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ObjectivesThis study aimed to compare contraceptive efficacy and safety of drospirenone 4 mg in a 24/4-day regimen in nonobese and obese users and describe pharmacokinetics according to bodyweight.Study designWe analyzed data from three drospirenone 4 mg trials (2 European and 1 United States) to report outcomes in nonobese (body mass index

Astroviruses cause a spectrum of diseases spanning asymptomatic infections to severe diarrhea, but little is understood about their pathogenesis. We previously determined that small intestinal goblet cells were the main cell type infected by murine astrovirus-1. Here, we focused on the host immune response to infection and inadvertently discovered a role for indoleamine 2,3-dioxygenase 1 (Ido1), a host tryptophan catabolizing enzyme, in the cellular tropism of murine and human astroviruses. We identified that Ido1 expression was highly enriched among infected goblet cells, and spatially corresponded to the zonation of infection. Because Ido1 can act as a negative regulator of inflammation, we hypothesized it could dampen host antiviral responses. Despite robust interferon signaling in goblet cells, as well as tuft cell and enterocyte bystanders, we observed delayed cytokine induction and suppressed levels of fecal lipocalin-2. Although we found Ido-/- animals were more resistant to infection, this was not associated with fewer goblet cells nor could it be rescued by knocking out interferon responses, suggesting that IDO1 instead regulates cell permissivity. We characterized IDO1-/- Caco-2 cells and observed significantly reduced human astrovirus-1 infection. Together this study highlights a role for Ido1 in astrovirus infection and epithelial cell maturation.

We introduce the Open Force Field (OpenFF) 2.0.0 small molecule force field for drug-like molecules, code-named Sage, which builds upon our previous iteration, Parsley. OpenFF force fields are based on direct chemical perception, which generalizes easily to highly diverse sets of chemistries based on substructure queries. Like the previous OpenFF iterations, the Sage generation of OpenFF force fields was validated in protein-ligand simulations to be compatible with AMBER biopolymer force fields. In this work, we detail the methodology used to develop this force field, as well as the innovations and improvements introduced since the release of Parsley 1.0.0. One particularly significant feature of Sage is a set of improved Lennard-Jones (LJ) parameters retrained against condensed phase mixture data, the first refit of LJ parameters in the OpenFF small molecule force field line. Sage also includes valence parameters refit to a larger database of quantum chemical calculations than previous versions, as well as improvements in how this fitting is performed. Force field benchmarks show improvements in general metrics of performance against quantum chemistry reference data such as root-mean-square deviations (RMSD) of optimized conformer geometries, torsion fingerprint deviations (TFD), and improved relative conformer energetics (ΔΔE). We present a variety of benchmarks for these metrics against our previous force fields as well as in some cases other small molecule force fields. Sage also demonstrates improved performance in estimating physical properties, including comparison against experimental data from various thermodynamic databases for small molecule properties such as ΔHmix, ρ(x), ΔGsolv, and ΔGtrans. Additionally, we benchmarked against protein-ligand binding free energies (ΔGbind), where Sage yields results statistically similar to previous force fields. All the data is made publicly available along with complete details on how to reproduce the training results at https://github.com/openforcefield/openff-sage.

Angiopoietin-2 (Ang-2) is associated with vascular endothelial injury and permeability in the acute respiratory distress syndrome (ARDS) and sepsis. Elevated circulating Ang-2 levels may identify critically ill patients with distinct pathobiology amenable to targeted therapy. We hypothesized that plasma Ang-2 measured shortly after hospitalization among patients with sepsis would be associated with the development of ARDS and poor clinical outcomes. To test this hypothesis, we measured plasma Ang-2 in a cohort of 757 patients with sepsis, including 267 with ARDS, enrolled in the emergency department or early in their ICU course before the COVID-19 pandemic. Multivariable models were used to test the association of Ang-2 with the development of ARDS and 30-day morality. We found that early plasma Ang-2 in sepsis was associated with higher baseline severity of illness, the development of ARDS, and mortality risk. The association between Ang-2 and mortality was strongest among patients with ARDS and sepsis as compared to those with sepsis alone (OR 1.81 vs. 1.52 per log Ang-2 increase). These findings might inform models testing patient risk prediction and strengthen the evidence for Ang-2 as an appealing biomarker for patient selection for novel therapeutic agents to target vascular injury in sepsis and ARDS.

Carbon fixation is the process by which CO2 is converted from a gas into biomass. The Calvin-Benson-Bassham cycle (CBB) is the dominant carbon-consuming pathway on Earth, driving >99.5% of the ∼120 billion tons of carbon that are converted to sugar by plants, algae, and cyanobacteria. The carboxylase enzyme in the CBB, ribulose-1,5-bisphosphate carboxylase/oxygenase (rubisco), fixes one CO2 molecule per turn of the cycle into bioavailable sugars. Despite being critical to the assimilation of carbon, rubisco's kinetic rate is not very fast, limiting flux through the pathway. This bottleneck presents a paradox: Why has rubisco not evolved to be a better catalyst? Many hypothesize that the catalytic mechanism of rubisco is subject to one or more trade-offs and that rubisco variants have been optimized for their native physiological environment. Here, we review the evolution and biochemistry of rubisco through the lens of structure and mechanism in order to understand what trade-offs limit its improvement. We also review the many attempts to improve rubisco itself and thereby promote plant growth.

This study aimed to explore Omani teachers' self-efficacy beliefs for teaching science as inquiry and investigate the influence of demographic characteristics such as gender, teaching experience, and preparation programme on their beliefs. The study was conducted with a sample of science teachers for grades 5-8 (n=588). Data collected from administering the standardized Teaching Science as Inquiry instrument (TSI) to the sample were analysed using a cross-sectional design. The results showed that teachers perceived themselves as highly successful in teaching science as inquiry. Female teachers had higher perceptions of themselves as highly successful in teaching science regarding Personal Self-efficacy beliefs (PE) and Outcome Expectations (OE) for science teaching as inquiry than male teachers. Moreover, teachers with more teaching experience perceived themselves as more highly successful in teaching science as inquiry than those with less experience. Regarding the type of teacher preparation programme, there was no statistically significant difference in teachers' self-efficacy beliefs. Omani teachers with more experience teaching science by enquiry reported higher mean scores on teaching science as inquiry. They had higher TSI scores than the teachers with low and moderate experience. Accordingly, new graduate science teachers need to increase their knowledge aspects and practices related to science as inquiry (SI). Therefore, the TSI could be used for science teachers in their training to examine how they conducted teaching science by enquiry in real classroom situations.

Introduction While incidentally discovered covert cerebrovascular diseases (id-CCD) are associated with future stroke, it is not known if patients with id-CCD are prescribed statins.Methods Patients age ≥50 with id-CCD on neuroimaging from 2009 to 2019 with no prior ischaemic stroke, transient ischaemic attack or dementia were identified using natural language processing in a large real-world cohort. Robust Poisson multivariable regression was used to assess statin prescription among patients without prior statins.Results Among 2 41 050 patients, 74 975 patients (31.1%; 4.7% with covert brain infarcts (CBI); 29.0% with white matter disease (WMD)) had id-CCD. 53.5% (95% CI 53.2 to 53.9%) were not on statins within 6 months prior to the scan. Of those, 12.0% (95% CI 11.7 to 12.3%) were prescribed statins in the next 6 months compared with 9.3% (95% CI 9.1 to 9.4%) in those without CCD, a 2.7% (95% CI 2.4 to 3.1%) absolute increase in statin prescription for those with id-CCD. In adjusted analyses, the presence of id-CCD was only associated with minor increases in statin prescription (CBI or WMD (risk ratio (RR) 1.09, 95% CI 1.05 to 1.13), CBI alone (RR 1.34, 95% CI 1.21 to 1.47), WMD alone (RR 1.05, 95% CI 1.01 to 1.09), and CBI and WMD (RR 1.23, 95% CI 1.12 to 1.35)).Discussion Identification of id-CCD is not associated with substantial changes in statin prescription in routine clinical practice.

Background: Acute ischemic stroke (AIS) imposes a major healthcare burden. It is hypothesized that bacterial infection could influence atherosclerosis and thrombus formation, potentially contributing to AIS. Objectives: We aim to systematically review all studies that have investigated the presence of bacterial signatures within thrombi retrieved following mechanical thrombectomy (MT) procedures in patients with AIS. Design: This systematic review is designed following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses 2020 checklist. Data sources and methods: A comprehensive search was conducted in the Web of Sciences, PubMed, Scopus, and Embase databases to identify relevant studies. Results: The literature search and screening included 11 studies involving 674 patients, with 414 (61.4%) being male and 260 (38.6%) females. Among all the patients, 393 (58.3%) were positive for bacterial presence in their retrieved thrombi. The most utilized technique for bacterial signature detection was bacterial DNA extraction followed by polymerase chain reaction amplification of the 16S rRNA gene sequence. Staphylococcus aureus was the most studied bacteria among the studies analyzed. Conclusion: Bacterial infections and the presence of bacteria within thrombi may significantly contribute to AIS by initiating or exacerbating atherosclerosis or thrombosis. Understanding the mechanisms by which bacteria affect vascular health is crucial for developing effective preventive and therapeutic strategies for stroke patients.

Background Altered structural brain development has been identified in fetuses with congenital heart disease (CHD), suggesting that the neurodevelopmental impairment observed later in life might originate in utero. There are many interacting factors that may perturb neurodevelopment during the fetal period and manifest as structural brain alterations, such as altered cerebral substrate delivery and aberrant fetal hemodynamics. Methods and Results We extracted structural covariance networks from the log Jacobian determinants of 435 in utero T2 weighted image magnetic resonance imaging scans, (n=67 controls, 368 with CHD) acquired during the third trimester. We fit general linear models to test whether age, sex, expected cerebral substrate delivery, and CHD diagnosis were significant predictors of structural covariance. We identified significant effects of age, sex, cerebral substrate delivery, and specific CHD diagnosis across a variety of structural covariance networks, including primary motor and sensory cortices, cerebellar regions, frontal cortex, extra‐axial cerebrospinal fluid, thalamus, brainstem, and insula, consistent with widespread coordinated aberrant maturation of specific brain regions over the third trimester. Conclusions Structural covariance networks offer a sensitive, data‐driven approach to explore whole‐brain structural changes without anatomical priors. We used them to stratify a heterogenous patient cohort with CHD, highlighting similarities and differences between diagnoses during fetal neurodevelopment. Although there was a clear effect of abnormal fetal hemodynamics on structural brain maturation, our results suggest that this alone does not explain all the variation in brain development between individuals with CHD.

Background The superorder Forcipulatacea is a major clade of sea stars with approximately 400 extant species across three orders (Forcipulatida, Brisingida, Zorocallida). Over the past century, the systematics of Forcipulatacea have undergone multiple revisions by various authors, with some considering numerous families such as Asteriidae, Zoroasteridae, Pedicellasteridae, Stichasteridae, Heliasteridae, Labidiasteridae, and Neomorphasteridae, while others recognized only two families (i.e., Asteriidae and Zoroasteridae). Recent molecular analyses have shown the artificial nature of some of these groupings. Notably, four well-supported clades (Zorocallida, Brisingida, Stichasteridae, and Asteriidae) emerged from a synthesis of morphological and molecular evidence. The majority of extinct forcipulatacean species have been placed in modern families. However, many of these fossil species are in need of revision, especially those species placed within the Asteriidae, the largest of all forcipulatacean families. Methods In light of recent advancements in forcipulatacean systematics, we comprehensively reassess six well-preserved Jurassic forcipulatacean taxa, including the earliest crown-group members from the Hettangian (∼201.4 Ma), and also describe two new Jurassic genera, Forbesasterias gen. nov. and Marbleaster gen. nov. We assembled the largest and most comprehensive phylogenetic matrix for this group, sampling 42 fossil and extant forcipulatacean species for 120 morphological characters. To infer phylogenetic relationships and construct an evolutionary timeline for the diversification of major clades, we conducted a Bayesian tip-dating analysis incorporating the fossilized birth-death process. A total of 13 fossil species were sampled in our analysis, including six taxonomically revaluated herein, two recently reappraised species from the Jurassic, and five additional species from the Cretaceous and Miocene. Results Contrary to prior assumptions, our results indicate that none of the Jurassic taxa investigated belong to Asteriidae or any other modern families, and instead represent stem-forcipulatids. Furthermore, our phylogenetic results suggest that Asteriidae likely originated during the late Cretaceous. Our findings highlight a greater early diversity within the Forcipulatacea than previously presumed, challenging existing perceptions of the evolutionary history of this significant clade of marine invertebrates.

ABSTRACT Background Patient susceptibility to cytokine release syndrome (CRS) resulting from immune‐modulating chemotherapy has profound implications for clinical outcome. This is particularly true for patients receiving CAR T‐cell therapy. First‐line pharmacotherapy for CRS includes the administration of the IL‐6 receptor‐binding monoclonal antibody tocilizumab, or tocilizumab and corticosteroids. Other agents, such as siltuximab, anakinra, and dasatinab are also being explored for refractory cases of CRS. This review summarizes the potential role of omega‐3 fatty acids, that is, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) at ameliorating CRS in cancer patients receiving immune‐modulating chemotherapy, and is compared with current treatment strategies to reduce the severity of the inflammatory response. Recent Findings Selective blockade of specific proinflammatory mediators (e.g., IL‐6) is effective, but carries a significant risk of serious opportunistic infections. In contrast, omega‐3 fatty acids affect multiple triggers underlying the inflammatory response (i.e., prostaglandins, leukotrienes, transcription factors, and specialized proresolving molecules), and its major limitation is avoidance of hypertriglyceridemia, which can be managed by reducing the rate of intravenous administration. This discussion proposes a novel approach by continuous infusion of omega‐3 fatty acids to modulate the intensity of the severe systemic inflammatory response from CRS. The purpose of this review is to highlight the potential clinical benefits of a specialized omega‐3 fatty acids dosage form to mitigate the severity of CRS as a hypothetical alternative to current treatment. Conclusion Optimizing the formulation, for example, enriched fish oil that meets drug concentration standards for EPA and DHA, a continuous infusion rate, reductions in long‐chain saturated fatty acids concentrations, and addition of medium‐chain triglycerides to improve EPA + DHA utilization and physical stability are key pharmaceutical factors. This may result in a safer and more effective option than targeted abrogation of cytokines and consequent risks of adverse drug reactions, but will require formal study in randomized control trials in humans.

While the significance of obtaining restful sleep at night and maintaining daytime alertness is well recognized for human performance and overall well-being, substantial variations exist in the development of sleepiness during diurnal waking periods. Despite the established roles of the hypothalamus and striatum in sleep-wake regulation, the specific contributions of this neural circuit in regulating individual sleep homeostasis remain elusive. This study utilized resting-state functional magnetic resonance imaging (fMRI) and mathematical modeling to investigate the role of hypothalamus-striatum connectivity in subjective sleepiness variation in a cohort of 71 healthy adults under strictly controlled in-laboratory conditions. Mathematical modeling results revealed remarkable individual differences in subjective sleepiness accumulation patterns measured by the Karolinska Sleepiness Scale (KSS). Brain imaging data demonstrated that morning hypothalamic connectivity to the dorsal striatum significantly predicts the individual accumulation of subjective sleepiness from morning to evening, while no such correlation was observed for the hypothalamus-ventral striatum connectivity. These findings underscore the distinct roles of hypothalamic connectivity to the dorsal and ventral striatum in individual sleep homeostasis, suggesting that hypothalamus-dorsal striatum circuit may be a promising target for interventions mitigating excessive sleepiness and promoting alertness.

Background The BioImpedance Spectroscopy to maintain Renal Output randomised controlled trial investigated the effect of bioimpedance spectroscopy added to a standardised fluid management protocol on the risk of anuria and preservation of residual kidney function (primary trial outcomes) in incident haemodialysis patients. Despite the economic burden of kidney disease, the cost-effectiveness of using bioimpedance measurements to guide fluid management in haemodialysis is not known. Objectives To assess the cost-effectiveness of bioimpedance-guided fluid management against current fluid management without bioimpedance. Design Within-trial economic evaluation (cost–utility analysis) carried out alongside the open-label, multicentre BioImpedance Spectroscopy to maintain Renal Output randomised controlled trial. Setting Thirty-four United Kingdom outpatient haemodialysis centres, both main and satellite units, and their associated inpatient hospitals. Participants Four hundred and thirty-nine adult haemodialysis patients with > 500 ml urine/day or residual glomerular filtration rate > 3 ml/minute/1.73 m2. Intervention The study intervention was the incorporation of bioimpedance technology-derived information about body composition into the clinical assessment of fluid status in patients with residual kidney function undergoing haemodialysis. Bioimpedance measurements were used in conjunction with usual clinical judgement to set a target weight that would avoid excessive fluid depletion at the end of a dialysis session. Main outcome measures The primary outcome measure of the BioImpedance Spectroscopy to maintain Renal Output economic evaluation was incremental cost per additional quality-adjusted life-year gained over 24 months following randomisation. In the main (base-case) analysis, this was calculated from the perspective of the National Health Service and Personal Social Services. Sensitivity analyses explored the impact of different scenarios, sources of resource use data and value sets. Results The bioimpedance-guided fluid management group was associated with £382 lower average cost per patient (95% CI −£3319 to £2556) and 0.043 more quality-adjusted life-years (95% CI −0.019 to 0.105) compared with the current fluid management group, with neither values being statistically significant. The probability of bioimpedance-guided fluid management being cost-effective was 76% and 83% at commonly cited willingness-to-pay threshold of £20,000 and £30,000 per quality-adjusted life-year gained, respectively. The results remained robust to a series of sensitivity analyses. Limitations The missing data level was high for some resource use categories collected through case report forms, due to COVID-19 disruptions and a significant dropout rate in the informing BioImpedance Spectroscopy to maintain Renal Output trial. Conclusions Compared with current fluid management, bioimpedance-guided fluid management produced a marginal reduction in costs and a small improvement in quality-adjusted life-years. Results from both the base-case and sensitivity analyses suggested that use of bioimpedance is likely to be cost-effective. Future work Future work exploring the association between primary outcomes and longer-term survival would be useful. Should an important link be established, and relevant evidence becomes available, it would be informative to determine whether and how this might affect longer-term costs and benefits associated with bioimpedance-guided fluid management. Funding details This article presents independent research funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme as award number HTA 14/216/01 (NIHR136142). Plain language summary ‘Bioimpedance’ is a measure of how difficult it is for an electric current to pass through a biological object. Bioimpedance is used in devices that assess fluid status (over- or under-hydration) because it is very sensitive to the amount of water in tissue. Bioimpedance can be used in addition to clinical judgement when deciding how much water should be removed from someone with kidney failure during a dialysis treatment session. This is the first study to examine whether using this treatment represents a cost-effective use of National Health Service resources. We carried out an economic evaluation within a large randomised controlled trial in patients with kidney disease undergoing haemodialysis. We calculated the additional costs and quality-adjusted life-years (a measure that combines quality and quantity of life) using established methods. Over 2 years, our study showed that taking into account bioimpedance measurements about target weight resulted in slightly lower costs and marginally more quality-adjusted life-years, although there is uncertainty around these findings.

Abstract The aim of this study was to explore the use of perinatal ketamine to see if it can be used for the reduction of postpartum depression (PPD) following cesarean section (C‐section). PubMed, Cochrane, and Web of Science were the primary databases used for this review. Search terms used on January 5, 2024 incorporated “ketamine,” “C‐section,” “postpartum depression,” and related synonyms. The criteria for inclusion centered on studies published between January 1, 2008 and January 5, 2024. The final selection of articles was screened based on extraction criteria leaving eight randomized control trials in the final review. The selected data from the studies incorporated sample characteristics, study and population characteristics, and quantitative analyses covering Edinburgh Postpartum Depression Scale (EPDS) scores and depression rates. The Risk of Bias assessment was utilized to gain a deeper understanding of the quality of methodology used by the research studies. The review showed that ketamine can reduce the symptoms of PPD in mothers who have recently undergone C‐sections. Some studies showed decreased EPDS scores following the administration of ketamine while two studies also reported no significant differences in PPD following ketamine administration in C‐section patients. For example, Ma et al. found that the EPDS score at postpartum day 4 was significantly lower in the ketamine group compared with the control group (p = 0.007) while Yang et al. found that there were no significant differences between the ketamine and control group at 3 days postpartum (p = 0.553). The research from this review suggests that ketamine administration can prevent or decrease the symptoms of PPD, but more research is needed to establish the causal relationship between ketamine dosage and PPD in C‐section patients.

Background We discovered a novel human endogenous retrovirus (CT-RCC HERV-E) that was selectively expressed in most clear cell renal cell carcinomas (ccRCC) and served as a source of antigens for T cell-mediated killing. Here, we described the cloning of a novel T cell receptor (TCR) targeting a CT-RCC HERV-E-derived antigen specific to ccRCC and characterized antitumor activity of HERV-E TCR-transduced T cells (HERV-E T cells).Methods We isolated a CD8+ T cell clone from a patient with immune-mediated regression of ccRCC post-allogeneic stem cell transplant that recognized the CT-RCC-1 HERV-E-derived peptide in an HLA-A11-restricted manner. We used 5’Rapid Amplification of cDNA Ends (RACE) to clone the full length HERV-E TCR and generated retrovirus encoding this TCR for transduction of T cells. We characterized HERV-E T cells for phenotype and function in vitro and in a murine xenograft model. Lastly, we implemented a good manufacturing practice-compliant method for scalable production of HERV-E T cells.Results The HLA-A11-restricted HERV-E-reactive TCR exhibited a CD8-dependent phenotype and demonstrated specific recognition of the CT-RCC-1 peptide. CD8+ T cells modified to express HERV-E TCR displayed potent antitumor activity against HLA-A11+ ccRCC cells expressing CT-RCC HERV-E compared with unmodified T cells. Killing by HERV-E T cells was lost when cocultured against HERV-E knockout ccRCC cells. HERV-E T cells induced regression of established ccRCC tumors in a murine model and improved survival of tumor-bearing mice. Large-scale production of HERV-E T cells under good manufacturing practice conditions generated from healthy donors retained specific antigen recognition and cytotoxicity against ccRCC.Conclusions This is the first report showing that human ccRCC cells can be selectively recognized and killed by TCR-engineered T cells targeting a HERV-derived antigen. These preclinical findings provided the foundation for evaluating HERV-E TCR-transduced T cell infusions in patients with metastatic ccRCC in a clinical trial (NCT03354390).

Eastern boundary upwelling systems (EBUS) host very productive marine ecosystems that provide services to many surrounding countries. The impact of global warming on their functioning is debated due to limited long-term observations, climate model uncertainties, and significant natural variability. This study utilizes the usefulness of a machine learning technique to document long-term variability in upwelling systems from 1993 to 2019, focusing on high-frequency synoptic upwelling events. Because the latter are modulated by the general atmospheric and oceanic circulation, it is hypothesized that changes in their statistics can reflect fluctuations and provide insights into the long-term variability of EBUS. A two-step approach using Self-Organizing Maps (SOM) and Hierarchical Agglomerative Clustering (HAC) algorithms was employed. These algorithms were applied to sets of upwelling events to characterize signatures in sea-level pressure, meridional wind, shortwave radiation, sea-surface temperature (SST), and Ekman pumping based on dominant spatial patterns. Results indicated that the dominant spatial pattern, accounting for 56%-75% of total variance, representing the seasonal pattern, due to the marked seasonality in along-shore wind activity. Findings showed that, except for the Canary-Iberian region, upwelling events have become longer in spring and more intense in summer. Southern Hemisphere systems (Humboldt and Benguela) had a higher occurrence of upwelling events in summer (up to 0.022 Events/km²) compared to spring (