Membrane protein chaperone and sodium chloride modulate the kinetics and morphology of amyloid beta aggregation.

Protein aggregation is a biological phenomenon caused by the accumulation of misfolded proteins. Amyloid beta (Aß) peptides are derived from the cleavage of a larger membrane protein molecule and accumulate to form plaques extracellularly. According to the amyloid hypothesis, accumulation of Aß aggregates in the brain is primarily responsible for the pathogenesis of Alzheimer's disease (AD). Therefore, the disassembly of Aß aggregates may provide opportunities for alleviating or treating AD. Here, we show that the novel protein targeting machinery from chloroplast, chloroplast signal recognition particle 43 (cpSRP43), is an ATP-independent membrane protein chaperone that can both prevent and reverse Aß aggregation effectively. Using of thioflavin T dye, we obtained the aggregation kinetics of Aß aggregation and determined that the chaperone prevents Aß aggregation in a concentration-dependent manner. Size exclusion chromatography and sedimentation assays showed that 10-fold excess of cpSRP43 can keep Aß in the soluble monomeric form. Electron microscopy showed that the fibril structure was disrupted in the presence of this chaperone. Importantly, cpSRP43 utilizes the binding energy to actively remodel the preformed Aß aggregates without assistance by a co-chaperone and ATP, emphasizing its unique function among protein chaperones. Moreover, when sodium chloride concentration is higher than 25 mm, the Aß aggregation rate increases drastically to form tightly associated aggregates and generate more oligomers. Our results demonstrate that the presence of cpSRP43 and low NaCl levels inhibit or retard Aß peptide aggregation, potentially opening new avenues to strategically develop an effective treatment for AD.

FIVE-YEAR INCIDENCE OF FELLOW EYE NEOVASCULAR INVOLVEMENT IN AGE-RELATED MACULAR DEGENERATION AND POLYPOIDAL CHOROIDAL VASCULOPATHY IN AN ASIAN POPULATION.

PURPOSE: To assess 5-year cumulative incidence and risk factors of fellow eye involvement in Asian neovascular age-related macular degeneration (nAMD) and polypoidal choroidal vasculopathy. METHODS: In a prospective cohort study of Asian nAMD and polypoidal choroidal vasculopathy, the fellow eyes were evaluated for exudation. The 5-year incidence of exudation was compared between nAMD and polypoidal choroidal vasculopathy. RESULTS: A total of 488 patients were studied. The 5-year incidence of exudation in fellow eyes was 16.2% (95% confidence interval: 12.0-20.2). Polypoidal choroidal vasculopathy compared with nAMD in the first eye was associated with lower fellow eye progression (9.8% [95% confidence interval: 5.1-14.3]) vs. 22.9% [95% confidence interval: 15.8-29.3], P < 0.01). Drusen (hazards ratio 2.11 [95% confidence interval: 1.10-4.06]), shallow irregular retinal pigment epithelium elevation (2.86 [1.58-5.18]), and pigment epithelial detachment (3.01 [1.27-7.17]) were associated with greater progression. A combination of soft drusens and subretinal drusenoid deposits, and specific pigment epithelial detachment subtypes (multilobular, and sharp peaked) were associated with progression. Pigment epithelial detachment, shallow irregular retinal pigment epithelium elevation, and new subretinal hyperreflective material occurred at 10.4 ± 4.2 months, 11.1 ± 6.0 months, and 6.9 ± 4.3 months, respectively, before exudation. CONCLUSION: The 5-year incidence of fellow eye involvement in Asian nAMD is lower than among Caucasians because of a higher polypoidal choroidal vasculopathy prevalence. Drusens, shallow irregular retinal pigment epithelium elevation, and pigment epithelial detachment are risk factors for fellow eye progression.

Practices for running a research-oriented shared cryo-EM facility.

The Harvard Cryo-Electron Microscopy Center for Structural Biology, which was formed as a consortium between Harvard Medical School, Boston Children's Hospital, Dana-Farber Cancer Institute, and Massachusetts General Hospital, serves both academic and commercial users in the greater Harvard community. The facility strives to optimize research productivity while training users to become expert electron microscopists. These two tasks may be at odds and require careful balance to keep research projects moving forward while still allowing trainees to develop independence and expertise. This article presents the model developed at Harvard Medical School for running a research-oriented cryo-EM facility. Being a research-oriented facility begins with training in cryo-sample preparation on a trainee's own sample, ideally producing grids that can be screened and optimized on the Talos Arctica via multiple established pipelines. The first option, staff assisted screening, requires no user experience and a staff member provides instant feedback about the suitability of the sample for cryo-EM investigation and discusses potential strategies for sample optimization. Another option, rapid access, allows users short sessions to screen samples and introductory training for basic microscope operation. Once a sample reaches the stage where data collection is warranted, new users are trained on setting up data collection for themselves on either the Talos Arctica or Titan Krios microscope until independence is established. By providing incremental training and screening pipelines, the bottleneck of sample preparation can be overcome in parallel with developing skills as an electron microscopist. This approach allows for the development of expertise without hindering breakthroughs in key research areas.

Normative Data and Associations of OCT Angiography Measurements of the Macula: The Singapore Malay Eye Study.

OBJECTIVE: To describe the normative quantitative parameters of the macular retinal vasculature, as well as their systemic and ocular associations using OCT angiography (OCTA). DESIGN: Population-based, cross-sectional study. SUBJECTS: Adults aged > 50 years were recruited from the third examination of the population-based Singapore Malay Eye Study. METHODS: All participants underwent a standardized comprehensive examination and spectral-domain OCTA (Optovue) of the macula. OCT angiography scans that revealed pre-existing retinal disease, revealed macular pathology, and had poor quality were excluded. MAIN OUTCOME MEASURES: The normative quantitative vessel densities of the superficial layer, deep layer, and foveal avascular zone (FAZ) were evaluated. Ocular and systemic associations with macular retinal vasculature parameters were also evaluated in a multivariable analysis using linear regression models with generalized estimating equation models. RESULTS: We included 1184 scans (1184 eyes) of 749 participants. The mean macular superficial vessel density (SVD) and deep vessel density (DVD) were 45.1 ± 4.2% (95% confidence interval [CI], 37.8%-51.4%) and 44.4 ± 5.2% (95% CI, 36.9%-53.2%), respectively. The mean SVD and DVD were highest in the superior quadrant (48.7 ± 5.9%) and nasal quadrant (52.7 ± 4.6%), respectively. The mean FAZ area and perimeter were 0.32 ± 0.11 mm2 (95% CI, 0.17-0.51 mm) and 2.14 ± 0.38 mm (95% CI, 1.54-2.75 mm), respectively. In the multivariable regression analysis, female sex was associated with higher SVD (ß = 1.25, P ≤ 0.001) and DVD (ß = 0.75, P = 0.021). Older age (ß = -0.67, P < 0.001) was associated with lower SVD, whereas longer axial length (ß = -0.42, P = 0.003) was associated with lower DVD. Female sex, shorter axial length, and worse best-corrected distance visual acuity were associated with a larger FAZ area. No association of a range of systemic parameters with vessel density was found. CONCLUSIONS: This study provided normative macular vasculature parameters in an adult Asian population, which may serve as reference values for quantitative interpretation of OCTA data in normal and disease states.

Increased emergency cardiovascular events among under-40 population in Israel during vaccine rollout and third COVID-19 wave.

Cardiovascular adverse conditions are caused by coronavirus disease 2019 (COVID-19) infections and reported as side-effects of the COVID-19 vaccines. Enriching current vaccine safety surveillance systems with additional data sources may improve the understanding of COVID-19 vaccine safety. Using a unique dataset from Israel National Emergency Medical Services (EMS) from 2019 to 2021, the study aims to evaluate the association between the volume of cardiac arrest and acute coronary syndrome EMS calls in the 16-39-year-old population with potential factors including COVID-19 infection and vaccination rates. An increase of over 25% was detected in both call types during January-May 2021, compared with the years 2019-2020. Using Negative Binomial regression models, the weekly emergency call counts were significantly associated with the rates of 1st and 2nd vaccine doses administered to this age group but were not with COVID-19 infection rates. While not establishing causal relationships, the findings raise concerns regarding vaccine-induced undetected severe cardiovascular side-effects and underscore the already established causal relationship between vaccines and myocarditis, a frequent cause of unexpected cardiac arrest in young individuals. Surveillance of potential vaccine side-effects and COVID-19 outcomes should incorporate EMS and other health data to identify public health trends (e.g., increased in EMS calls), and promptly investigate potential underlying causes.

Low-Volume Bowel Preparation Is Associated With Reduced Time to Colonoscopy in Hospitalized Patients: A Propensity-Matched Analysis.

INTRODUCTION: Delays in inpatient colonoscopy are commonly caused by inadequate bowel preparation and result in increased hospital length of stay (LOS) and healthcare costs. Low-volume bowel preparation (LV-BP; sodium sulfate, potassium sulfate, and magnesium sulfate ) has been shown to improve outpatient bowel preparation quality compared with standard high-volume bowel preparations (HV-BP; polyethylene glycol ). However, its efficacy in hospitalized patients has not been well-studied. We assessed the impact of LV-BP on time to colonoscopy, hospital LOS, and bowel preparation quality among inpatients. METHODS: We performed a propensity score-matched analysis of adult inpatients undergoing colonoscopy who received either LV-BP or HV-BP before colonoscopy at a quaternary academic medical center. Multivariate regression models with feature selection were developed to assess the association between LV-BP and study outcomes. RESULTS: Among 1,807 inpatients included in this study, 293 and 1,514 patients received LV-BP and HV-BP, respectively. Among the propensity score-matched population, LV-BP was associated with a shorter time to colonoscopy (ß: -0.43 [95% confidence interval: -0.56 to -0.30]) while having similar odds of adequate preparation (odds ratio: 1.02 [95% confidence interval: 0.71-1.46]; P = 0.92). LV-BP was also significantly associated with decreased hospital LOS among older patients (age ≥ 75 years), patients with chronic kidney disease, and patients who were hospitalized with gastrointestinal bleeding. DISCUSSION: LV-BP is associated with decreased time to colonoscopy in hospitalized patients. Older inpatients, inpatients with chronic kidney disease, and inpatients with gastrointestinal bleeding may particularly benefit from LV-BP. Prospective studies are needed to further establish the role of LV-BP for inpatient colonoscopies.

Moderating effects of out-of-hospital cardiac arrest characteristics on the association between EMS response time and survival.

BACKGROUND: Although several Utstein variables are known to independently improve survival, how they moderate the effect of emergency medical service (EMS) response times on survival is unknown. OBJECTIVES: To quantify how public location, witnessed status, bystander CPR, and bystander AED shock individually and jointly moderate the effect of EMS response time delays on OHCA survival. METHODS: This retrospective cohort study was a secondary analysis of the Resuscitation Outcomes Consortium Epistry-Cardiac Arrest database (December 2005 to June 2015). We included all adult, non-traumatic, non-EMS witnessed, and EMS-treated OHCAs from eleven sites across the US and Canada. We trained a logistic regression model with standard Utstein control variables and interaction terms between EMS response time and the four aforementioned OHCA characteristics. RESULTS: 102,216 patients were included. Three of the four characteristics - witnessed OHCAs (OR = 0.962), bystander CPR (OR = 0.968) and public location (OR = 0.980) - increased the negative effect of a one-minute delay on the odds of survival. In contrast, a bystander AED shock decreased the negative effect of a one-minute response time delay on the odds of survival (OR = 1.064). The magnitude of the effect of a one-minute delay in EMS response time on the odds of survival ranged from 1.3% to 9.8% (average: 5.3%), depending on the underlying OHCA characteristics. CONCLUSIONS: Delays in EMS response time had the largest reduction in survival odds for OHCAs that did not receive a bystander AED shock but were witnessed, occurred in public, and/or received bystander CPR. A bystander AED shock appears to be protective against a delay in EMS response time.

Implications for cardiac arrest coverage using straight-line versus route distance to nearest automated external defibrillator.

AIM: Quantifying the ratio describing the difference between "true route" and "straight-line" distances from out-of-hospital cardiac arrests (OHCAs) to the closest accessible automated external defibrillator (AED) can help correct likely overestimations in AED coverage. Furthermore, we aimed to examine to what extent the closest AED based on true route distance differed from the closest AED using "straight-line". METHODS: OHCAs (1994-2016) and AEDs (2016) in Copenhagen, Denmark and in Toronto, Canada (2007-2015 and 2015, respectively) were identified. Three distances were calculated between OHCA and target AED: 1) the straight-line distance ("straight-line") to the closest AED, 2) the corresponding true route distance to the same AED ("true route"), and 3) the closest AED based only on true route distance ("shortest true route"). The ratio between "true route" and "straight-line" distance was calculated and differences in AED coverage (an OHCA ≤ 100 m of an accessible AED) were examined. RESULTS: The "straight-line" AED coverage of 100 m was 24.2% (n = 2008/8295) in Copenhagen and 6.9% (n = 964/13916) in Toronto. The corresponding "true route" distance reduced coverage to 9.5% (n = 786) and 3.8% (n = 529), respectively. The median ratio between "true route" and "straight-line" distance was 1.6 in Copenhagen and 1.4 in Toronto. In 26.1% (n = 2167) and 22.9% (n = 3181) of all Copenhagen and Toronto OHCAs respectively, the closest AED in "shortest true route" was different than the closest AED initially found by "straight-line". CONCLUSIONS: Straight-line distance is not an accurate measure of distance and overestimates the actual AED coverage compared to a more realistic true route distance by a factor 1.4-1.6.

Worse Cardiac Arrest Outcomes During The COVID-19 Pandemic In Boston Can Be Attributed To Patient Reluctance To Seek Care.

Delays in seeking emergency care stemming from patient reluctance may explain the rise in cases of out-of-hospital cardiac arrest and associated poor health outcomes during the COVID-19 pandemic. In this study we used emergency medical services (EMS) call data from the Boston, Massachusetts, area to describe the association between patients' reluctance to call EMS for cardiac-related care and both excess out-of-hospital cardiac arrest incidence and related outcomes during the pandemic. During the initial COVID-19 wave, cardiac-related EMS calls decreased (-27.2 percent), calls with hospital transportation refusal increased (+32.5 percent), and out-of-hospital cardiac arrest incidence increased (+35.5 percent) compared with historical baselines. After the initial wave, although cardiac-related calls remained lower (-17.2 percent), out-of-hospital cardiac arrest incidence remained elevated (+24.8 percent) despite fewer COVID-19 infections and relaxed public health advisories. Throughout Boston's fourteen neighborhoods, out-of-hospital cardiac arrest incidence was significantly associated with decreased cardiac-related calls, but not with COVID-19 infection rates. These findings suggest that patients were reluctant to obtain emergency care. Efforts are needed to ensure that patients seek timely care both during and after the pandemic to reduce potentially avoidable excess cardiovascular disease deaths.

Predicting Coronavirus Disease 2019 Infection Risk and Related Risk Drivers in Nursing Homes: A Machine Learning Approach.

OBJECTIVE: Inform coronavirus disease 2019 (COVID-19) infection prevention measures by identifying and assessing risk and possible vectors of infection in nursing homes (NHs) using a machine-learning approach. DESIGN: This retrospective cohort study used a gradient boosting algorithm to evaluate risk of COVID-19 infection (ie, presence of at least 1 confirmed COVID-19 resident) in NHs. SETTING AND PARTICIPANTS: The model was trained on outcomes from 1146 NHs in Massachusetts, Georgia, and New Jersey, reporting COVID-19 case data on April 20, 2020. Risk indices generated from the model using data from May 4 were prospectively validated against outcomes reported on May 11 from 1021 NHs in California. METHODS: Model features, pertaining to facility and community characteristics, were obtained from a self-constructed dataset based on multiple public and private sources. The model was assessed via out-of-sample area under the receiver operating characteristic curve (AUC), sensitivity, and specificity in the training (via 10-fold cross-validation) and validation datasets. RESULTS: The mean AUC, sensitivity, and specificity of the model over 10-fold cross-validation were 0.729 [95% confidence interval (CI) 0.690‒0.767], 0.670 (95% CI 0.477‒0.862), and 0.611 (95% CI 0.412‒0.809), respectively. Prospective out-of-sample validation yielded similar performance measures (AUC 0.721; sensitivity 0.622; specificity 0.713). The strongest predictors of COVID-19 infection were identified as the NH's county's infection rate and the number of separate units in the NH; other predictors included the county's population density, historical Centers of Medicare and Medicaid Services cited health deficiencies, and the NH's resident density (in persons per 1000 square feet). In addition, the NH's historical percentage of non-Hispanic white residents was identified as a protective factor. CONCLUSIONS AND IMPLICATIONS: A machine-learning model can help quantify and predict NH infection risk. The identified risk factors support the early identification and management of presymptomatic and asymptomatic individuals (eg, staff) entering the NH from the surrounding community and the development of financially sustainable staff testing initiatives in preventing COVID-19 infection.

Effect of Optimized Versus Guidelines-Based Automated External Defibrillator Placement on Out-of-Hospital Cardiac Arrest Coverage: An In Silico Trial.

Background Mathematical optimization of automated external defibrillator (AED) placement may improve AED accessibility and out-of-hospital cardiac arrest (OHCA) outcomes compared with American Heart Association (AHA) and European Resuscitation Council (ERC) placement guidelines. We conducted an in silico trial (simulated prospective cohort study) comparing mathematically optimized placements with placements derived from current AHA and ERC guidelines, which recommend placement in locations where OHCAs are usually witnessed. Methods and Results We identified all public OHCAs of presumed cardiac cause from 2008 to 2016 in Copenhagen, Denmark. For the control, we computationally simulated placing 24/7-accessible AEDs at every unique, public, witnessed OHCA location at monthly intervals over the study period. The intervention consisted of an equal number of simulated AEDs placements, deployed monthly, at mathematically optimized locations, using a model that analyzed historical OHCAs before that month. For each approach, we calculated the number of OHCAs in the study period that occurred within a 100-m route distance based on Copenhagen's road network of an available AED after it was placed ("OHCA coverage"). Estimated impact on bystander defibrillation and 30-day survival was calculated by multivariate logistic regression. The control scenario involved 393 AEDs at historical, public, witnessed OHCA locations, covering 15.8% of the 653 public OHCAs from 2008 to 2016. The optimized locations provided significantly higher coverage (24.2%; P<0.001). Estimated bystander defibrillation and 30-day survival rates increased from 15.6% to 18.2% (P<0.05) and from 32.6% to 34.0% (P<0.05), respectively. As a baseline, the 1573 real AEDs in Copenhagen covered 14.4% of the OHCAs. Conclusions Mathematical optimization can significantly improve OHCA coverage and estimated clinical outcomes compared with a guidelines-based approach to AED placement.

Systemic hypertension associated retinal microvascular changes can be detected with optical coherence tomography angiography.

A major complication of hypertension is microvascular damage and capillary rarefaction is a known complication of hypertensive end-organ damage which confers a higher risk of systemic disease such as stroke and cardiovascular events. Our aim was to study the effect of hypertension on the retinal microvasculature using non-invasive optical coherence tomography angiography (OCTA). We performed a case-control study of 94 eyes of 94 participants with systemic hypertension and 46 normal control eyes from the Singapore Chinese Eye Study using a standardized protocol to collect data on past medical history of hypertension, including the number and type of hypertensive medications and assessed mean arterial pressure. Retinal vascular parameters were measured in all eyes using OCTA. In the multivariate analysis adjusting for confounders, compared to controls, eyes of hypertensive patients showed a decrease in the macular vessel density at the level of the superficial [OR 0.02; 95% CI, 0 to 0.64; P 0.027] and deep venous plexuses [OR 0.03; 95% CI, 0 to 0.41; P 0.009] and an increase in the deep foveal avascular zone. This shows that hypertension is associated with reduced retinal vessel density and an increased foveal avascular zone, especially in the deep venous plexus, as seen on OCTA and there is a potential role in using OCTA as a clinical tool to monitor hypertensive damage and identifying at risk patients.

Optimal in-hospital defibrillator placement.

AIMS: To determine if mathematical optimization of in-hospital defibrillator placements can reduce in-hospital cardiac arrest-to-defibrillator distance compared to existing defibrillators in a single hospital. METHODS: We identified treated IHCAs and defibrillator placements in St. Michael's Hospital in Toronto, Canada from Jan. 2013 to Jun. 2017 and mapped them to a 3-D computer model of the hospital. An optimization model identified an equal number of optimal defibrillator locations that minimized the average distance between IHCAs and the closest defibrillator using a 10-fold cross-validation approach. The optimized and existing defibrillator locations were compared in terms of average distance to the out-of-sample IHCAs. We repeated the analysis excluding intensive care units (ICUs), operating theatres (OTs), and the emergency department (ED). We also re-solved the model using fewer defibrillators to determine when the average distance matched the performance of existing defibrillators. RESULTS: We identified 433 treated IHCAs and 53 defibrillators. Of these, 167 IHCAs and 31 defibrillators were outside of ICUs, OTs, and the ED. Optimal defibrillator placements reduced the average IHCA-to-defibrillator distance from 16.1 m to 2.7 m (relative decrease of 83.0%; P = 0.002) compared to existing defibrillator placements. For non-ICU/OT/ED IHCAs, the average distance was reduced from 24.4 m to 11.9 m (relative decrease of 51.3%; P = 0.002. 8-9 optimized defibrillator locations were sufficient to match the average IHCA-to-defibrillator distance of existing defibrillator placements. CONCLUSIONS: Optimization-guided placement of in-hospital defibrillators can reduce the distance from an IHCA to the closest defibrillator. Equivalently, optimization can match existing defibrillator performance using far fewer defibrillators.

Improving bystander defibrillation in out-of-hospital cardiac arrests at home.

AIMS: Most out-of-hospital cardiac arrests occur at home with dismal bystander defibrillation rates. We investigated automated external defibrillator coverage of home arrests, and the proportion potentially reachable with an automated external defibrillator before emergency medical service arrival according to different bystander activation strategies. METHODS AND RESULTS: Cardiac arrests in homes (private/nursing/senior homes) in Copenhagen, Denmark (2008-2016) and registered automated external defibrillators (2007-2016), were identified. Automated external defibrillator coverage (distance from arrest to automated external defibrillator) and accessibility at the time of arrest were examined according to route distance to nearest automated external defibrillator and emergency medical service response time. The proportion of arrests reachable with an automated external defibrillator by bystander was calculated using two-way (from patient to automated external defibrillator and back) and one-way (from automated external defibrillator to patient) potential activation strategies. Of 1879 home arrests, automated external defibrillator coverage ≤100 m was low (6.3%) and a two-way bystander could potentially only retrieve an accessible automated external defibrillator before emergency medical service in 31.1% (n=37) of cases. If a bystander only needed to travel one-way to bring an automated external defibrillator (≤100 m, ≤250 m and ≤500 m), 45.4% (n=54/119), 37.1% (n=196/529) and 29.8% (n=350/1174) could potentially be reached before the emergency medical service based on current automated external defibrillator accessibility. CONCLUSIONS: Few home arrests were reachable with an automated external defibrillator before emergency medical service if bystanders needed to travel from patient to automated external defibrillator and back. However, nearly one-third of arrests ≤500 m of an automated external defibrillator could be reached before emergency medical service arrival if the bystander only needed to travel one-way from the automated external defibrillator to the patient.

In Silico Trial of Optimized Versus Actual Public Defibrillator Locations.

BACKGROUND: Automated external defibrillators (AEDs) are often placed in areas of low risk and limited temporal availability. Mathematical optimization can improve AED accessibility but has not been compared with current practices. OBJECTIVES: This study sought to determine whether, compared with real AED locations, optimized AED locations improve coverage of out-of-hospital cardiac arrests (OHCAs). METHODS: The authors conducted the first retrospective in silico trial of an AED placement intervention. This study identified all public OHCAs of presumed cardiac cause and real AED deployed (control group) from 2007 to 2016 in Copenhagen, Denmark. Optimization models trained on historical OHCAs (1994 to 2007) were used to optimize an equal number of AEDs to the control group in locations with availabilities based on building hours (intervention #1) or 24/7 access (intervention #2). The 2 interventions and control scenario were compared using the number of OHCAs that occurred within 100 m of an accessible AED ("OHCA coverage") during the 2007 to 2016 period. Change in bystander defibrillation and 30-day survival were estimated using multivariate logistic regression. RESULTS: There were 673 public OHCAs and 1,573 registered AEDs from 2007 to 2016. OHCA coverage of real AED placements was 22.0%. OHCA coverage of interventions #1 and #2 was significantly higher at 33.4% and 43.1%, respectively; relative gains of 52.0% to 95.9% (p < 0.001). Bystander defibrillation increased from 14.6% (control group) to 22.5% to 26.9% (intervention #1 to intervention #2); relative increase of 52.9% to 83.5% (p < 0.001). The 30-day survival rates increased from 31.3% (control group) to 34.7% to 35.4%, which is a relative increase of 11.0% to 13.3% (p < 0.001). CONCLUSIONS: Optimized AED placements increased OHCA coverage by approximately 50% to 100% over real AED placements, leading to significant predicted increases in bystander defibrillation and 30-day survival.