关键词： Adult critical care   bleeding   hemorrhage   resuscitation   shock   transfusion  

摘要： Purpose: Our goal was to describe resuscitation practices in critically ill medical patients with active hemorrhage requiring large volume resuscitation and identify factors associated with poor outcomes. Patients and Methods: This was a single center retrospective observational cohort study. Patients admitted to the medical intensive care unit from 2011 to 2017 who received >= 5 units of packed red blood cells (pRBCs) within 24 h were included. Data including volume of blood products and crystalloid administered, baseline sequential organ failure assessment (SOFA) scores, and outcomes were abstracted. Univariate and multivariate analyses were performed to determine clinical factors associated with hospital mortality. Results: Two hundred forty-six patients were identified. Mean volumes of 2,448 mL of pRBCs and 3.9L of crystalloid were transfused over 24 h. Inpatient mortality for the entire cohort was 48%. Multivariable analysis identified factors associated with hospital mortality;higher BMI (OR 1.047, 95% CI 1.013-1.083), higher ratio of fresh frozen plasma (FFP) to pRBCs (OR 2.744, 95% CI 1.1-6.844), and higher baseline SOFA scores (OR 1.3, 95% CI 1.175-1.437). Conclusion: In a cohort of critically ill medical patients undergoing resuscitation for hemorrhage, higher BMI, increased ratio of FFP to pRBCs, and higher SOFA scores were associated with increased mortality. Further studies are needed to clarify resuscitation practices associated with outcomes in this population.

关键词： Basal respiration   complex I respiration   lactate   microcirculation   mitochondrial dysfunction   sepsis   shock  

摘要： Introduction: In septic shock, mitochondrial dysfunction, and hypoperfusion are the main triggers of multi-organ failure. Little is known about the crosstalk between mitochondrial dysfunction and hemodynamic alterations, especially in the post-resuscitation phase. Here, we assess whether hypoperfusion and lactate levels are associated with oxygen consumption linked to mitochondrial bioenergetic activity in lymphocytes of patients admitted with septic shock. Patients and Methods: Prospective cohort study in patients with septic shock defined as the requirement of vasopressors to maintain a mean arterial pressure 65 mm Hg after initial fluid administration. Basal mitochondrial and Complex I respiration was measured to evaluate mitochondrial activity. Both variables and capillary refill time were compared with arterial lactate post-fluid resuscitation. We also compared mitochondrial activity measurements between patients with and without hypoperfusion status. Results: A total of 90 patients were included in analysis. The median arterial lactate at the time of septic shock diagnosis was 2.0 mmol/Dl (IQR 1.3-3.0). Baseline respiration at the time of septic shock diagnosis was correlated with lactate (Spearman -0.388, 95% CI -0.4893 to -0.1021;P = 0.003), as well as Complex I respiration (Spearman -0.403, 95% CI -0.567 to -0.208;P < 0.001). Patients with hypoperfusion status had no difference in basal respiration when compared with patients who did not have hypoperfusion status (P = 0.22) nor in Complex I respiration (P = 0.09). Conclusion: Changes in lymphocytic mitochondrial metabolism are associated with post-resuscitation arterial lactate in septic shock;however, they are not associated with the presence of a hypoperfusional status. In this scenario, it is therefore suggested that systemic perfusion and mitochondrial metabolism have different courses.

关键词： Acute kidney injury   KLF6   miR-223-3p   NLRP3   Caspase-1   IL-1 beta signaling pathway   oxidative stress   pyroptosis   renal tubular epithelial cell   sepsis  

摘要： Septic acute kidney injury (SAKI) represents a clinical challenge with high morbidity and mortality. The current study aimed to analyze the effects and molecular mechanism of Kruppel-like factor 6 (KLF6) on SAKI. First, SAKI mouse models were established by cecum ligation and puncture, while in vivo cell models were established using lipopolysaccharide (LPS). RT-qPCR assay was subsequently performed to detect the levels of KLF6 mRNA. SAKI mice and LPS-treated TCMK-1 cells were further treated with KLF6 siRNA. Afterward, HE staining, PAS staining, Western blot assay, and ELISA were adopted to ascertain the effects of KLF6 in pyroptosis. The binding relationships between KLF6 and miR-223-3p promoter /miR-223-3p and NLRP3 were analyzed with the help of CHIP and dual-luciferase reporter assays. RT-qPCR was adopted to determine the expression patterns of miR-223-3p and NLRP3. Lastly, a rescue experiment was designed to confirm the role of miR-223-3p. It was found that KLF6 was highly expressed in SAKI, whereas knockdown of KLF6 alleviated oxidative stress (OS) and pyroptosis in SAKI mice and LPS-treated TCMK-1 cells. Mechanistic results confirmed that KLF6 inhibited miR-223-3p via binding to the miR-223-3p promoter and promoted NLRP3. On the other hand, downregulation of miR-223-3p activated the NLRP3/Caspase-1/IL-1 beta pathway and aggravated OS and pyroptosis. Overall, our findings indicated that KLF6 inhibited miR-223-3p via binding to the miR-223-3p promoter and promoted NLRP3, and activated the NLRP3/Caspase-1/IL-1 beta pathway, thereby aggravating pyroptosis and SAKI.

关键词： Cardiogenic shock   epidemiology   outcomes research   ST-segment elevation myocardial infarction   United States  

摘要： Background: There are limited data on the temporal trends, incidence, and outcomes of ST-segment-elevation myocardial infarction-cardiogenic shock (STEMI-CS). Methods: Adult (>18 years) STEMI-CS admissions were identified using the National Inpatient Sample (2000-2017) and classified by tertiles of admission year (2000-2005, 2006-2011, 2012-2017). Outcomes of interest included temporal trends, acute organ failure, cardiac procedures, in-hospital mortality, hospitalization costs, and length of stay. Results: In similar to 4.3 million STEMI admissions, CS was noted in 368,820 (8.5%). STEMI-CS incidence increased from 5.8% in 2000 to 13.0% in 2017 (patient and hospital characteristics adjusted odds ratio [aOR] 2.45 [95% confidence interval {CI} 2.40-2.49];P < 0.001). Multiorgan failure increased from 55.5% (2000-2005) to 74.3% (2012-2017). Between 2000 and 2017, coronary angiography and percutaneous coronary intervention use increased from 58.8% to 80.1% and 38.6% to 70.6%, whereas coronary artery bypass grafting decreased from 14.9% to 10.4% (all P < 0.001). Over the study period, the use of intra-aortic balloon pump (40.6%-37.6%) decreased, and both percutaneous left ventricular assist devices (0%-12.9%) and extra-corporeal membrane oxygenation (0%-2.8%) increased (all P < 0.001). In hospital mortality decreased from 49.6% in 2000 to 32.7% in 2017 (aOR 0.29 [95% CI 0.28-0.31];P < 0.001). During the 18-year period, hospital lengths of stay decreased, hospitalization costs increased and use of durable left ventricular assist device /cardiac transplantation remained stable (P > 0.05). Conclusions: In the United States, incidence of CS in STEMI has increased 2.5-fold between 2000 and 2017, while in-hospital mortality has decreased during the study period. Use of coronary angiography and PCI increased during the study period.

关键词： factor VIII deficiency   gene therapy   haemophilia A   insurance design   value-based purchasing  

摘要： Introduction The emergence of durable and potentially curative cell and gene therapies (also known as advanced therapy medicinal products) with high price tags is challenging conventional health care payment systems. Among these are gene therapies in various phases of development for haemophilia A and B. The emergence of these therapies comes with clinical and economic uncertainties for payers, providers, patients, and manufacturers. These include uncertainties about expression of the intended physiological response, patient outcomes, and duration of treatment effect, along with potentially high upfront costs, variable additional costs, and uncertainties about uptake of the therapy among indicated patient populations. These clinical and economic uncertainties raise interest among payers, providers, and manufacturers in risk-sharing arrangements, including alternative payment models (APMs). APMs differ from traditional fee-for-service payment for health care. For example, some APMs are designed to reward clinicians and provider organizations for delivering high-quality and cost-effective care. The APMs described here, outcomes-based models (or value- or performance-based models) and finance-based models, are designed to mitigate or otherwise manage financial risks associated with health care payment, including instances in which patient outcomes for costly therapies are uncertain. We examine how such APMs may be applicable in the context of emerging gene therapies for haemophilia A, including considerations in determining whether any particular APM may be most suitable.

关键词： COVID-19   Complementary and alternative medicines   CAM   Herbal medicines   Patient education and counselling  

摘要： The COVID-19 pandemic has met international health systems with a low level of preparedness and emergency response. While the emergence of effective vaccines has offered the Governments, scientific communities, and members of the public a possible way out of the pandemic, effective pharmacotherapy, including immunotherapy for COVID-19 prevention and treatment, are yet to be established. Internationally, this has led to a surge in the demand and supply of many complementary and alternative medicines (CAM) and practices. Recent studies have shown increasing CAM information requests made to pharmacists and other healthcare staff from members of public and patients aimed at prevention, symptoms relief or treatment of COVID-19. In this context, it is imperative that healthcare professionals, including pharmacists, are acquainted with current practices, policies, and research in relation to CAM use in COVID-19. This narrative commentary will provide an update on global practices, policies and research in regards to CAM use in the context of COVID-19. Healthcare professionals' understanding of popular CAMs and those tipped for potential benefits in COVID-19, patient and consumer behaviors in relation to CAM use;and healthcare professionals' awareness of cultural, religious, and self-care practices associated with CAM use are imperative to inform effective communication and counselling practices and promote evidence based self-care when patients present for advice. This narrative provides relevant discussions specific to different continents and regions historically linked to diverse CAM practices.

关键词： Sanitaryware   Perlite   Ceramic material  

摘要： Perlite is an amorphous volcanic glass and an industrial mineral. Because of its relatively low price and density, perlite has a lot of commercial application. Generally, it is used in the horticultural and construction sector. Perlite is a candidate raw material for ceramic products due to its high amorphous phase. Perlite usage in ceramic sanitaryware is investigated with this work. For this purpose, albite was gradually decreased and perlite was added at rates of 3, 5, and 10% to the standard sanitaryware composition instead of albite. All tests and analyses were done under industrial conditions. The compositions were examined based on the rheological and technological properties, chemical analysis, phase analysis, and thermal analysis (thermal expansion coefficient and high-temperature deformation). According to the results, perlite addition increases fired shrinkage, fired strength, and dry shrinkage. Fired strength rose significantly up to 715 kg cm(-2). Water absorption values were under 0.02% for all test samples. Besides, the thermal expansion coefficient of the bodies increased up to 10% with perlite addition and then decreased. Thermal expansion coefficient values were determined between 60.1 and 64.9 x 10(-7) K-1. High-temperature deformation values decreased up to 10% with perlite addition. The composition which contains 3% perlite showed minimum deformation ( - 4.25%) at 1250 degrees C. As a result, it was determined that the use of perlite would be possible in ceramic sanitaryware compositions.

关键词： decoding mechanisms   network motifs   p53 dynamics   proteomics   transcriptomics  

摘要： The cell stress-responsive transcription factor p53 influences the expression of its target genes and subsequent cellular responses based in part on its dynamics (changes in level over time). The mechanisms decoding p53 dynamics into subsequent target mRNA and protein dynamics remain unclear. We systematically quantified p53 target mRNA and protein expression over time under two p53 dynamical regimes, oscillatory and rising, using RNA-sequencing and TMT mass spectrometry. Oscillatory dynamics allowed for a greater variety of dynamical patterns for both mRNAs and proteins. Mathematical modeling of empirical data revealed three distinct mechanisms that decode p53 dynamics. Specific combinations of these mechanisms at the transcriptional and post-transcriptional levels enabled exclusive induction of proteins under particular dynamics. In addition, rising induction of p53 led to higher induction of proteins regardless of their functional class, including proteins promoting arrest of proliferation, the primary cellular outcome under rising p53. Our results highlight the diverse mechanisms cells employ to distinguish complex transcription factor dynamics to regulate gene expression.

关键词： Microbiology   Biotechnology  

摘要： Biofilm plays an important role in the community and hospital-acquired infections. Especially E. coli biofilm that contributes towards the significant part of medical devices associated with microbial infections. OmpR/EnvZ, a two-component system, is one of the regulatory mechanisms involved in transcription regulation in response to environmental osmolarity changes. The main objective of this study was to elucidate the role of the OmpR/EnvZ two-component system in regulating the biofilm through curli and fimbriae (FimH gene), a contrary approach towards biofilm inhibition. In this study, the CRISPRi technique was used to suppress the expression of the OmpR gene. The RT-PCR assay was performed to quantify mRNA gene expression of curli and biofilm producing genes, and the data were further confirmed by different microscopic, spectroscopic and biofilm quantification assay (Crystal Violet). It is the first time we have shown downregulation of the OmpR gene in biofilm causing clinical isolates of E. coli, which further suppressed the FimH gene, leading to biofilm reduction. The crystal violet assay and microscopic studies also confirmed the biofilm reduction. We conclude that the OmpR gene of the OmpR/EnvZ two-component system could be one of the targets for biofilm mediated infection intervention. Our findings open new vistas to explore the pathways and targets to control biofilm mediated infections.

关键词： TEHTM   In silico   T-screen assay   hER and hAR reporter gene assays   Steroidogenesis   Medical devices  

摘要： Tri-(2-ethylhexyl) trimellitate (TEHTM) is a plasticizer for polyvinyl chloride (PVC) material used in medical devices. It is an alternative to di-(2-ethylhexyl) phthalate (DEHP), a well-known reprotoxic and endocrine disruptor. As plasticizers are known to easily migrate when in contact with fatty biological fluids, patient exposure to TEHTM is highly probable. However, there is currently no data on the potential endocrine-disrupting effects of its human metabolites. To evaluate the effects of TEHTM metabolites on endocrine activity, they were first synthesized and their effects on estrogen, androgen and thyroid receptors, as well as steroid synthesis, were investigated by combining in vitro and in silico approaches. Among the primary metabolites, only 4-MEHTM (4-mono-(2-ethylhexyl) trimellitate) showed agonist activities on ERs and TRs, while three diesters were TR antagonists at non-cytotoxic concentrations. These results were completed by docking experiments which specified the ER and TR isoforms involved. A mixture of 2/1-MEHTM significantly increased the estradiol level and reduced the testosterone level in H295R cell culture supernatants. The oxidized secondary metabolites of TEHTM had no effect on ER, AR, TR receptors or on steroid hormone synthesis. Among the fourteen metabolites, these data showed that two of them (4-MEHTM and 2/1-MEHTM) induced effect on hormonal activities in vitro. However, by comparing the concentrations of the primary metabolites found in human urine with the active concentrations determined in bioassays, it can be suggested that the metabolites will not be active with regard to estrogen, androgen, thyroid receptors and steroidogenesis-mediated effects.