Multiple Sclerosis: Current Knowledge and Future Outlook

Background: Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system characterized by demyelination and axonal loss. The etiology of MS is unknown; however, environmental and genetic factors play a key role in the development of MS. Diagnostic criteria have been adapted to facilitate earlier diagnosis with increased sensitivity and specificity. Our understanding of the pathophysiology of MS has deepened considerably in recent years, resulting in different therapies to modify the disease course. Furthermore, several drugs have lately shown efficacy in phase III studies and their approval is expected in the near future. As treatment options expand, a future challenge will be to find the optimal treatment for the individual patient. Summary: This mini-review gives an overview of the current knowledge of MS with emphasis on the latest diagnostic criteria and both current and upcoming treatment options. Key Messages: Treatment of MS changes rapidly as the knowledge and therapeutic options in MS expand. Clinical Impact: Diagnosis of MS is based on McDonald criteria. MS therapy can be divided into relapse, disease-modifying and symptomatic treatment. Relapses are commonly treated with intravenous methylprednisolone. First-line therapy consists of either interferon-β, glatiramer acetate or teriflunomide. In general, agents used as escalation therapies (natalizumab, fingolimod and mitoxantrone) are more potent than the agents used for first-line therapy; however, these have potentially serious side effects and should be used with care.

Self-esteem, coping styles, and quality of life in polish adolescents and young adults with unilateral cleft lip and palate.

Objectives : To evaluate self-esteem, coping styles, and health-related quality of life and their relationships in Polish adolescents and young adults with unilateral complete cleft lip and palate and related sex differences. Design and Participants : Self-report questionnaires measuring self-esteem (Multidimensional Self-Esteem Inventory), coping styles (Coping Inventory for Stressful Situations), and health-related quality of life (WHOQOL-BREF) were completed by 48 participants with cleft lip and palate (age, 16 to 23 years; 31 males, 17 females) and 48 controls without cleft lip and palate (age, 16 to 23 years; 28 males, 20 females) matched for age, place of residence, and socioeconomic status. Results : Regarding self-esteem, individuals with cleft lip and palate scored higher on body functioning (P < .01) and defensive self-enhancement (P < .05). Self-control showed an interaction effect: Females with cleft lip and palate scored higher than controls, but males did not differ between groups (P < .05). Males with cleft lip and palate scored lower than controls in personal power but higher in body functioning (P < .05); females showed no differences between groups. The groups did not differ with regard to coping styles or quality of life, but several correlations were found between self-esteem and coping styles, and quality of life (P < .01). Conclusions : Late adolescents and young adults with and without cleft lip and palate differed little in terms of psychological adjustment measures. The higher scores in defensive self-enhancement of individuals with cleft lip and palate suggest the need for instruments measuring social approval in psychosocial adjustment research involving this group.

Reporting of statistical results in prosthodontic and implantology journals: p values or confidence intervals?

PURPOSE Confidence intervals (CIs) are integral to the interpretation of the precision and clinical relevance of research findings. The aim of this study was to ascertain the frequency of reporting of CIs in leading prosthodontic and dental implantology journals and to explore possible factors associated with improved reporting. MATERIALS AND METHODS Thirty issues of nine journals in prosthodontics and implant dentistry were accessed, covering the years 2005 to 2012: The Journal of Prosthetic Dentistry, Journal of Oral Rehabilitation, The International Journal of Prosthodontics, The International Journal of Periodontics & Restorative Dentistry, Clinical Oral Implants Research, Clinical Implant Dentistry and Related Research, The International Journal of Oral & Maxillofacial Implants, Implant Dentistry, and Journal of Dentistry. Articles were screened and the reporting of CIs and P values recorded. Other information including study design, region of authorship, involvement of methodologists, and ethical approval was also obtained. Univariable and multivariable logistic regression was used to identify characteristics associated with reporting of CIs. RESULTS Interrater agreement for the data extraction performed was excellent (kappa = 0.88; 95% CI: 0.87 to 0.89). CI reporting was limited, with mean reporting across journals of 14%. CI reporting was associated with journal type, study design, and involvement of a methodologist or statistician. CONCLUSIONS Reporting of CI in implant dentistry and prosthodontic journals requires improvement. Improved reporting will aid appraisal of the clinical relevance of research findings by providing a range of values within which the effect size lies, thus giving the end user the opportunity to interpret the results in relation to clinical practice.

Transapical transcatheter aortic valve implantation using the second-generation self-expanding Symetis ACURATE TA valve

Transapical transcatheter aortic valve implantation (TA-TAVI) is the recognized first choice surgical TAVI access. Expansion of this well-established treatment modality with subsequent broader patient inclusion has accelerated development of second-generation TA-TAVI devices. The Swiss ACURATE TA Symetis valve allows for excellent anatomical positioning, resulting in a very low incidence of paravalvular leaks. The self-expanding stent features an hourglass shape to wedge the native aortic valve annulus. A specially designed delivery system facilitates controlled release aided by tactile operator feedback. The ACURATE TA valve made of three native porcine non-coronary leaflets has received CE approval in September 2011. Since then, this valve is the third most frequently implanted TAVI device with over 1200 implants in Europe and South America. Results from the Symetis ACURATE TA™ Valve Implantation ('SAVI') Registry showed a procedural success rate of 98.0% and a survival rate of 93.2% at 30 days. This presentation provides technical considerations and detailed procedural aspects of device implantation.

Using Factorial Surveys and Stated Choice Experiments to Investigate Discriminatory Attitudes and Preferences

Empirical research on discriminatory attitudes and behaviour grapples with the social undesirability of its object. In many studies using regular survey methods, estimates are biased, and the social context of discrimination is not taken into account. Several methods have been developed, especially to deal with the first problem. In this regard, the estimation of the ‘true value’ of discriminatory attitudes is at the centre of interest. However, methodological contributions focusing on the social context of attitude communication and discriminatory behaviour, as well as the correlation between both, are rare. We present two experimental methods which address those issues: factorial surveys and stated choice experiments. In a first study, the usefulness of factorial surveys is demonstrated with data on German anti-Semitism (N=279). We show that the rate of approval with anti-Semitic statements increases if (a) respondents are told that the majority of fellows agree with such statements, (b) the term “Jews” is replaced by the term “Israelis”, and (c) reference to the Holocaust is made. Apart from the main effects of these experimental factors, significant interaction effects regarding the political attitudes and social status of respondents are observed. In a second study, a stated choice experiment on the purchase of olive oil and tomatoes was conducted in Germany (N=440). We find that respondents prefer Italian and Dutch products (control treatment) compared to Israeli and Palestinian ones (discrimination treatments). There are no significant differences between preferences for a so called ‘Peace product’ (which is produced jointly by Israelis and Palestinians) and products from Italy as well as the Netherlands. Yet, taking discriminatory attitudes (anti-Semitic and anti-Arabic attitudes) into account, a strong correlation between those attitudes and stated behaviour (purchase of Israeli, Palestinian and jointly produced products) can be found. This adds support to the hypothesis that discriminatory attitudes hold behavioural consequences.

Predictors of healthcare professionals' attitudes towards family involvement in safety-relevant behaviours: a cross-sectional factorial survey study.

OBJECTIVES To investigate predictors of healthcare professionals' (HCPs) attitudes towards family involvement in safety-relevant behaviours. DESIGN A cross-sectional fractional factorial survey that assessed HCPs' attitudes towards family involvement in two error scenarios relating to hand hygiene and medication safety. Each survey comprised two randomised vignettes that described the potential error, how the family member communicated with the HCP about the error and how the HCP responded to the family member's question. SETTING 5 teaching hospitals in London, the Midlands and York. HCPs were approached on a range of medical and surgical wards. PARTICIPANTS 160 HCPs (73 doctors; 87 nurses) aged between 21 and 65 years (mean 37) 102 were female. OUTCOME MEASURES HCP approval of family member's behaviour; HCP reaction to the family member; anticipated effects on the family member-HCP relationship; HCP support for being questioned about hand hygiene/medication; affective rating responses. RESULTS HCPs supported family member's intervening (88%) but only 41% agreed this would have positive effects on the family member/HCP relationship. Across vignettes and error scenarios the strongest predictors of attitudes were how the HCP (in the scenario) responded to the family member and whether an error actually occurred. Doctors (vs nurses) provided systematically more positive affective ratings to the vignettes. CONCLUSIONS Important predictors of HCPs' attitudes towards family members' involvement in patient safety have been highlighted. In particular, a discouraging response from HCP's decreased support for family members being involved and had strong perceived negative effects on the family member/HCP relationship.

Comparison of gadoteric acid and gadobutrol for detection as well as morphologic and dynamic characterization of lesions on breast dynamic contrast-enhanced magnetic resonance imaging

OBJECTIVE In contrast to conventional breast imaging techniques, one major diagnostic benefit of breast magnetic resonance imaging (MRI) is the simultaneous acquisition of morphologic and dynamic enhancement characteristics, which are based on angiogenesis and therefore provide insights into tumor pathophysiology. The aim of this investigation was to intraindividually compare 2 macrocyclic MRI contrast agents, with low risk for nephrogenic systemic fibrosis, in the morphologic and dynamic characterization of histologically verified mass breast lesions, analyzed by blinded human evaluation and a fully automatic computer-assisted diagnosis (CAD) technique. MATERIALS AND METHODS Institutional review board approval and patient informed consent were obtained. In this prospective, single-center study, 45 women with 51 histopathologically verified (41 malignant, 10 benign) mass lesions underwent 2 identical examinations at 1.5 T (mean time interval, 2.1 days) with 0.1-mmol kg doses of gadoteric acid and gadobutrol. All magnetic resonance images were visually evaluated by 2 experienced, blinded breast radiologists in consensus and by an automatic CAD system, whereas the morphologic and dynamic characterization as well as the final human classification of lesions were performed based on the categories of the Breast imaging reporting and data system MRI atlas. Lesions were also classified by defining their probability of malignancy (morpho-dynamic index; 0%-100%) by the CAD system. Imaging results were correlated with histopathology as gold standard. RESULTS The CAD system coded 49 of 51 lesions with gadoteric acid and gadobutrol (detection rate, 96.1%); initial signal increase was significantly higher for gadobutrol than for gadoteric acid for all and the malignant coded lesions (P < 0.05). Gadoteric acid resulted in more postinitial washout curves and fewer continuous increases of all and the malignant lesions compared with gadobutrol (CAD hot spot regions, P < 0.05). Morphologically, the margins of the malignancies were different between the 2 agents, whereas gadobutrol demonstrated more spiculated and fewer smooth margins (P < 0.05). Lesion classifications by the human observers and by the morpho-dynamic index compared with the histopathologic results did not significantly differ between gadoteric acid and gadobutrol. CONCLUSIONS Macrocyclic contrast media can be reliably used for breast dynamic contrast-enhanced MRI. However, gadoteric acid and gadobutrol differed in some dynamic and morphologic characterization of histologically verified breast lesions in an intraindividual, comparison. Besides the standardization of technical parameters and imaging evaluation of breast MRI, the standardization of the applied contrast medium seems to be important to receive best comparable MRI interpretation.

The Prevention of Delirium and Complications Associated with Surgical Treatments (PODCAST) study: protocol for an international multicentre randomised controlled trial

INTRODUCTION Postoperative delirium is one of the most common complications of major surgery, affecting 10-70% of surgical patients 60 years and older. Delirium is an acute change in cognition that manifests as poor attention and illogical thinking and is associated with longer intensive care unit (ICU) and hospital stay, long-lasting cognitive deterioration and increased mortality. Ketamine has been used as an anaesthetic drug for over 50 years and has an established safety record. Recent research suggests that, in addition to preventing acute postoperative pain, a subanaesthetic dose of intraoperative ketamine could decrease the incidence of postoperative delirium as well as other neurological and psychiatric outcomes. However, these proposed benefits of ketamine have not been tested in a large clinical trial. METHODS The Prevention of Delirium and Complications Associated with Surgical Treatments (PODCAST) study is an international, multicentre, randomised controlled trial. 600 cardiac and major non-cardiac surgery patients will be randomised to receive ketamine (0.5 or 1 mg/kg) or placebo following anaesthetic induction and prior to surgical incision. For the primary outcome, blinded observers will assess delirium on the day of surgery (postoperative day 0) and twice daily from postoperative days 1-3 using the Confusion Assessment Method or the Confusion Assessment Method for the ICU. For the secondary outcomes, blinded observers will estimate pain using the Behavioral Pain Scale or the Behavioral Pain Scale for Non-Intubated Patients and patient self-report. ETHICS AND DISSEMINATION The PODCAST trial has been approved by the ethics boards of five participating institutions; approval is ongoing at other sites. Recruitment began in February 2014 and will continue until the end of 2016. Dissemination plans include presentations at scientific conferences, scientific publications, stakeholder engagement and popular media. REGISTRATION DETAILS The study is registered at clinicaltrials.gov, NCT01690988 (last updated March 2014). The PODCAST trial is being conducted under the auspices of the Neurological Outcomes Network for Surgery (NEURONS). TRIAL REGISTRATION NUMBER NCT01690988 (last updated December 2013).

Blind intubation of anaesthetised children with supraglottic airway devices AmbuAura-i and Air-Q cannot be recommended: A randomised controlled trial.

BACKGROUND Paediatric supraglottic airway devices AmbuAura-i and Air-Q were designed as conduits for tracheal intubation. Although fibreoptic-guided intubation has proved successful, blind intubation as a rescue technique has never been evaluated. OBJECTIVE Evaluation of blind intubation through AmbuAura-i and Air-Q. On the basis of fibreoptic view data, we hypothesised that the success rate with the AmbuAura-i would be higher than with the Air-Q. DESIGN A prospective, randomised controlled trial with institutional review board (IRB) approval and written informed consent. SETTING University Childrens' Hospital; September 2012 to July 2014. PATIENTS Eighty children, American Society of Anesthesiologists (ASA) class I to III, weight 5 to 50 kg. INTERVENTIONS Tracheal intubation was performed through the randomised device with the tip of a fibrescope placed inside and proximal to the tip of the tracheal tube. This permitted sight of tube advancement, but without fibreoptic guidance (visualised blind intubation). MAIN OUTCOME MEASURES Primary outcome was successfully visualised blind intubation; secondary outcomes included supraglottic airway device success, insertion times, airway leak pressure, fibreoptic view and adverse events. RESULTS Personal data did not differ between groups. In contrast to our hypothesis, blind intubation was possible in 15% with the Air-Q and in 3% with the AmbuAura-i [95% confidence interval (95% CI) 6 to 31 vs. 0 to 13%; P = 0.057]. First attempt supraglottic airway device insertion success rates were 95% (Air-Q) and 100% (AmbuAura-i; 95% CI 83 to 99 vs. 91 to 100; P = 0.49). Median leak pressures were 18 cmH2O (Air-Q) and 17 cmH2O [AmbuAura-i; interquartile range (IQR) 14 to 18 vs. 14 to 19 cmH2O; P = 0.66]. Air-Q insertion was slower (27 vs. 19 s, P < 0.001). There was no difference in fibreoptic view, or adverse events (P > 0.05). In one child (Air-Q size 1.5, tube size 3.5), the tube dislocated during device removal. CONCLUSION Ventilation with both devices is reliable, but success of blind intubation is unacceptably low and cannot be recommended for elective or rescue purposes. If intubation through a paediatric supraglottic airway device is desired, we suggest that fibreoptic guidance is used. TRIAL REGISTRATION Clinicaltrials.gov identifier: NCT01692522.

Ethical procedures and patient consent differ in Europe.

BACKGROUND Research ethics approvals, procedures and requirements for institutional research ethics committees vary considerably by country and by type of organisation. OBJECTIVE To evaluate the requirements and procedures of research ethics committees, details of patient information and informed consent based on a multicentre European trial. DESIGN Survey of European hospitals participating in the prospective observational study on chronic postsurgical pain (euCPSP) using electronic questionnaires. SETTING Twenty-four hospitals in 11 European countries. PARTICIPANTS From the 24 hospitals, 23 local investigators responded; 23 answers were analysed. OUTCOME MEASURES Comparison of research ethics procedures and committee requirements from the perspective of clinical researchers. Comparison of the institutions' procedures regarding patient information and consent. Description of further details such as costs and the duration of the approval process. RESULTS The approval process lasted from less than 2 weeks up to more than 2 months with financial fees varying between 0 and 575 &OV0556;. In 20 hospitals, a patient information sheet of variable length (half page up to two pages) was provided. Requirements for patients' informed consent differed. Written informed consent was mandatory at 12, oral at 10 and no form of consent at one hospital. Details such as enough time for consideration, possibility for withdrawal and risks/benefits of participation were provided in 25 to 30% of the institutions. CONCLUSION There is a considerable variation in the administrative requirements for approval procedures by research ethics committees in Europe. This results in variation of the extent of information and consent procedures for the patients involved. TRIAL REGISTRATION euCPSP in Clinicaltrials.gov identifier: NCT01467102; PAIN-OUT in Clinicaltrials.gov identifier: NCT02083835.

A pilot test of the new Swiss regulatory procedure for categorizing clinical trials by risk: A randomized controlled trial

BACKGROUND/AIMS Several countries are working to adapt clinical trial regulations to align the approval process to the level of risk for trial participants. The optimal framework to categorize clinical trials according to risk remains unclear, however. Switzerland is the first European country to adopt a risk-based categorization procedure in January 2014. We assessed how accurately and consistently clinical trials are categorized using two different approaches: an approach using criteria set forth in the new law (concept) or an intuitive approach (ad hoc). METHODS This was a randomized controlled trial with a method-comparison study nested in each arm. We used clinical trial protocols from eight Swiss ethics committees approved between 2010 and 2011. Protocols were randomly assigned to be categorized in one of three risk categories using the concept or the ad hoc approach. Each protocol was independently categorized by the trial's sponsor, a group of experts and the approving ethics committee. The primary outcome was the difference in categorization agreement between the expert group and sponsors across arms. Linear weighted kappa was used to quantify agreements, with the difference between kappas being the primary effect measure. RESULTS We included 142 of 231 protocols in the final analysis (concept = 78; ad hoc = 64). Raw agreement between the expert group and sponsors was 0.74 in the concept and 0.78 in the ad hoc arm. Chance-corrected agreement was higher in the ad hoc (kappa: 0.34 (95% confidence interval = 0.10-0.58)) than in the concept arm (0.27 (0.06-0.50)), but the difference was not significant (p = 0.67). LIMITATIONS The main limitation was the large number of protocols excluded from the analysis mostly because they did not fit with the clinical trial definition of the new law. CONCLUSION A structured risk categorization approach was not better than an ad hoc approach. Laws introducing risk-based approaches should provide guidelines, examples and templates to ensure correct application.

Protease inhibitors to treat hepatitis C in the Swiss HIV Cohort Study: high efficacy but low treatment uptake

OBJECTIVES Direct-acting antiviral agents (DAAs) have become the standard of care for the treatment of chronic hepatitis C virus (HCV) infection. We aimed to assess treatment uptake and efficacy in routine clinical settings among HIV/HCV coinfected patients after the introduction of the first generation DAAs. METHODS Data on all Swiss HIV Cohort Study (SHCS) participants starting HCV protease inhibitor (PI) treatment between September 2011 and August 2013 were collected prospectively. The uptake and efficacy of HCV therapy were compared with those in the time period before the availability of PIs. RESULTS Upon approval of PI treatment in Switzerland in September 2011, 516 SHCS participants had chronic HCV genotype 1 infection. Of these, 57 (11%) started HCV treatment during the following 2 years with either telaprevir, faldaprevir or boceprevir. Twenty-seven (47%) patients were treatment-naïve, nine (16%) were patients with relapse and 21 (37%) were partial or null responders. Twenty-nine (57%) had advanced fibrosis and 15 (29%) had cirrhosis. End-of-treatment virological response was 84% in treatment-naïve patients, 88% in patients with relapse and 62% in previous nonresponders. Sustained virological response was 78%, 86% and 40% in treatment-naïve patients, patients with relapse and nonresponders, respectively. Treatment uptake was similar before (3.8 per 100 patient-years) and after (6.1 per 100 patient-years) the introduction of PIs, while treatment efficacy increased considerably after the introduction of PIs. CONCLUSIONS The introduction of PI-based HCV treatment in HIV/HCV-coinfected patients improved virological response rates, while treatment uptake remained low. Therefore, the introduction of PIs into the clinical routine was beneficial at the individual level, but had only a modest effect on the burden of HCV infection at the population level.

Discussion: Food security and sustainable food systems: The role of soil

There is a general consensus that healthy soils are pivotal for food security. Food production is one of the main ecosystem services provided by and thus dependent on well-functioning soils. There are also intrinsic connections between the four pillars of food security: food availability, access, utilization, and stability; with how soils are managed, accessed and secured, in particular by food insecure and vulnerable populations. On the other hand, socio-political and economic processes that precipitate inequalities and heighten vulnerabilities among poor populations often increase pressure on soils due to unsustainable forms of land use and poor agricultural practises. This has often led to scenarios that can be described as: ‘poor soils, empty stomachs (hungry people) and poor livelihoods.' In 2015, in particular, as we head towards approval of the ‘Sustainable Development Goals' (SDGs), the role of Financing for Development is debated and agreed upon and a new climate pact is signed – these three political dimensions define how a new post-2015 agenda needs to be people-smart as well as resource-smart. For proposed SDG 2 (Food Security and Hunger), there can be so resolution without addressing people, policies and institutions.

Consensus report of the European Federation of Conservative Dentistry: erosive tooth wear-diagnosis and management

OBJECTIVE Due to an increased focus on erosive tooth wear (ETW), the European Federation of Conservative Dentistry (EFCD) considered ETW as a relevant topic for generating this consensus report. MATERIALS AND METHODS This report is based on a compilation of the scientific literature, an expert conference, and the approval by the General Assembly of EFCD. RESULTS ETW is a chemical-mechanical process resulting in a cumulative loss of hard dental tissue not caused by bacteria, and it is characterized by loss of the natural surface morphology and contour of the teeth. A suitable index for classification of ETW is the basic erosive wear examination (BEWE). Regarding the etiology, patient-related factors include the pre-disposition to erosion, reflux, vomiting, drinking and eating habits, as well as medications and dietary supplements. Nutritional factors relate to the composition of foods and beverages, e.g., with low pH and high buffer capacity (major risk factors), and calcium concentration (major protective factor). Occupational factors are exposition of workers to acidic liquids or vapors. Preventive management of ETW aims at reducing or stopping the progression of the lesions. Restorative management aims at reducing symptoms of pain and dentine hypersensitivity, or to restore esthetic and function, but it should only be used in conjunction with preventive strategies. CONCLUSIONS Effective management of ETW includes screening for early signs of ETW and evaluating all etiological factors. CLINICAL RELEVANCE ETW is a clinical condition, which calls for the increased attention of the dental community and is a challenge for the cooperation with other medical specialities.

Application, tolerance and safety of fondaparinux therapy in a German hospital: a prospective single-centre experience.

INTRODUCTION The pentasaccharide fondaparinux is widely approved for prophylaxis and treatment of thromboembolic diseases and therapy of acute coronary syndrome. It is also used off-label in patients with acute, suspected or antecedent heparin-induced thrombocytopenia (HIT). The aim of this prospective observational cohort study was to document fondaparinux' prescription practice, tolerance and therapy safety in a representative mixed German single-centre patient cohort. PATIENTS AND METHODS Between 09/2008 - 04/2009, 231 consecutive patients treated with fondaparinux were enrolled. Medical data were obtained from patient's records. The patients were clinically screened for thrombosis (Wells score), sequelae of HIT (4T's score), and bleeding complications (ISTH-criteria) and subjected to further assessment (i.e. sonography, HIT-diagnostics), if necessary. The mortality rate was assessed 30 days after therapy start. RESULTS Overall, 153/231 patients had a prophylactic, 74/231 patients a therapeutic, and 4/231 patients a successive prophylactic/therapeutic indication. In 11/231 patients fondaparinux was used due to suspected/antecedent HIT, in 5/231 patients due to a previous cutaneous delayed-type hypersensitivity to heparins. Other indications were rare. Three new/progressive thromboses were detected. No cases of HIT, major bleedings, or fatalities occurred. CONCLUSIONS Fondaparinux was well tolerated and was safe in prophylaxis and therapy; prescriptions mostly followed the current approval guidelines and were rarely related to HIT-associated indications (<5% of prescriptions), which is in contrast to previous study results in the U.S. (>94% of prescriptions were HIT-associated). A trend towards an individualised fondaparinux use based on the compound's inherent properties and the patients' risk profiles, i.e., antecedent HIT, bone fractures, heparin allergy, was observed.