High Fatality Rate Research Articles

Machine learning and multisource data analysis approach towards traffic accident risk prediction

Traffic accidents are continually a concern across the world bringing with them huge economic costs and high rates of fatality and injuries each single year. Predictive modeling can lessen such risks if the accident hotspots and timing can easily be ascertained. This study collects various data including historical accident reports, water and meteorological conditions, road characteristics, and telematics data, to form traffic accident risk predictive models. To construct and analyze these predictive models, we use various machine learning techniques such as logistic regression, decision trees, and ensemble methods (Random Forest and Gradient Boosting). The results bear out as efficient and effective, ensemble models are streets ahead than regression-based techniques with Gradient Boosting achieving AUC-ROC scores of up to 0.89. The results of this research can also assist in applying effective safety measures in a more cost-effective manner as well as facilitate the development of efficient transport management systems and policies.

Novel oxygen vacancies-rich 3D porous ZnO for highly sensitive 3-hydroxy-2-butanone biomarker gas sensors

Listeriosis can cause human death via infection by Listeria monocytogenes (LMs) with a high fatality rate of 20–30 %. Detection of 3-hydroxy-2-butanone (3H-2B) biomarker of LMs can achieve estimation of LMs content, which is of great significance for human health. Exploring porous metal oxide semiconductors (MOSs) with rich vacancies towards 3H-2B sensing is quite promising for achieving this goal. Herein, we report a highly sensitive 3H-2B sensor based on novel 3D porous ZnO with rich oxygen vacancies which was facilely obtained by sacrificing Zn foam in oxalic acid and subsequent thermal decomposition. The ZnO sensor displays ultrahigh sensor response of Ra/Rg = 328@5 ppm, super-low detection limit of 0.001 ppm, excellent cycling stability and selectivity and good linear response at 120 °C, showing great potential for precise detection of 3H-2B biomarker. The porous structure and increased oxygen vacancies contribute greatly to the adsorption of active oxygen species therefore the sensing reactions on ZnO surface, which accounts for the high sensing performance. Our work provides an ingenious strategy to produce novel 3D ZnO with rich oxygen vacancies as well as new insights for boosting the detection of LMs.

Crimean Congo hemorrhagic fever virus exposure among febrile patients, cattle herders, and cattle herds in Cameroon

Problem addressedCrimean Congo hemorrhagic fever (CCHF) is a tick-borne disease with high fatality rates and an expansive geographic distribution, yet disease prevalence data in Cameroon is lacking. ObjectiveThis study aimed to determine CCHF virus (CCHFV) seroprevalence and tick distribution among cattle herders and febrile patients in West and Centre Cameroon. Methods and approachTwo cross-sectional serological studies of human and cattle were conducted from October to December 2021 and from June to July 2022, which included the collection of ticks. Enzyme-linked immunosorbent assay (ELISA) were used to detect anti-CCHFV antibodies, while a knowledge, attitudes, and practice (KAP) survey assessed tick and tickborne disease related knowledge and behaviors among herders. Tick identification used morphological keys. ResultsThe KAP survey showed adequate tick knowledge (94.5 %) among herders but poor understanding of disease transmission, with favorable attitudes towards tick control (24.7 %) but inadequate implementation. Rhipicephalus annulatus (64.1 %) predominated among the 1,296 ticks collected during each rainy season. Among cattle, 27.4 % were seropositive, and seropositivity was associated with specific villages, cattle age (>4 years), and female sex. Herders had a 17.8 % seroprevalence, while febrile patients had 8.3 %, with higher rates in those >20 years old for both groups. Self-reported tick removal by herders after contact and grazing may increase CCHFV exposure. ConclusionsThis study confirms CCHFV circulation in rural West Cameroon and unexpected exposure risk in Yaounde, highlighting the need for active entomological surveillance and preventive measures in transhumance and cattle market activities. Establishing an occupation-based surveillance system can help identify CCHFV hotspots to prevent outbreaks.

Examining Geographic Disparities in Fatal Automobile Accidents Across Kuwait Using GIS

Traffic accidents are considered a major public health issue worldwide, causing more than a million deaths annually and roughly five times that many injuries. Studying such accidents from a geographic perspective may help policy makers form better mitigation strategies for reducing accident rates. A Geographic Information System (GIS) is a powerful tool for performing this task due to its ability to visualize the spatial distribution of traffic accident data. Our research focused upon analyzing the geographic disparities in fatal car accidents. We chose to examine data between October 1, 2022 and March 31, 2023 for the state of Kuwait, which has a relatively high fatal accident rate per capita. We used various GIS-based tools in this research, such as average nearest neighborhood, point density, and optimized hot spot analysis. The results showed a significant disparity in accidents between urban and rural areas. Furthermore, an accident rate comparison between winter and summer seasons also revealed seasonal geographic disparities.

Oroxylin A suppressed colorectal cancer metastasis by inhibiting the activation of the TGF-β/SMAD signal pathway

Metastatic colorectal cancer continues to have a high fatality rate, with approximately only 14% of patients surviving more than 5 years. To improve the survival rate of these patients, the development of new therapeutic drugs is a priority. In this study, we investigated the effects of Oroxylin A on the metastasis of human colorectal cancer cells and its potential molecular mechanism. This study utilised CCK8 assay, transwell assay, flow cytometry, western blot analysis, molecular docking, HE staining, immunofluorescence staining, and xenograft models. The proliferation, migration, and invasion of colon cancer cells were effectively suppressed by Oroxylin A in a dose-dependent manner. Oroxylin A has the potential to inhibit the process of epithelial‒mesenchymal transition (EMT) by upregulating the expression of E-cadherin, a marker associated with epithelial cells, while downregulating the levels of N-cadherin, Snail, vimentin, and slug, which are markers associated with mesenchymal cells. In addition, 200 mg/kg of Oroxylin A inhibited the growth of colorectal tumours. Molecular docking technology revealed that Oroxylin A can bind to TGFβ and inhibit the activation of the TGFβ-smad signalling pathway. The overexpression of TGFβ weakened the inhibitory effect of Oroxylin A on the proliferation, migration, and invasion of human colorectal cancer cells, as well as the promoting effect on apoptosis. Oroxylin A inhibited the activation of the TGF-smad signalling pathway and the EMT process, thereby suppressing the migration and invasion of human colorectal cancer cells.

Genetic characterization of Neisseria meningitidis isolates recovered from patients with invasive meningococcal disease in Lithuania.

Neisseria meningitidis is a gram-negative bacterium responsible for life-threatening invasive infections known as invasive meningococcal disease and is associated with high fatality rates and serious lifelong disabilities among survivors. This study aimed to characterize N. meningitidis isolates cultured from blood and cerebrospinal fluid collected between 2009 and 2021 in Lithuania, assess their genomic relationships with European strains, and evaluate the possibility of using a cost-effective method for strain characterization, thus improving the national molecular surveillance of invasive meningococcal disease. In total, 321 N. meningitidis isolates were collected and analyzed using multilocus restriction typing (MLRT). Amplification of the penA gene and restriction fragment length polymorphism analysis were performed to identify the modified penA genes. Based on the MLRT genotyping results, we selected 10 strains for additional analysis using whole-genome sequencing. The sequenced genomes were incorporated into a dataset of publicly available N. meningitidis genomes to evaluate genomic diversity and establish phylogenetic relationships within the Lithuanian and European circulating strains. We identified 83 different strains using MLRT genotyping. Genomic diversity of N. meningitidis genomes analysed revealed 21 different sequence types (STs) circulating in Lithuania. Among these, ST34 was the most prevalent. Notably, three isolates displayed unique combinations of seven housekeeping genes and were identified as novel STs: ST16969, ST16901, and ST16959. The analyzed strains were found to possess virulence factors not commonly found in N. meningitidis. Six distinct penA profiles were identified, each with different frequencies. In the present study, we also identified N. meningitidis strains with new penA, NEIS0123, NEIS1320, NEIS1525, NEIS1600, and NEIS1753 loci variants. In our study, using the cgMLST scheme, Minimum Spanning Tree (MST) analysis did not identify significant geographic relationships between Lithuanian N.meningitidis isolates and strains from Europe. Discussion: To our knowledge, this is the first study to employ whole genome sequencing (WGS) method for a comprehensive genetic characterization of invasive N. meningitidis isolates from Lithuania. This approach provides a more detailed and precise analysis of genomic relationships and diversity compared to prior studies relying on traditional molecular typing methods and antigen analysis.

Serum lipidome reveals lipid metabolic dysregulation in severe fever with thrombocytopenia syndrome

BackgroundSevere fever with thrombocytopenia syndrome (SFTS) is a rapidly progressing infectious disease with a high fatality rate caused by a novel bunyavirus (SFTSV). The role of lipids in viral infections is well-documented; however, the specific alterations in lipid metabolism during SFTSV infection remain elusive. This study aims to elucidate the lipid metabolic dysregulations in the early stages of SFTS patients.MethodsThis study prospectively collected peripheral blood sera from 11 critical SFTS patients, 37 mild SFTS patients, and 23 healthy controls during the early stages of infection for lipidomics analysis. A systematic bioinformatics analysis was conducted from three aspects integrating lipid differential expressions, lipid differential correlations, and lipid-clinical indices correlations to reveal the serum lipid metabolic dysregulation in SFTSV-infected individuals.ResultsOur findings reveal significant lipid metabolic dysregulation in SFTS patients. Specifically, compared to healthy controls, SFTS patients exhibited three distinct modes of lipid differential expression: increased levels of lipids including phosphatidylserine (PS), hexosylceramide (HexCer), and triglycerides (TG); decreased levels of lipids including lysophosphatidylcholine (LPC), acylcarnitine (AcCa), and cholesterol esters (ChE); and lipids showing “dual changes” including phosphatidylcholine (PC) and phosphatidylethanolamine (PE). Finally, based on lipid metabolic pathways and literature analysis, we systematically elucidated the potential mechanisms underlying lipid metabolic dysregulation in the early stage of SFTSV infection.ConclusionsOur study presents the first global serum lipidome profile and reveals the lipid metabolic dysregulation patterns in the early stage of SFTSV infection. These findings provide a new basis for the diagnosis, treatment, and further investigation of the disease.

A Study on Hollow Viscus Perforation in a Tertiary Care Hospital in South India.

Introduction Hollow viscus perforation refers to the perforation of the gastrointestinal tract, including the stomach, intestines, or other hollow organs, leading to leakage of the contents into the peritoneal cavity. This paper aims to explore the disease burden of hollow viscus perforation in Sree Balaji Medical College & Hospital in Chennai, India, and its relation to patients' age and sex and analyze the etiology of hollow viscus perforation. Materials and methods This single-center retrospective study was conducted between May 2022 and August 2023, with a sample size of 100 patients. Data were extracted from the hospital's medical records based on the study's parameters. Results Our study shows that among the study group, hollow viscus perforation was more common in males (n = 78; 78%) than females. The highest incidence was observed in the 41-50 age group (n = 35; 35%), with the mean age being 43 years. The most common cause of perforation was a duodenal ulcer. Wound infection was the most frequent postoperative complication, affecting less than one-third of the patients (n = 29; 29%), followed by pneumonia and acute respiratory distress syndrome. Although large intestinal pathology affected only eight patients in the sample, it showed a high case fatality rate, with one-quarter of the patients (n = 2; 25%) succumbing to the condition. Conclusion Hollow viscus perforation is a life-threatening condition that requires prompt recognition and treatment. The etiology is diverse, ranging from peptic ulcer disease and malignancy to trauma and inflammatory conditions. Early diagnosis and aggressive management are essential for improving the outcome for patients with this condition.

MERS-CoV-nsp5 expression in human epithelial BEAS 2b cells attenuates type I interferon production by inhibiting IRF3 nuclear translocation

Middle East Respiratory Syndrome Coronavirus (MERS-CoV) is an enveloped, positive-sense RNA virus that emerged in 2012, causing sporadic cases and localized outbreaks of severe respiratory illness with high fatality rates. A characteristic feature of the immune response to MERS-CoV infection is low type I IFN induction, despite its importance in viral clearance. The non-structural proteins (nsps) of other coronaviruses have been shown to block IFN production. However, the role of nsp5 from MERS-CoV in IFN induction of human respiratory cells is unclear. In this study, we elucidated the role of MERS-CoV-nsp5, the viral main protease, in modulating the host’s antiviral responses in human bronchial epithelial BEAS 2b cells. We found that overexpression of MERS-CoV-nsp5 had a dose-dependent inhibitory effect on IFN-β promoter activation and cytokine production induced by HMW-poly(I:C). It also suppressed IFN-β promoter activation triggered by overexpression of key components in the RIG-I-like receptor (RLR) pathway, including RIG-I, MAVS, IKK-ε and IRF3. Moreover, the overexpression of MERS-CoV-nsp5 did not impair expression or phosphorylation of IRF3, but suppressed the nuclear translocation of IRF3. Further investigation revealed that MERS-CoV-nsp5 specifically interacted with IRF3. Using docking and molecular dynamic (MD) simulations, we also found that amino acids on MERS-CoV-nsp5, IRF3, and KPNA4 may participate in protein-protein interactions. Additionally, we uncovered protein conformations that mask the nuclear localization signal (NLS) regions of IRF3 and KPNA4 when interacting with MERS-CoV-nsp5, suggesting a mechanism by which this viral protein blocks IRF3 nuclear translocation. Of note, the IFN-β expression was restored after administration of protease inhibitors targeting nsp5, indicating this suppression of IFN-β production was dependent on the enzyme activity of nsp5. Collectively, our findings elucidate a mechanism by which MERS-CoV-nsp5 disrupts the host’s innate antiviral immunity and thus provides insights into viral pathogenesis.

Orthohantavirus diversity in Central-East Argentina: Insights from complete genomic sequencing on phylogenetics, Geographic patterns and transmission scenarios.

Hantavirus Pulmonary Syndrome (HPS), characterized by its high fatality rate, poses a significant public health concern in Argentina due to the increasing evidence of person-to-person transmission of Andes virus. Several orthohantaviruses were described in the country, but their phylogenetic relationships were inferred from partial genomic sequences. The objectives of this work were to assess the viral diversity of the most prevalent orthohantaviruses associated with HPS cases in the Central-East (CE) region of Argentina, elucidate the geographic patterns of distribution of each variant and reconstruct comprehensive phylogenetic relationships utilizing complete genomic sequencing. To accomplish this, a detailed analysis was conducted of the geographic distribution of reported cases within the most impacted province of the region. A representative sample of cases was then selected to generate a geographic map illustrating the distribution of viral variants. Complete viral genomes were obtained from HPS cases reported in the region, including some from epidemiologically linked cases. The phylogenetic analysis based on complete genomes defined two separate clades in Argentina: Andes virus in the Southwestern region and Andes-like viruses in other parts of the country. In the CE region, Buenos Aires virus and Lechiguanas virus clearly segregate in two subclades. Complete genomes were useful to distinguish person-to-person transmission from environmental co-exposure to rodent population. This study enhances the understanding of the genetic diversity, geographical spread, and transmission dynamics of orthohantaviruses in Central Argentina and prompt to consider the inclusion of Buenos Aires virus and Lechiguanas virus in the species Orthohantavirus andesense, as named viruses.

Sensitivity analysis of human error in the steel industry: exploring the effects of psychosocial and mental health risk factors and burnout using Bayesian networks.

Human error and the high rates of fatalities and other occupational accidents in the steel industry are of significant global relevance. The aim of this study was to investigate the effect of psychosocial, mental health, and burnout risk factors on human error probabilities in an industrial environment using Bayesian networks. This cross-sectional study was conducted in 2023. The participants were 252 employees of a steel company. Error probabilities related to the tasks of participants were estimated using the Human Error Assessment and Reduction Technique (HEART). Other data was collected using a survey that consisted of demographic information, the Maslach Burnout Inventory, Depression Anxiety Stress Scales, and a short version of the Copenhagen Psychosocial Questionnaire. A theoretical model was drawn in GeNIe academic software (version 2.3). The results showed that all the studied variables were able to significantly affect the distribution of human error probabilities. Considering a distribution of 100% for the high state of these variables, the results showed that the greatest increases in error probability were related to two burnout dimensions: emotional exhaustion (29%) and depersonalization (28%). All the variables, with a probability of 100%, increased the probability of high human error probabilities by 46%. The most important variables in terms of their effect on human error probabilities were burnout dimensions, and these variables also had a mediation effect on the psychosocial and mental health variables. Therefore, preventive measures to control human error should first focus on managing the risks of burnout in workers. This, in turn, can also reduce the effect of psychosocial risk factors and mental health problems on human error in the workplace.

Structure of the Nipah virus polymerase phosphoprotein complex

The Nipah virus (NiV), a member of the Paramyxoviridae family, is notorious for its high fatality rate in humans. The RNA polymerase machinery of NiV, comprising the large protein L and the phosphoprotein P, is essential for viral replication. This study presents the 2.9-Å cryo-electron microscopy structure of the NiV L-P complex, shedding light on its assembly and functionality. The structure not only demonstrates the molecular details of the conserved N-terminal domain, RNA-dependent RNA polymerase (RdRp), and GDP polyribonucleotidyltransferase of the L protein, but also the intact central oligomerization domain and the C-terminal X domain of the P protein. The P protein interacts extensively with the L protein, forming an antiparallel β-sheet among the P protomers and with the fingers subdomain of RdRp. The flexible linker domain of one P promoter extends its contact with the fingers subdomain to reach near the nascent RNA exit, highlighting the distinct characteristic of the NiV L-P interface. This distinctive tetrameric organization of the P protein and its interaction with the L protein provide crucial molecular insights into the replication and transcription mechanisms of NiV polymerase, ultimately contributing to the development of effective treatments and preventive measures against this Paramyxoviridae family deadly pathogen.

A dual-targeted small-molecule photosensitizer with enhanced dual antitumor and anti-vascular effect for metastatic advanced prostate cancer photodynamic therapy

Advanced prostate cancer is regarded as a fatal disease, characterized by limited treatment options, poor prognosis and considerable tumor metastasis closely related to angiogenesis. Photodynamic therapy emerges as a promising and safe therapeutic modality for advanced prostate cancer with high metastasis and high fatality rate due to its focal damage to tumor cells, as well as its anti-angiogenesis and antitumor immunity capabilities. Herein, a tumor-targeting vascular disrupting agent ASA-404 was introduced to conjugate with a photosensitizer ZnPc for targeted prostate cancer treatment and enhanced vascular-disrupting efficiency. Notably, this novel organic small-molecule photosensitizer Pc-ASA possess a well-defined chemical structure and purity, as well as good photophysical and photochemical properties, which are of benefit for clinical approval and application. Pc-ASA prefers to accumulate in both prostate cancer cells and vascular endothelial cells. Moreover, the conjugation of ASA-404 boosts the photodynamic anticancer effect of Pc-ASA towards both prostate cancer cells and vascular endothelial cells. Ultimately, PC-ASA can successfully inhibit the migration and metastasis of prostate cancer cells, offering significant advantages in advanced prostate cancer management. Our study might open a window in the development of the tumor and vascular dual-targeted small-molecule photosensitizers, with the potential to achieve safe and efficient treatment of metastatic advanced prostate cancer through dual mode of antitumor and anti-vascular action.

A critical review on phytochemicals as antiviral medications for SARS-CoV-2 virus infection.

A pandemic of acute respiratory infection, which was specified as coronavirus disease 2019, was instigated by a different strain of the virulent coronavirus SARS-CoV-2 that first appeared in late 2019. Since viral infections spread fast and there is presently no effective treatment, the use of plants with a long history of use in treating these infections has been explored regularly. The pandemic of coronavirus disease 2019 (COVID-19) has brought to light the dearth of medications with approval to treat acute viral illnesses. Because of this, the illness had a high fatality rate. The mortality rate was initially quite high and varied according to the patient's geographic location. For instance, among Chinese patients, the rate was 3·6%, whereas 1·5% of COVID-19-related deaths were documented outside of China. As of 2020, India has a 1.4% case fatality rate (CFR) of COVID-19 mortality, compared to 2.8% in Brazil and 1.8% in the USA. Many studies are being conducted to create pharmaceutical compounds specifically targeting important SARS-CoV-2 proteins. Several drug discovery initiatives are being undertaken to find powerful inhibitors by combining biochemical assay and computer-aided drug design techniques. Although plant-derived compounds have not had much success in the dominion of antivirals, plants are, however, believed to be a limitless supply of medications for a variety of diseases and clinical conditions. The scientific foundation required for developing novel natural source medications is provided by the chemical characterization and analysis of plant components. Most viral infections treated by ethnobotanical applications and historical literature on ayurveda, and traditional medicine are generally attributed to phytochemicals, which are compounds derived from medicinal plants. In this review, we have described the application of vascular plant-derived chemicals, such as tannins, polyphenols, alkaloids, and flavonoids, as antivirals, especially for managing COVID-19. This article discusses novel bioactive compounds and their molecular structures that target the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) as prospective candidates for anti-coronavirus disease drugs. Moreover, to confirm the effectiveness of the phytochemicals that have demonstrated antiviral activity, clinical trials would need to be conducted in addition to the preclinical research that has already been done. To ensure spectacular findings, more applications of the compound would need to be studied to fully understand the effects of those phytochemicals whose clinical usefulness has already been established.

Acute bacterial meningitis without cerebrospinal fluid pleocytosis in children: results from a nationwide prospective surveillance system between 2001 and 2022

ObjectivesWe aimed to describe cases of acute bacterial meningitis (ABM) without cerebrospinal fluid (CSF) pleocytosis and the clinical and biological characteristics of affected children. MethodsWe analyzed results of a nation-wide population-based prospective surveillance study of acute ABM in children aged 3 months to 15 years in France. Absence of CSF pleocytosis was defined as CSF leukocyte count ≤5/mm3. ResultsWe included 4754 cases of acute ABM from 2001 to 2022: 173 patients (3.6%) did not have CSF pleocytosis. ABM cases without CSF pleocytosis were mainly related to meningococcus (70% vs 44% with CSF pleocytosis, P <0.001). When performed in CSF with normal leukocyte count, Gram staining results were positive for 33%, culture for 80%, polymerase chain reaction results for 41%, and antigen detection for 20% of cases. Case fatality rate was higher for cases without than those with CSF pleocytosis (18% vs 6%, P <0.001). On multivariate analysis, absence of CSF pleocytosis was associated only with seizures before hospital arrival (adjusted odds ratio 2.3, 95% confidence interval 1.2-4.6, P <0.01). ConclusionsABM without CSF pleocytosis is infrequent but not exceptional, particularly in children with seizures before hospital arrival. Extended vaccination against meningococcus could prevent this clinical form with a high case fatality rate.

A case of visual impairment due to HHV-6 encephalitis after allogeneic hematopoietic stem cell transplantation in childhood acute myeloid leukemia-M2 subtype.

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a crucial treatment option for children with M2 subtype acute myeloid leukemia (AML). Human herpesvirus 6 (HHV-6) encephalitis following transplantation is a rare postoperative complication, with a poor prognosis and a high fatality rate in allo-HSCT recipients. In this report, a juvenile patient with AMLwas successfully treated after developing visual impairment as a result of HHV-6B encephalitis during allo-HSCT therapy. HHV-6 encephalitis-associated visual impairment after transplantation is rare, and clinical diagnosis and treatment are challenging, requiring more attention in the future.

Mortality predictors in emergency department adult patients with sepsis: A systematic review

Background: Sepsis was regarded as a major global public health concern; it continues to be associated with a high death rate despite advancements in contemporary treatment. This research aims to evaluate the predictive effect of clinical scoring systems and biomarkers for sepsis patients in ED. Method: In accordance with PRISMA principles, we carried out this systematic review. We used the internet databases MEDLINE, Google Scholar, and EMBASE to conduct a thorough search of the literature. Articles written in English and released between 2015 and 2023 were involved in the search. Using predictors and ED, we first conducted a comprehensive search that included sepsis and infectious illnesses. Result: A total of 3029 patients from 7 publications—3 cohort, 2 observational, and 2 case control studies—were included in this study. The study by Song et al. in 2019 had the highest fatality rate (46.6%), while the study by Duplessis et al. in 2018 had the lowest mortality rate (6.4%). SIRS criteria, qSOFA score, International Sepsis Conference 2001, and American College of Chest Physicians Guidelines are the diagnostic criteria that are employed. AUC varied from 33.7 (MMP9) to 0.89 (IL-6). Conclusion: AUC was increased significantly when CSSs were combined with IgE, presepsin, IL-6 and PCT.

Ebola Virus Matrix Protein VP40 Single Mutations G198R and G201R Significantly Enhance Plasma Membrane Localization.

Viral proteins frequently undergo single or multiple amino acid mutations during replication, which can significantly alter their functionality. The Ebola virus matrix protein VP40 is multifunctional but primarily responsible for creating the viral envelope by binding to the inner leaflet of the host cell plasma membrane (PM). Changes to the VP40 surface cationic charge via mutations can influence PM interactions, resulting in altered viral assembly and budding. A recent mutagenesis study evaluated the effects of several mutations and found that mutations G198R and G201R enhanced VP40 assembly at the PM and virus-like particle budding. These two mutations lie in the loop region of the C-terminal domain (CTD), which directly interacts with the PM. To understand the role of these mutations in PM localization at the molecular level, we performed both all-atom and coarse-grained molecular dynamics simulations using a dimer-dimer configuration of VP40, which contains the CTD-CTD interface. Our studies indicate that the location of mutations on the outer surface of the CTD regions can lead to changes in membrane binding orientation and degree of membrane penetration. Direct PI(4,5)P2 interactions with the mutated residues seem to further stabilize and pull VP40 into the PM, thereby enhancing interactions with numerous amino acids that were otherwise infrequently or completely inaccessible. These multiscale computational studies provide new insights at the atomic and molecular level as to how VP40-PM interactions are altered through single amino acid mutations. Given the high case fatality rates associated with Ebola virus disease in humans, it is essential to explore the mechanisms of viral assembly in the presence of mutations to mitigate the severity of the disease and understand the potential of future outbreaks.

Optimization study of tail-lateral occupant injury and restraint system for an off-road vehicle ramp rollover

The process of rollover accidents involving specialized vehicles is characterized by intense motion and long duration. Although these accidents are infrequent, they often lead to a high fatality rate. In this study, we utilized LS-Dyna software to simulate the rollover of a vehicle on a side ramp. This simulation aimed to verify the reliability of our model establishment by comparing the vehicle’s motion attitude and center-of-mass acceleration with experimental results. Additionally, we sought to investigate the lateral occupant injuries that occur in the tail section of a certain type of specialized vehicle during a rollover. Initially, we obtained the vehicle’s motion trajectory and the dummy’s motion state through simulation. Subsequently, we extracted the injury response of each part of the dummy. We then simplified the entire vehicle model and made improvements to the occupant restraint system, ultimately designing an enhanced system. Finally, we approximated and replaced the entire vehicle model by establishing an approximation model. We combined this with an optimization algorithm to optimize the occupant restraint system. The simulation results demonstrate that the improved occupant restraint system significantly reduces the axial force on the neck of the occupant and the comprehensive evaluation index of injury. Furthermore, the simulation results for each component fall below the injury limit value specified in the FMVSS208 crash occupant protection standard. Therefore, the improved occupant restraint system proposed in this study effectively mitigates lateral occupant injury during rollover accidents.

Plasma Ceramide C24:0/C16:0 Ratio is Associated with Improved Survival in Patients with Pancreatic Ductal Adenocarcinoma.

Pancreatic ductal adenocarcinoma (PDAC) has a high fatality rate, with surgery as the only curative treatment. Identification of new biomarkers related to survival may help guide discovery of new pathophysiologic pathways and potential therapeutic targets. As long-chain ceramides have been linked to tumor proliferation, we sought to determine if ceramide levels were prognostic in PDAC. Patients from two phase I studies of PDAC were followed for all-cause mortality. Ceramide levels (C24:0, C22:0, and C16:0) were quantified before treatment and at study intervals. Multivariable Cox regression models assessed the association of ceramide levels and mortality after adjusting for other univariable predictors, including time-dependent tumor resection. The ability of repeated ceramide measures to discriminate patients at risk for mortality was also assessed using multivariable modeling and the c-statistic. Higher plasma C16:0 concentration was associated with higher all-cause mortality in univariable and multivariable analysis (adjusted hazard ratio [aHR] 1.41, 95% confidence interval [CI] 1.09-1.82; p<0.01). In contrast, a higher plasma C24:0/C16:0 ratio was associated with lower all-cause mortality in multivariable analysis (aHR 0.69, 95% CI 0.49-0.97; p=0.032). Discrimination of mortality was significantly improved with the addition of either plasma C16:0 or C24:0/C16:0 levels, with optimal discrimination occurring using repeated measures of the C24:0/C16:0 ratio (c-statistic 0.73 vs. c-statistic 0.66; p<0.001). Higher plasma C16:0 and lower C24:0/C16:0 ratios are independently associated with mortality in PDAC and show an ability to improve discrimination of mortality in this deadly disease. Further studies are needed to confirm this association and evaluate this novel pathway for potential therapeutic targets.