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Critical Care (London, England) Nov 2023Given the success of recent platform trials for COVID-19, Bayesian statistical methods have become an option for complex, heterogenous syndromes like sepsis. However,...
BACKGROUND
Given the success of recent platform trials for COVID-19, Bayesian statistical methods have become an option for complex, heterogenous syndromes like sepsis. However, study design will require careful consideration of how statistical power varies using Bayesian methods across different choices for how historical data are incorporated through a prior distribution and how the analysis is ultimately conducted. Our objective with the current analysis is to assess how different uses of historical data through a prior distribution, and type of analysis influence results of a proposed trial that will be analyzed using Bayesian statistical methods.
METHODS
We conducted a simulation study incorporating historical data from a published multicenter, randomized clinical trial in the US and Canada of polymyxin B hemadsorption for treatment of endotoxemic septic shock. Historical data come from a 179-patient subgroup of the previous trial of adult critically ill patients with septic shock, multiple organ failure and an endotoxin activity of 0.60-0.89. The trial intervention consisted of two polymyxin B hemoadsorption treatments (2 h each) completed within 24 h of enrollment.
RESULTS
In our simulations for a new trial of 150 patients, a range of hypothetical results were observed. Across a range of baseline risks and treatment effects and four ways of including historical data, we demonstrate an increase in power with the use of clinically defensible incorporation of historical data. In one possible trial result, for example, with an observed reduction in risk of mortality from 44 to 37%, the probability of benefit is 96% with a fixed weight of 75% on prior data and 90% with a commensurate (adaptive-weighting) prior; the same data give an 80% probability of benefit if historical data are ignored.
CONCLUSIONS
Using Bayesian methods and a biologically justifiable use of historical data in a prior distribution yields a study design with higher power than a conventional design that ignores relevant historical data. Bayesian methods may be a viable option for trials in critical care medicine where beneficial treatments have been elusive.
Topics: Adult; Humans; Bayes Theorem; Polymyxin B; Research Design; Sepsis; Shock, Septic
PubMed: 37940985
DOI: 10.1186/s13054-023-04717-x -
European Journal of Trauma and... Feb 2024Recently, retrospective registry-based studies have reported the decreasing incidence and increasing mortality of postinjury multiple organ failure (MOF). We aimed to...
BACKGROUND
Recently, retrospective registry-based studies have reported the decreasing incidence and increasing mortality of postinjury multiple organ failure (MOF). We aimed to describe the current epidemiology of MOF following the introduction of haemostatic resuscitation.
METHODS
A 10-year prospective cohort study was undertaken at a Level-1 Trauma Centre-based ending in December 2015. Inclusion criteria age ≥ 16 years, Injury Severity Score (ISS) > 15, Abbreviated Injury Scale (AIS) Head < 3 and survived > 48 h. Demographics, physiological and shock resuscitation parameters were collected. The primary outcome was MOF defined by a Denver Score > 3.
SECONDARY OUTCOMES
intensive care unit length of stay (ICU LOS), ventilation days and mortality.
RESULTS
Three hundred and forty-seven patients met inclusion criteria (age 48 ± 20; ISS 30 ± 11, 248 (71%) were males and 23 (6.6%) patients died. The 74 (21%) MOF patients (maximum Denver Score: 5.5 ± 1.8; Duration; 5.6 ± 5.8 days) had higher ISS (32 ± 11 versus 29 ± 11) and were older (54 ± 19 versus 46 ± 20 years) than non-MOF patients. Mean daily Denver scores adjusted for age, sex, MOF and ISS did not change over time. Crystalloid usage decreased over the 10-year period (p value < 0.01) and PRBC increased (p value < 0.01). Baseline cumulative incidence of MOF at 28 days was 9% and competing risk analyses showed that incidence of MOF increased over time (subdistribution hazard ratio 1.14, 95% CI 1.04 to 1.23, p value < 0.01). Mortality risk showed no temporal change. ICU LOS increased over time (subdistribution hazard ratio 0.95, 95% CI 0.92 to 0.98, p value < 0.01). Ventilator days increased over time (subdistribution hazard ratio 0.94, 95% CI 0.9 to 0.97, p value < 0.01).
CONCLUSION
The epidemiology of MOF continues to evolve. Our prospective cohort suggests an ageing population with increasing incidence of MOF, particularly in males, with little changes in injury or shock parameters, who are being resuscitated with less crystalloids, stay longer on ICU without improvement in survival.
Topics: Male; Humans; Adolescent; Adult; Middle Aged; Aged; Female; Prospective Studies; Retrospective Studies; Multiple Organ Failure; Crystalloid Solutions; Multiple Trauma; Injury Severity Score
PubMed: 36598541
DOI: 10.1007/s00068-022-02202-8 -
Biomedicine & Pharmacotherapy =... Apr 2024Fibrosis-related diseases (FRD) include conditions like myocardial fibrosis, pulmonary fibrosis, hepatic fibrosis, renal fibrosis, and others. The impact of fibrosis can... (Review)
Review
Fibrosis-related diseases (FRD) include conditions like myocardial fibrosis, pulmonary fibrosis, hepatic fibrosis, renal fibrosis, and others. The impact of fibrosis can be severe, causing organ dysfunction, reduced functionality, and even organ failure, leading to significant health issues. Currently, there is a lack of effective modern anti-fibrosis drugs in clinical practice. However, Chinese medicine has a certain beneficial effect on the treatment of such diseases. Angelica sinensis, with its considerable medicinal value, has garnered attention for its anti-fibrosis properties in recent investigations. In the past few years, there has been a growing number of experimental inquiries into the impact of angelica polysaccharide (ASP), angelica water extract, angelica injection, and angelica compound preparation on fibrosis-associated ailments, piquing the interest of researchers. This paper aims to consolidate recent advances in the study of Angelica sinensis for the treatment of fibrosis-related disorders, offering insights for prospective investigations. Literature retrieval included core electronic databases, including Baidu Literature, CNKI, Google-Scholar, PubMed, and Web of Science. The applied search utilized specified keywords to extract relevant information on the pharmacological and phytochemical attributes of plants. The investigation revealed that Angelica sinensis has the potential to impede the advancement of fibrotic diseases by modulating inflammation, oxidative stress, immune responses, and metabolism. ASP, Angelica sinensis extract, Angelica sinensis injection, and Angelica sinensis compound preparation were extensively examined and discussed. These constituents demonstrated significant anti-fibrosis activity. In essence, this review seeks to gain a profound understanding of the role of Angelica sinensis in treating fiber-related diseases. Organ fibrosis manifests in nearly all tissues and organs, posing a critical challenge to global public health due to its widespread occurrence, challenging early diagnosis, and unfavorable prognosis. Despite its prevalence, therapeutic options are limited, and their efficacy is constrained. Over the past few years, numerous studies have explored the protective effects of traditional Chinese medicine on organ fibrosis, with Angelica sinensis standing out as a multifunctional natural remedy. This paper provides a review of organ fibrosis pathogenesis and summarizes the recent two decades' progress in treating fibrosis in various organs such as the liver, lung, kidney, and heart. The review highlights the modulation of relevant signaling pathways through multiple targets and channels by the effective components of Angelica sinensis, whether used as a single medicine or in compound prescriptions.
Topics: Angelica sinensis; Prospective Studies; Phytotherapy; Medicine, Chinese Traditional; Pulmonary Fibrosis
PubMed: 38490157
DOI: 10.1016/j.biopha.2024.116429 -
Nature Communications May 2024Sepsis results from systemic, dysregulated inflammatory responses to infection, culminating in multiple organ failure. Here, we demonstrate the utility of CD5L for...
Sepsis results from systemic, dysregulated inflammatory responses to infection, culminating in multiple organ failure. Here, we demonstrate the utility of CD5L for treating experimental sepsis caused by cecal ligation and puncture (CLP). We show that CD5L's important features include its ability to enhance neutrophil recruitment and activation by increasing circulating levels of CXCL1, and to promote neutrophil phagocytosis. CD5L-deficient mice exhibit impaired neutrophil recruitment and compromised bacterial control, rendering them susceptible to attenuated CLP. CD5L peritoneal cells from mice subjected to medium-grade CLP exhibit a heightened pro-inflammatory transcriptional profile, reflecting a loss of control of the immune response to the infection. Intravenous administration of recombinant CD5L (rCD5L) in immunocompetent C57BL/6 wild-type (WT) mice significantly ameliorates measures of disease in the setting of high-grade CLP-induced sepsis. Furthermore, rCD5L lowers endotoxin and damage-associated molecular pattern (DAMP) levels, and protects WT mice from LPS-induced endotoxic shock. These findings warrant the investigation of rCD5L as a possible treatment for sepsis in humans.
Topics: Animals; Sepsis; Mice, Inbred C57BL; Mice; Neutrophils; Mice, Knockout; Phagocytosis; Chemokine CXCL1; Disease Models, Animal; Male; Neutrophil Infiltration; Cecum; Recombinant Proteins; Humans; Pore Forming Cytotoxic Proteins; Ligation; Lipopolysaccharides; Shock, Septic
PubMed: 38750020
DOI: 10.1038/s41467-024-48360-8 -
JHEP Reports : Innovation in Hepatology Jan 2024Retrospective studies have reported good results with liver transplantation (LTx) for acute-on-chronic liver failure (ACLF) in selected patients. The aim of this study...
BACKGROUND & AIMS
Retrospective studies have reported good results with liver transplantation (LTx) for acute-on-chronic liver failure (ACLF) in selected patients. The aim of this study was to evaluate the selection process for LTx in patients with ACLF admitted to the intensive care unit (ICU) and to assess outcomes.
METHODS
This prospective, non-interventional, single high-volume center study collected data on patients with ACLF admitted to the ICU between 2017-2020.
RESULTS
Among 200 patients (mean age: 55.0 ± 11.2 years and 74% male), 96 patients (48%) were considered potential candidates for LTx. Unfavourable addictology criteria (n = 76) was the main reason for LTx ineligibility. Overall, 69 patients were listed for LTx (34.5%) and 50 were transplanted (25% of the whole population). The 1-year survival in the LTx group was significantly higher than in the non-transplanted group (94% 15%, <0.0001). Among patients eligible for LTx, mechanical ventilation during the first 7 days of ICU stay and an increase in the number of organ failures at day 3 were associated with the absence of LTx or death (odds ratio 9.58; 95% CI 3.29-27.89; 0.0001 for mechanical ventilation and odds ratio 1.87; 95% CI 1.08-3.24; 0.027 for increasing organ failures). The probability of not being transplanted in patients with ACLF under mechanical ventilation is >85.4% in those experiencing an increase of 2 organ failures since admission or >91% if experiencing an increase >2 organ failures, at which point futility could be considered.
CONCLUSION
This prospective analysis of outcomes of patients with ACLF admitted to the ICU highlights the drastic nature of selection in this setting. Unfavourable addictology criteria, mechanical ventilation and increasing number of organ failures since admission were predictive of absence of LTx, futility and death.
IMPACT AND IMPLICATIONS
Liver transplantation (LT) is the best therapeutic option in selected cirrhotic patients admitted to the ICU with acute on chronic liver failure. However, the selection criteria are poorly described and based on retrospective studies. This is the first prospective study that aimed to describe the selection process for LT in a transplant center. Patients with ACLF should be admitted to the ICU and evaluated within a short period of time for LT. In the context of organ shortage, eligibility for LT and either absence of LT, futility of care or death are better clarified in our study. These are mainly determined by prolonged respiratory failure and worsening of organ failures since ICU admission. Considering worldwide variations in the etiology and definition of ACLF, transplant availability and a narrow therapeutic window for transplant further prospective studies are awaited.
PubMed: 38074503
DOI: 10.1016/j.jhepr.2023.100929 -
Annals of Transplantation Jun 2024BACKGROUND Kidney transplant recipients have higher life expectancy but may require subsequent transplantations, raising ethical concerns regarding organ allocation. We...
BACKGROUND Kidney transplant recipients have higher life expectancy but may require subsequent transplantations, raising ethical concerns regarding organ allocation. We assessed the safety of multiple kidney transplants through long-term follow-up. MATERIAL AND METHODS A retrospective cohort study was conducted at a single center, categorizing patients based on the number of kidney transplantations received. The primary outcome was the composite of death-censored graft failure and overall mortality. The secondary outcome was death-censored graft failure. RESULTS Between 2000 and 2019, our center performed 2152 kidney transplantations. Patients were divided into 3 groups: A (1 transplant; n=1850), B (2 transplants; n=285), and C (3 or more transplants; n=75). Group C patients were younger, had fewer comorbidities, and received more aggressive induction therapy. The primary outcomes, including death-censored graft loss and overall mortality, showed similar rates across groups (A: 21.3%, B: 25.2%, C: 21.7%, p=0.068). However, the secondary outcome of death-censored graft failure alone was significantly lower in group A compared to the other groups. No significant difference was observed between groups B and C (8% vs 16% and 13%, respectively, p=0.001, p=0.845). Multivariate analysis identified having a living donor as the strongest predictor of patient and graft survival in all study groups. CONCLUSIONS Graft and patient survival rates were similar between first and multiple transplant recipients. Multiple transplant recipients had lower death-censored graft failure risk compared to first transplant recipients. However, the risk did not differ among second and subsequent transplant recipients. Younger patients, especially those with a living donor, should be considered for repeat kidney transplantation.
Topics: Humans; Kidney Transplantation; Female; Male; Middle Aged; Retrospective Studies; Graft Survival; Adult; Reoperation; Graft Rejection; Aged; Survival Rate
PubMed: 38902916
DOI: 10.12659/AOT.943903 -
Critical Care Explorations Oct 2023Acute kidney injury (AKI) requiring continuous kidney replacement therapy is a significant complication in ICU patients with mortality rates exceeding 50%. A... (Review)
Review
Safety Summary of the Selective Cytopheretic Device: A Review of Safety Data Across Multiple Clinical Trials in ICU Patients With Acute Kidney Injury and Multiple Organ Failure.
OBJECTIVES
Acute kidney injury (AKI) requiring continuous kidney replacement therapy is a significant complication in ICU patients with mortality rates exceeding 50%. A dysregulated immune response can lead to systemic inflammation caused by hyperactivity of pro-inflammatory neutrophils and monocytes leading to tissue damage. The selective cytopheretic device (SCD) is an investigational medical device in a new class of cell-directed extracorporeal therapies distinct from cytokine adsorbers or filters, as it targets activated leukocytes. These leukocytes are the cellular sources driving this hyperinflammatory process. The objective of this report is to summarize the safety experience from clinical studies of the SCD in ICU patients with AKI or acute respiratory distress syndrome (ARDS) and multiple organ dysfunction (MOD).
DATA SOURCES AND STUDY SELECTION
The studies included in this report represent all relevant trials of the SCD conducted in patients with AKI or ARDS and MOD. Adverse event data, clinical laboratory data and mortality rates were described and summarized in this report.
DATA EXTRACTION AND DATA SYNTHESIS
Five clinical studies were included in this report, including four adult studies of AKI and/or ARDS and one pediatric AKI study, which involved 151 patients treated with the SCD in an ICU setting. Over 800 SCD sessions were deployed with an estimated 19,000 exposure hours with no device-related infections or attributable serious adverse events. Furthermore, there were no safety signals of leukopenia, thrombocytopenia, or other indications of immunodepletion or immunosuppression.
CONCLUSIONS
The SCD has shown to be a promising extracorporeal therapy with promising clinical results and a favorable safety profile. These studies support that the SCD can be added as a therapeutic intervention in critically ill AKI patient populations with multiple organ failure without adding additional safety risks.
PubMed: 37868028
DOI: 10.1097/CCE.0000000000000995 -
Leukemia Aug 2023Myeloid malignancies associated with germline predisposition syndromes account for up to 10% of myeloid neoplasms. They are classified into three categories by the... (Review)
Review
Myeloid malignancies associated with germline predisposition syndromes account for up to 10% of myeloid neoplasms. They are classified into three categories by the proposed 5 Edition of the World Health Organization Classification of Hematolymphoid Tumors: (1) neoplasms with germline predisposition without a pre-existing platelet disorder or organ dysfunction, (2) neoplasms with germline predisposition and pre-existing platelet disorder, or (3) neoplasms with germline predisposition and potential organ dysfunction. Recognizing these entities is critical because patients and affected family members benefit from interfacing with hematologists who specialize in these disorders and can facilitate tailored treatment strategies. However, identification of these syndromes in routine pathology practice is often challenging, as characteristic findings associated with these diagnoses at baseline are frequently absent, nonspecific, or impossible to evaluate in the setting of a myeloid malignancy. Here we review the formally classified germline predisposition syndromes associated with myeloid malignancies and summarize practical recommendations for pathologists evaluating a new myeloid malignancy diagnosis. Our intent is to empower clinicians to better screen for germline disorders in this common clinical setting. Recognizing when to suspect a germline predisposition syndrome, pursue additional ancillary testing, and ultimately recommend referral to a cancer predisposition clinic or hematology specialist, will ensure optimal patient care and expedite research to improve outcomes for these individuals.
Topics: Humans; Genetic Predisposition to Disease; Syndrome; Multiple Organ Failure; Germ-Line Mutation; Leukemia, Myeloid, Acute; Myeloproliferative Disorders
PubMed: 37393344
DOI: 10.1038/s41375-023-01955-4 -
Rheumatology International Jan 2024Recent reports have demonstrated that endothelial injury is critical in the pathogenesis of systemic sclerosis (SSc) and is associated with increased levels of...
Recent reports have demonstrated that endothelial injury is critical in the pathogenesis of systemic sclerosis (SSc) and is associated with increased levels of circulating inflammatory biomarkers. This study aims to analyze the serum concentrations of selected cytokines and evaluate their relationship with SSc clinics and the long-term course of the disease. This study included 43 SSc patients and 24 matched healthy controls. In both groups, we measured serum levels of inflammatory cytokines related to the inflammatory response, such as tumor necrosis factor (TNF)α, interferon (IFN)γ, interleukin (IL)-4, IL-6, IL-10, and IL-17, and fibroblast activation protein (FAP). Additionally, in SSc patients, we evaluated the presence of four single nucleotide polymorphisms (SNPs) located in the promotor region of the TNFA gene, namely rs361525, rs1800629, rs1799964, and rs1799724, which might be related to increased TNFα concentrations. The main aim consisted of associating inflammatory cytokines with (1) clinical disease characteristics and (2) longitudinal observation of survival and cancer prevalence. SSc patients were characterized by a 17% increase in serum TNFα. There was no other difference in serum cytokines between the studied groups and diffuse vs. limited SSc patients. As expected, evaluated serum cytokines correlated with inflammatory biomarkers (e.g., IL-6 and C-reactive protein). Interestingly, patients with higher IL-17 had decreased left ventricle ejection fraction. During the median 5-year follow-up, we recorded four cases of neoplastic diseases (lung cancer in two cases, squamous cell carcinoma of unknown origin, and breast cancer with concomitant multiple myeloma) and nine deaths. The causes of death included lung cancer (n = 2), renal crisis (n = 1), multiple-organ failure (n = 1), and unknown reasons in five cases. Surprisingly, higher TNFα was associated with an increased cancer prevalence, while elevated IL-17 with death risk in the follow-up. Furthermore, the AG rs361525 genotype referred to higher TNFα levels than GG carriers. Both AG rs361525 and CT rs1799964 genotypes were associated with increased cancer risk. Higher serum concentrations of TNFα characterize the SSc patients, with the highest values associated with cancer. On the other hand, increased IL-17 in peripheral blood might predict poor SSc prognosis. Further research is needed to validate these findings.
Topics: Humans; Biomarkers; Cytokines; Interleukin-17; Interleukin-6; Lung Neoplasms; Prognosis; Prospective Studies; Scleroderma, Systemic; Tumor Necrosis Factor-alpha
PubMed: 38051374
DOI: 10.1007/s00296-023-05499-9 -
Virology Journal Aug 2023SARS-CoV-2 has been responsible for the recent pandemic all over the world, which has caused many complications. One of the hallmarks of SARS-CoV-2 infection is an... (Review)
Review
SARS-CoV-2 has been responsible for the recent pandemic all over the world, which has caused many complications. One of the hallmarks of SARS-CoV-2 infection is an induced immune dysregulation, in some cases resulting in cytokine storm syndrome, acute respiratory distress syndrome and many organs such as lungs, brain, and heart that are affected during the SARS-CoV-2 infection. Several physiological parameters are altered as a result of infection and cytokine storm. Among them, microRNAs (miRNAs) might reflect this poor condition since they play a significant role in immune cellular performance including inflammatory responses. Both host and viral-encoded miRNAs are crucial for the successful infection of SARS-CoV-2. For instance, dysregulation of miRNAs that modulate multiple genes expressed in COVID-19 patients with comorbidities (e.g., type 2 diabetes, and cerebrovascular disorders) could affect the severity of the disease. Therefore, altered expression levels of circulating miRNAs might be helpful to diagnose this illness and forecast whether a COVID-19 patient could develop a severe state of the disease. Moreover, a number of miRNAs could inhibit the expression of proteins, such as ACE2, TMPRSS2, spike, and Nsp12, involved in the life cycle of SARS-CoV-2. Accordingly, miRNAs represent potential biomarkers and therapeutic targets for this devastating viral disease. In the current study, we investigated modifications in miRNA expression and their influence on COVID-19 disease recovery, which may be employed as a therapy strategy to minimize COVID-19-related disorders.
Topics: Humans; COVID-19; Diabetes Mellitus, Type 2; Inflammation; MicroRNAs; SARS-CoV-2; RNA, Viral
PubMed: 37559103
DOI: 10.1186/s12985-023-02152-6