Smoking is associated with higher risk of contracting bacterial infection and pneumonia, intensive care unit admission and death.

BACKGROUND: Smoking has been associated with a higher risk of contracting pneumonia, but contradictory results have shown that smoking may or may not decrease the risk of dying in pneumonia. The aim of this study is to investigate how smoking is associated with contracting any infection and pneumonia and death. METHOD AND FINDINGS: Participants were drawn from the population-based Cohort of Swedish Men and the Swedish Mammography Cohort, which are representative of the Swedish population. Participants have answered detailed lifestyle questionnaires and have been followed in national registers, such as the Patient Register, Cause of Death register and Swedish Intensive Care Registry. The risks of contracting infection and pneumonia or dying in infection and pneumonia were assessed using Cox regression. Of 62,902 cohort participants, 25,297 contracted an infection of which 4,505 died; and 10,471 contracted pneumonia of which 2,851 died. Compared to never smokers, former smokers at baseline had hazard ratio (HR) 1.08 (95% confidence interval (CI) 1.05-1.12) of contracting and HR 1.19 (95% CI 1.11-1.28) of dying in infection and HR 1.17 (95% CI 1.12-1.23) of contracting and HR 1.16 (95% CI 1.06-1.27) of dying in pneumonia during follow-up. Compared to never smokers, current smokers at baseline had HR 1.17 (95% CI 1.13-1.21) of contracting infection and HR 1.64 (95% CI 1.52-1.77) dying in infection; HR 1.42 (95% CI 1.35-1.49) of contracting pneumonia and HR 1.70 (95% CI 1.55-1.87) of dying in pneumonia during follow-up. The risk of contracting and dying in infection and pneumonia increased in a dose-response manner with number of pack years smoked and decreased with years since smoking cessation. CONCLUSION: Smoking is associated with contracting and dying in any infection and pneumonia and the risk increases with pack years smoked, highlighting the importance of both primary prevention and smoking cessation.

Physical activity is associated with a lower risk of contracting and dying in infection and sepsis: a Swedish population-based cohort study.

BACKGROUND: Sepsis is a condition where the immune response to infection becomes dysregulated and life-threatening. It is not known whether lifestyle factors influence the risk of sepsis. The aim of the present study is to investigate the association between physical activity and the risk of acquiring and dying in infection or sepsis. METHODS: The population-based Swedish Mammography Cohort and Cohort of Swedish Men sent participants lifestyle questionnaires in 1997 and have subsequently followed participants in national Swedish registers, including the National Patient Register, the Swedish Intensive Care Registry and the Cause of Death Register. The risk of contracting infection and sepsis, the risk of intensive care unit admission and the risk of death were estimated using multivariable Cox regression. RESULTS: Among 64,850 cohort participants, 26,124 individuals suffered at least one episode of infection or sepsis and 4708 individuals died of infection or sepsis during the study period. In adjusted analyses, compared to exercising less than one hour per week, stated exercise one hour per week was associated with lower risk of contracting infection or sepsis, hazard ratio (HR) 0.93 (95% confidence interval (CI) 0.90-0.97), and lower risk of dying in infection or sepsis, HR 0.87 (95% CI 0.80-0.96). Further exercise was associated with even lower risk, and similar patterns were observed for walking. The population-attributable risks of contracting and dying in infection or sepsis for not exercising were 2.6% and 4.5%, respectively. CONCLUSIONS: Exercise and walking demonstrate inverse dose-response associations with both the risk of contracting and dying in infection and sepsis, presenting possible preventative interventions for this critical condition.

Prior physical illness predicts death better than acute physiological derangement on intensive care unit admission in COVID-19: A Swedish registry study.

COVID-19 is associated with prolonged intensive care unit (ICU) stay and considerable mortality. The onset of persistent critical illness, defined as when prior illness predicts death better than acute physiological derangement, has not been studied in COVID-19. This national cohort study based on the Swedish Intensive Care Registry (SIR) included all patients admitted to a Swedish ICU due to COVID-19 from 6 March 2020 to 9 November 2021. Simplified Acute Physiology Score-3 (SAPS3) Box 1 was used as a measure of prior illness and Box 3 as a measure of acute derangement to evaluate the onset and importance of persistent critical illness in COVID-19. To compare predictive capacity, the area under receiver operating characteristic (AUC) of SAPS3 and its constituent Box 1 and 3 was calculated for 30-day mortality. In 7 969 patients, of which 1 878 (23.6%) died within 30 days of ICU admission, the complete SAPS3 score had acceptable discrimination: AUC 0.75 (95% CI 0.74 to 0.76) but showed under prediction in low-risk patients and over prediction in high-risk patients. SAPS3 Box 1 showed markedly better discrimination than Box 3 (AUC 0.74 vs 0.65, P<0,0001). Using custom logistic models, the difference in predictive performance of prior and acute illness was validated, AUC 0.76 vs AUC 0.69, p<0.0001. Prior physical illness predicts death in COVID-19 better than acute physiological derangement during ICU stay, and the whole SAPS3 score is not significantly better than just prior illness. The results suggests that COVID-19 may exhibit similarities to persistent critical illness immediately from ICU admission, potentially because of long median ICU length-of-stay. Alternatively, the variables in the acute physiological derangement model may not adequately capture the severity of illness in COVID-19.

Comprehensive analyses of circulating cardiometabolic proteins and objective measures of fat mass.

BACKGROUND: The underlying molecular pathways for the effect of excess fat mass on cardiometabolic diseases is not well understood. Since body mass index is a suboptimal measure of body fat content, we investigated the relationship of fat mass measured by dual-energy X-ray absorptiometry with circulating cardiometabolic proteins. METHODS: We used data from a population-based cohort of 4950 Swedish women (55-85 years), divided into discovery and replication samples; 276 proteins were assessed with three Olink Proseek Multiplex panels. We used random forest to identify the most relevant biomarker candidates related to fat mass index (FMI), multivariable linear regression to further investigate the associations between FMI characteristics and circulating proteins adjusted for potential confounders, and principal component analysis (PCA) for the detection of common covariance patterns among the proteins. RESULTS: Total FMI was associated with 66 proteins following adjustment for multiple testing in discovery and replication multivariable analyses. Five proteins not previously associated with body size were associated with either lower FMI (calsyntenin-2 (CLSTN2), kallikrein-10 (KLK10)), or higher FMI (scavenger receptor cysteine-rich domain-containing group B protein (SSC4D), trem-like transcript 2 protein (TLT-2), and interleukin-6 receptor subunit alpha (IL-6RA)). PCA provided an efficient summary of the main variation in FMI-related circulating proteins involved in glucose and lipid metabolism, appetite regulation, adipocyte differentiation, immune response and inflammation. Similar patterns were observed for regional fat mass measures. CONCLUSIONS: This is the first large study showing associations between fat mass and circulating cardiometabolic proteins. Proteins not previously linked to body size are implicated in modulation of postsynaptic signals, inflammation, and carcinogenesis.

Strain on the ICU resources and patient outcomes in the COVID-19 pandemic: A Swedish national registry cohort study.

BACKGROUND: The Coronavirus 2019 (COVID-19) pandemic has led to an unprecedented strain on the ICU resources. It is not known how the ICU resources employed in treating COVID-19 patients are related to inpatient characteristics, use of organ support or mortality. OBJECTIVES: To investigate how the use of ICU resources relate to use of organ support and mortality in COVID-19 patients. DESIGN: A national register-based cohort study. SETTING: All Swedish ICUs from March 2020 to November 2021. PATIENTS: All patients admitted to Swedish ICUs with a primary diagnosis of COVID-19 reported to the national Swedish Intensive Care Register (SIR). MAIN OUTCOME MEASURES: Organ support (mechanical ventilation, noninvasive ventilation, high-flow oxygen therapy, prone positioning, surgical and percutaneous tracheostomy, central venous catheterisation, continuous renal replacement therapy and intermittent haemodialysis), discharge at night, re-admission, transfer and ICU and 30-day mortality. RESULTS: Seven thousand nine hundred and sixty-nine patients had a median age of 63 years, and 70% were men. Median daily census was 167% of habitual census, daily new admissions were 20% of habitual census and the median occupancy was 82%. Census and new admissions were associated with mechanical ventilation, OR 1.37 (95% CI 1.28 to 1.48) and OR 1.44 (95% CI 1.13 to 1.84), respectively, but negatively associated with noninvasive ventilation, OR 0.83 (95% CI 0.77 to 0.89) and OR 0.40 (95% CI 0.30 to 52) and high-flow oxygen therapy, OR 0.72 (95% CI 0.67 to 0.77) and OR 0.77 (95% CI 0.61 to 0.97). Occupancy above 90% of available beds was not associated with mechanical ventilation or noninvasive ventilation, but with high-flow oxygen therapy, OR 1.36 (95% CI 1.21 to 1.53). All measures of pressure on resources were associated with transfer to other hospitals, but none were associated with discharge at night, ICU mortality or 30-day mortality. CONCLUSIONS: Pressure on ICU resources was associated with more invasive respiratory support, indicating that during these times, ICU resources were reserved for sicker patients.

ECG pathology and its association with death in critically ill COVID-19 patients, a cohort study.

BACKGROUND: We investigated the prevalence of ECG abnormalities and their association with mortality, organ dysfunction and cardiac biomarkers in a cohort of COVID-19 patients admitted to the intensive care unit (ICU). METHODS: This cohort study included patients with COVID-19 admitted to the ICU of a tertiary hospital in Sweden. ECG, clinical data and laboratory findings during ICU stay were extracted from medical records and ECGs obtained near ICU admission were reviewed by two independent physicians. RESULTS: Eighty patients had an acceptable ECG near ICU-admission. In the entire cohort 30-day mortality was 28%. Compared to patients with normal ECG, among whom 30-day mortality was 16%, patients with ECG fulfilling criteria for prior myocardial infarction had higher mortality, 63%, odds ratio (OR) 9.61 (95% confidence interval (CI) 2.02-55.6) adjusted for Simplified Acute Physiology Score 3 and patients with ST-T abnormalities had 50% mortality and OR 6.05 (95% CI 1.82-21.3) in univariable analysis. Both prior myocardial infarction pattern and ST-T pathology were associated with need for vasoactive treatment and higher peak plasma levels of troponin-I, NT-pro-BNP (N-terminal pro-Brain Natriuretic Peptide), and lactate during ICU stay compared to patients with normal ECG. CONCLUSION: ECG with prior myocardial infarction pattern or acute ST-T pathology at ICU admission is associated with death, need for vasoactive treatment and higher levels of biomarkers of cardiac damage and strain in severely ill COVID-19 patients, and should alert clinicians to a poor prognosis.

Fracture risk across a wide range of physical activity levels, from sedentary individuals to elite athletes.

OBJECTIVE: To examine how physical activity is associated with risk of different fracture outcomes across the full range of physical activity. METHODS: By combining information from three cohort studies and using generalized structural equation modelling, we estimated a continuous unitless latent variable reflecting physical activity that ranged from sedentary through elite athlete levels. Associations between physical activity and fracture outcomes were assessed with proportional hazards regression using restricted cubic splines with the mean physical activity (corresponding to 20-40 min walking or bicycling/day or 2-3 h exercise/week) as reference. RESULTS: Among 63,980 men and women (49-68 years) and during 13 years of follow-up, 8506 fractures occurred, including 2164 distal forearm, 779 proximal humerus, 346 clinical spine, and 908 hip fractures. Both lower and higher physical activity was associated with higher risk of any fracture compared to the mean. Physical activity at 1 standard deviation (SD) below the mean, corresponding to walking/bicycling <20 min/day or exercising <1-1 h/week, was associated with a lower risk of distal forearm fracture (hazard ratio [HR]: 0.92, 95% confidence interval [CI]: 0.85-0.99) and higher risk of hip fracture (HR: 1.24, 95% CI: 1.13-1.37), but no associations were seen above the mean physical activity level for these fractures. Physical activity was not associated with proximal humerus fracture but had a possible U-shaped association with clinical spine fracture. CONCLUSION: Physical activity was non-linearly associated with fracture risk and the association differed across fracture sites. Up to 2-3 h weekly exercise is beneficial for the prevention of hip fracture but may increase the risk of distal forearm fracture.

Point of care ultrasound screening for deep vein thrombosis in critically ill COVID-19 patients, an observational study.

BACKGROUND: Deep vein thrombosis (DVT) is common in critically ill patients with Coronavirus disease 2019 (COVID-19) and may cause fatal pulmonary embolism (PE) prior to diagnosis due to subtle clinical symptoms. The aim of this study was to explore the feasibility of bedside screening for DVT in critically ill COVID-19 patients performed by physicians with limited experience of venous ultrasound. We further aimed to compare inflammation, coagulation and organ dysfunction in patients with and without venous thromboembolism (VTE). METHODS: This observational study included patients with COVID-19 admitted to the intensive care unit (ICU) of a tertiary hospital in Sweden and screened for DVT with proximal compression ultrasound of the lower extremities between April and July 2020. Screening was performed by ICU residents having received a short online education and one hands-on-session. Pathological screening ultrasound was confirmed by formal ultrasound whereas patients with negative screening underwent formal ultrasound on clinical suspicion. Clinical data, laboratory findings and follow-up were extracted from medical records. RESULTS: Of 90 eligible patients, 56 were screened by seven ICU residents with no (n = 5) or limited (n = 2) previous experience of DVT ultrasound who performed a median of 4 (IQR 2-19) examinations. Four (7.1%) patients had pathological screening ultrasound of which three (5.6%) were confirmed by formal ultrasound. None of the 52 patients with negative screening ultrasound were diagnosed with DVT during follow-up. Six patients were diagnosed with PE of which four prior to negative screening and two following negative and positive screening respectively. Patients with VTE (n = 8) had higher median peak D-dimer (24.0 (IQR 14.2-50.5) vs. 2.8 (IQR 1.7-7.2) mg/L, p = 0.004), mean peak C-reactive protein (363 (SD 80) vs. 285 (SD 108) mg/L, p = 0.033) and median peak plasma creatinine (288 (IQR 131-328) vs. 94 (IQR 78-131) µmol/L, p = 0.009) compared to patients without VTE (n = 48). Five patients (63%) with VTE received continuous renal replacement therapy compared to six patients (13%) without VTE (p = 0.005). CONCLUSION: ICU residents with no or limited experience could detect DVT with ultrasound in critically ill COVID-19 patients following a short education. VTE was associated with kidney dysfunction and features of hyperinflammation and hypercoagulation. TRIAL REGISTRATION: ClinicalTrials ID: NCT04316884 . Registered 20 March 2020.

Physical activity is associated with a large number of cardiovascular-specific proteins: Cross-sectional analyses in two independent cohorts.

AIMS: We aimed to discover and replicate associations between leisure-time physical activity and cardiovascular candidate plasma protein biomarkers and to examine whether the associations were independent of body fat. METHODS: We used cross-sectional data from two population-based cohorts, the EpiHealth (discovery cohort; n = 2239) and the Swedish Mammography Cohort - Clinical (SMCC; replication cohort; n = 4320). Physical activity during leisure time was assessed using questionnaires, and plasma concentrations of 184 proteins were assayed using the Olink Proseek Multiplex Cardiovascular 2 and 3 kits. We applied adjusted linear regression models using the False Discovery Rate to control for multiple testing in discovery. RESULTS: In EpiHealth, physical activity was associated with 75 cardiovascular plasma biomarkers, of which 28 associations were verified (replicated) in SMCC. Findings include seven novel associations in human: paraoxonase 3, cystatin B, cathepsin Z, alpha-L-iduronidase, prostasin, growth differentiation factor 2 and tumour necrosis factor alpha receptor superfamily member 11A. Estimates for associations were similar across tertiles of body fat and physical activity was associated with four biomarkers independent of body fat percentage: paraoxonase 3, cystatin B, fatty acid-binding protein 4 and interleukin-1 receptor antagonist. CONCLUSION: Leisure-time physical activity was associated with 28 cardiovascular-specific proteins; four associations were independent of body fat. Biomarkers in novel associations are involved in several atherosclerotic processes including regulation of low-density lipoprotein oxidation, protein degradation and immune cell adhesion and migration. Further research into these pathways may yield new insights into how physical activity affects cardiovascular health.

Dietary Pattern Specific Protein Biomarkers for Cardiovascular Disease: A Cross-Sectional Study in 2 Independent Cohorts.

Background Mechanisms related to the influence of diet on the development of cardiovascular disease are not entirely understood, and protein biomarkers may help to understand these pathways. Studies of biomarkers identified with multiplex proteomic methods and dietary patterns are largely lacking. Methods and Results Dietary patterns were generated through principal component analysis in 2 population-based Swedish cohorts, the EpiHealth (EpiHealth study; n=20 817 men and women) and the SMCC (Swedish Mammography Cohort Clinical [n=4650 women]). A set of 184 protein cardiovascular disease biomarkers were measured with 2 high-throughput, multiplex immunoassays. Discovery and replication multivariable linear regression analyses were used to investigate the associations between the principal component analysis-generated dietary patterns and the cardiovascular disease-associated protein biomarkers, first in the EpiHealth (n=2240) and then in the Swedish Mammography Cohort Clinical. Four main dietary patterns were identified in the EpiHealth, and 3 patterns were identified in the Swedish Mammography Cohort Clinical. The healthy and the Western/traditional patterns were found in both cohorts. In the EpiHealth, 57 protein biomarkers were associated with 3 of the dietary patterns, and 41 of these associations were replicated in the Swedish Mammography Cohort Clinical, with effect estimates ranging from 0.057 to 0.083 (P-value range, 5.0×10-2-1.4×10-9) for each SD increase in the relative protein concentration. Independent associations were established between dietary patterns and the 21 protein biomarkers. Two proteins, myeloperoxidase and resistin, were associated with both the healthy and the light meal pattern but in opposite directions. Conclusions We have discovered and replicated independent associations between dietary patterns and 21 biomarkers linked to cardiovascular disease, which have a role in the pathways related to inflammation, endothelial and immune function, cell adhesion, and metabolism.

Decreased Hip, Lower Leg, and Humeral Fractures but Increased Forearm Fractures in Highly Active Individuals.

It is not known how physical exercise affects the risk of different types of fractures, especially in highly active individuals. To investigate this association, we studied a cohort of 118,204 men and 71,757 women who from 1991 to 2009 participated in Vasaloppet, a long-distance cross-country skiing race in Sweden, and 505,194 nonparticipants frequency-matched on sex, age, and county of residence from the Swedish population. Participants ranged from recreational exercisers to world-class skiers. Race participation, distance of race run, number of races participated in, and finishing time were used as proxies for physical exercise. Incident fractures from 1991 to 2010 were obtained from national Swedish registers. Over a median follow-up of 8.9 years, 53,175 fractures of any type, 2929 hip, 3107 proximal humerus, 11,875 lower leg, 11,733 forearm, and 2391 vertebral fractures occurred. In a Cox proportional hazard regression analysis using time-updated exposure and covariate information, participation in the race was associated with an increased risk of any type of fracture (hazard ratio [HR], 1.02; 95% CI, 1.00 to 1.05); forearm fractures had an HR, 1.11 with a 95% CI, 1.06 to 1.15. There was a lower risk of hip (HR, 0.75; 95% CI, 0.67 to 0.83), proximal humerus (HR, 0.90; 95% CI, 0.82 to 0.98), and lower leg fractures (HR, 0.93; 95% CI, 0.89 to 0.97), whereas the HR of vertebral fracture was 0.97 with a 95% CI, 0.88 to 1.07. Among participants, the risk of fracture was similar irrespective of race distance and number of races run. Participants close to the median finishing time had a lower risk of fracture compared with faster and slower participants. In summary, high levels of physical exercise were associated with a slightly higher risk of fractures of any type, including forearm fractures, but a lower risk of hip, proximal humerus, and lower leg fractures. © 2018 American Society for Bone and Mineral Research.

Leisure-Time Physical Activity and Risk of Fracture: A Cohort Study of 66,940 Men and Women.

Physical activity has been associated with reduced risk of fracture, but it is not known how the intensity or frequency of physical activity influences this risk reduction. We aim to compare the risk of hip fracture and fracture of any locale between men and women with different levels of leisure-time walking/bicycling and exercise. A total of 37,238 women (born 1914-1948) from the Swedish Mammography Cohort and 45,906 men (born 1918-1952) from the Cohort of Swedish Men were followed for a maximum of 17 years. Exposure and covariate information was collected through a self-administered questionnaire in 1997. Incident fractures (5153 individuals with hip fracture and 15,043 with any type of fracture) and comorbidities were gathered from national and local patient registries. Hazard ratios (HRs) were calculated using Cox proportional hazards regression. Individuals who walked/bicycled less than 20 minutes per day had a lower rate of hip fracture (multivariable adjusted HR = 0.77; 95% confidence interval [CI] 0.70 to 0.85) and any fracture (HR = 0.87; 95% CI 0.82 to 0.92) compared with those who hardly ever walked/bicycled. These reduced rates were also evident in both sexes, in different age categories, for vertebral fractures and for non-hip, non-vertebral fractures. Those who reported exercise 1 hour per week had a lower rate of hip fracture (HR = 0.87; 95% CI 0.80 to 0.96) and any fracture (HR = 0.94; 95% CI 0.89 to 0.99) compared with those who exercised less than 1 hour per week. Only minor differences in HRs were observed in individuals with moderate compared with higher levels of walking/bicycling or exercise. Walking/bicycling and exercise showed almost equal reductions in rate of fracture when compared with those in a joint category with lowest activity. In conclusion, both moderate and high self-reported frequency of physical activity is associated with reduced future risk of fracture. © 2017 American Society for Bone and Mineral Research.

The Risk of Distant Metastases and Cancer Specific Survival in Men with Serum Prostate Specific Antigen Values above 100 ng/ml.

PURPOSE: Current EAU (European Association of Urology) guidelines state that prostate specific antigen 100 ng/ml or greater at diagnosis indicates metastatic disease. We examined the association of prostate specific antigen 100 ng/ml or greater at diagnosis with distant metastasis and prostate cancer specific survival. MATERIAL AND METHODS: A total of 15,635 men with prostate cancer diagnosed between 1998 and 2009 who were identified in PCBaSe (Prostate Cancer Data Base Sweden 2.0) were included in a population based registry study. Prostate cancer specific survival was compared among 3 groups, including 1,879 men with prostate specific antigen 100 ng/ml or greater and negative imaging (M0), 5,642 with distant metastases on imaging (M1) and prostate specific antigen 100 ng/ml or greater, and 3,828 with M1 and prostate specific antigen less than 100 ng/ml. A fourth group consisted of 4,286 men with prostate specific antigen 100 ng/ml or greater who had not undergone imaging (Mx). The latter men were not included in the assessment of survival. RESULTS: Of 7,521 men with prostate specific antigen 100 ng/ml or greater who underwent imaging for staging 75% were classified with M1 disease. Only 59% of 3,527 men with prostate specific antigen 100 to 300 mg/ml had distant metastases on imaging. Five-year prostate cancer specific survival was 72% (95% CI 70-74) in men with prostate specific antigen 100 ng/ml or greater and M0, 24% (95% CI 23-25) in men with prostate specific antigen 100 ng/ml or greater and M1, and 39% (95% CI 37-40) in men with prostate specific antigen less than 100 ng/ml and M1. CONCLUSIONS: A fourth of men with prostate specific antigen 100 ng/ml or greater did not have distant metastases. They had twofold to threefold higher 5-year survival than men with distant metastases on imaging. Our findings strongly suggest that using prostate specific antigen 100 ng/ml or greater as an indicator of metastatic disease should be reconsidered.