Variant effect on splicing regulatory elements,branchpoint usage,and pseudoexonization: Strategies to enhance bioinformatic prediction using hereditary cancer genes as exemplars

It is possible to estimate the prior probability of pathogenicity for germline disease gene variants based on bioinformatic prediction of variant effect/s. However, routinely used approaches have likely led to the underestimation and underreporting of variants located outside donor and acceptor splice site motifs that affect messenger RNA (mRNA) processing. This review presents information about hereditary cancer gene germline variants, outside native splice sites, with experimentally validated splicing effects. We list 95 exonic variants that impact splicing regulatory elements (SREs) in BRCA1, BRCA2, MLH1, MSH2, MSH6, and PMS2. We utilized a pre‐existing large‐scale BRCA1 functional data set to map functional SREs, and assess the relative performance of different tools to predict effects of 283 variants on such elements. We also describe rare examples of intronic variants that impact branchpoint (BP) sites and create pseudoexons. We discuss the challenges in predicting variant effect on BP site usage and pseudoexonization, and suggest strategies to improve the bioinformatic prioritization of such variants for experimental validation. Importantly, our review and analysis highlights the value of considering impact of variants outside donor and acceptor motifs on mRNA splicing and disease causation.     

Inhibitory milieu at the multiple sclerosis lesion site and the challenges for remyelination

Regeneration of myelin, following injury, can occur within the central nervous system to reinstate proper axonal conductance and provide trophic support. Failure to do so renders the axons vulnerable, leading to eventual degeneration, and neuronal loss. Thus, it is essential to understand the mechanisms by which remyelination or failure to remyelinate occur, particularly in the context of demyelinating and neurodegenerative disorders. In multiple sclerosis, oligodendrocyte progenitor cells (OPCs) migrate to lesion sites to repair myelin. However, during disease progression, the ability of OPCs to participate in remyelination diminishes coincident with worsening of the symptoms. Remyelination is affected by a broad range of cues from intrinsic programming of OPCs and extrinsic local factors to the immune system and other systemic elements including diet and exercise. Here we review the literature on these diverse inhibitory factors and the challenges they pose to remyelination. Results spanning several disciplines from fundamental preclinical studies to knowledge gained in the clinic will be discussed.     

Results from a randomized trial of a web-based,tailored decision aid for women at high risk for breast cancer

Objective

To assess the impact of Guide to Decide (GtD), a web-based, personally-tailored decision aid designed to inform women's decisions about prophylactic tamoxifen and raloxifene use.

Methods

Postmenopausal women, age 46–74, with BCRAT 5-year risk ≥1.66% and no prior history of breast cancer were randomized to one of three study arms:intervention (n = 690), Time 1 control (n = 160), or 3-month control (n = 162). Intervention participants viewed GtD prior to completing a post-test and 3 month follow-up assessment. Controls did not. We assessed the impact of GtD on women's decisional conflict levels and treatment decision behavior at post-test and at 3 months, respectively.

Results

Intervention participants had significantly lower decisional conflict levels at post-test (p < 0.001) and significantly higher odds of making a decision about whether or not to take prophylactic tamoxifen or raloxifene at 3-month follow-up (p < 0.001) compared to control participants.

Conclusion

GtD lowered decisional conflict and helped women at high risk of breast cancer decide whether to take prophylactic tamoxifen or raloxifene to reduce their cancer risk.

Practice implications

Web-based, tailored decision aids should be used more routinely to facilitate informed medical decisions, reduce patients’ decisional conflict, and empower patients to choose the treatment strategy that best reflects their own values.     

Toward a research agenda for competency-based medical education

Competency-based medical education (CBME) is both an educational philosophy and an approach to educational design. CBME has already had a broad impact on medical schools, residency programs, and continuing professional development in health professions around the world. As the CBME movement evolves and CBME programs are implemented, a wide range of emerging research questions will warrant scholarly examination. In this paper, we describe a proposed CBME research agenda developed by the International CBME Collaborators. The resulting framework includes questions about the meaning of key concepts of CBME and their implications for learners, faculty members, and institutional structures. Other research questions relate to the learning process, the meaning of entrustment decisions, fundamental measurement issues, and the nature and definition of standards. The exploration of these questions will help to solidify the theoretical foundation of CBME, but many issues related to implementation also need to be addressed. These pertain to, among other things, nurturing independent learning, assembling and using assessment results to make decisions about competence, structuring feedback, supporting remediation, and how best to evaluate the longer-term outcomes of CBME. High-quality research on these questions will require rigorous outcome measures with strong validity evidence. The complexity of CBME necessitates theoretical and methodological diversity. It also requires multi-institutional studies that examine effects at multiple levels, from the learner to the team, the institution, and the health care system. Such a framework of research questions can guide and facilitate scholarly discourse on the theoretical and practical body of knowledge related to competency-based health professions education.     

Biodiversity and infrastructure interact to drive tourism to and within Costa Rica

Nature-based tourism has potential to sustain biodiversity and economic development, yet the degree to which biodiversity drives tourism patterns, especially relative to infrastructure, is poorly understood. Here, we examine relationships between different types of biodiversity and different types of tourism in Costa Rica to address three questions. First, what is the contribution of species richness in explaining patterns of tourism in protected areas and country-wide in Costa Rica? Second, how similar are the patterns for birdwatching tourism compared to those of overall tourism? Third, where in the country is biodiversity contributing more than other factors to birdwatching tourism and to overall tourism? We integrated environmental data and species occurrence records to build species distribution models for 66 species of amphibians, reptiles, and mammals, and for 699 bird species. We used built infrastructure variables (hotel density and distance to roads), protected area size, distance to protected areas, and distance to water as covariates to evaluate the relative importance of biodiversity in predicting birdwatching tourism (via eBird checklists) and overall tourism (via Flickr photographs) within Costa Rica. We found that while the role of infrastructure is larger than any other variable, it alone is not sufficient to explain birdwatching and tourism patterns. Including biodiversity adds predictive power and alters spatial patterns of predicted tourism. Our results suggest that investments in infrastructure must be paired with successful biodiversity conservation for tourism to generate the economic revenue that countries like Costa Rica derive from it, now and into the future.

The tourism sector is well-poised to generate win–win approaches to biodiversity conservation and sustainable development given its nonextractive nature and its dependence on scenic beauty (1). However, for sustainable tourism to succeed as a strategy for biodiversity conservation, the role that biodiversity plays in driving tourism patterns needs to be better understood. On one hand, wildlife and nature motivate a significant portion of global tourism (2), and protected areas with higher species richness tend to attract more tourists and yield higher economic benefits (3). On the other hand, tourism hotspots also tend to occur in places where more human-built infrastructure (e.g., hotels, roads, and airports) enables access (4, 5). Studies have reached mixed conclusions on the relative importance of biodiversity and accessibility for tourism, and little is known about how they work in concert (6–11). Given the potential negative impacts of infrastructure on biodiversity conservation, their relative contributions to tourism deserves explicit study, particularly in developing countries where both biodiversity conservation and sustainable development are urgently needed (7, 12).Drivers of tourism patterns across landscapes have been explored through questionnaire surveys and structured interviews that ask tourists about their affinity for landscape features (13–15) and through spatial models that predict recreation using photographs (e.g., geographically weighted regression, MaxEnt) (16, 17). Recently, geo-tagged photographs and species lists shared on social media platforms have become popular tools for tourism-focused research (18–22). These studies, however, typically focus narrowly on the role of single taxa (22, 23) and landscape attributes without accounting for species diversity (14, 20), or they focus only on the role of infrastructure as a driver of tourism (5). Recent advances in satellite Earth observations make it possible to capture more of the ecosystem heterogeneity that can drive variability in species distributions, compared to more conventional modeling based on land cover (24–26). An integrated approach is needed, linking species richness of multiple taxa along with infrastructure variables, both modeled and mapped through high resolution Earth observations. Such an approach could be scaled up to larger regions and applied globally, helping to identify where biodiversity is playing a significant role in driving tourism, such that governments and the tourism sector can prioritize investments in biodiversity conservation.Here, we ask three questions in the iconic case of Costa Rica. First, what is the contribution of species richness (of vertebrate taxa) in explaining patterns of tourism in protected areas and also country-wide? Second, how similar are the patterns for birdwatching tourism compared to those of overall tourism? Third, where in the country is biodiversity contributing more than other factors to birdwatching tourism and to overall tourism? We predict that vertebrate species richness is more important for driving tourism in protected areas than in the rest of the country, because nature-seeking tourists often go to protected areas to find wildlife (3). We also expect that birdwatching tourism is predicted by richness of threatened and endemic bird species rather than total species richness, given birdwatchers’ preferences for rare birds (27). We predict a saturating relationship between species richness and tourism, because beyond a large number of species additional species are unlikely to contribute more to tourism (28). Finally, we predict that national-level tourism is better explained by infrastructure (such as roads and hotels) and distance to water than by biodiversity, because tourists going to Costa Rica often seek activities such as surfing and relaxing in beach resorts (29, 30). We predict nonlinear effects of proximity to roads and water, because a place is deemed inaccessible if it is further away from roads, and a beach tourist destination is also either close to water or not a destination at all. Access diminishes rapidly over a few miles (31).To answer our research questions, we analyze patterns of tourism at two different spatial scales. First, we analyze tourism patterns in protected areas only. Many protected areas provide reliable data on visitation rates and biodiversity tends to be higher inside than outside protected areas (29). However, given that they are often visited by tourists who are already interested in biodiversity, protected areas are not representative of all tourism patterns (30). Second, we evaluate the relative importance of biodiversity to all tourism across Costa Rica (excluding offshore islands). Investigating tourism across the whole nation may give a better understanding of how biodiversity contributes to tourism writ large and not only for tourists with a predisposition for finding wildlife. At both the protected area and national scales, we use a modified MaxEnt model that integrates species distribution models for 66 terrestrial vertebrate species (including amphibians, reptiles, and mammals) and 699 bird species, based on remotely sensed climate and habitat variables, with spatial patterns of infrastructure (hotel density and distance to roads) and distance to water. We measure tourism in two ways for both scales: using eBird checklists as a proxy for birdwatching (32), and using Flickr photographs as a proxy for all international and domestic tourism (19).Costa Rica is an ideal country to explore these questions because tourism represents 7% of the national gross domestic product and employs 3% of the working population directly and a further 9% indirectly (33). Approximately 70% of all international visitors to Costa Rica state that the wildlife, dramatic scenery, and opportunities for adventure sports are the main motivation for visiting the country (33, 34). However, the importance of biodiversity as a factor that influences tourism to, or domestically within, the country has not been evaluated (apart from very local studies) (35, 36). The Central Bank of Costa Rica is currently piloting a nature-based tourism account under the United Nations System of Environmental Economic Accounts (UN SEEA). The state of the art with this methodology is to attribute value to different ecosystems, which may vary widely in their biodiversity. Understanding the relationships between biodiversity and tourism in Costa Rica is a key step toward maintaining the vibrant ecotourism industry and can serve as an example for other biodiverse nations that often look to Costa Rica as a leader in sustainable development (37).     

Canadian cost data associated with treating overactive bladder is lacking

IntroductionCost-effectiveness analysis forms an integral part of the approval process for new medical treatments in Canada, including drug and non-drug technologies. This study’s primary objective was to identify peer-reviewed studies that report Canadian-specific cost data for treating overactive bladder (OAB) based on the Canadian Urological Association (CUA) guideline. A secondary objective was to identify studies that report cost data from other healthcare jurisdictions that could be generalizable to the Canadian context.MethodsWe conducted a systematic review of the published peer-reviewed literature. We included studies from Organization for Economic Cooperation and Development countries, excluding the U.S., published in English since January 2009.ResultsFrom 165 abstracts identified in our initial search, 18 studies were ultimately included for analysis. This included one Canadian-based study reporting costs in Canadian dollars, all related to second-line treatments. The other studies were primarily from Europe, reporting costs in Euros or British pounds. There were no studies reporting costs for first-line treatments. Gaps in costs for select second-line and third-line treatments recommended by the CUA were also identified.ConclusionsCanadian-specific cost data for OAB treatments published in the peer-reviewed literature is limited to a single study reporting costs for only a few second-line treatments sourced from a single province over 10 years ago. Cost data from other healthcare jurisdictions are available, but the generalizability of costs associated with third-line treatments is questionable.