Previous studies have explored the links between problematic Internet use (PIU) or problematic smartphone use (PSU) and quality of life (QOL). In this systematic review, we (i) describe the instruments used to assess QOL or health-related quality of life (HRQOL) in these studies, (ii) critically examine the content validity of the instruments used, and (iii) examine the relationships between PIU, PSU, QOL, and HRQOL.We identified 17 PIU and 11 PSU studies in a systematic search. Evidence suggests that PIU and PSU negatively correlate with either QOL or HQOL and most of their domains . Multiple instruments were used to assess QOL or HRQOL in these studies. Our analysis showed an important heterogeneity in the domains covered by these instruments.Because of the widespread prevalence of PIU and PSU, which tend to be linked with lower QOL or HRQOL, in particular poor mental and physical health, a more systematic public health campaign is required to target the healthy use of these communication devices. Prevention programs should also target vulnerable individuals, focusing on the most affected domains of QOL and HRQOL . Among the existing instruments, the World Health Organization Quality of Life for adults and the Pediatric Quality of Life Inventory for adolescents (aged 13–18 years) proved to be the most relevant, although new measurement instruments are needed to target domains that are specifically relevant in the context of PIU and PSU . The use of the Internet and smartphones has become a global phenomenon. Digital technology advancements have resulted in a wide range of applications, including improved communication, health, education, and leisure. Nonetheless, during the last two decades, a growing number of studies reported links between problematic or uncontrolled digital technology use and various indices of psychological and health problems –3. MoreoInternet and smartphone-mediated problematic online behaviors have been conceptualized within a spectrum of related conditions associated with both shared and unique features and risk factors , 7. It wPrevious research has shown that problematic Internet use (PIU) and problematic smartphone use (PSU) are negatively associated with global life satisfaction , 15 and As the majority of investigators who studied PIU and PSU in previous work did not take into account related negative consequences or functional impairment, we decided to systematically review the available evidence regarding the relationships between these problematic behaviors and quality of life (QOL), assuming that the presence of problematic or pathological behavior would be associated with poor QOL. The World Health Organization defines QOL as “an individual’s perception of their position in life concerning their goals, expectations, standards, and concerns in the context of the culture and value systems in which they live .” It is Several definitions of HRQOL have been proposed •, and inIn the present systematic review, we thus (i) describe the instruments used to assess QOL or HRQOL in PIU and PSU research, (ii) critically examine the content validity of the instruments used in these studies, and (iii) examine relationships between PIU, PSU, QOL, and HRQOL.We followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement guidelines for systematic reviews , 28. TheIn the literature search, we aimed at identifying original empirical studies that reported correlations between PIU or PSU and QOL or HRQOL in the electronic databases Science Direct, PsycNET, and PubMed.Two systematic literature searches were performed, one for PIU and one for PSU. Regarding PIU, the following terms were used: “Internet AND use disorder (overuse OR addict* OR abuse OR use severity OR problematic OR dependence) AND .” Regarding PSU, the following terms were used: “smartphone (cellphone OR mobile phone) AND use disorder (overuse OR addict* OR abuse OR use severity OR problematic OR dependence) AND ”. The following number of articles were identified for PIU: Science Direct (438), PsycNET 221), and PubMed (549). The following number of articles were identified for PSU: Science Direct (102), PsycNET (1), and PubMed (46). Study selection was performed in two successive stages. First, the titles and abstracts of all potentially relevant articles were carefully scrutinized for eligibility according to inclusion criteria. Second, the full texts of the studies retained at the first stage were scrutinized for eligibility based on the same criteria. The PRISMA flowcharts illustrating the study selection process for each literature search are reported in Figs. , and PubThe following data were extracted from the full text of the articles: country, sample size, age of the participants, study design, study goal, measurement instruments used for PIU or PSU and QOL or HRQOL, and study results. In the present study, we used the term “case-control” study to describe a study in which groups of participants were compared based on a pre-established criterion . Information about content coverage (domains covered by the instruments) were extracted and analyzed. This information was used to establish content validity, that is, the extent to which a measure represents all facets of a given construct . Poor content validity generally implies that the measurement instrument assesses too narrowly a construct. In our case, an instrument with poor content validity would be one that does not assess important aspects of QOL or HRQOL that might be affected by PIU or PSU.r = −.13 to r = −.46 for PIU and r = −.09 to r = −.50 for PSU.This systematic review retained 17 studies for PIU that included 34,615 participants and 11 studies for PSU that included 204,118 participants. Six of 17 PIU studies (35.29%) and four of 11 PSU studies (36.36%) assessed HRQOL and the remainder of the studies examined QOL. All of the retained studies reported a negative correlation between QOL or HRQOL and PIU or PSU. The correlations reported in these studies ranged from The measurement instruments used in the retained studies differed in terms of the number of domains covered. Table All domains assessed by QOL or HRQOL instruments in the retained studies are described in Tables The WHOQOL was the most frequently used instrument in the retained studies. Domains and facets incorporated in this comprehensive instrument include physical health , psychological health , quality of social relationships , and quality of environment .In order to synthetize and compare the results of the studies retained in the present systematic review, we reclassified the domains covered by the measurement instruments used into six different domains and 14 subdomains: physical health , psychological health , relations , school performance, quality of environment , and satisfaction with life, as illustrated in Table An analysis of the domains covered by these instruments shows high heterogeneity. For instance, physical health is not assessed by the My Life as a Student questionnaire and the Subjective QOL questionnaire. Although all scales that we identified assessed psychological health, the specific aspects of psychological health that were measured differed among scales. For example, negative and positive affect  were assessed by almost all of the instruments, but loneliness was considered only in the KIDSCREEN and the WHOQOL.The studies included in the current systematic review mainly assessed PIU with Young’s Internet addiction test (YIAT) , Chen InRetained articles for PIU are synthesized in Table Studies conducted with other instruments globally reproduced the same patterns of results. Studies that used the PedsQL generally showed a negative association with domains of the HRQOL or QOL , 49. YetThe articles retained for PSU are synthesized in Table Buctot and colleagues  also shoIn this systematic review, we synthesized the studies that explored the relationships between PIU or PSU and QOL or HRQOL and critically evaluated the measurement instruments used to assess QOL or HRQOL in these studies. Addressing this topic is warranted, as a substantial part of previous research explored PIU and PSU while not necessarily considering the negative consequences associated with Internet or smartphone use, thus potentially overpathologizing normal technology use ••.Here, we provided a summary of the measurement instruments used to assess QOL or HRQOL in existing studies and examined their content validity in the context of PIU and PSU. It might be that QOL and HRQOL instruments not specifically developed in the context of PIU and PSU research do not include domains that are particularly relevant to these problematic behaviors. Our analysis showed that there was an important heterogeneity in the domains covered by QOL and HRQOL instruments used in the retained studies. Moreover, different instruments can assess similar domains with diverging items, thus further complicating the comparison among studies. For example, four of the nine identified instruments  evaluated the school domain, but with different items and concepts.This review shows that WHOQOL for adults and PedsQL, which targets participants aged 13–18 years, are the most used measurement instruments. In terms of the classification of domains in the current systematic review, these instruments cover physical health, psychological health, social relations, quality of the environment, and satisfaction with life (WHOQOL), or physical health, psychological health, social relations, and school performance (PedsQL), making them the most convenient instruments at hand. Notably, some of the instruments identified in this systematic review and synthesized in Table All retained studies reported negative correlations between QOL or HRQOL and PIU or PSU. The majority of studies were published within the last 3 years, indicating recent research interest, likely fueled by clinical demand or by the recognition that PIU and PSU have become internationally relevant public health issues . HoweverThis systematic review comes with several limitations. First, the number of studies was relatively limited, and most were cross-sectional studies conducted with self-selected participants, thus hindering causal interpretation and compromising the representativeness of the findings. Given the public health relevance of technology-mediated problematic behaviors, future research in this field should be conducted in nationally representative samples or should follow longitudinal designs. Moreover, few studies have surveyed clinical participants or tested the impact of prevention or treatment approaches on QOL or HRQOL. Second, we considered only studies written in English, and it is possible that relevant literature published in other languages was neglected. Much research published in national East-Asian journals  could have been relevant to the topic under study . Among existing instruments, WHOQOL for adults and PedsQL for adolescents (aged 13–18 years) proved to be the most relevant, as shown from the results of this systematic review, although there is a need for new measurement instruments that target domains that are specifically relevant in the context of PIU and PSU .


Applying Systems Thinking to Regenerative Medicine—A Workshop was organized by the National Academies of Sciences, Engineering, and Medicine’s Forum on Regenerative Medicine. The meeting brought together leaders from government, academia, industry, professional associations, foundations, patient communities, and other stakeholder groups to address the potential for cross-disciplinary systems thinking to advance regenerative medicine. Discussions during the meeting covered the role of data science in regenerative medicine and the importance of data science training and data literacy for the current and future regenerative medicine workforce. Regenerative Medicine and Advanced Therapies (RMAT) are complex products and often include “living” cellular materials. Every patient—and, for some applications, every product—is unique, and product manufacturing entails lengthy, complicated processes. Intricate relationships exist between the patient’s disease state, the donor starting material, the manufacturing process, supply-chain logistics, and the clinical response. RMAT products are stimulating a paradigm shift in biopharma manufacturing because it means understanding interrelated systems at multiple scales—from molecular and cellular processes to optimization of the manufacturing parameters and workflow, supply-chain logistics, and patient queuing. Therefore, the RMAT enterprise is well-suited to applications of systems thinking, i.e., the use of systems theory and system sciences to analyze relationships and develop effective action in complex contexts. The next-generation workforce can be prepared for this environment with modern data tools and methods and a systems-thinking mindset to extract insights using techniques like data mining and machine learning.1. Data science, data-driven models, and mathematics can link various disciplines, such as stem cell biology, physiology, immunology, and engineering, in effective transdisciplinary research2. It would be beneficial to prepare a workforce of “integrators” who can apply sophisticated computational approaches to regenerative medicine research, interpret multidimensional data across sectors of the RMAT enterprise, and translate results of basic research to manufacturing, effective regulations, and the clinic  held a workshop called 4. Efforts to integrate process and product analytics with quality control and to integrate manufacturing data with patient-queuing and supply-chain logistics could benefit from systems-level thinking that is currently unprecedented in biopharma and bioengineering. Providing broad-based coursework, hands-on training, and real-life experiences to support the well-versed RMAT practitioner may be challenging but could be advantageous for the clinical and commercial success of the industry. Although not everyone in the RMAT workforce need be a data science and modeling expert, all workers may need a basic understanding of data handling, analytics, and interpretation.Interpretation of data to characterize RMAT products and predict clinical success involves advanced statistical methods and mechanistic models. Advanced quantitative methods may be essential knowledge for the modern technical expert, yet these are not currently a core component of biological research training. Indeed, concepts such as entropy, stochasticity, and critical phenomena are relatively new to cell biology applications5. Rooted in disciplines such as computer science, statistics, and mathematics, data science is an interdisciplinary field enriched by collaborations between several disciplines. In addition to the technical aspects of data science and applications to specific scientific domains, the societal considerations of data science merit special attention for RMAT practitioners. Societal and ethical issues include how data and communities interact and the role of inclusion and equity in collection, interpretation, and application of data.A recent series of NASEM meetings highlighted the intersection of data science with traditional domain sciences and how this interplay impacts data science teachingIn this perspective, we discuss the challenges facing the next-generation RMAT workforce in utilizing data encountered in this field. We consider a wide range of data issues that will be critical for the diverse field of RMAT products. Our goal is to raise awareness of this critical aspect of RMAT for educators and industry professionals. We believe that training the future workforce may occur in traditional and nontraditional ways, and can include 2-year colleges, research universities, graduate and postdoctoral training as well as training opportunities for the existing biopharma workforce.Areas of the RMAT development enterprise where data science will play an important role include both technical, scientific issues and related social and ethical issues Fig. .9. As has been widely acknowledged, such algorithms can be biased10. Since AI/ML strategies contain proxies for true variables of interest, label-choice bias can exist. Recent studies applying AI/ML to healthcare are instructive for the regenerative medicine field because “health”—like “cell quality”—is inherently subjective, holistic, and multidimensional; there is no single, precise way to measure it. A recent study in healthcare, for example, found that bias occurs when an AI/ML algorithm uses health costs as a proxy for health needs11. Further, datasets may be biased in terms of demographics like race, gender, or socioeconomic status. Bias can occur during labeling of training data, as a result of how data are collected, or due to self-selection by members of the target populations. For instance, in one study, 87% of patients were white, and most were relatively affluent12. The preponderance of data from this demographic may not provide an adequate training set to apply to non-white, non-affluent populations.Artificial intelligence/machine learning (AI/ML) algorithms are increasingly applied to analyze data and make predictions in regenerative medicine13. Privacy, accountability, safety, transparency, fairness and non-discrimination, human control of technology, professional responsibility, and effectiveness are among the key elements14. These playbooks and principles could be adapted for regenerative medicine contexts and incorporated into workforce training. Data science training can also prepare the workforce to work with large datasets and leverage other efforts to alleviate health data disparities16.To begin addressing these issues, guides were developed about how to define, measure, and mitigate bias in algorithms17. Protecting patient and company data, including intellectual property and sensitive health information, is critical and challenging. Cybersecurity is a critical feature of establishing a robust RMAT supply chain. The National Institute of Standards and Technology (NIST) defined a framework for cybersecurity in 2018 and has since updated guidance19. The framework provides general guidance for assessing cybersecurity risk, managing cybersecurity within the supply chain, and reducing risk to critical infrastructure. Again, adapting this framework for regenerative medicine could help assure secure RMAT supply chains in accord with federal and institutional standards.The RMAT workforce should be prepared to address issues of cybersecurity. Biotech has been the target of cyberattacks, putting the health of patients in jeopardy22, widespread data sharing has been uncommon to-date in cell biology, clinical research, and manufacturing. Data sharing can advance regenerative medicine by enabling studies with greater statistical power, a wider range of variables, and a more diverse patient base than single studies can achieve. Collaboration can harness new and existing data sources to promote data-driven scientific discovery and innovation across the private and public sectors globally24. Incorporating FAIR Guiding Principles for scientific data  in research practices and workforce training encourages open access and furthers the public good25. Such approaches can provide advantages for RMAT akin to those from the Bermuda Principles, which enabled the Human Genome Project to share data shortly after sequencing and strengthened international cooperation27.A systems-based approach to solving the complex challenges faced in regenerative medicine requires data sharing across stakeholders, and the up-and-coming workforce can be instrumental in achieving that aim. Although encouraged by some funding agencies, including the National Institutes of Health (NIH)29. Data sharing could substantially advance the field but remains contingent on appropriate data management and security practices; creating such infrastructure is ongoing30.Data sharing also facilitates comparability studies and the development of standards for RMAT products. Reproducibility remains a challenge in RMAT research and product development and is largely attributable to complex and highly manual manufacturing processes, variability in donor and patient cells, reagent quality variability, and the lack of standards and comparability metrics. Data sharing and standardization could alleviate these issues and significantly improve outcomes in trials with RMAT products. Finally, the regenerative medicine workforce should be cognizant of the legal challenges of data sharing related to intellectual property and how data sharing may impact the security of patient dataEducation pathways must continue to evolve so that students are data-literate and prepared for careers in domains like regenerative medicine. Integration of data science perspectives into data-intensive domain courses can yield transformative researchers and practitioners educated in both the foundations and domain-specific applications of data science. Integrating data science education throughout the RMAT training pipeline can assure that students are versed in the language of data collection, analysis, interpretation, management, and security.2018 Moore-Sloan Foundation’s report on the status of data science highlights approaches to data science at universities. Approaches vary across investment strategy , curricular emphasis , and organization 31.Implementation of data literacy programs ensures a critical mass of workforce talent. Indeed, many universities have launched data science institutes, programs, or schools. The 32. A 2018 NASEM report details various routes for data science training at the undergraduate level33, yet training opportunities could be expanded.Many institutions recognize the increasing role of data in the workplace and the commensurate importance of data literacy for new graduates. Attempts to meet the need for data science training range from specialized coursework housed in existing statistics or computer science departments to new programs and majors, such as the Data Theory Major at the University of California, Los AngelesCompetencies for these programs comprise data science foundations and applications and may incorporate ethics, legal and regulatory issues, and social concerns. Flexibility and incentives for sharing courses, materials, and faculty would support nascent programs. A key challenge of incorporating additional data science courses in undergraduate curricula is the constraint of not increasing the total credit hours for degree programs—i.e., another course must be removed to accommodate the data science course(s). Gaining consensus among programs on reallocating course content would be challenging, but doable, and advantageous. An alternative or complementary approach could be adding data science training and projects to existing courses with domain-specific examples.Graduate education could include innovative programs in data science, delivered through modular and nontraditional methods, including applying asynchronous pedagogical strategies to residential and non-residential digital learning. Masters and doctoral students could enroll in data science programs or domain-specific programs with a data science certificate. Possibilities include modular, stackable graduate certificate programs and three graduate degrees in data science: (i) professional science masters, (ii) masters, and (iii) doctoral.Graduates of data science programs work in all job sectors and serve in many roles. Although not everyone in the RMAT workforce needs data science expertise, most workers—across all levels—should understand the language of data science well enough to interpret analysis of RMAT products and to communicate with data science specialists. Students will acquire data science literacy through exposure to data science throughout the graduate and undergraduate curriculum.5. For example, the Northeast Wisconsin Technical College offers a Data Analytics Associate’s Degree to prepare students to work in fields like advanced manufacturing and healthcare. Through partnerships with 4-year colleges and national or regional centers focused on biomanufacturing or data sciences , biotechnology programs at 2-year colleges can offer experiential, project-based learning and enhanced training opportunities for entry-level workforce. For example, the National Science Foundation Engineering Research Center for Cell Manufacturing Technologies (CMaT) offers hands-on research and training opportunities for 2-year college students in Georgia and Wisconsin and works with 2-year college instructors to develop curriculum.Complementary educational pathways could fill gaps in the RMAT training pipeline. Community or technical colleges are one avenue for providing data science training and guiding individuals into regenerative medicine. Two-year colleges are already developing courses, certificates, and associate degrees in data science, analytics, and data management to meet the demand for a data-literate workforce5. Internships can also supplement the education of new graduates from traditional academic programs who may lack industry experience. Experienced employees might benefit from continuing education programs that leverage and repurpose the on-the-job workforce34. The future of workforce development will also include educational opportunities outside of academic institutions, and online workshops, webinars, and courses could be further expanded and supported by various sectors of the regenerative medicine field. Moreover, virtual learning opportunities may be accessed anywhere by individuals with varying levels of experience and education, and asynchronous options may be accessed anytime, thus supporting diversity, equity, and inclusion in the workforce. An example is a recent 12-lecture virtual and asynchronous course launched jointly by the International Society for Cell and Gene Therapy (ISCT) and CMaT; the course covers concepts in regenerative medicine and cell manufacturing, is open to anyone around the world, and is co-taught by academic and industry leaders35.Data science boot camps, which are intensive skill-building programs, can complement other academic or industry experience and better connect participants with industry demandsThe demand for a data-literate workforce creates a need for synergy between stakeholders across sectors  of the RMAT enterprise. In academic settings, curricula to prepare data scientists for work in regenerative medicine fields might include topics in regulatory affairs, clinical development, and manufacturing. These topics will equip students to understand the unique context of regenerative medicine and appreciate systems thinking. Academia can also bolster the RMAT ecosystem by increasing the knowledge base of educators and providing resources for students interested in nonacademic careers. Synergy occurs from sectors working together on key areas of interest and providing both formal and informal educational opportunities that bridge data science and regenerative medicine. The organizations mentioned below are examples of strong multisector activities that can play an effective role in developing the RMAT workforce.Workforce development in data-dependent regulatory issues warrants special attention. Because RMAT products are highly variable and customizable, the regulatory landscape continually evolves, and the regulatory sector must keep pace with advancements. To facilitate crosstalk and opportunities to use data science for regulatory decision-making, the regulatory affairs workforce needs to understand data science fundamentals, and the data science workforce needs a basic understanding of regulatory issues. Now is a key time to train a data science workforce to manage the regulatory environment of a rapidly evolving product and application space.36. The U.S. Food and Drug Administration (FDA) interfaces with several academic institutions within the Centers of Excellence in Regulatory Science and Innovation (CERSI) program to help train students in regulatory science37. However, regulatory instruction could also be incorporated into existing courses. Reallocating modest portions of curricula across multiple academic stages could better prepare students to interact with regulatory guidance and to prepare documents for regulatory agencies. Statistics courses could train students to analyze large datasets with the goal of introducing regulatory concepts such as critical quality attributes (CQAs), critical process parameters (CPPs), normal operating range (NOR), and proven acceptable range (PAR). Lab-based courses could teach students to prepare process descriptions in accordance with FDA guidance documents and to describe theoretical process-characterization strategies based on risk-assessment exercises conducted in class. Advanced courses could encourage students to discuss the applicability of data science approaches  for regulatory decision-making through answering questions such as:How can real-world data address regulatory filing requirements from clinical, preclinical, and manufacturing perspectives?How can data science tools help establish the safety and efficacy of a regenerative medicine product?Regulatory training can begin through academic courses and degree programsDiscoveries in stem cell biology and associated technologies often occur in basic science laboratories, but the promise of regenerative medicine is realized in the clinic. Academia can prepare students with interest in clinically oriented roles by emphasizing data science and theoretical analysis in programs like the Institute for Clinical and Translational Research (ICTR) at the University of Wisconsin–Madison, which offers minors in Clinical Investigation for PhD students, or the Georgia Clinical & Translational Science Alliance (CTSA), an NIH-funded program across Georgia-based universities that offer a Master of Science in Clinical Research and certificate program in translational research for PhD trainees. Such programs encourage students to consider the human impact of scientific discoveries and promote translational research.38, CMaT39, and others. CMaT, for example, works to standardize methods across its eight-university ecosystem and partners with companies to record data in a unified format via batch recording software. Data can be stored in the cloud for collaborators across partner organizations to access and analyze.Ranging from data acquisition and harmonization to patient privacy, data-related challenges can impede the translation of regenerative medicine discoveries to the clinic. Small sample sizes often limit research in the rare disease space, and data integration among research groups and datasets can hamper progress. To contend with these issues, several institutions established their own data-sharing capabilities, including Johns Hopkins, the Mayo Clinic34. The National Heart, Lung, and Blood Institute (NHLBI), including the NIH-wide Regenerative Medicine Innovation Project (RMIP)40, also established a data-sharing platform for NIH-funded projects—the Biodata Catalyst—which is intended to serve as a central data repository for open sharing among eligible researchers20. Moreover, a workforce that can manage, interpret, and deploy data science efficiently and securely will allow the RMAT industry to capitalize on potential benefits, both nationally and globally41.Started by nine medical research organizations, another initiative, the National Center for Data to Health (CD2H), facilitates data sharing and collaboration across the community of health informatics researchersAs the RMAT industry grows and new, increasingly complex products enter the pipeline, highly trained and appropriately certified workers will be in-demand to manufacture high-quality products, at scale, with low batch failure rates and maximal reproducibility—all while ensuring efficacy and patient safety and maintaining strict regulatory standards. Biomanufacturing is increasingly digital and therefore requires proficiency in both quantitative methods and biology-based lab techniques. Moreover, a potential future model of manufacturing is decentralized, remote manufacturing in hospital settings. To support this scheme and other distributed manufacturing approaches in the future, understanding remote access, digital networks, and AI would benefit the workforce.42. When designing curricula, academic entities could integrate discussions with industry and clinical manufacturers to better understand the skillsets needed for biomanufacturing. Manufacturing sciences as a separate discipline is only available at a few academic centers; rather, manufacturing is often taught through mechanical or chemical engineering departments. Collaboration between experts in manufacturing sciences and other specialized domains  would help ensure curricula and training materials reflect domain knowledge in the context of broader manufacturing principles. This collaborative, transdisciplinary effort across engineering, cell biology, clinical translation, and industrial manufacturing will be critical to prepare the next generation of RMAT workforce.Academia can leverage guidance documents designed for industry to better prepare students for roles in manufacturing regenerative medicinesBeyond educational efforts, academic scientists can better coordinate with industry by considering manufacturing guidelines, such as Good Manufacturing Practice (GMP) regulations, in their research. To facilitate translation from bench to bedside and increase uptake of innovations in the clinic, academic laboratories and researchers could aim to develop new devices, tools, software, and technologies that are GMP-compatible, follow Quality-by-Design principles, incorporate standardized analytical tools and measurements, and implement regulatory constraints.Collaborative course module development for both technical and ethics/regulatory competencies.Collaborations with 2-year college systems for hands-on training and curriculum development.NSF-funded Future Manufacturing Network (FMNet) Consortium for “Building a Network to create the Workforce Foundation, Actionable Roadmap, and Infrastructure Design to Integrate Data Science, AI, and Predictive Analytics throughout Biomanufacturing”.Finally, key technology hubs and public-private partnerships play an important role in integrating data knowledge into workforce development. Organizations focused on RMAT manufacturing include the aforementioned CMaT, Marcus Center for Therapeutic Cell Characterization and Manufacturing (MC3M), National Institute for Innovation in Manufacturing Biopharmaceuticals (NIIMBL), BioFabUSA by the Advanced Regenerative Manufacturing Institute (ARMI), the Catapult Network in the UK, and the Centre for Commercialization of Regenerative Medicine (CCRM) in Canada. Examples of important steps these organizations have taken to build a dynamic workforce include:Notably, most of these efforts are in the early stages and need investment to scale up nationally or internationally. Community-based, distributed workforce training programs that build industry-identified skillsets and incorporate robust certification could significantly advance the successful use of large-scale data in regenerative medicine.The rapidly evolving field of RMAT requires a workforce trained to take full advantage of data from different sources and at scale. Addressing the challenges of the complex systems that define the RMAT enterprise may entail forming large, unbiased datasets for statistically meaningful analysis. A workforce equipped with both the scientific and technical knowledge and the collaboration skills to integrate expertise can move the field forward in all aspects of regenerative medicine, including basic research, regulation, and manufacturing.To deliver on the promise of regenerative medicine relies on the field to work together across sectors to train the future workforce to leverage modern tools of data science and facilitate the success of RMAT products as science and technology continue to progress. This paper is a call to bring attention to the integration of data science and the application of systems thinking for addressing the challenges faced in developing regenerative medicines.


The current unprecedented Monkeypox outbreaks emergence and spread on non-endemic countries has led to over 3413 laboratory confirmed cases and one death, and yet, does not constitute a public health emergency of international concern as June 23th 2022. We urgently call for collective regional and global partnership, leadership commitment and investment to rapidly strengthen and implement Monkeypox World Health Organization outbreak Preparedness and emergency response actions plans implementation against Monkeypox outbreak. Given the importance of human–animal–environment interface and transmission dynamics, fostering global and regional One Health approach partnership and multisectoral collaboration programs have timely and robust sustained investment benefits on poverty-linked Monkeypox and other emerging epidemics population-based programs, while leveraging from lessons learnt. Moving forward requires addressing priority research questions listed and closing the knowledge gaps for Monkeypox and others neglected tropical diseases roadmap implementation in vulnerable and at risk countries. It should be noted that Monkeypox is known to be endemic and appear circulating below levels detectable by routine surveillance and sustained direct and/or indirect human–human transmission in 11 African countries: Benin, Cameroon, the Central African Republic, the Democratic Republic of the Congo, Gabon, Cote d’Ivoire, Liberia, Nigeria, the Republic of the Congo, Sierra Leone and South Sudan [On 19th May, Portugal reported the first draft genome sequence of the Monkeypox virus associated with this major outbreak affecting multiple countries worldwide. Until 8th June, cases of 16 countries indicated the 2022 virus belongs to the West African clade and is most closely related to viruses associated with the exportation of Monkeypox virus from Nigeria to several countries in 2018 and 2019, namely the United Kingdom, Israel and Singapore . Indeed,The emergence and re-emergence of new and old infectious diseases has widely been linked to poverty and vulnerability, malnutrition and poor healthcare behavior that is more prevalent in low-income countries mainly in sub Saharan Africa. Previous studies and reports have showed a significant relationship between poverty and vulnerability to poverty related outbreak or infectious outbreak emergence and spread in developing and developed countries . This emAlthough the factors influencing the current Monkeypox outbreak in non-endemic areas are unclear. However, the COVID-19 pandemic, unemployment, international trade and travel have an impact on the cross-country transmission of Monkeypox. Moreover, the lack of surveillance and detection capacity due to poverty in endemic areas affects the prevention and control response to Monkeypox. Yet, ongoing Monkeypox outbreak emergence and rapid spread in non-endemic countries is still poorly understood. However, global travel and trade, job loss and COVID-19 pandemic economic and social conditions effects to unhealthy sexual and reproductive activities have been linked to the ongoing outbreak and transmission in non-endemic developed countries. It has long be recognized that poverty is one of the major social and economic determinants of health, hunger, ill-health and poor environment, inadequate sanitation and poor potable drinking water related vulnerability amongst at risk groups. Since the poor populations face a higher spark risk and spread related health and economic shocks, understanding why and how the poor or rich are more vulnerable to neglected tropical disease outbreak and pandemic burden is crucial. Analyzing and understanding aspects of what protections are required and how they affect individuals and societies due to under investment in health system preparedness, lack of effective Monkeypox vaccine and therapies, weaker health systems, limited capacity and how impoverishment reflects the painful choices facing poor African countries at greatest risk, undetected longer and smolder spread will go far in aiding address the increasing outbreaks dynamics around management and control of outbreaks , 4.It has been demonstrated that poverty in time of pandemic or epidemic infection rates showed no significant difference under non-intervention, the peak case is maximized across poor and rich people. Also, larger populations, higher fraction of poor and long durations of interventions are found to progressively worsen outcomes for the poor mainly stigmatization and social deprivations. Addressing Monkeypox outbreak poverty related vicious cycle and challenges requires a deep and rigorous operational research to understanding structural poverty and epidemic. Syndemic or comorbidity of COVID-19 and ubiquitous malnutrition linked to rapid expansions of human settlements and climate change, intensifying livestock production and amplifying outbreaks threats continue to bear the brunt and a toll on vulnerable and marginalized groups in Africa and others low income countries. Noting the absence of regular and sustained Monkeypox surveillance and monitoring mechanisms in both endemic and non-endemic countries, the syndemic of COVID-19 pandemic and Monkeypox epidemic could be of more significant health, socioeconomic and global health security consequences if effective and sustained programs and interventions failed to respond to poverty vicious cycle needs amongst the most vulnerable and marginalized groups.Ongoing epidemiological investigation reported that most cases are linked to men–men sexual intercourse and have no travel history in endemic settings. Hence, non-travel reported case is atypical and could serve as outbreak alertness and strengthening of international health regulations 2005 and global health security measures . The uneHence, we urgently call for collective partnership and action by global and regional leadership and investment commitment to rapidly strengthen and implement Monkeypox WHO outbreak preparedness and response actions plans, neglected tropical diseases (NTDs) roadmap operationalization for contextual and practical evidence-based guidelines and actions , 5. ThesThus, Monkeypox outbreak and COVID-19 pandemic risk communication and community engagement, building outbreak communities’ resilience and containment interventions should preferentially target at risk and marginalized populations in endemic countries, equal protection to all citizens whether poor or rich. Investing in equitable access to novel tools including vaccines and medicines, food security and nutrition, are critical factors influencing health and behavior in response and recovery programs. These efforts contribute in upholding national and regional health security and capacity to prevent, detect and respond to poverty related diseases outbreaks and pandemics in both rural and urban settings. Scaling up access and adherence to critical services to HIV/TB, Cancer and others immune-depressive diseases, to building capacity on early warning alerts, preparedness and emergency response pro-activeness and response to curb and stop the onward Monkeypox widespread.Given the importance of human–animal–environment interface in the emergence and spread of outbreak, fostering One Health approach activities and multisectoral collaboration have benefits through timely and robust sustained investment on Monkeypox and other emerging epidemics population-based programs to reduce poverty, while leveraging from lessons learnt from others pandemics or outbreaks implementation. Increasing the most vulnerable poor health education and awareness outreach, coupled with evidence-based COVID-19 response and recovery programs, financial mechanisms and interventions, community health workers training and capacity building in COVID-19 and other routine vaccination programs efficient and sustainable delivery is needed. In addition, increasing effective mitigating and information communication against the social media rumors, and misinformation to prevent and control the growing Monkeypox outbreak coupled with COVID-19 pandemic public and global health effects , 6. FurtStrengthening International Health regulations and global security actions against Monkeypox outbreak, should include effficient preventative and precautionary measures, prompt clinical management and vaccines research collaboration. Most importantly, fostering One Health approach implementation, are crucial implementation after understanding Zoonotic viral diseases including Monkeypox and COVID-19 animal reservoirs–human link, environment transmission and interconnections for evidence based solutions. Interestingly, two smallpox vaccines (ACAM-2000 and MVA-BN) have been recommended for vaccination against Monkeypox to people at risk of occupational exposure  by the European Medicines Agency in 2013 and US Food and Drug Administration (FDA) in 2019 respectively . HoweverPrompt, reliable and secured information sources ought to continue rise citizens and country awareness and education outreach, healthcare decentralization and transparency for readiness by governments and stakeholders to prevent, monitor and tackle any eventual outbreak of Monkeypox. Country-led poverty alleviation strategies and efforts in improving effective partnership and governance, strengthening quality care delivery services, vaccination stockpile, coverage and effectiveness are vital for resilience building and improved health outcomes. These are required to prepare and strengthen at risk and marginalized communities, enhanced empowerment and knowledge of all risk populations including travelers, pilgrims and tourists, to such unprecedented global outbreak effects on travel medicine, global trade and health agenda , 7, 8. Mi.Contagiousness and transmission routes, Is the incubation period really non-infectious? Interpersonal transmission routes and patterns ? Detoxification pattern and its impact on transmission? The length of the infectious period and its influencing factors, and the possibility of cross-species transmission?ii.Natural history of the disease: clinical manifestations, severity, organs involved and pathological effects, influencing factors.iii.Co-infections: Infection status with chickenpox, sexually transmitted diseases, malaria, etc.Better understanding of the impact on virus transmission and disease severity (pathophysiology) could focus on:iv.Clinical treatment: Optimal regimen, long-term effects and prognosis .v.Disease prevention and control: Virus viability of external environment and object surfaces, disinfection methods, optimal ventilation protocols, optimal isolation protocols, effluent monitoring.vi.Occupational population prevention and control: infection status of occupational population, risk assessment of occupational exposure and corresponding means of prevention, evaluation of the effectiveness of vaccines and drugs used after exposure, vaccination of occupational population and effective waste management.To address what level of concerns need to be taken for controlling Monkeypox outbreak, in the wake of the current outbreak in non-endemic and endemic regions, It is essential to close the knowledge gaps and address priority research questions for Monkeypox and other NTDs operational research and roadmap implementation  includin


Zimbabwe has been experiencing food insecurity for many centuries. This study sought to explore and learn from Zimbabwe’s past and current food security (FS) efforts and challenges, through three historical periods, namely the precolonial, colonial and postcolonial, from about 1430 to 2020. The year 1430 marks the establishment of the Monomotapa state, one of the starting points for Zimbabwe’s own national reconstruction. Adopting a qualitative paradigm, data were obtained using document review and interviewing 85 purposively selected key informants, some of whom were found using snowballing. The study found that the adopted FS strategies during the precolonial, colonial and postcolonial periods were dynamic and mainly derived by new political agendas and crises. The food production and storage aspects of the colonial period were built around agricultural extension services and Grain Marketing Board strategies. The postcolonial period FS initiatives pivoted on humanitarian and development programs. Zimbabwe’s FS initiatives across the three historical periods remain susceptible to various challenges . As such, Zimbabwe’s food insecurity levels remain far away from being a reality, unless the identified challenges are taken head-on by all stakeholders. Therefore, the study recommends that informed local wisdom be given space in finding a lasting solution to food insecurity. Meanwhile, multistakeholder inclusivity, knowledge development and management should be made the crux of FS-related initiatives. This could foster new partnerships and encourage the ethic of working together and participation towards ensuring FS. Worldwide, efforts to ensure food security (FS) are an old phenomenon, intertwined with humanity’s struggles with disaster risks that negatively impact livelihoods. Food security efforts date back to folklore, legends and religious stories (Van Niekerk The Southern African Development Community (SADC) region has always committed to ensuring FS for its 280 million inhabitants  strategies and initiatives to mitigate food insecurity-induced calamities. Hence, the understanding of concepts is critical. Food security has been subjected to an array of transdisciplinary debates and given approximately 200 definitions over the years Ignowski . MaxwellMlambo  provides2, between 1430 AD and 1760 AD  and as food during ritual ceremonies  for use during lean seasons  mechanism Kramer . These eThe technology transfers extension (TTE)The advisory extensionFacilitation for empowermentMaster farmer training (MFT).isiphala and zunde concepts of the precolonial period in terms of purpose. Zhou  (reference number NWU-01665-20-A9).Ethical standards were followed by explaining the purpose of the research and by giving participants the assurance that confidentiality would be maintained. Participants were assured that the information they provided would be used solely for educational purposes.This section focuses on the presentation of the data collected in the field, zeroing in on FS initiatives in Zimbabwe.The participants had three distinct age range categories. About 29 respondents were aged between 18 and 35 years, 32 were in the 36–50-year-old range and 24 were over 51 years old. The average age of the study participants was 31 years, and the oldest participant was 84 years old. The majority were male (55%) and 45% were female.Government officials interviewed explained that Zimbabwe’s FS initiatives span over three periods, the precolonial, colonial and postcolonial. Of the three periods, the postcolonial period has seen an increase in the number of players and investments working towards the implementation of FS initiatives. Some of these players are the GOZ, the FAO, the World Food Programme, World Vision International, the Organization of Rural Associations for Progress and Compassionate Development Services, amongst others. This was also corroborated by NGO staff who were involved in FS programs in the country. One NGO staff member had this to say during in-depth interviews:conservation agriculture] scaling up programed banking through the provision of seed; fodder production through hay bale production training, and taking social service ministry to the communities.’ ‘Our organization is implementing livelihoods and food security programs using technology to increase yields and prevent serious food insecurities in moments of climate variability; CA ; command livestock agriculture, now called smart agriculture; cash transfer programs; seed bank; small livestock; nutrition gardens; water and sanitation [WASH]; food for assets programme [people work for something in return]; school feeding programmes; subsidised stock feed program and free tillage program for the vulnerable.’ ‘We have DRP [It was highlighted during FGDs that projects targeted the vulnerable members of the community and individuals who showed interest in the projects, especially those that build resilience, empower the communities and make them feel like being part of whatever is happening in the area to develop a sense of ownership.Observation during data collection revealed that about 2020 scores of FS-related projects had varying impacts and had been implemented in most districts of Zimbabwe. Participants noted that many NGOs were duplicating programs in bits and pieces and brought a lot of confusion. The number of implemented projects was too high and geographically spaced to show a significant impact on communities. Observations and perceptions of the participants revealed that agriculture-related projects, feeding programs, poverty eradication and drought relief programs were the most popular. Drawing from these findings, earlier history initiatives in the precolonial states have been reinvented in new names and refreshed processes. As a result, a new multistakeholder approach to FS has been born, whereby the government has built partnership with various implementing partners (NGOs). This new approach has seen the government implement massive agriculture-related projects, whilst the NGOs focused on capacity-building and food distribution, respectively. In general, respondents understood FS initiatives existed to build community resilience, ensure FS, socio-economically empower communities , eradicate poverty, capacitate the community, safeguard national assets and develop a sense of program ownership. zunde or isiphala and the GMB) that were also used cut across the three historical periods to mitigate food shortages in the event of calamities. Conversely, capacity development and socio-economic empowerment were viewed as key facets for ensuring long-lasting FS during the colonial and postcolonial periods. Drawing from the above discussions, the perception of FS has evolved from being mainly a household worry to a government and international concern. As a result, all forms of commitment in terms of policies, budgetary, support and resources have been mostly observed during the postcolonial era  and traditional leaders, revealed that some of the postcolonial-period FS initiatives  are the following:Drought relief programmes (DRPs)Land Reform and Resettlement Programme (LRRP)Command AgricultureZimbabwe Agenda for Sustainable Socio-Economic Transformation (ZimASSET) (Government of Zimbabwe (GOZ) Zimbabwe’s food security and nutrition policy (FSNSP).According to Munro , the DroMutasa  stressesCommand agriculture refers to a contract farming scheme rolled out in 2005 after the land redistribution, as well as a strategy to combat food shortages  provides a fertile ground (lessons and practices) on which new FS programs can be designed and modelled. The study further noted an increase in the number of FS players and strategies during the colonial and postcolonial periods; this could be influenced by the returns that come with implementing FS programs and projects. Consequently, this increase resulted in duplication of programs and antagonism amongst some stakeholders between 1980 and 2020, hence the demise of the FS initiatives during these periods especially. The study also found that despite a decorated history of FS strategies, Zimbabwe’s FS initiatives across the three historical periods between 1430 and 2020 remain susceptible to various challenges. These challenges can be categorised as family , power  and in recent times, the 2020 corruption malpractices, amongst others . As such, it should be adopted by all FS stakeholders and communities that already use it, be revived and be promoted to mitigate current and future food insecurity; that stakeholder participation, knowledge development and management should be made a top priority in all FS-related efforts. Based on the scholarly works of Marakas  and Bhat


The topmost authors' keywords commonly used in the studied research area were citrus pulp (n = 48), pectin (n = 26), performance (n = 22), and citrus (n = 33), which created a hint on associated studies on citrus waste and livestock feed. The present study provides a global trend to traverse the intellectual quandary on citrus waste and livestock feed research, and guidance for further studies in this field. It is essential to stress that the present study only dealt with core areas of citrus waste and livestock feed research, hence, it is anticipated that new empirical research and prospective solutions would afford new knowledge insight on citrus waste and livestock feed as new studies evolve.The present study aimed to reveal the abundant tapestry of research on citrus waste and livestock feed, taking into account the recurring challenges posed by feed shortage and high price of conventional animal feed in livestock farming. In total, 565 articles were retrieved in a BibTeX format for analysis using bibliometric package in R studio. The retrieved data included, but not restricted to authors, citations, keywords, journals, and institutions. Published outputs on citrus waste and animal feed for livestock production obtained from Scopus and web of science (WOS) databases were used in this study. The field of citrus waste and livestock feed research experienced an increase in terms of research outputs with an annual growth of 10.20% during the study period. Based on the country level, Brazil was rated first with an aggregate sum of publications ( Shortage of good quality livestock feeds required to sustain livestock production and performance, especially during drought or dry seasons has been reported to affect the advancement of animal production in most countries and especially in developing countries. Non-conventional feed resources including crop residues are in regular search to lower the over-reliance on conventional feedstuff resources and to reduce feeding costs during animal production. The moderately high prices of livestock feed in many countries are part of the identifiable challenges in animal production among others  obtained from farms and agro-allied industries after processing. However, the waste from citrus may cause several potential economic and environmental problems because of its fermentability if not properly converted to environmentally friendly value-added products , by analytically discussing the scholarly position in the production of livestock production using citrus waste, which presently is a growing interest globally and they are the two interconnecting areas of the present study.Conversely, the present study reported several high-flying categories on the utilization of citrus waste for livestock production studies, for instance, authors, research outputs, distribution of countries, the global trends of citation, thematic evolution of authors' keywords, words, keywords, and trending topics on the subject matter. The outcomes from this study have a robust prospect of increasing the disciplinary knowledge bank of citrus waste as an alternative feed resource for livestock production. By exploring outputs on scholarly high-flying work, this study will help in recognizing areas of potential research gaps and research dynamics on citrus waste and livestock production globally. Furthermore, we are optimistic that this study will be valuable to research experts, livestock industry, and other stakeholders in this field. The study will also help to advance and explore scientific studies done in livestock production and propose probable future research prospects.The analysis package (Bibliometrix) that was used for this study is a suitable tool known for precise/accurate package employed for processing data from articles/publications including file conversion, duplicate matching and merging, similarity normalization for network analysis, descriptive analysis term extraction, and matrix building  archive on 15 July 2021. Scopus and WOS databases hosted reliable and efficient high-impact scientific publications )) AND (ruminant* OR livestock OR poultry OR sheep OR goat* OR rumen OR broiler* OR pig* OR swine OR turkey) AND ).578 document results(TITLE (citrus* AND (waste* OR feed* OR peel* OR pulp) (Title)Refined By: Search within all fields: Ruminant* Or Livestock Or Poultry Or Sheep Or Goat* Or Rumen Or Broiler* Or Pig* Or Swine Or Turkey187 results from Web of Science Core Collection for:citrusDocument Types: Articles Clear all.The current study analyzed all collected data from Scopus and WOS databases by using RStudio v. 4.0.4 software with bibliometrix R-package for scientometric elements  = X × NT;In addition, we employed necessary commands/functions of bibliometrix R-package to analyzed retrieved data for the following descriptive result, citation assessment, authors' scientific performance/productivity. Bibliometric scientific collaboration and networks  and bibliometric graphical coupling (keyword co-occurrences and co-citation) were calculated and visualized from bibliometric bipartite (two-way) collaborations/networks of rectangular yardsticks/matrices of research articles × attributes/traits. For instance, the formula for a characteristic bibliometric connection/network is given as Network (X is a bipartite/biclustering (two-way) network matrix consisting of research articles × attribute/traits .Where N is a dimensional/symmetrical matrix N = NT.Likewise, a graphical model was created for all collaborations/networks by utilizing the force-directed algorithms (Fruchterman) applied in the networkPlot command/function of the bibliometrix R-package. Consequently, all the collaborations/networks were normalized/standardized by utilizing Salton's cosine coefficient, proximity indices (association strength), Simpson's coefficient (inclusion indices), and Jaccard's similarity indices among nodes of a network , followed by China (n = 55), India (n = 39), Turkey (n = 38), and Korea (n= 34), respectively, among other nations. In n =179), United Kingdom (n = 118), Israel (n = 52.80), and Germany (n = 50.66) lead the chart, respectively (n = 81), the next country was China (n = 55), followed by India (n = 39) and Turkey (n = 38) among others, respectively. The frequency of research outputs varied among the top 20 nations from 0.00951 to 0.15399. Furthermore, the nations that topped the chart with multiple country publications and networking include Italy which is placed in the first position (n = 5), Brazil, Korea, and Iran which are tied in the second position (n =3), then followed by China and Egypt (n = 2), which are tied in the third position, respectively. Conversely, the nations ranked in top positions for single country publication of research outputs in the field of citrus waste and animal feed research for livestock production are Brazil (n = 78), China (n = 53), India (n = 38), Turkey (n = 37), and Korea (n = 31) among others  was ranked first, followed by citrus (n = 32), performance (n = 23), and pectin (n = 22), among other keywords used by authors (n = 14) based on the number of articles; while I, Susin was ranked in the second position (n = 13), meanwhile G, Rodrigues was placed in the third position. Two authors, namely, R, Gentil and U, Ruiz, however, maintained the fourth position with 10 article publications each. Based on total citations, the H_index was 6 (TC = 140) for A, Pires who maintained the first position. However, author I, Susin was in the second position with H_index of 6 (TC = 151). The third position was maintained by G, Rodrigues with H_index of 4 (TC = 142).Among the most relevant author keywords in the field of citrus waste and animal feed, citrus pulp ( authors . FurtherZea mays), as alternative feedstuffs  and as medicinal plants  for improving livestock performance and metabolism (Z. mays) or as a processed feed meal (citrus fruit or citrus peels). The orange cluster showed citrus waste as food for cattle. The purple cluster showed the use of citrus waste as a supplement with maize while the red cluster indicated the parts  of citrus waste that can be used for livestock feed to improve digestibility and growth of livestock. The blue cluster showed the utilization of citrus waste as medicinal plants (antioxidant), whereas the green cluster revealed the potential of citrus waste for improving animal metabolism , to improve livestock performance (growth and digestibility), as feed supplements to maize  among the journals with the most published articles. This was followed by Arquivo Brasileiro de Medicina Veterinaria E Zootecnia . The Journal of Agricultural and Food Chemistry and Revista Brasileira de Zootecnia [Brazilian Journal of Animal Science] were ranked in the third position with the number of publications being 11 each and H_index being 9 and 7, respectively. Conversely, the Journal of Animal Science was ranked in the fourth position among the journals with the most published articles , followed by the United States (n = 19), and Iran (n = 13). However, collaboration links for developing countries such as Egypt, Nigeria, and Indonesia had very few links/networks compared to those from developed countries.From statistical assessment of the articles related to the use of citrus waste for animal feed production revealed that we can deduce that animal feed produced from citrus waste for livestock farming involves several research directions, including Animal Husbandry (such as cattle and sheep farming), Chemistry , and Medicinal Botany , among others. The current study presents a better motivation for the advancement and a large space for research in the field of citrus waste recovery and animal feed . FurtherThe top 10 most prolific institutions with at least 10 publications are listed in n = 6) to 2020 (n = 59) resulting in an annual increase of 10.20% of article publications. The increase in research on citrus waste and animal feed suggests that more researchers have now developed more interest in this area in the past 15 years. This trend may likely be a result of the continual exploration of plant-based alternative feed resources to advance the search for cheaper and helpful animal feed for livestock production. Several authors have reported the prospects of using citrus waste (pulp) as animal feed to improve milk yield in cattle  as an alternative animal feed resource for livestock production were mostly from developed countries such as China, Brazil, the United States, Korea, and Turkey, with a few from very low-income countries (such as Nigeria and Egypt), thus follow the associated trend of low productivity of these countries. The foremost countries with collaboration links on citrus waste and animal feed research studies showed a collaboration allied was mostly among researchers from developed and highly financially stable countries, including the United States and Italy. This observation appears to be a similar trend for collaboration networks of countries in many other research fields  are known to be high in lingo-cellulosic substances, which are reported to be a rich source of compounds for the production of new and sustainable chemicals and fuels  Increase the PCDD/F-contamination of milk, butter, and meat samples by use of contaminated citrus pulp  The voluntary feed intake of pigs given feeds based on wheat bran, dried citrus pulp, and grass meal, in relation to measurements of feed bulk  on the growth rate of tilapia (Oreochromis mossambicus), and possible disease resistance against Streptococcus iniae  Evaluation of the effects of essential oil extracted from sweet orange peel  as observed from the present study . This obn = 5) as seen in There are very few observed situations of countries with multiple collaborations (multiple country publications) on citrus waste and animal feed research with Italy having the highest occurrence of multiple collaborations  per nation . A similC. sinensis) utilized to formulate food for improvement of livestock , citrus medicinal potentials , and the effect of citrus waste feed on livestock performance , which are commonly linked to citrus waste and animal feed research. The hotspot focus for citrus waste and animal field span through some disciplines such as animal feed nutrition, chemistry, bio-medicinal research, among others .As envisaged, the present study provided some hints of the recent research hotspots in the field of citrus waste and livestock feed for the study period. A co-word biclustering (two-way) evaluation was done to reveal the scientific research hotspots in the niche area, where there were five clusters representing the hotspots, respectively. From the k-means analysis, the most regularly focused hotspot research and research disciplines (including article outlets) associated with citrus waste and animal feed study revealed the research hotspot during the surveyed period which included citrus waste  on the growth rate of tilapia fish when compared to the basal feed. Likewise, Acar et al.  were supported by other conceptual framework indicators such as the treemap and the keywords network visualization diagram . More imr et al.  reportedthe fish . The novthe fish  is an esThe use of citrus waste as animal feed to improve milk yield in cattle Malisch, , feed inJournal of Agricultural and Food Chemistry. In this study, the authors proposed in their findings that the application of heat to citrus peel substrate has the potential of improving the antioxidant properties of citrus waste as an antioxidant agent for animals. Other authors have also reported similar studies on the activities of citrus waste as an excellent antioxidant agent  peel, a byproduct of the essential oil industry” was published in the Journal of Applied Microbiology in 2007 by Mandalari et al. In the study, the authors suggested that citrus waste (peel) may be exploited from a commercial essential oil industry as a potential source of natural antimicrobials that are active against Gram-negative bacteria. From the aforementioned studies, it may be safe to state that the use of citrus waste may further be employed in addressing research questions in other areas of scientific fields.The most cited article—“Effect of heat treatment on the phenolic compounds and antioxidant capacity of citrus peel extract” was authored by Xu et al. . This stTo date, this manuscript appears to be the first scientometric study that assessed the outputs of peer-reviewed publications on citrus waste and animal feed research at a global level. Although, we are aware that there might be some shortcomings to the current study which may include and not limited toa. Missing publications that we might not have included in the analysis of citrus waste and animal feed or its associated words during the retrieval of data from Scopus and WOS.b. Second, shortcomings may arise from our observations since this study did not include publications on citrus waste and animal feed research that were in non-indexed journals and thus, would not have been available in Scopus and WOS databases, such as those published in some Chinese or other non-English journals.c. The current study might also be limited due to the exclusions of other document types including meeting abstracts, review articles, and note papers.Our scientometric analysis revealed a global increase in the use of citrus waste as the animal feed for livestock production, with greater research outputs from high-income nations when compared to low- and middle-income nations and limited collaboration with developing nations based on the Scopus and WOS databases. The less number of research publications in developing nations on the current subject matter mirrored similar happenings of outputs in other research fields. Furthermore, the current study revealed lesser research outputs on the use of citrus peels (wastes) as animal feed for livestock production when compared to the use of citrus pulps for similar reasons. Despite the appreciable progress illustrating the utilization of citrus waste as animal feed over the past 40 years, many questions remained to fully address their  relevance as a standard livestock feed to curb the challenge of the ever-increasing prices of conventional feed when searching for a cheaper alternative feed resource.The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.EI: conceptualization, data curation, analysis, visualization, writing original draft, and manuscript editing. YH: logistics and supervision. All authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


It is a main reason for the development of adverse events in many chronic inflammatory diseases. Despite many efforts in the development of therapeutics for fibrosis, success has been very limited. However, recent advancements in single cell omics' tools are helping to delineate the molecular and cellular mechanisms that contribute to fibrosis and provide the opportunity for more targeted new approaches for treatment of fibrosis. Fibrosis contributes to disorders in many tissues and organs including liver and heart dysfunction, rheumatoid arthritis, diabetic nephropathy and retinopathy, age-related macular degeneration, corneal wound healing, and glaucoma.,3 However, the underlying cellular and molecular mechanisms may vary in different organs, and the commonality among these diverse fibrotic diseases is not fully delineated. Connective tissue growth factor (CTGF) has been recognized as an important mediator of fibrosis and scar formation.,9,10,11 A recent study utilizing computational strategies identified CTGF as the common key molecule regulating fibrogenesis among eight different fibrotic diseases including ocular fibrosis. Thus, many efforts have focused on interfering with the expression and activity of CTGF, such as function blocking antibodies,,14,15,16 siRNA,,18 shRNA, microRNA,,21 Yap/Taz inhibitor,,23,24 and most recently CRISPER-Cas9 system to mitigate fibrosis in different cells, tissues, and organs including the eye. Fibrosis is a complex and active process, which is impacted by various cell types, differentiation and signaling pathways, genes, and crosstalk.,26Fibrosis is the increased accumulation of fibrous connective tissue in and around tissues with inflammation or damage, which initiates irreversible scar formation.,28,29 Perivascular supporting cells, which are also tissue resident mesenchymal stem cells, are recently recognized as being the cells primarily involved in fibrotic responses in many organs and tissues. We have noted that retinal and choroidal perivascular supporting cells express higher levels of CTGF compared to retinal or choroidal endothelial cells but lower than microglial and retinal pigment epithelial cells (our unpublished observations). The high levels of CTGF in microglial cells decreases while that of pericytes increases in response to high glucose conditions, and may drive migration and/or loss of perivascular cells from retinal blood vessels during diabetes. Immune cells, such as macrophages, mediate inflammatory responses that are integrated with other pro-fibrotic processes.,33,34,35 However, the details of these interactions remain poorly understood, but single-cell genomic, proteomic, and transcriptomic techniques are further unraveling the specific cell subtypes and their interactions in pathophysiology of fibrosis in various tissues.The deposition of excessive extracellular matrix proteins by myofibroblasts is common to many fibrotic conditions. Since the protein is made as an inactive precursor and deposited in the extracellular matrix (ECM), its mechanisms of activation by αvβ6 integrin, autotaxin, and galectin-3 have been targeted for potential therapeutics.,3 Unfortunately, targeting these mechanisms of TGF-β activation have been ineffective in treating and/or preventing fibrosis, especially in idiopathic pulmonary fibrosis. These failures have been attributed, at least in part, to normal physiological functions of TGF-β, and its systemic inactivation could have many adverse effects. Thus, not only the identification of pathways involved are important but determining their hierarchy is essential to their successful targeting for therapeutic intentions. CTGF is a downstream target of TGF-β in tissue remodeling and ECM synthesis. It is also proinflammatory and is recognized as a common key driver of fibrosis in various fibrotic disorders. Thus, focusing on the role of inflammatory cells and their mediators in modulation of innate immune cell responses in driving fibrosis could be beneficial. Revealing the identity, organization, and mechanical properties of the ECM environment in fibrosis could also provide additional unique clues to the mechanisms that drives inappropriate activation of target cells.In terms of signaling pathways, TGF-β has been extensively recognized as key mediator of pro-fibrotic activity.,37 It is well-established that CTGF expression is significantly upregulated during this fibrotic response and targeting CTGF using various modalities, as stated above, are shown to prevent fibrotic signaling including proliferation, ECM deposition, and proinflammatory activity in fibroblasts and retinal pigment epithelial cells, and in in vivo preclinical models. In a manuscript in this issue of JOVR, Hassanpour and colleagues demonstrate subconjunctival delivery of anti-CTGF is efficacious in prolonging the bleb life in a rabbit model of trabeculectomy. They did a careful analysis of the microstructural features of the bleb areas and provide histological proof on the inhibition or reduction of fibrosis in anti-CTGF treated trabeculectomy blebs. The changes in response to anti-CTGF were comparable with those noted in mitomycin C (MMC) treatment. They also showed MMC treatment was concomitant with decreased production of CTGF, likely as a result of the inhibition of cell proliferation by MMC. Growth arrested cells, a limitation with use of MMC, are however metabolically active and could release other factors, which could exacerbate fibrosis.Trabeculectomy is a surgical treatment to lower intraocular pressure in glaucoma patients. However, excess scaring leads to failure of the filtering bleb and adversely affect the treatment outcome.,16,39 Thus, a better understanding of the mechanisms of CTGF action and its cell autonomous activities may aid in development of new and complementary agents with effective antifibrotic activity. Recent studies have also identified the hippo signaling pathway and its downstream effectors YAP/TAZ as important modulator of CTGF production and activity. The YAP/TAZ inhibitor, verteporfin, suppresses CTGF production and mitigates fibrosis in the eye and heart.,40,41 We are beginning to know more about the expression and function of CTGF using transgenic mice including CTGF reporter, and global and conditional CTGF null mice.,42,43,44 We are learning about the role of CTGF in normal developmental and repair processes. A recent study targeting the deletion of CTGF in endothelial cells demonstrated an import role for CTGF-YAP axis for retinal angiogenesis and barrier formation. In addition, deletion of CTGF in corneal epithelial cells interfere with proper corneal wound healing. Thus, a better understanding of how CTGF, and perhaps other mediators, aberrant expression and downstream signaling events are regulated during early and late stages of fibrotic diseases will help to identify the common and unique regulatory mechanisms involved. We recently identified Bim expression, a proapoptotic member of Bcl-2 family, as essential for clearance of macrophages and mitigation of fibrosis in a preclinical model of choroidal neovascularization and scar formation. Although there are some common pathways engaged by fibrosis in different organs, there are also unique pathways which we know little about. Identification of these unique pathways and elucidation of their interactions will allow development of organ specific anti-fibrotic agents, which are tissue specific and more effective for treatment of fibrosis.The recognition of CTGF as the common factor in driving fibrosis in various organs with fibrosis supports an import role for antagonism of CTGF for treatment of these diseases. The same group has previously shown that anti-CTGF is efficacious in mitigating fibrosis in preclinical models of neovascular age-related macular degeneration and proliferative vitreoretinopathy with minimal adverse effect on vision.None.There are no conflicts of interest.


Furthermore, a positive relationship between social participation and episodic memory  was observed. The mediating effect of functional health explained 7.7% of the total effect of social participation on episodic memory. These findings may contribute to research concerning the potential explanation of the association between social capital and cognition as well as interventions aimed at improving cognitive performance in older adults.This study evaluated the association between cognition and social capital among Chinese older adults and analyzed the mediating role of functional health in that interaction. The baseline and follow-up data were acquired from the 2011 and 2015 China Health and Retirement Longitudinal Study (CHARLS). The sample included 6291 adults aged 55 years and above in 2011. The dimensions of social capital included social trust, social support, social participation, and reciprocity. Cognition was measured based on mental state and episodic memory. The Karlson–Holm–Breen method was employed to explore the association between social capital at the baseline and cognition four years later, and the mediating role of baseline functional health. There was a positive relationship between financial support  and reciprocity, and mental state (β = 0.186,  As the proportion of older adults rapidly increases in China, the economic status and social role of this population face dramatic changes, the most prominent being the growing number of elderly patients with declining cognition, as demonstrated by an increase in dementia cases . A previCognition refers to a psychological process crucial to activities of daily living, such as understanding, perception, memory, imagination, and thinking . CognitiThe positive role of social capital in cognition has been gradually confirmed . From thExisting studies on older adults focus on the following two dimensions of social capital: social participation and social support. Regarding social participation, Chinese scholars have found that lower levels of social participation could be a risk factor for cognitive impairment among older adults , and engThe existing literature on social participation has revealed complicated effects on the different domains of cognition. Mortimer  and JameRegarding social support, Andrew and Rockwood  found thSome studies have found that different types of social support may cause varied effects on the same cognitive dimension, while the same type of social support has different effects on the different dimensions of cognition . Ellwardt  found thThe literature shows that the influence of different dimensions of social capital on cognition may be multifaceted and varied, and hence worthy of further analysis. To remedy the knowledge gap, a comprehensive framework of social capital indicators is necessary to go beyond social support and social participation and explore the relationship between different dimensions of social capital and different cognitive capabilities. The present study aims to address the limitations of the previous studies in two aspects. First, most researchers have focused on the association between one exclusive social capital dimension, such as social support or social participation, and cognition, while not fully considering the comprehensive scope of social capital, and dismissing the roles of social trust and reciprocity . While sFunctional health may partly explain the relationship between social capital and cognition . SeveralThis study aims to (1) measure social capital based on the four dimensions of social trust, social participation, social support, and reciprocity; (2) use nationally representative data to test the associations between the different types of social capital and cognitive domains; and (3) analyze the extent to which functional health plays a mediating role in the relationship between social capital and cognition. The conceptual framework of this study is shown in http://charls.pku.edu.cn/) (accessed on 15 January 2020). The survey began in 2011 and follow-up interviews were conducted biennially thereafter. All the participants signed an informed consent form prior to the data collection. The data applied in this study and other detailed information on CHARLS are available online (http://charls.pku.edu.cn/) (accessed on 15 January 2020). The data were acquired from the China Health and Retirement Longitudinal Study (CHARLS). Community-dwelling adults aged 45 years and above were selected using a multistage, stratified probability sampling design from 450 villages and 150 counties in 28 provinces in China  aged 55 years and older as of 2011, since people over 55 years old had already begun to show mild cognitive impairment (MCI) ; (2) didCognition was measured using the Chinese version of the Mini-Mental State Examination (MMSE), which includes the perspective of two domains, that is, mental state and episodic memory . Mental According to Putnam’s social capital theory , the meaSocial support was measured in terms of financial support and care. The respondents were asked whether they had received financial support from their children in the past year. They answered either “yes” or “no”. Care was assessed by asking the respondents “Do relatives (except spouse) or friends provide long-term care when you need it?” We defined care as “yes” if the answer was “yes, they do”, and “no” if the answer was “no, they don’t” . RegardiFunctional health was measured using activities of daily life (ADL), including dressing, bathing, eating, getting on and off the bed, going to the toilet, and controlling bowel movements), and instrumental activities of daily living (IADL), including doing housework, cooking, shopping, managing money, and taking medicine. Both are commonly used tools for screening poor functional health . The reshukou status. Hukou refers to household or residential administration regulations and includes rural hukou, non-rural hukou and unified hukou . Self-rated health conditions and sleep were used as health-related variables. The respondents were asked to rate their health on a five-point scale ranging from 1 = very good to 5 = very poor. The answers were recorded as good (very good/good), fair (fair), or bad (poor/very poor) [The control variables were drawn from the previous studies on the cognition of older adults, including demographics, socioeconomic status, and health-related variables ,37. The ry poor) . Sleep wry poor) . The basThe data for social capital, functional health, and the control variables were collected from the 2011 baseline survey, and the data for the dependent variables (cognition in 2015) were collected from the results of the 2015 survey. First, the demographic characteristics using the mean (standard deviation) or frequencies (percentages) were depicted. Second, Spearman’s coefficients were used to test the correlation between the cognitive variables; t-tests and an ANOVA analysis or Kruskal–Wallis equality of populations rank test were used to compare the cognitive scores across different subgroups of older adults. If the Bartlett test for equal variances among different groups was not statistically significant, an ANOVA analysis was used to test the differences of the means; otherwise, the Kruskal–Wallis equality of populations rank test was used See . Third, to test the mediation effect of functional health on the association between the different dimensions of social capital and cognition, we conducted a linear regression model, based on the Karlson–Holm–Breen (KHB) method . Since tp value less than 0.05.Taking the different dimensions of social capital as independent variables, this study conducted a linear regression analysis for each cognitive result while controlling for the control variables. As shown in hukou, better self-rated health and healthier functional health, and slept about 6–7 h at night. This study included 6291 participants; their baseline characteristics are presented in p = 0.009), and the older adults with higher levels of financial support were more likely to have a higher mental state score. Reciprocity was significantly associated with high mental state scores , and the older adults with higher levels of reciprocity were more likely to have higher mental state scores. However, no significant relationships were found between the other social capital dimensions and mental state (p > 0.05) (As shown in  > 0.05) . p = 0.002), and the older adults with higher levels of social participation were more likely to have a higher episodic memory score. However, this study did not reveal significant relationships between any other social capital dimensions and episodic memory (p > 0.05) (As shown in  > 0.05) .p = 0.021)  .Cognition is critical to the quality of life of older adults. Therefore, it is imperative to study and understand cognition to prevent and treat cognitive impairments. Although previous studies showed that some dimensions of social capital could protect cognition, and functional health could be affected by social capital and closely related to cognition, it remained ambiguous whether and to what extent functional health played a mediating role in the relationship between social capital and cognition. The results indicated that financial support and reciprocity were associated with a better mental state, and social participation was associated with better episodic memory. A further mediation analysis found that functional health did not mediate the association between financial support or reciprocity and mental state, whereas the association between social participation and episodic memory was partially mediated by functional health among older adults. The previous studies demonstrated that financial support and reciprocity were associated with better cognition, as well . The schAdditionally, we found that financial support and reciprocity were more likely to benefit the mental state of the older adults than their episodic memories. The study participants were distributed in rural areas with relatively low socioeconomic status , and the elderly in rural areas could not meet their healthcare needs owing to the limited healthcare resources and heavy financial burden in rural areas. Adequate economic support can relieve the living pressure and reduce the mental burden; therefore, economic support significantly affects the mental state of the elderly. Regarding reciprocity, in traditional Chinese culture, the spirit of “keeping watch and helping each other” has always been regarded as a kind of virtue. Therefore, the daily mutual assistance and support between neighbors has become a social expectation. Even under rapid economic and social changes, this tradition of mutual assistance continues to be practiced in vast rural areas of China. Mutual help from family, friends, and neighbors enhances the self-health management ability and long-term maintenance of the elderly, contributing to their physical and mental development. Meanwhile, compared with episodic memory, the individual mental state depends more on the long-term accumulation of material and human capital . TherefoFurthermore, we found that social participation was not significantly related to mental state. This implies that the role played by social participation is not only related to the existence of social participation but also to the autonomy of social participation. An existing study showed that social participation might not always benefit the health of the elderly. Participation in society on an autonomous basis benefits their mental state or mental health; however, on a mandatory basis, its impact may be negative. The positive and negative effects of social participation on mental state may offset each other; therefore, we did not observe any significant impact . SimultaOur study suggests that functional health mediates the association between social participation and episodic memory. Social participation can promote physical and mental activities in older adults. Physical activities can improve functional health, whereas mental activities can reduce memory decline. Physical activity in older adults can improve their cardiopulmonary and cerebrovascular function, prevent neuropathological changes, and help delay cognitive decline. Additionally, older adults often need to communicate with others in social activities, improve their vigilance, and observe and participate in their surroundings simultaneously. The repetition of these cognitive activities may be related to memory maintenance in older adults . HoweverOur study did not find any significant associations between social trust, receiving care, and cognition. The study of Zhang et al.  suggesteThis study had some limitations. First, although the methods of measuring social capital indicators in this study have been applied by other Chinese scholars , knowledThis study demonstrates that social capital dimensions such as financial support, reciprocity, and social participation are associated with cognition. Moreover, the association between social participation and episodic memory is partially mediated by functional health among older Chinese adults. However, the mediating effect of functional health constitutes only a small proportion of the total effect, and further studies are required to examine the mechanisms underlying this association in more detail. Our study suggests that primary healthcare providers should pay more attention to older adults who lack financial support, social interaction, and social participation; strengthen the screening of those with physical disabilities and limitations; and provide intervention and treatment related to cognitive improvement for older adults with poor functional health.