Piezo1 regulates meningeal lymphatic vessel drainage and alleviates excessive CSF accumulation.

Piezo1 regulates multiple aspects of the vascular system by converting mechanical signals generated by fluid flow into biological processes. Here, we find that Piezo1 is necessary for the proper development and function of meningeal lymphatic vessels and that activating Piezo1 through transgenic overexpression or treatment with the chemical agonist Yoda1 is sufficient to increase cerebrospinal fluid (CSF) outflow by improving lymphatic absorption and transport. The abnormal accumulation of CSF, which often leads to hydrocephalus and ventriculomegaly, currently lacks effective treatments. We discovered that meningeal lymphatics in mouse models of Down syndrome were incompletely developed and abnormally formed. Selective overexpression of Piezo1 in lymphatics or systemic administration of Yoda1 in mice with hydrocephalus or Down syndrome resulted in a notable decrease in pathological CSF accumulation, ventricular enlargement and other associated disease symptoms. Together, our study highlights the importance of Piezo1-mediated lymphatic mechanotransduction in maintaining brain fluid drainage and identifies Piezo1 as a promising therapeutic target for treating excessive CSF accumulation and ventricular enlargement.

Resuscitative Thoracotomy for Traumatic Cardiac Arrest: Potential Impact of Resource Constraint on Outcomes and Blood Product Utilization.

INTRODUCTION: Resuscitative thoracotomy (RT) in the setting of traumatic arrest serves as a vital but resource-intensive intervention. The COVID-19 pandemic has created critical shortages, sharpening the focus on efficient resource utilization. This study aims to compare RT performance and blood product utilization before and after the onset of the COVID-19 pandemic for patients in traumatic cardiac arrest. METHODS: All patients undergoing RT for traumatic cardiac arrest in the emergency department at our American College of Surgeons-verified Level 1 trauma center (August 01, 2017-July 31, 2022) were included in this retrospective observational study. Study groups were dichotomized into pre-COVID (before October 03, 2020) versus COVID (from October 03, 2020 on) based on patient arrival date demographics, clinical/injury data, and outcomes were collected. The primary outcome was blood product transfusion <4 h after presentation. RESULTS: 445 RTs (2% of 23,488 trauma encounters) were performed over the study period: Pre-COVID, n = 209 (2%) versus COVID, n = 236 (2%) (P = 0.697). Survival to discharge was equivalent Pre-COVID versus COVID (n = 22, 11% versus n = 21, 9%, P = 0.562). RT patients during COVID consumed a median of 1 unit less packed red blood cells at the 4 h measurement (3.0 [1.8-7.0] versus 3.9 [2.0-10.0] units, P = 0.012) and 1 unit less of platelets at the 4 h measurement (4.3 [2.6-10.0] versus 5.7 [2.9-14.4] units, P = 0.012) compared to Pre-COVID. These findings were persistent after performing multivariable negative binomial regression. CONCLUSIONS: Rates of RT and survival after RT remained consistent during the pandemic. Despite comparable RT frequency, packed red blood cells and platelet transfusions were reduced, likely reflecting resource expenditure minimization during the severe blood shortages that occurred during the pandemic. RT performance for patients in traumatic arrest may, therefore, be feasible during global pandemics at prepandemic frequencies as long as particular attention is paid to resource expenditure.

Piezo1-Regulated Mechanotransduction Controls Flow-Activated Lymphatic Expansion.

BACKGROUND: Mutations in PIEZO1 (Piezo type mechanosensitive ion channel component 1) cause human lymphatic malformations. We have previously uncovered an ORAI1 (ORAI calcium release-activated calcium modulator 1)-mediated mechanotransduction pathway that triggers lymphatic sprouting through Notch downregulation in response to fluid flow. However, the identity of its upstream mechanosensor remains unknown. This study aimed to identify and characterize the molecular sensor that translates the flow-mediated external signal to the Orai1-regulated lymphatic expansion. METHODS: Various mutant mouse models, cellular, biochemical, and molecular biology tools, and a mouse tail lymphedema model were employed to elucidate the role of Piezo1 in flow-induced lymphatic growth and regeneration. RESULTS: Piezo1 was found to be abundantly expressed in lymphatic endothelial cells. Piezo1 knockdown in cultured lymphatic endothelial cells inhibited the laminar flow-induced calcium influx and abrogated the flow-mediated regulation of the Orai1 downstream genes, such as KLF2 (Krüppel-like factor 2), DTX1 (Deltex E3 ubiquitin ligase 1), DTX3L (Deltex E3 ubiquitin ligase 3L,) and NOTCH1 (Notch receptor 1), which are involved in lymphatic sprouting. Conversely, stimulation of Piezo1 activated the Orai1-regulated mechanotransduction in the absence of fluid flow. Piezo1-mediated mechanotransduction was significantly blocked by Orai1 inhibition, establishing the epistatic relationship between Piezo1 and Orai1. Lymphatic-specific conditional Piezo1 knockout largely phenocopied sprouting defects shown in Orai1- or Klf2- knockout lymphatics during embryo development. Postnatal deletion of Piezo1 induced lymphatic regression in adults. Ectopic Dtx3L expression rescued the lymphatic defects caused by Piezo1 knockout, affirming that the Piezo1 promotes lymphatic sprouting through Notch downregulation. Consistently, transgenic Piezo1 expression or pharmacological Piezo1 activation enhanced lymphatic sprouting. Finally, we assessed a potential therapeutic value of Piezo1 activation in lymphatic regeneration and found that a Piezo1 agonist, Yoda1, effectively suppressed postsurgical lymphedema development. CONCLUSIONS: Piezo1 is an upstream mechanosensor for the lymphatic mechanotransduction pathway and regulates lymphatic growth in response to external physical stimuli. Piezo1 activation presents a novel therapeutic opportunity for preventing postsurgical lymphedema. The Piezo1-regulated lymphangiogenesis mechanism offers a molecular basis for Piezo1-associated lymphatic malformation in humans.

Telemedicine Experience of General Surgery Trainees: Impact on Patient Care and Education.

OBJECTIVE: The COVID-19 pandemic has had a significant impact on patient care, including the increased utilization of contact-free clinic visits using telemedicine. We looked to assess current utilization of, experience with, and opinions regarding telemedicine by general surgery residents at an academic university-based surgical training program. DESIGN: A response-anonymous 19-question survey was electronically distributed to all general surgery residents at a single academic university-based general surgery residency program. SETTING: University of Southern California (USC) general surgery residency participants: Voluntarily participating general surgery residents at the University of Southern California. RESULTS: The response rate from USC general surgery residents was 100%. A majority of residents (76%) had utilized either video- or telephone-based visits during their careers. No resident had undergone formal training to provide telemedicine, although most residents indicated a desire for training (57.1%) and acknowledged that telemedicine should be a part of surgical training (75.6%). A wide variety of opinions regarding the educational experience of residents participating in telemedicine visits was elicited. CONCLUSIONS: The COVID-19 pandemic brought telemedicine to the forefront as an integral part of future patient care, including for surgical patients. Additional investigations into nationwide telemedicine exposure and practice among United States general surgery residencies is imperative, and the impact of the implementation of telemedicine curricula on general surgery resident telemedicine utilization, comfort with telemedicine technology, and patient outcomes are further warranted. COMPETENCIES: Practice-based learning, systems-based practice, interpersonal and communication skills.