<p>Sepsis and septic shock are life-threating conditions, which resulted from a continuum of the body’s response to overwhelming infection. Elimination of bacteria through antibiotics is not sufficient, because the host is still left with a large amount of lipopolysaccharide (LPS) that prevents the host immune system from returning to normal homeostasis. Synthetic LPS antagonists that can bind to LPS via electrostatic and/or hydrophobic interactions cause systemic toxicities. Moreover, LPS elimination alone may not address already established complications of sepsis. To address these challenges, we propose to develop nanoparticle formulations of LPS antagonists (D-TZP) that can be delivered systemically. Specifically, cholecalciferol (vitamin D) was encapsulated in a self-assembly of tannic acid/Fe³⁺ coordination complex (pTA) capsule, forming a core that could be surface-modified with LPS adsorbents, such as low molecular weight succinylated chitosan (LMZWC) and polymyxin B (PMB). D-TZP suppressed pro-inflammatory effects of LPS on the engineered human monocytes with significantly less cytotoxicity than free PMB at the equivalent dose. D-TZP increased the maximum tolerated dose of PMB by both intraperitoneal and intravenous administration. In the LPS-induced mouse model of sepsis, systemic administration of D-TZP immediately after LPS challenge neutralized the lethal effect of LPS. D-TZP also reduced the mortality of mice when given 2 h after the LPS challenge. D-TZP inhibited the mortality in the cecal ligation and puncture (CLP)-induced bacteremia mouse model when given IV 2 h after the insult. In the CLP model, the D-TZP-treated animals also showed lower levels of both TNF-α and IL-10 cytokines as well as D-dimer levels, reflecting the attenuation of disseminated intravascular coagulation, compared to the vehicle-treated control group. Collectively, these results support that the D-TZP is a safe and effective systemic intervention of sepsis.<br></p>

In patients after cardiac surgery, there is an increase in the level of molecules with both pro-inflammatory and anti-inflammatory effects. This increase is influenced by the patient's clinical condition, but also by the nature of the operation itself, which uses conventional extracorporeal circulation. This technique leads to damage to blood elements by direct contact with air and parts of the extracorporeal circulation, as well as to ischemia-reperfusion injury. The specifics of cardiac surgery then affect possible postoperative complications such as multiorgan failure or septic shock. The diploma thesis is divided into a theoretical and a practical part. The theoretical part describes the principle and influence of cardiopulmonary bypass on the human body and the complications that are associated with its use. Furthermore, IFN-γ is described herein as a potential marker of septic conditions that could reflect the clinical postoperative condition of patients. The practical part of the diploma thesis monitored the percentage change of selected cell populations and the production of IFN-γ in the peripheral blood of patients before and after cardiac surgery. Furthermore, the response of individual isolated populations of healthy volunteers to selected stimulators was investigated. The percentage of...

Patients with connective tissue diseases (CTD) such as systemic lupus erythematosus (SLE) have an increased risk for infections. This study investigated the outcome and characteristics of CTD patients under intensive care unit (ICU) treatment for sepsis

Skin related injuries are some of the most dangerous forms of wounds. In addition to treating the wound itself, health care providers must be cautious of microbial infections. In this study, we evaluate a novel all-natural antimicrobial gel compound (AMG) designed to kill planktonic bacteria, penetrate bacterial biofilms, and accelerate wound healing. In -vitro experiments demonstrate that AMG is effective in inhibiting planktonic growth and biofilm development of eight common pathogens. LIVE/DEAD staining and confocal microscopy reveal that planktonic growth and three-dimensional structure of biofilms were significantly reduced. Reverse Transcriptase Polymerase Chain Reaction (RT-PCR) was used to investigate a small panel of genes (PrsA, Sprx) and showed potential targets for future study. A physiologically relevant wound model was created for treating S. aureus infections by using AMG alone or in combination with a common topical antibiotic, Mupirocin. AMG is a safe and effective treatment option for skin related infection.

This research aims to further explore the linkages between poor WaSH realities and women’s development to understand how the burdens and risks associated with inadequate water resources diminishes both their health and safety. Specifically, a significant goal of this project is to understand the way in which rates of violent attacks increase as access to water decreases. Attempting to capture this violence in all its various forms, this study hosts conversation surrounding the way that a lack of clean, dependable water sources can increase a woman’s chances of experiencing various forms of violence. / Accessing clean water and adequate sanitation poses significant risks to the health and wellbeing of women and girls in East Africa. Without having access to local and dependable sources of water, the prevalence of water-borne diseases, health and safety hazards, and social barriers increase. Grounded in Feminist and Structural Functionalism theories, this research was designed to better understand Water, Sanitation, and Hygiene (WaSH) realities and the various types of associated burdens and risks. Using focus groups and key informant interviews, 36 health care professionals from various East African countries, such as Uganda, Tanzania, Ghana, and South Sudan, were solicited in an effort to capture the real, lived experiences of practitioners working most intimately with these issues. All data were gathered at Uganda Christian University in Mukono, Uganda, and reflect both the personal and professional accounts of health care professionals living and working throughout communities within these countries. The findings of this study indicate that for as long as poor water and sanitation access and hygiene practices continue to plague the development of women in urban and rural communities, women and pregnant women will continue to suffer from dangerous diseases and brutal attacks of violence. Honing in on the latter concept, this study uncovered a significant link between inadequate water access and rates of domestic violence, sexual assault, and animal attacks. Understanding the health professional perspective is crucial in gathering relevant data. Through this effort, the findings of this study have been informed by those most knowledgeable on the WaSH realities identified and therefore has the ability to influence both policy and programs in realistic and productive ways. With the goal of determining and then diminishing identified risks, the data gathered from this research are meant to be used as evidence to help empower and advance women throughout East Africa. / Thesis / Master of Social Work (MSW)

Neonatal sepsis is associated with most cases ofmortality in the neonatal intensive care unit. Major challengesin detecting sepsis using suitable biomarkers has lead people tolook for alternative approaches in the form of Machine Learningtechniques. In this project, Random Forest classification wasperformed on a sepsis data set provided by Karolinska Hospital.We particularly focused on tackling class imbalance in the datausing sampling and cost-sensitive techniques. We compare theclassification performances of Random Forests in six differentsetups; four using oversampling and undersampling techniques;one using cost-sensitive learning and one basic Random Forest.The performance with the oversampling techniques were betterand could identify more sepsis patients than the other setups.The overall performances were also good, making the methodspotentially useful in practice. / Neonatal sepsis är orsaken till majoriteten av mortaliteten i neonatal intensivvården. Svårigheten i att detektera sepsis med hjälp av biomarkörer har lett många att leta efter alternativa metoder. Maskininlärningstekniker är en sådan alternativ metod som har i senaste tider ökat i användning inom vård och andra sektorer. I detta project användes Random Forest klassifikations algoritmen på en sepsis datamängd given av Karolinska Sjukhuset. Vi fokuserade på att hantera klassimbalansen i datan genom att använda olika provtagningsoch kostnadskänsliga metoder. Vi jämförde klassificeringsprestanda för Random Forest med sex olika inställningar; fyra av de använde provtagingsmetoderna; en av de använde en kostnadskänslig metod och en var en vanlig Random Forest. Det visade sig att modellens prestanda ökade som mest med översamplings metoderna. Den generella klassificeringsprestandan var också bra, vilket gör Random Forests tillsammans med ingsmetoderna potentiellt användbar i praktiken. / Kandidatexjobb i elektroteknik 2022, KTH, Stockholm

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Introduction: Sepsis impaired vascular integrity results in multiple organ failure. Circulating lactate level is positively correlated with sepsis-induced mortality. We investigated whether lactate plays a role in causing endothelial barrier dysfunction in sepsis. Methods: Polymicrobial sepsis was induced in mice by cecal ligation and puncture (CLP). Lactic acid was injected i.p. (pH 6.8, 0.5 g/kg body weight) 6 h after CLP or sham surgery. To elucidate the role of heat shock protein A12B (HSPA12B), wild-type, HSPA12B-transgenic, and endothelial HSPA12B-deficient mice were subjected to CLP or sham surgery. To suppress lactate signaling, 3OBA (120 μM) was injected i.p. 3 h before surgery. Vascular permeability was evaluated with the Evans blue dye penetration assay. Results: We found that administration of lactate elevated CLP-induced vascular permeability. Vascular endothelial cadherin (VE-cadherin), claudin 5, and zonula occluden 1 (ZO-1) play a crucial role in the maintenance of endothelial cell junction and vascular integrity. Lactate administration significantly decreased VE-cadherin, claudin 5, and ZO-1 expression in the heart of septic mice. Our in vitro data showed that lactate (10 mM) treatment disrupted VE-cadherin, claudin 5, and ZO-1 in endothelial cells. Mechanistically, we observed that lactate promoted VE-cadherin endocytosis by reducing the expression of HSPA12B. Overexpression of HSPA12B prevented lactate-induced VE-cadherin disorganization. G protein-coupled receptor 81 (GPR81) is a specific receptor for lactate. Inhibition of GPR81 with its antagonist 3OBA attenuated vascular permeability and reversed HSPA12B expression in septic mice. Conclusions: The present study demonstrated a novel role of lactate in promoting vascular permeability by decreasing VE-cadherin junctions and tight junctions in endothelial cells. The deleterious effects of lactate in vascular hyperpermeability are mediated via HSPA12B- and GPR81-dependent signaling.

Yes / In English hospitals, the patient’s vital signs are monitored and summarised into a National Early Warning Score (NEWS). NEWS is more accurate than the quick sepsis related organ failure assessment (qSOFA) score at identifying patients with sepsis. We investigate the extent to which the accuracy of the NEWS is enhanced by developing computer-aided NEWS (cNEWS) models. We compared three cNEWS models (M0=NEWS alone; M1=M0 + age + sex; M2=M1 + subcomponents of NEWS + diastolic blood pressure) to predict the risk of sepsis. Methods: All adult emergency medical admissions discharged over 24-months from two acute hospitals (YH–York Hospital for model development; NH–Northern Lincolnshire and Goole Hospital for external model validation). We used a validated Canadian method for defining sepsis from administrative hospital data. Findings: The prevalence of sepsis was lower in YH (4.5%=1596/35807) than NH (8.5%=2983/35161). The c-statistic increased across models (YH: M0: 0.705, M1:0.763, M2:0.777; NH:M0: 0.708, M1:0.777, M2:0.791). At NEWS 5+, sensitivity increased (YH: 47.24% vs 50.56% vs 52.69%; NH: 37.91% vs 43.35% vs 48.07%)., the positive likelihood ratio increased (YH: 2.77 vs 2.99 vs 3.06; NH: 3.18 vs 3.32 vs 3.45) and the positive predictive value increased (YH: 11.44% vs 12.24% vs 12.49%; NH: 22.75% vs 23.55% vs 24.21%). Interpretation: From the three cNEWS models, Model M2 is the most accurate. Since it places no additional data collection burden on clinicians and can be automated, it may now be carefully introduced and evaluated in hospitals with sufficient informatics infrastructure. / The Health Foundation, National Institute for Health Research (NIHR) Yorkshire and Humberside Patient Safety Translational Research Centre / Research Development Fund Publication Prize Award winner, April 2019.