Supplementary Figure 1 shows flowchart of the study population.

Abstract Objectives This study aims to examine changes in incidence and mortality in Staphylococcus aureus bacteraemia (SAB) over time and between sexes, describe clinical characteristics and asses their associations with 30-day mortality. Methods We included 837 first-time SAB episodes from 1996 to 2022 in patients aged 18 years or older recorded in the Nord-Trøndelag Hospital Trust Sepsis Registry. Logistic regression was used to investigate time trends and associations with mortality. The study period was divided into early- (1996–2004), mid- (2005–2013) and late- (2014–2022) periods, and results are reported for each period and overall. Results The incidence of SAB increased from 20.0 to 40.3 per 100 000 person years from the early- to the late periods, with males accounting for 522 (62.4%) of all cases. Mortality decreased from 22.6% to 19.0% in males and 29.2% to 20.0% in females. Higher age, malignancy, congestive heart failure, pulmonary infection focus, and unknown focus were associated with increased 30-days mortality. Conclusion The incidence rate of SAB increased significantly from 1996 to 2022, with a consistently higher rate in males compared to females. While the highest mortality rate was observed in females in the earliest period, the mortality rate was similar between the sexes in the last period. The decline in mortality occurred despite an ageing patient population and a stable burden of comorbidities. With the exception of age, none of the variables associated with increased or decreased mortality changed significantly over time. Clinical trial number Not applicable.

Purpose To describe the epidemiology of blood cultures (BCs) drawn from patients with suspected sepsis by a rural ambulance service. Methods Patients were included if they had clinically suspected sepsis and at least one BC was drawn. Variables associated with positive BCs were identified with logistic regression, culture results before and after ambulance antimicrobial therapy were compared and the susceptibility to empirical antimicrobial therapy in bacterial isolates was determined. Results Among 392 included patients, sepsis severity score were higher when BCs were positive than negative, but there was no significant difference in 30-day all-cause mortality between BC negative and positive patients. In 47 patients ambulance blood cultures were positive (47/347 (13,5%)). Fever (OR 1.54, 95% CI 1.11-2.15) was associated with higher odds of positive cultures, while lower respiratory tract infection was associated with lower odds of positive cultures (OR 0.10, 95% CI 0.04-0.30). In 205 patients who had both ambulance and hospital BCs drawn and received ambulance antimicrobial therapy, only the ambulance BCs were positive in 16 patients, whereas in 4 patients only hospital cultures were positive. Bacterial isolates from positive BCs were susceptible to the empirical antimicrobial regimen in 80% of cases. Conclusion Positive ambulance BCs were associated with higher sepsis severity, and ambulance cultures were most useful in febrile patients with a suspected focus of infection other than the lower airways. Repeated BCs after hospital admission added only limited diagnostic value if an adequate ambulance BC had already been drawn.

Abstract Whole-genome sequencing (WGS) is increasingly being utilised in microbial diagnostics, surveillance, and research. In this paper we assess the performance of one leading long-read sequencing technology, Oxford Nanopore Technology (ONT), on 836 Staphylococcus aureus bacteraemia isolates. We compare the results to that of a leading short-read sequencing technology, Illumina. All isolates were sequenced using ONT MinION Mk1B and Illumina HiSeq or MiSeq. Libraries were prepared according to manufacturers’ instructions. Preprocessing and downstream bioinformatic analyses were performed using a combination of in-house pipelines and publicly available software tools. The average base substitution error rate in ONT assemblies was low but varied between sequence types, possibly due to lineage-specific methylation patterns. Multi locus sequence typing was similar between the technologies, while ONT assemblies allowed for better spa typing than Illumina assemblies. The reported detection rate was similar between ONT and Illumina assemblies for most virulence- and AMR-associated genes and variants. For 42 (22.2%) of 189 genes/variants, the two technologies disagreed in gene detection in 5 isolates or more, and in 39 (20.6.%) of these the highest detection rate was found with ONT. Discrepancies were mainly associated with low GC content, multiple repetitive segments, and small plasmids. Polishing of ONT data resulted in minor changes in gene/variant calling. Our study supports the use of ONT WGS for bacterial population genomic studies on a large collection of S. aureus isolates. While assembly of ONT reads may be affected by its own methodological limitations, it was superior to Illumina assemblies in detection of potentially clinically relevant genes and variants at a low read error rate. Understanding the advantages and limitations of WGS technologies is essential before undertaking studies involving such methods on large sets of bacteria. Author summary In this paper, we present a practical assessment of one important whole genome sequencing (WGS) method, Oxford Nanopore Technology (ONT), and compare its performance in bacterial population genomics to that of WGS with Illumina technology. Our goal was to investigate the usefulness of ONT in studies aiming to identify clinically relevant bacterial characteristics in large collections of bacteria, such as genotype-phenotype studies. We sequenced a large set of clinical S. aureus isolates from episodes of bloodstream infections using both ONT and Illumina technologies and performed analyses with widely used software and bioinformatic pipelines. We have elucidated inherent strengths and limitations of ONT and Illumina sequencing and report some of the practical consequences of these on bacterial typing and detection of clinically relevant genes. With this study, we present one of the most comprehensive assessments of long-read sequencing technology for the genomic characterisation of clinical bacterial isolates, and the findings provide guidance for researchers considering WGS in large-scale bacterial genomics.

Background Early prediction of the clinical course may aid clinical decisions for patients with suspected sepsis. We examined how variables observed by ambulance personnel predicted the clinical course in patients with suspected sepsis. Methods We prospectively collected prehospital data from patients with suspected sepsis in the ambulance service and supplemented the data with in-hospital findings. Prehospital data were used to calculate outputs of quick Sequential Organ Failure Assessment (qSOFA) and National Early Warning Score-2 (NEWS2). Outcomes were (1) sepsis severity after hospital admission, measured by Sequential Organ Failure Assessment (SOFA) score; (2) development of septic shock, defined by need for intravenous fluid resuscitation and pressors; and (3) 30-day all-cause mortality. Factors that predicted the three outcomes were identified with regression analysis. We performed receiver operating characteristic curve analysis to find the discriminatory abilities of prehospital scores. Results We included 398 patients with a median age of 76 years and a 30-day all-cause mortality of 10.1%. Oxygen saturation, systolic blood pressure and qSOFA were associated with sepsis severity and septic shock; Glasgow Coma Score and male sex with sepsis severity and mortality; age with sepsis severity; ashen or marbled skin and focus of infection with septic shock; cyanosis, nursing home resident and comorbidity with mortality. No variable predicted all three outcomes. Area under the curve (AUC) for septic shock was higher for qSOFA than for NEWS2 (p=0.033). AUC for septic shock was higher for males than for females if NEWS2 score was used (p=0.049), indicating that NEWS2 is better at predicting shock among males compared with females. Conclusions While there may be a role for the use of prehospital scoring systems in patients who are critically ill on presentation, established clinical decision aids must be used with caution and predictive information is lost if the tools are applied alone.

Supplementary Table S2A shows Hospital mortality in male cancer patients with sepsis by cancer subtype and metastatic status, Norwegian hospitals 2008 to 2021.Supplementary Table S2B shows Hospital mortality in female cancer patients with sepsis by cancer subtype and metastatic status, Norwegian hospitals 2008 to 2021.

Supplementary Table S1 shows Hospital mortality in cancer patients with sepsis by cancer subtype, Norwegian hospitals 2008 to 2021.

BACKGROUND:Patients with cancer who had sepsis experience a higher mortality risk than noncancer patients. However, it remains unclear how this risk varies with cancer type and metastasis status, sex, age, and infecting microbe. METHODS:This nationwide cohort study included all noncancer patients and those with cancer ≥18 years hospitalized with sepsis in Norway from 2008 to 2021. Cancer status, sepsis, and hospital mortality were identified from the Norwegian Patient Registry (International Classification of Diseases 10th revision codes). Multivariable regression analyses estimated absolute and relative risks (RR) of hospital mortality across subgroups. RESULTS:Of 222,832 hospitalized patients with sepsis, 37,692 (16.9%) had cancer. Hospital mortality was higher in patients with cancer, at 16.9% (males) and 16.2% (females) with nonmetastatic disease, and at 27.1% (males) and 26.2% (females) with metastatic disease. Compared with noncancer patients, adjusted RRs (95% confidence interval) of hospital death were 1.39 (1.34-1.44, males) and 1.63 (1.55-1.71, females) for nonmetastatic cancer and 2.27 (2.18-2.37, males) and 2.75 (2.62-2.89, females) for metastatic cancer. The type of cancer was a key prognostic factor. The association between cancer and mortality was strongest in metastatic patients below 50 years [males 40-49 years: RR, 5.94 (4.43-7.97); females 18-39 years: RR, 8.28 (5.12-13.37)] and in those with gram-negative sepsis. CONCLUSIONS:The increased hospital mortality in patients with cancer varied with cancer type and the presence of metastasis. The association between cancer and mortality was strongest in females and young adults, as well as in gram-negative sepsis. IMPACT:Knowledge of the specific aspects of sepsis in patients with cancer may improve cancer care and guide future research on targeted sepsis therapies.

Supplementary Methods shows ICD-10 codes used to define sepsis, cancer, and comorbidity.

Supplementary Table S3 shows Distribution of cancer patients with neutropenia and Absolute Risks (AR) (95% CI) and Relative Risks (RR) (95% CI) of hospital mortality by sex and the presence of neutropenia. Norwegian hospitals, 2008 to 2021.

BACKGROUND:Necrotising soft tissue infections (NSTI) are life-threatening conditions caused by diverse bacteria. Treatment strategies have remained largely universal and unchanged, and only modest improvements in patient outcomes have been observed. Emerging insights into NSTI pathogenesis may enable more targeted approaches. Because microbial aetiology is central to guiding appropriate therapy, we aimed to develop and externally validate machine learning models capable of predicting microbial aetiology using only data available at an early stage. In parallel, we explored whether similar models could predict selected clinical endpoints related to surgical management, patient handling, and organ support. METHODS:We used data from the INFECT study, an international multicentre prospective cohort investigating NSTI characteristics and pathogenesis. A total of 409 adults with surgically confirmed NSTI were enrolled between February 2013 and June 2017 from five Scandinavian hospitals. More than 700 clinical variables were collected from hospital admission to intensive care unit entry. Machine learning models were developed to predict the presence of Streptococcus pyogenes (GAS, Group A streptococcus) and five clinical endpoints: risk of amputation, size of skin defect, maximum skin defect size, length of intensive care (ICU) stay, and need for renal replacement therapy. Unsupervised variable selection was implemented, and Shapley Additive explanations were used for model interpretability. External validation employed a retrospective multicentre cohort of 216 NSTI patients treated in 11 Dutch hospitals between January 2013 and December 2017. RESULTS:Eight presurgical variables (age, diabetes, affected area, prior surgical intervention, and blood creatinine and haemoglobin concentrations) were sufficient for predicting GAS aetiology with high discriminatory power. Performance was good in both the development cohort (ROC-AUC 0.828; 95% CI 0.763-0.883) and the external validation cohort (ROC-AUC 0.758; 95% CI 0.696-0.821). Prediction of clinical endpoints related to surgical management, ICU stay, and organ support was unsuccessful. CONCLUSIONS:We developed and externally validated a model predicting GAS aetiology in NSTI using presurgical data alone. Early identification of GAS may improve clinical handling and support tailored decisions on treatment and infection control, including management of close contacts and reduction of hospital transmission risk.

Abstract Background Early diagnosis and antibiotic therapy in patients with sepsis reduce morbidity and mortality, thus pre-hospital management is likely to affect patient outcomes. Pre-hospital administration may increase the risk of unnecessary use of broad-spectrum antibiotics, but identification of an infectious focus enables more targeted antibiotic therapy. The aim of this study was to investigate how paramedics, with or without the assistance of general practitioners, can administer empiric intravenous antibiotic treatment against sepsis in a timely manner. Methods Cohort study of patients with suspected sepsis that received pre-hospital intravenous antibiotics and were transported to hospital. The setting was mainly rural with long average distance to hospital. Patients received targeted antibiotic treatment after an assessment based on clinical work-up supported by scoring systems. Patients were prospectively included from May 2018 to August 2022. Results are presented as median or absolute values, and chi-square tests were used to compare categorical data. Results We included 328 patients. Median age was 76 years (IQR 64, 83) and 48.5% of patients were female. 30-days all-cause mortality was 10.4%. In cases where a suspected infectious focus was determined, the hospital discharge papers confirmed the pre-hospital diagnosis focus in 195 cases (79.3%). The presence of a general practitioner during the pre-hospital assessment increased the rate of correctly identified infectious focus from 72.6% to 86.1% (p = 0.009). Concordance between pre-hospital identification of a tentative focus and discharge diagnosis was highest for lower respiratory tract (p = 0.02) and urinary tract infections (p = 0.03). Antibiotic treatment was initiated 44 min (median) after arrival of ambulance, and median transportation time to hospital was 69 min. Antibiotic therapy was started 76 min (median) before arrival at hospital. Conclusions Pre-hospital identification of infectious focus in suspected sepsis was feasible, and collaboration with primary care physicians increased level of diagnostic accuracy. This allowed initiation of intravenous focus-directed antibiotics more than one hour before arrival in hospital in a rural setting. The effect of pre-hospital therapy on timing was much stronger than in previous studies from more urban areas.

Background Our goal was to identify genetic and modifiable risk factors for upper urinary tract infections (UTIs).Methods We used data from UK Biobank, the Tr & oslash;ndelag Health Study, and the Michigan Genomics Initiative to conduct genome-wide association studies and sex-stratified analyses on upper UTI. Mendelian randomization (MR) analyses were conducted to examine potential causal relationships between cardiometabolic risk factors and upper UTIs.Results One genome-wide significant (P <= 5E-08) locus was associated with the susceptibility to upper UTI, located near TSN in the female-only analysis. Additionally, we identified suggestive (P <= 5E-06) loci near DNAI3 for females, SCAMP1-AS1 for males, and near TSN, LINC00603, and HLA-DQA2 for both sexes. In MR analyses, higher genetically predicted lifetime smoking scores were associated with an increased risk of developing upper UTI for females and both sexes (odds ratio [OR], 4.84, P = 4.50E-06 and OR, 2.79, P = 3.02E-05, respectively).Conclusions We found that genetic variants near TSN was associated with the risk of upper UTIs among females. In addition, we found several genetic loci with suggestive associations with the risk of upper UTIs. Finally, MR analyses found smoking to be a potential causal risk factor for upper UTIs. Genome-wide association studies identify genome-wide significant variants near the TSN locus associated with increased risk of upper urinary tract infection (UTI) for females. Suggestive loci were identified in the analysis of females, males, and both sexes. Mendelian randomization analysis links smoking to increased risk of upper UTI.

Objectives: To develop and externally validate machine learning models for predicting microbial aetiology and clinical endpoints, encompassing surgery, patient management, and organ support in Necrotising Soft Tissue Infections (NSTI). Methods: Predictive models for the presence of Group A Streptococcus (GAS) and for five clinical endpoints (risk of amputation, size of skin defect, maximum skin defect size, length of ICU stay, and need for renal replacement therapy) were built and trained using data from the prospective, international INFECT cohort (409 patients, 2013-2017), implementing unsupervised variable selection, and comparing several algorithms. SHapley Additive exPlanations (SHAP) analysis was used to interpret the model. GAS predictive models were externally validated using data from a Dutch retrospective multicenter cohort from the same calendar period (216 patients). Results: Eight variables available pre-surgery (age, diabetes, affected anatomical locations, prior surgical interventions, and creatinine and haemoglobin levels) sufficed for prediction of GAS aetiology with high discriminatory power in both the development (ROC-AUC: 0.828; 95%CI 0.763, 0.883) and validation cohort (ROC-AUC: 0.758; 95%CI 0.696, 0.821). The prediction of clinical endpoints related to surgical, patient management, and organs support aspects was unsuccessful. Conclusion: An externally validated prediction model for GAS aetiology before organ support aspects was unsuccessful, having implications for targeted treatment decisions of NSTI. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This study has received funding from the Swedish Governmental Agency for Innovation Systems (VINNOVA), Innovation Fund Denmark, and the Research Council of Norway under the frame of NordForsk (project No. 90456, PerAID), the Swedish Research Council, Innovation Fund Denmark, the Research Council of Norway, the Netherlands Organisation for Health Research and Development (ZonMW), and DLR Federal Ministry of Education and Research, through the PERMIT project (Personalized Medicine in Infections: from Systems Biomedicine and Immunometabolism to Precision Diagnosis and Stratification Permitting Individualized Therapies, project number 456008002) under the PerMed Joint Transnational call JTC 2018 (Research projects on personalised medicinesmart combination of preclinical and clinical research with data and ICT solutions; and from the European Unions Horizon 2020 research and innovation programme under the Marie Sklodowska-Curie grant agreement No. 860895 TranSYS. ### 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: Subjects and data of the cohort used to develop and train the prediction models were obtained from the INFECT study (https://permedinfect.com/; https://www.clinicaltrials.gov/study/[NCT01790698][1]). Subjects and the predictive models were obtained from a Dutch retrospective multicenter cohort (described in Suijker, Jaco, et al. "Identification of Potentially Modifiable Factors to Improve Recognition and Outcome of Necrotizing Soft-Tissue Infections." Shock (2023): 10-1097.) 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 All source code and computational results for the models predicting the bacterial GAS aetiology is available at https://github.com/sonjakatz/permit-nsti-gas. [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT01790698&atom=%2Fmedrxiv%2Fearly%2F2024%2F06%2F07%2F2024.06.05.24308478.atom

Bloodstream infections (BSI) and sepsis are important causes of hospitalization, loss of health, and death globally. Targetable risk factors need to be identified to improve prevention and treatment. In this study, we aimed to evaluate the association of chronic kidney disease (CKD) and risk of and mortality from BSI and sepsis in the general population during a 22-year period. We conducted a prospective cohort study among participants in the population-based Norwegian HUNT Study, where 68,438 participated. The median follow-up time was 17.4 years. The exposures were estimated glomerular filtration rate (eGFR) and albumin–creatinine ratio (ACR) in urine. The outcomes were hazard ratios (HR) of hospital admission or death due to BSI or sepsis. The associations were adjusted for age, sex, diabetes, obesity, systolic blood pressure, smoking status, and cardiovascular disease. Participants with eGFR < 30 ml/min/1.732 had HR 3.35 for BSI (95

OBJECTIVES:. Treatments that prevent sepsis complications are needed. Circulating lipid and protein assemblies—lipoproteins play critical roles in clearing pathogens from the bloodstream. We investigated whether early inhibition of proprotein convertase subtilisin/kexin type 9 (PCSK9) may accelerate bloodstream clearance of immunogenic bacterial lipids and improve sepsis outcomes. DESIGN:. Genetic and clinical epidemiology, and experimental models. SETTING:. Human genetics cohorts, secondary analysis of a phase 3 randomized clinical trial enrolling patients with cardiovascular disease (Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab [ODYSSEY OUTCOMES]; NCT01663402), and experimental murine models of sepsis. PATIENTS OR SUBJECTS:. Nine human cohorts with sepsis (total n = 12,514) were assessed for an association between sepsis mortality and PCSK9 loss-of-function (LOF) variants. Incident or fatal sepsis rates were evaluated among 18,884 participants in a post hoc analysis of ODYSSEY OUTCOMES. C57BI/6J mice were used in Pseudomonas aeruginosa and Staphylococcus aureus bacteremia sepsis models, and in lipopolysaccharide-induced animal models. INTERVENTIONS:. Observational human cohort studies used genetic PCSK9 LOF variants as instrumental variables. ODYSSEY OUTCOMES participants were randomized to alirocumab or placebo. Mice were administered alirocumab, a PCSK9 inhibitor, at 5 mg/kg or 25 mg/kg subcutaneously, or isotype-matched control, 48 hours prior to the induction of bacterial sepsis. Mice did not receive other treatments for sepsis. MEASUREMENTS AND MAIN RESULTS:. Across human cohort studies, the effect estimate for 28-day mortality after sepsis diagnosis associated with genetic PCSK9 LOF was odds ratio = 0.86 (95% CI, 0.67–1.10; p = 0.24). A significant association was present in antibiotic-treated patients. In ODYSSEY OUTCOMES, sepsis frequency and mortality were infrequent and did not significantly differ by group, although both were numerically lower with alirocumab vs. placebo (relative risk of death from sepsis for alirocumab vs. placebo, 0.62; 95% CI, 0.32–1.20; p = 0.15). Mice treated with alirocumab had lower endotoxin levels and improved survival. CONCLUSIONS:. PCSK9 inhibition may improve clinical outcomes in sepsis in preventive, pretreatment settings.

Few studies have reported on mortality beyond one year after sepsis. We aim to describe trends in short- and long-term mortality among patients admitted with sepsis, and to describe the association between clinical characteristics and mortality for improved monitoring, treatment and prognosis. Patients ≥ 18 years admitted to all Norwegian hospitals (2008–2021) with a first sepsis episode were identified using Norwegian Patient Registry and International Classification of Diseases 10th Revision codes. Sepsis was classified as implicit (known infection site plus organ dysfunction), explicit (unknown infection site), or COVID-19-related sepsis. The outcome was all-cause mortality. We describe age-standardized 30-day, 90-day, 1-, 5- and 10-year mortality for each admission year and estimated the annual percentage change with 95

BACKGROUND:Socioeconomic status (SES) may influence risk of sepsis and sepsis-related mortality, but to what extent lifestyle and health-related factors mediate this effect is not known. METHODS:The study included 65 227 participants of the population-based HUNT Study in Norway linked with hospital records to identify incident sepsis and sepsis-related deaths. Cox regression estimated HRs of sepsis risk and mortality associated with different indicators of SES, whereas mediation analyses were based on an inverse odds weighting approach. RESULTS:During ~23 years of follow-up (1.3 million person-years), 4200 sepsis cases and 1277 sepsis-related deaths occurred. Overall, participants with low SES had a consistently increased sepsis risk and sepsis-related mortality using education, occupational class and financial difficulties as indicators of SES. Smoking and alcohol consumption explained 57% of the sepsis risk related to low education, whereas adding risk factors of cardiovascular disease and chronic diseases to the model increased the explained proportion to 78% and 82%, respectively. CONCLUSION:This study shows that SES is inversely associated with sepsis risk and mortality. Approximately 80% of the effect of education on sepsis risk was explained by modifiable lifestyle and health-related factors that could be targets for prevention.

Background Preterm birth is associated with increased risk of childhood infections. Whether this risk persists into adulthood is unknown and limited information is available on risk patterns across the full range of gestational ages.Methods In this longitudinal, register-based, cohort study, we linked individual-level data on all individuals born in Norway (January 01, 1967-December 31, 2016) to nationwide hospital data (January 01, 2008-December 31, 2017). Gestational age was categorised as 23-27, 28-31, 32-33, 34-36, 37-38, 39-41, and 42-44 completed weeks. The analyses were stratified by age at follow-up: 0-11 months and 1-5, 6-14, 15-29, and 30-50 years. The primary outcome was hospitalisation due to any infectious disease, with major infectious disease groups as secondary outcomes. Adjusted hospitalisation rate ratios (RRs) for any infection and infectious disease groups were estimated using negative binomial regression. Models were adjusted for year of birth, maternal age at birth, parity, and sex, and included an offset parameter adjusted for person-time at risk.Findings Among 2,695,830 individuals with 313,940 hospitalisations for infections, we found a pattern of higher hospitalisation risk in lower gestational age groups, which was the strongest in childhood but still evident in adulthood. Comparing those born very preterm (28-31) and late preterm (34-36) to full-term (39-41 weeks), RRs (95% confidence interval) for hospitalisation for any infectious disease at ages 1-5 were 3.3 (3.0-3.7) and 1.7 (1.6-1.8), respectively. At 30-50 years, the corresponding estimates were 1.4 (1.2-1.7) and 1.2 (1.1-1.3). The patterns were similar for the infectious disease groups, including bacterial and viral infections, respiratory tract infections (RTIs), and infections not attributable to RTIs. Interpretation Increasing risk of hospitalisations for infections in lower gestational age groups was most prominent in children but still evident in adolescents and adults. Possible mechanisms and groups that could benefit from vac-cinations and other prevention strategies should be investigated.Funding St. Olav's University Hospital and Norwegian University of Science and Technology, Norwegian Research Council, Liaison Committee for education, research and innovation in Central Norway, European Commission, Academy of Finland, Sigrid Juselius Foundation, Foundation for Pediatric Research, and Signe and Ane Gyllenberg Foundation.Copyright & COPY; 2023 The Author(s). Published by Elsevier Ltd. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

Objectives To estimate temporal trends in incidence rate (IR) and case fatality during a 14-year period from 2008 to 2021, and to assess possible shifts in these trends during the COVID-19 pandemic. Setting All Norwegian hospitals 2008–2021. Participants 317 705 patients ≥18 year with a sepsis International Classification of Diseases 10th revision code retrieved from The Norwegian Patient Registry. Primary and secondary measures Annual age-standardised IRs with 95% CIs. Poisson regression was used to estimate changes in IRs across time, and logistic regression was used to estimate ORs for in-hospital death. Results Among 12 619 803 adult hospitalisations, a total of 317 705 (2.5%) hospitalisations in 222 832 (70.0%) unique patients met the sepsis criteria. The overall age-standardised IR of a first sepsis admission was 246/100 000 (95% CI 245 to 247), whereas the age-standardised IR of all sepsis admissions was 352/100 000 (95% CI 351 to 354). In the period 2009–2019, the annual IR for a first sepsis episode was stable (IR ratio (IRR) per year, 0.999; 95% CI 0.994 to 1.004), whereas for recurrent sepsis the IR increased (annual IRR, 1.048; 95% CI 1.037 to 1.059). During the COVID-19 pandemic, the IRR for a first sepsis was 0.877 (95% CI 0.829 to 0.927) in 2020 and 0.929 (95% CI 0.870 to 0.992) in 2021, and for all sepsis it was 0.870 (95% CI 0.810 to 0.935) in 2020 and 0.908 (95% CI 0.840 to 0.980) in 2021, compared with the previous 11-year period. Case fatality among first sepsis admissions declined in the period 2009–2019 (annual OR 0.954 (95% CI 0.950 to 0.958)), whereas case fatality increased during the COVID-19 pandemic in 2020 (OR 1.061 (95% CI 1.001 to 1.124) and in 2021 (OR 1.164 (95% CI 1.098 to 1.233)). Conclusion The overall IR of sepsis increased from 2009 to 2019, due to an increasing IR of recurrent sepsis, and indicates that sepsis awareness with updated guidelines and education must continue.