Impairment in ventricular relaxation and preserved left ventricular ejection fraction are the two main features of heart failure with preserved ejection fraction (HFpEF) a difficult clinical condition. Therapeutic choices for HFpEF patients are still scarce despite its rising frequency and negative effects on morbidity and mortality, necessitating creative methods to enhance results. The increased thromboembolic risk seen in these individuals raises questions about the relevance of anticoagulation in the therapy of HFpEF. Although anticoagulation has been shown to be beneficial in heart failure with decreased ejection fraction (HFrEF) and other high-risk cardiovascular disorders, its efficacy and safety in HFpEF present a challenging therapeutic challenge. Anticoagulants have been the subject of clinical trials in HFpEF, but the results have been conflicting, giving clinicians only a little information with which to make decisions. The decision-making process is made more difficult by worries about potential bleeding hazards, particularly in susceptible elderly HFpEF patients with other comorbidities. The link between heart failure and anticoagulant medication in HFpEF is thoroughly analyzed in this narrative review. In HFpEF, cardiac fibrosis and endothelial dysfunction create a prothrombotic milieu, as is highlighted in this passage. Also covered are recent developments in innovative biomarker research and cutting-edge imaging techniques, which may provide ways to spot HFpEF patients who might benefit from anticoagulation. This therapeutic conundrum may be resolved by using precision medicine strategies based on risk classification and individualized therapy choices. This review emphasizes the need for more research to establish the best use of anticoagulation in HFpEF within the framework of personalized therapy and shared decision-making. To successfully manage thromboembolic risk and reduce bleeding consequences in HFpEF patients, it is essential to perform well-designed clinical studies and advance our understanding of the pathophysiology of HFpEF. These developments may ultimately improve the prognosis and quality of life for people who suffer from this difficult and mysterious ailment.  A crucial clinical entity in cardiovascular medicine, heart failure with preserved ejection fraction (HFpEF), is quickly gaining awareness. Heart failure with preserved ejection fraction (HFpEF), which accounts for around 50% of all cases of heart failure but has historically been overshadowed by heart failure with reduced ejection fraction (HFrEF), has now become a common and difficult condition . Its incAs their underlying pathophysiological mechanisms differ, it is crucial to distinguish between HFpEF and HFrEF. As a result of poor myocardial contractility, HFrEF has a lower ejection fraction than HFpEF, which is predominantly caused by diastolic dysfunction and a maintained ejection fraction ,4. In HFDue to the intricacy of HFpEF, there are difficult therapeutic problems that are made even more difficult by the lack of specific, effective pharmacological treatments. Contrary to HFrEF, which has benefited from medicinal treatments based on clinical guidelines such as beta-blockers and angiotensin-converting enzyme inhibitors, HFpEF lacks targeted treatments with proven efficacy . As a reIn this narrative review, we seek to present a thorough examination of the complex interaction between HFpEF and anticoagulant medication. We will examine the underlying pathophysiology of HFpEF and the thromboembolic risk factors that are related to it. To further shed light on the possible advantages and safety concerns of anticoagulant usage in HFpEF, we will carefully review the current information from clinical trials and observational research. We'll also look at recent studies on cutting-edge imaging techniques and novel biomarkers that could help us pinpoint which HFpEF patients will benefit from anticoagulation the most. Finally, we will go over the difficulties and limitations of anticoagulant therapy in HFpEF and stress the significance of patient-centered, individualized strategies for managing this therapeutic dilemma. Pathophysiology of HFpEF: unraveling the complexityDiastolic Dysfunction and Myocardial Fibrosis: Major Contributors to HFpEFDiastolic dysfunction and a preserved left ventricular ejection fraction are the two main features of heart failure with preserved ejection fraction, or HFpEF. Diastolic dysfunction and myocardial fibrosis are two important characteristics that are crucial to the pathogenesis of HFpEF. Clarifying the mechanisms of HFpEF and creating specialized treatment plans require an understanding of how these factors interact.HFpEF-related myocardial fibrosis is the excessive buildup of extracellular matrix elements, such as collagen, in the myocardium is referred to as myocardial fibrosis. It is brought on by an imbalance between collagen synthesis and breakdown, which worsens diastolic relaxation and increases myocardial stiffness. Myocardial fibrosis is a characteristic histological trait seen in the myocardium of people with HFpEF . MyocardMyocardial fibrosis's effects on HFpEF increase myocardial stiffness brought on by myocardial fibrosis and prevent ventricular relaxation during diastole. As a result, the ventricles are unable to fill properly, and left ventricular filling pressures are increased. As a result of the increased stiffness, ventricular-vascular coupling is also impacted, which results in decreased cardiac compliance and diastolic dysfunction . In addiDiastolic dysfunction and myocardial fibrosis are major contributors to the pathogenesis of HFpEF. For the purpose of creating focused therapy strategies to enhance outcomes in HFpEF patients, it is essential to comprehend the mechanisms behind these characteristics. Potential approaches to lessen myocardial fibrosis and relieve diastolic dysfunction in HFpEF include focusing on inflammation, oxidative stress, neurohormonal pathways, and comorbidities.The Impact of Endothelial Dysfunction and Inflammation on the Progression of Heart Failure with Preserved Ejection FractionThe progression of HFpEF is significantly influenced by endothelial dysfunction and inflammation. Endothelial dysfunction is characterized by the compromised functionality of the endothelium, the inner lining of blood vessels. The endothelium plays a crucial role in maintaining vascular homeostasis and regulating vascular tone. Endothelial dysfunction plays a significant role in contributing to various pathophysiological processes that worsen the condition of HFpEF.Nitric oxide deficiency bioavailability: Nitric oxide (NO) is produced by endothelial cells, which act as vasodilators to regulate blood flow and support vascular health. In patients with HFpEF, the availability of nitric oxide (NO) is diminished as a result of reduced activity of endothelial nitric oxide synthase (eNOS) and heightened oxidative stress . This reEndothelial-cardiomyocyte interactions: The endothelium and cardiomyocytes engage in bidirectional communication via paracrine signaling. Endothelial-derived factors, including endothelin-1 and angiotensin II, have the potential to stimulate profibrotic pathways, thereby playing a role in the development of myocardial fibrosis and diastolic dysfunction . On the Clinical implications and therapeutic targets: This study explores the clinical implications and potential therapeutic targets associated with the identified phenomenon. The potential therapeutic targets in HFpEF include endothelial dysfunction and inflammation. Strategies focused on enhancing endothelial function and mitigating inflammation may potentially yield favorable outcomes in terms of the progression and symptoms of heart failure with preserved ejection fraction. For example, pharmaceuticals that facilitate vasodilation and improve the availability of nitric oxide, such as angiotensin receptor-neprilysin inhibitors (ARNIs) and phosphodiesterase-5 (PDE-5) inhibitors, have exhibited potential in preliminary research . FurtherThe Interplay between Comorbidities and Risk Factors in the Development of Heart Failure with Preserved Ejection FractionThe occurrence of HFpEF is influenced by a multifaceted interaction between comorbidities and risk factors. HFpEF frequently manifests in individuals who have multiple concurrent medical conditions. The existence of these comorbidities plays a role in the pathophysiological mechanisms that drive the onset and advancement of HFpEF. Hypertension is a prevalent comorbidity frequently observed in patients with HFpEF. The persistent increase in blood pressure results in the development of left ventricular hypertrophy and fibrosis, which negatively affects the ability of the heart to relax during diastole and increases the stiffness of the myocardium. Consequently, this leads to increased left ventricular filling pressures and diastolic dysfunction, which are prominent characteristics of HFpEF . DiabeteClinical implications and management: In light of the wide range of comorbidities and risk factors associated with the development of HFpEF, it is imperative to adopt a comprehensive and multidisciplinary approach to its management. Improving outcomes for HFpEF can be achieved by implementing proactive measures to address comorbidities such as aggressive blood pressure control, glycemic management in diabetes, weight reduction strategies in obesity, and anticoagulation in AF. In addition, it is imperative to optimize the management of CKD and COPD in patients with HFpEF in order to minimize the impact of these conditions and improve overall quality of life. In summary, the development of HFpEF is influenced by a complex interplay of comorbidities and risk factors. It is crucial to comprehend the correlation between these conditions and HFpEF pathophysiology in order to customize personalized therapeutic approaches and enhance clinical outcomes in patients who are affected.Thromboembolic risk in HFpEF: evaluating the evidenceThe Relationship Between Atrial Fibrillation and Stroke Risk in Heart Failure with Preserved Ejection FractionAF and HFpEF are two cardiovascular conditions that frequently occur together and have a synergistic interaction, resulting in heightened morbidity and mortality rates. AF is widely recognized as the most prevalent form of sustained arrhythmia. It poses a substantial risk for stroke, particularly when accompanied by HFpEF. AF is commonly observed in patients with HFpEF, with a reported prevalence ranging from 25% to 50% in various studies . The simMechanisms connecting atrial fibrillation and stroke in HFpEF: There are multiple mechanisms that contribute to the elevated risk of stroke observed in patients with HFpEF who also have atrial fibrillation. AF is characterized by irregular and rapid contractions of the atria, leading to the accumulation of blood within the left atrium. The lack of blood flow in this particular area increases the likelihood of thrombus formation, particularly in the left atrial appendage. If these thrombi become dislodged, they have the potential to embolize the cerebral arteries, resulting in a stroke . Both atStroke prevention strategies: It is of utmost importance to implement effective stroke prevention strategies due to the heightened risk of stroke in patients with HFpEF and AF. The primary method for preventing strokes in patients with atrial fibrillation is through the use of oral anticoagulation, which can be achieved with either direct oral anticoagulants (DOACs) or vitamin K antagonists (VKAs). When considering the initiation of anticoagulation, it is important to take into account the CHA2DS2-VASc score. This scoring system evaluates the risk of stroke based on comorbidities and other relevant risk factors .Challenges and considerations: The management of anticoagulation in patients with HFpEF and AF necessitates meticulous consideration, given the intricate balance between stroke prevention and the potential for bleeding, especially in older individuals with multiple comorbidities. The process of making treatment decisions should incorporate shared decision-making, taking into account the patient's individual bleeding risk and personal preferences.Exploring novel therapies and examining future perspectives: Promising alternative stroke prevention strategies in patients with HFpEF and atrial fibrillation include emerging therapies such as left atrial appendage occlusion devices and non-vitamin K antagonist oral anticoagulants (NOACs). Further research is required to establish the safety and efficacy of these interventions in this particular population . Atrial Non-Atrial Fibrillation Related Thromboembolic Events in Heart Failure with Preserved Ejection FractionHFpEF is a clinical syndrome that is distinguished by the presence of heart failure symptoms alongside a preserved left ventricular ejection fraction. While AF is widely recognized as a risk factor for thromboembolic events in patients with HFpEF, it is important to acknowledge that non-AF related thromboembolic events also play a significant role in the morbidity and mortality of this particular group of patients. The purpose of this article is to provide a detailed explanation of two important non-AF-related thromboembolic events in HFpEF and analyze their potential consequences. Arterial thromboembolism is a medical condition characterized by the obstruction of arterial blood flow due to the presence of a blood clot that originates from either the heart or large arteries. Arterial thromboembolism is frequently observed in patients with HFpEF, primarily attributed to the development of intracardiac thrombi. Thrombi frequently form in the left atrial appendage, left ventricle, or both, as a result of blood flow stagnation, endothelial dysfunction, and a prothrombotic state associated with HFpEF . The occUnderlying mechanisms: Multiple mechanisms are involved in the heightened risk of non-AF-related thromboembolic events in HFpEF. Chronic inflammation and endothelial dysfunction are frequently observed in patients with HFpEF. These factors contribute to the activation of platelets, the formation of thrombus, and the impairment of fibrinolysis, resulting in the development of a prothrombotic environment . The preManagement: Regarding the management of non-AF-related thromboembolic events in HFpEF, it is imperative to prioritize both primary prevention and the implementation of suitable treatment strategies. In patients with high-risk HFpEF who have a history of thromboembolism, it may be appropriate to consider long-term anticoagulation therapy using medications such as warfarin or DOACs in order to prevent future events . In the Non-AF-related thromboembolic events play a substantial role in the morbidity and mortality experienced by patients with HFpEF. Gaining a comprehensive understanding of the underlying mechanisms and effectively implementing appropriate prevention and treatment strategies are essential factors in enhancing patient outcomes. Further research in this field has the potential to advance our comprehension and facilitate the development of more efficacious therapeutic interventions.The Significance of Endothelial Dysfunction in Thromboembolic ComplicationsEndothelial dysfunction is a multifaceted pathological process characterized by compromised endothelial cell function and diminished bioavailability of nitric oxide (NO). It plays a substantial role in the development of various cardiovascular disorders, such as thromboembolic complications. In the following section, we will examine the significance of endothelial dysfunction in thromboembolic events and its impact on patient management and treatment. The anticoagulant function is impaired. The endothelium plays a pivotal role in the regulation of coagulation through the production of several anticoagulant factors, including tissue factor pathway inhibitor (TFPI) and thrombomodulin. The impairment of endothelial function hinders the production and release of anticoagulant factors, resulting in a state that promotes blood clot formation . The dowPlatelet function modification: Endothelial cells secrete NO, which hinders platelet activation and aggregation. Endothelial dysfunction is characterized by a reduction in the availability of NO, which subsequently leads to an increase in platelet activation and adhesion to the endothelium . This phClinical implications: The presence of endothelial dysfunction in thromboembolic complications holds considerable clinical significance. Markers of endothelial dysfunction, such as impaired flow-mediated dilation (FMD) or elevated levels of circulating endothelial microparticles, have been linked to a heightened risk of thromboembolic events . These mAnticoagulation therapy in HFpEF: balancing risks and benefitsThe Management of Anticoagulation Therapy in Heart Failure with Preserved Ejection Fraction: Striking a Balance Between Risks and BenefitsCurrent guidelines and recommendations for anticoagulation in HFpEF: Patients diagnosed with HFpEF are known to have a heightened susceptibility to thromboembolic events, such as stroke and systemic embolism. Nevertheless, the most appropriate antithrombotic therapy for HFpEF continues to be a subject of discussion owing to the limited availability of comprehensive clinical trial data that specifically addresses this patient population. Consequently, the current guidelines and recommendations for anticoagulation in HFpEF primarily rely on expert consensus and extrapolation from studies conducted in other cardiovascular conditions. The guidelines on HF management by the American Heart Association (AHA) and the American College of Cardiology (ACC), last revised in 2017, recognize the heightened risk of thromboembolism in patients with HFpEF who also have comorbidities such as AF, hypertension, or diabetes. According to the guidelines, it is recommended to administer oral anticoagulants (OACs) for patients with HFpEF and AF based on their CHA2DS2-VASc score . NeverthComparing the Efficacy and Safety of Anticoagulants and Antiplatelet AgentsWhen deciding between anticoagulants and antiplatelet agents for patients with HFpEF and no AF, it is important to thoroughly evaluate the efficacy and safety profiles of each option. Anticoagulants, such as warfarin or DOACs, are designed to specifically target the coagulation cascade and effectively prevent the formation of thrombin. On the other hand, antiplatelet agents, such as aspirin or clopidogrel, are intended to inhibit platelet activation and aggregation. The findings from trials, such as the Warfarin versus Aspirin in Reduced Cardiac Ejection Fraction (WARCEF) study, indicate that warfarin may not yield substantial advantages in terms of mitigating the risk of stroke or mortality in patients with heart failure who do not have atrial fibrillation . AdditioAssessment of Bleeding Risk in Patients with Heart Failure with Preserved Ejection FractionIt is essential to conduct a thorough assessment of bleeding risk prior to initiating antithrombotic therapy in patients with HFpEF. Patients with HFpEF frequently present with comorbidities, including renal dysfunction and frailty, which can significantly elevate the likelihood of experiencing bleeding complications. Numerous bleeding risk scores, including the HAS-BLED score, have been validated in various cardiovascular conditions . It is iCustomizing Anticoagulation Therapy to Suit Individual Patient ProfilesConsidering the limited availability of conclusive evidence in HFpEF, it is imperative to personalize the decision-making process regarding the initiation of anticoagulation or antiplatelet therapy. This should be done by taking into account the patient's unique clinical characteristics, thromboembolic risk, and bleeding risk. Anticoagulation with OACs is recommended for patients with HFpEF who also have AF, in accordance with established guidelines for AF . When maClinical evidence and real-world data on anticoagulation in HFpEFConducting a Comprehensive Analysis of Pivotal Clinical Trials and Observational StudiesIn the realm of managing HFpEF, numerous significant clinical trials and observational studies have investigated the potential impact of anticoagulation therapy. It is worth noting that the majority of these trials primarily focused on patients diagnosed with HFrEF. Consequently, the available evidence supporting the use of anticoagulation in HFpEF is still limited, and it is important to exercise caution when applying findings from trials conducted on HFrEF to this context. The Warfarin and Antiplatelet Therapy in Chronic Heart Failure (WATCH) trial is a prominent study that examined the use of anticoagulation in patients with HFpEF. During the course of this clinical trial, patients diagnosed with heart failure, including individuals with preserved and reduced ejection fraction, were randomly assigned to receive either warfarin, aspirin, or a combination of both medications. The study revealed that there was no statistically significant disparity in the primary outcome of all-cause mortality among the various treatment groups. Nevertheless, subgroup analyses have revealed a potential advantage of aspirin in patients with HFpEF . AnotherMeta-analyses and Systematic Reviews: A Comprehensive Analysis of the Impact of AnticoagulationIn order to obtain additional knowledge regarding the effects of anticoagulation in the management of HFpEF, researchers have conducted meta-analyses and systematic reviews to consolidate data from various studies. A comprehensive meta-analysis was conducted to analyze data from multiple trials and observational studies regarding the utilization of anticoagulation in patients with heart failure, both with and without atrial fibrillation. The analysis indicated that anticoagulation therapy was linked to a reduced risk of stroke, but it also carried a higher risk of major bleeding. This underscores the importance of adopting a personalized approach that takes into account individual risk factors . In a siPractical Application of Anticoagulation in the Management of Heart Failure with Preserved Ejection Fraction Real-world data offer valuable insights into the practical utilization and outcomes of anticoagulation in patients with HFpEF within routine clinical practice. Research conducted using real-world data has revealed diverse trends in the utilization of anticoagulation therapy among patients with HFpEF. These patterns are influenced by several factors, including the presence of AF, the risk of stroke, and the risk of bleeding. The study employed data from a comprehensive administrative database to evaluate the utilization patterns of anticoagulation in patients with heart failure, both with and without atrial fibrillation. According to the study, patients with HF who also had AF were more inclined to be prescribed anticoagulation therapy in comparison to those without AF. This observation underscores the impact of AF on the decision-making process regarding treatment options . A separBiomarkers and imaging modalities: paving the way for precision medicineNovel Biomarkers for Thromboembolic Risk Prediction in Heart Failure with Preserved Ejection FractionThromboembolic events, such as stroke and systemic embolism, are notable complications observed in patients diagnosed with HFpEF. The identification of novel biomarkers that can effectively predict thromboembolic risk in this specific population is currently a subject of ongoing research. A number of biomarkers have demonstrated potential in this context:The D-dimer is a substance that is produced during the breakdown of fibrin, a protein involved in blood clotting. It serves as an indicator of the ongoing process of fibrinolysis. An association has been observed between elevated D-dimer levels and an increased risk of thromboembolic events in patients with HFpEF . The obsExploration of Imaging Techniques for the Identification of High-Risk Patients with Heart Failure with Preserved Ejection FractionImaging techniques are of significant importance in the identification of high-risk HFpEF patients, as they offer valuable insights into cardiac structure, function, and hemodynamics. Several imaging modalities are employed for risk stratification. Echocardiography serves as the principal imaging modality for the diagnosis of HFpEF and evaluation of left ventricular diastolic function. There have been associations found between specific echocardiographic parameters, such as the E/e' ratio , and adverse outcomes as well as an increased risk of thromboembolism in patients with HFpEF . The utiIncorporation of Biomarkers and Imaging in Clinical Practice: Addressing Challenges and Exploring OpportunitiesIncorporating novel biomarkers and advanced imaging techniques into routine clinical practice presents several challenges, despite their potential. Standardization of biomarkers and imaging measurements is imperative across various centers and platforms to guarantee the attainment of consistent and dependable outcomes. Certain biomarkers and imaging techniques may present cost constraints or limited accessibility within various healthcare settings, thereby impeding their widespread utilization. Expertise is necessary for the interpretation of biomarkers and imaging results. The process of integrating this information with other clinical data to make informed treatment decisions can be intricate. Although there is potential in the use of novel biomarkers and imaging techniques for predicting thromboembolic risk in HFpEF, it is crucial to validate their utility through large-scale, prospective studies. Notwithstanding these challenges, the integration of biomarkers and imaging into clinical practice presents substantial prospects for personalized risk assessment and targeted therapy in HFpEF. The early identification of high-risk patients may facilitate prompt interventions aimed at preventing thromboembolic complications and enhancing patient outcomes.Challenges and limitations in anticoagulation therapy for HFpEFInsufficient Clinical Trial Data in Heart Failure with Preserved Ejection Fraction SubgroupHFpEF is a multifaceted and diverse condition, and there has been a scarcity of clinical trial data specifically focused on this subgroup. In the past, the majority of significant randomized clinical trials in heart failure have primarily concentrated on patients with reduced ejection fraction, resulting in a lack of adequate representation of patients with HFpEF in these studies. Establishing evidence-based treatment guidelines for HFpEF has proven to be a challenging endeavor. One of the notable challenges encountered in the execution of clinical trials in HFpEF pertains to the heterogeneity observed within the patient population. HFpEF encompasses a diverse array of etiologies, comorbidities, and clinical presentations, thereby posing challenges in determining a universally applicable therapeutic approach for all patients. Furthermore, the absence of a clearly defined HFpEF phenotype adds further complexity to trial design and the process of selecting patients. Numerous clinical trials have made efforts to incorporate patients with HFpEF. However, these trials have encountered difficulties in attaining sufficient sample sizes, and certain trials have been prematurely discontinued due to futility or the absence of significant treatment effects. The TOPCAT trial, known as the Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist, examined the efficacy of spironolactone in patients with HFpEF. The trial yielded neutral findings in relation to the primary outcome, which encompassed cardiovascular death, hospitalization due to heart failure, or aborted cardiac arrest . In receAddressing the Risk of Bleeding in Elderly Patients with Heart Failure with Preserved Ejection FractionHFpEF is frequently observed among the elderly demographic. These individuals may exhibit various coexisting medical conditions and are often prescribed multiple medications, factors that can contribute to an elevated susceptibility to bleeding. When evaluating the use of anticoagulation in elderly patients with HFpEF, it is imperative to thoroughly evaluate the delicate equilibrium between the potential advantages of preventing thromboembolic events and the heightened risk of bleeding. Several factors contribute to the risk of bleeding in elderly patients with HFpEF. These factors include age-related alterations in renal function, the presence of other medical conditions such as chronic kidney disease, and the simultaneous use of other medications like nonsteroidal anti-inflammatory drugs. Furthermore, it is imperative to take into account frailty, cognitive impairment, and falls as significant factors that must be considered during the assessment of the appropriateness of anticoagulation in this particular population. To mitigate the risk of bleeding in elderly patients with HFpEF, various strategies can be implemented. The Comprehensive Geriatric Assessment (CGA) is a thorough evaluation conducted to assess the overall health and well-being of older adults. CGA is a comprehensive evaluation that assesses multiple dimensions of an older patient's health, encompassing physical, cognitive, and psychosocial functioning. The integration of CGA into the evaluation process can effectively identify patients who are at a heightened risk of bleeding and provide valuable guidance for treatment decisions. If it is determined that anticoagulation is necessary, optimizing safety can be achieved through dose adjustment that takes into account renal function and comorbidities. The utilization of DOACs is advantageous due to their predictable pharmacokinetics and reduced likelihood of drug interactions when compared to warfarin. Consequently, DOACs may be considered as potentially safer alternatives for elderly patients. Research, such as the ENGAGE AF-TIMI 48 trial, has provided evidence showing that DOACs are not inferior to warfarin in terms of reducing the risk of thromboembolism while also carrying a lower risk of intracranial hemorrhage . It is iEthical Considerations Play a Significant Role in the Decision-Making Process Regarding Anticoagulation in Patients with Heart Failure with Preserved Ejection FractionOne of the key ethical considerations involves effectively managing the delicate balance between the risk of thromboembolism and the risk of bleeding. Autonomy and informed consent are crucial in ensuring that patients are provided with comprehensive information regarding the potential risks and benefits associated with anticoagulation. It is essential to incorporate comprehensive information regarding the potential risks of thromboembolic events, bleeding complications, and their respective implications into discussions surrounding informed consent. The principle of beneficence underscores the importance of promoting the well-being of the patient, while the principle of non-maleficence highlights the imperative to prevent harm. The determination to commence anticoagulation therapy should be made through a thorough evaluation of risks, taking into consideration whether the potential advantages outweigh the associated risks. The decision regarding anticoagulation in patients with HFpEF may involve considerations of justice and equity. Ensuring equitable access to treatment options is of utmost importance, taking into consideration various factors, including age, race, and socioeconomic status. In cases of advanced HFpEF, where the emphasis of care may transition towards palliative management, it is important to ensure that decisions regarding anticoagulation are in line with the patient's goals and preferences. The topic of discussion revolves around the concept of shared decision-making and its significance in considering patient values. Shared decision-making is a collaborative process wherein healthcare providers and patients work together to make informed decisions regarding treatment options. It is imperative to have a comprehensive understanding of the patient's values, beliefs, and preferences when making decisions regarding anticoagulation.The limited availability of comprehensive clinical trial data pertaining to HFpEF, along with the intricate nature of the patient demographic, poses significant obstacles in the process of making anticoagulation decisions. The identification of new biomarkers and the utilization of advanced imaging techniques have the potential to enhance risk stratification in patients with HFpEF. The evaluation and management of bleeding risk, particularly in elderly individuals, necessitates a meticulous assessment and thoughtful consideration of multiple factors. Ethical considerations, such as obtaining informed consent, respecting patient autonomy, and ensuring justice, are integral to the collaborative decision-making process. These considerations are crucial in facilitating personalized and patient-centered care in the management of HFpEF.Future perspectives: unraveling the conundrumOngoing Clinical Trials and Studies: Influencing the Future of Heart Failure with Preserved Ejection Fraction ManagementOngoing clinical trials and studies are currently addressing the knowledge gaps and challenges associated with managing HFpEF. These efforts are actively shaping the future of HFpEF management. The purpose of these trials is to enhance our comprehension of the pathophysiology, ascertain effective treatments, and cater to the specific requirements of patients with HFpEF. One of the notable ongoing trials in HFpEF is the PARAMOUNT-HF trial, also known as the Prospective Comparison of ARNI with ARB on Management of Heart Failure with Preserved Ejection Fraction. The purpose of this trial is to assess the effectiveness and safety of sacubitril/valsartan, an angiotensin receptor neprilysin inhibitor (ARNI), in patients with HFpEF. The findings from the PARAGON-HF trial, also known as the Prospective Comparison of ARNI with ARB Global Outcomes in HFpEF, have demonstrated encouraging results regarding the efficacy of sacubitril/valsartan in reducing the incidence of total hospitalizations for heart failure and cardiovascular mortality among patients with HFpEF . In addiApproaches to Personalized Medicine in the Treatment of Heart Failure with Preserved Ejection FractionThe diverse nature of HFpEF requires the implementation of a personalized medicine strategy in order to maximize patient outcomes. The concept of personalized medicine entails the customization of treatment strategies based on specific patient attributes, such as demographics, comorbidities, genetics, and biomarker profiles. Personalized approaches can offer significant benefits in the management of HFpEF across various aspects. The utilization of innovative biomarkers and imaging techniques can aid in the identification of high-risk HFpEF patients who may derive benefits from targeted treatments or enhanced monitoring. It is imperative to prioritize the management of comorbidities, such as hypertension, diabetes, and obesity when addressing HFpEF. Customizing treatment plans to effectively manage individual comorbidities has the potential to enhance overall outcomes. When making treatment decisions for patients with HFpEF, it is important to take into account various factors, such as the patient's renal function, potential drug interactions, and individual preferences. These considerations can help guide the selection between anticoagulants or antiplatelet agents, whether the patient has atrial fibrillation or not. Achieving optimal diuretic therapy necessitates tailoring the dosage to individual patients, taking into account their renal function and fluid status. The goal is to effectively alleviate congestion without causing hypotension or exacerbating renal function. In specific cases of patients with HFpEF, the utilization of implantable devices such as cardiac resynchronization therapy (CRT) has shown potential to enhance symptoms and mitigate the need for hospitalizations. Promoting personalized lifestyle adjustments, such as dietary modifications, exercise, and weight management, can yield substantial advantages in the management of HFpEF.Exploring the Potential Role of Novel Anticoagulants in Heart Failure with Preserved Ejection FractionDue to the increased susceptibility to thromboembolic events in patients with HFpEF, there is an ongoing investigation into the potential use of novel anticoagulants to mitigate the risk of stroke and systemic embolism in this specific patient group. DOACs have become increasingly appealing due to their predictable pharmacokinetics, minimal drug interactions, and decreased necessity for frequent monitoring in comparison to warfarin. One potential application of DOACs in HFpEF is in patients who also have coexisting AF. AF is a frequently observed comorbidity in patients with HFpEF, and it substantially elevates their susceptibility to thromboembolic events. DOACs, including apixaban, dabigatran, edoxaban, and rivaroxaban, have exhibited non-inferiority or superiority compared to warfarin in the prevention of stroke and systemic embolism among patients with atrial fibrillation . The potPatient-centric approaches: shared decision-making and adherenceImportance of Patient Education and Engagement in Anticoagulation TherapyPatient education and engagement are crucial components of anticoagulation therapy in HFpEF patients. Anticoagulation can be a complex and lifelong treatment, and informed and engaged patients are more likely to adhere to therapy, understand potential risks and benefits, and actively participate in shared decision-making. Effective patient education should include the following components. Educating patients about HFpEF, its underlying mechanisms, and the increased risk of thromboembolic events helps them comprehend the importance of anticoagulation therapy. Explaining the purpose of anticoagulation in HFpEF patients, particularly in those with atrial fibrillation, helps patients understand how it reduces the risk of stroke and systemic embolism. Setting clear treatment goals and explaining expected outcomes help manage patient expectations and enhance treatment compliance. Educating patients about the potential risks of bleeding and the benefits of anticoagulation helps them make informed decisions and actively participate in their care. Emphasizing the importance of consistent medication adherence to achieve optimal outcomes is vital, as non-adherence is a significant concern in long-term anticoagulation therapy. Encouraging lifestyle changes, such as a heart-healthy diet, regular exercise, and smoking cessation, can complement anticoagulation therapy and improve overall cardiovascular health. Discussing the need for regular monitoring and follow-up visits helps patients understand the importance of ongoing care and allows healthcare providers to assess treatment efficacy and safety. Engaging patients in their care and decision-making process empowers them to take an active role in managing their health, leading to improved treatment adherence and overall outcomes.Shared Decision-Making in HFpEF ManagementShared decision-making is a collaborative approach between healthcare providers and patients, involving the exchange of information, exploration of treatment options, and incorporation of patient preferences in clinical decisions. In the context of HFpEF management and anticoagulation therapy, shared decision-making is particularly relevant, considering the complexity of treatment choices and the potential risks and benefits involved. Shared decision-making in HFpEF management involves the following steps:Information exchange: Healthcare providers should present patients with comprehensive information about HFpEF, thromboembolic risk, and anticoagulation options. This includes discussing the different anticoagulant agents, their mechanisms of action, dosing, potential side effects, and monitoring requirements.Patient values and preferences: Understanding a patient's values, beliefs, lifestyle, and treatment preferences is crucial in aligning therapeutic choices with individual patient goals. For some patients, avoiding the inconvenience of regular monitoring may lead to a preference for DOACs over warfarin.Risk-benefit analysis: Healthcare providers should guide patients through a risk-benefit analysis of anticoagulation therapy, considering the patient's individual thromboembolic risk, bleeding risk, and other comorbidities.Exploring alternatives: In cases where anticoagulation is contraindicated or not preferred by the patient, exploring alternative treatment strategies, such as antiplatelet agents or left atrial appendage closure devices, can be part of the shared decision-making process.Addressing concerns: Patient concerns, fears, and misconceptions about anticoagulation should be openly addressed to build trust and facilitate shared decision-making.By involving patients in the decision-making process, healthcare providers can help patients feel more in control of their treatment, improve treatment adherence, and ultimately enhance patient satisfaction and outcomes.Improving Adherence to Anticoagulation in HFpEF PatientsAdherence to anticoagulation therapy is essential to achieve the desired clinical outcomes, particularly in HFpEF patients at increased risk of thromboembolic events. Improving adherence in this population requires a multifaceted approach:Patient education: Thorough patient education about the importance of anticoagulation, the potential benefits in reducing thromboembolic risk, and the risks of non-adherence is the foundation of improving adherence.Tailored treatment plans: Personalizing treatment plans based on individual patient characteristics and preferences can improve treatment acceptance and adherence.Simplifying regimens: Simplifying medication regimens, such as using once-daily dosing or reducing the number of medications, can improve adherence by reducing complexity.Reminder systems: Implementing reminder systems, such as smartphone applications or pill organizers, can help patients remember to take their medications as prescribed.Regular follow-up: Regular follow-up visits with healthcare providers allow for the assessment of adherence, addressing any challenges, and reinforcing the importance of treatment compliance.Addressing barriers: Identifying and addressing barriers to adherence, such as medication cost, side effects, or forgetfulness, can help patients overcome obstacles to treatment compliance.Involving caregivers: Involving caregivers or family members in the patient's care can provide additional support and encouragement for adherence.Digital health solutions: Utilizing digital health solutions, such as telehealth and remote monitoring, can enhance communication between patients and healthcare providers and facilitate better management of anticoagulation therapy.Health literacy and cultural sensitivity: Ensuring that educational materials are easily understandable and culturally sensitive can improve patients' comprehension and engagement in their care.Patient education and engagement are integral to the success of anticoagulation therapy in HFpEF patients. Shared decision-making empowers patients to actively participate in their treatment choices, fostering treatment adherence and patient satisfaction. Improving adherence to anticoagulation requires a multifaceted approach that includes personalized education, simplified regimens, reminder systems, regular follow-up, and addressing individual barriers . By inteThe management of anticoagulation in patients with HFpEF presents a therapeutic challenge due to the intricate nature of the condition and the diverse characteristics of the patient population. However, implementing a multidimensional approach can assist healthcare providers in optimizing anticoagulation therapy and effectively managing HFpEF. By capitalizing on research advancements, well-designed clinical trials that are specific to HFpEF can provide valuable evidence-based guidelines and offer insights into innovative therapies. The integration of personalized medicine, which involves the identification of subgroups within HFpEF and the utilization of biomarkers for risk stratification, enables the customization of treatments for individual patients. The adoption of shared decision-making enables patients to take an active role in their healthcare, ensuring that treatment plans are in line with their preferences and enhancing adherence. Healthcare providers can effectively address therapeutic challenges, improve outcomes, and enhance the well-being of patients in the management of HFpEF by adopting a patient-centered approach. This involves considering the holistic needs of patients and leveraging digital health solutions.


MKK4  is a dual-specificity protein kinase that phosphorylates and regulates both JNK  and p38 MAPK (p38 mitogen-activated protein kinase) signaling pathways and therefore has a great impact on cell proliferation, differentiation and apoptosis. Overexpression of MKK4 has been associated with aggressive cancer types, including metastatic prostate and ovarian cancer and triple-negative breast cancer. In addition, MKK4 has been identified as a key regulator in liver regeneration. Therefore, MKK4 is a promising target both for cancer therapeutics and for the treatment of liver-associated diseases, offering an alternative to liver transplantation. The recent reports on new inhibitors, as well as the formation of a startup company investigating an inhibitor in clinical trials, show the importance and interest of MKK4 in drug discovery. In this review, we highlight the significance of MKK4 in cancer development and other diseases, as well as its unique role in liver regeneration. Furthermore, we present the most recent progress in MKK4 drug discovery and future challenges in the development of MKK4-targeting drugs. Kinases have been one of the main challenges of drug discovery in the past 20 years as they regulate nearly all aspects of cell life and alterations that cause cancer or other diseases in a wide range ,2. To daThe mitogen-activated protein kinase (MAPK) pathway refers to a series of multistep signal transduction pathways involved in the regulation of embryogenesis, cell differentiation, cell growth and programmed cell death, among others . UsuallyS-X-A-K-T (Ser257 and Thr261) located in the T-loop of the kinase domain between subdomains VII and VIII [Human MKK4, also referred to as MAP2K4, or MAPK/ERK-Kinase 4 (MEK4), JNK kinase 1 (JNKK1), SAPK/ERK kinase-1 (SEK1), consists of 399 amino acids ,14,15,16and VIII ,18,19,20and VIII . It has and VIII . Human nand VIII . Recent and VIII . MKK4 shand VIII , as willT-P-Y motif of JNKs and, unlike MKK7, is also able to phosphorylate the T-G-Y motif of p38 MAPK [During cell response to stress, heat shock, growth factors and proinflammatory cytokines, MKK4 is phosphorylated and activated by the majority of MAP3Ks, including ASK, MEKK, MLK and TAK . While tp38 MAPK . While Mp38 MAPK ,38. Phosp38 MAPK . p38 MAPp38 MAPK ,40. The p38 MAPK ,42.MAP2K4 (the gene encoding MKK4) is restricted to the CNS until embryonic day 10 [MAP2K4 mRNA is found in high levels in the developing liver while the liver cells undergo differentiation up to embryonic day 16 when the transcript levels rapidly drop [MAP2K4(−/−) homozygous mice have a high number of proliferating hepatoblasts that cannot differentiate into hepatocytes and undergo apoptosis, leading to death [In adult mice, MKK4 is ubiquitously expressed . Howeverc day 10 . Startindly drop . MAP2K4 as they take part in cell migration, positioning of neuronal cells and commissural fibers development ,47. MKK4There have been conflicting reports on the role of MKK4 in the immune system. Earlier studies attribute a central role to MKK4 for cell survival signaling in T-cell development and proliferation ,51, wherMAP2K4 located on chromosomal segment 17p11.2, which can be lost with 7–10% in human epithelial cancers, particularly ovarian and breast cancers [MAP2K4 loss-of-function (LOF) mutations in 11 tumors, supporting MKK4’s suppressive role [MAP2K4 is often accompanied by mutations of TP53 (encoding major tumor suppressor p53) and KRAS (encoding common tumor promoter K-Ras) in lung adenocarcinomas [MKK4’s role in tumor development is controversial as it can both act as a tumor suppressor and a tumor promoter. MKK4 is encoded by  cancers ,56, and  cancers ,58. Addiive role ,60,61. Hrcinomas . Howeverrcinomas ,64,65,66rcinomas . Prostatrcinomas ,69. Whilrcinomas ,70,71. Arcinomas . Furtherrcinomas . Hence, rcinomas . Moreovercinomas .Taken together, depending on the genetic setting of the tumor, MKK4 can act as tumor-suppressive or tumor-promoting, a common characteristic of many kinases . In part1  was shown to increase it. For a better understanding, the downstream processes of TGF-β were further investigated. TGF-β activates MKK4, which upon activation phosphorylates downstream effector proteins, including p38 MAPK. p38 MAPK phosphorylates MAPK-activated protein kinase 2 (MAPKAPK2), which itself phosphorylates heat shock protein 27 (HSP27). This finally leads to the expression of matrix metalloproteinase-2 (MMP-2) and the increase in cell invasion [50 value of 400 nM. In a phase II clinical study, higher expression of MKK4 was associated with higher MMP-2 expression and cell invasion, giving evidence for the anti-invasive activity of Genistein in prostate cancer treatment. Ultimately, the clinical study had limitations and it could not be proven that Genistein binds to MKK4’s active site, even though it was predicted through computer-simulated structural modeling that Genistein directly inhibits MKK4 activity [clinicaltrials.gov), along with a phase II clinical trial investigating Genistein treatment for metastatic prostate cancer [Genistein 4, is the minvasion ,92. In factivity . Howevere cancer . It has e cancer ,95, cycle cancer ,97, poloe cancer ,99,100 ae cancer .5, Dehydroglyasperin C (DGC) 5,  is a nat6, 50 values of 6 µM on MKK4 and 10 µM on MKK7 in vitro were reported. Protoberberine alkaloids are present in many plant families, including poppies, barberries and laurels [The protoberberine derivative HWY336 6,  was iden laurels , and can laurels ,114. The laurels .Subsequently, human embryonic kidney 293 (HEK293T) cells that were treated with D-sorbitol, to activate JNK, were incubated with HWY336 in increasing concentrations. The phosphorylation of JNKs was reduced after 3 h of incubation with 9 µM HWY336 and disappeared after 4 h of treatment with 12 µM HWY336. These experiments and the performed wash experiments indicate that the inhibition is directed to MKK4, is reversible and is non-covalent. For a better understanding of the inhibitory selectivity, molecular docking and phylogenetic analysis based on sequence homology was performed. The structural model supported the hypothesis that HWY336 is a non-ATP competitive inhibitor of MKK4/MKK7. It also led to the assumption that HWY336 inhibits the phosphorylation of MKK4/MKK7 inside the activation loop or hinders the substrate to access the kinase .7, 50 value of 190 nM towards MKK4 [7 has a 30- to 60-fold selectivity to MKK1 with an IC50 value of 12 µM which marks the highest inhibition in the MKK family after MKK4. The modeling of 7 with MKK4 led to predictions of key interactions. Hydrogen bond interactions in the hinge region with the residues Leu180 and Met181, as well as electrostatic interaction of the carboxylate of 7 and Lys187, were observed. Furthermore, there appeared to be a hydrophobic back pocket that could be occupied starting from the 5- and 6- positions of the indazole core. Based on this, 6-fluoro-3-arylindazole , tyrosine kinase-like kinases (TKL), serine/threonine kinases (STE), cyclin-dependent kinases, mitogen-activated protein kinases, glycogen synthase kinases and CDK-like kinases [9 and 10 with an MKK1/2 inhibitor (U0126) in pancreatic cancer cell proliferation was examined. For the noncovalent approach, replacing the carboxylic acid of mpound 9  with imped to 10  with an  kinases . In othe8 as a starting point, different electrophilic warheads were added to the ortho-position of the aryl ring while the carboxylic acid was removed. However, none of the compounds were able to bind covalently and did not show activity in the noncovalent control.Computational modeling also suggested a covalent approach and several proposed covalent inhibitors were generated. Using 11, 11 were synthesized, resulting in BSJ-04-122  showed values above 10 µM. The covalent binding was confirmed with liquid chromatography-mass spectrometry (LC-MS) showing a molecular weight shift according to the adduct of MKK4 and 12. Chymotrypsin digestion followed by MS analysis of the protein fragments revealed that Cys247 in MKK4 and Cys261 in MKK7 were covalently connected to BSJ-04.122. Upon treatment of cells with 12, a competition-based pulldown assay showed that kinases MKK1/2/3/5/6 were not engaged, which suggested high selectivity among the MKK family. Docking experiments of 12 with MKK4  predictK4 , despitMAP2K4 resulted in rapid apoptosis of the primordial liver and ultimately led to the death of mice embryos. Contrariwise, an in vivo RNAi screen has identified MKK4 as a key enzyme in liver regeneration [In the previous section, MKK4’s significance in the differentiation of early-stage hepatocytes for the development of embryonic livers was described. The abundance of neration . As illuneration . Moreoveneration . In the EU and U.S., more than 250,000 patients per year suffer from acute liver disease and 700,000 patients suffer from chronic liver disease . There aV600E (serine/threonine-protein kinase B-Raf) inhibitor Vemurafenib, which showed off-target activity towards MKK4, a multi-parameter optimization process emphasizing a distinct SAR (structure–activity relationship) was performed, leading to compounds 13, 14 and 15 , this demonstrated the design of new inhibitors with a high affinity to MKK4 , with selectivity over the off-targets MKK7, JNK1, B-Raf, MAP4K5 and ZAK in the range of factors 40 to 190, being the first-in-class inhibitors targeting MKK4 for hepatocyte proliferation [Following a target-hopping strategy from FDA-approved B-Raf4 and 15 . To deteferation .16 . However, the selectivity was poor towards B-Raf, showing even higher activity (POCB-Raf = 0 @ 0.1 µM). In compound 17, the alkyl side chain was replaced by a benzyl, dramatically shifting the selectivity from B-Raf (POCB-Raf = 76 @ 0.1 µM) to MKK4 (POCMKK4 = 0.4 @ 0.1 µM) with an IC50 value of 146 nM. KD values of 17 showed remarkable selectivity towards the off- and anti-targets by factors of >100, >250, >600 and almost 3000 against JNK1, B-Raf, MAP4K5, MKK7 and ZAK, respectively. 17 was screened against a panel of 97 kinases at 1 µM, a concentration that is 500 times higher than 17s Kd value for MKK4. Only two kinases (AURKB and SNARK) showed a POC value of <35%, demonstrating the high kinome selectivity of 17 [Further exploration of the core structure led to changing the azaindole to pyrazolopyridine. SAR experiments resulted in compound 16 . It contty of 17 .18  signaling pathway associated with remodeling and arrhythmogenesis with age, and has been suggested as a potential therapeutic target for the treatment of atrial fibrillation [To date, little is known about MKK4’s influence on other diseases, but reports have risen in the past few years. MKK4 is a negative regulator of the TGF-illation . It has illation . MKK4 waillation  and has illation . In addiillation .19, 50 value of 239 nM [20, 50 value of 127 nM. In addition, PQA-11 inhibited neurotoxin-induced cell death. MKK4 was identified as the target of PQA-11 being responsible for JNK activation and ultimately caspase-3 activation, leading to diminished apoptosis. The effect was confirmed with MKK4 siRNA in vitro. The quartz crystal microbalance (QCM) method was used to verify the direct interaction of PQA-11 with MKK4 in a concentration-dependent manner. Notably, no interaction was observed with a constitutively active type of MKK4, suggesting the binding of PQA-11 to inactive MKK4. It has been proposed that sphingosine is involved in JNK pathway activation [Ppc-1 19,  is a secf 239 nM . Furthertivation . StudyinMKK4 is a dual-specificity kinase that regulates cellular signaling pathways by activating JNK and p38 MAPK. Recently, even a cross-communication between MKK4 and NFκB was reported, opening the possibility to tune this pathway and related pathologies by MKK4 inhibition.Research into the function of MKK4 and diseases associated with it has led to increasing interest in drug development, especially in recent years. Previous approaches used natural products as active ingredients with activity on MKK4 to study and validate the kinase as a pharmacological target. Thus, MKK4 was identified not only in certain cancer types but also as being responsible for transformation into cell invasion and metastasis in high-impact cancer types, such as prostate and ovarian cancer. This laid the foundation for the targeted development of selective MKK4 inhibitors, which quickly achieved success with nanomolar inhibitory small molecules that bind not only reversibly but also covalently. However, more challenges lie ahead in the field of cancer therapy. The effectiveness of the inhibitors still needs to be demonstrated in suitable in vivo models.The identification of MKK4 as a key regulator in liver regeneration has generated great interest as it offers a solution to the current lack of alternatives to liver therapies such as transplantation. Notably, unlike in cancer therapies, where inhibitors are often developed as dual-specific against MKK4 and MKK7, high selectivity towards MKK7 is essential in liver regeneration. Recently, several structures serving this purpose have been published and the entry of inhibitor HRX-0215 (structure not disclosed) into clinical trials marked a milestone in the drug development of MKK4, as it is the first clinically studied inhibitor to target one of the “non-classical” MKKs (MKK3-7).MKK4 has also been shown to be a target in other conditions, including osteoarthritis, atrial fibrillation and neurodegenerative diseases such as Alzheimer’s and Parkinson’s disease. It has been shown to prevent cells from apoptosis, autodegradation and senescence. Although studies on in vivo models are still required to prove the efficacy, MKK4 inhibitors show great potential to be used as therapy, which highlights the need for novel MKK4 therapeutic agents.In summary, MKK4 has been validated for certain cancer diseases and liver regeneration therapies. While dual-inhibitor specificity towards MKK7 can be beneficial for a complete MKK4/MKK7/JNK pathway shut down in cancer cells, high MKK4 selectivity is mandatory in liver regeneration. While the first small molecules inhibited MKK4 only nonselectively in the μM range, mostly originating from natural products, several highly selective inhibitors, effective at nanomolar concentrations, have recently been published that even involve covalent strategies and have a clinical candidate in the pipeline.However, there are still challenges ahead. These include further investigation of the role of MKK4 in other diseases, especially in neuroprotection, and a possible application of an MKK4 inhibitor for neurodegenerative diseases. So far, the binding modes of inhibitors have been established only by homology models. For rational drug design, a crystal structure that represents the binding mode at high resolution would be a breakthrough. Most structures are thought to be ATP-competitive type 1 kinase inhibitors. Since the ATP binding pockets are often conserved, obtaining selectivity is problematic. In addition, these inhibitors must overcome high endogenous ATP levels to be effective intracellularly. Accordingly, covalent or allosteric inhibitors are promising options, which have also been discussed in previous sections. Particularly, resolving the molecular mechanism of the latter would help transform lead structures into drug candidates.


Overall survival is the “gold standard” endpoint in cancer clinical trials. It plays a key role in determining the clinical- and cost-effectiveness of a new intervention and whether it is recommended for use in standard of care. The assessment of overall survival usually requires trial participants to be followed up for a long period of time. In this time, they may stop receiving the trial intervention and receive subsequent anti-cancer treatments, which also aim to extend survival, during trial follow-up. This can potentially change the interpretation of overall survival in the context of the clinical trial. This review aimed to determine how overall survival has been assessed in cancer clinical trials and whether subsequent anti-cancer treatments are considered.Two searches were conducted using MEDLINE within OVID© on the 9th of November 2021. The first sought to identify papers publishing overall survival results from randomised controlled trials in eight reputable journals and the second to identify papers mentioning or considering subsequent treatments. Papers published since 2010 were included if presenting or discussing overall survival in the context of treating cancer.One hundred and thirty-four papers were included. The majority of these were presenting clinical trial results . Of these, 45 (46%) reported overall survival as a (co-) primary endpoint. A lower proportion of papers including overall survival as a (co-) primary endpoint compared to a secondary endpoint were published in recent years. The primary analysis of overall survival varied across the papers. Fifty-nine (60%) mentioned subsequent treatments. Seven papers performed additional analysis, primarily when patients in the control arm received the experimental treatment during trial follow-up (treatment switching).Overall survival has steadily moved from being the primary to a secondary endpoint. However, it is still of interest with papers presenting overall survival results with the caveat of subsequent treatments, but little or no investigation into their effect. This review shows that there is a methodological gap for what researchers should do when trial participants receive anti-cancer treatment during trial follow-up. Future research will identify the stakeholder opinions, on how this methodological gap should be addressed.The online version contains supplementary material available at 10.1186/s13063-023-07730-1. Overall survival (OS), disease-free survival, progression-free survival and cause-specific survival are all used to assess the clinical effectiveness of experimental treatments in cancer clinical trials. However, due to subjectivity and variability in the definitions of response, progression, and cause of death. OS is the only endpoint that has a definite event which cannot be questioned. As a result of this, OS is often referred to as the “gold standard” endpoint for assessing the clinical effectiveness of experimental interventions for the treatment of cancer. In England, OS is used in conjunction with other evidence in appraisals by NICE  to determine whether interventions should be recommended for use in the NHS. A recent review of Health Technology Assessment (HTA) systems in the European Union, UK, Canada and Australia, found that the model in England which uses clinical and cost-effectiveness data in their review alongside other evidence is similar to eight other HTA bodies including France and Sweden. In addition, there were 46 other HTA bodies across multiple countries including Italy, The Netherlands and Spain which also use both clinical and cost-effectiveness data in their appraisals .To ensure consistency between clinical trials, guidance exists on their analysis and interpretation. The International Council on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) topic E9 is entitled “Statistical Principles for Clinical Trials” and includes, for example, advice on how to analyse a trial when stratification factors are used during randomisation . In addiThe assessment of OS requires trial participants to be followed up for what can be a considerable length of time. This poses a problem when it comes to interpreting the trial results, as participants may discontinue their trial intervention prior to death. For example, participants may discontinue at disease progression or earlier due to withdrawal from trial treatment (as a result of toxicity or patient choice), or an intervention stopping rule. Trial participants may then go on to receive multiple subsequent lines of anti-cancer treatment during trial follow-up. These subsequent treatments will also aim to control a patient’s cancer and therefore may improve OS. This improvement may reduce the number of OS events observed in the trial and in turn reduce the power available to detect a difference in OS between the experimental and control interventions. Consequentially, using England as an example, this could lead to a beneficial intervention not being recommended for use in the NHS, resulting in sub-optimal patient outcomes.This issue with interpretation is well known and is referenced in clinical trial recommendations . MethodoIt is currently unknown how widely the published guidance on the analysis of OS is followed and how researchers at present perceive subsequent treatment lines as a whole compared to the specific scenario of treatment switching. Therefore, the aim of this systematic review was to determine how OS is currently analysed in practice and whether subsequent lines of treatment are mentioned in the main manuscript or supplementary material of cancer clinical trials publications.Lancet, Lancet Oncology, JCO, PLOS One, PLOS Medicine, BMJ, JAMA and New England Journal of Medicine. The second approach aimed to target papers which were specifically discussing the issue around subsequent treatments in conjunction with the analysis of OS in cancer clinical trials. Both searches were restricted to the English language and to papers published since 1 January 2010. The results of the two searches were combined with the Boolean operator OR and all abstracts were extracted into Microsoft Excel  and EndnoteTM .The electronic database MEDLINE using OVID® was searched on 9 November 2021. To ensure that the search was not biased towards trials that did or did not report the limitations surrounding the analysis of OS in terms of subsequent treatments, two approaches were taken , amber , and green (relevant) Fig. . Any papAll amber and green papers which remained were read in full by K-LR. and categorised as presenting clinical effectiveness results of a clinical trial, presenting a cost-effectiveness analysis, or a methodology or review paper discussing multiple treatment lines. Category-specific information was extracted from each publication Table  and summA total of 415 results were identified from the literature search. Following the screening process 281 (68%) were classed as red, 26 (6%) amber and 108 (26%) green  papers. Two papers (2%) defined the starting point to be diagnosis, three papers (3%) intervention initiation, one paper enrolment (1%) and one paper pre-inclusion (1%), but it was unclear what these meant in relation to the point of randomisation. Four papers (4%) did not explicitly define OS within the text, two of which were not presenting OS results.Most papers  presented a Kaplan-Meier curve for OS in the main manuscript. Of these, the majority included the numbers at risk 79/86, 92%). However, only a small proportion included the number of events or number censored in their at-risk table . None of the papers provided confidence intervals on their Kaplan-Meier curve. Eight papers, with mature OS data, did not present a Kaplan-Meier curve for OS in their main manuscript. Four papers included them in the appendix 9/86, 92% and fourp-value from a logrank test and the hazard ratio from a Cox proportional hazards model. In total 36 of the 98 papers (37%) papers interpreted OS results using the p-value from a stratified or unstratified logrank test and the hazard ratio from an adjusted or unadjusted Cox model. Of the 98 papers, 15 (15%) used a hazard ratio and p-value from an adjusted Cox model to interpret OS. Of these 15, 12 (80%), were when OS was a primary or co-primary endpoint. When considered by year  papers mentioned subsequent treatment lines in the main manuscript or supplementary material. Of those that mentioned subsequent treatment lines, the majority  provided the number or percentage of participants who received a later treatment line during trial follow-up. Four of the 59 (7%) papers provided a breakdown of the number of later lines a participant received. However, 45 of the 59 (76%) provided a summary of the types of treatments participants received during follow-up. Finally, seven of the 59 12%) papers performed additional analysis addressing subsequent treatments. The most common reason for the additional analysis was due to participants switching to receive the experimental intervention , 19–21. % papers In total nine papers whose primary purpose was to report cost-effectiveness analysis were identified during the literature review  used a partitioned survival analysis model where the OS estimate was extrapolated from a Kaplan-Meier plot . Five of the nine (56%) papers included subsequent costs and four of the nine (44%) papers performed additional analysis to account for subsequent lines of therapy. One paper used the rank preserving structural failure time model (RPSFTM) , anotherIn total, 27 methodology/review papers were identified  [The main finding in terms of the analysis of OS is that whilst it is generally defined consistently as an endpoint, and is commonly visualised with the Kaplan-Meier curve, the primary analysis is not as consistent as might have been expected. The authors expected that the majority of papers would report the results of a Cox proportional hazards model adjusted for at least the trial’s stratification factors, where both the hazard ratio and the nalysis” . HoweverHE9 (R1) . These rHE9 (R1)  which waHE9 (R1)  no paperThe findings around subsequent treatment lines were less surprising. As whilst the majority which mentioned subsequent treatment lines summarised the types of treatments being received. A finding which complements a recent review by Oliver et al.  which waConversely, whilst only nine cost-effectiveness papers were identified they did seem to have a consistent approach to their primary analysis. In addition, where it was clear, the majority of papers did include subsequent treatment costs with a good proportion going further and including additional analysis which adjusted the OS estimate for subsequent treatment lines. Given the contrast to the clinical effectiveness papers, there is a question as to whether adjusting for subsequent lines is being left to be considered by those that evaluate the intervention for HTA review, which often requires cost-effectiveness to be fully analysed, rather than at the publication of the primary clinical effectiveness results.The majority of the identified methodology/review papers were discussing treatment as a whole and did not consider subsequent lines in the context being considered here. As expected, a number of the methodology papers mentioned subsequent lines as a reason for assessing surrogate endpoints in their field , 30, 35 This review provides evidence that whilst OS is less frequently the primary endpoint, it is still of interest, and even when treatment switching is not the case, subsequent treatments are being considered as a limitation. This is the same across the different perspectives from the clinical effectiveness papers to the methodological and cost-effectiveness papers. At present, the approach to the assessment of both OS and subsequent treatment lines is not consistent. Whilst there will never be a one size fits all to the analysis of clinical trials, there is a need for an approach to subsequent treatment lines to aid interpretation of clinical trial results as more interventions are developed and recommended for use in standard or care.There are some limitations to this systematic review. As there was only one researcher conducting the review, the more general search to gauge practice was restricted to only include top UK and international journals. It may be that the exploratory analysis which we are interested in here is reported in other, less-prominent journals. However, this was accounted for in the two approaches where the first search was not restricted by journal. In addition, articles prior to 2010 were excluded from the search. However, this is considered to be less of an issue as the technology support document advocating accounting for subsequent lines in the form of treatment switching was published in 2014 . Having Over the last decade, OS has changed from being the primary endpoint of cancer clinical trials to more commonly a secondary endpoint. Despite this, subsequent treatment lines in relation to OS are being consistently mentioned in articles, confirming that whilst OS may not be the primary endpoint, the analysis and results are still of interest. The majority of articles concluded that subsequent lines were a limitation of the interpretation of their OS analysis. However, analysis accounting for subsequent lines was generally only conducted in the event of treatment switching. The implemented methods were often naïve, and researchers did not utilise the more sophisticated and less well-known methods of IPCW or the RPSFTM. In fact, RPSFTM was only observed in one paper aiming to determine cost-effectiveness rather than clinical effectiveness. There is a question of whether researchers are aware of these more advanced methods  or whether they are just not being published (a reporting gap). This will be explored through the next stage of this research, in which stakeholders  will be invited to complete a questionnaire on their views of OS and its analysis. Within the questionnaire, statisticians and other data analysts  will be asked to answer whether they have heard of and whether they have applied the various methods to analyse OS in cancer clinical trials. The overarching aim of the questionnaire will be to agree a consensus across the stakeholder groups in terms of the direction of this research and how statistical methodology should be extended or developed to account for subsequent treatment lines in the analysis of cancer clinical trials.Additional file 1: Supplementary Table 1. PRISMA Abstract Checklist. Supplementary Table 2. PRISMA Reporting Checklist. Supplementary Table 3. Summarised clinical effectiveness papers. Supplementary Table 4. Summary of the clinical effectiveness papers by year of publication. Supplementary Table 5. Summary of the Effectiveness papers by cancer. Supplementary Table 6. Summarised cost-effectiveness papers. Supplementary Table 7. Summarised Methodology / Review papers.


De novo mutations arising in the germline are a source of genetic variation and their discovery broadens our understanding of genetic disorders and evolutionary patterns. Although the number of de novo single nucleotide variants (dnSNVs) has been studied in a number of species, relatively little is known about the occurrence of de novo structural variants (dnSVs). In this study, we investigated 37 deeply sequenced pig trios from two commercial lines to identify dnSVs present in the offspring. The identified dnSVs were characterised by identifying their parent of origin, their functional annotations and characterizing sequence homology at the breakpoints.de novo duplication, a dnSNV and a de novo deletion. Mutation cluster 2 contains a de novo deletion and three de novo duplications, of which one is inverted. Mutation cluster 2 is 25 kb in size, whereas mutation cluster 1 (197 bp) and the other two individual dnSVs (64 and 573 bp) are smaller. Only mutation cluster 2 could be phased and is located on the paternal haplotype. Mutation cluster 2 originates from both micro-homology as well as non-homology mutation mechanisms, where mutation cluster 1 and the other two dnSVs are caused by mutation mechanisms lacking sequence homology. The 64 bp deletion and mutation cluster 1 were validated through PCR. Lastly, the 64 bp deletion and the 573 bp duplication were validated in sequenced offspring of probands with three generations of sequence data.We identified four swine germline dnSVs, all located in intronic regions of protein-coding genes. Our conservative, first estimate of the swine germline dnSV rate is 0.108 (95% CI 0.038–0.255) per generation (one dnSV per nine offspring), detected using short-read sequencing. Two detected dnSVs are clusters of mutations. Mutation cluster 1 contains a Our estimate of 0.108 dnSVs per generation in the swine germline is conservative, due to our small sample size and restricted possibilities of dnSV detection from short-read sequencing. The current study highlights the complexity of dnSVs and shows the potential of breeding programs for pigs and livestock species in general, to provide a suitable population structure for identification and characterisation of dnSVs.The online version contains supplementary material available at 10.1186/s12864-023-09296-3. De novo mutations (DNMs) are spontaneous mutations in the germline and a source of genetic variation that occur during gametogenesis )  was > 1.Inversions passed if the minimum allelic balance for the proband was > 0.2; there were a minimum of five reads supporting the dnSV in the proband; maximum allelic balance for parents was < 0.1; there was a maximum of three reads supporting the dnSV in either parent; and the inversion was not called a dnSV in > 1 sample.Finally, candidate sites were manually inspected using Integrative Genomics Viewer (IGV)   to removThe dnSV rate was estimated by dividing the number of identified true dnSVs with the number of trios analysed. Confidence intervals of the dnSV rate estimate were calculated using the Wilson method .The detected dnSVs were compared with the public SV database of Ensembl   and withPCR primers were designed to span each of the breakpoints identified in the sequence data. Mutation cluster 2 was too complex for PCR primer design. For the remaining three dnSVs and the mosaic deletion, PCR assays were designed  and the other heterozygous. The allele with a higher than expected number of reads (causing the 2:1 ratio) indicated the parental haplotype the duplication originated from .Genes located within the dnSVs were retrieved from Ensembl  and NCBI annotation  using NCBI Genome Data Viewer . GeneCarWe identified the most likely causal mechanisms for dnSV formation based on split reads spanning the breakpoints of the dnSVs. The dnSVs were grouped into two broad categories based on the degree of sequence homology at the junctions, using methodology from a similar analysis of dnSVs in human families . dnSVs wBelow is the link to the electronic supplementary material.Supplementary Material 1Supplementary Material 2


Kinase domains are highly conserved within protein kinases in both sequence and structure. Many factors, including phosphorylation, amino acid substitutions or mutations, and small molecule inhibitor binding, influence conformations of the kinase domain and enzymatic activity. The serine/threonine kinases ULK1 and ULK2 are highly conserved with N- and C-terminal domains, phosphate-binding P-loops, αC-helix, regulatory and catalytic spines, and activation loop DFG and APE motifs. Here, we performed molecular dynamics (MD) simulations to understand better the potency and selectivity of the ULK1/2 small molecule inhibitor, ULK-101. We observed stable bound states for ULK-101 to the adenosine triphosphate (ATP)-binding site of ULK2, coordinated by hydrogen bonding with the hinge backbone and the catalytic lysine sidechain. Notably, ULK-101 occupies a hydrophobic pocket associated with the N-terminus of the αC-helix. Large movements in the P-loop are also associated with ULK-101 inhibitor binding and exit from ULK2. Our data further suggests that ULK-101 could induce a folded P-loop conformation and hydrophobic pocket reflected in its nanomolar potency and kinome selectivity. It begins with the formation of phagophores, which evolve into double-membraned autophagosomes, engulfing cytoplasmic components. These autophagosomes then merge with lysosomes, where their contents are broken down into amino acids, lipids, and carbohydrates, available for reuse by the cell2. This efficient system helps cells survive during stressful conditions, such as nutrient scarcity. Autophagy plays a complex role in cancer, particularly in KRAS-driven tumors4. Consequently, inhibiting autophagy is now being explored to enhance current cancer treatments5.Macroautophagy, commonly referred to as autophagy, is an essential cellular recycling process6. ULK1/2 forms a complex with ATG13, RB1CC1 , and ATG101. This complex allows ULK1/2 to integrate signals from nutrient-sensing (mTORC1) and energy-sensing (AMPK) pathways7, triggering the early stages of autophagic membrane production. The critical role of ULK1/2 in autophagy has been demonstrated in studies showing that depleting or inhibiting ULK1/2 impairs autophagy, making them targets for autophagy inhibition. Accordingly, several small molecule inhibitors of ULK1/2 have been developed, offering insights into its structure and the effectiveness of ULK1/2 inhibition in suppressing autophagy11. However, these inhibitors vary in potency, specificity, and cellular activity. ULK-101 shows improved potency and selectivity compared to existing inhibitors, and effectively blocks autophagy induction and reduces autophagic flux in various conditions8. Here, we focus on the small molecule inhibitor, ULK-101, in molecular dynamics (MD) simulations and report the first MD simulations of ULK2 binding with ULK-101.Autophagy is initiated by the serine/threonine kinases ULK1/2 (unc-51 like autophagy initiating kinase 1/2), mammalian equivalents of yeast ATG18. ULK-101 inhibits ULK1 with an IC50 of 8.3 nM (95% CI: 7.2–9.6 nM) and ULK2 with an IC50 of 30 nM (95% CI: 26–35 nM) for ULK2 (8).In order to understand molecular details of the high-affinity interactions between ULK-101  and the 13. The free energy of the system is shown with respect to two different collective variables  was to 0, the closer ULK-101 was bound to the active site of ULK2. In one MD simulation, totaling 790 ns, we achieved stable poses for ULK-101 near the ATP-binding pocket of the ULK2 kinase domain  corresponding to amino acids 1–276 of ULK2 . Noteworariables . Each coe domain , occurrie domain .To further elucidate critical factors for ULK-101 binding to ULK2, we first identified hydrogen bonds between the two molecules as a function of simulated time . The two8.The P-loop rearrangement is visible when comparing the starting state of the simulation (relaxed and equilibrated) with a stable bound state . In the 17. What remains, however, is that high affinity ligands for ULK1 maintain high affinity for ULK210.To understand the relative selectivity of ULK-101 as an inhibitor of ULK1/2, we set up a host of simulations between ULK1, ULK2, and other known kinase inhibitors. The various experiments were between 500 to 2500 ns in total of adaptively biased simulation time. Of those efforts, we achieved a stable bound pose for ULK-101 with ULK2 that lasted roughly 120 ns from a single 790 ns simulation. Notably, the entry and exit of ULK-101 interaction with ULK2 appears driven largely by a hydrophobic pocket in the αC-helix, which carries a bend at the N-terminus in both ULK1  and ULK218, and the P-loop is involved in nucleotide recognition19. Further, the P-loop undergoes a conformational change to accommodate ULK-101 binding  than other solved structures for ULK2 .Visual representation of existing structural models  was performed with PyMOL8. Briefly, IC50 data for ULK1 and ULK2 was generated using 10-point IC50 Profiler assays with half-log dilutions from top concentrations of 10 μM (4 replicates) and 1 μM (4 replicates), giving 8 data points for most concentrations in the curve. The percent activity remaining and percent inhibition were calculated from negative control wells. GraphPad Prism was used for IC50 determinations by fitting curves with variable slope (four-parameter) non-linear regression models using top and bottom constraints of 100% and 0%, respectively.Eurofins Pharma Discovery Services UK Limited performed all kinase assays, as we have previously reported11) was the structural basis for our simulation. We began with the coordinates of a monomeric ULK2 kinase domain (a.a. 1–276) that was engineered with a phosphomimetic T173D in the activation loop. The inhibitor and water molecules were removed from the crystal structure, and unresolved loop residues were modeled with Chimera v1.1523. The refined ULK2 kinase was brought into GROMACS v5.0.524 with the CHARMM 36 force field25. To prepare ULK-101 for simulation, the inhibitor was first converted from SMILES to .mol2 and then parameterized using SwissParam27. The coordinates for ULK-101 and ULK2 were combined (ULK-101 out of the kinase pocket) and solvated in TIP3P water with 150 nM NaCl, followed by steepest descent for 5,000 steps (converged to Fmax < 1000 in 1425 steps), a 0.1 ns relaxation in the canonical ensemble, and then 5 ns pressure equilibration in the isothermal-isobaric ensemble. Free energy of ULK-101 binding to ULK2 was computed with adaptive biasing potential and overfill protection13 in the canonical ensemble with the adaptive biasing potential parameters c = 0.01, b = 0.9, α = 8 and an overfill limit of 70 kJ/mol. See All naming and numbering are according to UniProt. The X-ray crystal of ULK2 in complex with inhibitor SBI-0206965 . RMSD were calculated for each CV relative to an approximation of the ATP binding pocket . The RMSD Trajectory Tool in VMD was used to measure the RMSD of the following kinase features: P-loop , αC-helix , hinge region , after alignment of all frames to the top frame . The Hydrogen Bond tool in VMD was used to identify and count the frequency of hydrogen bonds made between ULK2 and ULK-101 with a distance and angle cutoff of 3 angstroms and 20 degrees, respectively. The distance between ULK-101 and indicated atoms was generated using the labels function in VMD.To represent free energy calculation as a function of ULK-101 location, two groups of three atoms were selected on each end of ULK-101 as collective variables (CVSupplement 1


To explore short-term changes in corneal astigmatism after combined silicone oil removal and cataract (SORC) surgery.  We enrolled 89 patients (43 men and 46 women). Zeiss IOLMaster was used to measure corneal astigmatism status and axial length on the day before and after the SORC surgery. Best-corrected visual acuity (BCVA) and intraocular pressure (IOP) were recorded. The results were compared to the outcomes at 3 days, 1 week, and 1 month postoperatively. P = 0.016), 1 week (P = 0.009), and 1 month (P = 0.035), while K2 increased significantly at 3 days postoperatively (P = 0.002), 1 week (P < 0.001), and 1 month (P = 0.001), as well as corneal astigmatism . Compared to that at the baseline, BCVA significantly improved at 3 days, 1 week, and 1 month postoperatively . Meanwhile, IOP decreased significantly at 3 days postoperatively (P < 0.001), 1 week (P = 0.005), and 1 month (P = 0.007). Similarly, axial length decreased at all follow-up time points .  Compared to baseline, K1 decreased significantly at 3 days postoperatively ( Corneal astigmatism increased in the short term after the SORC operation but gradually decreased at 1 month postoperatively. BCVA improved steadily, and SORC was widely used in the clinic. Pars plana vitrectomy (PPV) has been highly developed for various vitreoretinal diseases , and traLong-term silicone oil tamponade causes a series of complications, including cataracts, glaucoma, and corneal degeneration; therefore, silicone oil should be removed 3–6 months postoperatively –9. SinceAs a common refractive error, astigmatism can cause blurred vision and visual fatigue, which directly influence quality of life. Surgically induced astigmatism (SIA), an important component of astigmatism, affects visual quality and visual rehabilitation postoperatively , 16. HowThis study aimed to explore the short-term changes in corneal astigmatism after SORC surgery to reduce postoperative astigmatism in future clinical work.Eighty-nine patients (43 men and 46 women) were enrolled in the Department of Ophthalmology at Renmin Hospital of Wuhan University. Patients with rhegmatogenous retinal detachment and proliferative diabetic retinopathy who underwent SORC surgery between November 2021 and June 2022 were included in this study. Only one eye was enrolled for every indivious condition. The study conformed to the Declaration of Helsinki, and ethical approval was obtained from the Medical Ethics Committee of the Renmin Hospital of Wuhan University. All patients signed informed consent forms after being informed of the purposes, contents, and potential risks.The inclusion criteria were eyes with rhegmatogenous retinal detachment and proliferative diabetic retinopathy undergoing SORC surgery by an experienced surgeon with no history of any ocular surgery, phakic eyes, and capable of IOLMaster examination. We excluded eyes with other retinal detachments, such as exudative retinal detachment; vitreous hemorrhage caused by other reasons, such as retinal hole, retinal vein occlusion, wet age-related macular degeneration; or any other eye diseases, keratopathy, uveitis, glaucoma, orbital tumors, eye trauma, or any history of ocular surgery. Patients who did not follow scheduled visits postoperatively were excluded.Each subject was evaluated by an experienced ophthalmologist using a slit lamp . An tonometer , B-ultrasound , an ultra-wide-field scanning laser ophthalmoscope , and optical coherence tomography  were used to further confirm the diagnosis.All surgeries were performed under retrobulbar anesthesia by the same professional surgeon (Tao He) . SORC suThe refractive status was determined using IOLMaster  preoperatively and at 3 days, 1 week, and 1 month postoperatively. All examinations were performed three times by a blinded observer. The following data were compiled postoperatively: best-corrected visual acuity (BCVA), refraction, intraocular pressure (IOP), retinal and macular status, and complications over a minimum 1-month follow-up period.P < 0.05 was considered statistically significant.Statistical analyses were performed using SPSS 26.0 . Quantitative data are presented as mean ± standard deviation. The differences at every follow-up time point were analyzed using one-way analysis of variance with Dunnett's multiple comparison two-sided test. We enrolled 89 eyes of 89 patients, including 41 right and 48 left eyes; 43 patients were men while 46 were women. The average age was 59.31 ± 7.57 years (range: 41–75). The primary diseases included rhegmatogenous retinal detachment and proliferative diabetic retinopathy .P = 0.016), 1 week (P = 0.009), and 1 month (P = 0.035), while K2 increased significantly at 3 days postoperatively (P = 0.002), 1 week (P < 0.001), and 1 month (P = 0.001), as well as corneal astigmatism .The differences in K1, K2, and corneal astigmatism at the different follow-up time points are shown in P=0.029 and 0.021, respectively), while there was no statistical difference at 1 week . Corneal astigmatism exhibited significant differences both at 1 week and 1 month postoperatively when compared with that at 3 days . Meanwhile, IOP decreased significantly at 3 days postoperatively (P < 0.001), 1 week (P=0.005), and 1 month (P=0.007). Similarly, axial length decreased at all follow-up time points .Differences in BCVA, IOP, and axial length at different follow-up time points are shown in P < 0.001), as well as the IOP . However, the axial length showed no statistical differences at either 1 week or 1 month postoperatively when compared with 3 days .To investigate the changes in BCVA, IOP, and axial length postoperatively, we further compared each follow-up time point at 3 days postoperatively . The BCVAfter SORC surgery, the retina remained attached in 60 eyes (96.8%), and two eyes (3.2%) in RRD patients developed re-detachment. Vitreous hemorrhage occurred in two eyes (7.4%) postoperatively in PDR patients.Many studies have reported on corneal astigmatism after cataract surgery. However, studies on corneal astigmatism after SORC surgery are lacking, especially in the short term. To our knowledge, this study is the first to explore short-term changes in astigmatism after SORC surgery, which has clinical significance for guiding surgical operations.Our study found that corneal astigmatism increased significantly in the short-term postoperatively. Corneal astigmatism increased significantly 3 days postoperatively, which lasted until 1 week postoperatively, and gradually decreased 1 month postoperatively, approaching the preoperative level. Some studies on cataract surgery showed that corneal astigmatism increased significantly at one week and two weeks postoperatively, while corneal astigmatism gradually decreased at 4 weeks postoperatively, which was close to the preoperative state , 19. ThiIn addition, there was some controversy regarding whether scleral tunnel incision could cause corneal SIA. Some studies suggested that simple PPV surgery will not lead to changes in corneal astigmatism , 25. HowSome studies have suggested that the length of the eye axis changes after the removal of silicone oil. Some researchers believe that there is no statistically significant difference in axial length pre- and postoperatively –29. OtheIn terms of visual acuity, although the corneal astigmatism of the patients increased at 3 days and 1 week postoperatively, the postoperative visual acuity improved compared with that preoperatively. In addition, the corneal astigmatism in the two groups of patients was significantly different at 1 week and 1 month postoperatively, and the difference in visual acuity was not obvious. Visual acuity was mostly affected by the diopter reserved and condition of the fundus.Our study had some limitations. First, we were unable to observe any longer after the SORC surgery. Meanwhile, the patient population was small, and a larger sample size should be considered in further investigations.In general, SORC surgery is a safe and effective method for improving BCVA. The corneal astigmatism gradually decreases postoperatively.