Beyond Sterilization: A Comprehensive Review on the Safety and Efficacy of Opportunistic Salpingectomy as a Preventative Strategy for Ovarian Cancer.

Ovarian cancer (OC) is Canada's third most common gynecological cancer, with an estimated 3000 new cases and 1950 deaths projected in 2022. No effective screening has been found to identify OC, especially the most common subtype, high-grade serous carcinoma (HGSC), at an earlier, curable stage. In patients with hereditary predispositions such as BRCA mutations, the rates of HGSC are significantly elevated, leading to the use of risk-reducing salpingo-oophorectomy as the key preventative intervention. Although surgery has been shown to prevent HGSC in high-risk women, the associated premature menopause has adverse long-term sequelae and mortality due to non-cancer causes. The fact that 75% of HGSCs are sporadic means that most women diagnosed with HGSC will not have had the option to avail of either screening or prevention. Recent research suggests that the fimbrial distal fallopian tube is the most likely origin of HGSC. This has led to the development of a prevention plan for the general population: opportunistic salpingectomy, the removal of both fallopian tubes. This article aims to compile and review the studies evaluating the effect of opportunistic salpingectomy on surgical-related complications, ovarian reserve, cost, and OC incidence when performed along with hysterectomy or instead of tubal ligation in the general population.

Effectiveness of stop smoking interventions among adults: protocol for an overview of systematic reviews and an updated systematic review.

BACKGROUND: Tobacco smoking is the leading cause of cancer, preventable death, and disability. Smoking cessation can increase life expectancy by nearly a decade if achieved in the third or fourth decades of life. Various stop smoking interventions are available including pharmacotherapies, electronic cigarettes, behavioural support, and alternative therapies. This protocol outlines an evidence review which will evaluate the benefits and harms of stop smoking interventions in adults. METHODS: The evidence review will consist of two stages. First, an overview of systematic reviews evaluating the benefits and harms of various stop smoking interventions delivered in or referred from the primary care setting will be conducted. The second stage will involve updating a systematic review on electronic cigarettes identified in the overview; randomized controlled trials will be considered for outcomes relating to benefits while randomized controlled trials, non-randomized controlled trials, and comparative observational studies will be considered for evaluating harms. Search strategies will be developed and peer-reviewed by medical information specialists. The search strategy for the updated review on e-cigarettes will be developed using that of the candidate systematic review. The MEDLINE®, PsycINFO, Embase, and the Cochrane Library electronic databases will be searched as of 2008 for the overview of reviews and from the last search date of the selected review for the updated review. Organizational websites and trial registries will be searched for unpublished or ongoing reviews/studies. Two reviewers will independently screen the title and abstracts of citations using the liberal accelerated method. Full-text screening will be performed independently by two reviewers. Extracted data will be verified by a second reviewer. Disagreements regarding full-text screening and data extraction will be resolved by consensus or third-party adjudication. The methodological quality of systematic reviews, risk of bias of randomized and non-randomized trials, and methodological quality of cohort studies will be evaluated using AMSTAR 2, the Cochrane risk of bias tool, and a modified version of the Scottish Intercollegiate Guidelines Network critical appraisal tool, respectively. The GRADE framework will be used to assess the quality of the evidence for outcomes. DISCUSSION: The evidence review will evaluate the benefits and harms of various stop smoking interventions for adults. Findings will be used to inform a national tobacco cessation guideline by the Canadian Task Force on Preventive Health Care. SYSTEMATIC REVIEW REGISTRATION: PROSPERO (CRD42018099691, CRD42018099692).

Screening for chlamydia and/or gonorrhea in primary health care: protocol for systematic review.

BACKGROUND: Chlamydia trachomatis and Neisseria gonorrhoeae are the most commonly reported sexually transmitted infections in Canada. Existing national guidance on screening for these infections was not based on a systematic review, and recommendations as well as implementation considerations (e.g., population groups, testing and case management) should be explicit and reflect the quality of evidence. The aim of this systematic review is to synthesize research on screening for these infections in sexually active individuals within primary care. We will also review evidence on how people weigh the relative importance of the potential outcomes from screening, rated as most important by the Canadian Task Force on Preventive Health Care (CTFPHC) with input from patients and stakeholders. METHODS: We have developed a peer-reviewed strategy to comprehensively search MEDLINE, Embase, Cochrane Library, CINAHL, and PsycINFO for English and French literature published 1996 onwards. We will also search trial registries and conference proceedings, and mine references lists. Screening, study selection, risk of bias assessments, and quality of findings across studies (for each outcome) will be independently undertaken by two reviewers with consensus for final decisions. Data extraction will be conducted by one reviewer and checked by another for accuracy and completeness. The CTFPHC and content experts will provide input for decisions on study design (i.e., when and whether to include uncontrolled studies for screening effectiveness) and for interpretation of the findings. DISCUSSION: The results section of the review will include a description of all studies, results of all analyses, including planned subgroup and sensitivity analyses, and evidence profiles and summary of findings tables incorporating assessment based on Grading of Recommendations Assessment, Development and Evaluation (GRADE) methods to communicate our confidence in the estimates of effect. We will compare our findings to others and discuss limitations of the review and available literature. The findings will be used by the CTFPHC-supplemented by consultations with patients and stakeholders and from other sources on issues of feasibility, acceptability, costs/resources, and equity-to inform recommendations on screening to support primary health care providers in delivering preventive care. SYSTEMATIC REVIEW REGISTRATION: International Prospective Register of Systematic Reviews (PROSPERO), registration number CRD42018100733.

Cytosolic Delivery of Multidomain Cargos by the N Terminus of Pasteurella multocida Toxin.

The zoonotic pathogen Pasteurella multocida produces a 146-kDa modular toxin (PMT) that enters host cells and manipulates intracellular signaling through action on its Gα protein targets. The N terminus of PMT (PMT-N) mediates cellular uptake through receptor-mediated endocytosis, followed by the delivery of the C-terminal catalytic domain from acidic endosomes into the cytosol. The putative native cargo of PMT consists of a 710-residue polypeptide with three distinct modular subdomains (C1-C2-C3), where C1 contains a membrane localization domain (MLD), C2 has an as-yet-undefined function, and C3 catalyzes the deamidation of a specific active-site glutamine residue in Gα protein targets. However, whether the three cargo subdomains are delivered intact or undergo further proteolytic processing during or after translocation from the late endosome is unclear. Here, we demonstrate that PMT-N mediates the delivery of its native C-terminal cargo as a single polypeptide, corresponding to C1-C2-C3, including the MLD, with no evidence of cleavage between subdomains. We show that PMT-N also delivers nonnative green fluorescent protein (GFP) cargo into the cytosol, further supporting that the receptor-binding and translocation functions reside within PMT-N. Our findings further show that PMT-N can deliver C1-C2 alone but that the presence of C1-C2 is important for the cytosolic delivery of the catalytic C3 subdomain by PMT-N. In addition, we further refine the minimum C3 domain required for intracellular activity as comprising residues 1105 to 1278. These findings reinforce that PMT-N serves as the cytosolic delivery vehicle for C-terminal cargo and demonstrate that its native cargo is delivered intact as C1-C2-C3.

CNF1-like deamidase domains: common Lego bricks among cancer-promoting immunomodulatory bacterial virulence factors.

Alterations of the cellular proteome over time due to spontaneous or toxin-mediated enzymatic deamidation of glutamine (Gln) and asparagine (Asn) residues contribute to bacterial infection and might represent a source of aging-related diseases. Here, we put into perspective what is known about the mode of action of the CNF1 toxin from pathogenic Escherichia coli, a paradigm of bacterial deamidases that activate Rho GTPases, to illustrate the importance of determining whether exposure to these factors are risk factors in the etiology age-related diseases, such as cancer. In particular, through in silico analysis of the distribution of the CNF1-like deamidase active site Gly-Cys-(Xaa)n-His sequence motif in bacterial genomes, we unveil the wide distribution of the super-family of CNF-like toxins and CNF-like deamidase domains among members of the Enterobacteriacae and in association with a large variety of toxin delivery systems. We extent our discussion with recent findings concerning cellular systems that control activated Rac1 GTPase stability and provide protection against cancer. These findings point to the urgency for developing holistic approaches toward personalized medicine that include monitoring for asymptomatic carriage of pathogenic toxin-producing bacteria and that ultimately might lead to improved public health and increased lifespans.

Role of Psychosocial Factors and Health Literacy in Pregnant Women's Intention to Use a Decision Aid for Down Syndrome Screening: A Theory-Based Web Survey.

BACKGROUND: Deciding about undergoing prenatal screening is difficult, as it entails risks, potential loss and regrets, and challenges to personal values. Shared decision making and decision aids (DAs) can help pregnant women give informed and values-based consent or refusal to prenatal screening, but little is known about factors influencing the use of DAs. OBJECTIVE: The objective of this study was to identify the influence of psychosocial factors on pregnant women's intention to use a DA for prenatal screening for Down syndrome (DS). We also added health literacy variables to explore their influence on pregnant women's intention. METHODS: We conducted a survey of pregnant women in the province of Quebec (Canada) using a Web panel. Eligibility criteria included age >18 years, >16 weeks pregnant, low-risk pregnancy, and having decided about prenatal screening for the current pregnancy. We collected data based on an extended version of the Theory of Planned Behavior assessing 7 psychosocial constructs (intention, attitude, anticipated regret, subjective norm, descriptive norm, moral norm, and perceived control), 3 related sets of beliefs (behavioral, normative, and control beliefs), 4 health literacy variables, and sociodemographics. Eligible women watched a video depicting the behavior of interest before completing a Web-based questionnaire. We performed descriptive, bivariate, and ordinal logistic regression analyses. RESULTS: Of the 383 eligible pregnant women who agreed to participate, 350 pregnant women completed the Web-based questionnaire and 346 were retained for analysis (completion rate 350/383, 91.4%; mean age 30.1, SD 4.3, years). In order of importance, factors influencing intention to use a DA for prenatal screening for DS were attitude (odds ratio, OR, 9.16, 95% CI 4.02-20.85), moral norm (OR 7.97, 95% CI 4.49-14.14), descriptive norm (OR 2.83, 95% CI 1.63-4.92), and anticipated regret (OR 2.43, 95% CI 1.71-3.46). Specific attitudinal beliefs significantly related to intention were that using a DA would reassure them (OR 2.55, 95% CI 1.73-4.01), facilitate their reflections with their spouse (OR 1.55, 95% CI 1.05-2.29), and let them know about the advantages of doing or not doing the test (OR 1.53, 95% CI 1.05-2.24). Health literacy did not add to the predictive power of our model (P values range .43-.92). CONCLUSIONS: Implementation interventions targeting the use of a DA for prenatal screening for DS by pregnant women should address a number of modifiable factors, especially by introducing the advantages of using the DA (attitude), informing pregnant women that they might regret not using it (anticipated regret), and presenting the use of DAs as a common practice (descriptive norm). However, interventions on moral norms related to the use of DA should be treated with caution. Further studies that include populations with low health literacy are needed before decisive claims can be made.

Supporting genetics in primary care: investigating how theory can inform professional education.

Evidence indicates that many barriers exist to the integration of genetic case finding into primary care. We conducted an exploratory study of the determinants of three specific behaviours related to using breast cancer genetics referral guidelines effectively: 'taking a family history', 'making a risk assessment', and 'making a referral decision'. We developed vignettes of primary care consultations with hypothetical patients, representing a wide range of genetic risk for which different referral decisions would be appropriate. We used the Theory of Planned Behavior to develop a survey instrument to capture data on behavioural intention and its predictors (attitude, subjective norm, and perceived behavioural control) for each of the three behaviours and mailed it to a sample of Canadian family physicians. We used correlation and regression analyses to explore the relationships between predictor and dependent variables. The response rate was 96/125 (77%). The predictor variables explained 38-83% of the variance in intention across the three behaviours. Family physicians' intentions were lower for 'making a risk assessment' (perceived as the most difficult) than for the other two behaviours. We illustrate how understanding psychological factors salient to behaviour can be used to tailor professional educational interventions; for example, considering the approach of behavioural rehearsal to improve confidence in skills (perceived behavioural control), or vicarious reinforcement as where participants are sceptical that genetics is consistent with their role (subjective norm).

Attitudes to incorporating genomic risk assessments into population screening programs: the importance of purpose, context and deliberation.

BACKGROUND: The use of an overall risk assessment based on genomic information is consistent with precision medicine. Despite the enthusiasm, there is a need for public engagement on the appropriate use of such emerging technologies in order to frame meaningful evaluations of utility, including the practical implementation and acceptability issues that might emerge. Doing so requires the involvement of the end users of these services, including patients, and sections of the public who are the target group for population based screening. In the present study we sought to explore public attitudes to the potential integration of personal genomic profiling within existing population screening programs; and to explore the evolution of these attitudes as part of a deliberative process. METHODS: We conducted a mixed methods study presented in the format of a deliberative workshop. Participants were drawn from communities in Ottawa, Ontario (ON) and St John's, Newfoundland and Labrador (NL), Canada. Individuals were approached to take part in a workshop on the incorporation of genomic risk profiling for either colorectal cancer screening (CRC), or newborn screening for type 1 diabetes mellitus (T1DM). RESULTS: A total of N = 148 (N = 65 ON, N = 83 NL) participants provided data for analysis. Participants in both groups were supportive of public funding for genomic risk profiling, although participants in the T1DM groups expressed more guarded positive attitudes than participants in the CRC groups. These views were stable throughout the workshop (CRC, p = 0.15, T1DM, p =0.39). Participants were less positive about individual testing, with a significant decrease in support over the course of the workshop (CRC p = 0.02, T1DM, p = 0.003). Common concerns related to access to test results by third parties. CONCLUSIONS: The findings of this study suggest that members of the target populations for potential genomic profiling tests (designed for screening or risk prediction purposes) can engage in meaningful deliberation about their general acceptability and personal utility. Evaluations of whether a test would be personally useful may depend on the experience of the participants in personal health decision making, the purpose of the test, and the availability of interventions to reduce disease risk.