Background and Motivation: Parkinson’s disease (PD) is one of the most serious, non-curable, and expensive to treat. Recently, machine learning (ML) has shown to be able to predict cardiovascular/stroke risk in PD patients. The presence of COVID-19 causes the ML systems to become severely non-linear and poses challenges in cardiovascular/stroke risk stratification. Further, due to comorbidity, sample size constraints, and poor scientific and clinical validation techniques, there have been no well-explained ML paradigms. Deep neural networks are powerful learning machines that generalize non-linear conditions. This study presents a novel investigation of deep learning (DL) solutions for CVD/stroke risk prediction in PD patients affected by the COVID-19 framework. Method: The PRISMA search strategy was used for the selection of 292 studies closely associated with the effect of PD on CVD risk in the COVID-19 framework. We study the hypothesis that PD in the presence of COVID-19 can cause more harm to the heart and brain than in non-COVID-19 conditions. COVID-19 lung damage severity can be used as a covariate during DL training model designs. We, therefore, propose a DL model for the estimation of, (i) COVID-19 lesions in computed tomography (CT) scans and (ii) combining the covariates of PD, COVID-19 lesions, office and laboratory arterial atherosclerotic image-based biomarkers, and medicine usage for the PD patients for the design of DL point-based models for CVD/stroke risk stratification. Results: We validated the feasibility of CVD/stroke risk stratification in PD patients in the presence of a COVID-19 environment and this was also verified. DL architectures like long short-term memory (LSTM), and recurrent neural network (RNN) were studied for CVD/stroke risk stratification showing powerful designs. Lastly, we examined the artificial intelligence bias and provided recommendations for early detection of CVD/stroke in PD patients in the presence of COVID-19. Conclusion: The DL is a very powerful tool for predicting CVD/stroke risk in PD patients affected by COVID-19. Parkinson’s disease (PD) is a progressive neurodegenerative condition characterized by movement impairments. In 1817, British physician James Parkinson described the condition for the first time . AccordiA coronavirus 2 (SARS-CoV-2)-related acute, respiratory distress disease was found in Wuhan, China, in late December 2019 ,6. The iDuring the period of lockdown, less importance was given to PD-affected patients, leading to heart attack and stroke in PD patients . The conAs per recent studies ,19,20, PIn recent years, it has been seen that artificial intelligence (AI) has played an important role in computer-aided diagnosis ,31, partThe focus of this research was to design, develop, and validate the hypothesis, (i) CVD/stroke risk stratification of PD patients in the COVID-19 framework and (ii) understanding the non-linearity of PD combined with COVID-19 symptoms against the CVD/stroke gold standard; (iii) develop a DL-based lesion detection system and its quantification, which could then be used as a covariate in a machine learning framework; (iv) DL-based CVD/stroke risk stratification by combining office-based biomarkers (OBBMs), laboratory-based biomarkers (LBBMs), carotid ultrasound image-based (CUSIP), medicine usage (MedUSE), PD-based biomarkers, and CT-based COVID-19 lesion biomarkers.IEEE Xplore, Google Scholar, PubMed, and Science Direct were used to conduct an overall writing search. ‘CHD’, ‘PD patients and stroke risk stratification, ‘neurodegenerative disease and symptoms’, ‘AI’, ‘machine learning, ‘deep learning, and ‘neurodegenerative disease’ were some of the key watchwords used in the study selection process. The research article was chosen for the studies that cover a wide range of topics, including CVD, and stroke risk stratification of PD patients in the COVID-19 framework using ML, DL, hybrid deep learning (HDL), and AI. The categorization of normal vs. PD-affected persons.Information from the data was considered for the PD with COVID-19 studies data, searches were: (i) name of the author, (ii) publication year of research article, (iii) objective of the research studies, (iv) effect of COVID-19 on PD, heart, and brain, (v) PD year (vi), PD with other comorbidities, (vii) diagnosis method, (viii) PD symptoms worsening factor due to COVID-19, and (ix) treatment of PD with COVID-19. The identified research studies were assessed using the unique and effective application of the AI, hybrid AI, PD with other comorbidities diagnosis techniques, and biomarker-based strategies for detecting CVD and stroke risk stratification of PD patients in the COVID-19 framework.The effect of COVID-19 on PD, the heart, and the brain is still unknown due to the limited literature, especially since we know that the lungs are badly affected by COVID-19 ,55. NoteThe effect of coronavirus on lungs results in lower levels of ACE2 proliferating in the lung parenchyma cells. It leads to exacerbated neutrophil buildup, increased vascular permeability, and the production of diffuse alveolar and interstitial exudates in the lung. Pneumonia and acute respiratory distress syndrome (ARDS) are the results of this process . As a reTo diagnose the abnormalities in the lung we need an imaging technique, and x-rays and computer tomography are the two medical imaging techniques that are most important in the detection and diagnosis of COVID-19 ,62. CT hVascular disorders create a threat to the heart and the brain . The aorDopamine acts as an intermediary between both the brain and the sensory systems that control and regulate movement . The subThe cause of developing PD is still unknown, there is no specific reason why it happens in the aging population. Environmental factors may potentially increase a person’s likelihood of developing PD . HoweverThe most common consequences of PD on the heart are heart failure, abrupt death, and edema . As a reIt was shown that in 20–30% of hospitalized patients, 40% of COVID-19-related fatalities were due to cardiac damage . Due to An artery’s epithelium becomes thickened or blocked as a result of plaque aggregation in the epithelium . The autPatients with PD who are exposed to, (i) a cold environment, (ii) muscular activity in the early morning, (iii) standing positions, and (iv) over age, all have much higher sympathetic neuronal discharges, which leads to an increased myocardial oxygen requirement ,109. In People with PD and a COVID-19 infection have a risk factor that causes myocardial infarction, as shown in Stroke is one of the major causes of mortality in patients with PD ,116, andLevodopa  is the best treatment for PD . HomocysThe COVID-19 infection had quickly spread over the world since December 2019, resulting in a worldwide coronavirus pandemic in 2020 ,129. PD Several studies have shown the effect of COVID-19 on other comorbidities such as cardiovascular stroke ,137, braCOVID-19 significantly exacerbated both motor and non-motor symptoms in PD, according to the current study, however, cognitive functioning was only minimally influenced . Figure This section explains the role of various comorbidities that trigger the motor and non-motor symptoms of the PD patient, and whether the patient falls under the high-risk category. Dementia develops when neurons die, causing chemical changes in the brain ,12. In tDepression is a mental illness that can decrease a human’s capacity to carry out everyday tasks, and anxiety affects around half of the people with PD . This isPersons with PD have a higher chance of having TMD than people without PD . In mostPeople with PD have trouble passing urine since their bladders will not contract as they should. Furthermore, their sphincter muscles don’t allow urine to pass out . This isOsteoporosis and osteopenia are common among PD patients, with women experiencing the condition at a higher rate than men . DecreasPD patients with underlying diseases like CVD, diabetes mellitus, and hypertension are more vulnerable due to COVID-19 as it increases cardiac events . MeanwhiMany reports regarding hospitalized patients have indicated that 12% to 26% of them had suffered heart damage. The cytokines generated during the COVID-19 infection may affect the patients’ intracellular coronary arteries. In individuals with COVID-19-affected lungs, cardiovascular illnesses have a significant impact on the ARDS . These pACE2 receptors are highly expressed in dopaminergic neurons and are lowered in PD due to the degenerative changes . CentralThe biochemical link between PD with COVID-19 and CVD is seen in Oxidative stress has been proven in several studies to be the most essential contributor to the development of PD that leads to CVD ,171. MitThe substantial nigra’s selective loss of dopaminergic neurons involves oxidative stress as a critical stage  and is eTo stratify an early CVD/stroke risk in PD patients embraced by the COVID-19 framework, AI is the most promising and optimal solution due to its ability to handle non-linearity during the training process . The claDL has been shown to have penetrated all walks of life and more recently into healthcare imaging ,200. A dThe power of DL for COVID-19 lesion detection has been shown in previous studies using different imaging modalities ,212,213.Here, we focus on CT-based lung lesion segmentation and its quantification, which acts as a covariate (or feature) during the DL paradigm. In DL, manual delineations of CT lung lesions are challenging and are also vital for the design of offline DL training models. DL is a strong framework because it has the ability to derive the automated features using the inherent knowledge base and further offers a superior training paradigm where the non-linearity between covariates and the gold standard is dynamically adjusted. One such typical system for DL design is shown in The DL-based detection of PD can be conducted by using symptoms of PD as an input parameter for the algorithm. There are numerous investigations that link changes in voice  to a diaLong short-term memory (LSTM) is one of the DL algorithms that can be used to assess the risk of CVD/stroke . The abi(i)AI systems that use office-based biomarkers as input covariateIn previous sections, we demonstrated how patients having PD with COVID-19 increase CVD/stroke-related complications. We propose in All the studies in Reva et al.  describe(ii)AI systems that use laboratory-based biomarkers as input covariateBiomarkers are chemicals released into the blood by a damaged or stressed heart. These indicators are used to diagnose acute coronary syndrome and myocardial ischemia. Cardiovascular biomarker tests can also be used to assess a patient’s risk of developing CVD or heart ischemia. There are various LBBM related to the heart such as low-density lipoprotein, high-density lipoprotein, myoglobin, creatine kinase, troponin, atrial natriuretic peptide, etc. For example, the study by the Unnikrishnan et al.  describe(iii)AI systems that use carotid ultrasound image phenotype as a covariateIn order to perform a comprehensive risk assessment, we must be able to automatically and precisely quantify CUSIP , which c(iv)AI systems that use Parkinson’s disease symptoms as input covariateThe PD input covariates are voice, gait, sketch pattern, and abnormalities in EEG. The motor and non-motor symptoms result in a better understanding of whether patients have PD or not. Another study by Park et al.  used EEG(v)AI systems that use COVID-19 as input covariateThe DL algorithm is used by the vast majority of AI-based systems for COVID-19 identification and categorization. To improve the amount of COVID-19 data available for training, some researchers have adopted data augmentation techniques. Scientists must modify the number of convolution layers in accordance with their intuition when working with this hyperparameter. However, for COVID-19, DL-focused AI systems must be adjusted based on the link between enhancement, the number of convolution layers, and classification accuracy. The study by Suri et al.  presenteAnother study by Handy et al.  explaineHence, we hypothesize that DL models are capable of performing a specific task, such as automated disease diagnosis, with greater precision and efficiency than ML models and act as a second level of confirmation for the diagnosis . Models Cardiovascular disease (CVD) is the most prominent cause of global mortality and morbidity. Annually, ~17.9 million people die due to CVD, which accounts for 31% of the overall deaths worldwide. Atherosclerosis is the main cause of CVD and future cardiovascular events. Ultrasound-based carotid artery imaging is a well-established surrogate imaging for coronary heart disease and is typically adopted in office-based settings. Studies have recently shown that image-based biomarkers or phenotypes when combined with conventional risk factors are even more effective in CVD risk prediction. Such image data, when collected or derived from a cohort, can be even more useful in predicting CVD risk. Recently such an approach setup for CVD risk assessment using the combination of carotid ultrasound plaque imaging and conventional cardiovascular risk factors (such as patients’ demographics and laboratory-based parameters) in the ML framework was proposed. Granularity in expressing CVD risk is crucial for personalized medicine and better drug monitoring. Thus, one can improve the system by using multiclass–multilabel-based (MCML) algorithms by assessing carotid ultrasound imaging for predicting the presence of significant coronary artery disease than traditional risk scoring methods. Specifically, our aims were to: (i) design a carotid image-based MCML CVD risk assessment calculator, (ii) study the effect of clustering risk predictors on MCML performance, and (iii) benchmark the MCML-based calculator against three types of conventional CVD risk calculators (CCVRC) such as the Framingham risk score, the systematic coronary risk evaluation score, and the atherosclerotic CVD score.. The AtheroEdge 3.0 ML using camaging is reliable, accurate, and superior to traditional CVD risk scoring methods for predicting the CVD/stroke risk due to coronary artery disease.(i)Implementation of Training SystemFor generating the training model, one needs to define the type of the training model based on the number of samples in the training system. This is done under the subsystem called cross-validation. Typically, the cross-validation is categorized by the symbol “K”. Examples of cross-validation systems are K2, K3, K4, K5, K10, and TT. K2 means 50% training and 50% testing data, K3 means 66% training data and 33% testing data, K4 means 75% training data and 25% testing data, K5 means 80% training data and 20% testing data, K10 means 90% training data and 10% testing data, and finally, TT means “Training equals Testing protocol”, where training data is 100% and testing data is also 100%. Typically, the TT protocol is adapted to validate the AI systems.(ii)Implementation of Prediction SystemThis is the first study that combined conventional predictors with eight other clinical clusters of different features in an MCML using the coronary angiogram as the gold standard. Such a system can then leverage the cohort’s knowledge of nonlinearity between input predictors and the gold standard in an MCML framework by automatically and accurately predicting and stratifying the stroke/CVD risk into four granular classes. Thus, the AtheroEdge 3.0 MCML system uniquely overcomes such nonlinearity in a multiclass framework, especially by using the carotid plaque image phenotypes, providing a powerful paradigm similar to an office-based setup, where only the offline training coefficients are needed for such an accurate prediction. To address the challenge of class imbalance in the dataset, which is the most common problem in medical datasets, we used the commonly used SMOTE algorithm that generated independent samples to balance each of the minority risk classes.(iii)PerformanceOur study was highly novel and has demonstrated the superior performance of the MCML-based algorithm compared with previous similar studies. We compared our study results with five recent ML-based studies using the AUC as a common performance evaluation metric. Recently, Kakadiaris et al.  have pre(iv)MaintenanceOur system works using Python, and Java in a windows 11.0 platform and for maintenance of the system, the following items are kept in mind namely: upgrade of windows platform, upgrade of open-source python system, upgrade of Java system, upgrade of the database system from Oracle, update version of the PDF distiller as needed for report generation. Furthermore, there are bug trackers as usual, which are proprietary and cannot be shared or released.There are several distribution strategies for the potential benefits of commercial ML/AI models. Since AI models are online systems that need “test data sets” for execution, such models can be integrated into, (i) cloud-based settings, or (ii) embedded in the scanning devices, something like “Intel processor chip in Dell computer”.The cloud-based strategies are most effective because the system can be executed from “any computer” and “any time”. The cloud-based system can be launched in offline settings and the ultrasonic data can be physically moved from the ultrasound machines to the “local computer”. This is one way the data can be distributed to the local computer and the benefit of ML/AI can be realized.The second distribution strategy is when the offline training models can be embedded into the scanning devices that hold the data. This kind of distribution strategy raises the price of the system, and the cost of maintenance is high due to the evolution of the ML/DL model generations. The profits are high since AI models are embedded in the system itself. If the interface of the models is smooth and the graphical user interfaces are ergonomic or user-friendly, the overall systems can be very powerful. Such distribution strategies are compact but surely encounter a higher price tag for customers. The shipping of such scanners has higher maintenance costs and is typically passed to the customers. Upgrades are more frequent due to scientific evolutions, which are again passed to the customers.No matter which distribution strategy one chooses for benefitting the AI models, “cloud vs. embedded-based solution”, and the interface design must incorporate multi-threaded and multi-tasking architectures enveloping higher CPU clock speed, preferably GPU-based settings or even pruned models having the explainable AI-based paradigms.In this review, we focused on the CVD/Stoke risk stratification of PD patients in the COVID-19 framework. Furthermore, it is clear from a detailed evaluation of several investigations that PD patients with COVID-19 are at an elevated risk of CVD/stroke. As a result, in addition to COVID-19 on PD patients and its monitoring, a low-cost approach should be used to prevent a patient’s CVD/stroke symptoms from worsening. With the aid of a DL-based AI model, these patients may be efficiently monitored, and long-term effects can be averted. In the presence of the COVID-19 framework, DL can assist in CVD/stroke risk stratification in PD patients, with improved sensitivity and specificity. Clinicians can use this model to counsel COVID-19-positive patients with PD along with carotid arterial imaging, and provide further guidance on the CVD/stroke risk.PD and COVID-19 have been linked in a few studies utilizing OBBM, LBBM, CUSIP, and MedUSE, according to an overview of the data. AI’s function in the diagnosis of joint COVID-19 and PD is rarely discussed in the literature. Only a few articles in the COVID-19 framework use the AI model to describe the severity of PD. The study by Antonini et al.  explainsBaschi et al.  mentioneSorbera et al.  explaineThe training model design step of the DL algorithms is highly dependent on the sample size employed. Furthermore, due to a lack of, (i) clinical testing of AI techniques, (ii) scientific validation, (iii) not satisfying the gold standard, (iv) comorbidities, (v) lack of big data configuration, and (vi) not judging the proper disease severity ratio, these all lead to bias in the AI. As a result, when COVID-19-associated PD symptoms (or risk factors) are examined as inputs into an AI model, it is critical that the AI model be stable, accurate, and has minimal AI bias ,272,273.The field of artificial intelligence (AI) has an effect on virtually every aspect of life , particuMital et al.  conducteCardiovascular disease (CVD) is one of the major causes of mortalities and morbidities in the world . AnnuallFor CVD/stroke risk prediction in PD patients in the COVID-19 framework, the same set of AI benefits apply here as well. The deep learning automated model can be used for COVID-19 detection and quantification in CT scans . This isIn summary, the main attributes of economic benefits for using AI-based solutions are, (i) early detection of the disease, (ii) prevention of surgery at a delayed time, (iii) use of off-line in-built training models embedded in the systems, and (iv) Usage of cloud-based AI technologies. While AI is powerful and proving to be an economic solution, there are ethical concerns , lack ofThe main strength of the current system is the role of DL for CVD/stroke risk assessment in PD patients in the presence of COVID-19. DL offers better training and risk prediction due to superior non-linear adjustment between the covariates and the gold standard. Further, the system offers better coverage of covariates such as OBBM, LBBM, CUSIP, MedUSE, PD covariates, and COVID-19 covariates along with lesion sizes estimated from the CT scans of the lungs. Further, the role of LSTM, a very powerful approach for the DL system design for CVD/stroke risk prediction was presented. Lastly, the DL system is generalized which can be altered by adding more covariates and comorbidities such as diabetes, rheumatoid arthritis, renal disease, coronary artery disease, etc.The AI-based solution for CVD/stroke risk assessment of PD patients in COVID-19 framework is the first to introduce the use of a machine learning system for CVD/stroke risk assessment and is easily amendable for adjustment of more parameters. This means more covariates can be added and the machine learning system will perform better once optimized. The deep learning paradigms are powerful solutions for lesion detection.The first time the system is developed it computes CVD/stroke risk in PD patients in the COVID-19 framework.While DL offers strengths to the system, it also needs to be ensured that the system is optimized always. This requires several iterations of hit-and-trial attempts to achieve optimal DL solutions. Further, the DL system requires a solid gold standard for, (a) during CT lesion annotations, and (b) CVD/stroke gold standard collection in cohorts, which also requires time and cost. Lastly, as pointed out before, DL systems are susceptible to AI bias due to overperformance in terms of accuracy and lack of interpretability. In terms of extensions, superior DL systems can be designed using ensemble-based methods. Big data can be considered as an option for improving the DL system by taking more sources of data and in a larger sample size. The DL system can be improved by adding the augmentation designs should the cohort size be small. Lastly, the new wave of pruning needs to be incorporated into the DL system for smaller-size training storage models  and evolThe importance of CVD/stroke risk prediction for PD patients in the COVID-19 environment was highlighted in this comprehensive investigation. We also illustrated how PD with COVID-19 can cause vascular and cerebral strokes. This review highlighted how PD with COVID-19 may aggravate complexity in CVD/stroke. Thus, PD patients’ CVD/stroke risk categorization in the COVID-19 paradigm is critical. Carotid imaging is a non-invasive, low-cost alternative to conventional imaging for monitoring CVD/stroke in PD patients. This low-cost B-mode ultrasonography also will help characterize plaque tissue in PD patients with COVID-19, improving CVD/stroke risk assessment. CT scan images of lung lesions can help diagnose and quantify COVID-19 infection severity, which is useable as a covariate during DL design. As a result, we explained the role of an AI-based model that can be used to accurately classify PD patients into risk groups for CVD/stroke based on their COVID-19 risk profile. The COVID-19 framework was used to describe an AI-based model for predicting CVD/stroke risk in PD patients. Finally, we discussed the involvement of joint PD with COVID-19 in the CVD/stroke paradigm, as well as the role of AI in this context.


Background: The association between inflammation and dietary sterols remains poorly assessed at the population level. Aims: To assess the possible association between serum levels of various phytosterols (PS) and inflammatory markers. Methods: Serum levels of six PS , four cholesterol synthesis markers  and one cholesterol absorption marker (cholestanol) were measured together with levels of CRP, IL-6 and TNF-α in two cross-sectional surveys of a population-based, prospective study. Results: CRP levels were negatively associated with levels of cholestanol and of sterols of plant origin, although some associations were not statistically significant. CRP levels were positively associated with cholesterol synthesis markers in the first but not in the second follow-up. IL-6 levels were negatively associated with cholestanol in both follow-ups. No associations between IL-6 levels and PS were found in the first follow-up, while significant negative associations with campesterol, sitosterol, brassicasterol, sitostanol and campesterol:TC ratio were found in the second follow-up. TNF-α levels were negatively associated with cholestanol in both follow-ups. These associations did not withstand adjusting for sex, age, BMI and statin administration. Conclusions: In a population-based study, PS serum levels were not significantly associated with inflammatory markers. Cardiovascular disease (CVD) remains the leading cause of death in Western societies and worldwide ,2. PlantPhytosterols (PS) are naturally occurring cholesterol-like substances belonging to the triterpene family and are present in the cell membrane of most plant cells. They are commonly found in highest amounts in vegetable oils, nuts and oily seeds but can also be found in cereals and legumes, fruit and vegetables being the poorest food sources ,16. SitoEvidence is scarce with regard to a supposed anti-inflammatory effect of PS . Long-teHence, our objective was to assess the association between serum levels of various phytosterols and inflammatory markers using data from two cross-sectional evaluations of a population-based cohort.www.colaus-psycolaus.ch) is a prospective cohort study established in 2003, following a sample of the inhabitants of the city of Lausanne (Switzerland), aged 35 to 75 years at baseline every 5 years  for continuous variables. Bivariate associations were computed using Spearman nonparametric test. Multivariable analyses were conducted using robust regression, and results were expressed as multivariable-adjusted slope and 95% confidence interval (CI). For multivariable analyses, adjustments were performed on age (continuous), sex , BMI (continuous), diabetes  and statin use . A second analysis was conducted replacing diabetes by metformin use . Statistical significance was considered for a two-sided test with www.cer-vd.ch), approved the baseline CoLaus study. The approval was renewed for the first and the second follow-up. The study was performed in agreement with the Helsinki Declaration and its former amendments, and in accordance with the applicable Swiss legislation. All participants gave their signed informed consent before entering the study.The institutional Ethics Committee of the University of Lausanne, which afterward became the Ethics Commission of Canton Vaud (The samples from the two follow-ups are described in The values of the 11 sterols from the two follow-ups are described in p-values are summarized in CRP levels were negatively associated with levels of cholestanol and of sterols of plant origin, although some associations were not statistically significant. CRP levels were positively associated with most cholesterol synthesis markers in FU1 but not in FU2 .IL-6 levels were negatively associated with cholestanol in both follow-ups. No associations between IL-6 levels and sterols of plant origin were found in FU1, while significantly negative associations with campesterol, sitosterol, brassicasterol, sitostanol and campesterol:TC ratio were found in FU2 .TNF-α levels were negatively associated with cholestanol in both follow-ups and with campesterol, sitostanol and brassicasterol in FU2 .The results of the multivariable analysis are summarized in Negative associations between CRP, IL-6 and TNF-α and sterols of vegetal origin were found in bivariate analysis, but those associations were no longer significant after adjusting for confounders. Overall, our results suggest that the effect of PS on inflammation is nonexistent or very limited.PS serum levels in our study were very close to those reported in German volunteers , probablNegative associations between CPR, cholestanol and PS levels were found in both follow-ups. Negative associations between IL-6 and TNF-α with cholestanol and PS were found in FU2 but not in FU1. Our findings are partly in agreement with a study conducted in Japan, where negative associations were found between IL-6 and TNF-α with sitosterol but not with campesterol . In the In our community-dwelling, population-based study, the dietary intake of PS was insufficient to influence inflammatory markers. The Adventist Health Study-2 reported an average total PS intake below 450 mg/day . This vaOne of the strengths of this study is that it measured a large number of different PS and cholesterol absorption and synthesis markers in a large sample of a community-dwelling population. Furthermore, two different follow-ups were performed, which enabled replication of the findings in terms of the absolute and cholesterol-standardized PS serum levels, thus allowing for an internal validation of the procedure. To our knowledge, this is one of few studies reporting serum concentration levels for a wide array of PS under normal dietary conditions. Most reports so far came from randomized controlled trials that assessed PS levels in a small number of subjects ,44,45 orThere are several limitations to this study, pertaining to intrinsic characteristics of a cross-sectional observational study. First, normally occurring PS serum levels in this study fell within a narrow range as compared to variations achieved in interventional studies when using PS-enriched foods. Still, the values were comparable to those obtained in other countries, thus suggesting that the ranges observed might well fall within physiological values. Second, the assessment methods for IL-6 and TNF-α differed between studies, which might partly explain the observed inconsistencies; still, CRP levels were assessed in the same laboratory using the same method for both follow-ups, and inconsistencies were found. Third, the study was conducted in a geographically limited region, and it has been shown that dietary intakes vary between regions in Switzerland . Hence, Our results failed to indicate a significant association between inflammatory markers and phytosterols levels in a community-dwelling Swiss population. Further studies should investigate the possibility of such an association under dietary conditions providing a higher phytosterol intake.


Autoimmune neutropenia (AIN) is divided into primary and secondary forms. The former is more prevalent in children and is usually a self-limiting disease. Secondary AIN is more common in adults and often occurs in the setting of another autoimmune disorder or secondary to infections, malignancies or medications. Several viral and bacterial pathogens were described to trigger AIN. Here we report a case of AIN in an adult woman associated with human herpesvirus-6 (HHV-6) infection.We report a case of AIN in an adult woman associated with HHV-6 infection. The patient presented to the emergency department with fever and painful genital ulcers. Upon arrival, her laboratory workup demonstrated severe neutropenia and elevated inflammatory markers. She was hospitalized and underwent a thorough infectious, hematological, autoimmune and inflammatory workup. Malignancy was also excluded using an advanced whole body radiological scan. Serological tests confirmed the presence of both acute and chronic types of HHV-6 antibodies, at very high titers. Polymerase chain reaction demonstrated a numerous copies of the virus in the patient’s blood. Specific immunofluorescence test confirmed the diagnosis of autoimmune neutropenia.Secondary AIN is a rare disease that may affect all range of ages. The adult type is a challenging disorder that has different etiologies and may be triggered by a variable infectious pathogen. The finding of HHV-6 as a possible culprit pathogen may warrant physicians into widening the evaluation and include HHV-6 in the analysis. Autoimmune neutropenia (AIN) is caused by increased destruction of peripheral neutrophils due to granulocyte-specific autoantibodies . The etiWe report a case of a 30-year-old female who presented with fever and painful genital ulcers eventually diagnosed with autoimmune neutropenia associated with human herpesvirus type 6 (HHV-6) infection.A 30-year-old female presented with fever and painful genital lesions, beginning three weeks prior to her admission. At that time, she suffered from abscesses located on the fingers of her left hand, which were attributed to trauma. She began a course of antibiotic therapy with a first-generation cephalosporin and then switched to amoxicillin and clavulanate due to gastrointestinal adverse effects. Afterward, she reported painful gingivitis that was attributed to periodontitis. One infected tooth was extracted, and a prophylactic course of amoxicillin was prescribed. She consumed over-the-counter analgesics as non-steroidal anti-inflammatory drugs and dipyrone.Her medical history included bipolar disorder, iron deficiency anemia, and an anal fissure treated conservatively. She also underwent bariatric surgery and a cholecystectomy ten years prior.Physical examination was notable for several genital, labial and perineal, pus-secreting ulcers, fever of up to 38°C, and normal vital signs. Laboratory workup was remarkable for severe neutropenia of 0.13 K/microL neutrophils (range: 1.8-7.7 K/microL) with other than that unremarkable blood smear; acute kidney injury with creatinine 1.27 mg/dl (range: 0.51-0.95 mg/dl) and normal urinalysis. Markedly elevated inflammatory markers with C-reactive protein of 367 mg/l (range: 0-5 mg/l), and erythrocyte sedimentation rate were 84 mm/hour.She was primarily treated with intravascular hydration with fast recovery of kidney function, paracetamol, granulocyte colony-stimulating factor (G-CSF) and empiric broad-spectrum antibiotic. Further testing included cultures from genital ulcers swabs that were positive for Escherichia coli resistant to fluoroquinolones and Enterococcus faecium, leading to designated antibiotic treatment with vancomycin and aztreonam. A total body computed tomography scan did not demonstrate any source of infection and a positron emission tomography (PET) demonstrated high Fludeoxyglucose (FDG) uptake in the sternum and clavicles, mainly due to G-CSF therapy, but no evidence of other pathologies. A bone marrow biopsy demonstrated hypocellular bone marrow with agranulocytosis and evidence of stromal damage Figure 1Daily treatment with G-CSF was not efficacious, and a trial of hydrocortisone therapy induced a flare of mania that required treatment discontinuation. The patient received a pre-treatment psychiatric consultation, treatment with olanzapine for two days and then treatments with 125 mg methylprednisolone for two consecutive days followed by oral glucocorticoids. After two days of methylprednisolone therapy, she was afebrile, and neutrophil count began to recover.An additional workup reveled prolonged partial thromboplastin time (PTT), positive test for lupus anticoagulant and low complement of C3 and C4. A wide laboratory autoimmune panel including other anti-phospholipids antibodies was unremarkable. Avast rheumatological and immunological panel, including ANA, c-ANCA, p-ANCA, anti-dsDNA, anti-CCP, rheumatoid-factor, anti-RO, ani-LA and thyroid function was unremarkable. She underwent an extensive infectious workup that resulted in sterile blood and urine cultures. A test for HLA-B5 was negative excluding Behcet’s disease, although except the genital lesions, she had no other clinical signs or demographic background towards the disease. Viral serology and polymerase chain reaction (PCR) for cytomegalovirus (CMV), Ebstein-Barr virus (EBV), human immunodeficiency virus (HIV), herpes simplex (HSV), and varicella-zoster virus (VZV), were negative. Whereas a positive PCR with numerous copies of human herpesvirus 6 (HHV-6) was demonstrated in the patient’s blood, followed by positive serology for HHV-6 that was compatible with a very high IgG and IgM antibodies against the virus.Eventually, a diagnosis of autoimmune neutropenia associated with HHV-6 infection was suggested and the patient was discharged with a very slow taper down regimen of glucocorticoids, and additional low dose aspirin. Her white blood cell count continued to recover until full normalization with no glucocorticoid therapy, and her genital ulcers gradually healed Figure 2Several factors can trigger secondary autoimmune neutropenia. Infections are of the most common etiologies, including bacterial skin infections, upper respiratory tract, and otitis media. Viral infections can also be associated with secondary AIN, mainly human-immunodeficiency virus (HIV), hepatitis, and parvovirus B19. In this case report, we demonstrated the association of an HHV-6 infection with adult-onset AIN confirmed by the presence of anti-neutrophil antibodies. Adult-onset AIN is associated with underlying autoimmune diseases, infections or malignancies, and an extensive workup is frequently required to reach the etiological basis. In this case, our entire workup was negative; except for detection of HHV-6 is the patient’s blood and skin tissue.There are no specific clinical manifestations of AIN, and the suspicion for this autoimmune disease is raised following a peripheral blood sample showing absolute neutrophil count of < 500 neutrophils/μL. There is no particular feature for AIN on bone marrow examination, however hypocellularity and stromal hyperplasia suggests an immune-mediated etiology, as was documented herein.Establishing a diagnosis of AIN is a 2-step process. Initially, peripheral neutropenia, and secondly the demonstration of autoantibodies against neutrophils. For the diagnosis we used the granulocyte immunofluorescence test (GIFT), which is the most sensitive test . In the HHV-6 is a member of the beta-herpesvirus subgroup, typically affecting children or immunosuppressed individuals. It is mainly known for causing exanthem subitum, characterized by a prodrome of high fever lasting up to 5 days followed by a sudden onset of rash upon fever descent. Other clinical manifestations may include flu-like symptoms and even cause encephalitis. Our patient suffered from several painful genital and labial lesions.There are two types of HHV-6, A and B, that cause distinct diseases . We assuSeveral autoimmune disorders have been suggested to be associated with HHV-6, albeit an underlying mechanism is still unclear. These include multiple sclerosis, myocarditis, idiopathic thrombocytopenia, and Sjogren’s syndrome . In the To the best of our knowledge, adult-onset AIN associated with HHV-6 infection has not been reported in the literature. Two reports described patients up to 12 months of age with HHV-6 infection manifested as transient erythroblastopenia and multiple brain abscesses , 9. Our A possible limitation of our case is that although we demonstrated a high viral load and positive serology during the acute illness, an entity of chromosomally-inherited HHV-6 (ci-HHV-6) was not excluded. About 1% of the population have an integrated viral DNA on the telomeres of each cell . This poTo conclude, secondary AIN is an uncommon autoimmune disease that can be triggered by infectious agents as viral infections among patients of a wide range of ages. In particularly adult onset AIN is yet a challenging event, which requires a broad-spectrum assessment. The present finding of HHV-6 as a plausible viral trigger of AIN is reported here for the first time to the best of our knowledge, and is an addition to the scope of this disease. This may alert physicians treating patients with adult-onset AIN to expand evaluation and include HHV-6 analysis.The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.KF, NS, and AL wrote the original draft and the final version of the manuscript. All authors contributed to manuscript revision, read, and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


With the augmentation of family migration, the number and proportion of elderly migrants have increased dramatically in China. The well-being of this group has a profound impact on the whole society. Subjective well-being is a comprehensive reflection of whether a person’s needs are met. In this cross-sectional study, we established a multiple mediation model to evaluate the mediating effects of loneliness and self-esteem on intergenerational emotional support and, consequently, on subjective well-being in elderly migrants. The study population consisted of 728 elderly migrants living in Nanjing , including 219 men (30.1%) and 509 women (69.9%). The participants’ loneliness and self-esteem were measured using the R-UCLA Loneliness Scale, the Rosenberg Self-Esteem Scale, and the Philadelphia Senior Center Confidence Scale. Multiple regression analyses revealed a significant correlation between intergenerational emotional support and subjective well-being, and mediation analysis revealed that intergenerational emotional support indirectly influenced subjective well-being through three mediators: loneliness , self-esteem , and loneliness and self-esteem . We conclude that loneliness and self-esteem mediate the relationship between intergenerational emotional support and subjective well-being in elderly migrants and can be regulated to improve elderly migrants’ subjective well-being. Great attention should be paid to the emotional needs of elderly migrants, and communication and exchange with elderly migrants should be emphasized to enhance their subjective sense of well-being. With the acceleration of ageing and urbanization in China, an increasing population of elderly migrants, moving mainly from rural areas to cities to live with their children, has emerged . ChineseOlder adults’ well-being is an important indicator of mental health and quality of life , and subLoneliness and isolation are common problems among elderly migrants. Compared to younger migrants, elderly migrants are less able to socially integrate and interact. Several studies have shown that elderly migrants have a higher level of loneliness . LonelinSelf-esteem, also termed self-worth, determines one’s perception of quality of life . Self-esIn this study, we explored the mediating effects of loneliness and self-esteem in the relationship between intergenerational emotional support and subjective well-being among elderly migrants in China. Therefore, we designed four hypotheses to develop the model . First, Although previous studies have elucidated the mechanisms by which intergenerational support enhances subjective well-being, there is room for further exploration. First, few of the previous studies have focused on elderly migrants, a group whose number is increasing year by year. Second, few of the previous studies have explored the relationship here studied using intergenerational emotional support as an independent variable and loneliness and self-esteem as mediating variables. The present study is expected to provide an in-depth understanding of the mechanisms by which intergenerational emotional support may improve the subjective well-being of elderly migrants.The data in this study were provided by the Social Science Foundation Project of the People’s Republic of China “A follow-up study on the mechanism by which intergenerational relationships influence the mental health of elderly migrants”. This project was performed from September 2019 to September 2020 in Nanjing, China. Elderly migrants were recruited from 21 communities in 7 districts of Nanjing , with 3 communities in each district. All participants were voluntary, informed of the purpose of the study, and face-to-face interviewed using a structured questionnaire. All interviewers had experience in medical research and received standardized training for the present study. Only the first-phase survey data were used. A total of 728 elderly migrants were included, comprising 219 (30.1%) males and 509 (69.9%) females.The 3-item R-UCLA Loneliness Scale was used to measure loneliness in the elderly migrants . Each itSelf-esteem was measured by the Rosenberg Self-Esteem Scale (RSES), which consists of 10 self-esteem-related items such as “On the whole, I am satisfied with myself” and “All in all, I am inclined to feel that I am a failure” . Each itIntergenerational emotional support was evaluated according to the emotional closeness between the elderly migrants and their children. The elderly migrants were asked the following three questions: 1. “Do you feel  close to this child?” ; 2. “Do you feel that you get along well with this child?” ; 3. “When you want to talk to this child about your problems or difficulties, do you think he will want to listen to you?” . Scores range from 3 to 9, with a higher score indicating a smoother emotional relationship between the elderly migrants and their children. The Cronbach’s alpha for the present sample was 0.734.This variable was measured using the Philadelphia Geriatric Center scale , developp value of 0.05 was considered statistically significant. The study set the bootstrap confidence interval (CI) at 95% based on a bootstrap sample of 5000. If zero was not included in the 95% confidence interval, it indicated a significant mediation effect.In this study, we used the Statistical Package for Social Sciences (SPSS) to complete all data analysis and processing. Firstly, we used descriptive, one-way, and multi-factor analyses of the data. Count data were described as number of cases and percentages; measurement data were described as means and standard deviations; secondly, Pearson correlation was used to test for the correlation between continuous variables; in univariate analysis, statistically significant variables were included as covariates in the moderation model. We used PROCESS macro version 3.5 (model 6) provided by Hayes for the analysis, with intergenerational emotional support as the independent variable, loneliness and self-esteem as mediating variables, and subjective well-being as the dependent variable. A We used distributed questionnaires, which could lead to be common methodological bias. Therefore, we adopted methods such as using measurement tools with high reliability and effectiveness and conducting reverse scoring on projects. Prior to the analysis, the common method bias was evaluated by the Hamann single factor test on four questionnaires . PrincipThe basic characteristics of the participants are shown in p < 0.01; self-esteem: r = 0.257, p < 0.01). Loneliness was negatively associated with both intergenerational emotional support and self-esteem . Subjective well-being was negatively correlated with loneliness and positively correlated with self-esteem .The correlation matrix for the key variables is presented in The multiple mediation model was constructed to explore the mediating effects of loneliness and self-esteem among the elderly migrants. The variables included gender, age, education level, smoking status, and alcohol consumption. Intergenerational emotional support was set as an independent variable, and subjective well-being as a dependent variable. Loneliness and self-esteem were estimated as two mediators.p < 0.001) and self-esteem , respectively. Loneliness was negatively correlated with self-esteem . In addition, loneliness  and self-esteem  were negatively and positively correlated with subjective well-being, respectively. Intergenerational emotional support was positively correlated with subjective well-being .The analysis  showed tThe mediation pathways are shown in This study verified that loneliness and self-esteem mediate the relationship between intergenerational emotional support and subjective well-being among elderly migrants in China. Significant correlations exist between intergenerational emotional support, loneliness, self-esteem, and subjective well-being. These findings provide more details about the relationship between intergenerational support and subjective well-being (see As shown by the regression model, intergenerational emotional support significantly and positively affected subjective well-being, with a direct effect of 61.10%. This result is consistent with that from a previous empirical study exploring the effect of intergenerational emotional support on subjective well-being among elderly migrants in China . NumerouAs shown by the multiple mediation model, loneliness and self-esteem linked intergenerational emotional support with subjective well-being, suggesting that intergenerational emotional support enhances subjective well-being by reducing loneliness as well as by increasing self-esteem. The total mediating effect of the two mediators was 38.90%, indicating that both play a key role in the relationship between intergenerational emotional support and subjective well-being. Moreover, loneliness exerted the strongest mediating effect of 17.78%. Therefore, hypothesis 2 of this study was confirmed: intergenerational emotional support can enhance subjective well-being by reducing loneliness in elderly migrants. Intergenerational emotional support can provide motivation to the elderly to participate in social activities, which in turn relieves their loneliness and enhances their subjective well-being ,46. WithWe also found that self-esteem mediated the relationship between intergenerational emotional support and subjective well-being among elderly migrants in China. Therefore, hypothesis 3 was also confirmed. Intergenerational emotional support can enhance subjective well-being by increasing the self-esteem of elderly migrants. The mediating effect of this path was 16.23%, suggesting that self-esteem is strongly related to subjective well-being. This may be explained by the fact that people with a high level of self-esteem are more positive or optimistic in facing difficulties ,51,52. TOur study showed that loneliness and self-esteem played serial mediating roles between intergenerational emotional support and subjective well-being, which proved the trueness of hypothesis 4. Intergenerational emotional support can enhance subjective well-being through serially reducing loneliness and increasing self-esteem. Migration can aggravate the loneliness of the elderly, especially when emotional support from their families lacks ,54. AccoSome limitations of this study need to be acknowledged. First, the data collected through questionnaires and evaluated by scales in the form of “face-to-face” interviews may be subjective, and multiple methods should be used to collect information. Second, this was a cross-sectional study, so future experimental and longitudinal studies should be conducted to examine the relationship between intergenerational emotional support, loneliness, self-esteem, and subjective well-being. Third, the data were only collected from elderly migrants in Nanjing, and subsequent studies should expand the sample size and study area to obtain more representative data.Our study shows that loneliness and self-esteem sequentially mediate the positive relationship between intergenerational emotional support and subjective well-being in Chinese elderly migrants. The subjective well-being of elderly migrants can be enhanced through strategies to increase intergenerational emotional support. First of all, the government should pay attention to the mental health of these migrant elderly, optimize the social environment of the area they have moved to, use community services to build a communication platform for them, and implement activities to promote family communication. Secondly, migrant children should increase their emotional communication with their parents, understand their elders’ inner world, ease their loneliness, and offer them understanding and support. In future studies, larger samples should be examined to verify our findings.


Life-threatening infections such as infective endocarditis (IE) are increasing simultaneously with the injection drug use epidemic in West Virginia (WV). We utilized a newly developed, statewide database to describe epidemiologic characteristics and healthcare utilization among patients with (DU-IE) and without (non-DU-IE) drug use-associated IE in WV over five years.This retrospective, observational study, incorporating manual review of electronic medical records, included all patients aged 18–90 years who had their first admission for IE in any of the four university-affiliated referral hospitals in WV during 2014–2018. IE was identified using ICD-10-CM codes and confirmed by chart review. Demographics, clinical characteristics, and healthcare utilization were compared between patients with DU-IE and non-DU-IE using Chi-square/Fisher’s exact test or Wilcoxon rank sum test. Multivariable logistic regression analysis was conducted with discharge against medical advice/in-hospital mortality vs. discharge alive as the outcome variable and drug use as the predictor variable.Staphylococcus aureus (MRSA) isolates , psychiatric disorders , cardiac surgeries , and discharges against medical advice . Multivariable regression analysis showed drug use was an independent predictor of the combined outcome of discharge against medical advice/in-hospital mortality .Overall 780 unique patients had confirmed first IE admission, with a six-fold increase during study period (p = .004). Most patients (70.9%) had used drugs before hospital admission, primarily by injection. Compared to patients with non-DU-IE, patients with DU-IE were significantly younger ; were hospitalized longer ; had a higher proportion of methicillin-resistant This multisite study reveals a 681% increase in IE admissions in WV over five years primarily attributable to injection drug use, underscoring the urgent need for both prevention efforts and specialized strategies to improve outcomes. Infective endocarditis (IE) is a devastating disease that has been associated with injection drug use , 2, resuWest Virginia (WV), the epicenter of the Appalachian opioid epidemic in the U.S., is experiencing multiple injection drug use syndemics, including the highest rates of fatal overdose, acute hepatitis B and neonatal abstinence syndrome in the U.S., as well as unprecedented increases in cases of acute hepatitis C, HIV, and life-threatening bacterial infections such as IE , 9. A stIE results from a bacterial or fungal bloodstream infection that affects the heart valves. In DU-IE, the use of unsterile or shared syringes, contaminated drugs or other equipment, injection behaviors such as licking the needle, and injection through unclean skin facilitates pathogen entry . The resA critical barrier to advancing DU-IE treatment and prevention is the limited information available on patients with DU-IE, including substance use behaviors, clinical characteristics, and healthcare utilization, especially in studies relying just on hospital discharge data and ICD codes –7. To fiThis study was a multicenter retrospective electronic medical records (EMR) review of adults 18 to 90 years of age who had their first hospital admission for IE between January 1, 2014 and December 31, 2018 at any of the four university-affiliated referral hospitals with advanced cardiac care capability in WV. As IE is not a reportable condition, there are no published data for the number of IE cases at each healthcare facility in WV; however, state experts in infectious diseases and cardiology estimate that given the emergent need for sophisticated cardiac and/or surgical intervention, most of the IE cases statewide are transferred to the four facilities.Patients were initially identified using the International Classification of Diseases, Tenth Revision, Clinical Modification (ICD-10-CM) codes for IE , followed by a detailed manual review of the electronic medical records (EMR) of all admissions to confirm diagnosis of IE. We used the General Equivalence Mappings from the Centers for Medicare and Medicaid Services to convert ICD-10-CM to ICD-9-CM codes from previous years . The stuEMR data collected from each of the four hospitals were entered into a single, standardized, coded dataset using the Research Electronic Data Capture (REDCap) system . REDCap We abstracted individual patient information from history and physical examination notes, provider notes, consultation notes, hospital narratives, laboratory tests and imaging results, operative notes, and discharge summaries for each patient. Variables were as follows:Demographics: sex  and age ; race (dichotomized as White vs. others since WV population is predominantly White (93.5%)).Substance use: smoking status ; alcohol use ; drug use , type of drug, method of drug use, participation in MOUD before, during, and at discharge from hospital. Categories for method of drug use  were not mutually exclusive.Clinical characteristics: causative organisms identified and co-morbid medical conditions.Hospital resource utilization: consultations received; surgery for IE ; length of hospital stay; discharge status ; discharge location; readmission during the study period; and death.p < 0.05.Only the first admission of each unique patient during the study period was analyzed. The number of subsequent admissions was recorded to obtain data on the frequency of readmissions during the study period. Categorical variables are presented as counts and percentages. DU-IE and non-DU-IE groups were compared using Chi-square test or Fisher’s exact test when expected cell count was <5. Continuous variables are presented as median and interquartile range (IQR); medians were compared using Wilcoxon rank-sum test. To examine the relationship of drug use and the combined endpoint of discharge AMA/in-hospital mortality, crude and multivariable logistic regression analyses were conducted with discharge against medical advice/in-hospital mortality vs. discharge alive as the outcome variable and drug use as the predictor variable. Discharge AMA and in-hospital mortality were combined due to the small number of AMA discharges among non-DU-IE and the fact that both are negative outcomes compared to referent category of discharged home. Multivariable analysis was adjusted for sex , age , number of comorbidities , and surgery . All statistical analyses were conducted in R version 4.0.2 . The significance level was set at A total of 780 patients with confirmed IE were admitted between January 1, 2014 and December 31, 2018 across the four study sites; the majority (63%) were admitted at one site, Ruby Hospital at West Virginia University. Staphylococcus aureus (MRSA) compared with non-DU-IE patients . Compared with patients with DU-IE, patients with non-DU-IE had significantly more co-morbid conditions, such as hypertension, type 2 diabetes, chronic lung disease, coronary artery disease, hyperlipidemia, chronic kidney disease, stroke, peripheral vascular disease, and cancer (p < .001). Psychiatric disorders were more prevalent among those with DU-IE compared with patients with non-DU-IE . These diagnoses did not solely reflect substance use disorder (SUD): 22.9% of patients with DU-IE were diagnosed with psychiatric disorders other than SUD. No patients with non-DU-IE had a diagnosed SUD, but 40.7% of those with DU-IE had an SUD. Psychiatric diagnoses, such as depression, anxiety, posttraumatic stress disorder, bipolar disorder, were common among those with SUD.Causative organisms and comorbidities presented in Most patients with IE (70.9%) had used drugs before hospital admission . Among tPatients had a median hospital stay of 20 days, IQR: 32 . The medIn the multivariable regression analysis controlling for sex, age, number of comorbidities, and surgery, patients with DU-IE were three times as likely to be discharged AMA/have in-hospital mortality compared to patients with non-DU-IE , driven by the high AMA discharge rate for this group . Sex, agIn this retrospective study, we document a striking 458% increase in overall IE admissions in West Virginia over a five-year period ending in 2018, largely attributable to the 681% increase in DU-IE. Findings also show drug use was an independent predictor of discharge against medical advice/in-hospital mortality. There was a significant burden of care in patients with DU-IE who more commonly underwent cardiac surgery and received psychiatric services/consultations compared with patients with non-DU-IE. Multidisciplinary care involving three or more consultative services was common across the entire study population reflecting the serious nature of an IE diagnosis.This study supports other recent reports of increases in IE cases, particularly among people who inject drugs –7, 14. WHowever, our IE population had a higher proportion of DU-IE cases (71%) than that reported for other regions of the U.S. Data from the U.S. National Inpatient Sample (NIS) indicated that DU-IE cases accounted for up to 23.5% of IE cases during January 2010 –August 2015 , while aThe younger median age of patients with DU-IE compared to non-DU-IE patients in our sample aligns with several other studies , 18–22; Staphylococcus aureus has changed in the US in recent years. CDC data show that injection drug use-associated MRSA infections have more than doubled from 4.1% in 2012 to 9.2% in 2016 [Our results show a significantly higher proportion of MRSA IE cases among the DU-IE patients. The epidemiology of  in 2016 . MRSA in in 2016 . Data fr in 2016 .That patients with DU-IE were approximately half as likely to die during their hospitalization than those with non-DU-IE may be attributable to their considerably younger age and significantly fewer cormorbid medical conditions. Readmission of patients with DU-IE was more than double that for non-DU-IE, which may be related to having been discharged against medical advice and complications due to recrudescent injection drug use. Moreover, the readmission rate for DU-IE is likely an underestimate since patients may have been admitted to a local hospital without cardiac surgery availability and not transferred to a study hospital.Our study identified drug-use as an independent risk-factor for patients who were discharged AMA or who died during hospitalization, after controlling for other potential confounders. This aligns with an analysis from the representative National Inpatient Sample of over 30,000 IE hospitalizations between 2010 and 2015 that also found injection drug use to be significantly associated with increased odds of discharge AMA .Our studDue to its retrospective design, our study was limited by the lack of availability of baseline variables such as education, income, duration of all drug use and specifically of injection drug use. Errors in diagnostic coding may have introduced misclassification of some patients. In addition, patients may not have consistently reported, or the EMR may not have consistently captured, relevant information on drug, alcohol, and cigarette use, and some DU-IE cases may have been misclassified. We also found that three quarters of patients receiving MOUD during hospitalization had an SUD diagnosis, which suggests underreporting of SUD. Finally, we lack long-term follow-up data on patient outcomes such as out of hospital mortality or subsequent admissions to other hospitals.Despite these potential limitations, a major strength of our study is that rather than relying solely on ICD codes as multiple prior studies have done , 29, 30,Additionally, we examined individual patients, and not hospitalizations based on discharge databases, as was done in other studies. By focusing on the four academic hospitals, three of which are the only hospitals in WV that offer cardiac surgery, our study included the largest number of IE patients who are routinely transferred to hospitals where state-of-the-art care can be provided. Thus, our database captured most of the IE cases in WV during the five-year study period, which is close to comprising a state registry of all IE cases in this period.In summary, robust statewide EMR data reveal a 456% increase in overall IE admissions over five years in WV, primarily attributable to increases in DU–IE. Compared with patients with non-DU-IE, those with DU-IE exhibited a significant burden of psychiatric conditions, in addition to SUD. Despite lower in-hospital mortality, individuals with DU-IE had significantly higher resource utilization and required not only usual multidisciplinary care, but also cardiac surgery and MOUD. These data provide a crucial foundation to focus on preventive harm reduction efforts and to develop strategies for specialized treatment of DU-IE to improve outcomes, limit the proportion who are discharged against medical advice, and prevent readmissions.


Immunotherapy has greatly enhanced the effectiveness of cancer treatments, but the efficacy of many current immunotherapies is still limited by the tumor-suppressive immune microenvironment. Multiple studies have shown that activating the stimulation of IFN genes (STING) pathway and inducing innate immunity can significantly impact the tumor immune microenvironment and improve antitumor therapy. While natural or synthetic STING agonists have been identified or developed for preclinical and clinical use, small molecule agonists have limited utility due to degradation and lack of targeting. As such, the delivery and release of STING agonists into tumor tissue is a major challenge that must be addressed in order to further advance the use of STING agonists. To address this challenge, various nanomedicines have been developed. In this paper, we concisely review the antitumor immunotherapeutic mechanisms of STING agonists, highlighting the latest developments in STING agonists and the current progress of nanomedicines for activating STING. We classify the different nanomedicines according to the STING agonists they utilize in order to facilitate understanding of recent advances in this field. Finally, we also discuss the prospects and challenges of this field. Conventional oncology therapies  often treat tumors at the expense of the patient’s immunity and quality of life. This means that conventional oncology therapies can be harmful to the patient’s body while achieving their therapeutic goals. In the past decade, the field of cancer treatment has undergone an immunological revolution. Immunocellular therapy with lower side effects is receiving increasing attention from researchers as a powerful complement to traditional therapies. Immune checkpoint blockade (ICB) is considered to be the first generation of immunotherapy. The main therapeutic mechanism of ICB is to block the mutual recognition process of surface inhibitory receptors and ligands between tumor cells and T cells. This will enable T cells to exert their cytotoxic effects normally . There hThe tumor microenvironment (TME) is the complex tissue environment surrounding the tumor cells. It consists of tumor cells, immune cells, stromal cells, vascular cells, other cellular and non-cellular components . Dependi+ cells, which may be used to eliminate in situ tumors as well as lung metastases through systemic adaptive immunity  signaling pathway, is a promising approach to cancer immunotherapy . This apimmunity .It is currently the primary clinical approach to inject STING agonists directly into tumors by intra-tumoral injections since STING is widely distributed in somatic cells. However, it should be noted that intra-tumor injections may not always be feasible in clinical practice due to uneven drug diffusion and possible drug leakage issues. Besides, the activity of STING is mediated through the delivery of STING agonists into the cytosol of the cell . This meA brief description of the mechanisms of tumor immunotherapy associated with activation of the STING pathway will be presented in this article, as well as a summary of recent advances in nanomedicines aimed at activating STING. There is excellent spatiotemporal controllability of nanomedicines incorporating STING agonists, as well as the ability to control immune activation in response to TME signaling. The results of these studies are of significant value in improving some of the limitations and drawbacks of conventional immunotherapy. In addition, they enable more effective translation and application of cancer immunotherapy.Most immunotherapies are aimed at enhancing adaptive antitumor immunity at the present time. It’s important to note that adaptive antitumor immunity is heavily dependent on the strength of the innate immunity . ThroughIn recent years, researchers have been able to demonstrate that the cGAS-STING pathway plays a crucial role in linking innate and adaptive immune responses against tumors. It would therefore be feasible to treat cancer by pharmacologically activating the cGAS-STING pathway. Natural or synthetic CDNs such as 2’3’-cGAMP, ADU-S100 were first identified as direct STING agonists. Furthermore, small molecules that are non-nucleotidyl agonists of STING were found, such as 5,6-dimethylxanthenone-4-acetic acid (DMXAA), dimeric amidobenzimidazoles (diABZI), MSA-2 and SR-717  , and cyclic dipolyadenosine phosphate (CDA). Among them, 2’3’-cGAMP, as a second messenger of information transmission in mammals, is a strong-affinity STING stimulator. The unique 2’-5’ bond in 2’3’-cGAMP makes it the most dynamic hSTING activator of all CDNs. First discovered in bacteria, 3’3’-cGAMP, CDG, and CDA molecules are analogs of 2’3’-cGAMP molecules, and they all have a certain affinity for STING proteins . However2) for long-range on-demand release of agonists to activate the STING pathway under NIR-II photoirradiation, thus constructing mild photothermal-enhanced chemodynamic-immunotherapy  enhances antitumor immune function, thereby promoting the infiltration of effector T cells into tumor tissues. As a result, it is achieved that restraint of both primary tumors and distant ones, as well as suppression of liver and lung metastases.There is a growing interest in the use of lipid nanoparticles (LNPs), including liposomes, solid lipid nanoparticles (SLNs), and positively charged lipid-nucleic acid complexes (lipoplexes), to deliver STING agonists . For exaotherapy . In this+ T cells and NK cells. The experimental results showed that CDG/YSK05 liposome could enhance the expression of CD80, CD86, and MHC-I. These results suggest that CDG enters the cytoplasm under the transfer of YSK05 liposomes and plays a momentous role in activating the innate immune system. Subsequently, Harashima’s group reported a combinatorial strategy to combine CDG-loaded nanoliposomes (STING-LNP) with immune checkpoint inhibitors (ICIs), which reduced the drug resistance of ICIs and exerted a synergistic effect on antitumor  DCs, thereby mediating the entry of liposomes into CD103+ DCs and activating the STING pathway. Importantly, CD103+ DCs have been shown to be major producers of CXCL9 and CXCL10, which are IFN-I-induced chemokines that recruit T cells in a STING-dependent manner. As a result, SA-TL can accurately induce the infiltration of T cells in the tumor site by targeting CD103+DC, and achieve remodeling of the TME and potent antitumor immunotherapy. In this study, SA-TL exhibited robust immune responses and significant antitumor effects, whether used as monotherapy or in combination with anti-PD-L1.Compared to natural CDNs, the sulfur-substituted analog ML RR-CDA (ADU-S100) stands out for its stability, lipophilicity, and high efficiency. As a result, it is considered as the most promising CDN encapsulated in nanoparticles. For instance, Doshi and coworkers recently developed a targeted cationic liposomal nanoparticle (SA-TL) loaded with ADU-S100  for systemic intravenous administration . By modiin vivo studies, intravenously administered ZnCDA prolongs CDA half-life and facilitates tumor targeting, providing an important pharmacokinetic advantage. At a single dose, antitumor effects were observed in a variety of preclinical tumor models. Notably, this study demonstrated that ZnCDA enhanced tumor accumulation by destroying endothelial cells in the tumor vasculature, revealing a novel mechanism of ZnCDA tumor accumulation. Moreover, ZnCDA was found to preferentially target and regulate antigen processing and presentation by tumor-associated macrophages (TAM), thereby further promoting antitumor T cells responses. In conclusion, ZnCDA enhances tumor targeting of CDA, and modulates TAM to improve TME. Additionally, it can be combined with ICB or IR to overcome tumor resistance.In contrast to conventional nanoparticles, Lin et al. identified a tumor-targeting nanoscale coordination polymer (ZnCDA) loaded with CDA and zinc (Zn) . AccordiTo overcome the CDNs-related delivery barriers, many nanoplatforms have been developed to achieve effective delivery of CDNs. Despite the fact that CDNs in a variety of molecular structures have been shown to stimulate the immune system’s ability to combat tumors in mice, their inability to easily pass through cell membranes and their lack of stability in metabolism hinder their effectiveness and potential medical use . TherefoIn a recent study, Ramanjulu and co-workers at GlaxoSmithKline discovered a series of small molecules containing the active structure of amidobenzimidazole (ABZI) with potential STING agonism through high-throughput screening . Among tIn 2021, the research group led by Zhishen Ge developed a type of nanoreactor called DiABZI and glucose oxidase (GOD)-co-loaded PEG-b-P(FcMA-co-PEMA) polymersome nanoreactors (D/G@PFc) . These n+ T cells, NK cells and DCs as well as antigen cross-presentation.Based on high-throughput screening, Lairson et al. eventually identified a non-nucleotidyl analog of the small molecule STING agonist SR-717, which exhibited higher stability under physiological conditions compared to CDNs . The co-Wang et al. developed a drug delivery system for non-nucleotide STING agonist SR-717 that can be administered intravenously and effectively targets glioma brain tumors. Specifically, The N-terminus of the human heavy-chain ferritin (HFn) protein subunit was modified with tumor-targeting polypeptide RGE the by genetic engineering to endow the HFn nanocarrier with tumor-targeting and tissue-penetrating properties. Subsequently, SR-717 was encapsulated in RGE-HFn nanocarriers by pH-mediated depolymerization-reassembly to obtain SR717@RGE-HFn NPs   inhibitor NLG919 . Subsequin vitro and in vivo. Based on the two characteristics of different binding sites and different action time from traditional agonists, it indicates that the combination of PC7A and 2’3’-cGAMP can achieve a synergistic therapeutic effect (Nanoparticle vaccine (nanovaccine) for tumor immunotherapy is an emerging hot area that has caused extensive exploration. For instance, Gao and coworkers developed a library of ultra-pH-sensitive (UPS) NPs and screened out some NPs  capable of delivering STING agonists directly to immune cells and demonstrating significant therapeutic effects in several murine tumor models. The concept of ‘metalloimmunotherapy’ was presented for the first time in this study, and the potential of nanomedicine-based cancer metalloimmunotherapy was revealed.A study conducted by James J. Moon et al. examined the potential synergistic effects of various metal ions with STING agonists and reported that Mnagonists . This st4:ND@NaLuF4 (radiosensitizer) via metal-phenolic coordination to obtain biocompatible nanoparticles, and the remaining phenolic moieties were complexed with Mn2+ to form DSPM. In this DSPM, amphiphilic PEG-polyphenol provides abundant coordination to lanthanide-doped radiosensitizer and Mn2+ to ensure stability, while ensuring the release of them due to pH-responsive. Following intravenous administration, DSPM effectively exerted the co-delivery of Mn2+ and radiosensitizer within the TME, resulting in the activation of the STING pathway and enhancing the sensitivity of tumor cells to X-ray. The effect of DSPM was verified to be an efficient therapeutic nanoplatforms for optimizing cancer radiotherapy in primary, distant, and lung metastatic tumor modes. In this study, the synergy between radiosensitization and Mn2+-mediated immunomodulation is highlighted in tumor therapy. Based on metal-phenolic coordination, Dai’s group also explore the performance of phenolic nanoadjuvant (PIMS NPs), which was self-assembled by sonosensitizer polymer (PEG-b-IR), glutathione (GSH) inhibitor (sabutoclax), TME acidic sensitive phenolic polymer (PEG-b-Pho) and Mn2+ , which was employed to potentiate radio-sensitization and activate the cGAS-STING pathway simultaneously, thereafter promote DC maturation and motivate robust antitumor immunity . The ampand Mn2+ . Among tIn general, we have reviewed nanomedicines containing different STING agonists. From the view of STING activators, there have been developed into the current diverse situation through continuous exploration and synthesis. Not only laterally explored and designed agonists for inducing the “closed” conformation of STING, but also longitudinally discovered DNA stimulation upstream of the pathway and agonists that bond to non-competitive STING surface sites. Although a variety of STING agonists have been discovered, there are still some disadvantages in physiological barriers and targeted distribution. Furthermore, the establishment of tumor models corresponding to human tumor histology and developmental patterns is also necessary to evaluate the effects of STING agonists and to prepare for clinical translation.As an ideal platform, the nano-delivery of cGAS-STING agonists is still in its infancy. From the perspective of drug delivery platforms, significant progress has been made in the synthesis and application of multipurpose nano-formulation materials, which greatly improving the feasibility of STING agonists for tumor immunotherapy. Moreover, modified nanoplatforms with diverse properties and functions are required to improve drug stability and achieve targeted delivery and release based on tumor cell specificity. This is significant both for improving antitumor activity and reducing the risk of the immune storm. However, multifunctional nanoplatforms present manufacturing challenges, including the complexity of large-scale production, the quality stability of different batches, tricky storage conditions, and high production costs. These are the issues that must be paid attention to and resolved for clinical translation in the future.From the perspective of cancer immunotherapy, a single strategy cannot eliminate the tumor, and the combination strategy is more suitable to deal with the multifaceted nature of the tumor. Growing evidence suggests that STING agonists can act synergistically with other immune agents as sensitizers, including immune checkpoint inhibitors, IDO inhibitors as well as tumor antigens. In addition to immune agents, STING agonists have been proven to be synergistic with other approaches, such as chemotherapy, radiotherapy, phototherapy, and chemodynamic therapy, to effectively clear tumor masses and induce durable antitumor immune memory. Modular nanoparticles provide a platform for the co-delivery of different classes of molecules, such as tumor antigens and immunomodulators, maximizing the effect of a single drug. Moving forward, combination therapies delivered by nanoplatforms may become mainstream in cancer treatment.SC and AP wrote the manuscript. MC performed the design of the review. MC and MZ read and revised the manuscript. All authors contributed to the article and approved the submitted version.


With advancements in cancer treatment, the life expectancy of oncology patients has improved. Thus, transcatheter aortic valve replacement (TAVR) may be considered as a feasible option for oncology patients with severe symptomatic aortic stenosis (AS). We aim to evaluate the difference in short- and long-term all-cause mortality in cancer and non-cancer patients treated with TAVR for severe AS.Medline, PubMed, and Cochrane Central Register of Controlled Trials were searched for relevant studies. Patients with cancer who underwent treatment with TAVR for severe AS were included and compared to an identical population without cancer. The primary endpoints were short- and long-term all-cause mortality.P < 0.01). Four studies evaluated short-term mortality after TAVR and demonstrated no difference in it in patients with and without cancer .Of 899 studies included, 8 met inclusion criteria. Cancer patients had significantly higher long-term all-cause mortality after TAVR when compared to patients without cancer  1.26–1.62; Patients with cancer and severe AS have higher long-term all-cause mortality after TAVR. However, we found no difference in short-term all-cause mortality when comparing patients with and without cancer. The decision to perform TAVR in cancer patients should be individualized based on life expectancy and existing co-morbidities.The online version contains supplementary material available at 10.1186/s12872-022-02651-4. Due to the lower risk of complications, transcatheter aortic valve replacement (TAVR) has become the treatment of choice over surgical aortic valve replacement (SAVR) for frail patients with symptomatic aortic stenosis (AS) . The incTAVR has been proven to improve the hemodynamics and functional status of patients with severe symptomatic AS –11. Its www.clinicaltrialresults.org, www.clinicaltrials.gov, and presentations from major cardiovascular proceedings were also searched. All citations retrieved from the search were transferred to EndNote X7.5 Reference Manager  and duplicates were removed.This systematic review and meta-analysis was reported according to Preferred Reporting Items for Systematic Review and Meta-Analyses (PRISMA) guidelines . MedlineAll citations were screened by two independent reviewers (MUS and OY) on the basis of eligibility criteria. Inclusion criteria in the included studies comprised of adults with a diagnosis of cancer identified to have severe AS and underwent treatment with TAVR. Patients in whom TAVR was contraindicated or did not have TAVR performed and patients who had SAVR for treatment of severe AS were excluded. Studies that did not compare TAVR outcomes in patients without a history of active cancer were excluded. The primary endpoint in the included studies comprised of short- and long-term all-cause mortality. Short-term mortality was defined as death within 30 days after TAVR. Long-term mortality was defined as death 30 days after TAVR. Secondary analyses were performed to identify the risk of cardiac mortality, myocardial infarction (MI), stroke, acute kidney injury (AKI), and major bleeding among patients with and without cancer after TAVR.Two independent reviewers (MUS and OY) extracted the data on year of publication, study design, inclusion criteria, primary endpoints, type of cancer, and follow-up time using a standardized data extraction form.2-statistic was quantified to measure heterogeneity with values > 25%, 50%, and 75% consistent with low, moderate, and high degrees of heterogeneity, respectively [P-values less than 0.05 were considered statistically significant. Certainty in the evidence , was assessed using the GRADE approach  based on the risk of bias, imprecision, indirectness, inconsistency, and publication bias.Outcomes from each study were pooled and compared using a random effects model to account for potential between study variances. Treatment effect was reported as risk ratio (RR) and was supplemented by 95% confidence intervals (CI). The Iectively . Review Risk of bias was assessed using the Modified Newcastle–Ottawa scale for observational studies, which assesses 3 domains: patient selection, comparability, and outcome assessment  and adjusted  subgroups similar to the overall result  . However, the heterogeneity decreased , MI , stroke , AKI , or major bleeding  between patients with and without cancer who underwent TAVR  and long term mortality 42% (low). The I2 value for secondary outcomes ranged from 0 to 83%. Overall, the certainty in the estimates in all the outcomes was judged to be moderate. Additional file The included studies were observational with variable methodological quality and thus are at increased risk of selection and confounding bias. The estimates were precise for short term mortality, long term mortality, and all the secondary endpoints except for MI which had less than 100 events. There was no indirectness or evidence of publication bias. Heterogeneity was noted among the included studies. The quantified IWe investigated the short- and long-term all-cause mortality in patients undergoing TAVR for AS with underlying malignancy compared to those without. There was no difference in short-term mortality among patients with cancer compared to those without who underwent TAVR. However, patients with malignancy had increased long-term all-cause mortality after TAVR. Subgroup analyses demonstrated that the higher risk of all-cause long-term mortality was apparent in those with active and past cancer. No significant difference was noted in the secondary endpoints between groups, including long-term cardiac mortality.Our analysis differs from two previous meta-analyses published on this topic. The meta-analysis performed by Murphy et al. included studies that exclusively enrolled patients who received thoracic irradiation for cancer treatment . These pThe introduction of TAVR has allowed physicians to treat many patients with AS in whom aortic valve replacement (AVR) was initially thought to be contraindicated. Namely due to the risks and potential complications associated with open surgery. Severe symptomatic AS has a prognosis that is worse than many cancers with respect to both morbidity and mortality. The prognosis and expected length of survival is further worsened when patients with severe AS also have comorbid cancer. This raises the question whether these patients who have malignancy along with severe AS should be offered AVR.The treatment of cancer, which includes oncologic surgery, chemotherapy, or radiation therapy, might lead to worsening of aortic valve disease, either because of effects on the valve or on myocardial function. In turn, this may result in withholding effective cancer therapy in patients suffering from severe AS. The European Society of Cardiology recommends afterload reduction with medical therapy in patients with left ventricle dysfunction or heart failure induced by anthracycline or antineoplastic therapy . The mosOur study agrees with the findings from Mangner et al., Nuis et al., and Bleiziffer et al., who reported that malignancy was associated with increased odds of long-term mortality post TAVR. This is in contrast to the prospective studies by Watanabe et al. and Biancari et al., where they showed no difference in long-term mortality in patients with or without malignancy post-TAVR. We believe that this difference is likely due to the variability in cancer type and stage, duration of treatment, and ejection fraction (EF) in the population studied. It is important to recognize that long-term mortality post-TAVR is unlikely to be related to the TAVR procedure itself, but more likely to be driven by underlying pre-existing comorbidities. Participants included in the trial conducted by Watanabe et al. had a higher mean EF in both cancer and non-cancer groups compared to the study conducted by Mangner et al. Berkovitch et al. reported that patients with malignancy who underwent cancer related treatment < 1 year ago had a higher long-term mortality after TAVR . Thus, tWe found no difference in periprocedural complications in patients with and without cancer after TAVR. Despite this, it is important to be conscious that performing TAVR in patients with cancer is still high-risk. These patients are at greater risk of cardiopulmonary dysfunction from prior chemoradiotherapy. Additionally, they are at increased risk of significant aortic valve and annular calcification. This makes treatment with self-expanding prostheses challenging due to under-expansion, which places patients at higher odds of paravalvular regurgitation , 36.This meta-analysis has limitations primarily due to limitations in the studies that were included. The studies are non-randomized, introducing the possibility of selection and sample biases. There was a difference in baseline characteristics, including baseline cardiac function, malignancy type, TAVR approach, valve type and follow-up duration, which introduces heterogeneity. This limitation was reduced by performing subgroup and leave one out analyses. Meta-regression could not be performed due to the number of studies being less than 10. As the studies were not blinded, a moderate risk of performance bias was observed among the included studies. Finally, we restricted this study to include articles from PubMed and Cochrane databases. Hence, it is possible that there are other studies matching our inclusion criteria that are not included in our meta-analysis.This study offers insight into the mortality among cancer patients who undergo TAVR. Our meta-analysis identified higher risk of long-term all-cause mortality among patients with active and past cancer who undergo TAVR. The increased mortality is likely multifactorial and could be related to cancer stage, cancer type, chemotherapy utilized, and pre-existing co-morbidities. There was no difference in short-term mortality, cardiac mortality, or periprocedural complications between cancer and non-cancer patients who undergo TAVR. A multidisciplinary approach, including with oncologists and cardiac surgeons, is required to create a comprehensive plan for cancer patients being considered for TAVR. The decision to undergo TAVR in this population should always be individualized after contemplating the risks associated with the procedure as well as complications that could arise due to cancer.Additional file 1. Supplementary Material.