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Circulating soluble urokinase plasminogen activator receptor (suPAR) is a marker of inflammation with prognostic value for elevated risk of morbidity and mortality. It has not yet been shown how the inflammatory process induced by cardiac surgery affects suPAR concentrations postoperatively.In a prospective observational study, plasma suPAR levels were measured in 30 patients undergoing cardiac surgery with cardiopulmonary bypass (CPB), pre-, peri, post-operatively, and 3-5 days after surgery. Fifteen patients underwent coronary artery bypass grafting (CABG) and 15 underwent complex procedures with longer CPB duration. Concentrations of suPAR at each time point were compared to the preoperative levels and compared between the two groups.In both groups, plasma suPAR concentrations were significantly higher on the first postoperative day (3.27 (interquartile range (IQR) 2.75-3.86) µg/L compared to baseline (2.62 (1.98-3.86)) µg/L,After a transient rise on the first postoperative day, the suPAR levels returned to the preoperative levels by the third postoperative day. There was no significant difference in suPAR levels between the routine CABG and complex group with longer CPB time.

Objectives To explore the preoperative, intraoperative, and postoperative dynamics of heparin-binding protein (HBP) in cardiothoracic surgery. Design This was a prospective, observational study. Setting The study was conducted at a single university hospital. Participants Thirty patients undergoing cardiac surgery with cardiopulmonary bypass (CPB) were included, 15 of whom underwent coronary artery bypass grafting surgery and 15 of whom underwent complex procedures. Ten patients undergoing lung surgery also were included as a conventional surgery reference group. Interventions No interventions were performed. Measurements and Main Results HBP was measured at nine different perioperative times. HBP levels increased immediately after heparin administration, further increased during CPB, but decreased rapidly after protamine administration. At arrival to the intensive care unit, median HBP levels were 24.8 (15.6-38.1) ng/mL for coronary artery bypass grafting patients and 51.2 (34.0-117.7) ng/mL for complex surgery patients (p = 0.011). One day after surgery, HBP levels in all three groups were below the proposed cutoff of 30 ng/mL, which previously was found to predict development of organ dysfunction in patients with infection. Conclusions HBP levels are elevated by the administration of heparin and the use of CPB but reduced by protamine administration. At postoperative day one, HBP levels were less than the threshold for organ dysfunction in patients with infection. The usefulness of HBP for predicting postoperative infections in cardiothoracic surgery should be investigated in future studies.

The statistical validation of peptide and protein identifications in mass spectrometry proteomics is a critical step in the analytical workflow. This is particularly important in discovery experiments to ensure only confident identifications are accumulated for downstream analysis and biomarker consideration. However, the inherent nature of discovery proteomics experiments leads to scenarios where the search space will inflate substantially due to the increased number of potential proteins that are being queried in each sample. In these cases, issues will begin to arise when the machine learning algorithms that are trained on an experiment specific basis cannot accurately distinguish between correct and incorrect identifications and will struggle to accurately control the false discovery rate. Here, we propose an alternative validation algorithm trained on a curated external data set of 2.8 million extracted peakgroups that leverages advanced machine learning techniques to create a generalizable peakgroup scoring (GPS) method for data independent acquisition (DIA) mass spectrometry. By breaking the reliance on the experimental data at hand and instead training on a curated external dataset, GPS can confidently control the false discovery rate while increasing the number of identifications and providing more accurate quantification in different search space scenarios. To first test the performance of GPS in a standard experimental environment and to provide a benchmark against other methods, a novel spike-in data set with known varying concentrations was analyzed. When compared to existing methods GPS increased the nunmber of identifications by 5-18% and was able to provide more accurate quantification by increasing the number of ratio validated identifications by 24-74%. To evaluate GPS in a larger search space, a novel data set of 141 blood plasma samples from patients developing acute kidney injury after sepsis was searched with a human tissue spectral library (10000+ proteins). Using GPS, we were able to provide a 207-377% increase in the number of candidate differentially abundant proteins compared to the existing methods while maintaining competitive numbers of global identifications. Finally, using an optimized human tissue library and workflow we were able to identify 1205 proteins from the 141 plasma samples and increase the number of candidate differentially abundant proteins by 70.87%. With the addition of machine learning aided differential expression, we were able to identify potential new biomarkers for stratifying subphenotypes of acute kidney injury in sepsis. These findings suggest that by using a generalized model such as GPS in tandem with a massive scale spectral library it is possible to expand the boundaries of discovery experiments in DIA proteomics. GPS is open source and freely available on github at (https://github.com/InfectionMedicineProteomics/gscore).

Objective: Diagnosis of ventriculostomy related infections (VRI) in the neuro-intensive care unit remains chal-lenging and current biomarkers lack adequate precision. The aim of this study was to explore the potential of Heparin-binding protein (HBP) in cerebrospinal fluid (CSF) as a diagnostic biomarker of VRI. Methods: All patients treated with an external ventricular drain (EVD) between January 2009 and March 2010 at Skane university hospital in Lund, Sweden, were consecutively included. CSF samples obtained during routine care were analyzed for HBP. VRI was defined as a positive bacterial microbiology test result on a CSF sample with an erythrocyte-corrected leukocyte count of > 50 x 106/l. HBP levels at VRI diagnosis was compared to peak HBP levels in non-VRI controls. Results: In total, 394 CSF samples from 103 patients were analyzed for HBP. Seven patients (6.8%) fulfilled VRI criteria. Levels of HBP were significantly higher in VRI subjects (31.7 ng/mL [IQR 26.9-40.7 ng/mL]) compared to non-VRI controls (7.7 ng/mL [IQR 4.1-24.5 ng/mL]) (p = 0.024). The AUC of the receiver operating char-acteristic (ROC) curve was 0.76 (95% confidence interval [CI], 0.62-0.90). Among non-VRI patients, HBP was highest in patients with acute bacterial meningitis. Patients with subarachnoid hemorrhage displayed higher HBP levels than those with traumatic brain injury or shunt dysfunction. Conclusions: HBP levels were higher in VRI subjects and varied between patients and different diagnoses. To validate the clinical usefulness and added value of HBP as a biomarker for VRI, the results need to be confirmed in larger studies with head-to-head comparisons to current biomarkers.

Objective S. pneumoniae is the most common cause of bacterial meningitis, a disease that, despite treatment with antibiotics, still is associated with a high mortality and morbidity worldwide. Diffuse brain swelling is a leading cause of morbidity in S. pneumoniae meningitis. We hypothesized that neutrophil extracellular traps (NETs) disrupt CSF transport by the glymphatic system and contribute to edema formation in S. pneumoniae meningitis. Methods We used DNase I treatment to disrupt NETs and then assessed glymphatic function by cisterna magna injections of CSF tracers in a rat model of S. pneumoniae meningitis. Results Our analysis showed that CSF influx into the brain parenchyma, as well as CSF drainage to the cervical lymph nodes, were significantly reduced in the rat model of S. pneumoniae meningitis. Degrading neutrophil extracellular traps (NETs) by DNase treatment restored glymphatic transport and eliminated the increase in brain weight in the rats. In contrast, first-line antibiotic treatment had no such effect on restoring fluid dynamics. Interpretation This study suggests that CSF accumulation is responsible for cerebral edema formation and identifies the glymphatic system and NETs as possible new treatment targets in S. pneumoniae meningitis. This article is protected by copyright. All rights reserved.

OBJECTIVES Sequential Organ Failure Assessment score is the basis of the Sepsis-3 criteria and requires arterial blood gas analysis to assess respiratory function. Peripheral oxygen saturation is a noninvasive alternative but is not included in neither Sequential Organ Failure Assessment score nor Sepsis-3. We aimed to assess the association between worst peripheral oxygen saturation during onset of suspected infection and mortality. DESIGN Cohort study of hospital admissions from a main cohort and emergency department visits from four external validation cohorts between year 2011 and 2018. Data were collected from electronic health records and prospectively by study investigators. SETTING Eight academic and community hospitals in Sweden and Canada. PATIENTS Adult patients with suspected infection episodes. INTERVENTIONS None. MEASUREMENTS AND MAIN RESULTS The main cohort included 19,396 episodes (median age, 67.0 [53.0-77.0]; 9,007 [46.4%] women; 1,044 [5.4%] died). The validation cohorts included 10,586 episodes (range of median age, 61.0-76.0; women 42.1-50.2%; mortality 2.3-13.3%). Peripheral oxygen saturation levels 96-95% were not significantly associated with increased mortality in the main or pooled validation cohorts. At peripheral oxygen saturation 94%, the adjusted odds ratio of death was 1.56 (95% CI, 1.10-2.23) in the main cohort and 1.36 (95% CI, 1.00-1.85) in the pooled validation cohorts and increased gradually below this level. Respiratory assessment using peripheral oxygen saturation 94-91% and less than 91% to generate 1 and 2 Sequential Organ Failure Assessment points, respectively, improved the discrimination of the Sequential Organ Failure Assessment score from area under the receiver operating characteristics 0.75 (95% CI, 0.74-0.77) to 0.78 (95% CI, 0.77-0.80; p < 0.001). Peripheral oxygen saturation/FIO2 ratio had slightly better predictive performance compared with peripheral oxygen saturation alone, but the clinical impact was minor. CONCLUSIONS These findings provide evidence for assessing respiratory function with peripheral oxygen saturation in the Sequential Organ Failure Assessment score and the Sepsis-3 criteria. Our data support using peripheral oxygen saturation thresholds 94% and 90% to get 1 and 2 Sequential Organ Failure Assessment respiratory points, respectively. This has important implications primarily for emergency practice, rapid response teams, surveillance, research, and resource-limited settings.

Sepsis is the major cause of mortality across intensive care units globally, yet details of accompanying pathological molecular events remains unclear. This knowledge gap has resulted in ineffective development of sepsis-specific biomarkers and therapies, and suboptimal treatment regimens to prevent or reverse organ damage. Here, we used pharmacoproteomics to score treatment effects in a murine Escherichia coli sepsis model based on changes in the organ, cell, and plasma proteome landscapes. A combination of pathophysiological read-outs and time-resolved proteome maps of organs and blood enabled us to define time-dependent and organotypic proteotypes of dysfunction and damage upon administration of several combinations of the broad-spectrum beta-lactam antibiotic meropenem (Mem) and/or the immunomodulatory glucocorticoid methylprednisolone (Gcc). Three distinct response patterns were identified, defined as intervention-specific reversions, non-reversions, and specific intervention-induced effects, which depended on the underlying proteotype and varied significantly across organs. In the later stages of the disease, Gcc enhanced some positive treatment effects of Mem with superior reduction of the inflammatory response in the kidneys and partial restoration of sepsis-induced metabolic dysfunction. Unexpectedly, Mem introduced sepsis-independent perturbations in the mitochondrial proteome that were to some degree counteracted by Gcc. In summary, this study provides a pharmacoproteomic resource describing the time-resolved septic organ failure landscape across organs and blood, coupled to a novel scoring strategy that captures unintended secondary drug effects as an important criterion to consider when assessing therapeutic efficacy. Such information is critical for quantitative, objective, and organotypic assessment of benefits and unintended effects of candidate treatments in relationship to dosing, timing, and potential synergistic combinations in murine sepsis models.

Objective: To evaluate the success rate of Extracorporeal Shock Wave Lithotripsy (ESWL) therapy and identify relevant treatment-specific factors affecting stone-free rate (SFR) after ESWL. Materials and methods: All ESWL treatments in the years 2016–2019, in Ängelholm Hospital, Skåne, Sweden were analysed retrospectively. Primary outcome was stone-free rate (SFR) at 3 months. Univariate logistic regression was used followed by multivariable regression. Lasso analysis was made to adjust for treatment-specific factors such as age, stone size, skin-to-stone distance (SSD), stone attenuation, number of treatments, stone location and presence of a urinary stent. Results: Factors affecting successful ESWL treatment were lower age (p < 0.001), smaller stone size and volume (both p = 0.001). SSD, stone attenuation, sex, laterality and drainage did not have an effect on SFR in this study. After the first ESWL treatment session, 46.7% of the patients were stone-free. Conclusion: Results indicate that stone size and age are the most predictive factors for ESWL outcome. Based on this, we present a simple model for prediction of SFR after ESWL, to be used when counseling patients before ESWL treatment.

IntroductionAdministration of large volumes of fluids is associated with poor outcome in septic shock. Recent data suggest that non-resuscitation fluids are the major source of fluids in the intensive care unit (ICU) patients suffering from septic shock. The present trial is designed to test the hypothesis that a protocol targeting this source of fluids can reduce fluid administration compared with usual care.Methods and analysisThe design will be a multicentre, randomised, feasibility trial. Adult patients admitted to ICUs with septic shock will be randomised within 12 hours of admission to receive non-resuscitation fluids either according to a restrictive protocol or to receive usual care. The healthcare providers involved in the care of participants will not be blinded. The participants, outcome assessors at the 6-month follow-up and statisticians will be blinded. Primary outcome will be litres of fluids administered within 3 days of randomisation. Secondary outcomes will be proportion of randomised participants with outcome data on all-cause mortality; days alive and free of mechanical ventilation within 90 days of inclusion; any acute kidney injury and ischaemic events in the ICU (cerebral, cardiac, intestinal or limb ischaemia); proportion of surviving randomised patients who were assessed by European Quality of Life 5-Dimensions 5-Level questionnaire and Montreal Cognitive Assessment; proportion of all eligible patients who were randomised and proportion of participants experiencing at least one protocol violation.Ethics and disseminationEthics approval has been obtained in Sweden. Results of the primary and secondary outcomes will be submitted for publication in a peer-reviewed journal.Trial registration numberNCT05249088.

With the emergence of severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2), a need for diagnostic tests has surfaced. Point‐of‐care (POC) antibody tests can detect immunoglobulin (Ig) G and M against SARS‐CoV‐2 in serum, plasma or whole blood and give results within 15 minutes. Validation of the performance of such tests is needed if they are to be used in clinical practice. In this study we evaluated three POC antibody tests. Convalescent serum samples from 47 reverse transcription polymerase chain reaction (RT‐PCR) verified coronavirus disease 2019 (COVID‐19) patients collected at least 28 days post RT‐PCR diagnosis as well as 50 negative pre‐COVID‐19 controls were tested. The three tests (denoted the J‐, N‐ and Z‐tests) displayed the sensitivities of 87, 96 and 85 percent, respectively, for the detection of IgG. All tests had the same specificity for IgG (98 percent). The tests did not differ significantly for the detection of IgG. The sensitivities for IgM were lower (15, 67 and 70 percent) and the specificities were 90, 98 and 90 percent, respectively. The positive and negative predictive values were similar among the tests. Our results indicate that these POC antibody tests might be accurate enough to use in routine clinical practice. This article is protected by copyright. All rights reserved.

Background Heparin Binding Protein (HBP) is a promising new biomarker for the development and severity of sepsis. To guide the use of HBP as a biomarker it is important to understand the factors that may lead to false positive or negative results. The mechanisms that could lead to falsely elevated HBP levels include inappropriate release and inadequate clearance of HBP by the responsible cells and organs. HBP is presumably released only by neutrophils and the organs responsible for its elimination are unknown. Therefore, in this study we aimed to determine whether non-neutrophil cells can be a source of HBP in the circulation and which organs are responsible for its removal.Results We measured HBP in two cohorts of neutropenic patients and found that 12% and 19% of patients in each cohort respectively had detectable HBP levels. In vitro, we found that three leukemia-derived monocytic cell lines and healthy CD14 + monocytes constitutively released detectable levels of HBP. Next we injected HBP intravenously in rats found that plasma levels of HBP decreased rapidly, with a distribution half-life below 10 minutes and an elimination half-life of 1–2 hours. We measured HBP levels in the liver, spleen, kidneys, lungs, and urine using both ELISA and immunofluorescence quantitation and found that the majority of HBP was present in the liver and a small amount was present in the spleen. Immunofluorescence imaging indicated that HBP is associated mainly with hepatocytes in the liver and monocytes/macrophages in the spleen.Conclusions HBP can be found in some neutropenic patients. Other than neutrophils, malignant myeloid cells and monocytic cells may be an additional source of HBP. HBP disappears rapidly from the circulation and distributes primarily to liver hepatocytes and spleen monocytes/macrophages. The impact of hematologic malignancies and liver diseases on plasma HBP levels should be explored further in clinical studies.

Objectives The aim of this study was to assess the incidence of infection after transrectal prostate biopsy (TRbx). Secondary objectives were to describe infection characteristics, antibiotic resistance patterns, ICD-10 coding, and costs. Methods TRbx carried out at the hospitals of Angelholm and Helsingborg, Scania, Sweden, between October 2017 and March 2019, were identified based on the NOMESCO Classification of Surgical Procedures code for TRbx, TKE00. All patients received per oral antibiotic prophylaxis, usually 750 mg ciprofloxacin at biopsy. Other preventative measures were not used. Medical care within 30 days of the biopsy was evaluated through a manual retrospective medical chart review. Data on patient and infection characteristics were collected. The costs of infections causing hospitalization were estimated. Results After 36 (5.4%) of 670 biopsies, the patient developed post-biopsy infection within 30 days after TRbx. Twenty-six patients (3.9%) required hospitalization for an average of 6 days, at an estimated direct cost of USD 9174 (EUR 8031) per patient. Nine patients (1.3%) had a complicated infection leading to intensive care, multiple hospitalizations or emergency department visits. The inpatient care episodes for the 26 hospitalized patients were categorized with 15 different ICD-codes. In 6 episodes no ICD-code related to infection was used. Conclusions In this study, we found an infection rate of 5.4% after TRbx; 3.9% of the patients were hospitalized for a post-TRbx infection and 1.3% had complicated infections. A specific ICD code for post-TRbx infections would facilitate evaluation and monitoring of this common, costly, and sometimes serious complication.

Severe infectious diseases are often characterized by an overwhelming and unbalanced systemic immune response to microbial infections. Human antithrombin (hAT) is a crucial coagulation inhibitor with anti-inflammatory activities. Here we identify three hAT-binding proteins (CD13, CD300f and LRP-1) on human monocytes that are involved in blocking the activity of nuclear factor-κB. We found that the modulating effect is primarily restricted to the less abundant β-isoform (hβAT) of hAT that lacks N-glycosylation at position 135. Individuals with a mutation at this position have increased production of hβAT and analysis of their blood, which was stimulated ex vivo with lipopolysaccharide, showed a decreased inflammatory response. Similar findings were recorded when heterozygotic mice expressing hAT or hβAT were challenged with lipopolysaccharide or infected with Escherichia coli bacteria. Our results finally demonstrate that in a lethal E. coli infection model, survival rates increased when mice were treated with hβAT one hour and five hours after infection. The treatment also resulted in a reduction of the inflammatory response and less severe organ damage.

Background Reduced activity of proprotein convertase subtilisin/kexin type 9 (PCSK9) has been associated with decreased short-term death in patients with septic shock. Whether PCSK9 genotype influences long-term outcomes in sepsis survivors is unknown. Methods We evaluated the impact of PCSK9 loss-of-function (LOF) genotype on both 1-year mortality and infection-related readmission (IRR) after an index sepsis admission. The Derivation cohort included 342 patients who survived 28 days after a sepsis admission in a tertiary hospital (Vancouver/Canada, 2004–2014), while an independent Validation cohort included 1079 septic shock patients admitted at the same hospital (2000–2006). All patients were genotyped for three common missense PCSK9 LOF variants rs11591147, rs11583680, rs562556 and were classified in 3 groups: Wildtype, single PCSK9 LOF, and multiple PCSK9 LOF, according to the number of LOF alleles per patient. We also performed a meta-analysis using both cohorts to investigate the effects of PCSK9 genotype on 90-day survival. Findings In the Derivation cohort, patients carrying multiple PCSK9 LOF alleles showed lower risk for the composite outcome 1-year death or IRR (HR: 0.40, P = 0.006), accelerated reduction on neutrophil counts (P = 0.010), and decreased levels of PCSK9 (P = 0.037) compared with WT/single LOF groups. Our meta-analysis revealed that the presence of multiple LOF alleles was associated with lower 90-day mortality risk (OR = 0.69, P = 0.020). Interpretation The presence of multiple PCSK9 LOF alleles decreased the risk of 1-year death or IRR in sepsis survivors. Biological measures suggest this may be related to an enhanced resolution of the initial infection. Funding Canadian Institutes of Health Research (PJT-156056).

Transrectal prostate biopsy (TRbx) transfers colonic bacteria into prostatic tissue, potentially causing infectious complications, including sepsis. Our objective was to determine whether biopsy needle shape, surface properties and sampling mechanism affect the number of bacteria transferred through the colon wall, and evaluate a novel needle with improved properties.The standard Tru-Cut biopsy needle used today was evaluated for mechanisms of bacterial transfer in a pilot study. A novel Tru-Cut needle (Forsvall needle prototype) was developed. TRbx was simulated using human colons ex-vivo. Four subtypes of the prototype needle were compared with a standard Tru-Cut needle (BARD 18 G). Prototype and standard needles were used to puncture 4 different colon specimens in 10 randomized sites per colon. Needles were submerged into culture media to capture translocated bacteria. The media was cultured on blood agar and then the total amount of transferred bacteria was calculated for each needle. The primary outcome measure was the percent reduction of bacteria translocated by the prototype needles relative to the standard needle. Secondary outcome measures were the effects of tip design and coating on the percent reduction of translocated bacteria.Prototype needles reduced the number of translocated bacteria by, on average, 96.0% (95% confidence interval 93.0-97.7%;The Forsvall needle significantly reduces colonic bacterial translocation, suggesting that it could reduce infectious complications in prostate biopsy. A clinical trial has been initiated.

Transrectal prostate biopsy (TRbx) carries an increasing risk of infection. The Forsvall Needle Prototype (FNP) is a novel biopsy needle that reduces bacterial load brought across the rectum and may therefore reduce infection risk. The objective of this study was to compare biopsy length, quality and patient experience for the FNP Version 2 (FNP2) versus a standard Tru-Cut needle.We conducted a randomized, parallel-group, non-inferiority trial with twenty consecutive patients eligible for TRbx. Participants were randomized to undergo TRbx using either FNP2 or a standard Tru-Cut needle. The primary outcome was difference in mean biopsy lengths measured by the pathologist. FNP2 biopsy lengths ≤1.35 mm of the standard needle length were considered non-inferior. Secondary outcomes were biopsy length in the needle chamber and immediately after removal, biopsy quality, biopsy fragmentation, patient discomfort/pain, and complications (immediate and after 14 and 30 days).Mean pathologist-measured FNP2 biopsy length was non-inferior compared to the standard Tru-Cut needle (0.02 mm longer, 95%CI-0.73 to 0.76 mm). Biopsy length in the needle chamber and immediately after removal were also non-inferior. Biopsy quality and patient discomfort were not significantly different for the FNP2 and the standard Tru-Cut needle. Biopsy fragmentation was more common in the FNP2 group.The FNP2 biopsy needle is non-inferior to the Tru-Cut needle in terms of biopsy length and not significantly different in terms of biopsy quality and patient experience. Future studies will evaluate the Forsvall needle design's effect on post-biopsy infection risk.

Severe coronavirus disease 2019 (COVID-19) can result in pneumonia and acute respiratory failure. Accumulation of mucus in the airways is a hallmark of the disease and can result in hypoxemia. Here, we show that quantitative proteome analysis of the sputum from severe patients with COVID-19 reveal high levels of neutrophil extracellular trap (NET) components, which was confirmed by microscopy. Extracellular DNA from excessive NET formation can increase sputum viscosity and lead to acute respiratory distress syndrome. Recombinant human DNase (Pulmozyme; Roche) has been shown to be beneficial in reducing sputum viscosity and improve lung function. We treated five patients pwith COVID-19 resenting acute symptoms with clinically approved aerosolized Pulmozyme. No adverse reactions to the drug were seen, and improved oxygen saturation and recovery in all severely ill patients with COVID-19 was observed after therapy. Immunofluorescence and proteome analysis of sputum and blood plasma samples after treatment revealed a marked reduction of NETs and a set of statistically significant proteome changes that indicate reduction of hemorrhage, plasma leakage and inflammation in the airways, and reduced systemic inflammatory state in the blood plasma of patients. Taken together, the results indicate that NETs contribute to acute respiratory failure in COVID-19 and that degrading NETs may reduce dependency on external high-flow oxygen therapy in patients. Targeting NETs using recombinant human DNase may have significant therapeutic implications in COVID-19 disease and warrants further studies.

One can falsely assume that it is well known that bacteremia is associated with higher mortality in sepsis. Only a handful of studies specifically focus on the comparison of culture-negative and culture-positive sepsis with different conclusions depending on study design. The aim of this study was to describe outcome for critically ill patients with either culture-positive or -negative sepsis in a clinical review. We also aimed to identify subphenotypes of sepsis with culture status included as candidate clinical variables. Out of 784 patients treated in intensive care with a sepsis diagnosis, blood cultures were missing in 140 excluded patients and 95 excluded patients did not fulfill a sepsis diagnosis. Of 549 included patients, 295 (54%) had bacteremia, 90 (16%) were non-bacteremic but with relevant pathogens detected and in 164 (30%) no relevant pathogen was detected. After adjusting for confounders, 90-day mortality was higher in bacteremic patients, 47%, than in non-bacteremic patients, 36%, p = 0.04. We identified 8 subphenotypes, with different mortality rates, where pathogen detection in microbial samples were important for subphenotype distinction and outcome. In conclusion, bacteremic patients had higher mortality than their non-bacteremic counter-parts and bacteremia is more common in sepsis when studied in a clinical review. For reducing population heterogeneity and improve the outcome of trials and treatment for sepsis, distinction of subphenotypes might be useful and pathogen detection an important factor.

Background Sepsis is a critical illness with high morbidity and mortality rates. Each year, sepsis affects about 48.9 million people all over the world. This study aims to illuminate how sepsis survivors experience sepsis and the impact of sepsis, as well as the health-related quality of life thereafter. Methods An interview study with eight sepsis survivors was carried out in Sweden with an inductive qualitative method. The data were analyzed with content analysis. Results Four themes were identified during the analysis; The experience of health care and being a sepsis patient, New circumstances´ impact on life, Family and social interactions, and The psychological impact on life. The lack of information about how sepsis can impact the survivors’ lives and what to expect can lead to prolonged agony. The long recovery time comes as an unexpected and unpleasant surprise to those affected. Initially, the sepsis survivors are almost euphoric that they have survived, which can later lead to chock and trauma when they realize that they could have died. This insight needs to be processed in order to reach reconciliation with life after sepsis. Conclusion Sepsis has a huge impact on both physical and mental aspects of life. Many survivors suffer from persistent residual symptoms of varying degrees, to which they have to adapt. The sepsis survivors need individually adjusted information about the sepsis recovery trajectory, and what to expect during and after the hospital stay.

BackgroundSepsis is a highly heterogenous disease which needs to be thoroughly mapped. The aim of this study was to describe characteristics and outcome for critically ill patients with sepsis-3 with either culture-positive or -negative sepsis.Methods Patients with severe sepsis or septic shock were retrospectively identified in the local quality registry from a general mixed Intensive Care Unit (ICU) at a University Hospital in 2007-2014. Data were collected through manual review of medical charts. Patients were included if they fulfilled sepsis-3 criteria and at least one blood culture was sampled ±48h from ICU admission. In a propensity score analysis bacteremic and non-bacteremic patients were matched 1:1 with regard to age, comorbidities, site of infection and antimicrobial therapy prior to blood cultures. A Latent Class Analysis (LCA) was performed to identify unmeasured class membership.Results784 patients were identified as treated in the ICU with a sepsis diagnosis. Blood cultures were missing in 140 excluded patients and additionally 95 patients did not fulfill a sepsis diagnosis and were also excluded. In total 549 patients were included, 295 (54%) with bacteremia, 90 (16%) were non-bacteremic but had relevant pathogens detected from another body location and in 164 (30%) no relevant pathogen was detected in microbial samples. After the propensity score analysis (n=172 in each group) 90-day mortality was higher in bacteremic patients, 47%, than in non-bacteremic patients, 36%, p =0.04. Patients without antibiotic treatment before sample collection (n=352) were more often bacteremic, 63%. Non-bacteremic patients without prior antibiotic treatment had lower mortality, 31% (n=129), compared to non-bacteremic patients with prior antibiotic treatment, 51% (n=124), p

Background and aimsNeutrophil-derived heparin binding protein (HBP; also known as azurocidin or CAP-37) is a key player in bacterial sepsis and a promising biomarker in severe infections. The aims of this study were to assess whether HBP is involved in the pathophysiology of COVID-19 and, if so, whether it can be used to predict severe disease preferably using a point-of-care test.MethodsThis was a prospective convenience sample study of biomarkers in patients admitted to Skåne University hospital in Sweden with a confirmed COVID-19 diagnosis. Plasma samples and clinical data were collected within 72h after admission, during hospital stay and at discharge. Plasma HBP concentrations samples were measured both with enzyme-linked immunosorbent assay (ELISA) and with a novel dry immunofluorescence analyzer (Joinstar) point-of-care test.ResultsThirty-five COVID-19 patients were enrolled in the study. Twenty-nine patients had blood samples taken within 72h after admission. We compared the highest HBP value taken within 72h after admission in patients who eventually developed organ dysfunction (n = 23) compared to those who did not (n = 6), and found that HBP was significantly elevated in those who developed organ dysfunction (25.0 ng/mL (interquartile range (IQR) 16.6-48.5) vs 10.6 ng/mL (IQR 4.8-21.7 ng/mL), p = 0.03). Point-of-care test measurements correlated well with ELISA measurements (R = 0.83). HBP measured by the POC device predicted development of COVID-induced organ dysfunction with an AUC of 0.88 (95% confidence interval (CI) 0.70-1.0).ConclusionsHBP is elevated prior to onset of organ dysfunction in patients with severe COVID-19 using a newly developed point-of-care test and hence HBP could be used in a clinical setting as a prognostic marker in COVID-19.

Meningitis is a potentially life-threatening infection characterized by the inflammation of the leptomeningeal membranes. Many different viral and bacterial pathogens can cause meningitis, with differences in mortality rates, risk of developing neurological sequelae and treatment options. Here we constructed a compendium of digital cerebrospinal fluid (CSF) proteome maps to define pathogen-specific host response patterns in meningitis. The results revealed a drastic and pathogen-type specific influx of tissue-, cell- and plasma proteins in the CSF, where in particular a large increase of neutrophil derived proteins in the CSF correlated with acute bacterial meningitis. Additionally, both acute bacterial and viral meningitis result in marked reduction of brain-enriched proteins. Generation of a multi-protein LASSO regression model resulted in an 18-protein panel of cell and tissue associated proteins capable of classifying acute bacterial meningitis and viral meningitis. The same protein panel also enabled classification of tick-borne encephalitis, a subgroup of viral meningitis, with high sensitivity and specificity. The work provides insights into pathogen specific host response patterns in CSF from different disease etiologies to support future classification of pathogen-type based on host response patterns in meningitis.

BackgroundSurgical trauma and cardiopulmonary bypass (CPB) cause an inflammatory response, difficult to differentiate from postoperative infections. Heparin-binding protein (HBP) is released from neutrophils and has been shown to predict infection-related organ dysfunction and disease progression to severe sepsis. In order to explore the potential of HBP as a biomarker for postoperative infections and asess possible confounding effects of concomitant medications, this study aimed to investigate the pre-, intra- and postoperative dynamics of HBP in cardiac surgery with CPB.Methods Thirty patients undergoing cardiac surgery with CPB were included, of which 15 underwent coronary artery bypass grafting (CABG) surgery and 15 underwent complex procedures with longer CPB duration. Ten patients undergoing lung surgery without CPB were also included as a conventional surgery reference group. HBP was measured at nine different perioperative time points.Results Our results showed that HBP levels were not affected by surgical trauma by itself. An increase in HBP levels was observed immediately following heparin administration and further increased during CPB. Prior to protaminization, we measured higher peak HBP-levels in the complex group (345.7 (287.8-472.6) ng/mL) compared with the CABG group (152.7 (85.3-204.0) ng/mL, pp=0.004). One day after surgery, HBP levels in all three groups were below the proposed cutoff of 30 ng/mL, previously found to predict development of organ dysfunction during infection, while other biomarkers for infections remained elevated.ConclusionsHBP levels are elevated by administration of heparin and the use of CPB but reduced by protamine administration. At postoperative day one, HBP levels were below the threshold for infection with organ dysfunction, indicating that postoperative HBP measurement may be a better screening tool for postoperative infections than other biomarkers of infections that remain elevated after surgery.

Background: This study aims to illuminate how sepsis survivors experience sepsis and the impact of sepsis as well as the quality of life thereafter. Methods: A qualitative open interview study with eight sepsis survivors was performed. A content analysis inspired by Burnard was made. Results: Four main categories emerged during the analysis; The experience of health care and being a sepsis patient, New circumstances´ impact on life, Family and social interactions, and The psychological impact on life. The lack of information on how sepsis can impact the survivors’ lives and what to expect can lead to prolonged agony. The long recovery time comes as an unexpected and unpleasant surprise to those affected. Initially, the sepsis survivors are almost euphoric that they have survived, which can later lead to chock and trauma when they realize that they could have died. This insight needs to be processed in order to reach reconciliation with how life will turn out after sepsis. Conclusion: Sepsis has a huge impact on both physical and mental aspects of life. Many survivors suffer from persistent residual symptoms of varying degrees to which they have to adapt. The sepsis survivors need individually adjusted information about the sepsis recovery trajectory and what to expect during and after the hospital stay.

Background: The pathophysiology of severe COVID-19 has been implicated to involve neutrophil activation in the blood and in the lungs and endothelial dysfunction. Heparin binding protein (HBP) is a neutrophil protein that plays an important role in bacterial sepsis and is a promising biomarker in severe infections. Syndecans and glypicans are potential markers of sheeding of the glycocalyx and endothelial dysfunction.The primary aims of this study were to assess whether HBP or syndecans and glypicans are involved in the pathophysiology of COVID-19 and if so, whether they can be used to predict severe disease preferably using a point-of-care test (POC) that can substitute more time-consuming analysis with enzyme-linked immunosorbent assay (ELISA).Methods: A prospective convenience sample study of biomarkers. The main cohort consisted of patients admitted to hospital with a confirmed COVID-19 diagnosis. Samples and clinical data were collected at admission, during admission and at discharge and samples were analyzed with ELISA kit (Axis-Shield Diagnostics) for measuring HBP concentration and a novel dry immunofluorescence analyzer (Jet-iStar 800) (Joinstar) for point-of-care testing.Results: Thirty-five COVID-19 patients were prospectively enrolled in the study. HBP was significantly elevated in COVID-19 patients with organ dysfunction (n= 23) compared to those without organ dysfunction (n=6), 24.7 ng/mL (95% CI 17.3-48.4) vs 10.6 ng/mL (95% CI 6.2-17.1 ng/mL), p=0.03. Syndecan-1 and Glypican-4 were not significantly elevated in patients with organ dysfunction. Syndecan-1, 62.1 ng/mL (44.4-102.0) vs 57.5 ng/mL (95% CI 46.0- 63.7), p=0.44 and glypican-4, 3292.4 pg/mL (95% CI 1707.5- 6790.6) vs 3962.7 pg/mL (95% CI 2653.6- 5823.5), p=0.80. The point-of-care (POC) HBP test showed good correlation to the standard ELISA with an R-value of 0.83. HBP measured by the POC device predicted development of COVID-induced organ dysfunction within 72 hours with an AUC of 0.88.Conclusions: The neutrophil-derived HBP is elevated prior to onset of organ dysfunction in patients with severe COVID-19 using a newly developed point-of-care test and hence HBP could be used in a clinical setting as a prognostic marker in COVID-19.