bluuebunny/crossref_metadata_2025_split huggingface dataset:
A multicenter prospective cohort study of cardiac ultrasound phenotypes in patients with sepsis: Study protocol for a multicenter prospective cohort trial
Authors: Zhang Hongxuan , Wang Xiaoting , Yin Wanhong , Zhang Hongmin , Liu Lixia , Pan Pan , Zhu Ying , Huang Wei , Xing Zhiqun , Yao Bo , Wang Cui , Lin Tianlai , Yu Rongguo , Shang Xiuling 
Published: July 2022

BackgroundSepsis-induced cardiomyopathy significantly increased the mortality of patients with sepsis. The diagnostic criteria for septic cardiomyopathy has not been unified, which brings serious difficulties to clinical treatment. This study aimed to provide evidence for the early identification and intervention in patients with sepsis by clarifying the relationship between the ultrasound phenotype of septic cardiomyopathy and the prognosis of patients with sepsis.MethodsThis was a multicenter, prospective cohort study. The study population will consist of all eligible consecutive patients with sepsis or septic shock who meet the Sepsis 3.0 diagnostic criteria and were aged ≥18 years. Clinical data and echocardiographic measurements will be recorded within 2 h, at the 24th hour, at the 72nd hour, and on the 7th day after admission. The prevalence of each phenotype will be described as well, and their association with prognosis will be analyzed statistically.DiscussionTo achieve early recognition, prevent reinjury, achieve precise treatment, and reduce mortality in patients with sepsis, it is important to identify septic cardiac alterations and classify the phenotypes at all stages of sepsis. First, there is a lack of studies on the prevalence of each phenotype in Chinese populations. Second, each phenotype and its corresponding prognosis are not clear. In addition, the prognosis of patients with normal cardiac ultrasound phenotypes vs. those with suppressed or hyperdynamic cardiac phenotypes is unclear. Finally, this study was designed to collect data at four specific timing, then the timing of occurrence, duration, changes over time, impact to outcomes of each phenotype will probably be found. This study is expected to establish a standard and objective method to assess the ultrasound phenotype of septic cardiomyopathy due to its advantages of visualization, non-invasiveness and reproducibility, and to provide more precise information for the hemodynamic management of septic patients. In addition, this research will promote the clinical application of critical care ultrasound, which will play an important role in medical education and make ultrasound the best method to assess cardiac changes in sepsis.Trial registrationhttps://clinicaltrials.gov/ct2/show/NCT05161104, identifier NCT05161104.
Cognition impairment and risk of subclinical cardiovascular disease in older adults: The atherosclerosis risk in communities study
Authors: Li Dongze , Jia Yu , Yu Jing , Liu Yi , Li Fanghui , Zhang Wei , Gao Yongli , Liao Xiaoyang , Wan Zhi , Zeng Zhi , Zeng Rui 
Published: July 2022

BackgroundClinical cardiovascular disease (CVD) and cognition impairment are common and often coexist in aging populations, and CVD is associated with greater cognition impairment risk; however, the association between cognition impairment and CVD risk is inconsistent. It is unknown if pathways that contribute to CVD are caused by impaired cognition. We hypothesized that cognition impairment would be associated with greater subclinical CVD including subclinical myocardial damage [assessed by high-sensitivity cardiac troponin T (hs-cTnT)] and cardiac strain or dysfunction [assessed by N-terminal pro-B-type natriuretic peptide (NT-proBNP)].MethodsThis analysis included Atherosclerosis Risk in Communities Study (ARIC) participants who underwent global cognition z-score tests between 1991 and 1993. Cardiac biomarkers were measured from stored plasma samples collected between 1996 and 1999. Logistic regression models were used to determine the association of cognitive function with subclinical CVD risk.ResultsThere were 558/9216 (6.1%) and 447/9097 (5.0%) participants with incident elevated hs-CTnT (≥14 ng/L) and NT-proBNP (≥300 pg/mL) levels, respectively. Comparing the lowest and highest quartiles of global cognition z-scores, a higher incidence of elevated hs-CTnT [odds ratio (OR) = 1.511, 95% confidence interval (CI): 1.093–2.088, P = 0.013] and NT-proBNP (OR = 1.929, 95% CI: 1.350–2.755, P &lt; 0.001) were observed, respectively. In structural equation modeling, the indirect effect of global cognition z-score on major adverse cardiac events was 42.1% (P &lt; 0.05).ConclusionImpairments in baseline cognitive function were associated with subclinical myocardial damage or wall strain. Although future studies are warranted to investigate the pathophysiological mechanisms behind these associations, our study suggests common pathways between cognitive and cardiac dysfunction.
Enhanced hippocampal neurogenesis mediated by PGC-1α-activated OXPHOS after neonatal low-dose Propofol exposure
Authors: Chen Keyu , Lu Dihan , Yang Xiaoyu , Zhou Rui , Lan Liangtian , Wu Yan , Wang Chen , Xu Xuanxian , Jiang Mei Hua , Wei Ming , Feng Xia 
Published: July 2022

BackgroundDeveloping brain is highly plastic and can be easily affected. Growing pediatric usage of anesthetics during painless procedures has raised concerns about the effect of low-dose anesthetics on neurodevelopment. It is urgent to ascertain the neuronal effect of low-dose Propofol, a widely used anesthetic in pediatrics, on developing brains.MethodsThe behavioral tests after neonatal exposure to low-dose/high-dose Propofol in mice were conducted to clarify the cognitive effect. The nascent cells undergoing proliferation and differentiation stage in the hippocampus and cultured neural stem cells (NSCs) were further identified. In addition, single-nuclei RNA sequencing (snRNA-seq), NSCs bulk RNA-seq, and metabolism trials were performed for pathway investigation. Furthermore, small interfering RNA and stereotactic adenovirus injection were, respectively, used in NSCs and hippocampal to confirm the underlying mechanism.ResultsBehavioral tests in mice showed enhanced spatial cognitive ability after being exposed to low-dose Propofol. Activated neurogenesis was observed both in hippocampal and cultured NSCs. Moreover, transcriptome analysis of snRNA-seq, bulk RNA-seq, and metabolism trials revealed a significantly enhanced oxidative phosphorylation (OXPHOS) level in NSCs. Furthermore, PGC-1α, a master regulator in mitochondria metabolism, was found upregulated after Propofol exposure both in vivo and in vitro. Importantly, downregulation of PGC-1α remarkably prevented the effects of low-dose Propofol in activating OXPHOS and neurogenesis.ConclusionsTaken together, this study demonstrates a novel alteration of mitochondrial function in hippocampal neurogenesis after low-dose Propofol exposure, suggesting the safety, even potentially beneficial effect, of low-dose Propofol in pediatric use.
Net water uptake, a neuroimaging marker of early brain edema, as a predictor of symptomatic intracranial hemorrhage after acute ischemic stroke
Authors: Xu Tianqi , Yang Jianhong , Han Qing , Wu Yuefei , Gao Xiang , Xu Yao , Huang Yi , Wang Aiju , Parsons Mark W. , Lin Longting 
Published: July 2022

ObjectiveWe hypothesized that quantitative net water uptake (NWU), a novel neuroimaging marker of early brain edema, can predict symptomatic intracranial hemorrhage (sICH) after acute ischemic stroke (AIS).MethodsWe enrolled patients with AIS who completed admission multimodal computed tomography (CT) within 24 h after stroke onset. NWU within the ischemic core and penumbra was calculated based on admission CT, namely NWU-core and NWU-penumbra. sICH was defined as the presence of ICH in the infarct area within 7 days after stroke onset, accompanied by clinical deterioration. The predictive value of NWU-core and NWU-penumbra on sICH was evaluated by logistic regression analyses and the receiver operating characteristic (ROC) curve. A pure neuroimaging prediction model was built considering imaging markers, which has the potential to be automatically quantified with an artificial algorithm on image workstation.Results154 patients were included, of which 93 underwent mechanical thrombectomy (MT). The median time from symptom onset to admission CT was 262 min (interquartile range, 198–368). In patients with MT, NWU-penumbra (OR =1.442; 95% CI = 1.177–1.766; P &lt; 0.001) and NWU-core (OR = 1.155; 95% CI = 1.027–1.299; P = 0.016) were independently associated with sICH with adjustments for age, sex, time from symptom onset to CT, hypertension, lesion volume, and admission National Institutes of Health Stroke Scale (NIHSS) score. ROC curve showed that NWU-penumbra had better predictive performance than NWU-core on sICH [area under the curve (AUC): 0.773 vs. 0.673]. The diagnostic efficiency of the predictive model was improved with the containing of NWU-penumbra (AUC: 0.853 vs. 0.760). A pure imaging model also presented stable predictive power (AUC = 0.812). In patients without MT, however, only admission NIHSS score (OR = 1.440; 95% CI = 1.055–1.965; P = 0.022) showed significance in predicting sICH in multivariate analyses.ConclusionsNWU-penumbra may have better predictive performance than NWU-core on sICH after MT. A pure imaging model showed potential value to automatically screen patients with sICH risk by image recognition, which may optimize treatment strategy.
Analysis of routine blood parameters in patients with amyotrophic lateral sclerosis and evaluation of a possible correlation with disease progression—a multicenter study
Authors: Hertel Nora , Kuzma-Kozakiewicz Magdalena , Gromicho Marta , Grosskreutz Julian , de Carvalho Mamede , Uysal Hilmi , Dengler Reinhard , Petri Susanne , Körner Sonja 
Published: July 2022

ObjectiveAmyotrophic lateral sclerosis (ALS) pathogenesis is still unclear, its course is considerably variable, and prognosis is hard to determine. Despite much research, there is still a lack of easily accessible markers predicting prognosis. We investigated routine blood parameters in ALS patients regarding correlations with disease severity, progression rate, and survival. Additionally, we analyzed disease and patients' characteristics relating to baseline blood parameter levels.MethodsWe analyzed creatine kinase (CK), albumin (ALB), creatinine (CREA), total cholesterol (TC), high-density lipoprotein cholesterol (HDL), low-density lipoprotein cholesterol (LDL), and triglycerides (TG) levels around time of diagnosis in 1,084 ALS patients. We carried out linear regression analyses including disease and patients' characteristics with each blood parameter to detect correlations with them. Linear regression models were performed for ALSFRS-R at study entry, its retrospectively defined rate of decay and prospectively collected progression rate. Different survival analysis methods were used to examine associations between blood parameters and survival.ResultsWe found higher CK (p-value 0.001), ALB (p-value &lt;0.001), CREA (p-value &lt;0.001), and HDL levels (p-value 0.044) at time of diagnosis being associated with better functional status according to ALSFRS-R scores at study entry. Additionally, higher CREA levels were associated with lower risk of death (p-value 0.003).ConclusionsOur results indicate potential of CK, ALB, CREA, and HDL as disease severity or progression markers, and may also provide clues to ALS pathogenesis. However, these values are highly dependent on other variables, and further careful, longitudinal analyses will be necessary to prove the relevance of our findings.
Comprehensive Analysis of the Immunogenomics of Triple-Negative Breast Cancer Brain Metastases From LCCC1419
Authors: Routh Eric D. , Van Swearingen Amanda E. D. , Sambade Maria J. , Vensko Steven , McClure Marni B. , Woodcock Mark G. , Chai Shengjie , Cuaboy Luz A. , Wheless Amy , Garrett Amy , Carey Lisa A. , Hoyle Alan P. , Parker Joel S. , Vincent Benjamin G. , Anders Carey K. 
Published: July 2022

BackgroundTriple negative breast cancer (TNBC) is an aggressive variant of breast cancer that lacks the expression of estrogen and progesterone receptors (ER and PR) and HER2. Nearly 50% of patients with advanced TNBC will develop brain metastases (BrM), commonly with progressive extracranial disease. Immunotherapy has shown promise in the treatment of advanced TNBC; however, the immune contexture of BrM remains largely unknown. We conducted a comprehensive analysis of TNBC BrM and matched primary tumors to characterize the genomic and immune landscape of TNBC BrM to inform the development of immunotherapy strategies in this aggressive disease.MethodsWhole-exome sequencing (WES) and RNA sequencing were conducted on formalin-fixed, paraffin-embedded samples of BrM and primary tumors of patients with clinical TNBC (n = 25, n = 9 matched pairs) from the LCCC1419 biobank at UNC—Chapel Hill. Matched blood was analyzed by DNA sequencing as a comparison for tumor WES for the identification of somatic variants. A comprehensive genomics assessment, including mutational and copy number alteration analyses, neoantigen prediction, and transcriptomic analysis of the tumor immune microenvironment were performed.ResultsPrimary and BrM tissues were confirmed as TNBC (23/25 primaries, 16/17 BrM) by immunohistochemistry and of the basal intrinsic subtype (13/15 primaries and 16/19 BrM) by PAM50. Compared to primary tumors, BrM demonstrated a higher tumor mutational burden. TP53 was the most frequently mutated gene and was altered in 50% of the samples. Neoantigen prediction showed elevated cancer testis antigen- and endogenous retrovirus-derived MHC class I-binding peptides in both primary tumors and BrM and predicted that single-nucleotide variant (SNV)-derived peptides were significantly higher in BrM. BrM demonstrated a reduced immune gene signature expression, although a signature associated with fibroblast-associated wound healing was elevated in BrM. Metrics of T and B cell receptor diversity were also reduced in BrM.ConclusionsBrM harbored higher mutational burden and SNV-derived neoantigen expression along with reduced immune gene signature expression relative to primary TNBC. Immune signatures correlated with improved survival, including T cell signatures. Further research will expand these findings to other breast cancer subtypes in the same biobank. Exploration of immunomodulatory approaches including vaccine applications and immune checkpoint inhibition to enhance anti-tumor immunity in TNBC BrM is warranted.
5-Fluorouracil combined with cisplatin via arterial induction for advanced T-stage nasopharyngeal carcinoma: A 10-year outcome of a phase I/II study
Authors: Xiang Li , Zheng Yun , Ren PeiRong , Lin Sheng , Zhang JianWen , Wen QingLian , He LiJia , Shang ChangLing , Wu JingBo 
Published: July 2022

Background and PurposeCurrently, there is no optimal dose recommendation for a 120-h continuous infusion of 5-fluorouracil via arterial cannulation for advanced T-stage nasopharyngeal carcinoma (NPC). Thus, the aim of this study was to determine the maximum tolerated dose (MDT), along with the efficacy, late adverse events, and 10-year survival outcome of 5-fluorouracil administered continuously for 120 h combined with cisplatin via the superficial temporal artery in patients with advanced T-stage NPC.Materials and MethodsFifty-one patients with histologically confirmed advanced T-stage NPC were eligible for inclusion in this clinical trial. The patients received induction chemotherapy consisting of cisplatin (20 mg/m2/d for 1–5 d) and 5-fluorouracil, administered continuously for 120 h at different dose gradients via a superficial temporal artery. To identify the MTD of 5-fluorouracil infused arterially, we employed a 3 + 3 design during study phase I. The initial dose administered was 200 mg/m2/d, which then was gradually escalated by 50 mg/m2/d until the MTD was reached. Following two cycles of induction chemotherapy, current radical chemoradiotherapy commenced. We assessed the efficacy, survival, toxicity, and quality of life of patients following treatment.ResultsThe overall response (complete response + partial response) rates following induction chemotherapy in the primary mass and lymph nodes were 100% and 100%, respectively. All 51 (100%) patients achieved T-category down-staging after intra-arterial chemotherapy. The MTD was 450 mg/m2/d for 120 h. No late neurological toxicities, such as brain stem injury, temporal lobe necrosis, and spinal cord injury, were observed. The 5- and 10-year overall survival (OS) rates were 78.0% and 71.7%, respectively, with a median OS of 131 months.ConclusionContinuous infusion of 5-fluorouracil combined with cisplatin via the superficial temporal artery showed promising survival benefits and few toxicities in patients with advanced T-stage NPC.
Onco-immunomodulatory properties of pharmacological interference with RAS-RAF-MEK-ERK pathway hyperactivation
Authors: Avery Thomas Yul , Köhler Natalie , Zeiser Robert , Brummer Tilman , Ruess Dietrich Alexander 
Published: July 2022

Hyperactivation of the RAS-RAF-MEK-ERK cascade - a mitogen-activated protein kinase pathway – has a well-known association with oncogenesis of leading tumor entities, including non-small cell lung cancer, colorectal carcinoma, pancreatic ductal adenocarcinoma, and malignant melanoma. Increasing evidence shows that genetic alterations leading to RAS-RAF-MEK-ERK pathway hyperactivation mediate contact- and soluble-dependent crosstalk between tumor, tumor microenvironment (TME) and the immune system resulting in immune escape mechanisms and establishment of a tumor-sustaining environment. Consequently, pharmacological interruption of this pathway not only leads to tumor-cell intrinsic disruptive effects but also modification of the TME and anti-tumor immunomodulation. At the same time, the importance of ERK signaling in immune cell physiology and potentiation of anti-tumor immune responses through ERK signaling inhibition within immune cell subsets has received growing appreciation. Specifically, a strong case was made for targeted MEK inhibition due to promising associated immune cell intrinsic modulatory effects. However, the successful transition of therapeutic agents interrupting RAS-RAF-MEK-ERK hyperactivation is still being hampered by significant limitations regarding durable efficacy, therapy resistance and toxicity. We here collate and summarize the multifaceted role of RAS-RAF-MEK-ERK signaling in physiology and oncoimmunology and outline the rationale and concepts for exploitation of immunomodulatory properties of RAS-RAF-MEK-ERK inhibition while accentuating the role of MEK inhibition in combinatorial and intermittent anticancer therapy. Furthermore, we point out the extensive scientific efforts dedicated to overcoming the challenges encountered during the clinical transition of various therapeutic agents in the search for the most effective and safe patient- and tumor-tailored treatment approach.
Vaccination timeliness and associated factors among children aged 12–23 months in Debre Libanos district of North Shewa Zone, Oromia Regional State, Ethiopia
Authors: Dejene Hiwot , Girma Derara , Geleta Leta Adugna , Legesse Elsabeth 
Published: July 2022

BackgroundGlobally, vaccination is one of the most cost-effective interventions in promoting child survival, preventing 2–3 million child deaths annually from vaccine-preventable diseases (VPDs). In Ethiopia, timely vaccination is stated as key to the prevention of unnecessary childhood mortality from measles, pneumonia, diarrheal diseases, and other VPDs. However, Ethiopia ranked fifth among the ten countries with the most unprotected children. Furthermore, previous vaccine timeliness studies produced widely disparate results. As a result, it was suggested that more research be conducted to investigate the potential factors behind the high proportion of untimely vaccination. Therefore, this study was intended to explore the association between different factors and the proportion of vaccination timeliness administered under the Expanded Program on Immunization in Debre Libanos district, Ethiopia.MethodsA community-based cross-sectional study design was employed from 1 May to 30 May 2021 among children aged 12 to 23 months with their mother/caregiver, who had started vaccination and had vaccination cards in the Debre Libanos. Simple random sampling techniques and pretested semi-structured questionnaires were used for data collection. At last, a multivariable logistic regression was used to identify factors associated with the vaccination timeliness.ResultIn this study, 413 children aged 12 to 23 months were interviewed with their mother/caregiver. Overall, 33.7% [95% CI (29.1–38.3)] of children received their vaccines timely. Having a female child [AOR: 2.9, 95% CI: 1.58–5.35], mother/caregiver attending primary [AOR: 6.33, 95% CI: 2.66–15.06] and secondary/above education [AOR: 5.61, 95% CI: 2.41–13.04], sufficient vaccination knowledge [AOR: 3.46, 95% CI: 1.87–6.38], mother/caregiver with least hesitant [AOR: 3.35, 95% CI: 1.51–7.41] and middle hesitant [AOR: 1.89, 95% CI: 1.05–3.58], utilization of ANC [AOR: 2.89, 95% CI: 1.32–6.33], and giving birth at health facility [AOR: 4.32, 95% CI: 1.95–9.59] were the factors independently associated with vaccination timeliness.ConclusionIn comparison to Ethiopia’s existing vaccination coverage, the proportion of children immunized at the recommended time interval is low in the study district. Policymakers should prioritize vaccine timeliness and integrate it into childhood vaccination strategies.