Factors influencing physiotherapy decisions between restorative and compensatory gait rehabilitation: an Italian multicenter study.

Background and purpose: This study aimed to investigate the factors that influence physiotherapists' decision in choosing restorative or compensatory rehabilitation during gait training in people with neurological disorders (PwNDs) and the different treatments used in the approaches. Methods: This cross-sectional analysis used the baseline data from an observational cohort study. We analyzed data from 83 PwNDs (65 people after stroke, 5 with multiple sclerosis, and 13 with Parkinson's disease) who underwent at least 10 sessions of physiotherapy (PT) focusing on gait function. Performance was quantified using the modified Dynamic Gait Index (MDGI), three impairment domains of Fugl-Meyer Assessment for lower extremity (mFM-LL), Activities-specific Balance Confidence (ABC), modified Barthel Index (mBI), Mini-Mental State Examination (MMSE), and Motivational Index (MI). Forty-three physiotherapists completed a treatment report form categorizing the rehabilitation approach and specifying treatments used (e.g., resistance training and proprioceptive exercises). Results: Fifty-six subjects underwent restorative rehabilitation approach. The univariate predictors of restorative approach were being in the subacute phase with a disease onset of less than 180 days, (odds ratio [95%CI]; 3.27[1.19-9.24]), mFM-LL (1.25[1.11-1.44]), MMSE (0.85[0.67-1.00]), and number of sessions (1.03[1-1.01]). The backward stepwise analysis revealed an association between restorative and subacute phase (36.32[4.11-545.50]), mFM-LL (3.11[1.55-9.73]), mBI (1.79[1.08-3.77]), MMSE (0.46[0.25-0.71]), and the interaction between mFM-LL and mBI (0.99[0.98-1.00]). No statistically significant association between treatments used and approach was found (p = 0.46). Discussion and conclusion: The restorative approach was more commonly used to improve gait. The main variables associated with this approach were: being in the subacute phase of the disease, a low level of impairment, and a high level of functional independence at baseline. However, few differences were found between the treatments used for the restorative or compensatory approaches, as similar PT treatments were used for both.

Classification and Quantification of Physical Therapy Interventions across Multiple Neurological Disorders: An Italian Multicenter Network.

Despite their relevance in neurorehabilitation, physical therapy (PT) goals and interventions are poorly described, compromising a proper understanding of PT effectiveness in everyday clinical practice. Thus, this paper aims to describe the prevalence of PT goals and interventions in people with neurological disorders, along with the participants' clinical features, setting characteristics of the clinical units involved, and PT impact on outcome measures. A multicenter longitudinal observational study involving hospitals and rehabilitation centers across Italy has been conducted. We recruited people with stroke (n = 119), multiple sclerosis (n = 48), and Parkinson's disease (n = 35) who underwent the PT sessions foreseen by the National Healthcare System. Clinical outcomes were administered before and after the intervention, and for each participant the physical therapists completed a semi-structured interview to report the goals and interventions of the PT sessions. Results showed that the most relevant PT goals were related to the ICF activities with "walking" showing the highest prevalence. The most used interventions aimed at improving walking performance, followed by those aimed at improving organ/body system functioning, while interventions targeting the cognitive-affective and educational aspects have been poorly considered. Considering PT effectiveness, 83 participants experienced a clinically significant improvement in the outcome measures assessing gait and balance functions.

Prevention of COVID-19 with oral vitamin D supplemental therapy in essential healthcare teams (PROTECT): protocol for a multicentre, triple-blind, randomised, placebo-controlled trial.

INTRODUCTION: In the COVID-19 pandemic, healthcare workers (HCWs) were at high risk of infection due to their exposure to COVID infections. HCWs were the backbone of our healthcare response to this pandemic; every HCW withdrawn or lost due to infection had a substantial impact on our capacity to deliver care. Primary prevention was a key approach to reduce infection. Vitamin D insufficiency is highly prevalent in Canadians and worldwide. Vitamin D supplementation has been shown to significantly decrease the risk of respiratory infections. Whether this risk reduction would apply to COVID-19 infections remained to be determined. This study aimed to determine the impact of high-dose vitamin D supplementation on incidence of laboratory-confirmed COVID-19 infection rate and severity in HCWs working in high COVID incidence areas. METHODS AND ANALYSIS: PROTECT was a triple-blind, placebo-controlled, parallel-group multicentre trial of vitamin D supplementation in HCWs. Participants were randomly allocated in a 1:1 ratio in variable block size to intervention (one oral loading dose of 100 000 IU vitamin D3+10 000 IU weekly vitamin D3) or control (identical placebo loading dose+weekly placebo). The primary outcome was the incidence of laboratory-confirmed COVID-19 infection, documented by RT-qPCR on salivary (or nasopharyngeal) specimens obtained for screening or diagnostic purposes, as well as self-obtained salivary specimens and COVID-19 seroconversion at endpoint. Secondary outcomes included disease severity; duration of COVID-19-related symptoms; COVID-19 seroconversion documented at endpoint; duration of work absenteeism; duration of unemployment support; and adverse health events. The trial was terminated prematurely, due to recruitment difficulty. ETHICS AND DISSEMINATION: This study involves human participants and was approved by the Research Ethics Board (REB) of the Centre hospitalier universitaire (CHU) Sainte-Justine serving as central committee for participating institutions (#MP-21-2021-3044). Participants provided written informed consent to participate in the study before taking part. Results are being disseminated to the medical community via national/international conferences and publications in peer-reviewed journals. TRIAL REGISTRATION NUMBER: https://clinicaltrials.gov/ct2/show/NCT04483635.

Association between annual exposure to air pollution and systolic blood pressure among adolescents in Montréal, Canada. / Association entre l'exposition annuelle à la pollution atmosphérique et la pression artérielle systolique chez des adolescents à Montréal (Canada).

INTRODUCTION: In adults, chronic exposure to air pollution is associated with elevated blood pressure, but few studies have examined this relationship in youth. We investigated the association between annual ambient concentrations of air pollutants (fine particulate matter [PM2.5] and nitrogen dioxide [NO2]) and systolic blood pressure (SBP) among adolescents in Montréal, Canada. METHODS: Participants were students aged 15 to 17 years who provided SBP and residential postal code data in 2004/05 through their enrolment in the Nicotine Dependence in Teens study. Annual estimates for 2004 of residential exposure to NO2 and PM2.5 were provided by the Canadian Urban Environmental Health Research Consortium and linked to participants' residential postal code. Elevated SBP was defined as SBP ≥ 90th percentile adjusted for age, sex and height. Logistic regression was used to estimate odds ratios and 95% confidence intervals (CIs) for each pollutant with respect to elevated SBP, adjusted for relevant confounders. RESULTS: The sample consisted of 508 adolescents (mean age: 16.9, 46% male); 4% had elevated SBP. Although estimates were not statistically significant, there were generally modest positive associations between pollutant levels and SBP. The adjusted prevalence odds ratio of elevated SBP was 1.33 (95% CI: 0.64, 3.05) for every interquartile range (IQR) increase in residential PM2.5 levels (2.1µg/m3). Similarly, the adjusted prevalence odds ratio of elevated SBP was 1.17 (95% CI: 0.47, 2.70) for every IQR increase in residential NO2 levels (10.2 ppb). CONCLUSION: Findings support a possible relationship between exposure to air pollutants and increased SBP in adolescents, warranting further investigation for this important public health concern.

Pharmacokinetics and pharmacodynamics of imatinib for optimal drug repurposing from cancer to COVID-19.

INTRODUCTION: In the randomized double-blind placebo-controlled CounterCOVID study, oral imatinib treatment conferred a positive clinical outcome and a signal for reduced mortality in COVID-19 patients. High concentrations of alpha-1 acid glycoprotein (AAG) were observed in these patients and were associated with increased total imatinib concentrations. AIMS: This post-hoc study aimed to compare the difference in exposure following oral imatinib administration in COVID-19 patients to cancer patients and assess assocations between pharmacokinetic (PK) parameters and pharmacodynamic (PD) outcomes of imatinib in COVID-19 patients. We hypothesize that a relatively higher drug exposure of imatinib in severe COVID-19 patients leads to improved pharmacodynamic outcome parameters. METHODS: 648 total concentration plasma samples obtained from 168 COVID-19 patients were compared to 475 samples of 105 cancer patients, using an AAG-binding model. Total trough concentration at steady state (Cttrough) and total average area under the concentration-time curve (AUCtave) were associated with ratio between partial oxygen pressure and fraction of inspired oxygen (P/F), WHO ordinal scale (WHO-score) and liberation of oxygen supplementation (O2lib). Linear regression, linear mixed effects models and time-to-event analysis were adjusted for possible confounders. RESULTS: AUCtave and Cttrough were respectively 2.21-fold (95%CI 2.07-2.37) and 1.53-fold (95%CI 1.44-1.63) lower for cancer compared to COVID-19 patients. Cttrough, not AUCtave, associated significantly with P/F (ß=-19,64; p-value=0.014) and O2lib (HR 0.78; p-value= 0.032), after adjusting for sex, age, neutrophil-lymphocyte ratio, dexamethasone concomitant treatment, AAG and baseline P/F-and WHO-score. Cttrough, but not AUCtave associated significantly with WHO-score. These results suggest an inverse relationship between PK-parameters, Cttrough and AUCtave, and PD outcomes. CONCLUSION: COVID-19 patients exhibit higher total imatinib exposure compared to cancer patients, attributed to differences in plasma protein concentrations. Higher imatinib exposure in COVID-19 patients did not associate with improved clinical outcomes. Cttrough and AUCtave inversely associated with some PD-outcomes, which may be biased by disease course, variability in metabolic rate and protein binding. Therefore, additional PKPD analyses into unbound imatinib and its main metabolite may better explain exposure-response.

Oral vitamin D supplemental therapy to attain a desired serum 25-hydroxyvitamin D concentration in essential healthcare teams.

BACKGROUND: The study objectives were to ascertain the efficacy of vitamin D supplementation in rapidly increasing serum vitamin D and of implementation of a hybrid (virtual and in-person) trial. METHODS: In a randomized triple-blind controlled trial, healthcare workers were allocated to receive an oral bolus of 100,000 IU with 10,000 IU/week of vitamin D3 or placebo. The co-primary outcomes were the change from baseline in serum 25-hydroxyvitamin D [(Δ) 25(OH)D] and proportion with vitamin D sufficiency (25(OH)D ≥ 75 nmol/L), at endpoint. Adherence to supplements and procedures as well as adverse event rates were documented. RESULTS: Thirty-four (19 intervention, 15 control) subjects were randomized, with 28 (41%) virtual visits. After 44.78 ± 11.00 days from baseline, a significant adjusted group difference of 44.2 (34.7, 53.8) nmol/L was observed in the Δ 25(OH)D (95% CI) in favor of supplementation; 77.8% of intervention, and 13.3% of control, patients were vitamin D sufficient (OR:6.11, 95% CI:1.6, 22.9). The adherence to intervention was 94.7% in the intervention and 100% in the control groups. Irrespective of visit type, high adherence was observed in sampling procedures and completion of fortnightly online questionnaire. No adverse events attributable to vitamin D were reported. CONCLUSION: The vitamin D supplementation rapidly and safely raised 25(OH)D levels to sufficient levels for a biological effect. Similarly high adherence to study procedures was observed with virtual and in-person participation. TRIAL REGISTRATION: This trial was registered at https://clinicaltrials.gov on July 23, 2020 (# NCT04483635 ).

Methodological Reflections of a Student- and Community-based Partnership on Operationalizing a Community-based Participatory Research Model: Recommendations for Building, Securing, and Sustaining Partnerships.

BACKGROUND: Community-based participatory research (CBPR) is an approach that values community expertise and ownership in creating knowledge. This approach's success is challenged by inherent cultural imbalances, making it difficult to sustain partnerships and build from what has been learned from a project as it develops. As student researchers and community members, we reflected on the challenges in CBPR and gave guidance to future novice researchers pursuing CBPR. OBJECTIVES: From the application of an initial CBPR model as a framework to our partnership, we propose empirical avenues to continuously adapt the CBPR approach. METHODS: A CBPR partnership between McGill's Family Medicine Graduate Student Society and Share the Warmth, a community-based organization aiming to fight poverty and hunger, was formed to collaboratively assess a music program offered in a socioeconomically disadvantaged community. The partnership process was based on a model that we conceptualized in three phases of our framework: building, securing, and sustaining. We reflect on the facilitators and challenges of this project and propose solutions to overcome identified barriers within the context of our partnership. RESULTS: We highlight the importance of integrating student partners in the community, reevaluating formal research agreements, and coordinating the transition of new partners in this adaptive CBPR model. We argue that this systematic and reflexive process has made the model especially useful as a framework for student and community partnerships. CONCLUSIONS: We propose adaptive components to the CBPR model. Our recommendations could help other partnerships cultivate CBPR to be more applicable in community health research.

Persistence of parental-reported asthma at early ages: A longitudinal twin study.

BACKGROUND: Currently, we cannot predict whether a pre-school child with asthma-like symptoms will have asthma at school age. Whether genetic information can help in this prediction depends on the role of genetic factors in persistence of pre-school to school-age asthma. We examined to what extent genetic and environmental factors contribute to persistence of asthma-like symptoms at ages 3 to asthma at age 7 using a bivariate genetic model for longitudinal twin data. METHODS: We performed a cohort study in monozygotic and dizygotic twins from the Netherlands Twin Register (NTR, n = 21,541 twin pairs). Bivariate genetic models were fitted to longitudinal data on asthma-like symptoms reported by parents at age 3 and 7 years to estimate the contribution of genetic and environmental factors. RESULTS: Bivariate genetic modeling showed a correlation on the liability scale between asthma-like symptoms at age 3 and asthma at age 7 of 0.746 and the contribution of genetics was estimated to be 0.917. The genetic analyses indicated a substantial influence of genetic factors on asthma-like symptoms at ages 3 and 7 (heritability 80% and 90%, respectively); hence, contribution of environmental factors was low. Persistence was explained by a high (rg = 0.807) genetic correlation. CONCLUSION: Parental-reported asthma-like symptoms at age 3 and asthma at age 7 are highly heritably. The phenotype of asthma-like symptoms at age 3 and 7 was highly correlated and mainly due to heritable factors, indicating high persistence of asthma development over ages 3 and 7.

A potential outcomes approach to defining and estimating gestational age-specific exposure effects during pregnancy.

Many studies seek to evaluate the effects of potentially harmful pregnancy exposures during specific gestational periods. We consider an observational pregnancy cohort where pregnant individuals can initiate medication usage or become exposed to a drug at various times during their pregnancy. An important statistical challenge involves how to define and estimate exposure effects when pregnancy loss or delivery can occur over time. Without proper consideration, the results of standard analysis may be vulnerable to selection bias, immortal time-bias, and time-dependent confounding. In this study, we apply the "target trials" framework of Hernán and Robins in order to define effects based on the counterfactual approach often used in causal inference. This effect is defined relative to a hypothetical randomized trial of timed pregnancy exposures where delivery may precede and thus potentially interrupt exposure initiation. We describe specific implementations of inverse probability weighting, G-computation, and Targeted Maximum Likelihood Estimation to estimate the effects of interest. We demonstrate the performance of all estimators using simulated data and show that a standard implementation of inverse probability weighting is biased. We then apply our proposed methods to a pharmacoepidemiology study to evaluate the potentially time-dependent effect of exposure to inhaled corticosteroids on birthweight in pregnant people with mild asthma.

Association Between Asthma Control Trajectories in Preschoolers and Long-Term Asthma Control.

BACKGROUND: The potential influence of asthma control in early life on long-term outcomes in childhood remains largely unknown. OBJECTIVE: To examine whether asthma control trajectories in the 2 years after diagnosis in preschoolers are associated with long-term unsatisfactory asthma control. METHODS: We conducted a multicenter population-based retrospective cohort study, including four Canadian provincial birth cohorts derived from administrative databases. We included preschoolers (aged <5 years) with a diagnosis of asthma, defined as having one hospitalization or two physician visits for asthma within 2 years. Asthma control trajectories, ascertained over four 6-month periods after diagnosis using a validated index, were classified as controlled throughout, improving control, fluctuating control, worsening control, and out of control throughout. Long-term unsatisfactory control was defined as four or more short-acting ß2-agonist average doses per week or an exacerbation, measured within 6 months before index ages 6, 8, 10, 12, 14, and 16 years. Average risk ratios for long-term unsatisfactory control across all index ages were estimated using a robust Poisson model by province and meta-analyzed with a random effects model. RESULTS: In 50,188 preschoolers with asthma, the pooled average risk of having unsatisfactory control at any index age was 42% (95% confidence interval, 34.6-49.4). Compared with children who were controlled throughout, incrementally higher average risk ratios (95% confidence interval) of long-term unsatisfactory control were observed in each trajectory: improving control, 1.38 (1.28-1.49); fluctuating control, 1.54 (1.40-1.68); worsening control, 1.70 (1.55-1.86) and out of control throughout, 2.00 (1.80-2.21). CONCLUSIONS: Suboptimal asthma control trajectories shortly after a preschool diagnosis were associated with long-term unsatisfactory asthma control. Early control trajectories appear to be promising for predicting the risk for long-term adverse outcomes.

Overuse of Oral Corticosteroids, Underuse of Inhaled Corticosteroids, and Implications for Biologic Therapy in Asthma.

BACKGROUND: Asthma patients using high cumulative doses of oral corticosteroids (OCSs) are at risk of serious adverse events and are increasingly being treated with steroid-sparing asthma biologics. However, it is unknown whether prescribing these expensive biologics is always justified. OBJECTIVES: This study aimed to (1) assess the prevalence of asthma patients using high cumulative doses of OCSs, (2) explore the role of suboptimal inhaler therapy, and (3) estimate the proportion of patients to whom asthma biologics might be prescribed unnecessarily. METHODS: All adults (n = 5,002) with at least 1 prescription of high-dose inhaled corticosteroids (≥500-1,000 mcg/day fluticasone-equivalent) and/or OCSs (GINA step 4-5) in 2010 were selected from a pharmacy database including 500,500 Dutch inhabitants, and sent questionnaires. Of 2,312 patients who returned questionnaires, 929 had asthma. We calculated the annual cumulative OCS dose and prescription fillings and checked inhaler technique in a sample of 60 patients. Patients estimated to have good adherence and inhaler proficiency who still required high doses of OCSs (≥420 mg/year) were considered candidates for initiating biologic treatment. RESULTS: 29.5% of asthma patients on GINA 4-5 therapy used high doses of OCSs, of which 78.1% were likely to have poor therapy adherence or inadequate inhaler technique. Only 21.9% were considered definitive candidates for biologic therapy. CONCLUSION: High OCS use in Dutch GINA 4-5 asthma patients was common. However, in 4 out of 5 patients adherence to inhaled corticosteroid therapy and/or inhalation technique was considered suboptimal. Since optimizing inhaler therapy may reduce the need for OCSs, this should be mandatory before prescribing expensive steroid-sparing drugs.

Assessing the quality of deliberative stakeholder consultations involving allied health professionals in pediatric palliative care and hematology/oncology in Canada.

BACKGROUND: In this paper we assess the quality of six deliberative stakeholder consultations regarding the implementation of a precision diagnostic for life-threatening pediatric brain tumors. Decision makers who base policy recommendations on the outputs of consultative exercises can presuppose that all deliberants are well informed of the policy issue, that participation in the deliberative process was fair, and that overcoming implementation barriers will necessarily result in practice change. Additional evidence is therefore needed to substantiate the informational quality of the deliberation, measure the equality of participation and study the effects on stakeholder reasoning to appropriately guide uptake of proposed recommendation(s). METHODS: Using the DeVries framework for assessing the deliberative quality, we analyzed data from 44 post-consultation evaluation surveys completed by pediatric oncology and palliative care teams at two tertiary pediatric healthcare centers in Canada. We also conducted turn-taking and word-contribution analyses from the text transcriptions of each deliberation to assess equality of participation using descriptive statistics. RESULTS: Deliberants agreed the quality of the deliberative process was fair (median ratings ranging from 9-10 out of 10) and the opportunities to receive expert information and discuss with others about the implementation of a new LDT were helpful (9.5 out of 10). While the session improved understanding of the implementation barriers and opportunities, it had marginal effects on deliberants' reasoning about whether LDTs would change their own clinical practice (3-10 out of 10). Participation was proportionate in at least four of the six deliberations, where no deliberant took more than 20% of total turns and contributed equal to, or less than 20% of total words. CONCLUSION: The quality assessment we performed demonstrates high informational value and perceived fairness of two deliberative stakeholder consultations involving pediatric palliative care and oncology teams in Canada. Quality assessments can reveal how the process of deliberation unfolds, whether deliberative outputs are the result of equitable participation among deliberants and what, if any, stakeholder voices may be missing. Such assessments should be routinely reported as a condition of methodological rigor and trustworthiness of deliberative stakeholder engagement research.

The Influence of Smoking Status on Exhaled Breath Profiles in Asthma and COPD Patients.

Breath analysis using eNose technology can be used to discriminate between asthma and COPD patients, but it remains unclear whether results are influenced by smoking status. We aim to study whether eNose can discriminate between ever- vs. never-smokers and smoking <24 vs. >24 h before the exhaled breath, and if smoking can be considered a confounder that influences eNose results. We performed a cross-sectional analysis in adults with asthma or chronic obstructive pulmonary disease (COPD), and healthy controls. Ever-smokers were defined as patients with current or past smoking habits. eNose measurements were performed by using the SpiroNose. The principal component (PC) described the eNose signals, and linear discriminant analysis determined if PCs classified ever-smokers vs. never-smokers and smoking <24 vs. >24 h. The area under the receiver-operator characteristic curve (AUC) assessed the accuracy of the models. We selected 593 ever-smokers (167 smoked <24 h before measurement) and 303 never-smokers and measured the exhaled breath profiles of discriminated ever- and never-smokers (AUC: 0.74; 95% CI: 0.66-0.81), and no cigarette consumption <24h (AUC 0.54, 95% CI: 0.43-0.65). In healthy controls, the eNose did not discriminate between ever or never-smokers (AUC 0.54; 95% CI: 0.49-0.60) and recent cigarette consumption (AUC 0.60; 95% CI: 0.50-0.69). The eNose could distinguish between ever and never-smokers in asthma and COPD patients, but not recent smokers. Recent smoking is not a confounding factor of eNose breath profiles.

The Impact of Short-Term Exposure to Air Pollution on the Exhaled Breath of Healthy Adults.

Environmental factors, such as air pollution, can affect the composition of exhaled breath, and should be well understood before biomarkers in exhaled breath can be used in clinical practice. Our objective was to investigate whether short-term exposures to air pollution can be detected in the exhaled breath profile of healthy adults. In this study, 20 healthy young adults were exposed 2-4 times to the ambient air near a major airport and two highways. Before and after each 5 h exposure, exhaled breath was analyzed using an electronic nose (eNose) consisting of seven different cross-reactive metal-oxide sensors. The discrimination between pre and post-exposure was investigated with multilevel partial least square discriminant analysis (PLSDA), followed by linear discriminant and receiver operating characteristic (ROC) analysis, for all data (71 visits), and for a training (51 visits) and validation set (20 visits). Using all eNose measurements and the training set, discrimination between pre and post-exposure resulted in an area under the ROC curve of 0.83 (95% CI = 0.76-0.89) and 0.84 (95% CI = 0.75-0.92), whereas it decreased to 0.66 (95% CI = 0.48-0.84) in the validation set. Short-term exposure to high levels of air pollution potentially influences the exhaled breath profiles of healthy adults, however, the effects may be minimal for regular daily exposures.

Genome-wide association studies of exacerbations in children using long-acting beta2-agonists.

BACKGROUND: Some children with asthma experience exacerbations despite long-acting beta2-agonist (LABA) treatment. While this variability is partly caused by genetic variation, no genome-wide study until now has investigated which genetic factors associated with risk of exacerbations despite LABA use in children with asthma. We aimed to assess whether genetic variation was associated with exacerbations in children treated with LABA from a global consortium. METHODS: A meta-analysis of genome-wide association studies (meta-GWAS) was performed in 1,425 children and young adults with asthma (age 6-21 years) with reported regular use of LABA from six studies within the PiCA consortium using a random effects model. The primary outcome of each study was defined as any exacerbation within the past 6 or 12 months, including at least one of the following: 1) hospital admissions for asthma, 2) a course of oral corticosteroids or 3) emergency room visits because of asthma. RESULTS: Genome-wide association results for a total of 82 996 common single nucleotide polymorphisms (SNPs, MAF ≥1%) with high imputation quality were meta-analysed. Eight independent variants were suggestively (P-value threshold ≤5 × 10-6 ) associated with exacerbations despite LABA use. CONCLUSION: No strong effects of single nucleotide polymorphisms (SNPs) on exacerbations during LABA use were identified. We identified two loci (TBX3 and EPHA7) that were previously implicated in the response to short-acting beta2-agonists (SABA). These loci merit further investigation in response to LABA and SABA use.

Pharmacoepidemiology: A time for a new multidisciplinary approach to precision medicine.

The advent of the genomic age has created a rapid increase in complexity for the development and selection of drug treatments. A key component of precision medicine is the use of genetic information to improve therapeutic effectiveness of drugs and prevent potential adverse drug reactions. Pharmacoepidemiology, as a field, uses observational methods to evaluate the safety and effectiveness of drug treatments in populations. Pharmacoepidemiology by virtue of its focus, tradition, and research orientation can provide appropriate study designs and analysis methods for precision medicine. The objective of this manuscript is to demonstrate how pharmacoepidemiology can impact and shape precision medicine and serve as a reference for pharmacoepidemiologists interested in contributing to the science of precision medicine. This paper depicts the state of the science with respect to the need for pharmacoepidemiology and pharmacoepidemiological methods, tools and approaches for precision medicine; the need for and how pharmacoepidemiologists use their skills to engage with the precision medicine community; and recommendations for moving the science of precision medicine pharmacoepidemiology forward. We propose a new integrated multidisciplinary approach dedicated to the emerging science of precision medicine pharmacoepidemiology.

Association between the timing of asthma diagnosis and medication use during pregnancy.

STUDY OBJECTIVE: To assess whether asthma medication use during pregnancy differs in women newly diagnosed with asthma early in pregnancy (first 19 weeks of pregnancy) compared to those newly diagnosed up to 2 years pre-pregnancy. DESIGN: A retrospective population-based cohort study. DATA SOURCE: To conduct this study, we used the Quebec Asthma and Pregnancy Database (QAPD) constructed by linking two administrative health databases from the province of Quebec (Canada): the Régie de l'Assurance Maladie du Québec and Maintenance et Exploitation des Données pour l'Étude de la Clientèle Hospitalière databases. PATIENTS: A cohort comprising pregnant women newly diagnosed with asthma at any time in the 2 years prior to pregnancy or during the first 19 weeks of pregnancy was selected from the QAPD. MEASUREMENTS AND MAIN RESULTS: We assessed the number of filled prescriptions of inhaled corticosteroids (ICS), ICS/long-acting ß2 agonists (LABA), and short-acting ß2 agonists (SABA), as well as the number of days' supply of oral corticosteroid (OCS) from the 20th week of pregnancy until delivery. Poisson regression was used to compare the rates of asthma medication use in women diagnosed pre-pregnancy versus early in pregnancy. The cohort included 1731 women newly diagnosed with asthma pre-pregnancy and 359 women newly diagnosed with asthma early in pregnancy. Women diagnosed early in pregnancy were more likely to use ICS (adjusted rate ratio: 1.9, 95% confidence interval (CI): 1.6-2.3) and SABA (adjusted rate ratio: 2.0, 95% CI: 1.7-2.4) from the 20th week of pregnancy until delivery than those newly diagnosed pre-pregnancy. No significant differences were observed in the use of ICS/LABA [adjusted rate ratio: 0.9, 95% CI: 0.7-1.3] and OCS [adjusted rate ratio: 0.8, 95% CI: 0.6-1.2]. CONCLUSION: The higher use of ICS and SABA observed in women newly diagnosed with asthma early in pregnancy may suggest a more persistent asthma phenotype caused by pregnancy-triggered hormonal changes.

Nonadherence to inhaled corticosteroids: A characteristic of the pediatric obese-asthma phenotype?

BACKGROUND: Children with excess weight and asthma tend to respond less well to inhaled corticosteroids (ICS) than children with normal weight, potentially resulting in nonadherence to ICS. OBJECTIVES: To assess whether excess weight (body mass index ≥85th percentile) was associated with general, unintentional, and intentional nonadherence to ICS in children with asthma. METHODS: We analyzed data from 566 children aged 4-13 years with asthma, who used ICS as maintenance therapy, from the cross-sectional Pharmacogenetics of Asthma medication in Children: Medication with Anti-inflammatory effects study. General nonadherence was measured objectively with the proportion of days covered (<50%) and subjectively with the parent-reported Medication Adherence Rating Scale (MARS <21) reflecting parent-reported nonadherent behavior. Unintentional and intentional nonadherence were defined as forgetting to take medication and deliberately changing or skipping doses, respectively, from specific items of the MARS. We performed logistic regression analyses, stratifying estimates by asthma severity and age group. RESULTS: Excess weight was associated with a trend towards increased odds of parent-reported nonadherent behavior (odds ratio [OR]: 1.54; 95% confidence interval [CI]: 0.84-2.81) and objectively measured general nonadherence, but only in moderate-to-severe asthma (OR: 1.71; 95% CI: 0.84-3.48). The odds of intentional, but not unintentional, nonadherence seemed to be greater in children with excess weight than normal weight (OR: 1.94; 95% CI: 0.94-4.01), and the association appeared to be stronger in younger (OR: 2.17; 95% CI 1.00-4.73) versus older children (OR: 1.18; 95% CI: 0.36-3.94). CONCLUSIONS: Excess weight was associated with general nonadherence to ICS, but only in children with moderate-to-severe asthma, and nonadherent behavior, which seemed to be intentional.

Communication of Pharmacogenomic test results and treatment plans in pediatric oncology: deliberative stakeholder consultations with parents.

BACKGROUND: Effective communication in support of clinical decision-making is central to the pediatric cancer care experience for families. A new laboratory derived pharmacogenetic test (LDT) that can diagnose difficult-to-treat brain cancers has been developed to stratify children based on their ability to respond to available treatment; however, the potential implementation of the LDT may make effective communication challenging since it can potentially remove the option for curative treatment in those children identified as non-responders, i.e. those with a catastrophic diagnosis. OBJECTIVE: We solicited the perspectives of parents of children with difficult-to-treat brain cancer on communication preferences surrounding the potential implementation of the LDT in standard care using deliberative stakeholder consultations. METHODS: Eight bereaved parents of children who succumbed to difficult-to-treat brain cancer, and four parents of children currently undergoing treatment for similar cancers attended separate small-group deliberative consultations - a stakeholder engagement method that enables the co-creation of recommendations following the consideration of competing arguments and diverse opinions of parents with different experiences. In the small-group consultations (Phase I), parents discussed four questions about potential communication issues that may arise with the LDT in practice. In Phase II, a total of five parents from both stakeholder groups (4 bereaved and 1 in current treatment) attended a consultation, known as the 'mixed' consultation, with the purpose of co-developing concrete recommendations for implementation of the LDT. RESULTS: Explaining the risks, benefits, and accuracy of the LDT were considered essential to parents. Once an LDT-based diagnosis/prognosis can be made, parents valued honesty, empathy, and clarity in communication. Parents also requested that all results and treatment options be presented to them in measured doses, and in an unbiased manner over the course of several meetings. This communication strategy allowed sufficient time to understand and accept the diagnosis/prognosis, particularly if it was catastrophic. Continuous access to the appropriate psychological and social support or counselling at and post-diagnosis was also strongly recommended. CONCLUSIONS: Deliberants co-created family-centered recommendations surrounding communication issues of the LDT, providing guidance to pediatric oncologists that could implement the test in practice.