Health Canada advisory impacts on the prevalence of oral codeine use in the Pediatric Canadian population: comparative study across provinces.

Health Canada (HC) has, since 2013, issued safety alerts restricting the use of codeine-containing drugs among breastfeeding women and children/adolescents under 18 years of age. These products are linked to breathing problems among ultra-rapid CYP2D6 metabolizers and early use of opioid can lead to future opioid misuse. Using a multi-province population-based cohort study, we estimate the impact of federal safety alerts on annual rates of codeine use in the Canadian pediatric population. We analyzed data from 8,156,948 children/adolescents in five Canadian provinces between 1996 and 2021, using a common protocol. Children/adolescents were categorized as: ≤ 12 years (children) or > 12 years (adolescents). We defined codeine exposure by ≥ 1 prescription filled for codeine alone or combined with other medications. For both age categories, we obtained province-specific codeine prescription filling rates per calendar year by dividing the number of children/adolescents with ≥ 1 codeine prescription filled by the number of person-time. Annual rates of codeine use per 1000 persons vary by province from 3.0 (Quebec) to 10.1 (Manitoba) in children, and from 5.5 to 51.3 in adolescents. After the 2013 HC advisory, exposure decreased in all provinces (adjusted level change from - 0.6 to - 18.4%) in children and from - 2.1 to - 17.9% in adolescents after the 2016 advisory. Annual rates declined over time in all provinces, following HC safety alerts specific to each of the two age categories.

Tumour necrosis factor inhibitors and serious infections in reproductive-age women and their offspring: a narrative review.

Tumour necrosis factor inhibitors (TNFi) are commonly used to treat patients with chronic inflammatory diseases, and function by inhibiting the pro-inflammatory cytokine tumour necrosis factor-α (TNF-α). Although beneficial in reducing disease activity, they are associated with an increased risk of serious infections. Data on the risk of serious infections associated with TNFi use during the reproductive years, particularly in pregnancy, are limited. For pregnant women, there is an additional risk of immunosuppression in the offspring as TNFi can be actively transported across the placenta, which increases in the second and third trimesters. Several studies have explored the risk of serious infections with TNFi exposure in non-pregnant and pregnant patients and offspring exposed in utero, indicating an increased risk in non-pregnant patients and a potentially increased risk in pregnant patients. The studies on TNFi-exposed offspring showed conflicting results between in utero TNFi exposure and serious infections during the offspring's first year. Further research is needed to understand differential risks based on TNFi subtypes. Guidelines conditionally recommend the rotavirus vaccine before 6 months of age for offspring exposed to TNFi in utero, but more data are needed to support these recommendations because of limited evidence. This narrative review provides an overview of the risk in non-pregnant patients and summarizes evidence on how pregnancy can increase vulnerability to certain infections and how TNFi may influence this susceptibility. This review focuses on the evidence regarding the risk of serious infections in pregnant patients exposed to TNFi and the risk of infections in their offspring.

Mass spectrometry analysis of gut tissue in acute SIV-infection in rhesus macaques identifies early proteome alterations preceding the interferon inflammatory response.

HIV infection damages the gut mucosa leading to chronic immune activation, increased morbidities and mortality, and antiretroviral therapies, do not completely ameliorate mucosal dysfunction. Understanding early molecular changes in acute infection may identify new biomarkers underlying gut dysfunction. Here we utilized a proteomics approach, coupled with flow cytometry, to characterize early molecular and immunological alterations during acute SIV infection in gut tissue of rhesus macaques. Gut tissue biopsies were obtained at 2 times pre-infection and 4 times post-infection from 6 macaques. The tissue proteome was analyzed by mass spectrometry, and immune cell populations in tissue and blood by flow cytometry. Significant proteome changes (p < 0.05) occurred at 3 days post-infection (dpi) (13.0%), 14 dpi (13.7%), 28 dpi (16.9%) and 63 dpi (14.8%). At 3 dpi, proteome changes included cellular structural activity, barrier integrity, and activation of epithelial to mesenchymal transition (EMT) (FDR < 0.0001) prior to the antiviral response at 14 dpi (IFNa/g pathways, p < 0.001). Novel EMT proteomic biomarkers (keratins 2, 6A and 20, collagen 12A1, desmoplakin) and inflammatory biomarkers (PSMB9, FGL2) were associated with early infection and barrier dysfunction. These findings identify new biomarkers preceding inflammation in SIV infection involved with EMT activation. This warrants further investigation of the role of these biomarkers in chronic infection, mucosal inflammation, and disease pathogenesis of HIV.

Complex chronic conditions among children born to women with schizophrenia.

PURPOSE: Maternal schizophrenia is linked to complications in offspring near the time of birth. Whether there is also a higher future risk of the child having a complex chronic condition (CCC) - a pediatric condition affecting any bodily system expected to last at least 12 months that is severe enough to require specialty care and/or a period of hospitalization - is not known. METHODS: In this population-based health administrative data cohort study (Ontario, Canada, 1995-2018), the risk for CCC was compared in 5066 children of women with schizophrenia (the exposed) vs. 2,939,320 unexposed children. Adjusted hazard ratios (aHR) were generated for occurrence of any CCC, by CCC category, and stratified by child sex, and child prematurity. RESULTS: CCC was more frequent in the exposed (7.7 per 1000 person-years [268 children]) than unexposed (4.2 per 100 person-years [124,452 children]) - an aHR of 1.25 (95% CI 1.10-1.41). aHRs were notably higher in 5 of 9 CCC categories: neuromuscular (1.73, 1.28-2.33), cardiovascular (1.94, 1.64-2.29), respiratory (1.83, 1.32-2.54), hematology/immunodeficiency (2.24, 1.24-4.05) and other congenital or genetic defect (1.59, 1.16-2.17). The aHR for CCC was more pronounced among boys (1.32, 1.13-1.55) than girls (1.16, 0.96-1.40), and of similar magnitude in term (1.22, 1.05-1.42) and preterm infants (1.18, 0.95-1.46). CONCLUSIONS: The risk for a CCC appears to be higher in children born to women with schizophrenia. This finding introduces opportunities for targeted preconception counselling, optimization of maternal risk factors, and intervention to support a vulnerable parent population who will experience unique challenges caring for a child with CCCs.

A high-quality genome sequence of Rosa chinensis to elucidate ornamental traits.

Rose is the world's most important ornamental plant, with economic, cultural and symbolic value. Roses are cultivated worldwide and sold as garden roses, cut flowers and potted plants. Roses are outbred and can have various ploidy levels. Our objectives were to develop a high-quality reference genome sequence for the genus Rosa by sequencing a doubled haploid, combining long and short reads, and anchoring to a high-density genetic map, and to study the genome structure and genetic basis of major ornamental traits. We produced a doubled haploid rose line ('HapOB') from Rosa chinensis 'Old Blush' and generated a rose genome assembly anchored to seven pseudo-chromosomes (512 Mb with N50 of 3.4 Mb and 564 contigs). The length of 512 Mb represents 90.1-96.1% of the estimated haploid genome size of rose. Of the assembly, 95% is contained in only 196 contigs. The anchoring was validated using high-density diploid and tetraploid genetic maps. We delineated hallmark chromosomal features, including the pericentromeric regions, through annotation of transposable element families and positioned centromeric repeats using fluorescent in situ hybridization. The rose genome displays extensive synteny with the Fragaria vesca genome, and we delineated only two major rearrangements. Genetic diversity was analysed using resequencing data of seven diploid and one tetraploid Rosa species selected from various sections of the genus. Combining genetic and genomic approaches, we identified potential genetic regulators of key ornamental traits, including prickle density and the number of flower petals. A rose APETALA2/TOE homologue is proposed to be the major regulator of petal number in rose. This reference sequence is an important resource for studying polyploidization, meiosis and developmental processes, as we demonstrated for flower and prickle development. It will also accelerate breeding through the development of molecular markers linked to traits, the identification of the genes underlying them and the exploitation of synteny across Rosaceae.

New resources for genetic studies in Populus nigra: genome-wide SNP discovery and development of a 12k Infinium array.

Whole genome resequencing of 51 Populus nigra (L.) individuals from across Western Europe was performed using Illumina platforms. A total number of 1 878 727 SNPs distributed along the P. nigra reference sequence were identified. The SNP calling accuracy was validated with Sanger sequencing. SNPs were selected within 14 previously identified QTL regions, 2916 expressional candidate genes related to rust resistance, wood properties, water-use efficiency and bud phenology and 1732 genes randomly spread across the genome. Over 10 000 SNPs were selected for the construction of a 12k Infinium Bead-Chip array dedicated to association mapping. The SNP genotyping assay was performed with 888 P. nigra individuals. The genotyping success rate was 91%. Our high success rate was due to the discovery panel design and the stringent parameters applied for SNP calling and selection. In the same set of P. nigra genotypes, linkage disequilibrium throughout the genome decayed on average within 5-7 kb to half of its maximum value. As an application test, ADMIXTURE analysis was performed with a selection of 600 SNPs spread throughout the genome and 706 individuals collected along 12 river basins. The admixture pattern was consistent with genetic diversity revealed by neutral markers and the geographical distribution of the populations. These newly developed SNP resources and genotyping array provide a valuable tool for population genetic studies and identification of QTLs through natural-population based genetic association studies in P. nigra.

Quantitative trait loci for magnitude of the plasma cortisol response to confinement in rainbow trout.

Better understanding of the mechanisms underlying interindividual variation in stress responses and their links with production traits is a key issue for sustainable animal breeding. In this study, we searched for quantitative trait loci (QTL) controlling the magnitude of the plasma cortisol stress response and compared them to body size traits in five F2 full-sib families issued from two rainbow trout lines divergently selected for high or low post-confinement plasma cortisol level. Approximately 1000 F2 individuals were individually tagged and exposed to two successive acute confinement challenges (1 month interval). Post-stress plasma cortisol concentrations were determined for each fish. A medium density genome scan was carried out (268 markers, overall marker spacing less than 10 cM). QTL detection was performed using qtlmap software, based on an interval mapping method (http://www.inra.fr/qtlmap). Overall, QTL of medium individual effects on cortisol responsiveness (<10% of phenotypic variance) were detected on 18 chromosomes, strongly supporting the hypothesis that control of the trait is polygenic. Although a core array of QTL controlled cortisol concentrations at both challenges, several QTL seemed challenge specific, suggesting that responses to the first and to a subsequent exposure to the confinement stressor are distinct traits sharing only part of their genetic control. Chromosomal location of the steroidogenic acute regulatory protein (STAR) makes it a good potential candidate gene for one of the QTL. Finally, comparison of body size traits QTL (weight, length and body conformation) with cortisol-associated QTL did not support evidence for negative genetic relationships between the two types of traits.

Measuring the international spreading of the knowledge produced by French dental master theses.

We estimated the international spreading of the knowledge produced by French dental master theses by searching for corresponding publications, either as articles in Medline-indexed journals or abstracts of IADR meetings published in the Journal of Dental Research. From the 634 theses defended in 2010 in the 16 French odontology faculties, we found only one article, in a journal without impact factor, and six abstracts, over a 3-year period (2009-2011). This corresponds to a spreading rate of 0.6%. The participation rate of French odontology faculties at IADR meetings varies from 37.5% to 81.3% depending on the year. Although there are very few studies available on the matter, it appears that this international spreading rate is much lower than both the one found by Nieminen for odontology in Finland (8.2%) and typical spreading rates of medical theses (from 6% to 41% depending on the country). This great discrepancy could be explained by the lack of specific training provided to the students; the low awareness and little engagement of the students themselves, usually more concerned with their own private practice work; and the inadequate involvement of their supervisors. To tackle the lack of appropriate training, we suggest that a specific course on scientific writing should be offered to the students in the last year of their dental master studies.

Do drug warnings and market withdrawals have an impact on the number of calls to teratogen information services?

BACKGROUND: IMAGe provides information on risks and benefits of medication use during pregnancy and lactation. OBJECTIVE: The aim of this study was to determine the impact of Health Canada warnings on the number of calls received at IMAGe. METHODS: We analyzed calls received between January 2003 and March 2008. The impact of the following warning/withdrawal were studied: paroxetine and risk of cardiac malformations (09/29/2005), selective serotonin reuptake inhibitors (SSRIs) and risk of persistent pulmonary hypertension of the newborn (PPHN) (03/10/2006), and impact of rofecoxib market withdrawal (09/30/2004). Interrupted auto-regressive integrated -moving average (ARIMA) analyses were used to test the impact of each warning on the number of calls received to IMAGe. RESULTS: 61,505 calls were analyzed. The paroxetine warning had a temporary impact increasing the overall number of calls to IMAGe, and an abrupt permanent effect on the number of calls related to antidepressant exposures. The PPHN warning had no impact but we observed a significant increase in the number of calls following rofecoxib market withdrawal. CONCLUSION: Health Canada needs to consider the increase in the demand of information to IMAGe following warnings on the risk of medication use during pregnancy.

Exposure to anti-infective drugs during pregnancy and the risk of small-for-gestational-age newborns: a case-control study.

OBJECTIVE: To determine the association between anti-infective exposure during the last two trimesters of pregnancy and the risk of small-for-gestational-age (SGA) newborns. DESIGN: Case-control study within the Québec Pregnancy Registry. SETTING: Province of Québec, Canada. SAMPLE: Analyses were performed on prospectively collected data of 63,338 pregnant women that met eligibility criteria for the study (8192 cases and 55,146 controls). METHODS: Unconditional logistic regression models were used to quantify the association between exposure to anti-infective drugs and the risk of SGA. MAIN OUTCOME MEASURES: A case of SGA was defined as a pregnancy resulting in a baby that weighs below the tenth percentile, adjusted for gestational age and gender, according to the Canadian gender-specific reference curves. A control was defined as a pregnancy resulting in a baby that weighs greater or equal to the tenth percentile, adjusted for gestational age and gender. RESULTS: Exposure to all combined anti-infective drugs was not associated with the risk of SGA (OR 0.97; 95% CI 0.91-1.04). The use of sulfamethoxazole/trimethoprim was associated with SGA (OR 1.61; 95% CI 1.16-2.23), whereas the use of urinary anti-infective drugs decreased the risk (OR 0.80; 95% CI 0.65-0.97). CONCLUSIONS: Exposure to sulfamethoxazole/trimethoprim during the last two trimesters of pregnancy was associated with SGA. Further research is needed to address the use of other therapeutic alternatives in the management of infections that predispose infants being born SGA in pregnant women with other risk factors for this condition.

Antihypertensive medication use during pregnancy and the risk of major congenital malformations or small-for-gestational-age newborns.

BACKGROUND: In spite of the widespread use of antihypertensives during pregnancy, data on their risks and benefits for the newborn are limited. We investigated the risk of major congenital malformations or small-for-gestational-age newborns (SGA) in relation to gestational use of antihypertensives. METHODS: Within the Quebec Pregnancy Registry, we conducted two case-control studies. First, cases were defined as major congenital malformations diagnosed during the first year of life and controls were selected from the same cohort; index date was date of delivery. Gestational exposure was defined as filling a prescription for an antihypertensive during the 1st trimester of pregnancy. Next, cases (SGA) were defined as newborns with a birth weight <10th percentile for that gestational age and gender; controls were the newborns with a birth weight > or =10 percentile. Gestational exposure was defined as filling a prescription for an antihypertensive during the 2nd or 3rd trimester. Multivariate logistic regression models were used to estimate odds ratios (ORs) and 95% confidence intervals (95% CI). RESULTS: We found that overall antihypertensives use during the 2nd or 3rd trimesters of pregnancy was associated with a higher risk of SGA (OR 1.53, 95% CI 1.17-1.99). Moreover, selective beta-blocker (OR 6.00, 95% CI 1.06-33.87), alpha beta blocker (OR 2.26, 95% CI 1.04-4.88), or centrally-acting adrenergic agents use (OR 1.70, 95% CI 1.00-2.89) was associated with a higher risk of SGA compared to non-use. CONCLUSION: Gestational use of antihypertensives, especially beta-blocker, alpha beta blocker, or centrally-acting adrenergic agents, may increase the risk of SGA.

Prescriptions filled during pregnancy for drugs with the potential of fetal harm.

OBJECTIVE: To assess the extent of prescriptions filled by pregnant women for drugs with recognised potential of fetal harm, and to document the outcomes of these pregnancies. DESIGN: Cross-sectional study. POPULATION: Quebec Pregnancy Registry. METHODS: We identified women who were pregnant during a five-year period and who were insured for prescription medications under the provincial drug plan. We obtained information on prescriptions filled during pregnancy for drugs with known potential of fetal harm. MAIN OUTCOME MEASURES: Prescriptions filled for study drugs during the first, second and third trimesters of pregnancy; termination of pregnancy (TOP) or delivery, and whether the baby was diagnosed with a major congenital malformation (MCM). RESULTS: Of 109 344 women, 56% filled at least one prescription for a medication during pregnancy; 6.3% filled at least one prescription for a drug known to pose a risk to the fetus. Overall, 47% (95% CI, 45.8-48.2) of pregnancies exposed to drugs under study ended in TOP versus 36.2% (95% CI, 35.9-36.5) of those not exposed; 8.2% (95% CI, 8.0-10.0) of live births were diagnosed with an MCM during the first year of life versus 7.1% (95% CI, 6.9-7.3) of those not exposed. CONCLUSIONS: This study documents an important level of prescriptions filled during pregnancy for drugs harmful to the developing fetus. The proportions of both TOPs and babies born with MCMs were elevated compared with the expected values. Clinicians caring for women during pregnancy should conduct a medication inventory prior to a planned pregnancy, or as soon as an unplanned pregnancy is recognised.

Better adherence to antihypertensive agents and risk reduction of chronic heart failure.

AIMS: Antihypertensive (AH) agents have been shown to reduce the risk of major cardiovascular events including chronic heart failure (CHF). However, the impact of changes in patterns of AH agents use on CHF is unknown. Our objective was to estimate to which different patterns of AH agent use is associated with the occurrence of CHF in a population-based study. METHOD AND RESULTS: A cohort of 82 320 patients was reconstructed using the Régie de l'assurance maladie du Québec's databases. Patients were eligible if they were between 45 to 85 years of age, had no indication of cardiovascular disease and were newly treated with AH therapy between 1999 and 2004. A nested case-control design was used to study the occurrence of CHF. Every case of CHF was matched for age and duration of follow-up to a maximum of 15 randomly selected controls. Adherence level was reported as a medication possession ratio. Conditional logistic regression models were used to estimate the rate ratio (RR) of CHF adjusting for different covariables. The mean patient age was 65 years, 37% were male, 8% had diabetes, 19% had dyslipidaemia and mean time of follow-up at 2.7 years. High adherence level (95%) to AH therapy compared with lower adherence level (60%) was associated with an additional reduction of CHF events (RR: 0.89; 0.80-0.99). Risk factors for CHF were being on social assistance, diabetes, dyslipidaemia, higher chronic disease score and developing a cardiovascular condition during follow-up. CONCLUSION: Our study suggests that a better adherence is associated with a significant risk reduction of CHF. Adherence to AH therapy needs to be improved to optimize benefits.

[Construction-cost assessment of a program designed to promote physical and sports activities and prevent doping behaviors: PN-APSD - on 2002-2007]. / Coûts de construction du programme de "promotion de la santé par les activités physiques et sportives et de prévention des conduites dopantes : PN-APSD - 2002-2007".

BACKGROUND: According to the framework legislation promulgated as part of the reform of finance laws in France, quality is a mandatory feature of all governmental actions. In this context, this work was conducted to assess the construction cost of a national health program designed to promote physical and sports activities and prevent doping behaviors. This program was considered to have the characteristic features of a successful governmental health intervention. METHODS: Four cost categories were evaluated: cost of the activity itself, transportation costs, communication costs and promotion costs. RESULTS: It was found that the program costs for 2002-2007 were 100,000 euro, with 15% of the costs in the communication category. CONCLUSION: Economic elements could be associated with factors of successful health service interventions in order to help decision makers responsible for the public interest and the consistency of public health actions.

The effects of the genetic background on herbicide resistance fitness cost and its associated dominance in Arabidopsis thaliana.

The advantage of the resistance conferred by a mutation can sometimes be offset by a high fitness-cost penalty. This balance will affect possible fate of the resistance allele. Few studies have explored the impact of the genetic background on the expression of the resistance fitness cost and none has attempted to measure the variation in fitness-cost dominance. However, both the fitness penalty and its dominance may modify evolutionary trajectory and outcome. Here the impact of Arabidopsis thaliana intraspecific genetic diversity on fitness cost and its associated dominance was investigated by analysing 12 quantitative traits in crosses between a mutant conferring resistance to the herbicide 2,4-D and nine different natural genetic backgrounds. Fitness cost values were found to be more affected by intraspecific genetic diversity than fitness cost dominance, even though this effect depends on the quantitative trait measured. This observation has implications for the choice of the best strategy for preventing herbicide resistance development. In addition, our results pinpoint a potential compensatory improvement of the resistance fitness cost and its associated dominance by the genetic diversity locally present within a species.

Nausea and vomiting of pregnancy: what about quality of life?

OBJECTIVE: The objective of this study was to determine the impact of nausea and vomiting of pregnancy (NVP) and other determinants on generic and NVP-specific health-related quality of life (QOL) in the first trimester of pregnancy. DESIGN: Prospective study. SETTING: Centre Hospitalier Universitaire (CHU) Sainte-Justine or René-Laennec clinics, Montreal, Quebec, Canada. POPULATION: Pregnant women attending the clinics for their prenatal care from 2004 to 2006. Women were eligible if they were > or =18 years of age and < or =16 weeks of gestation at the time of their first prenatal visit. METHODS: After their first prenatal visit, women were asked to fill out a questionnaire covering maternal characteristics, presence and severity of NVP, and health-related QOL. MAIN OUTCOME MEASURES: QOL was measured by the generic 12-item Short Form Health Survey v.1 (SF-12) and the NVP-specific Quality of Life for Nausea and Vomiting during Pregnancy. RESULTS: Of the 367 pregnant women included in the study, 78.5% of women reported NVP in the first trimester of pregnancy. Multivariable linear models showed that presence of NVP in the first trimester of pregnancy was significantly associated with a lower physical component summary scale (P < 0.0001) and mental component summary scale (P = 0.0066) of the SF-12 scores. More severe NVP (moderate versus mild: P = 0.0002; severe versus mild: P = 0.0177 as measured by the validated modified Pregnancy-Unique Quantification of Emesis and Nausea index), intensity of nausea symptoms reported on a visual analogue scale (P < 0.0001), and nonpharmacological methods used to ease NVP symptoms in the first trimester of pregnancy (P = 0.0059) were significantly associated with poorer NVP-specific QOL among women suffering from NVP. CONCLUSION: These findings show that presence and severity of NVP have a negative impact on health-related QOL, which emphasises the importance of an optimal management of NVP.

[Clinical value of the blood measurement of the free light chains of immunoglobulins]. / Intérêt du dosage des chaînes légères libres des immunoglobulines.

Monoclonal free light chains are found in the serum and urine of patients with B-cell proliferative disorders, including multiple myeloma. Measuring free light chains in serum is useful for the diagnosis and monitoring of free light chains diseases. Moreover it could be interesting in the monitoring of treated multiple myeloma with complete immunoglobulin and of monoclonal gammapathy of undetermined significance (MGUS). The goal of our work was to analyze a large cohort of patients with multiple myeloma or MGUS from January 2003 to August 2006 in order to better understand the interest of free light chains.

Measuring quality of patient information documents with an expanded EQIP scale.

OBJECTIVE: To develop an expanded version of the ensuring quality information for patients (EQIP) scale to measure quality of patient information documents. METHODS: We added 16 new items to the 20-item EQIP scale. The 36 items addressed document content, structure, and identification data. The new tool was used to rate the quality of 73 leaflets describing medical care procedures, used at a university hospital. Assessment rules were clarified on 25 documents; the remaining 48 leaflets were independently rated by two assessors. RESULTS: Inter-rater reliability was very good (mean item-specific kappa statistic on 48 documents=0.84). The intraclass correlation coefficient for the global score was 0.95. The mean global conformity score on all items was 44 (range: 21-76, S.D.=10). Most documents stated the purpose of the medical intervention (74% fully adequate), described qualitative risks (64%), used a respectful tone (80%), provided clear information (64%) in a logical order (73%). Fewer quantified risks (7%), were balanced (33%), used everyday language (22%), provided contact details (28%), identified authors (25%) and funding sources (4%). None gave evidence-based references nor clearly mentioned patient participation. CONCLUSIONS: The expanded EQIP scale was reliable, and proved useful for analysis of patient information documents. Documents partially met international standards for quality patient information. PRACTICE IMPLICATIONS: Document producers' efforts should focus on respecting guidelines and including patients.