Design, synthesis, and anticancer assessment of structural analogues of (E)-1-((3,4,5-trimethoxybenzylidene)amino)-4-(3,4,5-trimethoxyphenyl)imidazo[1,2-a]quinoxaline-2-carbonitrile (6b), an imidazo[1,2-a]quinoxaline-based non-covalent EGFR inhibitor.

In our quest to find improved anticancer therapeutics, we expedite the lead optimization of (E)-1-((3,4,5-trimethoxybenzylidene)amino)-4-(3,4,5-trimethoxyphenyl)imidazo[1,2-a]quinoxaline-2-carbonitrile (6b), an EGFR inhibitor previously discovered in our laboratory through an in-house screening program. The lead optimization was rationally initiated considering the catalytic site of EGFR. We synthesized twenty-nine new analogues of 6b and assessed their anticancer activities. SAR studies highlighted the role of important groups in controlling anticancer activities. Among all, 5a and 5l were found to exhibit improved EGFR inhibition with anticancer asset potential. In silico studies corroborated with in vitro EGFR inhibitory results. The deeper analysis of 5a and 5l revealed that these synthetics could alter the MMP (ΔΨ m) and significantly reduce the ROS levels in lung cancer cells. This is a vital prerequisite for better plausible EGFR inhibitors devoid of cardiotoxicity. qPCR analysis further revealed that the investigational compounds 5a and 5l were able to downregulate the expression of key oncogenes, viz., KRAS, MAP2K, and EGFR. The downregulation of these genes suggests that the investigational compounds could interact and inhibit key players in the signalling cascade along with the EGFR, which may lead to the inhibition of the growth and prognosis of cancer cells via a holistic approach.

Near field communication tag to provide a unique identification aid for custom ocular prostheses.

This technique describes a smartphone-enabled near field communication tag used as an identification aid for a custom ocular prosthesis for a pediatric patient. Near field communication tags are straightforward to read, can be readily connected to smartphone devices without the need for specialized equipment, store data in a variety of ways, are inexpensive, exceptionally thin, and flexible, and tolerate resin polymerization temperatures, making them suitable as an identification aid for an ocular prosthesis.

Beta-Site APP-Cleaving Enzyme-1 Inhibitory Role of Natural Flavonoids in the Treatment of Alzheimer's Disease.

Alzheimer's Disease (AD) is a devastating neurological condition characterized by a progressive decline in cognitive function, including memory loss, reasoning difficulties, and disorientation. Its hallmark features include the formation of neurofibrillary tangles and neuritic plaques in the brain, disrupting normal neuronal function. Neurofibrillary tangles, composed of phosphorylated tau protein and neuritic plaques, containing amyloid-ß protein (Aß) aggregates, contribute to the degenerative process. The discovery of the beta-site amyloid precursor protein cleaving enzyme 1 (BACE1) in 1999 revolutionized our understanding of AD pathogenesis. BACE1 plays a crucial role in the production of Aß, the toxic protein implicated in AD progression. Elevated levels of BACE1 have been observed in AD brains and bodily fluids, underscoring its significance in disease onset and progression. Despite setbacks in clinical trials of BACE1 inhibitors due to efficacy and safety concerns, targeting BACE1 remains a promising therapeutic strategy for early-stage AD. Natural flavonoids have emerged as potential BACE1 inhibitors, demonstrating the ability to reduce Aß production in neuronal cells and inhibit BACE1 activity. In our review, we delve into the pathophysiology of AD, highlighting the central role of BACE1 in Aß production and disease progression. We explore the therapeutic potential of BACE1 inhibitors, including natural flavonoids, in controlling AD symptoms. Additionally, we provide insights into ongoing clinical trials and available patents in this field, shedding light on future directions for AD treatment research.

A Quest for Potential Role of Vitamin D in Type II Diabetes Mellitus Induced Diabetic Kidney Disease.

Diabetes mellitus is a metabolic disorder characterized by high blood sugar levels. In recent years, T2DM has become a worldwide health issue due to an increase in incidence and prevalence. Diabetic kidney disease (DKD) is one of the devastating consequences of diabetes, especially owing to T2DM and the key clinical manifestation of DKD is weakened renal function and progressive proteinuria. DKD affects approximately 1/3rd of patients with diabetes mellitus, and T2DM is the predominant cause of end-stage kidney disease (ESKD). Several lines of studies have observed the association between vitamin D deficiency and the progression and etiology of type II diabetes mellitus. Emerging experimental evidence has shown that T2DM is associated with various kinds of kidney diseases. Recent evidence has also shown that an alteration in VDR (vitamin D receptor) signaling in podocytes leads to DKD. The present review aims to examine vitamin D metabolism and its correlation with T2DM. Furthermore, we discuss the potential role of vitamin D and VDR in diabetic kidney disease.

Surgery compared to fibrinolytic therapy for symptomatic left-sided prosthetic heart valve thrombosis (SAFE-PVT): Rationale and design of a randomized controlled trial.

BACKGROUND: Left-sided mechanical prosthetic heart valve thrombosis (PVT) occurs because of suboptimal anticoagulation and is common in low-resource settings. Urgent surgery and fibrinolytic therapy (FT) are the two treatment options available for this condition. Urgent surgery is a high-risk procedure but results in successful restoration of valve function more often and is the treatment of choice in developed countries. In low-resource countries, FT is used as the default treatment strategy, though it is associated with lower success rates and a higher rate of bleeding and embolic complications. There are no randomized trials comparing the two modalities. METHODS: We performed a single center randomized controlled trial comparing urgent surgery (valve replacement or thrombectomy) with FT (low-dose, slow infusion tissue plasminogen activator, tPA) in patients with symptomatic left-sided PVT. The primary outcome was the occurrence of a complete clinical response, defined as discharge from hospital with completely restored valve function, in the absence of stroke, major bleeding or non-CNS systemic embolism. Outcome assessment was done by investigators blinded to treatment allocation. The principal safety outcome was the occurrence of a composite of in-hospital death, non-fatal stroke, non-fatal major bleed or non-CNS systemic embolism. Outcomes will be assessed both in the intention-to-treat, and in the as-treated population. We will also report outcomes at one year of follow-up. The trial has completed recruitment. CONCLUSION: This is the first randomized trial to compare urgent surgery with FT for the treatment of left-sided PVT. The results will provide evidence to help clinicians make treatment choices for these patients. (Clinical trial registration: CTRI/2017/10/010159).

Linking orthodontic treatment and sleep apnea among adult Indian patients.

The differences in the effects of orthodontic treatment on airway and craniocervical posture in patients with OSA (obstructive sleep apnea) having skeletal class II high-angle malocclusion is of interest. Hence, 48 individuals with OSA and skeletal class II high-angle malocclusion were chosen from among all patients in need of orthodontic therapy. Every patients had CBCT (cone beam computed tomography) taken both before and after receiving orthodontic therapy. All parameters were assessed on the lateral cephalogram from CBCT in order to assess the indices of craniocervical posture, hyoid position, skeletal and dental conditions. Parameters of upper airway (position of hyoid) showed statistically significant increase in values after orthodontic treatments. Thus, there was increase in values of dimensions of upper airway, post orthodontic treatment. Hence, orthodontic therapy help improve the upper airway morphology and craniocervical posture in patients of OSA with hyperdivergent skeletal class II malocclusion.

Functionalized azirine based scaffolds as endothelin inhibitors for the selective anti-angiogenic activity.

Anti-angiogenic therapy has long been used as an adjunct therapy for the resolution of tumor burden. The current findings describe the synthesis of novel marine-based azirine-containing compounds that exhibit anti-angiogenic mediated anti-tumor activity. Azirine-2-carboxylate inhibited HUVEC-mediated tubulogenesis without causing cell death in a dose-dependent manner. Ex-vivo CAM, in-vivo Matrigel implantation, and ear angiogenesis experiments have all shown that azirine-2-carboxylate effectively inhibits angiogenesis. Furthermore, azirine-2-carboxylate inhibits the migration of ECs without disrupting the preformed tubule network. Azirine-2-carboxylate had adequate intramuscular systemic exposure and inhibited tumor growth in a xenograft mouse model. DARTS analysis, competitive binding assay, and gene expression investigations revealed that azirine-2-carboxylate inhibits endothelin-1-mediated angiogenesis. Overall, the discovery of azirine-2-carboxylate demonstrated a potent inhibition of angiogenesis targeting ET1 and a possible application in anti-angiogenic therapy.

Elevated cardiovascular risk and acute events in hospitalized colon cancer survivors: A decade-apart study of two nationwide cohorts.

BACKGROUND: Over the years, strides in colon cancer detection and treatment have boosted survival rates; yet, post-colon cancer survival entails cardiovascular disease (CVD) risks. Research on CVD risks and acute cardiovascular events in colorectal cancer survivors has been limited. AIM: To compare the CVD risk and adverse cardiovascular outcomes in current colon cancer survivors compared to a decade ago. METHODS: We analyzed 2007 and 2017 hospitalization data from the National Inpatient Sample, studying two colon cancer survivor groups for CVD risk factors, mortality rates, and major adverse events like pulmonary embolism, arrhythmia, cardiac arrest, and stroke, adjusting for confounders via multivariable regression analysis. RESULTS: Of total colon cancer survivors hospitalized in 2007 (n = 177542) and 2017 (n = 178325), the 2017 cohort often consisted of younger (76 vs 77 years), male, African-American, and Hispanic patients admitted non-electively vs the 2007 cohort. Furthermore, the 2017 cohort had higher rates of smoking, alcohol abuse, drug abuse, coagulopathy, liver disease, weight loss, and renal failure. Patients in the 2017 cohort also had higher rates of cardiovascular comorbidities, including hypertension, hyperlipidemia, diabetes, obesity, peripheral vascular disease, congestive heart failure, and at least one traditional CVD (P < 0.001) vs the 2007 cohort. On adjusted multivariable analysis, the 2017 cohort had a significantly higher risk of pulmonary embolism (PE) (OR: 1.47, 95%CI: 1.37-1.48), arrhythmia (OR: 1.41, 95%CI: 1.38-1.43), atrial fibrillation/flutter (OR: 1.61, 95%CI: 1.58-1.64), cardiac arrest including ventricular tachyarrhythmia (OR: 1.63, 95%CI: 1.46-1.82), and stroke (OR: 1.28, 95%CI: 1.22-1.34) with comparable all-cause mortality and fewer routine discharges (48.4% vs 55.0%) (P < 0.001) vs the 2007 cohort. CONCLUSION: Colon cancer survivors hospitalized 10 years apart in the United States showed an increased CVD risk with an increased risk of acute cardiovascular events (stroke 28%, PE 47%, arrhythmia 41%, and cardiac arrest 63%). It is vital to regularly screen colon cancer survivors with concomitant CVD risk factors to curtail long-term cardiovascular complications.

Imaging Characteristics and Clinical Utility of Half-Dose versus Full-Dose Ultrawidefield Fundus Fluorescein Angiography.

PURPOSE: In early 2022, a fluorescein shortage occurred in the United States. To meet the standard of care for patients who required ultrawidefield fundus fluorescein angiography (UWFFA), a regimen of half-dose (250 mg) sodium fluorescein (10%) was adopted instead of the full dose (500 mg) at the Cole Eye Institute (CEI). In this paper, we compare the image quality, clinical utility, and the side-effect profile of half-dose versus full-dose fluorescein in UWFFA for a cohort of stable patients. DESIGN: Retrospective chart review. PARTICIPANTS: Patients with retinal vascular disease were included if they received half-dose and full-dose UWFFA (Optos California) within 6 months at the CEI. Eyes were excluded if they received intraocular injections, laser procedures, new immunosuppression, and worsened or improved inflammation on clinical examination. METHODS: Quantitative assessment of vascular leakage was performed using a machine learning-enhanced automated segmentation platform. Leakage from late-phase UWFFA images was compared between half-dose and full-dose images. Qualitative assessment of image quality and relative vascular leakage was performed by 2 masked independent reviewers. Side effects after fluorescein administration were recorded for each patient. MAIN OUTCOME MEASURES: Masked leakage grading and automated leakage scores. RESULTS: There were 52 eyes of 35 patients, 42 (81%) uveitic, 5 (9%) diabetic, and 4 (8%) normal controls. Patients had no change to their visual acuity (logarithm of the minimum angle of resolution mean, 0.3 ± 0.6), anterior chamber and vitreous cell between UFFWA's. UWFFA images were deemed of equal quality and leakage by both masked reviewers (78%-87% agreement; κ, 0.642). Automated leakage analysis showed mildly increased leakage in half-dose images overall (3.8% vs. 2.8%; P = 0.01) and in the macula (1.5% vs. 0.6%; P = 0.01). Side effects included nausea (half [n = 3, 9%] vs. full [n = 2, 6%]; P = 0.69) and urticaria (n = 0, 0% vs. n = 1, 2%; P = 0.99) and were not different between doses. CONCLUSIONS: In this cohort, half-dose UWFFA produced images that were of similar quality, clinical utility and with a similar side effect profile compared with full dose. Half-dose UWFFA can be used to accurately assess the retinal vasculature and could be used primarily as a method to save cost and prevent waste. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Role of nutraceutical against exposure to pesticide residues: power of bioactive compounds.

Pesticides play a crucial role in modern agriculture, aiding in the protection of crops from pests and diseases. However, their indiscriminate use has raised concerns about their potential adverse effects on human health and the environment. Pesticide residues in food and water supplies are a serious health hazards to the general public since long-term exposure can cause cancer, endocrine disruption, and neurotoxicity, among other health problems. In response to these concerns, researchers and health professionals have been exploring alternative approaches to mitigate the toxic effects of pesticide residues. Bioactive substances called nutraceuticals that come from whole foods including fruits, vegetables, herbs, and spices have drawn interest because of their ability to mitigate the negative effects of pesticide residues. These substances, which include minerals, vitamins, antioxidants, and polyphenols, have a variety of biological actions that may assist in the body's detoxification and healing of harm from pesticide exposure. In this context, this review aims to explore the potential of nutraceutical interventions as a promising strategy to mitigate the toxic effects of pesticide residues.

RTCpredictor: identification of read-through chimeric RNAs from RNA sequencing data.

Read-through chimeric RNAs are being recognized as a means to expand the functional transcriptome and contribute to cancer tumorigenesis when mis-regulated. However, current software tools often fail to predict them. We have developed RTCpredictor, utilizing a fast ripgrep tool to search for all possible exon-exon combinations of parental gene pairs. We also added exonic variants allowing searches containing common SNPs. To our knowledge, it is the first read-through chimeric RNA specific prediction method that also provides breakpoint coordinates. Compared with 10 other popular tools, RTCpredictor achieved high sensitivity on a simulated and three real datasets. In addition, RTCpredictor has less memory requirements and faster execution time, making it ideal for applying on large datasets.

Discovery of a polymorphic gene fusion via bottom-up chimeric RNA prediction.

Gene fusions and their chimeric products are commonly linked with cancer. However, recent studies have found chimeric transcripts in non-cancer tissues and cell lines. Large-scale efforts to annotate structural variations have identified gene fusions capable of generating chimeric transcripts even in normal tissues. In this study, we present a bottom-up approach targeting population-specific chimeric RNAs, identifying 58 such instances in the GTEx cohort, including notable cases such as SUZ12P1-CRLF3, TFG-ADGRG7 and TRPM4-PPFIA3, which possess distinct patterns across different ancestry groups. We provide direct evidence for an additional 29 polymorphic chimeric RNAs with associated structural variants, revealing 13 novel rare structural variants. Additionally, we utilize the All of Us dataset and a large cohort of clinical samples to characterize the association of the SUZ12P1-CRLF3-causing variant with patient phenotypes. Our study showcases SUZ12P1-CRLF3 as a representative example, illustrating the identification of elusive structural variants by focusing on those producing population-specific fusion transcripts.

Culture-Negative Neutrocytic Ascites in a Patient With Cardiac Ascites From End-Stage Heart Failure.

There are two significant groups of infection regarding ascitic fluid: spontaneous bacterial peritonitis (SBP) and culture-negative neutrocytic ascites (CNNA). SBP and CNNA typically occur in patients with cirrhosis. A 46-year-old male with end-stage biventricular heart failure presented with a heart failure exacerbation. He was treated with intravenous diuretics with the improvement of hypervolemia. He remained hospitalized to undergo an evaluation for tricuspid valve repair, but given the severity of his bi-ventricular heart failure, he underwent a heart transplant evaluation. As part of the work-up, he underwent an abdominal ultrasound that was significant for severe ascites but did not note an abnormal hepatic architecture suggestive of cirrhosis. A liver biopsy was then performed, which confirmed no evidence of cirrhosis. His hospitalization was complicated by refractory cardiac ascites, which required a bi-weekly paracentesis. The serum albumin-ascites gradient (SAAG) from his initial paracentesis was 1.4, indicating the etiology was from portal hypertension. The total protein was greater than 2.5 in multiple studies, so the etiology was less concerning for cirrhosis and secondary to his heart failure. About two weeks into his hospital course, he developed a leukocytosis but remained hemodynamically stable and asymptomatic from an infectious standpoint. Analysis of his ascitic fluid initially was negative for infection, but he later developed an elevated total neutrophil count on a subsequent ascitic fluid analysis study. The body fluid culture remained negative for bacterial growth. Hepatology was consulted, and he met the criteria for CNNA, so treatment with ceftriaxone was initiated. After initiating antibiotics, his leukocytosis and elevated ascitic fluid total neutrophil count resolved. Ascitic infections such as CNNA generally occur in patients with liver cirrhosis but may occur in patients without cirrhosis, as observed in our patient. This case highlights that patients with cardiac ascites can develop ascitic fluid infections that may have an impact on their mortality. The precipitating factor that enabled the patient to develop CNNA is unclear but may be related to the translocation of bacteria during his congestive heart failure exacerbation. Although uncommon in a patient with cardiac ascites, an early diagnosis of CNNA and the initiation of antibiotics can be important in preventing patient mortality.

Investigating the Association between Obstructive Sleep Apnea and Temporomandibular Joint Disorders: A Case-Control Study.

Background: This study aims to explore the connection between obstructive sleep apnea (OSA) and temporomandibular joint disorders (TMD) through a case-control investigation. OSA is a sleep-related breathing disorder that affects breathing during sleep, whereas TMD involves pain and dysfunction in the jaw joint. Understanding any potential association between these two conditions could contribute to improved diagnostic and therapeutic approaches. Materials and Methods: A total of 50 participants were included in both the OSA group and the control group. Participants with diagnosed OSA constituted the OSA group, whereas individuals without OSA formed the control group. TMD symptoms were assessed using standardized diagnostic criteria. Statistical analysis was performed to compare the prevalence of TMD symptoms between the two groups. Results: In the OSA group, 36 out of 50 participants exhibited TMD symptoms, whereas in the control group, 18 out of 50 participants displayed such symptoms. The calculated P value was found to be 0.023, indicating a statistically significant association between OSA and TMD. Conclusion: The findings of this study suggest a notable association between OSA and TMD. Individuals with OSA are more likely to experience TMD symptoms compared to those without OSA. This underscores the importance of considering TMD symptoms in individuals with OSA and vice versa for a comprehensive approach to diagnosis and management.

Intranasal Delivery of Carvedilol- and Quercetin-Encapsulated Cationic Nanoliposomes for Cardiovascular Targeting: Formulation and In Vitro and Ex Vivo Studies.

Carvedilol (CVD), an adrenoreceptor blocker, is a hydrophobic Biopharmaceutics Classification System class II drug with poor oral bioavailability due to which frequent dosing is essential to attain pharmacological effects. Quercetin (QC), a polyphenolic compound, is a potent natural antioxidant, but its oral dosing is restricted due to poor aqueous solubility and low oral bioavailability. To overcome the common limitations of both drugs and to attain synergistic cardioprotective effects, we formulated CVD- and QC-encapsulated cationic nanoliposomes (NLPs) in situ gel (CVD/QC-L.O.F.) for intranasal administration. We designed CVD- and QC-loaded cationic nanoliposomal (NLPs) in situ gel (CVD/QC-L.O.F.) for intranasal administration. In vitro drug release studies of CVD/QC-L.O.F. (16.25%) exhibited 18.78 ± 0.57% of QC release and 91.38 ± 0.93% of CVD release for 120 h. Ex vivo nasal permeation studies of CVD/QC-L.O.F. demonstrated better permeation of QC (within 96 h), i.e., 75.09% compared to in vitro drug release, whereas CVD permeates within 48 h, indicating the better interaction between cationic NLPs and the negatively charged biological membrane. The developed nasal gel showed a sufficient mucoadhesive property, good spreadability, higher firmness, consistency, and cohesiveness, indicating suitability for membrane application and intranasal administration. CVD-NLPs, QC-NLPs, and CVD/QC-NLPs were evaluated for in vitro cytotoxicity, in vitro ROS-induced cell viability assessment, and a cellular uptake study using H9c2 rat cardiomyocytes. The highest in vitro cellular uptake of CVD/QC-cationic NLPs by H9c2 cells implies the benefit of QC loading within the CVD nanoliposomal carrier system and gives evidence for better interaction of NLPs carrying positive charges with the negatively charged biological cells. The in vitro H2O2-induced oxidative stress cell viability assessment of H9c2 cells established the intracellular antioxidant activity and cardioprotective effect of CVD/QC-cationic NLPs with low cytotoxicity. These findings suggest the potential of cationic NLPs as a suitable drug delivery carrier for CVD and QC combination for the intranasal route in the treatment of various cardiovascular diseases like hypertension, angina pectoris, etc. and for treating neurodegenerative disorders.

Rehabilitation Using Hybrid Technique for Feeding Plate Fabrication in a 3-Month-Old Infant with Cleft Palate Defect Utilising Digital and Conventional Method: A Case Report.

ABSTRACT: Cleft palate leads to difficulty in suckling, speech abnormalities, dental problems, hearing loss and middle ear infections. Feeding plate acts as a barrier between the oral and nasal cavities allowing the normal development of jaws and enhanced nutritional supply to the patient. Fabrication of the feeding plate using digital means provide better adaptability due to the engagement of all the possible favourable anatomic undercuts, thereby, providing better retention. This case report discusses the hybrid technique including both the digital and conventional means for fabrication of a feeding plate to obturate the defect between the oral and nasal cavity.

Unveiling the Silent Intruder: H. pylori's Hidden Link to Ischemic Heart Disease.

Cardiovascular disease is the leading cause of death. In addition to the well-known risk factors associated with cardiovascular disease, such as age, diabetes mellitus, smoking, hypertension, and obesity, there has been a growing concern regarding cardiac complications stemming from the Gram-negative bacteria Helicobacter pylori. While H. pylori is most commonly associated with chronic gastritis, peptic ulcer disease, gastric adenocarcinoma, and gastric lymphoma, it has also been implicated in extra gastric manifestations, encompassing cardiac, neurologic, ocular, and dermatologic issues. Key virulent factors for coronary artery disease include the vacuolating cytotoxin gene A and the cytotoxin-associated gene A. The most likely pathogenic mechanism of the relationship between H. pylori and coronary artery disease is initiating a chronic inflammatory process associated with infection and the modifications of classic risk factors. These alterations lead to the creation of prothrombotic and procoagulant environments. Here, we review the cardiac manifestations of H. pylori and the underlying pathophysiological mechanisms.

Polymer-Based Drug Delivery Systems for Cancer Therapeutics.

Chemotherapy together with surgery and/or radiotherapy are the most common therapeutic methods for treating cancer. However, the off-target effects of chemotherapy are known to produce side effects and dose-limiting toxicities. Novel delivery platforms based on natural and synthetic polymers with enhanced pharmacokinetic and therapeutic potential for the treatment of cancer have grown tremendously over the past 10 years. Polymers can facilitate selective targeting, enhance and prolong circulation, improve delivery, and provide the controlled release of cargos through various mechanisms, including physical adsorption, chemical conjugation, and/or internal loading. Notably, polymers that are biodegradable, biocompatible, and physicochemically stable are considered to be ideal delivery carriers. This biomimetic and bio-inspired system offers a bright future for effective drug delivery with the potential to overcome the obstacles encountered. This review focuses on the barriers that impact the success of chemotherapy drug delivery as well as the recent developments based on natural and synthetic polymers as platforms for improving drug delivery for treating cancer.

TransCatheter aortic valve implantation and fractional flow reserve-guided percutaneous coronary intervention versus conventional surgical aortic valve replacement and coronary bypass grafting for treatment of patients with aortic valve stenosis and multivessel or advanced coronary disease: The transcatheter valve and vessels trial (TCW trial): Design and rationale.

BACKGROUND: Patients with severe aortic stenosis (AS) frequently present with concomitant obstructive coronary artery disease (CAD). In those, current guidelines recommend combined coronary artery bypass grafting (CABG) and surgical aortic valve replacement (SAVR) as the preferred treatment option, although this surgical approach is associated with a high rate of clinical events. Combined transcatheter aortic valve implantation (TAVI) and percutaneous coronary intervention (PCI) with or without FFR have evolved as a valid alternative for cardiac surgery in patients with AS and multivessel or advanced CAD. To date, no dedicated trial has prospectively evaluated the outcomes of a percutaneous versus surgical treatment for patients with both severe AS and CAD. AIMS: To investigate whether fractional-flow reserve (FFR)-guided PCI and TAVI is noninferior to combined CABG and SAVR for the treatment of severe AS and multivessel or advanced CAD. METHODS: The Transcatheter Valve and Vessels (TCW) trial (clinicaltrial.gov: NCT03424941) is a prospective, randomized, controlled, open label, international trial. Patients ≥ 70 years with severe AS and multivessel (≥ 2 vessels) or advanced CAD, deemed feasible by the heart team for both; a full percutaneous or surgical treatment, will be randomised in a 1:1 fashion to either FFR-guided PCI followed by TAVI (intervention arm) vs. CABG and SAVR (control arm). The primary endpoint is a patient-oriented composite of all-cause mortality, myocardial infarction, disabling stroke, unscheduled clinically-driven target vessel revascularization, valve reintervention, and life threatening or disabling bleeding at 1 year. The TCW trial is powered for noninferiority, and if met, superiority will be tested. Assuming a primary endpoint rate of 30% in the CABG-SAVR arm, with a significance level α of 5%, a noninferiority limit delta of 15% and a loss to follow-up of 2%, a total of 328 patients are needed to obtain a power of 90%. The primary endpoint analysis is performed on an intention-to-treat basis. SUMMARY: The TCW Trial is the first prospective randomized trial that will study if a less invasive percutaneous treatment for severe AS and concomitant advanced CAD (i.e., FFR-guided PCI-TAVI) is noninferior to the guidelines recommended approach (CABG-SAVR).