Variation in lung function and nutritional decline in cystic fibrosis by genotype: An analysis of the Canadian cystic fibrosis registry.

BACKGROUND: This study aimed to improve our understanding of the natural history of cystic fibrosis (CF) by comparing lung function and body mass index z-score (zBMI) between patients with different genotypes and identify a genotype with outcomes most comparable to homozygous ΔF508 patients. METHODS: Data was obtained from the Canadian CF Registry between January 1st 2007-January 1st 2016. Patients were categorized into one of five groups based on their genotype. A mixed-effects model was conducted with adjustments for age, sex, age of diagnosis, and baseline clinical measures. RESULTS: Among 2612 patients, those with non-mild forms of CF, and particularly adult patients with the same functional allele classification were found to have a lung function trajectory comparable to individuals with the homozygous ∆F508 genotype (annual change in percent predicted forced expiratory volume in 1 s of -0.83, 95% CI: -0.93, -0.73). The rates of zBMI change over the study period were not significantly different between the genotype groups. CONCLUSION: This population-based study of Canadian CF patients provides adjusted rates of lung function decline and zBMI over ten years. The finding that there are different genotypes with comparable rates of lung function decline to patients of the homozygous ∆F508 group supports the use of multiple comparison groups to assess the long-term efficacy of emerging CF therapies.

Mapping the preclinical to clinical evidence and development trajectory of the oncolytic virus talimogene laherparepvec (T-VEC): a systematic review.

OBJECTIVE: This study aimed to conduct a systematic review of preclinical and clinical evidence to chart the successful trajectory of talimogene laherparepvec (T-VEC) from the bench to the clinic. DESIGN: This study was a systematic review. The primary outcome of interest was the efficacy of treatment, determined by complete response. Abstract and full-text selection as well as data extraction were done by two independent reviewers. The Cochrane risk of bias tool was used to assess the risk of bias in studies. SETTING: Embase, Embase Classic and OvidMedline were searched from inception until May 2016 to assess its development trajectory to approval in 2015. PARTICIPANTS: Preclinical and clinical controlled comparison studies, as well as observational studies. INTERVENTIONS: T-VEC for the treatment of any malignancy. RESULTS: 8852 records were screened and five preclinical (n=150 animals) and seven clinical studies (n=589 patients) were included. We saw large decreases in T-VEC's efficacy as studies moved from the laboratory to patients, and as studies became more methodologically rigorous. Preclinical studies reported complete regression rates up to 100% for injected tumours and 80% for contralateral tumours, while the highest degree of efficacy seen in the clinical setting was a 24% complete response rate, with one study experiencing a complete response rate of 0%. We were unable to reliably assess safety due to the lack of reporting, as well as the heterogeneity seen in adverse event definitions. All preclinical studies had high or unclear risk of bias, and all clinical studies were at a high risk of bias in at least one domain. CONCLUSIONS: Our findings illustrate that even successful biotherapeutics may not demonstrate a clear translational road map. This emphasises the need to consider increasing rigour and transparency along the translational pathway. PROSPERO REGISTRATION NUMBER: CRD42016043541.

Assessing the Completeness of Reporting in Preclinical Oncolytic Virus Therapy Studies.

Irreproducibility of preclinical findings could be a significant barrier to the "bench-to-bedside" development of oncolytic viruses (OVs). A contributing factor is the incomplete and non-transparent reporting of study methodology and design. Using the NIH Principles and Guidelines for Reporting Preclinical Research, a core set of seven recommendations, we evaluated the completeness of reporting of preclinical OV studies. We also developed an evidence map identifying the current trends in OV research. A systematic search of MEDLINE and Embase identified all relevant articles published over an 18 month period. We screened 1,554 articles, and 236 met our a priori-defined inclusion criteria. Adenovirus (43%) was the most commonly used viral platform. Frequently investigated cancers included colorectal (14%), skin (12%), and breast (11%). Xenograft implantation (61%) in mice (96%) was the most common animal model. The use of preclinical reporting guidelines was listed in 0.4% of articles. Biological and technical replicates were completely reported in 1% of studies, statistics in 49%, randomization in 1%, blinding in 2%, sample size estimation in 0%, and inclusion/exclusion criteria in 0%. Overall, completeness of reporting in the preclinical OV therapy literature is poor. This may hinder efforts to interpret, replicate, and ultimately translate promising preclinical OV findings.

Comparing Twitter data to routine data sources in public health surveillance for the 2015 Pan/Parapan American Games: an ecological study.

OBJECTIVES: This study examined Twitter for public health surveillance during a mass gathering in Canada with two objectives: to explore the feasibility of acquiring, categorizing and using geolocated Twitter data and to compare Twitter data against other data sources used for Pan Parapan American Games (P/PAG) surveillance. METHODS: Syndrome definitions were created using keyword categorization to extract posts from Twitter. Categories were developed iteratively for four relevant syndromes: respiratory, gastrointestinal, heat-related illness, and influenza-like illness (ILI). All data sources corresponded to the location of Toronto, Canada. Twitter data were acquired from a publicly available stream representing a 1% random sample of tweets from June 26 to September 10, 2015. Cross-correlation analyses of time series data were conducted between Twitter and comparator surveillance data sources: emergency department visits, telephone helpline calls, laboratory testing positivity rate, reportable disease data, and temperature. RESULTS: The frequency of daily tweets that were classified into syndromes was low, with the highest mean number of daily tweets being for ILI and respiratory syndromes (22.0 and 21.6, respectively) and the lowest, for the heat syndrome (4.1). Cross-correlation analyses of Twitter data demonstrated significant correlations for heat syndrome with two data sources: telephone helpline calls (r = 0.4) and temperature data (r = 0.5). CONCLUSION: Using simple syndromes based on keyword classification of geolocated tweets, we found a correlation between tweets and two routine data sources for heat alerts, the only public health event detected during P/PAG. Further research is needed to understand the role for Twitter in surveillance.

Osteoarthritis of the hand I: aetiology and pathogenesis, risk factors, investigation and diagnosis.

OBJECTIVE: Osteoarthritis (OA) of the hand can be a debilitating condition that hinders an individual's quality of life. With multiple joints within the hand that are commonly affected OA, an individual's ability to use their hand in everyday movements become more limited. The article aims to review literature on the aetiology and pathogenesis of OA, risk factors, characteristics of hand OA and the steps of diagnosis. KEY FINDINGS: The aetiology and pathogenesis of OA, in particular hand OA, is not fully understood. However, it is known that several factors play a role. Environmental factors, such as stress from mechanical loading, especially to vulnerable joints predispose individuals to developing OA. Extracellular matrix changes in protein levels have also been noted in individuals with OA. Linked to hand OA development are boney enlargements (Herbeden's and Bouchard's nodes). Several risk factors for OA include: age, obesity, gender, smoking, genetics, diet and occupation. Various diagnostic methods include a combination of using radiographic methods, clinical presentation, a number of developed measurements and scales. SUMMARY: With OA having several risk factors and various causes and contributing elements, it is important to elucidate the pathogenesis of OA and determine exactly how risk factors play a role in its development. Because of the contributions from several elements, diagnosis is best when it uses multiple methods. In turn, understanding OA and making better diagnoses could lead to improved management of the condition through both pharmacological and non-pharmacological interventions.

Osteoarthritis of the hand II: chemistry, pharmacokinetics and pharmacodynamics of naproxen, and clinical outcome studies.

OBJECTIVE: This article aims to review osteoarthritis of the hand and the role of the non-steroidal anti-inflammatory drug (NSAID) naproxen on its management. We discuss the chemical and pharmacological properties of naproxen and the NSAID class, with an emphasis on its mechanism and adverse reactions. In the context of part I of this paper in characterizing hand osteoarthritis (OA), we review clinical trials that have been conducted involving hand OA and naproxen. KEY FINDINGS: The therapeutic effect of NSAIDs stems from its role on inhibiting cyclo-oxygenase (COX)-1 or COX-2 enzyme activity in the body. These enzymes play a major role in maintaining several functions in the body and due NSAIDs' inhibitory effects; many principle adverse reactions occur with the use of NSAIDs such as: gastrointestinal tract issues, cardiovascular risks, renal, hepatic, central nervous system and cutaneous. Review of clinical trials involving naproxen and hand OA show that it is significantly more efficacious when compared with placebo. SUMMARY: These studies, along with the finding that naproxen is of least cardiovascular risk in the NSAID class, may show that it can be part of one of the approaches in managing the condition. It is important to note that the optimal NSAID to use varies for each individual. The finding that the use of naproxen leads to the smallest increase in cardiovascular risk appeals to those at-risk individuals who suffer from OA and require pharmacological treatment for relief.