Systematic exploration of Escherichia coli phage-host interactions with the BASEL phage collection.

Bacteriophages, the viruses infecting bacteria, hold great potential for the treatment of multidrug-resistant bacterial infections and other applications due to their unparalleled diversity and recent breakthroughs in their genetic engineering. However, fundamental knowledge of the molecular mechanisms underlying phage-host interactions is mostly confined to a few traditional model systems and did not keep pace with the recent massive expansion of the field. The true potential of molecular biology encoded by these viruses has therefore remained largely untapped, and phages for therapy or other applications are often still selected empirically. We therefore sought to promote a systematic exploration of phage-host interactions by composing a well-assorted library of 68 newly isolated phages infecting the model organism Escherichia coli that we share with the community as the BASEL (BActeriophage SElection for your Laboratory) collection. This collection is largely representative of natural E. coli phage diversity and was intensively characterized phenotypically and genomically alongside 10 well-studied traditional model phages. We experimentally determined essential host receptors of all phages, quantified their sensitivity to 11 defense systems across different layers of bacterial immunity, and matched these results to the phages' host range across a panel of pathogenic enterobacterial strains. Clear patterns in the distribution of phage phenotypes and genomic features highlighted systematic differences in the potency of different immunity systems and suggested the molecular basis of receptor specificity in several phage groups. Our results also indicate strong trade-offs between fitness traits like broad host recognition and resistance to bacterial immunity that might drive the divergent adaptation of different phage groups to specific ecological niches. We envision that the BASEL collection will inspire future work exploring the biology of bacteriophages and their hosts by facilitating the discovery of underlying molecular mechanisms as the basis for an effective translation into biotechnology or therapeutic applications.

Mechanisms, predictors, and evolution of severe peri-device leaks with two different left atrial appendage occluders.

AIMS: Incomplete left atrial appendage occlusion (LAAO) due to peri-device leak (PDL) is a limitation of the therapy. The Amulet IDE trial is the largest randomized head-to-head trial comparing the Amulet and Watchman 2.5 LAAO devices with fundamentally different designs. The predictors and mechanistic factors impacting differences in PDLs within the Amulet IDE trial are assessed in the current analysis. METHODS AND RESULTS: An independent core lab analysed all images for the presence or absence of severe PDL (>5 mm). The incidence, mechanistic factors, predictors using propensity score-matched controls, and evolution of severe PDLs through 18 months were assessed. Of the 1878 patients randomized in the trial, the Amulet occluder had significantly fewer severe PDLs than the Watchman device at 45 days (1.1 vs. 3.2%, P < 0.001) and 12 months (0.1 vs. 1.1%, P < 0.001). Off-axis deployment or missed lobes were leading mechanistic PDL factors in each device group. Larger left atrial appendage (LAA) dimensions including orifice diameter, landing zone diameter, and depth predicted severe PDL with the Watchman device, with no significant anatomical limitations noted with the Amulet occluder. Procedural and device implant predictors were found with the Amulet occluder attributed to the learning curve with the device. A majority of Watchman device severe PDLs did not resolve over time through 18 months. CONCLUSION: The dual-occlusive Amplatzer Amulet LAA occluder provided improved LAA closure compared with the Watchman 2.5 device. Predictors and temporal observations of severe PDLs were identified in the Amulet IDE trial. CLINICAL TRIAL REGISTRATION: https://clinicaltrials.gov Unique identifier NCT02879448.

Amplatzer Amulet Left Atrial Appendage Occluder Versus Watchman Device for Stroke Prophylaxis (Amulet IDE): A Randomized, Controlled Trial.

BACKGROUND: Percutaneous closure of the left atrial appendage (LAA) is an alternative to chronic oral anticoagulation to reduce stroke risk in patients with nonvalvular atrial fibrillation. The Amulet IDE trial (Amplatzer Amulet Left Atrial Appendage Occluder IDE Trial) was designed to evaluate the safety and effectiveness of the dual-seal mechanism of the Amulet LAA occluder compared with the Watchman device. METHODS: Patients with nonvalvular atrial fibrillation at increased risk of stroke were randomly assigned (1:1) to undergo percutaneous implantation of a LAA occluder with the Amulet occluder or Watchman device. The primary end points included safety (composite of procedure-related complications, all-cause death, or major bleeding at 12 months), effectiveness (composite of ischemic stroke or systemic embolism at 18 months), and the rate of LAA occlusion at 45 days. Prespecified secondary end points included a composite of all stroke, systemic embolism, or cardiovascular/unexplained death at 18 months, major bleeding at 18 months, and superiority test of the 3 primary end points. RESULTS: A total of 1878 patients were enrolled. The Amulet occluder was noninferior to the Watchman device for the primary safety end point (14.5% versus 14.7%; difference=-0.14 [95% CI, -3.42 to 3.13]; P<0.001 for noninferiority). Major bleeding and all-cause death were similar between groups (10.6% versus 10.0% and 3.9% versus 5.1%, respectively). Procedure-related complications were higher for the Amulet occluder (4.5% versus 2.5%), largely related to more frequent pericardial effusion and device embolization. The Amulet occluder was noninferior to the Watchman device for the primary effectiveness end point (2.8% versus 2.8%; difference=0.00 [95% CI, -1.55 to 1.55]; P<0.001 for noninferiority), and the composite of stroke, systemic embolism, or cardiovascular/unexplained death (5.6% versus 7.7%, difference=-2.12 [95% CI, -4.45 to 0.21]; P<0.001 for noninferiority). The rate of major bleeding was similar between groups (11.6% versus 12.3%; difference=-0.71 [95% CI, -3.72 to 2.31]; P=0.32 for superiority). LAA occlusion was higher for the Amulet occluder than for the Watchman device (98.9% versus 96.8%; difference=2.03 [95% CI, 0.41-3.66]; P<0.001 for noninferiority; P=0.003 for superiority). CONCLUSIONS: The Amulet occluder was noninferior for safety and effectiveness of stroke prevention for nonvalvular atrial fibrillation compared with the Watchman device and superior for LAA occlusion. Procedure-related complications were higher with the Amulet occluder and decreased with operator experience. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02879448.

Archiving time series sewage samples as biological records of built environments.

This commentary encourages the regular archiving of nucleic-acid-stabilized serial samples of wastewaters and/or sewage. Stabilized samples would facilitate retrospective reconstitution of built environments' biological fluids. Biological time capsules would allow retrospective searches for nucleic acids from viruses such as SARS-CoV-2. Current resources for testing need not be diverted if samples are saved in case they become important in the future. Systematic storage would facilitate investigation into the origin and prevalence of viruses and other agents. Comparison of prevalence data from individual and clinical samplings with community wastewater would allow valuable comparison, contrast and correlation among different testing modalities. Current interest is focused on SARS-CoV-2, but archived samples could become valuable in many contexts including surveys for other infectious and chemical agents whose identity is not currently known. Archived time series of wastewater will take their place alongside other biological repositories and records including those from medical facilities, museums, eDNA, living cell and tissue collections. Together these will prove invaluable records of the evolving Anthropocene.

Heterogeneity of Treatment Effects in an Analysis of Pooled Individual Patient Data From Randomized Trials of Device Closure of Patent Foramen Ovale After Stroke.

Importance: Patent foramen ovale (PFO)-associated strokes comprise approximately 10% of ischemic strokes in adults aged 18 to 60 years. While device closure decreases stroke recurrence risk overall, the best treatment for any individual is often unclear. Objective: To evaluate heterogeneity of treatment effect of PFO closure on stroke recurrence based on previously developed scoring systems. Design, Setting, and Participants: Investigators for the Systematic, Collaborative, PFO Closure Evaluation (SCOPE) Consortium pooled individual patient data from all 6 randomized clinical trials that compared PFO closure plus medical therapy vs medical therapy alone in patients with PFO-associated stroke, and included a total of 3740 participants. The trials were conducted worldwide from 2000 to 2017. Exposures: PFO closure plus medical therapy vs medical therapy alone. Subgroup analyses used the Risk of Paradoxical Embolism (RoPE) Score (a 10-point scoring system in which higher scores reflect younger age and the absence of vascular risk factors) and the PFO-Associated Stroke Causal Likelihood (PASCAL) Classification System, which combines the RoPE Score with high-risk PFO features (either an atrial septal aneurysm or a large-sized shunt) to classify patients into 3 categories of causal relatedness: unlikely, possible, and probable. Main Outcomes and Measures: Ischemic stroke. Results: Over a median follow-up of 57 months (IQR, 24-64), 121 outcomes occurred in 3740 patients. The annualized incidence of stroke with medical therapy was 1.09% (95% CI, 0.88%-1.36%) and with device closure was 0.47% (95% CI, 0.35%-0.65%) (adjusted hazard ratio [HR], 0.41 [95% CI, 0.28-0.60]). The subgroup analyses showed statistically significant interaction effects. Patients with low vs high RoPE Score had HRs of 0.61 (95% CI, 0.37-1.00) and 0.21 (95% CI, 0.11-0.42), respectively (P for interaction = .02). Patients classified as unlikely, possible, and probable using the PASCAL Classification System had HRs of 1.14 (95% CI, 0.53-2.46), 0.38 (95% CI, 0.22-0.65), and 0.10 (95% CI, 0.03-0.35), respectively (P for interaction = .003). The 2-year absolute risk reduction was -0.7% (95% CI, -4.0% to 2.6%), 2.1% (95% CI, 0.6%-3.6%), and 2.1% (95% CI, 0.9%-3.4%) in the unlikely, possible, and probable PASCAL categories, respectively. Device-associated adverse events were generally higher among patients classified as unlikely; the absolute risk increases in atrial fibrillation beyond day 45 after randomization with a device were 4.41% (95% CI, 1.02% to 7.80%), 1.53% (95% CI, 0.33% to 2.72%), and 0.65% (95% CI, -0.41% to 1.71%) in the unlikely, possible, and probable PASCAL categories, respectively. Conclusions and Relevance: Among patients aged 18 to 60 years with PFO-associated stroke, risk reduction for recurrent stroke with device closure varied across groups classified by their probabilities that the stroke was causally related to the PFO. Application of this classification system has the potential to guide individualized decision-making.

Risk of Paradoxical Embolism (RoPE)-Estimated Attributable Fraction Correlates With the Benefit of Patent Foramen Ovale Closure: An Analysis of 3 Trials.

BACKGROUND AND PURPOSE: In patients with cryptogenic stroke and patent foramen ovale (PFO), the Risk of Paradoxical Embolism (RoPE) Score has been proposed as a method to estimate a patient-specific "PFO-attributable fraction"-the probability that a documented PFO is causally-related to the stroke, rather than an incidental finding. The objective of this research is to examine the relationship between this RoPE-estimated PFO-attributable fraction and the effect of closure in 3 randomized trials. METHODS: We pooled data from the CLOSURE-I (Evaluation of the STARFlex Septal Closure System in Patients With a Stroke and/or Transient Ischemic Attack due to Presumed Paradoxical Embolism through a Patent Foramen Ovale), RESPECT (Randomized Evaluation of Recurrent Stroke Comparing PFO Closure to Established Current Standard of Care Treatment), and PC (Clinical Trial Comparing Percutaneous Closure of Patent Foramen Ovale [PFO] Using the Amplatzer PFO Occluder With Medical Treatment in Patients With Cryptogenic Embolism) trials. We examine the treatment effect of closure in high RoPE score (≥7) versus low RoPE score (<7) patients. We also estimated the relative risk reduction associated with PFO closure across each level of the RoPE score using Cox proportional hazard analysis. We estimated a patient-specific attributable fraction using a PC trial-compatible (9-point) RoPE equation (omitting the neuroradiology variable), as well as a 2-trial analysis using the original (10-point) RoPE equation. We examined the Pearson correlation between the estimated attributable fraction and the relative risk reduction across RoPE strata. RESULTS: In the low RoPE score group (<7, n=912), the rate of recurrent strokes per 100 person-years was 1.37 in the device arm versus 1.68 in the medical arm (hazard ratio, 0.82 [0.42-1.59] P=0.56) compared with 0.30 versus 1.03 (hazard ratio, 0.31 [0.11-0.85] P=0.02) in the high RoPE score group (≥7, n=1221); treatment-by-RoPE score group interaction, P=0.12. The RoPE score estimated attributable fraction anticipated the relative risk reduction across all levels of the RoPE score, in both the 3-trial (r=0.95, P<0.001) and 2-trial (r=0.92, P<0.001) analyses. CONCLUSIONS: The RoPE score estimated attributable fraction is highly correlated to the relative risk reduction of device versus medical therapy. This observation suggests the RoPE score identifies patients with cryptogenic stroke who are likely to have a PFO that is pathogenic rather than incidental.

Long-Term Outcomes of Patent Foramen Ovale Closure or Medical Therapy after Stroke.

BACKGROUND: Whether closure of a patent foramen ovale reduces the risk of recurrence of ischemic stroke in patients who have had a cryptogenic ischemic stroke is unknown. METHODS: In a multicenter, randomized, open-label trial, with blinded adjudication of end-point events, we randomly assigned patients 18 to 60 years of age who had a patent foramen ovale (PFO) and had had a cryptogenic ischemic stroke to undergo closure of the PFO (PFO closure group) or to receive medical therapy alone (aspirin, warfarin, clopidogrel, or aspirin combined with extended-release dipyridamole; medical-therapy group). The primary efficacy end point was a composite of recurrent nonfatal ischemic stroke, fatal ischemic stroke, or early death after randomization. The results of the analysis of the primary outcome from the original trial period have been reported previously; the current analysis of data from the extended follow-up period was considered to be exploratory. RESULTS: We enrolled 980 patients (mean age, 45.9 years) at 69 sites. Patients were followed for a median of 5.9 years. Treatment exposure in the two groups was unequal (3141 patient-years in the PFO closure group vs. 2669 patient-years in the medical-therapy group), owing to a higher dropout rate in the medical-therapy group. In the intention-to-treat population, recurrent ischemic stroke occurred in 18 patients in the PFO closure group and in 28 patients in the medical-therapy group, resulting in rates of 0.58 events per 100 patient-years and 1.07 events per 100 patient-years, respectively (hazard ratio with PFO closure vs. medical therapy, 0.55; 95% confidence interval [CI], 0.31 to 0.999; P=0.046 by the log-rank test). Recurrent ischemic stroke of undetermined cause occurred in 10 patients in the PFO closure group and in 23 patients in the medical-therapy group (hazard ratio, 0.38; 95% CI, 0.18 to 0.79; P=0.007). Venous thromboembolism (which comprised events of pulmonary embolism and deep-vein thrombosis) was more common in the PFO closure group than in the medical-therapy group. CONCLUSIONS: Among adults who had had a cryptogenic ischemic stroke, closure of a PFO was associated with a lower rate of recurrent ischemic strokes than medical therapy alone during extended follow-up. (Funded by St. Jude Medical; RESPECT ClinicalTrials.gov number, NCT00465270 .).

Differences in presenting symptoms of acute stroke among young and older adults.

BACKGROUND: Prior studies demonstrated that young adults with stroke present later to medical attention, have lower initial NIHSS, and are frequently misdiagnosed as compared to older adults. We sought to assess potential differences in temporal and clinical characteristics of stroke symptoms between young (age 18-50 years) and older adults (age > 50). METHODS: This retrospective cohort study included patients age ≥ 18 years hospitalized at a comprehensive stroke center with acute ischemic stroke (AIS), transient ischemic attack (TIA), or intracerebral hemorrhage (ICH). Outcomes included progression of neurologic deficits over the first 24 h, fluctuation in neurologic deficits, and characterization of the triage chief complaint as typical or atypical (less specific) for stroke. Univariate analyses for baseline covariates were performed with Chi-square and Mann-Whitney U tests. Associations with the three outcomes were assessed with multivariable logistic regression. RESULTS: 432 adults (73 young adults, 359 older adults) were included in the analysis. Overall, 28% demonstrated progression of neurologic deficits, 14% had fluctuating deficits, and 26% presented with symptoms considered atypical for stroke. After adjustment for demographics, stroke subtype, diabetes, admission blood pressure, and acute revascularization treatments, increased age was inversely associated with progression of deficits (OR 0.97 per year of age, 95% CI 0.95-0.98) and fluctuation in deficits (OR 0.98 per year of age, 95% CI 0.96-0.99). Hemorrhagic stroke subtype was inversely associated with fluctuation in neurologic deficits (OR 0.050, CI 0.0028-0.24). CONCLUSION: Young adults are more likely to have progression or fluctuation of neurologic deficits in acute stroke. Patients with ischemic stroke are more likely to have fluctuation in neurologic deficits.

Spontaneous Coronary Artery Dissection: Current State of the Science: A Scientific Statement From the American Heart Association.

Spontaneous coronary artery dissection (SCAD) has emerged as an important cause of acute coronary syndrome, myocardial infarction, and sudden death, particularly among young women and individuals with few conventional atherosclerotic risk factors. Patient-initiated research has spurred increased awareness of SCAD, and improved diagnostic capabilities and findings from large case series have led to changes in approaches to initial and long-term management and increasing evidence that SCAD not only is more common than previously believed but also must be evaluated and treated differently from atherosclerotic myocardial infarction. High rates of recurrent SCAD; its association with female sex, pregnancy, and physical and emotional stress triggers; and concurrent systemic arteriopathies, particularly fibromuscular dysplasia, highlight the differences in clinical characteristics of SCAD compared with atherosclerotic disease. Recent insights into the causes of, clinical course of, treatment options for, outcomes of, and associated conditions of SCAD and the many persistent knowledge gaps are presented.

Rationale and design for AMPLATZER Amulet Left Atrial Appendage Occluder IDE randomized controlled trial (Amulet IDE Trial).

The Amulet IDE Trial is an ongoing, prospective, randomized, multi-national trial, designed to evaluate the safety and effectiveness of the AMPLATZER Amulet Left Atrial Appendage Occluder for stroke prevention in comparison to the WATCHMAN Left Atrial Appendage Closure Device in patients with non-valvular atrial fibrillation. METHODS: Non-valvular atrial fibrillation patients at high risk of stroke (CHADS2 score ≥2 or a CHA2DS2-VASc score of ≥3) who are suitable candidates for left atrial appendage occlusion (LAAO) will be fully informed and requested to participate in the trial. A total of 1878 patients at up to 150 sites worldwide will be randomized in a 1:1 ratio between the AMPLATZER Amulet device (investigational) and the Boston Scientific WATCHMAN device (control). Each patient will be followed for 5 years, with follow-up assessments at discharge, 45 days, 3, 6, 9, 12, 18, and 24 months and then annually. The trial has three primary endpoints: A composite of procedure-related complications, or all-cause death, or major bleeding through 12 months (safety); a composite of ischemic stroke or systemic embolism through 18 months (effectiveness); and effective device LAAO, defined as residual jet around the device ≤5 mm at the 45-day visit (mechanism of action). SUMMARY: The Amulet IDE Trial is the first randomized head-to-head LAAO device trial and will provide data for the AMPLATZER Amulet occluder in a population with a high risk of stroke and bleeding.

Microwave detection and quantification of water hidden in and on building materials: implications for healthy buildings and microbiome studies.

BACKGROUND: Excess water in all its forms (moisture, dampness, hidden water) in buildings negatively impacts occupant health but is hard to reliably detect and quantify. Recent advances in through-wall imaging recommend microwaves as a tool with a high potential to noninvasively detect and quantify water throughout buildings. METHODS: Microwaves in both transmission and reflection (radar) modes were used to perform a simple demonstration of the detection of water both on and hidden within building materials. RESULTS: We used both transmission and reflection modes to detect as little as 1 mL of water between two 7 cm thicknesses of concrete. The reflection mode was also used to detect 1 mL of water on a metal surface. We observed oscillations in transmitted and reflected microwave amplitude as a function of microwave wavelength and water layer thickness, which we attribute to thin-film interference effects. CONCLUSIONS: Improving the detection of water in buildings could help design, maintenance, and remediation become more efficient and effective and perhaps increase the value of microbiome sequence data. Microwave characterization of all forms of water throughout buildings is possible; its practical development would require new collaborations among microwave physicists or engineers, architects, building engineers, remediation practitioners, epidemiologists, and microbiologists.

Precision public health to inhibit the contagion of disease and move toward a future in which microbes spread health.

Antimicrobial resistance continues to outpace the development of new chemotherapeutics. Novel pathogens continue to evolve and emerge. Public health innovation has the potential to open a new front in the war of "our wits against their genes" (Joshua Lederberg). Dense sampling coupled to next generation sequencing can increase the spatial and temporal resolution of microbial characterization while sensor technologies precisely map physical parameters relevant to microbial survival and spread. Microbial, physical, and epidemiological big data could be combined to improve prospective risk identification. However, applied in the wrong way, these approaches may not realize their maximum potential benefits and could even do harm. Minimizing microbial-human interactions would be a mistake. There is evidence that microbes previously thought of at best "benign" may actually enhance human health. Benign and health-promoting microbiomes may, or may not, spread via mechanisms similar to pathogens. Infectious vaccines are approaching readiness to make enhanced contributions to herd immunity. The rigorously defined nature of infectious vaccines contrasts with indigenous "benign or health-promoting microbiomes" but they may converge. A "microbial Neolithic revolution" is a possible future in which human microbial-associations are understood and managed analogously to the macro-agriculture of plants and animals. Tradeoffs need to be framed in order to understand health-promoting potentials of benign, and/or health-promoting microbiomes and infectious vaccines while also discouraging pathogens. Super-spreaders are currently defined as individuals who play an outsized role in the contagion of infectious disease. A key unanswered question is whether the super-spreader concept may apply similarly to health-promoting microbes. The complex interactions of individual rights, community health, pathogen contagion, the spread of benign, and of health-promoting microbiomes including infectious vaccines require study. Advancing the detailed understanding of heterogeneity in microbial spread is very likely to yield important insights relevant to public health.

Cost-Effectiveness of Patent Foramen Ovale Closure Versus Medical Therapy for Secondary Stroke Prevention.

BACKGROUND AND PURPOSE: Percutaneous transcatheter closure of patent foramen ovale (PFO closure) plus antiplatelet therapy has been shown to reduce the risk of recurrent stroke compared with medical therapy alone in carefully selected patients after cryptogenic stroke presumed to be from paradoxical embolism. Our objective was to determine the cost-effectiveness of PFO closure after cryptogenic stroke compared with conservative medical management from a US healthcare payer perspective. METHODS: A decision analytic Markov model estimated the 15-year cost and outcomes associated with the additional benefit of PFO closure compared with medical management alone. Model inputs were obtained from published literature, national databases, and a meta-analysis of 5 published randomized clinical trials on PFO closure. Health outcomes were measured in quality-adjusted life years (QALY). Cost-effectiveness used the incremental cost per QALY gained, whereas the net monetary benefit assumed a willingness to pay of $150 000/QALY. One-way and probabilistic sensitivity analyses estimated the uncertainty of model results. RESULTS: At 15 years, PFO closure compared with medical therapy alone improved QALY by 0.33 at a cost saving of $3568, representing an incremental net monetary benefit of $52 761 (95% interval -$8284 to $158 910). When the meta-analysis hazard ratio for stroke was increased to the 95% interval's upper bound of 0.77, one-way sensitivity analyses suggested that PFO closure's cost-effectiveness was $458 558 per additional QALY. Probabilistic sensitivity analysis suggested cost-effectiveness in 90% of simulation runs. CONCLUSIONS: PFO closure for cryptogenic strokes in the right setting is cost-effective, producing benefit in QALYs gained and potential cost savings. However, patient selection remains vitally important as marginal declines in treatment effectiveness can dramatically affect cost-effectiveness.

Closure of Patent Foramen Ovale and Cryptogenic Stroke: Unresolved Issues.

PURPOSE OF REVIEW: This review summarises the results of randomised trials comparing closure of patent foramen ovale (PFO) with antithrombotic therapy in patients with cryptogenic stroke. RECENT FINDINGS: Initially, three randomised trials failed to show superiority of PFO closure over antithrombotic therapy in patients with cryptogenic stroke. Three recently performed trials and the prolongation of an earlier trial provided evidence that PFO closure in patients with cryptogenic stroke and an age range of 18-60 years is superior to stroke prevention with antiplatelet therapy. PFO closure was not superior to anticoagulation. Anticoagulation, however, has a higher long-term bleeding risk. PFO closure could result in atrial fibrillation (AF) in a small number of patients. In most patients, AF was transient in duration. Optimal patient selection requires future research. In patients with cryptogenic stroke aged < 60 years, PFO closure is superior to antiplatelet therapy in the prevention of recurrent stroke.

Closure of patent foramen ovale versus medical therapy after cryptogenic stroke.

BACKGROUND: Whether closure of a patent foramen ovale is effective in the prevention of recurrent ischemic stroke in patients who have had a cryptogenic stroke is unknown. We conducted a trial to evaluate whether closure is superior to medical therapy alone in preventing recurrent ischemic stroke or early death in patients 18 to 60 years of age. METHODS: In this prospective, multicenter, randomized, event-driven trial, we randomly assigned patients, in a 1:1 ratio, to medical therapy alone or closure of the patent foramen ovale. The primary results of the trial were analyzed when the target of 25 primary end-point events had been observed and adjudicated. RESULTS: We enrolled 980 patients (mean age, 45.9 years) at 69 sites. The medical-therapy group received one or more antiplatelet medications (74.8%) or warfarin (25.2%). Treatment exposure between the two groups was unequal (1375 patient-years in the closure group vs. 1184 patient-years in the medical-therapy group, P=0.009) owing to a higher dropout rate in the medical-therapy group. In the intention-to-treat cohort, 9 patients in the closure group and 16 in the medical-therapy group had a recurrence of stroke (hazard ratio with closure, 0.49; 95% confidence interval [CI], 0.22 to 1.11; P=0.08). The between-group difference in the rate of recurrent stroke was significant in the prespecified per-protocol cohort (6 events in the closure group vs. 14 events in the medical-therapy group; hazard ratio, 0.37; 95% CI, 0.14 to 0.96; P=0.03) and in the as-treated cohort (5 events vs. 16 events; hazard ratio, 0.27; 95% CI, 0.10 to 0.75; P=0.007). Serious adverse events occurred in 23.0% of the patients in the closure group and in 21.6% in the medical-therapy group (P=0.65). Procedure-related or device-related serious adverse events occurred in 21 of 499 patients in the closure group (4.2%), but the rate of atrial fibrillation or device thrombus was not increased. CONCLUSIONS: In the primary intention-to-treat analysis, there was no significant benefit associated with closure of a patent foramen ovale in adults who had had a cryptogenic ischemic stroke. However, closure was superior to medical therapy alone in the prespecified per-protocol and as-treated analyses, with a low rate of associated risks. (Funded by St. Jude Medical; RESPECT ClinicalTrials.gov number, NCT00465270.).

Anticoagulant vs. antiplatelet therapy in patients with cryptogenic stroke and patent foramen ovale: an individual participant data meta-analysis.

AIMS: The preferred antithrombotic strategy for secondary prevention in patients with cryptogenic stroke (CS) and patent foramen ovale (PFO) is unknown. We pooled multiple observational studies and used propensity score-based methods to estimate the comparative effectiveness of oral anticoagulation (OAC) compared with antiplatelet therapy (APT). METHODS AND RESULTS: Individual participant data from 12 databases of medically treated patients with CS and PFO were analysed with Cox regression models, to estimate database-specific hazard ratios (HRs) comparing OAC with APT, for both the primary composite outcome [recurrent stroke, transient ischaemic attack (TIA), or death] and stroke alone. Propensity scores were applied via inverse probability of treatment weighting to control for confounding. We synthesized database-specific HRs using random-effects meta-analysis models. This analysis included 2385 (OAC = 804 and APT = 1581) patients with 227 composite endpoints (stroke/TIA/death). The difference between OAC and APT was not statistically significant for the primary composite outcome [adjusted HR = 0.76, 95% confidence interval (CI) 0.52-1.12] or for the secondary outcome of stroke alone (adjusted HR = 0.75, 95% CI 0.44-1.27). Results were consistent in analyses applying alternative weighting schemes, with the exception that OAC had a statistically significant beneficial effect on the composite outcome in analyses standardized to the patient population who actually received APT (adjusted HR = 0.64, 95% CI 0.42-0.99). Subgroup analyses did not detect statistically significant heterogeneity of treatment effects across clinically important patient groups. CONCLUSION: We did not find a statistically significant difference comparing OAC with APT; our results justify randomized trials comparing different antithrombotic approaches in these patients.

The RoPE Score and Right-to-Left Shunt Severity by Transcranial Doppler in the CODICIA Study.

BACKGROUND: For patients with cryptogenic stroke (CS) and patent foramen ovale (PFO), it is unknown whether the magnitude of right-to-left shunt (RLSh) measured by contrast transcranial Doppler (c-TCD) is correlated with the likelihood an identified PFO is related to CS as determined by the Risk of Paradoxical Embolism (RoPE) score. Additionally, for patients with CS, it is unknown whether PFO assessment by c-TCD is more sensitive for identifying RLSh compared with transesophageal echocardiography (TEE). Our aim was to determine the significance of RLSh grade by c-TCD in patients with PFO and CS. METHODS: We evaluated patients with CS who had RLSh quantified by c-TCD in the Multicenter Study into RLSh in Cryptogenic Stroke (CODICIA) to determine whether there is an association between c-TCD shunt grade and the RoPE Score. For patients who underwent c-TCD and TEE, we determined whether there is agreement in identifying and grading RLSh between these two modalities. RESULTS: The RoPE score predicted the presence versus the absence of RLSh documented by c-TCD (c-statistic = 0.66). For patients with documented RLSh by c-TCD, shunt severity was correlated with increasing RoPE score (rank correlation (r) = 0.15, p = 0.01). Among 293 patients who had both c-TCD and TEE performed, c-TCD was more sensitive (98.7%) for detecting RLSh. Of the 97 patients with no PFO identified on TEE, 28 (29%) had a large amount of RLSh seen on c-TCD. CONCLUSIONS: For patients with CS, severity of RLSh by c-TCD is positively correlated with the RoPE score, indicating that this technique for shunt grading identifies patients more likely to have pathogenic rather than incidental PFOs. c-TCD is also more sensitive in detecting RLSh than TEE. These findings suggest an important role for c-TCD in the evaluation of PFO in the setting of CS.