Comparative effectiveness of perioperative physical activity in older adults with lung cancer and their family caregivers: design of a multicenter pragmatic randomized trial.

BACKGROUND: With a median age at diagnosis of 70, lung cancer remains a significant public health challenge for older Americans. Surgery is a key component in treating most patients with non-metastatic lung cancer. These patients experience postoperative pain, fatigue, loss of respiratory capacity, and decreased physical function. Data on quality of life (QOL) in older adults undergoing lung cancer surgery is limited, and few interventions are designed to target the needs of older adults and their family caregivers (FCGs). The primary aim of this comparative effectiveness trial is to determine whether telephone-based physical activity coaching before and after surgery will be more beneficial than physical activity self-monitoring alone for older adults and their FCGs. METHODS: In this multicenter comparative effectiveness trial, 382 older adults (≥ 65 years) with lung cancer and their FCGs will be recruited before surgery and randomized to either telephone-based physical activity coaching or physical activity self-monitoring alone. Participants allocated to the telephone-based coaching comparator will receive five telephone sessions with coaches (1 pre and 4 post surgery), an intervention resource manual, and a wristband pedometer. Participants in the self-monitoring only arm will receive American Society of Clinical Oncology (ASCO) physical activity information and wristband pedometers. All participants will be assessed at before surgery (baseline), at discharge, and at days 30, 60, and 180 post-discharge. The primary endpoint is the 6-minute walk test (6MWT) at 30 days post-discharge. Geriatric assessment, lower extremity function, self-reported physical function, self-efficacy, and QOL will also be assessed. DISCUSSION: The trial will determine whether this telephone-based physical activity coaching approach can enhance postoperative functional capacity and QOL outcomes for older adults with lung cancer and their FCGs. Trial results will provide critical findings to inform models of postoperative care for older adults with cancer and their FCGs. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT06196008.

Longitudinal Improvement in Public Speaking Skills Through Participation in a Resident Public Speaking Curriculum.

OBJECTIVE: To promote public speaking skills, a pediatrics residency program developed a longitudinal public speaking curriculum grounded in deliberate practice and reflective practice. METHODS: Residents delivered annual presentations and received formal feedback. Audience evaluation forms from 2005-2017 were included for analysis. The form used 5-point scales (5= best) for specific presentation elements (clarity, eye contact/body language, pace, succinct text, minimally distracting delivery, clear conclusion, appropriate learning objectives, achieving learning objectives, and answering questions) and for overall quality. Longitudinal changes in scores were analyzed with paired t tests. RESULTS: Overall, 5,771 evaluations of 276 presentations given by 97 residents were analyzed. Between post-graduate year (PGY)-1 and PGY-3 presentations, mean overall rating increased from 4.38 to 4.59 (P<.001, d=0.51). The median percentage of 5-point scores increased from 50.0% (IQR, 24.3%-65.4%) to 72.5% (IQR, 53.3%-81.2%). Eight of 9 specific elements showed significant increases (median effect size 0.55). Residents whose initial presentations ranked in the bottom quartile had larger improvements than residents initially ranked in the top quartile. CONCLUSIONS: After pediatric residents participated in a public speaking curriculum with targeted objectives, formal feedback, and repeated practice, their public speaking skills improved. Public speaking curricula can and should be adopted more broadly in graduate medical education.

Active mutual conjoint estimation of multiple contrast sensitivity functions.

Recent advances in nonparametric contrast sensitivity function (CSF) estimation have yielded a new tradeoff between accuracy and efficiency not available to classical parametric estimators. An additional advantage of this new framework is the ability to independently tune multiple aspects of the estimator to seek further improvements. Machine learning CSF estimation with Gaussian processes allows for design optimization in the kernel, acquisition function, and underlying task representation, to name a few. This article describes a novel kernel for CSF estimation that is more flexible than a kernel based on strictly functional forms. Despite being more flexible, it can result in a more efficient estimator. Further, trial selection for data acquisition that is generalized beyond pure information gain can also improve estimator quality. Finally, introducing latent variable representations underlying general CSF shapes can enable simultaneous estimation of multiple CSFs, such as from different eyes, eccentricities, or luminances. The conditions under which the new procedures perform better than previous nonparametric estimation procedures are presented and quantified.

Changes in higher order cognitive function between four watch keeping schedules.

Maritime industries utilize many different watch keeping schedules to maintain vigilance and crew safety around the clock. These schedules can be fatiguing, negatively impacting vigilant attention. This has led to the consideration of schedules that might allow for more sleep time, but how these schedules impact higher order cognitive function remains unclear. These schedules require assessment with tasks that are relevant to real-world operations on maritime vessels. This study investigated the effect of four schedules on higher order cognitive function. N = 27 (16 female) participants were recruited to a 10-day laboratory study, comparing four schedules. The schedules investigated were eight-on/eight-off/four-on/four-off (8/8/4/4) with sleep from 09:30 to 16:00 (condition A); six-on/six-off (6/6) with sleep from 08:30 to 12:30 and 21:30 to 00:00 (condition B); four-on/four-off (4/4/4/4/4/4) with sleep from 18:00 to 00:30 (condition C); and four-on/four-off (4/4/4/4/4/4) with sleep from 01:30 to 08:00 (condition D). Higher order cognitive function was assessed 2-3× daily whilst "on watch" using tests of visual scanning, learning, working memory, mental flexibility, and visuomotor control. Conditions were ranked and stability of performance on watch was compared between conditions using Kruskal-Wallis tests. Cognitive function within condition B was ranked the worst for most of the tasks. However, the stability of higher order cognitive function was poorest across the waking day within condition A. These findings highlight the variability in cognitive capacities during different watch keeping schedules.

12-Lipoxygenase inhibition suppresses islet immune and inflammatory responses and delays autoimmune diabetes in human gene replacement mice.

Type 1 diabetes (T1D) is characterized by the autoimmune destruction of insulin-producing ß cells and involves an interplay between ß cells and cells of the innate and adaptive immune systems. We investigated the therapeutic potential of targeting 12-lipoxygenase (12-LOX), an enzyme implicated in inflammatory pathways in ß cells and macrophages, using a mouse model in which the endogenous mouse Alox15 gene is replaced by the human ALOX12 gene. Our findings demonstrate that VLX-1005, a potent 12-LOX inhibitor, effectively delays the onset of autoimmune diabetes in human gene replacement non-obese diabetic (NOD) mice. By spatial proteomics analysis, VLX-1005 treatment resulted in marked reductions in infiltrating T and B cells and macrophages with accompanying increases in immune checkpoint molecules PD-L1 and PD-1, suggesting a shift towards an immune-suppressive microenvironment. RNA sequencing analysis of isolated islets from inhibitor-treated mice revealed significant alteration of cytokine-responsive pathways. RNA sequencing of polarized proinflammatory macrophages showed that VLX-1005 significantly reduced the interferon response. Our studies demonstrate that the ALOX12 human replacement gene mouse provides a platform for the preclinical evaluation of LOX inhibitors and supports VLX-1005 as an inhibitor of human 12-LOX that engages the enzymatic target and alters the inflammatory phenotypes of islets and macrophages to promote the delay of autoimmune diabetes.

Frameshift Mutations in Leukemia-Associated Genes Correlate With Superior Outcomes in Patients Undergoing Allogeneic Stem Cell Transplant for De Novo Acute Myeloid Leukemia.

Background: Allogeneic stem cell transplant (allo-SCT) is a mainstay of treatment for acute myeloid leukemia (AML). Its success depends largely on response of donor T lymphocytes against leukemia cells, known as graft-vs-leukemia (GvL) effect. A key potential driver of GvL is immune response to mutation-derived neoantigens. Previous studies in solid tumors have demonstrated enhanced immunogenicity of frameshift (FS)-derived peptides vs. those from non-synonymous single nucleotide variants (SNVs). We therefore hypothesized that AML cases bearing FS mutations in leukemia-associated genes would be more immunogenic than those with only other types of mutations (non-FS), and thus benefit more from allo-SCT via more robust GvL. Methods: We identified AML patients who had undergone allo-SCT between 2010 and 2022 and had next-generation sequencing data available on diagnostic specimens using a 42-gene hot spot panel. We compared the impact of tumor mutations present at diagnosis on overall survival and relapse-free survival based on FS versus non-FS status. Results: Ninety-five AML allo-SCT patients were identified. We observed superior relapse-free survival (P = 0.038, hazard ratio (HR): 0.24) and borderline superior overall survival (P = 0.058, HR: 0.55) post-transplant in de novo AML patients, who had at least one FS mutation (other than NPM1) in one of the 42 assessed genes versus those with only non-FS mutations. Conclusions: Our findings suggest that FS-mutated AML cases may benefit more from allo-SCT than those with only non-FS mutations, possibly due to increased generation of immunogenic neoepitopes. If validated in an expanded study, incorporation of somatic FS mutation status in AML could improve patient selection algorithms for bone marrow transplant and thereby lead to superior outcomes.

Inertial Measurement Unit and Heart Rate Monitoring to Assess Cardiovascular Fitness of Manual Wheelchair Users during the Six-Minute Push Test.

Manual wheelchair users (MWUs) are prone to a sedentary life that can negatively affect their physical and cardiovascular health, making regular assessment important to identify appropriate interventions and lifestyle modifications. One mean of assessing MWUs' physical health is the 6 min push test (6MPT), where the user propels themselves as far as they can in six minutes. However, reliance on observer input introduces subjectivity, while limited quantitative data inhibit comprehensive assessment. Incorporating sensors into the 6MPT can address these limitations. Here, ten MWUs performed the 6MPT with additional sensors: two inertial measurement units (IMUs)-one on the wheelchair and one on the wrist together with a heart rate wristwatch. The conventional measurements of distance and laps were recorded by the observer, and the IMU data were used to calculate laps, distance, speed, and cadence. The results demonstrated that the IMU can provide the metrics of the traditional 6MPT with strong significant correlations between calculated laps and observer lap counts (r = 0.947, p < 0.001) and distances (r = 0.970, p < 0.001). Moreover, heart rate during the final minute was significantly correlated with calculated distance (r = 0.762, p = 0.017). Enhanced 6MPT assessment can provide objective, quantitative, and comprehensive data for clinicians to effectively inform interventions in rehabilitation.

Impacts of a herring gull colony on runoff water quality from an urban green roof.

Green infrastructure (GI) strategies, including green roofs, have become a common, decentralized, nature-based strategy for reducing urban runoff and restoring ecosystem services to the urban environment. In this study, we examined the water quality of incident rainfall and runoff from a green roof installed on top of the Jacob K. Javits Convention Center in New York City. Since the 2014 installation of this green roof, one of the largest in North America, a colony of nesting herring gulls grew to approximately 100 nesting pairs in 2018 and 150 nesting pairs in 2019. Water quality monitoring took place between September 2018 and October 2019. Except for phosphorus on some occasions, we found concentrations of nitrate, nitrite, chlorine, sulfate to be below federal drinking water standards. Levels of the fecal indicator bacteria (FIB), total coliform, E. coli, and Enterococcus, were consistently higher in runoff samples than rainwater, ranging from 150 to over 20,000 CFU/100 mL for E. coli and 100 to over 140,000 CFU/100 mL for total coliform. Quantitative polymerase chain reaction (qPCR) methods were used to search for potential opportunistic pathogens, including Legionella spp., Mycobacterium spp., Campylobacter spp., and Salmonella spp. Discovery of the presence of Catellicoccus marimammalium, a gull-associated marker in runoff water indicates that herring gulls are the likely source of contamination. Due to habitat loss, herring gulls, and other Larus gull species are increasingly nesting on urban roofs, both green (such as at the Javits Center) and conventional (such as on Rikers and Governors Islands). Habitat creation is one of the target ecosystem services desired from GI systems. Although the discharge from the green roof of the Javits Center is directed to the city's sewer system, this study demonstrates the need to treat runoff from green roofs with nesting gull populations if its intended use involves reuse or human contact.

Ketogenesis supports hepatic polyunsaturated fatty acid homeostasis via fatty acid elongation.

Therapeutic interventions targeting hepatic lipid metabolism in metabolic dysfunction-associated steatotic liver disease (MASLD) and steatohepatitis (MASH) remain elusive. Using mass spectrometry-based stable isotope tracing and shotgun lipidomics, we established a novel link between ketogenesis and MASLD pathophysiology. Our findings show that mouse liver and primary hepatocytes consume ketone bodies to support fatty acid (FA) biosynthesis via both de novo lipogenesis (DNL) and FA elongation. Analysis of 13 C-labeled FAs in hepatocytes lacking mitochondrial D-ß-hydroxybutyrate dehydrogenase (BDH1) revealed a partial reliance on mitochondrial conversion of D-ßOHB to acetoacetate (AcAc) for cytoplasmic DNL contribution, whereas FA elongation from ketone bodies was fully dependent on cytosolic acetoacetyl-CoA synthetase (AACS). Ketone bodies were essential for polyunsaturated FA (PUFA) homeostasis in hepatocytes, as loss of AACS diminished both free and esterified PUFAs. Ketogenic insufficiency depleted liver PUFAs and increased triacylglycerols, mimicking human MASLD, suggesting that ketogenesis supports PUFA homeostasis, and may mitigate MASLD-MASH progression in humans.

A Measure of the Impact on Real-Time Patient Care of Evidence-based Medicine Logs.

Introduction: Evidence-based medicine (EBM) is a critical skill for physicians, and EBM competency has been shown to increase implementation of best medical practices, reduce medical errors, and increase patient-centered care. Like any skill, EBM must be practiced, receiving iterative feedback to improve learners' comprehension. Having residents document patient interactions in logbooks to allow for residency program review, feedback, and documentation of competency has been previously described as a best practice within emergency medicine (EM) to document practice-based learning (PBL) competency. Quantifying how residents use the information they query, locate, evaluate, and apply while providing direct patient care can measure the efficacy of EBM education and provide insight into more efficient ways of providing medical care. Methods: Practice-based learning logs were surveys created to record resident EBM activity on-shift and were placed into our residency management software program. Residents were required to submit 3-5 surveys of EBM activity performed during a 28-day rotation during which additional information was sought. This study included all PBL logs completed by EM residents from June 1, 2013-May 11, 2020. Using qualitative methodology, a codebook was created to analyze residents' free-text responses to the prompt: "Based on your research, would you have done anything differently?" The codebook was designed to generate a three-digit code conveying the effect of the researched information on the patient about whom the log was written, as well as whether the information would affect future patient care and whether these decisions were based on scientific evidence. Results: A total of 10,574 logs were included for primary analysis. In total, 1,977 (18.7%) logs indicated that the evidence acquired through research would affect future patient care. Of these, 392 (3.7%) explicitly stated that the EBM activity conducted as part of our project led to real-time changes in patient care in the ED and would change future management of patients as well. Conclusion: We present a proof of concept that PBL log activity can lead to integration of evidence-based medicine into real-time patient care. While a convenience sample, our cohort recorded evidence of both lifelong learning and application to patient care.

How to Prepare Neuroanatomical Image Data (an Update).

Image data from a single animal in neuroscientific experiments can be comprised of terabytes of information. Full studies can thus be challenging to analyze, store, view, and manage. What follows is an updated guide for preparing and sharing big neuroanatomical image data. © 2024 Wiley Periodicals LLC. Basic Protocol 1: Naming and organizing images and metadata Basic Protocol 2: Preparing and annotating images for presentations and figures Basic Protocol 3: Assessing the internet environment and optimizing images.

Sleeping Beauty mRNA-LNP enables stable rAAV transgene expression in mouse and NHP hepatocytes and improves vector potency.

Recombinant adeno-associated virus (rAAV) vector gene delivery systems have demonstrated great promise in clinical trials but continue to face durability and dose-related challenges. Unlike rAAV gene therapy, integrating gene addition approaches can provide curative expression in mitotically active cells and pediatric populations. We explored a novel in vivo delivery approach based on an engineered transposase, Sleeping Beauty (SB100X), delivered as an mRNA within a lipid nanoparticle (LNP), in combination with an rAAV-delivered transposable transgene. This combinatorial approach achieved correction of ornithine transcarbamylase deficiency in the neonatal Spfash mouse model following a single delivery to dividing hepatocytes in the newborn liver. Correction remained stable into adulthood, while a conventional rAAV approach resulted in a return to the disease state. In non-human primates, integration by transposition, mediated by this technology, improved gene expression 10-fold over conventional rAAV-mediated gene transfer while requiring 5-fold less vector. Additionally, integration site analysis confirmed a random profile while specifically targeting TA dinucleotides across the genome. Together, these findings demonstrate that transposable elements can improve rAAV-delivered therapies by lowering the vector dose requirement and associated toxicity while expanding target cell types.

Children's confidence on mathematical equivalence and fraction problems.

Metacognition is how people think about their own thinking, and it includes children's confidence in their problem-solving solutions. We assessed children's metacognition in two areas of mathematics that are often plagued by misconceptions and often studied separately-mathematical equivalence (e.g., 3 + 4 = 5 +__) and fraction magnitude (e.g., 1/3 = 2/__). Specifically, we quantified children's metacognitive skills across these topics, examined whether these skills are topic-specific, and determined how these skills covary with domain-general executive functioning. A total of 80 elementary school children (Mage = 7.70 years, SD = 0.69) provided trial-by-trial performance data and confidence judgments on equivalence and fraction problems as well as assessments of executive function. Children's metacognitive skills were especially impaired when using incorrect strategies based on misconceptions, and we did not find robust evidence for cross-topic associations. We found modest associations between children's metacognitive skills and their working memory and inhibitory control. Findings have theoretical and practical implications for understanding which children struggle with these important mathematics concepts and why.

Transcriptome analysis of resistant and susceptible Medicago truncatula genotypes in response to spring black stem and leaf spot disease.

Ascochyta blights cause yield losses in all major legume crops. Spring black stem (SBS) and leaf spot disease is a major foliar disease of Medicago truncatula and Medicago sativa (alfalfa) caused by the necrotrophic fungus Ascochyta medicaginicola. This present study sought to identify candidate genes for SBS disease resistance for future functional validation. We employed RNA-seq to profile the transcriptomes of a resistant (HM078) and susceptible (A17) genotype of M. truncatula at 24, 48, and 72 h post inoculation. Preliminary microscopic examination showed reduced pathogen growth on the resistant genotype. In total, 192 and 2,908 differentially expressed genes (DEGs) were observed in the resistant and susceptible genotype, respectively. Functional enrichment analysis revealed the susceptible genotype engaged in processes in the cell periphery and plasma membrane, as well as flavonoid biosynthesis whereas the resistant genotype utilized calcium ion binding, cell wall modifications, and external encapsulating structures. Candidate genes for disease resistance were selected based on the following criteria; among the top ten upregulated or downregulated genes in the resistant genotype, upregulated over time in the resistant genotype, hormone pathway genes, plant disease resistance genes, receptor-like kinases, contrasting expression profiles in QTL for disease resistance, and upregulated genes in enriched pathways. Overall, 22 candidate genes for SBS disease resistance were identified with support from the literature. These genes will be sources for future targeted mutagenesis and candidate gene validation potentially helping to improve disease resistance to this devastating foliar pathogen.

Analysis of Protein Cysteine Acylation Using a Modified Suspension Trap (Acyl-Trap).

Proteins undergo reversible S-acylation via a thioester linkage in vivo. S-palmitoylation, modification by C16:0 fatty acid, is a common S-acylation that mediates critical protein-membrane and protein-protein interactions. The most widely used S-acylation assays, including acyl-biotin exchange and acyl resin-assisted capture, utilize blocking of free Cys thiols, hydroxylamine-dependent cleavage of the thioester and subsequent labeling of nascent thiol. These assays generally require >500 µg of protein input material per sample and numerous reagent removal and washing steps, making them laborious and ill-suited for high throughput and low input applications. To overcome these limitations, we devised "Acyl-Trap", a suspension trap-based assay that utilizes a thiol-reactive quartz to enable buffer exchange and hydroxylamine-mediated S-acyl enrichment. We show that the method is compatible with protein-level detection of S-acylated proteins (e.g., H-Ras) as well as S-acyl site identification and quantification using "on trap" isobaric labeling and LC-MS/MS from as little as 20 µg of protein input. In mouse brain, Acyl-Trap identified 279 reported sites of S-acylation and 1298 previously unreported putative sites. Also described are conditions for long-term hydroxylamine storage, which streamline the assay. More generally, Acyl-Trap serves as a proof-of-concept for PTM-tailored suspension traps suitable for both traditional protein detection and chemoproteomic workflows.

2D capsid formation within an oscillatory energy landscape: orderly self-assembly depends on the interplay between a dynamic potential and intrinsic relaxation times.

Multiple dissipative self-assembly protocols designed to create novel structures or to reduce kinetic traps have recently emerged. Specifically, temporal oscillations of particle interactions have been shown effective at both aims, but investigations thus far have focused on systems of simple colloids or their binary mixtures. In this work, we expand our understanding of the effect of temporally oscillating interactions to a two-dimensional coarse-grained viral capsid-like model that undergoes a self-limited assembly. This model includes multiple intrinsic relaxation times due to the internal structure of the capsid subunits and, under certain interaction regimes, proceeds via a two-step nucleation mechanism. We find that oscillations much faster than the local intrinsic relaxation times can be described via a time averaged inter-particle potential across a wide range of interaction strengths, while oscillations much slower than these relaxation times result in structures that adapt to the attraction strength of the current half-cycle. Interestingly, oscillation periods similar to these relaxation times shift the interaction window over which orderly assembly occurs by enabling error correction during the half-cycles with weaker attractions. Our results provide fundamental insights to non-equilibrium self-assembly on temporally variant energy landscapes.