Mid-term Outcomes of the Viabahn VBX® Balloon-Expandable Covered Stent for Fenestrations During Complex Endovascular Aortic Aneurysm Repair (EVAR).

OBJECTIVES: The optimal bridging stent for fenestrations during complex endovascular aortic aneurysm repair (EVAR) has not been defined. At our institution, the Viabahn VBX® is frequently used given its availability and mechanical and heparin-bonding characteristics. This study aims to assess the performance of the Viabahn VBX® versus the iCast® balloon-expandable covered stents as bridging stents for fenestrations during complex EVAR. METHODS: A retrospective study of consecutive patients undergoing complex EVAR between 2015 and 2021 was performed. Celiac arteries (CAs), superior mesenteric arteries (SMAs), left renal arteries (LRAs), and right renal arteries (RRAs) stented with fenestrations were grouped according to the type of bridging stent, VBX® versus iCast®. Target vessels (TV) stented with a branch or scallop were excluded. The primary endpoints included primary patency and freedom from target vessel instability (TVI). RESULTS: A total of 292 patients undergoing complex EVAR were treated using VBX® or iCast® with a mean follow-up of 190 days (interquartile range [IQR], 36-384) for the VBX® cohort and 804 days (IQR, 384-1507) for the iCast® cohort. A total of 677 TVs were stented, including 134 (20%) CAs, 175 (26%) SMAs, 182 (27%) LRAs, 186 (27%) RRAs, and 12 (2%) additional vessels. Proximal reinforcement was more frequent with VBX than with iCast® stent (23% vs. 2.4%, P <.0001). There was no difference in primary patency rates at 2-year between VBX® and iCast® stent for CA (100% vs. 96.4%; P=.32), SMA (97.8% vs. 100%; P=.14) and renal arteries (96.7% vs. 99.4%; P=.11). There was no difference between VBX® and iCast® in the cumulative incidence of type Ic and type IIIc endoleaks (3.2% vs. 5.6%; P=.69) or freedom from TVI at 2 years. CONCLUSION: Viabahn VBX® stents are a safe and effective option as bridging stents in fenestrations during complex EVAR with comparable mid-term outcomes to iCast® stents. However, proximal stent reinforcement may be required with VBX stent to ensure adequate sealing at the fenestrations. Longer follow-ups and larger series are required to assess long-term outcomes and durability.

Imperative role of adaptor proteins in macrophage toll-like receptor signaling pathways.

Macrophages are integral part of the body's defense against pathogens and serve as vital regulators of inflammation. Adaptor molecules, featuring diverse domains, intricately orchestrate the recruitment and transmission of inflammatory responses through signaling cascades. Key domains involved in macrophage polarization include Toll-like receptors (TLRs), Src Homology2 (SH2) and other small domains, alongside receptor tyrosine kinases, crucial for pathway activation. This review aims to elucidate the enigmatic role of macrophage adaptor molecules in modulating macrophage activation, emphasizing their diverse roles and potential therapeutic and investigative avenues for further exploration.

In our manuscript, we explore the vital role of adaptor proteins regarding ways, our immune cells, specifically macrophages, detect and respond to threats. These proteins act as crucial messengers, helping macrophages recognize harmful invaders and initiate the body's defense mechanisms. Understanding this process not only sheds light on how our immune system works but also holds promise for developing new therapies to combat infections and inflammatory diseases. Our findings offer insight into the intricate world of immune response, potentially paving the way for improved treatments for a range of health conditions.

Key regulators of hepatic stellate cell activation in alcohol liver Disease: A comprehensive review.

Alcoholic liver disease (ALD) is a broad category of disorders that begin with liver injury, lead to liver fibrosis, and ultimately conclude in alcohol-induced liver cirrhosis, the most chronic and irreversible liver damage. Liver fibrosis (LF) is a common pathological characteristic observed in most chronic liver inflammatory conditions that involve prolonged inflammation. In this review, we have summarized ethanol-mediated hepatic stellate cell (HSCs) activation and its role in liver fibrosis progression. We highlight important molecular mechanisms that are modulated by ethanol, play a role in the activation of HSCs and the progression of liver fibrosis and identifying potential targets to ameliorate liver fibrosis.

In-hospital cardiac arrest survival before and after the COVID-19 pandemic: Have higher performing hospitals stayed high-performing?

BACKGROUND: Survival for in-hospital cardiac arrest (IHCA) has declined since the COVID-19 pandemic. Because the burden of COVID-19 was uneven throughout the U.S., it remains unknown if top-performer hospitals in IHCA survival have remained top-performers since the pandemic. METHODS: Within Get With The Guidelines®-Resuscitation, we identified hospitals with at least 2 years of registry participation pre-pandemic (2017-2019) and post-pandemic (July 2020-2022) and with at least 20 IHCA cases in both periods. Using multivariable hierarchical models with hospital as a random effect and adjusting for patient and arrest characteristics, we calculated risk-standardized survival rates to discharge (RSSR) for IHCA at each hospital during the pre- and post-pandemic periods. We then assessed the correlation between a hospital's pre-pandemic and post-pandemic RSSR for IHCA, and whether the correlation differed by the proportion of Black or Hispanic IHCA patients at each hospital. RESULTS: A total of 243 hospitals were included, comprising 122,561 IHCAs (pre-pandemic: 57,601; post-pandemic: 64,960). Pre-pandemic, the mean RSSR was 26.8% (SD, 5.2%) whereas the mean RSSR post-pandemic was 21.7% (SD, 5.5%). There was good correlation between a hospital's pre- and post-pandemic RSSR: correlation of 0.55. When hospitals were categorized into tertiles based on the proportion of their IHCA patients who were Black or Hispanic, this correlation remained similar: 0.48, 0.68, and 0.45 (interaction P-value: 0.69) for hospitals in the upper, middle and lower tertiles, respectively. CONCLUSION: Although the COVID-19 pandemic affected the U.S. unevenly, there was good correlation in a hospital's performance for IHCA survival before and after the pandemic, even at hospitals caring for a larger proportion of Black and Hispanic patients. Future studies are needed to understand what characteristics of high-performing hospitals pre-pandemic allowed many to continue to excel in the post-pandemic period.

Pharmacological targeting of adaptor proteins in chronic inflammation.

BACKGROUND: Inflammation, a biological response of the immune system, can be triggered by various factors such as pathogens, damaged cells, and toxic compounds. These factors can lead to chronic inflammatory responses, potentially causing tissue damage or disease. Both infectious and non-infectious agents, as well as cell damage, activate inflammatory cells and trigger common inflammatory signalling pathways, including NF-κB, MAPK, and JAK-STAT pathways. These pathways are activated through adaptor proteins, which possess distinct protein binding domains that connect corresponding interacting molecules to facilitate downstream signalling. Adaptor molecules have gained widespread attention in recent years due to their key role in chronic inflammatory diseases. METHODS: In this review, we explore potential pharmacological agents that can be used to target adaptor molecules in chronic inflammatory responses. A comprehensive analysis of published studies was performed to obtain information on pharmacological agents. CONCLUSION: This review highlights the therapeutic strategies involving small molecule inhibitors, antisense oligonucleotide therapy, and traditional medicinal compounds that have been found to inhibit the inflammatory response and pro-inflammatory cytokine production. These strategies primarily block the protein-protein interactions in the inflammatory signaling cascade. Nevertheless, extensive preclinical studies and risk assessment methodologies are necessary to ensure their safety.

Walking time to nearest public automated external defibrillator for out-of-hospital cardiac arrest in a major U.S. city.

Background: How frequently out-of-hospital cardiac arrest (OHCA) occurs within a reasonable walking distance to the nearest public automated external defibrillator (AED) has not been well studied. Methods: As Kansas City, Missouri has a comprehensive city-wide public AED registry, we identified adults with an OHCA in Kansas City during 2019-2022 in the Cardiac Arrest Registry to Enhance Survival. Using AED location data from the registry, we computed walking times between OHCAs and the nearest registered AED using the Haversine formula, a mapping algorithm to calculate walking distance in miles from one location to another. Results were stratified by OHCA location (home vs. public) and by whether the patient received bystander cardiopulmonary resuscitation (CPR). Results: Of 1,522 OHCAs, 1,291 (84.8%) occurred at home and 231 (15.2%) in public. Among at-home OHCAs, 634 (49.1%) received bystander CPR and no patients had an AED applied even as 297 (23.0%) were within a 4-minute walk to the closest public AED. Among OHCAs in public, 108 (46.8%) were within a 4-minute walk to the closest public AED. For public OHCAs within a 4-minute walk, bystanders applied an AED in 13 (12.0%) of these cases and in 24.5% (13/53) of those who received bystander CPR. Conclusion: In one U.S. city with a publicly available AED registry, there were no instances in which a bystander accessed a public AED for an OHCA at home. For OHCAs in public, nearly half occurred within a 4-minute walk to the closest AED but bystander use of an AED was low.

Early experience with patient-specific unibody bifurcated fenestrated-branched devices for complex endovascular aortic aneurysm repair.

OBJECTIVE: Short distances between the lowest visceral/renal artery and the aortic bifurcation are technically challenging during complex endovascular aortic aneurysm repair (EVAR), particularly after previous infrarenal repair. Traditionally, inverted limb bifurcated devices have been used in addition to fenestrated-branched (FB) endografts, but short overlap, difficult cannulation, and potential crushing of bridging stents are limitations for their use. This study reviews the early experience of patient-specific company manufactured devices (PS-CMDs) with a unibody bifurcated FB design for complex EVAR. METHODS: Consecutive complex EVAR procedures over a 34-month period with unibody bifurcated FB-devices as part of physician-sponsored investigational device exemption studies at two institutions were reviewed. Unibody bifurcated FB designs included FB bifurcated or fenestrated inverted limb devices. End points included technical success, survival, frequency of type I or III endoleaks, limb occlusion, and secondary interventions. RESULTS: Among 168 patients undergoing complex EVAR, 33 patients (19.6%; 78.7% male; mean age, 77 years) received unibody bifurcated FB PS-CMDs. FB bifurcated and fenestrated inverted limb devices were used in 31 (93.9%) and 2 (6.06%) patients, respectively. The median maximum aneurysm diameter was 61 mm (interquartile range [IQR], 55-69 mm). Prior EVAR was reported by 29 patients (87.9%), of whom 2 (6.06%) had suprarenal stents. A short distance between the lowest renal artery and aortic bifurcation was demonstrated in 30 patients (90.9%), with median distance of 47 mm (IQR, 38-54 mm). Preloaded devices were used in 23 patients (69.7%). A total of 128 fenestrations were planned; 22 (17.2%) were preloaded with guidewires and 5 (3.9%) with catheters. The median operative time was 238 minutes (226-300 minutes), with a median fluoroscopy time of 65.5 minutes (IQR, 56.0-77.7 minutes) and a median dose area product of 147 mGy∗cm2 (IQR, 105-194 mGy∗cm2). Exclusive femoral access was used in 14 procedures (42.4%). Technical success was 100%. Target vessel primary patency was 100% at a median follow-up time of 11.7 months (IQR, 3.5-18.6 months). Two patients (6.06%) required reintervention for iliac occlusion; one patient required stenting and the other a femoral-femoral bypass. No aortic-related deaths occurred after the procedure. During follow-up, 11 type II endoleaks (33.3%) and 1 type Ib endoleak (3.03%) were detected; the latter was treated with leg extension. No type Ia or III endoleaks occurred. CONCLUSIONS: Complex EVAR using unibody bifurcated FB-PS-CMDs is a simple, safe, and cost-effective alternative for the treatment of patients with short distances between the renal arteries and the aortic bifurcation. Further studies are required to assess benefits and durability of unibody bifurcated FB devices.

Generalizable Approach to Quantifying Guideline-Directed Medical Therapy.

BACKGROUND: Quantifying guideline-directed medical therapy (GDMT) intensity is foundational for improving heart failure (HF) care. Existing measures discount dose intensity or use inconsistent weighting. METHODS: The Kansas City Medical Optimization (KCMO) score is the average of total daily to target dose percentages for eligible GDMT, reflecting the percentage of optimal GDMT prescribed (range, 0-100). In Change the Management of Patients With HF, we computed KCMO, HF collaboratory (0-7), and modified HF Collaboratory (0-100) scores for each patient at baseline and for 1-year change in established GDMT at the time (mineralocorticoid receptor antagonist, ß-blocker, ACE [angiotensin-converting enzyme] inhibitor/angiotensin receptor blocker/angiotensin receptor neprilysin inhibitor). We compared baseline and 1-year change distributions and the coefficient of variation (SD/mean) across scores. RESULTS: Among 4532 patients at baseline, mean KCMO, HF collaboratory, and modified HF Collaboratory scores were 38.8 (SD, 25.7), 3.4 (1.7), and 42.2 (22.2), respectively. The mean 1-year change (n=4061) for KCMO was -1.94 (17.8); HF collaborator, -0.11 (1.32); and modified HF Collaboratory, -1.35 (19.8). KCMO had the highest coefficient of variation (0.66), indicating greater variability around the mean than the HF collaboratory (0.49) and modified HF Collaboratory (0.53) scores, reflecting higher resolution of the variability in GDMT intensity across patients. CONCLUSIONS: KCMO measures GDMT intensity by incorporating dosing and treatment eligibility, provides more granularity than existing methods, is easily interpretable (percentage of ideal GDMT), and can be adapted as performance measures evolve. Further study of its association with outcomes and its usefulness for quality assessment and improvement is needed.

Early results of transcatheter electrosurgical aortic septotomy for endovascular repair of chronic dissecting aortoiliac aneurysms.

Objective: Endovascular repair of chronic dissecting aortoiliac aneurysms is challenging given the rigid septum, compressed true lumen (TL), and target vessels frequently originating in the false lumen. We have used transcatheter electrosurgical aortic septotomy (TEAS) before stent graft implantation under intravascular ultrasound (IVUS) and fusion guidance. The purpose of this study is to assess the outcomes of TEAS during complex endovascular repair of dissecting aneurysms. Methods: From 2021 to 2023, 17 patients underwent TEAS. The primary end point was technical success, with secondary end points of proximal and distal seals, target vessel instability, aortic and iliac TL and cross-sectional area (CSA) expansion, and aortic-related death. During the procedure, the aortic septum is crossed through a pre-existing entry or via electrocautery-activated 0.018-in. Astato XS20 wire (Asahi-Intecc) under IVUS and fusion guidance. The penetrated wire is then snared in the false lumen and pulled through the ipsilateral femoral access. A 1-cm length of the middle of the Astato wire coating is kinked in a three-sided polygonal configuration, denuded the inner surface of the wire using a no. 15 blade, and positioned at the apex of the septum. Both ends of the Astato wire are insulated with 0.018-in. microcatheters, and the back end of the wire is denuded and connected to cautery. Gentle traction is applied to the wire, and short bursts of electrocautery cutting are applied at 60 to 80 W. Results: The technical success of the septotomy was 100%. No incidence of visceral or lower extremity malperfusion, vascular injury, or distal embolization occurred. Of the 17 patients, 4 underwent thoracic endovascular aneurysm repair, 2 underwent endovascular aortic repair, and 11 underwent fenestrated/branched endovascular aneurysm repair after septotomy. All target vessels were successfully stented. A distal landing zone seal with exclusion of the false lumen was achieved in 16 of the 17 patients (94.1%). One patient required embolization of the false lumen of the celiac artery after septotomy. The TL mean diameter and CSA of the descending thoracic aorta after septotomy was expanded by 7.01 ± 1.9 mm (relative mean diameter expansion, 42.3%; P < .0001) and 2.71 ± 0.4 cm2 (relative mean CSA expansion, 57.3%, P<.0001). For patients who required septotomy through the common iliac arteries, the mean TL was expanded by 8.1 ± 3.7 mm (relative mean diameter expansion, 76%; P < .0001) and 1.76 ± 0.91 cm2 (relative mean CSA expansion, 209%; P < .0001). The 1-year freedom from target vessel instability was 91%. Conclusions: The use of IVUS and fusion-guided TEAS offers a promising technique to facilitate TL expansion and false lumen exclusion in chronic dissecting aortic aneurysms before repair. The durability and long-term outcomes of this technique in a larger cohort remain to be elucidated.

Adaptor molecules mediate negative regulation of macrophage inflammatory pathways: a closer look.

Macrophages play a central role in initiating, maintaining, and terminating inflammation. For that, macrophages respond to various external stimuli in changing environments through signaling pathways that are tightly regulated and interconnected. This process involves, among others, autoregulatory loops that activate and deactivate macrophages through various cytokines, stimulants, and other chemical mediators. Adaptor proteins play an indispensable role in facilitating various inflammatory signals. These proteins are dynamic and flexible modulators of immune cell signaling and act as molecular bridges between cell surface receptors and intracellular effector molecules. They are involved in regulating physiological inflammation and also contribute significantly to the development of chronic inflammatory processes. This is at least partly due to their involvement in the activation and deactivation of macrophages, leading to changes in the macrophages' activation/phenotype. This review provides a comprehensive overview of the 20 adaptor molecules and proteins that act as negative regulators of inflammation in macrophages and effectively suppress inflammatory signaling pathways. We emphasize the functional role of adaptors in signal transduction in macrophages and their influence on the phenotypic transition of macrophages from pro-inflammatory M1-like states to anti-inflammatory M2-like phenotypes. This endeavor mainly aims at highlighting and orchestrating the intricate dynamics of adaptor molecules by elucidating the associated key roles along with respective domains and opening avenues for therapeutic and investigative purposes in clinical practice.

An improved mouse model of sepsis based on intraperitoneal injections of the enriched culture of cecum slurry.

AIM: Sepsis is a life-threatening clinical syndrome comprising multiorgan dysfunctions caused by a disproportionate body immune response. There are several animal sepsis models which are based on cecum ligation, cecal puncture, and cecum slurry injection. The major limitation of all current sepsis models is the high variability owing to the variable degree of ligation, puncture and inconsistent microbial composition used for sepsis initiation. The primary objective of this work is to demonstrate the feasibility of a standardized method for sepsis development. MATERIALS AND METHODS: The cecal slurry bacterial culture was developed and preserved in glycerol stocks. Antibiotics aztreonam and vancomycin were used for generating several defined, enriched cecal slurry bacterial cultures. Mice survival was assessed until 48 hrs post injection, and the tissue samples were collected after 10 hrs from sepsis initiation. KEY FINDINGS: The results indicate that increasing polymicrobial load resulted in lower survival rates and was associated with the higher number of infiltrating immune cells and necrosis. H&E (haematoxylin & eosin) staining & serum markers revealed that septic mice exhibited increased inflammation and significant damage to the liver and kidneys. The defined Gram-negative and Gram-positive specific cecal slurry bacterial cultures were developed and their efficiency in inducing sepsis was characterized. SIGNIFICANCE: Enriched cecal slurry bacterial cultures can be stored in glycerol stocks at -80 °C. This has an ethical advantage of avoiding unnecessary animal euthanasia for each experiment and provides a standardization capability of sepsis development.

Up and over staged endoconduit technique for endovascular aortic aneurysm repair.

Adverse iliofemoral anatomy can preclude complex endovascular aortic aneurysm repair. This study aims to describe the "up-and-over" staged endoconduit technique to improve access and avoid vascular injury before complex endovascular aneurysm repair. A staged procedure for complex endovascular aortic aneurysm repair is performed using an endoconduit (W.L. Gore & Associates). After obtaining contralateral femoral access, the extension of iliofemoral disease is assessed using angiography. The endoconduit is advanced "up and over" the aortic bifurcation and delivered percutaneously into the common femoral artery to treat a diseased access site and maintain intact the ipsilateral femoral access for future stent graft deployment. Internal iliac artery patency is maintained when feasible. During complex aneurysm repair, the endoconduit is accessed directly under ultrasound guidance using sequential dilation to avoid vascular injury. PerClose sutures (Abbott Vascular) are used to close the endoconduit femoral access site. This study found that staged "up and over" endoconduit creation is a useful technique before complex endovascular aneurysm repair in patients with adverse iliofemoral anatomy. Avoiding accessing the main femoral access site during the first stage prevents vascular or access site injuries and allows for both iliac and femoral disease to be addressed.

Effect of reactive oxygen, nitrogen, and sulfur species on signaling pathways in atherosclerosis.

Atherosclerosis is a chronic inflammatory disease in which fats, lipids, cholesterol, calcium, proliferating smooth muscle cells, and immune cells accumulate in the intima of the large arteries, forming atherosclerotic plaques. A complex interplay of various vascular and immune cells takes place during the initiation and progression of atherosclerosis. Multiple reports indicate that tight control of reactive oxygen species (ROS), reactive nitrogen species (RNS), and reactive sulfur species (RSS) production is critical for maintaining vascular health. Unrestricted ROS and RNS generation may lead to activation of various inflammatory signaling pathways, facilitating atherosclerosis. Given these deleterious consequences, it is important to understand how ROS and RNS affect the signaling processes involved in atherogenesis. Conversely, RSS appears to exhibit an atheroprotective potential and can alleviate the deleterious effects of ROS and RNS. Herein, we review the literature describing the effects of ROS, RNS, and RSS on vascular smooth muscle cells, endothelial cells, and macrophages and focus on how changes in their production affect the initiation and progression of atherosclerosis. This review also discusses the contribution of ROS, RNS, and RSS in mediating various post-translational modifications, such as oxidation, nitrosylation, and sulfation, of the molecules involved in inflammatory signaling.

Long-term outcomes of staged iliofemoral endoconduits prior to complex endovascular aortic aneurysm repair.

OBJECTIVE: Adverse iliofemoral anatomy may preclude complex endovascular aortic aneurysm repair (EVAR). In our practice, staged iliofemoral endoconduits (ECs) are planned prior to complex EVAR to improve vascular access and decrease operative time while allowing the stented vessel to heal. This study describes the long-term results of iliofemoral ECs prior to complex EVAR. METHODS: Between 2012 and 2023, 59 patients (44% male; median age, 75 ± 6 years) underwent ECs before complex EVAR using self-expanding covered stents (Viabahn). For common femoral artery (CFA) disease, ECs were delivered percutaneously from contralateral femoral access and extended into the CFA to preserve the future access site for stent graft delivery. Internal iliac artery patency was maintained when feasible. During complex EVAR, the EC extended into the CFA was directly accessed and sequentially dilated until it could accommodate the endograft. Technical success was defined as successful access, closure, and delivery of the endograft during complex EVAR. Endpoints were vascular injury or EC disruption, secondary interventions, and EC patency. RESULTS: Unilateral EC was performed in 45 patients (76%). ECs were extended into the CFA in 21 patients (35%). Median diameters of the native common iliac, external iliac, and CFA were 7 mm (interquartile range [IQR], 6-8 mm), 6 mm (IQR, 5-7 mm), and 6 mm (IQR, 6-7 mm), respectively. Internal iliac artery was inadvertently excluded in 10 patients (17%). Six patients (10%) had an intraoperative vascular injury during the EC procedure, and six patients (10%) had EC disruption during complex EVAR, including five EC collapses requiring re-stenting and one EC fracture requiring open cut-down and reconstruction with patch angioplasty. In 23 patients (39%), 22 Fr OD devices were used; 20 Fr were used in 22 patients (37%), and 18 Fr in 14 patients (24%). Technical success for accessing EC was 89%. There was no difference in major adverse events at 30 days between the iliac ECs and iliofemoral ECs. Primary patency by Kaplan-Meier estimates at 1, 3, and 5 years were 97.5%, 89%, and 82%, respectively. There was no difference in primary patency between iliac and iliofemoral ECs. Six secondary interventions (10%) were required. The mean follow-up was 34 ± 27 months; no limb loss or amputations occurred during the follow-up. CONCLUSIONS: ECs improve vascular access, and their use prior to complex EVAR is associated with low rates of vascular injury, high technical success, and optimal long-term patency. Complex EVAR procedures can be performed percutaneously by accessing the EC directly under ultrasound guidance and using sequential dilation to avoid EC disruption.

Automated External Defibrillator Use After Out-of-Hospital Cardiac Arrest at Recreational Facilities.

This cohort study examines bystander automated external defibrillator (AED) application and survival outcomes for out-of-hospital cardiac arrest at recreational facilities in US states with and without AED legislation.

Structural and accessibility studies highlight the differential binding of clemizole to TRPC5 and TRPC6.

Transient Receptor Potential Canonical 5 (T RP C5) and T RP C6 channels play critical physiological roles in various cell types. Their involvement in numerous disease progression mechanisms has led to extensive searches for their inhibitors. Although several potent T RP C inhibitors have been developed and the structure of their binding sites were mapped using cryo electron microscopy, a comprehensive understanding of the molecular interactions within the inhibitor binding site of T RP Cs remains elusive. This study aimed to decipher the structural determinants and molecular mechanisms contributing to the differential binding of clemizole to T RP C5 and T RP C6, with a particular focus on the accessibility of binding site residues. This information can help better understand what molecular features allow for selective binding, which is a key characteristic of clinically effective pharmacological agents. Using computational methodologies, we conducted an in-depth molecular docking analysis of clemizole with T RP C5 and T RP C6 channels. The protein structures were retrieved from publicly accessible protein databases. Discovery Studio 2020 Client Visualizer and Chimera software facilitated our in-silico mutation experiments and enabled us to identify the critical structural elements influencing clemizole binding. Our study reveals key molecular determinants at the clemizole binding site, specifically outlining the role of residues' Accessible Surface Area (ASA) and Relative Accessible Surface Area (RASA) in differential binding. We found that lower accessibility of T RP C6 binding site residues, compared to those in T RP C5, could account for the lower affinity binding of clemizole to T RP C6. This work illuminates the pivotal role of binding site residue accessibility in determining the affinity of clemizole to T RP C5 and T RP C6. A nuanced understanding of the distinct binding properties between these homologous proteins may pave the way for the development of more selective inhibitors, promising improved therapeutic efficacy and fewer off-target effects. By demystifying the structural and molecular subtleties of T RP C inhibitors, this research could significantly accelerate the drug discovery process, offering hope to patients afflicted with T RP C-related diseases.

Helicobacter pylori and Epstein-Barr virus infection in cell polarity alterations.

The asymmetrical distribution of the cellular organelles inside the cell is maintained by a group of cell polarity proteins. The maintenance of polarity is one of the vital host defense mechanisms against pathogens, and the loss of it contributes to infection facilitation and cancer progression. Studies have suggested that infection of viruses and bacteria alters cell polarity. Helicobacter pylori and Epstein-Barr virus are group I carcinogens involved in the progression of multiple clinical conditions besides gastric cancer (GC) and Burkitt's lymphoma, respectively. Moreover, the coinfection of both these pathogens contributes to a highly aggressive form of GC. H. pylori and EBV target the host cell polarity complexes for their pathogenesis. H. pylori-associated proteins like CagA, VacA OipA, and urease were shown to imbalance the cellular homeostasis by altering the cell polarity. Similarly, EBV-associated genes LMP1, LMP2A, LMP2B, EBNA3C, and EBNA1 also contribute to altered cell asymmetry. This review summarized all the possible mechanisms involved in cell polarity deformation in H. pylori and EBV-infected epithelial cells. We have also discussed deregulated molecular pathways like NF-κB, TGF-ß/SMAD, and ß-catenin in H. pylori, EBV, and their coinfection that further modulate PAR, SCRIB, or CRB polarity complexes in epithelial cells.

Impact of routine surveillance duplex ultrasound and subsequent reintervention after superficial femoral artery stenting.

OBJECTIVE: Superficial femoral artery (SFA) stenting is a common treatment for peripheral artery disease. It is effective in the short term; however, in-stent restenosis (ISR) limits long-term success. Surveillance with duplex ultrasound (DUS) can identify patients who develop ISR leading to early reintervention, but data to support this practice is sparce. The purpose of this study was to evaluate whether surveillance and subsequent reintervention improves outcomes in patients with SFA stents. METHODS: A single-center, retrospective study was performed with patients undergoing SFA stenting between 2005 and 2020 who had a follow-up with DUS. Five groups were identified based on the presence of ISR on DUS (ISR vs no ISR [NISR]), recurrence of symptoms (symptomatic [SX] vs asymptomatic [ASX]), and if any reintervention was performed (reintervention [R] vs no reintervention [NR]): (1) ISR+SX+R; (2) ISR+SX+NR; (3) ISR+ASX+R; (4) ISR+ASX+NR; and (5) NISR+NR. The primary endpoint was amputation-free survival, and the secondary endpoint was patency. Predictors of mortality and surveillance were identified by multivariable logistic regressions and Cox multivariate regression models. Survival curves were presented as Kaplan-Meier plots using log-rank test for subgroup comparison. RESULTS: Two hundred fifty-seven patients were included in the analysis. The indication for intervention was claudication in 28% and chronic limb-threatening ischemia in 72%. A total of 161 patients (63%) underwent reintervention for ISR. Of patients who had restenosis on DUS, those who were symptomatic and did not undergo reintervention (ISR+SX+NR) did the worst, with 50% amputation rate. In contrast, those who were asymptomatic but did undergo reintervention (ISR+ASX+R) had the lowest amputation rate of 13%. Active smoking was a predictor of both loss of patency and amputation (1.72; 95% confidence interval [CI], 1.00-2.98; P = .050; 3.55; 95% CI, 1.53-8.25; P = .003). Post procedure dual antiplatelet therapy had a positive association with limb salvage (hazard ratio [HR], 0.23; 95% CI, 0.09-0.58; P = .001), whereas diabetes (HR, 2.61; 95% CI, 1.21-6.01; P = .019), stent occlusion (HR, 17.0; 95% CI, 5.93-63.1; P < .001), and chronic limb-threatening ischemia presentations (HR, 4.31; 95% CI, 1.86-11.7; P=.002) were negatively associated with limb salvage. CONCLUSIONS: Routine surveillance DUS and subsequent reintervention on ISR after SFA stenting is associated with improved patency and amputation-free survival. Surveillance DUS should be routine for patients after stenting, with reintervention strongly considered if ISR is identified for both symptomatic and asymptomatic.