Navigating bottlenecks and trade-offs in genomic data analysis.

Genome sequencing and analysis allow researchers to decode the functional information hidden in DNA sequences as well as to study cell to cell variation within a cell population. Traditionally, the primary bottleneck in genomic analysis pipelines has been the sequencing itself, which has been much more expensive than the computational analyses that follow. However, an important consequence of the continued drive to expand the throughput of sequencing platforms at lower cost is that often the analytical pipelines are struggling to keep up with the sheer amount of raw data produced. Computational cost and efficiency have thus become of ever increasing importance. Recent methodological advances, such as data sketching, accelerators and domain-specific libraries/languages, promise to address these modern computational challenges. However, despite being more efficient, these innovations come with a new set of trade-offs, both expected, such as accuracy versus memory and expense versus time, and more subtle, including the human expertise needed to use non-standard programming interfaces and set up complex infrastructure. In this Review, we discuss how to navigate these new methodological advances and their trade-offs.

Proving sequence aligners can guarantee accuracy in almost O(m log n) time through an average-case analysis of the seed-chain-extend heuristic.

Seed-chain-extend with k-mer seeds is a powerful heuristic technique for sequence alignment used by modern sequence aligners. Although effective in practice for both runtime and accuracy, theoretical guarantees on the resulting alignment do not exist for seed-chain-extend. In this work, we give the first rigorous bounds for the efficacy of seed-chain-extend with k-mers in expectation Assume we are given a random nucleotide sequence of length ∼n that is indexed (or seeded) and a mutated substring of length ∼m ≤ n with mutation rate θ < 0.206. We prove that we can find a k = Θ(log n) for the k-mer size such that the expected runtime of seed-chain-extend under optimal linear-gap cost chaining and quadratic time gap extension is O(mn f (θ) log n), where f(θ) < 2.43 · θ holds as a loose bound. The alignment also turns out to be good; we prove that more than [Formula: see text] fraction of the homologous bases is recoverable under an optimal chain. We also show that our bounds work when k-mers are sketched, that is, only a subset of all k-mers is selected, and that sketching reduces chaining time without increasing alignment time or decreasing accuracy too much, justifying the effectiveness of sketching as a practical speedup in sequence alignment. We verify our results in simulation and on real noisy long-read data and show that our theoretical runtimes can predict real runtimes accurately. We conjecture that our bounds can be improved further, and in particular, f(θ) can be further reduced.

Fast and robust metagenomic sequence comparison through sparse chaining with skani.

Sequence comparison tools for metagenome-assembled genomes (MAGs) struggle with high-volume or low-quality data. We present skani ( https://github.com/bluenote-1577/skani ), a method for determining average nucleotide identity (ANI) via sparse approximate alignments. skani outperforms FastANI in accuracy and speed (>20× faster) for fragmented, incomplete MAGs. skani can query genomes against >65,000 prokaryotic genomes in seconds and 6 GB memory. skani unlocks higher-resolution insights for extensive, noisy metagenomic datasets.

Author Correction: The Apostasia genome and the evolution of orchids.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Complement contributes to antibody-mediated protection against repeated SHIV challenge.

The first clinical efficacy trials of a broadly neutralizing antibody (bNAb) resulted in less benefit than expected and suggested that improvements are needed to prevent HIV infection. While considerable effort has focused on optimizing neutralization breadth and potency, it remains unclear whether augmenting the effector functions elicited by broadly neutralizing antibodies (bNAbs) may also improve their clinical potential. Among these effector functions, complement-mediated activities, which can culminate in the lysis of virions or infected cells, have been the least well studied. Here, functionally modified variants of the second-generation bNAb 10-1074 with ablated and enhanced complement activation profiles were used to examine the role of complement-associated effector functions. When administered prophylactically against simian-HIV challenge in rhesus macaques, more bNAb was required to prevent plasma viremia when complement activity was eliminated. Conversely, less bNAb was required to protect animals from plasma viremia when complement activity was enhanced. These results suggest that complement-mediated effector functions contribute to in vivo antiviral activity, and that their engineering may contribute to the further improvements in the efficacy of antibody-mediated prevention strategies.

Sodium-glucose cotransporter-2 inhibitors and their potential role in dementia onset and cognitive function in patients with diabetes mellitus: a systematic review and meta-analysis.

This systematic review and meta-analysis aimed to determine the association between the use of sodium-glucose cotransporter 2 (SGLT-2) inhibitors and dementia onset as well as cognitive function in patients with diabetes mellitus. We comprehensively searched the MEDLINE, Embase, and CENTRAL databases to select relevant studies published up to August 2023. The use of SGLT-2 inhibitors significantly lowers dementia risk compared to SGLT-2i non-users (Hazard ratio: 0.68, 95 % CI: 0.50-0.92). Furthermore, our findings indicated a positive effect of SGLT-2 inhibitor use on cognitive function score improvement, as demonstrated by the standardized mean difference of 0.88 (95 % CI: 0.32-1.44), particularly among populations with mild cognitive impairment or dementia. This systematic review and meta-analysis indicate a potential role of SGLT-2 inhibitors in reducing the risk of dementia in patients with diabetes mellitus. These findings underscore the need for well-controlled large clinical trials and future research in this field.

skandiver: a divergence-based analysis tool for identifying intercellular mobile genetic elements.

Motivation: Mobile genetic elements (MGEs) are as ubiquitous in nature as they are varied in type, ranging from viral insertions to transposons to incorporated plasmids. Horizontal transfer of MGEs across bacterial species may also pose a significant threat to global health due to their capability to harbor antibiotic resistance genes. However, despite cheap and rapid whole-genome sequencing, the varied nature of MGEs makes it difficult to fully characterize them, and existing methods for detecting MGEs often do not agree on what should count. In this manuscript, we first define and argue in favor of a divergence-based characterization of mobile-genetic elements. Results: Using that paradigm, we present skandiver, a tool designed to efficiently detect MGEs from whole-genome assemblies without the need for gene annotation or markers. skandiver determines mobile elements via genome fragmentation, average nucleotide identity (ANI), and divergence time. By building on the scalable skani software for ANI computation, skandiver can query hundreds of complete assemblies against >65 000 representative genomes in a few minutes and 19 GB memory, providing scalable and efficient method for elucidating mobile element profiles in incomplete, uncharacterized genomic sequences. For isolated and integrated large plasmids (>10 kb), skandiver's recall was 48% and 47%, MobileElementFinder was 59% and 17%, and geNomad was 86% and 32%, respectively. For isolated large plasmids, skandiver's recall (48%) is lower than state-of-the-art reference-based methods geNomad (86%) and MobileElementFinder (59%). However, skandiver achieves higher recall on integrated plasmids and, unlike other methods, without comparing against a curated database, making skandiver suitable for discovery of novel MGEs. AVAILABILITY AND IMPLEMENTATION: https://github.com/YoukaiFromAccounting/skandiver.

Floria: fast and accurate strain haplotyping in metagenomes.

SUMMARY: Shotgun metagenomics allows for direct analysis of microbial community genetics, but scalable computational methods for the recovery of bacterial strain genomes from microbiomes remains a key challenge. We introduce Floria, a novel method designed for rapid and accurate recovery of strain haplotypes from short and long-read metagenome sequencing data, based on minimum error correction (MEC) read clustering and a strain-preserving network flow model. Floria can function as a standalone haplotyping method, outputting alleles and reads that co-occur on the same strain, as well as an end-to-end read-to-assembly pipeline (Floria-PL) for strain-level assembly. Benchmarking evaluations on synthetic metagenomes show that Floria is > 3× faster and recovers 21% more strain content than base-level assembly methods (Strainberry) while being over an order of magnitude faster when only phasing is required. Applying Floria to a set of 109 deeply sequenced nanopore metagenomes took <20 min on average per sample and identified several species that have consistent strain heterogeneity. Applying Floria's short-read haplotyping to a longitudinal gut metagenomics dataset revealed a dynamic multi-strain Anaerostipes hadrus community with frequent strain loss and emergence events over 636 days. With Floria, accurate haplotyping of metagenomic datasets takes mere minutes on standard workstations, paving the way for extensive strain-level metagenomic analyses. AVAILABILITY AND IMPLEMENTATION: Floria is available at https://github.com/bluenote-1577/floria, and the Floria-PL pipeline is available at https://github.com/jsgounot/Floria_analysis_workflow along with code for reproducing the benchmarks.

Lipopolysaccharide Triggers Luminal Acidification to Promote Defense Against Bacterial Infection in Vaginal Epithelium.

The vaginal epithelium plays pivotal roles in host defense against pathogen invasion, contributing to the maintenance of an acidic microenvironment within the vaginal lumen through the activity of acid-base transport proteins. However, the precise defense mechanisms of the vaginal epithelium after a bacterial infection remain incompletely understood. This study showed that bacterial lipopolysaccharide (LPS) potentiated net proton efflux by up-regulating the expression of Na+-H+ exchanger 1 (NHE1) without affecting other acid-base transport proteins in vaginal epithelial cells. Pharmacologic inhibition or genetic knockdown of Toll-like receptor-4 and the extracellular signal-regulated protein kinase signaling pathway effectively counteracted the up-regulation of NHE1 and the enhanced proton efflux triggered by LPS in vaginal epithelial cells. In vivo studies revealed that LPS administration led to luminal acidification through the up-regulation of NHE1 expression in the rat vagina. Moreover, inhibition of NHE exhibited an impaired defense against acute bacterial infection in the rat vagina. These findings collectively indicate the active involvement of vaginal epithelial cells in facilitating luminal acidification during acute bacterial infection, offering potential insights into the treatment of bacterial vaginosis.

A systematic review and meta-analysis on the transcriptomic signatures in alcohol use disorder.

Currently available clinical treatments on alcohol use disorder (AUD) exhibit limited efficacy and new druggable targets are required. One promising approach to discover new molecular treatment targets involves the transcriptomic profiling of brain regions within the addiction neurocircuitry, utilizing animal models and postmortem brain tissue from deceased patients with AUD. Unfortunately, such studies suffer from large heterogeneity and small sample sizes. To address these limitations, we conducted a cross-species meta-analysis on transcriptome-wide data obtained from brain tissue of patients with AUD and animal models. We integrated 36 cross-species transcriptome-wide RNA-expression datasets with an alcohol-dependent phenotype vs. controls, following the PRISMA guidelines. In total, we meta-analyzed 964 samples - 502 samples from the prefrontal cortex (PFC), 282 nucleus accumbens (NAc) samples, and 180 from amygdala (AMY). The PFC had the highest number of differentially expressed genes (DEGs) across rodents, monkeys, and humans. Commonly dysregulated DEGs suggest conserved cross-species mechanisms for chronic alcohol consumption/AUD comprising MAPKs as well as STAT, IRF7, and TNF. Furthermore, we identified numerous unique gene sets that might contribute individually to these conserved mechanisms and also suggest novel molecular aspects of AUD. Validation of the transcriptomic alterations on the protein level revealed interesting targets for further investigation. Finally, we identified a combination of DEGs that are commonly regulated across different brain tissues as potential biomarkers for AUD. In summary, we provide a compendium of genes that are assessable via a shiny app, and describe signaling pathways, and physiological and cellular processes that are altered in AUD that require future studies for functional validation.

Mora: abundance aware metagenomic read re-assignment for disentangling similar strains.

BACKGROUND: Taxonomic classification of reads obtained by metagenomic sequencing is often a first step for understanding a microbial community, but correctly assigning sequencing reads to the strain or sub-species level has remained a challenging computational problem. RESULTS: We introduce Mora, a MetagenOmic read Re-Assignment algorithm capable of assigning short and long metagenomic reads with high precision, even at the strain level. Mora is able to accurately re-assign reads by first estimating abundances through an expectation-maximization algorithm and then utilizing abundance information to re-assign query reads. The key idea behind Mora is to maximize read re-assignment qualities while simultaneously minimizing the difference from estimated abundance levels, allowing Mora to avoid over assigning reads to the same genomes. On simulated diverse reads, this allows Mora to achieve F1 scores comparable to other algorithms while having less runtime. However, Mora significantly outshines other algorithms on very similar reads. We show that the high penalty of over assigning reads to a common reference genome allows Mora to accurately infer correct strains for real data in the form of E. coli reads. CONCLUSIONS: Mora is a fast and accurate read re-assignment algorithm that is modularized, allowing it to be incorporated into general metagenomics and genomics workflows. It is freely available at https://github.com/AfZheng126/MORA .

Comprehensive analysis of environmental exposure to hazardous trace elements and lung function: a national cross-sectional study.

BACKGROUND: There is growing interest in the joint effects of hazardous trace elements (HTEs) on lung function deficits, but the data are limited. This is a critical research gap given increased global industrialisation. METHODS: A national cross-sectional study including spirometry was performed among 2112 adults across 11 provinces in China between 2020 and 2021. A total of 27 HTEs were quantified from urine samples. Generalised linear models and quantile-based g-computation were used to explore the individual and joint effects of urinary HTEs on lung function, respectively. RESULTS: Overall, there were negative associations between forced expiratory volume in 1 s (FEV1) and urinary arsenic (As) (z-score coefficient, -0.150; 95% CI, -0.262 to -0.038 per 1 ln-unit increase), barium (Ba) (-0.148, 95% CI: -0.258 to -0.039), cadmium (Cd) (-0.132, 95% CI: -0.236 to -0.028), thallium (Tl) (-0.137, 95% CI: -0.257 to -0.018), strontium (Sr) (-0.147, 95% CI: -0.273 to -0.022) and lead (Pb) (-0.121, 95% CI: -0.219 to -0.023). Similar results were observed for forced vital capacity (FVC) with urinary As, Ba and Pb and FEV1/FVC with titanium (Ti), As, Sr, Cd, Tl and Pb. We found borderline associations between the ln-quartile of joint HTEs and decreased FEV1 (-20 mL, 95% CI: -48 to +8) and FVC (-14 mL, 95% CI: -49 to+2). Ba and Ti were assigned the largest negative weights for FEV1 and FVC within the model, respectively. CONCLUSION: Our study investigating a wide range of HTEs in a highly polluted setting suggests that higher urinary HTE concentrations are associated with lower lung function, especially for emerging Ti and Ba, which need to be monitored or regulated to improve lung health.

Establishment of epidemiological cut-off values for eravacycline, against Escherichia coli, Klebsiella pneumoniae, Enterobacter cloacae, Acinetobacter baumannii and Staphylococcus aureus.

OBJECTIVES: To establish the epidemiology cut-off (ECOFF) values of eravacycline against Escherichia coli, Klebsiella pneumoniae, Enterobacter cloacae, Acinetobacter baumannii and Staphylococcus aureus, from a multi-centre study in China. METHODS: We collected 2500 clinical isolates from five hospitals in China from 2017 to 2020. The MICs of eravacycline were determined using broth microdilution. The ECOFF values of eravacycline against the five species commonly causing cIAIs were calculated using visual estimation and ECOFFinder following the EUCAST guideline. RESULTS: The MICs of eravacycline against all the strains were in the range of 0.004-16 mg/L. The ECOFF values of eravacycline were 0.5 mg/L for E. coli, 2 mg/L for K. pneumonia and E. cloacae, and 0.25 mg/L for A. baumannii and S. aureus, consistent with the newest EUCAST publication of eravacycline ECOFF values for the populations. No discrepancy was found between the visually estimated and 99.00% ECOFF values calculated using ECOFFinder. CONCLUSIONS: The determined ECOFF values of eravacycline against the five species can assist in distinguishing wild-type from non-wild-type strains. Given its promising activity, eravacycline may represent a member of the tetracycline class in treating cIAIs caused by commonly encountered Gram-negative and Gram-positive pathogens.

HAMPLE: deciphering TF-DNA binding mechanism in different cellular environments by characterizing higher-order nucleotide dependency.

MOTIVATION: Transcription factor (TF) binds to conservative DNA binding sites in different cellular environments and development stages by physical interaction with interdependent nucleotides. However, systematic computational characterization of the relationship between higher-order nucleotide dependency and TF-DNA binding mechanism in diverse cell types remains challenging. RESULTS: Here, we propose a novel multi-task learning framework HAMPLE to simultaneously predict TF binding sites (TFBS) in distinct cell types by characterizing higher-order nucleotide dependencies. Specifically, HAMPLE first represents a DNA sequence through three higher-order nucleotide dependencies, including k-mer encoding, DNA shape and histone modification. Then, HAMPLE uses the customized gate control and the channel attention convolutional architecture to further capture cell-type-specific and cell-type-shared DNA binding motifs and epigenomic languages. Finally, HAMPLE exploits the joint loss function to optimize the TFBS prediction for different cell types in an end-to-end manner. Extensive experimental results on seven datasets demonstrate that HAMPLE significantly outperforms the state-of-the-art approaches in terms of auROC. In addition, feature importance analysis illustrates that k-mer encoding, DNA shape, and histone modification have predictive power for TF-DNA binding in different cellular environments and are complementary to each other. Furthermore, ablation study, and interpretable analysis validate the effectiveness of the customized gate control and the channel attention convolutional architecture in characterizing higher-order nucleotide dependencies. AVAILABILITY AND IMPLEMENTATION: The source code is available at https://github.com/ZhangLab312/Hample.

Tissue-resident C1q + macrophages exert anti-aging potential through the Sirt1 pathway.

OBJECTIVE: Resident immune cells are at the forefront of sensory organ-specific signals, and changes in these cells are closely related to the aging process. The Sirt pathway can regulate NAD + metabolism during aging, thereby affecting the accumulation of ROS. However, the role of the Sirt pathway in resident immune cells in aged tissues is currently unclear. METHODS: We investigated Sirt1 signalling in resident immune cells during chronic inflammation in an aged mouse model. Integrated single-cell RNA sequencing data from young and aged mice were used to refine the characterization of immune cells in aged tissues RESULTS: We found that C1q + macrophages could affect chronic inflammation during aging. C1q + macrophages acted in an opposing manner to Il1b + macrophages and were responsible for anti-inflammatory effects during aging. Sirt1 agonists inhibited the decrease in C1qb in macrophages during aging, and anti-aging drugs could affect the expression of C1qb in macrophages via the Sirt1 pathway. CONCLUSIONS: In this study, we first identified the relevance of C1q + macrophages in chronic inflammation during aging. The potential anti-aging effect of C1q + macrophages was mediated by the Sirt1 pathway, suggesting new strategies for aging immunotherapy.

PReferentially Expressed Antigen in MElanoma Expression in Uterine and Ovarian Carcinosarcomas.

Carcinosarcoma (CS) is an aggressive form of gynecologic malignancy that accounts for ~5% of carcinomas in the endometrium and ovaries. There has been no significant improvement in survival over the last decades despite additional treatment options. PReferentially Expressed Antigen in MElanoma (PRAME) is an immunotherapy target used for the treatment of several solid tumors. We explored the PRAME protein expression levels in ovarian and uterine CS (n = 29). The expression levels were recorded by H-score (percentage of positively stained cells multiplied by staining intensity) in carcinomatous and sarcomatous components separately and compared by paired t-test. The marker expression levels of ovarian and uterine CS were tested against each other in the CS group. Sarcoma-predominant samples (>50% of the sampled tissue) were compared with samples without predominant sarcomatous components by a 2-sample pooled t-test. In addition, high-grade carcinomatous components of CS samples were tested against low-grade endometrioid carcinoma (International Federation of Gynecology and Obstetrics grades 1 and 2; n = 13), and sarcomatous components against uterine leiomyosarcoma (n = 14). There was no significant difference between any subgroups except for sarcomatous elements of CS and leiomyosarcoma ( P < 0.001). A weak positive correlation was found between H-scores of carcinomatous and sarcomatous components ( P = 0.062, r = 0.36). In the ovarian CS group, there was a moderate inverse correlation between age and the mean H-score of the carcinomatous component ( r = -0.683, P = 0.02). Our results further support PRAME overexpression in gynecologic cancers, including CS with similar expression levels in epithelial and mesenchymal components. PRAME might have a role in epithelial-mesenchymal transition in this group of cancers.

First Insight into Fetal Exposure to Legacy and Emerging Plasticizers Revealed by Infant Hair and Meconium: Occurrence, Biotransformation, and Accumulation.

Epidemiological studies have demonstrated the embryonic and developmental toxicity of plasticizers. Thus, understanding the in utero biotransformation and accumulation of plasticizers is essential to assessing their fate and potential toxicity in early life. In the present study, 311 infant hair samples and 271 paired meconium samples were collected at birth in Guangzhou, China, to characterize fetal exposure to legacy and emerging plasticizers and their metabolites. Results showed that most of the target plasticizers were detected in infant hair, with medians of 9.30, 27.6, and 0.145 ng/g for phthalate esters (PAEs), organic phosphate ester (OPEs), and alternative plasticizers (APs), and 1.44, 0.313, and 0.066 ng/g for the metabolites of PAEs, OPEs, and APs, respectively. Positive correlations between plasticizers and their corresponding primary metabolites, as well as correlations among the oxidative metabolites of bis(2-ethylhexyl) phthalate (DEHP) and 1,2-cyclohexane dicarboxylic acid diisononyl ester (DINCH), were observed, indicating that infant hair retained the major phase-I metabolism of the target plasticizers. While no positive correlations were found in parent compounds or their primary metabolites between paired infant hair and meconium, significant positive correlations were observed among secondary oxidative metabolites of DEHP and DINCH in hair and meconium, suggesting that the primary metabolites in meconium come from hydrolysis of plasticizers in the fetus but most of the oxidative metabolites come from maternal-fetal transmission. The parent compound/metabolite ratios in infant hair showed a decreasing trend across pregnancy, suggesting in utero accumulation and deposition of plasticizers. To the best of our knowledge, this study is the first to report in utero exposure to both parent compounds and metabolites of plasticizers by using paired infant hair and meconium as noninvasive biomonitoring matrices and provides novel insights into the fetal biotransformation and accumulation of plasticizers across pregnancy.

Association between selective serotonin reuptake inhibitor use and developing irritable bowel syndrome through retrospective analysis.

BACKGROUND AND AIM: Serotonin affects the balance and integrity of the gut microbiome; however, studies have confirmed the influence of selective serotonin reuptake inhibitors (SSRIs) on irritable bowel syndrome (IBS). We evaluated the association between SSRI use and subsequent IBS occurrence in a real-world setting. METHODS: A multivariate Cox proportional hazard model was adopted, and the National Health Insurance Service cohort claims database between 2010 and 2019 was used. Non-SSRI users were selected using the propensity score matching method. Subgroup analyses were performed using the point of use, cumulative dose, and duration of SSRI use. Additional analysis was performed using a control group without psychiatric medications. RESULTS: We included 2901 SSRI users and 2727 non-SSRI users. After adjusting covariates, the risk of developing IBS in SSRI users was 1.54 times that in non-SSRI users (95% confidence interval [CI]: 1.01-2.33). The hazard ratio (HR) of the recent, heavy, and short-term user groups were 3.19 (95% CI: 2.03-4.99), 2.22 (95% CI: 1.50-3.29), and 4.83 (95% CI: 3.02-7.73), respectively, compared with that of non-users. In patients without a history of psychiatric medications, the risk of IBS incidence after SSRI use increased significantly (HR: 1.61, 95% CI: 1.06-2.42), whereas HR was insignificant in patients with a history of psychiatric medications (HR: 1.25, 95% CI: 0.98-1.60). CONCLUSIONS: The risk of subsequent IBS occurrence following SSRI use was high in patients who initially took a heavy SSRI dose and those who did not have a history of psychiatric drug use.

A study on user willingness to participate in an adverse drug event information sharing system.

BACKGROUND: To prevent the recurrence of Adverse Drug Events (ADEs), particularly drug allergies, it is essential to avoid re-exposure to causative drugs. Awareness of previous ADEs is crucial for patients because they can share accurate information with healthcare providers (HCPs). This study aims to assess users' willingness to share ADE information and evaluate the factors related to this willingness by utilizing a prospective ADE information-sharing system currently under consideration in South Korea. METHODS: In September 2023, a self-administered questionnaire was collected from a sex-, age-, and regionally stratified nationwide convenience sample of adults recruited through a commercial panel in South Korea. Factors contributing to the willingness to share ADE information and create electronic ADE cards (e-ADE cards) were investigated using multivariate logistic regression analysis. RESULTS: Among the 1,000 respondents, 458 (45.8%) were willing to share ADE information, and 521 (52.1%) were willing to create e-ADE cards. The willingness to share personal ADE information and create e-ADE cards was positively associated with the perceived benefits of sharing ADE, trust in HCPs and positive experiences. Notably, older adult patients demonstrated a higher willingness to share information and use e-ADE cards, with rates of 56% and 62%, respectively. CONCLUSIONS: Our findings indicate that the approach to sharing personal ADE information should be distinct from that of sharing comprehensive health information. Notably, users are likely to willingly disclose their personal information even if they are not anonymized, owing to the significant perceived benefits of sharing. The findings of this study can enhance awareness about sharing personal ADE information and contribute to the successful establishment of an ADE information-sharing system, thereby improving the patient safety environment.

Associations of arterial oxygen partial pressure with all­cause mortality in critically ill ischemic stroke patients: a retrospective cohort study from MIMIC IV 2.2.

BACKGROUND: As a supportive treatment, the effectiveness of oxygen therapy in ischemic stroke (IS) patients remains unclear. This study aimed to evaluate the relationships between arterial partial pressure of oxygen (PaO2) and both consciousness at discharge and all-cause mortality risk in ICU IS patients. METHODS: Blood gas measurements for all patients diagnosed with IS were extracted from the MIMIC-IV database. Patients were classified into four groups based on their average PaO2 during the first ICU day: hypoxemia (PaO2 < 80 mmHg), normoxemia (PaO2 80-120 mmHg), mild hyperoxemia (PaO2 121-199 mmHg), and moderate/severe hyperoxemia (PaO2 ≥ 200 mmHg). The primary endpoint was 90-day all-cause mortality. Secondary outcomes included the level of consciousness at discharge, assessed by the Glasgow Coma Scale (GCS), and 30-day all-cause mortality. Multivariate Cox regression and Restricted cubic spline (RCS) analysis were used to investigate the relationship between mean PaO2 and mortality, and to assess the nonlinear association between exposure and outcomes. RESULTS: This study included a total of 946 IS patients. The cumulative incidence of 30-day and 90-day all-cause mortality increased with decreasing PaO2 levels. RCS analysis revealed a nonlinear relationship between PaO2 and the risk of 30-day all-cause mortality (nonlinear P < 0.0001, overall P < 0.0001), as well as a nonlinear association between PaO2 and 90-day all-cause mortality (nonlinear P < 0.0001, overall P < 0.0001). The results remained consistent after excluding the small subset of patients who received reperfusion therapy. Sensitivity analysis indicated that the favorable impact on survival tends to increase with the extended duration of elevated PaO2. CONCLUSIONS: For IS patients who do not receive reperfusion therapy or whose recanalization status is unknown, a lower PaO2 early during ICU admission is considered an independent risk factor for short-term and recent mortality. Adjusting respiratory parameters to maintain supraphysiological levels of PaO2 appears to be beneficial for survival, although this finding requires further validation through additional studies. TRIAL REGISTRATION: Not applicable.