Okay. Thanks very much, Molly and everyone, for the opportunity. I'll be speaking about the evidence behind the 2022 SkyPFO guidelines. This is my conflict slide. That's a conflict. Okay. The PFO guidelines were developed using the GRADE methodology. GRADE stands for Grading of Recommendations, Assessment, Development, and Evaluation. This is a methodology that's endorsed by the Institute of Medicine, follows the Institute of Medicine recommendations in terms of assessment of the quality of evidence, as well as the certainty of recommendations. The GRADE methodology has five components. Development of questions, specifically focusing on clinically important outcomes, systematic review of the literature, risk of bias assessment, synthesis of evidence, principally using meta-analysis, and assessment of certainty. This is the process that was used to develop the SkyPFO guidelines. First question development. Five clinically important questions were developed by the Sky guideline panel, narrowed down from a field of 30-some questions. Those questions were rendered in the PICO format, patient or population, intervention, comparator, and outcome. It's a busy slide, but these are the five PICO questions rendered in that format. So question number one. In adults without prior PFO-associated stroke, should PFO closure be selected in preference to medical therapy to prevent outcomes of stroke, migraine, decompression illness among divers, and platypnea orthodeoxia syndrome? Two, in adults with prior PFO-associated stroke, should PFO closure be selected in preference to antiplatelet therapy to prevent stroke recurrence? Three, in adults with PFO-associated stroke, should PFO closure be selected in preference to anticoagulation to prevent stroke recurrence? So three, the same as two, but anticoagulation instead of antiplatelet therapy. And in both of these cases, should the recommendations differ for different subgroups of patients? Four, in adults with a PFO-associated stroke with some indication for lifelong anticoagulation, should PFO closure be used in addition to anticoagulation, in preference to anticoagulation alone to prevent stroke recurrence? And five, for patients who are undergoing percutaneous PFO closure, should one month of dual anticoagulation therapy followed by five months of aspirin be used as a medical regimen as opposed to some other anti-thrombotic regimen to minimize the risks of stroke or bleeding? To answer these five questions, a systematic review was conducted. Here's the PRISMA flow diagram. PubMed, Embase, and Cochrane were queried. Primary studies and systematic reviews were included. The date range for the query was 2015 to 2021, which allowed us to exclude studies of discontinued devices from informing the guidelines. Studies needed to be in the English language, and case reports and narrative reviews were excluded. This query generated 2,701 manuscripts, which, thanks to the Sky Technical Review team, were reviewed by title and abstract to winnow down to 299 full-text manuscripts that were read, screened, and yielded 30 studies included in the technical review. Risk of bias assessment was conducted separately for randomized and non-randomized studies. This is a figure from the appendix of the technical review. It shows the risk of bias assessment for the randomized studies. You can see the domains in which risk of bias is assessed, randomization, allocation concealment, blinding of participants and personnel, blinding of outcome assessment, completeness of outcome assessment, selective reporting. Of note in many of the PFO studies, blinding was an issue. As you might imagine, most studies did not include a sham procedure, so patients and personnel were not blinded. But other than that, the quality of the randomized studies was certainly very high. Data were then synthesized using meta-analysis. Here we see, as a representative example, the meta-analysis the technical review team performed for cessation of migraine headaches. There were three randomized control trials, MIST, PREMIUM, and PRIMA, including a total of 230 patients in the PFO closure arm and 217 in the control arm. In meta-analysis, the risk ratio was 3.46, favoring migraine cessation, but as you can see, the confidence interval crosses unity, crosses one, so not a statistically significant difference shown there in the forest plot. Pulling together the risk of bias assessment and the meta-analysis then, the final step is the assessment of certainty of the evidence. So here again, continuing with our migraine cessation example, the number of studies, three. These were randomized trials. The risk of bias was not serious. Inconsistency between the studies, not serious. Indirectness, did the studies directly assess the question being asked? They did indeed, that was not serious. Imprecision, now that's serious because the confidence intervals were very wide, in fact crossed unity. Here's the meta-analysis data, right, with the risk ratio of 3.46. Putting that in absolute terms, that's a range from six fewer to 321 more patients being free of migraine as a result of the intervention. Assessing this all, we come up with a moderate degree of certainty, and the panel determined that this was an important contribution to answer the question. Recommendations then are phrased in terms of their strength. A strong recommendation is a recommendation that most individuals would want to pursue the recommended course of action, whereas a conditional recommendation is a recommendation where the majority of individuals would want the recommended course of action, but many would not if it's inconsistent with their values and preferences. So in the case of migraine, in adults with migraine without a prior PFO-associated stroke, the SKY guideline panel based on the technical review data we just saw would suggest against the routine use of PFO closure for the treatment of migraine, a conditional recommendation with moderate certainty of evidence. This process was then repeated for each element of each of the five PICO questions. Oh, looks like a pop quiz snuck in. I'm going to wake everybody up. The acronym PFO, I learned, has multiple meanings. If you exclude the word patent, so we're not looking at patent for immunovalue anymore, which website is the top Google hit for PFO? You see the search algorithm there. It's PFO, acronym, minus patent. Is it yahoofinance.com, stsimontheapostleschool.org, tripadvisor.com, or urbandictionary.com? Anybody for A? B? Audience response, C? D? Well, I'll tell you, they're all hits. Yahoo Finance, Flaherty and Crumrine preferred an income opportunity fund, does use the ticker symbol PFO, but it is not the number one hit. St. Simon the Apostle School has a parent faculty organization. It's like a PTO, but it's a PFO, but they are also not the number one hit. Have a great trip. TripAdvisor will take you to the Poffos Airport in Cyprus. Their call letters are PFO, but it turns out the number one hit is indeed urbandictionary.com, PFO, or rejection letter after a job interview. Did you hear back from your audition last week? Yeah, I got a PFO a couple of days ago. So in summary, the PFO guidelines were developed using the GRADE methodology, grading of recommendations, assessment, development, and evaluation, through a rigorous process of development of relevant clinical questions with important clinical outcomes, systematic review of literature, risk of bias assessment, synthesis of evidence through meta-analysis, and assessment of certainty to generate guideline recommendations. Thank you very much. Here's my contact info. Thank you.

2022 SkyPFO guidelines

GRADE methodology

systematic review

assessment of certainty

PFO acronym