Traditional non-steroidal anti-inflammatory drugs (NSAIDs) are a widely used class of therapy in the treatment of chronic pain and inflammation. The drugs are effective and can be relatively inexpensive thanks to available generic versions. Unfortunately the traditional NSAIDs are associated with gastrointestinal complications in a small proportion of patients, requiring costly co-therapy with gastro-protective agents. Recently, a new class of non-steroidal anti-inflammatory agents known as coxibs has become available, fashioned to be safer than the traditional NSAIDs but priced considerably higher than the traditional generics. To help physicians choose appropriately and cost-effectively from the expanded number of anti-inflammatory therapies, scientific bodies have issued clinical practice guidelines and third party payers have published restricted reimbursement policies. The objective of this study is to determine whether an educational intervention can prompt physicians to adjust their prescribing in accordance with these expert recommendations.This is an ongoing, randomized controlled trial. All primary care physicians in Manitoba, Canada have been randomly assigned to a control group or an intervention study group. The educational intervention being evaluated consists of an audit and feedback mechanism combined with optional participation in a Continuing Medical Education interactive workshop. The primary outcome of the study is the change, from pre-to post-intervention, in physicians' appropriate prescribing of non-steroidal anti-inflammatory therapies for patients requiring chronic treatment. Three classes of non-steroidal anti-inflammatory therapies have been identified: coxib therapy, traditional NSAID monotherapy, and traditional NSAID therapy combined with gastro-protective agents. Appropriate prescribing is defined based on international clinical practice guidelines and the provincial drug reimbursement policy in Manitoba. Traditional non-steroidal anti-inflammatory drugs (NSAIDs) are a widely prescribed class of therapy used to relieve pain and inflammation. The drugs have been shown to be effective for a variety of common disorders (hence their widespread use), most notably chronic osteoarthritis and rheumatoid arthritis. They are relatively inexpensive due to the available generic versions, but unfortunately have clinically important drawbacks related to their gastrointestinal (GI) toxicity . Each yeIn the last five years, a new class of non-steroidal anti-inflammatory agents has become available to physicians, fashioned specifically to be safer than the traditional NSAIDs but priced at least two to three times higher than the generic versions of traditional NSAIDs . The newTo assist physicians in selecting from the different classes of anti-inflammatory agents, various scientific bodies have published clinical guidelines and third party payers have issued restricted reimbursement criteria -24. ThesWith these guidelines and policies on prescribing in place, it is now important for physicians to adjust their prescribing practices accordingly. This is true both for rheumatology specialists and for physicians in the primary care setting where osteoarthritis patients are frequently managed. Unfortunately, experience and educational research show that simply making guidelines available does not elicit behavioural change from physicians -33. In tThe current use of anti-inflammatory drugs suggests a need for strategies that will prompt physicians to change their prescribing practice in accordance with the expert recommendations. Preferably, strategies should be investigated that have proved successful at altering physician behaviour in other settings.In this paper, we describe a randomized controlled study, which we are presently conducting, to evaluate the impact of an educational intervention on primary care physicians' prescribing of non-steroidal anti-inflammatory therapies. The study, being conducted in the province of Manitoba, Canada, tests the hypothesis that this intervention will significantly improve physician appropriate prescribing of anti-inflammatory drugs in compliance with international clinical practice guidelines and Manitoba's restricted drug reimbursement policy -22. The MAAUI is a province-wide population-based study. All primary care physicians  registered with the College of Physicians and Surgeons of Manitoba and practicing in Manitoba since July 1995 were eligible to enter MAAUI. The study excluded residents, new physician graduates, physicians registered as specialists, and physicians who started practicing in the province of Manitoba after July 1995. The eligible study population thus totalled approximately 884 physicians.All eligible physicians were automatically entered into the MAAUI protocol. Physicians who were randomized to intervention group of the research were given the option to withdraw from the study. Six family physicians who agreed to act as facilitators for the MAAUI CME workshop were not included in the study population.The MAAUI study design is depicted in Figure This study design was chosen for several reasons. First, it offered the scientific rigour that is associated with randomization and the use of a control group. It also ensured that both rural and urban Manitoban physician groups had an equal opportunity to take part in and learn from the study intervention. The study design was also particularly amenable to testing an intervention that required physicians to congregate in common locations (i.e. for the CME workshop). The 1:2 ratio of study groups helped to ensure that there were a sufficient number of study participants who would consider attending the CME workshops.Physicians allocated to the intervention arm of MAAUI were mailed a package that included an introduction to the study, audit and feedback material, and an invitation to participate in a CME workshop. Physicians in the control arm received no package.The audit and feedback material consisted of a "Personalised Prescribing Profile"  at the University of Manitoba, using administrative data from the Population Health Research Data Repository. This repository contains anonymized encounter-based records of individuals' interactions with the provincial health care system and is derived from information received by the Department of Health, Province of Manitoba, as part of the routine provision of health care in the province. The repository includes Physician Registry files, Medical Claims and Hospital discharge files, as well as Drug Programs Information Network (DPIN) files. The DPIN contains records of all drugs dispensed by Manitoba pharmacies, regardless of who is responsible for payment.Because of the sensitive nature of the Personalised Prescribing Profiles, the individualized profiles were not seen by the MAAUI research team. Instead the packages containing the profiles were assembled and mailed out by Manitoba Health with the assistance of an independent researcher, hired by the MAAUI research team, who signed a confidentiality agreement with Manitoba Health.The CME workshop for MAAUI was entitled "The Utilization and Prescribing of Anti-inflammatory Drugs in Osteoarthritis". The workshop focused specifically on the prescribing for osteoarthritis, as it was felt that people with this disease account for a large proportion of the chronic non-steroidal anti-inflammatory use by primary care practices .Eleven CME workshops were held throughout Manitoba (four within Winnipeg and seven outside of Winnipeg) and physicians in the intervention group were invited to voluntarily attend one of the 11. The workshops were free of charge and were approved for 3.0 hours of MAINPRO-M1 credits (continuing education credits awarded by the College of Family Physicians of Canada for group learning activities). Each workshop was facilitated by a trained family physician.The workshops included three components: an introductory video, a decision tree, and a case study portion. The introductory video provided the history and rationale of MAAUI, explained aspects of the Personalised Prescribing Profile, and introduced the decision tree. The decision tree depicted a stepwise approach to the diagnosis and treatment of osteoarthritis. This aid was designed by a rheumatologist on the MAAUI research team specifically for use in the study and was based on international clinical practice guidelines and Manitoba's drug reimbursement policy -22. A taThe overall MAAUI educational intervention, including both the audit and feedback material and the optional CME interactive workshop, was chosen by the MAAUI research team based on the success of similar interventions in the past. Audit and feedback mechanisms have shown moderate success in changing physician behaviour in past studies . EquallyThe primary goal of MAAUI is to evaluate the impact of the educational intervention on physician appropriate prescribing of non-steroidal anti-inflammatory therapies for patients requiring long-term treatment. To this end, four principal outcome measures have been developed:• the change in appropriate prescribing of all non-steroidal anti-inflammatory therapy  from pre-to post-intervention;• the change in appropriate prescribing of coxibs from pre-to post-intervention;• the change in appropriate prescribing of traditional NSAID/GPA combination therapy from pre-to post-intervention; and• the change in appropriate prescribing of traditional NSAID monotherapy from pre-to post-intervention.st 2001 to March 31st 2002) minus this rate during a 10-month period immediately pre-intervention . The rate of appropriate prescribing will be defined as the number of patients prescribed long-term treatment in whom the treatment was appropriate, divided by the total number of patients prescribed long-term treatment, multiplied by 100%. Otherwise expressed:These primary outcomes will be evaluated at the level of the individual physician and will be calculated using administrative data similar to that used to create the Personalised Prescribing Profiles. The change in appropriate prescribing (AP) for a given physician will be calculated by the physician's rate of appropriate prescribing during a 6-month period post-intervention . A separate focus group will be held for the workshop facilitators.st, 2000 to July 31st, 2001) as control measurements: i) physician demographics including sex, urban or rural practice location, and the number of years in practice; ii) physician volume of non-steroidal anti-inflammatory therapies prescribed annually for patients requiring chronic therapy; and iii) physician rate of appropriate prescribing of NSAIDs. These latter two measures were assessed for each of coxibs, traditional NSAID/GPA combination therapy, and traditional NSAID monotherapy.The following data were collected at baseline  on the steering committee, which is the governing body responsible for approving all aspects of study development and implementation. Merck Frosst will not participate in data analysis and will not have access to confidential individual patient or physician data.AK, CM, and GT have received speaking fees from Merck Frosst Canada. KR is the scientific writer for this manuscript, employed by the PHCRU.All of these competing interests were not specifically disclosed to study participants. Merck Frosst's sponsorship of the study, however, was disclosed in the consent form signed by participants at the MAAUI CME workshops.MD, AK, BK, and CM conceived of the study. MD, AK, L-JM, CM, and GT contributed to the development of the protocol. GT created the decision tree and list of criteria for appropriate prescribing. GT also chaired the MAAUI project steering committee. LM is project managing the study. KR performed the literature review for this manuscript and wrote the first draft and coordinated all subsequent revisions. All authors approved the final manuscript.The pre-publication history for this paper can be accessed here:Decision Tree: take-home copyThe decision tree was a component of the MAAUI CME workshop. Physicians were introduced to the decision tree during the workshop and were provided with a two-sided take-home copy. The decision tree depicts a stepwise approach to the diagnosis and treatment of osteoarthritis. a/ Side 1. b/ Side 2. Of note, on side 2 of the decision tree the term "NSAID" denotes traditional NSAIDs.click here for file


Computational protein annotation methods occasionally introduce errors. False-positive (FP) errors are annotations that are mistakenly associated with a protein. Such false annotations introduce errors that may spread into databases through similarity with other proteins. Generally, methods used to minimize the chance for FPs result in decreased sensitivity or low throughput. We present a novel protein-clustering method that enables automatic separation of FP from true hits. The method quantifies the biological similarity between pairs of proteins by examining each protein's annotations, and then proceeds by clustering sets of proteins that received similar annotation into biological groups.Using a test set of all PROSITE signatures that are marked as FPs, we show that the method successfully separates FPs in 69% of the 327 test cases supplied by PROSITE. Furthermore, we constructed an extensive random FP simulation test and show a high degree of success in detecting FP, indicating that the method is not specifically tuned for PROSITE and performs well on larger scales. We also suggest some means of predicting in which cases this approach would be successful.Automatic detection of FPs may greatly facilitate the manual validation process and increase annotation sensitivity. With the increasing number of automatic annotations, the tendency of biological properties to be clustered, once a biological similarity measure is introduced, may become exceedingly helpful in the development of such automatic methods. Computational protein annotation is a major goal of bioinformatics and annotation methods are widely used. A wide variety of annotation methods exist, many of which rely on some kind of scoring. Typically, when testing whether a protein should be given a certain annotation, a score threshold is set, and proteins that score higher than the threshold are given the annotation. Obviously, some annotation mistakes may occur. Such mistakes can be divided into false positives (FPs) and false negatives (FNs). FPs  are annotations that were mistakenly assigned to a protein (type I error). FNs (or misses) are annotations that should have been assigned to a protein but were not (type II error). Adjustment of score thresholds allows tradeoff between these two types of mistakes. FPs annotations are considered to be of graver consequence than FNs. This is partially due to the fact that introduction of a false positive annotation into a protein database may cause other proteins to become incorrectly annotated on the basis of sequence similarity ,2. A sysDue to the importance of minimizing the amount of false annotations and maintaining highly reliable protein databases, three methods are generally used to avoid false annotations. The first method is manual validation of the annotation of each protein, which creates a serious bottleneck in the addition of new proteins and annotations to the database. The second method is using high score thresholds, thus lowering the rate of FPs but also increasing the rate of FNs (resulting in a loss of sensitivity). The third method is requirement for hits from different detection methods, eliminating advantages that are unique to some methods. Thus it would be beneficial to develop means by which FP annotations could be detected automatically, allowing both high throughput and high sensitivity.Here we present such a method that uses clustering of protein functional groups to separate true positives (TPs) from FPs automatically. Our method is based on the following notions: (a) protein annotations represent biological properties; (b) protein functional groups share specific combinations of biological properties, essentially constituting "property clusters"; (c) if two proteins have very different combinations of annotations, they are unlikely to share a single functional annotation and therefore there is a high chance that one of them was given that annotation incorrectly. These notions are not obvious, but were shown to correctly indicate false annotations in some individual cases tested manually using the graphical annotation-analysis tool of PANDORA . We aim Using these ideas, the method attempts to separate a group of proteins into "property clusters", by introducing a measure that quantifies the similarity between the annotation combinations of two proteins. According to our basic notions, these clusters are likely to be in accordance with false and true hits.all the TPs were clustered together without any FPs. We applied a stringent scoring, where a partial success is considered failure.We tested our method on the PROSITE protein signature database . The datFurthermore, we constructed a random FP simulation test in order to provide a more extensive test. In this test, all 5,551 InterPro  annotatiWe begin by describing the method of property-based clustering. Given a set P of all proteins that were given a certain annotation, and that there are both FPs and TPs in P, we would like to separate the set into disjoint subsets, so that one of the subsets will include all TPs and no FPs (leaving one or more subsets containing the FPs).Annotation-based clustering is used to detect these subsets. We define an annotation as a binary property assigned to a protein (each protein may or may not have a "hit"). At the first stage, annotations from GO (Gene Ontology) , InterPrp1 and p2 is defined as:The clustering works in the following way: between each two proteins we define a similarity score that tries to quantify how much do the two proteins have in common from a biological perspective. The score between two proteins A1 and A2 are the set of annotations of proteins p1 and p2 respectively, i is the current annotation, and f(i) is the frequency of i in the database. This score uses the following logic: if two proteins share an annotation, they are biologically similar in some manner. The more annotations these proteins share, the more cause we have to believe that they are similar biologically. However, two proteins sharing an annotation like "Enzyme"  should receive a worse similarity score than two proteins that share a much uncommon annotation like "Heat Shock Protein" (that appears only 832 times). This is taken into account by using log(f(i)). Obviously, one could think of different scoring schemes that would quantify this differently. For a specific example of how the score is calculated see Table where The similarity score is calculated between every two proteins in P. Next, we define the similarity score between two clusters as the arithmetic average of scores of all inter-cluster protein pairs:C1 and C2 are clusters of proteins. Starting with clusters of 1 protein each, the method begins by an initial one-step clustering which merges all clusters that have the exact same combination of annotations. Following this the primary clustering commences: At each clustering step the two clusters that have the highest similarity score are merged. At each step the contents of the clusters are evaluated, and if all TP proteins appear in one cluster without any FPs, we say that the clustering process successfully separated the TPs from the FPs. Note that we do not require all the FPs to be grouped into one cluster, due to the fact that they cannot be expected to share biological similarity amongst themselves.where Out of 327 sets of proteins that share a PROSITE signature, the method showed successful separation (as defined previously) in 227 sets, i.e. 69% of the cases. The average size of the protein sets was 156.1 and the median 76. Altogether 58,254 proteins were used for this test. The average and median FP rates (FP rate is defined as: FP/(TP+FP)) of the sets were 0.12 and 0.07 respectively. These general statistics about the test set indicate that the sets were large enough and had a high enough amount of TPs and FPs so that the chance of random success would be minimal.In order to demonstrate the method's performance in this test, we provide the following example of testing a single protein set. The set presented here is the set of all 37 proteins that matched the PROSITE "Serum albumin family" signature. Each protein in the set contains an average of 18.2 annotations . First, the score between every pair of proteins is calculated, based on their mutual annotations. Next, the proteins undergo a preliminary clustering step in which all proteins that have the exact same combination of annotations are merged into clusters. Following this, the proteins are clustered together based on their mutual similarity score. Finally, once the clustering has finished we examine the tree to see if the true positives were separated from the false positives. In the given example, there are 5 proteins that were incorrectly assigned the PROSITE annotation (FPs), and in Figure 5,551 sets of proteins were tested 15 times each and showed successful separation in 74% of the cases. Altogether 99,076 proteins were used for this test. This can be subdivided into 78% success for the sets that had 1 random protein added, 74% success for the sets that had 5 random proteins added and 68% for the sets that had 10 random proteins added. The average set size was 78 proteins. The drop in the performance by increasing the level of FPs is due to the fact that there is a higher chance that one of the randomly selected proteins will be biologically similar to the TPs. Since we consider only cases in which all FPs are detected, then there would be a higher chance of failure as the number of randomly-generated FPs increases.While the simulation of FP errors randomly provides endless amounts of test sets, which is a clear advantage over the limited test sets provided by a real database such as PROSITE, the simulation has its own limitations. The hidden assumption made by this approach is that the FP hits are independent of each other. This assumption is not necessarily true: for example, if annotation is done by means of sequence similarity, false hits may be more likely to be biologically similar to each other (e.g. belong to the same family). In fact, in many cases in the PROSITE test we find that the correct separation separates the TP proteins into one cluster and the FP into one or two clusters, suggesting that the FPs share some degree of biological similarity . This difference in the way that FP annotations are generated may also account for the difference in success rates between the PROSITE test set and the simulated test set. The way FP annotations are introduced into databases is impossible to model, but the combined success of the method on both a real database test set and on an extensive simulated test set seems promising.A further issue which concerns the simulation method is determining the amount of FPs to add to each set. Here we chose to add 1, 5 or 10 proteins to each set. This does not necessarily reflect the amount of FPs in real databases. Understandably, each database's average FP rate depends on its specific characteristics. However, the PROSITE database's average FP rate of 0.12 (median of 0.08) might give an indication as to what a typical rate is. In comparison, the average FP rate for our random simulation set was 0.11 (median of 0.07), which suggests that our choice was reasonable.We call a clustering process successful if it managed at any step to separate the false annotations. However, this step must be somehow determined automatically. There are two approaches to this: one is to use an intrinsic parameter of the clustering process that would indicate where the correct halting step is located; the other is selecting a predetermined step of the process. We chose the similarity score at each merging step as an intrinsic process parameter. When plotting the score against the progression of the clustering Figure , a knee Interestingly, we found that with certain sets the method tended to be more successful than with other sets, probably indicating that these sets are more coherent biologically. This might suggest exploring an approach in which for each annotation one could predict the level of success provided by this method. Furthermore, we used the InterPro categorization of annotations into types in order to check success in specific annotation types. InterPro divides its annotations into different categories, such as "domain", "repeat" and "family". Understandably, "family" type annotations had a ~30% higher success rate than the other annotation types, primarily due to the fact that the "family" annotations often represent protein sets that are biologically coherent whereas other types such as "repeat" or "domain" annotations are biologically diverse. This result would be expected by a method that performs a clustering based on biological similarity. This indicates that this approach should be aimed primarily at functional family annotations.However, functional families can be defined at different resolutions: an alcohol dehydrogenase belongs to the enzyme family, the dehydrogenase family and the alcohol dehydrogenase family. The test sets of the PROSITE and InterPro databases mainly represent mid-level and low-level annotations, with a typical size of tens or a few hundreds of proteins (see the statistics given previously). In order to further our understanding of the resolution in which this method is successful, we divided the protein groups into size categories and studied the relative amount of success in every size category. Figure Because multiple annotation sources were used, concerns arose regarding interdependencies amongst them. For example, InterPro is highly dependent on PROSITE, so proteins that have a PROSITE annotation will very likely be assigned an InterPro annotation as well automatically. In order to minimize this effect, we did not allow the algorithm to use the InterPro annotations that matched the PROSITE annotation which was being tested. Furthermore, in order to increase reliability of the random FP simulation test, all known PROSITE FPs were removed from InterPro prior to the test. Still, there is some concern that the results are partially biased due to annotation source interdependencies. Furthermore, it is difficult to determine whether these dependencies represent true biologically dependent properties, or simply a duplication of the same property in different sources. Keeping this difficulty in mind, our results which show different levels of success for different types of annotations (see "Prediction of success") indicate that the success of the method is more likely due to biological dependency rather than artificial duplication.It should be stressed that the clustering process is based on sufficient annotation. Therefore, it may be difficult to apply this method to proteins that are poorly annotated. Still, these cases should be relatively rare: Nearly 77% of the ~1,600,000 proteins in TrEMBL  have at It is worthwhile noting that amongst the 58,254 proteins used in these sets there were 3,587 (6%) proteins annotated by SwissProt as "hypothetical proteins". 18% of the sets that were successfully separated contained such hypothetical proteins, with an average of 8% hypothetical proteins for each such set. These results suggest that the method is capable of handling to some extent hypothetical proteins of unknown function.Another helpful approach to the problem of insufficient annotation could be the introduction of quantitative protein properties that are easily determined and show some correlation with function  into this method. Preliminary testing showed some positive correlation between protein length and Isoelectric point with function in certain cases (not shown).Introduction of FP annotations into protein databases can be harmful. It has been shown that once a mistaken annotation is introduced into a database, it often transfers to other proteins that are sequentially similar causing a propagation of false annotation . Due to Based on the notion that protein functional groups share specific combinations of annotations, we have introduced a method that by separating a set of proteins into biological "property clusters" shows successful separation of incorrectly annotated proteins from correctly annotated proteins. We test the method both with a manually validated test set and with a randomly constructed test set, and in both cases show a high degree of success. These results suggest that this tendency of certain annotations to appear in groups may be used as a basis of automatic methods that detect FPs. Naturally, different computer learning methods can be used to take advantage of these interdependencies of biological properties (for example see ).We created a database that includes all proteins from SwissProt 40.28  . The datAnnotation source and the number of annotation for each (in parenthesis) are: SwissProt version 40.28 (865 keywords), InterPro version 5.2 , GO as of July 2002 , PROSITE version 17.5 .NK and ML conceived of the study. NK designed the method. NK implemented and developed the method. NK designed the tests and analyzed the results. NK and ML wrote the manuscript.


Hepatitis C virus (HCV) infection is a significant problem among patients undergoing maintenance hemodialysis (HD). We conducted a prospective multi-center study to evaluate the effect of dialysis machine separation on the spread of HCV infection.Twelve randomly selected dialysis centers in Tehran, Iran were randomly divided into two groups; those using dedicated machines (D) for HCV infected individuals and those using non-dedicated HD machines (ND). 593 HD cases including 51 HCV positive (RT-PCR) cases and 542 HCV negative patients were enrolled in this study. The prevalence of HCV infection in the D group was 10.1% (range: 4.6%– 13.2%) and it was 7.1% (range: 4.2%–16.8%) in the ND group. During the study conduction 5 new HCV positive cases and 169 new HCV negative cases were added. In the D group, PCR positive patients were dialyzed on dedicated machines. In the ND group all patients shared the same machines.In the first follow-up period, the incidence of HCV infection was 1.6% and 4.7% in the D and ND group respectively (p = 0.05). In the second follow-up period, the incidence of HCV infection was 1.3% in the D group and 5.7% in the ND group (p < 0.05).In this study the incidence of HCV in HD patients decreased by the use of dedicated HD machines for HCV infected patients. Additional studies may help to clarify the role of machine dedication in conjunction with application of universal precautions in reducing HCV transmission. Hepatitis C virus (HCV) transmission occurs mainly through large or repeated direct percutaneous punctures to blood vessels; for example repeated injections for drug abuse . Less frMolecular virological studies have clearly shown the nosocomial transmission of HCV to hemodialysis patients,,17 but tAmong 40 HD centers in Tehran, we randomly selected centers one by one to reach a total number of 593 patients (12 centers) to enroll in this study. Selected centers were randomly divided in to dedicated (D) and non-dedicated (ND) HD machine groups, including 297 patients in D (4 centers) and 296 patients in ND group (8 centers). ELISA III checked all patients for HCV antibody detection before enrolling in the study. Positive cases were confirmed by RT-PCR. Only patients who were HCV positive by RT-PCR were considered to be HCV infected. Out of 593 HD cases 51 were RT-PCR positive (30 in the D groups and 21 in the ND group), and 542 were HCV negative (267 in the D group and 275 in the ND group). The prevalence of HCV infection in the D group was 10.1% (range: 4.6%– 13.2%) and was 7.1% (range: 4.2%–16.8%) in ND group. During the study conduction, 5 new HCV positive cases (1 in D group and 4 in ND group) and 169 new HCV negative cases entered the study. Information regarding age, sex, occupation , HCV infected relatives, previous peritoneal dialysis, surgery during last 2 months, duration of hemodialysis, number of blood product transfusions, history of organ transplantation, and the causes of ESRD was collected. The obtained history of IV drug abuse, tattooing, and multiple sex partners was not reliable.442 patients (254 cases in the D and 192 in the ND group) were followed for 9 months (first follow up population). 281 patients (160 cases in the D and 121 cases in the ND group) who remained within our study were followed for an additional 9 months (Second follow up population). Histories of surgeries or blood product transfusion were obtained at each follow-up; with no significant difference found between the D and the ND groups. There were no significant differences between the D and the ND groups in the number of patients lost to follow-up due to death, renal transplantation or transfer to a different hospital change (data not shown).Patients were dialyzed for 4 or 4.5 hours, 2 or 3 times weekly, using standard HD techniques by Cuprophane and Polysulfone dialyzers. All included HD patients were HIV and HBs-Ag negative. Dialysis membranes were low-pressure and used only once and HD machines were bleached and rinsed between dialysis sessions according to the manufacturers' instruction. Socioeconomic level was essentially similar between D and ND groups. The only difference between two groups of HD centers was that in-group D, HCV positive patients were assigned to a dedicated HD machine, but in-group ND, HD HCV positive and negative patients were not assigned to dedicated machines. All machines were located in dialysis wards and not in separate rooms in both groups.Patient to staff ratio in the D and the ND groups was not statistically different (3.1 and 3.4 respectively) and all staff members were negative for anti-HCV. To prevent HCV transmission, educational courses were held for the staff to reemphasize the CDC hygienic guidelines; however, an interview of all nurses directly involved in patient care disclosed some deviation from CDC hygienic guidelines. The minority of nurses remembered situations when they had failed to change their gloves due to an urgent adjustment of a hemodialysis machine. A checklist was used respecting hemodialysis-specific infection control practices and new gloves were applied for each individual patient. Nevertheless, masks, aprons and protective glasses were not universally used. In all centers, all patients had specific dialysis stations assigned to them, and chairs and beds were cleaned after each use. Handling and storage of medications and hand washing were not done in the same or adjacent areas to those where used equipment or blood samples were handled. One of the ND centers was excluded from the study due to non-adherence to CDC hygienic guidelines in the first months of the study.Statistical analysis was performed using SPSS 10.5 software. Comparisons between groups were made by the chi-square test method for categorical variables and by the t-test for quantitative variables.The mean age was 49.5 years (range from 12–84), 58.7% were male, and the mean HD duration was 21.6 months. The etiology of end-stage renal disease was hypertension in 36% followed by diabetes in 28% and glomerulonephritis in 10.5%. 15.5% of patients in the dialysis centers had a one-time history of kidney transplantation, and 2.2% had undergone transplantation twice. The demographic data for two groups is illustrated in table In the first follow-up period, the incidence of HCV infection was 1.6% and 4.7% in the dedicated and the non-dedicated groups (p = 0.05). In the second follow-up period, the incidence was 1.3% in the dedicated and 5.7% in the non-dedicated groups (p < 0.05) table .The possibility of an intradialytic spread of HCV appeared to be very low and the treatment of HCV infected patients with dedicated machines was not strictly required -26. AlthSome authors recommended that it is sufficient to treat every dialysis patient as potentially infectious, strictly adhering to the "universal precautions for prevention of HCV transmission", to prevent the spread of HCV in dialysis units ,33 and iIn our study population, the prevalence of HCV infection was approximately the same in both groups at the beginning of the study, but significantly lower incidence of HCV infection in D group may show that machine dedication strategies can be effective to reduce HCV transmission at least in our HD centers.Considering the prevalence of HCV infection and adherence to adequate infection control measures, HD machine dedication may help to decrease transmission of HCV infection in our dialysis units.However rigorous implementation of precaution measures remains a cornerstone for prevention of HCV transmission among patients undergoing maintenance hemodialysis, but as unpredictable accidents can always take place in hemodialysis units; machine dedication may play a more important role in prevention of HCV transmission. Further studies are needed to evaluate the possible roles of machine dedication in the presence of strict adherence to hygienic precautions.Dr AA Shamshirsaz designed the draft questionnaires and study protocol, managed the coordination of the surveys and drafted the manuscript. . Dr. Kamgar participated in drafting the manuscript and data collection, coordinated the study and designed the protocol. Dr Bekheirnia conceived of and designed the study, performed the statistical analysis, drafted the manuscript and helped design the protocol. Dr Bouzari helped draft the manuscript, participated in statistical analysis and managed paraclinical surveys. Dr Habibzadeh drafts the manuscript, participated in statistical analysis and helped in data collection and physical examination. Dr Pourzahedgilani participated in physical exam, filled out questionnaires and searched scientific sources. Dr V Broumand participated in drafting the manuscript. Dr Moradi participated in statistical analysis. Dr. Ayazi, Dr. Hashemi, Dr. A.H Shamshirsaz, Dr. Borghei and Dr. Haghighi took part in physical exams and filling questionnaires. Dr. B Broumand facilitated the study design and progress.The pre-publication history for this paper can be accessed here:


Many Canadian cities are experiencing ongoing infectious disease and overdose epidemics among injection drug users (IDUs). In particular, Human Immunodeficiency Virus (HIV) and hepatitis C Virus (HCV) have become endemic in many settings and bacterial and viral infections, such as endocarditis and cellulitis, have become extremely common among this population. In an effort to reduce these public health concerns and the public order problems associated with public injection drug use, in September 2003, Vancouver, Canada opened a pilot medically supervised safer injecting facility (SIF), where IDUs can inject pre-obtained illicit drugs under the supervision of medical staff. The SIF was granted a legal exemption to operate on the condition that its impacts be rigorously evaluated. In order to ensure that the evaluation is appropriately open to scrutiny among the public health community, the present article was prepared to outline the methodology for evaluating the SIF and report on some preliminary observations. The evaluation is primarily structured around a prospective cohort of SIF users, that will examine risk behavior, blood-borne infection transmission, overdose, and health service use. These analyses will be augmented with process data from within the SIF, as well as survey's of local residents and qualitative interviews with users, staff, and key stakeholders, and standardised evaluations of public order changes. Preliminary observations suggest that the site has been successful in attracting IDUs into its programs and in turn helped to reduce public drug use. However, each of the indicators described above is the subject of a rigorous scientific evaluation that is attempting to quantify the overall impacts of the site and identify both benefits and potentially harmful consequences and it will take several years before the SIF's impacts can be appropriately examined. Many Canadian cities are currently experiencing Human Immunodeficiency Virus (HIV) and hepatitis C virus (HCV) epidemics as a result of illicit injection drug use ,2. OtherIn over two dozen European cities and more recently in Sydney, Australia, safer injection facilities (SIFs), where injection drug users can inject pre-obtained illicit drugs, have been implemented in an effort to reduce the community and public health impacts of illicit drug use . SIF typWhile it must be stressed that limited quantitative data are presently available, various reports have credited SIFs with a number of public health and community benefits including: improving the health and social functioning of their clients , while rOn September 22, 2003 Vancouver, Canada opened North America's first government sanctioned SIF pilot study . FederalPrior to the opening of the SIF, a major concern with the evaluation related to willingness of the target community to use the injection facility . In ordeIn brief, the aims of Insite are to reduce public injection drug use and the unsafe disposal of syringes in public spaces, the reduction of overdoses and infectious disease risk, and improve access to healthcare services among IDUs. The methodology for evaluating these aims is described below and involves both a prospective cohort design and additional data sources including evaluation of community impacts.The framework for the Vancouver SIF evaluation was designed prior to the SIF's opening and involved a number of methodological approaches. In light of the lack of existing quantitative efficacy data , the exiThe Vancouver SIF evaluation is somewhat unique because of the availability of a number of pre-existing data sources. These data sources include the community health and safety evaluation (CHASE) cohort, which is a community recruited virtual cohort of Downtown Eastside residents that prospectively and retrospectively examines health service use in the community by linking to administrative health record databases. In addition, the Vancouver Injection Drug Users Study (VIDUS) is an ongoing prospective cohort study of injection drug users that involves semi-annual serology of HIV and HCV as well as a semi-annual questionnaire . VIDUS ap > 0.05).In addition, in order to augment these data sources and to allow for close examination of the characteristics of Insite clients over time, a prospective cohort of Insite users has also been established. The Scientific Evaluation of Supervised Injecting (SEOSI) cohort is based on a representative sample of Insite users. The sample is derived through random recruitment of Insite users who are offered an informed consent to enroll into the study. Random recruitment involves attending the SIF at times of the day that are randomly selected using a random number generation program in SPSS, and inviting all users who use the SIF at this time to enroll in the study. As with VIDUS, participants provide a blood sample and conduct an interviewer-administered questionnaire. The SEOSI questionnaire deals with items that are particularly relevant to Insite, such as risk behaviours, public drug use, satisfaction with Insite, and access to medical care and addiction treatment services. All SEOSI participants provide informed consent to link to the Insite database so that SIF use can be tracked, as well as informed consent to access administrative health record databases in the community. As of September 1, 2004 over 900 Insite users have been enrolled into SEOSI and comparisons of socio-demographic variables  has shown that the SEOSI cohort is statistically similar to the overall cohort of insight users ; Reliability ; Responsiveness ; Assurance ; and Empathy . Similarly, reasons for avoiding the service are measured among IDUs in VIDUS who have not used Insite.These above prospective cohort data will be augmented by a number of other data sources including: process indicators, measures of community satisfaction and perceived impact, standardized measures of public order, and qualitative and quantitative measures of the health of the target population. The collection of each of these data sources is described below.In order to track service use in the database at an individual level, while allowing for participant anonymity, each client must select a unique client 'handle' or nickname. The SIF database has a search function that allows for rapid searches based on demographic information, such as birth date, if an individual forgets their handle. Similar anonymous tracking of individual clients is commonly used at needle exchanges and other services for illicit injection drug users .A primary purpose of the evaluation is to measure process indicators related to service uptake within the SIF, and this is enabled through the Insite database. The database tracks what drugs participants are consuming  and what services, such as nursing care and counseling services, are accessed by each client. For instance, in the month of May 2004, over 1300 unique visits were logged into the database.Community satisfaction and the perceived impact of the SIF on business persons are measured through a community survey that is performed in person among street recruited residents and at street-level businesses. The survey is similar to surveys being used in the Sydney SIF trial, and examines perceived changes in the neighborhood after the SIF's opening. In addition, staff satisfaction with the operation of the facility is measured through focus groups and qualitative interviews with staff persons. These interviews focus on how service delivery can be improved and on what measures can be taken to ensure staff safety and satisfaction.Standardized measures of public order were undertaken to examine the impact of the SIF on several indicators of public injection drug use. In brief, the survey protocol involves measuring specified public order indicators within an a priori defined geographical area in the neighborhood and at a priori defined times of the week. Data collection times are spread evenly throughout the week and involved walking through the study zone in the same pattern. Measures of discarded syringes, injection-related litter, and public injection drug use are all measured prospectively. An evaluation of these indicators has recently been described in detail .Following the opening of the SIF in September 2003, there was widespread support among the target population with a steady increase in uptake during the first few weeks. The site reached virtual capacity within two months and currently an approximate average of 500 injections take place each day in the site. The busiest times of the day are mid-afternoon and early evening at which times demand often exceeds capacity and waiting times to get into the 12 seat injection room can result in participants obtaining syringes and injecting elsewhere. Whether the wait times are disproportionately affecting specific populations is presently being investigated. Utilization also fluctuates daily, peaking on the days leading up to, and following welfare day. Exit surveys of IDU clients have been widely supportive of the service and high levels of satisfaction with the service among Insite staff have been reported. Contrary to the suggestion that cocaine users would be unwilling to use the SIF , approxiDespite the chaotic behaviours often associated with injection drug use, overall staff safety has been high and the instances of verbal or physical abuse by clients are managed efficiently as per the service's protocols. In outstanding circumstances, Vancouver Police Department has been called to remove disruptive clients, and support and assistance from the police in this regard has been very positive. Overall the staff remains very committed to the activities at Insite and staff satisfaction has been high.Overdoses, from a range of illicit drugs, are commonly observed in the SIF. The severity of these overdoses range from lowered respiration rate to severe emergency situations that have required the administration of naloxone and ambulance responses. Given the high levels of illness (for instance HIV and hepatitis C co-infection) and drug using behaviours (unknown substances of unknown purity) of the target population, it is not inconceivable that a fatality could occur in the SIF despite staff supervision and emergency response.There have been no instances where used syringe borrowing has been seen within Insite. These behaviours are common among street based injectors and it is well recognized that these activities promote the spread of blood-borne infections. It is also noteworthy that alcohol swabs to clean the injection site, and clean water and cookers are all provided to optimize hygenic injection procedures. Research of street-based IDU in Vancouver has shown that alcohol swabs are rarely used, and that non-hygenic water sources, such as puddle water, are commonly used. It is also noteworthy that within the SIF, safer hygenic injection practices are taught by the nursing staff to IDUs who have never been shown how to inject safely.In addition to supervising injections, teaching safer injecting practices, and responding to overdoses, there has been substantial health intervention within Insite. In particular, referrals to medical care at St Paul's Hospital are common as well as referrals to community health centres. Early intervention for primary medical care concerns, such as abscesses, is commonly provided by the Insite nursing team, and coverage with public health interventions, such as flu shots, has been provided to Insite users. In addition, addictions counseling occurs on site and there have been many referrals to detoxification programs and methadone maintenance therapy.Overall, Insite has attracted the target population and preliminary evidence suggests that the experiences within Insite as well as the community impact have been consistent with the experience of over two dozen European settings where SIF exist, and more recently Sydney, Australia. The examination of early changes in public order has been completed and there is strong evidence of improvement in several indicators including public drug use .However, each of the indicators described above is the subject of a rigorous scientific evaluation that is attempting to quantify the overall impacts of the site and identify both benefits and potentially harmful consequences over a multi-year period. This evaluation is primarily structured around a prospective cohort design that will involve the longitudinal measurement of health and community indicators over the next several years. As such, it will be some time before the overall impact of Insite on a number of outcomes, such as blood-borne infections and IDUs behavior, can be adequately quantified.


Drosophila genes wingless (wg) and decapentaplegic (dpp) comprise the top level of a hierarchical gene cascade involved in proximal-distal (PD) patterning of the legs. It remains unclear, whether this cascade is common to the appendages of all arthropods. Here, wg and dpp are studied in the millipede Glomeris marginata, a representative of the Myriapoda.The Glomeris wg (Gm-wg) is expressed along the ventral side of the appendages compatible with functioning during the patterning of both the PD and dorsal-ventral (DV) axes. Gm-wg may also be involved in sensory organ formation in the gnathal appendages by inducing the expression of Distal-less (Dll) and H15 in the organ primordia. Expression of Glomeris dpp (Gm-dpp) is found at the tip of the trunk legs as well as weakly along the dorsal side of the legs in early stages. Taking data from other arthropods into account, these results may be interpreted in favor of a conserved mode of WG/DPP signaling. Apart from the main PD axis, many arthropod appendages have additional branches (e.g. endites). It is debated whether these extra branches develop their PD axis via the same mechanism as the main PD axis, or whether branch-specific mechanisms exist. Gene expression in possible endite homologs in Glomeris argues for the latter alternative.All available data argue in favor of a conserved role of WG/DPP morphogen gradients in guiding the development of the main PD axis. Additional branches in multibranched (multiramous) appendage types apparently do not utilize the WG/DPP signaling system for their PD development. This further supports recent work on crustaceans and insects, that lead to similar conclusions. Both genes encode secreted morphogens that generate combinatorial gradients across the developing imaginal leg discs , dachshund (dac)) (e.g. )or-blind . Further endites ,24-26. T endites ), these Glomeris mandible develops two lobes, the internal and external mandibular lobe. Both lobes express Gm-dpp, but not at a position suggestive of a role in PD axis formation . These two sensory structures grow from the internal side of the stipes . The poGlomeris appear to utilize conventional WG/DPP signaling to organize PD growth. Similar results have been obtained recently for the endites in the grasshopper Schistocerca and the beetle Tribolium [Schistocerca at least one endite  grows without dpp expression  [omb as dorsal instructor is evolutionarily conserved, but H15 does not seem to be a general ventralizing factor in all arthropods. Thus, the dorsal, but not the ventral developmental mechanisms seem to be conserved. It is interesting that the expression data of wg and dpp suggest that the opposite is true. The wg expression on the ventral side is highly conserved among the arthropods, but the dpp patterns differ between species and in most part expression is not localized to the entire dorsal side. This paradox clearly demonstrates the limited understanding of the evolution of DV axis formation in arthropod appendages.A second role of the legs ,29. wg, s salei) ,17. The Glomeris has several sensory organs. Recent studies have identified the genes Dll, dac and H15, which show a restricted expression pattern in the primordia of the maxillary sensory organs [Dll and H15, are known from Drosophila to be activated upon signaling through the wingless pathway [Gm-wg surrounds the sensory primordia in the Glomeris maxilla. It may therefore be the case that cells expressing Gm-wg in the surrounding of the primordia signal to their neighbors within the primordia and stimulate them to activate Gm-Dll and Gm-H15. Minimally the activation of Dll appears to be a general feature of appendicular sensory organs in arthropods since Dll expression has been observed in appendicular sensory organs in chelicerates, crustaceans, myriapods and insects  [The maxilla of y organs ,17. Two  pathway ,30. It its e.g. ,25,31). ,31. Glomanlagen) ,33.Gm-wg and Gm-dpp during appendage development indicates a role for both genes in guiding this process. Involvement of wg and dpp in appendage development appears to be conserved among all extant arthropod classes including myriapods. The data from Glomeris and other arthropods suggest that the WG/DPP morphogen signaling system as it is known from Drosophila leg discs is present in all arthropods. However, this morphogen system apparently functions in only the main branch of the appendages, the so-called telopodite [Glomeris mouthparts supports this notion. Aside from the role in PD axis formation, the expression profile of Gm-wg suggests an additional role for this gene in patterning appendicular sensory organs.The expression of lopodite . Limb tyAnimals were collected during Spring 2003 in beech forests in the vicinity of Cologne, Germany and near Kranenburg, Germany. They have been treated as described before ,14. The Glomeris embryos of all developmental stages up to stage 6.1  and dpp-bw-1 (CKR CAN CCR CAN CCN CAN AC) were used in the initial PCR, and the primers dpp-fw-2 (GGN TAY GAY GCN TAY TAY TG) and dpp-bw-1 were used in the nested PCR. Additional sequence information was gained by RACE PCR. No full-length fragment could be obtained and several artificial clones were encountered, probably representing chimeric products resulting from jumping PCR between different TGF-beta-like cDNAs. Using species specific primers, artificial and genuine fragments were identified. A confirmed genuine fragment of almost 360 bp was isolated and cloned. This fragment was used for sequence analysis and probe synthesis. The isolation of Gm-wg has been previously reported [Gm-wg (AJ616907); Gm-dpp (AJ843875).The cloning assays were based on cDNA transcribed from polyA-RNA extracted from selected 6.1 (see ,35 for areported . The GenPairwise alignments of aminoacid sequences were performed by searching GenBank  using thIn situ hybridization with digoxigenin-labeled RNA probes has been performed as previously described . Whole-m


Administrative health care databases may be particularly useful for injury surveillance, given that they are population-based, readily available, and relatively complete. Surveillance based on administrative data, though, is often restricted to injuries that result in hospitalization. Adding physician billing data to administrative data-based surveillance efforts may improve comprehensiveness, but the feasibility of such an approach has rarely been examined. It is also not clear how injury surveillance information obtained using administrative health care databases compares with that obtained using self-report surveys. This study explored the value of using physician billing data along with hospitalization data for the surveillance of adolescent injuries in Ontario, Canada. We aimed i) to document the burden of adolescent injury using administrative health care data, focusing on the relative contribution of physician billing information; and ii) to explore data quality issues by directly comparing adolescent injuries identified in administrative and self-report data.The sample included adolescents aged 12 to 19 years who participated in the 1996–1997 cross-sectional Ontario Health Survey, and whose survey responses were linked to administrative health care datasets (N = 2067). Descriptive analysis was used to document the burden of injuries as a proportion of all physician care by gender and location of care, and to examine the distribution of both administratively-defined and self-reported activity-limiting injuries according to demographic characteristics. Administratively-defined and self-reported injuries were also directly compared at the individual level.Approximately 10% of physician care for the sample was identified as injury-related. While 18.8% of adolescents had self-reported injury in the previous year, 25.0% had documented administratively-defined injury. The distribution of injuries according to demographic characteristics was similar across data sources, but congruence was low at the individual level. Possible reasons for discrepancies between the data sources included recall errors in the survey data and errors in the physician billing data algorithm.If further validated, physician billing data could be used along with hospital inpatient data to make an important and unique contribution to adolescent injury surveillance. The limitations inherent in different datasets highlight the need to continue rely on multiple information sources for complete injury surveillance information. The contribution of surveillance systems in providing valuable information for injury prevention and control is widely recognized; for example, surveillance data can be used to highlight the burden of injury, set priorities for prevention, and evaluate preventive strategies ,2. EstimAdministrative health care databases, due to their presumed near complete coverage of injuries requiring medical care and their lack of reliance on self-reports, may be particularly useful for injury surveillance. Such databases allow for local or regional estimates of the burden of injury, which has been identified as an important goal ,6,7, andIn Ontario, Canada, administrative health care databases that may provide information on the incidence of non-fatal injuries include hospital discharge and physician billing data. Although hospital discharge data have been widely used in Canada to study injury, the feasibility of using physician billing information for injury surveillance has rarely been investigated . These dIt is not clear how the injury information provided by administrative databases compares with that obtained from population-based surveys. A study of adolescent injuries we conducted using data from the Ontario Health Survey (OHS)  presenteThe overall purpose of this study was to explore the feasibility and value of using physician billing data for Ontario, Canada, along with hospitalization data, for the surveillance of adolescent injuries. The first objective was to document the burden of adolescent injury based on administrative health care data, focusing on the relative contribution of physician billing information and comparing overall estimates with surveillance information from survey data. The second objective was to examine data quality issues, by directly comparing adolescent injuries identified using administrative health care databases ("administratively-defined injuries") with those identified using self-report survey data ("self-reported injuries").The study sample included adolescents aged 12 to 19 years who participated in the health component of the 1996–1997 OHS (N = 3331), which was part of the National Population Health Survey (NPHS) . Survey Inpatient hospitalizations for injuries were identified using the Discharge Abstract Database (DAD) of the Canadian Institute for Health Information (CIHI) . All OntOHS respondents were asked a series of questions related to acute injuries in the past 12 months that were, from the perspective of the respondent, serious enough to limit normal activities  . Particith revision [Inpatient hospitalizations for injury were identified for the 365-day period prior to the OHS interview, for each adolescent. An adolescent was considered to have an injury-related hospitalization if, during the one-year period, he or she had at least one documented hospital discharge with an External Cause of Injury Code (E Code) in the range 800–999 , based on the International Classification of Disease (ICD), 9revision .The OHIP physician claims database does not contain codes representing causes of injury. Rather, injuries were identified based on codes that reflect billable services ("procedure codes"), and the diagnoses associated with such services ("diagnostic codes"). To improve sensitivity, a combination of both diagnostic and procedure codes from the database was used to create an injury algorithm that would identify physician care for injury during the one-year study period, based on the methods of Tamblyn and colleagues . The devAdolescents who had at least one documented injury in either the hospitalization or the physician billing database were considered to have an administratively-defined injury. Adolescents with documented injury-related physician care at a physician's office or outpatient facility were considered to have a physicians' office visit for injury. Adolescents with documented injury-related physician care at an emergency department were considered to have an emergency visit for injury.Two alternative injury outcomes were created to examine the impact of decisions made in developing the physician billing algorithm. These outcomes were based on diagnoses that were relatively common and were captured only as possible injuries in the algorithm, including non-specific conditions of the musculoskeletal system and adverse effects of drugs and medications.First, the injury algorithm was used with the full sample of 2067 adolescents, resulting in estimates of adolescent injury-related physician care by gender and location of care. Descriptive analysis was then carried out for adolescents with non-missing data on important OHS variables (N = 2047). In addition to examining differences in the overall observed burden of adolescent injury between administrative and survey data, we also explored whether there were differences within demographic subsets of the sample where the types of injuries experienced or the types of injury care received were likely to differ. Thus, we examined the proportion of adolescents with administratively-defined and self-reported injuries separately by gender, age group, and rural versus urban residence. Since numerous comparisons were possible within the results related to the burden of injury, we chose to report 95% confidence intervals around each proportion, rather than presenting statistical tests. Because the OHS used a complex sampling design to yield a provincially representative sample, weighted proportions were calculated. Variance estimates were adjusted using bootstrap replicate weights to account for clustering within the sample .Two analyses were conducted to explore data quality. First, as a sensitivity analysis for the physician billing database, we examined the impact of re-classifying two common "possible injury" diagnoses as actual injuries in the physician billing database. These diagnoses included i) non-specific musculoskeletal system diagnoses, and ii) adverse reactions to drugs and/or medications. These diagnoses were viewed as potentially problematic because they were not specific enough to injuries to warrant inclusion as "definite" injuries, but we believed that they might be commonly used by physicians providing injury-related care.Secondly, we directly compared self-reported and administratively-defined injuries at an individual level, to provide further insight into data quality. Not all self-reported injuries identified using the survey data would be expected to have led to medical treatment, and conversely, it is possible that some medically treated injuries may not have led to a restriction in normal activity. Some overlap between the survey data and administrative data was expected, though, in terms of injuries identified. Thus, we examined discrepancies between the injury variables at the level of the individual adolescent . Odds ratios, based on two-way data tables, were used as a measure of association for these direct comparisons of injury variables across data sources. We also explored possible reasons for the discrepancies observed, including potential recall error in the survey data, and potential error in both datasets resulting from overlap between acute injuries and repetitive strain injuries. These exploratory analyses involved, where appropriate, descriptive statistics  or odds ratios (as a measure of association for two dichotomous variables). All of the data quality analyses were used to examine within-sample methodologic issues. Therefore, as we did not wish to generalize the results from these analyses to a target population, unweighted analyses were conducted, and confidence intervals were not included.During the one-year period prior to the OHS interview, there were a total of 13501 physician visits for any cause among the 2067 adolescents in the initial sample , based on the physician billing data. Of these, 1390 visits were identified as being related to injury, representing 10.3% of all physician care. The proportion of visits due to injury varied across locations of care. For example, 8.6% of physicians' office visits (n = 604) and 45.6% of emergency department visits (n = 402) were identified as injury-related. A greater proportion of physician care was injury-related among males (14.2%), relative to females (7.3%).Within the final sample (N = 2047), while 18.8% of adolescents self-reported an activity-limiting injury in the past year, 25.0% had at least one administratively-defined injury, based on the hospitalization and physician billing databases .The results of the within-sample analysis used to compare injuries identified using different data sources are shown in Table In order to investigate the possibility that recall error may have led to underreporting in the survey, we investigated the relationship to recall time , and to explore whether the algorithm used with the physician billing database may have led to misclassification of some repetitive strain injuries as acute injuries, we examined the relationship to self-reported repetitive strain injuries. Both self-reported acute injury and administratively-defined acute injury appeared to be related to self-reported repetitive strain injury  to capture a broader spectrum of injury severity compared with the administrative data . The higher proportion of adolescents with administratively-defined injury, though, suggests that there may also be a subset of medically treated injuries that do not in fact limit normal activities; in other words, perhaps the definition of injuries used in the survey was actually more restrictive. Although neither data source can be viewed as a "gold standard", these results suggest that administrative health care data may actually provide a more sensitive means of ascertaining injuries, relative to self-reported survey data. Injuries identified as medically treated using administrative data may also be viewed as representing the health concerns of the person seeking care, and they have an impact on the health care system.These findings highlight the potential importance of administrative databases as a source of population-based injury information that can be used for affordable ongoing surveillance and for examining health care system issues such as patterns of service delivery. Despite these advantages, a limitation of many claims datasets, including the OHIP database, is a lack of detail on the circumstances surrounding the occurrence of injuries. The billing data contained no external cause information, such that description of injuries by mechanism and intent was not possible.Although the distribution of injuries, particularly for gender and age, was fairly similar for self-reported and administratively-defined injuries Table , congrueIn the survey data, we found some evidence of recall errors , and the unique sampling weights created for this sub-sample may have improved representativeness. Finally, because this study capitalized on an opportunity presented by a larger study on youth injuries, we focused specifically on adolescents. Further research could examine the generalizability of both the approach and the findings to other age groups, where the types of injuries experienced and care-seeking patterns may differ. Studies in jurisdictions with similar medical claims databases would also help in assessing the generalizability of our research.Collectively, our findings allow us to draw two main conclusions. First, the results suggest that there is potential value in using physician billing data along with other administrative health care databases for the surveillance of injuries among adolescents. Although they are lacking in details about the circumstances surrounding injuries, comprehensive administrative injury datasets may be particularly useful for describing the overall occurrence of injury at local or regional levels, and for describing the economic implications of injury for the health care system. Secondly, we identified data quality concerns in both the survey and administrative databases that suggest a need for improvement and further study; for example, further research could help to identify appropriate recall periods and question wording for minimizing errors in survey data, and to determine the level of detail needed to accurately identify injuries in administrative databases. Because various sources of data are susceptible to different limitations, it remains important to consult multiple sources of information to fully document the burden of injury ,4,7.The author(s) declare that they have no competing interests.BKP participated in the design and coordination of the study and the development of the physician billing algorithm, carried out all statistical analyses, and drafted the manuscript. DM participated in the design, coordination, and supervision of the study and development of the physician billing algorithm, as well as revisions to the manuscript. KNS participated in the design, coordination, and supervision of the study, as well as revisions to the manuscript. IAG participated in the design of the study and development of the physician billing algorithm, as well as revisions to the manuscript. MKC participated in the design of the study and revisions to the manuscript. JJK participated in the design of the study and revisions to the manuscript, and provided statistical guidance. All authors read and approved the final manuscript.The pre-publication history for this paper can be accessed here:


Several studies have linked low birth weight to adverse levels of cardiovascular risk factors and related diseases. However, information is sparse at a community level in the U.S. general population regarding the effects of low birth weight on the longitudinal trends in cardiovascular risk factor variables measured concurrently from childhood to adolescence.th percentile; n = 123) and control  groups.Longitudinal analysis was performed retrospectively on data collected from the Bogalusa Heart Study cohort  followed from childhood to adolescence by repeated surveys between 1973 and 1996. Subjects were categorized into low birth weight (below the race-specific 10Low birth weight group vs control group had lower mean HDL cholesterol (p = 0.05) and higher LDL cholesterol (p = 0.05) during childhood (ages 4–11 years); higher glucose (p = 0.02) during adolescence. Yearly rates of change from childhood to adolescence in systolic blood pressure (p = 0.02), LDL cholesterol (p = 0.05), and glucose (p = 0.07) were faster, and body mass index (p = 0.03) slower among the low birth weight group. In a multivariate analysis, low birth weight was related independently and adversely to longitudinal trends in systolic blood pressure (p = 0.004), triglycerides (p = 0.03), and glucose (p = 0.07), regardless of race or gender. These adverse associations became amplified with age.Low birth weight is characterized by adverse developmental trends in metabolic and hemodynamic variables during childhood and adolescence; and thus, it may be an early risk factor in this regard. The growth of a fetus in an undernourished intrauterine environment is considered to result in adaptive fetal programming or metabolic imprinting with pathophysiologic consequences later in life -4. It isSeveral studies including our own have examined the association between low birth weight and selected cardiovascular risk factor variables in childhood and adolescence -27. HoweBetween 1973 and 1996, 7 cross-sectional surveys of children and adolescents were conducted in the community  of Bogalusa, LA. This panel design, based on repeated cross-sectional examinations performed every 3 to 4 years, resulted in serial observations required for the longitudinal analysis. For the present report, two sets of data were merged as described previously : 1) singth percentile  were categorized as low birth weight group; those (n = 296) in the upper normal range of 50–75th percentile  as control group. Birth weights above the 75th percentile were not included in the control group because of the u-shaped associations between birth weight and risk factors or disease [Low birth weight and control groups were selected from the eligible cohort, according to birth weight percentile cut points . Subject disease . Race-sp disease .Identical protocols were used by trained examiners across all surveys . SubjectHeight and weight were measured 2 times; subscapular skinfold thickness 3 times. Body mass index (BMI) calculated as weight in kg divided by the square of the height in meters was used as a measure of overall adiposity; subscapular skinfold for truncal fatness. The reproducibility in terms of intraclass (intra-observer) correlation coefficient was greater than 0.99 for weight and height, and greater than 0.97 for subscapular skinfold.Blood pressure levels were measured in 6 replicates by 2 randomly assigned nurses on the right arm of subjects in a relaxed, sitting position. Systolic and diastolic blood pressures were recorded at the first, fourth, and fifth Korotkoff phases using mercury sphygmomanometer. For this analysis fourth phase was used for diastolic blood pressure because in our experience the fourth phase is more reliably measured in children and more predictive of adult hypertension .From 1973 to 1986 cholesterol and triglyceride levels in serum were measured using chemical procedures on Technicon Autoanalyzer II . Since then these measurements were done using enzymatic procedures on Abbott VP instrument . Serum lipoprotein cholesterols were analyzed by a combination of heparin-calcium precipitation and agar-agarose gel electrophoresis procedures . Both chPlasma immunoreactive insulin levels were measured by a commercial radioimmunoassay kit . Plasma glucose was measured by a glucose oxidase method either using a Beckman glucose analyzer  or as part of a multichemistry (SMA20) profile. The intraclass correlation coefficient between blind duplicate values ranged from 0.94 to 0.98 for insulin and 0.86 to 0.98 for glucose. An index of insulin resistance was calculated according to the homeostasis assessment model formula : HOMA-IR2, race and gender and their interaction with birth weight (low vs control). A backward stepwise method was used to remove nonsignificant terms.For test of significance glucose and insulin were logarithmically transformed to approach normality. The average of multiple measurements for subjects within age groups 4 to 11 and 12 to 18 years corresponding to childhood and adolescence periods was used to calculate mean levels of risk variables by birth weight status and age groups. Mean levels of risk variables within each age group were compared between low birth weight and control group by a general linear model, adjusting for age, race, and gender. The longitudinal rates of change in risk variables was assessed by the generalized estimation equation (GEE) method  with ageMean levels of cardiovascular risk variables during childhood ages 4–11 years) and adolescence (ages 12–18 years) periods are shown in table 1 years aLongitudinal rates of change in cardiovascular risk variables from childhood to adolescence, adjusted for race and gender, are presented in table In a multivariate analysis, low birth weight was retained as an independent predictor variable for adverse longitudinal trends in systolic blood pressure, triglycerides, and glucose  from childhood to adolescence, regardless of race or gender table . FurtherInformation is sparse at a community level in the U.S. general population regarding the effects of low birth weight on the longitudinal trends in C-V risk factor variables measured serially and concurrently from childhood to adolescence. The present community-based study demonstrates the adverse effects of low birth weight on the longitudinal  trends in systolic blood pressure, triglycerides, and glucose during childhood and adolescence, regardless of race or gender. These observations are in accord with the emerging evidence supporting the concept of intrauterine imprinting and its pathophysiologic consequences enunciated by the fetal origin or thrifty phenotype hypothesis .Many, but not all, previous studies in children and adolescents have found adverse associations between birth weight and levels of cardiovascular risk factor variables -27. In tAlthough observational studies like the present one can not establish causality, several putative mechanisms link low birth weight to adverse trends in risk factor variables. It has been suggested that insulin resistance may be one mechanism by which intrauterine events may program disease risk . UndernuThis study has certain limitations. The lack of information on the duration of gestation precluded us from adjusting the birth weight for gestational age, a potential confounder. However, earlier studies have found that adverse effects of low birth weight on cardiovascular risk factor variables were independent of gestation period ,17,49. FLow birth is characterized by adverse developmental trends in metabolic and hemodynamic variables during childhood and adolescence, especially as the children get older. These observations in conjunction with earlier findings support the view that low birth weight, albeit a crude marker of prenatal growth and physiological environment, is a potential early risk factor for the emergence of metabolic and hemodynamic disorders and related diseases ,50.BMI, body mass index; LDL, low-density lipoprotein; HDL, high-density lipoproteinThe author(s) declare that they have no competing interests.MGF participated in study design, data analysis and manuscript preparation. SRS and GSB contributed to study concept and design, data collection, acquisition of funding and manuscript preparation. JX was involved in measurements of laboratory variables. All authors read and approved the final manuscript.The pre-publication history for this paper can be accessed here:


NeuroEngineering and Rehabilitation (JNER) is intended to fill this gap and foster cross-fertilizations among these disciplines. By making readily available to clinicians selected studies with potential impact on physical medicine & rehabilitation, JNER is anticipated to foster the development of novel and more effective rehabilitation strategies. Conversely, by presenting clinical problems to a readership of neuroscientists and engineers, JNER is expected to generate innovative work in neuroscience and biomedical engineering with future applications to physical medicine & rehabilitation. JNER will leverage on Open Access as a means to guarantee that its content is readily available to scientists, clinicians, and the general public thus promoting scientific and technological advances that are relevant to rehabilitation. JNER is an Open Access initiative. Open Access assures dissemination to the widest possible audience and is seen by many as essential for publicly funded research. BioMed Central offers an outstanding platform to make JNER possible and allow neuroscientists, biomedical engineers, and clinicians to see their work published in a timely manner and thus make an immediate impact in the field of rehabilitation. JNER will focus on innovative work with higher likelihood of a dramatic impact on rehabilitation. Thus, priority will be given to outstanding and visionary scientific reports, i.e. those proposing exceptionally innovative concepts with great potential in the field.Advances in neuroscience and biomedical engineering deeply affect the clinical practice of physical medicine & rehabilitation. New research findings and engineering tools are continuously made available that have the potential of dramatically enhancing the ability of clinicians to design effective rehabilitation interventions. This quickly evolving research field is difficult to track because related literature appears in a wide range of scientific journals. There is a need for a scientific journal that offers to its readership a forum at the intersection of neuroscience, biomedical engineering, and physical medicine & rehabilitation. The Journal of  During the past decade, we have witnessed profound changes in physical medicine & rehabilitation originated by advances in neuroscience and biomedical engineering. For example, imaging and neurological assessment methods have dramatically improved the management of patients with motor impairments; robotics and artificial muscle research have generated revolutionary concepts in orthotics and prosthetics; and advances in cortical recordings and the understanding of central nervous system mechanisms have changed the way clinicians look at movement disorders. These techniques and others have brought about, and will continue to give rise in the future to, dramatic advances in physical medicine & rehabilitation.Journal of NeuroEngineering and Rehabilitation (JNER) aims to provide such an outlet, hosting the introduction of new methods and the discussion of their clinical implications, and offering an opportunity to publish, in a timely manner, articles relevant to the cross-fertilization of neuroscience, biomedical engineering, and physical medicine & rehabilitation.As advances in neuroscience and biomedical engineering continue to generate new techniques, with tremendous impact in the field of physical medicine & rehabilitation, it becomes apparent that there is an urgent need for establishing an outlet for the intersection of these three research fields. JNER's editorial board [al board  demonstrJNER's Open Access policy changes the way in which articles are made available to the scientific community. First, all articles become freely and universally accessible online, and so an author's work can be read by anyone at no cost. Second, the authors hold copyright for their work and grant anyone the right to reproduce and disseminate the article, provided that it is correctly cited and no errors are introduced [JNER's articles are archived in PubMed Central [troduced . Third,  Central , the US  Central  in Germa Central  in Franc Central , the NatOpen Access has four broad benefits for science and the general public. First, authors are assured that their work is disseminated to the widest possible audience, given that there are no barriers to access their work. This is accentuated by the authors being free to reproduce and distribute their work, for example by placing it on their institution's website. It has been suggested that free online articles are more highly cited because of their easier availability . Second,JNER will contribute to make the latest advances in neuroscience and biomedical engineering, which have the potential to impact on the clinical practice of physical medicine & rehabilitation, readily available to scientists, clinicians, and the general public. Because of its inherent interdisciplinary nature, JNER will foster further advances in the field thanks to the cross-fertilization among science, technology, and clinical practice. Science and technology are expected to offer new tools to design clinical interventions and, vice versa, clinical problems are anticipated to foster basic research in neuroscience and the development of new technologies. Besides, increased awareness of the way science and technology can improve clinical outcomes will lead to better quality of healthcare in rehabilitation. Changes currently occurring in this field are so dramatic that we expect, in a few years, that modernized rehabilitation inpatient and outpatient units will be completely different from what is the state-of-the-art today. For instance, we envision that continuous monitoring of patient status will be performed via miniature, wireless, wearable sensors which not only allow clinicians to monitor vital signs, but also track motor activities and provide a means to analyze motor patterns associated with recovery. Furthermore, robotic devices will be used to enhance physical therapy, ad hoc protocols will be designed for each patient, and augmented and virtual reality tools will enhance rehabilitation by becoming part of routine exercise protocols.Open Access will increasingly become an accepted way to disseminate information to the scientific community and the public at large. By becoming part of the movement for Open Access, JNER intends to provide a forum for ideas and concepts that could make a difference in physical medicine & rehabilitation by innovating the design of clinical interventions.Open Access to outstanding and visionary scientific reports appears to be a tremendous tool to increase the speed at which clinical practice changes as a result of advances in neuroscience and biomedical engineering. By prioritizing outstanding and visionary publications, JNER is free for the first 6 months following the launch of the journal. Manuscripts submitted after this period will be subject to an article-processing charge on acceptance. Waiver requests will be considered on a case-by-case basis, by the Editor-in-Chief. Authors can circumvent the charge by getting their institution to become a 'member' of BioMed Central, whereby the annual membership fee covers the article processing charges for authors publishing in any of the BioMed Central journals. Current members include NHS England, the World Health Organization, the US National Institutes of Health, Harvard, Princeton and Yale universities, and all UK universities [Publication in ersities . No charersities .JNER's editorial board will be solely used to further promote the journal and to continuously increase the scientific quality of JNER's articles.The article-processing charges pay for efficient and thorough peer review, for the article to be freely and universally accessible in various formats online, and for the processes required for inclusion in PubMed and archiving in PubMed Central, e-Depot, Potsdam and INIST. Funding available to JNER to high quality, prioritizing visionary work, and focusing on research that has the potential of a great impact on physical medicine & rehabilitation. Forthcoming articles will further prove such commitment. Topics of interest to come in the next few months are virtual and augmented reality in rehabilitation, wearable technology in rehabilitation, methods for the analysis of movement, and robotics applied to rehabilitation. These are all topics of great relevance for the research at the intersection of neuroscience, biomedical engineering, and physical medicine & rehabilitation.The first articles published in the journal demonstrate the commitment of JNER as well as to the authors who submit their manuscripts in the future and support our journal and the Open Access initiative. Members of the editorial board and reviewers have done some excellent work; special thanks to them and the Managing Editor, Sara Midwood, for their contributions to JNER.Special thanks to the authors of the first articles published in