Geographical epidemiology of Hyalomma anatolicum and Rhipicephalus microplus in Pakistan: A systematic review.

The livestock sector contributes almost 11% of Pakistan's GDP and is crucial to 35 million people's livelihoods. Ticks are a major economic threat, as over 80% of livestock, such as bovines, are tick-infested with Hyalomma and Rhipicephalus tick species. Hyalomma anatolicum and Rhipicephalus microplus are the most common tick species collected from livestock, transmitting primarily anaplasmosis, babesiosis, and theileriosis. We aimed to identify the geographical distribution of these two tick species and hot spot areas where the risk of these diseases being transmitted by these ticks is high. Following the PRISMA guideline, two authors conducted an independent review of literature sourced from various databases. We screened 326 research articles published between January 1, 1990, and December 31, 2023, focused on identifying the tick species at the district level. Thirty studies from 75 districts, representing 49.3% of the country's total area, detected at least one tick species through collection from animals. R. microplus was present in 81% (n = 61) and H. anatolicum in 82% (n = 62) of these sampled districts. We employed spatial and conventional statistical methods with Geographic Information Systems (GIS) after mapping the weighted distribution of both ticks (the number of ticks per standard unit of sampling effort). We identified northwestern and northcentral regions of the country as hotspots with the highest tick distribution, which aligned with the documented high prevalence of anaplasmosis, babesiosis, Crimean-Congo hemorrhagic fever (CCHF), and theileriosis in these regions. This underscores the urgent need for robust tick control measures in these districts to safeguard animal health and boost the livestock economy.

Species distribution modeling for disease ecology: A multi-scale case study for schistosomiasis host snails in Brazil.

Species distribution models (SDMs) are increasingly popular tools for profiling disease risk in ecology, particularly for infectious diseases of public health importance that include an obligate non-human host in their transmission cycle. SDMs can create high-resolution maps of host distribution across geographical scales, reflecting baseline risk of disease. However, as SDM computational methods have rapidly expanded, there are many outstanding methodological questions. Here we address key questions about SDM application, using schistosomiasis risk in Brazil as a case study. Schistosomiasis is transmitted to humans through contact with the free-living infectious stage of Schistosoma spp. parasites released from freshwater snails, the parasite's obligate intermediate hosts. In this study, we compared snail SDM performance across machine learning (ML) approaches (MaxEnt, Random Forest, and Boosted Regression Trees), geographic extents (national, regional, and state), types of presence data (expert-collected and publicly-available), and snail species (Biomphalaria glabrata, B. straminea, and B. tenagophila). We used high-resolution (1km) climate, hydrology, land-use/land-cover (LULC), and soil property data to describe the snails' ecological niche and evaluated models on multiple criteria. Although all ML approaches produced comparable spatially cross-validated performance metrics, their suitability maps showed major qualitative differences that required validation based on local expert knowledge. Additionally, our findings revealed varying importance of LULC and bioclimatic variables for different snail species at different spatial scales. Finally, we found that models using publicly-available data predicted snail distribution with comparable AUC values to models using expert-collected data. This work serves as an instructional guide to SDM methods that can be applied to a range of vector-borne and zoonotic diseases. In addition, it advances our understanding of the relevant environment and bioclimatic determinants of schistosomiasis risk in Brazil.

Sex-specific variation in species interactions matters in ecological communities.

Understanding how natural communities and ecosystems are structured and respond to anthropogenic pressures in a rapidly changing world is key to successful management and conservation. A fundamental but often overlooked biological characteristic of organisms is sex. Sex-based responses are often considered when conducting studies at organismal and population levels, but are rarely investigated in community ecology. Focusing on kelp forests as a model system, and through a review of other marine and terrestrial ecosystems, we found evidence of widespread sex-based variation in species interactions. Sex-based variation in species interactions is expected to affect ecosystem structure and functioning via multiple trophic and nontrophic pathways. Understanding the drivers and consequences of sex-based variation in species interactions can inform more effective management and restoration.

Arrhythmic Risk Stratification in Cardiac Amyloidosis: A Review of the Current Literature.

Cardiac amyloidosis is the most frequent infiltrative disease caused by the deposition of misfolded proteins in the cardiac tissue, leading to heart failure, brady- and tachyarrhythmia and death. Conduction disorders, atrial fibrillation (AF) and ventricular arrhythmia (VA) significantly impact patient outcomes and demand recognition. However, several issues remain unresolved regarding early diagnosis and optimal management. Extreme bradycardia is the most common cause of arrhythmic death, while fast and sustained VAs can be found even in the early phases of the disease. Risk stratification and the prevention of sudden cardiac death are therefore to be considered in these patients, although the time for defibrillator implantation is still a subject of debate. Moreover, atrial impairment due to amyloid fibrils is associated with an increased risk of AF resistant to antiarrhythmic therapy, as well as recurrent thromboembolic events despite adequate anticoagulation. In the last few years, the aging of the population and progressive improvements in imaging methods have led to increases in the diagnosis of cardiac amyloidosis. Novel therapies have been developed to improve patients' functional status, quality of life and mortality, without data regarding their effect on arrhythmia prevention. In this review, we consider the latest evidence regarding the arrhythmic risk stratification of cardiac amyloidosis, as well as the available therapeutic strategies.

Re-assessing thermal response of schistosomiasis transmission risk: evidence for a higher thermal optimum than previously predicted.

The geographical range of schistosomiasis is affected by the ecology of schistosome parasites and their obligate host snails, including their response to temperature. Previous models predicted schistosomiasis' thermal optimum at 21.7 °C, which is not compatible with the temperature in sub-Saharan Africa (SSA) regions where schistosomiasis is hyperendemic. We performed an extensive literature search for empirical data on the effect of temperature on physiological and epidemiological parameters regulating the free-living stages of S. mansoni and S. haematobium and their obligate host snails, i.e., Biomphalaria spp. and Bulinus spp., respectively. We derived nonlinear thermal responses fitted on these data to parameterize a mechanistic, process-based model of schistosomiasis. We then re-cast the basic reproduction number and the prevalence of schistosome infection as functions of temperature. We found that the thermal optima for transmission of S. mansoni and S. haematobium range between 23.1-27.3 °C and 23.6-27.9 °C (95 % CI) respectively. We also found that the thermal optimum shifts toward higher temperatures as the human water contact rate increases with temperature. Our findings align with an extensive dataset of schistosomiasis prevalence in SSA. The refined nonlinear thermal-response model developed here suggests a more suitable current climate and a greater risk of increased transmission with future warming for more than half of the schistosomiasis suitable regions with mean annual temperature below the thermal optimum.

Development of a trash classification system to map potential Aedes aegypti breeding grounds using unmanned aerial vehicle imaging.

Aedes aegypti mosquitos are the primary vector for dengue, chikungunya, and Zika viruses and tend to breed in small containers of water, with a propensity to breed in small piles of trash and abandoned tires. This study piloted the use of aerial imaging to map and classify potential Ae. aegypti breeding sites with a specific focus on trash, including discarded tires. Aerial images of coastal and inland sites in Kenya were obtained using an unmanned aerial vehicle. Aerial images were reviewed for identification of trash and suspected trash mimics, followed by extensive community walk-throughs to identify trash types and mimics by description and ground photography. An expert panel reviewed aerial images and ground photos to develop a classification scheme and evaluate the advantages and disadvantages of aerial imaging versus walk-through trash mapping. A trash classification scheme was created based on trash density, surface area, potential for frequent disturbance, and overall likelihood of being a productive Ae. aegypti breeding site. Aerial imaging offers a novel strategy to characterize, map, and quantify trash at risk of promoting Ae. aegypti proliferation, generating opportunities for further research on trash associations with disease and trash interventions.

Re-assessing thermal response of schistosomiasis transmission risk: Evidence for a higher thermal optimum than previously predicted.

The geographical range of schistosomiasis is affected by the ecology of schistosome parasites and their obligate host snails, including their response to temperature. Previous models predicted schistosomiasis' thermal optimum at 21.7°C, which is not compatible with the temperature in sub-Saharan Africa (SSA) regions where schistosomiasis is hyperendemic. We performed an extensive literature search for empirical data on the effect of temperature on physiological and epidemiological parameters regulating the free-living stages of S. mansoni and S. haematobium and their obligate host snails, i.e., Biomphalaria spp. and Bulinus spp., respectively. We derived nonlinear thermal responses fitted on these data to parameterize a mechanistic, process-based model of schistosomiasis. We then re-cast the basic reproduction number and the prevalence of schistosome infection as functions of temperature. We found that the thermal optima for transmission of S. mansoni and S. haematobium range between 23.1-27.3°C and 23.6-27.9°C (95% CI) respectively. We also found that the thermal optimum shifts toward higher temperatures as the human water contact rate increases with temperature. Our findings align with an extensive dataset of schistosomiasis prevalence in SSA. The refined nonlinear thermal-response model developed here suggests a more suitable current climate and a greater risk of increased transmission with future warming for more than half of the schistosomiasis suitable regions with mean annual temperature below the thermal optimum.

Climate and urbanization drive changes in the habitat suitability of Schistosoma mansoni competent snails in Brazil.

Schistosomiasis is a neglected tropical disease caused by Schistosoma parasites. Schistosoma are obligate parasites of freshwater Biomphalaria and Bulinus snails, thus controlling snail populations is critical to reducing transmission risk. As snails are sensitive to environmental conditions, we expect their distribution is significantly impacted by global change. Here, we used machine learning, remote sensing, and 30 years of snail occurrence records to map the historical and current distribution of forward-transmitting Biomphalaria hosts throughout Brazil. We identified key features influencing the distribution of suitable habitat and determined how Biomphalaria habitat has changed with climate and urbanization over the last three decades. Our models show that climate change has driven broad shifts in snail host range, whereas expansion of urban and peri-urban areas has driven localized increases in habitat suitability. Elucidating change in Biomphalaria distribution-while accounting for non-linearities that are difficult to detect from local case studies-can help inform schistosomiasis control strategies.

Predicting Increased Incidence of Common Antibiotic-Resistant and Antibiotic-Associated Pathogens Using Ensemble Species Distribution Modeling.

The Centers for Disease Control estimates antibiotic-associated pathogens result in 2.8 million infections and 38,000 deaths annually in the United States. This study applies species distribution modeling to elucidate the impact of environmental determinants of human infectious disease in an era of rapid global change. We modeled methicillin-resistant Staphylococcus aureus and Clostridioides difficile using 31 publicly accessible bioclimatic, healthcare, and sociodemographic variables. Ensemble models were created from 8 unique statistical and machine learning algorithms. Using International Classification of Diseases, 10th Edition codes, we identified 305,528 diagnoses of methicillin-resistant S.aureus and 302,001 diagnoses of C.difficile presence. Three environmental factors - average maximum temperature, specific humidity, and agricultural land density - emerged as major predictors of increased methicillin-resistant S.aureus and C.difficile presence; variables representing healthcare availability were less important. Species distribution modeling may be a powerful tool for identifying areas at increased risk for disease presence and have important implications for disease surveillance systems.

Climate and urbanization drive changes in the habitat suitability of Schistosoma mansoni competent snails in Brazil.

Schistosomiasis is a neglected tropical disease caused by Schistosoma parasites. Schistosoma are obligate parasites of freshwater Biomphalaria snails, so controlling snail populations is critical to reducing transmission risk. As snails are sensitive to environmental conditions, we expect their distribution is significantly impacted by global change. Here, we leveraged machine learning, remote sensing, and 30 years of snail occurrence records to map the historical and current distribution of competent Biomphalaria throughout Brazil. We identified key features influencing the distribution of suitable habitat and determined how Biomphalaria habitat has changed with climate and urbanization over the last three decades. Our models show that climate change has driven broad shifts in snail host range, whereas expansion of urban and peri-urban areas has driven localized increases in habitat suitability. Elucidating change in Biomphalaria distribution - while accounting for non-linearities that are difficult to detect from local case studies - can help inform schistosomiasis control strategies.

Atrial fibrillation before and after transcatheter aortic valve implantation: short- and long-term clinical implications.

BACKGROUND: Patients with atrial fibrillation (AF) undergoing transcatheter aortic valve implantation (TAVI) have been associated with worse short-term outcomes compared with patients in sinus rhythm but data on long-term outcomes are limited. The aim of our study was to evaluate the association between AF and short- and long-term outcomes in patients undergoing TAVI. METHODS: We retrospectively evaluated patients undergoing TAVI between 2012 and 2022 in four tertiary centres. Two different analyses were conducted: (i) in-hospital and (ii) postdischarge analysis. First, we evaluated the association between preexisting AF and short-term outcomes according to VARC-3 criteria. Second, we analyzed the association between AF at discharge (defined as both preexisting and new-onset AF occurring after TAVI) and long-term outcomes at median follow-up of 3.2 years (i.e. all-cause death, hospitalization and major adverse cardiovascular events). RESULTS: A total of 759 patients were initially categorized according to the presence of preexisting AF (241 vs. 518 patients). The preexisting AF group had a higher occurrence of acute kidney injury [odds ratio (OR) 1.65; 95%confidence interval ( CI) 1.15-2.38] and major bleeding (OR 1.86, 95% CI 1.06-3.27). Subsequently, the population was categorized according to the presence of AF at discharge. At the adjusted Cox regression analysis, AF was independently associated with an increased risk of all-cause death and cardiovascular hospitalization [adjusted hazard ratio (aHR) 1.42, 95% CI 1.09-1.86], all-cause death and all-cause hospitalization (aHR 1.38, 95% CI 1.06-1.78) and all-cause hospitalization (aHR 1.59, 95% CI 1.14.2.22). CONCLUSIONS: In a real-world cohort of patients undergoing TAVI, the presence of AF (preexisting and new-onset) was independently associated with both short- and long-term adverse outcomes.

Temperature affects predation of schistosome-competent snails by a novel invader, the marbled crayfish Procambarus virginalis.

The human burden of environmentally transmitted infectious diseases can depend strongly on ecological factors, including the presence or absence of natural enemies. The marbled crayfish (Procambarus virginalis) is a novel invasive species that can tolerate a wide range of ecological conditions and colonize diverse habitats. Marbled crayfish first appeared in Madagascar in 2005 and quickly spread across the country, overlapping with the distribution of freshwater snails that serve as the intermediate host of schistosomiasis-a parasitic disease of poverty with human prevalence ranging up to 94% in Madagascar. It has been hypothesized that the marbled crayfish may serve as a predator of schistosome-competent snails in areas where native predators cannot and yet no systematic study to date has been conducted to estimate its predation rate on snails. Here, we experimentally assessed marbled crayfish consumption of uninfected and infected schistosome-competent snails (Biomphalaria glabrata and Bulinus truncatus) across a range of temperatures, reflective of the habitat range of the marbled crayfish in Madagascar. We found that the relationship between crayfish consumption and temperature is unimodal with a peak at ~27.5°C. Per-capita consumption increased with body size and was not affected either by snail species or their infectious status. We detected a possible satiation effect, i.e., a small but significant reduction in per-capita consumption rate over the 72-hour duration of the predation experiment. Our results suggest that ecological parameters, such as temperature and crayfish weight, influence rates of consumption and, in turn, the potential impact of the marbled crayfish invasion on snail host populations.

Baseline Characteristics and 3-Year Outcome of Nonvalvular Atrial Fibrillation Patients Treated with the Four Direct Oral Anticoagulants (DOACs).

Direct oral anticoagulants (DOACs) represent the cornerstone therapy for cardioembolic events prevention in patients with nonvalvular atrial fibrillation (NVAF). In practice, the choice of one DOAC over another is guided by the decision-making process of the physician, which considers specific patient and drug characteristics. This study aimed to evaluate the clinical features and long-term outcomes of a real-world population treated with DOACs, where the use of the 4 different DOACs is quite equal. We conducted a retrospective observational, single-center, multidisciplinary study enrolling consecutive NVAF patients treated with one of the 4 DOACs. From an initial number of 753 patients, we excluded 72 patients because of loss to follow-up, at the end we enrolled 681:174 (23%) treated with dabigatran, 175 (23%) with apixaban, 190 (25%) with rivaroxaban, and 214 (29%) with edoxaban. Patients treated with apixaban were significantly older, more women represented (p <0.001), and with a higher cardioembolic and bleeding risk (p <0.001). Dabigatran was preferred in patients with liver failure (p = 0.008), whereas Apixaban and Edoxaban were chosen in chronic kidney disease (p = 0.002). At 3-year follow-up, 20 patients (2.7%) experienced a systemic thromboembolic event without significant differences in the 4 DOACs. In the same period, an International Society of Thrombosis and Hemostasis classification major bleeding event occurred in 26 patients (3.6%), more statistically correlated to edoxaban (6.1%) (p = 0.038). Thromboembolic events or major bleeding were higher in the edoxaban group (10%) compared with the others (p = 0.014). In our single-center real-world experience, the choice of the DOAC for a patient with NVAF was tailored to specific clinical features and drug pharmacokinetics of the patient. As a result, a small number of adverse events were observed.

Direct oral anticoagulants versus percutaneous left atrial appendage occlusion in atrial fibrillation: 5-year outcomes.

BACKGROUND: LAAO is an emerging option for thromboembolic event prevention in patients with NVAF. We previously reported data on comparison between LAAO and DOAC at two-year follow-up in NVAF patients at HBR (HAS-BLED ≥3). AIMS: Limited data are available on long term follow-up. We aimed to evaluate the efficacy and safety of DOACs versus LAAO indication after 5 years. METHODS: We enrolled 193 HBR treated with LAAO and 189 HBR patients with DOACs. At baseline, LAAO group had higher HAS-BLED (4.2 vs 3.3, p < 0.001) and lower CHADS-VASc (4.3 vs. 4.7, p = 0.005). After 1:1 PSM, 192 patients were included (LAAO n = 96; DOACs n = 96). RESULTS: At 5-year follow-up the rate of the combined safety and effectiveness endpoint (ISTH major bleeding and thromboembolic events) was significantly higher in LAAO group (p = 0.042), driven by a higher number of thromboembolic events (p = 0.047). The rate of ISTH-major bleeding events was similar (p = 0.221). After PSM no significant difference in the primary effectiveness (LAAO 13.3% vs DOACs 9.5%, p = 0.357) and safety endpoint (LAAO 7.5% vs DOACs 7.5%; p = 0.918) were evident. Overall bleeding rate was significantly higher in DOACs group (25.0% vs 13.7%, p = 0.048), while a non-significant higher number of TIA was reported in LAAO group (5.4% vs 1.1%, p = 0.098). All-cause and cardiovascular mortality were higher in LAAO group at both unmatched and matched analysis. CONCLUSION: We confirmed safety and effectiveness of both DOAC and LAAO in NVAF patients at HBR, with no significant differences in thromboembolic events or major bleeding were at 5-year follow-up. The observed increased mortality after LAAO warrants further investigations in RCTs.

A planetary health innovation for disease, food and water challenges in Africa.

Many communities in low- and middle-income countries globally lack sustainable, cost-effective and mutually beneficial solutions for infectious disease, food, water and poverty challenges, despite their inherent interdependence1-7. Here we provide support for the hypothesis that agricultural development and fertilizer use in West Africa increase the burden of the parasitic disease schistosomiasis by fuelling the growth of submerged aquatic vegetation that chokes out water access points and serves as habitat for freshwater snails that transmit Schistosoma parasites to more than 200 million people globally8-10. In a cluster randomized controlled trial (ClinicalTrials.gov: NCT03187366) in which we removed invasive submerged vegetation from water points at 8 of 16 villages (that is, clusters), control sites had 1.46 times higher intestinal Schistosoma infection rates in schoolchildren and lower open water access than removal sites. Vegetation removal did not have any detectable long-term adverse effects on local water quality or freshwater biodiversity. In feeding trials, the removed vegetation was as effective as traditional livestock feed but 41 to 179 times cheaper and converting the vegetation to compost provided private crop production and total (public health plus crop production benefits) benefit-to-cost ratios as high as 4.0 and 8.8, respectively. Thus, the approach yielded an economic incentive-with important public health co-benefits-to maintain cleared waterways and return nutrients captured in aquatic plants back to agriculture with promise of breaking poverty-disease traps. To facilitate targeting and scaling of the intervention, we lay the foundation for using remote sensing technology to detect snail habitats. By offering a rare, profitable, win-win approach to addressing food and water access, poverty alleviation, infectious disease control and environmental sustainability, we hope to inspire the interdisciplinary search for planetary health solutions11 to the many and formidable, co-dependent global grand challenges of the twenty-first century.

The Importance of Mehran Score to Predict Acute Kidney Injury in Patients with TAVI: A Large Multicenter Cohort Study.

BACKGROUND: Transcatheter aortic valve implantation (TAVI) has developed as an alternative to surgery for symptomatic high-risk patients with aortic stenosis (AS). An important complication of TAVI is acute kidney injury. The purpose of the study was to investigate if the Mehran Score (MS) could be used to predict acute kidney injury (AKI) in TAVI patients. METHODS: This is a multicenter, retrospective, observational study including 1180 patients with severe AS. The MS comprised eight clinical and procedural variables: hypotension, congestive heart failure class, glomerular filtration rate, diabetes, age >75 years, anemia, need for intra-aortic balloon pump, and contrast agent volume use. We assessed the sensitivity and specificity of the MS in predicting AKI following TAVI, as well as the predictive value of MS with each AKI-related characteristic. RESULTS: Patients were categorized into four risk groups based on MS: low (≤5), moderate (6-10), high (11-15), and very high (≥16). Post-procedural AKI was observed in 139 patients (11.8%). MS classes had a higher risk of AKI in the multivariate analysis (HR 1.38, 95% CI, 1.43-1.63, p < 0.01). The best cutoff for MS to predict the onset of AKI was 13.0 (AUC, 0.62; 95% CI, 0.57-0.67), whereas the best cutoff for eGFR was 42.0 mL/min/1.73 m2 (AUC, 0.61; 95% CI, 0.56-0.67). CONCLUSIONS: MS was shown to be a predictor of AKI development in TAVI patients.

Reframing Optimal Control Problems for Infectious Disease Management in Low-Income Countries.

Optimal control theory can be a useful tool to identify the best strategies for the management of infectious diseases. In most of the applications to disease control with ordinary differential equations, the objective functional to be optimized is formulated in monetary terms as the sum of intervention costs and the cost associated with the burden of disease. We present alternate formulations that express epidemiological outcomes via health metrics and reframe the problem to include features such as budget constraints and epidemiological targets. These alternate formulations are illustrated with a compartmental cholera model. The alternate formulations permit us to better explore the sensitivity of the optimal control solutions to changes in available budget or the desired epidemiological target. We also discuss some limitations of comprehensive cost assessment in epidemiology.

Climatic, land-use and socio-economic factors can predict malaria dynamics at fine spatial scales relevant to local health actors: Evidence from rural Madagascar.

While much progress has been achieved over the last decades, malaria surveillance and control remain a challenge in countries with limited health care access and resources. High-resolution predictions of malaria incidence using routine surveillance data could represent a powerful tool to health practitioners by targeting malaria control activities where and when they are most needed. Here, we investigate the predictors of spatio-temporal malaria dynamics in rural Madagascar, estimated from facility-based passive surveillance data. Specifically, this study integrates climate, land-use, and representative household survey data to explain and predict malaria dynamics at a high spatial resolution (i.e., by Fokontany, a cluster of villages) relevant to health care practitioners. Combining generalized linear mixed models (GLMM) and path analyses, we found that socio-economic, land use and climatic variables are all important predictors of monthly malaria incidence at fine spatial scales, via both direct and indirect effects. In addition, out-of-sample predictions from our model were able to identify 58% of the Fokontany in the top quintile for malaria incidence and account for 77% of the variation in the Fokontany incidence rank. These results suggest that it is possible to build a predictive framework using environmental and social predictors that can be complementary to standard surveillance systems and help inform control strategies by field actors at local scales.

Left atrial appendage closure: a new strategy for cardioembolic events despite oral anticoagulation.

BACKGROUND: Patients with non-valvular atrial fibrillation (nvAF) who experienced a cardioembolic (CE) event despite adequate oral anticoagulation (OAC) are at high risk of recurrence, and further prevention strategies are deemed necessary. The present study aimed to evaluate the safety and efficacy of off-label use of left atrial appendage closure (LAAC) in this subset of patients. METHODS: Seventy-five consecutive patients with nvAF who experienced a CE event despite adequate OAC therapy were retrospectively enrolled from two Italian centers. Patients were divided according to the treatment strategy following the index event: DOAC group (49 patients who continued OAC therapy with DOACs) and LAAC group (26 patients who underwent LAAC procedure). 1:1 propensity-score matching between the two groups was performed. LAAC group was made up of two subgroups according to the post-procedural pharmacological regimen: 1) dual antiplatelet therapy (DAPT) for 3 months followed by indefinite single antiplatelet therapy (LAAC+SAPT); or 2) aspirin plus DOAC for 3 months followed by indefinite DOAC therapy (LAAC+DOAC). The primary endpoint was a composite of CE event, major bleeding, or procedure-related major complication. RESULTS: During a median follow-up of 3.4 years (IQR: 2.0-5.3), LAAC was a predictor of primary endpoint-free survival (HR=0.28, 95% CI: 0.08-0.97; P=0.044); within LAAC group, no procedure-related major complication occurred. Moreover, a trend toward a lower rate of both CE events and major bleedings was observed in LAAC group, particularly in the subgroup LAAC+DOAC. CONCLUSIONS: LAAC is a reasonable therapeutic option in nvAF patients who suffered a CE event despite adequate OAC therapy.