OBJECTIVE:Prostate biopsy is associated with a risk of significant infectious complications including sepsis. We investigated the risk of infections after transrectal (TR) biopsy compared to transperineal (TP) biopsy. MATERIALS AND METHODS:Men who had undergone prostate biopsy and diagnosed with prostate cancer were identified in the National Prostate Cancer Register (NPCR) of Sweden. Linkage with Swedish health care registers provided information on hospitalization, antibiotic prescriptions and comorbidities. Rate ratios for hospitalization, for infections, after TR and TP biopsies over day 1-7, 1-14, and 1-30 were estimated with Poisson regression. Filled prescriptions for urinary tract related antibiotics were also assessed. RESULTS:Thirty-one thousand two hundred twenty-two men underwent biopsy between 1 January 2020 and 31 December 2023. 87% underwent TR and 13% TP biopsy. Hospitalization occurred in 0.6% of men (n = 24) after TP biopsy and 2.0% (n = 548) after TR biopsy. Rate ratios for hospitalization in the TR group compared to TP were 8.0 (95% confidence interval [CI]: 4.0-16.2) for day 1-7, 6.2 (3.2-11.9) for day 1-14, and 4.1 (2.4-6.8) for day 1-30. Filled antibiotic prescriptions were found for 4.5% of men (n = 187) after TP biopsy and 6.9% (n = 1,883) after TR biopsy. For antibiotic prescriptions, the rate ratios were 2.3 (1.8-2.9) for day 1-7 as well as day 1-14, and 1.6 (1.3-1.9) for day 1-30. CONCLUSIONS:A transrectal prostate biopsy was associated with a significantly higher risk of post-biopsy infectious complications compared to transperineal biopsy. These findings support the use of transperineal biopsy.

OBJECTIVES:To quantify the risk of incident psychiatric morbidity after community-acquired sepsis and assess whether new chronic diseases mediate the association. DESIGN:Nationwide, population-based matched register cohort; hazards estimated with weighted Cox regression. SETTING:Sweden, linking the National Quality Sepsis Registry, National Patient Register, Prescribed Drug Register, and population registers. PATIENTS:Ten thousand three hundred eight adults (≥ 18 yr) treated in an ICU for sepsis (2008-2019), matched to 155,705 population controls by sex, age, region, and year. Individuals with a psychiatric diagnosis within 5 years or psychotropic medication within 1 year before index were excluded. INTERVENTIONS:None. MEASUREMENTS AND MAIN RESULTS:The primary outcome, psychiatric event, was first occurrence after index date of either initiation of a psychotropic medication (anatomic therapeutic chemical classification system code N05A, N05BA, N05C, N06A) in the Prescribed Drug Register (capturing prescriptions from primary and specialist care) or a new International Classification of Diseases , 10th Edition mood (F3) or anxiety (F4) diagnosis in specialist care. Weighted Cox models balanced baseline covariates. We used a Landmark approach with risk sets at 0-30, 31-90, 91-365 days; 1-3, 3-5, and greater than or equal to 5 years after the index date. Sepsis was associated with increased hazards of psychiatric events vs. matched controls, with the strongest associations in the first year (0-30 d: adjusted hazard ratio [aHR], 6.2 [5.0-7.7]; 31-90 d: aHR, 7.4 [6.5-8.6]; and 91-365 d: aHR, 2.3 [2.1-2.5]) attenuating over time but remaining elevated through 5 years (1-3 yr: aHR, 1.2 [1.1-1.5]; 3-5 yr: aHR, 1.3 [1.1-1.5]; and ≥ 5 yr: aHR, 1.1 [0.9-1.3]). In mediation analyses considering incident chronic diseases, estimates changed little, suggesting that these conditions did not mediate the association. CONCLUSIONS:Patients with sepsis had a higher subsequent incidence of psychiatric events compared with matched population controls, with a persistently elevated risk for at least 5 years. This increased risk suggests that sepsis may have a long-term impact on psychiatric health, warranting consideration of preventive strategies.

In this nationwide cohort study, we assessed the long-term risk of major cardiovascular events following intensive care unit (ICU) treatment for community-acquired sepsis and septic shock, compared to the general population. We included 20313 adults admitted to Swedish ICUs between 2008 and 2019, identified through national healthcare registries, and matched each case to 20 randomly selected population controls. Entropy balancing adjusted for baseline co-morbidities, healthcare utilization, and socio-demographics. The association between sepsis and subsequent cardiovascular events (hospitalizations or deaths due to myocardial infarction, heart failure, or cerebral infarction) was analysed using Cox proportional hazards models. Sepsis was associated with increased cardiovascular risk, particularly during the first year (days 0-30 adjusted hazard ratio [aHR] 6.1 (95% CI 4.7-7.9); days 31-90; aHR 2.4 (95% CI 1.8-3.2); days 91-365 aHR 1.4 (95% CI 1.2-1.6)), with risk persisting through years 2-5 (aHRs 1.1-1.3). Heart failure risk remained elevated across all intervals, while risks of myocardial and cerebral infarction were mainly short term. The highest relative risks were observed in patients without prior heart disease or with low baseline cardiovascular risk. These findings suggest that sepsis might be an independent and under-recognized driver of long-term cardiovascular disease, highlighting the need for preventive strategies.

Background Sepsis-induced coagulopathy (SIC) is a scoring system developed for early detection of coagulopathy in sepsis and selection of patients for interventional studies. Our aim was to define the prevalence of SIC in a critically ill population and investigate if SIC at intensive care unit (ICU) admission is associated with morbidity and mortality. Methods Patients admitted with septic shock between 2011, and March 2024 were propensity matched into 2 groups (control and SIC). Primary outcome was 28-day mortality. Other outcomes were 90-, 180-day and ICU-mortality, days alive and free of vasopressors, mechanical ventilation and renal replacement therapy (RRT) along with the use of RRT, number of critical bleeding events and red blood cell transfusion. Results 1367 patients with septic shock were identified, 422 (31%) had SIC at ICU admission. Propensity matching resulted in 340 patients in each group. SIC was not associated with higher 28-day mortality (44% versus 37%, p = 0.091). ICU-mortality was higher in the SIC group (30% versus 22%, p = 0.016) and it had fewer median days alive and free of vasopressors (20 versus 22, p = 0.046). Incidence of critical bleeding events was higher in the SIC group (17% versus 10%, p = 0.009). More patients in the SIC group required red blood cell transfusion (63% versus 53%, p = 0.009). There was no significant difference in other outcomes. Conclusion SIC was prevalent in 31% of patients at ICU admission and was associated with higher ICU-mortality, fewer days alive and free of vasopressors, more critical bleeding events and more red blood cell transfusions.

BACKGROUND:Early identification of patients with suspected infection who are at risk of clinical deterioration in the Emergency Department (ED) is challenging, yet crucial for timely initiation of appropriate care and prevention of clinical deterioration. This multicenter international study evaluates the performance of established scores (SIRS, LODS, qSOFA, SOFA, NEWS) in predicting severe outcomes in ED patients with suspected infection. METHODS:We combined data from five different ED cohort studies (n = 4044 adult patients) from the Netherlands and Sweden. Suspected infection was defined as obtaining a microbiological culture combined with starting antibiotics. The scores were evaluated for their accuracy in predicting the composite outcome of intensive care unit (ICU) admission and in-hospital mortality. FINDINGS:Of 4044 patients, 655 (16 %) experienced a severe outcome, defined as ICU admission (n = 429, 11 %) or in-hospital mortality (n = 327, 8 %). SOFA (AUC 0.75 [95 %CI:0.73-0.77]) and LODS (AUC 0.73 [95 %CI:0.71-0.75]) showed the highest predictive accuracy. NEWS ≥ 5 yielded fair sensitivity (78 %) but low specificity (40 %), whereas NEWS ≥ 7 (sensitivity 71 %, specificity 59 %) performed similarly to SOFA ≥ 2 (69 %, 68 %) and LODS ≥ 2 (70 %, 66 %). In contrast, qSOFA (AUC 0.66 [95 %CI:0.64-0.69]) and SIRS (AUC 0.54 [95 %CI:0.52-0.57]) performed poorly for ED risk stratification. INTERPRETATION:SOFA and LODS showed the highest accuracy but are limited by their complexity and the requirement for laboratory data. The NEWS score, simpler and more accessible, is a practical tool for rapid ED screening with comparable accuracy as SOFA and LODS.

Background:Lung injury in COVID-19 is characterized by neutrophil invasion and the release of neutrophil extracellular traps (NETs). An aberrant NET formation may induce local inflammation and increase sputum viscosity. Inhalation of DNase I (dornase alfa) is a treatment option that degrades NETs in the airways. Previous case series have indicated positive clinical effects of inhaled dornase alfa. Methods:Patients admitted to the hospital with acute COVID-19 and hypoxia (oxygen saturation <90%) were randomly assigned to receive aerosolized dornase alfa twice daily for 5 days or a placebo in addition to standard of care. The primary outcome was discharge from the hospital or an oxygen saturation >93% without respiratory support. Results:In total, 76 patients were randomized. The study was stopped when the Omicron virus variant appeared. The clinical response rate did not differ between patients receiving the active substance and placebo. Secondary outcomes were similar across groups, such as mortality, a new episode of hypoxia, length of stay in the hospital, and adverse events. A subanalysis of patients older or younger than 65 years showed no differences in primary or secondary outcomes. Conclusions:Aerosolized dornase alfa failed to improve hypoxia in hospitalized patients with acute COVID-19. The study was conducted during a time of heterogeneity in viral variants and vaccination status of participants. Whether dornase alfa affects the outcomes in other respiratory infections requires further study.

Rationale: Early detection, standardized therapy, adequate infrastructure, and strategies for quality improvement should constitute essential components of every hospital's sepsis plan. Objectives: To investigate the extent to which recommendations from the sepsis guidelines are implemented and the availability of infrastructure for the care of patients with sepsis in acute-care hospitals. Methods: A multidisciplinary cross-sectional questionnaire was used to investigate sepsis care in hospitals. This included the use of sepsis definitions, the implementation of sepsis guideline recommendations, diagnostic and therapeutic infrastructure, antibiotic stewardship, and quality improvement initiatives (QIIs) in hospitals. Measurements and Main Results: A total of 1,023 hospitals in 69 countries were included. Most of them, 835 (81.6%), were in Europe. Sepsis screening was used in 54.2% of emergency departments (EDs), 47.9% of wards, and 61.7% of ICUs. Sepsis management was standardized in 57.3% of EDs, 45.2% of wards, and 70.7% of ICUs. The implementation of comprehensive QIIs was associated with increased screening (EDs, +33.3%; wards, +44.4%; ICUs, +23.8% absolute difference) and increased standardized sepsis management (EDs, +33.6%; wards, +40.0%; ICUs, +17.7% absolute difference) compared with hospitals without QIIs. A total of 9.8% of hospitals had implemented ongoing QIIs, and 4.6% had invested in sepsis programs. Conclusions: The findings indicate that there is considerable room for improvement in a large number of mainly European hospitals, particularly with regard to early identification and standardized management of sepsis, the availability of guidelines, diagnostic and therapeutic infrastructure, and the implementation of QIIs. Further efforts are required to implement a more comprehensive and appropriate quality of care.

In septic shock, administration of large fluid volumes is associated with poor outcomes. Recent evidence shows that non-resuscitation fluids are the major modifiable source of fluids for patients with septic shock in intensive care units (ICUs). This clinical trial is designed to test the hypothesis that restrictive administration of non-resuscitation fluids improves outcomes compared to usual care. Adult patients admitted to ICUs with septic shock will be randomly assigned within 12 h of admission to receive protocolized restrictive administration of non-resuscitation fluids or usual care. The primary outcome is all-cause mortality at 90 days. Secondary outcomes are complications during ICU stay up to 90 days (defined as any acute kidney injury or cerebral, coronary, intestinal, or limb ischemia), mechanical ventilation free days within 90 days, and for survivors cognitive function (by the Montreal Cognitive Assessment [MOCA-BLIND]) and Health-Related Quality of Life (by the EQ Visual Analogue Scale [EQ-VAS]), both at 6 months. In addition, the climate impact of the interventions will be assessed. To detect an absolute reduction in mortality of 7.5%, with an alpha of 5% and a power of 90%, we aim to include 1850 patients. The trial is approved by the Swedish Ethical Review Authority. Results of primary and secondary clinical outcomes and the environmental outcome will be submitted for publication in a peer-reviewed journal. Trial Registration: NCT06140147.

Soluble urokinase plasminogen activator receptor (suPAR) is an inflammatory marker that has been shown to predict poorer outcomes in cardiovascular disease and after cardiac surgery. The relationship between suPAR concentrations and postoperative complications after valvular surgery, however, remains unclear. This study aims to evaluate the predictive value of suPAR concentrations for infection, acute kidney injury (AKI) and prolonged mechanical ventilation after valvular surgery. This prospective, observational, single-centre study included 414 patients who underwent valvular cardiac surgery at Skåne University Hospital between 1 February 2020 and 22 September 2021. Early postoperative suPAR levels were measured, and multivariable logistic regression was used to identify significant risk factors for postoperative infection, AKI and prolonged mechanical ventilation. Left ventricular ejection fraction (LVEF) 30-50% (OR 3.57 [1.29-9.86], p = 0.014) and suPAR concentration (OR 1.41 [1.56-1.71], p <0.001) were found to be predictive risk factors for developing postoperative infection. Additionally, suPAR concentration (OR 1.23 [1.05-1.43], p = 0.008), cardiopulmonary bypass (CPB) time (OR 1.01 [1.00-1.02], p = 0.004) and age (OR 1.04 [1.01-1.08], p = 0.007) were found to be predictive risk factors for postoperative AKI. However, suPAR concentration did not predict prolonged mechanical ventilation. Plasma suPAR levels after cardiac valve surgery were found to be predictive of postoperative AKI and infection. Our results indicate that early postoperative suPAR measurements may be a valuable tool for identifying patients at higher risk for developing postoperative complications.

Background:Blood cultures (BCs) are key diagnostic elements for sepsis patients. Accurate preanalytical procedures are substantial, and results should be available as soon as possible to guide adequate antimicrobial treatment. This study aimed to evaluate BC collection practices and diagnostic capacity across European hospitals. Methods:This cross-sectional survey investigated BC diagnostics in acute care hospitals across 37 European countries in the years 2021 and 2022. Analyses included BC guidelines, collection sites, number of BC sets in emergency departments (EDs), wards, and intensive care units (ICUs). We also examined transfer after collection, the use of on-site vs. external laboratories, opening hours, rapid testing capacity, and turn-around times of BCs processed in microbiology laboratories with different infrastructures. Findings:Responses were collected from 907 hospitals in Europe. BC guidelines were available in 84·4% (741/878) of the hospitals. BCs were preferably collected by multiple-site sampling in EDs (62·7%, 461/735), in wards (64·0%, 513/802) and ICUs (68·5%, 518/756). One BC set was preferred in EDs in 38·4% (270/704), in wards in 40·5% (314/775), and ICUs in 34·9% (261/748). Two BC sets were preferred in EDs in 31·0% (218/704), in wards in 28·1% (218/775), and ICUs in 39·2% (293/748). 48·0% (402/838) of hospitals used on-site and 52·0% (436/838) external microbiology laboratories. Around-the-clock microbiological services were available in 10⋅0% (91/907), and rapid pathogen identification in 43·7% (396/907) of hospitals. Infrastructure with around-the-clock microbiological service and rapid testing was available in 7·4% (62/840) of hospitals, and probability of a final microbiological result within two days was highest in these hospitals compared to hospitals with limited microbiology service (for BC collected on wards: 19·6% vs. 52·7%, Odds Ratio 4·59 [95% CI 2·50-7·79], p < 0·0001). Interpretation:Despite the availability of BC guidelines in many hospitals, current recommendations for BC collection were often neglected. Rapid testing capacity was limited in most microbiological laboratories, and around-the-clock service for BCs was very rare. As delay in results may have a detrimental impact on patient outcomes, strategies to improve these processes are urgently needed. Funding:The European Sepsis Alliance and a grant by Becton and Dickinson.

The plasma proteome is maintained by the influx and efflux of proteins from surrounding organs and cells. To quantify the extent to which different organs and cells impact the plasma proteome in healthy and diseased conditions, we developed a mass-spectrometry-based proteomics strategy to infer the tissue origin of proteins detected in human plasma. We first constructed an extensive human proteome atlas from 18 vascularized organs and the 8 most abundant cell types in blood. The atlas was interfaced with previous RNA and protein atlases to objectively define proteome-wide protein-organ associations to infer the origin and enable the reproducible quantification of organ-specific proteins in plasma. We demonstrate that the resource can determine disease-specific quantitative changes of organ-enriched protein panels in six separate patient cohorts, including sepsis, pancreatitis, and myocardial injury. The strategy can be extended to other diseases to advance our understanding of the processes contributing to plasma proteome dynamics.

The recently published European Sepsis Care Survey (ESCS) by the European Sepsis Alliance (ESA) showed that the standard-of-care strategies regarding infrastructure and logistics on diagnosis and management of sepsis were beyond what is considered satisfactory. This led to a position statement by the Steering Committee of the ESA. A literature search was conducted to compare the compliance with the Surviving Sepsis Campaign Guidelines and/or other medical societies reported by the health care practitioners participating in the ESCS regarding first line fluids and vasopressors, biomarkers, continuous availability for microbiology service and antibiotic stewardship team. In all suggested practices for sepsis care the feedback of the health-care professionals who completed the ESCS showed that the average adherence was more than 80

The plasma proteome is maintained by the influx and efflux of proteins from surrounding organs and cells. To quantify the extent different organs and cells contribute to the plasma proteome composition, we developed a mass spectrometry-based proteomics strategy to infer the origin of proteins detected in human plasma in health and disease. First, we constructed an extensive human proteome atlas from 18 vascularized organs and the most abundant cell types in blood. Second, the atlas was interfaced with previous RNA/protein atlases to objectively define proteome wide protein-organ associations to enable both the inference of origin and the reproducible quantification of organ-specific proteins in plasma. We demonstrate that the resource can determine disease specific quantitative changes of organ-enriched protein panels in three separate patient cohorts with infection, pancreatitis, and myocardial injury. The strategy can be extended to other diseases to advance our understanding of the processes contributing to plasma proteome dynamics.

Non-resuscitation fluids constitute the majority of fluid administered for septic shock patients in the intensive care unit (ICU). This multicentre, randomized, feasibility trial was conducted to test the hypothesis that a restrictive protocol targeting non-resuscitation fluids reduces the overall volume administered compared with usual care. Adults with septic shock in six Swedish ICUs were randomized within 12 h of ICU admission to receive either protocolized reduction of non-resuscitation fluids or usual care. The primary outcome was the total volume of fluid administered within three days of inclusion. Median (IQR) total volume of fluid in the first three days, was 6008 ml (interquartile range [IQR] 3960–8123) in the restrictive fluid group (n = 44), and 9765 ml (IQR 6804–12,401) in the control group (n = 48); corresponding to a Hodges–Lehmann median difference of 3560 ml [95 https://clinicaltrials.gov/ct2/show/NCT05249088

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 Statement The authors have declared no competing interest. ### Funding Statement L.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 Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The 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. Yes I 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). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes Data produced in the present study are available upon reasonable request to the authors

Background. Survivors of sepsis may experience long-term risk of increased morbidity and mortality, but estimations of cause-specific effects beyond 1 year after a sepsis episode are lacking. Method. This nationwide population-based cohort study linked data from national registers to compare patients aged >= 18 years in Sweden admitted to an intensive care unit from 2008 to 2019 with severe community-acquired sepsis. Patients were identified through the Swedish Intensive Care Registry, and randomly selected population controls were matched for age, sex, calendar year, and county of residence. Confounding from comorbidities, health care use, and socioeconomic and demographic factors was accounted for by using entropy-balancing methods. Long-term mortality and readmission rates, total and cause specific, were compared for 20 313 patients with sepsis and 396 976 controls via Cox regression. Results. During the total follow-up period, 56% of patients with sepsis died, as opposed to 26% of the weighted controls. The hazard ratio for all-cause mortality was attenuated with time but remained elevated in all periods: 3.0 (95% CI, 2.8-3.2) at 2 to 12 months after admission, 1.8 to 1.9 between 1 and 5 years, and 1.6 (95% CI, 1.5-1.8) at >5 years. The major causes of death and readmission among the sepsis cases were infectious diseases, cancer, and cardiovascular diseases. The hazard ratios were larger among those without underlying comorbidities. Conclusions. Severe community-acquired sepsis was associated with substantial long-term effects beyond 1 year, as measured by mortality and rehospitalization. The cause-specific rates indicate the importance of underlying or undetected comorbidities while suggesting that survivors of sepsis may face increased long-term mortality and morbidity not explained by underlying health factors.