Airway smooth muscle area to predict steroid responsiveness in COPD patients receiving triple therapy (HISTORIC): a randomised, placebo-controlled, double-blind, investigator-initiated trial.

BACKGROUND: Although inhaled corticosteroids (ICS) are highly effective in asthma, they provide significant, but modest, clinical benefit in COPD. Here, we tested the hypothesis that high bronchial airway smooth muscle cell (ASMC) area in COPD is associated with ICS responsiveness. METHODS: In this investigator-initiated and -driven, double-blind, randomised, placebo-controlled trial (HISTORIC), 190 COPD patients, Global Initiative for Chronic Obstructive Lung Disease stage B-D, underwent bronchoscopy with endobronchial biopsy. Patients were divided into groups A and B, with high ASMC area (HASMC: >20% of the bronchial tissue area) and low ASMC area (LASMC: ≤20% of the bronchial tissue area), respectively, and followed a run-in period of 6 weeks on open-label triple inhaled therapy with aclidinium (ACL)/formoterol (FOR)/budesonide (BUD) (400/12/400 µg twice daily). Subsequently, patients were randomised to receive either ACL/FOR/BUD or ACL/FOR/placebo and followed for 12 months. The primary end-point of the study was the difference in post-bronchodilator forced expiratory volume in 1 s (FEV1) over 12 months between patients with LASMC and HASMC receiving or not receiving ICS. RESULTS: In patients with LASMC, ACL/FOR/BUD did not significantly improve FEV1 over 12 months, as compared to ACL/FOR/placebo (p=0.675). However, in patients with HASMC, ACL/FOR/BUD significantly improved FEV1, as compared to ACL/FOR/placebo (p=0.020). Over 12 months, the difference of FEV1 change between the ACL/FOR/BUD group and the ACL/FOR/placebo group was 50.6 mL·year-1 within the group of patients with LASMC and 183.0 mL·year-1 within the group of patients with HASMC. CONCLUSION: COPD patients with ΗASMC respond better to ICS than patients with LASMC, suggesting that this type of histological analysis may predict ICS responsiveness in COPD patients receiving triple therapy.

Staphylococcus aureus enterotoxin A- and B-specific IgE in chronic obstructive pulmonary disease.

Sensitization to Staphylococcus aureus enterotoxins A (SEA) and B (SEB) has been associated with asthma severity, exacerbations, and disease control. Our study aimed to investigate if there are differences in serum SEA-IgE and SEB-IgE levels between patients with chronic obstructive pulmonary disease (COPD), asthma, and controls, and to assess the association between SE sensitization and COPD clinical parameters and Th2 inflammation biomarkers in two well-defined COPD cohorts. Our findings suggest that COPD patients do not exhibit higher SEA and SEB sensitization compared to asthma patients and controls. However, in COPD patients, the presence of atopy and allergy is associated with positivity for SEA-IgE and SEB-IgE. Consequently, these allergens may aid in identifying atopic or allergic subgroups within the COPD population, but they are not directly associated with the diagnosis of COPD, elevated circulating blood eosinophils, or fractional exhaled nitric oxide (FENO) levels.

Variability of fractional exhaled nitric oxide is associated with the risk and aetiology of COPD exacerbations.

BACKGROUND AND OBJECTIVE: Acute exacerbations of chronic obstructive pulmonary disease (AECOPD) are heterogeneous in aetiology and accelerate disease progression. Here, we aimed to investigate the association of fractional exhaled nitric oxide (FeNO) and its variability with AECOPD of different aetiology. METHODS: FeNO was determined in 2157 visits (1697 stable, 133 AECOPD and 327 follow-up) of 421 COPD patients from the PREVENT study, an investigator-initiated, longitudinal and interventional study, who were on daily treatment with inhaled corticosteroids/long-acting ß2-agonists. RESULTS: Longitudinal measurements of FeNO revealed an intra-subject variability of FeNO that was significantly higher in exacerbators compared to non-exacerbators (p < 0.001) and positively associated with the number of AECOPD. As FeNO variability increased, the probability of patients to remain AECOPD-free decreased. In patients included in the highest FeNO variability quartile (≥15.0 ppb) the probability to remain free of AECOPD was only 35% as compared to 80% for patients included in the lowest FeNO variability quartile (0.50-4.39 ppb). The change of FeNO from the last stable visit to AECOPD was positively associated with the probability of viral infections and this association was stronger in current smokers than ex-smokers. In contrast, the change in FeNO from the last stable visit to an AECOPD visit was inversely associated with the probability of bacterial infections in ex-smokers but not in current smokers. CONCLUSION: FeNO variability was associated with the risk and aetiology of AECOPD differentially in current and ex-smokers.

Ηeparan sulphate in infectious and non-infectious exacerbations of COPD.

BACKGROUND AND OBJECTIVE: Acute exacerbations of chronic obstructive pulmonary disease (AECOPD) are associated with worsening health outcomes and effective treatment of each episode is essential. In this study, we aimed to investigate if plasma levels of heparan sulphate (HS) are associated with the aetiology of AECOPD. METHODS: COPD patients (N = 1189), GOLD grade II-IV, from a discovery cohort (N = 638) and from a validation cohort (N = 551), were included in the study. HS and heparanase (HSPE-1) were measured longitudinally in plasma at stable state, at AECOPD and at 4 weeks follow-up. RESULTS: Plasma HS was higher in patients with COPD as compared with non-COPD controls and was significantly increased at AECOPD as compared to stable state (p < 0.001) in the discovery and in the validation cohorts. Four distinct exacerbation groups were classified based on aetiology (no-infection/bacterial-infection/viral-infection/bacterial and viral coinfection) in the validation cohort. The fold-increase of HS from stable state to AECOPD was associated with the aetiology of exacerbation and was higher in cases with bacterial and viral coinfections. HSPE-1 was also significantly increased at AECOPD, however, there was no association of HSPE-1 levels with the aetiology of these events. The probability of having an infection at AECOPD was raised as HS levels increased from stable state to AECOPD. This probability was higher for bacterial infections than viral infections. CONCLUSION: The results of our study indicate that circulating levels of HS are increased at AECOPD and this increase may be associated with the aetiology of these events.

Determinants of Low Bone Turnover in Type 2 Diabetes-the Role of PTH.

Determinants of low bone turnover in type 2 diabetes (T2DM) are poorly understood. To investigate the relationship between markers of bone turnover, glycaemic control, disease duration and calciotropic hormones in T2DM we assessed baseline biochemical data from the DiabOS Study, a prospective multicenter observational cohort study. In a cross-sectional study-design data from 110 postmenopausal women and men aged 50-75 years diagnosed with T2DM for at least 3 years and 92 non-diabetic controls were evaluated. Biochemical markers of bone formation (N-terminal propeptide of type I procollagen [PINP]), bone-specific alkaline phosphatase [BAP]) and resorption (C-terminal cross-linking telopeptide of type I collagen [CTX]), measures of calcium homeostasis (intact parathormone [iPTH], 25-Hydroxyvitamin D, calcium, magnesium) and glycaemic control were assessed. After adjustment for age, gender and body mass index (BMI), patients with T2DM had lower serum levels of PINP (p < 0.001), CTX (p < 0.001), iPTH (p = 0.03) and magnesium (p < 0.001) compared to controls. Serum calcium, creatinine, 25-Hydroxyvitamin D and sclerostin did not differ between both groups. In multivariate linear regression analyses only serum iPTH remained an independent determinant of bone turnover markers in T2DM (PINP: p = 0.02; CTX: p < 0.001 and BAP: p < 0.01), whereas glycated haemoglobin (HbA1c), disease duration, age and BMI were not associated with bone turnover. In conclusion low bone turnover in T2DM is associated with low iPTH. The underlying mechanism remains to be elucidated.

Copeptin, pro-atrial natriuretic peptide and pro-adrenomedullin as markers of hypoxic stress in patients with obstructive sleep apnea-a prospective intervention study.

STUDY OBJECTIVES: Obstructive sleep apnea (OSA) might lead to oxidative stress, inflammation and elevated circulating copeptin, proANP and proADM levels. We aimed to evaluate whether the levels of these prohormones are higher in patients with OSA and whether they might change under continuous positive airway pressure (CPAP) therapy, serving as potential proxies for the diagnosis and therapy-response in OSA. METHODS: A total of 310 patients with suspicion of OSA were recruited. Screening for OSA was performed using overnight pulse oximetry followed by polygraphy and a venous puncture in the morning. All patients diagnosed with OSA underwent CPAP adaptation. A venous puncture was conducted in the night before CPAP and in the following morning. At 1 and 6 months of treatment, polygraphy was performed, followed by a venous puncture in the morning. In the acquired blood, copeptin, proANP and proADM levels were measured. RESULTS: We analyzed 232 patients with OSA and 30 patients without OSA. Our results indicated that only copeptin levels differed significantly among patients with and without OSA at baseline. In OSA patients, the levels of proADM significantly changed after 1 and 6 months on CPAP therapy, when compared to baseline (p < 0.001 and p = 0.020). Additionally, proANP levels significantly decreased after 12 h on CPAP therapy, as compared to baseline levels (p < 0.001). CONCLUSIONS: Copeptin is significantly associated with the presence of OSA. ProANP levels might serve as a potential proxy for the acute response to non-invasive ventilation (12 h), while proADM reflects the long-term response (1 and 6 months).

Bronchial thermoplasty in asthma: an exploratory histopathological evaluation in distinct asthma endotypes/phenotypes.

BACKGROUND: Bronchial thermoplasty regulates structural abnormalities involved in airway narrowing in asthma. In the present study we aimed to investigate the effect of bronchial thermoplasty on histopathological bronchial structures in distinct asthma endotypes/phenotypes. METHODS: Endobronchial biopsies (n = 450) were collected from 30 patients with severe uncontrolled asthma before bronchial thermoplasty and after 3 sequential bronchial thermoplasties. Patients were classified based on blood eosinophils, atopy, allergy and smoke exposure. Tissue sections were assessed for histopathological parameters and expression of heat-shock proteins and glucocorticoid receptor. Proliferating cells were determined by Ki67-staining. RESULTS: In all patients, bronchial thermoplasty improved asthma control (p < 0.001), reduced airway smooth muscle (p = 0.014) and increased proliferative (Ki67 +) epithelial cells (p = 0.014). After bronchial thermoplasty, airway smooth muscle decreased predominantly in patients with T2 high asthma endotype. Epithelial cell proliferation was increased after bronchial thermoplasty in patients with low blood eosinophils (p = 0.016), patients with no allergy (p = 0.028) and patients without smoke exposure (p = 0.034). In all patients, bronchial thermoplasty increased the expression of glucocorticoid receptor in epithelial cells (p = 0.018) and subepithelial mesenchymal cells (p = 0.033) and the translocation of glucocorticoid receptor in the nucleus (p = 0.036). Furthermore, bronchial thermoplasty increased the expression of heat shock protein-70 (p = 0.002) and heat shock protein-90 (p = 0.001) in epithelial cells and decreased the expression of heat shock protein-70 (p = 0.009) and heat shock protein-90 (p = 0.002) in subepithelial mesenchymal cells. The effect of bronchial thermoplasty on the expression of heat shock proteins -70 and -90 was distinctive across different asthma endotypes/phenotypes. CONCLUSIONS: Bronchial thermoplasty leads to a diminishment of airway smooth muscle, to epithelial cell regeneration, increased expression and activation of glucocorticoid receptor in the airways and increased expression of heat shock proteins in the epithelium. Histopathological effects appear to be distinct in different endotypes/phenotypes indicating that the beneficial effects of bronchial thermoplasty are achieved by diverse molecular targets associated with asthma endotypes/phenotypes.

Dental and periodontal health in a Swiss population-based sample of older adults: a cross-sectional study.

In this cross-sectional study, the prevalences of tooth loss, prosthetic dental restorations, and probing pocket depths (PPD) ≥4 mm, and their relationship to sociodemographic factors, were investigated in older Swiss adults. There were up to 1,673 participants aged ≥55 yr in the fourth survey of the Swiss Cohort Study on Air Pollution And Lung And Heart Disease In Adults (SAPALDIA4). Missing teeth, prosthetic dental restorations, and PPD ≥4 mm were recorded in clinical examinations conducted by field workers and compared with self-reported information from questionnaires. Examination data showed that participants were missing five teeth on average, 74.8% had a prosthetic dental restoration, and 21.1% had PPD of ≥4 mm. The mean number of missing teeth and the prevalences of tooth loss, fixed dental prostheses, and removable dental prostheses were associated with age, education level, smoking status, and time since last visit to a dentist. Comparison of data obtained by field workers and that from self-reports show a high level of agreement for the number of missing teeth and the prevalence of removable dental prostheses, but a lower level of agreement for self-reports of fixed dental prostheses and periodontitis.

Time-course of upper respiratory tract viral infection and COPD exacerbation.

Viral respiratory tract infections have been implicated as the predominant risk factor for acute exacerbations of chronic obstructive pulmonary disease (AECOPD). We aimed to evaluate, longitudinally, the association between upper respiratory tract infections (URTI) caused by viruses and AECOPD.Detection of 18 viruses was performed in naso- and orοpharyngeal swabs from 450 COPD patients (Global Initiative for Chronic Obstructive Lung Disease stages 2-4) who were followed for a mean of 27 months. Swabs were taken during stable periods (n=1909), at URTI onset (n=391), 10 days after the URTI (n=356) and during an AECOPD (n=177) and tested using a multiplex nucleic acid amplification test.Evidence of at least one respiratory virus was significantly higher at URTI onset (52.7%), 10 days after the URTI (15.2%) and during an AECOPD (38.4%), compared with the stable period (5.3%, p<0.001). During stable visits, rhinovirus accounted for 54.2% of all viral infections, followed by coronavirus (20.5%). None of the viruses were identified in two consecutive stable visits. Patients with a viral infection at URTI onset did not have a higher incidence of exacerbation than patients without viral infection (p=0.993). Τhe incidence of any viral infection during an AECOPD was similar between URTI-related AECOPD and non-URTI-related AECOPD (p=0.359). Only 24% of the patients that had a URTI-related AECOPD had the same virus at URTI onset and during an AECOPD. Detection of parainfluenza 3 at URTI onset was associated with a higher risk of an AECOPD (p=0.003). Rhinovirus and coronavirus were the most frequently detected viruses during AECOPD visits, accounting for 35.7% and 25.9% of all viral infections, respectively.The prevalence of viral infection during the stable period of COPD was low. The risk of exacerbation following the onset of URTI symptoms depends on the particular virus associated with the event and was significant only for parainfluenza 3.

Peripheral neuropathy in patients with human immunodeficiency viral infection at a tertiary hospital in Ghana.

Peripheral neuropathy (PN) is the most frequent neurological complication in people living with HIV/AIDS. Neurological damage was identified to not only be caused by the viral infection itself but also through neurotoxic antiretroviral therapy (ART). PN is associated with a variety of risk factors; however, detailed knowledge is scarce for sub-Saharan African populations, bearing among the highest HIV/AIDS infection burden.In a cross-sectional study, we assessed the prevalence of PN in 525 adult outpatients suffering from HIV/AIDS and admitted to the largest tertiary hospital in Ghana. Through a detailed questionnaire and clinical examination including neurologic assessment and laboratory blood sample testing, this study investigated associations of PN with demographic and health determinants and identified risk factors associated with sensory neuropathy.The prevalence of PN in the Ghanaian cohort was 17.7% and increased odd ratios (OR) when patients were taller (> 1.57 m; OR = 3.84; 95% CI 1.38-10.66) or reached the age > 34 years (p = 0.124). Respondents with longer education duration had significantly less PN (≥ 9 years of education; OR = 0.49; 95% CI 0.26-0.92). The study also identified significant association of PN to both waist and hip girth and neutrophil counts. Curiously, higher adjusted odd ratios (aOR) of PN of patients under ART treatment were observed when CD4 lymphocytes were elevated (aOR = 0.81; 95% CI 0.36-1.83 and aOR = 2.17; 95% CI 0.93-5.05, for 300 and 600 counts, respectively). For patients on ART, an increase of 10 CD4 cell count units increased their chance of developing PN by 1% (aOR = 1.01; 95% CI 1.00 to 1.03).Despite current drug application regulations, prevalence of PN is still unacceptably high in sub-Saharan African populations. Reduction in chronic morbidity through a health system with routine monitoring, early diagnosis and prompt intervention, and effective case management can improve people living with HIV/AIDS' quality of life.

Intensified Therapy with Inhaled Corticosteroids and Long-Acting ß2-Agonists at the Onset of Upper Respiratory Tract Infection to Prevent Chronic Obstructive Pulmonary Disease Exacerbations. A Multicenter, Randomized, Double-Blind, Placebo-controlled Trial.

RATIONALE: The efficacy of intensified combination therapy with inhaled corticosteroids (ICS) and long-acting ß2-agonists (LABA) at the onset of upper respiratory tract infection (URTI) symptoms in chronic obstructive pulmonary disease (COPD) is unknown. OBJECTIVES: To evaluate whether intensified combination therapy with ICS/LABA, at the onset of URTI symptoms, decreases the incidence of COPD exacerbation occurring within 21 days of the URTI. METHODS: A total of 450 patients with stable, moderate to very severe COPD, were included in this investigator-initiated and -driven, double-blind, randomized, placebo-controlled study. At inclusion, patients were assigned to open-labeled low-maintenance dose ICS/LABA. Each patient was randomized either to intensified-dose ICS/LABA or placebo and instructed to start using this medication only in case of a URTI, at the onset of symptoms, twice daily, for 10 days. MEASUREMENTS AND MAIN RESULTS: The incidence of any exacerbation following a URTI was not significantly decreased in the ICS/LABA group, as compared with placebo (14.6% vs. 16.2%; hazard ratio, 0.77; 95% confidence interval, 0.46-1.33; P = 0.321) but the risk of severe exacerbation was decreased by 72% (hazard ratio, 0.28; 95% confidence interval, 0.11-0.74%; P = 0.010). In the stratified analysis, effect size was modified by disease severity, fractional exhaled nitric oxide, and the body mass index-airflow obstruction-dyspnea, and exercise score. Compared with the stable period, evidence of at least one virus was significantly more common at URTI, 10 days after URTI, and at exacerbation. CONCLUSIONS: Intensified combination therapy with ICS/LABA for 10 days at URTI onset did not decrease the incidence of any COPD exacerbation but prevented severe exacerbation. Patients with more severe disease had a significant risk reduction for any exacerbation. Clinical trial registered with www.isrctn.com (ISRCTN45572998).

Associations between Dietary Patterns and Post-Bronchodilation Lung Function in the SAPALDIA Cohort.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is not restricted to smokers. Dietary habits may contribute to the disease occurrence. Epidemiological studies point to a protective effect of fruit and vegetable intake against COPD. OBJECTIVE: To investigate the associations between dietary patterns and parameters of lung function related to COPD in the Swiss Cohort Study on Air Pollution and Lung and Heart Diseases in Adults (SAPALDIA). METHODS: Data were included from the second follow-up assessment of the SAPALDIA cohort in 2010-2011 using a food frequency questionnaire. Principal component factor analysis was used to derive dietary patterns, whose association with FEV1, FEV1/FVC, FEF2575, and COPD was investigated by applying multivariate regression analyses. RESULTS: After adjustment for potential confounders, the "prudent dietary pattern" characterised by the predominant food groups vegetables, fruits, water, tea and coffee, fish, and nuts was positively associated with FEV1 (increase of 40 mL per SD, p < 0.001). Also for factor 3 ("high-carbohydrate diet"), we found a significant positive association with FEV1 (with an increase per SD of 36 mL, p = 0.006). CONCLUSIONS: The main results are consistent with a protective effect of a diet rich in fruits, vegetables, fish, and nuts against age-related chronic respiratory disease. If confirmed in prospective cohorts, our results may guide nutritional counselling towards respiratory health promotion.

Metal hypersensitivity in patients with orthopaedic implant complications-A retrospective clinical study.

BACKGROUND: Hypersensitivity to metals as a cause of implant-related complications has been a subject of controversy. Projections indicate an increase in the frequency of joint replacements of between 300% and 600% by the year 2030; therefore, this issue is of considerable interest. OBJECTIVE: To evaluate sensitization to implant materials in patients with implant-related complications, to identify allergens, and to clarify whether hypersensitivity is a relevant cause. METHODS: Patients with implant-related complications or a positive history of contact allergy and planned total joint replacements referred for allergological investigation between 2004 and 2017 were retrospectively analysed. RESULTS: In total, 311 patients were included. A positive patch test reaction to a metal was seen in 64.4% of preoperative patients and in 54.6% of patients with implant-related complications. Common alloy metals such as cobalt, chromium and titanium gave positive reactions in up to 2.9% of patients with implant-related complications. None of the patients with skin changes had a positive patch test reaction to an implant metal. CONCLUSION: Other factors, such as the type of replaced joint and mechanical stress, seem to be more relevant for implant-related complications. Sensitization to metals or other materials seems to rarely play a role, and is overestimated.

Bone mineral density and its determinants in men with opioid dependence.

Data on the influence of opioid substitution therapy (OST) on skeletal health in men is limited. This cross-sectional study aimed to determine the prevalence of low bone mass in male drug users and to evaluate the relationship between endogenous testosterone and bone mass. We recruited 144 men on long-term opioid maintenance therapy followed in the Center of Addiction Medicine in Basel, Switzerland. Data on medical and drug history, fracture risk and history of falls were collected. Bone mineral density (BMD) was evaluated by densitometry and serum was collected for measurements of gonadal hormones and bone markers. 35 healthy age- and BMI-matched men served as the control group. The study participants received OST with methadone (69 %), morphine (25 %) or buprenorphine (6 %). Overall, 74.3 % of men had low bone mass, with comparable bone mass irrespective of OST type. In older men (≥40 years, n = 106), 29.2 % of individuals were osteoporotic (mean T-score -3.0 ± 0.4 SD) and 48.1 % were diagnosed with osteopenia (mean T-score -1.7 ± 0.4 SD). In younger men (n = 38), 65.8 % of men had low bone mass. In all age groups, BMD was significantly lower than in age-and BMI-matched controls. In multivariate analyses, serum free testosterone (fT) was significantly associated with low BMD at the lumbar spine (p = 0.02), but not at the hip. When analysed by quartiles of fT, lumbar spine BMD decreased progressively with decreasing testosterone levels. We conclude that low bone mass is highly prevalent in middle-aged men on long-term opioid dependency, a finding which may partly be determined by partial androgen deficiency.

Quality of life as predictor for the development of cardiac ischemia in high-risk asymptomatic diabetic patients.

BACKGROUND: Ischemia induced by psychological stress and depression is a common phenomenon in stable coronary artery disease (CAD). We evaluated the quality of life (QoL) of diabetic patients screened for CAD and assessed the prognostic value of mental and physical QoL scores to predict the development of new cardiac ischemia. METHODS: Prospective multicentre outcome study. The study comprised 400 asymptomatic diabetic patients without history or symptoms of CAD. They underwent myocardial perfusion single-photon emission computed tomography (MPS) and assessment of QoL by two questionnaires: Hospital Depression and Anxiety Scale (HADS-D and HADS-A) and Medical Outcomes Study Short Form 36 (SF-36) at baseline and after 2 years. Patients with normal MPS received usual care; those with abnormal MPS received medical or combined invasive and medical management. RESULTS: Only mental QoL scores but not physical QoL scores or traditional cardiovascular risk factors were predictive of new ischemia (n = 11/306) during follow-up. The prognostic value for new ischemia as quantified by the area under the receiver operating characteristics curve (AUC) amounted to 0.784 (95% confidence interval (CI) 0.654-0.914, P = 0.002) for HADS-D and to 0.737 (95% CI 0.580-0.893, P = 0.011) for HADS-A. This finding was confirmed by SF-36 mental sum score (AUC 0.688, 95% CI 0.539-0.836, P = 0.036), but not SF-36 physical sum score. QoL scores did not change after 2 years in patients with ischemia at baseline. CONCLUSIONS: QoL scores assessing mental health, particularly depression and anxiety, predicted the development of new cardiac ischemia in asymptomatic diabetic patients. The study is limited by a small number of events (new ischemia) and so the results should be considered hypothesis generating rather than conclusive.

Histological assessment of hard and soft tissues surrounding a novel ceramic implant: a pilot study in the minipig.

OBJECTIVE: The aim of this study was to investigate clinical and soft/hard tissues histomorphological outcomes of a ceramic implant comparatively to a titanium implant in a minipig model. MATERIAL AND METHODS: Eighteen soft tissue level implants (9 Ceramic with ZLA(®) surface as test, and 9 titanium SLActive(®) as control, Institut Straumann, Basel, Switzerland) were randomly placed into the mandible of 6 minipigs (n = 6). Two months later, animals were sacrificed and block biopsies were obtained to assess histomorphological outcomes. Unadjusted paired comparisons, of both groups were performed using the Wilcoxon signed rank test. The Dunnett-Hsu test was used to adjust for multiple comparisons. RESULTS: All implants showed excellent integration into bone and soft tissue. The fBIC (distance implant shoulder to most coronal implant contact) and BIC% (percentage bone-to-implant contact) were for both groups; test: 3.95 mm and 85.4%; control 3.97 mm and 84.3% respectively. No difference in peri-implant mucosa height was found, however, the sulcular epithelium was significantly shorter for the ZrO2 (mean: 0.76, 95%CI: 0.46-1.06) than for the Ti (mean: 1.40, 95%CI: 1.10-1.70) (p = 0.0090). CONCLUSIONS: Within the limits of this pilot study, no difference was found between the ceramic implant with ZLA(®) surface and a titanium implant in terms of bone tissue integration. Furthermore, the epithelial attachment favoured this ceramic implant over titanium.

Benefits of smoking bans on preterm and early-term births: a natural experimental design in Switzerland.

BACKGROUND: Birth outcomes are relevant for future children's heath. Capitalising on a natural experimental design in Switzerland, we evaluated how regional smoking bans introduced at different time points affected birth outcomes, including preterm and early-term births. METHODOLOGY: We used birth registry data of all singleton neonates born in Switzerland (2007-2012). We developed canton-specific interrupted time-series followed by random meta-analysis to evaluate the benefits of smoking bans on preterm (<37 gestational weeks) and early-term (37-38 gestational weeks) births. Heterogeneity across type of ban and contextual characteristics was explored through metaregression. A time-to-event approach was used for evaluating duration of pregnancy under the smoking bans and effects, taking into account individual maternal factors. RESULTS: We observed a decrease in the risk of preterm birth of 3.6% (95% CI, -9.3% to 2.5%), and early-term birth of 5.0% (95% CI -7.5% to -2.5%). Results showed a clear dose-response relationship. Greater risk reductions were obtained for preterm births in areas with more comprehensive bans (-6.8%; 95% CI -12.1% to 0.1%), and for pregnancies with the longest gestational time under smoking bans (HR, 0.991; 95% CI 0.984 to 0.997 per 10% increase in duration). Benefits were unequal across outcomes and characteristics of cantons and mothers. CONCLUSION: Smoking bans resulted in improved birth outcomes in Switzerland with cantons that adopted more comprehensive smoking bans achieving greater benefits. Early-term births constitute a previously ignored though important group.

Associations of daily levels of PM10 and NO2 with emergency hospital admissions and mortality in Switzerland: Trends and missed prevention potential over the last decade.

BACKGROUND: In most regions of the world, levels and constituents of the air pollution mixture have substantially changed over the last decades. AIMS: To evaluate if the effects of PM10 and NO2 on daily emergency hospital admissions and mortality have changed during a ~10 year period in Switzerland; to retrospectively estimate prevention potential of different policy choices. METHODS: Thirteen Poisson-regression models across Switzerland were developed using daily PM10 and NO2 levels from central monitors and accounting for several temporal and seasonal confounders. Time trends of effects were evaluated with an interaction variable. Distributed lag models with 28 days exposure window were used to retrospectively predict missed prevention potential for each region. RESULTS: Overall, emergency hospitalizations and mortality from any medical cause increased by 0.2% (95% Confidence Interval [95% CI]: 0.01, 0.33) and 0.2% (95% CI: -0.1, 0.6) for a 10 µg/m(3) increment of PM10, and 0.7% (95% CI: 0.1, 1.3) for NO2 and mortality. Over the study period, the association between respiratory emergencies and PM10 changed by a factor of 1.017 (95% CI: 1.001, 1.034) and by a factor of 0.977 [95% CI: 0.956, 0.998]) for respiratory mortality among the elderly for NO2. During the study period, abatement strategies targeting a 20% lower overall mean would have prevented four times more cases than abating days exceeding daily standards. CONCLUSION: During the last decade, the short term effects of PM10 and NO2 on hospitalizations and mortality in Switzerland have almost not changed. More ambitious strategies of air pollutant reduction in Switzerland would have had non negligible public health benefits.

Combined visual and motor evoked potentials predict multiple sclerosis disability after 20 years.

BACKGROUND: The development of predictors of multiple sclerosis (MS) disability is difficult due to the complex interplay of pathophysiological and adaptive processes. OBJECTIVE: The purpose of this study was to investigate whether combined evoked potential (EP)-measures allow prediction of MS disability after 20 years. METHODS: We examined 28 patients with clinically definite MS according to Poser's criteria with Expanded Disability Status Scale (EDSS) scores, combined visual and motor EPs at entry (T0), 6 (T1), 12 (T2) and 24 (T3) months, and a cranial magnetic resonance imaging (MRI) scan at T0 and T2. EDSS testing was repeated at year 14 (T4) and year 20 (T5). Spearman rank correlation was used. We performed a multivariable regression analysis to examine predictive relationships of the sum of z-transformed EP latencies (s-EPT0) and other baseline variables with EDSST5. RESULTS: We found that s-EPT0 correlated with EDSST5 (rho=0.72, p<0.0001) and ΔEDSST5-T0 (rho=0.50, p=0.006). Backward selection resulted in the prediction model: E (EDSST5)=3.91-2.22×therapy+0.079×age+0.057×s-EPT0 (Model 1, R (2)=0.58) with therapy as binary variable (1=any disease-modifying therapy between T3 and T5, 0=no therapy). Neither EDSST0 nor T2-lesion or gadolinium (Gd)-enhancing lesion quantities at T0 improved prediction of EDSST5. The area under the receiver operating characteristic (ROC) curve was 0.89 for model 1. CONCLUSIONS: These results further support a role for combined EP-measures as predictors of long-term disability in MS.

Electrophysiological markers and predictors of the disease course in primary progressive multiple sclerosis.

BACKGROUND: Currently no valid surrogate marker exists for primary progressive multiple sclerosis (PPMS). OBJECTIVE: Our aim was to prospectively investigate multimodal evoked potentials (EPs) as markers and predictors of the disease course in PPMS. METHODS: Twenty-two PPMS patients were prospectively examined with visual, somatosensory and motor EPs and Expanded Disability Status Scale (EDSS) assessments at baseline (T0) and at six-month intervals over three years. Spearman rank correlation was used to determine the relationship between EP measures and EDSS. The relationship between disease evolution and a numerical score derived from z-transformed EP-latencies (s-EP-Q) and baseline characteristics was further assessed using multivariable linear regression analysis. RESULTS: s-EP-Q correlated with EDSS score at all points in time in cross-sectional comparison (0.53≤rs ≤0.68; 0.0007≤p≤0.0232) and also longitudinally by trend (rs=0.46, p=0.0740). The s-EP-QT0 correlated with the EDSS score at year 3 (T6) (r s=0.77, p<0.0001). The s-EP-Q changes became statistically significant six months before corresponding changes were seen in the EDSS score. EDSST6 as predicted by EDSST6 = -1.027+0.037* age+0.217* s-EP-QT0 + 0.695* EDSST0 correlated with the observed values (rs=0.92, p<0.0001). CONCLUSIONS: Multimodal EPs correlate well with disability in PPMS, and allow some prediction of the disease course over three years. These findings support a role of EPs as surrogate markers in clinical trials in PPMS.