The association of objectively ascertained sibling fracture history with major osteoporotic fractures: a population-based cohort study.

We investigated the association of objectively ascertained sibling fracture history with major osteoporotic fracture (hip, forearm, humerus, or clinical spine) risk in a population-based cohort using administrative databases. Sibling fracture history is associated with increased major osteoporotic fracture risk, which has implications for fracture risk prediction. INTRODUCTION: We aimed to determine whether objectively ascertained sibling fracture history is associated with major osteoporotic fracture (MOF; hip, forearm, humerus, or clinical spine) risk. METHODS: This retrospective cohort study used administrative databases from the province of Manitoba, Canada, which has a universal healthcare system. The cohort included men and women 40+ years between 1997 and 2015 with linkage to at least one sibling. The exposure was sibling MOF diagnosis occurring after age 40 years and prior to the outcome. The outcome was incident MOF identified in hospital and physician records using established case definitions. A multivariable Cox proportional hazards regression model was used to estimate the risk of MOF after adjustment for known fracture risk factors. RESULTS: The cohort included 217,527 individuals; 91.9% were linked to full siblings (siblings having the same father and mother) and 49.0% were females. By the end of the study period, 6255 (2.9%) of the siblings had a MOF. During a median follow-up of 11 years (IQR 5-15), 5235 (2.4%) incident MOF were identified in the study cohort, including 234 hip fractures. Sibling MOF history was associated with an increased risk of MOF (hazard ratio [HR] 1.67, 95% confidence interval [CI] 1.44-1.92). The risk was elevated in both men (HR 1.57, 95% CI 1.24-1.98) and women (HR 1.74, 95% CI 1.45-2.08). The highest risk was associated with a sibling diagnosis of forearm fracture (HR 1.81, 95% CI 1.53-2.15). CONCLUSION: Sibling fracture history is associated with increased MOF risk and should be considered as a candidate risk factor for improving fracture risk prediction.

Smokers Display Reduced Glucocorticoid Sensitivity Prior to Symptomatic Chronic Disease Development.

Background: Chronic stress plays a critical role in many of today's diseases and causes of death. Tobacco use reliably increases the likelihood of chronic disease development and premature death. In addition, habitual tobacco use elevates risk of chronic inflammatory diseases, and glucocorticoid therapy is often less effective in smokers compared with nonsmokers. Taken together, smokers may develop glucocorticoid insensitivity, thereby removing the body's greatest anti-inflammatory mechanism. Purpose: The purpose of this study was to examine glucocorticoid sensitivity among 24 smokers and 24 age-, sex-, and body mass index-matched never smokers who were clinically healthy individuals (i.e., no diagnosis or medication use for chronic diseases and normotensive). Method: Participants visited the lab after a 12 hr fast, provided a blood sample, and completed a series of psychosocial questionnaires. Smokers continued smoking ad libitum before the lab visit. Group differences in glucocorticoid sensitivity were examined using ANCOVA and repeated with linear mixed model to account for possible dependence among immune outcomes that matching participants on age, sex, and body mass index may have introduced. Results: Prior to clinical disease onset, smokers' peripheral blood mononuclear cells (PBMCs) exhibited reduced glucocorticoid sensitivity as well as a diminished inflammatory response to lipopolysaccharide compared with never smokers' PBMCs; results were identical regardless of statistical modeling used. Conclusions: Cigarette smoking, a self-initiated pharmacological chronic stressor, may provide a unique opportunity to examine early wear and tear on physiological functioning that may lead to chronic disease development. Additional research into PBMCs' intracellular changes must be examined as well as repeating this study in a larger, more heterogeneous population.

The causes of burn wounds among adult patients treated at Pelonomi Tertiary Hospital, Bloemfontein.

BACKGROUND: Burn injuries account for approximately 180 000 deaths per annum, mostly in low- and middle-income countries. METHOD: This was a prospective, cross-sectional study. The target population consisted of adult patients, hospitalised for burn wounds at Pelonomi Tertiary Hospital in Bloemfontein, between July 2016 and early January 2017. Relevant data was collected by means of a structured interview using a questionnaire. RESULTS: A total of 49 patients were interviewed during the study period. Almost two-thirds of the patients were male (65.3%, n=32). The median age was 33 years (range 18 to 64 years). In most cases, the injury occurred at home (77.6%, n=38). Three quarters of the reported incidents (77.6%, n=38) were considered accidental of which 68.4% (n=26) were related to domestic activities. At the time of the accidental incident, 39.5% (n=15) patients had consumed alcohol. Eleven (22.4%) of the incidents were intentional with 63.6% (n=7) attributed to assault. The two main causes of burn injuries were flames including flaming liquids (59.2%, n=29) and hot liquids (22.5%, n=11). The most frequent area of injury was the left front thigh. CONCLUSION: The predominant cause of burn wounds was flames including flaming liquids, and injuries were mostly accidental in nature. Alcohol consumption and domestic activities were common in accidental burns.

[A PhD completed. Factors subjectively and objectively influencing children's need for orthodontic treatment and their related quality of life]. / Serie: Hora est. Factoren die subjectieve en objectieve orthodontische behandelbehoefte en gerelateerde levenskwaliteit van kinderen beïnvloeden.

Oral health can be measured from the perspective of the professional (objectively) and from the perspective of the patient (subjectively). However, objective and subjective oral health do not match well. The focus of this research, then, is the relationship between objective oral health, subjective oral health and oral health-related quality of life (OHRQoL) in children. These relationships were considered in connection with orthodontic problems. The research was carried out as part of the Generation R Study, a prospective study of the health of 10,000 children in Rotterdam, the Netherlands. Besides malocclusions and caries, several non-clinical factors, such as environmental factors and personal qualities, seemed to have an influence on the subjective need for orthodontic treatment and OHRQoL. Age, gender, ethnicity, and a feeling of self-worth are just like socio-economic factors that result in a variable relationship between subjective and objective oral health. This knowledge cannot only help to support effective communication between professional and patient, but also to develop targeted interventions to promote children's oral health.

Trunk muscle strength tests to predict injuries, attrition and military ability in soldiers.

AIM: Physical fitness is related to injuries, attrition and military ability in military organisations. Therefore, all military organizations of the North Atlantic Treaty Organizations (NATO) test their employees' physical fitness at least once a year. The sit-up test is part of most of the fitness test batteries used. A possible alternative to the sit-up test is the global trunk muscle strength test (TMS). The aim of the present study was to compare the predictability of injuries, attrition and military ability between TMS and sit-up test performances. METHODS: A total of 230 male recruits in a Swiss Army fusilier company completed TMS and sit-up tests in week 1 of military training school. During the following 13 weeks, injuries, attrition and military ability data were collected. Statistical analysis included backward binary regression and receiver operating characteristic (ROC) curve analysis to compare the discriminative power of TMS and the sit-up test to predict injuries, attrition and military ability. RESULTS: ROC analysis revealed larger areas under the curve for total injuries, attrition and military ability for the TMS (areatotal injuries=0.58; areaattrition=0.60; areamilitary ability=0.59) than for the sit-up test (areatotal injuries=0.53; areaattrition=0.50; areamilitary ability=0.56). Binary logistic regression analysis revealed low body mass index, low TMS performance and cigarette smoking to be potential risk factors for injuries; while sit-up performance was extracted from the model. CONCLUSION: The TMS seems to be a valid alternative to the sit-up test in a military setting due to its appropriate results in predicting injuries in the present study.

A homozygous mutation in a consanguineous family consolidates the role of ALDH1A3 in autosomal recessive microphthalmia.

Anomalies of eye development can lead to the rare eye malformations microphthalmia and anophthalmia (small or absent ocular globes), which are genetically very heterogeneous. Several genes have been associated with microphthalmia and anophthalmia, and exome sequencing has contributed to the identification of new genes. Very recently, homozygous variations within ALDH1A3 have been associated with autosomal recessive microphthalmia with or without cysts or coloboma, and with variable subphenotypes of developmental delay/autism spectrum disorder in eight families. In a consanguineous family where three of the five siblings were affected with microphthalmia/coloboma, we identified a novel homozygous missense mutation in ALDH1A3 using exome sequencing. Of the three affected siblings, one had intellectual disability and one had intellectual disability and autism, while the last one presented with normal development. This study contributes further to the description of the clinical spectrum associated with ALDH1A3 mutations, and illustrates the interfamilial clinical variation observed in individuals with ALDH1A3 mutations.

Paclitaxel in self-micro emulsifying formulations: oral bioavailability study in mice.

The anticancer drug paclitaxel is formulated for i.v. administration in a mixture of Cremophor EL and ethanol.Its oral bioavailability is very low due to the action of P-glycoproteinin the gut wall and CYP450 in gut wall and liver.However, proof-of-concept studies using the i.v. formulation diluted in drinking water have demonstrated the feasibility of the oral route as an alternative when given in combination with inhibitors of P-glycoprotein and CYP450. Because of the unacceptable pharmaceutical properties of the drinking solution, a better formulation for oral application is needed.We have evaluated the suitability of various self-micro emulsifying oily formulations (SMEOF's) of paclitaxel for oral application using wild-type and P-glycoprotein knockout mice and cyclosporin A (CsA) as P-glycoprotein and CYP450 inhibitor. The oral bioavailability of paclitaxel in all SMEOF's without concomitant CsA was low in wild-type mice, showing that this vehicle does not enhance intestinal uptake by itself.Paclitaxel (10 mg/kg) in SMEOF#3 given with CsA resulted in plasma levels that were comparable to the Cremophor ELethanol containing drinking solution plus CsA. Whereas the AUC increased linearly with the oral paclitaxel dose in P-glycoprotein knockout mice, it increased less than proportional in wild-type mice given with CsA. In both strains more unchanged paclitaxel was recovered in the feces at higher doses. This observation most likely reflects more profound precipitation of paclitaxel within the gastro-intestinal tract at higher doses. The resulting absolute reduction in absorption of paclitaxel from the gut was possibly concealed by partial saturation of first-pass metabolism when P-glycoprotein was absent. In conclusion, SMEOF's maybe a useful vehicle for oral delivery of paclitaxel in combination with CsA, although the physical stability within the gastro-intestinal tract remains a critical issue, especially when applied at higher dose levels.

Population pharmacokinetics of intravenously and orally administered docetaxel with or without co-administration of ritonavir in patients with advanced cancer.

AIM: Docetaxel has a low oral bioavailability due to affinity for P-glycoprotein and cytochrome P450 (CYP) 3A4 enzymes. Inhibition of the CYP3A4 enzymes by ritonavir resulted in increased oral bioavailability. The aim of this study was to develop a population pharmacokinetic (PK) model and to evaluate and quantify the influence of ritonavir on the PK of docetaxel. METHODS: Data from two clinical trials were included in the data analysis, in which docetaxel (75 mg m(-2) or 100 mg) had been administered intravenously or orally (10 mg or 100 mg) with or without co-administration of oral ritonavir (100 mg). Population modelling was performed using non-linear mixed effects modelling. A three-compartment model was used to describe the i.v. data. PK data after oral administration, with or without co-administration of ritonavir, were incorporated into the model. RESULTS: Gut bioavailability of docetaxel increased approximately two-fold from 19 to 39% (CV 13%) with ritonavir co-administration. The hepatic extraction ratio and the elimination rate of docetaxel were best described by estimating the intrinsic clearance. Ritonavir was found to inhibit in a concentration dependent manner the intrinsic clearance of docetaxel, which was described by an inhibition constant of 0.028 microg ml(-1) (CV 36%). A maximum inhibition of docetaxel clearance of more then 90% was reached. CONCLUSIONS: A PK model describing both the PK of orally and intravenously administered docetaxel in combination with ritonavir, was successfully developed. Co-administration of ritonavir lead to increased oral absorption and reduced elimination rate of docetaxel.

A new microduplication syndrome encompassing the region of the Miller-Dieker (17p13 deletion) syndrome.

BACKGROUND: The use of array comparative genome hybridisation (CGH) analyses for investigation of children with mental retardation has led to the identification of a growing number of new microdeletion and microduplication syndromes, some of which have become clinically well characterised and some that await further delineation. This report describes three children with de novo 17p13.1 duplications encompassing the PAFAH1B1 gene, who had similar phenotypic features, including mild to moderate developmental delay, hypotonia and facial dysmorphism, and compares them to the few previously reported cases with this duplication. METHODS: Multiplex ligation-dependent probe amplification (MLPA) or array-CGH was used to diagnose three developmentally delayed children with duplications of 17p13. The duplications were characterised further using Agilent array technology, revealing duplication sizes from 1.8 to 4.0 Mb, with a region of overlap corresponding to 1.8 Mb. Detailed clinical information was obtained from patient files and personal examinations. RESULTS: The developmental delay and similar clinical features in the three patients were most likely due to a common microduplication of 17p13. CONCLUSIONS: In contrast to patients with deletion of the region (Miller-Dieker syndrome) the patients reported here had mild to moderate retardation and displayed no lissencephaly or gross brain malformations. Further cases with similar duplications are expected to be diagnosed, and will contribute to the delineation of a potential new microduplication syndrome of 17p13.

Effect of Study Duration and Outcome Measurement Frequency on Estimates of Change for Longitudinal Cohort Studies in Routinely-Collected Administrative Data.

INTRODUCTION: When designing longitudinal cohort studies, investigators must make decisions about study duration (i.e. length of follow-up) and frequency of outcome measurement. This research explores these design decisions for longitudinal cohort studies constructed using routinely-collected administrative data. OBJECTIVES: To illustrate the effects of varying study duration and frequency of outcome measurement in longitudinal cohort studies conducted using routinely-collected administrative data using a numeric example. METHODS: Linked administrative data from Manitoba, Canada were used. The cohort included mothers who experienced the death of an infant between April 1, 1999 and March 31, 2012 and a matched (three:one) group of mothers who did not experience an infant death. A generalized linear model was used to test for differences between groups in the non-linear (i.e. quadratic) and linear trend over time for the number of healthcare contacts. Holding sample size constant, models were fit to the data for various combinations of study duration and measurement frequency. Regression coefficient estimates and their standard errors were compared. RESULTS: A total of 2576 mothers were included; 644 experienced an infant death and 1932 were matches. Thirteen combinations of measurement frequency (one, two, three, four periods/year) and study duration (one, two, three, four years) were investigated. As frequency increased from one to four periods/year, the standard errors of the regression coefficients for the group difference in the non-linear trend (i.e. group-time-time interaction) decreased up to 98.9%. As duration increased from one to fours years, the standard errors decreased up to 96.9%. As frequency and duration increased, the estimated regression coefficients trended toward zero. Similar results were observed for the linear trend model. CONCLUSION: Longitudinal cohort studies based on administrative data offer flexibility in time-related design elements, but present potential challenges. Recommendations about how to select and report design decisions in studies should be included in reporting guidelines.

Organic anion-transporting polypeptide 1B1 mediates transport of Gimatecan and BNP1350 and can be inhibited by several classic ATP-binding cassette (ABC) B1 and/or ABCG2 inhibitors.

Organic anion-transporting polypeptides (OATPs) are important uptake transporters that can have a profound impact on the systemic pharmacokinetics, tissue distribution, and elimination of several drugs. Previous in vivo studies of the pharmacokinetics of the lipophilic camptothecin (CPT) analog gimatecan suggested that the ATP-binding cassette (ABC) B1 (P-glycoprotein) and/or ABCG2 (breast cancer resistance protein) inhibitors elacridar and pantoprazole could inhibit transporters other than ABCB1 and ABCG2. In this study, we tested the possible role of OATP1B1 in this interaction by screening a number of CPT analogs for their transport affinity by human OATP1B1 in vitro. In addition, the impact of several widely used ABCB1 and/or ABCG2 modulators on this OATP1B1-mediated transport was assessed. We identified two novel CPT anticancer drugs, gimatecan and BNP1350, as OATP1B1 substrates, whereas irinotecan, topotecan, and lurtotecan were not transported by OATP1B1. It is interesting to note that transport of 17beta-estradiol 17beta-d-glucuronide (control), gimatecan, and BNP1350 by OATP1B1 could be completely inhibited by the classic ABCB1 and/or ABCG2 inhibitors elacridar, valspodar, pantoprazole, and, to a lesser extent, zosuquidar and verapamil. Therefore, the effect of these ABCB1 and ABCG2 modulators on the plasma pharmacokinetics of gimatecan and BNP1350 (and possibly also other OATP1B1 substrates) may be partly because of inhibition of OATP1B1 besides inhibition of ABCB1 and/or ABCG2. The findings of this study suggest that OATP1B1 polymorphisms or coadministration with one of the ABCB1/ABCG2 inhibitors could affect drug uptake, tissue distribution, and elimination of some CPT anticancer drugs, thereby modifying their efficacy and/or safety profile.

The Concept Dictionary and Glossary at MCHP: Tools and Techniques to Support a Population Research Data Repository.

The Manitoba Centre for Health Policy's Concept Dictionary and Glossary, and the Data Repository they document, broaden the analytic possibilities associated with administrative data. The aim of the Repository is to describe and explain patterns of health care and illness, while the Concept Dictionary and Glossary create consistency in documenting research methodologies. The Concept Dictionary alone contains detailed operational definitions and programming code for measures used in MCHP research that are reusable in future projects. Making these tools available on the internet allows reaching a heterogeneous audience of academic and government health service partners, epidemiologists, planners, programmers, clinicians, and students extending around the globe. They aid in the retention of corporate knowledge, facilitate researcher/analyst communication, and enhance the Centre's knowledge translation activities. Such documentation has saved countless hours for programmers, analysts and researchers who frequently need to tread paths previously taken by others.

Dizygotic monochorionic twin pregnancy conceived following intracytoplasmic sperm injection treatment and complicated by twin-twin transfusion syndrome and blood chimerism.

We report a case of a dizygotic monochorionic twin pregnancy preceded by intracytoplasmic sperm injection treatment including assisted hatching. On ultrasound examination at 25 weeks' gestation the twins, which had been assumed to be monochorionic, were found to be of different sexes. Karyotyping and zygocity determination were performed on amniotic fluid and showed the twins to be dizygotic with normal female and male karyotypes. There were clinical and sonographic signs of twin-twin transfusion syndrome (TTTS), and Cesarean delivery was performed at 32 weeks' gestation. At birth the twins were phenotypically a normal male and a normal female. Histology of the placenta showed it to be monochorionic diamniotic. Blood chimerism was found postnatally as both infants had the karyotypes 46,XX[13]/46,XY[17]. Chimerism was not found in cells from a buccal swab at 6 months of age. This is one of only a few reported cases of dizygotic monochorionic twins. Nearly all of these cases have been conceived after assisted reproductive technology procedures. It is of clinical importance to be aware of this rare phenomenon in relation to TTTS, prenatal screening and parental counseling.

In vitro transport of gimatecan (7-t-butoxyiminomethylcamptothecin) by breast cancer resistance protein, P-glycoprotein, and multidrug resistance protein 2.

Lipophilic camptothecin derivatives are considered to have negligible affinity for breast cancer resistance protein (BCRP; ABCG2). Gimatecan, a new orally available 7-t-butoxyiminomethyl-substituted lipophilic camptothecin derivative, has been previously reported to be not a substrate for BCRP. Using a panel of in vitro models, we tested whether gimatecan is a substrate for BCRP as well as for P-glycoprotein (MDR1) or multidrug resistance protein 2 (MRP2; ABCC2), ATP-binding cassette drug efflux transporters involved in anticancer drug resistance, and able to affect the pharmacokinetics of substrate drugs. Cell survival, drug transport, accumulation, and efflux were studied in IGROV1 and (human BCRP overexpressing) T8 cells, Madin-Darby canine kidney II (MDCKII-WT, MDCKII-Bcrp1, MDCKII-MDR1, and MDCKII-MRP2), and LLCPK (LLCPK-WT and LLCPK-MDR1) cells. Competition with methotrexate uptake was studied in Sf9-BCRP membrane vesicles. In vitro, expression of BCRP resulted in 8- to 10-fold resistance to gimatecan. In Transwell experiments, gimatecan was transported by Bcrp1 and transport was inhibited by the BCRP/P-glycoprotein inhibitors elacridar and pantoprazole. Efflux of gimatecan from MDCKII-Bcrp1 cells was faster than in WT cells. In Sf9-BCRP membrane vesicles, gimatecan significantly inhibited BCRP-mediated transport of methotrexate. In contrast, gimatecan was not transported by MDR1 or MRP2. Gimatecan is transported by BCRP/Bcrp1 in vitro, although to a lesser extent than the camptothecin analogue topotecan. Implications of BCRP expression in the gut for the oral development of gimatecan and the interaction between gimatecan and other BCRP substrate drugs and/or inhibitors warrant further clinical investigation.

Using routinely collected data to evaluate risk factors for mortality of veal calves.

From 2009 to 2012 a gradual increase in on-farm mortality of Dutch veal calves was observed. In 2012, the cattle industry decided that more information was needed on risk factors for mortality in both veal herds and herds of origin to enable implementation of risk mitigating measures. Routinely collected data were available from seven different data sources and contained information from 2.4 million white veal calves that were fattened in the period between 1 January 2011 and 30 June 2014. Survival analysis techniques (Kaplan-Meier), multilevel Poisson and multilevel Logistic regression models were applied to analyse the data. Two different models were assembled in which risk factors for veal calf mortality in respectively veal herds and herds of origin were identified. Univariable and multivariable regression techniques were used to detect risk factors significantly associated with mortality of veal calves during the fattening period. During the study period, the mean mortality was 4.9% per production cycle. The probability to die was highest during the first weeks after arrival in the veal herds and declined thereafter. Important risk factors included a veal herds with a higher use of antimicrobials, hair colour as proxy for breed, certain countries of origin, veal herd management with a limited amount of supplied feed and a not having an all-in / all-out system. A higher body weight at arrival in the veal herd was associated with lower mortality as well as veal calves that were fed an above median amount of milk, roughage and concentrates. From the calves that were fattened during the study period, observations of 1.1 million calves originated from the Netherlands and were available to study risk factors for veal calf mortality associated with the herd of origin. Important risk factors included purchase, herds with high mortality rates in the quarter in which the calf was born, fast growth in herd size, high cattle replacement rates and a higher antibiotic use in the quarter of birth. Calves that originated from herds that were certified BVD-free, Salmonella-unsuspected or Paratuberculosis-unsuspected, had a lower odds to die during the subsequent fattening period in a veal herd. Veal calf mortality was influenced by risk factors at the herd of origin as well as at veal herds. Adequate collaboration between the different industries is necessary to optimize veal calf management leading to a reduction in veal calf mortality during the fattening period.

The effect of hydroxyurea on P-glycoprotein/BCRP-mediated transport and CYP3A metabolism of imatinib mesylate.

PURPOSE: It has been reported that the combination therapy of imatinib mesylate, a tyrosine kinase inhibitor, plus hydroxyurea, a ribonucleotide reductase inhibitor, is associated with remarkable antitumor activity in patients with recurrent glioblastoma multiforme. However, the mechanism of the added activity of hydroxyurea to imatinib is not known. The purpose of this study was to investigate in vitro, whether hydroxyurea could enhance the central nervous system penetration of imatinib, by inhibition of the ATP-dependent transporter proteins P-glycoprotein (ABCB1; MDR1; Pgp) and Breast Cancer Resistance Protein (ABCG2; BCRP), or by inhibition of cytochrome P450 3A (CYP3A) metabolism of imatinib. METHODS: The effect of hydroxyurea on the Pgp and BCRP mediated transport of imatinib was investigated by the sulforhodamine-B (SRB) drug cytotoxicity assay and transepithelial transport assay. In vitro biotransformation studies with supersomes expressing human CYP3A4 were performed to investigate whether hydroxyurea inhibited CYP3A4. RESULTS: In both in vitro cytotoxicity and transport assays, hydroxyurea did not affect Pgp and BCRP mediated transport of imatinib. In a biotransformation assay, hydroxyurea had no influence on the metabolic degradation of imatinib either. CONCLUSION: The results indicate that hydroxyurea does not interact with imatinib by inhibition of Pgp and BCRP mediated transport or by CYP3A4 mediated metabolism of imatinib.

Genome-wide association study of lifetime cannabis use based on a large meta-analytic sample of 32 330 subjects from the International Cannabis Consortium.

Cannabis is the most widely produced and consumed illicit psychoactive substance worldwide. Occasional cannabis use can progress to frequent use, abuse and dependence with all known adverse physical, psychological and social consequences. Individual differences in cannabis initiation are heritable (40-48%). The International Cannabis Consortium was established with the aim to identify genetic risk variants of cannabis use. We conducted a meta-analysis of genome-wide association data of 13 cohorts (N=32 330) and four replication samples (N=5627). In addition, we performed a gene-based test of association, estimated single-nucleotide polymorphism (SNP)-based heritability and explored the genetic correlation between lifetime cannabis use and cigarette use using LD score regression. No individual SNPs reached genome-wide significance. Nonetheless, gene-based tests identified four genes significantly associated with lifetime cannabis use: NCAM1, CADM2, SCOC and KCNT2. Previous studies reported associations of NCAM1 with cigarette smoking and other substance use, and those of CADM2 with body mass index, processing speed and autism disorders, which are phenotypes previously reported to be associated with cannabis use. Furthermore, we showed that, combined across the genome, all common SNPs explained 13-20% (P<0.001) of the liability of lifetime cannabis use. Finally, there was a strong genetic correlation (rg=0.83; P=1.85 × 10(-8)) between lifetime cannabis use and lifetime cigarette smoking implying that the SNP effect sizes of the two traits are highly correlated. This is the largest meta-analysis of cannabis GWA studies to date, revealing important new insights into the genetic pathways of lifetime cannabis use. Future functional studies should explore the impact of the identified genes on the biological mechanisms of cannabis use.

Development and validation of the Ontario acute myocardial infarction mortality prediction rules.

OBJECTIVES: To develop and validate simple statistical models that can be used with hospital discharge administrative databases to predict 30-day and one-year mortality after an acute myocardial infarction (AMI). BACKGROUND: There is increasing interest in developing AMI "report cards" using population-based hospital discharge databases. However, there is a lack of simple statistical models that can be used to adjust for regional and interinstitutional differences in patient case-mix. METHODS: We used linked administrative databases on 52,616 patients having an AMI in Ontario, Canada, between 1994 and 1997 to develop logistic regression statistical models to predict 30-day and one-year mortality after an AMI. These models were subsequently validated in two external cohorts of AMI patients derived from administrative datasets from Manitoba, Canada, and California, U.S. RESULTS: The 11-variable Ontario AMI mortality prediction rules accurately predicted mortality with an area under the receiver operating characteristic (ROC) curve of 0.78 for 30-day mortality and 0.79 for one-year mortality in the Ontario dataset from which they were derived. In an independent validation dataset of 4,836 AMI patients from Manitoba, the ROC areas were 0.77 and 0.78, respectively. In a second validation dataset of 112,234 AMI patients from California, the ROC areas were 0.77 and 0.78 respectively. CONCLUSIONS: The Ontario AMI mortality prediction rules predict quite accurately 30-day and one-year mortality after an AMI in linked hospital discharge databases of AMI patients from Ontario, Manitoba and California. These models may also be useful to outcomes and quality measurement researchers in other jurisdictions.

Targeting cellular adhesion molecules, chemokines and chemokine receptors in rheumatoid arthritis.

The development of specific targeted therapies, such as anti-TNF-alpha treatment, for chronic inflammatory disorders such as rheumatoid arthritis, has significantly improved treatment, although not all patients respond. Targeting cellular adhesion molecules and chemokines/chemokine receptors as regulators of the extravasation and migration of leukocytes may provide a novel approach for the treatment of these diseases. Moreover, the possibility of developing small-molecule antagonists offers an excellent method for the oral delivery of compounds with a short half-life.