Identification of Cuproptosis-related Gene Lipoyltransferase 1 as a Promising Biomarker in Oral Squamous Cell Carcinoma.

OBJECTIVE: To find efficient cuproptosis-related biomarkers to explore the oncogenesis and progression of oral squamous cell carcinoma (OSCC). METHODS: All the original data were downloaded from the Cancer Genome Atlas (TCGA) database. Univariate Cox analysis and Kaplan-Meier survival analysis were used to identify the gene related to survival. Tumor Immune Estimation Resource 2.0 (TIMER 2.0) was used to reveal the different expression of cuproptosis-related gene lipoyltransferase 1 (LIPT1) in various kinds of tumours. RESULTS: LIPT1, as a cuproptosis-related gene, was found to be differentially expressed in the OSCC group and the control group. It was also found to be related to the prognosis of OSCC. Pan cancer analysis showed LIPT1 was also involved in various kinds of tumours. CONCLUSION: All the results demonstrate that the cuproptosis-related gene LIPT1 is highly involved in the oncogenesis and progression of OSCC. These findings give new insight for further research into the cuproptosis-related biomarkers in OSCC.

Discovery of Dual MER/AXL Kinase Inhibitors as Bifunctional Small Molecules for Inhibiting Tumor Growth and Enhancing Tumor Immune Microenvironment.

A series of bifunctional compounds have been discovered for their dual functionality as MER/AXL inhibitors and immune modulators. The furanopyrimidine scaffold, renowned for its suitability in kinase inhibitor discovery, offers at least three distinct pharmacophore access points. Insights from molecular modeling studies guided hit-to-lead optimization, which revealed that the 1,3-diketone side chain hybridized with furanopyrimidine scaffold that respectively combined amino-type substituent and 1H-pyrazol-4-yl substituent on the top and bottom of the aryl regions to produce 22 and 33, exhibiting potent antitumor activities in various syngeneic and xenograft models. More importantly, 33 demonstrated remarkable immune-modulating activity by upregulating the expression of total T-cells, cytotoxic CD8+ T-cells, and helper CD4+ T-cells in the spleen. These findings underscored the bifunctional capabilities of 33 (BPR5K230) with excellent oral bioavailability (F = 54.6%), inhibiting both MER and AXL while modulating the tumor microenvironment and highlighting its diverse applicability for further studies to advance its therapeutic potential.

Diastolic/systolic blood pressure ratio for predicting febrile children with sepsis and progress to septic shock in the emergency department.

OBJECTIVE: Given the scarcity of studies analyzing the clinical predictors of pediatric septic cases that would progress to septic shock, this study aimed to determine strong predictors for pediatric emergency department (PED) patients with sepsis at risk for septic shock and mortality. METHODS: We conducted chart reviews of patients with ≥ 2 age-adjusted quick Sequential Organ Failure Assessment score (qSOFA) criteria to recognize patients with an infectious disease in two tertiary PEDs between January 1, 2021, and April 30, 2022. The age range of included patients was 1 month to 18 years. The primary outcome was development of septic shock within 48 h of PED attendance. The secondary outcome was sepsis-related 28-day mortality. Initial important variables in the PED and hemodynamics with the highest and lowest values during the first 24 h of admission were also analyzed. RESULTS: Overall, 417 patients were admitted because of sepsis and met the eligibility criteria for the study. Forty-nine cases progressed to septic shock within 48 h after admission and 368 were discharged without progression. General demographics, laboratory data, and hemodynamics were analyzed by multivariate analysis. Only the minimum diastolic blood pressure/systolic blood pressure ratio (D/S ratio) during the first 24 h after admission remained as an independent predictor of progression to septic shock and 28-day mortality. The best cutoff values of the D/S ratio for predicting septic shock and 28-day mortality were 0.52 and 0.47, respectively. CONCLUSIONS: The D/S ratio is a practical bedside scoring system in the PED and had good discriminative ability in predicting the progression of septic shock and in-hospital mortality in PED patients. Further validation is essential in other settings.

Apigenin targets fetuin-A to ameliorate obesity-induced insulin resistance.

Fetuin-A, a hepatokine secreted by hepatocytes, binds to insulin receptors and consequently impairs the activation of the insulin signaling pathway, leading to insulin resistance. Apigenin, a flavonoid isolated from plants, has beneficial effects on insulin resistance; however, its regulatory mechanisms are not fully understood. In the present study, we investigated the molecular mechanisms underlying the protective effects of apigenin on insulin resistance. In Huh7 cells, treatment with apigenin decreased the mRNA expression of fetuin-A by decreasing reactive oxygen species-mediated casein kinase 2α (CK2α)-nuclear factor kappa-light-chain-enhancer of activated B activation; besides, apigenin decreased the levels of CK2α-dependent fetuin-A phosphorylation and thus promoted fetuin-A degradation through the autophagic pathway, resulting in a decrease in the protein levels of fetuin-A. Moreover, apigenin prevented the formation of the fetuin-A-insulin receptor (IR) complex and thereby rescued the PA-induced impairment of the insulin signaling pathway, as evidenced by increased phosphorylation of IR substrate-1 and Akt, and translocation of glucose transporter 2 from the cytosol to the plasma membrane. Similar results were observed in the liver of HFD-fed mice treated with apigenin. Collectively, our findings revealed that apigenin ameliorates obesity-induced insulin resistance in the liver by targeting fetuin-A.

Development and validation of a prediction model for self-reported hypoglycemia risk in patients with type 2 diabetes: A longitudinal cohort study.

AIMS/INTRODUCTION: To develop and validate a simple prediction model for hypoglycemia risk in patients with type 2 diabetes. MATERIALS AND METHODS: We prospectively analyzed the data of 1,303 subjects in a third-class hospital in Tianjin and followed up their hypoglycemia events at 3 and 6 months. The hypoglycemia risk prediction models for 3 and 6 months were developed and the model performance was evaluated. RESULTS: A total of 340 (28.4%) patients experienced hypoglycemia within 3 months and 462 (37.2%) within 6 months during the follow-up period. Age, central obesity, intensive insulin therapy, frequency of hypoglycemia in the past year, and hypoglycemia prevention education entered both model3month and model6month. The area under the receiver operating characteristic curve of model3month and model6month were 0.711 and 0.723, respectively. The Youden index was 0.315 and 0.361, while the sensitivities were 0.615 and 0.714, and the specificities were 0.717 and 0.631. The calibration curves showed that the models were similar to reality. The decision curves implied that the clinical net benefit of the model was clear. CONCLUSIONS: The study developed 3 and 6 month hypoglycemia risk prediction models for patients with type 2 diabetes. The discrimination and calibration of the two prediction models were good, and might help to improve clinical decision-making and guide patients to more reasonable self-care and hypoglycemia prevention at home.

Ferritin as an Effective Predictor of Neurological Outcomes in Children With Acute Necrotizing Encephalopathy.

BACKGROUND: Acute necrotizing encephalopathy (ANE) is a fulminant disease with poor prognosis. Cytokine storm is the important phenomenon of ANE that affects the brain and multiple organs. The study aimed to identify whether hyperferritinemia was associated with poor prognosis in patients with ANE. METHODS: All patients with ANE had multiple symmetric lesions located in the bilateral thalami and other regions such as brainstem tegmentum, cerebral white matter, and cerebellum. Neurological outcome at discharge was evaluated by pediatric neurologists using the Pediatric Cerebral Performance Category Scale. All risk factors associated with poor prognosis were further analyzed using receiver operating characteristic curve analysis. RESULTS: Twenty-nine patients with ANE were enrolled in the current study. Nine (31%) patients achieved a favorable neurological outcome, and 20 (69%) patients had poor neurological outcomes. results The group of poor neurological outcome had significantly higher proportion of shock on admission and brainstem involvement. Based on multivariate logistic regression analysis, ferritin, aspartate aminotransferase (AST), and ANE severity score (ANE-SS) were the predictors associated with outcomes. The appropriate cutoff value for predicting neurological outcomes in patients with ANE was 1823 ng/mL for ferritin, 78 U/L for AST, and 4.5 for ANE-SS. Besides, comparison analyses showed that higher level of ferritin and ANE-SS were significantly correlated with brainstem involvement (P < 0.05). CONCLUSIONS: Ferritin may potentially be a prognostic factor in patients with ANE. Hyperferritinemia is associated with poor neurological outcomes in patients with ANE and ferritin levels more than 1823 ng/mL have about eightfold increased risk of poor neurological outcome.

Intracranial mesenchymal tumor with multiple extracranial metastases: A case report and literature review.

This study presents a rare case of an older woman with an intracranial mesenchymal tumor in the right frontal and parietal lobes. Despite prompt surgical intervention, her condition rapidly deteriorated because of tumor dissemination, leading to her demise. We highlight the tumor's marked invasiveness and heterogeneity, coupled with a propensity for distant systemic metastasis, which negatively impacted the patient's prognosis. This particular clinical behavior had not been previously reported, making this a novel observation. Thus, through a comprehensive review of relevant literature, we aim to provide valuable insights for further understanding, diagnosing, and treating such tumors.

Diastolic blood pressure impact on pediatric refractory septic shock outcomes.

BACKGROUND: Septic shock is the progression of sepsis, defined as cardiovascular dysfunction during systemic infection, and it has a mortality rate of 40 %-80 %. Loss of vascular tone is an important pathophysiological feature of septic shock. Diastolic blood pressure (DBP) was reported to be associated with vascular tone. This study aimed to identify the associations of several hemodynamic indices, especially DBP, with outcome in pediatric septic shock to allow for timely interventions. METHODS: Children with persistent catecholamine-resistant shock had a pulse index continuous cardiac output (PiCCO®) system implanted for invasive hemodynamic monitoring and were enrolled in the current study. Serial cardiac index, systemic vascular resistance index (SVRI), systolic blood pressure (SBP), mean arterial pressure (MAP), and DBP were recorded during the first 24 h following PiCCO® initiation. All hemodynamic parameters associated with 28-day mortality were further analyzed using receiver operating characteristic curve analysis. RESULTS: Thirty-three children with persistent catecholamine-resistant shock were enrolled. The median age was 12 years and the youngest children were 5 years old. Univariate analysis noted that SVRI, SBP, MAP, and DBP were significantly higher, and shock index was significant lower, in survivors compared with non-survivors (p < 0.05). In the multivariate analysis, only SVRI and DBP remained independent predictors of 28-day mortality. DBP had the best correlation with SVRI (r = 0.718, n = 219, p < 0.001). The area under the receiver operating characteristic curves of SVRI and DBP for predicting 28-day mortality during the first 24 h of persistent catecholamine-resistant shock were >0.75, indicating a good prediction for mortality. CONCLUSIONS: DBP correlated well with SVRI and it can serve as a predictor for mortality in pediatric septic shock. Furthermore, DBP was a superior discriminator of mortality when compared with SBP and MAP. A lower DBP was an independent hemodynamic factor associated with 28-day mortality.

Predictors of disease severity and outcomes in pediatric patients with croup and COVID-19 in the pediatric emergency department.

BACKGROUND: Croup caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is an emerging disease, and data on the risk factors associated with disease severity are still limited. The Westley croup score (WS) is widely used to assess croup severity. The current study aimed to analyze biomarkers associated with the WS and clinical outcomes in patients with croup and coronavirus disease 2019 in the pediatric emergency department (PED). POPULATION AND METHOD: Patients diagnosed with croup caused by SARS-CoV-2 were admitted at two PEDs. Clinical data including age, WS, length of hospital stay, initial laboratory data, and treatment were analyzed. Clinical parameters were evaluated via multivariate logistic regression analysis. The best cutoff values for predicting croup severity and outcomes were identified using the receiver operating characteristic curve. RESULT: In total, 250 patients were assessed. Moreover, 128 (51.2%) patients were discharged from the PED, and 122 (48.8%) were admitted to the hospital. Mild, moderate, and severe croup accounted for 63.6% (n = 159), 32% (n = 80), and 4.4% (n = 11) of all cases, respectively. A high mean age (years), neutrophil count (%), neutrophil-to-lymphocyte ratio (NLR), ALT (U/L), procalcitonin (ng/mL), and hemoglobin (g/dL) level, and length of hospital stay (days), and a low lymphocyte count (%) and blood pH were associated with croup severity and need for intensive care. Based on the multivariate logistic regression model, the NLR remained independent factors associated with croup severity and prognosis. Further, NLR was significantly correlated with WS. The area under the receiver operating characteristic curve of NLR for predicting a WS of ≥3 was 0.895 (0.842-0.948, p < 0.001), and that for predicting ICU admission was 0.795 (0.711-0.879, p < 0.001). The best cutoff values for a WS of ≥3 and ICU admission were 1.65 and 2.06, respectively. CONCLUSION: NLR is correlated with WS and is a reliable, easy-to-use, and cheap biomarker for the early screening and prognosis of croup severity in the PED. A higher NLR may indicate severe croup and the need for further treatment. And the WS score remains reliable for estimating the severity of croup caused by SARS-CoV-2 and the risk of intensive care.

The maturation and aging trajectory of Marchantia polymorpha at single-cell resolution.

Bryophytes represent a sister to the rest of land plants. Despite their evolutionary importance and relatively simple body plan, a comprehensive understanding of the cell types and transcriptional states that underpin the temporal development of bryophytes has not been achieved. Using time-resolved single-cell RNA sequencing, we define the cellular taxonomy of Marchantia polymorpha across asexual reproduction phases. We identify two maturation and aging trajectories of the main plant body of M. polymorpha at single-cell resolution: the gradual maturation of tissues and organs along the tip-to-base axis of the midvein and the progressive decline of meristem activities in the tip along the chronological axis. Specifically, we observe that the latter aging axis is temporally correlated with the formation of clonal propagules, suggesting an ancient strategy to optimize allocation of resources to producing offspring. Our work thus provides insights into the cellular heterogeneity that underpins the temporal development and aging of bryophytes.

Children with infectious pneumonia caused by Ralstonia insidiosa: A case report.

BACKGROUND: Ralstonia is a Gram-negative non-fermentative bacterium widespread in nature, and includes four species, Ralstonia pickettii, Ralstonia solanacearum, Ralstonia mannitolilytica, and Ralstonia insidiosa, which were proposed in 2003. Ralstonia is mainly found in the external water environment, including municipal and medical water purification systems. This bacterium has low toxicity and is a conditional pathogen. It has been reported in recent years that infections due to Ralstonia are increasing. Previous studies have shown that most cases of infection are caused by Ralstonia pickettii, a few by Ralstonia mannitolilytica, and infections caused by Ralstonia insidiosa are rare. CASE SUMMARY: A 2-year-old Chinese child suffered from intermittent fever and cough for 20 d and was admitted to hospital with bronchial pneumonia. Bronchoscopy and alveolar lavage fluid culture confirmed Ralstonia insidiosa pneumonia. The infection was well controlled after treatment with meropenem and azithromycin. CONCLUSION: Ralstonia infections are increasing, and we report a rare case of Ralstonia insidiosa infection in a child. Clinicians should be vigilant about Ralstonia infections.

Development of Furanopyrimidine-Based Orally Active Third-Generation EGFR Inhibitors for the Treatment of Non-Small Cell Lung Cancer.

The development of orally bioavailable, furanopyrimidine-based double-mutant (L858R/T790M) EGFR inhibitors is described. First, selectivity for mutant EGFR was accomplished by replacing the (S)-2-phenylglycinol moiety of 12 with either an ethanol or an alkyl substituent. Then, the cellular potency and physicochemical properties were optimized through insights from molecular modeling studies by implanting various solubilizing groups in phenyl rings A and B. Optimized lead 52 shows 8-fold selective inhibition of H1975 (EGFRL858R/T790M overexpressing) cancer cells over A431 (EGFRWT overexpressing) cancer cells; western blot analysis further confirmed EGFR mutant-selective target modulation inside the cancer cells by 52. Notably, 52 displayed in vivo antitumor effects in two different mouse xenograft models (BaF3 transfected with mutant EGFR and H1975 tumors) with TGI = 74.9 and 97.5% after oral administration (F = 27%), respectively. With an extraordinary kinome selectivity (S(10) score of 0.017), 52 undergoes detailed preclinical development.

Increased endogenous PKG I activity attenuates EGF-induced proliferation and migration of epithelial ovarian cancer via the MAPK/ERK pathway.

The type I cGMP-dependent protein kinase (PKG I) is recognized as a tumor suppressor, but its role in EGFR regulated epithelial ovarian cancer (EOC) progression remains unclear. We evaluated the in vivo and in vitro effects of activated PKG I in EGF-induced EOC cell proliferation, migration, and invasion. The expressions of EGFR and PKG I were elevated, but the activated PKG I was decreased in EOC tissues of patients and cells lines. The addition of 8-Br-cGMP, a specific PKG I activator, attenuated the EGF-induced EOC cell proliferation, migration, and invasion in vitro. Similarly, activated PKG I also attenuated EOC progression in vivo using an EOC xenograft nude mouse model. The activated PKG I interacted with EGFR, causing increased threonine (693) phosphorylation and decreased tyrosine (1068) phosphorylation of EGFR, which resulted in disrupted EGFR-SOS1-Grb2 combination. Subsequently, the cytoplasmic phosphorylation of downstream proteins (c-Raf, MEK1/2, and ERK1/2) were declined, impeding the phosphorylated ERK1/2's nucleus translocation, and this reduction of phosphorylated tyrosine (1068) EGFR and ERK1/2 were also abolished by Rp-8-Br-cGMPS. Our results suggest that the activation of PKG I attenuates EGF-induced EOC progression, and the 8-Br-cGMP-PKG I-EGFR/MEK/ERK axis might be a potential target for EOC therapy.

Incidence of accidental falls and development of a fall risk prediction model among elderly patients with diabetes mellitus: A prospective cohort study.

AIMS: To investigate the incidence of accidental falls and develop a fall risk prediction tool in elderly patients with diabetes mellitus. BACKGROUND: The risk of fall in elderly patients with diabetes is higher than that in the general elderly, there is fewer fall assessment tools for elderly patients with diabetes. DESIGN: A prospective cohort study. METHODS: Between June and September 2019, a total of 1007 elderly patients with diabetes were enrolled from a tertiary specialist diabetes hospital in Tianjin and were prospectively followed up for 6 months to determine outcomes of accidental falls through telephone. Demographic and diseases related factors were collected at baseline. Incidence of falls was investigated, and a nomogram was developed based on logistic regression model. SPSS 21.0 and R 3.6.3 were used to analyse the data. The article was reported in accordance with STROBE guidelines. RESULTS: Among 1007 elderly patients, 950 finished the follow-up. A total of 133 falls occurred in 93 patients during the follow-up period, with a fall rate of 9.79%. Diabetic peripheral neuropathy, walking aids, depression, fall history, fatigue and sex were independent predictors of accidental fall in diabetes elderly patients. The sensitivity and specificity of the predictive model were 73.12% and 52.63%, respectively, and a fall risk prediction nomogram was developed based on the regression model. CONCLUSIONS: A nomogram including 6 easily available prediction factors (diabetic peripheral neuropathy, walking aids, depression, fall history within 1 year, fatigue, sex) was developed, and it can be used in safety management among Chinese elderly patients diagnosed with diabetes. RELEVANCE TO CLINICAL PRACTICE: Nomogram can be used to identify diabetic elderly patients at high risk of accidental falls.

An Intelligent Motor Assessment Method Utilizing a Bi-Lateral Virtual-Reality Task for Stroke Rehabilitation on Upper Extremity.

Virtual reality (VR) has been widely adopted by therapists to provide rich motor training tasks. Time series data of motion trajectory accompanied with the interaction of VR system may contain important clues in regard to the assessment of motor function, however, clinical evaluation scales such as Fugl-Meyer Assessment (FMA), Wolf Motor Function Test (WMFT), and Test D'évaluation Des Membres Supérieurs Des Personnes Âgées (TEMPA) are highly depended in clinic. Further, there is not yet an assessment method that simultaneously consider motion trajectory and clinical evaluation scales. The objective of this study is to establish an evidence-based assessment model by machine-learning method that integrated motion trajectory of a VR task with clinical evaluation scales. In this study, a VR system for upper-limb motor training was proposed for stroke rehabilitation. Clinical trials with 20 stroke patients were performed. A variety of motor indicators that derived via motion trajectory were proposed. The correlations between motor indicators and clinical evaluation scales were examined. Further, motor indicators were integrated with evaluation scales to develop a machine-learning based model that represents an evidence-based motor assessment approach. Clinical evaluation scales, FMA, TEMPA and WMFT, were significantly progressed. A few motor indicators were found significantly correlated with clinical evaluation scales. The accuracy of machine-learning based assessment model was up to 86%. The proposed VR system is validated to be effective in motor rehabilitation. Motor indicators derived from motor trajectory were with potential for clinical motor assessment. Machine learning could be a promising tool to perform automatic assessment. Clinical and Translational Impact Statement-A VR task for motor rehabilitation was exanimated via clinical trials. Integrating motor indices with clinical assessment, a machine-learning model with accuracy of 86% was developed to evaluate motor function.

Electrical Performance of 28 nm-Node Varying Channel-Width nMOSFETs under DPN Process Treatments.

The decoupled-plasma nitridation treatment process is an effective recipe for repairing the trap issues when depositing high-k gate dielectric. Because of this effect, electrical performance is not only increased with the relative dielectric constant, but there is also a reduction in gate leakage. In the past, the effect of nitridation treatment on channel-length was revealed, but a channel-width effect with that treatment was not found. Sensing the different nano-node channel-width n-channel MOSFETs, the electrical characteristics of these test devices with nitridation treatments were studied and the relationship among them was analyzed. Based on measurement of the VT, SS, Gm, ION, and IOFF values of the tested devices, the electrical performance of them related to process treatment is improved, including the roll-off effect of channel-width devices. On the whole, the lower thermal budget in nitridation treatment shows better electrical performance for the tested channel-width devices.

A critical overview of current progress for COVID-19: development of vaccines, antiviral drugs, and therapeutic antibodies.

The novel coronavirus disease (COVID-19) pandemic remains a global public health crisis, presenting a broad range of challenges. To help address some of the main problems, the scientific community has designed vaccines, diagnostic tools and therapeutics for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. The rapid pace of technology development, especially with regard to vaccines, represents a stunning and historic scientific achievement. Nevertheless, many challenges remain to be overcome, such as improving vaccine and drug treatment efficacies for emergent mutant strains of SARS-CoV-2. Outbreaks of more infectious variants continue to diminish the utility of available vaccines and drugs. Thus, the effectiveness of vaccines and drugs against the most current variants is a primary consideration in the continual analyses of clinical data that supports updated regulatory decisions. The first two vaccines granted Emergency Use Authorizations (EUAs), BNT162b2 and mRNA-1273, still show more than 60% protection efficacy against the most widespread current SARS-CoV-2 variant, Omicron. This variant carries more than 30 mutations in the spike protein, which has largely abrogated the neutralizing effects of therapeutic antibodies. Fortunately, some neutralizing antibodies and antiviral COVID-19 drugs treatments have shown continued clinical benefits. In this review, we provide a framework for understanding the ongoing development efforts for different types of vaccines and therapeutics, including small molecule and antibody drugs. The ripple effects of newly emergent variants, including updates to vaccines and drug repurposing efforts, are summarized. In addition, we summarize the clinical trials supporting the development and distribution of vaccines, small molecule drugs, and therapeutic antibodies with broad-spectrum activity against SARS-CoV-2 strains.

Skin sympathetic nerve activity and ventricular arrhythmias in acute coronary syndrome.

BACKGROUND: Acute coronary syndrome (ACS) is major cause of ventricular arrhythmias (VAs) and sudden death. neuECG is a noninvasive method to simultaneously record skin sympathetic nerve activity (SKNA) and electrocardiogram. OBJECTIVE: The purpose of this study was to test the hypotheses that (1) ACS increases average SKNA (aSKNA), (2) the magnitude of aSKNA elevation is associated with VAs during ACS, and (3) there is a gender difference in aSKNA between patients without and with ACS. METHODS: We prospectively studied 128 ACS and 165 control participants. The neuECG was recorded with electrodes at Lead I configuration at baseline, during mental math stress, and during recovery (5 minutes for each phase). All recordings were done in the morning. RESULTS: In the control group, women have higher aSKNA than do men at baseline (0.82 ± 0.25 µV vs 0.73 ± 0.20 µV; P = .009) but not during mental stress (1.21 ± 0.36 µV vs 1.16 ± 0.36 µV; P = .394), suggesting women had lower sympathetic reserve. In comparison, ACS is associated with equally elevated aSKNA in women vs men at baseline (1.14 ± 0.33 µV vs 1.04 ± 0.35 µV; P = .531), during mental stress (1.46 ± 0.32 µV vs 1.33 ± 0.37 µV; P = .113), and during recovery (1.30 ± 0.33 µV vs 1.11 ± 0.30 µV; P = .075). After adjusting for age and gender, the adjusted odds ratio for VAs including ventricular tachycardia and ventricular fibrillation is 1.23 (95% confidence interval 1.05-1.44) for each 0.1 µV aSKNA elevation. aSKNA is positively correlated with plasma norepinephrine level. CONCLUSION: ACS is associated with elevated aSKNA, and the magnitude of aSKNA elevation is associated with the occurrence of VAs. Women have higher aSKNA and lower SKNA reserve than do men among controls but not among patients with ACS.

FindIT2: an R/Bioconductor package to identify influential transcription factor and targets based on multi-omics data.

BACKGROUND: Transcription factors (TFs) play central roles in regulating gene expression. With the rapid growth in the use of high-throughput sequencing methods, there is a need to develop a comprehensive data processing and analyzing framework for inferring influential TFs based on ChIP-seq/ATAC-seq datasets. RESULTS: Here, we introduce FindIT2 (Find Influential TFs and Targets), an R/Bioconductor package for annotating and processing high-throughput multi-omics data. FindIT2 supports a complete framework for annotating ChIP-seq/ATAC-seq peaks, identifying TF targets by the combination of ChIP-seq and RNA-seq datasets, and inferring influential TFs based on different types of data input. Moreover, benefited from the annotation framework based on Bioconductor, FindIT2 can be applied to any species with genomic annotations, which is particularly useful for the non-model species that are less well-studied. CONCLUSION: FindIT2 provides a user-friendly and flexible framework to generate results at different levels according to the richness of the annotation information of user's species. FindIT2 is compatible with all the operating systems and is released under Artistic-2.0 License. The source code and documents are freely available through Bioconductor ( https://bioconductor.org/packages/devel/bioc/html/FindIT2.html ).

Antibiotic Stewardship Related to Delayed Diagnosis and Poor Prognosis of Critically Ill Patients with Vancomycin-Resistant Enterococcal Bacteremia: A Retrospective Cohort Study.

Purpose: Patients with septicemia caused by vancomycin-resistant Enterococcus (VRE) bacteremia have higher mortality rates than patients infected by VSE. Vancomycin or teicoplanin is selected as the antibiotic stewardship intervention to cover methicillin-resistant Staphylococcus aureus infections before blood culture reveals VRE bacteremia in critically ill patients with Gram-positive cocci (GPC) bacteremia; this may require linezolid or daptomycin treatment instead. We thus evaluated antibiotic stewardship practices, such as appropriate timing of antibiotic use in GPC bacteremia, and clinical outcomes of critically ill patients with VRE infection. Patients and Methods: This retrospective study enrolled 191 critically ill patients with enterococcal bacteremia at the Taipei Tzu Chi Hospital during January 1, 2019-December 31, 2020. Demographic and clinical characteristics, as well as disease outcomes and appropriate antibiotic use after GPC bacteremia diagnosis, were compared between the VRE and VSE groups. Results: Of 191 patients, 55 had VRE bacteremia (case group) and 136 had VSE bacteremia (control group). The rate of antibiotic change after initial antibiotic use for GPC bacteremia was higher in the VRE bacteremia group (100% vs 10.3%; p<0.001). The time to appropriate antibiotic administration after GPC bacteremia diagnosis was longer in the VRE bacteremia group (3.3±2.1 vs 1.5±1.8 days; p<0.001). Patients with VRE bacteremia had higher 28-day mortality rates (relative risk, 1.997; 95% confidence interval [CI], 1.041-3.83). Multivariate Cox regression analysis showed that delayed appropriate antibiotic administration of >3 days after GPC bacteremia diagnosis increased the risks of 28-day all-cause mortality (adjusted hazard ratio, 2.045; 95% CI, 1.089-3.84; p=0.026) in patients with VRE infection. Conclusion: Patients with VRE bacteremia with delayed appropriate antibiotic administration of >3 days after GPC bacteremia diagnosis had increased 28-day mortality risks. New strategies for early VRE detection in GPC bacteremia may shorten the time to administer appropriate antibiotics and lower mortality rates.