Sexual health of ethnic minority MSM in Britain (MESH project): design and methods

Background Men who have sex with men (MSM) remain the group most at risk of acquiring HIV infection in Britain. HIV prevalence appears to vary widely between MSM from different ethnic minority groups in this country for reasons that are not fully understood. The aim of the MESH project was to examine in detail the sexual health of ethnic minority MSM living in Britain. Methods/Design The main objectives of the MESH project were to explore among ethnic minority MSM living in Britain: (i) sexual risk behaviour and HIV prevalence; (ii) their experience of stigma and discrimination; (iii) disclosure of sexuality; (iv) use of, and satisfaction with sexual health services; (v) the extent to which sexual health services (for treatment and prevention) are aware of the needs of ethnic minority MSM. The research was conducted between 2006 and 2008 in four national samples: (i) ethnic minority MSM living in Britain; (ii) a comparison group of white British MSM living in Britain; (iii) NHS sexual health clinic staff in 15 British towns and cities with significant ethnic minority communities and; (iv) sexual health promotion/HIV prevention service providers. We also recruited men from two "key migrant" groups living in Britain: MSM born in Central or Eastern Europe and MSM born in Central or South America. Internet-based quantitative and qualitative research methods were used. Ethnic minority MSM were recruited through advertisements on websites, in community venues, via informal networks and in sexual health clinics. White and "key migrant" MSM were recruited mostly through Gaydar, one of the most popular dating sites used by gay men in Britain. MSM who agreed to take part completed a questionnaire online. Ethnic minority MSM who completed the online questionnaire were asked if they would be willing to take part in an online qualitative interview using email. Service providers were identified through the British Association of Sexual Health and HIV (BASHH) and the Terrence Higgins Trust (THT) CHAPS partnerships. Staff who agreed to take part were asked to complete a questionnaire online. The online survey was completed by 1241 ethnic minority MSM, 416 men born in South and Central America or Central and Eastern Europe, and 13,717 white British MSM; 67 ethnic minority MSM took part in the online qualitative interview. In addition 364 people working in sexual health clinics and 124 health promotion workers from around Britain completed an online questionnaire. Discussion The findings from this study will improve our understanding of the sexual health and needs of ethnic minority MSM in Britain.

Preventing vasospasm improves outcome after aneurysmal subarachnoid hemorrhage: rationale and design of CONSCIOUS-2 and CONSCIOUS-3 trials

Cerebral vasospasm after aneurysmal subarachnoid hemorrhage (aSAH) is a frequent but unpredictable complication associated with poor outcome. Current vasospasm therapies are suboptimal; new therapies are needed. Clazosentan, an endothelin receptor antagonist, has shown promise in phase 2 studies, and two randomized, double-blind, placebo-controlled phase 3 trials (CONSCIOUS-2 and CONSCIOUS-3) are underway to further investigate its impact on vasospasm-related outcome after aSAH. Here, we describe the design of these studies, which was challenging with respect to defining endpoints and standardizing endpoint interpretation and patient care. Main inclusion criteria are: age 18-75 years; SAH due to ruptured saccular aneurysm secured by surgical clipping (CONSCIOUS-2) or endovascular coiling (CONSCIOUS-3); substantial subarachnoid clot; and World Federation of Neurosurgical Societies grades I-IV prior to aneurysm-securing procedure. In CONSCIOUS-2, patients are randomized 2:1 to clazosentan (5 mg/h) or placebo. In CONSCIOUS-3, patients are randomized 1:1:1 to clazosentan 5, 15 mg/h, or placebo. Treatment is initiated within 56 h of aSAH and continued until 14 days after aSAH. Primary endpoint is a composite of mortality and vasospasm-related morbidity within 6 weeks of aSAH (all-cause mortality, vasospasm-related new cerebral infarction, vasospasm-related delayed ischemic neurological deficit, neurological signs or symptoms in the presence of angiographic vasospasm leading to rescue therapy initiation). Main secondary endpoint is extended Glasgow Outcome Scale at week 12. A critical events committee assesses all data centrally to ensure consistency in interpretation, and patient management guidelines are used to standardize care. Results are expected at the end of 2010 and 2011 for CONSCIOUS-2 and CONSCIOUS-3, respectively.

Randomized clinical trial comparing percutaneous closure of patent foramen ovale (PFO) using the Amplatzer PFO Occluder with medical treatment in patients with cryptogenic embolism (PC-Trial): rationale and design

Background Several studies have shown an association of cryptogenic stroke and embolism with patent foramen ovale (PFO), but the question how to prevent further events in such patients is unresolved. Options include antithrombotic treatment with warfarin or antiplatelet agents or surgical or endovascular closure of the PFO. The PC-Trial was set up to compare endovascular closure and best medical treatment for prevention of recurrent events. Methods The PC-Trial is a randomized clinical trial comparing the efficacy of percutaneous closure of the PFO using the Amplatzer PFO occluder with best medical treatment in patients with cryptogenic embolism, i.e. mostly cryptogenic stroke. Warfarin for 6 months followed by antiplatelet agents is recommended as medical treatment. Randomization is stratified according to patients age (<45 versus ≥45 years), presence of atrial septal aneurysm (ASA yes or no) and number of embolic events before randomization (one versus more than one event). Primary endpoints are death, nonfatal stroke and peripheral embolism. Discussion patients were randomized in 29 centers of Europe, Canada, and Australia. Randomization started February 2000. Enrollment of 414 patients was completed in February 2009. All patients will be followed-up longitudinally. Follow-up is maintained until the last enrolled patient is beyond 2.5 years of follow-up (expected in 2011).

Long-term consequences of an intensive care unit stay in older critically ill patients: design of a longitudinal study

Background Modern methods in intensive care medicine often enable the survival of older critically ill patients. The short-term outcomes for patients treated in intensive care units (ICUs), such as survival to hospital discharge, are well documented. However, relatively little is known about subsequent long-term outcomes. Pain, anxiety and agitation are important stress factors for many critically ill patients. There are very few studies concerned with pain, anxiety and agitation and the consequences in older critically ill patients. The overall aim of this study is to identify how an ICU stay influences an older person's experiences later in life. More specific, this study has the following objectives: (1) to explore the relationship between pain, anxiety and agitation during ICU stays and experiences of the same symptoms in later life; and (2) to explore the associations between pain, anxiety and agitation experienced during ICU stays and their effect on subsequent health-related quality of life, use of the health care system (readmissions, doctor visits, rehabilitation, medication use), living situation, and survival after discharge and at 6 and 12 months of follow-up. Methods/Design A prospective, longitudinal study will be used for this study. A total of 150 older critically ill patients in the ICU will participate (ICU group). Pain, anxiety, agitation, morbidity, mortality, use of the health care system, and health-related quality of life will be measured at 3 intervals after a baseline assessment. Baseline measurements will be taken 48 hours after ICU admission and one week thereafter. Follow-up measurements will take place 6 months and 12 months after discharge from the ICU. To be able to interpret trends in scores on outcome variables in the ICU group, a comparison group of 150 participants, matched by age and gender, recruited from the Swiss population, will be interviewed at the same intervals as the ICU group. Discussion Little research has focused on long term consequences after ICU admission in older critically ill patients. The present study is specifically focussing on long term consequences of stress factors experienced during ICU admission.

Learning from failure--rationale and design for a study about discontinuation of randomized trials (DISCO study)

Background Randomized controlled trials (RCTs) may be discontinued because of apparent harm, benefit, or futility. Other RCTs are discontinued early because of insufficient recruitment. Trial discontinuation has ethical implications, because participants consent on the premise of contributing to new medical knowledge, Research Ethics Committees (RECs) spend considerable effort reviewing study protocols, and limited resources for conducting research are wasted. Currently, little is known regarding the frequency and characteristics of discontinued RCTs. Methods/Design Our aims are, first, to determine the prevalence of RCT discontinuation for specific reasons; second, to determine whether the risk of RCT discontinuation for specific reasons differs between investigator- and industry-initiated RCTs; third, to identify risk factors for RCT discontinuation due to insufficient recruitment; fourth, to determine at what stage RCTs are discontinued; and fifth, to examine the publication history of discontinued RCTs. We are currently assembling a multicenter cohort of RCTs based on protocols approved between 2000 and 2002/3 by 6 RECs in Switzerland, Germany, and Canada. We are extracting data on RCT characteristics and planned recruitment for all included protocols. Completion and publication status is determined using information from correspondence between investigators and RECs, publications identified through literature searches, or by contacting the investigators. We will use multivariable regression models to identify risk factors for trial discontinuation due to insufficient recruitment. We aim to include over 1000 RCTs of which an anticipated 150 will have been discontinued due to insufficient recruitment. Discussion Our study will provide insights into the prevalence and characteristics of RCTs that were discontinued. Effective recruitment strategies and the anticipation of problems are key issues in the planning and evaluation of trials by investigators, Clinical Trial Units, RECs and funding agencies. Identification and modification of barriers to successful study completion at an early stage could help to reduce the risk of trial discontinuation, save limited resources, and enable RCTs to better meet their ethical requirements.

Determination of caries risk at resin composite margins

PURPOSE: To design an artificial mouth in order to evaluate if a new diagnostic tool (Clinpro Cario Diagnosis) can be used for early detection of secondary caries at resin composite margins in vitro. METHODS: 32 intact human third molars received standardized Class-V resin composite restorations (Tetric Ceram bonded with Syntac SC). After storage for 4 weeks at 37 degrees C, teeth were subjected to 5,000 or 10,000 thermocycles (+/- 5 degrees C and +/- 55 degrees C) and polysiloxane impressions were taken. Streptococcus mutans 10449 (SM) was used in a nutrition medium to initiate a secondary caries process. Daily, the teeth were incubated for 2 x 2.5 hours in SM containing nutrition medium followed by 2 x 9.5 hours incubation in artificial saliva. Teeth were investigated after total incubation periods of 4, 6, and 8 weeks. After the different incubation protocols, the restoration margins were evaluated for infection and secondary caries processes in using Clinpro Cario Diagnosis which measures site-specifically the lactic acid production of SM in response to a sucrose challenge. The color signal was read 5 minutes after removal of the diagnostic impression. After thermocycling and biological load cycling, precision polysiloxane impressions were taken and replicas were investigated under a light microscope for gap widths at enamel and dentin margins. Demineralization was evaluated by fluorescence microscopy in using a special FITC filter. The demineralization depths at the cavity margin were calculated with Xpert for Windows using a pixel distance of 5 microm. RESULTS: After the different thermocycling protocols, no differences in gap widths and demineralization depths were found (P > 0.05). After SM incubation, gap widths and demineralization depths were significantly dependent on SM incubation time and previous number of thermocycles (P < 0.05). Lactic acid formations of SM were detectable by Clinpro Cario Diagnosis at dentin cavosurface margins formed after 6 weeks of incubation with SM (P < 0.05).

The blood-central nervous system barriers actively control immune cell entry into the central nervous system

Before entering the central nervous system (CNS) immune cells have to penetrate any one of its barriers, namely either the endothelial blood-brain barrier, the epithelial blood-cerebrospinal fluid barrier or the tanycytic barrier around the circumventricular organs, all of which maintain homeostasis within the CNS. The presence of these barriers in combination with the lack of lymphatic vessels and the absence of classical MHC-positive antigen presenting cells characterizes the CNS as an immunologically privileged site. In multiple sclerosis a large number of inflammatory cells gains access to the CNS parenchyma. Studies performed in experimental autoimmune encephalomyelitis (EAE), a rodent model for multiple sclerosis, have enabled us to understand some of the molecular mechanisms involved in immune cell entry into the CNS. In particular, the realization that /alpha4-integrins play a predominant role in leukocyte trafficking to the CNS has led to the development of a novel drug for the treatment of relapsing-remitting multiple sclerosis, which targets /alpha4-integrin mediated immune cell migration to the CNS. At the same time, the involvement of other adhesion and signalling molecules in this process remains to be investigated and novel molecules contributing to immune cell entry into the CNS are still being identified. The entire process of immune cell trafficking into the CNS is strictly controlled by the brain barriers not only under physiological conditions but also during neuroinflammation, when some barrier properties are lost. Thus, immune cell entry into the CNS critically depends on the unique characteristics of the brain barriers maintaining CNS homeostasis.

Strategic Emergency department design: An approach to capacity planning in healthcare provision in overcrowded emergency rooms

Healthcare professionals and the public have increasing concerns about the ability of emergency departments to meet current demands. Increased demand for emergency services, mainly caused by a growing number of minor and moderate injuries has reached crisis proportions, especially in the United Kingdom. Numerous efforts have been made to explore the complex causes because it is becoming more and more important to provide adequate healthcare within tight budgets. Optimisation of patient pathways in the emergency department is therefore an important factor. This paper explores the possibilities offered by dynamic simulation tools to improve patient pathways using the emergency department of a busy university teaching hospital in Switzerland as an example.

Sampling-Design Effects on Properties of Species-Area Relationships - A Case Study from Estonian Dry Grassland Communities

Despite widespread use of species-area relationships (SARs), dispute remains over the most representative SAR model. Using data of small-scale SARs of Estonian dry grassland communities, we address three questions: (1) Which model describes these SARs best when known artifacts are excluded? (2) How do deviating sampling procedures (marginal instead of central position of the smaller plots in relation to the largest plot; single values instead of average values; randomly located subplots instead of nested subplots) influence the properties of the SARs? (3) Are those effects likely to bias the selection of the best model? Our general dataset consisted of 16 series of nested-plots (1 cm(2)-100 m(2), any-part system), each of which comprised five series of subplots located in the four corners and the centre of the 100-m(2) plot. Data for the three pairs of compared sampling designs were generated from this dataset by subsampling. Five function types (power, quadratic power, logarithmic, Michaelis-Menten, Lomolino) were fitted with non-linear regression. In some of the communities, we found extremely high species densities (including bryophytes and lichens), namely up to eight species in 1 cm(2) and up to 140 species in 100 m(2), which appear to be the highest documented values on these scales. For SARs constructed from nested-plot average-value data, the regular power function generally was the best model, closely followed by the quadratic power function, while the logarithmic and Michaelis-Menten functions performed poorly throughout. However, the relative fit of the latter two models increased significantly relative to the respective best model when the single-value or random-sampling method was applied, however, the power function normally remained far superior. These results confirm the hypothesis that both single-value and random-sampling approaches cause artifacts by increasing stochasticity in the data, which can lead to the selection of inappropriate models.

Transesophageal echocardiography for verification of the position of the electrocardiographically-placed central venous catheter

OBJECTIVE: Compare changes in P-wave amplitude of the intra-atrial electrocardiogram (ECG) and its corresponding transesophageal echocardiography (TEE)-controlled position to verify the exact localization of a central venous catheter (CVC) tip. DESIGN: A prospective study. SETTING: University, single-institutional setting. PARTICIPANTS: Two hundred patients undergoing elective cardiac surgery. INTERVENTIONS: CVC placement via the right internal jugular vein with ECG control using the guidewire technique and TEE control in 4 different phases: phase 1: CVC placement with normalized P wave and measurement of distance from the crista terminalis to the CVC tip; phase 2: TEE-controlled placement of the CVC tip; parallel to the superior vena cava (SVC) and measurements of P-wave amplitude; phase 3: influence of head positioning on CVC migration; and phase 4: evaluation of positioning of the CVC postoperatively using a chest x-ray. MEASUREMENTS AND MAIN RESULTS: The CVC tip could only be visualized in 67 patients on TEE with a normalized P wave. In 198 patients with the CVC parallel to the SVC wall controlled by TEE (phase 2), an elevated P wave was observed. Different head movements led to no significant migration of the CVC (phase 3). On a postoperative chest-x-ray, the CVC position was correct in 87.6% (phase 4). CONCLUSION: The study suggests that the position of the CVC tip is located parallel to the SVC and 1.5 cm above the crista terminalis if the P wave starts to decrease during withdrawal of the catheter. The authors recommend that ECG control as per their study should be routinely used for placement of central venous catheters via the right internal jugular vein.

SWiss Atorvastatin and interferon Beta-1b trial In Multiple Sclerosis (SWABIMS)--rationale, design and methodology

Statins have anti-inflammatory and immunomodulatory properties in addition to their lipid-lowering effects. Currently, the effects of statins on multiple sclerosis are still controversial. Therefore, randomized clinical trials are needed to provide better evidence on the therapeutic potential of statins in multiple sclerosis. The SWiss Atorvastatin and Interferon Beta-1b trial in Multiple Sclerosis (SWABIMS) evaluates the efficacy, safety and tolerability of atorvastatin 40 mg per os daily and subcutaneous interferon beta-1b every other day compared to monotherapy with subcutaneous interferon beta-1b every other day in patients with relapsing-remitting multiple sclerosis.

Rationale and design of a randomized, double-blind, parallel-group study of terutroban 30 mg/day versus aspirin 100 mg/day in stroke patients: the prevention of cerebrovascular and cardiovascular events of ischemic origin with terutroban in patients with a history of ischemic stroke or transient ischemic attack (PERFORM) study

BACKGROUND: Ischemic stroke is the leading cause of mortality worldwide and a major contributor to neurological disability and dementia. Terutroban is a specific TP receptor antagonist with antithrombotic, antivasoconstrictive, and antiatherosclerotic properties, which may be of interest for the secondary prevention of ischemic stroke. This article describes the rationale and design of the Prevention of cerebrovascular and cardiovascular Events of ischemic origin with teRutroban in patients with a history oF ischemic strOke or tRansient ischeMic Attack (PERFORM) Study, which aims to demonstrate the superiority of the efficacy of terutroban versus aspirin in secondary prevention of cerebrovascular and cardiovascular events. METHODS AND RESULTS: The PERFORM Study is a multicenter, randomized, double-blind, parallel-group study being carried out in 802 centers in 46 countries. The study population includes patients aged > or =55 years, having suffered an ischemic stroke (< or =3 months) or a transient ischemic attack (< or =8 days). Participants are randomly allocated to terutroban (30 mg/day) or aspirin (100 mg/day). The primary efficacy endpoint is a composite of ischemic stroke (fatal or nonfatal), myocardial infarction (fatal or nonfatal), or other vascular death (excluding hemorrhagic death of any origin). Safety is being evaluated by assessing hemorrhagic events. Follow-up is expected to last for 2-4 years. Assuming a relative risk reduction of 13%, the expected number of primary events is 2,340. To obtain statistical power of 90%, this requires inclusion of at least 18,000 patients in this event-driven trial. The first patient was randomized in February 2006. CONCLUSIONS: The PERFORM Study will explore the benefits and safety of terutroban in secondary cardiovascular prevention after a cerebral ischemic event.

In vitro precision of fit of computer-aided design and computer-aided manufacturing titanium and zirconium dioxide bars

OBJECTIVES Optical scanners combined with computer-aided design and computer-aided manufacturing (CAD/CAM) technology provide high accuracy in the fabrication of titanium (TIT) and zirconium dioxide (ZrO) bars. The aim of this study was to compare the precision of fit of CAD/CAM TIT bars produced with a photogrammetric and a laser scanner. METHODS Twenty rigid CAD/CAM bars were fabricated on one single edentulous master cast with 6 implants in the positions of the second premolars, canines and central incisors. A photogrammetric scanner (P) provided digitized data for TIT-P (n=5) while a laser scanner (L) was used for TIT-L (n=5). The control groups consisted of soldered gold bars (gold, n=5) and ZrO-P with similar bar design. Median vertical distance between implant and bar platforms from non-tightened implants (one-screw test) was calculated from mesial, buccal and distal scanning electron microscope measurements. RESULTS Vertical microgaps were not significantly different between TIT-P (median 16μm; 95% CI 10-27μm) and TIT-L (25μm; 13-32μm). Gold (49μm; 12-69μm) had higher values than TIT-P (p=0.001) and TIT-L (p=0.008), while ZrO-P (35μm; 17-55μm) exhibited higher values than TIT-P (p=0.023). Misfit values increased in all groups from implant position 23 (3 units) to 15 (10 units), while in gold and TIT-P values decreased from implant 11 toward the most distal implant 15. SIGNIFICANCE CAD/CAM titanium bars showed high precision of fit using photogrammetric and laser scanners. In comparison, the misfit of ZrO bars (CAM/CAM, photogrammetric scanner) and soldered gold bars was statistically higher but values were clinically acceptable.

Design and establishment of a biobank in a multicenter prospective cohort study of elderly patients with venous thromboembolism (SWITCO65+)

In the field of thrombosis and haemostasis, many preanalytical variables influence the results of coagulation assays and measures to limit potential results variations should be taken. To our knowledge, no paper describing the development and maintenance of a haemostasis biobank has been previously published. Our description of the biobank of the Swiss cohort of elderly patients with venous thromboembolism (SWITCO65+) is intended to facilitate the set-up of other biobanks in the field of thrombosis and haemostasis. SWITCO65+ is a multicentre cohort that prospectively enrolled consecutive patients aged ≥65 years with venous thromboembolism at nine Swiss hospitals from 09/2009 to 03/2012. Patients will be followed up until December 2013. The cohort includes a biobank with biological material from each participant taken at baseline and after 12 months of follow-up. Whole blood from all participants is assayed with a standard haematology panel, for which fresh samples are required. Two buffy coat vials, one PAXgene Blood RNA System tube and one EDTA-whole blood sample are also collected at baseline for RNA/DNA extraction. Blood samples are processed and vialed within 1 h of collection and transported in batches to a central laboratory where they are stored in ultra-low temperature archives. All analyses of the same type are performed in the same laboratory in batches. Using multiple core laboratories increased the speed of sample analyses and reduced storage time. After recruiting, processing and analyzing the blood of more than 1,000 patients, we determined that the adopted methods and technologies were fit-for-purpose and robust.

Mineralization of calcium phosphate crystals in starch template inducing a brushite kidney stone biomimetic composite

Dicalcium phosphate dihydrate (brushite) and octacalcium phosphate (OCP) crystals are precursors of hydroxyapatite (HAp) for tooth enamel, dentine, and bones formation in living organisms. Here, we introduce a new method for biomimicking brushite and OCP in starch using single and double diffusion techniques. Brushite and OCP crystals were grown by precipitation in starch after gelation. The obtained materials were analyzed by infrared spectroscopy (IR), scanning electron microscopy (SEM), X-ray diffraction (XRD), and confocal laser scanning microscopy (CLSM). IR spectra demonstrate starch inclusion by peak shifts in the 2900–3500 cm–1 region. SEM showed two different morphologies: plate-shaped and needle-like crystals. Calcium phosphate/starch aggregates bear strong resemblance to prismatic brushite kidney stones. This may open up a clue to understand the mechanism of kidney stone formation.