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Genetically engineered pigs are thought to be an alternative organ source for patients in end-stage heart failure unable to receive a timely allograft. However, cardiac xenografts exhibit growth and diastolic heart failure within 1 month after transplantation. Grafts function for up to 6 months, but only after administration of temsirolimus and afterload-reducing agents to reduce this growth. In this study we investigated the growth and hemodynamics of growth hormone receptor (GHR) knockout xenografts, without the use of adjuncts to prevent intrinsic graft growth after transplantation. Genetically engineered pig hearts were transplanted orthotopically into weight-matched baboons between 15 and 30 kg, using continuous perfusion preservation before implantation (n = 5). Xenografts included knockout of carbohydrate antigens and knockin of human transgenes for thromboregulation, complement regulation, and inflammation reduction (grafts with intact growth hormone, n = 2). Three grafts contained the additional knockout of GHR (GHR knockout grafts; n = 3). Transthoracic echocardiograms were obtained twice monthly and comprehensively analyzed by a blinded cardiologist. Hemodynamics were measured longitudinally after transplantation. All xenografts demonstrated life-supporting function after transplantation. There was no difference in intrinsic growth, measured using septal and posterior wall thickness and left ventricular mass, on transthoracic echocardiogram out to 1 month in either GHR knockout or GHR intact grafts. However, hypertrophy of the septal and posterior wall was markedly elevated by 2 months post transplantation. There was minimal hypertrophy out to 6 months in GHR knockout grafts. Physiologic mismatch was present in all grafts after transplantation, which is largely independent of growth. Xenografts with GHR knockout show reduced post-transplantation xenograft growth using echocardiography >6 months after transplantation, without the need for other adjuncts. Post-transplantation xenograft growth is a life-limiting phenomenon in recipients after cardiac xenotransplantation. In this study, genetically engineered hearts expressing multiple human transgenes, with or without intact growth hormone receptor, were transplanted orthotopically into weight-matched baboons after continuous perfusion preservation. Post-transplantation xenograft growth was investigated using echocardiography and physiologic mismatch was characterized. Results indicate markedly elevated heart rates and mean arterial pressures experienced by all transplanted xenografts. Growth hormone intact grafts showed marked post-transplantation xenograft growth compared with those with growth hormone receptor knocked out. This study demonstrates reduced xenograft growth after transplantation by using xenografts with multiple human transgenes and growth hormone receptor knockout. Implications include the possible elimination for the need for adjuncts to reduce post-transplantation cardiac xenograft growth. [Display omitted] [ABSTRACT FROM AUTHOR]

Recent initiation of the first FDA-approved cardiac xenotransplantation suggests xenotransplantation could soon become a therapeutic option for patients unable to undergo allotransplantation. Until xenotransplantation is widely applied in clinical practice, consideration of benefit versus risk and approaches to management of clinical xenografts will based at least in part on observations made in experimental xenotransplantation in non-human primates. Indeed, the decision to proceed with clinical trials reflects significant progress in last few years in experimental solid organ and cellular xenotransplantation. Our laboratory at the NIH and now at University of Maryland contributed to this progress, with heterotopic cardiac xenografts surviving more than two years and life-supporting cardiac xenografts survival up to 9 months. Here we describe our contributions to the understanding of the mechanism of cardiac xenograft rejection and development of methods to overcome past hurdles, and finally we share our opinion on the remaining barriers to clinical translation. We also discuss how the first in human xenotransplants might be performed, recipients managed, and graft function monitored. [ABSTRACT FROM AUTHOR]

This study evaluates the impact of uncertainty on successful start-ups (SSU) and how the start-up opportunities (SOP) mediate this relationship. A survey questionnaire has been used for data collection and SmartPLS was used for data analysis. Start-up Techno-preneurs based in Vietnam have responded our questionnaire in August, 2020. The findings suggest a significant positive impact of uncertainties on SSU and availability of SOP positively influence the relationship between them. Availability of entrepreneurial opportunities incite prospective techno-preneurs to undertake a start-up venture despite uncertainty. It demonstrates how uncertainty and start-up opportunity influence the success of start-up ventures. Out study shows that adequately assessing business opportunities in the pre-start-up stage will significantly contribute to advance planning and avoid probable constraints, and ensure start-up success. Entrepreneurs and policymakers may use the outcomes of this study to boost start-ups' strategy and support services for successful implementation. [ABSTRACT FROM AUTHOR]

We report the intraoperative management of an orthotopic cardiac xenotransplant in a 57-year-old man with nonischemic cardiomyopathy requiring venoarterial extracorporeal membrane oxygenation. Transesophageal echocardiography was used for preharvest assessment. Continuous ex vivo perfusion of the heart was performed. Steps were taken to avoid potential xenozoonosis transmission to other patients and staff. Preclinical experience guided our intraoperative management in controlling hemodynamics and using prophylactic antiarrhythmic medications. Echocardiography aided in the diagnosis of aortic dissection in the patient after transplant. Intraoperative cardiac function was excellent. The patient was weaned from all mechanical support 4 days after transplant. [ABSTRACT FROM AUTHOR]

This study seeks to investigate the association of emotional labour with emotional exhaustion among employees. This study focuses on the moderating role of cultural intelligence between emotional labour and emotional exhaustion. The proposed model has been tested through quantitative method approach in light of Conservation of Resources Theory (COR). The data collected from 520 employees from hotel sector under multistage sampling technique has been analysed. The gathered data will be examined through statistical techniques, are estimated to prove the proposed relationships. The study will be beneficial for industry practitioners, managers and leaders who can take advantage from the study and make strategies to minimise the negative effects of emotional labour in their respective organisations. [ABSTRACT FROM AUTHOR]

Perioperative cardiac xenograft dysfunction (PCXD) was described by McGregor and colleagues as a major barrier to the translation of heterotopic cardiac xenotransplantation into the orthotopic position. It is characterized by graft dysfunction in the absence of rejection within 24 to 48 hours of transplantation. We describe our experience with PCXD at a single program. Orthotopic transplantation of genetically engineered pig hearts was performed in 6 healthy baboons. The immunosuppression regimen included induction by anti-CD20 monoclonal antibodies (mAb), thymoglobulin, cobra venom factor, and anti-CD40 mAb, and maintenance with anti-CD40 mAb, mycophenolate mofetil, and tapering doses of steroids. Telemetry was used to assess graft function. Extracorporeal membrane oxygenation was used to support 1 recipient. A full human clinical transplantation team was involved in these experiments and the procedure was performed by skilled transplantation surgeons. A maximal survival of 40 hours was achieved in these experiments. The surgical procedures were uneventful, and all hearts were weaned from cardiopulmonary bypass without issue. Support with inotropes and vasopressors was generally required after separation from cardiopulmonary bypass. The cardiac xenografts performed well immediately, but within the first several hours they required increasing support and ultimately resulted in arrest despite maximal interventions. All hearts were explanted immediately; histology showed no signs of rejection. Despite excellent surgical technique, uneventful weaning from cardiopulmonary bypass, and adequate initial function, orthotopic cardiac xenografts slowly fail within 24 to 48 hours without evidence of rejection. Modification of preservation techniques and minimizing donor organ ischemic time may be able to ameliorate PCXD. [ABSTRACT FROM AUTHOR]

Start-ups are built by the charismatic leaders with innovative ideas, creativity, and distinguished expertise. However, they face huge challenges for growth and survival in an uncertain and competitive business eco-system. The aim of the present study is to examine the effect of entrepreneurial orientations with social media mediation on digital start-up sustainability. To conduct this research, active start-ups at the science and technology park of Tehran, Shiraz and Yazd universities have been identified in 2021. A 25-item questionnaire was used to collect data from 195 digital start-up managers. Data analysis has been done using SmartPLS3 software. The findings indicate that an innovative atmosphere, knowledge sharing and efficient communications have positive effects on the sustainability of digital startups, and the social media plays role as mediator. The results showed that social media contributes to increasing participation of employees in decision making process. Social media helps employees to share their knowledge, and establishes better interactions with the customers and stakeholders. As a result of better interaction, the company can respond to business challenges faster and operate in a more stable environment. Therefore, in today's turbulent market, attention to sustainability to achieve economic growth and development has been the focus of knowledge-based companies. [ABSTRACT FROM AUTHOR]

Offshore outsourcing has evolved from cost-only strategy to growth strategy in knowledge-intensive industries (KIIs) such as the pharmaceutical industry. This paper explores the case of offshore outsourcing of pharmaceutical manufacturing to India. An extensive literature review shows that firms do engage in offshore outsourcing to India have access to talents, infrastructure as well as markets. Despite the bright future of offshore outsourcing of pharmaceutical industries to India, inadequate protection of intellectual property rights (IPRs), scarcity of highly skilled manpower and institutional shortcomings can pose serious challenges. The study finds that institutional policy framework for promotion of collaborative research and development (R&D) as well as investment in infrastructures and human capital development can keep the momentum in this sector of high-tech industry. [ABSTRACT FROM AUTHOR]

Objectives Cardiac transplantation and available mechanical alternatives are the only possible solutions for end-stage cardiac disease. Unfortunately, because of the limited supply of human organs, xenotransplantation may be the ideal method to overcome this shortage. We have recently seen significant prolongation of heterotopic cardiac xenograft survival from 3 to 12 months and beyond. Methods Hearts from genetically engineered piglets that were alpha 1-3 galactosidase transferase knockout and expressed the human complement regulatory gene, CD46 (groups A-C), and the human thrombomodulin gene (group D) were heterotropically transplanted in baboons treated with antithymocyte globulin, cobra venom factor, anti-CD20 antibody, and costimulation blockade (anti-CD154 antibody [clone 5C8]) in group A, anti-CD40 antibody (clone 3A8; 20 mg/kg) in group B, clone 2C10R4 (25 mg/kg) in group C, or clone 2C10R4 (50 mg/kg) in group D, along with conventional nonspecific immunosuppressive agents. Results Group A grafts (n = 8) survived for an average of 70 days, with the longest survival of 236 days. Some animals in this group (n = 3) developed microvascular thrombosis due to platelet activation and consumption, which resulted in spontaneous hemorrhage. The median survival time was 21 days in group B (n = 3), 80 days in group C (n = 6), and more than 200 days in group D (n = 5). Three grafts in group D are still contracting well, with the longest ongoing graft survival surpassing the 1-year mark. Conclusions Genetically engineered pig hearts (GTKOhTg.hCD46.hTBM) with modified targeted immunosuppression (anti-CD40 monoclonal antibody) achieved long-term cardiac xenograft survival. This potentially paves the way for clinical xenotransplantation if similar survival can be reproduced in an orthotopic transplantation model. [ABSTRACT FROM AUTHOR]

Objectives We sought to investigate if autologous freshly isolated regulatory T cells (Tregs) provide a protective and supportive role when cotransplanted with mesenchymal stem cells (MSCs). Methods In a porcine model of chronic ischemia, autologous MSCs were isolated and expanded ex vivo for 4 weeks. Autologous Treg cells were freshly isolated from 100 mL peripheral blood and purified by fluorescence-activated cell sorting. MSCs and Treg cells were then cotransplanted into the chronic ischemic myocardium of Yorkshire pigs by direct intramyocardial injection (1.2 x 108 MSCs plus an average of 1.5 million Treg cells in 25 injection sites). Animals were killed 6 weeks postinjection to study the fate of the cells and compare the effect of combined MSCs + Treg cells transplantation versus MSCs alone. Results The coinjection of MSCs along with Tregs was safe and no deleterious side effects were observed. Six weeks after injection of the cell combination, spherical MSCs clusters with thin layer capsules were found in the injected areas. In animals treated with MSCs only, the MSC clusters were less organized and not encapsulated. Immunofluorescent staining showed CD25+ cells among the CD90+ (MSC marker) cells, suggesting that the injected Treg cells remained present locally, and survived. Factor VIII+ cells were also prevalent suggesting new angiogenesis. We found no evidence that coinjections were associated with the generation of cardiac myocytes. Conclusions The cotransplantation of Treg cells with MSCs dramatically increased the MSC survival rate, proliferation, and augmented their role in angiogenesis, which suggests a new way for future clinical application of cell-based therapy. [ABSTRACT FROM AUTHOR]

Success of market based entrepreneurial projects embedded with a social mission contributed to growing interest to social entrepreneurship in existing entrepreneurship literature. The purpose of this study is to examine whether the widely accepted motivational factors influencing entrepreneurial process have similar influence on social entrepreneurs in Bangladesh. Based on the seminal work of Shane et al. (2003) on entrepreneurial motivation, a survey was conducted among the social entrepreneurs in Bangladesh and collected data was analyzed. A regression analysis shows that some of widely accepted factors have significant influence while others have less or non-significant influence on Bangladeshi social entrepreneurs. This empirical paper contributes to better understanding of behavioral aspect of social entrepreneurship in Bangladesh where a high number of world’s leading social ventures were formed and expanded world-wide. [ABSTRACT FROM AUTHOR]

This paper discusses the results of the first comprehensive study of semiconductor industry in Malaysia. It primarily consists of the operations set up by transnational corporations in high technology centres of Penang and Kuala Lumpur. The goal of this study was to determine the most effective leadership style to increase employee job satisfaction and to offer recommendations to improve the industry. We examined the relationship between three independent variables, two moderating factors, and employee job satisfaction as the dependent variable. In establishing a research framework, we formed hypotheses, collected extensive data, developed statistical models, and used multiple regression technique to analyze the field data. It is concluded that collaboration among the transnational semiconductor corporations, Malaysia’s government investment agency MIDA, and the Malaysian semiconductor firms have succeeded in creating a semiconductor workforce that is productive and enjoys a reasonably high level of job satisfaction. [ABSTRACT FROM AUTHOR]

We explore the relationship between strategic orientations (market orientation and entrepreneurial orientation), organizational ambidexterity, and sustained competitive advantage under the mediation of Industry 4.0 readiness. Based on data from a sample of 144 SMEs belonging to different economic sectors, we employed partial least squares–structural equation modeling to test our hypotheses. Empirical research suggests that market orientation and entrepreneurial orientation have a favorable relationship with Industry 4.0 readiness and sustainable competitive advantage. Moreover, our findings reveal that entrepreneurial orientation has a greater effect on SCA than market orientation in emerging markets. Furthermore, Industry 4.0 readiness acts as a full intermediary between strategic orientations and sustainable competitive advantage. This study contributes to the existing literature by exploring the relationship between strategic orientation and sustainable competitive advantage through Industry 4.0 as the mediator. SMEs' managers can use these findings to rethink their technology adoption strategies and exploitative and explorative approaches. [ABSTRACT FROM AUTHOR]

This paper explores farmers' perceptions of climate change vulnerability as well as the effects of socioeconomic factors and adaptation barriers on climate change adaptation practices in the Malaysian agricultural sector. To accomplish these aims, a multiple regression analysis was performed, and the severity index (SI) was estimated to measure perceived vulnerability context. The results revealed that age, education level, farm income, farm experience, limited access to agricultural extension, lack of credit facilities, limited access to agricultural markets, and farm size are factors which have significant impacts on adaptation practices. The value of the SI suggests that farmers have favourable attitudes towards climate change adaptation and they are agreeable to addressing climate change issues through appropriate adaptation strategies. However, the study found several adaptation barriers that hinder farmers from implementing climate change adaptation policies. It is realized that at present, no specific policy in Malaysia seeks to counter the impacts of climate change on individual sectors and their productivity. Therefore, the findings of this study will assist policymakers to make an appropriate policy framework considering most suitable adaptation strategies to overcome all the barriers associated with adaptation practices to tackle the adverse effects of climate change in Malaysian agriculture sector. [ABSTRACT FROM AUTHOR]

Background Observational studies suggest that cell‐free DNA (cfDNA) is a biomarker of tissue injury in a range of conditions including organ transplantation. However, the lack of model systems to study cfDNA and its relevance to tissue injury has limited the advancements in this field. We hypothesized that the predictable course of acute humoral xenograft rejection (AHXR) in organ transplants from genetically engineered donors provides an ideal system for assessing circulating cfDNA as a marker of tissue injury. Methods Genetically modified pig donor hearts were heterotopically transplanted into baboons ( n = 7). Cell-free DNA was extracted from pre-transplant and post-transplant baboon plasma samples for shotgun sequencing. After alignment of sequence reads to pig and baboon reference sequences, we computed the percentage of xenograft-derived cfDNA (xdcfDNA) relative to recipient by counting uniquely aligned pig and baboon sequence reads. Results The xdcfDNA percentage was high early post-transplantation and decayed exponentially to low stable levels (baseline); the decay half-life was 3.0 days. Post-transplantation baseline xdcfDNA levels were higher for transplant recipients that subsequently developed graft loss than in the 1 animal that did not reject the graft (3.2% vs 0.5%). Elevations in xdcfDNA percentage coincided with increased troponin and clinical evidence of rejection. Importantly, elevations in xdcfDNA percentage preceded clinical signs of rejection or increases in troponin levels. Conclusion Cross‐species xdcfDNA kinetics in relation to acute rejection are similar to the patterns in human allografts. These observations in a xenotransplantation model support the body of evidence suggesting that circulating cfDNA is a marker of tissue injury. [ABSTRACT FROM AUTHOR]

Abstract Cardiovascular disease (CVD) is a major cause of morbidity and mortality worldwide. Compared to traditional therapeutic strategies, three-dimensional (3D) bioprinting is one of the most advanced techniques for creating complicated cardiovascular implants with biomimetic features, which are capable of recapitulating both the native physiochemical and biomechanical characteristics of the cardiovascular system. The present review provides an overview of the cardiovascular system, as well as describes the principles of, and recent advances in, 3D bioprinting cardiovascular tissues and models. Moreover, this review will focus on the applications of 3D bioprinting technology in cardiovascular repair/regeneration and pharmacological modeling, further discussing current challenges and perspectives. Graphical abstract Unlabelled Image [ABSTRACT FROM AUTHOR]