Characterizing the Crosstalk Between Programmed Cell Death Pathways in Cytokine Storm With an Agent-Based Model.

Background: There is increasing recognition of extensive crosstalk between programmed cell death pathways (PCDPs), such as apoptosis, pyroptosis, and necroptosis, resulting in a highly redundant system responsive to a breadth of potential pathogens. However, because pyroptosis and necroptosis propagate inflammation, these redundancies also present challenges for therapeutic control of dysregulated hyperinflammation seen in cytokine storm (CS) generated organ dysfunction. Hypothesis: We hypothesize that the conversion of existing knowledge regarding apoptosis, pyroptosis, and necroptosis into a computational model can enhance our understanding of the crosstalk between PCDPs via simulation experiments of microbe interactions and experimental interventions. Materials and Methods: Literature regarding apoptosis, pyroptosis, and necroptosis was reviewed and transposed into an agent-based model, the programmed cell death agent-based model (PCDABM). Computational experiments were performed to simulate the activation of various PCDPs as seen by differing microbes, specifically: influenza A virus (IAV), enteropathic Escherichia coli (EPEC), and Salmonella enterica (SE). The potential protective value of PCDP crosstalk was evaluated by silencing either pyroptosis, necroptosis, or both. Computational experiments were also performed simulating the effect of potential therapies blocking tumor necrosis factor (TNF) and interleukin (IL)-1. Results: The PCDABM was implemented in the agent-based modeling toolkit NetLogo. Computational experiments of infection with IAV, EPEC, and SE reproduced cross-activation of PCDPs with effective microbial clearance. Simulations of anti-TNF and anti-IL-1 did not reduce the aggregated amount of inflammation-generated system damage, the surrogate for CS-generated tissue damage. Conclusions: Redundancies have evolved in host PCDPs to maintain protection against a wide range of pathogens. However, these redundancies also challenge attempts at dampening the pathogenic hyperinflammatory state of CS using therapeutic immunomodulation. Integrative simulation models such as the PCDABM can aid in identifying potentially targetable inflection points to mitigate CS while maintaining effective host defense.

Management of acute cholecystitis in patients on anti-thrombotic therapy: A single center experience.

Background: Acute cholecystitis in patients on anti-thrombotic therapy (ATT) presents a clinical dilemma at the intersection between conflicting guidelines, specifically between timing of early operative management (OM) versus time-to-reversal of certain ATT agents. With growing recognition that nonoperative management (NOM) is associated with considerable morbidity, and evidence in the literature that early OM in patients on ATT is safe, we reviewed our own practice to examine how we addressed these conflicting guidelines. Materials and methods: We performed a retrospective review of patients with acute cholecystitis between December 2017 and March 2022. Patients were classified as ATT or non-ATT; ATT patients were subdivided into anticoagulation (AC) and antiplatelet (AP) groups. Rates of OM were compared. Results: 502 patients with acute cholecystitis were identified, 464 non-ATT and 38 ATT. 30 ATT patients were on AC, 7 on AP, and 1 on both. Non-ATT patients were significantly more likely to receive OM at index presentation compared to those on ATT: 89.9 % vs 63.2 % (p < 0.05). Subgroup analysis of the ATT group showed AP patients were significantly less likely to receive OM compared to those on AC, 12.5 % vs 77 % (p < 0.05). Conclusions: At our institution, patients on ATT were significantly less likely to undergo OM for acute cholecystitis compared with non-ATT patients. Those on AC received OM significantly more than patients on AP. Further study is needed to better define the management of this growing population so that acute cholecystitis guidelines might address this issue in the future.

Appendicitis and Cholecystitis in Pregnancy.

Up to 2% of pregnant women develop a disease that requires nonobstetrical operative intervention during pregnancy. We discuss the issues unique to pregnant patients as they pertain to the presentation, diagnosis, and management of nonobstetric surgical disease, with an emphasis on 2 of the most common diseases that affect pregnant women: appendicitis and cholecystitis. Surgery has been demonstrated to be safe and effective during pregnancy, provided proper precautions are taken into account. It is the consensus of multiple professional committees and societies that no pregnant women should be delayed or denied a necessary surgery because of pregnancy.

Improving Patient Satisfaction by Using Design Thinking: Patient Advocate Role in the Emergency Department.

The emergency department (ED) serves a pivotal role in the healthcare system, but it is often a source of anxiety and confusion for patients at a time already shrouded by fear of illness and uncertainty. Common patient needs include receiving information about different stages of their care, assurance that they are safe, and knowledge of a plan for proper follow-up care prior to discharge. Due to well-known restraints on the clinician's time, meeting this level of patient satisfaction has often fallen short. Design thinking is a well-known methodology used to generate solutions to a wide variety of problems with an approach that is inherently iterative in nature. The key feature of the process is a strong focus on practicing empathy as an approach to human-centered design. Utilizing this method, we created a role, filled by preclinical medical students, who are placed in the ED during peak hours to focus on making the patients more comfortable and tend to their more "non-clinical" needs. We posit that this new role will do the following: 1) make patients feel more satisfied with their care in the ED, 2) allow students to gain a robust appreciation for the flow of the ED and the hospital in general, and 3) teach students to actively solve patient's frustrations.

A novel approach to the management of carotid blowout syndrome: the use of thrombin in a case of failed covered stenting.

Acute hemorrhage relating to an expanding pseudoaneurysm of the carotid artery is referred to as carotid blowout syndrome (CBS). CBS is associated with a high morbidity and mortality. We describe the case of a patient who presented with dysphagia and a pulsatile mass in the neck. Imaging revealed a pseudoaneurysm originating from the bifurcation of the distal right common carotid artery. On neuroangiography the patient lacked sufficient collaterals to allow for vessel sacrifice. A decision was made to use covered stents to prevent flow into the pseudoaneurysm while maintaining vessel patency. Despite placement of multiple covered stents there was residual slow filling of the pseudoaneurysm. We augmented this therapy with direct percutaneous thrombin injection into the pseudoaneurysm. This resulted in complete thrombosis of the pseudoaneurysm. For recalcitrant lesions in which the usual methods of stopping blood flow to the pseudoaneurysmal sac fail, an adjuvant approach with thrombin should be considered.

A novel approach to the management of carotid blowout syndrome: the use of thrombin in a case of failed covered stenting.

Acute hemorrhage relating to an expanding pseudoaneurysm of the carotid artery is referred to as carotid blowout syndrome (CBS). CBS is associated with a high morbidity and mortality. We describe the case of a patient who presented with dysphagia and a pulsatile mass in the neck. Imaging revealed a pseudoaneurysm originating from the bifurcation of the distal right common carotid artery. On neuroangiography the patient lacked sufficient collaterals to allow for vessel sacrifice. A decision was made to use covered stents to prevent flow into the pseudoaneurysm while maintaining vessel patency. Despite placement of multiple covered stents there was residual slow filling of the pseudoaneurysm. We augmented this therapy with direct percutaneous thrombin injection into the pseudoaneurysm. This resulted in complete thrombosis of the pseudoaneurysm. For recalcitrant lesions in which the usual methods of stopping blood flow to the pseudoaneurysmal sac fail, an adjuvant approach with thrombin should be considered.