sphingomonas and facilitate applications in bioremediation.

BackgroundAlthough electronic health information sharing is expanding nationally, it is unclear whether electronic health information sharing improves patient outcomes, particularly for patients who are at the highest risk of communication challenges, such as older adults with Alzheimer disease. ObjectiveTo determine the association between hospital-level health information exchange (HIE) participation and in-hospital or postdischarge mortality among Medicare beneficiaries with Alzheimer disease or 30-day readmissions to a different hospital following an admission for one of several common conditions. MethodsThis was a cohort study of Medicare beneficiaries with Alzheimer disease who had one or more 30-day readmissions in 2018 following an initial admission for select Hospital Readmission Reduction Program conditions (acute myocardial infarction, congestive heart failure, chronic obstructive pulmonary disease, and pneumonia) or common reasons for hospitalization among older adults with Alzheimer disease (dehydration, syncope, urinary tract infection, or behavioral issues). Using unadjusted and adjusted logistic regression, we examined the association between electronic information sharing and in-hospital mortality during the readmission or mortality in the 30 days following the readmission. ResultsA total of 28,946 admission-readmission pairs were included. Beneficiaries with same-hospital readmissions were older (aged 81.1, SD 8.6 years) than beneficiaries with readmissions to different hospitals (age range 79.8-80.3 years, P

Introduction Although intravenous thrombolysis (IVT) represents standard‐of‐care treatment for acute ischemic stroke (AIS) in eligible adult patients, definitive evidence‐based guidelines and randomized clinical trial data evaluating its safety and efficacy in the pediatric population remain absent from the literature. We aim to evaluate the utilization and outcomes of IVT for the treatment of pediatric AIS using a large national registry. Methods Weighted hospitalizations for pediatric (

Objective: To apply a normalized competitive index over a 20-year period to analyse applicant trends in orthopaedic surgery residency programs. Design: A retrospective analysis of orthopaedic surgery residency program data from the National Resident Matching Program (NRMP) Main Residency Match data from 2003 to 2022 and NRMP Charting Outcomes data from 2007 to 2021 was performed. A competitive index (CI) was utilized by dividing the number of programs ranked per applicant, multiplied by available positions, and by the match rate for each year. Next, the index was normalized to a value of 1 to establish a normalized competitive index (NCI) by dividing the yearly CI by the average CI. Setting: National Resident Matching Program (NRMP) Main Residency Match data from 1992 to 2021 and NRMP Charting Outcomes data from 2007 to 2021. Participants: Orthopaedic surgery residency applicants. Results: The NCI was significantly different over time (R2= 0.95, p < 0.001) with an upward trending NCI slope. Total applicants have nearly doubled over the past two decades (2003, 830 vs. 2022, 1460; p0.83, p < 0.001). Research output quadrupled over the 2007–2021 period (3 vs. 14, p < 0.001). Conclusion: Despite match rates remaining constant over time, the NCI metric demonstrated the increasing competitiveness of orthopaedic surgery residency programs over twenty years. Match rates have inherent limitations as a singular metric and should only be used in conjunction with additional metrics. Establishing a more comprehensive index with applicant metrics provides insight into the growing competitiveness of orthopaedic programs and a more comprehensive outlook for future applicants.

Renal cell carcinomas present with locally advanced or metastatic disease in 25% of patients. Thermal ablation may be considered in selected patients with single-site or oligometastatic disease in selected patients. We describe single-session transarterial particle embolization with the assistance of a balloon-occlusion catheter and microwave ablation of a large hypervascular adrenal metastasis using cone beam CT and fluoroscopic XperGuide needle guidance.

The “gunsight approach” was initially described as the use of overlapping snares and through- and-through puncture of the portal vein and inferior vena cava for the creation of a transcaval portosystemic shunt. This technique can be adapted for the creation of an extra-anatomic chan- nel between any 2 locations where snares can be deployed. We explain the technique, discuss finer technical points, and describe 2 cases where refractory vascular occlusions are crossed using this technique. The first case involves an extensively calcified femoral arterial chronic total occlusion where subintimal tracking past the occlusion is achieved, but luminal re-entry is ham- pered by dense calcific plaque refractory to multiple re-entry devices. The second case involves a chronic venous occlusion along the femoral vein with loss of in-line flow due to prior stenting. In both cases, the gunsight technique was successfully used as a bailout option after standard recanalization techniques were unsuccessful.

Abstract Sotatercept is an activin receptor type IIA-Fc (ActRIIA-Fc) fusion protein that improves cardiopulmonary function in patients with pulmonary arterial hypertension (PAH) by selectively trapping activins and growth differentiation factors. However, the cellular and molecular mechanisms of ActRIIA-Fc action are incompletely understood. Here, we determined through genome-wide expression profiling that inflammatory and immune responses are prominently upregulated in the lungs of a Sugen-hypoxia rat model of severe angio-obliterative PAH, concordant with profiles observed in PAH patients. Therapeutic treatment with ActRIIA-Fc—but not with a vasodilator—strikingly reversed proinflammatory and proliferative gene expression profiles and normalized macrophage infiltration in diseased rodent lungs. Furthermore, ActRIIA-Fc normalized pulmonary macrophage infiltration and corrected cardiopulmonary structure and function in Bmpr2 haploinsufficient mice subjected to hypoxia, a model of heritable PAH. Three high-affinity ligands of ActRIIA-Fc each induced macrophage activation in vitro, and their combined immunoneutralization in PAH rats produced cardiopulmonary benefits comparable to those elicited by ActRIIA-Fc. Our results in complementary experimental and genetic models of PAH reveal therapeutic anti-inflammatory activities of ActRIIA-Fc that, together with its known anti-proliferative effects on vascular cell types, could underlie clinical activity of sotatercept as either monotherapy or add-on to current PAH therapies.

Abstract Objective This scoping review describes the relationship between tooth retention, health, and quality of life in older adults. Methods Seven databases were searched for English language articles for subjects ≥ 65 y from 1981 to 2021. Exposure was tooth retention (≥ 20), and outcomes were general/systemic health and quality of life. Methodological quality was assessed using the Newcastle–Ottawa Scale and Cochrane Risk of Bias 2.0 tool. Results 140 articles were included, only four were randomized trials. Inter-rater agreement (κ) regarding study inclusion was 0.924. Most were assessed with low risk of bias (n = 103) and of good quality (n = 96). Most studies were conducted in Japan (n = 60) and Europe (n = 51) and only nine in the US. Tooth retention was referred to as “functional dentition” in 132 studies and “shortened dental arch” in 19 studies. Study outcomes were broadly synthesized as (1) cognitive decline/functional dependence, (2) health status/chronic diseases, (3) nutrition, and (4) quality of life. Discussion There is a positive relationship between tooth retention, overall health, and quality of life. Older adults retaining ≥ 20 teeth are less likely to experience poorer health. Having

Abstract Objective Surgical education is changing in an era of new regulations and evolving training cultures. We sought to understand the factors that affect operative experiences during otolaryngology residency. Methods From December 2019 to December 2020, five otolaryngology training programs used the SIMPL OR smartphone application to evaluate residents after each operation. Residents and attendings rated the trainee's autonomy on a 4‐level Zwisch scale, performance on a 5‐level scale, and case complexity on a 3‐level scale. We examined associations between ratings of autonomy and performance with variables including postgraduate year (PGY), case complexity, gender, week of the academic year (AY), and whether multiple procedures were logged. Results 78 attendings and 92 residents logged 2984 evaluations. PGY level and week of the AY were positively associated with attending ratings of autonomy and performance (PGY3 vs. PGY2: B = 0.63, p

CD28 costimulatory signalling can be suppressed by immune checkpoints, such as CTLA-4 and PD-1. Here the authors describe the design of the fusion therapeutic davoceticept (ALPN-202), based on a variant CD80 extracellular domain engineered to bind PD-L1 as well as CD28 and CTLA-4, providing direct T cell costimulation and dual checkpoint inhibition to enable anti-tumor immune responses.