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It is not well investigated whether exposure to specific drug classes is associated with COVID-19. We investigated the risk of SARS-CoV-2 infection and severe COVID-19 among healthcare workers according to prescription drug use. We conducted an observational study among Danish healthcare workers. SARS-CoV-2 positivity was defined as a positive PCR/ELISA test throughout 2020 and severe COVID-19 as any above 48-hour hospitalization within 14 days after infection. Patient characteristics came from online surveys while data on SARS-CoV-2, drugs and hospitalizations came from Danish Health Registers. Infected individuals were matched with uninfected controls based on age, sex, and chronic diseases. Drug exposure was defined as any prescription redemption in the past six and one month(s) before infection for each drug class. Models assessing the risk of infection (conditional logistic regression) and severe COVID-19 (logistic regressions) versus drug usage were adjusted for BMI, smoking, alcohol, education, region, and patient contact when possible. We matched 5,710 SARS-CoV-2-infected cases with 57,021 controls. The odds of infection were reduced by calcium channel blocker (adjusted odds ratio (aOR) 0.81, 95% Confidence Interval (CI): 0.66-1.00) and vasoprotective drug (aOR 0.77, CI: 0.62-0.95) usage during the six months before infection compared to no usage. Exposure to antibacterials in the past month increased the odds of infection (aOR 1.27, CI: 1.09-1.48). Among infected participants, the odds of severe COVID-19 were higher with usage of almost any investigated drug, especially, diuretics (crude odds radio (OR) 4.82, CI:2.15-10.83), obstructive airway disease drugs (OR 4.49, CI: 2.49-8.08), and antibacterials (OR 2.74 CI:1.62-4.61). In conclusion, antibacterials were associated with more SARS-CoV-2 infections and calcium channel blockers with less. Once infected, users of prescription drugs had higher odds of developing severe COVID-19. These findings suggest a need for studies to clarify interactions between specific drug groups, behaviour, known risk factors, and disease susceptibility/severity., Competing Interests: S.B.’s research salary was sponsored by Sygesikring Danmark and the Capital Region of Denmark’s Research Foundation. K.I. received grants from Lundbeck Foundation to his institution [grant number R349-2020-731]. A.D.K has received a grant from The Danish Heart Foundation and a grant from the European Commission (EU 7th Framework [grant number 603266]). C.T-P. has received grants from Bayer and Novo- Nordisk for studies not related to the current study. F.F. has received research grant from the Novo Nordisk Foundation and an unrestricted research grant from the Laerdal Foundation to the Copenhagen EMS. S.D.N received an unrestricted research grants from the Novo Nordic Foundation, Augustinus Foundation, Kirsten and Freddy Johansen’s Foundation. U.F.R.’s research salary was sponsored by a grant from Kirsten and Freddy Johansen’s Foundation. A.E., M.V., H.B., J.R., R.B.H., J.H.K., P.B.N., M.M.P-H., K.F., J.B.N., O.A., T.K.F., R.B.D., S.R.O., S.B.D., M.G-B., E.S., L.H.H., T.B., F.N.E., H.E.P., H.U., and J.R. have no conflicts of interest to declare., (Copyright: © 2024 Eiken et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: Young children are among the most frequent patients at medical call centers, even though they are rarely severely ill. Respiratory tract symptoms are among the most prevalent reasons for contact in pediatric calls. Triage of children without visual cues and through second-hand information is perceived as difficult, with risks of over- and under-triage., Objective: To study the safety and feasibility of introducing video triage of young children with respiratory symptoms at the medical helpline 1813 (MH1813) in Copenhagen, Denmark, as well as impact on patient outcome., Methods: Prospective quality improvement study including 617 patients enrolled to video or standard telephone triage (1:1) from February 2019-March 2020. Data originated from MH1813 patient records, survey responses, and hospital charts. Primary outcome was difference in patients staying at home eight hours after the call. Secondary outcomes weas hospital outcome, feasibility and acceptability. Adverse events (intensive care unit admittance, lasting injuries, death) were registered. Logistic regression was used to test the effect on outcomes. The COVID-19 pandemic shut the study down prematurely., Results: In total, 54% of the included patients were video-triaged., and 63% of video triaged patients and 58% of telephone triaged patients were triaged to stay at home, (p = 0.19). Within eight and 24 hours, there was a tendency of fewer video-triaged patients being assessed at hospitals: 39% versus 46% (p = 0.07) and 41% versus 49% (p = 0.07), respectively. At 24 hours after the call, 2.8% of the patients were hospitalized for at least 12 hours. Video triage was highly feasible and acceptable (>90%) and no adverse events were registered., Conclusion: Video triage of young children with respiratory symptoms at a medical call center was safe and feasible. Only about 3% of all children needed hospitalization for at least 12 hours. Video triage may optimize hospital referrals and increase health care accessibility., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Gren et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: Pediatric out-of-hours calls are common, as parents worry and seek reassurance and shared responsibility. Nevertheless, most children assessed in this context are not seriously ill. Conventional telephone triage lacks visual cues and is further limited by third part communication in calls concerning children. We investigated implementation of video triage in two previous studies. The aim of the present study was to investigate 1) How video triage versus telephone triage in children was experienced by parents and call-handlers, and 2) call-handlers' evaluation of the video triage projects., Methods: We triangulated data from surveys and interviews in five sub-studies. Sub-study 1: Parents' experience of video triage reported in closed-ended questionnaire items using quantitative analysis; Sub-study 2: Parents' experience of video triage reported as questionnaire free-text using qualitative content analysis; Sub-study 3: Call-handlers' experience of video triage reported in closed-ended questionnaire items using quantitative analysis; and Sub-studies 4 and 5: Individual interviews of call-handlers' experience of 1) video triage using thematic analysis and 2) the video triage project using process evaluation., Results: Most parents' comments regarding video triage were positive (n = 164, 83%). Video triage was perceived as reassuring and reducing the likelihood of misunderstandings and unnecessary hospital visits. Call-handlers experienced that video triage improved patient assessment and caller reassurance. Some call-handlers complained that the time allocated for study participation was inadequate and requested a more accessible video set-up. Both parents and call-handlers were significantly more satisfied and reassured after video triage than after telephone triage and suggested video triage as a permanent option., Conclusion: Video triage was appreciated by parents and call-handlers and was recommended as a permanent option. The call-handlers suggested that designated time for participation in the studies would have been desirable in this busy call-center. We recommend video triage as a contemporary solution in out-of-hours service., Competing Interests: The authors have declared that no competing interests exist.

Background: Majority of active tuberculosis (TB) cases in children in low-incidence countries are due to rapid progression of infection (latent TB infection (LTBI)) to disease. We aimed to assess common practice for managing paediatric LTBI in Austria, Germany and Switzerland prior to the publication of the first joint national guideline for paediatric TB in 2017., Methods: Online-based survey amongst pediatricians, practitioners and staff working in the public health sector between July and November 2017. Data analysis was conducted using IBM SPSS., Results: A total of 191 individuals participated in the survey with 173 questionnaires included for final analysis. Twelve percent of respondents were from Austria, 60% from Germany and 28% from Switzerland. Proportion of children with LTBI and migrant background was estimated by the respondents to be >50% by 58%. Tuberculin skin test (TST) and interferon-γ-release-assay (IGRA), particularly Quantiferon-gold-test, were reported to be used in 86% and 88%, respectively. In children > 5 years with a positive TST or IGRA a chest x-ray was commonly reported to be performed (28%). Fifty-three percent reported to take a different diagnostic approach in children ≤ 5 years, mainly combining TST, IGRA and chest x-ray for initial testing (31%). Sixty-eight percent reported to prescribe isoniazid-monotherapy: for 9 (62%), or 6 months (6%), 31% reported to prescribe combination therapy of isoniazid and rifampicin. Dosing of isoniazid and rifampicin below current recommendations was reported by up to 22% of respondents. Blood-sampling before/during LTBI treatment was reported in >90% of respondents, performing a chest-X-ray at the end of treatment by 51%., Conclusion: This survey showed reported heterogeneity in the management of paediatric LTBI. Thus, regular and easily accessible educational activities and national up-to-date guidelines are key to ensure awareness and quality of care for children and adolescents with LTBI in low-incidence countries., Competing Interests: The authors have declared that no competing interests exist.

Background and Objectives: The objective of this study was to investigate whether a soluble polymer and aldehyde-scavenger, polyvinylalcohol-carbazate (PVAC), can inhibit hemolysis in the storage of red blood cells (RBC)., Study Design and Methods: The effect of PVAC was assessed over a wide range of concentrations, using absorption spectroscopy to evaluate the level of hemolysis. Moreover, osmotic stability and aldehyde-scavenging potential of RBC were assessed after storage in PVAC., Results: After test tube storage for two weeks, red blood cell hemolysis was lower with PVAC compared to controls (mean difference 23%, 95% CI 16-29%, p < 0.001). A higher level of hemolysis led to a pronounced effect with PVAC. RBC stored in PVAC improved both the binding of free aldehydes (p <0.001) and the osmotic stability (p = 0.0036)., Conclusion: Erythrocytes stored with PVAC showed less hemolysis, which might be explained by the ability of PVACs to stabilize the cell membrane and decrease oxidative injury., Competing Interests: DB, FK, TE and TB have applied for patent protection using PVAC to decrease hemolysis during erythrocyte storage. The patent is filed but is not yet public and thus is not assigned a searchable identifier. TE, DB and TB are shareholders in a company, PVAC Medical Technologies LTD (PMT), developing PVAC for clinical applications. TE is an employee of PMT. DB and TB have acted as consultants towards PMT. The other authors have no conflict of interest. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Background: Heparin-binding protein (HBP) is released by neutrophils upon activation, and elevated plasma levels are seen in inflammatory states like sepsis, shock, cardiac arrest, and burns. However, little is known about the elimination of HBP. We wanted to study renal clearance of HBP in healthy individuals and in burn patients in intensive care units (ICUs). We also wished to examine the levels of HBP in the effluent of renal replacement circuits in ICU patients undergoing continuous renal replacement therapy (CRRT)., Methods: We measured plasma and urine levels of HBP and urine flow rate in 8 healthy individuals and 20 patients in a burn ICU. In 32 patients on CRRT, we measured levels of HBP in plasma and in the effluent of the CRRT circuit., Results: Renal clearance of HBP (median (IQR) ml/min) was 0.19 (0.08-0.33) in healthy individuals and 0.30 (0.01-1.04) in burn ICU patients. In ICU patients with cystatin C levels exceeding 1.44 mg/l, clearance was 0.45 (0.15-2.81), and in patients with cystatin C below 1.44 mg/l clearance was lower 0.28 (0.14-0.55) (p = 0.04). Starting CRRT did not significantly alter plasma levels of HBP (p = 0.14), and the median HBP level in the effluent on CRRT was 9.1 ng/ml (IQR 7.8-14.4 ng/ml)., Conclusion: In healthy individuals and critically ill burn patients, renal clearance of HBP is low. It is increased when renal function is impaired. Starting CRRT in critically ill patients does not alter plasma levels of HBP significantly, but HBP can be found in the effluent. It seems unlikely that impaired kidney function needs to be considered when interpreting concentrations of HBP in previous studies. Starting CRRT does not appear to be an effective way of reducing HBP concentrations., Competing Interests: I have read the journal´s policy and the authors of this manuscript have the following competing interests: The company Hansa Medical has filed a patent (Patent No.: US 9,784,741 B2) for HBP as a diagnostic tool in sepsis. Heiko Herwald is listed as one of the inventors. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Patients and Methods: Surgically managed burn patients admitted between 2010-14 were included. Operative stay was defined as the time from admission until the last operation, postoperative stay as the time from the last operation until discharge. The difference in variation was analysed with F-test. A retrospective review of medical records was done to explore reasons for extended postoperative stay. Multivariable regression was used to assess factors associated with operative stay and postoperative stay., Results: Operative stay/TBSA% showed less variation than total duration/TBSA% (F test = 2.38, p<0.01). The size of the burn, and the number of operations, were the independent factors that influenced operative stay (R2 0.65). Except for the size of the burn other factors were associated with duration of postoperative stay: wound related, psychological and other medical causes, advanced medical support, and accommodation arrangements before discharge, of which the two last were the most important with an increase of (mean) 12 and 17 days (p<0.001, R2 0.51)., Conclusion: Adjusted operative stay showed less variation than total hospital stay and thus can be considered a more accurate outcome measure for surgically managed burns. The size of burn and number of operations are the factors affecting this outcome measure.

Ventilator-induced or ventilator-associated lung injury (VILI/VALI) is common and there is an increasing demand for a tool that can optimize ventilator settings. Electrical impedance tomography (EIT) can detect changes in impedance caused by pulmonary ventilation and perfusion, but the effect of changes in the position of the body and in the placing of the electrode belt on the impedance signal have not to our knowledge been thoroughly evaluated. We therefore studied ventilation-related and perfusion-related changes in impedance during spontaneous breathing in 10 healthy subjects in five different body positions and with the electrode belt placed at three different thoracic positions using a 32-electrode EIT system. We found differences between regions of interest that could be attributed to changes in the position of the body, and differences in impedance amplitudes when the position of the electrode belt was changed. Ventilation-related changes in impedance could therefore be related to changes in the position of both the body and the electrode belt. Perfusion-related changes in impedance were probably related to the interference of major vessels. While these findings give us some insight into the sources of variation in impedance signals as a result of changes in the positions of both the body and the electrode belt, further studies on the origin of the perfusion-related impedance signal are needed to improve EIT further as a tool for the monitoring of pulmonary ventilation and perfusion.

Background: The lower airways harbor a community of bacterial species which is altered in asthma., Objectives: We examined whether the lower airway microbiota were related to measures of asthma severity., Methods: We prospectively recruited 26 severe asthma, 18 non-severe asthma and 12 healthy subjects. DNA was extracted from induced sputum and PCR amplification of the V3-V5 region of bacterial 16S rRNA gene was performed., Results: We obtained 138,218 high quality sequences which were rarefied at 133 sequences/sample. Twenty OTUs had sequences ≥1% of total. There were marked differences in the distribution of Phyla between groups (P = 2.8x10-118). Bacteroidetes and Fusobacteria were reduced in non-severe and severe asthmatic groups. Proteobacteria were more common in non-severe asthmatics compared to controls (OR = 2.26; 95% CI = 1.94-2.64) and Firmicutes were increased in severe asthmatics compared to controls (OR = 2.15; 95%CI = 1.89-2.45). Streptococcal OTUs amongst the Firmicutes were associated with recent onset asthma, rhinosinusitis and sputum eosinophilia., Conclusions: Sputum microbiota in severe asthma differs from healthy controls and non-severe asthmatics, and is characterized by the presence of Streptococcus spp with eosinophilia. Whether these organisms are causative for the pathophysiology of asthma remains to be determined.

Purpose: Heparin-binding protein (HBP) is released by granulocytes and has been shown to increase vascular permeability in experimental investigations. Increased vascular permeability in the lungs can lead to fluid accumulation in alveoli and respiratory failure. A generalized increase in vascular permeability leads to loss of circulating blood volume and circulatory failure. We hypothesized that plasma concentrations of HBP on admission to the intensive care unit (ICU) would be associated with decreased oxygenation or circulatory failure., Methods: This is a prospective, observational study in a mixed 8-bed ICU. We investigated concentrations of HBP in plasma at admission to the ICU from 278 patients. Simplified acute physiology score (SAPS) 3 was recorded on admission. Sequential organ failure assessment (SOFA) scores were recorded daily for three days., Results: Median SAPS 3 was 58.8 (48-70) and 30-day mortality 64/278 (23%). There was an association between high plasma concentrations of HBP on admission with decreased oxygenation (p<0.001) as well as with circulatory failure (p<0.001), after 48-72 hours in the ICU. There was an association between concentrations of HBP on admission and 30-day mortality (p = 0.002). ROC curves showed areas under the curve of 0,62 for decreased oxygenation, 0,65 for circulatory failure and 0,64 for mortality., Conclusions: A high concentration of HBP in plasma on admission to the ICU is associated with respiratory and circulatory failure later during the ICU care period. It is also associated with increased 30-day mortality. Despite being an interesting biomarker for the composite ICU population it's predictive value at the individual patient level is low.

Introduction: Microvascular changes in the skin due to pharmacological and physiological provocations can be used as a marker for vascular function. While laser Doppler flowmetry (LDF) has been used extensively for measurement of skin microvascular responses, Laser Speckle Contrast Imaging (LSCI) and Tissue Viability Imaging (TiVi) are novel imaging techniques. TiVi measures red blood cell concentration, while LDF and LSCI measure perfusion. Therefore, the aim of this study was to compare responses to provocations in the skin using these different techniques., Method: Changes in skin microcirculation were measured in healthy subjects during (1) iontophoresis of sodium nitroprusside (SNP) and noradrenaline (NA), (2) local heating and (3) post-occlusive reactive hyperemia (PORH) using LDF, LSCI and TiVi., Results: Iontophoresis of SNP increased perfusion (LSCI: baseline 40.9±6.2 PU; 10-min 100±25 PU; p<0.001) and RBC concentration (TiVi: baseline 119±18; 10-min 150±41 AU; p = 0.011). No change in perfusion (LSCI) was observed after iontophoresis of NA (baseline 38.0±4.4 PU; 10-min 38.9±5.0 PU; p = 0.64), while RBC concentration decreased (TiVi: baseline 59.6±11.8 AU; 10-min 54.4±13.3 AU; p = 0.021). Local heating increased perfusion (LDF: baseline 8.8±3.6 PU; max 112±55 PU; p<0.001, LSCI: baseline 50.8±8.0 PU; max 151±22 PU; p<0.001) and RBC concentration (TiVi: baseline 49.2±32.9 AU; max 99.3±28.3 AU; p<0.001). After 5 minutes of forearm occlusion with prior exsanguination, a decrease was seen in perfusion (LDF: p = 0.027; LSCI: p<0.001) and in RBC concentration (p = 0.045). Only LSCI showed a significant decrease in perfusion after 5 minutes of occlusion without prior exsanguination (p<0.001). Coefficients of variation were lower for LSCI and TiVi compared to LDF for most responses., Conclusion: LSCI is more sensitive than TiVi for measuring microvascular changes during SNP-induced vasodilatation and forearm occlusion. TiVi is more sensitive to noradrenaline-induced vasoconstriction. LSCI and TiVi show lower inter-subject variability than LDF. These findings are important to consider when choosing measurement techniques for studying skin microvascular responses.

Background: Clinical symptoms in children with pulmonary diseases are frequently non-specific. Rare diseases such as primary ciliary dyskinesia (PCD), cystic fibrosis (CF) or protracted bacterial bronchitis (PBB) can be easily missed at the general practitioner (GP)., Objective: To develop and test a questionnaire-based and data mining-supported tool providing diagnostic support for selected pulmonary diseases., Methods: First, interviews with parents of affected children were conducted and analysed. These parental observations during the pre-diagnostic time formed the basis for a new questionnaire addressing the parents' view on the disease. Secondly, parents with a sick child (e.g. PCD, PBB) answered the questionnaire and a data base was set up. Finally, a computer program consisting of eight different classifiers (support vector machine (SVM), artificial neural network (ANN), fuzzy rule-based, random forest, logistic regression, linear discriminant analysis, naive Bayes and nearest neighbour) and an ensemble classifier was developed and trained to categorise any given new questionnaire and suggest a diagnosis. For estimating the diagnostic accuracy, we applied ten-fold stratified cross validation., Results: All questionnaires of patients suffering from CF, asthma (AS), PCD, acute bronchitis (AB) and the healthy control group were correctly diagnosed by the fusion algorithm. For the pneumonia (PM) group 19/21 (90.5%) and for the PBB group 17/18 (94.4%) correct diagnoses could be reached. The program detected the correct diagnoses with an overall sensitivity of 98.8%. Receiver operating characteristics (ROC) analyses confirmed the accuracy of this diagnostic tool. Case studies highlighted the applicability of the tool in the daily work of a GP., Conclusion: For children with symptoms of pulmonary diseases a questionnaire-based diagnostic support tool using data mining techniques exhibited good results in arriving at diagnostic suggestions. In the hands of a doctor, this tool could be of value in arousing awareness for rare pulmonary diseases such as PCD or CF.

Steroidal glycoalkaloids (SGA) are toxic secondary metabolites naturally occurring in the potato, as well as in certain other Solanaceous plant species, such as tomato, eggplant and pepper. To investigate the steroidal origin of SGA biosynthesis, cut potato shoots were fed cholesterol labelled with deuterium (D) in the sterol ring structure (D5- or D6-labelled), or side chain (D7-labelled), and analysed after three or five weeks. The labelled cholesterol and presence of D-labelled SGA were analysed by GC-MS and LC-MS/MS, respectively. When feeding D-labelled cholesterol solubilised in Tween-80, labelled cholesterol in free form became present in both leaves and stems, although the major part was recovered as steryl esters. Minor amounts of D-labelled SGA (α-solanine and α-chaconine) were identified in cholesterol-treated shoots, but not in blank controls, or in shoots fed D6-27-hydroxycholesterol. Solubilising the labelled cholesterol in methyl-β-cyclodextrin instead of Tween-80 increased the levels of labelled SGA up to 100-fold, and about 1 mole% of the labelled cholesterol was recovered as labelled SGA in potato leaves. Both side chain and ring structure D labels were retained in SGA, showing that the entire cholesterol molecule is converted to SGA. However, feeding side chain D7-labelled cholesterol resulted in D5-labelled SGA, indicating that two hydrogen atoms were released during formation of the SGA nitrogen-containing ring system. Feeding with D7-sitosterol did not produce any labelled SGA, indicating that cholesterol is a specific SGA precursor. In conclusion, we have demonstrated a superior performance of methyl-β-cyclodextrin for delivery of cholesterol in plant tissue feeding experiments, and given firm evidence for cholesterol as a specific sterol precursor of SGA in potato.

Elevated systemic pentraxin 3 (PTX3) levels appear to be a powerful marker of inflammatory status and a superior outcome predictor in patients with chronic kidney disease (CKD). As previous data imply that PTX3 is involved in vascular pathology and that adipose tissue mass may influence circulating PTX3 levels, we aimed to study the importance of adipose tissue expression of PTX3 in the uremic milieu and its relation to endothelial dysfunction parameters. Plasma PTX3 and abdominal subcutaneous adipose tissue (SAT) PTX3 mRNA levels were quantified in 56 stage 5 CKD patients (median age 57 [range 25-75] years, 30 males) and 40 age and gender matched controls (median age 58 [range 20-79] years, 27 males). Associations between PTX3 measures and an extensive panel of clinical parameters, including surrogate markers of endothelial function, were assessed. Functional ex vivo studies on endothelial status and immunohistochemical staining for PTX3 were conducted in resistance subcutaneous arteries isolated from SAT. SAT PTX3 mRNA expression correlated with plasma PTX3 concentrations (rho = 0.54, p = 0.0001) and was increased (3.7 [0.4-70.3] vs. 1.2 [0.2-49.3] RQ, p = 0.02) in CKD patients with cardiovascular disease (CVD), but was not significantly different between patients and controls. The association to CVD was lost after adjustments. SAT PTX3 mRNA levels were independently correlated to asymmetric dimethylarginine and basal resistance artery tone developed after inhibition with nitric oxide synthase and cyclooxygenase (rho = -0.58, p = 0.002). Apparent positive PTX3 immunoreactivity was observed in both patient and control arteries. In conclusion, fat PTX3 mRNA levels are associated with measures of endothelial cell function in patients with CKD. PTX3 may be involved in adipose tissue-orchestrated mechanisms that are restricted to the uremic milieu and modify inflammation and vascular complications in CKD patients.

Background: Non steroidal anti-inflammatory drugs (NSAIDs) increase mortality and morbidity after myocardial infarction (MI). We examined cause-specific mortality and morbidity associated with NSAIDs in a nationwide cohort of MI patients., Methods and Results: By individual-level linkage of nationwide registries of hospitalization and drug dispensing from pharmacies in Denmark, patients aged >30 years admitted with first-time MI during 1997-2009 and their subsequent NSAID use were identified. The risk of three cardiovascular specific endpoints: cardiovascular death, the composite of coronary death and nonfatal MI, and the composite of fatal and nonfatal stroke, associated with NSAID use was analyzed by Cox proportional hazard analyses. Of 97,698 patients included 44.0% received NSAIDs during follow-up. Overall use of NSAIDs was associated with an increased risk of cardiovascular death (hazard ratio [HR] 1.42, 95% confidence interval [CI] 1.36-1.49). In particular use of the nonselective NSAID diclofenac and the selective cyclooxygenase-2 inhibitor rofecoxib was associated with increased risk of cardiovascular death (HR 1.96 [1.79-2.15] and HR1.66 [1.44-1.91], respectively) with a dose dependent increase in risk. Use of ibuprofen was associated with increased risk of cardiovascular death (HR 1.34[1.26-1.44]), whereas naproxen was associated with the lowest risk of (e.g., HR 1.27[1.01-1.59]., Conclusion: Use of individual NSAIDs is associated with different cause-specific cardiovascular risk and in particular rofecoxib and diclofenac were associated with increased cardiovascular morbidity and mortality. These results support caution with use of all NSAIDs in patients with prior MI.

Cardiovascular disease is the number one cause of death globally and air pollution can be a contributing cause. Acute myocardial infarction and cardiac arrest are frequent manifestations of coronary heart disease. The objectives of the study were to investigate the association between 4 657 out-of-hospital cardiac arrests (OHCA) and hourly and daily outdoor levels of PM(10), PM(2.5), coarse fraction of PM (PM(10-2.5)), ultrafine particle proxies, NO(x), NO(2), O(3) and CO in Copenhagen, Denmark, for the period 2000-2010. Susceptible groups by age and sex was also investigated. A case-crossover design was applied. None of the hourly lags of any of the pollutants were significantly associated with OHCA events. The strongest association with OHCA events was observed for the daily lag4 of PM(2.5), lag3 of PM(10), lag3 of PM(10-2.5), lag3 of NO(x) and lag4 of CO. An IQR increase of PM(2.5) and PM(10) was associated with a significant increase of 4% (95% CI: 0%; 9%) and 5% (95% CI: 1%; 9%) in OHCA events with 3 days lag, respectively. None of the other daily lags or other pollutants was significantly associated with OHCA events. Adjustment for O(3) slightly increased the association between OHCA and PM(2.5) and PM(10). No susceptible groups were identified.

The study focuses on the mechanisms of endothelial dysfunction in the uremic milieu. Subcutaneous resistance arteries from 35 end-stage renal disease (ESRD) patients and 28 matched controls were studied ex-vivo. Basal and receptor-dependent effects of endothelium-derived factors, expression of endothelial NO synthase (eNOS), prerequisites for myoendothelial gap junctions (MEGJ), and associations between endothelium-dependent responses and plasma levels of endothelial dysfunction markers were assessed. The contribution of endothelium-derived hyperpolarizing factor (EDHF) to endothelium-dependent relaxation was impaired in uremic arteries after stimulation with bradykinin, but not acetylcholine, reflecting the agonist-specific differences. Diminished vasodilator influences of the endothelium on basal tone and enhanced plasma levels of asymmetrical dimethyl L-arginine (ADMA) suggest impairment in NO-mediated regulation of uremic arteries. eNOS expression and contribution of MEGJs to EDHF type responses were unaltered. Plasma levels of ADMA were negatively associated with endothelium-dependent responses in uremic arteries. Preserved responses of smooth muscle to pinacidil and NO-donor indicate alterations within the endothelium and tolerance of vasodilator mechanisms to the uremic retention products at the level of smooth muscle. We conclude that both EDHF and NO pathways that control resistance artery tone are impaired in the uremic milieu. For the first time, we validate the alterations in EDHF type responses linked to kinin receptors in ESRD patients. The association between plasma ADMA concentrations and endothelial function in uremic resistance vasculature may have diagnostic and future therapeutic implications.

Background: Neonates with airways colonized by Haemophilus influenzae, Streptococcus pneumoniae or Moraxella catarrhalis are at increased risk for recurrent wheeze which may resemble asthma early in life. It is not clear whether chronic colonization by these pathogens is causative for severe persistent wheeze in some preschool children and whether these children might benefit from antibiotic treatment. We assessed the relevance of bacterial colonization and chronic airway infection in preschool children with severe persistent wheezing and evaluated the outcome of long-time antibiotic treatment on the clinical course in such children., Methodology/principal Findings: Preschool children (n = 42) with severe persistent wheeze but no symptoms of acute pulmonary infection were investigated by bronchoscopy and bronchoalveolar lavage (BAL). Differential cell counts and microbiological and virological analyses were performed on BAL samples. Patients diagnosed with bacterial infection were treated with antibiotics for 2-16 weeks (n = 29). A modified ISAAC questionnaire was used for follow-up assessment of children at least 6 months after bronchoscopy. Of the 42 children with severe wheezing, 34 (81%) showed a neutrophilic inflammation and 20 (59%) of this subgroup had elevated bacterial counts (≥ 10⁴ colony forming units per milliliter) suggesting infection. Haemophilus influenzae, Streptococcus pneumoniae and Moraxella catarrhalis were the most frequently isolated species. After treatment with appropriate antibiotics 92% of patients showed a marked improvement of symptoms upon follow-up examination., Conclusions/significance: Chronic bacterial infections are relevant in a subgroup of preschool children with persistent wheezing and such children benefit significantly from antibiotic therapy.