bluuebunny/crossref_metadata_2025_split huggingface dataset:
OBESE MICE WITH PNEUMONIA HAVE HYPERLEPTINEMIA AND INCREASED PULMONARY SIGNAL TRANSDUCER AND ACTIVATOR OF TRANSCRIPTION 3 ACTIVATION
Authors: Bodilly Lauren , Williamson Lauren , Howell Kendra , Alder Matthew N. , Kaplan Jennifer M. 
Published: January 2023

ABSTRACT
Obesity is an ongoing epidemic that influences pathobiology in numerous disease states. Obesity is associated with increased plasma leptin levels, a hormone that activates the signal transducer and activator of transcription 3 (STAT3) pathway. Pneumonia is a significant cause of morbidity and mortality. During pneumonia, inflammatory pathways including STAT3 are activated. Outcomes in obese patients with pneumonia are mixed, with some studies showing obesity increases harm and others showing benefit. It is unclear whether obesity alters STAT3 activation during bacterial pneumonia and how this might impact outcomes from pneumonia. We used a murine model of obesity and pneumonia challenge with Pseudomonas aeruginosa in obese and nonobese mice to investigate the effect of obesity on STAT3 activation. We found obese mice with bacterial pneumonia had increased mortality compared with nonobese mice. Inflammatory markers, IL-6 and TNF-α, and lung neutrophil infiltration were elevated at 6 h after pneumonia in both nonobese and obese mice. Obese mice had greater lung injury compared with nonobese mice at 6 h after pneumonia. Leptin and insulin levels were higher in obese mice compared with nonobese mice, and obese mice with pneumonia had higher pulmonary STAT3 activation compared with nonobese mice.
ROLE OF PEPTIDYLARGININE DEIMINASE AND NEUTROPHIL EXTRACELLULAR TRAPS IN INJURIES: FUTURE NOVEL DIAGNOSTICS AND THERAPEUTIC TARGETS
Authors: Ho Jessie W. , Quan Chao , Gauger Megan A. , Alam Hasan B. , Li Yongqing 
Published: January 2023

ABSTRACT
Injuries lead to an early systemic inflammatory state with innate immune system activation. Neutrophil extracellular traps (NETs) are a complex of chromatin and proteins released from the activated neutrophils. Although initially described as a response to bacterial infections, NETs have also been identified in the sterile postinjury inflammatory state. Peptidylarginine deiminases (PADs) are a group of isoenzymes that catalyze the conversion of arginine to citrulline, termed citrullination or deimination. PAD2 and PAD4 have been demonstrated to play a role in NET formation through citrullinated histone 3. PAD2 and PAD4 have a variety of substrates with variable organ distribution. Preclinical and clinical studies have evaluated the role of PADs and NETs in major trauma, hemorrhage, burns, and traumatic brain injury. Neutrophil extracellular trap formation and PAD activation have been shown to contribute to the postinjury inflammatory state leading to a detrimental effect on organ systems. This review describes our current understanding of the role of PAD and NET formation following injury and burn. This is a new field of study, and the emerging data appear promising for the future development of targeted biomarkers and therapies in trauma.
ACETAMINOPHEN ATTENUATES PULMONARY VASCULAR RESISTANCE AND PULMONARY ARTERIAL PRESSURE AND INHIBITS CARDIOVASCULAR COLLAPSE IN A PORCINE MODEL OF ENDOTOXEMIA
Authors: Bergström Anna , Lipcsey Miklós , Larsson Anders , Yang Bei , Engblom David , Chew Michelle S. , Elander Louise 
Published: January 2023

ABSTRACT
Acetaminophen (paracetamol) is often used in critically ill patients with fever and pain; however, little is known about the effects of acetaminophen on cardiovascular function during systemic inflammation. Here, we investigated the effect of acetaminophen on changes in the systemic and pulmonary circulation induced by endotoxin (0.5 μg/kg per hour) in anesthetized pigs. Endotoxin infusion led to a rapid increase in pulmonary artery pressure and pulmonary vascular resistance index. Acetaminophen delayed and attenuated this increase. Furthermore, acetaminophen reduced tachycardia and decreased stroke volume, accompanied by systemic inflammation, without affecting inflammatory parameters such as white blood cell count and TNF-α in blood. As a proof of concept, we injected a high dose of endotoxin (100 μg), which induced rapid cardiovascular collapse in pigs. Pigs treated with acetaminophen survived with no obvious hemodynamic instability during the 50-min observation period. In conclusion, acetaminophen attenuates the effects of endotoxin on pulmonary circulation in anesthetized pigs. This may play a role in severe systemic inflammation.
A PREVENTIVE TOOL FOR PREDICTING BLOODSTREAM INFECTIONS IN CHILDREN WITH BURNS
Authors: Tsurumi Amy , Flaherty Patrick J. , Que Yok-Ai , Ryan Colleen M. , Banerjee Ankita , Chakraborty Arijit , Almpani Marianna , Shankar Malavika , Goverman Jeremy , Schulz John T. , Sheridan Robert L. , Friedstat Jonathan , Hickey Sean A. , Tompkins Ronald G. , Rahme Laurence G. 
Published: January 2023

ABSTRACT

Introduction: Despite significant advances in pediatric burn care, bloodstream infections (BSIs) remain a compelling challenge during recovery. A personalized medicine approach for accurate prediction of BSIs before they occur would contribute to prevention efforts and improve patient outcomes. Methods: We analyzed the blood transcriptome of severely burned (total burn surface area [TBSA] ≥20%) patients in the multicenter Inflammation and Host Response to Injury (“Glue Grant”) cohort. Our study included 82 pediatric (aged <16 years) patients, with blood samples at least 3 days before the observed BSI episode. We applied the least absolute shrinkage and selection operator (LASSO) machine-learning algorithm to select a panel of biomarkers predictive of BSI outcome. Results: We developed a panel of 10 probe sets corresponding to six annotated genes (ARG2 [arginase 2], CPT1A [carnitine palmitoyltransferase 1A], FYB [FYN binding protein], ITCH [itchy E3 ubiquitin protein ligase], MACF1 [microtubule actin crosslinking factor 1], and SSH2 [slingshot protein phosphatase 2]), two uncharacterized (LOC101928635, LOC101929599), and two unannotated regions. Our multibiomarker panel model yielded highly accurate prediction (area under the receiver operating characteristic curve, 0.938; 95% confidence interval [CI], 0.881–0.981) compared with models with TBSA (0.708; 95% CI, 0.588–0.824) or TBSA and inhalation injury status (0.792; 95% CI, 0.676–0.892). A model combining the multibiomarker panel with TBSA and inhalation injury status further improved prediction (0.978; 95% CI, 0.941–1.000). Conclusions: The multibiomarker panel model yielded a highly accurate prediction of BSIs before their onset. Knowing patients' risk profile early will guide clinicians to take rapid preventive measures for limiting infections, promote antibiotic stewardship that may aid in alleviating the current antibiotic resistance crisis, shorten hospital length of stay and burden on health care resources, reduce health care costs, and significantly improve patients' outcomes. In addition, the biomarkers' identity and molecular functions may contribute to developing novel preventive interventions.
CIRC_0114428 INFLUENCES THE PROGRESSION OF SEPTIC ACUTE KIDNEY INJURY VIA REGULATING MIR-370-3P/TIMP2 AXIS
Authors: Zhang Bihong , You Ting , Liu Yu , Li Pei 
Published: January 2023

ABSTRACT

Background: Septic acute kidney injury (AKI) is a serious complication of sepsis, which greatly threatened the life safety of critically ill patients. Recently, circular RNA is considered to be implicated in sepsis-induced renal cell damage. However, the role of circ_0114428 in sepsis AKI is still unclear. Methods: LPS was used to establish a sepsis-related AKI cell model. The expression of circ_0114428, microRNA (miR)-370-3p, tissue inhibitor of metalloproteinase-2 (TIMP2), Proliferating cell nuclear antigen, Bax, and Bcl-2 were detected by quantitative real-time polymerase chain reaction and Western blot. Cell counting kit 8 and enzyme-linked immunosorbent assay were used to measure cell proliferation ability and the secretion of inflammatory factors (tumor necrosis factor α, interleukin 1β, and interleukin 6), respectively. Cell cycle and apoptosis rate were analyzed by flow cytometry. Caspase-3 assay kits were used to detect Caspase-3 activity. Interaction between miR-370-3p and circ_0114428 or TIMP2 was analyzed by bioinformatics analysis, a dual-luciferase reporter assay, and RNA immunoprecipitation assay. Results: Circ_0114428 was upregulated in septic AKI serum samples and LPS-induced HK2 cells. The knockdown of circ_0114428 notably promoted cell proliferation and cycle, whereas it restrained cell inflammation and apoptosis in LPS-stimulated HK2 cells. Subsequent mechanism analysis revealed that miR-370-3p was a target of circ_0114428, and miR-370-3p inhibition could rescue the effects of circ_0114428 downregulation on LPS-induced cell injury. Meanwhile, TIMP2 was a target gene of miR-370-3p. miR-370-3p mimic could attenuate LPS-induced cell injury, whereas these impacts were overturned by overexpressed TIMP2. Furthermore, circ_0114428 enhanced TIMP2 protein expression by sponging miR-370-3p. Conclusion: Our data demonstrated that circ_0114428 contributed to septic AKI progression by regulating miR-370-3p–mediated TIMP2 expression, which provided a promising target for septic AKI treatment.
Infiltrating anti-inflammatory monocytes modulate microglial activation through toll-like receptor 4/interferon–dependent pathways following traumatic brain injury
Authors: El Baassiri Mahmoud G. , Chun Young H. , Rahal Simon S. , Fulton William B. , Sodhi Chhinder P. , Hackam David J. , Nasr Isam W. 
Published: January 2023

BACKGROUND
Traumatic brain injury (TBI) is the leading cause of morbidity and mortality in the pediatric population. Microglia and infiltrating monocyte-derived macrophages are crucial immune cells that modulate the neuroinflammatory response following TBI. Using C34, a novel pharmacologic toll-like receptor 4 inhibitor, we investigated the intricate interactions between these cells in a murine TBI model.

METHODS
A murine controlled cortical impact model was used, and the results were analyzed on postinjury days 1, 7, 28, and 35. The experimental groups are as follows: (1) sham C57BL/6 wild-type (WT), (2) TBI WT, (3) sham WT + C34, and (4) TBI WT + C34. Quantitative real-time polymerase chain reaction was used to quantify gene expression associated with microglial activation, apoptotic pathways, and type 1 interferon pathway. Flow cytometry was used to isolate microglia and infiltrating monocytes. Brain lesion volumes were assessed using magnetic resonance imaging. Last, neurocognitive outcomes were evaluated using the Morris Water Maze test. Student's t test and one-way analysis of variance were used for statistical analysis with significance achieved when p < 0.05.

RESULTS
Toll-like receptor 4 inhibition leads to improved neurological sequela post-TBI, possibly because of an increase in infiltrating anti-inflammatory monocytes and a decrease in IFN regulatory factor 7 during acute inflammation, followed by a reduction in apoptosis and M2 microglial expression during chronic inflammation.

CONCLUSION
Toll-like receptor 4 inhibition with C34 skews infiltrating monocytes toward an anti-inflammatory phenotype, leading to enhanced neurocognitive outcomes. Moreover, although M2 microglia have been consistently shown as inducers of neuroprotection, our results clearly demonstrate their detrimental role during the chronic phases of healing post-TBI.
Attitudes towards booster, testing and isolation, and their impact on COVID-19 response in winter 2022/2023 in France, Belgium, and Italy
Authors: de Meijere Giulia , Valdano Eugenio , Castellano Claudio , Debin Marion , Kengne-Kuetche Charly , Turbelin Clément , Noël Harold , Weitz Joshua , Paolotti Daniela , Hermans Lisa , Hens Niel , Colizza Vittoria 
Published: January 2023

AbstractEuropean countries are focusing on testing, isolation, and boosting strategies to counter the 2022/2023 winter surge due to Omicron subvariants. However, widespread pandemic fatigue and limited compliance potentially undermine mitigation efforts. To establish a baseline for interventions, we ran a multicountry survey to assess respondents’ willingness to receive booster vaccination and comply with testing and isolation mandates. The vast majority of survey participants (N=4,594) was willing to adhere to testing (>91%) and rapid isolation (>88%) across the three countries. Pronounced differences emerged in the declared senior adherence to booster vaccination (73% in France, 94% in Belgium, 86% in Italy). Next, we inferred the vaccine-induced population immunity profile at the winter start from prior vaccination data, immunity waning, and declared booster uptake. Integrating survey and estimated immunity data in a branching process epidemic spreading model, we evaluated the effectiveness and costs of current protocols in France, Belgium, and Italy to manage the winter wave. Model results estimate that testing and isolation protocols would confer significant benefit in reducing transmission (17-24%) with declared adherence. Achieving a mitigating level similar to the French protocol, the Belgian protocol would require 30% fewer tests and avoid the long isolation periods of the Italian protocol (average of 6 days vs. 11). A cost barrier to test would significantly decrease adherence in France and Belgium, undermining protocols’ effectiveness. Simpler mandates for isolation may increase awareness and actual compliance, reducing testing costs, without compromising mitigation. High booster vaccination uptake remains key for the control of the winter wave.
Methods for a population-based Comprehensive Eye care Workload Assessment (CEWA) Study in Southern India
Authors: Vardhan Ashok , Rajendran Vinoth Kumar , Joseph Sanil , Pooludaiyar Lakshmanan , Datta Dipankar , Fletcher Astrid E , Ravilla Thulasiraj 
Published: January 2023

AbstractEye care programs, in developing countries, are often planned using the cataract surgical rate (CSR) targets - retrospectively estimated from Rapid Assessment (RAAB) surveys. A limitation of this approach is that it ignores the annual overall eye care requirements for a given population. Moreover, targets set are arbitrary, often influenced by capacity rather than need. To address this lacunae, we implemented a novel study design to estimate the annual need for comprehensive eye care in a 1.2 million population.We conducted a population-based longitudinal study in Theni district, Tamil Nadu, India. All permanent residents of all ages were included. We conducted the study in three phases, (i) household-level enumeration and enrolment, (ii) basic eye examination (BEE) at household one-year post-enrolment, and (iii) assessment of eye care utilization and full eye examination (FEE) at central locations. All people aged 40 and above were invited to the FEE. Those aged less than 40 years were invited to the when FEE if indicated.We conducted three pilot studies to test the study and clinical examination protocols. In the main study we enrolled 24,327 subjects (58% aged below 40 years and 42% aged 40 years and above). Of those less than 40 years, 72% completed the BEE, of whom 20% were referred for FEE and 70% of people aged ≥40 years underwent a comprehensive eye examination at central location.Our study design provides appropriate long-term public health intervention planning, resource allocation, efficient delivery of care, and designing of eye care services for resource-limited settings.
L-shape distribution of the relative substitution rate (c/μ) observed for SARS-COV-2’s genome, inconsistent with the selectionist theory, the neutral theory and the nearly neutral theory but a near-neutral balanced selection theory: implication on “neutralist-selectionist” debate
Authors: Wu Chun , Paradis Nicholas J. , Lakernick Phillip M. , Hryb Mariya 
Published: January 2023

AbstractThe genomic substitution rate (GSR) of SARS-CoV-2 exhibits a molecular clock feature and does not change under fluctuating environmental factors such as the infected human population (100-107), vaccination etc.. The molecular clock feature is believed to be inconsistent with the selectionist theory (ST). The GSR shows lack of dependence on the effective population size, suggesting Ohta’s nearly neutral theory (ONNT) is not applicable to this virus. Big variation of the substitution rate within its genome is also inconsistent with Kimura’s neutral theory (KNT). Thus, all three existing evolution theories fail to explain the evolutionary nature of this virus. In this paper, we proposed a Segment Substitution Rate Model (SSRM) under non-neutral selections and pointed out that a balanced mechanism between negative and positive selection of some segments that could also lead to the molecular clock feature. We named this hybrid mechanism as near-neutral balanced selection theory (NNBST) and examined if it was followed by SARS-CoV-2 using the three independent sets of SARS-CoV-2 genomes selected by the Nextstrain team. Intriguingly, the relative substitution rate of this virus exhibited an L-shaped probability distribution consisting with NNBST rather than Poisson distribution predicted by KNT or an asymmetric distribution predicted by ONNT in which nearly neutral sites are believed to be slightly deleterious only, or the distribution that is lack of nearly neutral sites predicted by ST. The time-dependence of the substitution rates for some segments and their correlation with the vaccination were observed, supporting NNBST. Our relative substitution rate method provides a tool to resolve the long standing “neutralist-selectionist” controversy. Implications of NNBST in resolving Lewontin’s Paradox is also discussed.
Participant Demographics and Testing Trends: A Community Pandemic Response Program
Authors: García Yury E. , Solis Leslie , Daza–Torres Maria L. , Montesinos-López Cricelio , Pollock Brad H. , Nuño Miriam 
Published: January 2023

ObjectiveThis study aimed to identify demographic characteristics of test participants and changes in testing participation over time in a community pandemic-response program launched in a college town in California, USA.MethodsWe described overall testing participation, identified demographic characteristics of frequent testers, and evaluated changes in testing participation over four different periods of the COVID-19 pandemic.ResultsA total of 770,165 tests were performed between November 18, 2020, and June 30, 2022, among 89,924 residents of Yolo County (41.1% of population), with significant participation from racially/ethnically diverse participants and across age groups. Most positive cases (49.9%) were captured during Omicron, which also corresponds to the period with the highest daily participation (895 per 100K population). The proportion of participants which we considered “frequent testers” (28.9% vs. 39.7%,p <0.0001) and individuals that tested once (39.5% vs. 47.9%,p <0.0001) increased significantly from Delta to Omicron. Women (58.8%), participants of age 19-34 years (38.8%), and White (53.2%) tested more frequently throughout the program. The proportion of tests conducted among Latinos remained steady around 18% over time, with the exception of the post-Omicron period (13%).ConclusionThe unique features of a pandemic response program that supported communitywide access to free asymptomatic testing provides a unique opportunity to evaluate adherence to testing recommendations, and testing trends over time. Identification of individual and group-level factors associated with testing behaviors is essential to improve access and protect communities at-large.
The time between vaccination and infection impacts immunity against SARS-CoV-2 variants
Authors: Bates Timothy A. , Leier Hans C. , McBride Savannah K. , Schoen Devin , Lyski Zoe L. , Lee David X. , Messer William B. , Curlin Marcel E. , Tafesse Fikadu G. 
Published: January 2023

AbstractAs the COVID-19 pandemic continues, long-term immunity against SARS-CoV-2 will be globally important. Official weekly cases have not dropped below 2 million since September of 2020, and continued emergence of novel variants have created a moving target for our immune systems and public health alike. The temporal aspects of COVID-19 immunity, particularly from repeated vaccination and infection, are less well understood than short-term vaccine efficacy. In this study, we explore the impact of combined vaccination and infection, also known as hybrid immunity, and the timing thereof on the quality and quantity of antibodies produced by a cohort of 96 health care workers. We find robust neutralizing antibody responses among those with hybrid immunity against all variants, including Omicron BA.2, and we further found significantly improved neutralizing titers with longer vaccine-infection intervals up to 400 days. These results indicate that anti-SARS-CoV-2 antibody responses undergo continual maturation following primary exposure by either vaccination or infection for at least 400 days after last antigen exposure. We show that neutralizing antibody responses improved upon secondary boosting with greater impact seen after extended intervals. Our findings may also extend to booster vaccine doses, a critical consideration in future vaccine campaign strategies.
Genomic characterization and molecular evolution of SARS-CoV-2 in Rio Grande do Sul State, Brazil
Authors: de Menezes Mayer Amanda , Gröhs Ferrareze Patrícia Aline , de Oliveira Luiz Felipe Valter , Gregianini Tatiana Schäffer , Moreira Neves Carla Lucia Andretta , Caldana Gabriel Dickin , Kmetzsch Lívia , Thompson Claudia Elizabeth 
Published: January 2023

AbstractThe SARS-CoV-2 is the virus responsible for the COVID-19 pandemic and is plaguing the world since the end of 2019. Different lineages have been discovered ever since and the Gamma lineage, which started the second wave of infections, was first described in Brazil, one of the most affected countries by pandemic. Describing the viral genome and how the virus behaves is essential to contain its propagation and to the development of medications and vaccines. Therefore, this study analyzed SARS-CoV-2 sequenced genomes from Esteio city in Rio Grande do Sul, Southern Brazil. We also comparatively analyzed genomes of the two first years of the pandemic from Rio Grande do Sul state for understanding their genomic and evolutionary patterns. The phylogenomic analysis showed monophyletic groups for Alpha, Gamma, Delta and Omicron, as well as for other circulating lineages in the state. Molecular evolutionary analysis identified several sites under adaptive selection in membrane and nucleocapsid proteins which could be related to a prevalent stabilizing effect on membrane protein structure, as well as majoritarily destabilizing effects on C-terminal nucleocapsid domain.