bluuebunny/crossref_metadata_2025_split huggingface dataset:
Blackwater fever and acute kidney injury in children hospitalized with an acute febrile illness: pathophysiology and prognostic significance
Authors: Conroy Andrea L. , Hawkes Michael T. , Leligdowicz Aleksandra , Mufumba Ivan , Starr Michelle C. , Zhong Kathleen , Namasopo Sophie , John Chandy C. , Opoka Robert O. , Kain Kevin C. 
Published: July 2022

AbstractBackgroundAcute kidney injury (AKI) and blackwater fever (BWF) are related but distinct renal complications of acute febrile illness in East Africa. The pathogenesis and prognostic significance of BWF and AKI are not well understood.MethodsA prospective observational cohort study was conducted to evaluate the association between BWF and AKI in children hospitalized with an acute febrile illness. Secondary objectives were to examine the association of AKI and BWF with (i) host response biomarkers and (ii) mortality. AKI was defined using the Kidney Disease: Improving Global Outcomes criteria and BWF was based on parental report of tea-colored urine. Host markers of immune and endothelial activation were quantified on admission plasma samples. The relationships between BWF and AKI and clinical and biologic factors were evaluated using multivariable regression.ResultsWe evaluated BWF and AKI in 999 children with acute febrile illness (mean age 1.7 years (standard deviation 1.06), 55.7% male). At enrollment, 8.2% of children had a history of BWF, 49.5% had AKI, and 11.1% had severe AKI. A history of BWF was independently associated with 2.18-fold increased odds of AKI (95% CI 1.15 to 4.16). When examining host response, severe AKI was associated with increased immune and endothelial activation (increased CHI3L1, sTNFR1, sTREM-1, IL-8, Angpt-2, sFlt-1) while BWF was predominantly associated with endothelial activation (increased Angpt-2 and sFlt-1, decreased Angpt-1). The presence of severe AKI, not BWF, was associated with increased risk of in-hospital death (RR, 2.17 95% CI 1.01 to 4.64) adjusting for age, sex, and disease severity.ConclusionsBWF is associated with severe AKI in children hospitalized with a severe febrile illness. Increased awareness of AKI in the setting of BWF, and improved access to AKI diagnostics, is needed to reduce disease progression and in-hospital mortality in this high-risk group of children through early implementation of kidney-protective measures.
Placenta-derived proteins across gestation in healthy pregnancies—a novel approach to assess placental function?
Authors: Degnes Maren-Helene Langeland , Westerberg Ane Cecilie , Zucknick Manuela , Powell Theresa L. , Jansson Thomas , Henriksen Tore , Roland Marie Cecilie Paasche , Michelsen Trond Melbye 
Published: July 2022

AbstractBackgroundPlacenta-derived proteins in the systemic maternal circulation are suggested as potential biomarkers for placental function. However, the identity and longitudinal patterns of such proteins are largely unknown due to the inaccessibility of the human placenta and limitations in assay technologies. We aimed to identify proteins derived from and taken up by the placenta in the maternal circulation. Furthermore, we aimed to describe the longitudinal patterns across gestation of placenta-derived proteins as well as identify placenta-derived proteins that can serve as reference curves for placental function.MethodsWe analyzed proteins in plasma samples collected in two cohorts using the Somalogic 5000-plex platform. Antecubital vein samples were collected at three time points (gestational weeks 14–16, 22–24, and 30–32) across gestation in 70 healthy pregnancies in the longitudinal STORK cohort. In the cross sectional 4-vessel cohort, blood samples were collected simultaneously from the maternal antecubital vein (AV), radial artery (RA), and uterine vein (UV) during cesarean section in 75 healthy pregnancies. Placenta-derived proteins and proteins taken up by the placenta were identified using venoarterial differences (UV-RA). Placenta-derived proteins were defined as placenta-specific by comparison to the venoarterial difference in the antecubital vein-radial artery (AV-RA). These proteins were described longitudinally based on the STORK cohort samples using a linear mixed effects model per protein. Using a machine learning algorithm, we identified placenta-derived proteins that could predict gestational age, meaning that they closely tracked gestation, and were potential read-outs of placental function.ResultsAmong the nearly 5000 measured proteins, we identified 256 placenta-derived proteins and 101 proteins taken up by the placenta (FDR < 0.05). Among the 256 placenta-derived proteins released to maternal circulation, 101 proteins were defined as placenta-specific. These proteins formed two clusters with distinct developmental patterns across gestation. We identified five placenta-derived proteins that closely tracked gestational age when measured in the systemic maternal circulation, termed a “placental proteomic clock.”ConclusionsTogether, these data may serve as a first step towards a reference for the healthy placenta-derived proteome that can be measured in the systemic maternal circulation and potentially serve as biomarkers of placental function. The “placental proteomic clock” represents a novel concept that warrants further investigation. Deviations in the proteomic pattern across gestation of such proteomic clock proteins may serve as an indication of placental dysfunction.
Mutational landscape of pan-cancer patients with PIK3CA alterations in Chinese population
Authors: Huang Qingfeng , Zhou Yang , Wang Bowen , Zhao Yi , Zhang Fengxia , Ding Bowen 
Published: July 2022

Abstract
Purpose
To analyze the mutational landscape of pan-cancer patients with PIK3CA mutations in Chinese population in real-world.

Methods
We analyzed PIK3CA mutation status in sequencing data of cell-free DNA from plasma and genomic DNA from matched peripheral blood lymphocyte in 11,904 Chinese pan-cancer patients, and compared them with genomic data from the Catalogue of Somatic Mutations in Cancer (COSMIC) database. Besides, concomitant genomic aberrations in PIK3CA-mutated samples were detected to investigate cancer driver genes, as well as their enriched pathways. Meanwhile, the mutations of Alpelisib targeting genes were screened and their co-alterations were analyzed according to OncoKB definition to identify the potential actionable ones.

Results
The proportion of patients with PIK3CA mutations varied among 21 types of cancer, with the top being BRCA, CESC, SCL, and UCEC. The most common PIK3CA mutation hotspots were found to be E545K, E542K and H1047R. The Chinese cohort had significantly lower frequencies of PIK3CA mutations in breast and stomach cancers, but markedly higher PIK3CA mutation frequencies in large intestine, kidney and lung cancers than the COSMIC cohort. Compared with COSMIC cohort, the mutation frequencies of Alpelisib-targeted genes in breast cancer were significantly reduced in the Chinese cohort. All PIK3CA-mutated patients had concomitant genomic aberrations. While the most common concomitant genomic alterations occurred in TP53, EGFR and FAT1, these co-mutated genes were mainly enriched in RTK/RAS pathway, PI3K pathway and P53 pathway. Moreover, 83.6% of patients carrying mutations in Alpelisib-targeted genes had at least one actionable concomitant alteration. Level 1 actionable alteration was identified in LUAD, BRCA, COAD, LUSC, READ, and STAD.

Conclusion
Compared with the Western cohort, the mutation frequency of PIK3CA in breast cancer was reduced in the Chinese cohort. RTK/RAS pathway, PI3K pathway and P53 pathway were identified as the most common co-mutation pathways, suggesting that they may potentially serve as targets for possible Alpelisib-based combination therapy.
Comprehensive characterization reveals sputum supernatant as a valuable alternative liquid biopsy for genome profiling in advanced non-small cell lung cancer
Authors: Xie Xiaohong , Wu Jianhui , Guo Bingpeng , Wang Liqiang , Deng Haiyi , Lin Xinqing , Liu Ming , Qin Yinyin , Luo Wei , Yang Yilin , Zou Xiao , Hou Ting , Xiang Jianxing , Chen Zhange , Zhou Chengzhi 
Published: July 2022

Abstract
Background
Sputum biopsies offer unique advantages such as non-invasiveness and convenient collection. The one investigation so far on sputum for genome profiling in advanced non-small cell lung cancer (aNSCLC) suggested promising performance. However, it remains undefined whether clinicohistologic characteristics were associated with performance and how this knowledge could help guide choice of liquid biopsy.

Methods
Targeted sequencing with a 520-gene panel was performed on prospectively collected matched tumor tissue (TIS), plasma (PLA), and sputum supernatant (SPU) from 71 aNSCLC patients (NCT05034445). Genomic alteration detection was characterized in a series of aspects and interrogated for association with 14 clinicohistologic features. Nomograms were constructed with logistic regression for predicting the liquid biopsy type with greater sensitivity.

Results
Compared with PLA, SPU showed comparable quality control metrics, mutation detection rate (SPU: 67.6%, PLA: 70.4%), concordance with tumor tissue (67.6% vs. 73.2%), and correlation with tissue-based tumor mutation burden levels (r = 0.92 vs. 0.94). For driver alterations, detection was less sensitive with SPU (50.0%) than PLA (63.5%) in the entire cohort but similarly or more sensitive in patients with centrally located lung tumors or smoking history or for altered ALK or KRAS. Two nomograms were constructed and enabled predicting the probability of superior sensitivity with SPU with moderate to borderline high accuracy.

Conclusion
In addition to demonstrating comparable performance in multiple aspects, this study is the first to propose nomograms for choosing liquid biopsy based on clinicohistologic characteristics. Future research is warranted to delineate the clinical utility of sputum for genome profiling.
TyG index is positively associated with risk of CHD and coronary atherosclerosis severity among NAFLD patients
Authors: Zhao Jianqi , Fan Hongxuan , Wang Ting , Yu Bing , Mao Shaobin , Wang Xun , Zhang Wenjing , Wang Leigang , Zhang Yao , Ren Zhaoyu , Liang Bin 
Published: July 2022

Abstract
Background
Insulin resistance (IR), endothelial dysfunction, inflammation, glucose and lipid metabolism disorders, and thrombosis are believed involved in coronary heart disease (CHD) and non-alcoholic fatty liver disease (NAFLD). Triglyceride-glucose (TyG) index, a new IR indicator, is correlated with NAFLD occurrence and severity, but its relationship with CHD risk remains unclear. This study investigated the correlation between TyG index and CHD risk among NAFLD patients.

Methods
This cross-sectional study included 424 patients with NAFLD and chest pain in the Department of Cardiology, The Second Hospital of Shanxi Medical University, from January 2021 to December 2021. The TyG index was calculated and coronary angiography performed. All individuals were divided into NAFLD + CHD and NAFLD groups and then by TyG index level. The t-test, Mann–Whitney U-test, or one-way analysis of variance compared differences in continuous variables, while the chi-square test or Fisher’s exact test compared differences in categorical variables. Logistic regression analysis determined the independent protective or hazardous factors of NAFLD with CHD. The receiver operating characteristic curve evaluated the ability of different TyG index rule-in thresholds to predict CHD. The relationship between Gensini score and TyG index was evaluated using linear correlation and multiple linear regression.

Results
CHD was detected in 255 of 424 patients. Compared to NAFLD group, multivariate logistic regression showed that TyG index was a risk factor for CHD among NAFLD patients after adjustment for age, sex, hypertension, and diabetes mellitus with the highest odds ratio (OR, 2.519; 95% CI, 1.559–4.069; P < 0.001). TG, low-density lipoprotein cholesterol, FBG and TYG–body mass index were also risk factors for CHD among NAFLD patients. High-density lipoprotein cholesterol level was a protective factor for CHD events in patients with NAFLD. In an in-depth analysis, multivariate logistic regression analysis showed that each 1-unit increase in TyG index was associated with a 2.06-fold increased risk of CHD (OR, 2.06; 95% CI, 1.16–3.65; P = 0.013). The multifactor linear regression analysis showed each 0.1-unit increase in TyG in the NAFLD-CHD group was associated with a 2.44 increase in Gensini score (β = 2.44; 95% CI, 0.97–3.91; P = 0.002).

Conclusions
The TyG index was positively correlated with CHD risk in NAFLD patients and reflected coronary atherosclerosis severity.
Emerging vancomycin-non susceptible coagulase negative Staphylococci associated with skin and soft tissue infections
Authors: Akinduti Paul A. , Obafemi Yemisi Dorcas , Ugboko Harriet , El-Ashker Maged , Akinnola Olayemi , Agunsoye Chioma Jane , Oladotun Abiola , Phiri Bruno S. J. , Oranusi Solomon U. 
Published: July 2022

Abstract
Backgrounds
Observable emergence of Vancomycin-Non susceptible Coagulase-negative Staphylococci (VNS-CoNS) associated with skin and soft tissue infections spreading among the urban and rural populace is gradually intensifying severe complications. The isolated VNS-CoNS were evaluated with Matrix-assisted Laser Desorption/ionization Time of Flight Mass Spectrometry (MALDI ToF MS) for species characterization and pan-antimicrobial resistance pattern.

Methods
Out of 256 clinical samples collected including pus, abscess, ear swabs, eye swabs, and aspirates, 91 CoNS isolates were biotyped and further characterized with MALDI-TOF MS. Staphylococci marker genes, Vancomycin susceptibility, and biofilm assays were performed.

Results
Of 91 CoNS isolates, S.cohnii (2.3%), S.condimentii (3.4%), S. saprophyticus (6.7%), and S.scuri (21.1%) were characterized with MALDI-TOF with significant detection rate (99.4%; CI 95, 0.775–0.997, positive predictive values, 90.2%) compared to lower biotyping detection rate (p = 0.001). Hemolytic VNS-CoNS lacked nuc, pvl and spa genes from wound, ear, and aspirates of more 0.83 MARI clustered into a separate phylo-diverse group and were widely distributed in urban and peri-urban locations. MALDI TOF–MS yielded a high discriminatory potential of AUC-ROC score of 0.963 with true-positivity prediction. VNS-CoNS of MIC ≥ 16 µg/mL were observed among all the ages with significant resistance at 25th and 75th quartiles. More than 10.5% of CoNS expressed multi-antibiotic resistance with more than 8 µg/mL vancomycin cut-off values (p < 0.05).

Conclusion
Antibiotic resistant CoNS should be considered significant pathogens rather than contaminant. Biofilm producing VNS-S. sciuri and S. condimentii are potential strains with high pathological tropism for skin, soft tissues and wound infections, and these strains require urgent surveillance in peri-urban and rural communities.
Effects of body mass index and serum albumin on overall survival in patients with cancer undergoing pancreaticoduodenectomy: a single-center retrospective cohort study
Authors: Cui Lei , Yu Huiping , Sun Qingmei , Miao Yi , Jiang Kuirong , Fang Xiaoping 
Published: July 2022

Abstract
Objectives
We aimed to explore whether body mass index (BMI) and albumin were associated with overall survival (OS) in individuals who underwent pancreaticoduodenectomy (PD) for cancer.

Methods
Three-hundred twenty-nine consecutive patients who underwent PD for cancer were enrolled from January 2020 to December 2020. All clinicopathological information was extracted based on medical records. The survival follow-ups were regularly performed and ended on June 30, 2021. The Kaplan-Meier survival analysis and univariate and multivariate Cox proportional-hazards models were used to assess the association of BMI and albumin with OS.

Results
Of the 329 patients, 186 (56.5%) were male, and median age at admission was 65.0 (56.0–71.0) years. There were 258 patients (78.4%) with BMI < 25.0 kg/m2 and 89 patients (27.05%) with albumin < 35.0 g/L respectively. In overall cohort, BMI < 25.0 kg/m2 was associated with OS (adjusted HR = 3.516, 95% CI = 1.076–11.492, P = 0.037). In contrast, albumin < 35.0 g/L did not affect OS. Subgroup analysis showed, in patients with pancreas lesion, BMI < 25.0 kg/m2 had a higher risk for OS compared to BMI ≥ 25.0 kg/m2 (adjusted HR = 3.209, 95% CI = 0.985–10.451, P = 0.048), while albumin < 35.0 g/L was not linked to OS. In patients with lesion in ampulla of Vater, duodenum, or common bile duct, there was no significant association of BMI and albumin with OS.

Conclusions
BMI, rather than serum albumin, was associated with OS in patients who underwent PD for cancer.
Population pharmacokinetic modeling of CSF to blood clearance: prospective tracer study of 161 patients under work-up for CSF disorders
Authors: Hovd Markus Herberg , Mariussen Espen , Uggerud Hilde , Lashkarivand Aslan , Christensen Hege , Ringstad Geir , Eide Per Kristian 
Published: July 2022

Abstract
Background
Quantitative measurements of cerebrospinal fluid to blood clearance has previously not been established for neurological diseases. Possibly, variability in cerebrospinal fluid clearance may affect the underlying disease process and may possibly be a source of under- or over-dosage of intrathecally administered drugs. The aim of this study was to characterize the cerebrospinal fluid to blood clearance of the intrathecally administered magnetic resonance imaging contrast agent gadobutrol (Gadovist, Bayer Pharma AG, GE). For this, we established a population pharmacokinetic model, hypothesizing that cerebrospinal fluid to blood clearance differs between cerebrospinal fluid diseases.

Methods
Gadobutrol served as a surrogate tracer for extra-vascular pathways taken by several brain metabolites and drugs in cerebrospinal fluid. We estimated cerebrospinal fluid to blood clearance in patients with different cerebrospinal fluid disorders, i.e. symptomatic pineal and arachnoid cysts, as well as tentative spontaneous intracranial hypotension due to cerebrospinal fluid leakage, idiopathic intracranial hypertension, or different types of hydrocephalus (idiopathic normal pressure hydrocephalus, communicating- and non-communicating hydrocephalus). Individuals with no verified cerebrospinal fluid disturbance at clinical work-up were denoted references.

Results
Population pharmacokinetic modelling based on 1,140 blood samples from 161 individuals revealed marked inter-individual variability in pharmacokinetic profiles, including differences in absorption half-life (time to 50% of tracer absorbed from cerebrospinal fluid to blood), time to maximum concentration in blood and the maximum concentration in blood as well as the area under the plasma concentration time curve from zero to infinity. In addition, the different disease categories of cerebrospinal fluid diseases demonstrated different profiles.

Conclusions
The present observations of considerable variation in cerebrospinal fluid to blood clearance between individuals in general and across neurological diseases, may suggest that defining cerebrospinal fluid to blood clearance can become a useful diagnostic adjunct for work-up of cerebrospinal fluid disorders. We also suggest that it may become useful for assessing clearance capacity of endogenous brain metabolites from cerebrospinal fluid, as well as measuring individual cerebrospinal fluid to blood clearance of intrathecal drugs.
The effects of lumbar fusion and non-fusion surgery on the development of Modic changes
Authors: Mu Xiaoping , Kim Seong Woong , Uhl Eberhard , Schöller Karsten 
Published: July 2022

Abstract
Background
The aim of this study was to investigate the influence of lumbar fusion and non-fusion surgery on the postoperative development of Modic changes (MCs).

Methods
A total of 270 patients who underwent lumbar fusion, microsequestrectomy, microdiscectomy, and microdecompression, and who were examined by pre- and postoperative magnetic resonance imaging during the period of January 2012 to December 2018, were included in this retrospective study. The incidence of new postoperative MCs and the change of volume of preexisting MCs after surgery were investigated.

Results
The total incidence of new MCs following lumbar surgical procedures was 36.3%. Lumbar fusion showed a tendency towards a lower postoperative incidence of new MCs than the other three lumbar surgical procedures. The first postoperative year seems to be the most active phase for the development of new MCs. The postoperative volumes of MCs in patients who underwent lumbar non-fusion procedures were significantly greater than those before surgery (P < 0.01). However, no significant difference was detected between pre- and postoperative volumes of MCs in patients with lumbar fusion (P > 0.05).

Conclusion
Lumbar surgical procedures contribute to the development of new MCs, particularly non-fusion surgeries. However, further studies are needed to confirm the clinical relevance of these findings.
Aberrant miR-874-3p/leptin/EGFR/c-Myc signaling contributes to nasopharyngeal carcinoma pathogenesis
Authors: Luo Sheng-Dean , Tsai Hsin-Ting , Hwang Chung-Feng , Chiu Tai‐Jan , Li Shau‐Hsuan , Hsu Ya-Ling , Hsiao Chang-Chun , Chen Chang-Han 
Published: July 2022

Abstract
Background
Leptin is important in physiological and pathological functions in various cancers, however, the significance and mechanisms of leptin in nasopharyngeal carcinoma remain ambiguous.

Methods
Leptin expression was analyzed by QPCR, immunohistochemistry, Western blotting, and TCGA database. The impact of gain- or loss-of-function of leptin were determined by MTT, colony formation, wound healing, and Transwell assays in NPC cells, and by a xenograft tumor model. Leptin-modulated glucose consumption and lactate production were assessed by ELISA. Furthermore, leptin-regulated signaling pathways were examined by QPCR and Western blotting assays. The immunoprecipitation assay was conducted to determine interaction between leptin and EGFR. In addition, miR-874-3p-regulated leptin expression was evaluated using bioinformatics, QPCR, luciferase assay, AGO2-RIP assay, and Western blotting.

Results
In this study, we found that leptin was highly expressed in the sera and tumor tissues of patients with NPC, and elevated leptin expression was associated with advanced clinical features and poor prognosis. Functional assays demonstrated that leptin remarkably promoted NPC cell growth, motility, and glycolysis in vitro and in vivo. Mechanistically, leptin associated with EGFR, resulting in enhanced cell growth through the regulation of cell-cycle related markers, glycolysis-related genes, and EGFR/AKT/c-Myc signaling. Moreover, leptin potentiated the invasive capacity of NPC cells by promoting EMT. We further explored that miR-874-3p influenced leptin-mediated NPC progression. Overexpression of miR-874-3p prevented cell growth, motility, glucose consumption, and lactate production in NPC cells, whereas miR-874-3p inhibition had the opposite effects. AGO-RIP assays confirmed that Argonaute 2 (AGO2), a protein associated with miR-874-3p, regulated leptin expression in NPC cells. The rescue assays indicated that inhibition of leptin suppressed the effects of miR-874-3p inhibitor. In clinical specimens, miR-874-3p was negatively correlated with leptin.

Conclusions
Leptin may serve as a novel prognostic factor and potential therapeutic target for patients with NPC. In addition, a newly discovered regulatory axis of leptin/EGFR/AKT/c-Myc can provide a novel therapeutic strategy for NPC.