Next step in molecular genetics of hereditary breast/ovarian cancer: Multigene panel testing in clinical actionably genes and prioritization algorithms in the study of variants of uncertain significance

IntroductionBRCA1 and BRCA2 are the two main genes causing hereditary breast and ovarian cancer (HBOC). However, thanks to the development of Next Generation Sequencing (NGS), other genes linked to this syndrome (CHEK2, BRIP1, ATM and PALB2 among others) can be analysed.Material and methodsan analysis by multigene panel testing was performed in 138 index cases (ICs) from HBOC Spanish families with a previous non-informative result for BRCA1/2. The BRCA Hereditary Cancer Master? Plus kit, including 26 actionable and candidate genes related to HBOC was employed. Once classified, an algorithm was employed to prioritized those variants of unknown significance with a higher risk of having a deleterious effect. Moreover, a mRNA splicing assay was performed for the prioritized VUS c.3402+3A > C in ATM, located at intron 23.ResultsA total of 82 variants were found: 70 VUS and 12 pathogenic or probably pathogenic variants. The diagnostic yield in actionable genes non-BRCA was 7.97% of the total tested ICs. Overall, 19 VUS were prioritized, which meant 27% of the 70 total VUS. RNA analysis of the variant 3402+3A > C confirmed a deleterious impact on splicing.DiscussionThe implementation of a multigene panel in HBOC studied families improved the diagnostic yield, concordant with results obtained in previous publications. Due to the important number of VUS obtained in NGS, the application of a prioritization algorithm is needed in order to select those variants in which it is necessary to conduct further studies.     

Exposure to combinations of substances: a system for assessing health risks

Combined exposures may be categorised as specified combinations or mixtures of substances, depending on composition and exposure scenario. The major characteristic of a specified combination is known composition and that of a mixture simultaneous exposure. A framework was developed as a guide for safety evaluation of combined exposures. This framework offers the possibility to evaluate mixtures as a single entity, or as a number of fractions or individual constituents. The evaluation of specified combinations will often focus on the individual components. To reduce the safety evaluation of complex exposures to manageable proportions, the “top n” and “pseudo top n” approaches were introduced, n representing the n most “risky” chemicals or groups of chemicals, respectively. To select the best method, the framework should always be walked through in its entirety, considering all options. The Mumtaz–Durkin weight-of-evidence approach is included as a prioritization instrument for combined exposures. It is based on hazard indices supplemented with qualitative and quantitative weighting and interaction factors.     

Liver transplantation in adults: Choosing the appropriate timing

Liver transplantation is indicated in patients with acute liver failure,decompensated cirrhosis,hepatocellular carcinoma and rare liver-based genetic defects that trigger damage of other organs.Early referral to a transplant center is crucial in acute liver failure due to the high mortality with medical therapy and its unpredictable evolution.Referral to a transplant center should be considered when at least one complication of cirrhosis occurs during its natural history.However,because of the shortage of organ donors and the short-term mortality after liver transplantation on one hand and the possibility of managing the complications of cirrhosis with other treatments on the other,patients are carefully selected by the transplant center to ensure that transplantation is indicated and that there are no medical,surgical and psychological contraindications.Patients approved for transplantation are placed on the transplant waiting list and prioritized according to disease severity.Thus,the appropriate timing of transplantation depends on recipient disease severity and,although this is still a matter of debate,also on donor quality.These two variables are known to determine the "transplant benefit"(i.e.,when the expected patient survival is better with,than without,transplantation) and should guide donor allocation.     

Priority-based initiative for updating existing evidence-based clinical practice guidelines: the results of two iterations

ObjectivesNew evidence continues to emerge and requires attention after the release of a clinical practice guideline (CPG). The objective of this article is to describe the Document Assessment and Review (DAR) strategy designed to ensue that the CPGs remain current and their quality maintained and to present the results of two iteration of its implementation.Study Design and SettingThe DAR process involves an annual assessment of our CPGs and a review of documents that require an update search. Two questionnaires are used to conduct the annual assessment and the review. The review involves evidence search, evidence review, and review approval.ResultsIn 2011, 109 documents were assessed; 22 (20%) were archived, 1 (1%) was deferred for assessment in 2012, 24 (22%) were considered special cases and 62 (57%) needed a new systematic review of the evidence. Of those 62, 19 (31%) were categorized as urgent, 16 (26%) as high, and others as medium or low priority. In 2012, 88 total documents were assessed; 15 (17%) were archived, 32 (36%) deferred, 3 (3%) were considered special cases, and 38 (43%) were prioritized for review.ConclusionsAssessment and prioritization of existing CPGs are effective ways of ensuring that resources are directed toward the upkeep of those that are relevant and of highest priority.     

Strategy for childhood immunization in India

A simple scoring system is presented to evaluate the necessity, efficacy and safety of vaccines so that priority may be assigned to them for routine use in children. Eleven common vaccines are listed according to priority and the high priority items are those against measles, poliomyelitis, diphtheria, tetanus and pertussis. Therefore measles, polio and DPT vaccines are recomended as the core group of vaccines for routine use in children in India. The continued use of smallpox vaccine seems unwarranted. The low priority vaccines namely BCG, typhoid and cholera may be used in special groups, endemic areas or epidemics. Rubella and mumps vaccines are also of low priority and need not be introduced at present. The opinions expressed here are those of the authors and not necessarily those of the supporting institutions.     

A new organ transplantation location–allocation policy: a case study of Italy

In this paper, we propose a location model for the optimal organization of transplant system. Instead of simulation approach, which is typical when facing many health care applications, our approach is distinctively based on a mathematical programming formulation of the relevant problem. In particular, we focus on the critical role of time in transplantation process as well as on a spatial distribution of transplant centers. The allocation of transplantable organs across regions with the objective of attaining regional equity in health care, is the aim of this paper. Our model differs from previous modeling approaches in that it considers the nationwide reorganization of the transplant system, identifying system barriers that may impair equity and efficiency. The demolition of these barriers may leads on a reduction of waiting lists and of wasted organs. We provide the basic structure and the properties of the model, and validate it on a real case study. The experimental validation of the model demonstrates the effectiveness and robustness of our proposal.     

Ethical prioritization of patients during disaster triage: A systematic review of current evidence

IntroductionTriage is a dynamic and complex decision-making process in order to determine priority of access to medical care in a disaster situation. The elements which should govern an ethical decision-making in prioritizing of victims have been debated for a long time. This paper aims to identify ethical principles guiding patient prioritization during disaster triage.MethodElectronic databases were searched via structured search strategy from 1990 until July 2017. The studies investigating patients’ prioritization in disaster situation were eligible for inclusion. All types of articles and guidelines were included.ResultOf 7167 titles identified in the search, 35 studies were included. The important factors identified in patient prioritization were grouped into two categories: medical measures (medical need, likelihood of benefit and survivability) and Nonmedical measures (saving the most lives, youngest first, preserving function of society, protecting vulnerable groups, required resources and unbiased selection). Demographic characteristics, health status of patients, social value of patient, and unbiased selection are discriminatory factors in disaster triage.ConclusionVarious factors have been introduced to consider ethical patient prioritization in disaster triage. Providers’ engagement, public education, and ongoing training are required to reach a fair decision.     

La priorización comunitaria en el programa Barcelona Salut als Barris

Prioritizing corresponds to the process of selecting and managing health needs identified after diagnosing the community's health needs and assets. Recently, the health needs assessment has been reinforced with the community perspective, providing multiple benefits: it sensitizes and empowers the community about their health, encourages mutual support among its members and promotes their importance by making them responsible for the process of improving their own reality. The objective of this paper is to describe the prioritization of Barcelona Salut als Barris, a community health strategy led by the Barcelona Public Health Agency to promote equity in health in the most disadvantaged neighborhoods of the city.     

Effects of gender on dual-tasking and prioritization in older adults

BackgroundThe ability to produce effective posture and balance while distracted (dual-tasking; DT), is critical for mobility. In particular, individuals implicit prioritization across posture and secondary, distracting stimuli may impact fall risk. However, the impact of gender on DT and prioritization during gait is poorly understood.Research questionDoes gender impact DT effects or prioritization while DT walking?MethodsOne hundred older adults participated. The timed up and go (TUG) was completed with and without a secondary cognitive task (counting backwards by 3′s). Gait (time to complete the TUG), and cognitive (rate of correct numbers listed) performance was recorded during both single tasks and while dual-tasking. DT effects were calculated for cognitive and gait performance. Prioritization was calculated as the difference between cognitive and gait DT effects. The effect of gender on DT and prioritization was assessed, controlling for age and cognitive ability.ResultsGender by condition (single vs. dual-task) interaction effects were observed (Gait: F_1,96 =8.7; p = 0.004; Cognition: F_1,96 =5.2; p = 0.024) such that, compared to male participants, females exhibited smaller cognitive DT effects, and larger gait DT effects. Further, females exhibited significantly larger prioritization scores (F_1,95 =10.0, p = 0.002), indicating a cognitive prioritization compared to males.SignificanceGiven the link between posture-second strategies and falls, the current findings may provide some insight into previous results suggesting an increased fall-risk in older-adult women. However, this study did not investigate falls. Therefore, additional work is necessary to confirm current findings and further investigate the relationship between gender, prioritization, and falls; and its possible clinical relevance.