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Introduction Ventilator-associated pneumonia (VAP) is a common healthcare-associated infection in the intensive care unit (ICU). Probiotics are defined as live microorganisms that may confer health benefits when ingested. Prior randomised trials suggest that probiotics may prevent infections such as VAP and Clostridioides difficile–associated diarrhoea (CDAD). PROSPECT (Probiotics to Prevent Severe Pneumonia and Endotracheal Colonization Trial) is a multicentre, double-blinded, randomised controlled trial comparing the efficacy of the probiotic Lactobacillus rhamnosus GG with usual care versus usual care without probiotics in preventing VAP and other clinically important outcomes in critically ill patients admitted to the ICU.Methods and analysis The objective of E-PROSPECT is to determine the incremental cost-effectiveness of L. rhamnosus GG plus usual care versus usual care without probiotics in critically ill patients. E-PROSPECT will be performed from the public healthcare payer’s perspective over a time horizon from ICU admission to hospital discharge.We will determine probabilities of in-ICU and in-hospital events from all patients alongside PROSPECT. We will retrieve unit costs for each resource use item using jurisdiction-specific public databases, supplemented by individual site unit costs if such databases are unavailable. Direct costs will include medications, personnel costs, radiology/laboratory testing, operative/non-operative procedures and per-day hospital ‘hoteling’ costs not otherwise encompassed. The primary outcome is the incremental cost per VAP prevented between the two treatment groups. Other clinical events such as CDAD, antibiotic-associated diarrhoea and in-hospital mortality will be included as secondary outcomes. We will perform pre-specified subgroup analyses (medical/surgical/trauma; age; frailty status; antibiotic use; prevalent vs no prevalent pneumonia) and probabilistic sensitivity analyses for VAP, then generate confidence intervals using the non-parametric bootstrapping approach.Ethics and dissemination Study approval for E-PROSPECT was granted by the Hamilton Integrated Research Ethics Board of McMaster University on 29 July 2019. Informed consent was obtained from the patient or substitute decision-maker in PROSPECT. The findings of this study will be published in peer-reviewed journals.Trial registration number NCT01782755; Pre-results.

The early and late stages of human immunodeficiency virus (HIV) replication are orchestrated by the capsid (CA) protein, which self-assembles into a conical protein shell during viral maturation. Small molecule drugs known as capsid inhibitors (CIs) impede the highly regulated activity of CA. Intriguingly, a few CIs, such as PF-3450074 (PF74) and GS-CA1, exhibit effects at multiple stages of the viral lifecycle at effective concentrations in the pM to nM regimes, while the majority of CIs target a single stage of the viral lifecycle and are effective at nM to μM concentrations. In this work, we use coarse-grained molecular dynamics simulations to elucidate the molecular mechanisms that enable CIs to have such curious broad-spectrum activity. Our quantitatively analyzed findings show that CIs can have a profound impact on the hierarchical self-assembly of CA by perturbing populations of small CA oligomers. The self-assembly process is accelerated by the emergence of alternative assembly pathways that favor the rapid incorporation of CA pentamers, and leads to increased structural pleomorphism in mature capsids. Two relevant phenotypes are observed: (1) eccentric capsid formation that may fail to encase the viral genome and (2) rapid disassembly of the capsid, which express at late and early stages of infection, respectively. Finally, our study emphasizes the importance of adopting a dynamical perspective on inhibitory mechanisms and provides a basis for the design of future therapeutics that are effective at low stoichiometric ratios of drug to protein.

BackgroundDespite focused research in conventional therapies and considerable advances in the understanding of the molecular carcinogenesis of head and neck squamous cell carcinoma (HNSCC), the 5-year survival rate for patients with advanced disease remains ∼15-20%. The major causes of HNSCC-related deaths are cervical node and distant metastasis. E-cadherin has a key role in epithelial intercellular adhesion and its downregulation is a hallmark of epithelial-mesenchymal transition (EMT), which is associated with invasion, metastasis, and poor prognosis. Epithelial-mesenchymal transition is the major mechanism responsible for mediating invasiveness and metastasis of epithelial cancers. Recently, we reported the role of E-cadherin transcriptional repressors in the inflammation-induced promotion of EMT in HNSCC, which is mediated by COX-2. These findings suggest that therapies targeting the cyclooxygenase pathway may diminish the propensity for tumour metastasis in HNSCC by blocking the PGE2-mediated induction of E-cadherin transcriptional repressors.MethodsHerein, we evaluate the efficacy of the COX-2 inhibitor, apricoxib, in HNSCC cell lines. Apricoxib is effective in preventing tumour cell growth in three-dimensional, and anchorage-independent growth assays, as well as decreasing the capacity for tumour cell migration.ResultsHerein, we evaluate the efficacy of the COX-2 inhibitor, apricoxib, in HNSCC cell lines. Apricoxib is effective in preventing tumour cell growth in three-dimensional, and anchorage-independent growth assays, as well as decreasing the capacity for tumour cell migration. Treatment of HNSCC cells with apricoxib also causes greater upregulation of E-cadherin and Muc1 expression and downregulation of vimentin, as compared with celecoxib treatment. This has significant implications for targeted chemoprevention and anti-cancer therapy because E-cadherin expression has been implicated as a marker of sensitivity to epidermal growth factor receptor tyrosine kinase inhibitor and other therapies. We show for the first time the molecular mechanisms underlying the efficacy of apricoxib in HNSCC cells.ConclusionIn addition to reversing EMT via inhibition of COX-2, apricoxib upregulates 15-prostaglandin dehydrogenase and the prostaglandin transporter, thereby reducing the levels of active PGE2 by both suppressing its synthesis and increasing its catabolism. These findings have significant implications for metastasis and tumour progression in HNSCC.

Abstract Endometriosis is a chronic systemic disease, which results in endometrial-type tissue growing outside the uterus, and affects approximately 10% of reproductive-aged women worldwide. Its aetiology is poorly understood, and there is currently no long-term cure. Development and persistence of the disease depend on several coexisting factors including the vaginal microbiome. However, the role played by this important entity in endometriosis and its systemic involvement is not fully understood. Here, we investigated the vaginal microbiota, the serum and urine glycome, and antibody glycosylation in endometriosis patients. We reveal an endometriosis-specific vaginal microbiota in patients, being distinct from that present in a control group. Endometriosis patients were typified by a loss of the dominant Lactobacillus species, i.e. Lactobacillus iners, increased bacterial diversity and the presence of species such as Anaerococcus senegalensis, Prevotella jejuni, Porphyromonas bennonis and Anaerococcus octavius. The presence of trigalactosylated and triantennary serum glycans and urine core fucosylated mono-antennary glycans from IgG correlated with the vaginal presence of the bacterium A. senegalensis in endometriosis patients. Urine glycans did not differ in endometriosis, but urine IgG identified four novel sulfated glycans differing from serum IgG indicating functional relevance. Our findings contribute to understanding the relationships between the vaginal microbiota and the serum and urine glycome on the one hand, and endometriosis on the other. Further functional studies are warranted.

Abstract Background The number of major operations performed in obese patients is expected to increase given the growing prevalence of obesity. Obesity is a risk factor for a range of postoperative complications including perioperative neurocognitive disorders. However, the mechanisms underlying this vulnerability are not well defined. We hypothesize that obese subjects are more vulnerable to general anaesthesia induced neurotoxicity due to reduced levels of adiponectin. This hypothesis was tested using a murine surgical model in obese and adiponectin knockout mice exposed to the volatile anaesthetic agent sevoflurane. Methods Obese mice were bred by subjecting C57BL/6 mice to a high fat diet. Cognitive function, neuroinflammatory responses and neuronal degeneration were assessed in both obese and lean mice following exposure to 2 h of sevoflurane to confirm sevoflurane-induced neurotoxicity. Thereafter, to confirm the role of adiponectin deficiency in, adiponectin knockout mice were established and exposed to the sevoflurane. Finally, the neuroprotective effects of adiponectin receptor agonist (AdipoRon) were examined. Results Sevoflurane triggered significant cognitive dysfunction, neuroinflammatory responses and neuronal degeneration in the obese mice while no significant impact was observed in the lean mice. Similar cognitive dysfunction and neuronal degeneration were also observed in the adiponectin knockout mice after sevoflurane exposure. Administration of AdipoRon partially prevented the deleterious effects of sevoflurane in both obese and adiponectin knockout mice. Conclusions Our findings demonstrate that obese mice are more susceptible to sevoflurane-induced neurotoxicity and cognitive impairment in which adiponectin deficiency is one of the underlying mechanisms. Treatment with adiponectin receptor agonist ameliorates this vulnerability. These findings may have therapeutic implications in reducing the incidence of anaesthesia related neurotoxicity in obese subjects.

Abstract Quantum computing with qudits is an emerging approach that exploits a larger, more connected computational space, providing advantages for many applications, including quantum simulation and quantum error correction. Nonetheless, qudits are typically afflicted by more complex errors and suffer greater noise sensitivity which renders their scaling difficult. In this work, we introduce techniques to tailor arbitrary qudit Markovian noise to stochastic Weyl–Heisenberg channels and mitigate noise that commutes with our Clifford and universal two-qudit gate in generic qudit circuits. We experimentally demonstrate these methods on a superconducting transmon qutrit processor, and benchmark their effectiveness for multipartite qutrit entanglement and random circuit sampling, obtaining up to 3× improvement in our results. To the best of our knowledge, this constitutes the first-ever error mitigation experiment performed on qutrits. Our work shows that despite the intrinsic complexity of manipulating higher-dimensional quantum systems, noise tailoring and error mitigation can significantly extend the computational reach of today’s qudit processors.

Semi-autonomous vehicles (AVs) enable drivers to engage in non-driving tasks but require them to be ready to take control during critical situations. This “out-of-the-loop” problem demands a quick transition to active information processing, raising safety concerns and anxiety. Multimodal signals in AVs aim to deliver take-over requests and facilitate driver–vehicle cooperation. However, the effectiveness of auditory, visual, or combined signals in improving situational awareness and reaction time for safe maneuvering remains unclear. This study investigates how signal modalities affect drivers’ behavior using virtual reality (VR). We measured drivers’ reaction times from signal onset to take-over response and gaze dwell time for situational awareness across twelve critical events. Furthermore, we assessed self-reported anxiety and trust levels using the Autonomous Vehicle Acceptance Model questionnaire. The results showed that visual signals significantly reduced reaction times, whereas auditory signals did not. Additionally, any warning signal, together with seeing driving hazards, increased successful maneuvering. The analysis of gaze dwell time on driving hazards revealed that audio and visual signals improved situational awareness. Lastly, warning signals reduced anxiety and increased trust. These results highlight the distinct effectiveness of signal modalities in improving driver reaction times, situational awareness, and perceived safety, mitigating the “out-of-the-loop” problem and fostering human–vehicle cooperation.

Abstract Introduction Disparities in HIV and other sexually transmitted infections (STIs) persist among cisgender sexually minoritized men in the United States, driven in part by sexual behavior stigma, which is a barrier to clinic-based HIV/STI testing. HIV/STI biospecimen self-collection (HSBS) is a novel testing approach that mitigates stigma by allowing for some testing-related procedures to be conducted by oneself in one’s home or any private location rather than a facility that requires interpersonal interactions and exposure to other members of the public. HSBS has demonstrated acceptability, feasibility, and effectiveness in testing uptake, but the extent to which stigma persists in HSBS and the quantification of stigma’s role in HSBS is limited. Methods From 2019–2020, a nationwide sample of sexually minoritized men completed an online biobehavioral survey. Those who agreed to be recontacted (N = 4147) were invited to participate in HSBS; consented participants received self-collection kits that were laboratory-tested if completed. Sexual behavior stigma and HSBS associations were assessed with logistic regression. Results Mean age of participants was 35 years, 58% (2421/4147) were non-Hispanic white, 82% (3391/4147) were gay-identifying, 47% (1967/4147) had at least a college degree, and 56% (2342/4147) earned ≥ $40,000 annually; 27% (1112/4147) expressed HSBS interest, and 67% (689/1034) completed HSBS. HSBS interest and completion were less common among non-Hispanic Black sexually minoritized men and sexually minoritized men of lower socioeconomic status. Stigma from family and friends was significantly, negatively associated with HSBS interest (aOR = 0.72, 95% CI = 0.56, 0.93). Among those who had not tested for HIV/STIs in the past year, anticipated healthcare stigma was marginally, negatively associated with HSBS completion (aOR = 0.40, 95% CI = 0.15, 1.07). Among those who had never previously tested for HIV/STIs, anticipated healthcare stigma was significantly, negatively associated with HSBS interest (aOR = 0.32, 95% CI = 0.14, 0.72). Conclusions Sexual behavior stigma persists as an HIV/STI testing barrier, even in the case of HSBS, limiting its utilization. Increasing HSBS among sexually minoritized men in the US necessitates stigma mitigation efforts that directly address equity in implementation.

ABSTRACT: Excessive concentrations of free fatty acids (FFA) are the main factors causing immune dysfunction and inflammation in dairy cows with ketosis. Polarization of macrophages (the process of macrophages freely switching from one phenotype to another) into M1 or M2 phenotypes is an important event during inflammation induced by environmental stimuli. In nonruminants, mammalian target of rapamycin (mTOR)-mediated autophagy (a major waste degradation process) regulates macrophage polarization. Thus, our objective was to unravel the role of mTOR-mediated autophagy on macrophage polarization in ketotic dairy cows. We performed 4 experiments: (1) In vitro differentiated monocyte-derived macrophages from healthy dairy cows or dairy cows with clinical ketosis (CK) were treated for 24 h with 100 ng/mL LPS and 100 ng/mL IFN-γ or with 10 ng/mL IL4 and 10 ng/mL IL10; (2) Immortalized bovine macrophages were treated for 24 h with 0, 0.3, 0.6, or 1.2 mM FFA, LPS, and IFN-γ, or with IL4 and IL10; (3) Macrophages were pretreated with 2 μM 4,6-dimorpholino-N-(4-nitrophenyl)-1,3,5-triazin-2-amine (MHY1485) for 30 min before treatment with LPS and IFN-γ or IL4 and IL10; (4) Macrophages were pretreated with 100 nM rapamycin (RAPA) for 2 h before treatment with LPS and IFN-γ or IL4 and IL10. Compared with healthy cows, cows with CK had a greater mean fluorescence intensity (MFI) of CD86+, but lower MFI of CD206+ and lower number of autophagosomes and autolysosomes in macrophages. Exogenous FFA treatment upregulated protein abundance of inducible nitric oxide synthase (iNOS) and the MFI of CD86, whereas it downregulated the protein abundance of arginase 1 and the MFI of CD206. In addition, FFA increased the p-p65/p65 protein abundance and tumor necrosis factor α, IL1B, and IL6 mRNA abundance, but decreased LC3-phosphatidylethanolamine conjugate protein abundance and the number of autophagosomes and autolysosomes number. Pretreatment with MHY1485 promoted macrophage M1 polarization and inhibited macrophage M2 polarization via decreased mTOR-mediated autophagy. Activation of mTOR-mediated autophagy by pretreatment with RAPA attenuated the upregulation of inflammation in M1 macrophages that was induced by FFA. These data revealed that high concentrations of FFA promote macrophage M1 polarization in ketotic dairy cows by impairing mTOR-mediated autophagy.

Abstract Osteosarcoma is the most common primary bone malignancy in children and young adults, and it has few treatment options. As a result, there has been little improvement in survival outcomes in the past few decades. The need for models to test novel therapies is especially great in this disease since it is both rare and does not respond to most therapies. To address this, an NCI-funded consortium has characterized and utilized a panel of patient-derived xenograft models of osteosarcoma for drug testing. The exomes, transcriptomes, and copy number landscapes of these models have been presented previously. This study now adds whole genome sequencing and reverse-phase protein array profiling data, which can be correlated with drug testing results. In addition, four additional osteosarcoma models are described for use in the research community.

Abstract Aesthetic judgements are partly predicted by image statistics, although the extent to which they are calibrated to the statistics of real-world scenes and the ‘visual diet’ of daily life is unclear. Here, we investigated the extent to which the beauty ratings of Western oil paintings from the JenAesthetics dataset can be accounted for by real-world scene statistics. We computed spatial and chromatic image statistics for the paintings and a set of real-world scenes captured by a head-mounted camera as participants went about daily lives. Partial least squares regression (PLSR) indicated that 6–15% of the variance in beauty ratings of the art can be accounted for by the art’s image statistics. The luminance contrast of paintings made an important contribution to the PLSR models: paintings were perceived as more beautiful the greater the variation in luminance. PLSR models which expressed the art’s image statistics relative to real-world scene statistics explained a similar amount of variance to models using the art’s image statistics. The importance of an image statistic to perceived beauty was not related to how closely art reproduces the value from the real world. The findings suggest that beauty judgements of art are not strongly calibrated to the scene statistics of the real world.

Abstract Introduction Atrial fibrillation (AF) and heart failure (HF) commonly coexist, resulting in adverse health and economic consequences such as declining ventricular function, heightened mortality, and reduced quality of life. However, limited information exists on the impact of COVID‐19 on AF patients that hospitalized for HF. Methods We analyzed the 2020 U.S. National Inpatient Sample to investigate the effects of COVID‐19 on AF patients that primarily hospitalized for HF. Participants aged 18 and above were identified using relevant ICD‐10 CM codes. Adjusted odds ratios for outcomes were calculated through multivariable logistic regression. The primary outcome was inpatient mortality, with secondary outcomes including system‐based complications. Results We identified 322,090 patients with primary discharge diagnosis of HF with comorbid AF. Among them, 0.73% (2355/322,090) also had a concurrent diagnosis of COVID‐19. In a survey multivariable logistic and linear regression model adjusting for patient and hospital factors, COVID‐19 infection was associated with higher in‐hospital mortality (aOR 3.17; 95% CI 2.25, 4.47, p

Abstract A theoretical perspective on grandiose narcissism suggests four forms of it (sanctity, admiration, heroism, rivalry) and states that these forms conduce to different ways of thinking and acting. Guided by this perspective, we examined in a multinational and multicultural study (61 countries; N = 15,039) how narcissism forms are linked to cognitions and behaviors prompted by the COVID-19 pandemic. As expected, differences in cognitions and behaviors across narcissism forms emerged. For example, higher narcissistic rivalry predicted lower likelihood of enactment of COVID-19 prevention behaviors, but higher narcissistic sanctity predicted higher likelihood of enactment of COVID-19 prevention behaviors. Further, whereas the heroism, admiration, and rivalry narcissism forms acted in a typically antisocial manner, with high narcissism predicting greater endorsement of unfounded health beliefs, the sanctity form acted in a prosocial manner, with higher narcissism being linked to lower endorsement of unfounded COVID-19 health beliefs. Thus, the findings (a) support the idea of four narcissism forms acting differently, and (b) show that these differences reflect a double-edged sword, sometimes linking to an anti-social orientation, and sometimes linking to a pro-social orientation.

Abstract Background When caring for critically ill patients, health workers often need to ‘call-for-help’ to get assistance from colleagues in the hospital. Systems are required to facilitate calling-for-help and enable the timely provision of care for critically ill patients. Evidence around calling-for-help systems is mostly from high income countries and the state of calling-for-help in hospitals in Tanzania and Kenya has not been formally studied. This study aims to describe health workers’ experiences about calling-for-help when taking care of critically ill patients in hospitals in Tanzania and Kenya. Methods Ten hospitals across Kenya and Tanzania were visited and in-depth interviews conducted with 30 health workers who had experience of caring for critically ill patients. The interviews were transcribed, translated and the data thematically analyzed. Results The study identified three thematic areas concerning the systems for calling-for-help when taking care of critically ill patients: 1) Calling-for-help structures: there is lack of functioning structures for calling-for-help; 2) Calling-for-help processes: the calling-for-help processes are innovative and improvised; and 3) Calling-for-help outcomes: the help that is provided is not as requested. Conclusion Calling-for-help when taking care of a critically ill patient is a necessary life-saving part of care, but health workers in Tanzanian and Kenyan hospitals experience a range of significant challenges. Hospitals lack functioning structures, processes for calling-for-help are improvised and help that is provided is not as requested. These challenges likely cause delays and decrease the quality of care, potentially resulting in unnecessary mortality and morbidity.

Abstract Single-cell RNA-sequencing enables testing for differential expression (DE) between conditions at a cell type level. While powerful, one of the limitations of such approaches is that the sensitivity of DE testing is dictated by the sensitivity of clustering, which is often suboptimal. To overcome this, we present miloDE—a cluster-free framework for DE testing (available as an open-source R package). We illustrate the performance of miloDE on both simulated and real data. Using miloDE, we identify a transient hemogenic endothelia-like state in mouse embryos lacking Tal1 and detect distinct programs during macrophage activation in idiopathic pulmonary fibrosis.