Search Results (77)

Background: Coronary heart disease (CHD) remains the most prevalent pathology within the circulatory system. Among its chronic complications, ischemic mitral valve regurgitation (IMR) is observed in approximately 15% of patients with sustained myocardial ischemia. The presence of this complex valvular defect significantly increases both overall mortality and the incidence of adverse cardiovascular events. Notably, the presence of moderate to severe mitral regurgitation in patients undergoing surgical revascularization has been shown to double the risk of death. Despite the well-established etiology of IMR, data regarding the efficacy of surgical interventions and the determinants of postoperative outcomes remain inconclusive. Methods: The objective of the present study was to evaluate both early and long-term outcomes of surgical treatment of mitral regurgitation in patients undergoing coronary artery bypass grafting (CABG) due to ischemic heart disease. Particular attention was given to the influence of the severity of regurgitation, left ventricular ejection fraction (LVEF), and the dimensions of the left atrium (LA) and left ventricle (LV) on the postoperative prognosis. An additional aim was to identify preoperative risk factors associated with increased postoperative mortality and morbidity. A retrospective analysis was conducted on 421 patients diagnosed with ischemic mitral regurgitation who underwent concomitant mitral valve surgery and CABG. Exclusion criteria included emergent and urgent procedures as well as non-ischemic etiologies of mitral valve dysfunction. Results: The study cohort comprised 34.9% women and 65.1% men, with the mean age of 65.7 years (±7.57). A substantial proportion (76.7%) of patients were aged over 60 years. More than half (51.5%) presented with severe heart failure symptoms, classified as NYHA class III or IV, while over 70% were categorized as CCS class II or III. Among the surgical procedures performed, 344 patients underwent mitral valve repair, and 77 patients required mitral valve replacement. Additionally, 119 individuals underwent concomitant tricuspid valve repair. Short-term survival was significantly affected by the presence of hypertension, prior cerebrovascular events, and chronic kidney disease. In contrast, hypertension and chronic obstructive pulmonary disease were identified as significant predictors of adverse late-term outcomes. Conclusions: Interestingly, neither the preoperative severity of mitral regurgitation nor the echocardiographic measurements of LA and LV dimensions were found to significantly influence surgical outcomes. The perioperative risk, as assessed by the EuroSCORE II (average score: 10.0%), corresponded closely with observed mortality rates following mitral valve repair (9.9%) and replacement (10.4%). Notably, the need for concomitant tricuspid valve surgery was associated with an elevated mortality rate (12.4%). Furthermore, the preoperative echocardiographic evaluation of LA regurgitation severity, as well as LA and LV dimensions, did not exhibit a statistically significant impact on either early or long-term surgical outcomes. However, a reduced LVEF was correlated with increased long-term mortality. The presence of advanced clinical symptoms and the necessity for tricuspid valve repair were independently associated with a poorer late-term prognosis. Importantly, the annual mortality rate observed in the late-term follow-up of patients who underwent surgical treatment of ischemic mitral regurgitation was lower than rates reported in the literature for patients managed conservatively. The EuroSCORE II scale proved to be a reliable and precise tool in predicting surgical risk and outcomes in this patient population. Full article

This study aims to investigate the mechanism by which the total flavones of Rhododendron (TFR) protect against cerebral ischemic injury through the endothelial-derived H₂S-mediated regulation of RhoA phosphorylation at the Ser188 and Rho kinase 2 (ROCK₂) phosphorylation at Thr436. For experimental design, mouse or rat cerebrovascular endothelial cells (ECs) were cultured with or without neurons and subjected to hypoxia/reoxygenation (H/R) injury. The vasodilation of the cerebral basilar artery was assessed. Cerebral ischemia/reperfusion (I/R) injury was induced in mice by bilateral carotid artery ligation, followed by Morris water maze and open field behavioral assessments. The protein levels of cystathionine-γ-lyase (CSE), 3-mercaptopyruvate sulfurtransferase (3-MST), RhoA, ROCK₂, p-RhoA (RhoA phosphorylated at Ser188), and p-ROCK₂ (ROCK₂ phosphorylated at Thr436) were quantified. Additionally, the activities of RhoA and ROCK₂ were measured. Notably, TFR significantly inhibited H/R-induced H₂S reduction and suppressed the increased expression and activity of RhoA and ROCK₂ in ECs, effects attenuated by CSE or 3-MST knockout. Moreover, TFR-mediated cerebrovascular dilation was reduced by RhoA or ROCK₂ inhibitors, while the protective effect of TFR against cerebral I/R injury in mice was markedly attenuated by the heterozygous knockout of ROCK₂. In the ECs-co-cultured neurons, the inhibition of TFR on H/R-induced neuronal injury and decrease in H₂S level in the co-culture was attenuated by the knockout of CSE or 3-MST in the ECs. TFR notably inhibited the H/R-induced upregulation of neuronal RhoA, ROCK₂, and p-ROCK₂ protein levels, as well as the activities of RhoA and ROCK₂, while reversing the decrease in p-RhoA. However, the knockout of CSE or 3-MST in the ECs significantly attenuated the inhibition of TFR on these increases. Furthermore, 3-MST knockout in ECs attenuated the TFR-mediated suppression of p-RhoA reduction. Additionally, CSE or 3-MST knockout in ECs exacerbated H/R-induced neuronal injury, reduced H₂S level in the co-culture system, and increased RhoA activity and ROCK₂ expression in neurons. In summary, TFR protected against ischemic cerebral injury by endothelial-derived H₂S promoting the phosphorylation of RhoA at Ser188 but inhibited the phosphorylation of ROCK₂ at Thr436 to inhibit the RhoA-ROCK₂ pathway in neurons. Full article

Background/Objectives: Aneurysmal subarachnoid hemorrhage (aSAH) remains a life-threatening cerebrovascular event with high rates of mortality and long-term morbidity. Among its complications, delayed cerebral ischemia (DCI) is a major contributor to poor clinical outcomes. Although cerebral vasospasm has traditionally been considered the primary mechanism underlying DCI, recent studies have revealed the multifactorial nature of this condition. This review aims to provide a comprehensive overview of the pathophysiology, preventive strategies, and current treatment options for DCI following aSAH. Methods: A narrative literature review was conducted using the PubMed database to identify peer-reviewed articles relevant to the prevention and treatment of DCI following aSAH. The search strategy employed the following terms: (“Subarachnoid Hemorrhage” [MeSH]) AND “Delayed Cerebral Ischemia” AND (“Prevention and Control” [Subheading] OR “Secondary Prevention” [MeSH]). This search strategy was designed to capture studies addressing both pharmacological and non-pharmacological preventive measures for DCI. Results: A comprehensive PubMed search identified a total of 113 relevant articles. Among these, 40 publications primarily addressed pharmacological interventions, while 22 focused on neuromonitoring techniques. An additional 20 articles explored the pathophysiological mechanisms underlying DCI, and 15 involved preclinical studies utilizing animal models. The remaining 16 articles encompassed diverse topics, including prophylactic endovascular therapies, newly proposed definitions of DCI, treatment algorithm development, functional outcome analyses, and entries in clinical trial registries. Emerging evidence highlights that vasospasm alone does not account for all cases of DCI. Pharmacological approaches such as nimodipine, clazosentan, and fasudil have shown varying degrees of efficacy. Circulatory management and removal of subarachnoid hematoma via CSF drainage or thrombolytics may reduce DCI risk, although their impact on long-term neurological outcomes remains controversial. Endovascular therapy and adjunctive agents such as cilostazol or anticoagulants have demonstrated potential but require further validation through large-scale trials. Conclusions: Effective DCI prevention and treatment require a multimodal approach targeting diverse pathological mechanisms beyond vasospasm. Improved risk stratification, early detection, and individualized therapy are essential for advancing the management of patients with aSAH. Full article

Background: Intracranial artery calcification detected on CT imaging is a recognized risk factor for ischemic cerebrovascular diseases, but the underlying etiology of this association remains unclear. Differences in objective morphometric characteristics of these calcifications may partially explain this association, yet these measurements are largely absent in the literature. We investigated intracranial artery calcification morphometry in patients with recent anterior ischemic stroke or TIA, assessing potential differences between calcifications in both intracranial carotid arteries (ICAs) located ipsilateral and contralateral to the cerebral ischemia. Methods: Among 100 patients (mean age 69.6 (SD 8.8) years) presenting to academic neurology departments, 3D reconstructions of both ICAs were based on clinical CT-angiography images. On these reconstructions, a luminal centerline and cross-sections perpendicular to this centerline were created, facilitating the assessment of calcification morphometry, spatial orientation and stenosis severity. Differences in calcification characteristics between ICAs were assessed using two-sided Wilcoxon signed-rank and χ² tests. Results: Among 200 arteries, a median of four (IQR 2–6) individual calcifications were counted, with a mean area of 1.8 (IQR 1.2–2.7) mm², a mean arc width of 43.5 (IQR 32.3–53.2) degrees, and median longitudinal extent of 15.4 (IQR 5.9–27.0) mm. Calcifications were most often present in the anatomical C4 section (56.0%), with predominantly posterosuperior orientation (38.5%) and 42.0% had a local stenosis severity > 70%. None of these aspects significantly differed between ICAs, and this remained after restricting analyses to patients with undetermined etiology. Conclusions: We found no differences in morphometrical or spatial aspects of calcifications between ICAs ipsilateral and contralateral to the cerebral ischemia. Full article

Background and Objectives: The purpose of this study was to determine the factors that cause delay time in patients admitted to the hospital with STEMI. In addition, the effect of this delay on the patient’s prognosis has also been investigated. Materials and Methods: a total of 301 patients diagnosed with STEMI treated with primary percutaneous coronary intervention (pPCI) were included in the study. Reinfarction, revascularization, cerebrovascular event, and cardiac death were determined as major cardiac clinical events. The follow-up period of our study was 475 ± 193 days. Results: Univariate analysis revealed that factors influencing delay time included BMI, hypertension diabetes, smoking habit and variability in pain intensity. In multivariate logistic regression analysis, BMI, diabetes, hypertension, smoking, variation in pain intensity, and infarct-related artery other than the LAD were identified as independent factors associated with increased delay times. We determined the cut-off values predicting the composite endpoint as 122.5 min for patient delay, 95.5 min for system delay, and 371 min for total ischemic time. It was observed that the in-hospital NT pro-BNP values of the patients presenting early were lower (181 vs. 594 pg/mL p < 0.001), had a higher ejection fraction at the first measurement, and even improved at the sixth week of follow-up (p = 0.047). Conclusions: Prolonged ischemia duration was associated with several factors. Early reperfusion in STEMI patients reduces both cardiac death and clinical events. Delays are influenced by patient awareness, emergency care efficiency, and hospital-specific factors. Improving education, response times, and hospital protocols is essential to minimize delays and improve outcomes. Full article

Background and Objectives: The primary objective of this study was to determine the predictive factors of limb salvage and wound healing in patients presenting with diabetic foot ulcers (DFUs) following successful below-the-knee endovascular angioplasty. Materials and Methods: Between January 2014 and January 2019, we retrospectively analyzed the wound healing and limb salvage rates of 85 patients (88 limbs) who underwent infra-popliteal endovascular treatment (EVT) for DFUs. Numerous variables were explored, including age, sex, comorbidities, and the scores from three DFU grading systems (Wagner grade, University of Texas (UT) grade and stage, and Wound, Ischemia, and foot Infection (WIfI) stage). Univariate and multivariate Cox proportional hazards analyses were conducted to determine the associations between adverse events and these variables. Results: During follow-up, 44 wounds healed completely, 47 limb amputations (major, 25; minor, 22) were required, and 17 limbs needed reintervention for wound healing. Nine patients who received treatment died of cardiovascular and cerebrovascular diseases, pneumonia, and other causes. At 1, 3, 6, 9, and 12 months, total wound healing rates were 4.6%, 16.9%, 27.5%, 34.5%, and 64.5%, respectively. At 6 months, 1 year, 2 years, and 5 years, amputation-free survival rates were 77.6%, 72.4%, 63.3%, and 63.3%, respectively. In multivariate Cox analyses, the UT grade and stage were associated with increased wound non-healing, while the UT grade and Wagner grade were associated with increased major lower-extremity amputation rates. Importantly, the UT grade was the only simultaneous risk factor predicting both wound healing and limb salvage. Conclusions: Despite successful below-the-knee angioplasty, a significant proportion of patients experienced wound non-healing and major amputation. The UT grade may serve as a predictor for both wound healing and limb salvage outcomes. Full article

Background and Objectives: This study aimed to identify asymptomatic brain lesions in patients with β-thalassemia major (TM) and sickle cell anemia (SCA) and evaluate the correlation of these lesions with factors such as splenectomy, thrombocytosis, and blood transfusions. Materials and Methods: A total of 26 patients with thalassemia major and 23 patients with sickle cell anemia were included. Ischemic lesions were categorized as lacunar, small vessel, or multifocal. Variables including age, years of education, presence and type of MRI-detected ischemia, smoking status, hemoglobin, hematocrit, platelet count, ferritin levels, vitamin B12 levels, fasting blood sugar, splenectomy status, chelation therapy, and hydroxyurea treatment were compared between the two groups. Results: The mean age was 27.33 years in the thalassemia major group and 32.65 years in the sickle cell anemia group (p = 0.010). No statistically significant difference was observed in the distribution of ischemia types between the groups (p = 0.303). The thalassemia major group had a lower mean hemoglobin level (8.37 g/dL) compared to the sickle cell anemia group (9.57 g/dL) (p = 0.003). Ferritin levels were significantly higher in the thalassemia major group (2018.92 ng/mL) than in the sickle cell anemia group (660.39 ng/mL) (p < 0.001). Conclusions: Although ischemic lesions were more frequently observed in patients with sickle cell anemia, the difference was not statistically significant. These findings emphasize the importance of ongoing surveillance and individualized management to mitigate cerebrovascular risks in both patient populations. Full article

Cardiovascular diseases (CVDs) are one of the most critical public health problems in the contemporary world because they are the leading cause of morbidity and mortality. Diabetes mellitus (DM) is one of the most substantial risk factors for developing CVDs. Glycated hemoglobin is a product of the non-enzymatic glycation of hemoglobin present in erythrocytes. The determination of the percentage of glycated hemoglobin (HbA1c) is commonly used in clinical practice to assess glycemic control in patients diagnosed with DM. This method is much more informative than repeated blood glucose tests, because the HbA1c value reflects the degree of glycemic control over the last three months. It is, therefore, not surprising that the HbA1c value correlates with the presence and severity of diabetes complications, including CVDs, in the population of diabetic patients. The purpose of this publication was to present the results of a literature review on the relationship between the HbA1c value in people without DM, the presence and severity of subclinical cardiovascular dysfunction, and the presence of clinically overt CVDs. The most important tools used to assess subclinical cardiovascular dysfunction included the measurement of intima-media thickness (IMT), especially carotid IMT (cIMT), arterial stiffness assessment by the measurement of pulse wave velocity (PWV), and ankle–brachial index (ABI). According to the results of the studies cited in this literature review, it can be concluded that there are certain relationships between HbA1c, the presence and severity of subclinical cardiovascular dysfunction, and the presence of clinically overt CVDs such as coronary heart disease, cerebrovascular disease, and chronic lower extremity ischemia in non-diabetic patients. It is worth noting, however, that the results of studies conducted so far in this area are not fully unambiguous. Further studies are needed to better understand the influence of additional factors on the relationship between HbA1c and cardiovascular dysfunction in non-diabetic patients. Full article

Migraine and stroke are neurological disorders with significant global prevalence and impact. Recent advances in migraine therapy have focused on the calcitonin gene-related peptide (CGRP) pathway. This review examines the shared pathomechanisms between migraine and stroke, with emphasis on the role of CGRP. We analyze the current literature on CGRP’s functions in cerebrovascular regulation, edema formation, neuroinflammation, and neuroprotection. CGRP acts as a potent vasodilator and plays a crucial role in trigeminovascular activation during migraine attacks. In stroke, CGRP has demonstrated neuroprotective effects by improving collateral circulation and reducing ischemia-reperfusion injury. Concerns have been raised about the potential impact of CGRP inhibitors on stroke risk and outcomes. Studies in animals suggest that CGRP receptor antagonists may worsen cerebral ischemia by impairing collateral flow. We discuss the implications of these findings for the use of CGRP-targeting therapies in migraine patients, especially those at increased risk of stroke. Additionally, we explore the complex interplay between CGRP, endothelial function, and platelet activity in both conditions. This review highlights the need for further research to elucidate the long-term cerebrovascular safety of CGRP pathway inhibitors and to identify potential subgroups of migraine patients who may be at higher risk of adverse cerebrovascular events with these novel therapies. Full article

The authors propose a novel approach to a comprehensive evaluation of neuroprotective effects using both in vitro and in vivo methods. This approach allows for the initial screening of numerous newly synthesized chemical compounds and substances from plant and animal sources while saving animal life by reducing the number of animals used in research. In vitro techniques, including mitochondrial suspensions and neuronal cell cultures, enable the assessment of neuroprotective activity, which can be challenging in intact organisms. The preliminary methods help outline the neuroprotection mechanism depending on the neurodestruction agent. The authors have validated a model of acute cerebrovascular accident, which simulates key cerebrovascular phenomena such as reduced cerebral blood flow, energy deficit, glutamate–calcium excitotoxicity, oxidative stress, and early gene expression. A significant advantage of this model is its ability to reproduce the clinical picture of cerebral ischemia: impaired motor activity; signs of neurological deficits (paresis, paralysis, etc.); as well as disturbances in attention, learning, and memory. Crucial to this approach is the selection of biochemical, molecular, and cellular markers to evaluate nerve tissue damage and characterize potential neuroprotective agents. Additionally, a comprehensive set of molecular, biochemical, histological, and immunohistochemical methods is proposed for evaluating neuroprotective effects and underlying mechanisms of potential pharmaceutical compounds. Full article

Background: Pancreas transplantation (PTX) remains the most effective treatment to prevent long-term complications and provide consistent euglycemia in patients with endocrine pancreatic insufficiency, mainly in type I diabetic patients. Considering early graft loss (EGL) and the perioperative complication rate, an optimal risk stratification based on donor risk factors is paramount. Methods: In our single-center study, we retrospectively assessed the risk factors for EGL and reduced graft survival in 97 PTXs (82 simultaneous pancreas and kidney [SPK], 11 pancreases transplanted after kidney [PAK] and 4 pancreases transplanted alone [PTA]) between 2010 and 2021. By statistically analyzing the incorporation of different donor risk factors using the Kaplan–Meier method and a log-rank test, we introduced a composite risk model for the evaluation of offered pancreas grafts. Results: The overall EGL rate was 6.5%. In the univariate analysis of donor characteristics, age > 45 years, BMI > 25 kg/m², lipase > 60 U/L, cerebrovascular accident (CVA) as the cause of death, mechanical cardiopulmonary resuscitation (mCPR), cold ischemia time (CIT) > 600 min and retrieval by another center were identified as potential risk factors; however, they lacked statistical significance. In a multivariate model, age > 45 years (HR 2.05, p = 0.355), BMI > 25 kg/m² (HR 3.18, p = 0.051), lipase > 60 U/L (HR 2.32, p = 0.148), mCPR (HR 8.62, p < 0.0001) and CIT > 600 min (HR 1.89, p = 0.142) had the greatest impact on pancreas graft survival. We subsumed these factors in a composite risk model. The combination of three risk factors increased the rate of EGL significantly (p = 0.003). Comparing the pancreas graft survival curves for ≥3 risk factors to <3 risk factors in a Kaplan–Meier model revealed significant inferiority in the pancreas graft survival rate (p = 0.029). Conclusions: When evaluating a potential donor organ, grafts with a combination of three or more risk factors should only be accepted after careful consideration to reduce the risk of EGL and to significantly improve outcomes after PTX. Full article

Ischemic stroke is a common cerebrovascular disease with high mortality, high morbidity, and high disability. Cerebral ischemia/reperfusion injury seriously affects the quality of life of patients. Luteolin-7-O-β-d-glucuronide (LGU) is a major active flavonoid compound extracted from Ixeris sonchifolia (Bge.) Hance, a Chinese medicinal herb mainly used for the treatment of coronary heart disease, angina pectoris, cerebral infarction, etc. In the present study, the protective effect of LGU on cerebral ischemia/reperfusion injury was investigated in an oxygen–glucose deprivation/reoxygenation (OGD/R) neuronal model and a transient middle cerebral artery occlusion (tMCAO) rat model. In in vitro experiments, LGU was found to improve the OGD/R-induced decrease in neuronal viability effectively by the MTT assay. In in vivo experiments, neurological deficit scores, infarction volume rates, and brain water content rates were improved after a single intravenous administration of LGU. These findings suggest that LGU has significant protective effects on cerebral ischemia/reperfusion injury in vitro and in vivo. To further explore the potential mechanism of LGU on cerebral ischemia/reperfusion injury, we performed a series of tests. The results showed that a single administration of LGU decreased the content of EB and S100B and ameliorated the abnormal expression of tight junction proteins ZO-1 and occludin and metalloproteinase MMP-9 in the ischemic cerebral cortex of the tMCAO 24-h injury model. In addition, LGU also improved the tight junction structure between endothelial cells and the degree of basement membrane degradation and reduced the content of TNF-α and IL-1β in the brain tissue. Thereby, LGU attenuated cerebral ischemia/reperfusion injury by improving the permeability of the blood–brain barrier. The present study provides new insights into the therapeutic potential of LGU in cerebral ischemia. Full article

Stroke represents one of the neurological diseases most responsible for death and permanent disability in the world. Different factors, such as thrombus, emboli and atherosclerosis, take part in the intricate pathophysiology of stroke. Comprehending the molecular processes involved in this mechanism is crucial to developing new, specific and efficient treatments. Some common mechanisms are excitotoxicity and calcium overload, oxidative stress and neuroinflammation. Furthermore, non-coding RNAs (ncRNAs) are critical in pathophysiology and recovery after cerebral ischemia. ncRNAs, particularly microRNAs, and long non-coding RNAs (lncRNAs) are essential for angiogenesis and neuroprotection, and they have been suggested to be therapeutic, diagnostic and prognostic tools in cerebrovascular diseases, including stroke. This review summarizes the intricate molecular mechanisms underlying ischemic and hemorrhagic stroke and delves into the function of miRNAs in the development of brain damage. Furthermore, we will analyze new perspectives on treatment based on molecular mechanisms in addition to traditional stroke therapies. Full article

Recent research suggests that photobiomodulation therapy (PBMT) positively impacts the vascular function associated with various cerebrovascular diseases. Nevertheless, the specific mechanisms by which PBMT improves vascular function remain ambiguous. Since endothelial nitric oxide synthase (eNOS) is crucial in regulating vascular function following cerebral ischemia, we investigated whether eNOS is a key element controlling cerebrovascular function and the senescence of vascular endothelial cells following PBMT treatment. Both rat photothrombotic (PT) stroke and in vitro oxygen–glucose deprivation (OGD)-induced vascular endothelial injury models were utilized. We demonstrated that treatment with PBMT (808 nm, 350 mW/cm², 2 min/day) for 7 days significantly reduced PT-stroke-induced vascular permeability. Additionally, PBMT inhibited the levels of endothelial senescence markers (senescence green and p21) and antiangiogenic factor (endostatin), while increasing the phospho-eNOS (Ser1177) in the peri-infarct region following PT stroke. In vitro study further indicated that OGD increased p21, endostatin, and DNA damage (γH2AX) levels in the brain endothelial cell line, but they were reversed by PBMT. Intriguingly, the beneficial effects of PBMT were attenuated by a NOS inhibitor. In summary, these findings provide novel insights into the role of eNOS in PBMT-mediated protection against cerebrovascular senescence and endothelial dysfunction following ischemia. The use of PBMT as a therapeutic is a promising strategy to improve endothelial function in cerebrovascular disease. Full article

The incidence and prevalence of cardiac and cerebrovascular diseases are constantly increasing, with chronic coronary syndrome and ischemic stroke as the leading causes of morbidity and mortality worldwide. According to current knowledge, the heart–brain axis is more than a theoretical concept, with many common pathophysiological mechanisms involved in the onset and evolution of both coronary and cerebral ischemia. Moreover, the focus is on the prevention and early intervention of risk factors in searching for targeted and personalized medical treatment. In this context, this narrative review aims to offer, in a didactic and practice-oriented manner, an up-to-date overview of the role played by lipid-derived biomarkers (from low-density lipoprotein cholesterol to oxylipin and apolipoproteins) in chronic coronary syndrome and ischemic stroke. Firstly, the authors highlight, via relevant epidemiological data, the significant burden of chronic coronary syndrome and ischemic stroke in the general population, thus explaining the need for updated information on this topic. Subsequently, the most important lipid-derived biomarkers and their multiple roles in the pathogenesis of these two disorders are listed. Currently available and experimental targeted therapies based on these lipid-derived biomarkers are presented in the final part of this paper, representing this manuscript’s original and novel input. Full article