Background: Several genes and genomic regions have been implicated in COVID-19 susceptibility and severity, but their clinical relevance remains uncertain. We comprehensively assessed both copy number variants (CNVs) and single-nucleotide variants (SNVs) disrupting genes implicated in COVID-19 in a Swedish cohort of ICU-treated COVID-19 patients with detailed phenotype data. Methods: Patients (n = 301) with severe COVID-19 treated in intensive care units (ICU) between March 2020 and January 2021 at two large Swedish university hospitals were included. Whole exome sequencing (WES) was performed to identify both large copy number variations (CNVs) and single-nucleotide variants (SNVs), including small indels, using the Genome Analysis Toolkit (GATK) pipelines. We focused our analyses on variants disrupting coding genes implicated in severe COVID-19, but also assessed variants known to cause human disease. Results: We identified 11 rare CNVs and several SNVs potentially linked to severe COVID-19. Patients carrying a CNV spanning a COVID-19-implicated gene had higher levels of the heart failure marker NT-proBNP (median 4440 [1558–8160] vs. 1170 [329–3152], p = 0.017), worse renal function at ICU admission (p = 0.0026), and a higher need for continuous renal replacement therapy (CRRT) (28% vs. 10%, p = 0.045) compared to patients without a potentially damaging CNV. Conclusions: Although patients with a potentially damaging CNV or SNV exhibited some differences in cardiac and renal markers, our findings do not support broad genetic screening as a predictive tool for COVID-19 severity.

Mixed venous oxygen saturation (SvO2) is a valuable indicator of the balance between oxygen delivery and consumption in the body. However, the invasiveness and risk of complications limit its use. This study aimed to test the feasibility of continuously monitoring variations in SvO2 from photoplethysmography (PPG) measurements of sternal intramedullary oxygen saturation. In an animal model, including anesthetized pigs (n = 15, mean 33.1 (SD 2.0) kg), alterations in SvO2 were instituted by separate sessions: incremental decrease in arterial oxygen saturation using hypoxic gas mixtures (N2/air), and hemorrhage of 20

Introduction Longitudinal studies of lung function following COVID-19 remain limited. This study examined lung function in COVID-19 patients for two years after discharge from an intensive care unit (ICU).Methods Patients treated for COVID-19 in Uppsala ICU (mean 11.1 days) were assessed at four months, one year, and two years post-discharge. Lung function tests included spirometry, diffusing capacity for carbon monoxide (DLco), and body plethysmography. Logistic regression adjusted for age, sex, and body mass index (BMI) assessed the association between impaired DLco and patients’ characteristics.Result A total of 104 patients (32% female, with a mean age of 60 years) participated in four months follow-up, 40 in one year follow-up, and 21 in two years follow-up after discharge. Impaired DLco was observed in 50%, 58%, and 33% of patients at four months, one year, and two years, respectively. A comparison showed that DLco% predicted declined from four months to one year (mean 79.0, SD 14.7, to 74.3, SD 15.7; p< 0.001), then improved between one and two years (p< 0.001). Forced vital capacity (FVC) % predicted improved between four months and one year (p < 0.001) and between one and two years (p = 0.004). Forced expiratory volume during the first second (FEV1) % predicted improved only between four months and one year (p = 0.002). Total lung capacity improved between the one- and two-year follow-ups (p = 0.006). Impaired DLco at four months was significantly associated with age ≥60 years (adjusted odds ratios, 95% confidence interval: 6.73 (2.64-17.12), mechanical ventilation (4.74 (1.82-12.34), longer ICU stay (5.84 (2.13-16.01), minimum lymphocyte count at ICU (0.19 (0.04-0.83), and FVC % predicted (0.93 (0.89-0.96)) and FEV1 % predicted (0.93 (0.89-0.97)).Conclusion Despite recovery between one and two years, one-third of patients exhibited impaired DLco two years after critical COVID-19, highlighting the need for pulmonary follow-up to address persistent lung function deficits.

Skeletal muscle capillary density is correlated with physical performance and whole-body metabolic properties. Thus, we performed a genome-wide association study of skeletal muscle capillary-to-fiber ratio (C:F) (n = 603 males) and found that the rs115660502 G allele was associated (p < 5 × 10-8) with increased C:F and reduced skeletal muscle expression of RAB3 GTPase-activating non-catalytic protein subunit 2 (RAB3GAP2). The capillary-increasing G allele was more prevalent in elite endurance athletes than in power athletes and non-athlete controls in two independent cohorts. Low-muscle-expressing RAB3GAP2 expression quantitative trait locus (eQTL) alleles were associated with muscle damage in athletes. In healthy individuals, RAB3GAP2 expression was reduced by high-intensity intermittent training. RAB3GAP2 protein was not uniformly expressed in muscle but predominantly expressed in the endothelium and capillaries. RAB3GAP2 expression was lower in endurance compared with power athletes and was negatively associated with type I (oxidative) muscle fiber density. Experimental reduction of RAB3GAP2 in human endothelial cells led to (1) increased proliferation and tube formation in vitro, (2) regulation of secreted factors (e.g., CD70 and TNC) promoting angiogenesis and T cell activation, and (3) increased in vivo endothelial cell density in mice. RAB3GAP2 expression in skeletal muscle was negatively correlated with exercise-induced release of TNC in vivo in humans. In conclusion, RAB3GAP2 is expressed in the microvascular endothelium and is suggested to be a negative regulator of angiogenesis through a decrease in endothelial cell proliferation, possibly mediated by RAB18, with its low-expressing variant associated with higher muscle C:F and elite endurance performance.

BACKGROUND:Postoperative acute kidney injury (AKI) is associated with substantial morbidity and mortality. Reliable estimates of AKI after surgery in children are lacking. To address this gap, we aimed to synthesize the available evidence on the incidence of AKI after pediatric noncardiac surgery. METHODS:We searched PubMed, Cochrane and Web of Science for studies reporting the incidence of AKI, defined according to the Kidney Disease: Improving Global Outcomes (KDIGO) criteria, within 7 postoperative days. Observational studies and clinical trials including patients aged < 18 years were eligible. The review followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, and certainty of evidence was assessed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. RESULTS:Twenty-seven studies (n = 21 908) were included. Considerable heterogeneity (I2 = 98.7%) and likely overrepresentation of clinically distinct high-risk populations limited the interpretability of a single overall pooled incidence estimate. The incidence was 22.3% (95% CI, 11.2-39.3) after neonatal surgery, 30.1% (95% CI, 21.4-40.6) after pediatric liver transplantation, and 9.2% (95% CI, 3.3-23.6) in mixed pediatric surgical populations. The certainty of evidence was rated low to very low. In mixed pediatric surgical populations, AKI incidence increased from 2.4% in American Society of Anesthesiologists (ASA) class 1-2 to 7.5% in ASA 3 (p < 0.001) and 18.9% in ASA 4-5 (p < 0.001), and decreased from 9.8% at 0-2 years to 4.0% at 12-18 years (p < 0.001). CONCLUSION:The reported incidence of postoperative AKI in children undergoing noncardiac surgery remains uncertain due to substantial heterogeneity and overrepresentation of high-risk populations. AKI incidence was high in neonates and liver transplant recipients and was associated with younger age and higher ASA class, although data were limited. Further prospective studies in broader pediatric surgical populations are needed to better assess the risk of postoperative AKI in children. TRIAL REGISTRATION:PROSPERO registration no.: CRD42024518832.

Accurate evaluation of kidney function is vital in the pediatric intensive care unit (PICU), where even small changes in cystatin C and creatinine concentrations can affect clinical decision-making. Diurnal patterns in renal biomarkers have been reported in adults, but their relevance in critically ill children remains unclear. Understanding whether sampling time contributes to biological variability is essential for reliable interpretation of kidney function tests. This retrospective study included 8619 cystatin C and 9314 creatinine results collected in a tertiary PICU between April 2014 and September 2025. The hourly distribution of sampling and hourly biomarker percentiles (0.10, 0.25, and 0.50) were evaluated across the 24-h cycle. Diurnal variation was quantified using coefficients of variation (CVs). Sampling was strongly clustered in the early morning, with 38.6

BACKGROUND:Long-term symptoms are common after the acute phase of COVID-19. We hypothesized that sick leave as an estimate of functional recovery, adjusted for confounding, differs between intensive care unit (ICU) and hospitalized COVID-19 patients and population controls. METHODS:In this cohort study, we identified all working-age individuals with COVID-19 admitted to ICUs or hospitals until July 20, 2020 from national registries. Matched population controls were randomly assigned to each ICU patient. Using logistic regression to adjust for confounding, we compared ICU patients to hospital patients and population controls on the number of sick leave-free days alive during the first year after hospital discharge and the proportion of alive individuals on sick leave after 1 year. RESULTS:We included 1020 COVID-19 ICU patients, 5306 COVID-19 hospital patients, and 4387 population controls. The ICU patients had a median of 271 (interquartile range, 33-349) sick leave-free days alive, while hospital patients had 354 (334-365) and population controls 365 (365-365). ICU patients had an odds ratio (OR) of 0.14 (0.12-0.16, 95% confidence interval) compared to hospital patients, and 0.02 (0.02-0.03, both p < 0.001) compared to population controls for at least one more sick leave-free day alive. Being on sick leave 1 year after inclusion had similar but inverse ORs. CONCLUSION:This national cohort study, in ICU and hospitalized patients with COVID-19, shows that the severity of COVID-19 disease, functional and health status before COVID-19, and demographic factors had a major impact on recovery. TRIAL REGISTRATION:NCT05054608.

Hemorrhage and hypotension leading to renal hypoperfusion are common causes of acute kidney injury (AKI). Anesthetic agents may affect renal hemodynamics, potentially altering renal outcomes during hypovolemia. This study evaluated the effects of two commonly used anesthetics, propofol and sevoflurane, on renal blood flow (RBF) and oxygenation during hemorrhage. Fourteen pigs (30 ± 2 kg) were anesthetized with either propofol or sevoflurane, with fentanyl as an opioid supplement in both groups. Following baseline measurements, hemorrhage was induced to maintain a mean arterial pressure (MAP) below 50 mmHg for 30 min, after which resuscitation was performed using a 1:1 replacement of whole blood and Ringer's acetate. Acute renal function recovery was evaluated 1 h post resuscitation. At baseline, sevoflurane-anesthetized animals had lower RBF and renal oxygen delivery, and higher renal vascular resistance compared with the propofol group. During hemorrhage, the change in these variables was comparable. After resuscitation, cardiovascular and RBF recovery were similar between the groups. However, oxygen delivery remained significantly lower in the sevoflurane group compared with the propofol group. In addition, renal vascular resistance was significantly higher during sevoflurane anesthesia compared with propofol after recovery. In conclusion, compared with propofol anesthesia, sevoflurane anesthesia reduced RBF and renal oxygen delivery already at baseline. The difference in oxygen delivery persisted after hemorrhage, even though RBF was comparable between groups.NEW & NOTEWORTHY In a pig model of major hemorrhage, we investigated whether the choice of anesthetic agent impacts renal blood flow and oxygen delivery after hemorrhage. The volatile anesthetic sevoflurane reduced renal blood flow and oxygen delivery compared with the intravenous agent propofol before hemorrhage. Following hemorrhage, oxygen delivery remained lower, accompanied by sustained renal vasoconstriction, in subjects anesthetized with sevoflurane compared with those anesthetized with propofol.

OBJECTIVES:To investigate how lifestyle factors interact to affect the risk of contracting or dying of infection. STUDY DESIGN:Cohort study. METHODS:The UK Biobank is a large population-based cohort study that collected lifestyle factors and subsequently followed participants through healthcare records. The associations between physical activity, smoking and alcohol consumption and the risk of contracting or dying of infection was investigated. Lifestyle factors were analysed separately and in combination. RESULTS:Of 353,834 individuals, 47,075 suffered at least one infection and 4594 died of infection. Walking, moderate and vigorous physical activity demonstrated threshold patterns, where the greatest risk difference was between inactive individuals and individuals performing any activity. Smoking exhibited dose-response patterns, where more smoking was associated with higher risks. Alcohol demonstrated a J-shaped association, where both low and high consumption were associated with higher risk of contracting and dying of infection. Presence of adverse lifestyle factors in combination was associated with additively higher risk of contracting and dying of infection. CONCLUSIONS:Physical inactivity, smoking and alcohol consumption are associated with the risk of both contracting and dying of infection, with multiple factors having an additive effect. We suggest that infection be viewed as a lifestyle condition potentially amenable to preventative public health interventions.

The aim of this study is to investigate the association between alcohol consumption and the risk of bacterial infection and its dose-response association. Participants in the Swedish Mammography Cohort and Cohort of Swedish Men answered lifestyle questionnaires in 1997 and have since been followed in national registers. The risks of acquiring infection, intensive care unit (ICU) admission and dying due to infection were assessed with Cox regression. Among 58,078 cohort participants followed for 23 years, 23,035 participants were diagnosed with an infection and 4,030 died from infection. Alcohol consumption exhibited a J-shaped association with the risk of acquiring infection and dying due to infection: compared to consuming 5-10 g of alcohol per day, consuming < 0.5 g/day and consuming > 30 g/day were both associated with higher risk of acquiring infection, ICU admission and dying due to infection, whereas alcohol consumption between 5 and 30 g/day was not associated with acquiring infection, ICU admission or death due to infection. In conclusion, moderate alcohol consumption was not associated with infection, but both very low and high levels of consumption were associated with acquiring infection, ICU admission and death. If replicated, this suggests that reduction of alcohol consumption might reduce mortality from bacterial infections.

BACKGROUND:Preoperative fasting regimens designed to minimise the risk of pulmonary aspiration have undergone significant changes, but unequivocal evidence of the safety of reducing clear fluid fasting has been lacking. We compared the risk of pulmonary aspiration in children using three different recommendations for clear fluid fasting. METHODS:In this prospective multicentre cohort study, centres with >1000 paediatric anaesthesia cases per year were eligible. Regurgitation events, whether they were transient or led to consequences affecting postoperative care, were reported in detail. All centres also reported the number of anaesthetised children per year and which preoperative fasting regimen they used. RESULTS:The 31 participating centres contributed a total of 306 900 anaesthetic procedures. The incidence of confirmed pulmonary aspiration was 1.18:10 000 in the sip-til-send group, 0.96:10 000 in the ≥1 h group, and 1.83:10 000 in the control group. There was no mortality as a result of aspiration. The 95% confidence intervals of the differences in confirmed pulmonary aspiration between the control group and the ≥1 h clear fluid fasting and the sip-til-send group were -0.344 to 3.76 and -1.48 to 3.63, respectively. Both sip-til-send and ≥1 h clear fluid fasting were statistically noninferior to ≥2 h clear fluid fasting regarding the incidence of confirmed aspiration, transient regurgitation, and regurgitation leading to escalation of care or intensive care. CONCLUSIONS:The study provides evidence for the safety of reducing preoperative fasting time for clear fluids in children aged <16 yr from 2 h to ≤1 h.

INTRODUCTION:A decrease in renal perfusion during acute kidney injury (AKI) due to critical COVID-19 has previously been demonstrated. The objective of this study was to compare the effects of plasma expansion with a standardized fluid bolus on renal perfusion in critically ill patients with AKI compared to similar patients without AKI. METHODS:A case control study design was used to investigate group differences before and after a standardized intervention. ICU-treated COVID-19 patients without underlying kidney disease were assigned to two groups based on KDIGO Creatinine criteria for AKI. Renal perfusion was assessed by magnetic resonance imaging using phase contrast and arterial spin labeling before and directly after plasma expansion with 7.5 mL/kg Ringer's Acetate (Baxter). Arithmetic means of mean arterial pressures (MAP) recorded before and after plasma infusion were compared. Data was analyzed with a mixed model repeated measures ANOVA for all kidneys using a random effect to account for research subjects. RESULTS:Nine patients with AKI and eight without were included in the study. The hemodynamic response to plasma expansion was similar in both groups, with increases in MAP by 9 mmHg (95% CI 0.5-18) and 15 mmHg (95% CI 5-24) in patients with and without AKI, respectively. Total renal perfusion and cortical perfusion were not significantly changed by plasma expansion in either group. There was a reduction of medullary perfusion in patients without AKI from 55 (95% CI 39-79) to 34 (95% CI 24-48) mL/min/100 g (p = .0027). CONCLUSION:Plasma expansion with a standardized fluid bolus did not increase renal perfusion in critically ill patients with COVID-19, with or without AKI.

Severe coronavirus disease 2019 (COVID-19) is characterized by systemic hyperinflammation with cytokine and chemokine release, alongside elevations in conventional laboratory biomarkers such as C-reactive protein (CRP), ferritin, and procalcitonin (PCT). However, the interplay between cytokines, chemokines, growth factors (CCGFs), and standard biomarkers remains incompletely understood. Therefore, we aimed to evaluate associations between CCGFs and conventional biomarkers from a broad aspect, utilizing the prospective PronMed cohort of critically ill COVID-19 patients admitted to the intensive care unit (ICU) at Uppsala University Hospital. Plasma concentrations of 92 CCGFs were analyzed in each patient using the Olink Target 96 Cardiovascular II panel and analyzed in relation to conventional biomarkers and peripheral blood cell counts. Associations were evaluated using Spearman rank correlations with Benjamini-Hochberg correction for multiple testing. A total of 114 patients (median age 61 years (IQR: 19), 75% male, median SAPS-3 52 (IQR: 10) were included. Significant correlations confirmed CRP as a robust surrogate of cytokine-driven inflammation. Ferritin was strongly associated with macrophage-related markers, including IL-18, sCD163-related factors, and PARP1. PCT correlated with a wide range of CCGFs, including ADM, PGF, TRAILR2, and IL-6. Blood cell subsets also showed distinct associations with CCGFs, suggesting functional connections between cytokine signaling and hematological disturbances. Our findings demonstrate that conventional biomarkers of inflammation in COVID-19 reflect complex and distinct interaction patterns with cytokines, chemokines, and growth factors. Mapping these associations improves understanding of COVID-19 immunopathology and may inform biomarker-guided risk stratification in critical illness.

Hyperosmolality is increasingly recognized as a factor contributing to severe COVID-19. Recently, a genetic variant near the aquaporin 3 (AQP3) water channel was associated with severe COVID-19 [rs60840586:G; odds ratio (OR): 1.07, P = 2.5 × 10-9]. The variant is known to increase gene expression of AQP3 in several organs, including the lung [normalized expression scores (NES) = 0.33, P = 4.1 × 10-20] in GTEx. In this study, we investigated 576 patients in the Biobanque Quebecoise de la COVID-19 (BQC-19) with both genetic and clinical data available. We estimated plasma osmolality using the formula: eOSM = 2 × [Na+] + 2 × [K+] + [Urea] + [Glucose]. Using a logistic regression of mortality against eOSM, genotype at rs60840586, sex, age, and the first 10 genetic principal components, we confirm that hyperosmolality is associated with COVID-19 mortality (OR = 2.06 [95% CI = 1.62-2.65], P = 9.13 × 10-9). Interestingly, we found that the risk of death linked to hyperosmolality is influenced by the AQP3 variant rs60840586:G genotype (OR = 1.95 [95% CI = 1.22-3.28], P = 0.0075). However, the rs60840586 genotype did not independently affect mortality in this cohort. These findings suggest that the body's ability to regulate and accommodate hyperosmolality may be disrupted by overexpression of AQP3, potentially worsening outcomes in COVID-19. Given the role of AQP3 in water transport and homeostasis, further defining the functionality of its variants may provide key insights into COVID-19 severity and guide clinical management strategies, particularly in critically ill patients with hyperosmolality.NEW & NOTEWORTHY A genetic variant near water channel AQP3, linked to severe COVID-19, amplifies the risk of death in patients with elevated plasma osmolality. In patients hospitalized with COVID-19, we show that although the variant does not affect systemic osmolality directly, it interacts with hyperosmolality to increase mortality risk. These findings highlight a potential mechanism where AQP3 overexpression disrupts cellular water handling during critical illness, offering new insight into the role of water balance in COVID-19 pathophysiology.

BACKGROUND:Negative postoperative behaviour changes (NPOBC) are known to occur after general anaesthesia in children. A significantly increased risk of NPOBC has been reported in children who exhibited a reduction in cerebral regional oxygen saturation (crSO2) of as little as 5% below baseline levels. These results were unexpected, and we therefore aimed to investigate the association between degrees of regional cerebral desaturation and NPOBC after routine surgery in young children. METHODS:In this prospective cohort study, 180 healthy children between 2 and 6 years old undergoing routine surgery were enrolled. The primary outcome was NPOBC, assessed using the Post Hospitalization Behavior Questionnaire (PHBQ), reported by parents and evaluated on Postoperative Day 7. The results were stratified according to decreases in crSO2 from baseline of at least 5, 10, 15 or 20 percentage points sustained for a minimum duration of 2 min. The χ2 or Fisher's exact test was used to analyse differences in categorical variables. Using logistic regression, outcome data were expressed as odds ratios with 95% confidence intervals. RESULTS:The incidence of NPOBC was 13% on Day 7, and 15% on Day 30, respectively. No significant differences were found between children with or without NPOBC for any of the thresholds of crSO2 reduction (≥ 5%: 2 [11%] vs. 2 [1.8%] cases, p = 0.09; ≥ 10%: 1 [5.6%] vs. 2 [1.8%] cases, p = 0.36; ≥ 15% and ≥ 20%: 0 vs. 0 cases). The rate of NPOBC was not associated with intraoperative reduction in crSO2 (OR 1.25, CI 0.71-2.20, p = 0.46). Older age was associated with lower odds of NPOBCs (OR 0.39, CI 0.15-0.99, p = 0.048). Using the area under the curve for quantifying crSO2 changes did not result in a statistically significant correlation between crSO2 and NPBOCs (r = 0.11). CONCLUSION:Regional cerebral desaturation and negative postoperative behaviour may be less common than previously reported in young children undergoing uneventful general anaesthesia. We could not corroborate the strong association between these entities reported previously. Studies investigating the effects of cerebral desaturation on patient-centred outcomes will need large sample sizes. EDITORIAL COMMENT:This prospective observational study describes a low incidence and magnitude of NIRS desaturation in healthy children. In contrast to previous reporting, there was no association with new negative postoperative behaviours in children in this cohort. TRIAL REGISTRATION:ISCRTN11799594.

BACKGROUND:Paediatric acute kidney injury (AKI) is associated with significant adverse outcomes such as increased mortality, progression to chronic kidney disease and longer length of stay in hospital. Postoperative AKI is a common and recognized complication after surgery in adults. In the paediatric population, AKI postoperatively to cardiac surgery has been extensively studied. However, the incidence of postoperative AKI after non-cardiac surgery is less clear. Therefore, we aim to assess the available literature on this topic. METHODS:We will conduct a systematic review of observational and randomized controlled trials assessing the incidence of paediatric postoperative AKI after non-cardiac surgery. Pairs of reviewers will independently screen the literature and extract data and assess risk of bias from eligible studies. The databases Pubmed, Cochrane and Web of Sciences will be searched. We will conduct the review in accordance with the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) guidelines and the Grading of Recommendation, Assessment, Development and Evaluation (GRADE) approach. If sufficient homogeneity within the included trials we will conduct meta-analyses. DISCUSSION:This systematic review aims to investigate the incidence of postoperative AKI in the paediatric non-cardiac surgery population. The results of this review will provide a foundation for future research in the field of paediatric postoperative AKI.