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Cancer Discovery Apr 2024In this phase 2 multicenter study, we evaluated the efficacy and safety of lifileucel (LN-145), an autologous tumor-infiltrating lymphocyte cell therapy, in patients...
In this phase 2 multicenter study, we evaluated the efficacy and safety of lifileucel (LN-145), an autologous tumor-infiltrating lymphocyte cell therapy, in patients with metastatic non-small cell lung cancer (mNSCLC) who had received prior immunotherapy and progressed on their most recent therapy. The median number of prior systemic therapies was 2 (range, 1-6). Lifileucel was successfully manufactured using tumor tissue from different anatomic sites, predominantly lung. The objective response rate was 21.4% (6/28). Responses occurred in tumors with profiles typically resistant to immunotherapy, such as PD-L1-negative, low tumor mutational burden, and STK11 mutation. Two responses were ongoing at the time of data cutoff, including one complete metabolic response in a PD-L1-negative tumor. Adverse events were generally as expected and manageable. Two patients died of treatment-emergent adverse events: cardiac failure and multiple organ failure. Lifileucel is a potential treatment option for patients with mNSCLC refractory to prior therapy.
PubMed: 38563600
DOI: 10.1158/2159-8290.CD-23-1334 -
Human & Experimental Toxicology 2024Thioacetamide (TAA), a widely employed hepatotoxic substance, has gained significant traction in the induction of liver failure disease models. Upon administration of... (Review)
Review
Thioacetamide (TAA), a widely employed hepatotoxic substance, has gained significant traction in the induction of liver failure disease models. Upon administration of TAA to experimental animals, the production of potent oxidative derivatives ensues, culminating in the activation of oxidative stress and subsequent infliction of severe damage upon multiple organs via dissemination through the bloodstream. This review summarized the various organ damages and corresponding mechanistic explanations observed in previous studies using TAA in toxicological animal experiments. The principal pathological consequences arising from TAA exposure encompass oxidative stress, inflammation, lipid peroxidation, fibrosis, apoptosis induction, DNA damage, and osteoclast formation. Recent in vivo and in vitro studies on TAA bone toxicity have confirmed that long-term high-dose use of TAA not only induces liver damage in experimental animals but also accompanies bone damage, which was neglected for a long time. By using TAA to model diseases in experimental animals and controlling TAA dosage, duration of use, and animal exposure environment, we can induce various organ injury models. It should be noted that TAA-induced injuries have a time-dependent effect. Finally, in our daily lives, especially for researchers, we should take precautions to minimize TAA exposure and reduce the probability of related organ injuries.
Topics: Animals; Thioacetamide; Liver Diseases; Oxidative Stress; Fibrosis; Oxidation-Reduction; Liver
PubMed: 38531387
DOI: 10.1177/09603271241241807 -
Cureus Sep 2023Severe leptospirosis is defined by multiple organ failure. Cardiac involvement is an uncommon complication in patients with leptospirosis, and the pathophysiology of it...
Severe leptospirosis is defined by multiple organ failure. Cardiac involvement is an uncommon complication in patients with leptospirosis, and the pathophysiology of it is not well understood. Diffuse myocardial calcifications connected with sepsis are infrequent, and their effect on heart function is hard to predict. They can lead to conduction disorders and arrhythmias, thereby causing sudden death. Myocardial calcifications are usually revealed incidentally by radiological investigations such as computed tomography (CT) scan in patients with or after sepsis and are commonly unidentified in practice because most cases progress gradually. This case report involves a 51-year-old male who presented to the emergency department with sepsis. The patient was diagnosed with leptospirosis, causing septic cardiomyopathy and diffuse calcifications of the myocardium of the left ventricle. This case highlights the importance of multimodality imaging and a multidisciplinary approach to diagnoses since early recognition and treatment are essential. Follow-up of such patients is necessary to monitor the systolic function of the left ventricle and cardiac arrhythmia.
PubMed: 37849598
DOI: 10.7759/cureus.45345 -
RSC Advances Apr 2024Burns are a global public health problem, which brings great challenges to public health and the economy. Severe burns often lead to systemic infection, shock, multiple... (Review)
Review
Burns are a global public health problem, which brings great challenges to public health and the economy. Severe burns often lead to systemic infection, shock, multiple organ failure, and even death. With the increasing demand for the therapeutic effect of burn wounds, traditional dressings have been unable to meet people's needs due to their single function and many side effects. In this context, electrospinning shows a great prospect on the way to open up advanced wound dressings that promote wound repairing and prevent infection. With its large specific surface area, high porosity, and similar to natural extracellular matrix (ECM), electrospun nanofibers can load drugs and accelerate wound healing. It provides a promising solution for the treatment and management of burn wounds. This review article introduces the concept of burn and the types of electrospun nanofibers, then summarizes the polymers used in electrospun nanofiber dressings. Finally, the drugs (plant extracts, small molecule drugs and nanoparticles) loaded with electrospun burn dressings are summarized. Some promising aspects for developing commercial electrospun burn dressings are proposed.
PubMed: 38694552
DOI: 10.1039/d4ra01514b -
Journal of Clinical and Translational... Mar 2024The impact of the characteristics of extrahepatic organ failure (EHOF) including the onset time, number, type, and sequence on the prognosis of acute-on-chronic liver...
BACKGROUND AND AIMS
The impact of the characteristics of extrahepatic organ failure (EHOF) including the onset time, number, type, and sequence on the prognosis of acute-on-chronic liver failure (ACLF) patients remains unknown. This study aimed to identify the association between the characteristics of EHOF and the prognosis of ACLF patients.
METHODS
ACLF subjects enrolled at six hospitals in China were included in the analysis. The risk of mortality based on the characteristics of EHOF was evaluated. Survival of study groups was compared by Kaplan-Meier analysis and log-rank tests.
RESULTS
A total of 736 patients with ACLF were included. EHOF was observed in 402 patients (54.6%), of which 295 (73.4%) developed single EHOF (SEHOF) and 107 (26.6%) developed multiple EHOF (MEHOF). The most commonly observed EHOF was coagulation failure (47.0%), followed by renal (13.0%), brain (4.9%), respiratory (4.3%), and circulatory (2.3%) failure. Survival analysis found that MEHOF or SEHOF patients with brain failure had a worse prognosis. However, no significant outcome was found in the analysis of the effect of onset time and sequence of failed organs on prognosis. Patients were further divided into three risk subgroups by the EHOF characteristics. Kaplan-Meier analysis showed that risk stratification resulted in the differentiation of patients with different risks of mortality both in the training and validation cohorts.
CONCLUSIONS
The mortality of ACLF patients was determined by the number and type, but not the onset time and sequence of EHOF. Risk stratification applicable to clinical practice was established.
PubMed: 38426199
DOI: 10.14218/JCTH.2023.00379 -
Cureus Jul 2023Kidney transplantation is most commonly performed for end-stage renal disease (ESRD) and provides the best chance for a cure. The surgery is shown to be beneficial to a...
BACKGROUND
Kidney transplantation is most commonly performed for end-stage renal disease (ESRD) and provides the best chance for a cure. The surgery is shown to be beneficial to a patient's quality of life after transplantation in multiple studies. But graft failure is a serious consequence that might happen. The term graft failure refers to the failure of a transplanted kidney to function properly. There are various reasons why this can happen, such as rejection, infection, or medication complications.
METHODS
A retrospective cohort study of comorbid conditions in patients who underwent renal transplantation at King Abdulaziz Medical City (KAMC) between 2016 and 2022. Data were collected by chart review using the BestCare system. The data collected included patients' demographics, comorbidities, calculated Charlson Comorbidity Index (CCI), surgery-related data, laboratory data, and the outcome of transplantation. The categorical data were presented using percentages and frequencies, while the numerical data were presented as mean and standard deviation. The Chi-square test was used for inferential statistics to find the association between categorical variables.
RESULTS
A total of 669 patients were included in the current study. Of these, 422 (63.1%) were men, and the mean age was 44 years. The incidence of graft failure within one year at KAMC was found to be 1.2% (eight cases). Regarding the CCI and its association with graft failure within one year, 37 (5.5%) patients had a myocardial infarction (MI) and 17 (2.5%) had congestive heart failure; however, no patients with MI or congestive heart failure experienced graft failure, and no significant association was found between MI or congestive heart failure and graft failure (p-value = 1.000 for both). A total of 417 (62.3%) patients had no or diet-controlled diabetes, 122 (18.2%) had uncomplicated diabetes mellitus (DM), and 130 (19.4%) had end-organ damage. DM and graft failure were not significantly associated (p-value = 1.000). A total of 286 (42.8%) patients had ESRD of unknown etiology, 109 (16.3%) patients had ESRD caused by diabetic nephropathy, and 100 (14.9%) had ESRD resulting from hypertension, apart from other causes.
CONCLUSION
Most patients were found to have ESRD of unknown etiology and the most frequently reported known risk factor for ESRD and subsequent transplantation was found to be diabetic nephropathy, followed by hypertension.
PubMed: 37546132
DOI: 10.7759/cureus.41355 -
Infection Dec 2023Few studies have reported on mortality beyond one year after sepsis. We aim to describe trends in short- and long-term mortality among patients admitted with sepsis, and...
BACKGROUND
Few studies have reported on mortality beyond one year after sepsis. We aim to describe trends in short- and long-term mortality among patients admitted with sepsis, and to describe the association between clinical characteristics and mortality for improved monitoring, treatment and prognosis.
METHODS
Patients ≥ 18 years admitted to all Norwegian hospitals (2008-2021) with a first sepsis episode were identified using Norwegian Patient Registry and International Classification of Diseases 10th Revision codes. Sepsis was classified as implicit (known infection site plus organ dysfunction), explicit (unknown infection site), or COVID-19-related sepsis. The outcome was all-cause mortality. We describe age-standardized 30-day, 90-day, 1-, 5- and 10-year mortality for each admission year and estimated the annual percentage change with 95% confidence interval (CI). The association between clinical characteristics and all-cause mortality is reported as hazard ratios (HRs) adjusted for age, sex and calendar year in Cox regression.
RESULTS
The study included 222,832 patients, of whom 127,059 (57.1%) had implicit, 92,928 (41.7%) had explicit, and 2,845 (1.3%) had COVID-19-related sepsis (data from 2020 and 2021). Trends in overall age-standardized 30-day, 90-day, 1- and 5-year mortality decreased by 0.29 (95% CI - 0.39 to - 0.19), 0.43 (95% CI - 0.56 to - 0.29), 0.61 (95% CI - 0.73 to - 0.49) and 0.66 (95% CI - 0.84 to - 0.48) percent per year, respectively. The decrease was observed for all infections sites but was largest among patients with respiratory tract infections. Implicit, explicit and COVID-19-related sepsis had largely similar overall mortality, with explicit sepsis having an adjusted HR of 0.980 (95% CI 0.969 to 0.991) and COVID-19-related sepsis an adjusted HR of 0.916 (95% CI 0.836 to 1.003) compared to implicit sepsis. Patients with respiratory tract infections have somewhat higher mortality than those with other infection sites. Number of comorbidities was positively associated with mortality, but mortality varied considerably between different comorbidities. Similarly, number of acute organ dysfunctions was strongly associated with mortality, whereas the risk varied for each type of organ dysfunction.
CONCLUSION
Overall mortality has declined over the past 14 years among patients with a first sepsis admission. Comorbidity, site of infection, and acute organ dysfunction are patient characteristics that are associated with mortality. This could inform health care workers and raise the awareness toward subgroups of patients that needs particular attention to improve long-term mortality.
Topics: Humans; Multiple Organ Failure; Hospital Mortality; Sepsis; Hospitalization; Registries; Respiratory Tract Infections; COVID-19; Retrospective Studies
PubMed: 37572240
DOI: 10.1007/s15010-023-02082-z -
The Journal of Clinical Investigation Apr 2024BACKGROUNDThe molecular signature of pediatric acute respiratory distress syndrome (ARDS) is poorly described, and the degree to which hyperinflammation or specific... (Clinical Trial)
Clinical Trial
BACKGROUNDThe molecular signature of pediatric acute respiratory distress syndrome (ARDS) is poorly described, and the degree to which hyperinflammation or specific tissue injury contributes to outcomes is unknown. Therefore, we profiled inflammation and tissue injury dynamics over the first 7 days of ARDS, and associated specific biomarkers with mortality, persistent ARDS, and persistent multiple organ dysfunction syndrome (MODS).METHODSIn a single-center prospective cohort of intubated pediatric patients with ARDS, we collected plasma on days 0, 3, and 7. Nineteen biomarkers reflecting inflammation, tissue injury, and damage-associated molecular patterns (DAMPs) were measured. We assessed the relationship between biomarkers and trajectories with mortality, persistent ARDS, or persistent MODS using multivariable mixed effect models.RESULTSIn 279 patients (64 [23%] nonsurvivors), hyperinflammatory cytokines, tissue injury markers, and DAMPs were higher in nonsurvivors. Survivors and nonsurvivors showed different biomarker trajectories. IL-1α, soluble tumor necrosis factor receptor 1, angiopoietin 2 (ANG2), and surfactant protein D increased in nonsurvivors, while DAMPs remained persistently elevated. ANG2 and procollagen type III N-terminal peptide were associated with persistent ARDS, whereas multiple cytokines, tissue injury markers, and DAMPs were associated with persistent MODS. Corticosteroid use did not impact the association of biomarker levels or trajectory with mortality.CONCLUSIONSPediatric ARDS survivors and nonsurvivors had distinct biomarker trajectories, with cytokines, endothelial and alveolar epithelial injury, and DAMPs elevated in nonsurvivors. Mortality markers overlapped with markers associated with persistent MODS, rather than persistent ARDS.FUNDINGNIH (K23HL-136688, R01-HL148054).
Topics: Humans; Biomarkers; Male; Female; Child; Child, Preschool; Respiratory Distress Syndrome; Infant; Inflammation; Prospective Studies; Adolescent; Multiple Organ Failure; Cytokines
PubMed: 38573766
DOI: 10.1172/JCI177896 -
JAMA Network Open Sep 2023Efforts to quantify the burden of SARS-CoV-2-associated sepsis have been limited by inconsistent definitions and underrecognition of viral sepsis.
IMPORTANCE
Efforts to quantify the burden of SARS-CoV-2-associated sepsis have been limited by inconsistent definitions and underrecognition of viral sepsis.
OBJECTIVE
To describe the incidence and outcomes of SARS-CoV-2-associated sepsis vs presumed bacterial sepsis using objective electronic clinical criteria.
DESIGN, SETTING, AND PARTICIPANTS
This retrospective cohort study included adults hospitalized at 5 Massachusetts hospitals between March 2020 and November 2022.
EXPOSURES
SARS-CoV-2-associated sepsis was defined as a positive SARS-CoV-2 polymerase chain reaction test and concurrent organ dysfunction (ie, oxygen support above simple nasal cannula, vasopressors, elevated lactate level, rise in creatine or bilirubin level, and/or decline in platelets). Presumed bacterial sepsis was defined by modified US Centers for Disease Control and Prevention adult sepsis event criteria (ie, blood culture order, sustained treatment with antibiotics, and organ dysfunction using identical thresholds as for SARS-CoV-2-associated sepsis).
MAIN OUTCOMES AND MEASURES
Trends in the quarterly incidence (ie, proportion of hospitalizations) and in-hospital mortality for SARS-CoV-2-associated and presumed bacterial sepsis were assessed using negative binomial and logistic regression models.
RESULTS
This study included 431 017 hospital encounters from 261 595 individuals (mean [SD] age 57.9 [19.8] years, 241 131 (55.9%) females, 286 397 [66.5%] from academic hospital site). Of these encounters, 23 276 (5.4%) were from SARS-CoV-2, 6558 (1.5%) had SARS-CoV-2-associated sepsis, and 30 604 patients (7.1%) had presumed bacterial sepsis without SARS-CoV-2 infection. Crude in-hospital mortality for SARS-CoV-2-associated sepsis declined from 490 of 1469 (33.4%) in the first quarter to 67 of 450 (14.9%) in the last (adjusted odds ratio [aOR], 0.88 [95% CI, 0.85-0.90] per quarter). Crude mortality for presumed bacterial sepsis was 4451 of 30 604 patients (14.5%) and stable across quarters (aOR, 1.00 [95% CI, 0.99-1.01]). Medical record reviews of 200 SARS-CoV-2-positive hospitalizations confirmed electronic health record (EHR)-based SARS-CoV-2-associated sepsis criteria performed well relative to sepsis-3 criteria (90.6% [95% CI, 80.7%-96.5%] sensitivity; 91.2% [95% CI, 85.1%-95.4%] specificity).
CONCLUSIONS AND RELEVANCE
In this retrospective cohort study of hospitalized adults, SARS-CoV-2 accounted for approximately 1 in 6 cases of sepsis during the first 33 months of the COVID-19 pandemic. In-hospital mortality rates for SARS-CoV-2-associated sepsis were high but declined over time and ultimately were similar to presumed bacterial sepsis. These findings highlight the high burden of SARS-CoV-2-associated sepsis and demonstrate the utility of EHR-based algorithms to conduct surveillance for viral and bacterial sepsis.
Topics: Adult; Female; Humans; Middle Aged; Male; SARS-CoV-2; COVID-19; Retrospective Studies; Multiple Organ Failure; Incidence; Pandemics; Sepsis
PubMed: 37773495
DOI: 10.1001/jamanetworkopen.2023.35728 -
Critical Care (London, England) Mar 2024Sepsis is characterized by organ dysfunction resulting from a dysregulated inflammatory response triggered by infection, involving multifactorial and intricate molecular... (Review)
Review
Sepsis is characterized by organ dysfunction resulting from a dysregulated inflammatory response triggered by infection, involving multifactorial and intricate molecular mechanisms. Hypoxia-inducible factor-1α (HIF-1α), a notable transcription factor, assumes a pivotal role in the onset and progression of sepsis. This review aims to furnish a comprehensive overview of HIF-1α's mechanism of action in sepsis, scrutinizing its involvement in inflammatory regulation, hypoxia adaptation, immune response, and organ dysfunction. The review encompasses an analysis of the structural features, regulatory activation, and downstream signaling pathways of HIF-1α, alongside its mechanism of action in the pathophysiological processes of sepsis. Furthermore, it will delve into the roles of HIF-1α in modulating the inflammatory response, including its association with inflammatory mediators, immune cell activation, and vasodilation. Additionally, attention will be directed toward the regulatory function of HIF-1α in hypoxic environments and its linkage with intracellular signaling, oxidative stress, and mitochondrial damage. Finally, the potential therapeutic value of HIF-1α as a targeted therapy and its significance in the clinical management of sepsis will be discussed, aiming to serve as a significant reference for an in-depth understanding of sepsis pathogenesis and potential therapeutic targets, as well as to establish a theoretical foundation for clinical applications.
Topics: Humans; Multiple Organ Failure; Signal Transduction; Sepsis; Hypoxia-Inducible Factor 1, alpha Subunit
PubMed: 38539163
DOI: 10.1186/s13054-024-04885-4