| 1. |
- Abazajian, Kevork, et al.
(författare)
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CMB-S4 : Forecasting Constraints on Primordial Gravitational Waves
- 2022
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Ingår i: Astrophysical Journal. - : American Astronomical Society. - 0004-637X .- 1538-4357. ; 926:1
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Tidskriftsartikel (refereegranskat)abstract
- CMB-S4—the next-generation ground-based cosmic microwave background (CMB) experiment—is set to significantly advance the sensitivity of CMB measurements and enhance our understanding of the origin and evolution of the universe. Among the science cases pursued with CMB-S4, the quest for detecting primordial gravitational waves is a central driver of the experimental design. This work details the development of a forecasting framework that includes a power-spectrum-based semianalytic projection tool, targeted explicitly toward optimizing constraints on the tensor-to-scalar ratio, r, in the presence of Galactic foregrounds and gravitational lensing of the CMB. This framework is unique in its direct use of information from the achieved performance of current Stage 2–3 CMB experiments to robustly forecast the science reach of upcoming CMB-polarization endeavors. The methodology allows for rapid iteration over experimental configurations and offers a flexible way to optimize the design of future experiments, given a desired scientific goal. To form a closed-loop process, we couple this semianalytic tool with map-based validation studies, which allow for the injection of additional complexity and verification of our forecasts with several independent analysis methods. We document multiple rounds of forecasts for CMB-S4 using this process and the resulting establishment of the current reference design of the primordial gravitational-wave component of the Stage-4 experiment, optimized to achieve our science goals of detecting primordial gravitational waves for r > 0.003 at greater than 5σ, or in the absence of a detection, of reaching an upper limit of r < 0.001 at 95% CL.
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| 2. |
- Hayden, Brian, et al.
(författare)
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The HST See Change Program. I. Survey Design, Pipeline, and Supernova Discoveries
- 2021
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Ingår i: Astrophysical Journal. - : American Astronomical Society. - 0004-637X .- 1538-4357. ; 912:2
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Tidskriftsartikel (refereegranskat)abstract
- The See Change survey was designed to make z > 1 cosmological measurements by efficiently discovering high-redshift Type Ia supernovae (SNe Ia) and improving cluster mass measurements through weak lensing. This survey observed twelve galaxy clusters with the Hubble Space Telescope (HST) spanning the redshift range z = 1.13-1.75, discovering 57 likely transients and 27 likely SNe Ia at z similar to 0.8-2.3. As in similar previous surveys, this proved to be a highly efficient use of HST for supernova observations; the See Change survey additionally tested the feasibility of maintaining, or further increasing, the efficiency at yet higher redshifts, where we have less detailed information on the expected cluster masses and star formation rates. We find that the resulting number of SNe Ia per orbit is a factor of similar to 8 higher than for a field search, and 45% of our orbits contained an active SN Ia within 22 rest-frame days of peak, with one of the clusters by itself yielding 6 of the SNe Ia. We present the survey design, pipeline, and supernova discoveries. Novel features include fully blinded supernova searches, the first random forest candidate classifier for undersampled IR data (with a 50% detection threshold within 0.05 mag of human searchers), real-time forward-modeling photometry of candidates, and semi-automated photometric classifications and follow-up forecasts. We also describe the spectroscopic follow-up, instrumental in measuring host galaxy redshifts. The cosmology analysis of our sample will be presented in a companion paper.
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| 3. |
- Apitzsch, Sabine, et al.
(författare)
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The physical and mental impact of surviving sepsis – a qualitative study of experiences and perceptions among a Swedish sample
- 2021
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Ingår i: Archives of Public Health. - : Springer Science and Business Media LLC. - 0778-7367 .- 2049-3258. ; 79:1
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Tidskriftsartikel (refereegranskat)abstract
- 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.
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| 4. |
- Bakochi, Anahita, et al.
(författare)
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Cerebrospinal fluid proteome maps detect pathogen-specific host response patterns in meningitis
- 2021
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Ingår i: eLife. - 2050-084X. ; 10
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Tidskriftsartikel (refereegranskat)abstract
- 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.
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| 5. |
- Dahlberg, Jacob, et al.
(författare)
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Use of healthcare before and after sepsis in Sweden : a case-control study
- 2023
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Ingår i: BMJ Open. - : BMJ. - 2044-6055. ; 13:2, s. 065967-065967
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVES: The aim of this study was to compare readmissions and death between sepsis and non-sepsis hospitalisations the first year after discharge, and to investigate what diagnoses patients with sepsis present with at readmission. The aim was also to evaluate to what degree patients hospitalised for sepsis seek medical attention prior to hospitalisation. DESIGN: Retrospective case-control study with data validated through clinical chart review. A disproportionate stratified sampling model was used to include a relatively larger number of sepsis hospitalisations. SETTING: All eight public hospitals in region Scania, Sweden (1 January to 3 December 2019). PARTICIPANTS: There were 447 patients hospitalised for sepsis (cases), and 541 hospitalised for other causes (control) identified through clinical chart review. OUTCOME MEASURES: Cox regression was used to analyse readmission and death the year after discharge, and logistic regression was used to analyse healthcare the week prior to hospitalisation. Both analyses were made unadjusted, and adjusted for age, sex and comorbidities. RESULTS: Out of patients who survived a sepsis hospitalisation, 48% were readmitted the year after discharge, compared with 39% for patients without sepsis (HR 1.50, 95% CI 1.03 to 2.19), p=0.04. The majority (52%) of readmissions occurred within 90 days and 75% within 180 days. The readmissions were most often caused by infection (32%), and 18% by cardiovascular disease. Finally, 34% of patients with sepsis had sought prehospital contact with a physician the week before hospitalisation, compared with 22% for patients without sepsis (OR 1.80, 95% CI 1.06 to 3.04), p=0.03. CONCLUSION: Patients hospitalised for sepsis had a higher risk of readmission the year after discharge compared with patients without sepsis. The most common diagnoses at readmission were infection followed by cardiovascular disease. With better follow-up, some of these readmissions could potentially be prevented. Patients hospitalised for sepsis had sought prehospital contact the week prior to hospitalisation to a greater extent than patients without sepsis.
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| 6. |
- Dardashti, Alain, et al.
(författare)
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Impact of cardiopulmonary bypass and surgical complexity on plasma soluble urokinase-type plasminogen activator receptor levels after cardiac surgery
- 2021
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Ingår i: Scandinavian Journal of Clinical and Laboratory Investigation. - : Informa UK Limited. - 0036-5513 .- 1502-7686. ; 81:8, s. 634-640
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Tidskriftsartikel (refereegranskat)abstract
- Background: 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 Methods: 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. Results: 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, p <.001. There were no significant differences in suPAR concentrations between the groups at any time point. Preoperatively, the median suPAR concentration was 2.57 (2.01–3.60) µg/L in the CABG group versus 2.67 (1.89–3.97) µg/L in the complex group (p =.567). At ICU arrival 2.48 (2.34–3.23) µg/L versus 2.73 (2.28–3.44) µg/L in CABG and complex patients, respectively (p =.914). There was no difference in suPAR concentrations between the groups on postoperative day 1 (3.34 (2.89–3.89) versus 3.19 (2.57–3.62) p =.967) or 3–5 days after surgery (2.72 (1.98–3.16) versus 2.96 (2.39–4.28) p =.085. Conclusions: 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.
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| 7. |
- Fisher, Jane, et al.
(författare)
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A functional observational battery for evaluation of neurological outcomes in a rat model of acute bacterial meningitis
- 2020
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Ingår i: Intensive Care Medicine Experimental. - : Springer Science and Business Media LLC. - 2197-425X. ; 8
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Tidskriftsartikel (refereegranskat)abstract
- Background Acute bacterial meningitis is a disease with a high mortality and a high incidence of neurological sequelae in survivors. There is an acute need to develop new adjuvant therapies. To ensure that new therapies evaluated in animal models are translatable to humans, studies must evaluate clinically relevant and patient-important outcomes, including neurological symptoms and sequelae. Methods We developed and tested a functional observational battery to quantify the severity of a variety of relevant neurological and clinical symptoms in a rat model of bacterial meningitis. The functional observational battery included symptoms relating to general clinical signs, gait and posture abnormalities, involuntary motor movements, focal neurological signs, and neuromotor abnormalities which were scored according to severity and summed to obtain a combined clinical and neurological score. To test the functional observational battery, adult Sprague-Dawley rats were infected by intracisternal injection of a clinical isolate of Streptococcus pneumoniae. Rats were evaluated for 6 days following the infection. Results Pneumococcal meningitis was not lethal in this model; however, it induced severe neurological symptoms. Most common symptoms were hearing loss (75% of infected vs 0% of control rats; p = 0.0003), involuntary motor movements (75% of infected vs 0% of control rats; p = 0.0003), and gait and posture abnormality (67% of infected vs 0% of control rats; p = 0.0013). Infected rats had a higher combined score when determined by the functional observational battery than control rats at all time points (24 h 12.7 ± 4.0 vs 4.0 ± 2.0; 48 h 17.3 ± 7.1 vs 3.4 ± 1.8; 6 days 17.8 ± 7.4 vs 1.7 ± 2.4; p < 0.0001 for all). Conclusions The functional observational battery described here detects clinically relevant neurological sequelae of bacterial meningitis and could be a useful tool when testing new therapeutics in rat models of meningitis.
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| 8. |
- Fisher, Jane, et al.
(författare)
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Non-corticosteroid adjuvant therapies for acute bacterial meningitis
- 2021
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Ingår i: Cochrane Database of Systematic Reviews. - 1465-1858. ; 2021:11
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Forskningsöversikt (refereegranskat)abstract
- Background: Acute bacterial meningitis is a bacterial infection of the membranes that surround and protect the brain, known as the meninges. The primary therapy for bacterial meningitis is antibiotics and corticosteroids. Although these therapies significantly improve outcomes, bacterial meningitis still has a high risk of death and a high risk of neurological sequelae in survivors. New adjuvant therapies are needed to further reduce the risk of death and neurological sequelae in bacterial meningitis. Objectives: To assess the effects of non-corticosteroid adjuvant pharmacological therapies for mortality, hearing loss, and other neurological sequelae in people with acute bacterial meningitis. Search methods: We searched CENTRAL, MEDLINE, Embase, CINAHL, and LILACS databases and ClinicalTrials.gov and WHO ICTRP trials registers up to 30 September 2021, together with reference checking, citation searching, and contact with study authors to identify additional studies. Selection criteria: We included randomised controlled trials (RCTs) of any pharmacological adjuvant therapy for acute bacterial meningitis. Data collection and analysis: Two review authors independently assessed and extracted data on methods, participants, interventions, and outcomes. We assessed risk of bias of studies with the Cochrane risk of bias tool and the certainty of the evidence using the GRADE approach. We presented results using risk ratios (RR) and 95% confidence intervals (CI) when meta-analysis was possible. All other results are presented in a narrative synthesis. Main results: We found that five different adjuvant therapies have been tested in RCTs for bacterial meningitis. These include paracetamol (3 studies, 1274 participants who were children); immunoglobulins (2 studies, 49 participants; one study included children, and the other adults); heparin (1 study, 15 participants who were adults); pentoxifylline (1 study, 57 participants who were children); and a mixture of succinic acid, inosine, nicotinamide, and riboflavin mononucleotide (1 study, 30 participants who were children). Paracetamol may make little or no difference to mortality (paracetamol 35.2% versus placebo 37.4%, 95% CI 30.3% to 40.8%; RR 0.94, 95% CI 0.81 to 1.09; 3 studies, 1274 participants; I² = 0%; low certainty evidence); hearing loss (RR 1.04, 95% CI 0.80 to 1.34; 2 studies, 901 participants; I² = 0%; low certainty evidence); neurological sequelae other than hearing loss (RR 1.56, 95% CI 0.98 to 2.50; 3 studies, 1274 participants; I² = 60%; low certainty evidence); and severe hearing loss (RR 0.96, 95% CI 0.67 to 1.36; 2 studies, 901 participants; I² = 0%; low certainty evidence). Paracetamol may lead to slightly more short-term neurological sequelae other than hearing loss (RR 1.99, 95% CI 1.40 to 2.81; 2 studies, 1096 participants; I² = 0%; low certainty evidence) and slightly more long-term neurological sequelae other than hearing loss (RR 2.32, 95% CI 1.34 to 4.04; 2 studies, 901 participants; I² = 0%; low certainty evidence). No adverse events were reported in either group in any of the paracetamol studies (very low certainty evidence). Two paracetamol studies had a low risk of bias in most domains, and one had low or unclear risk of bias in all domains. We judged the certainty of evidence to be low for mortality due to limitations in study design (unclear risk of bias in at least one domain and imprecision (high level of uncertainty in absolute effects), and low for all other outcomes due to limitations in study design (unclear risk of bias in at least one domain), and imprecision (low sample size and few events) or inconsistency in effect estimates (heterogeneity). We were not able to perform meta-analysis for any of the other adjuvant therapies due to the limited number of included studies. It is uncertain whether immunoglobulins, heparin, or pentoxifylline improves mortality outcomes due to the very low certainty of the evidence. Zero adverse events were reported for immunoglobulins (very low certainty evidence), and allergic reactions occurred at a rate of 3.3% in participants receiving a mixture of succinic acid, inosine, nicotinamide, and riboflavin mononucleotide (intervention group) (very low certainty evidence). None of our other outcomes (hearing loss, neurological sequelae other than hearing loss, severe hearing loss, and short-term or long-term neurological sequelae other than hearing loss) were reported in these studies, and all of these studies were judged to have a high risk of bias. All reported outcomes for all included adjuvant therapies, other than paracetamol, were graded as very low certainty of evidence due to limitations in study design (unclear or high risk of bias in at least four domains) and imprecision (extremely low sample size and few events). Authors' conclusions: Few adjuvant therapies for bacterial meningitis have been tested in RCTs. Paracetamol may make little or no difference to mortality, with a high level of uncertainty in the absolute effects (low certainty evidence). Paracetamol may make little or no difference to hearing loss, neurological sequelae other than hearing loss, and severe hearing loss (all low certainty evidence). Paracetamol may lead to slightly more short-term and long-term neurological sequelae other than hearing loss (both outcomes low certainty evidence). There is insufficient evidence to determine whether any of the adjuvant therapies included in this review (paracetamol, immunoglobulins, heparin, pentoxifylline, or a mixture of succinic acid, inosine, nicotinamide, and riboflavin mononucleotide) are beneficial or detrimental in acute bacterial meningitis.
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| 9. |
- Fisher, Jane, et al.
(författare)
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Proteome profiling of recombinant DNase therapy in reducing NETs and aiding recovery in COVID-19 patients
- 2021
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Ingår i: Molecular and Cellular Proteomics. - : Elsevier BV. - 1535-9484 .- 1535-9476. ; 20
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Tidskriftsartikel (refereegranskat)abstract
- Severe COVID-19 can result in pneumonia and acute respiratory failure. Accumulation of mucus in the airways is a hall mark of the disease and can result in hypoxemia. Here, we show that quantitative proteome analysis of the sputum from severe COVID-19 patients reveal high levels of neutrophil extracellular trap(s) (NETs) components, which was confirmed by microscopy. Extracellular DNA from excessive NET formation can increase sputum viscosity and can lead to acute respiratory distress syndrome (ARDS). Recombinant human DNase (rhDNase/Pulmozyme) has been shown to be beneficial in reducing sputum viscosity and improve lung function. We treated 5 COVID-19 patients presenting 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 COVID-19 patients 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 haemorrhage, 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 rhDNase may have significant therapeutic implications in COVID-19 disease and warrants further studies.
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| 10. |
- Fisher, Jane, et al.
(författare)
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The Dynamics of Circulating Heparin-Binding Protein : Implications for Its Use as a Biomarker
- 2022
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Ingår i: Journal of Innate Immunity. - : S. Karger AG. - 1662-811X .- 1662-8128. ; 14:5, s. 447-460
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Tidskriftsartikel (refereegranskat)abstract
- Heparin-binding protein (HBP) is a promising biomarker for the development and severity of sepsis. To guide its use, it is important to understand the factors that could lead to false-positive or negative results, such as inappropriate release and inadequate clearance of HBP. HBP is presumably released only by neutrophils, and the organs responsible for its elimination are unknown. In this study, we aimed to determine whether non-neutrophil cells can be a source of circulating HBP and which organs are responsible for its removal. We found that in two cohorts of neutropenic patients, 12% and 19% of patients in each cohort, respectively, had detectable plasma HBP levels. In vitro, three leukemia-derived monocytic cell lines and healthy CD14+ monocytes constitutively released detectable levels of HBP. When HBP was injected intravenously in rats, we found that plasma levels of HBP decreased rapidly, with a distribution half-life below 10 min and an elimination half-life of 1-2 h. 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. The impact of hematologic malignancies and liver diseases on plasma HBP levels should be explored further in clinical studies.
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| 11. |
- Forsvall, Andreas, et al.
(författare)
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Evaluation of the Forsvall biopsy needle in an ex vivo model of transrectal prostate biopsy - a novel needle design with the objective to reduce the risk of post-biopsy infection
- 2021
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Ingår i: Scandinavian Journal of Urology. - : Medical Journals Sweden AB. - 2168-1805 .- 2168-1813. ; 55:3, s. 227-234
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Tidskriftsartikel (refereegranskat)abstract
- Background 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. Methods 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. Results Prototype needles reduced the number of translocated bacteria by, on average, 96.0% (95% confidence interval 93.0-97.7%; p < 0.001) relative to the standard needle. This percent reduction was not significantly affected by prototype needle tip style or surface coating. Conclusions The Forsvall needle significantly reduces colonic bacterial translocation, suggesting that it could reduce infectious complications in prostate biopsy. A clinical trial has been initiated.
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| 12. |
- Forsvall, Andreas, et al.
(författare)
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Prostate biopsy quality and patient experience with the novel Forsvall biopsy needle - a randomized controlled non-inferiority trial
- 2021
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Ingår i: Scandinavian Journal of Urology. - : Medical Journals Sweden AB. - 2168-1805 .- 2168-1813. ; 55:3, s. 235-241
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Tidskriftsartikel (refereegranskat)abstract
- Background 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. Methods 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). Results 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. Conclusions 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.
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| 13. |
- Forsvall, Andreas, et al.
(författare)
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Rate and characteristics of infection after transrectal prostate biopsy: a retrospective observational study
- 2021
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Ingår i: Scandinavian Journal of Urology. - : Medical Journals Sweden AB. - 2168-1805 .- 2168-1813. ; 55:4, s. 317-323
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Tidskriftsartikel (refereegranskat)abstract
- 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.
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| 14. |
- Hartman, Erik, et al.
(författare)
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Interpreting biologically informed neural networks for enhanced proteomic biomarker discovery and pathway analysis
- 2023
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Ingår i: Nature Communications. - 2041-1723. ; 14, s. 1-13
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Tidskriftsartikel (refereegranskat)abstract
- The incorporation of machine learning methods into proteomics workflows improves the identification of disease-relevant biomarkers and biological pathways. However, machine learning models, such as deep neural networks, typically suffer from lack of interpretability. Here, we present a deep learning approach to combine biological pathway analysis and biomarker identification to increase the interpretability of proteomics experiments. Our approach integrates a priori knowledge of the relationships between proteins and biological pathways and biological processes into sparse neural networks to create biologically informed neural networks. We employ these networks to differentiate between clinical subphenotypes of septic acute kidney injury and COVID-19, as well as acute respiratory distress syndrome of different aetiologies. To gain biological insight into the complex syndromes, we utilize feature attribution-methods to introspect the networks for the identification of proteins and pathways important for distinguishing between subtypes. The algorithms are implemented in a freely available open source Python-package ( https://github.com/InfectionMedicineProteomics/BINN ).
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| 15. |
- Johannesson, Emilia, et al.
(författare)
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Utility of heparin-binding protein following cardiothoracic surgery using cardiopulmonary bypass
- 2023
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Ingår i: Scientific Reports. - 2045-2322. ; 13:1
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Tidskriftsartikel (refereegranskat)abstract
- Cardiothoracic surgery using cardiopulmonary bypass (CPB) triggers an inflammatory state that may be difficult to differentiate from infection. Heparin-binding protein (HBP) is a candidate biomarker for sepsis. As data indicates that HBP normalizes rapidly after cardiothoracic surgery, it may be a suitable early marker of postoperative infection. We therefore aimed to investigate which variables influence postoperative HBP levels and whether elevated HBP concentration is associated with poor surgical outcome. This exploratory, prospective, observational study enrolled 1475 patients undergoing cardiothoracic surgery using CPB, where HBP was measured at ICU arrival. Patients with HBP in the highest tercile were compared to remaining patients. Multivariable logistic regressions were performed to identify factors predictive of elevated HBP and 30-day mortality. Overall median HBP was 30.0 ng/mL. Patients undergoing isolated CABG or surgery with CPB-duration ≤ 60 min had a median HBP of 24.9 ng/mL and 23.2 ng/mL, respectively. Independent predictors of elevated postoperative HBP included increased EuroSCORE, prolonged CPB-duration and high intraoperative temperature. Increased HBP was an independent predictor of 30-day mortality. This study confirms the promising characteristics of HBP as a biomarker for identification of postoperative sepsis, especially after routine procedures. Further studies are required to investigate whether HBP may detect postoperative infections.
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| 16. |
- Juul, Sophie, et al.
(författare)
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Interventions for treatment of COVID-19 : A protocol for a living systematic review with network meta-analysis including individual patient data (The LIVING Project)
- 2020
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Ingår i: Systematic Reviews. - : Springer Science and Business Media LLC. - 2046-4053. ; 9:1
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Forskningsöversikt (refereegranskat)abstract
- Background: COVID-19 is a rapidly spreading virus infection that has quickly caused extensive burden to individual, families, countries, and the globe. No intervention has yet been proven effective for the treatment of COVID-19. Some randomized clinical trials assessing the effects of different drugs have been published, and more are currently underway. There is an urgent need for a living, dynamic systematic review that continuously evaluates the beneficial and harmful effects of all available interventions for COVID-19. Methods/design: We will conduct a living systematic review based on searches of major medical databases (e.g., MEDLINE, EMBASE, CENTRAL) and clinical trial registries from their inception onwards to identify relevant randomized clinical trials. We will update the literature search once a week to continuously assess if new evidence is available. Two review authors will independently extract data and perform risk of bias assessment. We will include randomized clinical trials comparing any intervention for the treatment of COVID-19 (e.g., pharmacological interventions, fluid therapy, invasive or noninvasive ventilation, or similar interventions) with any comparator (e.g., an "active" comparator, standard care, placebo, no intervention, or "active placebo") for participants in all age groups with a diagnosis of COVID-19. Primary outcomes will be all-cause mortality and serious adverse events. Secondary outcomes will be admission to intensive care, mechanical ventilation, renal replacement therapy, quality of life, and non-serious adverse events. The living systematic review will include aggregate data meta-analyses, Trial Sequential Analyses, network meta-analysis, and individual patient data meta-analyses. Risk of bias will be assessed with domains, an eight-step procedure will be used to assess if the thresholds for clinical significance are crossed, and the certainty of the evidence will be assessed by Grading of Recommendations, Assessment, Development and Evaluations (GRADE). Discussion: COVID-19 has become a pandemic with substantial mortality. A living systematic review evaluating the beneficial and harmful effects of pharmacological and other interventions is urgently needed. This review will continuously inform best practice in treatment and clinical research of this highly prevalent disease.
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| 17. |
- Karlsson Valik, John, et al.
(författare)
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Peripheral Oxygen Saturation Facilitates Assessment of Respiratory Dysfunction in the Sequential Organ Failure Assessment Score With Implications for the Sepsis-3 Criteria
- 2022
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Ingår i: Critical Care Medicine. - 0090-3493 .- 1530-0293. ; 50:3, s. e272-e283
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Tidskriftsartikel (refereegranskat)abstract
- 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.
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| 18. |
- Lindén, Anja, et al.
(författare)
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Protocolised reduction of non-resuscitation fluids versus usual care in patients with septic shock (REDUSE): a protocol for a multicentre feasibility trial
- 2023
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Ingår i: Bmj Open. - : BMJ. - 2044-6055. ; 13:2
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Tidskriftsartikel (refereegranskat)abstract
- Introduction Administration 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 analysis The 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 dissemination Ethics approval has been obtained in Sweden. Results of the primary and secondary outcomes will be submitted for publication in a peer-reviewed journal.
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| 19. |
- Linder, Adam, et al.
(författare)
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The specific organism : Not bacterial gram type: Drives the inflammatory response in septic shock
- 2020
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Ingår i: Journal of Innate Immunity. - : S. Karger AG. - 1662-811X .- 1662-8128. ; 12:2, s. 182-190
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Tidskriftsartikel (refereegranskat)abstract
- Background and Hypothesis: The inflammatory response was targeted by unsuccessful therapies but ignored pathogen. We hypothesized that the inflammatory response differs according to organism in human septic shock. Materials and Methods: We measured 39 cytokines at baseline and 24 h in patients (n = 363) in the Vasopressin and Septic Shock Trial (VASST). We compared cytokine profiles (cytokine functional class) at baseline and at 24 h by organism and used hierarchical clustering to classify cytokines according to 28-day outcomes. Results: In 363 patients, 88 and 176 patients had at least 1 species isolated from blood and other sites, respectively. Cytokine levels differed significantly according to organism: Neisseria meningitidis and Streptococcus pneumoniae had the highest (baseline and at 24 h), while Enterococcus faecalis (blood) had the lowest mean cytokine levels. N. meningitidis and Klebsiella pneumoniae had significantly higher cytokine levels at baseline versus 24 h (p = 0.01 and 0.02, respectively); E. faecalis had significantly higher cytokine levels at 24 h versus baseline. Hierarchical clustering heat maps showed that pathogens elicited similar cytokine responses not related to the functional cytokine class. Conclusion: The organism type induces different cytokine profiles in septic shock. Specific gram-positive and gram-negative pathogens stimulated similar plasma cytokine-level patterns.
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| 20. |
- Linné, Erik, et al.
(författare)
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Cystatin C and derived measures of renal function as risk factors for mortality and acute kidney injury in sepsis – A post-hoc analysis of the FINNAKI cohort
- 2022
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Ingår i: Journal of Critical Care. - : Elsevier BV. - 0883-9441. ; 72
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: To assess the association between cystatin C-derived estimates of kidney function and mortality and acute kidney injury (AKI) in sepsis. Materials and methods: Post-hoc analysis of sepsis patients in the FINNAKI-cohort (n = 802). Primary outcome was 90-day mortality. We measured plasma cystatin C and creatinine at intensive care unit (ICU) admission and estimated glomerular filtration rates (eGFRcys, eGFRcrea) and shrunken pore syndrome (SPS; defined as eGFRcys/eGFRcrea ratio < 0.7). Associations were assessed using Cox- or logistic regression. Results: Increased cystatin C and decreased eGFRcys were associated with mortality in unadjusted analyses and in analyses adjusted for illness severity and creatinine. Hazard ratios (HRs) in unadjusted analyses were 3.30 (95% CI; 2.12–5.13, p < 0.001) and 3.26 (95% CI; 2.12–5.02, p < 0.001) respectively. SPS was associated with mortality in an unadjusted- (HR 1.78, 95% CI; 1.33–2.37, p < 0.001) and in an adjusted analysis (HR 1.54, 95% CI; 1.07–2.22, p = 0.021). All cystatin C-derived measures were associated with mortality also after adjustment for AKI development. Cystatin C was associated with AKI in unadjusted analyses but not in analyses adjusted for creatinine. Conclusion: Cystatin C and derived measures of kidney function at ICU admission are associated with an increased 90-day mortality. Increased AKI incidence does not fully explain this association.
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| 21. |
- Mellhammar, Lisa, et al.
(författare)
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Bacteremic sepsis leads to higher mortality when adjusting for confounders with propensity score matching
- 2021
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Ingår i: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 11
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Tidskriftsartikel (refereegranskat)abstract
- 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.
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| 22. |
- Mellhammar, Lisa, et al.
(författare)
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Estimating Sepsis Incidence Using Administrative Data and Clinical Medical Record Review
- 2023
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Ingår i: JAMA Network Open. - 2574-3805. ; 6:8, s. 2331168-2331168
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Tidskriftsartikel (refereegranskat)abstract
- Importance: Despite the large health burden, reliable data on sepsis epidemiology are lacking; studies using International Statistical Classification of Diseases and Related Health Problems (ICD)-coded hospital discharge diagnosis for sepsis identification suffer from limited sensitivity. Also, ICD data do not allow investigation of underlying pathogens and antimicrobial resistance. Objectives: To generate reliable epidemiological estimates by linking data from a population-based database to a reference standard of clinical medical record review. Design, Setting, and Participants: This was a retrospective, observational cohort study using a population-based administrative database including all acute care hospitals of the Scania region in Sweden in 2019 and 2020 to identify hospital-treated sepsis cases by ICD codes. From this database, clinical medical records were also selected for review within 6 strata defined by ICD discharge diagnosis (both with and without sepsis diagnosis). Data were analyzed from April to October 2022. Main outcomes and measures: Hospital and population incidences of sepsis, case fatality, antimicrobial resistance, and temporal dynamics due to COVID-19 were assessed, as well as validity of ICD-10 case identification methods compared with the reference standard of clinical medical record review. Results: Out of 295 531 hospitalizations in 2019 in the Scania region of Sweden, 997 patient medical records were reviewed, among which 457 had sepsis according to clinical criteria. Of the patients with clinical sepsis, 232 (51%) were female, and 357 (78%) had at least 1 comorbidity. The median (IQR) age of the cohort was 76 (67-85) years. The incidence of sepsis in hospitalized patients according to the Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3) criteria in 2019 was 4.1% (95% CI, 3.6-4.5) by medical record review. This corresponds to an annual incidence rate of 747 (95% CI, 663-832) patients with sepsis per 100 000 population. No significant increase in sepsis during the COVID-19 pandemic nor a decrease in sepsis incidence when excluding COVID-19 sepsis was observed. Few sepsis cases caused by pathogens with antimicrobial resistance were found. The validity of ICD-10-based case identification in administrative data was low. Conclusions and Relevance: In this cohort study of sepsis epidemiology, sepsis was a considerable burden to public health in Sweden. Supplying administrative data with information from clinical medical records can help to generate reliable data on sepsis epidemiology.
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| 23. |
- Mellhammar, Lisa, et al.
(författare)
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Heparin binding protein in severe COVID-19- A prospective observational cohort study
- 2021
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Ingår i: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 16:4 April
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Forskningsöversikt (refereegranskat)abstract
- Background and aims Neutrophil-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. Methods This 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. Results Thirty-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). Conclusions 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.
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| 24. |
- Mellhammar, Lisa, et al.
(författare)
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Scores for sepsis detection and risk stratification – construction of a novel score using a statistical approach and validation of RETTS
- 2020
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Ingår i: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 15:2
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Tidskriftsartikel (refereegranskat)abstract
- Background To allow early identification of patients at risk of sepsis in the emergency department (ED), a variety of risk stratification scores and/or triage systems are used. The first aim of this study was to develop a risk stratification score for sepsis based upon vital signs and biomarkers using a statistical approach. Second, we aimed to validate the Rapid Emergency Triage and Treatment System (RETTS) for sepsis. RETTS combines vital signs with symptoms for risk stratification. Methods We retrospectively analysed data from two prospective, observational, multicentre cohorts of patients from studies of biomarkers in ED. A candidate risk stratification score called Sepsis Heparin-binding protein-based Early Warning Score (SHEWS) was constructed using the Least Absolute Shrinkage and Selector Operator (LASSO) method. SHEWS and RETTS were compared to National Early Warning Score 2 (NEWS2) for infection-related organ dysfunction, intensive care or death within the first 72h after admission (i.e. sepsis). Results 506 patients with a diagnosed infection constituted cohort A, in which SHEWS was derived and RETTS was validated. 435 patients constituted cohort B of whom 184 had a diagnosed infection where both scores were validated. In both cohorts (A and B), AUC for infection-related organ dysfunction, intensive care or death was higher for NEWS2, 0.80 (95% CI 0.76–0.84) and 0.69 (95% CI 0.63–0.74), than RETTS, 0.74 (95% CI 0.70–0.79) and 0.55 (95% CI 0.49–0.60), p = 0.05 and p <0.01, respectively. SHEWS had the highest AUC, 0.73 (95% CI 0.68–0.79) p = 0.32 in cohort B. Conclusions Even with a statistical approach, we could not construct better risk stratification scores for sepsis than NEWS2. RETTS was inferior to NEWS2 for screening for sepsis.
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| 25. |
- Mohanty, Tirthankar, et al.
(författare)
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A pharmacoproteomic landscape of organotypic intervention responses in Gram-negative sepsis
- 2023
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Ingår i: Nature Communications. - 2041-1723. ; 14, s. 1-17
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Tidskriftsartikel (refereegranskat)abstract
- Sepsis is the major cause of mortality across intensive care units globally, yet details of accompanying pathological molecular events remain unclear. This knowledge gap has resulted in ineffective biomarker development and suboptimal treatment regimens to prevent and manage organ dysfunction/damage. Here, we used pharmacoproteomics to score time-dependent treatment impact in a murine Escherichia coli sepsis model after administering beta-lactam antibiotic meropenem (Mem) and/or the immunomodulatory glucocorticoid methylprednisolone (Gcc). Three distinct proteome response patterns were identified, which depended on the underlying proteotype for each organ. Gcc enhanced some positive proteome responses of Mem, including superior reduction of the inflammatory response in kidneys and partial restoration of sepsis-induced metabolic dysfunction. Mem introduced sepsis-independent perturbations in the mitochondrial proteome that Gcc counteracted. We provide a strategy for the quantitative and organotypic assessment of treatment effects of candidate therapies in relationship to dosing, timing, and potential synergistic intervention combinations during sepsis.
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| 26. |
- Paulsson, Magnus, et al.
(författare)
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Heparin-binding protein in lower airway samples as a biomarker for pneumonia
- 2021
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Ingår i: Respiratory Research. - : Springer Science and Business Media LLC. - 1465-9921 .- 1465-993X. ; 22:1
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Tidskriftsartikel (refereegranskat)abstract
- Objectives: Ventilator-associated pneumonia (VAP) is difficult to diagnose using clinical criteria and no biomarkers have yet been proved to be sufficiently accurate. The use of the neutrophil-derived Heparin-binding protein (HBP) as a biomarker for pneumonia was investigated in this exploratory case–control study in two intensive care units at a tertiary referral hospital. Methods: Patients with clinical signs of pneumonia were recruited and bronchoalveolar lavage fluid (BALF) or bronchial wash (BW) samples were collected. Mechanically ventilated and lung healthy subjects were recruited as controls. HBP was measured with enzyme-linked immunosorbent assay. Results: BALF was collected from 14 patients with pneumonia and 14 healthy controls. Median HBP in BALF pneumonia samples was 14,690 ng/ml and controls 16.2 ng/ml (p < 0.0001). BW was collected from 10 pneumonia patients and 10 mechanically ventilated controls. Median HBP in BW pneumonia was 9002 ng/ml and controls 7.6 ng/ml (p < 0.0001). Conclusions: These data indicate that HBP concentrations is significantly higher in lower airway samples from patients with pneumonia than control subjects and is a potentially useful biomarker for diagnosis of VAP.
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| 27. |
- Pavan, Chiara, et al.
(författare)
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DNase Treatment Prevents Cerebrospinal Fluid Block in Early Experimental Pneumococcal Meningitis
- 2021
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Ingår i: Annals of Neurology. - : Wiley. - 0364-5134 .- 1531-8249. ; 90:4, s. 653-669
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Tidskriftsartikel (refereegranskat)abstract
- Objective: Streptococcus pneumoniae is the most common cause of bacterial meningitis, a disease that, despite treatment with antibiotics, still is associated with 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 cerebrospinal fluid (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, was significantly reduced in the rat model of S pneumoniae meningitis. Degrading 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. ANN NEUROL 2021.
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| 28. |
- Scott, Aaron M, et al.
(författare)
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Generalized precursor prediction boosts identification rates and accuracy in mass spectrometry based proteomics
- 2023
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Ingår i: Communications Biology. - 2399-3642. ; 6, s. 1-13
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Tidskriftsartikel (refereegranskat)abstract
- Data independent acquisition mass spectrometry (DIA-MS) has recently emerged as an important method for the identification of blood-based biomarkers. However, the large search space required to identify novel biomarkers from the plasma proteome can introduce a high rate of false positives that compromise the accuracy of false discovery rates (FDR) using existing validation methods. We developed a generalized precursor scoring (GPS) method trained on 2.75 million precursors that can confidently control FDR while increasing the number of identified proteins in DIA-MS independent of the search space. We demonstrate how GPS can generalize to new data, increase protein identification rates, and increase the overall quantitative accuracy. Finally, we apply GPS to the identification of blood-based biomarkers and identify a panel of proteins that are highly accurate in discriminating between subphenotypes of septic acute kidney injury from undepleted plasma to showcase the utility of GPS in discovery DIA-MS proteomics.
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| 29. |
- Scott, Aaron M., et al.
(författare)
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Population scale proteomics enables adaptive digital twin modelling in sepsis
- 2024
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Sepsis is one of the leading causes of mortality in the world. Currently, the heterogeneity of sepsis makes it challenging to determine the molecular mechanisms that define the syndrome. Here, we leverage population scale proteomics to analyze a well-defined cohort of 1364 blood samples taken at time-of-admission to the emergency department from patients suspected of sepsis. We identified panels of proteins using explainable artificial intelligence that predict clinical outcomes and applied these panels to reduce high-dimensional proteomics data to a low-dimensional interpretable latent space (ILS). Using the ILS, we constructed an adaptive digital twin model that accurately predicted organ dysfunction, mortality, and early-mortality-risk patients using only data available at time-of-admission. In addition to being highly effective for investigating sepsis, this approach supports the flexible incorporation of new data and can generalize to other diseases to aid in translational research and the development of precision medicine.Competing Interest StatementThe authors have declared no competing interest.Funding StatementL.M. is funded by the Swedish Research Council (grant number VR-2020-02419), the Wallenberg foundation (grant number 2016.0023) and Alfred Österlunds Foundation. J.M. is a Wallenberg academy fellow (KAW 2017.0271) and is also funded by the Swedish Research Council (Vetenskapsrådet, VR) (2019-01646 and 2018-05795), the Wallenberg foundation (KAW2016.0023, KAW2019.0353 and KAW2020.0299), and Alfred Österlunds Foundation. E.M. is funded by Wenner-Gren Foundation (FT2020-0003), the Crafoord Foundation, and the Swedish Society of Medicine (SLS-985287). F.K. is funded by Region Skåne ALF project and the Crafoord Foundation. A.L. is funded by the Swedish Research Council VR 2023-02707 and Region Skåne ALF project 2022-0146.Author DeclarationsI confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.YesThe details of the IRB/oversight body that provided approval or exemption for the research described are given below:Ethical approval for the study was obtained from the Swedish National Ethics Committee (file numbers 2022-01454-01, 2014/741 and 2016/271).I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.YesI understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).YesI have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable.YesData produced in the present study are available upon reasonable request to the authors
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| 30. |
- Sterner, Niklas, et al.
(författare)
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The Dynamics of Heparin-Binding Protein in Cardiothoracic Surgery—A Pilot Study
- 2021
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Ingår i: Journal of Cardiothoracic and Vascular Anesthesia. - : Elsevier BV. - 1053-0770. ; 35:9, s. 2640-2650
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Tidskriftsartikel (refereegranskat)abstract
- 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.
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| 31. |
- Strand, Rasmus, et al.
(författare)
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Rapid diagnostic testing for SARS-CoV-2 : Validation and comparison of three point-of-care antibody tests
- 2021
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Ingår i: Journal of Medical Virology. - : Wiley. - 0146-6615 .- 1096-9071. ; 93:7, s. 4592-4596
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Tidskriftsartikel (refereegranskat)abstract
- 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 min. 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 patients with coronavirus disease 2019 (COVID-19) 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%, respectively, for the detection of IgG. All tests had the same specificity for IgG (98%). The tests did not differ significantly for the detection of IgG. The sensitivities for IgM were lower (15%, 67%, and 70%) and the specificities were 90%, 98%, and 90%, 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.
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| 32. |
- Strålin, Kristoffer, et al.
(författare)
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Design of a national patient-centred clinical pathway for sepsis in Sweden
- 2023
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Ingår i: Infectious Diseases. - : Taylor & Francis. - 2374-4235 .- 2374-4243. ; 55:10, s. 716-724
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: The World Health Organization has adopted a resolution on sepsis and urged member states to develop national processes to improve sepsis care. In Sweden, sepsis was selected as one of the ten first diagnoses to be addressed, when the Swedish government in 2019 allocated funds for patient-centred clinical pathways in healthcare. A national multidisciplinary working group, including a patient representative, was appointed to develop the patient-centred clinical pathway for sepsis.METHODS: The working group mapped challenges and needs surrounding sepsis care and included a survey sent to all emergency departments (ED) in Sweden, and then designed a patient-centred clinical pathway for sepsis.RESULTS: The working group decided to focus on the following four areas: (1) sepsis alert for early detection and management optimisation for the most severely ill sepsis patients in the ED; (2) accurate sepsis diagnosis coding; (3) structured information to patients at discharge after sepsis care and (4) structured telephone follow-up after sepsis care. A health-economic analysis indicated that the implementation of the clinical pathway for sepsis will most likely not drive costs. An important aspect of the clinical pathway is implementing continuous monitoring of performance and process indicators. A national working group is currently building up such a system for monitoring, focusing on extraction of this information from the electronic health records systems.CONCLUSION: A national patient-centred clinical pathway for sepsis has been developed and is currently being implemented in Swedish healthcare. We believe that the clinical pathway and the accompanying monitoring will provide a more efficient and equal sepsis care and improved possibilities to monitor and further develop sepsis care in Sweden.
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| 33. |
- Tverring, Jonas, et al.
(författare)
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Repeated measures of Heparin-binding protein (HBP) and procalcitonin during septic shock : biomarker kinetics and association with cardiovascular organ dysfunction
- 2020
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Ingår i: Intensive Care Medicine Experimental. - : Springer Science and Business Media LLC. - 2197-425X. ; 8:1
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Heparin-binding protein (HBP) is a neutrophil-derived pro-inflammatory protein, an inducer of endothelial dysfunction and vascular permeability and a promising prognostic biomarker in sepsis. This exploratory study aims to describe the kinetics of plasma HBP during septic shock and investigate an association between repeated measures of HBP concentration and cardiovascular organ dysfunction severity.METHODS: We included patients at or above 18 years with suspected septic shock on admission to the intensive care unit (ICU) during 2014 and 2016 to 2018. Plasma samples were collected from ICU admission and every 4 h for 72 h or until death or ICU discharge and batch analysed for HBP. Mean arterial blood pressure (MAP) and noradrenaline dose (NA dose) were recorded at each sampling time point, and systemic vascular resistance index (SVRI) was recorded when available from non-invasive monitoring. The association between HBP, NA dose, MAP and SVRI was assessed respectively using mixed-effects linear regression models. Procalcitonin (PCT) was used as a comparator.RESULTS: A total of 24 patients were included. The kinetics of plasma HBP was highly variable over time, with occasional >2-fold increases and decreases in between 4-h measurements. Every 100 ng/mL increase in HBP corresponded to a 30% increase in NA dose in a crude model (95% CI 3 to 60%, p = 0.03, nobs = 340), a 1.4-mmHg decrease in MAP in an adjusted model (95% CI - 1 to - 2.3 mmHg, p = 0.04) or a 99 dyne s cm-5 m-2 decrease in SVRI in another adjusted model (95% CI - 36 to - 162, p = 0.002, npat = 13). PCT had a stronger association to NA dose than HBP in a crude model but was not significantly associated to NA dose, MAP or SVRI in any time-adjusted model.CONCLUSIONS: Plasma HBP displayed a highly variable kinetic pattern during septic shock and was significantly associated to cardiovascular organ dysfunction severity over time.
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| 34. |
- van der Slikke, Elisabeth C., et al.
(författare)
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Understanding Post-Sepsis Syndrome : How Can Clinicians Help?
- 2023
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Ingår i: Infection and Drug Resistance. - 1178-6973. ; 16, s. 6493-6511
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Forskningsöversikt (refereegranskat)abstract
- Sepsis is a global health challenge, with over 49 million cases annually. Recent medical advancements have increased in-hospital survival rates to approximately 80%, but the escalating incidence of sepsis, owing to an ageing population, rise in chronic diseases, and antibiotic resistance, have also increased the number of sepsis survivors. Subsequently, there is a growing prevalence of “post-sepsis syndrome” (PSS). This syndrome includes long-term physical, medical, cognitive, and psychological issues after recovering from sepsis. PSS puts survivors at risk for hospital readmission and is associated with a reduction in health-and life span, both at short and long term, after hospital discharge. Comprehensive understanding of PSS symptoms and causative factors is vital for developing optimal care for sepsis survivors, a task of prime importance for clinicians. This review aims to elucidate our current knowledge of PSS and its relevance in enhancing post-sepsis care provided by clinicians.
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| 35. |
- Wagenius, Magnus, et al.
(författare)
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Factors influencing stone-free rate of Extracorporeal Shock Wave Lithotripsy (ESWL) : a cohort study
- 2022
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Ingår i: Scandinavian journal of urology. - : Taylor & Francis. - 2168-1805 .- 2168-1813. ; 56:3, s. 237-243
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Tidskriftsartikel (refereegranskat)abstract
- 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 angelholm Hospital, Skane, 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.
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| 36. |
- Wagenius, Magnus, et al.
(författare)
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Percutaneous nephrolithotomy and modern aspects of complications and antibiotic treatment
- 2020
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Ingår i: Scandinavian Journal of Urology. - : Medical Journals Sweden AB. - 2168-1805 .- 2168-1813. ; 54:2, s. 162-170
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Tidskriftsartikel (refereegranskat)abstract
- Objective: The incidence of urinary stones is increasing across the globe. Surgical treatment includes extracorporal shock-wave lithotripsy (ESWL), ureterolithotripsy (URS), percutaneous nephrolitotomy (PCNL) and rarely open surgery. This single center study describes complications to PCNL focusing on infections, bacterial growth/resistance and antibiotic prophylaxis/treatment. Materials and methods: All patients treated for kidney stones with PCNL at Ängelholm Hospital in north-western Scania, Sweden from January 2009 to December 2015 were included. A dipstick test and a bacterial culture was made on all patients. Kidney stones were analysed for composition and cultured for bacteria. Results: In total, 186 patients underwent PCNL, all receiving perioperative antibiotics. Thirty percent (56/186) had a positive urinary culture taken before surgery and 33.3% (62/186) had positive stone culture. The concordance between urinary and stone culture was 57.1%. Both positive stone and urinary culture increased the risk of complications after surgery (p = 0.002 and p = 0.017, respectively). Complications occurred in 16% (30/186). Eight patients (4.3%) developed sepsis. The most common bacteria in urine were Enterococcus faecalis and Escherichia coli, both 20%. The most common stone-bacteria reported was Enterococcus faecalis (26%). Conclusion: This study has a total complication rate of 16%, approximately 10% of those are severe. The most common complication to PCNL was infection (60%), followed by bleeding (5.4%), reoperation (1.6%) and pain (0.5%). The high prevalence of E. faecalis might need to be considered, however the results should be validated in a larger cohort, possibly with a higher rate of antibiotic resistance, before a change of guidelines regarding prophylactic antibiotics could be proposed.
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| 37. |
- Wedin, Johan O, et al.
(författare)
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Heparin-binding protein as a marker of ventriculostomy related infection and central nervous system inflammation in neuro-intensive care
- 2023
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Ingår i: Clinical neurology and neurosurgery. - : Elsevier BV. - 0303-8467 .- 1872-6968. ; 229
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Tidskriftsartikel (refereegranskat)abstract
- 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.
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| 38. |
- Wiersema, Renske, et al.
(författare)
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Two subphenotypes of septic acute kidney injury are associated with different 90-day mortality and renal recovery
- 2020
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Ingår i: Critical Care. - : Springer Science and Business Media LLC. - 1364-8535. ; 24:1
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Tidskriftsartikel (refereegranskat)abstract
- Background: The pathophysiology of septic acute kidney injury is inadequately understood. Recently, subphenotypes for sepsis and AKI have been derived. The objective of this study was to assess whether a combination of comorbidities, baseline clinical data, and biomarkers could classify meaningful subphenotypes in septic AKI with different outcomes. Methods: We performed a post hoc analysis of the prospective Finnish Acute Kidney Injury (FINNAKI) study cohort. We included patients admitted with sepsis and acute kidney injury during the first 48 h from admission to intensive care (according to Kidney Disease Improving Global Outcome criteria). Primary outcomes were 90-day mortality and renal recovery on day 5. We performed latent class analysis using 30 variables obtained on admission to classify subphenotypes. Second, we used logistic regression to assess the association of derived subphenotypes with 90-day mortality and renal recovery on day 5. Results: In total, 301 patients with septic acute kidney injury were included. Based on the latent class analysis, a two-class model was chosen. Subphenotype 1 was assigned to 133 patients (44%) and subphenotype 2 to 168 patients (56%). Increased levels of inflammatory and endothelial injury markers characterized subphenotype 2. At 90 days, 29% of patients in subphenotype 1 and 41% of patients in subphenotype 2 had died. Subphenotype 2 was associated with a lower probability of short-term renal recovery and increased 90-day mortality. Conclusions: In this post hoc analysis, we identified two subphenotypes of septic acute kidney injury with different clinical outcomes. Future studies are warranted to validate the suggested subphenotypes of septic acute kidney injury.
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