While the effects of microgravity on inducing skeletal muscle atrophy have been extensively studied, the impacts of microgravity on myogenesis and its mechanisms remain unclear. In this study, we developed a microphysiological system of engineered muscle tissue (EMT) fabricated using a collagen / Matrigel composite hydrogel and murine skeletal myoblasts. This 3D EMT model allows non-invasive quantitative assessment of contractile function. After applying a 7-day differentiation protocol to induce myotube formation, the EMTs clearly exhibited sarcomerogenesis, myofilament formation, and synchronous twitch and tetanic contractions with electrical stimuli. Using this 3D EMT system, we investigated the effects of simulated microgravity at 10 −3 G on myogenesis and contractile function utilizing a random positioning machine. EMTs cultured for 5 days in simulated microgravity exhibited significantly reduced contractile forces, myofiber size, and differential expression of muscle contractile, myogenesis regulatory, and mitochondrial biogenesis-related proteins. These results indicate simulated microgravity attenuates myogenesis, resulting in impaired muscle function.

Microgravity Based Biomanufacturing In article 2300157, Peter H. U. Lee, Deok-Ho Kim, and co-workers discuss simulated and real microgravity platforms used to improve biomanufacturing of 3D tissue constructs and their use in studying pathophysiology of long duration space missions. Various microphysiological systems are presented, including organoid and organ-on-a-chip, which are fabricated and flown in microgravity to model specific human diseases and aging effects.

The growing interest in bioengineering in-vivo-like 3D functional tissues has led to novel approaches to the biomanufacturing process as well as expanded applications for these unique tissue constructs. Microgravity, as seen in spaceflight, is a unique environment that may be beneficial to the tissue-engineering process but cannot be completely replicated on Earth. Additionally, the expense and practical challenges of conducting human and animal research in space make bioengineered microphysiological systems an attractive research model. In this review, published research that exploits real and simulated microgravity to improve the biomanufacturing of a wide range of tissue types as well as those studies that use microphysiological systems, such as organ/tissue chips and multicellular organoids, for modeling human diseases in space are summarized. This review discusses real and simulated microgravity platforms and applications in tissue-engineered microphysiological systems across three topics: 1) application of microgravity to improve the biomanufacturing of tissue constructs, 2) use of tissue constructs fabricated in microgravity as models for human diseases on Earth, and 3) investigating the effects of microgravity on human tissues using biofabricated in vitro models. These current achievements represent important progress in understanding the physiological effects of microgravity and exploiting their advantages for tissue biomanufacturing.

Central MessageLong noncoding RNA GAS5 may play a role in mediating neurologic injury after deep hypothermic circulatory arrest and serve as a potential therapeutic target.See Article page 50. Long noncoding RNA GAS5 may play a role in mediating neurologic injury after deep hypothermic circulatory arrest and serve as a potential therapeutic target. See Article page 50. The renowned late theoretical physicist Stephen Hawking once said that “the missing link in cosmology is the nature of dark matter and dark energy.” For centuries, space was believed to be, as the name implies, empty and void. It is now hypothesized, however, that approximately 95% of the universe is made up of dark matter and dark energy.1Bahcall N.A. Dark matter universe.Proc Natl Acad Sci U S A. 2015; 112: 12243-12245Crossref Scopus (8) Google Scholar And although these mysterious forms of matter and energy are invisible and essentially undetectable, they both are presumed to exist and have a profound effect on the nature of galaxies and the universe. Similarly, the dogma that DNA is transcribed into messenger RNA, which is then translated into peptides and proteins, has historically dominated our understanding. Or so we thought. The surprising discovery of the noncoding RNAs, and more specifically long noncoding RNA (lncRNA), has revolutionized our understanding of the critical role these seemingly unimportant strands of RNA have in the essential function of many, if not most, biologic processes, including neurological injury.2Kaur H. Sarmah D. Saraf J. Vats K. Kalia K. Borah A. et al.Noncoding RNAs in ischemic stroke: time to translate.Ann N Y Acad Sci. 2018; 1421: 19-36Crossref Scopus (39) Google Scholar And as we learn more about the ubiquitous nature of lncRNAs, their potential clinical value as a biomarker or therapeutic target or agent for diagnosing and treating a variety clinical conditions is becoming increasingly evident.3Chen Y. Zhou J. LncRNAs: macromolecules with big roles in neurobiology and neurological diseases.Metab Brain Dis. 2017; 32: 281-291Crossref Scopus (47) Google Scholar In this issue of the Journal, Gao and colleagues4Gao S. Gu T. Shi E. Tang R. Liu J. Shi J. Inhibition of long noncoding RNA growth arrest–specific 5 attenuates cerebral injury induced by deep hypothermic circulatory arrest in rats.J Thorac Cardiovasc Surg. 2020; 159: 50-59Abstract Full Text Full Text PDF Scopus (5) Google Scholar describe an elegant study that demonstrates for the first time the potential role of a lncRNA (GAS5) in mediating neurologic injury caused by deep hypothermic circulatory arrest (DHCA). Gao and colleagues4Gao S. Gu T. Shi E. Tang R. Liu J. Shi J. Inhibition of long noncoding RNA growth arrest–specific 5 attenuates cerebral injury induced by deep hypothermic circulatory arrest in rats.J Thorac Cardiovasc Surg. 2020; 159: 50-59Abstract Full Text Full Text PDF Scopus (5) Google Scholar demonstrated that downregulation of GAS5 reduced neuronal damage and neurologic function in mice after DHCA. Despite the inherent limitations of rodent experiments and of extrapolating these results to the clinical setting, this study does provide some clear and promising evidence of the potential role of a lncRNA in mediating neurologic injury after DHCA. Most significantly, the putative cerebral protection seen with GAS5 inhibition points to the potential utility of this and other lncRNAs as both powerful biomarkers and therapeutic targets for neuroprotection after DHCA. Neurologic injury remains the Achilles' heel of DHCA, and this study represents a clear demonstration of mitigation of downstream injury after DHCA. And although multiple pathways are involved, in this case, this lncRNA may indeed be a missing link between DHCA and neurologic injury. Just as the existence and critical role of dark matter and dark energy in the universe are becoming increasingly evident, despite still being largely an enigma, we are also just starting to appreciate better the critical function that noncoding RNAs once considered unimportant may have in mediating significant clinical problems. In the words of British novelist Matt Haig, “Dark matter is needed to hold galaxies together. Your mind is a galaxy.”5Haig M. The humans: a novel. Simon & Schuster, New York2013Google Scholar Perhaps, in our effort to keep our mind together after DHCA, we have found our missing lnc! Inhibition of long noncoding RNA growth arrest–specific 5 attenuates cerebral injury induced by deep hypothermic circulatory arrest in ratsThe Journal of Thoracic and Cardiovascular SurgeryVol. 159Issue 1PreviewWe sought to investigate cerebroprotection by targeting long noncoding RNA growth arrest–specific 5 in a rat model of prolonged deep hypothermic circulatory arrest. Full-Text PDF Open Archive

Since its identification in 2009, multiple studies have indicated the importance of MG53 in muscle physiology. The protein is produced in striated muscles but has physiologic implications reaching beyond the confines of striated muscles. Roles in muscle regeneration, calcium homeostasis, excitation-contraction coupling, myogenesis, and the mitochondria highlight the protein’s wide-reaching impact. Numerous therapeutic applications could potentially emerge from these physiologic roles. This review summarizes the current literature regarding the role of MG53 in the skeletal muscle. Therapeutic applications are discussed.

OBJECTIVES:Thromboembolic and bleeding events are potential complications following left ventricular assist device implantation. A tight control of the international normalized ratio (INR) is believed to be crucial in the reduction of postimplant complications. There is significant variability among institutions as to whether a device implanting centre should be managing the INR. In this study, we evaluated the effect of INR management strategies in maintaining a therapeutic INR.METHODS:A retrospective review was utilized to identify patients implanted with either the HeartMate II or the HeartWare HVAD between January 2011 and February 2016. Patients were stratified into 4 groups based on the post-discharge INR management strategy: outside hospital system anticoagulation clinic, outside hospital primary care provider, implanting centre anticoagulation clinic or implanting centre ventricular assist device office. The INR data were collected and analysed for both the early (discharge, 7, 14, 21 and 30 days) and late (3, 6, 9 and 12 months) postoperative periods.RESULTS:There were 163 patients identified during the study period who met the study inclusion criteria: 49 (30%) patients were managed by an outside hospital system anticoagulation clinic, 59 (36.2%) patients by an outside hospital physician/primary care provider, 22 (13.5%) patients by the implanting centre anticoagulation clinic and 33 (20.2%) patients by the implanting centre ventricular assist device office. There were no statistically significant differences found between management strategies across all time points.CONCLUSIONS:There was no statistically significant difference found between the management strategies examined. Regardless of the chosen INR management strategy, patients have similar INR values and postoperative outcomes.

With extended stays aboard the International Space Station (ISS) becoming commonplace as humanity prepares for exploration-class space missions, the need to better understand the effects of cardiac function during spaceflight is critical. However, primary human heart tissues, which would be useful for in vitro studies on heart function, are difficult to obtain and maintain. As a model system, we utilized cardiomyocytes (CMs) derived from human induced pluripotent stem cells (hiPSCs) to study the effects of microgravity on human cardiac function and gene expression at the cellular level. We derived hiPSCs from three healthy volunteers and produced hiPSC-CMs using a high-efficiency hiPSC-CM differentiation protocol. We cultured hiPSC-CMs in a microgravity environment aboard the ISS for approximately one month, during which weekly media changes were conducted. We analyzed the gene expression, structure, and function of flight, post-flight, and ground control hiPSC-CM samples using RNA-sequencing, immunofluorescence, calcium imaging, and contractility assessment. Exposure to microgravity on the ISS resulted in decreased contractile velocity and calcium recycling in the hiPSC-CM, along with increased beating irregularities. RNA-sequencing analysis demonstrated that there were 2635 genes differentially expressed with p≤0.05 between flight, post-flight, and ground control samples. These included genes involved in metabolism, DNA/RNA modification, and molecular transport, indicating that these pathways may be permanently altered by long-term space flight . This study represents the first time that hiPSC technology has been used to study the effects of microgravity on human cardiac function and is the first to demonstrate that microgravity affects human heart function on the cellular level.

Wound care is a major healthcare expenditure. Treatment of burns, surgical and trauma wounds, diabetic lower limb ulcers and skin wounds is a major medical challenge with current therapies largely focused on supportive care measures. Successful wound repair requires a series of tightly coordinated steps including coagulation, inflammation, angiogenesis, new tissue formation and extracellular matrix remodelling. Zinc is an essential trace element (micronutrient) which plays important roles in human physiology. Zinc is a cofactor for many metalloenzymes required for cell membrane repair, cell proliferation, growth and immune system function. The pathological effects of zinc deficiency include the occurrence of skin lesions, growth retardation, impaired immune function and compromised would healing. Here, we discuss investigations on the cellular and molecular mechanisms of zinc in modulating the wound healing process. Knowledge gained from this body of research will help to translate these findings into future clinical management of wound healing.

The Bellagio II Summit sought to correlate current ISS (International Space Station) Space Medicine practice in the screening/assessment and management of CAD (Coronary Artery Disease) and to identify terrestrial applications for the general population pertaining to primary, secondary and tertiary diagnoses and treatments. We identified current Space Medicine practice for screening and monitoring cosmonaut and astronaut in the pre-, in-, and post-flight mission phases. We will discuss current Space Medicine standards and guidelines in the recognition and monitoring of CAD development, stabilization, and regression.

Septic pulmonary emboli (SPE) can be a difficult clinical entity to distinguish from thromboembolic pulmonary embolism (TPE) in a patient with history of IV drug abuse (IVDA). We present a case of a patient who presented with failure to thrive and presumed diagnosis of recurrent PE that ultimately was discovered to have fungal pulmonary valve endocarditis resulting in a right ventricular outflow obstruction. This required replacement of the pulmonary valve and repair of the right ventricular outflow tract. This case highlights difficulty in differentiating pulmonary valve endocarditis with septic emboli from chronic PE in a patient with a complex medical history.

RATIONALE:In 2005, the lung allocation score (LAS) was implemented to prioritize organ allocation to minimize waiting-list mortality and maximize 1-year survival. It resulted in transplantation of older and sicker patients without changing 1-year survival. Its effect on resource use is unknown. OBJECTIVES:To determine changes in resource use over time in lung transplant admissions. METHODS:Solid organ transplant recipients were identified within the Nationwide Inpatient Sample (NIS) data from 2000 to 2011. Joinpoint regression methodology was performed to identify a time point of change in mean total hospital charges among lung transplant and other solid-organ transplant recipients. Two temporal lung transplant recipient cohorts identified by joinpoint regression were compared for baseline characteristics and resource use, including total charges for index hospitalization, charges per day, length of stay, discharge disposition, tracheostomy, and need for extracorporeal membrane oxygenation. MEASUREMENTS AND MAIN RESULTS:A significant point of increased total hospital charges occurred for lung transplant recipients in 2005, corresponding to LAS implementation, which was not seen in other solid-organ transplant recipients. Total transplant hospital charges increased by 40% in the post-LAS cohort ($569,942 [$53,229] vs. $407,489 [$28,360]) along with an increased median length of stay, daily charges, and discharge disposition other than to home. Post-LAS recipients also had higher post-transplant use of extracorporeal membrane oxygenation (odds ratio, 2.35; 95% confidence interval, 1.56-3.55) and higher incidence of tracheostomy (odds ratio, 1.52; 95% confidence interval, 1.22-1.89). CONCLUSIONS:LAS implementation is associated with a significant increase in resource use during index hospitalization for lung transplant.

This article has been retracted: please see Elsevier Policy on Article Withdrawal (http://www.elsevier.com/locate/withdrawalpolicy).This article has been retracted at the request of the Editor-in-Chief.This article has been retracted for scientific misconduct and plagiarism. The case-study patient reported in this paper was previously reported in Kumar S, Wong G, Maysky M, Shulman M, Olenchock S, Falzon-Kirby M, and Oo TH. Amniotic fluid embolism complicated by paradoxical embolism and disseminated intravascular coagulation. American Journal of Critical Care 2010;19:379–382, http://dx.doi.org/10.4037/ajcc2009957. This article has been retracted: please see Elsevier Policy on Article Withdrawal (http://www.elsevier.com/locate/withdrawalpolicy). This article has been retracted at the request of the Editor-in-Chief. This article has been retracted for scientific misconduct and plagiarism. The case-study patient reported in this paper was previously reported in Kumar S, Wong G, Maysky M, Shulman M, Olenchock S, Falzon-Kirby M, and Oo TH. Amniotic fluid embolism complicated by paradoxical embolism and disseminated intravascular coagulation. American Journal of Critical Care 2010;19:379–382, http://dx.doi.org/10.4037/ajcc2009957. RETRACTED: Surgical Treatment of an Amniotic Fluid Embolism With Cardiopulmonary CollapseThe Annals of Thoracic SurgeryVol. 90Issue 5PreviewThis article has been retracted: please see Elsevier Policy on Article Withdrawal ( http://www.elsevier.com/locate/withdrawalpolicy ). This article has been retracted at the request of the Editor-in-Chief. This article has been retracted for scientific misconduct and plagiarism. The case-study patient reported in this paper was previously reported in Kumar, S., Wong, G., Maysky, M., Shulman, M., Olenchock, S., Falzon-Kirby, M. and Oo, T.H. Amniotic fluid embolism complicated by paradoxical embolism and disseminated intravascular coagulation. Full-Text PDF

Skeletal muscle atrophy is a well-known effect of spaceflight in both humans and animals. Although the mechanisms of this effect is multifactorial, it has previously been demonstrated in an in vitro model using tissue-engineered skeletal muscle (Bioartificial Muscles, BAMs) that spaceflight can cause skeletal muscle atrophy at the tissue level through down-regulation of total endogenous protein synthesis rates. In this study, BAMs were engineered from avian skeletal muscle cells genetically-engineered to secrete recombinant human growth hormone (rhGH) and flown aboard the space shuttle on a 9-day mission to determine the effects of spaceflight on the synthesis of a foreign protein whose gene is controlled by a constitutively expressed retroviral promoter. Spaceflight did not significantly affect the rate of BAM glucose metabolism, but compared to ground-control BAMs, space-flown BAMs secreted 47.5% less rhGH (p<0.05). Based on this study, it appears that spaceflight has a direct negative effect on skeletal muscle protein synthesis rate at the translational rather than transcriptional level.

Duodenal stents are frequently used for palliating malignant gastric outlet obstruction. Successful stent placement relieves obstructive symptoms, is cost effective, and has a relatively low complication rate. However, enteral stents have the potential of migrating distally and rarely, even lead to bowel perforation. We present a rare case of a duodenal stent placed as a palliative measure for gastric outlet obstruction due to unresectable pancreatic cancer that migrated distally after a gastrojejunostomy resulting in small bowel perforation.

Afluid embolism is a rare but devastating condition associated with a very high rate of morbidity and mortality. The treatment has traditionally been aggressive supportive care. We report a case of a term pregnant woman with complete cardiovascular collapse secondary to a paradoxical amniotic fluid embolism. The embolism was seen on transesophageal echocardiogram during an emergency Cesarean section as a free-floating interatrial clot through a patent foramen ovale. She was subsequently and successfully treated with immediate cardiopulmonary bypass, thromboembolectomy, and closure of the patent foramen ovale. (Ann Thorac Surg 2010;90:1694-6) (C) 2010 by The Society of Thoracic Surgeons

BACKGROUND:Recent studies have suggested increased renal complications and long-term mortality with aprotinin use in coronary artery bypass grafting (CABG) patients. However, these studies have been criticized for including multiple centers and different dosing strategies. We analyzed prospectively collected registry data from a single center hospital utilizing a full-dose aprotinin regimen to evaluate if aprotinin was associated with increased mortality and adverse outcomes compared with Amicar.METHODS:Data were prospectively collected from 1994 to 2006 at a teaching hospital. Long-term mortality was collected from a Social Security database. To account for differences between aprotinin and Amicar-treated patients, a propensity score was generated and propensity-stratified multivariate model for mortality were performed.RESULTS:Compared with Amicar-treated patients (n = 1,830), aprotinin-treated patients (n = 1,507) were older, more often female, had lower creatinine clearance, and more baseline risk factors. Blood loss was lower in aprotinin-treated patients (median 715 mL vs 918 mL, p < 0.001). Postoperative renal failure was significantly higher in aprotinin patients (6.2% vs 2.7%, p < 0.001). At median 5.4-year follow-up (up to 12.2 years), aprotinin-treated patients had higher mortality versus Amicar-treated patients (Kaplan-Meier failure rates 43.5% vs 23.7% at 8 years, p < 0.0001). In a propensity-stratified model with multivariate adjustment, aprotinin remained associated with increased mortality (hazard ratio 1.62, 95% CI 1.39 to 1.90, p < 0.001). There was a stepwise relationship between weight-based aprotinin dose and mortality (p-trend < 0.001).CONCLUSIONS:Among patients undergoing CABG in this registry, aprotinin use was associated with increased renal failure and higher mortality through 12 years in a propensity-stratified analysis. The increased mortality may be related to higher concentrations of aprotinin received.