Association of putative enteroaggregative Escherichia coli virulence genes and biofilm production in isolates from travelers to developing countries.

Enteroaggregative Escherichia coli (EAEC) is an emerging enteric pathogen that causes acute and chronic diarrhea among children, human immunodeficiency virus-infected patients, and travelers to developing regions of the world. The pathogenesis of EAEC strains involves the production of biofilm. In this study, we determined the association between presence of putative EAEC virulence genes and biofilm formation in 57 EAEC isolates (as defined by HEp-2 adherence) from travelers with diarrhea and in 18 EAEC isolates from travelers without diarrhea. Twelve nondiarrheagenic E. coli isolates from healthy travelers were used as controls. Biofilm formation was measured by using a microtiter plate assay with the crystal violet staining method, and the presence of the putative EAEC virulence genes aap, aatA, aggR, astA, irp2, pet, set1A, and shf was determined by PCR. EAEC isolates were more likely to produce biofilm than nondiarrheagenic E. coli isolates (P = 0.027), and the production of biofilm was associated with the virulence genes aggR, set1A, aatA, and irp2, which were found in 16 (40%), 17 (43%), 10 (25%), and 27 (68%) of the biofilm producers versus only 4 (11%), 6 (6%), 2 (6%), and 15 (43%) in non-biofilm producers (P = 0.008 for aggR, P = 0.0004 for set1A, P = 0.029 for aatA, and P = 0.04 for irp2). Although the proportion of EAEC isolates producing biofilm in patients with diarrhea (51%) was similar to that in patients without diarrhea (61%), biofilm production was related to the carriage of aggR (P = 0.015), set1A (P = 0.001), and aatA (P = 0.025). Since aggR is a master regulator of EAEC, the presence of aap (P = 0.004), astA (P = 0.001), irp2 (P = 0.0006), pet (P = 0.002), and set1A (P = 0.014) in an aggR versus an aggR-lacking background was investigated and was also found to be associated with biofilm production. This study suggests that biofilm formation is a common phenomenon among EAEC isolates derived from travelers with or without diarrhea and that multiple genes associated with biofilm formation are regulated by aggR.

Cement volume is the most important modifiable predictor for pain relief in BKP: results from SWISSspine, a nationwide registry

Purpose The effectiveness of vertebral augmentation techniques is a currently highly debated issue. The biomechanical literature suggests that cement filling volumes may play an important role in the ‘‘dosage’’ of vertebral augmentation and its pain alleviating effect. Good clinical data about filling volumes are scarce and most patient series are small. Therefore, we investigated the predictors of pain alleviation after balloon kyphoplasty in the nationwide SWISSspine registry where cement volumes are also recorded. Methods All single-level vertebral fractures with no additional fracture stabilization and availability of at least one follow-up within 6 months after surgery were included. The following potential predictors were assessed in a multivariate logistic regression model with the group’s average pain alleviation of 41 points on VAS as the desired outcome: patient age, patient sex, diagnosis, preoperative pain, level of fracture, type of fracture, age of fracture, segmental kyphotic deformity, cement volume, vertebral body filling volume, and cement extrusions. Results There were 194 female and 82 males with an average age of 70.4 and 65.3 years, respectively. Female patients were about twice as likely for achieving the average pain relief compared to males (p = 0.04). The preoperative pain level was the strongest predictor in that the likelihood for achieving an at least 41-point pain relief increased by about 8 % with each additional point of preoperative pain (p\0.001). A thoraco-lumbar fracture had a three times higher odds for the average pain relief compared with a lumbar fracture (p = 0.03). An A.3.1 fracture only had about a third of the probability for average pain relief compared with an A.1.1 fracture (p = 0.004). Cement volumes up to 4.5 ml only had an approximately 40 % chance for a minimum 41-point pain alleviation as compared with cement volumes of at least 4.5 ml (p = 0.007). In addition, the relationship between cement volume and pain alleviation followed a dose-dependent pattern. Conclusions Cement volume was revealed as a significant predictor for pain relief in BKP. Cement volume was the third most important influential covariate and the most important modifiable and operator dependent one. The clear dose-outcome relationship between cement filling volumes and pain relief additionally supports these findings. Cement volumes of [4.5 ml seem to be recommendable for achieving relevant pain alleviation. Patient sex and fracture type and location were further significant predictors and all these covariates should be recorded and reported in future studies about the pain alleviating effectiveness of vertebral augmentation procedures.

Factors determining the use of universal precautions by emergency department nurses

The Health Belief Model (HBM) provided the theoretical framework for examining Universal Precautions (UP) compliance factors by Emergency Department nurses. A random sample of Emergency Nurses Association (ENA) clinical nurses (n = 900) from five states (New York, New Jersey, California, Texas, and Florida), were surveyed to explore the factors related to their decision to comply with UP. Five-hundred-ninety-eight (598) useable questionnaires were analyzed. The responders were primarily female (84.9%), hospital based (94.6%), staff nurses (66.6%) who had a mean 8.5 years of emergency nursing experience. The nurses represented all levels of hospitals from rural (4.5%) to urban trauma centers (23.7%). The mean UP training hours was 3.0 (range 0-38 hours). Linear regression was used to analyze the four hypotheses. The first hypothesis evaluating perceived susceptibility and seriousness with reported UP use was not significant (p = $>$.05). Hypothesis 2 tested perceived benefits with internal and external barriers. Both perceived benefits and internal barriers as well as the overall regression were significant (F = 26.03, p = $<$0.001). Hypothesis 3 which tested modifying factors, cues to action, select demographic variables, and the main effects of the HBM with self reported UP compliance, was also significant (F = 12.39, p = $<$0.001). The additive effects were tested by use of a stepwise regression that assessed the contribution of each of the significant variables. The regression was significant (F = 12.39, p = $<$0.001) and explained 18% of the total variance. In descending order of contribution, the significant variables related to compliance were: internal barriers (t = $-$6.267; p = $<$0.001) such as the perception that because of the nature of the emergency care environment there is sometimes inadequate time to put on UP; cues to action (t = 3.195; p = 0.001) such as posted reminder signs or verbal reminders from peers; the number of Universal Precautions training hours (t = 3.667; p = $<$0.001) meaning that as the number of training hours increase so does compliance; perceived benefits (t = 3.466; p = 0.001) such as believing that UP will provide adequate barrier protection; and perceived susceptibility (t = 2.880; p = 0.004) such as feeling that they are at risk of exposure. ^

Effect of continuous gastric enteral feeding on tonometric measurement of gastric intramucosal carbon dioxide levels in healthy volunteers

Purpose. The aim of this research was to evaluate the effect of enteral feeding on tonometric measurement of gastric regional carbon dioxide levels (PrCO2) in normal healthy volunteers. Design and methods. The sample included 12 healthy volunteers recruited by the University Clinical Research Center (UCRC). An air tonometry system monitored PrCO2 levels using a tonometer placed in the lumen of the stomach via orogastric intubation. PrCO2 was automatically measured and recorded every 10 minutes throughout the five hour study period. An oral dose of famotidine 40 mg was self-administered the evening prior to and the morning of the study. Instillation of Isocal® High Nitrogen (HN) was used for enteral feeding in hourly escalating doses of 0, 40, 60, and 80 ml/hr with no feeding during the fifth hour. Results . PrCO2 measurements at time 0 and 10 minutes (41.4 ± 6.5 and 41.8 ± 5.7, respectively) demonstrated biologic precision (Levene's Test statistic = 0.085, p-value 0.774). Biologic precision was lost between T130 and T140 40 when compared to baseline TO (Levene's Test statistic = 1.70, p-value 0.205; and 3.205, p-value 0.042, respectively) and returned to non-significant levels between T270 and T280 (Levene's Test statistic = 3.083, p-value 0.043; and 2.307, p-value 0.143, respectively). Isocal® HN significantly affected the biologic accuracy of PrCO2 measurements (repeated measures ANOVA F 4.91, p-value <0.001). After 20 minutes of enteral feeding at 40 ml/hr, PrCO2 significantly increased (41.4 ± 6.5 to 46.6 ± 4.25, F = 5.4, p-value 0.029). Maximum variance from baseline (41.4 ± 6.5 to 61.3 ± 15.2, F = 17.22, p-value <0.001) was noted after 30 minutes of Isocal® HN at 80 ml/hr or 210 minutes from baseline. The significant elevations in PrCO2 continued throughout the study. Sixty minutes after discontinuation of enteral feeding, PrCO2 remained significantly elevated from baseline (41.4 ± 6.5 to 51.8 ± 9.2, F = 10.15, p-value 0.004). Conclusion. Enteral feeding with Isocal® HN significantly affects the precision and accuracy of PrCO2 measurements in healthy volunteers. ^

Investigating short- and long-term transfer effects of a Taiji beginner course in participants’ daily life

OBJECTIVE: In recent years research investigating various health benefits of Taiji practice has markedly increased. Despite this growing scientific interest, essential questions such as to what extent a Taiji course may exert noticeable effects in participants’ everyday life, what these effects are, and how and where potential transfer effects occur, have hardly been considered. The aim of our study was to explore transfer effects from a Taiji course into participants’ daily lives. METHODS: We conducted a longitudinal observational study in 45 healthy participants at the end of their three-month Taiji beginner course (tp1) and at two months (tp2) as well as one year after course completion (tp3). Participants were asked to report their Taiji practice behavior at all time points, as well as to rate and describe perceived transfer effects of Taiji course contents on their daily life at tp1 and tp3. RESULTS: Transfer effects were reported by 91.1% of all respondents after course completion (tp1) and persisted in 73.3% at the one-year follow-up assessment (tp3), counting “increase of self-efficacy”, “improvement of stress management”, and “increase of body awareness” as the most frequently mentioned effects. Transfer effects predominantly occurred in participants’ work and social environments, as well as during everyday activities in public areas. While selfreliant Taiji practice frequency significantly decreased from 82.2% at tp1 to 55.6% at tp3 (P < 0.001), the magnitude of self-reported transfer effects did not (P = 0.35). As explorative analyses revealed, regular Taiji course attendance was highly correlated with stronger transfer effects at tp1 (r = 0.51; P < 0.001) and tp3 (r = 0.35; P = 0.020). Participants reporting high self-reliant Taiji practice frequency at tp2 were likely to maintain a regular practice routine at tp3 (r = 0.42; P < 0.004), whereas self-reliant practice frequency and transfer effects at tp1 were positively correlated with self-reliant practice frequency at tp3 on a trend level (r < 0.27; P > 0.08). CONCLUSION: Our data underline the importance of regular course participation for pronounced and long lasting transfer effects into participants’ everyday life. We discuss that several context and process-related aspects of a Taiji intervention are potentially relevant factors for enhancement of transfer effect.

Reactive oxygen intermediates contribute to necrotic and apoptotic neuronal injury in an infant rat model of bacterial meningitis due to group B streptococci.

Reactive oxygen intermediates (ROI) contribute to neuronal injury in cerebral ischemia and trauma. In this study we explored the role of ROI in bacterial meningitis. Meningitis caused by group B streptococci in infant rats led to two distinct forms of neuronal injury, areas of necrosis in the cortex and neuronal loss in the dentate gyrus of the hippocampus, the latter showing evidence for apoptosis. Staining of brain sections with diaminobenzidine after perfusion with manganese buffer and measurement of lipid peroxidation products in brain homogenates both provided evidence that meningitis led to the generation of ROI. Treatment with the radical scavenger alpha-phenyl-tert-butyl nitrone (PBN) (100 mg/kg q8h i.p.) beginning at the time of infection completely abolished ROI detection and the increase in lipidperoxidation. Cerebral cortical perfusion was reduced in animals with meningitis to 37.5+/-21.0% of uninfected controls (P < 0.05), and PBN restored cortical perfusion to 72.0+/-8.1% of controls (P < 0.05 vs meningitis). PBN also completely prevented neuronal injury in the cortex and hippocampus, when started at the time of infection (P < 0.02), and significantly reduced both forms of injury, when started 18 h after infection together with antibiotics (P < 0.004 for cortex and P < 0.001 for hippocampus). These data indicate that the generation of ROI is a major contributor to cerebral ischemia and necrotic and apoptotic neuronal injury in this model of neonatal meningitis.

Gammaglobulin and selenium status in healthy neonatal dairy calves in Switzerland

Serum samples from 142 calves and their dams were analyzed for gammaglobulins (gammaG, calves) and selenium concentrations (Se, calves and dams). A questionnaire provided information about birth and colostrum management. The calves and their dams were distributed into two groups according the calves' gammaG concentration (< 10 and >= 10 g/L), Se concentrations were compared between groups. The correlation between gammaG and Se concentrations in the calves and their dams was analyzed. Risk factors for failure of passive transfer and Se deficiency were assessed based on the questionnaire. The gammaG concentration of 42.9 % of the calves was < 10 g/L (median: 10.9). Calves showed significantly higher gammaG values after optimized colostrum administration than calves with suboptimal colostrum administration (p < 0.004). The median Se concentration was 26.8 and 36.5 microg/L for the calves and dams, respectively. A high correlation was observed between the Se concentration of the dam and her calf (r = 0.72, p < 0.001). The calves' Se and gammaG concentrations were not significantly correlated. These results demonstrate that further efforts toward better information of farmers regarding colostrum management and Se supply are warranted.

Ultra-early intravenous stroke thrombolysis: do all patients benefit similarly?

BACKGROUND AND PURPOSE We previously reported increased benefit and reduced mortality after ultra-early stroke thrombolysis in a single center. We now explored in a large multicenter cohort whether extra benefit of treatment within 90 minutes from symptom onset is uniform across predefined stroke severity subgroups, as compared with later thrombolysis. METHODS Prospectively collected data of consecutive ischemic stroke patients who received i.v. thrombolysis in 10 European stroke centers were merged. Logistic regression tested association between treatment delays, as well as excellent 3-month outcome (modified Rankin scale, 0-1), and mortality. The association was tested separately in tertiles of baseline National Institutes of Health Stroke Scale. RESULTS In the whole cohort (n=6856), shorter onset-to-treatment time as a continuous variable was significantly associated with excellent outcome (P<0.001). Every fifth patient had onset-to-treatment time≤90 minutes, and these patients had lower frequency of intracranial hemorrhage. After adjusting for age, sex, admission glucose level, and year of treatment, onset-to-treatment time≤90 minutes was associated with excellent outcome in patients with National Institutes of Health Stroke Scale 7 to 12 (odds ratio, 1.37; 95% confidence interval, 1.11-1.70; P=0.004), but not in patients with baseline National Institutes of Health Stroke Scale>12 (odds ratio, 1.00; 95% confidence interval, 0.76-1.32; P=0.99) and baseline National Institutes of Health Stroke Scale 0 to 6 (odds ratio, 1.04; 95% confidence interval, 0.78-1.39; P=0.80). In the latter, however, an independent association (odds ratio, 1.51; 95% confidence interval, 1.14-2.01; P<0.01) was found when considering modified Rankin scale 0 as outcome (to overcome the possible ceiling effect from spontaneous better prognosis of patients with mild symptoms). Ultra-early treatment was not associated with mortality. CONCLUSIONS I.v. thrombolysis within 90 minutes is, compared with later thrombolysis, strongly and independently associated with excellent outcome in patients with moderate and mild stroke severity.

Additive effects of HLA alleles and innate immune genes determine viral outcome in HCV infection

BACKGROUND Chronic HCV infection is a leading cause of liver-related morbidity globally. The innate and adaptive immune responses are thought to be important in determining viral outcomes. Polymorphisms associated with the IFNL3 (IL28B) gene are strongly associated with spontaneous clearance and treatment outcomes. OBJECTIVE This study investigates the importance of HLA genes in the context of genetic variation associated with the innate immune genes IFNL3 and KIR2DS3. DESIGN We assess the collective influence of HLA and innate immune genes on viral outcomes in an Irish cohort of women (n=319) who had been infected from a single source as well as a more heterogeneous cohort (Swiss Cohort, n=461). In the Irish cohort, a number of HLA alleles are associated with different outcomes, and the impact of IFNL3-linked polymorphisms is profound. RESULTS Logistic regression was performed on data from the Irish cohort, and indicates that the HLA-A*03 (OR 0.36 (0.15 to 0.89), p=0.027) -B*27 (OR 0.12 (0.03 to 0.45), p=<0.001), -DRB1*01:01 (OR 0.2 (0.07 to 0.61), p=0.005), -DRB1*04:01 (OR 0.31 (0.12 to 0.85, p=0.02) and the CC IFNL3 rs12979860 genotypes (OR 0.1 (0.04 to 0.23), p<0.001) are significantly associated with viral clearance. Furthermore, DQB1*02:01 (OR 4.2 (2.04 to 8.66), p=0.008), KIR2DS3 (OR 4.36 (1.62 to 11.74), p=0.004) and the rs12979860 IFNL3 'T' allele are associated with chronic infection. This study finds no interactive effect between IFNL3 and these Class I and II alleles in relation to viral clearance. There is a clear additive effect, however. Data from the Swiss cohort also confirms independent and additive effects of HLA Class I, II and IFNL3 genes in their prediction of viral outcome. CONCLUSIONS This data supports a critical role for the adaptive immune response in the control of HCV in concert with the innate immune response.

Multiple Hypersensitivities Including Recurrent Airway Obstruction, Insect Bite Hypersensitivity, and Urticaria in 2 Warmblood Horse Populations.

BACKGROUND Multiple hypersensitivities (MHS) have been described in humans, cats, and dogs, but not horses. HYPOTHESES Horses suffering from recurrent airway obstruction (RAO), insect bite hypersensitivity (IBH), or urticaria (URT) will have an increased risk of also being affected by another one of these hypersensitivities. This predisposition for MHS also will be associated with decreased shedding of strongylid eggs in feces and with a single nucleotide polymorphism (SNP BIEC2-224511), previously shown to be associated with RAO. ANIMALS The first population (P1) included 119 randomly sampled horses representative of the Swiss sporthorse population; the replication population (P2) included 210 RAO-affected Warmblood horses and 264 RAO-unaffected controls. All horses were Warmbloods, 14 years or older. METHODS Associations between disease phenotypes (RAO, IBH, URT, MHS) fecal egg counts, the SNP BIEC2-224511 as well as management and environmental factors were investigated. RESULTS In P1, RAO-affected horses had a 13.1 times higher odds ratio (OR) of also suffering from IBH (P = .004). In P2, the respective OR was 7.4 (P = .002) and IBH-affected horses also showed a 7.1 times increased OR of concomitantly suffering from URT (P < .001). IBH, URT, and MHS phenotypes were significantly associated with the absence of nematode eggs in the feces. CONCLUSIONS AND CLINICAL IMPORTANCE This is the first report of MHS in horses. Specifically, an increased risk for IBH should be expected in RAO-affected horses.

Combined effect of a fluoride-, stannous- and chitosan-containing toothpaste and stannous-containing rinse on the prevention of initial enamel erosion-abrasion.

OBJECTIVES The aim of this study was to assess the preventive effect of a fluoride-, stannous- and chitosan-containing (F/Sn/chitosan-) toothpaste (TP) on initial enamel erosion and abrasion. METHODS In total, 150 human premolar enamel specimens were ground, polished and divided into 5 toothpaste/rinse groups (n=30): (G1) placebo-TP/tap water, (G2) sodium fluoride (NaF-) TP/tap water, (G3) F/Sn/chitosan-TP/tap water, (G4) F/Sn/chitosan-TP/Sn-rinse, (G5) NaF-TP/NaF-rinse. The 8-day erosion-abrasion cyclic treatment (one cycle/day) consisted of incubating the samples in artificial saliva (30min), then submitting the samples to toothbrush abrasion (2min incubation in toothpaste slurry; brushing with 20 toothbrush strokes) and rinsing (2min; 10ml) with the respective solution: tap water (G1-G3), Sn-rinse (G4) or NaF-rinse (G5). Afterwards, the samples were submitted to erosion (2min; 30ml 1% citric acid, pH=3.6). Surface microhardness (SMH) was measured initially and after every abrasion and erosion treatment. Enamel substance loss was calculated after each abrasion. Non-parametric ANOVA followed by Wilcoxon rank tests were used for analysis. RESULTS G1 presented the greatest SMH decrease, while G4 presented the least SMH decrease (p<0.001). G3 had a similar SMH decrease to G2 and G5. Substance loss was significantly lower in G4 than all other groups (p<0.05), closely followed by G3. Both G2 and G5 showed similar calculated enamel substance loss to G1. CONCLUSION The treatment with F/Sn/chitosan-TP and tap water provided a similar SMH decrease to both NaF-TP groups, but significantly lower substance loss. F/Sn/Chitosan-TP and Sn-rinse showed a better preventive effect, which promoted less SMH decrease and reduced substance loss. CLINICAL SIGNIFICANCE The toothpaste containing fluoride, stannous and chitosan shows promising results in reducing substance loss from erosion and abrasion. The combination of this toothpaste with the stannous-containing rinse showed even better prevention against erosion-abrasion.

Combined aerobic/inspiratory muscle training vs. aerobic training in patients with chronic heart failure: The Vent-HeFT trial: a European prospective multicentre randomized trial

AIMS Vent-HeFT is a multicentre randomized trial designed to investigate the potential additive benefits of inspiratory muscle training (IMT) on aerobic training (AT) in patients with chronic heart failure (CHF). METHODS AND RESULTS Forty-three CHF patients with a mean age of 58 ± 12 years, peak oxygen consumption (peak VO2 ) 17.9 ± 5 mL/kg/min, and LVEF 29.5 ± 5% were randomized to an AT/IMT group (n = 21) or to an AT/SHAM group (n = 22) in a 12-week exercise programme. AT involved 45 min of ergometer training at 70-80% of maximum heart rate, three times a week for both groups. In the AT/IMT group, IMT was performed at 60% of sustained maximal inspiratory pressure (SPImax ) while in the AT/SHAM group it was performed at 10% of SPImax , using a computer biofeedback trainer for 30 min, three times a week. At baseline and at 3 months, patients were evaluated for exercise capacity, lung function, inspiratory muscle strength (PImax ) and work capacity (SPImax ), quality of life (QoL), LVEF and LV diameter, dyspnoea, C-reactive protein (CRP), and NT-proBNP. IMT resulted in a significantly higher benefit in SPImax (P = 0.02), QoL (P = 0.002), dyspnoea (P = 0.004), CRP (P = 0.03), and NT-proBNP (P = 0.004). In both AT/IMT and AT/SHAM groups PImax (P < 0.001, P = 0.02), peak VO2 (P = 0.008, P = 0.04), and LVEF (P = 0.005, P = 0.002) improved significantly; however, without an additional benefit for either of the groups. CONCLUSION This randomized multicentre study demonstrates that IMT combined with aerobic training provides additional benefits in functional and serum biomarkers in patients with moderate CHF. These findings advocate for application of IMT in cardiac rehabilitation programmes.

Patient and physician gender concordance in preventive care in university primary care settings.

OBJECTIVE To assess the quality of preventive care according to physician and patient gender in a country with universal health care coverage. METHODS We assessed a retrospective cohort study of 1001 randomly selected patients aged 50-80 years followed over 2 years (2005-2006) in 4 Swiss university primary care settings (Basel, Geneva, Lausanne, Zürich). We used indicators derived from RAND's Quality Assessment Tools and examined percentages of recommended preventive care. Results were adjusted using hierarchical multivariate logistic regression models. RESULTS 1001 patients (44% women) were followed by 189 physicians (52% women). Female patients received less preventive care than male patients (65.2% vs. 72.1%, p<0.001). Female physicians provided significantly more preventive care than male physicians (p=0.01) to both female (66.7% vs. 63.6%) and male patients (73.4% vs. 70.7%). After multivariate adjustment, differences according to physician (p=0.02) and patient gender (p<0.001) remained statistically significant. Female physicians provided more recommended cancer screening than male physicians (78.4 vs. 71.9%, p=0.01). CONCLUSIONS In Swiss university primary care settings, female patients receive less preventive care than male patients, with female physicians providing more preventive care than male physicians. Greater attention should be paid to female patients in preventive care and to why female physicians tend to provide better preventive care.

Von Willebrand Factor Improves Risk Prediction in Addition to N-Terminal Pro-B-type Natriuretic Peptide in Patients Referred to Coronary Angiography and Signs and Symptoms of Heart Failure and Preserved Ejection Fraction.

BACKGROUND Heart failure with preserved ejection fraction (HFpEF) represents a growing health burden associated with substantial mortality and morbidity. Consequently, risk prediction is of highest importance. Endothelial dysfunction has been recently shown to play an important role in the complex pathophysiology of HFpEF. We therefore aimed to assess von Willebrand factor (vWF), a marker of endothelial damage, as potential biomarker for risk assessment in patients with HFpEF. METHODS AND RESULTS Concentrations of vWF were assessed in 457 patients with HFpEF enrolled as part of the LUdwigshafen Risk and Cardiovascular Health (LURIC) study. All-cause mortality was observed in 40% of patients during a median follow-up time of 9.7 years. vWF significantly predicted mortality with a hazard ratio (HR) per increase of 1 SD of 1.45 (95% confidence interval, 1.26-1.68; P<0.001) and remained a significant predictor after adjustment for age, sex, body mass index, N-terminal pro-B-type natriuretic peptide (NT-proBNP), renal function, and frequent HFpEF-related comorbidities (adjusted HR per 1 SD, 1.22; 95% confidence interval, 1.05-1.42; P=0.001). Most notably, vWF showed additional prognostic value beyond that achievable with NT-proBNP indicated by improvements in C-Statistic (vWF×NT-proBNP: 0.65 versus NT-proBNP: 0.63; P for comparison, 0.004) and category-free net reclassification index (37.6%; P<0.001). CONCLUSIONS vWF is an independent predictor of long-term outcome in patients with HFpEF, which is in line with endothelial dysfunction as potential mediator in the pathophysiology of HFpEF. In particular, combined assessment of vWF and NT-proBNP improved risk prediction in this vulnerable group of patients.

Clinical and biochemical profiles suggest fibromuscular dysplasia is a systemic disease with altered TGF-β expression and connective tissue features.

Fibromuscular dysplasia (FMD) is a rare, nonatherosclerotic arterial disease for which the molecular basis is unknown. We comprehensively studied 47 subjects with FMD, including physical examination, spine magnetic resonance imaging, bone densitometry, and brain magnetic resonance angiography. Inflammatory biomarkers in plasma and transforming growth factor β (TGF-β) cytokines in patient-derived dermal fibroblasts were measured by ELISA. Arterial pathology other than medial fibrodysplasia with multifocal stenosis included cerebral aneurysm, found in 12.8% of subjects. Extra-arterial pathology included low bone density (P<0.001); early onset degenerative spine disease (95.7%); increased incidence of Chiari I malformation (6.4%) and dural ectasia (42.6%); and physical examination findings of a mild connective tissue dysplasia (95.7%). Screening for mutations causing known genetically mediated arteriopathies was unrevealing. We found elevated plasma TGF-β1 (P=0.009), TGF-β2 (P=0.004) and additional inflammatory markers, and increased TGF-β1 (P=0.0009) and TGF-β2 (P=0.0001) secretion in dermal fibroblast cell lines from subjects with FMD compared to age- and gender-matched controls. Detailed phenotyping of patients with FMD allowed us to demonstrate that FMD is a systemic disease with alterations in common with the spectrum of genetic syndromes that involve altered TGF-β signaling and offers TGF-β as a marker of FMD.