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Hepatology Communications Jul 2024Identifying patients with undiagnosed advanced chronic liver disease (ACLD) is a public health challenge. Patients with advanced fibrosis or compensated cirrhosis have...
BACKGROUND
Identifying patients with undiagnosed advanced chronic liver disease (ACLD) is a public health challenge. Patients with advanced fibrosis or compensated cirrhosis have much better outcomes than those with decompensated disease and may be eligible for interventions to prevent disease progression.
METHODS
A cloud-based software solution ("the Liver Toolkit") was developed to access primary care practice software to identify patients at risk of ACLD. Clinical history and laboratory results were extracted to calculate aspartate aminotransferase-to-platelet ratio index and fibrosis 4 scores. Patients identified were recalled for assessment, including Liver Stiffness Measurement (LSM) via transient elastography. Those with an existing diagnosis of cirrhosis were excluded.
RESULTS
Existing laboratory results of more than 32,000 adults across nine general practices were assessed to identify 703 patients at increased risk of ACLD (2.2% of the cohort). One hundred seventy-nine patients (26%) were successfully recalled, and 23/179 (13%) were identified to have ACLD (LSM ≥10.0 kPa) (10% found at indeterminate risk [LSM 8.0-9.9 kPa] and 77% low risk of fibrosis [LSM <8.0 kPa]). In most cases, the diagnosis of liver disease was new, with the most common etiology being metabolic dysfunction-associated steatotic liver disease (n=20, 83%). Aspartate aminotransferase-to-platelet ratio index ≥1.0 and fibrosis 4 ≥3.25 had a positive predictive value for detecting ACLD of 19% and 24%, respectively. Patients who did not attend recall had markers of more severe disease with a higher median aspartate aminotransferase-to-platelet ratio index score (0.57 vs. 0.46, p=0.041).
CONCLUSIONS
This novel information technology system successfully screened a large primary care cohort using existing laboratory results to identify patients at increased risk ACLD. More than 1 in 5 patients recalled were found to have liver disease requiring specialist follow-up.
Topics: Humans; Female; Male; Middle Aged; Elasticity Imaging Techniques; General Practice; Adult; Liver Cirrhosis; Liver Diseases; Software; Mass Screening; Aged; Aspartate Aminotransferases; Chronic Disease; Platelet Count
PubMed: 38934697
DOI: 10.1097/HC9.0000000000000482 -
Kidney Research and Clinical Practice Jun 2024Identifying risk factors and improving prognostication for mortality among patients with sepsis-associated acute kidney injury (AKI) undergoing continuous kidney...
Association between systemic inflammation biomarkers and mortality in patients with sepsis-associated acute kidney injury receiving intensive care and continuous kidney replacement therapy: results from the RENERGY (REsearches for NEphRology and epidemioloGY) study.
BACKGROUND
Identifying risk factors and improving prognostication for mortality among patients with sepsis-associated acute kidney injury (AKI) undergoing continuous kidney replacement therapy (CKRT) is important in improving the adverse prognosis of this patient population. This study aimed to compare the prognostic value of existing systemic inflammation biomarkers and determine the optimal systemic inflammation biomarker in patients with sepsis-associated AKI receiving CKRT.
METHODS
This multi-center, retrospective, observational cohort study included 1,500 patients with sepsis-associated AKI treated with intensive care and CKRT. The main predictor was a panel of 13 different systemic inflammation biomarkers. The primary outcome was 28-day mortality after CKRT initiation. Secondary outcomes included 90-day mortality after CKRT initiation, CKRT duration, kidney replacement therapy dependence at discharge, and lengths of intensive care unit (ICU) and hospital stays.
RESULTS
When added to the widely accepted Acute Physiology and Chronic Health Evaluation II score, platelet-to-albumin ratio (PAR) and neutrophil-platelet score (NPS) had the highest improvements in prognostication of 28-day mortality, where the corresponding increases in C-statistic were 0.01 (95% confidence interval [CI], 0.00-0.02) and 0.02 (95% CI, 0.01-0.03). Similar findings were observed for 90-day mortality. The 28- and 90-day mortality rates were significantly lower for the higher PAR and NPS quartiles. These associations remained significant even after adjustment for potential confounding variables in multivariable Cox proportional hazards models.
CONCLUSION
Of the available systemic inflammation biomarkers, the addition of PAR or NPS to conventional ICU prediction models improved the prognostication of patients with sepsis-associated AKI receiving intensive care and CKRT.
PubMed: 38934032
DOI: 10.23876/j.krcp.23.321 -
Heliyon Jun 2024(PC) is a traditional Chinese medicine (TCM) and food as well as an important essential oil plant in China. PC essential oil exerts pharmacological effects such as...
GC-MS method for simultaneous determination and pharmacokinetic investigation of five volatile components in rat plasma after oral administration of the essential oil extract of .
(PC) is a traditional Chinese medicine (TCM) and food as well as an important essential oil plant in China. PC essential oil exerts pharmacological effects such as anti-inflammatory, anti-oxidant, anti-platelet, anti-thrombotic, and anti-depressant. This study established a reliable and sensitive gas chromatography-mass spectrometry (GC-MS) method for the simultaneous determination of the pharmacokinetics of patchouli alcohol, β-elemene, β-caryophyllene, caryophyllene oxide, and farnesol in the plasma of rats after oral administration of PC essential oil extract. Using ethyl acetate to prepare the plasma samples, and p-menthone was used as the internal standard (IS). An HP5-MS column (0.25 μm × 0.25 mm × 30 m) was used for chromatographic separation, and detection was performed in selected ion monitoring (SIM) mode. The accuracies of intra-day and inter-day for all analytes displayed a range of -6.7 %-9.2 %, with precision below 12.5 %. Extraction recoveries for analytes ranged from 74.0 to 106.4 % and matrix effects ranged from 92.4 to 106.9 %. Stability results have demonstrated that the relative standard deviations (RSD) of analytes were below 12.1 %. Therefore, the developed GC-MS method successfully evaluated the pharmacokinetics of five volatile components in PC essential oil extract administered orally to rats.
PubMed: 38933986
DOI: 10.1016/j.heliyon.2024.e32444 -
Vaccine: X Aug 2024Comirnaty, Pfizer-BioNTech's polyethylene-glycol (PEG)-containing Covid-19 vaccine, can cause hypersensitivity reactions (HSRs), or rarely, life-threatening anaphylaxis...
BACKGROUND
Comirnaty, Pfizer-BioNTech's polyethylene-glycol (PEG)-containing Covid-19 vaccine, can cause hypersensitivity reactions (HSRs), or rarely, life-threatening anaphylaxis in a small fraction of immunized people. A causal role of anti-PEG antibodies (Abs) has been proposed, but causality has not yet proven in an animal model. The aim of this study was to provide such evidence using pigs immunized against PEG, which displayed very high levels of anti-PEG antibodies (Abs). We also aimed to find evidence for a role of complement activation and thromboxane A2 release in blood to explore the mechanism of anaphylaxis.
METHODS
Pigs (n = 6) were immunized with 0.1 mg/kg PEGylated liposome (Doxebo) i.v., and the rise of anti-PEG IgG and IgM were measured in serial blood samples with ELISA. After ∼2-3 weeks the animals were injected i.v. with 1/3 human dose of the PEGylated mRNA vaccine, Comirnaty, and the hemodynamic (PAP, SAP) cardiopulmonary (HR, EtCO2,), hematological (WBC, granulocyte, lymphocyte and platelet counts) parameters and blood immune mediators (anti-PEG IgM and IgG antibodies, thromboxane B2, C3a) were measured as endpoints of HSRs (anaphylaxis).
RESULTS
The level of anti-PEG IgM and IgG rose 5-10-thousand-fold in all of 6 pigs immunized with Doxebo by day 6, after which time all animals developed anaphylactic shock to i.v. injection of 1/3 human dose of Comirnaty. The reaction, starting within 1 min involved maximal pulmonary hypertension and decreased systemic pulse pressure amplitude, tachycardia, granulo- and thrombocytopenia, and skin reactions (flushing or rash). These physiological changes or their absence were paralleled by C3a and TXB2 rises in blood.
CONCLUSIONS
Consistent with previous studies, these data show a causal role of anti-PEG Abs in the anaphylaxis to Comirnaty, which involves complement activation, and, hence, it represents C activation-related pseudo-anaphylaxis. The setup provides the first large-animal model for mRNA-vaccine-induced anaphylaxis in humans.
PubMed: 38933697
DOI: 10.1016/j.jvacx.2024.100497 -
Frontiers in Neurology 2024Acute Ischemic Stroke (AIS) remains a leading cause of mortality and disability worldwide. Rapid and precise prognostication of AIS is crucial for optimizing treatment...
BACKGROUND
Acute Ischemic Stroke (AIS) remains a leading cause of mortality and disability worldwide. Rapid and precise prognostication of AIS is crucial for optimizing treatment strategies and improving patient outcomes. This study explores the integration of machine learning-derived radiomics signatures from multi-parametric MRI with clinical factors to forecast AIS prognosis.
OBJECTIVE
To develop and validate a nomogram that combines a multi-MRI radiomics signature with clinical factors for predicting the prognosis of AIS.
METHODS
This retrospective study involved 506 AIS patients from two centers, divided into training (n = 277) and validation ( = 229) cohorts. 4,682 radiomic features were extracted from T1-weighted, T2-weighted, and diffusion-weighted imaging. Logistic regression analysis identified significant clinical risk factors, which, alongside radiomics features, were used to construct a predictive clinical-radiomics nomogram. The model's predictive accuracy was evaluated using calibration and ROC curves, focusing on distinguishing between favorable (mRS ≤ 2) and unfavorable (mRS > 2) outcomes.
RESULTS
Key findings highlight coronary heart disease, platelet-to-lymphocyte ratio, uric acid, glucose levels, homocysteine, and radiomics features as independent predictors of AIS outcomes. The clinical-radiomics model achieved a ROC-AUC of 0.940 (95% CI: 0.912-0.969) in the training set and 0.854 (95% CI: 0.781-0.926) in the validation set, underscoring its predictive reliability and clinical utility.
CONCLUSION
The study underscores the efficacy of the clinical-radiomics model in forecasting AIS prognosis, showcasing the pivotal role of artificial intelligence in fostering personalized treatment plans and enhancing patient care. This innovative approach promises to revolutionize AIS management, offering a significant leap toward more individualized and effective healthcare solutions.
PubMed: 38933326
DOI: 10.3389/fneur.2024.1379031 -
Frontiers in Immunology 2024Extracellular particles (EPs), particularly extracellular vesicles, play a crucial role in regulating various pathological mechanisms, including immune dysregulations...
BACKGROUND
Extracellular particles (EPs), particularly extracellular vesicles, play a crucial role in regulating various pathological mechanisms, including immune dysregulations post-trauma. Their distinctive expression of cell-specific markers and regulatory cargo such as cytokines or micro-ribonucleic acid suggests their potential as early biomarkers for organ-specific damage and for identifying patients at risk for complications and mortality. Given the critical need for reliable and easily assessable makers to identify at-risk patients and guide therapeutic decisions, we evaluated the early diagnostic value of circulating EPs regarding outcomes in severely injured multiple-trauma patients.
METHODS
Plasma samples were collected from 133 severely injured trauma patients (Injury Severity Score (ISS) ≥16) immediately upon arrival at the emergency department (ED). Patients were categorized into survivors and non-survivors. Injury characteristics and outcomes related to sepsis, pneumonia, or early (<1 day after admission) and late mortality were assessed. Circulating EPs, cytokine profiles, and blood counts of platelets and leukocytes were determined. Receiver operating characteristic analyses were conducted.
RESULTS
Despite no significant differences in injury pattern or severity, non-survivors exhibited significantly elevated counts of circulating EPs compared to survivors. The optimal cut-off for EPs <200 nm indicating non-survivors was 17380/µl plasma, with a sensitivity of 77% and a specificity of 61% in predicting in-hospital mortality. Later non-survivors received significantly higher numbers of units of packed red blood cells [8.54 ± 5.45 vs. 1.29 ± 0.36 units], had higher serum lactate [38.00 ± 7.51 vs. 26.98 ± 1.58 mg/dL], significantly lower platelet counts [181.30 ± 18.06 vs. 213.60 ± 5.85 *10³/µL] and lower heart rates [74.50 ± 4.93 vs. 90.18 ± 2.06 beats/minute] upon arrival at the ED compared to survivors.
CONCLUSION
Our results demonstrate the high diagnostic potential of elevated concentrations of circulating EPs <200 nm for identifying patients at risk of mortality after severe trauma. This parameter shows comparable sensitivity to established clinical predictors. Early evaluation of EPs concentration could complement assessment markers in guiding early therapeutic decisions.
Topics: Humans; Male; Female; Middle Aged; Adult; Hospital Mortality; Biomarkers; Extracellular Vesicles; Injury Severity Score; Aged; Wounds and Injuries; Prognosis; Cytokines; Multiple Trauma; ROC Curve
PubMed: 38933277
DOI: 10.3389/fimmu.2024.1390380 -
Frontiers in Immunology 2024The classical pathway of the complement system is activated by the binding of C1q in the C1 complex to the target activator, including immune complexes. Factor H is...
The classical pathway of the complement system is activated by the binding of C1q in the C1 complex to the target activator, including immune complexes. Factor H is regarded as the key downregulatory protein of the complement alternative pathway. However, both C1q and factor H bind to target surfaces via charge distribution patterns. For a few targets, C1q and factor H compete for binding to common or overlapping sites. Factor H, therefore, can effectively regulate the classical pathway activation through such targets, in addition to its previously characterized role in the alternative pathway. Both C1q and factor H are known to recognize foreign or altered-self materials, e.g., bacteria, viruses, and apoptotic/necrotic cells. Clots, formed by the coagulation system, are an example of altered self. Factor H is present abundantly in platelets and is a well-known substrate for FXIIIa. Here, we investigated whether clots activate the complement classical pathway and whether this is regulated by factor H. We show here that both C1q and factor H bind to the fibrin formed in microtiter plates and the fibrin clots formed under physiological conditions. Both C1q and factor H become covalently bound to fibrin clots, and this is mediated via FXIIIa. We also show that fibrin clots activate the classical pathway of complement, as demonstrated by C4 consumption and membrane attack complex detection assays. Thus, factor H downregulates the activation of the classical pathway induced by fibrin clots. These results elucidate the intricate molecular mechanisms through which the complement and coagulation pathways intersect and have regulatory consequences.
Topics: Humans; Complement Factor H; Fibrin; Blood Coagulation; Complement C1q; Complement Pathway, Classical; Protein Binding; Complement Activation; Blood Platelets
PubMed: 38933264
DOI: 10.3389/fimmu.2024.1368852 -
Viruses May 2024Severe fever with thrombocytopenia syndrome (SFTS) is a potentially fatal tick-borne zoonosis caused by SFTS virus (SFTSV). In addition to tick bites, animal-to-human...
Severe fever with thrombocytopenia syndrome (SFTS) is a potentially fatal tick-borne zoonosis caused by SFTS virus (SFTSV). In addition to tick bites, animal-to-human transmission of SFTSV has been reported, but little is known about feline SFTSV infection. In this study, we analyzed data on 187 cats with suspected SFTS to identify biomarkers for SFTS diagnosis and clinical outcome. Body weight, red and white blood cell and platelet counts, and serum aspartate aminotransferase and total bilirubin levels were useful for SFTS diagnosis, whereas alanine aminotransferase, aspartate aminotransferase and serum SFTSV RNA levels were associated with clinical outcome. We developed a scoring model to predict SFTSV infection. In addition, we performed a phylogenetic analysis to reveal the relationship between disease severity and viral strain. This study provides comprehensive information on feline SFTS and could contribute to the protection of cat owners, community members, and veterinarians from the risk of cat-transmitted SFTSV infection.
Topics: Animals; Cats; Phlebovirus; Cat Diseases; Phylogeny; Severe Fever with Thrombocytopenia Syndrome; Male; Female; Biomarkers; RNA, Viral; Severity of Illness Index; Aspartate Aminotransferases; Alanine Transaminase
PubMed: 38932167
DOI: 10.3390/v16060874 -
Pharmaceutics Jun 2024The inhibition of the immune response in the tumor microenvironment by therapy regimens can impede the eradication of tumors, potentially resulting in tumor metastasis....
The inhibition of the immune response in the tumor microenvironment by therapy regimens can impede the eradication of tumors, potentially resulting in tumor metastasis. As a non-invasive therapeutic method, radiotherapy is utilized for tumor ablation. In this study, we aimed to improve the therapeutic impact of radiotherapy and trigger an immune response by formulating a benzothiazole sulfinate (BTS)-loaded fusion liposome (BFL) nanoplatform, which was then combined with radiotherapy for anti-cancer treatment. The platelet cell membrane, equipped with distinctive surface receptors, enables BFL to effectively target tumors while evading the immune system and adhering to tumor cells. This facilitates BFL's engulfment by cancer cells, subsequently releasing BTS within them. Following the release, the BTS produces sulfur dioxide (SO) for gas therapy, initiating the oxidation of intracellular glutathione (GSH). This process demonstrates efficacy in repairing damage post-radiotherapy, thereby achieving effective radiosensitization. It was revealed that an immune response was triggered following the enhanced radiosensitization facilitated by BFL. This approach facilitated the maturation of dendritic cell (DC) within lymph nodes, leading to an increase in the proportion of T cells in distant tumors. This resulted in significant eradication of primary tumors and inhibition of growth in distant tumors. In summary, the integration of personalized BFL with radiotherapy shows potential in enhancing both tumor immune response and the elimination of tumors, including metastasis.
PubMed: 38931953
DOI: 10.3390/pharmaceutics16060833 -
Pharmaceutics May 2024The standard of care for glioblastoma (GBM) involves surgery followed by adjuvant radio- and chemotherapy, but often within months, patients relapse, and this has been...
The standard of care for glioblastoma (GBM) involves surgery followed by adjuvant radio- and chemotherapy, but often within months, patients relapse, and this has been linked to glioma stem cells (GSCs), self-renewing cells with increased therapy resistance. The identification of the epidermal growth factor receptor (EGFR) and platelet-derived growth factor receptor (PDGFR) as key players in gliomagenesis inspired the development of inhibitors targeting these tyrosine kinases (TKIs). However, results from clinical trials testing TKIs have been disappointing, and while the role of GSCs in conventional therapy resistance has been extensively studied, less is known about resistance of GSCs to TKIs. In this study, we have used compartmentalised proteomics to analyse the adaptive response of GSCs to ponatinib, a TKI with activity against PDGFR. The analysis of differentially expressed proteins revealed that GSCs respond to ponatinib by broadly rewiring lipid metabolism, involving fatty acid beta-oxidation, cholesterol synthesis, and sphingolipid degradation. Inhibiting each of these metabolic pathways overcame ponatinib adaptation of GSCs, but interrogation of patient data revealed sphingolipid degradation as the most relevant pathway in GBM. Our data highlight that targeting lipid metabolism, and particularly sphingolipid degradation in combinatorial therapies, could improve the outcome of TKI therapies using ponatinib in GBM.
PubMed: 38931850
DOI: 10.3390/pharmaceutics16060728