Controlled delivery of 5-chlorouracil using poly(ortho esters) in filtering surgery for glaucoma.

PURPOSE: To evaluate the antimitotic and toxic effects of 5-chlorouracil (5-CU) and 5-fluorouracil (5-FU) and study their potential to delay filtering bleb closure in the rabbit eye when released by poly(ortho esters) (POE). METHODS: Rabbit Tenon fibroblasts and human conjunctival cells were incubated with various 5-CU and 5-FU concentrations. Antiproliferative effects and toxicity were evaluated at 24 and 72 hours by monotetrazolium, neutral red, and Hoechst tests and cell counting. Mechanisms of cell death were evaluated using TUNEL assay, annexin V binding, immunohistochemistry for anti-apoptosis-inducing factor (AIF) and LEI/L-DNase II. Trabeculectomy was performed in pigmented rabbits. Two hundred microliters of POE loaded with 1% wt/wt 5-FU or 5-CU was injected into the subconjunctival space after surgery. Intraocular pressure (IOP) and bleb persistence were monitored for 150 days. RESULTS: In vitro, 5-FU showed a higher antiproliferative effect and a more toxic effect than 5-CU. 5-FU induced cell necrosis, whereas 5-CU induced mostly apoptosis. The apoptosis induced by 5-CU was driven through a non-caspase-dependent pathway involving AIF and LEI/L-DNase II. In vivo, at 34 days after surgery, the mean IOP in the POE/5-CU-treated group was 83% of the baseline level and only 40% in the POE/5-FU-treated group. At 100 days after surgery, IOP was still decreased in the POE/5-CU group when compared with the controls and still inferior to the preoperative value. The mean long-term IOP, with all time points considered, was significantly (P < 0.0001) decreased in the POE/5-CU-treated group (6.0 +/- 2.4 mm Hg) when compared with both control groups, the trabeculectomy alone group (7.6 +/- 2.9 mm Hg), and the POE alone group (7.5 +/- 2.6 mm Hg). Histologic analysis showed evidence of functioning blebs in the POE-5-CU-treated eyes along with a preserved structure of the conjunctiva epithelium. CONCLUSIONS: The slow release of 5-CU from POE has a longstanding effect on the decrease of IOP after glaucoma-filtering surgery in the rabbit eye. Thus, the slow release of POE/5-CU may be beneficial for the prevention of bleb closure in patients who undergo complicated trabeculectomy.

Brief alcohol intervention and alcohol assessment do not influence alcohol use in injured patients treated in the emergency department: a randomized controlled clinical trial.

AIMS: To evaluate the effectiveness of brief alcohol intervention (BAI) in reducing alcohol use among hazardous drinkers treated in the emergency department (ED) after an injury; in addition it tests whether assessment of alcohol use without BAI is sufficient to reduce hazardous drinking. DESIGN: Randomized controlled clinical trial with 12-month follow-up conducted between January 2003 and June 2005. SETTING: Urban academic emergency department (ED) of the Lausanne University Hospital, Lausanne, Switzerland. PARTICIPANTS: A total of 5136 consecutive patients attending ED after an injury completed a seven-item general and a three-item alcohol screen and 1472 (28.7%) were positive for hazardous drinking according to the National Institute on Alcohol Abuse and Addiction definition; of these 987 (67.1%) were randomized into a BAI group (n = 310) or a control group with screening and assessment (n = 342) or a control group with screening only (n = 335) and then a total of 770 patients (78.0%) completed the 12-month follow-up procedures. INTERVENTION: A single 10-15-minute session of standardized BAI conducted by a trained research assistant. MEASUREMENTS: Percentage of participants who have changed to low-risk drinking at follow-up. FINDINGS: Data obtained at 12 months indicated that similar proportions were low-risk drinkers in BAI versus control groups with and without assessment (35.6%, 34.0%, 37.0%, respectively, P = 0.71). Data also indicated similar reductions in drinking frequency, quantity, binge drinking frequency and Alcohol Use Disorders Identification Test (AUDIT) scores across groups. All groups reported similar numbers of days hospitalized and numbers of medical consults in the last 12 months. A model including age groups, gender, AUDIT and injury severity scores indicated that BAI had no influence on the main alcohol use outcome. CONCLUSIONS: This study provides the evidence that a 10-15-minute BAI does not decrease alcohol use and health resource utilization in hazardous drinkers treated in the ED, and demonstrates that commonly found decreases in hazardous alcohol use in control groups cannot be attributed to the baseline alcohol assessment.

Impact of controlled changes in grain size and pore space characteristics on the hydraulic conductivity and spectral induced polarization response of "proxies" of saturated alluvial sediments

Understanding the influence of pore space characteristics on the hydraulic conductivity and spectral induced polarization (SIP) response is critical for establishing relationships between the electrical and hydrological properties of surficial unconsolidated sedimentary deposits, which host the bulk of the world's readily accessible groundwater resources. Here, we present the results of laboratory SIP measurements on industrial-grade, saturated quartz samples with granulometric characteristics ranging from fine sand to fine gravel, which can be regarded as proxies for widespread alluvial deposits. We altered the pore space characteristics by changing (i) the grain size spectra, (ii) the degree of compaction, and (iii) the level of sorting. We then examined how these changes affect the SIP response, the hydraulic conductivity, and the specific surface area of the considered samples. In general, the results indicate a clear connection between the SIP response and the granulometric as well as pore space characteristics. In particular, we observe a systematic correlation between the hydraulic conductivity and the relaxation time of the Cole-Cole model describing the observed SIP effect for the entire range of considered grain sizes. The results do, however, also indicate that the detailed nature of these relations depends strongly on variations in the pore space characteristics, such as, for example, the degree of compaction. The results of this study underline the complexity of the origin of the SIP signal as well as the difficulty to relate it to a single structural factor of a studied sample, and hence raise some fundamental questions with regard to the practical use of SIP measurements as site- and/or sample-independent predictors of the hydraulic conductivity.

Stress intensity factor of wood from crack-tip displacement fields obtained from digital image processing

Abstract

Results from a prospective, randomized, controlled study evaluating the acceptability and effects of routine pre-IVF counselling.

BACKGROUND: The aim of this study was to evaluate a model of routine pre-IVF counselling focusing on the narrative capacities of couples. The acceptability of counselling, the effects on emotional factors and the participants' assessments were considered. METHODS: The study included 141 consecutive childless couples preparing for their first IVF. Randomization was carried out through sealed envelopes attributing participants to counselled and non-counselled groups and was accepted by 100 couples. Another 12 couples refused randomization because they wanted counselling and 29 because they did not. Questionnaires including the State-Trait Anxiety Inventory, the Beck Depression Inventory and assessments of help were mailed to couples before IVF and counselling, and after the IVF outcome. RESULTS: Counselling was accepted by 79% (112/141) of couples. There was no significant effect of counselling on anxiety and depression scores which were within normal ranges at both times. Counselling provided help for 86% (75/87) of initially non-demanding subjects and 96% (25/26) of those initially requesting a session. Help was noted in areas of psychological assistance, technical explanations and discussing relationships. CONCLUSIONS: This model of routine counselling centred on the narrative provides an acceptable form of psychological assistance for pre-IVF couples.

Diagnostic algorithm for a validated displacement grading of pediatric supracondylar fractures.

Background: The first AO comprehensive pediatric long bone fracture classification system has been established following a structured path of development and validation with experienced pediatric surgeons. Methods: A follow-up series of agreement studies was applied to specify and evaluate a grading system for displacement of pediatric supracondylar fractures. An iterative process comprising an international group of 5 experienced pediatric surgeons (Phase 1) followed by a pragmatic multicenter agreement study involving 26 raters (Phase 2) was used. The last evaluations were conducted on a consecutive collection of 154 supracondylar fractures documented by standard anteroposterior and lateral radiographs. Results: Fractures were classified according to 1 of 4 grades: I = incomplete fracture with no or minimal displacement; II = Incomplete fracture with continuity of the posterior (extension fracture) or anterior cortex (flexion fracture); III = lack of bone continuity (broken cortex), but still some contact between the fracture planes; IV = complete fracture with no bone continuity (broken cortex), and no contact between the fracture planes. A diagnostic algorithm to support the practical application of the grading system in a clinical setting, as well as an aid using a circle placed over the capitellum was proposed. The overall kappa coefficients were 0.68 and 0.61 in the Phase 1 and Phase 2 studies, respectively. In the Phase 1 study, fracture grades I, II, III, and IV were classified with median accuracies of 91%, 82%, 83%, and 99.5%, respectively. Similar median accuracies of 86% (Grade I), 73% (Grade II), 83%(Grade III), and 92% were reported for the Phase 2 study. Reliability was high in distinguishing complete, unstable fractures from stable injuries [ie, kappa coefficients of 0.84 (Phase 1) and 0.83 (Phase 2) were calculated]; in Phase 2, surgeons' accuracies in classifying complete fractures were all above 85%. Conclusions: With clear and unambiguous definition, this new grading system for supracondylar fracture displacement has proved to be sufficiently reliable and accurate when applied by pediatric surgeons in the framework of clinical routine as well as research.

Referral from primary care to a physical activity programme: establishing long-term adherence? A randomized controlled trial. Rationale and study design

Background: Declining physical activity is associated with a rising burden of global disease. There is little evidence about effective ways to increase adherence to physical activity. Therefore, interventions are needed that produce sustained increases in adherence to physical activity and are cost-effective. The purpose is to assess the effectiveness of a primary care physical activity intervention in increasing adherence to physical activity in the general population seen in primary care. Method and design: Randomized controlled trial with systematic random sampling. A total of 424 subjects of both sexes will participate; all will be over the age of 18 with a low level of physical activity (according to the International Physical Activity Questionnaire, IPAQ), self-employed and from 9 Primary Healthcare Centres (PHC). They will volunteer to participate in a physical activity programme during 3 months (24 sessions; 2 sessions a week, 60 minutes per session). Participants from each PHC will be randomly allocated to an intervention (IG) and control group (CG). The following parameters will be assessed pre and post intervention in both groups: (1) health-related quality of life (SF-12), (2) physical activity stage of change (Prochaska's stages of change), (3) level of physical activity (IPAQ-short version), (4) change in perception of health (vignettes from the Cooperative World Organization of National Colleges, Academies, and Academic Associations of Family Physicians, COOP/WONCA), (5) level of social support for the physical activity practice (Social Support for Physical Activity Scale, SSPAS), and (6) control based on analysis (HDL, LDL and glycated haemoglobin).Participants' frequency of visits to the PHC will be registered over the six months before and after the programme. There will be a follow up in a face to face interview three, six and twelve months after the programme, with the reduced version of IPAQ, SF-12, SSPAS, and Prochaska's stages. Discussion: The pilot study showed the effectiveness of an enhanced low-cost, evidence-based intervention in increased physical activity and improved social support. If successful in demonstrating long-term improvements, this randomised controlled trial will be the first sustainable physical activity intervention based in primary care in our country to demonstrate longterm adherence to physical activity. Trial Registration: A service of the U.S. National Institutes of Health. Developed by the National Library of Medicine. ClinicalTrials.gov ID: NCT00714831.

The Effect of a Physical Activity Program on the Total Number of Primary Care Visits in Inactive Patients: A 15-Month Randomized Controlled Trial

Abstract Background: Effective promotion of exercise could result in substantial savings in healthcare cost expenses in terms of direct medical costs, such as the number of medical appointments. However, this is hampered by our limited knowledge of how to achieve sustained increases in physical activity. Objectives: To assess the effectiveness of a Primary Health Care (PHC) based physical activity program in reducing the total number of visits to the healthcare center among inactive patients, over a 15-month period. Research Design: Randomized controlled trial. Subjects: Three hundred and sixty-two (n = 362) inactive patients suffering from at least one chronic condition were included. One hundred and eighty-three patients (n = 183; mean (SD); 68.3 (8.8) years; 118 women) were randomly allocated to the physical activity program (IG). One hundred and seventy-nine patients (n = 179; 67.2 (9.1) years; 106 women) were allocated to the control group (CG). The IG went through a three-month standardized physical activity program led by physical activity specialists and linked to community resources. Measures: The total number of medical appointments to the PHC, during twelve months before and after the program, was registered. Self-reported health status (SF-12 version 2) was assessed at baseline (month 0), at the end of the intervention (month 3), and at 12 months follow-up after the end of the intervention (month 15). Results: The IG had a significantly reduced number of visits during the 12 months after the intervention: 14.8 (8.5). The CG remained about the same: 18.2 (11.1) (P = .002). Conclusions: Our findings indicate that a 3-month physical activity program linked to community resources is a shortduration, effective and sustainable intervention in inactive patients to decrease rates of PHC visits. Trial Registration: ClinicalTrials.gov NCT00714831

Optimal CD8 T cell responsiveness is controlled within a defined TCR affinity window

Protective immune responses relyon TCR-mediated recognition of antigenspresented by MHC molecules. Tcells directed against tumor antigensare thought to express TCRs of loweraffinity/avidity than pathogen-specificT lymphocytes. An attractivestrategy to improve anti-tumor T cellresponses is to adoptively transferCD8+ T cells engineered with TCRsof optimized affinity. However, themechanisms that control optimal Tcell activation and responsiveness remainpoorly defined. We aim at characterizingTCR-pMHC binding parametersand downstream signalingevents that regulate T cell functionalityby using an in silico designedpanel of tumor antigen-specific TCRsof incremental affinity for pMHC(Kd100 M- 15 nM).We found that optimalT cell responses (cytokine secretionand target cell killing) occurredwithin a well-defined window ofTCR-pMHC binding affinity (5 M-1 M), while drastic functional declinewas detected in T cells expressingvery low and very high TCRaffinities,which was not caused by any increasein apoptosis. Whole-genomemicroarray analysis revealed that Tcells with optimal TCR affinitieshighly up-regulated transcription ofgenes typical of T cell activation (i.e.IFN-, NF-B and TNFR), while reducedexpression was detected in Tcells of very low or very high TCR affinity.Strikingly, hierarchical clusteringshowed that the latter two variantsclustered together with the un-stimulatedcontrol Tcells.Yet, despite commonclustering, several genes seemedto be differentially expressed, suggestingthat the mechanisms involvedin this "unresponsiveness state" maydiffer between those two variants. Finally,calcium influx assays also demonstratedattenuated responses in Tcells of very high TCR affinity. Ourresults indicate that optimal T cellfunction is tightly controlled within adefinedTCRaffinity window throughvery proximal TCR-mediated mechanisms,possibly at the TCR-pMHCbinding interface. Uncovering themechanisms regulating optimal/maximalT cell function is essential to understandand promote therapeutic designlike adoptive T cell therapy.

A randomised controlled clinical trial and gait analysis of fixed- and mobile-bearing total knee replacements with a five-year follow-up.

This study compared the outcome of total knee replacement (TKR) in adult patients with fixed- and mobile-bearing prostheses during the first post-operative year and at five years' follow-up, using gait parameters as a new objective measure. This double-blind randomised controlled clinical trial included 55 patients with mobile-bearing (n = 26) and fixed-bearing (n = 29) prostheses of the same design, evaluated pre-operatively and post-operatively at six weeks, three months, six months, one year and five years. Each participant undertook two walking trials of 30 m and completed the EuroQol questionnaire, Western Ontario and McMaster Universities osteoarthritis index, Knee Society score, and visual analogue scales for pain and stiffness. Gait analysis was performed using five miniature angular rate sensors mounted on the trunk (sacrum), each thigh and calf. The study population was divided into two groups according to age (≤ 70 years versus > 70 years). Improvements in most gait parameters at five years' follow-up were greater for fixed-bearing TKRs in older patients (> 70 years), and greater for mobile-bearing TKRs in younger patients (≤ 70 years). These findings should be confirmed by an extended age controlled study, as the ideal choice of prosthesis might depend on the age of the patient at the time of surgery.

A randomised controlled pilot study comparing Mepitel(®) and SurfaSoft(®) on paediatric donor sites treated with Recell(®).

This randomized controlled pilot study examined the effects of a silicone net dressing (Mepitel(®)) and a monofilament polyamide woven dressing (SurfaSoft(®)) on the rate of epithelialisation and epidermal maturation, pain, and ease of dressing removal on paediatric donor sites treated with epithelial cell suspension (ReCell(®)). Fifteen children (1-15 years) admitted for acute or reconstructive burns procedures in a tertiary referral hospital in Australia were randomly assigned to the experimental group, Mepitel(®) (n=8) and to the control group, SurfaSoft(®) (n=7). All donor sites were treated with ReCell(®) and covered with the assigned dressing. Measurements of rate of epithelialisation and epidermal maturation, pain, and ease of dressing removal were recorded every two days until the wound was healed. Results showed that there was no difference in the rate of epidermal maturation between the two groups. Less pain and force to remove the dressing was shown in the Mepitel(®) group when compared to SurfaSoft(®). The rate of epithelialisation was found to be an unreliable measure. Although additional research is required to support the results of this study, these results suggest that Mepitel's(®) pliable, self-adhesive and atraumatic properties may improve healing of ReCell(®) treated donor sites with less pain at dressing changes. This pilot study provides a strong base for further research in this area.

Efficacy and safety of a phospholipid emulsion (GR270773) in Gram-negative severe sepsis: results of a phase II multicenter, randomized, placebo-controlled, dose-finding clinical trial.

OBJECTIVE: To assess the survival benefit and safety profile of low-dose (850 mg/kg) and high-dose (1350 mg/kg) phospholipid emulsion vs. placebo administered as a continuous 3-day infusion in patients with confirmed or suspected Gram-negative severe sepsis. Preclinical and ex vivo studies show that lipoproteins bind and neutralize endotoxin, and experimental animal studies demonstrate protection from septic death when lipoproteins are administered. Endotoxin neutralization correlates with the amount of phospholipid in the lipoprotein particles. DESIGN: A three-arm, randomized, blinded, placebo-controlled trial. SETTING: Conducted at 235 centers worldwide between September 2004 and April 2006. PATIENTS: A total of 1379 patients participated in the study, 598 patients received low-dose phospholipid emulsion, and 599 patients received placebo. The high-dose phospholipid emulsion arm was stopped, on the recommendation of the Independent Data Monitoring Committee, due to an increase in life-threatening serious adverse events at the fourth interim analysis and included 182 patients. MEASUREMENTS AND MAIN RESULTS: A 28-day all-cause mortality and new-onset organ failure. There was no significant treatment benefit for low- or high-dose phospholipid emulsion vs. placebo for 28-day all-cause mortality, with rates of 25.8% (p = .329), 31.3% (p = .879), and 26.9%, respectively. The rate of new-onset organ failure was not statistically different among groups at 26.3%, 31.3%, 20.4% with low- and high-dose phospholipid emulsion, and placebo, respectively (one-sided p = .992, low vs. placebo; p = .999, high vs. placebo). Of the subjects treated, 45% had microbiologically confirmed Gram-negative infections. Maximal changes in mean hemoglobin levels were reached on day 10 (-1.04 g/dL) and day 5 (-1.36 g/dL) with low- and high-dose phospholipid emulsion, respectively, and on day 14 (-0.82 g/dL) with placebo. CONCLUSIONS: Treatment with phospholipid emulsion did not reduce 28-day all-cause mortality, or reduce the onset of new organ failure in patients with suspected or confirmed Gram-negative severe sepsis.

SWIVIT - Swiss video-intubation trial evaluating video-laryngoscopes in a simulated difficult airway scenario: study protocol for a multicenter prospective randomized controlled trial in Switzerland.

BACKGROUND: Video-laryngoscopes are marketed for intubation in difficult airway management. They provide a better view of the larynx and may facilitate tracheal intubation, but there is no adequately powered study comparing different types of video-laryngoscopes in a difficult airway scenario or in a simulated difficult airway situation. METHODS/DESIGN: The objective of this trial is to evaluate and to compare the clinical performance of three video-laryngoscopes with a guiding channel for intubation (Airtraq?, A. P. Advance?, King Vision?) and three video-laryngoscopes without an integrated tracheal tube guidance (C-MAC?, GlideScope?, McGrath?) in a simulated difficult airway situation in surgical patients. The working hypothesis is that each video-laryngoscope provides at least a 90% first intubation success rate (lower limit of the 95% confidence interval >0.9). It is a prospective, patient-blinded, multicenter, randomized controlled trial in 720 patients who are scheduled for elective surgery under general anesthesia, requiring tracheal intubation at one of the three participating hospitals. A difficult airway will be created using an extrication collar and taping the patients' head on the operating table to substantially reduce mouth opening and to minimize neck movement. Tracheal intubation will be performed with the help of one of the six devices according to randomization. Insertion success, time necessary for intubation, Cormack-Lehane grade and percentage of glottic opening (POGO) score at laryngoscopy, optimization maneuvers required to aid tracheal intubation, adverse events and technical problems will be recorded. Primary outcome is intubation success at first attempt. DISCUSSION: We will simulate the difficult airway and evaluate different video-laryngoscopes in this highly realistic and clinically challenging scenario, independently from manufacturers of the devices. Because of the sufficiently powered multicenter design this study will deliver important and cutting-edge results that will help clinicians decide which device to use for intubation of the expected and unexpected difficult airway. TRIAL REGISTRATION: NCT01692535.