BACKGROUND:Stringent donor-screening criteria and legislation prohibiting payment for donor gametes have contributed to the radical decline of donor insemination (DI) using sperm provided by Canadian men. Thus, many individuals rely on imported sperm. This paper examines the feasibility of an altruistic sperm donation (ASD) program to meet the needs of Canadians.METHODS:Using Canadian census data, published literature and expert opinions, two population-based, top-down mathematical models were developed to estimate the supply and demand for donor sperm and the feasibility of an ASD program.RESULTS:It was estimated that 63 donors would pass Canadian screening criteria, which would provide 1,575 donations. The demand for DI by women was 7,866 samples (4,319 same sex couples, 1,287 single women and 2,260 heterosexual couples).CONCLUSION:Considerable effort would be necessary to create the required increase in awareness of the program and change in societal behaviour towards sperm donation for an ASD program to be feasible in Canada.

Objectives Convolutional neural networks (CNNs) are a subtype of artificial neural network that have shown strong performance in computer vision tasks including image classification. To date, there has been limited application of CNNs to chest radiographs, the most frequently performed medical imaging study. We hypothesize CNNs can learn to classify frontal chest radiographs according to common findings from a sufficiently large data set. Materials and Methods Our institution's research ethics board approved a single-center retrospective review of 35,038 adult posterior-anterior chest radiographs and final reports performed between 2005 and 2015 (56% men, average age of 56, patient type: 24% inpatient, 39% outpatient, 37% emergency department) with a waiver for informed consent. The GoogLeNet CNN was trained using 3 graphics processing units to automatically classify radiographs as normal (n = 11,702) or into 1 or more of cardiomegaly (n = 9240), consolidation (n = 6788), pleural effusion (n = 7786), pulmonary edema (n = 1286), or pneumothorax (n = 1299). The network's performance was evaluated using receiver operating curve analysis on a test set of 2443 radiographs with the criterion standard being board-certified radiologist interpretation. Results Using 256 × 256-pixel images as input, the network achieved an overall sensitivity and specificity of 91% with an area under the curve of 0.964 for classifying a study as normal (n = 1203). For the abnormal categories, the sensitivity, specificity, and area under the curve, respectively, were 91%, 91%, and 0.962 for pleural effusion (n = 782), 82%, 82%, and 0.868 for pulmonary edema (n = 356), 74%, 75%, and 0.850 for consolidation (n = 214), 81%, 80%, and 0.875 for cardiomegaly (n = 482), and 78%, 78%, and 0.861 for pneumothorax (n = 167). Conclusions Current deep CNN architectures can be trained with modest-sized medical data sets to achieve clinically useful performance at detecting and excluding common pathology on chest radiographs.

To inform treatment decision making following inadequate response to first-line biologics in plaque psoriasis, a chronic, recurrent, autoimmune disorder. Markov modelling was used to estimate ten-year incremental costs and QALYs for two treatment strategies following partial response [PASI ≥50 and <75] to ustekinumab dosed every twelve weeks. Patients either continued on ustekinumab at an ‘optimized’ dosing of every eight weeks (45mg and 90mg) or ‘switched’ to anti-TNF treatment. Lack of published RCT data for second-line response to anti-TNFs resulted in the conservative selection of infliximab (a highly efficacious anti-TNF) to represent the anti-TNF class. Patients transitioned between ‘Response’ (higher utility) and ‘Best Supportive Care’ health states. Response (defined as PASI≥75) rates in a 26 week trial period were: ustekinumab 45mg = 44%, 90mg = 55% (n=91 and n = 75 respectively, PHOENIX trials); anti-TNF class = 72%, (n=94, EXPRESS II bio-experienced infliximab patients). Real world evidence informed treatment specific drug survival rates. Costs included biologics, supportive treatments, outpatient and inpatient care, and lost productivity. Input variables were subject to deterministic and probabilistic testing. Costs and QALYs were discounted at 5% p.a. and the ICER was used to compare strategies. In a probabilistic incremental analysis anti-TNF treatment was less costly per patient (45mg: CAN$149,577 versus CAN$181,234; 90mg: CAN$152,055 versus CAN$190,416) but attained fewer QALYs (45mg: 2.68 versus 3.21; 90mg: 2.68 versus 3.68) since survival on treatment was lower with anti-TNF by year three (45mg: 26.5% versus 35.7%; 90mg: 26.5% versus 44.4%). Dose optimization of ustekinumab reduced resource use and patients were more economically productive. The ICERs for ‘optimized’ versus ‘switched’ strategies were CAN$59,369 [95%CI $32,972-$254,949] in the 45mg analysis and CAN$38,028 [95%CI: $22,789-$72,538] in the 90mg analysis. At the commonly accepted thresholds of CAN$50,000 and CAN$100,000 per QALY gained, dose optimizing ustekinumab is likely to be cost-effective versus switching to anti-TNF therapy in partial responders to ustekinumab.

Background: Canadian inflammatory bowel disease patients treated with infliximab are predominantly managed through a nationwide case management system, named BioAdvance®. Methods: A web-based survey was provided to patients currently receiving infliximab therapy within BioAdvance®. Patients were categorized according to health trajectories: decliners, non-changers, moderate increasers and strong increasers. Factors associated with health trajectories were identified using multivariable multinomial logistic regression. Results: 918 of 1160 respondents were inflammatory bowel disease patients reporting health status. Strong increasers were more likely to use educational tools than non-changers (adjusted odds ratio [aOR]: 1.65; 95% CI: 1.03–2.64), to be treated for ulcerative colitis (aOR: 2.05; 95% CI: 1.16–3.64) and to perceive case management as important (aOR: 2.52; 95% CI: 1.56–4.09). Younger (aOR: 0.72; 95% CI: 0.63–0.83) and French-speaking (aOR: 0.34; 95% CI: 0.18–0.63) patients were less likely to miss workdays. Patients were more likely to have missed workdays prior to joining the case management program. Conclusions: Inflammatory bowel disease patients receiving infliximab within the nationwide case management system report a positive impact on health status and absenteeism.

Background EQ-5D-3L scoring algorithms vary amongst countries, not only in the values of regression coefficients but also in the independent variables included in the regression model (hereafter referred to as model specification). It is unclear how much of this variation is due to differences in health state selection, the relative frequencies with which health states were valued, and model diagnostics, rather than to genuine differences in population preferences. Methods Using aggregate data from a recent review, we noted all model specifications that were used. For each country the country’s own model was re-fitted, as were all other model specifications. This was done twice: once using all valued health states for each country, and again using a common set of 17 health states for all countries. Goodness of fit was assessed using the following model diagnostics: mean absolute error (MAE), mean squared error (MSE) and rho (the Pearson correlation coefficient between predicted and observed mean utilities), both with and without leave-one-out cross-validation. Results Thirteen countries contributed data. Even when using a common set of health states, the preferred model varied across countries. However, choice of health states did impact the preferred model specification: when using cross-validation, the preferred specification changed in five of ten countries when moving from 17 health states to all valued health states. The relative frequency with which health states were valued had little impact on the preferred model. Conclusions Variation in choices of health states to value is responsible for some, but not all, of the observed heterogeneity in model specification. Relative frequency of health state valuation and choice of model diagnostic has a limited impact on model preference, however, use of cross-validation has a substantial impact. The use of cross-validation, implemented through omitting health states rather than respondents, is recommended as one approach to assessing model fit.

Background. There has been a growing interest around the world in developing country-specific scoring algorithms for the EQ-5D. This study systematically reviews all existing EQ-5D valuation studies to highlight their strengths and limitations, explores heterogeneity in observed utilities using meta-regression, and proposes a methodological checklist for reporting EQ-5D valuation studies. Methods. We searched Medline, EMBASE, the National Health Service Economic Evaluation Database (NHS EED) via Wiley's Cochrane Library, and Wiley's Health Economic Evaluation Database from inception through November 2012, as well as bibliographies of key papers and the EuroQol Plenary Meeting Proceedings from 1991 to 2012 for English-language reports of EQ-5D valuation studies. Two reviewers independently screened the titles and abstracts for relevance. Three reviewers performed data extraction and compared the characteristics and scoring algorithms developed in the included valuation studies. Results. Of the 31 studies included in the review, 19 used the time trade-off (TTO) technique, 10 used the visual analogue scale (VAS) technique, and 2 used both TTO and VAS. Most studies included respondents from the general population selected by random or quota sampling and used face-to-face interviews or postal surveys. Studies valued between 7 and 198 total states, with 1-23 states valued per respondent. Different model specifications have been proposed for scoring. Some sample or demographic factors, including gender, education, percentage urban population, and national health care expenditure, were associated with differences in observed utilities for moderate or severe health states. Conclusions. EQ-5D valuation studies conducted to date have varied widely in their design and in the resulting scoring algorithms. Therefore, we propose the Checklist for Reporting Valuation Studies of the EQ-5D (CREATE) for those conducting valuation studies.

Background. There has been a growing interest around the world in developing country-specific scoring algorithms for the EQ-5D. This study systematically reviews all existing EQ-5D valuation studies to highlight their strengths and limitations, explores heterogeneity in observed utilities using meta-regression, and proposes a methodological checklist for reporting EQ-5D valuation studies. Methods. We searched Medline, EMBASE, the National Health Service Economic Evaluation Database (NHS EED) via Wiley’s Cochrane Library, and Wiley’s Health Economic Evaluation Database from inception through November 2012, as well as bibliographies of key papers and the EuroQol Plenary Meeting Proceedings from 1991 to 2012 for English-language reports of EQ-5D valuation studies. Two reviewers independently screened the titles and abstracts for relevance. Three reviewers performed data extraction and compared the characteristics and scoring algorithms developed in the included valuation studies. Results. Of the 31 studies included in the review, 19 used the time trade-off (TTO) technique, 10 used the visual analogue scale (VAS) technique, and 2 used both TTO and VAS. Most studies included respondents from the general population selected by random or quota sampling and used face-to-face interviews or postal surveys. Studies valued between 7 and 198 total states, with 1–23 states valued per respondent. Different model specifications have been proposed for scoring. Some sample or demographic factors, including gender, education, percentage urban population, and national health care expenditure, were associated with differences in observed utilities for moderate or severe health states. Conclusions. EQ-5D valuation studies conducted to date have varied widely in their design and in the resulting scoring algorithms. Therefore, we propose the Checklist for Reporting Valuation Studies of the EQ-5D (CREATE) for those conducting valuation studies.

Introduction: Chronic granulomatous disease (CGD) is an immunodeficiency syndrome caused by a defective NADPH oxidase complex. Afflicted patients are unable to produce adequate reactive oxygen metabolites to neutralize microorganisms within macrophages. Approximately 50% of CGD patients develop gastrointestinal (GI) disease that shares features of both Crohn's disease and ulcerative colitis. In patients with pediatric-onset ulcerative colitis, the cumulative risk for colorectal cancer (CRC) is 2% at 10 years (yrs) and 8% at 20 yrs. While the increased risk of CRC among patients with longstanding inflammatory bowel disease (IBD) is well established, the incidence of CRC among CGD patients with longstanding colitis has not been described. Methods: Patients with CGD colitis were identified from a database comprised of 279 CGD patients seen at the NIH from 1972 to 2011. To allow for adequate endoscopic, pathologic, and clinical follow-up, 78 patients with evidence of CGD colitis seen between 1990 and 2010 were identified, and patients with disease duration >10 yrs were used for formal analysis. The clinical and endoscopic reports over the 10 year follow-up period were reviewed, and the colonic biopsies were reexamined when available. Demographic information, duration of disease, endoscopic findings, and treatment and surgical history were extracted from the electronic medical records. The primary endpoint was the evidence of dysplasia or development of CRC. Results: Of the 78 patients, 20 had disease for >10 yrs. Notably, no colonic dysplasia or CRC were seen at the time of the biopsies in any of these patients. Of the 20 patients with disease > 10 yrs, 8 had biopsies available for formal reexamination. On reexamination, no patients were found to have colonic dysplasia or CRC. For all 20 patients, the average age at diagnosis was 10 years, with the median duration of disease of 16.7 yrs. Polyps were noted in 5 of 20 patients, 3 of which were inflammatory, 1 hyperplastic and 1 normal mucosa. No patients were diagnosed with colorectal cancer during follow-up. Conclusions: Despite long-standing inflammation, there was no dysplasia or CRC among 20 patients with CGD after a median of 16.7 years of follow up. In addition, no cases of colonic dysplasia or CRC were found in any patients with CGD colitis. The incidence of CRC among patients with CGD colitis appears to be lower than the incidence among patients with IBD. In fact, there are no reported cases of malignant polyps, dysplasia, or any gastrointestinal cancers in the short term or long term data. Although limited by a retrospective study design, these data suggest that the development of CRC in the setting of chronic inflammation may be influenced by NADPH activity, suggesting superoxide metabolism as a possible target to prevent oncogenesis.

Canadian inflammatory bowel disease (IBD) patients treated with infliximab are predominantly managed through a nationwide case management system, named BioAdvance, providing access to care, educational tools, supplies and assistance programs. The aim of this study was to identify underlying factors that were associated with positive changes in health outcomes. Between August 1 and September 30, 2012, a web-based survey was provided to patients currently receiving infliximab therapy within BioAdvance. The cross-sectional survey included items on demographic, disease characteristics, services usage and preference, and perception of health and work absenteeism. Patients were categorized according to health trajectories: declined in health (decliners), no improvement (non-changers), moderate improvement and large improvements (strong increasers). Multivariable multinomial logistic regression was used to determine which factors were associated with different health trajectories. 918 of 1160 respondents were IBD patients reporting health status. Patients were treated for Crohn’s disease [CD] (66.1%), Ulcerative Colitis [UC] (26.6%) or 2 or more conditions (7.3%). Strong increasers were most prevalent (53.2%) and decliners least prevalent (3.7%). Strong increasers were more likely to use educational tools than non-changers (adjusted odds ratio [aOR]: 1.65; 95% confidence interval [CI]: 1.03-2.64), to be treated for UC than CD (aOR: 2.05; 95%CI: 1.16-3.64) and to perceive BioAdvance as important (aOR: 2.52; 95%CI: 1.56-4.09). There were no factors distinguishing decliners from non-changers. Younger patients were less likely to miss workdays, as were French speaking patients and, consistent health trajectories, patients treated for UC (aOR: 0.68; 95%CI: 0.47-0.97). Patients were more likely to have missed workdays prior to joining BioAdvance (aOR: 2.76; 95%CI: 2.02-3.76). IBD patients receiving infliximab within the nationwide case management system report a positive impact on health status and absenteeism. Our study identified factors about the program that aremore impactful (educational tools) and patient factors that could improve program outcomes.

Purpose: In Canada, patients with ulcerative colitis and Crohn's disease treated with infliximab are predominantly managed through a nationwide case management system. The case management system assigns patients a case manager who coordinates treatment between the patient, physician and a network of infusion clinics. The aim of this study was to assess the patient's experience of infliximab therapy administered through a case management system. Methods: Patients currently receiving infliximab therapy within the case management system were given an informational brochure to access a web-based survey from August 1, 2012 to September 30, 2012. The survey included items on demographic and disease characteristics, and asked qualitative questions about the respondents' perception of their absenteeism and disability status before and after receiving therapy. Respondents were also asked to assess the effectiveness of the therapy and the case management system with regards to adherence and disease management. Results: Out of 10,000 brochures distributed, there were 1,160 respondents (11.6%), of which 888 reported being treated for IBD. Of the IBD respondents, 846 completed the survey. The IBD respondents were comprised of 51% (n=431) males with a mean age of 39 (SD=20), with 72% (n=609) reported as being treated for Crohn's disease and 28% (n=237) reported being treated for ulcerative colitis. In addition, 72% (n=611) of respondents reported being employed full time or part time, while 10%, 7%, 10% were unemployed, retired or students, respectively. When asked about time on therapy, 48% (n=407) of respondents reported to be receiving therapy for greater than two years, while 24% (n=206) and 28% (n=233) of respondents reported being on therapy for 1-2 years and 12 months or less, respectively. When asked about time missed from work/school prior to starting therapy, 33% (n=278) of respondents reported missing greater than five days of work/school prior to therapy, while only 7% (n=58) of respondents reported missing greater than five days of work/school after receiving therapy. When asked about their disability status prior to receiving therapy, 33% (n=282) of patients reported being on disability insurance prior to therapy, while only 9% (n=77) of patients reported being on disability insurance after receiving therapy. Overall, 58% (n=487) of respondents felt that the case management system was helpful in ensuring their medication was taken on time. Finally, 74% (n=624) of patients viewed the case management system as either important or very important in their disease management. Conclusion: IBD patients receiving infliximab within the nationwide case management system report a positive impact on absenteeism, disability, adherence and disease management. Disclosure - Kuhan Perampaladas- Manager of Health Economics and Reimbursement: Janssen Inc.

The EQ-5D is one of the most widely used instruments to estimate utility values. The scoring system of the EQ-5D were developed from valuation studies, which estimate a scoring function for all EQ-5D health states based on the general population's preference for a subset of health states. Due to the wide spread use of the EQ-5D a number of country-specific scoring systems have been developed. The objective of this study was to identify and compare all existing EQ-5D valuation studies and country-specific scoring systems. An electronic search of MEDLINE, EMBASE, NHS EED, HEED and a search through the past proceedings of the Euroqol group up to September of 2010 was conducted to identify all EQ-5D preference elicitation studies. The review included a summary and comparison of study design, model estimation, study demographics and scoring function. After screening 2940 citations identified from the literature search, 33 elicitation studies that contained a unique scoring system were included for final review. The key areas of divergence between the studies include: differences in methodology used to directly value health (i.e. SG, TTO, etc.), the number of health states that were directly valued, the transformation of the directly valued health states, the statistical methods used to derive the scoring system, and the model variables included in the scoring system. Differences in methods do exist between population studies. Knowing the extent, at which the identified methodological differences can explain the variation, will help determine whether a global preference for health exists.

The primary analysis of this study was to estimate the cost-effectiveness of TAVI compared to standard management (SM) in inoperable patients with severe, symptomatic aortic valve stenosis (SSAVS). The secondary analysis was to preliminarily explore both the cost-effectiveness and value of information of TAVI compared to surgical aortic valve replacement (SAVR) in operable patients at high surgical risk with SSAVS. A combined decision tree and Markov model was developed to compare the costs, life-years (LYs) and quality-adjusted life-years (QALYs) of TAVI (transfemoral (TF) and transapical (TA) approaches) to SM and SAVR over a 5-year time horizon. This evaluation was conducted from a third party payer's perspective. In the primary analysis, comparing TF and SM resulted in an incremental cost-effectiveness ratio (ICER) of $126,874/LY and $222,378/QALY. Comparing TA and SM resulted in an ICER of $262,672/LY and $1,454,241/QALY. In the secondary analysis, TF and SAVR were compared, resulting in an ICER of $39,676/LY and $81,758/QALY. Comparing TA and SAVR resulted in an ICER of $183,454/LY. TA was dominated by SAVR when comparing QALYs. The total expected value of perfect information (EVPI) was at a maximum with a value of $6,928 at a WTP threshold of $80,000/QALY. The expected value of partial perfect information (EVPPI) was highest for the 30-day clinical event rates when compared to the EVPPI values for the 1-year, 2-year and >3-year clinical event rates. This economic evaluation suggested that TAVI might not be a cost-effective option for inoperable patients in comparison to SM. The secondary analysis suggested that TAVI might be a cost effective option for operable patients compared to SAVR. To reduce the uncertainty in our estimate it might be worthwhile to obtain empirical evidence related to clinical event rates occurring 30-days post operation.

In many species, selection acts on males to recognize female reproductive status at a distance using pheromones. Unmated females may actively seek to attract males; however, mated females may become cryptic to avoid attracting additional males if multiple matings are costly. Although females of many species cease pheromone production after mating, it is often unclear whether this is a strategic part of a female reproductive strategy, or whether this is because of chemical manipulation by males. If variation in pheromone production is part of the female's strategy, then we predicted mated females should eventually re-advertise receptivity if the benefits of multiple mating increase with time since copulation (e.g. because of sperm depletion). Here, we tested this prediction in Australian redback spiders (Latrodectus hasselti). First, we replicated earlier results by showing that virgin males discriminate female maturity and mating status based exclusively on web-borne chemicals. Our results show this difference must arise from a change in chemical deposition in the web as we controlled for web volume differences between mated and virgin females. Male activity on extracts from webs of virgin females exceeded activity on a solvent control and on extracts of webs of just-mated females--confirming that female redbacks cease pheromone production immediately after mating. Second, we tested a new prediction that mated females might re-advertise receptivity near the end of their normal breeding season to replenish diminished sperm stores prior to overwintering. Consistent with the prediction of strategic advertisement, we show that male activity on extracts from females' webs increased significantly 3 mo after the female first mated (typical length of the breeding season). Thus, these females had begun to add pheromone to their web again. At this time, 26% of these females re-mated with a second male. If females re-advertise receptivity to ensure adequate sperm stores, then we predicted a positive relationship between female reproductive output during the 3-mo interval after copulation and the subsequent intensity of male response to web extracts. However, differences in male activity time were not related to the total number of spiderlings or the number of egg sacs a female had produced during the 3-mo interval after the first copulation. This result could arise if male chemical manipulation of female receptivity decreases with time after copulation, or if the testing interval used in our study was too long to reveal variation in sperm depletion in females. Thus, although our results are consistent with the idea that females strategically alter pheromonal advertisement, we cannot distinguish this from the hypothesis that female receptivity arises from chemical manipulation by males.