Intrinsically stretchable electrode array enabled in vivo electrophysiological mapping of atrial fibrillation at cellular resolution.
Proceedings of the National Academy of Sciences of the United States of America
Electrophysiological mapping of chronic atrial fibrillation (AF) at high throughput and high resolution is critical for understanding its underlying mechanism and guiding definitive treatment such as cardiac ablation, but current electrophysiological tools are limited by either low spatial resolution or electromechanical uncoupling of the beating heart. To overcome this limitation, we herein introduce a scalable method for fabricating a tissue-like, high-density, fully elastic electrode (elastrode) array capable of achieving real-time, stable, cellular level-resolution electrophysiological mapping in vivo. Testing with acute rabbit and porcine models, the device is proven to have robust and intimate tissue coupling while maintaining its chemical, mechanical, and electrical properties during the cardiac cycle. The elastrode array records epicardial atrial signals with comparable efficacy to currently available endocardial-mapping techniques but with 2 times higher atrial-to-ventricular signal ratio and >100 times higher spatial resolution and can reliably identify electrical local heterogeneity within an area of simultaneously identified rotor-like electrical patterns in a porcine model of chronic AF.
View details for DOI 10.1073/pnas.2000207117
View details for PubMedID 32541030
Diagnosing Epithelioid Hemangioendothelioma with Pericardial Involvement.
The Annals of thoracic surgery
Epithelioid hemangioendothelioma (EHE) is a rare vascular tumor that commonly affects lung, liver, and bone. Among all known EHE cases, only 20% have a pulmonary origin, with metastases to the pericardium occurring in less than 1% of these. Due to its low prevalence, variable presentation, and unknown latency period, a thoracic EHE diagnosis can be easily missed. This case outlines the unique pathologic features of EHE in a patient with cardiovascular disease, provides further insight into diagnosing a rare tumor, and provides a better understanding of the pathophysiology and progression of thoracic EHE.
View details for PubMedID 29689240
Mechanical stretch triggers rapid epithelial cell division through Piezo1.
2017; 543 (7643): 118–21
Despite acting as a barrier for the organs they encase, epithelial cells turn over at some of the fastest rates in the body. However, epithelial cell division must be tightly linked to cell death to preserve barrier function and prevent tumour formation. How does the number of dying cells match those dividing to maintain constant numbers? When epithelial cells become too crowded, they activate the stretch-activated channel Piezo1 to trigger extrusion of cells that later die. However, it is unclear how epithelial cell division is controlled to balance cell death at the steady state. Here we show that mammalian epithelial cell division occurs in regions of low cell density where cells are stretched. By experimentally stretching epithelia, we find that mechanical stretch itself rapidly stimulates cell division through activation of the Piezo1 channel. To stimulate cell division, stretch triggers cells that are paused in early G2 phase to activate calcium-dependent phosphorylation of ERK1/2, thereby activating the cyclin B transcription that is necessary to drive cells into mitosis. Although both epithelial cell division and cell extrusion require Piezo1 at the steady state, the type of mechanical force controls the outcome: stretch induces cell division, whereas crowding induces extrusion. How Piezo1-dependent calcium transients activate two opposing processes may depend on where and how Piezo1 is activated, as it accumulates in different subcellular sites with increasing cell density. In sparse epithelial regions in which cells divide, Piezo1 localizes to the plasma membrane and cytoplasm, whereas in dense regions in which cells extrude, it forms large cytoplasmic aggregates. Because Piezo1 senses both mechanical crowding and stretch, it may act as a homeostatic sensor to control epithelial cell numbers, triggering extrusion and apoptosis in crowded regions and cell division in sparse regions.
View details for DOI 10.1038/nature21407
View details for PubMedID 28199303
Use of Oxandrolone to Promote Growth in Neonates following Surgery for Complex Congenital Heart Disease: An Open-Label Pilot Trial.
Congenital heart disease
2016; 11 (6): 693–99
Malnutrition and poor weight gain, common in neonates following repair of complex congenital heart disease (CHD), are associated with increased morbidity and mortality. Oxandrolone, an anabolic steroid, improves weight gain in older children at high-risk for growth failure. We sought to determine feasibility, safety, and efficacy of oxandrolone therapy in neonates following surgery for complex CHD.Neonates with RACHS-1 score >3 were eligible to receive open-label oxandrolone for 28 days in this prospective pilot trial. There were 3 cohorts of 5 subjects receiving oxandrolone therapy under 3 specified dosage and preparation protocols: 0.1 mg/kg/day aqueous solution, 0.2 mg/kg/day aqueous solution, and 0.1 mg/kg/day preparation in medium chain triglyceride (MCT) oil. Age- and diagnosis-matched neonates who underwent surgery, but received no oxandrolone, served as a control cohort. Anthropometric measurements, physical examination for virilization, safety labs, and adverse events were monitored.Of 25 eligible patients, 15 consented (60%, 13/15 with Norwood procedure). There was no evidence of virilization, no changes in safety labs, and no serious adverse events related to oxandrolone among subjects receiving therapy. No subject met criteria for termination of study drug. There was a significant difference in change in weight-for-age z-score among the four cohorts, with subjects receiving 0.1 mg/kg/day in MCT oil having the lowest decline during the study period (-1.8 ± 0.5 for controls, -1.7 ± 0.4 for 0.1 mg/kg/day aqueous, -1.0 ± 0.4 for 0.2 mg/kg/day aqueous, and -0.6 ± 0.7 for 0.1 mg/kg/day MCT oil, P = .012).Oxandrolone therapy at the doses studied appears safe in neonates after surgery for complex CHD. The decline in weight-for-age z-score was lowest in those receiving the MCT oil preparation suggesting better bioavailability of this preparation and a potential growth benefit with oxandrolone therapy. Further investigation is needed to define optimal dosing and assess efficacy.
View details for DOI 10.1111/chd.12376
View details for PubMedID 27257953
Paravertebral regional blocks decrease length of stay following surgery for pectus excavatum in children
JOURNAL OF PEDIATRIC SURGERY
2016; 51 (1): 149-153
Management of postoperative pain following repair of pectus excavatum has traditionally included thoracic epidural analgesia, narcotics, and benzodiazepines. We hypothesized that the use of intercostal or paravertebral regional blocks could result in decreased inpatient length of stay (LOS).We conducted a retrospective cohort study of 137 patients (118 Nuss and 19 Ravitch - Nuss and Ravitch patients were analyzed separately) who underwent surgical repair of pectus excavatum with pain management via epidural, intercostal, or paravertebral analgesia from January 2009-December 2012. Measured outcomes included LOS, pain scores, benzodiazepine/narcotic requirements, emesis, professional fees, hospital cost, and total cost.In the Nuss patients, LOS was significantly reduced in the paravertebral group (p<0.005) and the intercostal group (p<0.005) compared to the epidural group, but was paradoxically countered by a nonsignificant increase in total cost (p=0.09). While benzodiazepine doses/day was not increased in the paravertebral group (p=0.08), an increase was seen in narcotic use (p<0.005). Despite increased narcotic use, no differences were seen in emesis between epidural and paravertebral use. Compared to epidural, pain scores were higher for both intercostal and paravertebral on day one (p<0.005), but equivalent for paravertebral on day three (p=0.62). The Ravitch group was too small for detailed independent statistical analysis but followed the same overall trend seen in the Nuss patients.Our use of paravertebral continuous infusion pain catheters for pectus excavatum repair was an effective alternative to epidural analgesia resulting in shorter LOS but not a decrease in overall cost.
View details for DOI 10.1016/j.jpedsurg.2015.10.037
View details for Web of Science ID 000367696600029
View details for PubMedID 26577910
Addressing challenges of training a new generation of clinician-innovators through an interdisciplinary medical technology design program: Bench-to-Bedside.
Clinical and translational medicine
2015; 4: 15-?
Graduate medical education has traditionally focused on training future physicians to be outstanding clinicians with basic and clinical science research skills. This focus has resulted in substantial knowledge gains, but a modest return on investment based on direct improvements in clinical care. In today's shifting healthcare landscape, a number of important challenges must be overcome to not only improve the delivery of healthcare, but to prepare future physicians to think outside the box, focus on and create healthcare innovations, and navigate the complex legal, business and regulatory hurdles of bringing innovation to the bedside. We created an interdisciplinary and experiential medical technology design competition to address these challenges and train medical students interested in moving new and innovative clinical solutions to the forefront of medicine. Medical students were partnered with business, law, design and engineering students to form interdisciplinary teams focused on developing solutions to unmet clinical needs. Over the course of six months teams were provided access to clinical and industry mentors, $500 prototyping funds, development facilities, and non-mandatory didactic lectures in ideation, design, intellectual property, FDA regulatory requirements, prototyping, market analysis, business plan development and capital acquisition. After four years of implementation, the program has supported 396 participants, seen the development of 91 novel medical devices, and launched the formation of 24 new companies. From our perspective, medical education programs that develop innovation training programs and shift incentives from purely traditional basic and clinical science research to also include high-risk innovation will see increased student engagement in improving healthcare delivery and an increase in the quality and quantity of innovative solutions to medical problems being brought to market.
View details for DOI 10.1186/s40169-015-0056-3
View details for PubMedID 25984273
Neonatal Flail Tricuspid Valve: Diagnosis and Management
ANNALS OF THORACIC SURGERY
2014; 98 (3): 1098-1101
Flail tricuspid valve in the neonate is a rare and often fatal condition requiring early diagnosis and intervention. We report 3 infants born without antenatal signs of cardiovascular compromise. Severe hypoxemia developed within hours of birth due to disruption of the anterior leaflet of the tricuspid valve. Each patient was stabilized and required differing levels of acute care including prostaglandin-E2 alone, prostaglandin-E2 plus nitric oxide and milrinone, or extracorporeal membrane oxygenation. All patients underwent successful tricuspid valve repair.
View details for DOI 10.1016/j.athoracsur.2013.11.003
View details for Web of Science ID 000341982700059
View details for PubMedID 25193198
Heart failure due to "disappearing" aortic valve in hypoplastic left heart syndrome.
World journal for pediatric & congenital heart surgery
2014; 5 (2): 334-337
We present the unusual case of a "disappearing" aortic valve in an infant with hypoplastic left heart syndrome (mitral and aortic stenosis) that underwent Norwood palliation at birth and subsequently a Glenn operation. Angiographic images at the time of operation showed no apparent insufficiency of the native aortic valve. Over the course of 14 months following operation, the patient developed significant cardiomegaly with a workup revealing severe native aortic valve insufficiency. Following orthotopic heart transplantation, examination of the explanted heart revealed a complete absence of native aortic valve leaflets.
View details for DOI 10.1177/2150135113512137
View details for PubMedID 24668988
Crowding induces live cell extrusion to maintain homeostatic cell numbers in epithelia
2012; 484 (7395): 546-U183
For an epithelium to provide a protective barrier, it must maintain homeostatic cell numbers by matching the number of dividing cells with the number of dying cells. Although compensatory cell division can be triggered by dying cells, it is unknown how cell death might relieve overcrowding due to proliferation. When we trigger apoptosis in epithelia, dying cells are extruded to preserve a functional barrier. Extrusion occurs by cells destined to die signalling to surrounding epithelial cells to contract an actomyosin ring that squeezes the dying cell out. However, it is not clear what drives cell death during normal homeostasis. Here we show in human, canine and zebrafish cells that overcrowding due to proliferation and migration induces extrusion of live cells to control epithelial cell numbers. Extrusion of live cells occurs at sites where the highest crowding occurs in vivo and can be induced by experimentally overcrowding monolayers in vitro. Like apoptotic cell extrusion, live cell extrusion resulting from overcrowding also requires sphingosine 1-phosphate signalling and Rho-kinase-dependent myosin contraction, but is distinguished by signalling through stretch-activated channels. Moreover, disruption of a stretch-activated channel, Piezo1, in zebrafish prevents extrusion and leads to the formation of epithelial cell masses. Our findings reveal that during homeostatic turnover, growth and division of epithelial cells on a confined substratum cause overcrowding that leads to their extrusion and consequent death owing to the loss of survival factors. These results suggest that live cell extrusion could be a tumour-suppressive mechanism that prevents the accumulation of excess epithelial cells.
View details for DOI 10.1038/nature10999
View details for Web of Science ID 000303200400058
View details for PubMedID 22504183