Long-Term Safety, Tolerability and Survival in Patients with Pulmonary Arterial Hypertension Treated with Macitentan: Results from the SERAPHIN Open-Label Extension

Introduction: In SERAPHIN, a long-term, event-driven, double-blind randomised controlled trial in pulmonary arterial hypertension (PAH), macitentan 10 mg significantly reduced the risk of morbidity/mortality compared with placebo. Its open-label extension study (SERAPHIN OL) further assessed long-term safety and tolerability of macitentan 10 mg in PAH patients. Methods: Patients in SERAPHIN who completed the double-blind treatment period or experienced a morbidity event during the study could enter SERAPHIN OL. Patients received macitentan 10 mg once daily, and safety and survival were assessed until end of treatment (+ 28 days). Two overlapping sets were analysed for safety: (1) all patients in SERAPHIN OL (OL safety set); (2) patients randomised to macitentan 10 mg in SERAPHIN (long-term safety/survival set). Survival was evaluated as an exploratory endpoint in the latter set. Results: Of 742 patients randomised in SERAPHIN, 550 (74.1%) entered SERAPHIN OL (OL safety set); 242 patients were randomised to macitentan 10 mg in SERAPHIN (long-term safety/survival set). Median (min, max) exposure to macitentan 10 mg was 40.1 (0.1, 130.5) months (2074.7 patient-years; OL safety set) and 54.7 (0.1, 141.3) months (1151.0 patient-years; long-term safety/survival set). Safety in both analysis sets was comparable to the known safety profile of macitentan. Kaplan-Meier survival estimates (95% CI) at 1, 5, 7 and 9 years were 95.0% (91.3, 97.1), 73.3% (66.6, 78.9), 62.6% (54.6, 69.6) and 52.7% (43.6, 61.0), respectively (long-term safety/survival set; median follow-up: 5.9 years). Conclusions: This analysis provides the longest follow-up for safety and survival published to date for any PAH therapy. The safety profile of macitentan 10 mg over this extensive treatment period was in line with that observed in SERAPHIN. As the majority of patients were receiving other PAH therapy at macitentan initiation, our study provides additional insight into the long-term safety of macitentan, including as part of combination therapy. Trial Registration: ClinicalTrials.gov Identifiers: NCT00660179 and NCT00667823

COST-EFFECTIVENESS EVALUATION OF A CARE BUNDLE INTERVENTION FOR PREVENTING FALLS AMONG ITALIAN AGED INPATIENTS IN A STEPPED-WEDGE CLUSTER RANDOMIZED CONTROLLED TRIAL

Objectives: Falls among hospitalized elderlies represent a frequent (20-30%) adverse event. About 30% of falls lead to injuries with different types of severity and can provoke long-time disability or death. The prevention of falls in the hospital is possible through the adoption of multimodal strategies. This study aimed at identifying the potential reduction in falls due to the Care Bundle implementation and its cost-effectiveness in real clinical environment Methods: 10 clusters (hospital units) of Bologna USL and University Hospital were randomized in a stepped-wedge design including 4 steps over the years 2015 and 2016. Incidence rates of falls in both the control and intervention periods were calculated considering the patientdays of exposure. The overall crude relative risk (RR) was calculated with its 95% confidence interval. The overall crude incremental cost-effectiveness ratio (ICER) per fall prevented has been calculated. The difference in the rate of patient falls during the intervention period compared with the control period was in the denominator of the ICER. The difference in intervention vs control costs (associated with implementation of the Care Bundle program, length of stay and hospital services provided to patients attributable to falls) was in the nominator. Results: A total of 11844 patients were randomized in this trial (intervention group n=6600, mean(SD) age=80.93(11.62); control group n=5244, mean(SD) age=78.14(12.68)) throughout the overall period. A 13% reduction (RR=0.87 (95% CI: 0.71-1.07)) in falls due to the Care Bundle intervention was observed, though it did not reach statistical significance. The overall ICER was €617.55 for fall prevented. Conclusions: The preliminary analyses showed a positive effect of Care Bundle intervention for preventing falls among aged inpatients at relatively low cost for fall prevented. Deeper statistical analyses to estimate precise cost-effectiveness of the Care Bundle intervention will be conducted shortly

Dietary fats, olive oil and respiratory diseases in Italian adults: A population-based study

BACKGROUND: Fat intake has been associated with respiratory diseases, with conflicting results. OBJECTIVE: We studied the association between asthma and rhinitis with dietary fats, and their food sources in an Italian population. METHODS: Clinical and nutritional information was collected for 871 subjects (aged 20-84) from the population-based multi-case-control study Genes Environment Interaction in Respiratory Diseases (GEIRD): 145 with current asthma (CA), 77 with past asthma (PA), 305 with rhinitis and 344 controls. Food intake was collected using the EPIC (European Investigation into Cancer and Nutrition) Food Frequency Questionnaire. The associations between fats and respiratory diseases were estimated by multinomial models. Fats and their dietary sources were analysed both as continuous variables and as quartiles. RESULTS: Monounsaturated fatty acids and oleic acid were associated with a reduced risk of CA in both continuous (RRR = 0.68, 95%CI: 0.48; 0.96; RRR = 0.69; 95%CI: 0.49; 0.97, per 10 g, respectively) and per-quartile analyses (p for trend = 0.028 and 0.024, respectively). Olive oil was associated with a decreased risk of CA (RRR = 0.80; 95%CI: 0.65; 0.98 per 10 g). An increased risk of rhinitis was associated with moderate total fat and SFA intake. CONCLUSIONS: High dietary intakes of oleic acid and of olive oil are associated with a lower risk of asthma but not of rhinitis

Postural control in childhood: Investigating the neurodevelopmental gradient hypothesis

Neurodevelopmental disorders (NDDs) have been suggested to lie on a gradient con-tinuum, all resulting from common brain disturbances, but with different degrees of impairment severity. This case-control study aimed to assess postural stability against such hypothesis in 104 chil-dren/adolescents aged 5–17, of whom 81 had NDDs and 23 were healthy controls. Compared to healthy controls, Autism Spectrum Disorder (ASD) resulted in the most severely impaired neurode-velopmental condition, followed by Attention Deficit Hyperactive Disorder (ADHD) and Tourette Syndrome (TS). In particular, while ASD children/adolescents performed worse than healthy controls in a number of sensory conditions across all parameters, ADHD children/adolescents performed worse than healthy controls only in the sway area for the most complex sensory conditions, when their vision and somatosensory functions were both compromised, and performance in Tourette Syndrome (TS) was roughly indistinguishable from that of healthy controls. Finally, differences were also observed between clinical groups, with ASD children/adolescents, and to a much lesser extent ADHD children/adolescents, performing worse than TS children/adolescents, especially when sensory systems were not operationally accurate. Evidence from this study indicates that poor postural control may be a useful biomarker for risk assessment during neurodevelopment, in line with predictions from the gradient hypothesis

Dietary fat in respiratory diseases: A multi-case control study

Epidemiological studies provide some evidence that dietary fat intake is important in asthma and other respiratory diseases, even though the results are often conflicting. In the frame of the Genes Environment Interaction in Respiratory Diseases, an Italian population-based multi-case control study, we studied the associations between respiratory diseases and intake of total, animal, vegetal, saturated, monounsaturated and polyunsaturated dietary fat. The European Investigation into Cancer and Nutrition Food Frequency Questionnaire was used for dietary assessment in controls (n=345) and in subjects with asthma (past, n=76, or current, n=147), rhinitis (allergic, n=303, or non allergic, n=164) and chronic bronchitis (n=77).The associations between fat and respiratory diseases were estimated by means of multinomial (for asthma and rhinitis) or logistic (for chronic bronchitis) regression models. The estimates were adjusted for age, gender, centre, BMI, smoking habits, alcohol intake, physical activity, educational level and total energy intake. Current asthma risk was inversely related to the intake of vegetable fat (RRR=0.49, 95% CI 0.27\u20130.91 for the highest quartile as compared with the lowest one, p for trend=0.036). Monounsaturated fat showed a trend similar to vegetable fat but this trend was not statistically significant (p=0.139). A significant increased risk of allergic rhinitis was observed with increasing saturated fat (RRR = 1.92, 95% CI 1.17\u20133.16 for the highest quartile, p for trend=0.030). No other significant association was found between fat and respiratory diseases. Our results suggest that vegetable fat is protective for asthma, whereas saturated fat is a possible risk factor for allergic rhinitis

White blood cells, FeNO, glutathione, 8-oxodG and 8-isoprostane in respiratory diseases

Inflammation and oxidative stress (OS) play an important role in pathogenesis of respiratory diseases. Such biomarkers as fractional exhaled nitric oxide (FeNO), white blood cells, glutathione, urinary 8-oxodG and 8-isoprostane can serve in evaluating clinical course of the disease. We aimed at estimating the association of biomarkers of OS and inflammation with current asthma (CA), past asthma (PA) and chronic bronchitis (CB). The data from GEIRD survey (www.geird.org) have been used in this study. The hierarchic outcome variable was built to achieve mutually exclusive diseases, i.e. Controls (no respiratory disorders, n=549), CA (no PA, n=404), PA (no CA, n=185), CB (no CA, PA, n=92). Multinomial logistic regressions were applied to analyze associations, adjusting for age, BMI, sex, cohort, centre, smoke, comorbidities and alcohol. Relative Risk Ratios (RRR) for one standard deviation increase were adduced for all biomarkers. Glutathione (mg/ml) was higher in subjects with CB (RRR=1.77, CI(1.18-3.07)). FeNO (ppm) was higher in CA (RRR=1.47, CI(1.19-1.82)). Basophils (e+06/ml) had higher levels in CA (RRR=1.48, CI(1.20-1.84)) and CB(RRR=1.51, CI(1.01-2.25)); eosinophils (e+06/ml) were higher in CA (RRR=2.37, CI(1.79-3.13)), PA (RRR=1.79, CI(1.30-2.47)) and CB (RRR=2.14, CI(1.42-3.22)); leucocytes (e+06/ml) were increased in CA (RRR=1.34, CI(1.07-1.67)); lymphocytes (e+06/ml) had higher levels in CA (RRR=1.27, CI(1.03-1.55)) and CB (RRR=1.53, CI(1.05-2.25)). Our results showed that biomarkers of inflammation and OS were differently associated with asthma and chronic bronchitis, suggesting that they might be useful in phenotyping respiratory diseases

Determination of adjusted reference intervals of urinary biomarkers of oxidative stress in healthy adults using GAMLSS models

In this study we aimed at identifying main demographic, laboratory and environmental factors influencing the level of urinary biomarkers (DNA-derived 8-oxodG and lipid membrane-derived 8-isoprostane), and deriving their adjusted 95% reference intervals (RI) in a sample of healthy people from the general population. Data from 281 healthy subjects from the Gene Environment Interactions in Respiratory Diseases survey were used in this study. Generalized additive models for location, scale and shape (GAMLSS) were used to find determinants of the biomarkers among gender, age, season and distance from collection (DFC), and to predict their RI. The RI of the biomarkers stratified by season and adjusted for DFC showed a slight statistically significant decrease in the biomarkers at the increasing DFC in two seasons, except the 8-oxodG during the warm season: median levels at the min and max values of DFC were (ng/mgcreat) 7.0–1.1 in the cold and 3.9–3.9 in the warm seasons for 8-oxodG, 0.7–0.2 in the cold and 1.3–0.6 in the warm seasons for 8-isoprostane. Both the biomarkers should be evaluated in association with the DFC and season in large epidemiological studies. The (semi)parametric GAMLSS method is a useful and flexible technique, which makes it possible to estimate adjusted RI

What can we learn from systematic segmental analysis of fetal heart by postmortem micro-CT: Is it time to change approach?

Background: Postmortem analysis of fetal heart is crucial but challenging. Alternative techniques to autopsy have been studied. We investigate micro-CT diagnostic accuracy in the analysis of fetal heart coming from early and late termination of pregnancy. Methods: Micro-CT and autopsy analyzed human fetal heart using twenty-six indices of cardiac anatomy derived from segmental approach. Sub-analysis of smaller specimens was performed. Primary outcome is the agreement between techniques. Secondary outcomes are sensitivity, specificity, positive and negative predictive value. Indices are defined “visible” or “non-visible” (primary end point) and “normal”, “abnormal” or “non-diagnostic” (secondary end point). Results: Fifty-five cases were included. Agreement was 74.5% and 65.2% for primary end point and 93.3% and 91.8% for secondary end point in general population and in the group of smaller specimens, respectively. Sensitivity, specificity, positive and negative predictive value were 92.8%, 51.8%, 67.1%, 87.2% in the general population and 92.8%, 47.8%, 54.3%, 90.9% in the subgroup of smaller specimens for primary end point. They were 97.3%, 68.3%, 95.1%, 80.0% in the general population and 95.7%, 75.6%, 94.2%, 81.0% in the subgroup of smaller specimens for secondary end point. 86.1% and 91.5% of indices defined as “non-diagnostic” at autopsy would be visible by micro-CT in the two studied populations. Conclusion: Micro-CT represents a valid alternative to autopsy for postmortem evaluation of human fetal heart. We proposed to use micro-CT for initial analysis of fetal heart and to perform autopsy only in unsolved cases or if histological analysis is needed