The Next 10 years in the Management of Peripheral Artery Disease: Perspectives from The 'PAD 2009' Conference

OBJECTIVES: To briefly inform on the conclusions from a conference on the next 10 years in the management of peripheral artery disease (PAD). DESIGN OF THE CONFERENCE: International participation, invited presentations and open discussion were based on the following issues: Why is PAD under-recognised? Health economic impact of PAD; funding of PAD research; changes of treatment options? Aspects on clinical trials and regulatory views; and the role of guidelines. RESULTS AND CONCLUSIONS: A relative lack of knowledge about cardiovascular risk and optimal management of PAD patients exists not only among the public, but also in parts of the health-care system. Specialists are required to act for improved information. More specific PAD research is needed for risk management and to apply the best possible evaluation of evidence for treatment strategies. Better strategies for funding are required based on, for example, public/private initiatives. The proportion of endovascular treatments is steadily increasing, more frequently based on observational studies than on randomised controlled trials. The role of guidelines is therefore important to guide the profession in the assessment of most relevant treatment.

The course of chronic and recurrent low back pain in the general population

Using latent class analysis (LCA), a previous study on patients attending primary care identified four courses of low back pain (LBP) over the subsequent 6 months. To date, no studies have used longitudinal pain recordings to examine the "natural" course of recurrent and chronic LBP in a population-based sample of individuals. This study examines the course of LBP in the general population and elaborates on the stability and criterion-related validity of the clusters derived. A random sample of 400 individuals reporting LBP in a population-based study was asked to complete a comprehensive questionnaire at the start and end of the year's survey, and 52 weekly pain diaries in between. The latter were analyzed using LCA. 305 individuals returned more than 50% of the diaries. Four clusters were identified (severe persistent, moderate persistent, mild persistent, and fluctuating). The clusters differed significantly with regards to pain and disability. Assessment of cluster stability showed that a considerable proportion of patients in the "fluctuating" group changed their classification over time. Three of the four clusters describing the typical course of pain matched the clusters described previously for patients in primary care. Due to the population-based design, this study achieves, for the first time, a close insight into the "natural" course of chronic and recurrent low back pain, including individuals that did not necessarily visit the general practitioner. The findings will help to understand better the nature of this pain in the general population.

Reporting of noninferiority trials was incomplete in trial registries

Objective To examine the registration of noninferiority trials, with a focus on the reporting of study design and noninferiority margins. Study Design and Setting Cross-sectional study of registry records of noninferiority trials published from 2005 to 2009 and records of noninferiority trials in the International Standard Randomized Controlled Trial Number (ISRCTN) or ClinicalTrials.gov trial registries. The main outcome was the proportion of records that reported the noninferiority design and margin. Results We analyzed 87 registry records of published noninferiority trials and 149 registry records describing noninferiority trials. Thirty-five (40%) of 87 records from published trials described the trial as a noninferiority trial; only two (2%) reported the noninferiority margin. Reporting of the noninferiority design was more frequent in the ISRCTN registry (13 of 18 records, 72%) compared with ClinicalTrials.gov (22 of 69 records, 32%; P = 0.002). Among the 149 records identified in the registries, 13 (9%) reported the noninferiority margin. Only one of the industry-sponsored trial compared with 11 of the publicly funded trials reported the margin (P = 0.001). Conclusion Most registry records of noninferiority trials do not mention the noninferiority design and do not include the noninferiority margin. The registration of noninferiority trials is unsatisfactory and must be improved.

Constrained pattern of viral evolution in acute and early HCV infection limits viral plasticity

Cellular immune responses during acute Hepatitis C virus (HCV) and HIV infection are a known correlate of infection outcome. Viral adaptation to these responses via mutation(s) within CD8+ T-cell epitopes allows these viruses to subvert host immune control. This study examined HCV evolution in 21 HCV genotype 1-infected subjects to characterise the level of viral adaptation during acute and early HCV infection. Of the total mutations observed 25% were within described CD8+ T-cell epitopes or at viral adaptation sites. Most mutations were maintained into the chronic phase of HCV infection (75%). The lack of reversion of adaptations and high proportion of silent substitutions suggests that HCV has structural and functional limitations that constrain evolution. These results were compared to the pattern of viral evolution observed in 98 subjects during a similar phase in HIV infection from a previous study. In contrast to HCV, evolution during acute HIV infection is marked by high levels of amino acid change relative to silent substitutions, including a higher proportion of adaptations, likely reflecting strong and continued CD8+ T-cell pressure combined with greater plasticity of the virus. Understanding viral escape dynamics for these two viruses is important for effective T cell vaccine design.

Evidence Based Development of a Novel Lateral Fibula Plate (VariAx Fibula) Using a Real CT Bone Data Based Optimization Process During Device Development

Development of novel implants in orthopaedic trauma surgery is based on limited datasets of cadaver trials or artificial bone models. A method has been developed whereby implants can be constructed in an evidence based method founded on a large anatomic database consisting of more than 2.000 datasets of bones extracted from CT scans. The aim of this study was the development and clinical application of an anatomically pre-contoured plate for the treatment of distal fibular fractures based on the anatomical database. 48 Caucasian and Asian bone models (left and right) from the database were used for the preliminary optimization process and validation of the fibula plate. The implant was constructed to fit bilaterally in a lateral position of the fibula. Then a biomechanical comparison of the designed implant to the current gold standard in the treatment of distal fibular fractures (locking 1/3 tubular plate) was conducted. Finally, a clinical surveillance study to evaluate the grade of implant fit achieved was performed. The results showed that with a virtual anatomic database it was possible to design a fibula plate with an optimized fit for a large proportion of the population. Biomechanical testing showed the novel fibula plate to be superior to 1/3 tubular plates in 4-point bending tests. The clinical application showed a very high degree of primary implant fit. Only in a small minority of cases further intra-operative implant bending was necessary. Therefore, the goal to develop an implant for the treatment of distal fibular fractures based on the evidence of a large anatomical database could be attained. Biomechanical testing showed good results regarding the stability and the clinical application confirmed the high grade of anatomical fit.

Sample sizes of studies on diagnostic accuracy: literature survey

OBJECTIVES: To determine sample sizes in studies on diagnostic accuracy and the proportion of studies that report calculations of sample size. DESIGN: Literature survey. DATA SOURCES: All issues of eight leading journals published in 2002. METHODS: Sample sizes, number of subgroup analyses, and how often studies reported calculations of sample size were extracted. RESULTS: 43 of 8999 articles were non-screening studies on diagnostic accuracy. The median sample size was 118 (interquartile range 71-350) and the median prevalence of the target condition was 43% (27-61%). The median number of patients with the target condition--needed to calculate a test's sensitivity--was 49 (28-91). The median number of patients without the target condition--needed to determine a test's specificity--was 76 (27-209). Two of the 43 studies (5%) reported a priori calculations of sample size. Twenty articles (47%) reported results for patient subgroups. The number of subgroups ranged from two to 19 (median four). No studies reported that sample size was calculated on the basis of preplanned analyses of subgroups. CONCLUSION: Few studies on diagnostic accuracy report considerations of sample size. The number of participants in most studies on diagnostic accuracy is probably too small to analyse variability of measures of accuracy across patient subgroups.

Partner notification of chlamydia infection in primary care: randomised controlled trial and analysis of resource use

OBJECTIVE: To evaluate the effectiveness of a practice nurse led strategy to improve the notification and treatment of partners of people with chlamydia infection. DESIGN: Randomised controlled trial. SETTING: 27 general practices in the Bristol and Birmingham areas. PARTICIPANTS: 140 men and women with chlamydia (index cases) diagnosed by screening of a home collected urine sample or vulval swab specimen. INTERVENTIONS: Partner notification at the general practice immediately after diagnosis by trained practice nurses, with telephone follow up by a health adviser; or referral to a specialist health adviser at a genitourinary medicine clinic. MAIN OUTCOME MEASURES: Primary outcome was the proportion of index cases with at least one treated sexual partner. Specified secondary outcomes included the number of sexual contacts elicited during a sexual history, positive test result for chlamydia six weeks after treatment, and the cost of each strategy in 2003 sterling prices. RESULTS: 65.3% (47/72) of participants receiving practice nurse led partner notification had at least one partner treated compared with 52.9% (39/68) of those referred to a genitourinary medicine clinic (risk difference 12.4%, 95% confidence interval -1.8% to 26.5%). Of 68 participants referred to the clinic, 21 (31%) did not attend. The costs per index case were 32.55 pounds sterling for the practice nurse led strategy and 32.62 pounds sterling for the specialist referral strategy. CONCLUSION: Practice based partner notification by trained nurses with telephone follow up by health advisers is at least as effective as referral to a specialist health adviser at a genitourinary medicine clinic, and costs the same. Trial registration Clinical trials: NCT00112255.

Vertebroplasty and kyphoplasty: a systematic review of 69 clinical studies

STUDY DESIGN: Systematic literature review. OBJECTIVE: To evaluate the safety and efficacy of vertebroplasty and kyphoplasty using the data presented in published clinical studies, with respect to patient pain relief, restoration of mobility and vertebral body height, complication rate, and incidence of new adjacent vertebral fractures. SUMMARY OF BACKGROUND DATA: Vertebroplasty and kyphoplasty have been gaining popularity for treating vertebral fractures. Current reviews provide an overview of the procedures but are not comprehensive and tend to rely heavily on personal experience. This article aimed to compile all available data and evaluate the clinical outcome of the 2 procedures. METHODS: This is a systematic review of all the available data presented in peer-reviewed published clinical trials. The methodological quality of included studies was evaluated, and data were collected targeting specific standard measurements. Where possible, a quantitative aggregation of the data was performed. RESULTS: A large proportion of subjects had some pain relief, including 87% with vertebroplasty and 92% with kyphoplasty. Vertebral height restoration was possible using kyphoplasty (average 6.6 degrees ) and for a subset of patients using vertebroplasty (average 6.6 degrees ). Cement leaks occurred for 41% and 9% of treated vertebrae for vertebroplasty and kyphoplasty, respectively. New fractures of adjacent vertebrae occurred for both procedures at rates that are higher than the general osteoporotic population but approximately equivalent to the general osteoporotic population that had a previous vertebral fracture. CONCLUSIONS: The problem with stating definitely that vertebroplasty and kyphoplasty are safe and effective procedures is the lack of comparative, blinded, randomized clinical trials. Standardized evaluative methods should be adopted.

Tubal sterilization: Complications of laparoscopy and minilaparotomy

OBJECTIVE: To evaluate whether intra- and post-operative morbidity varies according to the method used for female sterilization. STUDY DESIGN: The database of the Swiss obstetric study group was analyzed for a period of 9 years. After the exclusion of cases with extraneous factors that may have influenced the operative outcome, three groups of patients were identified: (1) interval laparoscopic sterilization unrelated to pregnancy (n=20,325); (2) postpartum laparoscopic sterilization (n=2233); (3) postpartum sterilization by minilaparotomy (n=5095). Intra-operative and post-operative complications were compared according to the surgical approach. RESULTS: A total of 27,653 patients were included in the study. The proportion of major complications was higher in group 3 than in group 1 (0.39% versus 0.10%, odds ratio 4.0, 95% CI 2.15-7.44, p<0.001) but not statistically different between groups 1 (0.10%) and 2 (0.18%). Minor complications were statistically significantly more frequent in group 3 (0.82%) than in group 1 (0.26%) or group 2 (0.27%). There was no case of intra-operative or post-operative death in the study population. CONCLUSION: When available, a laparoscopic approach should be chosen for female sterilization. After uneventful pregnancy course and delivery, it does not seem justified to delay the endoscopic sterilization to a later time.

Bibliographic study showed improving methodology of meta-analyses published in leading journals 1993-2002

OBJECTIVE: To assess the methodology of meta-analyses published in leading general and specialist medical journals over a 10-year period. STUDY DESIGN AND SETTING: Volumes 1993-2002 of four general medicine journals and four specialist journals were searched by hand for meta-analyses including at least five controlled trials. Characteristics were assessed using a standardized questionnaire. RESULTS: A total of 272 meta-analyses, which included a median of 11 trials (range 5-195), were assessed. Most (81%) were published in general medicine journals. The median (range) number of databases searched increased from 1 (1-9) in 1993/1994 to 3.5 (1-21) in 2001/2002, P<0.0001. The proportion of meta-analyses including searches by hand (10% in 1993/1994, 25% in 2001/2002, P=0.005), searches of the grey literature (29%, 51%, P=0.010 by chi-square test), and of trial registers (10%, 32%, P=0.025) also increased. Assessments of the quality of trials also became more common (45%, 70%, P=0.008), including whether allocation of patients to treatment groups had been concealed (24%, 60%, P=0.001). The methodological and reporting quality was consistently higher in general medicine compared to specialist journals. CONCLUSION: Many meta-analyses published in leading journals have important methodological limitations. The situation has improved in recent years but considerable room for further improvements remains.

Validation of candidate smear microscopy quality indicators, extracted from tuberculosis laboratory registers

SETTING: Kinshasa Province, Democratic Republic of Congo. OBJECTIVE: To identify and validate register-based indicators of acid-fast bacilli (AFB) microscopy quality. DESIGN: Selection of laboratories based on reliability and variation in routine smear rechecking results. Calculation of relative sensitivity (RS) compared to recheckers and its correlation coefficient (R) with candidate indicators based on a fully probabilistic analysis incorporating vague prior information using WinBUGS. RESULTS: The proportion of positive follow-up smears correlated well (median R 0.81, 95% credibility interval [CI] 0.58-0.93), and the proportion of first smear-positive cases fairly (median R 0.70, 95% CI 0.38-0.89) with RS. The proportions of both positive suspect and low positive case smears showed poor correlations (median R 0.27 and -0.22, respectively, with ranges including zero). CONCLUSIONS: The proportion of positives in follow-up smears is the most promising indicator of AFB smear sensitivity, while the proportion of positive suspects may be more indicative of accessibility and suspect selection. Both can be obtained from simple reports, and should be used for internal and external monitoring and as guidance for supervision. As proportion of low positive suspect smears and consistency within case series are more difficult to interpret, they should be used only on-site by laboratory professionals. All indicators require more research to define their optimal range in various settings.

Review of assessment, design, and mitigation of multiple hazards

Large parts of the world are subjected to one or more natural hazards, such as earthquakes, tsunamis, landslides, tropical storms (hurricanes, cyclones and typhoons), costal inundation and flooding. Virtually the entire world is at risk of man-made hazards. In recent decades, rapid population growth and economic development in hazard-prone areas have greatly increased the potential of multiple hazards to cause damage and destruction of buildings, bridges, power plants, and other infrastructure; thus posing a grave danger to the community and disruption of economic and societal activities. Although an individual hazard is significant in many parts of the United States (U.S.), in certain areas more than one hazard may pose a threat to the constructed environment. In such areas, structural design and construction practices should address multiple hazards in an integrated manner to achieve structural performance that is consistent with owner expectations and general societal objectives. The growing interest and importance of multiple-hazard engineering has been recognized recently. This has spurred the evolution of multiple-hazard risk-assessment frameworks and development of design approaches which have paved way for future research towards sustainable construction of new and improved structures and retrofitting of the existing structures. This report provides a review of literature and the current state of practice for assessment, design and mitigation of the impact of multiple hazards on structural infrastructure. It also presents an overview of future research needs related to multiple-hazard performance of constructed facilities.

Changing trends in causes and patterns of facial fractures in children

OBJECTIVE: To review the epidemiology of facial fractures in children and to analyze whether it has changed over time. STUDY DESIGN: Retrospective review of records of children aged < or = 15 years diagnosed for fracture during 2 10-year periods. RESULTS: A total of 378 children were diagnosed with fractures, 187 in 1980-1989 and 191 in 1993-2002. The proportion of children with mandibular fractures decreased by 13.6 percentage-points from the first period to the second, whereas the proportion of patients with midfacial fractures increased by 18.7 percentage-points. Assault as a causative factor increased by 5.5 percentage-points, almost exclusively among children aged 13-15 years, with a high percentage (23.5%). CONCLUSIONS: Recognition of a change in fracture patterns over time is probably due to the increased use of computerized tomographic scanning.

Mutation screening of the medium-chain acyl-CoA dehydrogenase (MCAD) and the ornithine transcarbamylase (OTC) genes by multiplex PCR amplification and sequencing

BACKGROUND: Sequencing based mutation screening assays of genes encompassing large numbers of exons could be substantially optimized by multiplex PCR, which enables simultaneous amplification of many targets in one reaction. In the present study, a multiplex PCR protocol originally developed for fragment analysis was evaluated for sequencing based mutation screening of the ornithine transcarbamylase (OTC) and the medium-chain acyl-CoA dehydrogenase (MCAD) genes. METHODS: Single exon and multiplex PCR protocols were applied to generate PCR templates for subsequent DNA sequencing of all exons of the OTC and the MCAD genes. For each PCR protocol and using the same DNA samples, 66 OTC and 98 MCAD sequence reads were generated. The sequences derived from the two different PCR methods were compared at the level of individual signal-to-noise ratios of the four bases and the proportion of high-quality base-signals. RESULTS: The single exon and the multiplex PCR protocol gave qualitatively comparable results for the two genes. CONCLUSIONS: Many existing sequencing based mutation analysis protocols may be easily optimized with the proposed method, since the multiplex PCR protocol was successfully applied without any re-design of the PCR primers and other optimization steps for generating sequencing templates for the OTC and MCAD genes, respectively.

Variation in precursor lesions of pancreatic cancer among high-risk groups

PURPOSE Pancreatic ductal adenocarcinoma (PDAC) surveillance programs are currently offered to high-risk individuals aiming to detect precursor lesions or PDAC at an early stage. We assessed differences in frequency and behavior of precursor lesions and PDAC between two high-risk groups. EXPERIMENTAL DESIGN Individuals with a p16-Leiden germline mutation (N = 116; median age 54 years) and individuals from familial pancreatic cancer (FPC) families (N = 125; median age 47 years) were offered annual surveillance by MRI and magnetic resonance cholangiopancreatography (MRCP) with or without endoscopic ultrasound (EUS) for a median surveillance period of 34 months (0-127 months) or 36 months (0-110 months), respectively. Detailed information was collected on pancreatic cystic lesions detected on MRCP and precursor lesions in surgical specimens of patients who underwent pancreatic surgery. RESULTS Cystic lesions were more common in the FPC cohort (42% vs. 16% in p16-Leiden cohort), whereas PDAC was more common in the p16-Leiden cohort (7% vs. 0.8% in FPC cohort). Intraductal papillary mucinous neoplasm (IPMN) was a common finding in surgical specimens of FPC-individuals, and was only found in two patients of the p16-Leiden cohort. In the p16-Leiden cohort, a substantial proportion of cystic lesions showed growth or malignant transformation during follow-up, whereas in FPC individuals most cystic lesions remain stable. CONCLUSION In p16-Leiden mutation carriers, cystic lesions have a higher malignant potential than in FPC-individuals. On the basis of these findings, a more intensive surveillance program may be considered in this high-risk group.