In Silico Design and Synthesis of Antifungal Peptides Guided by Quantitative Antifungal Activity.

Antifungal peptides (AFPs) are emerging as promising candidates for advanced antifungal therapies because of their broad-spectrum efficacy and reduced resistance development. In silico design of AFPs, however, remains challenging, due to the lack of an efficient and well-validated quantitative assessment of antifungal activity. This study introduced an AFP design approach that leverages an innovative quantitative metric, named the antifungal index (AFI), through a three-step process, i.e., segmentation, single-point mutation, and global multipoint optimization. An exhaustive search of 100 putative AFP sequences indicated that random modifications without guidance only have a 5.97-20.24% chance of enhancing antifungal activity. Analysis of the search results revealed that (1) N-terminus truncation is more effective in enhancing antifungal activity than the modifications at the C-terminus or both ends, (2) introducing the amino acids within the 10-60% sequence region that enhance aromaticity and hydrophobicity are more effective in increasing antifungal efficacy, and (3) incorporating alanine, cysteine, and phenylalanine during multiple point mutations has a synergistic effect on enhancing antifungal activity. Subsequently, 28 designed peptides were synthesized and tested against four typical fungal strains. The success rate for developing promising AFPs, with a minimal inhibitory concentration of ≤5.00 µM, was an impressive 82.14%. The predictive and design tool is accessible at https://antifungipept.chemoinfolab.com.

Thermal expansion, lattice vibration, and isotope effect on hydrogen diffusion in BCC Fe, Cr, and W from first-principles calculations.

Fe, Cr, and W are important elements in the alloys of in-reactor materials and operate in high-temperature environments with thermal expansion. Their tritium-impeding abilities are crucial to the radiation safety of various nuclear reactors. In this study, first-principles density functional theory is combined with quasi-harmonic approximation to evaluate factors that can affect the interstitial formation energy and diffusion coefficient of hydrogen isotopes in body-centered cubic (BCC) Fe, Cr, and W, including thermal expansion, metal host lattice vibrations, phonon density-of-states (pDOS) coupling diffusing atoms, and isotope effects. Calculation results indicate that the interstitial formation energy decreases as lattice expansion increases, whereas the jump barriers remain almost constant. Thermal expansion, host lattice vibration, and pDOS coupling minimally affect the diffusion coefficients of hydrogen isotopes in Fe, Cr, and W. The diffusion coefficient ratios between hydrogen isotopes are higher than the inverse ratio of the square root of the isotope mass at low temperatures. However, they decrease to the inverse ratio of the square root of the isotope mass at temperatures exceeding 800 K. This study comprehensively investigates factors that affect the diffusion coefficients of hydrogen isotopes in BCC Fe, Cr, and W, thus providing a firm theoretical foundation for predicting the diffusion coefficients of tritium at different temperatures using protium/deuterium diffusion coefficients.

Heme metabolism and HO-1 in the pathogenesis and potential intervention of endometriosis.

Endometriosis (EM) is one of the diseases related to retrograded menstruation and hemoglobin. Heme, released from hemoglobin, is degraded by heme oxygenase-1 (HO-1). In EM lesions, heme metabolites regulate processes such as inflammation, redox balance, autophagy, dysmenorrhea, malignancy, and invasion, where macrophages (Mø) play a fundamental role in their interactions. Regulation occurs at molecular, cellular, and pathological levels. Numerous studies suggest that heme is an indispensable component in EM and may contribute to its pathogenesis. The regulatory role of heme in EM encompasses cytokines, signaling pathways, and kinases that mediate cellular responses to external stimuli. HO-1, a catalytic enzyme in the catabolic phase of heme, mitigates heme's cytotoxicity in EM due to its antioxidant, anti-inflammatory, and anti-proliferative properties. Certain compounds may intervene in EM by targeting heme metabolism, guiding the development of appropriate treatments for all stages of endometriosis.

Protocol implementation during the COVID-19 pandemic: experiences from a randomized trial of stress ulcer prophylaxis.

BACKGROUND: During the COVID-19 pandemic, many intensive care units (ICUs) halted research to focus on COVID-19-specific studies. OBJECTIVE: To describe the conduct of an international randomized trial of stress ulcer prophylaxis (Re-Evaluating the Inhibition of Stress Erosions in the ICU [REVISE]) during the pandemic, addressing enrolment patterns, center engagement, informed consent processes, data collection, a COVID-specific substudy, patient transfers, and data monitoring. METHODS: REVISE is a randomized trial among mechanically ventilated patients, comparing pantoprazole 40 mg IV to placebo on the primary efficacy outcome of clinically important upper gastrointestinal bleeding and the primary safety outcome of 90-day mortality. We documented protocol implementation status from March 11th 2020-August 30th 2022. RESULTS: The Steering Committee did not change the scientific protocol. From the first enrolment on July 9th 2019 to March 10th 2020 (8 months preceding the pandemic), 267 patients were enrolled in 18 centers. From March 11th 2020-August 30th 2022 (30 months thereafter), 41 new centers joined; 59 were participating by August 30th 2022 which enrolled 2961 patients. During a total of 1235 enrolment-months in the pandemic phase, enrolment paused for 106 (8.6%) months in aggregate (median 3 months, interquartile range 2;6). Protocol implementation involved a shift from the a priori consent model pre-pandemic (188, 58.8%) to the consent to continue model (1615, 54.1%, p < 0.01). In one new center, an opt-out model was approved. The informed consent rate increased slightly (80.7% to 85.0%, p = 0.05). Telephone consent encounters increased (16.6% to 68.2%, p < 0.001). Surge capacity necessitated intra-institutional transfers; receiving centers continued protocol implementation whenever possible. We developed a nested COVID-19 substudy. The Methods Centers continued central statistical monitoring of trial metrics. Site monitoring was initially remote, then in-person when restrictions lifted. CONCLUSION: Protocol implementation adaptations during the pandemic included a shift in the consent model, a sustained high consent rate, and launch of a COVID-19 substudy. Recruitment increased as new centers joined, patient transfers were optimized, and monitoring methods were adapted.

Effect of Ambient Conditions on Acoustic Activation of the Perfluoropropane Droplets Within the Infarct Zone.

BACKGROUND: Acoustically activated perfluoropropane droplets (PD) formulated from lipid encapsulated microbubble preparations produce a delayed myocardial contrast enhancement that preferentially highlights the infarct zones (IZ). Since activation of PDs may be temperature sensitive, it is unclear what effect body temperature (BT) has on acoustic activation (AA). OBJECTIVE: We sought to determine whether the microvascular retention and degree of myocardial contrast intensity (MCI) would be affected by BT at the time of intravenous injection. METHODS: We administered intravenous (IV) PD in nine rats following 60 min of ischemia followed by reperfusion. Injections in these rats were given at temperatures above and below 36.5°C, with high MI activation in both groups at 3 or 6 min following IV injection (IVI). In six additional rats (three in each group), IV PDs were given only at one temperature (<36.5°C or ≥36.5°C), permitting a total of 12 comparisons of different BT. Differences in background subtracted MCI at 3-6 min post-injection were compared in the infarct zone (IZ) and remote zone (RZ). Post-mortem lung hematoxylin and eosin (H&E) staining was performed to assess the effect potential thermal activation on lung tissue. RESULTS: Selective MCI within the IZ was observed in 8 of 12 rats who received IVI of PDs at <36.5°C, but none of the 12 rats who had IVI at the higher temperature (p < 0.0001). Absolute MCI following droplet activation was significantly higher in both the IZ and RZ when given at the lower BT. H&E indicated significant red blood extravasation in 5/7 rats who had had IV injections at higher BT, and 0/7 rats who had IV PDs at <36.5°C. CONCLUSIONS: Selective IZ enhancement with AA of intravenous PDs is possible, but temperature sensitive. Thermal activation appears to occur when PDs are given at higher temperatures, preventing AA, and increasing unwanted bioeffects.

Alanyl-tRNA synthetase, AARS1, is a lactate sensor and lactyltransferase that lactylates p53 and contributes to tumorigenesis.

Lysine lactylation is a post-translational modification that links cellular metabolism to protein function. Here, we find that AARS1 functions as a lactate sensor that mediates global lysine lacylation in tumor cells. AARS1 binds to lactate and catalyzes the formation of lactate-AMP, followed by transfer of lactate to the lysince acceptor residue. Proteomics studies reveal a large number of AARS1 targets, including p53 where lysine 120 and lysine 139 in the DNA binding domain are lactylated. Generation and utilization of p53 variants carrying constitutively lactylated lysine residues revealed that AARS1 lactylation of p53 hinders its liquid-liquid phase separation, DNA binding, and transcriptional activation. AARS1 expression and p53 lacylation correlate with poor prognosis among cancer patients carrying wild type p53. ß-alanine disrupts lactate binding to AARS1, reduces p53 lacylation, and mitigates tumorigenesis in animal models. We propose that AARS1 contributes to tumorigenesis by coupling tumor cell metabolism to proteome alteration.

Health Fluctuations in Dementia and its Impact on the Assessment of Health-Related Quality of Life Using the EQ-5D-5L.

OBJECTIVES: To quantify health fluctuations, identify affected health-related quality of life (HRQoL) dimensions, and evaluate if fluctuations affect the HRQoL instruments recall period adherence in people living with dementia (PlwD). METHODS: Caregivers of PlwD completed a daily diary for 14 days, documenting if PlwD's health was better or worse than the day before and the affected HRQoL dimensions. Health fluctuation was categorized into low (0-4 fluctuations in 14 days), moderate (5-8), and high (9-14). Also, caregivers and PlwD completed the EQ-5D-5L (proxy- and self-reported) on days 1, 7, and 14. Subsequently, caregivers were interviewed to determine whether recurrent fluctuations were considered in the EQ-5D-5L assessment of today's health (recall period adherence). RESULTS: Fluctuations were reported for 96% of PlwD, on average, for 7 of the 14 days. Dimensions most frequently triggering fluctuations included memory, mobility, concentration, sleep, pain, and usual activities. Fluctuations were associated with higher EQ-5D-5L health-states variation and nonadherence to the EQ-5D-5L recall period "today." PlwD with moderate to high fluctuation had the highest EQ-5D-5L utility change between day 1 and 14 (0.157 and 0.134) and recall period nonadherence (31% and 26%) compared with PlwD with low fluctuation (0.010; 17%). Recall period nonadherence was higher in PlwD with improved compared with those with deteriorated health in the diary (37% vs 9%). CONCLUSIONS: Health fluctuations frequently occur in dementia and strongly affect HRQoL assessments. Further research is needed to evaluate if more extended recall periods and multiple, consecutive assessments could capture health fluctuations more appropriately in dementia.

Comprehensive overview of the anesthesiology research landscape: A machine Learning Analysis of 737 NIH-funded anesthesiology primary Investigator's publication trends.

Background: Anesthesiology plays a crucial role in perioperative care, critical care, and pain management, impacting patient experiences and clinical outcomes. However, our understanding of the anesthesiology research landscape is limited. Accordingly, we initiated a data-driven analysis through topic modeling to uncover research trends, enabling informed decision-making and fostering progress within the field. Methods: The easyPubMed R package was used to collect 32,300 PubMed abstracts spanning from 2000 to 2022. These abstracts were authored by 737 Anesthesiology Principal Investigators (PIs) who were recipients of National Institute of Health (NIH) funding from 2010 to 2022. Abstracts were preprocessed, vectorized, and analyzed with the state-of-the-art BERTopic algorithm to identify pillar topics and trending subtopics within anesthesiology research. Temporal trends were assessed using the Mann-Kendall test. Results: The publishing journals with most abstracts in this dataset were Anesthesia & Analgesia 1133, Anesthesiology 992, and Pain 671. Eight pillar topics were identified and categorized as basic or clinical sciences based on a hierarchical clustering analysis. Amongst the pillar topics, "Cells & Proteomics" had both the highest annual and total number of abstracts. Interestingly, there was an overall upward trend for all topics spanning the years 2000-2022. However, when focusing on the period from 2015 to 2022, topics "Cells & Proteomics" and "Pulmonology" exhibit a downward trajectory. Additionally, various subtopics were identified, with notable increasing trends in "Aneurysms", "Covid 19 Pandemic", and "Artificial intelligence & Machine Learning". Conclusion: Our work offers a comprehensive analysis of the anesthesiology research landscape by providing insights into pillar topics, and trending subtopics. These findings contribute to a better understanding of anesthesiology research and can guide future directions.

Creating a Multiply Imputed Value Set for the EQ-5D-5L in Canada: State-Level Misspecification Terms Are Needed to Characterize Parameter Uncertainty Correctly.

BACKGROUND: Parameter uncertainty in EQ-5D-5L value sets often exceeds the instrument's minimum important difference, yet this is routinely ignored. Multiple imputation (MI) accounts for parameter uncertainty in the value set; however, no valuation study has implemented this methodology. Our objective was to create a Canadian MI value set for the EQ-5D-5L, thus enabling users to account for parameter uncertainty in the value set. METHODS: Using the Canadian EQ-5D-5L valuation study (N = 1,073), we first refit the original model followed by models with state-level misspecification. Models were compared based on the adequacy of 95% credible interval (CrI) coverage for out-of-sample predictions. Using the best-fitting model, we took 100 draws from the posterior distribution to create 100 imputed value sets. We examined how much the standard error of the estimated mean health utilities increased after accounting for parameter uncertainty in the value set by using the MI and original value sets to score 2 data sets: 1) a sample of 1,208 individuals from the Canadian general public and 2) a sample of 401 women with breast cancer. RESULTS: The selected model with state-level misspecification outperformed the original model (95% CrI coverage: 94.2% v. 11.6%). We observed wider standard errors for the estimated mean utilities on using the MI value set for both the Canadian general public (MI: 0.0091; original: 0.0035) and patients with breast cancer (MI: 0.0169; original: 0.0066). DISCUSSION AND CONCLUSIONS: We provide 1) the first MI value sets for the EQ-5D-5L and 2) code to construct MI value sets while accounting for state-level model misspecification. Our study suggests that ignoring parameter uncertainty in value sets leads to falsely narrow SEs. HIGHLIGHTS: Value sets for health state utility instruments are estimated subject to parameter uncertainty; this parameter uncertainty may exceed the minimum important difference of the instrument, yet it is not fully captured using current methods.This study creates the first multiply imputed value set for a multiattribute utility instrument, the EQ-5D-5L, to fully capture this parameter uncertainty.We apply the multiply imputed value set to 2 data sets from 1) the Canadian general public and 2) women with invasive breast cancer.Scoring the EQ-5D-5L using a multiply imputed value set led to wider standard error estimates, suggesting that the current practice of ignoring parameter uncertainty in the value set leads to falsely low standard errors.Our work will be of interest to methodologists and developers of the EQ-5D-5L and users of the EQ-5D-5L, such as health economists, researchers, and policy makers.

A Systematic Review and Quality Assessment of Cardiovascular Disease-Specific Health-Related Quality-of-Life Instruments Part I: Instrument Development and Content Validity.

OBJECTIVES: Health-related quality-of-life (HRQoL) instruments for cardiovascular diseases (CVD) have been commonly used to measure important patient-reported outcomes (PROs) in clinical trials and practices. This study aimed at systematically identifying and assessing the content validity of CVD-specific HRQoL instruments in clinical studies. METHODS: The research team searched Cumulative Index to Nursing and Allied Health Literature, Embase, and PubMed from inception to January 20, 2022. The research team included studies that reported the development and content validity for CVD-specific instruments. Two reviewers independently assessed the methodological quality using the Consensus-based Standards for the Selection of Health Measurement Instruments methods on evaluating content validity of PROs. Content analysis was used to categorize the items included in the instruments. RESULTS: The research team found 69 studies reporting the content validity of 40 instruments specifically developed for CVD. Fourteen (35.0%) were rated "sufficient" with very low to moderate quality of evidence. For PRO development, all instruments were rated "doubtful" or "inadequate." Twenty-eight (70.0%) instruments cover the core concepts of HRQoL. CONCLUSIONS: The quality of development and content validity vary among existing CVD-specific instruments. The evidence on the content validity should be considered when choosing a HRQoL instrument in CVD clinical studies and health economic evaluations.

Computerized clinical decision support to improve stroke prevention therapy in primary care management of atrial fibrillation: a cluster randomized trial.

BACKGROUND: Despite guidelines supporting antithrombotic therapy use in atrial fibrillation (AF), under-prescribing persists. We assessed whether computerized clinical decision support (CDS) would enable guideline-based antithrombotic therapy for AF patients in primary care. METHODS: This cluster randomized trial of CDS versus usual care (UC) recruited participants from primary care practices across Nova Scotia, following them for 12 months. The CDS tool calculated bleeding and stroke risk scores and provided recommendations for using oral anticoagulants (OAC) per Canadian guidelines. RESULTS: From June 14, 2014 to December 15, 2016, 203 primary care providers (99 UC, 104 CDS) with access to high-speed Internet were recruited, enrolling 1,145 eligible patients (543 UC, 590 CDS) assigned to the same treatment arm as their provider. Patient mean age was 72.3 years; most were male (350, 64.5% UC, 351, 59.5% CDS) and from a rural area (298, 54.9% UC, 315, 53.4% CDS). At baseline, a higher than anticipated proportion of patients were receiving guideline-based OAC therapy (373, 68.7% UC, 442, 74.9% CDS; relative risk [RR] 0.97 (95% confidence interval [CI], 0.87-1.07; P = .511)). At 12 months, prescription data were available for 538 usual care and 570 CDS patients, and significantly more CDS patients were managed according to guidelines (415, 77.1% UC, 479, 84.0% CDS; RR 1.08 (95% CI, 1.01-1.15; P = .024)). CONCLUSION: Notwithstanding high baseline rates, primary care provider access to the CDS over 12 months further optimized the prescribing of OAC therapy per national guidelines to AF patients potentially eligible to receive it. This suggests that CDS can be effective in improving clinical process of care. TRIAL REGISTRATION: Clinical Trials NCT01927367. https://clinicaltrials.gov/ct2/show/NCT01927367?term=NCT01927367&draw=2&rank=1.

CD177 drives the transendothelial migration of Treg cells enriched in human colorectal cancer.

Objectives: Regulatory T (Treg) cells regulate immunity in autoimmune diseases and cancers. However, immunotherapies that target tumor-infiltrating Treg cells often induce unwanted immune responses and tissue inflammation. Our research focussed on exploring the expression pattern of CD177 in tumor-infiltrating Treg cells with the aim of identifying a potential target that can enhance immunotherapy effectiveness. Methods: Single-cell RNA sequencing (scRNA-seq) data and survival data were obtained from public databases. Twenty-one colorectal cancer patient samples, including fresh tumor tissues, peritumoral tissues and peripheral blood mononuclear cells (PBMCs), were analysed using flow cytometry. The transendothelial activity of CD177+ Treg cells was substantiated using in vitro experiments. Results: ScRNA-seq and flow cytometry results indicated that CD177 was exclusively expressed in intratumoral Treg cells. CD177+ Treg cells exhibited greater activation status and expressed elevated Treg cell canonical markers and immune checkpoint molecules than CD177- Treg cells. We further discovered that both intratumoral CD177+ Treg cells and CD177-overexpressing induced Treg (iTreg) cells had lower levels of PD-1 than their CD177- counterparts. Moreover, CD177 overexpression significantly enhanced the transendothelial migration of Treg cells in vitro. Conclusions: These results demonstrated that Treg cells with higher CD177 levels exhibited an enhanced activation status and transendothelial migration capacity. Our findings suggest that CD177 may serve as an immunotherapeutic target and that overexpression of CD177 may improve the efficacy of chimeric antigen receptor T (CAR-T) cell therapy.

Application of interpretable machine learning algorithms to predict distant metastasis in ovarian clear cell carcinoma.

BACKGROUND: Ovarian clear cell carcinoma (OCCC) represents a subtype of ovarian epithelial carcinoma (OEC) known for its limited responsiveness to chemotherapy, and the onset of distant metastasis significantly impacts patient prognoses. This study aimed to identify potential risk factors contributing to the occurrence of distant metastasis in OCCC. METHODS: Utilizing the Surveillance, Epidemiology, and End Results (SEER) database, we identified patients diagnosed with OCCC between 2004 and 2015. The most influential factors were selected through the application of Gaussian Naive Bayes (GNB) and Adaboost machine learning algorithms, employing a Venn test for further refinement. Subsequently, six machine learning (ML) techniques, namely XGBoost, LightGBM, Random Forest (RF), Adaptive Boosting (Adaboost), Support Vector Machine (SVM), and Multilayer Perceptron (MLP), were employed to construct predictive models for distant metastasis. Shapley Additive Interpretation (SHAP) analysis facilitated a visual interpretation for individual patient. Model validity was assessed using accuracy, sensitivity, specificity, positive predictive value, negative predictive value, F1 score, and the area under the receiver operating characteristic curve (AUC). RESULTS: In the realm of predicting distant metastasis, the Random Forest (RF) model outperformed the other five machine learning algorithms. The RF model demonstrated accuracy, sensitivity, specificity, positive predictive value, negative predictive value, F1 score, and AUC (95% CI) values of 0.792 (0.762-0.823), 0.904 (0.835-0.973), 0.759 (0.731-0.787), 0.221 (0.186-0.256), 0.974 (0.967-0.982), 0.353 (0.306-0.399), and 0.834 (0.696-0.967), respectively, surpassing the performance of other models. Additionally, the calibration curve's Brier Score (95%) for the RF model reached the minimum value of 0.06256 (0.05753-0.06759). SHAP analysis provided independent explanations, reaffirming the critical clinical factors associated with the risk of metastasis in OCCC patients. CONCLUSIONS: This study successfully established a precise predictive model for OCCC patient metastasis using machine learning techniques, offering valuable support to clinicians in making informed clinical decisions.

Lipopolysaccharide promotes cancer cell migration and invasion through METTL3/PI3K/AKT signaling in human cholangiocarcinoma.

Purpose: As a major structural component of the outer membrane of Gram-negative bacteria, lipopolysaccharide (LPS) has been detected in the blood circulation and tissues in patients with chronic diseases and cancers, which plays a critical role in the tumor formation and progression. However, the biological role of LPS in human intrahepatic cholangiocarcinoma remains unclear. The aims of this study were to investigate the role of LPS in the malignant progression of intrahepatic cholangiocarcinoma. Methods: The cell migration and invasion capacities of cholangiocarcinoma cell lines were evaluated by Boyden chamber assays. Expression levels of the key molecules involved in the PI3K/AKT signaling and METTL3 were detected by qPCR and western blot. The molecular mechanism by which LPS promotes the malignant behaviors was investigated by using siRNAs, plasmids and small molecule inhibitors. Results: In vitro experiments showed that exogenous LPS treatment promoted cell migration and invasion capacities in both QBC939 and HUCCT1 cell lines, while did not affect cell proliferation and apoptosis. Mechanistically, exogenous LPS treatment had been proved to induce the increased expression of METTL3 and activate the downstream PI3K/AKTsignaling pathway. In addition, suppression of METTL3 expression reduced cell proliferation, migration and invasion capacities in both cell lines. Furthermore, inhibition of METTL3 expression or inhibition of PI3K/AKT signaling decreased LPS-induced cell migration and invasion capacities. Moreover, knockdown of METTL3 or inhibition of METTL3 significantly inhibited LPS-induced activation of the PI3K/AKT signaling. Conclusion: In general, these results suggest that the LPS-METTL3-PI3K/AKT signal axis promotes cell migration and invasion in ICC, which contributes to a reduced overall survival in patients with ICC. It may broaden the horizon of cancer therapy with potential therapeutic targets.

A comparative analysis of phage classification methods in light of the recent ICTV taxonomic revisions.

Recent ICTV taxonomy updates significantly changed phage taxonomy, yet a thorough phage classification workflow doesn't exist. This study compares six categorization tools and establishes a novel multi-method approach, combining genome similarity and specialized protein analysis. Applying the method to APEC phage P151 showed consistent categorization across platforms. A possible workflow for phage classification is proposed; offering a versatile tool for phage research and development.

Acoustic Activation Imaging With Intravenous Perfluoropropane Nanodroplets Results in Selective Bioactivation of the Risk Area.

BACKGROUND: Acoustically activatable perfluoropropane droplets (PD) can be formulated from commercially available microbubble preparations. Diagnostic transthoracic ultrasound frequencies have resulted in acoustic activation (AA) predominately within myocardial infarct zones (IZ). OBJECTIVE: We hypothesized that the AA area following acute coronary ischemia/reperfusion (I/R) would selectively enhance the developing scar zone, and target bioeffects specifically to this region. METHODS: We administered intravenous PD in 36 rats and 20 pigs at various stages of myocardial scar formation (30 minutes, 1 day, and 7 days post I/R) to determine what effect infarct age had on the AA within the IZ. This was correlated with histology, myeloperoxidase activity, and tissue nitrite activity. RESULTS: The degree of AA within the IZ in rats was not associated with collagen content, neutrophil infiltration, or infarct age. AA within 24 hours of I/R was associated with increased nitric oxide utilization selectively within the IZ (P < .05 compared with remote zone). The spatial extent of AA in pigs correlated with infarct size only when performed before sacrifice at 7 days (r = .74, P < .01). CONCLUSIONS: Acoustic activation of intravenous PD enhances the developing scar zone following I/R, and results in selective tissue nitric oxide utilization.

Persistence of peripheral CD8 + CD28- T cells indicates a favourable outcome and tumour immunity in first-line HER2-positive metastatic breast cancer.

BACKGROUND: The contradictory role of CD8 + CD28- T cells in tumour immunity has been reported, while their biological and clinical significance in HER2-positive metastatic breast cancer (MBC) is still unknown. METHODS: HER2-positive MBC patients with no prior therapy in the metastatic setting were retrospectively recruited at two medical centres. Peripheral CD8 + CD28- T cells (pTCD8+CD28-) were detected at baseline and following therapeutic intervals. Progression-free survival (PFS) was compared according to pTCD8+CD28- levels. The molecular features of pTCD8+CD28- and its correlation with tumour immunity were also investigated. RESULTS: A total of 252 patients were enrolled, and the median follow-up time was 29.6 months. pTCD8+CD28- high at baseline has prolonged PFS compared to pTCD8+CD28- low (P = 0.001). Patients who maintained pTCD8+CD28- high had a longer PFS than those who kept pTCD8+CD28- low (P < 0.001). The enhanced pTCD8+CD28- level also indicates a longer PFS compared to pTCD8+CD28- low (P = 0.025). Here, pTCD8+CD28- was demonstrated as an antigen-experienced effector T cell. Higher IL-2 level (P = 0.034) and lower TGF-ß level (P = 0.016) in the serum and highly infiltrated CD8 + CD28- T cells (P = 0.037) were also connected to pTCD8+CD28- high. CONCLUSIONS: High pTCD8+CD28- level is associated with a favourable tumour immunity and a better PFS of HER2-targeting therapy in MBC patients.

Quality of life and cost-effectiveness of convalescent plasma compared to standard care for hospitalized COVID-19 patients in the CONCOR-1 trial.

BACKGROUND: The CONvalescent Plasma for Hospitalized Adults With COVID-19 Respiratory Illness (CONCOR-1) trial was a multicenter randomized controlled trial assessing convalescent plasma in hospitalized COVID-19 patients. This study evaluates the cost-effectiveness of convalescent plasma and its impact on quality-of-life to provide insight into its potential as an alternative treatment in resource-constrained settings. METHODS: Individual patient data on health outcomes and resource utilization from the CONCOR-1 trial were used to conduct the analysis from the Canadian public payer's perspective with a time horizon of 30 days post-randomization. Baseline and 30-day EQ-5D-5L were measured to calculate quality-adjusted survival. All costs are presented in 2021 Canadian dollars. The base case assessed the EQ-5D-5L scores of hospitalized inpatients reporting at both timepoints, and a utility score of 0 was assigned for patients who died within 30 days. Costs for all patients enrolled were used. The sensitivity analysis utilizes EQ-5D-5L scores from the same population but only uses costs from this population. RESULTS: 940 patients were randomized: 627 received CCP and 313 received standard care. The total costs were $28,716 (standard deviation, $25,380) and $24,258 ($22,939) for the convalescent plasma and standard care arms respectively. EQ-5D-5L scores were 0.61 in both arms (p = .85) at baseline. At 30 days, EQ-5D-5L scores were 0.63 and 0.64 for patients in the convalescent plasma and standard care arms, respectively (p = .46). The incremental cost was $4458 and the incremental quality-adjusted life day was -0.078. DISCUSSION: Convalescent plasma was less effective and more costly than standard care in treating hospitalized COVID-19.

Complete separation of benzene-cyclohexene-cyclohexane mixtures via temperature-dependent molecular sieving by a flexible chain-like coordination polymer.

The separation and purification of C6 cyclic hydrocarbons (benzene, cyclohexene, cyclohexane) represent a critically important but energy intensive process. Developing adsorptive separation technique to replace thermally driven distillation processes holds great promise to significantly reduce energy consumption. Here we report a flexible one-dimensional coordination polymer as an efficient adsorbent to discriminate ternary C6 cyclic hydrocarbons via an ideal molecular sieving mechanism. The compound undergoes fully reversible structural transformation associated with removal/re-coordination of water molecules and between activated and hydrocarbon-loaded forms. It exhibits distinct temperature- and adsorbate-dependent adsorption behavior which facilitates the complete separation of benzene, cyclohexene and cyclohexane from their binary and ternary mixtures, with the record-high uptake ratios for C6H6/C6H12 and C6H10/C6H12 in vapor phase and highest binary and ternary selectivities in liquid phase. In situ infrared spectroscopic analysis and ab initio calculations provide insight into the host-guest interactions and their effect on the preferential adsorption and structural transformation.

Predictive and Prognostic Potentials of Lymphocyte-C-Reactive Protein Ratio Upon Hospitalization in Adult Patients with Acute Pancreatitis.

Purpose: In this study, our objective was to investigate the potential utility of lymphocyte-C-reactive protein ratio (LCR) as a predictor of disease progression and a screening tool for intensive care unit (ICU) admission in adult patients with acute pancreatitis (AP). Methods: We included a total of 217 adult patients with AP who were admitted to the First Affiliated Hospital of Harbin Medical University between July 2019 and June 2022. These patients were categorized into three groups: mild AP (MAP), moderately severe AP (MSAP), and severe AP (SAP), based on the presence and duration of organ dysfunction. Various demographic and clinical data were collected and compared among different disease severity groups. Results: Height, diabetes, lymphocyte count (LYMPH), lymphocyte percentage (LYM%), platelet count (PLT), D-Dimer, albumin (ALB), blood urea nitrogen (BUN), serum creatinine (SCr), glucose (GLU), calcium ion (Ca2+), C-reactive protein (CRP), procalcitonin (PCT), hospitalization duration, ICU admission, need for BP, LCR, sequential organ failure assessment (SOFA) score, bedside index for severity in AP (BISAP) score, and modified Marshall score showed significant differences across different disease severity groups upon hospitalization. Notably, there were significant differences in LCR between the MAP group and the MSAP and SAP combined group, and the MAP and MSAP combined group and the SAP group, and adult AP patients with ICU admission and those without ICU admission upon hospitalization. Conclusion: In summary, LCR upon hospitalization can be utilized as a simple and reliable predictor of disease progression and a screening tool for ICU admission in adult patients with AP.