Search

Abstract Regulatory T cells (Tregs) with multifaceted functions suppress anti-tumor immunity by signaling surrounding cells. Here we report Tregs use the surface lymphotoxin (LT)α1β2 to preferentially stimulate LT beta receptor (LTβR) nonclassical NFκB signaling on both tumor cells and lymphatic endothelial cells (LECs) to accelerate tumor growth and metastasis. Selectively targeting LTβR nonclassical NFκB pathway inhibits tumor growth and migration in vitro. Leveraging in vivo Treg LTα1β2 interactions with LTβR on tumor cells and LECs, transfer of wild type but not LTα-/- Tregs promotes B16F10 melanoma growth and tumor cell-derived chemokines in LTβR-/- mice; and increases SOX18 and FLRT2 in lymphatic vessels of LTβR-/- melanoma. Blocking the nonclassical pathway suppresses tumor growth and lymphatic metastasis by reducing chemokine production, restricting Treg recruitment to tumors, and retaining intratumoral IFNγ+ CD8 T cells. Our data reveals that Treg LTα1β2 promotes LTβR nonclassical NFκB signaling in tumor cells and LECs providing a rational strategy to prevent Treg promoted tumor growth and metastasis.

Introduction Influenza causes significant morbidity and mortality, but influenza vaccine uptake remains below most countries’ targets. Vaccine policy recommendations vary, as do procedures for reviewing and appraising the evidence.Areas Covered During a series of roundtable discussions, we reviewed procedures and methodologies used by health ministries in four European countries to inform vaccine recommendations. We review the type of evidence currently recommended by each health ministry and the range of approaches toward considering randomized controlled trials (RCTs) and real-world evidence (RWE) studies when setting influenza vaccine recommendations.Expert Opinion Influenza vaccine recommendations should be based on data from both RCTs and RWE studies of efficacy, effectiveness, and safety. Such data should be considered alongside health-economic, cost-effectiveness, and budgetary factors. Although RCT data are more robust and less prone to bias, well-designed RWE studies permit timely evaluation of vaccine benefits, effectiveness comparisons over multiple seasons in large populations, and detection of rare adverse events, under real-world conditions. Given the variability of vaccine effectiveness due to influenza virus mutations and increasing diversification of influenza vaccines, we argue that consideration of both RWE and RCT evidence is the best approach to more nuanced and timely updates of influenza vaccine recommendations.

Abstract Background Preterm birth (PTB) is associated with adverse short- and long-term health. There are known racial, ethnic, and socioeconomic inequities in PTB. Because of historical de jure and modern-day de facto segregation and neighborhood divestment, neighborhoods are a source of structural racism and disenfranchisement and a potential target for policies and interventions to reduce PTB inequity. However, the role of neighborhoods on PTB, specifically among high-risk birthing people, is largely unexplored. Methods The Boston Birth Cohort is a longitudinal birth cohort of birthing people-infant dyads at a safety-net hospital in Boston, MA between 2000 and 2018. The primary outcome was preterm birth at 35 weeks or prior. The primary predictor was neighborhood defined by census tract. We used generalized linear mixed effects models to test our hypothesis that neighborhood accounts for a signficiant proportion of PTB risk among socially at-risk birthing people. Results In multilevel models, neighborhoods were a significant predictor of preterm birth, yet accounted for only 3% of the variability in outcome. In models stratified by race, individual-level factors such as prior preterm birth, nativity status, and advanced birthing person age were significant predictors of PTB. Conclusions Neighborhood is a significant, though small, predictor of preterm birth in a high-risk birthing population. These findings suggest that individual-level interventions, rather than neighborhood-level policies, may be more effective in reducing preterm birth among high-risk birthing populations.

The relationship between diabetes and the development of kidney complications is well known, but the understanding of prediabetes and insulin resistance with impaired kidney function has been scarcely assessed. Various factors could explain this phenomenon, from the lack of standardization in the definitions of prediabetes, to the erratic and inconsistent evidence in large-scale epidemiological and cohort studies. It seems that the pathophysiological pathway of prediabetes could be related to inflammation and neurohormonal hyperactivation, factors present even before the onset of diabetes, which might be the main drivers of glomerular hyperfiltration, albuminuria, and impaired glomerular filtration rate. It is possible that existing treatments for the management of diabetes, as metformin or SGLT2 inhibitors may also be useful in patients with prediabetes with evidence of functional and structural kidney damage. The purpose of this review is to summarize the evidence regarding the relationship between prediabetes (preDM) and the development of CKD. Resumen: La relación entre diabetes y el desarrollo de complicaciones renales es bien conocida; sin embargo la asociación entre prediabetes y la resistencia a la insulina con el daño en la función renal apenas ha sido evaluada. Varios factores podrían explicar este fenómeno, desde la falta de estandarización en las definiciones de prediabetes, hasta la errática e inconsistente evidencia en estudios epidemiológicos y de cohortes a gran escala. Parece que las vías fisiopatológicas en la prediabetes podrían estar relacionadas con inflamación y la hiperactivación del sistema neuro-hormonal, factores presentes incluso antes de la aparición de la diabetes, que podrían ser los principales impulsores de la hiperfiltración glomerular, albuminuria y alteración de la tasa de filtración glomerular. Es posible que los tratamientos existentes para el control de la diabetes, como metformina o los inhibidores SGLT2 también pueden ser útiles en pacientes con prediabetes con evidencia de daño renal funcional o estructural. El propósito de esta revisión es resumir la evidencia sobre la relación entre la prediabetes (preDM) y el desarrollo de la ERC.

Abstract Deep learning (DL) has proven to be important for computed tomography (CT) image denoising. However, such models are usually trained under supervision, requiring paired data that may be difficult to obtain in practice. Diffusion models offer unsupervised means of solving a wide range of inverse problems via posterior sampling. In particular, using the estimated unconditional score function of the prior distribution, obtained via unsupervised learning, one can sample from the desired posterior via hijacking and regularization. However, due to the iterative solvers used, the number of function evaluations (NFE) required may be orders of magnitudes larger than for single-step samplers. In this paper, we present a novel image denoising technique for photon-counting CT by extending the unsupervised approach to inverse problem solving to the case of Poisson flow generative models (PFGM)++. By hijacking and regularizing the sampling process we obtain a single-step sampler, that is NFE = 1. Our proposed method incorporates posterior sampling using diffusion models as a special case. We demonstrate that the added robustness afforded by the PFGM++ framework yields significant performance gains. Our results indicate competitive performance compared to popular supervised, including state-of-the-art diffusion-style models with NFE = 1 (consistency models), unsupervised, and non-DL-based image denoising techniques, on clinical low-dose CT data and clinical images from a prototype photon-counting CT system developed by GE HealthCare.

Abstract Surfaces – by breaking bulk symmetries, introducing roughness, or hosting defects – can significantly influence magnetic order in magnetic materials. Determining their effect on the complex nanometer-scale phases present in certain non-centrosymmetric magnets is an outstanding problem requiring high-resolution magnetic microscopy. Here, we use scanning SQUID microscopy to image the surface of bulk Cu2OSeO3 at low temperature and in a magnetic field applied along $$\left\langle 100\right\rangle$$ 100 . Real-space maps measured as a function of applied field reveal the microscopic structure of the magnetic phases and their transitions. In low applied field, we observe a magnetic texture consistent with an in-plane stripe phase, pointing to the existence of a distinct surface state. In the low-temperature skyrmion phase, the surface is populated by clusters of disordered skyrmions, which emerge from rupturing domains of the tilted spiral phase. Furthermore, we displace individual skyrmions from their pinning sites by applying an electric potential to the scanning probe, thereby demonstrating local skyrmion control at the surface of a magnetoelectric insulator.

Abstract Background In 2019, there was widespread presentation of respiratory distress as well as other organ system involvement in patients with a history of vaping. There continue to be reports of vaping-associated illness (VAI). This has come to be known as e-cigarette and vaping product associated lung injury (EVALI). The mechanism of injury remains unclear. Objectives This study reexamines the clinical characteristics of patients affected by vaping and suggests that lung injury may not be the primary organ dysfunction but be part of a larger systemic illness. Methods This is a retrospective chart review of all patients presenting to one hospital identified as having vaping-associated illness Results Fourteen patients were identified ranging in age from 15 to 33 years. Patients had a broad range of clinical severity. Respiratory symptoms occurred in 64%, gastrointestinal symptoms in 57%, fever in 78%, neurological symptoms in 15% and other constitutional symptoms in 50%. 35% presented with no respiratory symptoms. Conclusion While the lungs are certainly involved in vaping-associated illness, recognizing the extent of involvement of other organ systems may provide insight into the pathophysiology of the disease. Providers should be aware that vaping-associated illness presents with a multitude of symptoms outside of lung injury, such as abdominal pain, headache or even fever.

Abstract The quantitative nature of fusarium head blight (FHB) resistance requires further exploration of the wheat genome to identify regions conferring resistance. In this study, we explored the application of hyperspectral imaging of Fusarium-infected wheat kernels and identified regions of the wheat genome contributing significantly to the accumulation of Deoxynivalenol (DON) mycotoxin. Strong correlations were identified between hyperspectral reflectance values for 204 wavebands in the 397–673 nm range and DON mycotoxin. Dimensionality reduction using principal components was performed for all 204 wavebands and 38 sliding windows across the range of wavebands. The first principal component (PC1) of all 204 wavebands explained 70% of the total variation in waveband reflectance values and was highly correlated with DON mycotoxin. PC1 was used as a phenotype in a genome wide association study and a large effect QTL on chromosome 2D was identified for PC1 of all wavebands as well as nearly all 38 sliding windows. The allele contributing variation in PC1 values also led to a substantial reduction in DON. The 2D polymorphism affecting DON levels localized to the exon of TraesCS2D02G524600 which is upregulated in wheat spike and rachis tissues during FHB infection. This work demonstrates the value of hyperspectral imaging as a correlated trait for investigating the genetic basis of resistance and developing wheat varieties with enhanced resistance to FHB.

Abstract A hallmark of unconventional superconductors is a complex electronic phase diagram where intertwined orders of charge-spin-lattice degrees of freedom compete and coexist. While the kagome metals such as CsV3Sb5 also exhibit complex behavior, involving coexisting charge density wave order and superconductivity, much is unclear about the microscopic origin of the superconducting pairing. We study the vortex lattice in the superconducting state of Cs(V0.86Ta0.14)3Sb5, where the Ta-doping suppresses charge order and enhances superconductivity. Using small-angle neutron scattering, a strictly bulk probe, we show that the vortex lattice exhibits a strikingly conventional behavior. This includes a triangular symmetry with a period consistent with 2e-pairing, a field dependent scattering intensity that follows a London model, and a temperature dependence consistent with a uniform superconducting gap. Our results suggest that optimal bulk superconductivity in Cs(V1−x Ta x )3Sb5 arises from a conventional Bardeen-Cooper-Schrieffer electron-lattice coupling, different from spin fluctuation mediated unconventional copper- and iron-based superconductors.

Abstract Background Firearm homicide and opioid overdoses were already leading causes of death in the U.S. before both problems surged during the COVID-19 pandemic. Firearm violence, overdoses, and COVID-19 have all disproportionately harmed communities that are socially and economically marginalized, but the co-occurrence of these problems in the same communities has received little attention. To describe the co-occurrence of firearm homicides and opioid overdose deaths with COVID-19 mortality we used 2017–2021 medical examiner’s data from Chicago, IL. Deaths were assigned to zip codes based on decedents’ residence. We stratified zip codes into quartiles by COVID-19 mortality rate, then compared firearm homicide and fatal opioid overdose rates by COVID-19 quartile. Findings Throughout the study period, firearm homicide and opioid overdose rates were highest in the highest COVID-19 mortality quartile and lowest in the lowest COVID-19 mortality quartile. Increases in firearm homicide and opioid overdose were observed across all COVID-19 mortality quartiles. Conclusions High co-occurrence of these deaths at the community level call for addressing the systemic forces which made them most vulnerable before the pandemic. Such strategies should consider the environments where people reside, not only where fatal injuries occur.

Abstract Type II innate lymphoid cells (ILC2s) maintain homeostasis and barrier integrity in mucosal tissues. In both mice and humans, ILC2s poorly reconstitute after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Determining the mechanisms involved in their impaired reconstitution could improve transplant outcomes. By integrating single-cell chromatin and transcriptomic analyses of transplanted ILC2s, we identify a previously unreported population of converted ILC1-like cells in the mouse small intestine post-transplant. Exposure of ILC2s to proinflammatory cytokines resulted in a mixed ILC1-ILC2 phenotype but was able to convert only a small population of ILC2s to ILC1s, which were found post-transplant. Whereas ILC2s protected against acute graft-versus-host disease (aGVHD) mediated mortality, infusion of proinflammatory cytokine-exposed ILC2s accelerated aGvHD. Interestingly, murine ILC2 reconstitution post-HSCT is decreased in the presence of alloreactive T cells. Finally, peripheral blood cells from human patients with aGvHD have an altered ILC2-associated chromatin landscape compared to transplanted controls. These data demonstrate that following transplantation ILC2s convert to a pro-pathogenic population with an ILC1-like chromatin state and provide insights into the contribution of ILC plasticity to the impaired reconstitution of ILC2 cells, which is one of several potential mechanisms for the poor reconstitution of these important cells after allo-HSCT.

Background: While studies have assessed comparative rates of restoration of shoulder function and alleviation of symptoms, comparative systemic postoperative complication rates between biceps tenotomy and tenodesis have yet to be assessed. The purpose of the present study was to use a national administrative database to perform a comprehensive investigation into 30-day complication rates after biceps tenotomy versus tenodesis, thus providing valuable insights for informed decision-making by clinicians and patients regarding the optimal surgical approach for pathologies of the long head of the biceps tendon. Methods: The National Surgical Quality Improvement Program database was queried to analyze postoperative complication rates and metrics associated with biceps tenotomy and tenodesis. Patient data spanning from 2012 to 2021 was extracted, with relevant variables assessed to identify and compare these two surgical approaches. Adjusted and unadjusted analyses were utilized to analyze patient demographics, comorbidities, operative times, lengths of stay, readmissions, adverse events, and yearly surgical volume, along with trends in usage, across cohorts. Results: Of 11,527 total patients, 264 (2.29%), 6826 (59.22%), and 4437 (38.49%) underwent tenotomy, tenodesis with open repair, and tenodesis with arthroscopic repair, respectively. Tenotomy operative times ([mean ± SD]: 66.25 ± 44.76 minutes) were shorter than those for open tenodesis (78.83 ± 41.82) and arthroscopic tenodesis (75.98 ± 40.16). Conversely, tenotomy patients had longer hospital days (0.88 ± 4.86 days) relative to open tenodesis (.08 ± 1.55) and arthroscopic tenodesis (.12 ± 2.70). Multivariable logistic regression controlling for demographics and comorbidities demonstrated that patients undergoing tenodesis were less likely to be readmitted (adjusted odds ratio [AOR]: 0.42, 95% confidence interval [CI]: 0.17-0.98, P = .050) or sustain serious adverse events (AOR: 0.27, 95% CI: 0.13-0.57, P

Purpose: To (1) systematically assess which orthobiologic agents are being used in acetabular labral repairs and (2) report all available outcomes for patients undergoing operative management for labral repairs with orthobiologic agents. Methods: The PubMed, Embase, and Cochrane databases were queried in August 2023. Articles were included if they used an orthobiologic agent during hip arthroscopy for acetabular labral repair and reported functional outcomes. Each study was queried for demographic data, orthobiologic agent used, volume of agent used, imaging modality used to guide administration, follow-up period, and all reported outcomes. The following Boolean phrase was used to systematically search the current literature: ((Orthobiologics) OR (Platelet-rich plasma) OR (PRP) OR (Mesenchymal stem cells) OR (MSCs) OR (Hyaluronic acid) OR (Growth factors) OR (bone marrow aspirate) OR (BMAC)) AND (hip joint OR (acetabular labrum) OR (Chondrolabr∗ damage) OR (Chondrolabr∗ tear)) AND (outcome∗ OR function∗ OR PROM OR PRO OR arthr∗ OR image OR pain OR complication). Results: Three studies met the inclusion criteria and included 201 patients who received treatment with orthobiologic agents. Of these patients, 119 (59.7%) were women, with age ranging from 35 to 49 years. Ninety-seven patients (48.3%) received bone marrow aspirate concentrate (BMAC), and 104 (51.7%) received platelet-rich plasma (PRP). Both BMAC studies showed no significant improvements compared with controls; however, a subanalysis limited to patients with moderate cartilage damage who received BMAC showed significantly improved 2-year patient-reported outcome measures (International Hip Outcome Tool 33 score, 82.5 vs 69.5; P = .03). The one PRP study did not show significant improvements compared with controls. No complications were noted after either PRP or BMAC harvesting and application in any included study. Conclusions: Overall, BMAC and PRP do not significantly improve patient-reported outcome measures compared with controls. However, there is limited evidence that BMAC may help patients with moderate cartilage damage. Level of Evidence: Level III, systematic review of Level II and III studies.

The resource-use hypothesis proposed by Elisabeth S. Vrba suggests that lineages display varying tendencies toward generalism or specialization in biome occupancy, with a tendency towards the accumulation of specialists due to their higher rate of speciation through vicariance. It also posits differences in biome occupancy patterns driven by the environmental characteristics of biomes, with a higher presence of biome specialist species in biomes that are placed in the extremes of the global climatic gradients. Here, we tested this hypothesis in turtles, a very ancient and morphologically stable lineage, representing a remarkable diversity with 357 species, many of which are threatened with extinction. We analyzed the resource-use hypothesis in a phylogenetic context within the Testudines lineage. For this purpose, a presence/absence matrix was compiled for all species across all 10 terrestrial biomes. Their distribution across biomes was contrasted with 10,000 Monte Carlo simulations. The relationship between diversification rates and both the biomic specialization index and the biomes occupied by specialists species was evaluated. The results demonstrate strong consistency with Vrba`s hypothesis, revealing a higher number of biome specialist species than expected by chance, with a significant accumulation of species in tropical ecosystems. These trends also were observed for ecological groups (terrestrial and freshwater species). In addition, higher diversification rates were observed for biome specialist species, although the particular biome occupied did not significantly influence their diversification rates.

Introduction A reduction in platelet count in critically ill patients is a marker of severity of the clinical condition. However, whether this association holds true in acute kidney injury (AKI) is unknown. We analyzed the association between platelet reduction in patients with AKI and major adverse kidney events (MAKE).Methods In this retrospective cohort, we included AKI patients at the Hospital Civil of Guadalajara, in Jalisco, Mexico. Patients were divided according to whether their platelet count fell >21% during the first 10 days. Our objectives were to analyze the associations between a platelet reduction >21% and MAKE at 10 days (MAKE10) or at 30-90 days (MAKE30-90) and death.Results From 2017 to 2023, 400 AKI patients were included, 134 of whom had a > 21% reduction in platelet count. The mean age was 54 years, 60% were male, and 44% had sepsis. The mean baseline platelet count was 194 x 103 cells/µL, and 65% of the KDIGO3 patients met these criteria. Those who underwent hemodialysis (HD) had lower platelet counts. After multiple adjustments, a platelet reduction >21% was associated with MAKE10 (OR 4.2, CI 2.1-8.5) but not with MAKE30-90. The mortality risk increased 3-fold (OR 2.9, CI 1.1-7.7, p = 0.02) with a greater decrease in the platelets ( 21% reduction in platelet count was associated with MAKE. Our results are useful for generating hypotheses and motivating us to continue studying this association with a more robust design.

ABSTRACTWe report investigations of the magnetic textures in periodic multilayers [Pt(1 nm)/(CoFeB(0.8 nm)/Ru(1.4 nm)]10 using polarised neutron reflectometry (PNR) and small-angle neutron scattering (SANS). The multilayers are known to host skyrmions stabilized by Dzyaloshinskii-Moriya interactions induced by broken inversion symmetry and spin–orbit coupling at the asymmetric interfaces. From depth-dependent PNR measurements, we observed well-defined structural features and obtained the layer-resolved magnetization profiles. The in-plane magnetization of the CoFeB layers calculated from fitting of the PNR profiles is found to be in excellent agreement with magnetometry data. Using SANS as a bulk probe of the entire multilayer, we observe long-period magnetic stripe domains and skyrmion ensembles with full orientational disorder at room temperature. No sign of skyrmions is found below 250 K, which we suggest is due to an increase of an effective magnetic anisotropy in the CoFeB layer on cooling that suppresses skyrmion stability. Using polarised SANS at room temperature, we prove the existence of pure Néel-type windings in both stripe domain and skyrmion regimes. No Bloch-type winding admixture, i.e. an indication for hybrid windings, is detected within the measurement sensitivity, in good agreement with expectations according to our micromagnetic modelling of the multilayers. Our findings using neutron techniques provide valuable microscopic insights into the rich magnetic behavior of skyrmion-hosting multilayers, which are essential for the advancement of future skyrmion-based spintronic devices.

Background: Hypertensive disorders of pregnancy (HDP) are significant drivers of maternal and neonatal morbidity and mortality. Current management strategies include early identification and initiation of risk mitigating interventions facilitated by a rules-based checklist. Advanced analytic techniques, such as machine learning, can potentially offer improved and refined predictive capabilities. Objective: To develop and internally validate a machine learning prediction model for hypertensive disorders of pregnancy (HDP) when initiating prenatal care. Study Design: We developed a prediction model using data from the prospective multisite cohort Nulliparous Pregnancy Outcomes Study: Monitoring Mothers-to-Be (nuMoM2b) among low-risk individuals without a prior history of aspirin utilization for preeclampsia prevention. The primary outcome was the development of HDP. Random forest modeling was utilized to develop predictive models. Recursive feature elimination (RFE) was employed to create a reduced model for each outcome. Area under the curve (AUC), 95% confidence intervals (CI), and calibration curves were utilized to assess discrimination and accuracy. Sensitivity analyses were conducted to compare the sensitivity and specificity of the reduced model compared to existing risk factor-based algorithms. Results: Of 9,124 assessed low risk nulliparous individuals, 21% (n=1,927) developed HDP. The prediction model for HDP had satisfactory discrimination with an AUC of 0.73 (95% CI: 0.70, 0.75). After RFE, a parsimonious reduced model with 30 features was created with an AUC of 0.71 (95% CI: 0.68, 0.74). Variables included in the model after RFE included body mass index at the first study visit, pre-pregnancy weight, first trimester complete blood count results, and maximum systolic blood pressure at the first visit. Calibration curves for all models revealed relatively stable agreement between predicted and observed probabilities. Sensitivity analysis noted superior sensitivity (AUC 0.80 vs 0.65) and specificity (0.65 vs 0.53) of the model compared to traditional risk factor-based algorithms. Conclusion: In cohort of low-risk nulliparous pregnant individuals, a prediction model may accurately predict HDP diagnosis at the time of initiating prenatal care and aid employment of close interval monitoring and prophylactic measures earlier in pregnancy.

IntroductionAmyloid-specific antibodies have been shown to opsonize and enhance amyloid clearance in systemic amyloidosis mouse models. However, the immunological mechanisms by which amyloid is removed have not been clearly defined. Previous reports from preclinical in vivo studies suggest polymorphonuclear cells (i.e., neutrophils) can affect amyloid removal. Therefore, we sought to analyze how neutrophils may contribute to the clearance of human AL amyloid extracts, using a murine amyloidoma model.MethodsImmunocompromised nude mice injected subcutaneously with patient-derived AL amyloid extract (generating a localized “amyloidoma”) were used to circumvent confounding factors contributed by the adaptive immune system and served as the model system. Two representative AL amyloid extracts were used, ALλ(CLA), which is refractory to clearance, and ALκ(TAL), which is readily cleared in mice. Neutrophil recruitment to the amyloid masses, cellular activation, and propensity to engulf amyloid were assessed.ResultsImmunophenotyping of amyloidomas from animals implanted with 2 mg of either ALλ or ALκ revealed that more neutrophils were recruited to ALκ amyloid masses as compared to the ALλ material, which was generally devoid of neutrophils. Ex vivo analyses indicated neutrophils do not efficiently phagocytose amyloid directly. However, histological evaluation of the ALκ amyloidoma revealed the abundant presence of neutrophil extracellular traps, which were absent in the ALλ amyloidomas. Using neutrophil depletion experiments in mice, we determined that mice devoid of neutrophils cleared the human amyloid lesions less efficiently. Moreover, mice devoid of neutrophils also had significantly reduced intra-amyloid expression of inflammatory cytokines.DiscussionNeutrophils may not directly mediate amyloid clearance through phagocytosis; however, these cells can be stimulated by the amyloid and may function to facilitate phagocytosis and amyloid clearance by professional phagocytes (e.g., macrophages).

Background The relative contributions of common patient-reported social determinants of health on 30- and 90-day post-discharge outcomes among patients with acute coronary syndromes (ACS) is unclear. Objective The aim of this article is to examine the independent associations of social determinants with readmission or death, accounting for medical history. Methods Participants included adults who were hospitalized with ACS at an academic medical center. Domains measured were social support, health literacy/numeracy, and socioeconomic status (SES) (including education and difficulty paying bills). We employed multivariable Cox proportional hazard models to study associations with time to all-cause readmission or death, up to 30 or 90 days after discharge, and adjusted for demographics and medical history (prior admissions and Elixhauser comorbidity index). Key Results Among 1,168 patients with ACS and no history of heart failure, more prior admissions, and higher comorbidity index (the medical history domain) were associated with higher rates of 30- and 90-day readmission or death (domain p values

Background Ten percent of patients with melanoma develop in-transit metastases (ITM). Isolated limb infusion (ILI) is a well-established therapy for unresectable ITM on the extremities, but the ideal sequencing/line of therapy of ILI has not been defined. This study evaluates ILI as first-line, second-line, or third or later-line therapy. Methods A retrospective review included all patients with unresectable ITM who underwent ILI from 2006-2023. Results A total of 130 patients were identified, 61% female, median age of 71 (31-89) years. Median follow-up was 37.5 months. ILI was first-line therapy in 80% (n = 104), second-line in 15% (n = 19), and third or later-line in 5.4% (n = 7). Overall response rate (ORR) and complete response (CR) rates for ILI as any line of therapy were 74% and 41%, respectively. ORR for ILI as first, second, or third or later-line therapy were 78%, 63%, and 57%, respectively. CR rates for ILI as first, second, or third or later-line therapy were 42%, 37%, and 43%, respectively. There were no significant differences in ORR, progression-free survival (PFS), overall survival, or disease-free survival between therapy lines. Median PFS for ILI as first, second, or third or later-line therapy were 6.9, 5.4, and 18 months, respectively. Conclusion Patients responded well to ILI, whether or not they received previous therapies for unresectable ITM. First-line ILI appears to have a better ORR than later lines of ILI. Although sample size limited statistical significance, there was a 21% improvement in ORR when ILI was used as first-line vs third-line therapy, which is clinically meaningful. ILI is effective for unresectable melanoma ITM and can be used as salvage therapy.

STK11 (serine-threonine kinase 11), also known as LKB1 (liver kinase B1) is a highly conserved master kinase that regulates cellular metabolism and polarity through a complex signaling network involving AMPK and 12 other AMPK-related kinases. Germline mutations in LKB1 have been causatively linked to Peutz-Jeghers Syndrome (PJS), an autosomal dominant hereditary disease with high cancer susceptibility. The identification of inactivating somatic mutations in LKB1 in different types of cancer further supports its tumor suppressive role. Deleterious mutations in LKB1 are frequently observed in patients with epithelial ovarian cancer. However, its inconsistent effects on tumorigenesis and cancer progression suggest that its functional impact is genetic context-dependent, requiring cooperation with other oncogenic lesions. In this review, we summarize the pleiotropic functions of LKB1 and how its altered activity in cancer cells is linked to oncogenic proliferation and growth, metastasis, metabolic reprogramming, genomic instability, and immune modulation. We also review the current mechanistic understandings of this master kinase as well as therapeutic implications with particular focus on the effects of LKB1 deficiency in ovarian cancer pathogenesis. Lastly, we discuss whether LKB1 deficiency can be exploited as an Achilles heel in ovarian cancer.

Abstract Objectives This study aims to better understand the perspectives of emergency medicine physicians’ on the role that state‐mandated, topic‐specific continuing medical education (CME) plays in addressing knowledge gaps, its relevance to current emergency practice, its reported burden and costs of CME activities to emergency physicians, and its perceived improvement in patient care. Methods A cross‐sectional survey was designed by the Coalition of Board‐Certified Emergency Physicians (COBCEP) and distributed in February 2023 to all American Board of Emergency Medicine (ABEM)‐certified physicians. Statistical tests of significance (Pearson's chi‐square and Fisher's exact test) assessed the cost and time spent on CME as well as the perceived value placed on CME by ABEM‐certified physicians to improve patient care. Data were summarized using descriptive statistics. Results There were 5562 (13.0%) responses from the 43656 physicians who received the survey—5506 responses were included for analysis. Over half of the physicians (53.0%) had more than 15 years of post‐residency practice experience. Most physicians (57.3%) spent less than $5,000 per year on obtaining CME. Most physicians practicing in states with state‐mandated, topic‐specific CME requirements believed that participation in ABEM continuing certification could be used to reduce the need for state‐mandated, topic‐specific CME requirements (83.6%) and state‐mandated, topic‐specific requirements were believed to be unlikely to improve patient care (70.8%). Conclusions Although well‐intended, state CME requirements may lack relevancy and can, at times, place an undue burden on emergency physicians. Tailoring CME requirements to increase relevance to their patient populations and reduce barriers to completing CME could enhance knowledge translation and improve patient outcomes.

Objectives: Perioperative blood transfusion (PBT) has been associated with worse survival after radical cystectomy (RC) in patients with muscle-invasive bladder cancer (MIBC). Here, we evaluated the association between PBT and survival after RC that was preceded by neoadjuvant chemotherapy (NAC). Methods: A retrospective analysis was performed on 949 patients with cT2-4aN0M0 bladder cancer who received NAC prior to RC between 2000 and 2013 at 19 centers. Kaplan–Meier estimates of overall survival (OS) were made. Presumed risk factors for OS were analyzed using Cox regression analysis. PBT was defined by the administration of any packed red blood cells during surgery or during the post-operative hospital stay. Results: A transfusion was given to 608 patients (64%). Transfused patients were more likely to have adverse clinical and pathologic parameters, including clinical stage and performance status. Transfused patients had worse OS (p = 0.01). On multivariable Cox regression, PBT was found to be independently associated with worse OS (HR 1.53 (95% CI 1.13–2.08), p = 0.007). Conclusions: PBT is common after NAC and RC, which may be linked, in part, to the anemia induced by NAC. PBT was associated with several adverse risk factors that correlate with poor outcomes after NAC and RC, and it was an independent predictor of adverse OS on multivariable analysis. Further study should determine if measures to avoid blood loss can reduce the need for PBT and thereby improve patient outcomes.

Abstract Background Despite the availability of effective vaccines, human papillomavirus (HPV) vaccine uptake remains low in most resource-limited settings including Nigeria. Mobile health technology (mHealth) has the potential to empower patients to manage their health, reduce health disparities, and enhance the uptake of HPV vaccination. Aim The “mHealth-HPVac” study will assess the effects of mHealth using short text messages on the uptake of HPV vaccination among mothers of unvaccinated girls aged 9–14 years and also determine the factors influencing the uptake of HPV vaccination among these mothers. Methods This protocol highlights a randomised controlled trial involving women aged 25–65 years who will be enrolled on attendance for routine care at the General Outpatient clinics of Lagos University Teaching Hospital, Lagos, Nigeria between July and December 2024. At baseline, n = 123 women will be randomised to either a short text message or usual care (control) arm. The primary outcome is vaccination of the participant’s school-age girl(s) at any time during the 6 months of follow-up. The associations between any two groups of continuous variables will be assessed using the independent sample t-test for normally distributed data, or the Mann-Whitney U test for skewed data. For two groups of categorical variables, the Chi-square (X2) test or Fisher’s exact test will be used, as appropriate. Using the multivariable binary logistic regression model, we will examine the effects of all relevant sociodemographic and clinical variables on HPV vaccination uptake among mothers of unvaccinated but vaccine-eligible school-age girls. Statistical significance will be reported as P

Abstract Introduction A three-pronged approach to acne treatment combining an antibiotic, antimicrobial, and retinoid may be more efficacious than single/double treatments while potentially reducing antibiotic resistance. This study evaluated the efficacy and safety of the first fixed-dose, triple-combination topical acne product, clindamycin 1.2%/adapalene 0.15%/benzoyl peroxide (BPO) 3.1% gel (CAB) using pooled phase 3 data. Methods In two identical phase 3 (N = 183; N = 180), double-blind, 12-week studies, participants aged ≥ 9 years with moderate-to-severe acne were randomized 2:1 to receive once-daily CAB or vehicle gel. Endpoints included ≥ 2-grade reduction from baseline in Evaluator’s Global Severity Score and clear/almost clear skin (treatment success) and least-squares mean percent change from baseline in acne lesion counts. Treatment-emergent adverse events (TEAEs) and cutaneous safety/tolerability were evaluated. Results At week 12, 50.0% of participants achieved treatment success with CAB versus 22.6% with vehicle gel (P 70% reductions in inflammatory and noninflammatory lesions at week 12 (77.9% and 73.0%, respectively), which were significantly greater than vehicle (57.9% and 48.2%; P

Abstract In helimagnetic metals, ac current-driven spin motions can generate emergent electric fields acting on conduction electrons, leading to emergent electromagnetic induction (EEMI). Recent experiments reveal the EEMI signal generally shows a strongly current-nonlinear response. In this study, we investigate the EEMI of Tb5Sb3, a short-period helimagnet. Using small angle neutron scattering we show that Tb5Sb3 hosts highly disordered helimagnetism with a distribution of spin-helix periodicity. The current-nonlinear dynamics of the disordered spin helix in Tb5Sb3 indeed shows up as the nonlinear electrical resistivity (real part of ac resistivity), and even more clearly as a nonlinear and huge EEMI (imaginary part of ac resistivity) response. The magnitude of the EEMI reaches as large as several tens of μH for Tb5Sb3 devices on the scale of several tens of μm, originating to noncollinear spin textures possibly even without long-range helimagnetic order.

Abstract Van-der-Waals magnetic materials can be exfoliated to realize ultrathin sheets or interfaces with highly controllable optical or spintronics responses. In majority, these are collinear ferro-, ferri-, or antiferromagnets, with a particular scarcity of lattice-incommensurate helimagnets of defined left- or right-handed rotation sense, or helicity. Here, we report polarized neutron scattering experiments on DyTe3, whose layered structure has highly metallic tellurium layers separated by double-slabs of dysprosium square nets. We reveal cycloidal (conical) magnetic textures, with coupled commensurate and incommensurate order parameters, and probe the evolution of this ground state in a magnetic field. The observations are well explained by a one-dimensional spin model, with an off-diagonal on-site term that is spatially modulated by DyTe3’s unconventional charge density wave (CDW) order. The CDW-driven term couples to antiferromagnetism, or to the net magnetization in an applied magnetic field, and creates a complex magnetic phase diagram indicative of competing interactions in this easily cleavable van-der-Waals helimagnet.

Abstract Neoadjuvant cisplatin-based chemotherapy is standard of care for muscle-invasive bladder cancer (MIBC). Immune checkpoint inhibition (ICI) alone, and ICI in combination with chemotherapy, have demonstrated promising pathologic response (

Abstract Marburg virus (MARV) is a highly pathogenic filovirus and a causative agent of sporadic zoonotic viral hemorrhagic fever outbreaks with high case fatality rates. In humans, filoviruses like MARV and Zaire Ebola virus (EBOV) target, among others, innate immune cells like dendritic cells and macrophages (MΦs). Filovirus-infected dendritic cells display impaired maturation and antigen presentation, while MΦs become hyper-activated and secrete proinflammatory cytokines and chemokines. Our current understanding of human macrophage responses to MARV remains limited. Here, we used human monocyte-derived macrophages (moMΦs) to address how their phenotype, transcriptional profile, and protein expression change upon an in vitro infection with a bat isolate of MARV. Confirming its tropism for macrophages, we show that MARV induces notable shifts in their transcription distinct from responses induced by lipopolysaccharide (LPS), marked by upregulated gene expression of several chemokines, type I interferons, and IFN-stimulated genes. MARV infection also elicited pronounced inter-individually different transcriptional programs in moMΦs, the induction of Wnt signaling-associated genes, and the downregulation of multiple biological processes and molecular pathways.

Abstract Most lung cancer patients with metastatic cancer eventually relapse with drug-resistant disease following treatment and EGFR mutant lung cancer is no exception. Genome-wide CRISPR screens, to either knock out or overexpress all protein-coding genes in cancer cell lines, revealed the landscape of pathways that cause resistance to the EGFR inhibitors osimertinib or gefitinib in EGFR mutant lung cancer. Among the most recurrent resistance genes were those that regulate the Hippo pathway. Following osimertinib treatment a subpopulation of cancer cells are able to survive and over time develop stable resistance. These ‘persister’ cells can exploit non-genetic (transcriptional) programs that enable cancer cells to survive drug treatment. Using genetic and pharmacologic tools we identified Hippo signalling as an important non-genetic mechanism of cell survival following osimertinib treatment. Further, we show that combinatorial targeting of the Hippo pathway and EGFR is highly effective in EGFR mutant lung cancer cells and patient-derived organoids, suggesting a new therapeutic strategy for EGFR mutant lung cancer patients.

There is a well-recognized relationship between a person’s body burden of essential trace elements such as copper and their neurological function in which both deficiencies and exposures to excessive concentrations are associated with adverse clinical outcomes. Preclinical studies indicate chronic excess copper exposure is associated with altered motor function, dopaminergic neuronal loss, astrocytosis, and microgliosis. Copper also promotes oligomerization and fibrilization of α-synuclein suggesting it may hasten the course of an α-synucleinopathy. Here we report a rare case of early onset Lewy Body Dementia with Parkinsonism in a 53-year-old Caucasian woman exposed to copper contaminated drinking water for more than 10 years. Her hair and that of her daughter had streaks of blue-green discoloration as did the porcelain sinks in their home. Testing confirmed copper contamination of the drinking water. A neurologist diagnosed her with Lewy Body Dementia with Parkinsonism. Skin biopsy for phosphorylated α was consistent with a diagnosis of an α-synucleinopathy. These findings suggest chronic exposure to excessive copper may act as disease modifying factor in Lewy Body Dementia with Parkinsonism. It has previously been recommended that individuals at risk of Alzheimer’s disease (AD) avoid excessive intake of copper. Genetic studies indicate that Lewy Body Dementia shares risk factors and pathways with AD. Based on the observations in this patient we recommend that individuals at risk for an α-synucleinopathy based on a positive family history, genetic testing, and/or positive results on a skin biopsy for phosphorylated α-synuclein avoid exposure to excess copper.

Background: Lung nodule incidence is increasing. Many nodules require biopsy to discriminate between benign and malignant causes. The gold standard for minimally invasive biopsy, CT scan-guided transthoracic needle biopsy (CT-TTNB), has not been compared directly with navigational bronchoscopy, a method that recently has seen rapid technological innovation and is associated with improving diagnostic yield and lower complication rates. Current estimates of the diagnostic usefulness of both methods are based largely on noncomparative data with significant risk for selection, referral, and publication biases. Research Question: Is contemporary navigational bronchoscopy noninferior to CT scan-guided transthoracic needle biopsy for the diagnosis of indeterminate pulmonary nodules? Study Design and Methods: Navigation Endoscopy to Reach Indeterminate Lung Nodules vs Transthoracic Needle Aspiration, a Randomized Controlled Study, is a multicenter, 1:1 randomized, parallel-group trial designed to ascertain whether electromagnetic navigational bronchoscopy with integrated digital tomosynthesis is noninferior to CT-TTNB for the diagnosis of peripheral lung nodules 10 to 30 mm in diameter with before testing probability of malignancy of at least 10%. The primary end point is diagnostic accuracy through 12 months of follow-up. Secondary end points include diagnostic yield, complication rate, procedure duration, need for additional invasive diagnostic procedures, and radiation exposure. Results: This article describes the protocol and rationale for the Navigation Endoscopy to Reach Indeterminate Lung Nodules vs Transthoracic Needle Aspiration, a Randomized Controlled Study, designed to answer the study question. Interpretation: The results of this rigorously designed trial will provide high-quality data regarding the management of lung nodules, a common clinical entity that often represents the earliest and most treatable stage of lung cancer. Several design challenges are described. Notably, all nodules are reviewed centrally by an independent interventional pulmonology and radiology adjudication panel relying on prespecified exclusions to ensure enrolled nodules are amenable to sampling by both methods while protecting against selection bias favoring either method. Conservative diagnostic yield and accuracy definitions with prespecified criteria for what nonmalignant findings may be considered diagnostic were chosen to avoid inflation of estimates of diagnostic usefulness. Trial Registry: ClinicalTrials.gov; No.: NCT04250194; URL: www.clinicaltrials.gov

Purpose: (1) To systematically review treatments for partial extensor mechanism tendon tears in professional and amateur athletes and (2) to report outcomes for patients undergoing operative versus nonoperative management. Methods: PubMed, Cochrane, Scopus, Google Scholar, and Web of Science were queried in August 2023 using the following Boolean search: (quadriceps OR patella) AND (partial) AND (tear). Articles were included if they reported outcomes of operative or nonoperative management of partial extensor mechanism tears of the knee in athletes. The review adhered to the Preferred Reporting Items for Systematic Reviews and Meta-analyses criteria. Each study was queried for demographics, tendon injured, sport and level of athlete, prior treatments, final treatment modality, and return to sport (RTS) outcomes of that treatment. A qualitative subanalysis was performed for professional athletes. Results: Ten studies met inclusion criteria and included 191 partial patellar or quadriceps tendon tears. Of the patients, 81.6% were male and 18.4% were female, with average age ranging from 21 to 28 years; 97% of patients underwent initial nonoperative management. Ultimately, 111 patients (58.1%) were maintained on nonoperative management, and 80 (41.9%) progressed to surgery. Of surgeries, 39 (48.8%) were tendon debridements, 36 (45.0%) were repairs, and 5 (6.3%) were not specified. RTS rates ranged from 33% to 93% after surgery and 70% to 89% following conservative management. Of professional athletes, 23 (33%) underwent surgery, and 46 (67%) underwent ultimate conservative management. RTS rates ranged from 33% to 67% after surgery and were 89% for the applicable study of conservative management. Conclusions: Nearly all patients with partial extensor mechanism tears underwent initial nonoperative management. RTS rates were high but somewhat variable among both patients treated with final nonoperative versus surgical management. Even among professional athletes, most injuries were treated with initial nonoperative management and did not progress to surgery. Level of Evidence: Level V, systematic review of Level IV and V studies.

This Review summarizes a range of analytical techniques that can be used to detect, quantify, and/or distinguish between isotopes of iodine (e.g., long-lived 129I, short-lived 131I, stable 127I). One reason this is of interest is that understanding potential radioiodine release from nuclear processes is crucial to prevent environmental contamination and to protect human health as it can incorporate into the thyroid leading to cancer. It is also of interest for evaluating iodine retention performances of next-generation iodine off-gas capture materials and long-term waste forms for immobilizing radioiodine for disposal in geologic repositories. Depending upon the form of iodine (e.g., molecules, elemental, and ionic) and the matter state (i.e., solid, liquid, and gaseous), the available options can vary. In addition, several other key parameters vary between the methods discussed herein, including the destructive vs nondestructive nature of the measurement process (including in situ vs ex situ measurement options), the analytical data collection times, and the amount of sample required for analysis.

Abstract Asthma, the most common chronic disease in children, affects more than 4 million children in the United States, disproportionately affecting those who are economically disadvantaged and racial and ethnic minorities. Studies have shown that the racial and ethnic disparities in asthma outcomes can be largely explained by environmental, socioeconomic and other social determinants of health (SDoH). Utilizing new approaches to stratify disease severity and risk, which focus on the underlying SDoH that lead to asthma disparity, provides an opportunity to disentangle race and ethnicity from its confounding social determinants. In particular, with the growing use of geospatial information systems, geocoded data can enable researchers and clinicians to quantify social and environmental impacts of structural racism. When these data are systematically collected and tabulated, researchers, and ultimately clinicians at the bedside, can evaluate patients’ neighborhood context and create targeted interventions toward those factors most associated with asthma morbidity. To do this, we have designed a view (mPage in the Cerner electronic health record) that centralizes key clinical information and displays it alongside SDoH variables shown to be linked to asthma incidence and severity. Once refined and validated, which is the next step in our project, our goal is for emergency medicine clinicians to use these data in real time while caring for patients with asthma. Our multidisciplinary, patient‐centered approach that leverages modern informatics tools will create opportunities to better triage patients with asthma exacerbations, choose the best interventions, and target underlying determinants of disease.

Motor learning is often viewed as a unitary process that operates outside of conscious awareness. This perspective has led to the development of sophisticated models designed to elucidate the mechanisms of implicit sensorimotor learning. In this review, we argue for a broader perspective, emphasizing the contribution of explicit strategies to sensorimotor learning tasks. Furthermore, we propose a theoretical framework for motor learning that consists of three fundamental processes: reasoning, the process of understanding action–outcome relationships; refinement, the process of optimizing sensorimotor and cognitive parameters to achieve motor goals; and retrieval, the process of inferring the context and recalling a control policy. We anticipate that this ‘3R’ framework for understanding how complex movements are learned will open exciting avenues for future research at the intersection between cognition and action.

BackgroundHealthcare crowdsourcing events (e.g. hackathons) facilitate interdisciplinary collaboration and encourage innovation. Peer-reviewed research has not yet considered a healthcare crowdsourcing event focusing on generative artificial intelligence (GenAI), which generates text in response to detailed prompts and has vast potential for improving the efficiency of healthcare organizations. Our event, the New York University Langone Health (NYULH) Prompt-a-thon, primarily sought to inspire and build AI fluency within our diverse NYULH community, and foster collaboration and innovation. Secondarily, we sought to analyze how participants' experience was influenced by their prior GenAI exposure and whether they received sample prompts during the workshop.MethodsExecuting the event required the assembly of an expert planning committee, who recruited diverse participants, anticipated technological challenges, and prepared the event. The event was composed of didactics and workshop sessions, which educated and allowed participants to experiment with using GenAI on real healthcare data. Participants were given novel "project cards" associated with each dataset that illuminated the tasks GenAI could perform and, for a random set of teams, sample prompts to help them achieve each task (the public repository of project cards can be found at https://github.com/smallw03/NYULH-Generative-AI-Prompt-a-thon-Project-Cards). Afterwards, participants were asked to fill out a survey with 7-point Likert-style questions.ResultsOur event was successful in educating and inspiring hundreds of enthusiastic in-person and virtual participants across our organization on the responsible use of GenAI in a low-cost and technologically feasible manner. All participants responded positively, on average, to each of the survey questions (e.g., confidence in their ability to use and trust GenAI). Critically, participants reported a self-perceived increase in their likelihood of using and promoting colleagues' use of GenAI for their daily work. No significant differences were seen in the surveys of those who received sample prompts with their project task descriptions.ConclusionThe first healthcare Prompt-a-thon was an overwhelming success, with minimal technological failures, positive responses from diverse participants and staff, and evidence of post-event engagement. These findings will be integral to planning future events at our institution, and to others looking to engage their workforce in utilizing GenAI.

Background: Chondral injuries in the knee are commonly discovered during knee arthroscopy procedures. Due to the poor restoration potential and avascular nature of cartilage, large defects are commonly treated with such surgical procedures. Treatment utilizing an osteochondral allograft (OCA) transplant for symptomatic focal cartilage defects in the patellofemoral joint has demonstrated strong, lasting clinical and radiographic outcomes. Indications: Active and otherwise healthy patients are indicated for surgery when presenting with significant joint-line pain and a large focal chondral defect verified on advanced imaging after an extensive course of nonoperative management. Technique Description: Beginning with diagnostic arthroscopy to confirm the large defect of the medial femoral condyle, we proceeded with OCA transplantation. A small medial peripatellar arthrotomy is performed. The fat pad is removed for visualization and retractors are placed both medially and laterally to appropriately visualize the defect. The defect is then sized according to the appropriate sizing guide. The guide is then placed perpendicular to the defect, and a central guide pin is drilled. A scoring reamer is used to carefully cut the size of the defect followed by a central reamer to prepare the defect. Any debris is removed, and the incision is thoroughly irrigated. The defect is then carefully measured in all four quadrants to match the donor. Any underlying bone is impacted for a stable base. A drill is then used for appropriate marrow venting underneath the defect. The corresponding donor site is selected and reamed with continuous irrigation to prevent thermal necrosis. The plug is removed and carefully measured to match the recipient site. The plug is thoroughly irrigated with pulse lavage to remove marrow elements. The graft is carefully inserted with gentle manual pressure until it is seated perfectly flush with the surrounding cartilage. Results: Clinical research has demonstrated good-to-excellent long-term survivorship of OCA transplantation. Long-term return to sport rates for recreational and competitive athletes are upward of 75%. Discussion/Conclusion: As surgical techniques continue to develop, surgeons should consider utilizing OCA transplants to treat large chondral defects in the patellofemoral joint. Patient Consent Disclosure Statement: The author(s) attests that consent has been obtained from any patient(s) appearing in this publication. If the individual may be identifiable, the author(s) has included a statement of release or other written form of approval from the patient(s) with this submission for publication.

ABSTRACT Nanopore direct RNA sequencing (DRS) enables the capture and full-length sequencing of native RNAs, without recoding or amplification bias. Resulting data sets may be interrogated to define the identity and location of chemically modified ribonucleotides, as well as the length of poly(A) tails, on individual RNA molecules. The success of these analyses is highly dependent on the provision of high-resolution transcriptome annotations in combination with workflows that minimize misalignments and other analysis artifacts. Existing software solutions for generating high-resolution transcriptome annotations are poorly suited to small gene-dense genomes of viruses due to the challenge of identifying distinct transcript isoforms where alternative splicing and overlapping RNAs are prevalent. To resolve this, we identified key characteristics of DRS data sets that inform resulting read alignments and developed the nanopore guided annotation of transcriptome architectures (NAGATA) software package (https://github.com/DepledgeLab/NAGATA). We demonstrate, using a combination of synthetic and original DRS data sets derived from adenoviruses, herpesviruses, coronaviruses, and human cells, that NAGATA outperforms existing transcriptome annotation software and yields a consistently high level of precision and recall when reconstructing both gene sparse and gene-dense transcriptomes. Finally, we apply NAGATA to generate the first high-resolution transcriptome annotation of the neglected pathogen human adenovirus type F41 (HAdV-41) for which we identify 77 distinct transcripts encoding at least 23 different proteins.IMPORTANCEThe transcriptome of an organism denotes the full repertoire of encoded RNAs that may be expressed. This is critical to understanding the biology of an organism and for accurate transcriptomic and epitranscriptomic-based analyses. Annotating transcriptomes remains a complex task, particularly in small gene-dense organisms such as viruses which maximize their coding capacity through overlapping RNAs. To resolve this, we have developed a new software nanopore guided annotation of transcriptome architectures (NAGATA) which utilizes nanopore direct RNA sequencing (DRS) datasets to rapidly produce high-resolution transcriptome annotations for diverse viruses and other organisms.

Introduction Critical care, emergency medicine, and surgical trainees frequently perform surgical and Seldinger-technique tube thoracostomy, thoracentesis, and thoracic ultrasound. However, approaches to teaching these skills are highly heterogeneous. Over 10 years, we have developed a standardized, multidisciplinary curriculum to teach these procedures. Methods Emergency medicine residents, surgical residents, and critical care fellows, all in the first year of their respective programs, underwent training in surgical and Seldinger chest tube placement and securement, thoracentesis, and thoracic ultrasound. The curriculum included preworkshop instructional videos and 45-minute in-person practice stations (3.5 hours total). Sessions were co-led by faculty from emergency medicine, thoracic surgery, and pulmonary/critical care who performed real-time formative assessment with standardized procedural steps. Postcourse surveys assessed learners’ confidence before versus after the workshop in each procedure, learners’ evaluations of faculty by station and specialty, and the workshop overall. Results One hundred twenty-three trainees completed course evaluations, demonstrating stable and positive responses from learners of different backgrounds taught by a multidisciplinary group of instructors, as well as statistically significant improvement in learner confidence in each procedure. Over time, we have made incremental changes to our curriculum based on feedback from instructors and learners. Discussion We have developed a unique curriculum designed, revised, and taught by a multidisciplinary faculty over many years to teach a unified approach to the performance of common chest procedures to surgical, emergency medicine, and critical care trainees. Our curriculum can be readily adapted to the needs of institutions that desire a standardized, multidisciplinary approach to thoracic procedural education.

The growth of eggplant (Pusa Safed Baingan-1) was studied during the semi-arid (March to June) and humid sub-tropical (July to September) seasons of New Delhi, India. The individual effects of wheat straw biomass (WSBM), wheat straw biochar (WSBC) and compost versus the combined effect of WSBM plus compost and WSBC plus compost were determined under field conditions. The amendments were made at two different application rates: 1 wt% and 2 wt%. WSBC was successfully prepared in a proprietary kachcha reactor (Indian patent no. 380921), designed using locally sourced clay. Amendments were characterized using elemental analyzer, scanning electron microscopy (SEM), transmission electron (TEM) microscopy, Fourier transform infrared (FTIR) spectroscopy and X-Ray diffraction (XRD). The field study was conducted in 11 (1x1-meter) plots with two replicates. Basic soil health parameters including pH, electrical conductivity (EC), water holding capacity (WHC), bulk density (BD), cation exchange capacity (CEC), soil total nitrogen (STN), soil available nitrogen (SAN), soil organic carbon (SOC), soil available phosphorus (SAP), microbial biomass carbon (MBC) and mineral contents are analyzed. Observable plant growth characteristics (germination percentage, height, number of leaves, fruits, and plant biomass) were also recorded. Biochar amendment was most beneficial for enhancing the majority of these parameters. With respect to the control, a 20% decrease in bulk density, a 30% increase in water holding capacity, a 122% increase in organic carbon, a 175% increase in total nitrogen, a 23% increase in available nitrogen, and a 473% increase in available phosphorus were recorded. Furthermore, with respect to the control, a 115% increase in CEC was recorded using the compost amendment vs 84% with WSBC. Synergism between biochar and compost was reflected by high germination percentage (44%), number of fruits (600%), plant biomass weight (243%) and soil microbial biomass carbon (286%). Biomass amendment failed to show any positive influence. In summary, biochar emerges as a superior choice compared to both biomass and compost when it comes to soil amendments.

Abstract Typical multiomics studies employ separate methods for DNA, RNA, and protein sample preparation, which is labor intensive, costly, and prone to sampling bias. We describe a method for preparing high-quality, sequencing-ready DNA and RNA, and either intact proteins or mass-spectrometry-ready peptides for whole proteome analysis from a single sample. This method utilizes a reversible protein tagging scheme to covalently link all proteins in a lysate to a bead-based matrix and nucleic acid precipitation and selective solubilization to yield separate pools of protein and nucleic acids. We demonstrate the utility of this method to compare the genomes, transcriptomes, and proteomes of four triple-negative breast cancer cell lines with different degrees of malignancy. These data show the involvement of both RNA and associated proteins, and protein-only dependent pathways that distinguish these cell lines. We also demonstrate the utility of this multiomics workflow for tissue analysis using mouse brain, liver, and lung tissue.

Introduction: Despite the importance of peer review to publications, there is no generally accepted approach for editorial evaluation of a peer review’s value to a journal editor’s decision-making. The graduate medical education editors of the Western Journal of Emergency Medicine Special Issue in Educational Research & Practice (Special Issue) developed and studied the holistic editor’s scoring rubric (HESR) with the objective of assessing the quality of a review and an emphasis on the degree to which it informs a holistic appreciation for the submission under consideration. Methods: Using peer-review guidelines from several journals, the Special Issue’s editors formulated the rubric as descriptions of peer reviews of varying degree of quality from the ideal to the unacceptable. Once a review was assessed by each editor using the rubric, the score was submitted to a third party for blinding purposes. We compared the performance of the new rubric to a previously used semantic differential scale instrument. Kane’s validity framework guided the evaluation of the new scoring rubric around three basic assumptions: improved distribution of scores; relative consistency rather than absolute inter-rater reliability across editors; and statistical evidence that editors valued peer reviews that contributed most to their decision-making. Results: Ninety peer reviews were the subject of this study, all were assessed by two editors. Compared to the highly skewed distribution of the prior rating scale, the distribution of the new scoring rubric was bell shaped and demonstrated full use of the rubric scale. Absolute agreement between editors was low to moderate, while relative consistency between editor’s rubric ratings was high. Finally, we showed that recommendations of higher rated peer reviews were more likely to concur with the editor’s formal decision. Conclusion: Early evidence regarding the HESR supports the use of this instrument in determining the quality of peer reviews as well as its relative importance in informing editorial decision-making.

Abstract Bats are increasingly recognized as reservoirs of emerging zoonotic pathogens. Egyptian rousette bats (ERBs) are the known reservoir of Marburg virus (MARV), a filovirus that causes deadly Marburg virus disease (MVD) in humans. However, ERBs harbor MARV asymptomatically, likely due to a coadapted and specific host immunity-pathogen relationship. Recently, we measured transcriptional responses in MARV-infected ERB whole tissues, showing that these bats possess a disease tolerant strategy that limits pro-inflammatory gene induction, presumably averting MVD-linked immunopathology. However, the host resistant strategy by which ERBs actively limit MARV burden remains elusive, which we hypothesize requires localized inflammatory responses unresolvable at bulk-tissue scale. Here, we use dexamethasone to attenuate ERB pro-inflammatory responses and assess MARV replication, shedding and disease. We show that MARV-infected ERBs naturally mount coordinated pro-inflammatory responses at liver foci of infection, comprised of recruited mononuclear phagocytes and T cells, the latter of which proliferate with likely MARV-specificity. When pro-inflammatory responses are diminished, ERBs display heightened MARV replication, oral/rectal shedding and severe MVD-like liver pathology, demonstrating that ERBs balance immunoprotective tolerance with discreet MARV-resistant pro-inflammatory responses. These data further suggest that natural ERB immunomodulatory stressors like food scarcity and habitat disruption may potentiate viral shedding, transmission and therefore outbreak risk.

Abstract Viral clearance, antibody response and the mutagenic effect of molnupiravir has not been elucidated in at-risk populations. Non-hospitalised participants within 5 days of SARS-CoV-2 symptoms randomised to receive molnupiravir (n = 253) or Usual Care (n = 324) were recruited to study viral and antibody dynamics and the effect of molnupiravir on viral whole genome sequence from 1437 viral genomes. Molnupiravir accelerates viral load decline, but virus is detectable by Day 5 in most cases. At Day 14 (9 days post-treatment), molnupiravir is associated with significantly higher viral persistence and significantly lower anti-SARS-CoV-2 spike antibody titres compared to Usual Care. Serial sequencing reveals increased mutagenesis with molnupiravir treatment. Persistence of detectable viral RNA at Day 14 in the molnupiravir group is associated with higher transition mutations following treatment cessation. Viral viability at Day 14 is similar in both groups with post-molnupiravir treated samples cultured up to 9 days post cessation of treatment. The current 5-day molnupiravir course is too short. Longer courses should be tested to reduce the risk of potentially transmissible molnupiravir-mutated variants being generated. Trial registration: ISRCTN30448031