Cost effectiveness of newborn screening for cystic fibrosis: a simulation study.

BACKGROUND: Early detection of cystic fibrosis (CF) by newborn screening (NBS) reduces the rate of avoidable complications. NBS protocols vary by jurisdiction and the cost effectiveness of these different protocols is debated. OBJECTIVE: To compare the cost effectiveness of various CF NBS options. METHODS: A Markov model was built to simulate the cost effectiveness of various CF-NBS options for a hypothetical CF-NBS program over a 5-year time horizon assuming its integration into an existing universal NBS program. NBS simulated options were based on a combination of tests between the two commonly used immunoreactive trypsinogen (IRT) cutoffs (96th percentile and 99.5th percentile) as first tier tests, and, as a second tier test, either a second IRT, pancreatic-associated protein (PAP) or CFTR mutation panels. CFTR mutation panels were also considered as an eventual third tier test. Data input parameters used were retrieved from a thorough literature search. Outcomes considered were the direct costs borne by the Quebec public health care system and the number of cases of CF detected through each strategy, including the absence of screening option. RESULTS: IRT-PAP with an IRT cutoff at the 96th percentile is the most favorable option with a ratio of CAD$28,432 per CF case detected. The next most favorable alternative is the IRT1-IRT2 option with an IRT1 cutoff at the 96th percentile. The no-screening option is dominated by all NBS screening protocols considered. Results were robust in sensitivity analyses. CONCLUSION: This study suggests that NBS for cystic fibrosis is a cost-effective strategy compared to the absence of NBS. The IRT-PAP newborn screening algorithm with an IRT cutoff at the 96th percentile is the most cost effective NBS approach for Quebec.

[Determinants of the intention of post-secondary students to eat at least five servings of vegetables and fruit daily]. / Déterminants de l'intention de consommer au moins cinq portions de légumes et de fruits chaque jour chez des jeunes adultes aux études postsecondaires.

BACKGROUND: Vegetable and fruit consumption helps reduce the occurrence of overweight, obesity, and other chronic diseases. However, only 50% of young adults eat at least five servings of these foods daily. Based on the construct of the Theory of planned behaviour of Ajzen (1991) to which other constructs were added (descriptive norm, perceived regularity of the behaviour and past behaviour), this study aims at identifying the determinants in the intention of young adults in postsecondary education institutions to eat at least five servings of vegetables and fruit daily during the next three months. METHODS: A sample of 385 students in two CEGEP (junior college institutions) in the Quebec City area participated in this correlation study on a volunteer basis. While attending class, they completed a self-administered questionnaire. RESULTS: Hierarchical regression analyses showed that perceived behavioural controls and the perceived weight of facilitating factors and barriers to the behaviour, explained 75% of the intention variance. Another 4% was explained when the perceived regularity of the behaviour, the descriptive norm, and past-behaviour, were added to the analysis. Logistic regression analyses show that individuals presenting weak/strong intention can be differentiated among themselves as to the perception of benefits derived from a daily consumption of vegetables and fruit (such as maintaining good health, eating foods that taste good), and as to facilitating factors/barriers that assist or inhibit such consumption (possessing more information on the nutritional value and taste of vegetables and fruit, or disposing of sufficient time to prepare them). CONCLUSION: To our knowledge, this is the first study done in Quebec using a recognized theoretical model to identify the determinants of the intention to eat at least five servings of vegetables and fruit daily in a sample of young adults in postsecondary education institutions. The results may be helpful in designing the contents of interventions aimed at maintaining and increasing daily consumption of vegetables and fruit by young adults.

[Psychosocial determinants of drug users to use a new syringe]. / Déterminants psychosociaux d'utilisateurs de drogues d'utiliser une seringue neuve.

BACKGROUND: A limited number of injection drug users are hard to reach through needle-exchange programs. They obtain their injection material from drug-using peers. This dependence on others can make them more at risk of contracting HIV through sharing non-sterile syringes. The aim of this study is to identify determinants of the intention to systematically resort to use of a new syringe by injection drug users rarely or never involved in needle-exchange programs in Quebec. METHODS: A cross-sectional survey was conducted in Québec city by means of a questionnaire measuring variables from the theory of planned behavior and past behavior. Participants (n=97) were recruited by acquaintances who kept regular contacts with the local needle-exchange programs. Multiple linear regression was used to identify the psychosocial determinants of the intention, and beliefs underlying those determinants were identified using multiple logistic regression. RESULTS: Half of participants reported using a new syringe for each injection in the last month. In multivariate analyses, this past behavior together with theory of planned behavior constructs explained 70% of the variation in participants intent to use a new syringe for each injection (control beliefs: beta=0.39; past behavior: beta=0.27; attitude: beta=0.21; perceived behavioral control: beta=0.20; subjective norm: beta=0.12). In logistic regression, six important beliefs were identified. CONCLUSION: This study resulted in the development of a predictive model of intention to use always a new syringe for each injection among a population of injection drug users in Quebec. Study results could serve as the foundation for the development of interventions to promote this behavior.

Vascular calcifications in homozygote familial hypercholesterolemia.

BACKGROUND: Patients with homozygous familial hypercholesterolemia (hmzFH) attributable to LDL receptor gene mutations have shown a remarkable increase in survival over the last 20 years. Early onset coronary heart disease (CHD) and calcific aortic valve stenosis are the major complications of this disorder. We now report extensive premature calcification of the aorta in patients with hmzFH. METHODS AND RESULTS: We examined 25 hmzFH patients from Canada; mean age was 32 years (range 5 to 54), and mean baseline cholesterol before treatment was 19+/-5 mmol/L (737+/-206 mg/dL). Aortic calcification was quantified using computed tomography (CT). An elevated mean calcium score was found in patients by age 20 and correlated with age (r(2)=0.53, P=0.001). One quarter (24%) of patients underwent aortic valve surgery. CONCLUSIONS: We document premature severe aortic calcifications in all adult hmzFH patients studied. These presented considerable surgical management challenges. Strategies to identify and monitor aortic calcification in hmzFH by noninvasive techniques are required, as are clinical trials to determine whether additional or more intensive therapies will prevent the progression of such calcifications. Whether vascular calcifications in hmzFH subjects are related to sustained increases in LDL-C levels or to other mechanisms, such as abnormal osteoblast activity, remains to be determined.

Apo B versus cholesterol in estimating cardiovascular risk and in guiding therapy: report of the thirty-person/ten-country panel.

There is abundant evidence that the risk of atherosclerotic vascular disease is directly related to plasma cholesterol levels. Accordingly, all of the national and transnational screening and therapeutic guidelines are based on total or LDL cholesterol. This presumes that cholesterol is the most important lipoprotein-related proatherogenic risk variable. On the contrary, risk appears to be more directly related to the number of circulating atherogenic particles that contact and enter the arterial wall than to the measured concentration of cholesterol in these lipoprotein fractions. Each of the atherogenic lipoprotein particles contains a single molecule of apolipoprotein (apo) B and therefore the concentration of apo B provides a direct measure of the number of circulating atherogenic lipoproteins. Evidence from fundamental, epidemiological and clinical trial studies indicates that apo B is superior to any of the cholesterol indices to recognize those at increased risk of vascular disease and to judge the adequacy of lipid-lowering therapy. On the basis of this evidence, we believe that apo B should be included in all guidelines as an indicator of cardiovascular risk. In addition, the present target adopted by the Canadian guideline groups of an apo B <90 mg dL(-1) in high-risk patients should be reassessed in the light of the new clinical trial results and a new ultra-low target of <80 mg dL(-1) be considered. The evidence also indicates that the apo B/apo A-I ratio is superior to any of the conventional cholesterol ratios in patients without symptomatic vascular disease or diabetes to evaluate the lipoprotein-related risk of vascular disease.

Simulations of spinodal nucleation in systems with elastic interactions.

Systems with long-range interactions quenched into a metastable state near the pseudospinodal exhibit nucleation that is qualitatively different from classical nucleation near the coexistence curve. We observe nucleation droplets in Langevin simulations of a two-dimensional model of martensitic transformations and determine that the structure of the nucleating droplet differs from the stable martensite structure. Our results, together with experimental measurements of the phonon dispersion curve, allow us to predict the nature of the droplet. The results have implications for nucleation in many solid-solid transitions and the structure of the final state.

Factors explaining the intention to give blood among the general population.

BACKGROUND AND OBJECTIVES: The aim of this study was to identify factors explaining the intention to donate blood. MATERIALS AND METHODS: A random sample of 4000 respondents drawn from the general population received a questionnaire by mail. This questionnaire assessed variables as defined by the most prominent social cognitive theories. RESULTS: Overall, the respondents expressed a neutral mean level of intention to give blood in the next 6 months (2.84 on a five-point scale); 56.2% had never given blood in the past. The variables explaining 74% of the variance of intention were: perceived behavioural control (beta = 0.39; P < 0.001); factors facilitating taking action (beta = 0.25; P < 0.001); anticipated regret (beta = 0.16; P < 0.001); moral norm (beta = 0.11; P < 0.001); attitude (beta = 0.08; P < 0.01); level of education (beta = -0.03; P < 0.05); and past experience in giving blood (beta = 0.09; P < 0.001). Nonetheless, the predictive power of perceived behavioural control and moral norm was higher among the ever donors (both at P < 0.01) compared to the never donors, whereas the reverse was observed for attitude (P < 0.05). CONCLUSIONS: People's intentions are mainly determined by perceived barriers and obstacles regarding blood donations. This suggests that promotional strategies should focus on the elimination of barriers to action as well as the development of a higher perception of control. Also, messages should be adapted to the targeted population, based on their previous blood donation behaviour (i.e. never donors vs. ever donors).

Concussions among university football and soccer players: a pilot study.

OBJECTIVE: A pilot study to examine the incidence and characteristics of concussions for one season of university football and soccer. DESIGN: Retrospective survey. PARTICIPANTS: 60 football and 70 soccer players reporting to 1998 fall training camp. Of these, 44 football and 52 soccer players returned a completed questionnaire. MAIN OUTCOME MEASURES: Based on self-reported symptoms, calculations were made to determine the number of concussions experienced during the previous season, the duration of symptoms, the time for return to play and any associated risk factors for concussions. RESULTS: Of all the athletes who returned completed questionnaires, 34.1% of the football players and 46.2% of the soccer players had experienced symptoms of a concussion during the previous season. Only 16.7% of the concussed football players and 29.2% of the concussed soccer players realized they had suffered a concussion. All of the concussed football players and 75.0% of the concussed soccer players experienced more than one concussion during the season. The symptoms from the concussion lasted for at least 1 day in 28.6% of the football players and 18.1% of the soccer players. Variables that increased the odds of suffering a concussion during the previous season for football and soccer players included a past history of a recognized concussion. CONCLUSION: More university soccer players than football players may be experiencing sport related concussions. Variables that seem to increase the odds of suffering a concussion during the previous season for football and soccer players include a history of a recognized concussion. Despite being relatively common, many players may not recognize the symptoms of a concussion.

Relation and lexical priming during the interpretation of noun-noun combinations.

This research indicates that recent exposure to a similar combination (e.g., oil moisturizer or surgery treatment) influences the processing of a subsequent combination (e.g., oil treatment) by increasing the availability of the lexical entries for the modifier and head noun, and by altering the availability of the relation used to link the two nouns. The amount of lexical and relational priming obtained depends on whether the modifier or head noun is in common between the prime and target. The head noun prime yields more lexical priming than does the modifier prime and this finding suggests that the head noun is more strongly activated than the modifier. In contrast, relation priming is obtained only from the modifier prime and this finding is consistent with the CARIN theory (C. L. Gagné & E. J. Shoben, 1997) but inconsistent with schema-based theories of conceptual combination (e.g., G. L. Murphy, 1988; E. J. Wisniewski, 1996).

[Concomitant treatment of psychosis and drug addiction.]. / Traitement concomitant de la psychose et de la toxicomanie.

The high prevalence of addiction problems of people with psychosis and the lack of resources to respond to their complex reality has lead a multidisciplinary team at the Centre de santé mentale communautaire (CSMC) to establish a group allowing interventions on drug addiction and psychosis in a concomitant way. Following a brief presentation of problems and intervention models proposed in the literature, this article aims at summarizing the experience of the CSMC and their strategy in order to respond to the needs of these patients. Thus, this article presents the reasons for modifications made over the years, the relevance of the motivational approach with these patients who are often unmotivated in changing their behaviour regarding substance abuse and the strengths and limits of this approach. The objectives of the therapeutic group, the framework, content and clientele are then discussed. Finally the authors examine various perspectives.

Use of a standardized reconstructed epidermis kit to assess in vitro the tolerance and the efficacy of cosmetics.

The development and validation of alternative methods to animal testing is one of the major priorities for the cosmetic industry. These methods must be reproducible and predictive of the effect of cosmetics during normal use by the consumer. Among alternative methods recently proposed, those using reconstructed human epidermis kits are the most promising approach for this purpose, as these models mimic the site of product application, allow topical application and the assessment of some clinical reactions. However, the realistic use of these models requires reproducibility and relevance of the results. The achievement of these conditions could allow the evaluation of large amounts of products, their comparisons and the generation of data banks on finished products and their ingredients. Only kits manufactured on an industrial scale and in stringent conditions of quality assurance can meet these requirements. As an example, both the criteria for industrial scale usage and the results of reproducibility of results obtained over a 4-year period (135 batches) are reported here, in terms of histological and biochemical criteria (generally used to assess the efficacy or tolerance), for a reconstructed human epidermis elaborated as a kit, EPISKIN(R). These results may provide the framework for a validation and recognition of the model, within guidelines for the assessment of the efficacy and tolerance of cosmetics.

Fine mapping of low-density lipoprotein receptor gene by genetic linkage on chromosome 19p13.1-p13.3 and study of the founder effect of four French Canadian low-density lipoprotein receptor gene mutations.

Familial hypercholesterolemia (FH) is one of the most common autosomal codominant diseases. FH is caused by mutations in the low-density lipoprotein receptor (LDLR) gene and is characterized by raised plasma LDL-cholesterol, tendon xanthomas, and premature coronary heart disease. The frequency of FH among French Canadians in northeastern Quebec is higher than in most other populations, 1:154 vs. 1:500 due to high prevalence of few recurrent mutations in the LDLR gene. In the French Canadian population, 11 mutations in the LDLR gene have been found to occur in geographically diverse areas and account for > 90% of cases. We have first constructed a high-resolution genetic map to locate several highly polymorphic markers close to LDLR locus, thus providing the necessary tools to study the origin of the four most common mutations which account for approximately 80% of our FH patients. We have then genotyped five markers (D19S413, D19S865, D19S221, D19S914, D19S586) in 102 heterozygotes (38 del > 15kb; 36 W66G; 16 C646Y; 12 E207K), two compound heterozygotes (del > 15kb/W66G; del > 15kb/C646Y) and seven homozygotes (three del > 15 kb; three W66G: one E207K) with FH unrelated to the first and second degree. We have found that patients bearing the same LDLR gene mutation carry a common haplotype at the LDLR locus although there is evidence for the early occurrence of a recombinational event between the LDLR and the D19S221 locus in the French Canadian patients bearing the W66G mutation. The fine mapping of LDLR gene close to several highly informative microsatellite markers provide fine mapping details of the LDLR region and additional tools for studies of association between plasma lipoprotein levels and LDLR gene.

Contribution of receptor negative versus receptor defective mutations in the LDL-receptor gene to angiographically assessed coronary artery disease among young (25-49 years) versus middle-aged (50-64 years) men.

Elevated plasma LDL-cholesterol (LDL-C) levels are associated with an increased risk of coronary artery disease (CAD). Familial hypercholesterolemia (FH), a monogenic trait due to mutations in the LDL-receptor (R) gene is characterized by raised plasma LDL-C levels and premature CAD. The aim of the present investigation, derived from the study of a population of 1465 unrelated men aged 25 to 64 years, was to compare the expression of CAD assessed by coronary angiography in young (aged 25-49 years) versus middle-aged (50-64 years) heterozygous FH patients of French Canadian descent. Furthermore, the relationship of binding-defective versus receptor negative mutations in the LDL-R to premature CAD ( < 50 years) was examined and compared with men displaying a normal plasma lipoprotein-lipid profile. From the original study sample, a total of 100 men met the clinical criteria of heterozygous FH. Among them, 30 were carriers of a receptor negative mutation (deletion > 15 kb or point mutations Y468X or R329X) whereas 64 were carriers of a receptor defective mutation (W66G, E207K or C646Y). As expected, in both age groups (25-49 years vs. 50-64 years), carriers of a receptor negative mutation had higher plasma cholesterol and LDL-C levels than carriers of a defective allele or men with a normal plasma lipoprotein-lipid profile. In addition, the mean number of diseased vessels (with > 50% stenosis) was higher in men aged 50-64 years compared to those aged 25 49 years. In the two age groups, FH patients were characterized by a higher number of stenosed coronary vessels than the normal phenotype group. Within each group (either receptor negative, receptor defective or normal phenotype) plasma cholesterol, LDL-C, HDL-C, triglyceride and apolipoprotein B levels were similar irrespective of age (25 49 years vs. 50-64 years). Finally, multiple logistic regression analyses revealed that compared to non-FH men, the relative odds of being affected by CAD before the age of 50 years was 7.3-fold higher for carriers of a receptor negative mutation and 2.7-fold higher for men with a receptor defective mutation at the LDL-R locus. These results suggest that CAD could be an earlier event among heterozygous FH subjects bearing a receptor negative mutation compared to LDL-R defective patients. It also suggest that the selective screening for mutations in the LDL-R gene may allow a better assessment of the individual risk and facilitate the development of family-based preventive strategies or intervention programs in FH.

Relative contribution of low-density lipoprotein receptor and lipoprotein lipase gene mutations to angiographically assessed coronary artery disease among French Canadians.

Men with low-density lipoprotein receptor gene mutations causing familial hypercholesterolemia (FH) are at high risk of premature coronary artery disease (CAD). The dyslipidemic state found among patients who are heterozygous for mutations in the lipoprotein lipase (LPL) gene may also increase the risk of CAD. In the present study, the association of the heterozygous forms of low-density lipoprotein receptor gene mutations causing FH as well as of LPL gene mutations causing (P207L and G188E) or not causing (D9N and N291S) complete loss of LPL activity with angiographically assessed CAD was estimated in a cohort of 412 French Canadian men aged <60 years who consecutively underwent coronary angiography for the investigation of retrosternal pain. The frequency of FH as well as of LPL gene mutations tended to increase with the number of narrowed coronary arteries. However, CAD occurred earlier in FH patients than in partly LPL-deficient patients. Indeed, the proportion of men affected by FH was of 16.4% in those <45 years of age, and solely 4.3% among those between 56 and 60 years of age (p <0.0001). In contrast, the LPL gene defect was found in only 4.0% of men aged <45 years, whereas this prevalence reached 8.3% among those aged 56 to 60 years. In multivariate analyses, the association of LPL with CAD was not independent of age, high-density lipoprotein cholesterol concentrations, and other covariates included at baseline, and was not affected by the type of mutation in the LPL gene. In contrast, FH was associated with CAD with minimal contribution of other cardiovascular risk factors. However, the relation between FH and CAD was at least partly dependent on plasma apolipoprotein B concentrations. In the different regression models, fasting insulin and plasma high-density lipoprotein cholesterol concentrations were important covariates of CAD, whether or not patients were affected by FH or LPL deficiency. In conclusion, the association of LPL gene mutations with CAD was delayed compared with FH, appeared to be markedly exacerbated by the presence of additional risk factors, and was not affected by the type of mutation in the LPL gene.

Association of specific LDL receptor gene mutations with differential plasma lipoprotein response to simvastatin in young French Canadians with heterozygous familial hypercholesterolemia.

In familial hypercholesterolemia (FH), the efficacy of the inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase shows considerable interindividual variation, and several genetic and environmental factors can contribute to explaining this variability. A randomized, double-blind, placebo-controlled clinical trial with simvastatin, an HMG-CoA reductase inhibitor, was conducted in 63 children and adolescents with heterozygous FH. The patients were grouped according to known LDL receptor genotype. After 6 weeks of treatment with 20 mg/d simvastatin, the mean reduction in plasma LDL cholesterol in patients with the W66G mutation (n=14) was 31%, whereas in the deletion>15 kb (n=23) and the C646Y mutation groups (n=10), it was 38% and 42%, respectively (P<0.05). After treatment with simvastatin, HDL cholesterol levels were increased in all groups, and triglyceride concentrations were significantly reduced. Multiple regression analyses suggested that 42% of the variation of the LDL cholesterol response to simvastatin can be attributed to variation in the mutant LDL receptor locus, apolipoprotein E genotype, and body mass index, while 35% of the variation in HDL cholesterol response was explained by sex and baseline HDL cholesterol. These results show that simvastatin was an effective and well-tolerated therapy for FH in the pediatric population for all LDL receptor gene mutations. Moreover, the nature of LDL receptor gene mutations and other genetic and constitutional factors play a significant role in predicting the efficacy of simvastatin in the treatment of FH in children and adolescents.

Relationships of abdominal obesity and hyperinsulinemia to angiographically assessed coronary artery disease in men with known mutations in the LDL receptor gene.

BACKGROUND: Patients with a mutation in the LDL receptor gene (familial hypercholesterolemia, or FH) are characterized by substantial elevations in plasma LDL cholesterol and are at higher risk of developing coronary artery disease (CAD). Correlates of abdominal obesity may also contribute to the risk of ischemic cardiac events. Whether the hyperinsulinemic-insulin-resistant state of abdominal obesity affects coronary atherosclerosis among FH patients has not been determined. METHODS AND RESULTS: The relation of abdominal adiposity and hyperinsulinemia to angiographically assessed CAD was evaluated in a sample of 120 French Canadian men aged <60 years who were heterozygotes for FH and in a group of 280 men without FH. In the present study, the risk of CAD associated with abdominal obesity, as estimated by the waist circumference, was largely dependent on the concomitant variation in plasma lipoprotein and insulin concentrations. In contrast, the association between fasting insulin and CAD was independent of variations in waist girth, triglyceride, HDL, and apolipoprotein B concentrations (odds ratio, 1.86; P=.0005). However, the most substantial increase in the risk of CAD was observed among abdominally obese (waist circumference >95 cm) and hyperinsulinemic FH patients (odds ratio, 12.9; P=.0009). This increase in risk remained significant even after adjustment for LDL cholesterol or apolipoprotein B concentrations. CONCLUSIONS: Results of the present study provide support for the notion that the hyperinsulinemic-insulin-resistant state of abdominal obesity is a powerful predictor of CAD in men, even in a group of patients with raised LDL cholesterol concentrations due to FH.

Hyperinsulinemia and abdominal obesity affect the expression of hypertriglyceridemia in heterozygous familial lipoprotein lipase deficiency.

We have reported three missense mutations (G188E, P207L, and D250N) in the lipoprotein lipase (LPL) gene among French-Canadians, resulting in the absence of measurable postheparin plasma LPL activity in homozygotes. Presence of triglyceride- and cholesterol-rich VLDL, as well as cholesterol-poor HDL particles, has been shown in heterozygotes affected by partial reduction in postheparin LPL activity. However, significant heterogeneity in their plasma triglyceride levels has been found, even among individuals carrying the same LPL gene mutation, indicating that factors other than LPL deficiency could affect the phenotypic expression of hypertriglyceridemia in the heterozygous state. The aim of the present study was to examine the combined effects of abdominal fat accumulation and hyperinsulinemia on plasma triglyceride levels among heterozygous patients for familial LPL deficiency. Based on sex and BMI, 43 heterozygotes (25 women and 18 men) were matched with noncarrier control subjects. Our data indicate that heterozygotes with higher abdominal fat deposition, as defined as waist girth values above the 50th percentile, had higher plasma triglyceride levels than nonobese heterozygotes. However, an important proportion of male heterozygote subjects were hypertriglyceridemic, even in absence of abdominal obesity, suggesting that another factor(s) was involved in the modulation of hypertriglyceridemia in these subjects. Indeed, multivariate analyses revealed that fasting hyperinsulinemia was a significant correlate of hypertriglyceridemia among these heterozygotes. Results of the present study indicate that abdominal obesity and hyperinsulinemia both have deleterious effects on plasma triglyceride levels in familial LPL deficiency. It is suggested that heterozygotes with moderate obesity and/or insulin resistance may be at higher risk of coronary artery disease because of the expression of an atherogenic lipoprotein phenotype among these patients.