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BackgroundDuring pregnancy, maternal circulating antibodies cross the placenta. Offspring exposed in utero to tumour necrosis factor inhibitors (TNFi) may experience immunosuppression and subsequent infections in their first year of life due to TNFi entering the fetal bloodstream. TNFi subtypes have differential trans-placental passage capabilities. Most (i.e. adalimumab, infliximab, golimumab) are monoclonal antibodies, with adalimumab and infliximab having the highest transfer, reaching higher fetal than maternal levels. Certolizumab (a pegylated Fab fragment) and etanercept (a fusion protein) display the lowest passage. Thus, depending on the TNFi subtype, the risk of immunosuppression may differ, and some offspring may be exposed to supra-therapeutic doses of TNFi. Therefore, the risk of serious infections in offspring by TNFi subtype needs to be clarified.ObjectivesWe evaluated the risk of serious infections leading to hospitalization in offspring born to mothers with chronic inflammatory diseases who used TNFi during pregnancy depending on whether they had low or high placental transfer.MethodsIn this population cohort study, we identified offspring born in 2011-2019 to women with a prior diagnosis of rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis, psoriasis, and/or inflammatory bowel diseases in the IBM MarketScan commercial database using commercial claims only. Women were included if they had been continuously enrolled within MarketScan with medical and pharmacy coverage for ≥12 months prior to delivery and had a child linked to them. TNFi exposure was defined as ≥1 filled prescription and/or infusion procedure code during pregnancy. Exposure was further categorized into high (i.e. infliximab, adalimumab, golimumab) and low (i.e. certolizumab, etanercept) placental transfer ability. Serious infections were ascertained based on ≥1 hospitalization with infection as the primary diagnosis in the offspring’s first year of life. We performed multivariable time-to-event analysis using a Cox proportional hazards model, adjusting for maternal age at delivery, chronic inflammatory disease diagnosis, maternal co-morbidities (pre-gestational diabetes, asthma), pregnancy complications (gestational diabetes, preterm birth), and other drug use (corticosteroids and non-biologic DMARDs).ResultsWe identified 26,088 offspring, among whom 2,902 (11.1%) were exposed to TNFi during pregnancy. The majority of offspring (1,506; 51.9%) were born to mothers with inflammatory bowel diseases. Out of the 2,902 offspring with TNFi exposure, 797 (27.5%) and 2,105 (72.5%) were low and high placental transfer drugs, respectively. The frequency of serious infections was 1.3% and 1.8% in those offspring exposed to TNFi with low and high placental transfer, respectively. The incidence rate (IR) of serious infections in offspring exposed to TNFi with high vs. low placental transfer was, respectively, 2.27 (95% confidence interval, CI 1.61, 3.12) cases per 100 person-years at risk vs. IR 1.59 cases per 100 person-years at risk (95% CI 0.76, 2.92). In multivariable analyses, the adjusted hazard ratio for serious infections with the use of TNFi with high versus low placental transfer was 1.20 (95% CI 0.54, 2.64).ConclusionAlthough children exposed to high transfer TNFi may have a higher risk of serious infection, we saw no clear excess risk of serious infections in children exposed in utero to TNFi with high versus low placental transfer due to the wide confidence interval.ReferencesNoneDisclosure of InterestsNone declared

Etat de la question Les progres en transplantation hepatique et les changements epidemiologiques recents ont conduit a une augmentation du nombre de receveurs âges de plus de 65 ans, et ce malgre un contexte de penurie d’organes. Nous avons etudie l’impact de l’âge avance des receveurs sur la mortalite a cinq et dix ans d’une transplantation hepatique. Materiel et methodes Les patients majeurs transplantes pour la premiere fois entre 2007 et 2017, enregistres dans la base nationale de l’Agence de la biomedecine francaise etaient inclus. Des modeles flexibles de survie observee et de survie nette ont ete utilises pour tenir compte des effets dependants du temps et/ou non log-lineaires et de la mortalite attendue pour chaque patient compte tenu de son sexe et de son âge. Resultats Au total, 7610 patients ont ete inclus (âge moyen a la greffe de 55 ans [± 10,5]). Plus les receveurs etaient âges, meilleure etait leur fonction hepatique. Les analyses de survie observee comme de survie nette ont montre une association significative entre l’augmentation de l’âge du receveur et le risque de deces. Cependant si cet effet pejoratif etait majeur dans la premiere annee suivant la greffe, il diminuait progressivement au cours du suivi. Une difference absolue de 8 % (50 % versus 42 %) de survie nette persiste malgre tout a 10 ans entre des receveurs de 28 et 71 ans. Conclusion Malgre une selection des candidats âges, l’âge a la greffe etait associe a une augmentation du risque de deces, particulierement marquee dans la premiere annee suivant la transplantation. Cet effet diminuait ensuite mais restait present a cinq et dix ans de la greffe, y compris apres prise en compte de la mortalite attendue par âge et par sexe dans la population francaise.

BACKGROUND: Growing evidence suggests that asthma and Crohn’s disease (CD) commonly co-occur. The impact of asthma on the prognosis of CD is not known. Studies evaluating the risk of surgery in CD patients using health administrative data are limited by their inability to adjust for confounding variables not included in these data, such as smoking. AIMS: The aim of our study was to assess the impact of asthma on the need for intestinal resection in CD adjusting for smoking status, despite smoking status being unmeasured in health administrative data, using a secondary dataset and novel methodology. METHODS: Using population-based health administrative data from Alberta, we conducted a cohort study to assess the impact of asthma on the need for surgery in patients with CD diagnosed between April 1, 2002 and March 31, 2008 (n=2,113). Validated algorithms were used to identify incident CD cases, patients with co-occurring asthma, and intestinal resection surgeries. The association between asthma and intestinal resection was estimated using Cox proportional hazards regression. Smoking status was imputed using a method based on martingale residuals, leveraging information from a secondary dataset in which smoking status was measured. This second dataset included patients enrolled in the Alberta IBD Consortium between 2007 and 2014 who completed environmental questionnaires (n=485). All analyses were adjusted for age, sex, rural/urban status, and mean neighbourhood income quintile. RESULTS: Asthma did not increase the risk of surgery in either the health administrative data unadjusted for smoking status (HR 1.03, 95% CI 0.81 to 1.29) or in the secondary data adjusted for smoking status (HR 0.74, 95% CI 0.50 to 1.37). The association remained non-significant after using the secondary data to impute smoking status in the health administrative data (HR 0.92, 95% CI 0.75 to 1.15). CONCLUSIONS: Although asthma is associated with an increased risk of CD, co-occurring asthma was not associated with the risk of surgery in patients with CD. This null association persisted after adjusting for smoking status. This study also demonstrates a novel method to adjust for smoking status in research using health administrative data when it is measured in a smaller secondary dataset. FUNDING AGENCIES: CAG, CCC, CIHR

Table S2. OR estimates between smoking-related variables and lung cancer risk by respondent type. This table presents the association between ever smoking (or CSI) and the logit of the lung cancer risk by respondent type. (DOCX 15 kb)

Introduction The dose-response relationship is considered as one of the major criteria when the causality of a relationship between an exposure and an outcome is discussed. This criterion is mainly studied in observational studies but may be also of interest in Randomized Controlled Trial (RCT), particularly if the administered dose of treatment varies over time and between patients. Maintenance trials with a long follow-up meet these characteristics. We reanalyzed a maintenance trial in digestive oncology (PRODIGE 9 trial) in order to explore the dose-response relationship between the maintenance treatment and overall survival (OS). Methods The PRODIGE 9 study was a maintenance trial assessing the benefit of maintaining bevacizumab during chemotherapy-free intervals (CFI) in patients with a stage IV colon cancer. We defined five time-updated maintenance exposures: cumulative exposure (CE); relative exposure (RE) either expressed as a continuous (patient's CE divided by the standard deviation of the distribution of CE in the population at risk) or as a categorical variable (‘with quantiles of the distribution of the CE as cut-offs); and two variables that took into account delay since the administration thus allowing a decrease exposure over time: time-updated theoretical blood concentration (TBC) and weighted cumulative exposure (WCE). We defined these exposures using either bevacizumab received during the entire follow-up (total dose) or only during CFI, resulting in ten different exposures. These variables were then included in independent Cox models with an origin fixed at the beginning of the maintenance treatment, and with overall survival (OS) as the outcome. All models were adjusted on the group of randomization (group) and compared using the Akaike Information Criterium (AIC). Results Of the initial 494 patients included in the RCT, 382 were alive and had not experienced progression at the beginning of the maintenance treatment and were thus included in the present study. All exposure variables (CE, RE, TBC and WCE) improved the quality of the model that include only the group of randomization. The best AIC was obtained when adjusting on TBC and WCE. RE led to a moderate improvement of the goodness of fit and CE only led to a small improvement. WCE was associated with a strong protective effect during the first twenty days after administration, and after 200 days. For continuous and categorical RE the highest risk was observed for medium RE, in comparison with low and high REs which were associated with a lower risk. We did not observe major differences between models using the total dose of bevacizumab and those using only the dose received during CFI. Excluding the group of randomization also did not change the estimated effects. Discussion Of the many significant results observed in this reanalysis, only the effect of RE can be considered as a possible evidence of a protective effect of the treatment on overall survival. Indeed, even if TBC and WCE led to the best goodness of fit, their definition can induce immortal time bias and can lead them to act as a mediator variable. The protective effect of low RE is difficult to explain but might be related to an early immortal-time period. Adjustment on the treatment group did not modify the dose-effect relationship. Further analysis should rely on more complex models like structural equation models to disentangle the real impact of the administered dose of bevacizumab on outcomes.

Background Most rheumatoid arthritis (RA) patients initiate therapy with methotrexate (MTX), but only 1/3 will have low disease activity with this agent alone. Several therapeutic options are available for patients with MTX-resistant RA, including new Janus kinase (JAK) inhibitors (eg.: tofacitinib). Objectives To compare the effectiveness of traditional disease-modifying antirheumatic drugs (DMARDs), biologic DMARDs and tofacitinib for RA patients with inadequate response to MTX. Methods We used MarketScan® databases (2011–2014) to study adult RA individuals previously treated with methotrexate (oral or SQ) and newly prescribed one of the medications under study. The date of first filled prescription or infusion drug was defined as the cohort entry and a 12-month pre-period was used to exclude prior users of biologics or tofacitinib. We required subjects to be continuously enrolled in the medical and pharmacy plan 12 months before and after the cohort entry. Effectiveness was access through an algorithm previously validated 1 , based on the following criteria: 1) non-adherence; 2) switching/adding a new biologic or tofacitinib; 3) switching/adding a new DMARD; 4) increasing of the dose of the starting therapy; 5) use of glucocorticoid joint injections; and 6) increasing the dose of oral glucocorticoid. A patient9s therapy was defined as not effective if at least one of the criterion occurred during the first year of follow-up. Results 16,305 RA patients were included; 2,879 began therapy with DMARD, 13,345 with biologics and 81 with tofacitinib. Among all patients, 77.5% were female and the mean age was 56.2 years (standard deviation 12.6). Table 1 shows the proportion of patients that meet the individual criterion and that achieved effectiveness at the end of one-year follow-up. Conclusions Similar rates of therapy effectiveness were observed among groups, although the rates for the individual criteria differed. Fewer patients initiating biologic agents were non-adherent compared to DMARD and tofacitinib therapy, but switch/adding and injections tended to be higher in this group. References Curtis JR et al. Derivation and preliminary validation of an administrative claims-based algorithm for the effectiveness of medications for rheumatoid arthritis. Arthritis Res Ther. 2011;13(5). Disclosure of Interest None declared

Background In sub-Saharan Africa, problems of access to relevant and high-quality facility-based statistics hinder the assessment of safe motherhood programs. The objective of this study was to assess the quality of data collected in referral hospitals in Mali and Senegal after the routine information system (RIS) was strengthened. Methods This was a multicenter observational study conducted during the pre-intervention period of a randomized controlled trial (trial QUARITE). The RIS was strengthened based on technical, organizational and behavioral factors. We included all women who gave birth in the 46 referral hospitals from October 1, 2007 to October 30, 2008. The completeness, completion and accuracy rates were monitored every 3 months in each hospital. The cost of investment needed to strengthen the existing RIS was also determined. Results The mean completeness rate ranged from 94 to 97% depending on the study period. The completion and accuracy rates increased during the study period from 72% and 79% to 87% and 93%, respectively (significant differences). The average investment per hospital was less than 1% of state subsidies for public hospitals. Conclusion Strengthening the existing information system has set up an economically and technologically appropriate system for monitoring maternal and perinatal health in Senegal and Mali. We encourage policy makers and researchers from countries with limited resources to invest in RIS to improve and monitor the performance of health systems.

The 2010 Winter Olympic and Paralympic Games took place in Vancouver, British Columbia, Canada, on 12–28 February and 12–21 March 2010, respectively. Weather forecasting presents specific challenges at the various Olympic venues, which are located in complex coastal terrain and are often characterized by tricky weather conditions, such as high winds, low visibility, and rapidly varying precipitation types and intensity. In addition to its current operational products, and in order to provide the best possible guidance and support to the Olympic Forecast Team, Environment Canada has developed several experimental numerical weather prediction systems for the games. These include 1) a regional ensemble prediction system (REPS), 2) high-resolution numerical modeling (down to 1-km horizontal grid spacing), and 3) surface modeling at the microscales (100-m grid spacing). The REPS is based on the limited-area version of the Global Environmental Multiscale model (GEM-LAM), with 20 members at 33-km horizontal grid...

Background It is recommended that persons recently diagnosed with heart failure consult with a specialist in heart failure. Objectives To determine whether patients who were diagnosed with new-onset chronic heart failure (CHF) by a noncardiologist consulted with a cardiologist, and identify the factors associated with delayed consultation. Methods Physician reimbursement administrative data were obtained for all adults with suspected new-onset CHF in the year 2000 in Quebec, defined operationally as a physician visit for CHF (based on the International Classification of Diseases, 9th Revision diagnostic codes), with no previous physician visit code for CHF in the preceding three years. Among those first diagnosed by a noncardiologist, Cox regression modelling was used to identify patient and physician characteristics associated with time to cardiology consultation. Results Of the 13,523 persons coded as having incident CHF, 54.9% consulted a cardiologist within the next 2.5 to 3.5 years, and 67.4% were seen by an internist or cardiologist. Older patients, women, and those with lower comorbidity and socioeconomic status had significantly longer times to cardiology consultation. Conclusion The data suggest that many patients with suspected new-onset CHF do not receive prompt cardiology care, as stipulated by current recommendations. Equity of access for women and those with lower socioeconomic status appears to be problematic.

Excess visceral fat is a major risk factor for hypertension. Enhanced blood pressure (BP) reactivity and delayed BP recovery from physical and mental challenges predict future hypertension.Determine whether visceral fat is associated with higher BP reactivity and delayed BP recovery from physical and mental challenges during adolescence.In a community-based sample of 283 male and 308 female adolescents, we measured visceral fat with magnetic resonance imaging, total body fat with bioimpedance, and beat-by-beat BP with a Finometer at rest and during physical (10-min standing) and mental (2-min math stress) challenges.Males vs. females showed greater BP reactivity and no differences in BP recovery from either type of challenges. Visceral fat was positively associated with BP reactivity to standing up only and in males only (+8.4 ± 3.6 mmHg per 1 log cm(3) of visceral fat, P = 0.008), and this association was independent of total body fat. No association was seen between visceral fat and BP recovery from either type of challenge in either sex. All these associations were independent of age, puberty stage, height and initial BP.Adolescent males vs. females demonstrate greater BP reactivity but similar BP recovery from physical and mental challenges. Excess visceral fat enhances BP reactivity to physical but not mental challenges in males only.

Background:A. Longo’s circular staple procedure for the treatment of haemorrhoidal disease has given rise to controversies around the globe. The circular staple procedure enables patients to return to normal activity fairly quickly and is, as far as postoperative pain is concerned, superior to conventional procedures. However, long-term results are missing and possible complications remain under scrutiny. A study of this new operative procedure goes hand in hand with a critical evaluation of all surgical procedures for the treatment of haemorrhoidal disease. Methods: We operated on noduli haemorrhoidales interni (NHI) of all degrees. By means of a circular stapler, a mucosal cuff in the distal rectum is excised and prolapsed haemorrhoids are lifted into the proximal anal canal where they regress. No further operating step is required for additional noduli haemorrhoidales externi and fissures. Marisks and skin tags are ablated separately. Surgery is performed under general anaesthesia, only in rare cases under spinal anaesthesia. Postoperative wound care is not performed. Symptoms and findings were documented in linear, analogue charts and patients were interviewed preoperatively, on the day of surgery, as well as postoperatively on the second and eighth day and after 1, 6 and 12 months. Results: We operated on 258 patients with an age of 51.2 ± 13.3 years. The average length of surgery amounted to 28 (range: 15–55) minutes, patients were admitted as in-patients for 5.7 ± 2.35 days and the median recovery-phase lasted 7 (IQR: 4–10) days. Analgesia was standardised. All patients were given intravenous Tramadolhydrochloride (100–200 mg) postoperatively. 56.3% did not require additional analgesia and the remaining patients were given Tramadol (4.5 ± 2.0 capsules of 50 mg per patient) orally. 11.0% of the patients required additional strong analgesia parenterally. 13.6% developed urinary retention that required to be catheterized. 42 patients (16.6%) developed secondary bleeding and 10 patients (3.8%) required surgery for haemostasis. Urgent bowel movement was encountered as the most common side-effect with 30.0% of the cases. Major complications did not occur. The downstaging of the haemorrhoidal degree was satisfactory. 5 patients underwent postoperative rubber-band ligation for small remaining nodules and one patient required corretive Milligan haemorrhoidectomy. Conclusions:A. Longo’s stapler resection is a reliable therapy for haemorrhoidal disease causing minimal operative strain. It leads to immediate manageability of symptoms and initiates a healing process of the pathological anatomy of haemorrhoids. Rare cases with patients experiencing considerable pain are documented. Secondary bleeding may occur, but is easily suppressed. Urgent bowel movement is the most common and lengthy side-effect, but generally speaking, patients do not consider it impairing. With rare cases, remaining internal nodules have to be corrected by rubber-band ligation. External haemorrhoids regress spontaneously. If considered impairing, marisks and skin tags are ablated separately.

Introduction Les etudes pronostiques estiment souvent des courbes de survie qui decrivent comment la probabilite d’un evenement d’interet change avec la duree de suivi, pour des patients avec differents vecteurs de covariables. Cependant, la validite de ces estimations, et des predictions de risque qui en resultent, depend en grande partie de la precision de l’estimation des effets des covariables evaluees. Pour eviter les hypotheses de risques proportionnels et de linearite conventionnelles, des extensions flexibles du modele de Cox a risques proportionnels incorporent des effets non lineaires (NL) et/ou des effets dependants du temps (TD). Cependant, leur impact sur l’estimation des courbes de survie n’est pas clair. Methodes Nous proposons un modele multivarie flexible pour estimer des courbes de survie individuelles, conditionnelles aux effets NL et/ou TD des covariables. Les fonctions TD et NL ainsi que le logarithme de la fonction de risque de base sont representes par des fonctions splines. Nous validons par simulations nos estimations des courbes de survie et les comparons avec les estimations conventionnelles, basees sur le modele de Cox a risques proportionnels combine avec l’estimateur de Breslow. Nous appliquons alors notre methode pour reevaluer les effets de plusieurs facteurs pronostiques sur la mortalite apres un choc septique. La cohorte etudiee inclus tous les adultes avec un diagnostic de choc septique, admis dans 14 unites de soins intensifs dans 10 hopitaux du Nord-Est de la France, entre octobre 2009 et septembre 2011. L’instant initial est defini comme l’initiation de vasopresseurs en reponse au choc septique et l’evenement d’interet est le deces (toute cause confondue) dans les trois premiers mois suivant le choc septique. Les patients toujours vivants trois mois apres le choc septique ont ete censures a trois mois. La duree de suivie mediane est de 63,5 jours et on observe 433 deces parmi les 858 patients ayant des donnees completes. Resultats Les simulations demontrent que la prise en compte des effets TD et NL peut grandement ameliorer les resultats des etudes pronostiques et que nos estimations flexibles des courbes de survie etaient non biaisees et avaient des erreurs quadratiques moyennes beaucoup plus faibles que les estimations conventionnelles. Dans les analyses appliquees a la mortalite apres un choc septique, notre modele a tres significativement ameliore la deviance (LRT = 84,8, df = 20, p Conclusion La prise en compte des effets non lineaires et/ou dependants du temps des facteurs pronostiques peut considerablement ameliorer la precision des etudes pronostiques.

To determine the feasibility and value of using patient satisfaction ratings to evaluate the physician-patient relationship skills of medical residents.A cross-sectional survey was used to collect patient satisfaction information for medical residents from all patients attending the out-patient teaching clinics over a three-month period. The feasibility of patient rating was assessed by evaluating the reliability of resident satisfaction scores and potential sources of bias in rating. The value of using this method was assessed by evaluating the proportion of variance in ratings attributable to residents, the prevalence of residents with ratings substantially below average, and the effect of training on patient satisfaction.The medical clinics of two teaching hospitals at McGill University.91 medical residents and clinical clerks, 1,003 patients, and 1,219 visit ratings.An average of 12.2 satisfaction ratings were collected per resident, providing a reliability of 0.56 (intraclass correlation) for resident satisfaction score. Adjustment for differences in patient populations would be necessary to obtain comparable scores among residents. Fifteen percent of the residents had a substantially greater proportion of poor and fair satisfaction ratings than the study average. Residents were responsible for a substantial proportion of the variance in clinic waiting time and patient satisfaction rating. Training appeared to have no effect on improving satisfaction scores, except among women residents.Patient satisfaction ratings provide valuable information about a resident's ability to establish an effective physician-patient relationship. However, the number of ratings required to obtain a reliable estimate of resident skill may limit the feasibility of using patient ratings as part of residency evaluation.

One biceps muscle of 8 patients with Duchenne muscular dystrophy was injected at 55 sites with a total of 55 million viable, purified, and contamination-free normal myoblasts (myoblast transfer). The other biceps of each patient was injected with a placebo to serve as a control. The procedure was blinded to the patients, parents, and investigators. Myoblasts derived from a biopsy specimen of the fathers were cultured and purified under strict conditions and carefully screened for microbial contamination. All patients received cyclophosphamide for immunosuppression for 6 or 12 months. No serious complications were observed after myoblast transfer, indicating that the procedure is safe. The overall therapeutic efficiency of myoblast transfer was poor as judged by the results in maximal voluntary force generation, dystrophin content of the muscle, magnetic resonance imaging of the muscle, and the lack of donor-derived DNA and dystrophin messenger RNA in the injected muscle. An improved efficiency of the take of myoblasts might be achieved by using younger cells and injecting the myoblasts with a myonecrotic agent (to increase the prevalence of regeneration) and a basal laminal fenestrating agent.

In sub-Saharan Africa, problems of access to relevant and high-quality facility-based statistics hinder the assessment of safe motherhood programs. The objective of this study was to assess the quality of data collected in referral hospitals in Mali and Senegal after the routine information system (RIS) was strengthened.This was a multicenter observational study conducted during the pre-intervention period of a randomized controlled trial (trial QUARITE). The RIS was strengthened based on technical, organizational and behavioral factors. We included all women who gave birth in the 46 referral hospitals from October 1, 2007 to October 30, 2008. The completeness, completion and accuracy rates were monitored every 3 months in each hospital. The cost of investment needed to strengthen the existing RIS was also determined.The mean completeness rate ranged from 94 to 97% depending on the study period. The completion and accuracy rates increased during the study period from 72% and 79% to 87% and 93%, respectively (significant differences). The average investment per hospital was less than 1% of state subsidies for public hospitals.Strengthening the existing information system has set up an economically and technologically appropriate system for monitoring maternal and perinatal health in Senegal and Mali. We encourage policy makers and researchers from countries with limited resources to invest in RIS to improve and monitor the performance of health systems.

Background Disease-modifying anti-rheumatic drugs (DMARDs) generally have the greatest impact if they are initiated early in the course of the disease. We hypothesized that greater cumulative exposure to DMARDs soon after RA diagnosis is associated with longer time to joint surgeries. Objectives To evaluate early exposure to DMARDs and time to joint surgery, comparing incident rheumatoid arthritis (RA) populations from Ontario (ON) and Quebec (QC). Methods Using a standard protocol, we performed population-based cohort analyses on new-onset RA patients in ON and QC from 2000-2013. Incident RA patients were followed from cohort entry until their first joint surgery, or were censored at death date, or the end of study period, whichever came first. We studied all recipients of public drug coverage, aged 66 years and older. Analyses were confined to “new users” for the drug of interest. We used Cox proportional hazards regression with time-dependent variables measuring duration of drug use (daily exposures in the first year of follow-up), separately for methotrexate and other DMARDs, adjusting for baseline age, sex, urban vs. rural residence, socioeconomic status, co-existing osteoarthritis (OA), comorbidities, prior joint surgeries, extra-articular RA manifestations, time-varying number of physician visits, and drug exposures (anti-TNF inhibitors, COXIBs, NSAIDs, systemic steroids). Adjusted hazard ratios (HRs) along with 95% confidence intervals (CIs), were estimated. Results Among 20,918 ON and 6,740 QC RA patients, 68% were female and the mean (SD) age was 75 (6) years in each setting. During follow-up, 2,201 (11%) in ON and 494 (7%) patients in QC underwent joint surgery, for a rate of 2 events per 100 person-years in both settings. In the multivariable analyses, greater exposure to methotrexate (HR 0.97 95%CI 0.95-0.98), and other DMARDs (HR 0.98 95%CI 0.97-0.99) within the first year was associated with longer time to surgery in both settings. The strongest independent associations with shorter time to surgery in ON and QC, respectively, included previous joint surgeries [HR=1.9 vs. 2.8], co-existing OA [HR=1.5 vs. 1.8], and greater exposure to NSAIDs [HR=1.2 vs. 1.3], and COXIBs [HR=1.1 vs. 1.3]. Conclusions Greater cumulative exposures to methotrexate and other DMARDs, within 1 year after RA diagnosis, were associated with longer time to joint surgeries in both ON and QC. Our coordinated approach across provincial data sources identified highly comparable and consistent findings. Disclosure of Interest None declared

Background Comorbidity is an important prognosis and health outcome in rheumatic diseases and an important confounder or effect modifier in epidemiologic studies. Researchers face challenges regarding the optimal way to accurately measure comorbidity and there is a lack of information on the reporting and level of agreement of comorbidities obtained from different data sources. Objectives We investigated the prevalence of reporting and level of agreement of three specific comorbidities independently ascertained from rheumatologists, patients and health administrative data. Methods We studied patients enrolled in the Ontario Best Practices Research Initiative RA registry, which embeds clinical data collection into routine practice. Patients and rheumatologists independently report comorbidities using standardized questionnaires. To identify comorbidities ascertained from health administrative data, we performed deterministic linkage using coded health insurance numbers to link with the Ontario Cancer Registry, and the Ontario Diabetes Database and the Ontario Hypertension Database - the latter two of which are derived using validated administrative data case definitions. For these initial comorbidities of interest, we report the prevalence of each condition based on the method of ascertainment and the level agreement between data sources. Sensitivity, specificity and predictive values were calculated by alternating the reference standard (rheumatologist or patient) to assess the accuracy of the administrative data definitions. Results 1787 patients (97%) were successfully linked. The prevalence of cancer, diabetes and hypertension reported by rheumatologists were lower than those reported by both patients and administrative data (table). Patients reported more cancers than rheumatologists and administrative data, which is further illustrated in the lower sensitivity of administrative data in detecting cancers. There was substantial agreement between each of the three comorbidities ascertained from each data source (kappas ranging from 0.53-0.79). The accuracy of administrative data for comorbidity ascertainment was modest to excellent, regardless of the reference standard definition. Conclusions For the initial comorbidities we studied, there was substantial correlation between rheumatologists, patients and health administrative data, but the prevalence varied by data source. Patients reported more previous cancers, which may reflect that basal and squamous cell carcinomas are not registered in the Cancer Registry or cancers pre-dating capture in the Registry. Thus, linkages between clinical registries (which capture patient- and physician-reported outcomes) and administrative data may overcome some of the limitations of imperfect ascertainment from using one data source alone. Acknowledgements Disclosure of Interest None declared

Background Patients with rheumatoid arthritis (RA) have an increased mortality compared with the general population. 1 Established risk factors for premature mortality include active inflammation/disease activity, comorbidity and extra-articular disease manifestations. Thus, early and greater exposure to disease-modifying anti-rheumatic drugs (DMARDs) may mitigate these risk factors and improve survival in RA. Objectives Our aim was to evaluate the associations between RA drug exposures and survival in seniors with incident RA. Methods This retrospective cohort study investigated all incident cases of RA diagnosed from 2000 to 2013. We studied a subset of patients within the Ontario RA Database (ORAD) - a validated population-based cohort of all Ontarians with RA - who were aged 66 years and older who have comprehensive public drug insurance. We used Cox proportional hazards regression to investigate mortality, defined as death from any cause, exploring time-dependent cumulative drug exposures during the entire duration of follow-up, while adjusting for baseline age, sex, urban vs. rural residence, socioeconomic status, pre-existing comorbidities (e.g. hypertension, COPD, diabetes, coronary artery disease, cancer), past drug exposures, time-dependent number of physician visits, and extra-articular manifestations of RA (as proxies for RA severity). Adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated. Results Among 25,416 senior RA patients, 67.8% were female, the mean (SD) age was 75.2 (6.5) years, and 85.4% lived in urban areas. During median and maximum follow-up times of 4.4 and 13.2 years, respectively, 7,956 patients died (31.3%) for a mortality rate of 6.2 per 100 person-years. In multivariable analyses, we observed no association between greater cumulative exposure to methotrexate, other DMARDs, or anti-TNF agents and survival. Greater exposure to corticosteroids was associated with greater risk of mortality [HR 1.15 (95% CI 1.14-1.17)], as were greater baseline comorbidity [Charlson HR 1.36 (95% CI 1.34-1.38)] and extra articular disease [HR 1.53 (95% CI 1.47, 1.61)]. Females and residents living in urban areas had lower mortality risk [HR 0.78 (95% CI 0.75-0.82) and HR 0.92 (95% CI 0.86-0.98), respectively]. Conclusions Though we could not demonstrate an association between exposure to DMARDs and over-all survival in seniors with RA, cause-specific mortality warrants further investigation. Greater exposure to corticosteroids, comorbidity and extra articular RA was associated with pre-mature mortality in our sample. References Widdifield et al, Trends in Excess Mortality among Patients with Rheumatoid Arthritis in Ontario, Canada. Arthritis Care & Research 2015 [in press]. Disclosure of Interest None declared

Background Nonbiologic Disease-modifying anti-rheumatic drugs (nbDMARDs) and anti-tumor necrosis factor (anti-TNFs) have been used in AS patients who do not respond adequately to non-steroidal anti-inflammatories (NSAIDs). However, concerns exist regarding the risk of serious infections 1 . Objectives To assess the risk of serious infections associated with nbDMARDs or anti-TNF use in an AS cohort. Methods We assembled a cohort of potential AS patients identified from hospitalization discharge diagnoses or physician visit billing claims, using ICD-9 code 720 or ICD10 code M45. Patients were required to have two or more ICD codes and at least one anti-TNF or nbDMARD exposure between January 1, 2001 and December 31, 2011. Cohort entry was defined as the date of the first of these prescriptions and analysis was restricted to individuals who had not used anti-TNF drugs prior to cohort entry. Patients were excluded if they were not covered by the Quebec drug plan 1 year before the first prescription of nbDMARDs and/or an anti-TNF agent. We used Cox regression with the following three time-varying drug exposure categories: 1) nbDMARDs, 2) anti-TNF agents alone or in combination with nbDMARDs, and 3) neither drug. Models were adjusted for baseline patient sociodemographics, co-morbidity, prior health service use, and time-dependent use of NSAIDs, and corticosteroids. Current time-dependent corticosteroids dose was standardized according to the Defined Daily Dose (DDD) system. The outcome, first occurrence of an infection requiring hospitalization, was identified from hospitalization discharge diagnoses (primary or non-primary). Results We studied 714 AS patients; 469 (65.7%) were men, with a mean age of 50.3 (standard deviation 14.1) years at cohort entry. During this period, 57 cases of serious infections occurred, for an incidence rate of 3.07/100 PY. The median time from cohort entry to serious infection was 2.1 years. The incidence of serious infection was 4.12/100 PY in patients exposed to nbDMARDs alone, 2.44/100 PY in the anti-TNF +/- nbDMARDs group, and 2.25/100 PY in unexposed patients. Age, prior health service use, and use of corticosteroids in the previous year were associated with increased risk of infection in our multivariate analysis. The 95% confidence intervals, CIs, for the adjusted hazard ratios (HR) of infection (with the unexposed group as comparator) were wide and overlapping for both anti-TNF+/- nbDMARDs (HR=1.05; 95% CI 0.45-2.45) and nbDMARDs alone (HR=1.77; 95% CI 0.78-4.02). Conclusions We present novel findings demonstrating that the risk of serious infection in AS is 3% per year. In the current analyses, we were unable to draw definitive conclusions regarding the whether serious infections in AS are higher with anti-TNF or nbDMARDs use, versus non-use. However, older age, prior health service use, and use of corticosteroids appear to be important risk factors for serious infection in AS. References Grijalva CG et al. (2011). Initiation of tumor necrosis factor-α antagonists and the risk of hospitalization for infection in patients with autoimmune diseases. JAMA. 306(21):2331-9. Acknowledgements Canadian Institutes for Health Research (CIHR) Disclosure of Interest None declared

There is a growing demand for interdisciplinary rehabilitation services for children with developmental disabilities, however, information is lacking on service utilization patterns. This study describes the type, frequency and location of initial rehabilitation services provided to young children recently diagnosed with a developmental delay.A telephone survey was conducted on a consecutive cohort of children referred to subspecialists for the first investigation of their delay.Out of 129 respondents, only 30 (23%) did not receive any rehabilitation services within the first 6 months following medical evaluation, and 61 (47%) received two or more services. Services were provided most frequently in the hospital setting, especially for occupational or physical therapy (73-80%). Services were less often rendered in a rehabilitation centre (5-13%) or in the community (10%). Services were provided privately for a subset, particularly for speech language pathology and psychology (34% and 30% respectively). Interventions were typically given weekly or bi-weekly. Children receiving physical therapy were significantly younger whereas children referred to speech language pathology were older than the age of our cohort at intake. Overall, parents' educational level did not influence services received with the exception of private services, which were more likely to occur in children of fathers with university education.The findings would suggest that long waiting times and lack of resources may limit access to comprehensive services, particularly in community settings. Service utilization patterns were not consistent within types of developmental disability, suggesting that formal and co-ordinated interdisciplinary programmes are not in place for this population of interest.

Background Early DMARD use in RA may prevent damage and possibly, need for joint replacement. Objectives To assess joint replacements within incident RA patients in Quebec, Canada, and potential associations with early DMARD use. Methods A cohort of incident RA patients was identified from Quebec9s physician billing and hospitalization databases from 2002-2008; all patients covered by the provincial drug insurance for the duration of the study were included in analyses. We used Cox regression with time-dependent variables for: 1) methotrexate (MTX) use, 2) other non-biologic DMARDs and 3) anti-tumor necrosis factor (TNF) agents. Models were adjusted for baseline sociodemographic characteristics, co-morbidity including pre-existing osteoarthritis, and prior health service use, and for time-dependent variables reflecting cumulative use of other drugs (COXIBs, NSAIDs, and systemic steroids) and time-dependent indicators of disease severity (extra-articular RA features and number of rheumatology visits). The outcome (any joint replacement) was defined using procedure codes. Results During follow-up, 321 joint replacements occurred among 5,199 incident RA patients observed for a total of 19,693 years (1.6 events/100 person-years). The best-fitting models relied on cumulative duration of MTX and cumulative duration of non-MTX traditional DMARD use in the first year after RA diagnosis. Controlling for anti-TNF exposure, joint replacement rates throughout follow-up appeared to be significantly lower with greater cumulative MTX and with greater cumulative non-MTX traditional DMARD use in the first year of RA (Hazard ratio, HR=0.95 per month of MTX use, 95% Confidence Interval, CI 0.91-0.98; HR=0.93 per month of use of non-MTX traditional DMARDs, 95% CI 0.90-0.97). However, patients receiving both MTX and non-MTX traditional DMARDs, concurrently or sequentially, within the first year after RA onset, had a significantly higher risk of joint replacement than those who used only one of the two drug classes within the first year. We could not establish independent effects for anti-TNF agents. Conclusions Higher cumulative use of MTX and higher cumulative use of non-MTX traditional DMARDs within the first year after RA diagnosis appeared to be associated with fewer joint replacements. This may be consistent with joint-sparing effects of aggressive, early use of these drugs, though a causal link cannot be established with these observational data. The increased joint replacement risk in patients taking both MTX and other DMARDS, concurrently or sequentially, in the first year, suggests potential confounding by indication, as patients taking multiple drugs may have more severe disease, and greater risk for joint damage. References Gramling A, O9Dell JR (2012). Initial management of rheumatoid arthritis. Rheum. Dis. Clin. North Am. 38 (2): 311–25. Acknowledgements Canadian Institutes for Health Research/Drug Safety and Effectiveness Network (CIHR/DSEN) Disclosure of Interest : None declared DOI 10.1136/annrheumdis-2014-eular.3061

In perinatal research and clinical practice, gestational age is a crucial variable for measuring foetal 'growth' (birth weight for gestational age) and for estimating the risk of mortality and morbidity, yet reported gestational age values are affected by random and systematic errors due to the absence of a gold standard measure. Previous investigators have used birth weight (which is measured with greater validity and precision than is gestational age) to correct such errors, but existing methods are inadequate due to unreasonable assumptions about the distributions of birth weight and gestational age. We propose a new method for identifying and correcting implausible observations using the expectation-maximization (EM) algorithm. Using population-based data from U.S. birth certificates, we compare the resulting gestational ages, birth weight distributions at each gestational age, and gestational age-specific infant mortality based on the new method with those on the same population produced by previous published correction methods. The new method gives the best birth weight distributions for gestational age and the most realistic gestational-age-specific mortality rates, while each of the other methods has at least one significant flaw.

The frequency of coronary heart disease (CHD) and stroke are increased in systemic lupus erythematosus (SLE), but the extent of the increase is uncertain. We sought to determine to what extent the increase could not be explained by common risk factors.The participants at two SLE registries were assessed retrospectively for the baseline level of the Framingham study risk factors and for the presence of vascular outcomes: nonfatal myocardial infarction (MI), death due to CHD, overall CHD (nonfatal MI, death due to CHD, angina pectoris, and congestive heart failure due to CHD), and stroke. For each patient, the probability of the given outcome was estimated based on the individual's risk profile and the Framingham multiple logistic regression model, corrected for observed followup. Ninety-five percent confidence intervals (95% CIs) were estimated by bootstrap techniques.Of 296 SLE patients, 33 with a vascular event prior to baseline were excluded. Of the 263 remaining patients, 34 had CHD events (17 nonfatal MIs, 12 CHD deaths) and 16 had strokes over a mean followup period of 8.6 years. After controlling for common risk factors at baseline, the increase in relative risk for these outcomes was 10.1 for nonfatal MI (95% CI 5.8-15.6), 17.0 for death due to CHD (95% CI 8.1-29.7), 7.5 for overall CHD (95% CI 5.1-10.4), and 7.9 for stroke (95% CI 4.0-13.6).There is a substantial and statistically significant increase in CHD and stroke in SLE that cannot be fully explained by traditional Framingham risk factors alone.

The Cox model is widely used in the evaluation of prognostic factors in clinical research. In population-based studies, however, which assess long-term survival of unselected populations, relative survival models are often considered more appropriate. In both approaches, the validity of proportional hazard hypothesis should be evaluated. To explore the validity of the proportional hazard assumption in a population-based study of colon cancer, to propose non-proportional hazard relative survival models and to evaluate their utility. The use of a piecewise proportional hazard relative survival model in colon cancer has shown that the effects of most clinical prognostic factors such as age, period of diagnosis and stage are non-proportional. The non-proportional hazard relative survival models developed in this article have been found to be efficient tools for better understanding the time-dependent aspect of prognostic factors.

New scales for the clinical assessment of patients with systemic lupus erythematosus (SLE) are valid and reliable, and quantitate disease activity. We assessed the responsiveness to change of 2 widely used standardized multi-item lupus activity measures, the revised Systemic Lupus Activity Measure (SLAM-R) and the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI), and their ability to detect clinically relevant changes.Ninety-six (96) patients with definite SLE participated in this study. The group mean age was 45.0 (13.7) years, 91% were female, and the mean disease duration was 14.9 (7.5) years. Sociodemographic information, lupus activity (SLAM-R, SLEDAI), and damage were recorded at baseline. At each of the 5 monthly followup visits, the activity measures were repeated and a transition scale asked the physician if their patient's lupus activity had changed. Five different methods were used to compare the responsiveness of the activity measures studied: 1. the effect size; 2. the standardized response mean; 3. the control standardized response mean; 4. the area under the curve of a receiver operating characteristic (ROC) curve; and 5. a new multiple response modeling approach.Both SLAM-R and SLEDAI are responsive. SLAM-R is consistently, although moderately, more responsive than SLEDAI. All 5 methods of evaluating responsiveness yielded a consistent ranking of disease activity measures.SLAM-R and SLEDAI are responsive measures of lupus activity. SLAM-R appears to be more responsive than SLEDAI.

To determine whether the ability of baseline clinical stage, viremia, and CD4 cell counts to predict mortality in HIV-1-infected patients changes with duration of follow-up.Three hundred ninety-four patients were followed for an average of 29 months by the Swiss HIV Cohort Study, a practice-based registry of HIV-1-infected patients in Switzerland. Predictor variables were the baseline clinical stage, CD4 cell count, circulating HIV-1 RNA level, and the RNA/CD4 ratio; the outcome was death. The changes in relative risks of death over time were examined using survival models that extend the Cox model to allow for nonproportionality of hazards.During 949 person-years of follow-up, 169 patients died (mortality rate 17.8 per 100 person-years). Compared with clinical stage A, patients in stages B and C at baseline had much higher mortality rates in the subsequent year. The prognostic ability of stage C decayed over time (P = 0.03). By contrast, the relative risks associated with a 2-fold difference in CD4 counts remained remarkably stable, at approximately 0.6 (P = 0.81 for the time-dependence test). Relative hazards associated with a 10-fold difference in HIV RNA per milliliter and in HIV RNA per CD4 cell both tended to increase over time, but this trend failed to reach statistical significance (P = 0.21 and P = 0.08, respectively).Time-dependence patterns of prognostic ability varied widely among predictors, displaying gradual decay (clinical stage), stability (CD4 cells), and a trend to progressive increase (viremia). These results may affect clinical monitoring of HIV-infected patients and the interpretation of cohort studies of HIV-infected patients.

In the analysis of survival data using the Cox proportional hazard model, it is assumed that the magnitude of mortality risk for a predictor variable remains proportional over time. The time-dependent linear model and the piece-wise proportional hazard model (two or four intervals) take into account the variation of the risk over the entire follow-up period.The three existing models were applied to a series of 266 patients with acute myeloid leukaemia (AML), diagnosed between 1980 and 1992 and recorded by the Registry of Hematopoietic Neoplasms in Côte d'Or, France.A non-proportional effect of age, period of diagnosis, whether the illness was primary or secondary and French-American-British (FAB) subtype was found significant. In particular, the effect of M2 versus M4-M5 subtypes was revealed by the non-proportional analyses, although this effect was non-significant using the Cox model.The clinical explanation of the variation of these effects over time is discussed, for example, relating the increase over time of the positive effect of the period of diagnosis to therapeutic improvements. Confirmation of these results on an independent data set is required.

Context.—Clinical competence is a determinant of the quality of care delivered, and may be associated with use of health care resources by primary care physicians. Clinical competence is assumed to be assessed by licensing examinations, yet there is a paucity of information on whether scores achieved predict subsequent practice.Objective.—To determine if licensing examination scores were associated with selected aspects of quality of care and resource use in initial primary care practice.Design.—Prospective cohort study of recently licensed family physicians, followed up for the first 18 months of practice.Setting.—The Quebec health care system.Participants.—A total of 614 family physicians who passed the licensing examination between 1991 and 1993 and entered fee-for-service practice in Quebec.Main Outcome Measures.—All patients seen by physicians were identified by the universal health insurance board and all health services provided to these patients were retrieved for the 18 months prior to (baseline) and after (follow-up) the physicians' entry into practice. Medical service and prescription claims files were used to measure rates of resource use (specialty consultation, symptom-relief prescribing compared with disease-specific prescribing) and quality of care (inappropriate prescribing, mammography screening). Baseline data were used to adjust for differences in practice population.Results.—Study physicians saw a total of 1116389 patients, of whom 113535 (10.2%) were elderly and 83391 (7.5%) were women aged 50 to 69 years. Physicians with higher licensing examination scores referred more of their patients for consultation (3.8/1000 patients per SD increase in score; 95% confidence interval [CI], 1.2-7.0; P=.005), prescribed to elderly patients fewer inappropriate medications (−2.7/1000 patients per SD increase in score; 95% CI, −4.8 to −0.7; P =.009) and more disease-specific medications relative to symptom-relief medications (3.9/1000 patients per SD increase in score; 95% CI, 0.3 to 7.4; P=.03), and referred more women aged 50 to 69 years (6.6/1000 patients per SD increase in score; 95% CI, 1.2-11.9; P=.02) for mammography screening. If patients of physicians with the lowest scores had experienced the same rates of consultation, prescribing, and screening as patients of physicians with the highest scores, an additional 3027 patients would have been referred, 179 fewer elderly patients would have been prescribed symptom-relief medication, 912 more elderly patients would have been prescribed disease-specific medication, 189 fewer patients would have received inappropriate medication, and 121 more women would have received mammography screening.Conclusions.—Licensing examination scores are significant predictors of consultation, prescribing, and mammography screening rates in initial primary care practice.

Interest in the training and evaluation of laparoscopic skills is extending beyond the realm of the operating room to the use of laparoscopic simulators. The purpose of this study was to develop a series of structured tasks to objectively measure laparoscopic skills. This model was then used to test for the effects of level of training and practice on performance.Forty-two subjects (6 each of surgical residents PGY1 to PGY5, 6 surgeons who practice laparoscopy and 6 who do not) were evaluated. Each subject viewed a 20-minute introductory video, then was tested performing 7 laparoscopic tasks (peg transfers, pattern cutting, clip and divide, endolooping, mesh placement and fixation, suturing with intracorporeal or extracorporeal knots). Performance was measured using a scoring system rewarding precision and speed. Each candidate repeated all 7 tasks and was rescored. Data were analyzed by linear regression to assess the relationship of performance with level of residency training for each task, and by ANOVA with repeated measures to test for effects of level of training, of repetition, and of the interaction between level of training and repetition on overall performance. Student's t test was used to evaluate differences between laparoscopic and nonlaparoscopic surgeons and between each of these groups and the PGY 5 level of surgical residents.Significant predictors of overall performance were (a) level of training (P = 0.002), (b) repetition (P0.0001), and (c) interaction between level of training and practice (P = 0.001). There was also a significant interaction between level of training and the specific task on performance scores (P = 0.006). When each task was evaluated individually for the 30 residents, 4 of the 7 tasks (tasks 1, 2, 6, 7) showed significant correlation between PGY level and score. A significant difference in performance scores between laparoscopic and nonlaparoscopic surgeons was seen for tasks 1, 2, and 6.A model was developed to evaluate laparoscopic skills. Construct validity was demonstrated by measuring significant improvement in performance with increasing residency training, and with practice. Further validation will require correlation of performance in the model with skill in vivo.

To explore the relationship between patients' systemic lupus erythematosus (SLE) activity and physicians' decision to treat with steroids or alternative medication.Baseline information and clinical status was extracted from case histories of 30 patients with lupus and represented in clinical vignettes. These vignettes were then mailed to 60 physicians (rheumatologists and immunologists with experience in the treatment of lupus), asking them in each case whether they would initiate treatment or not. The relationship between the 38 complete responses and the SLE Activity Measure (SLAM-R) and SLE Disease Activity Index (SLEDAI) lupus activity scores was analyzed using a general additive model.SLE disease activity measured by SLAM-R or SLEDAI is a significant predictor (p0.0001) of physicians' decision to initiate treatment for patients with lupus. Variation between physicians was observed but was mostly due to a few outliers. Some other variations remained unexplained by patients' SLE disease activity, damage, or by specific organ involvement.We present reference tables and curves for research that may be used as a basis to derive standardized quantitative criteria for entry in clinical trials. More research is needed on how these tools can be used by clinicians to guide them in their decision to treat or not.

The distributions of sensory thresholds were estimated in a healthy population while controlling for potential covariates. Using the method of levels and the two-alternative forced choice, thermal and vibration thresholds respectively were measured in the hand and foot of 148 subjects. Age was uniformly distributed between 20 and 86 years. Independent effects of age, gender, height, and skin temperature were estimated using multiple linear regression. Parametric and nonparametric methods were used to estimate the distributions of interest. Significant age-related increases were observed for all vibration thresholds (P0.0001), and for thermal thresholds in the foot (P0.0002). Percentiles were estimated for thermal thresholds in the hand and age-adjusted continuous distributions were calculated for all other thresholds. Height was positively associated with vibration thresholds in the foot (P0.003), and appropriate corrections were made. Our results provide reference values for thermal and vibration sensory thresholds in a healthy population, allowing for the accurate diagnosis of disordered sensory function.

To quantify the factors associated with growth of very small premature infants during initial hospitalization.Study patients were 109 infants who were appropriate for gestational age, weighed1000 g at birth, and were fed intravenous hyperalimentation then calcium-supplemented 81-kcal preterm formula according to a protocol.Multiple regression analysis was performed for periods of 0 to 56, 0 to 14, and 15 to 56 days of age. Growth was determined as change in weight during the period. Variables assessed in the initial model were caloric intake, protein intake, respiratory support duration, patent ductus arteriosus, dexamethasone use, infection, birth weight ratio (weight divided by expected intrauterine weight for gestation), gestational age, sex, calendar time from study start, maternal betamethasone administration, and necrotizing enterocolitis. For the 0 to 14-day period, maximum oxygen requirement for respiratory distress syndrome replaced respiratory support duration, and 5-minute Apgar score was added, whereas dexamethasone and necrotizing enterocolitis were deleted.Mean change in weight was 785 g for 0 to 56 days, -16 g for 0 to 14 days, and 770 g for 15 to 56 days. Mean weight was 94% (13 SD) of mean intrauterine at birth, 73% (10 SD) at 14 days, and 73% (12 SD) at 56 days. Regression models explained 85%, 43%, and 80%, respectively, of variation in growth. Of the initial variables assessed, the following were the independent prognostic determinants of growth. There was a positive association with caloric intake at 0 to 56 days and 15 to 56 days, and with protein intake at 0 to 14 days. Negative associations were found for birth weight ratio and gestational age at 0 to 56 and 0 to 14 days. Respiratory support duration was negatively associated at 15 to 56 days, and dexamethasone was negatively associated at 0 to 56 and 15 to 56 days. Formulas to predict growth were established from the final regression models.The growth failure in appropriate-for-gestational-age,1000-g birth weight infants can be related in part to dexamethasone use and respiratory support duration. Increasing caloric intake and early protein intake improves growth. However, for the majority of these patients, early losses are not corrected completely by 56 days using currently recommended intakes.

Asymptomatic cervical atherosclerosis carries a variable risk of vascular events. We sought to identify patients with asymptomatic cervical bruits who may be at increased risk of developing ischemic events. We conducted a prospective multicenter cohort study of neurologically asymptomatic patients presenting a cervical bruit. Patients had biannual neurologic and carotid duplex evaluation. Association between ultrasonographic findings and vascular events, adjusting for common risk factors, was evaluated. Seven hundred fifteen patients were followed on average for 3.6 years. Mean age was 65 years. At initial visit, 357 subjects had aor = 50% stenosis. Overall, 237 events occurred in 177 patients. Annual rate of all primary vascular events in patients withor = 50% stenosis was 11.0% versus 4.2% in those with50% stenosis (p0.001). Annual rate of stroke and vascular death was 5.5% in theor = 50% group compared with 1.9% in the50% group (p0.001). Yearly rate of unheralded ischemic stroke was 4.2% in subjects withor = 80% stenosis and 1.4% in those with stenosis80% (p0.001). A stroke or TIA was ipsilateral to aor = 80% stenosis in 66% of patients. Progression of carotid stenosis particularly to more than 80% was associated both with a higher rate of ipsilateral neurologic events and overall combined vascular events. Our data suggest that severity of carotid stenosis is the main risk factor predicting occurrence of neurologic and other vascular events. Yearly rate of ipsilateral stroke withor = 50% carotid stenosis is low (1.4%) and most are nondisabling. Progression toor = 80% or occlusion is associated with worse outcome.

To evaluate the sensitivity, specificity, and likelihood ratios of anti-dsDNA, C3, C4, and Clq binding tests for predicting flares in systemic lupus erythematosus (SLE) and to evaluate the conflicting results reported in the recent literature.Test results from 9 to 3 months preceding 83 flares among 53 patients from a cohort study of 202 patients with SLE were assessed for their ability to predict renal and nonrenal flares and all flares combined. A flare was defined as a 6 point rise in a modified SLE Disease Activity Index.For all 4 tests, sensitivity approximated 50% and specificity was less than 75%. For anti-dsDNA, Clq binding, and C4, both positive and negative likelihood ratios were close to 1.0, suggesting little clinical value for routine testing. For C3, likelihood ratios for a positive test approximated 2.0, meeting the minimal level for clinical significance. Review of previous studies suggested that sample size, the use of a standardized disease activity measure to define a flare, the severity of the flare, and the study duration could not explain the discrepant results among studies. The 2 studies with testing every 4 to 6 weeks found that a rising anti-dsDNA predicted flares, while those with less frequent testing did not.While our study provided no major support for routine testing with anti-dsDNA, C3, C4, or Clq binding, additional longitudinal studies are needed to assess monthly testing of anti-dsDNA as a predictor of flare in SLE.

OBJECTIVES: To determine (a) whether the risk of a potentially inappropriate drug combination (PIDC) increases with the number of physicians involved in the medical management of an elderly patient and (b) whether the risk of a PIDC is reduced if a patient has a single primary care physician or a single dispensing pharmacy, or both. DESIGN: Cross-sectional retrospective provincial database study. PARTICIPANTS: A regionally stratified random sample of 51,587 elderly medicare registrants in Quebec who (a) visited at least one physician in 1990, (b) were not living in a health care institution for the entire year and (c) had been dispensed at least one prescription for a cardiovascular drug, a psychotropic drug or a nonsteroidal anti-inflammatory drug (NSAID). OUTCOME MEASURES: Information on all physician visits and drugs dispensed during 1990. Physician claims were used to identify the number of physicians involved in a patient's management and whether the patient had one primary care physician. Prescription claims were used to identify the number of PIDCs, prescribing physicians and dispensing pharmacies. RESULTS: The prevalence of PIDCs ranged from 4.0% (among those in the NSAID group) to 20.3% (among those in the psychotropic drug group). Of the PIDCs identified, 17.6% to 25.8% resulted from contemporaneous prescribing by different physicians. The number of prescribing physicians was the most important risk factor for a PIDC in all drug groups (odds ratio [OR] 1.44 to 1.71). The presence of a single primary care physician lowered the risk for cardiovascular and psychotropic PIDCs (OR 0.70 and 0.79 respectively) but not for NSAID PIDCs (OR 0.94). The use of a single dispensing pharmacy lowered the risk of a PIDC in all drug groups (OR 0.68 to 0.79). CONCLUSION: The greater the number of physicians prescribing medications for an elderly patient, the greater is the risk that the patient will receive a PIDC. A single primary care physician and a single dispensing pharmacy may be "protective" factors in preventing PIDCs.

To determine the effectiveness of aspirin in preventing ischemic events in patients with asymptomatic carotid stenosis.Double-blind, placebo-controlled trial.University-affiliated hospitals.372 neurologically asymptomatic patients with carotid stenosis of 50% or more in at least one artery as determined by luminal diameter reduction on duplex ultrasonography.Patients were randomly assigned to receive either enteric coated aspirin, 325 mg/d, or identically appearing placebo. Duration of therapy was 2.0 years for the aspirin recipients and 1.9 years for the placebo recipients.Patients were scheduled for a clinical examination every 6 months for assessment of the occurrence of any clinical event in the composite end point, which consisted of transient ischemic attack, stroke, myocardial infarction, unstable angina, or death.At baseline, the 188 patients receiving aspirin and the 184 patients receiving placebo had similar demographic, ultrasonographic, and laboratory characteristics. The median duration of follow-up was 2.3 years. The annual rate of all ischemic events and death from any cause was 12.3% for the placebo group and 11.0% for the aspirin group (P = 0.61). The Cox proportional hazards analysis yielded an adjusted hazard ratio (aspirin-placebo) of 0.99 (95% CI, 0.67 to 1.46; P = 0.95). The annual rates for vascular events only were 11% for the placebo group and 10.7% for the aspirin group (P = 0.99). The multivariate analysis yielded a hazard ratio of 1.08 (CI, 0.72 to 1.62; P = 0.71).Aspirin did not have a significant long-term protective effect in asymptomatic patients with high-grade (or = 50%) carotid stenosis.

A survey was undertaken in September 1991 to document current immunization practice across Canada. Information was obtained during interviews with provincial epidemiologists and key persons involved in immunization programs and recorded on standard data collection forms. Variations in practice are described in five areas: public/private health administration; legislation; monitoring system/coverage rates/surveillance; vaccine management and costs. As changes are being considered to immunization programs, a critical examination of issues such as standardization (in coding, in assessment of waste, in assessment of coverage), surveillance systems and the use of serosurveys would be beneficial.

Immunization has unequivocally contributed to large-scale reductions in mortality and morbidity due to infectious diseases. In general, consensus on the scheduling of immunizations has been achieved at the national or international level by immunization advisory committees. However, immunization delivery methods are varied and numerous. Although specific methods have been proposed, compared and evaluated, the available evidence has not been comprehensively summarized for informed public health action. This paper integrates evidence based on scientific documentation, a Canada-wide practice survey and expert opinion to formulate practice recommendations for immunization delivery methods and to identify areas for further research.