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• Published: 05 August 2020

Impact of the COVID-19 pandemic on clinical research

• Katherine R. Tuttle   ORCID: orcid.org/0000-0002-2235-0103 1 , 2  

Nature Reviews Nephrology volume  16 ,  pages 562–564 ( 2020 ) Cite this article

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• Acute kidney injury
• Clinical trials
• Infectious diseases

The COVID-19 pandemic has placed a tremendous strain on sustaining the clinical research enterprise and will also likely affect key study outcomes; these effects must be considered during data analysis and interpretation. Nevertheless, the responses to the pandemic have also introduced innovations that will advance the conduct of clinical research.

The first recognized case of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection leading to coronavirus disease 2019 (COVID-19) in the USA occurred during late January 2020 in the state of Washington 1 . Our state was hit hard by the outbreak that followed, as hospitals and emergency medical services became overwhelmed by severely ill patients in the major health-care hubs 2 , 3 , 4 , 5 . We first had a sprint, from March through to May 2020 when elective procedures and in-person patient visits were halted to reduce the risk of viral transmission, conserve personal protective equipment (PPE) and make more health-care workers available for the enormous clinical impact of COVID-19. As initial social distancing and other efforts to contain the virus dampened the spread, we began to gradually re-open in health-care systems and society at large. However, this was soon followed by another uptick in cases beginning in June 2020 that required backtracking to more restrictive measures. It is now clear that COVID-19 is with us for the long haul, a marathon that we will run for months or years to come.

COVID-19 is with us for the long haul, a marathon that we will run for months or years to come

SARS-CoV-2 infection spreads via extremely contagious respiratory droplets 6 . COVID-19 is commonly a mild upper respiratory illness, but a substantial minority of patients develop severe bilateral pneumonia leading to hospitalization for supplementary oxygen and supportive care, or respiratory failure requiring mechanical ventilation 7 , 8 , 9 . SARS-CoV-2 infection also spreads from the lungs to other organs 6 . Acute kidney injury is common in patients with COVID-19 and may be due to viral infiltration or other kidney injuries caused by a systemic inflammatory response, hypotension or nephrotoxins 2 , 3 , 4 , 7 , 10 . As a result, clinical nephrology services have been overwhelmed by the acute dialysis needs of patients hospitalized with COVID-19. Many of us, no matter how senior or focused on academic work, have been called to clinical service. I was the only nephrologist still in practice who knew how to implement acute peritoneal dialysis should we run short of resources for continuous kidney replacement therapy. This important skill has all but disappeared in contemporary nephrology practice, despite its practicality and effectiveness in acute care settings.

I began my career as an intern in 1982 when AIDS had started to wreak havoc at Northwestern Memorial Hospital in Chicago. I cared for more pneumocystis pneumonia than pneumococcal pneumonia and more Kaposi’s sarcoma than breast cancer. Nearly half of the medical services were AIDS wards when I finished my residency in 1985. HIV was identified as the cause around that time. However, intense research efforts led to HIV testing and novel treatment options, which have dramatically reduced the number of full-blown AIDS cases and turned HIV infection into a mostly manageable chronic condition. There are many lessons from HIV/AIDS that have informed my current thinking and response to COVID-19.

The Providence St Joseph Health hospitals in Washington state have had >7,000 admissions for COVID-19 as of 20 July 2020, and more come each day. Within this health-care system, I am executive director for research in the Providence Health Care region and, in this role, I rapidly turned old lessons from the HIV/AIDS era into new actions. Our overarching goal was to address the critical needs of COVID-19 research while maintaining research for essential concerns across other therapeutic areas in both adult and paediatric medicine. The main priority was to open the platform clinical trial of anti-viral treatments sponsored by the National Institutes of Allergy and Infectious Diseases/National Institutes of Health (NIAID/NIH), which required redirection of clinical research resources from other therapeutic areas to COVID-19 and a rapid administrative response. Our regulatory group and Institutional Review Board prepared, reviewed and approved the study protocol and informed consent form within 3 days over a weekend. Our budget and contracting groups similarly moved with record speed. As a result, our site was among the first ten sites activated on the initial NIAID/NIH clinical trial of remdesivir versus placebo. Our first participant was enrolled just 5 days after we received the study protocol.

Research groups from other therapeutic areas were quickly deployed, trained and certified by NIAID/NIH to ensure that enough investigators and study coordinators were available to manage this intense clinical trial activity. Our COVID-19 investigators are a multi-specialty team consisting of experts in infectious diseases, pulmonary and critical care, hospital medicine and nephrology. Similarly, research coordinators who normally manage studies in cardiology and nephrology were moved onto the COVID-19 team. We meet in a daily huddle to review all hospital admissions for COVID-19 with the goal of having a study option for every patient. The NIAID/NIH platform trial is continuing and we have since activated other new protocols for serology testing, biobanking and therapeutic interventions in those who have been excluded from the NIAID/NIH protocols, such as patients with an estimated glomerular filtration rate of <30 ml/min/1.73m 2 . Informed consent forms are currently available in five languages, and we have implemented Institutional Review Board-approved consent via remote technologies and using legally authorized representatives.

The COVID-19 pandemic has placed a tremendous strain on the clinical research enterprise. With the redirection of resources and temporary halting of in-person visits, studies in other therapeutic areas have been unavoidably constrained. However, the COVID-19 response has also introduced innovations that have advanced our overall conduct of clinical research (Table  1 ). Although recruitment and enrolment for most other studies stopped during the early stages of the pandemic, both our study sponsors and sites developed new approaches to conduct remote visits by telehealth, use home-based testing or monitoring technologies, and provide curbside or courier pick-up and delivery of participant samples and investigational products. Our research leaders, investigators and staff have made concerted efforts to provide study updates to participants — by telephone, email and through the electronic health record portal — during and after the pause in the studies. We re-opened for in-person visits on 18 May 2020 under strict enforcement of clinical protocols for viral infection prevention and the use of PPE according to the guidelines established by our health-care system. Study participants are given the option of a remote visit whenever possible. Every person who enters the clinical research centre is screened for COVID-19 symptoms, fever and potential exposure. Masks and physical distancing are required for all in-person interactions and no visitors are allowed, except for one parent in the case of paediatric patients, or one carer in the case of patients with disabilities.

The enrolment rates for our research programme are now similar to those recorded pre-pandemic. To the best of our knowledge, we have sustained retention in the ongoing studies. We will survey participants about their experiences and perspectives to facilitate research despite the risks associated with COVID-19. Notably, we must be cognizant that COVID-19 might affect key study outcomes. For example, SARS-CoV-2 infection could worsen glycaemic control in persons with diabetes, raise or lower blood pressure in those with hypertension, or accelerate progression of chronic kidney disease. Adverse events, particularly acute illnesses, hospitalizations and mortality may be caused by the viral infection or by deferral of care due to fear of contracting it. Participants are also likely to have changed their lifestyles to minimize contact with others, which may also affect outcomes. These are crucial considerations for study analysis and interpretation. Potential confounding may be addressed by examining pre-and post-pandemic outcome rates and COVID-19 surveillance with control for evidence of exposure or infection entered into data analysis plans. Nevertheless, with proactive measures, it is feasible to maintain interest, participation and quality in clinical research.

with proactive measures, it is feasible to maintain interest, participation and quality in clinical research

Investigators, coordinators and clinicians have a renewed sense of urgency and purpose to use science to solve problems that are important to patients and the public. We do get tired at times, and burnout is a real risk. Yet, we move forward with mutual support, encouragement and focus on tangible goals to keep making research better. All of these are positive changes that we will retain long after the COVID-19 pandemic subsides.

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Tuttle, K.R. Impact of the COVID-19 pandemic on clinical research. Nat Rev Nephrol 16 , 562–564 (2020). https://doi.org/10.1038/s41581-020-00336-9

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The Triple Aim of Clinical Research

E ray dorsey.

1. Center for Health + Technology, University of Rochester Medical Center, Rochester, NY

2. Department of Neurology, University of Rochester Medical Center, Rochester, NY

Karl Kieburtz

The proposed triple aim of health care – enhanced patient experience, improved population health, and reduced per capita costs – can be applied to clinical research. A triple aim for clinical research would: 1) improve the individual research participant’s experience; 2) promote the health of populations; and 3) reduce per capita costs of clinical research. Such an approach is possible by designing trials around the needs of participants rather than sites, embracing digital measures of health, and advancing decentralized studies. Recent studies, including those evaluating therapies for COVID-19, have demonstrated the value of such an approach. Accelerating the adoption of these methods can help fulfill this new triple aim of clinical research.

In 2008, Berwick and colleagues proposed a triple aim for health care: improving the experience of care, improving the health of populations, and reducing per capita costs. 1 Now is the time to extend Berwick’s triple aim from health care to clinical research ( Table 1 ).

The triple aim of health care and clinical research

While most individuals want to participate in research, few do. The demands and experiences of research “subjects” explain why. For example, in clinical trials individuals bearing the burden of a disease are asked to take experimental therapies with known and unknown safety risks and uncertain efficacy. They are also expected to take time off from work or other activities, travel to research centers (often with a partner or caregiver) at their own expense, undergo extensive and time-consuming assessments (some of which are uncomfortable or risky), and repeat the process several times over weeks, months, or years. In many cases, they have little voice in the design or conduct of the research. Often after the research is completed, participants are informed neither of their individual results nor of the study’s overall outcomes, even if harm from the intervention is identified. The result is that many participants, who bear the disproportionate share of the burden and risk in clinical studies, feel invisible, uninformed, and inadequately recognized.

Berwick critiqued health care as “physician-centric.” Current clinical research is investigator- or site-centric; all activities orbit around the site not the participant. To help change that orientation and to foster an inclusive approach to clinical trials, the U.S. Food and Drug Administration released a guidance in November 2020 that asks sponsors to “make trial participation less burdensome for participants.” 2 Decentralized studies that move research activities from an investigational site to a participant’s home are one important step to reducing that burden. These decentralized, or direct-to-participant, studies offer the promise of faster recruitment, improved retention, and greater control, convenience, comfort, and even confidentiality for study participants. 3 The hope is that such changes will also enhance the diversity of participants in clinical studies. But that promise has yet to be realized and will also require increased trustworthiness among investigators and medical centers. 4

Berwick’s second aim, to increase the health of populations, is consistent with the focus of clinical research on creating generalizable new knowledge. That knowledge, especially in clinical trials, is ultimately aimed at improving the health of populations. These populations, Berwick wrote, can be defined by a disease, a geography, or a demographic. 1 Consistent with this objective is the need to ensure that the populations who are likely to benefit from new therapies or advancement in scientific knowledge are included not only as participants 2 but also as partners in the research. As Berwick notes “populations” can be defined in many ways, and for earlier phase clinical trials (sometimes called explanatory) the population may be more narrowly defined (e.g., triple negative breast cancer) than in later stages of development (sometimes called pragmatic trials) where population definitions may be broader and more “real world.” Whatever the definition used for a population in a specific trial, the ultimate intent of research programs should be to improve the health of the largest possible number of individuals that the evidence justifies.

Just as decentralized studies change the principal location of research, they can also expand the ways health data are captured and the scale of research. Digital tools, such as smartphones, are increasingly ubiquitous and allow for unprecedented data collection. For example, the recent Apple Heart study, which used a smartwatch to evaluate for atrial fibrillation, enrolled over 400,000 participants from all 50 states and the District of Columbia in eight months. 5 These new objective measures of health and disease also offer the additional advantage of conducting assessments in the real world, where individuals spend 99.9% of their time, as opposed to just the clinic. Objective outcome measures can be useful both in earlier stage trials, such as for dosage selection, as well as for later, larger trials assessing broader populations. Such tools also provide an effective and efficient mechanism to return information to participants, both about their individual outcomes and those of the study overall. To realize their full potential, research results must be rapidly disseminated to, and implemented by, relevant clinicians and patients, a process that itself can take as long as generating those results, particularly in disadvantaged populations.

Berwick’s final aim is to reduce the per capita costs of health care. The costs of successfully developing a single drug has risen exponentially for the past 50 years and now exceeds $2 billion. 6 Further examination of these rising costs reveals that clinical, not basic, research is the principal driver of the increase. The time demands and complexity of clinical trials also drives the costs to participants in lost work, inconvenience and risk, often making research participation a luxury that only the affluent can afford. Decentralized studies offer the potential to increase the speed with which clinical trials are conducted and to lower the costs of studies – a potentially dominant strategy, for both study sponsors and participants. Trials evaluating treatments for COVID-19 have successfully implemented this approach. For example, in a study evaluating the efficacy of hydroxychloroquine for post-exposure prophylaxis, all activities were conducted remotely. Participants were recruited from Canada and the U.S. using both social and traditional media, enrollment was conducted electronically, investigation drug or placebo was shipped to a participant’s home, and outcome assessments were evaluated via surveys. In the end, the investigators enrolled 821 participants in less than two months and had no traditional research sites. 7 The cost savings also accrued to participants who need not miss work or devote time to travel and even to society, which faced a lower risk of spread of the disease. A typical site-based study would have taken far longer and cost much more. This same approach can be extended to the long-term evaluation of individuals who have been infected by COVID-19 or to those who are vaccinated against the novel coronavirus.

The pandemic has accelerated the adoption of new approaches to clinical care and clinical research. As the pandemic passes, we should continue to advance and refine these new approaches. Berwick’s triple aims have transformed our approach to health care. A similar transformation, born out of the shortcomings current clinical research – high participant burden, limited participation, artificial settings, rising costs, and long timelines – is now needed. The result will be improved experiences for research participants, increased health, and lower cost, aims that are worthy of our pursuit.

ACKNOWLEDGEMENTS

Conflict of interest disclosures: Dr. Dorsey has received honoraria for speaking at American Academy of Neurology courses, American Neurological Association, Stanford University and University of Michigan; received compensation for consulting services from 23andMe, Abbott, Abbvie, Acorda, American Well, Biogen, BrainNeuroBio, Clintrex, Curasen Therapeutics, DeciBio, Denali Therapeutics, Eli Lilly, GlaxoSmithKline, Grand Rounds, Karger, Lundbeck, MC10, MedAvante, medical-legal services, Mednick Associates, National Institute of Neurological Disorders and Stroke, Olson Research Group, Optio, Origent Data Sciences, Inc., Otsuka, Praxis, Prilenia, Putnam Associates, Roche, Sanofi, Shire, Spark, Sunovion Pharma, Teva, Theravance, UCB and Voyager Therapeutics; research support from Abbvie, Acadia Pharmaceuticals, AMC Health, Biosensics, Burroughs Wellcome Fund, Davis Phinney Foundation, Duke University, Food and Drug Administration, GlaxoSmithKline, Greater Rochester Health Foundation, Huntington Study Group, Michael J. Fox Foundation, National Institutes of Health/National Institute of Neurological Disorders and Stroke, National Science Foundation, Nuredis Pharmaceuticals, Patient-Centered Outcomes Research Institute, Pfizer, Prana Biotechnology, Raptor Pharmaceuticals, Roche, Safra Foundation, Teva Pharmaceuticals, University of California Irvine; editorial services for Karger Publications; and ownership interests with Grand Rounds (second opinion service).

Dr. Kieburtz has consulted for Clintrex LLC, Roche/Genentech, Novartis, and Blackfynn, received research support from National Institutes of Health and the Michael J. Fox Foundation, and has ownership interests in Clintrex LLC, Hoover Brown LLC, and Safe Therapeutics LLC.

Source of funding: This publication was supported by the National Institute of Neurological Disorders and Stroke of the National Institutes of Health under award number P50NS108676. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

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Prevention of vascular access device-associated hospital onset bacteremia and fungemia: a review of emerging perspectives and synthesis of technical aspects.

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Robert Garcia, Edward J Septimus, Jack LeDonne, Lisa K Sturm, Nancy Moureau, Michelle DeVries, Barbara DeBaun, Prevention of Vascular Access Device-Associated Hospital Onset Bacteremia and Fungemia: A Review of Emerging Perspectives and Synthesis of Technical Aspects, Clinical Infectious Diseases , 2024;, ciae245, https://doi.org/10.1093/cid/ciae245

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Significant events impacting healthcare over the last several years have been associated with escalating rates of healthcare-associated infections. This has resulted in increased efforts to reinstitute well-established and evidence-based infection prevention practices, particularly for central line associated bloodstream infections. However, implementation of prevention initiatives beyond central lines has not received the same level of acknowledgement and response as being a considerable risk to patients. This article, authored by infection prevention, infectious disease, and vascular access professionals, provides emerging perspectives and technical aspects associated with the complete lifecycle of a vascular access device. The intent is to provide insight and perspective into enhancing current IP practices in the acute care hospital setting. This will also help prepare hospitals for upcoming broader surveillance and intervention activities aimed at reducing Hospital Onset Bacteremia and Fungemia (HOB) associated with all types of vascular access devices.

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Cultural Relativity and Acceptance of Embryonic Stem Cell Research

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There is a debate about the ethical implications of using human embryos in stem cell research, which can be influenced by cultural, moral, and social values. This paper argues for an adaptable framework to accommodate diverse cultural and religious perspectives. By using an adaptive ethics model, research protections can reflect various populations and foster growth in stem cell research possibilities.

INTRODUCTION

Stem cell research combines biology, medicine, and technology, promising to alter health care and the understanding of human development. Yet, ethical contention exists because of individuals’ perceptions of using human embryos based on their various cultural, moral, and social values. While these disagreements concerning policy, use, and general acceptance have prompted the development of an international ethics policy, such a uniform approach can overlook the nuanced ethical landscapes between cultures. With diverse viewpoints in public health, a single global policy, especially one reflecting Western ethics or the ethics prevalent in high-income countries, is impractical. This paper argues for a culturally sensitive, adaptable framework for the use of embryonic stem cells. Stem cell policy should accommodate varying ethical viewpoints and promote an effective global dialogue. With an extension of an ethics model that can adapt to various cultures, we recommend localized guidelines that reflect the moral views of the people those guidelines serve.

Stem cells, characterized by their unique ability to differentiate into various cell types, enable the repair or replacement of damaged tissues. Two primary types of stem cells are somatic stem cells (adult stem cells) and embryonic stem cells. Adult stem cells exist in developed tissues and maintain the body’s repair processes. [1] Embryonic stem cells (ESC) are remarkably pluripotent or versatile, making them valuable in research. [2] However, the use of ESCs has sparked ethics debates. Considering the potential of embryonic stem cells, research guidelines are essential. The International Society for Stem Cell Research (ISSCR) provides international stem cell research guidelines. They call for “public conversations touching on the scientific significance as well as the societal and ethical issues raised by ESC research.” [3] The ISSCR also publishes updates about culturing human embryos 14 days post fertilization, suggesting local policies and regulations should continue to evolve as ESC research develops. [4]  Like the ISSCR, which calls for local law and policy to adapt to developing stem cell research given cultural acceptance, this paper highlights the importance of local social factors such as religion and culture.

I.     Global Cultural Perspective of Embryonic Stem Cells

Views on ESCs vary throughout the world. Some countries readily embrace stem cell research and therapies, while others have stricter regulations due to ethical concerns surrounding embryonic stem cells and when an embryo becomes entitled to moral consideration. The philosophical issue of when the “someone” begins to be a human after fertilization, in the morally relevant sense, [5] impacts when an embryo becomes not just worthy of protection but morally entitled to it. The process of creating embryonic stem cell lines involves the destruction of the embryos for research. [6] Consequently, global engagement in ESC research depends on social-cultural acceptability.

a.     US and Rights-Based Cultures

In the United States, attitudes toward stem cell therapies are diverse. The ethics and social approaches, which value individualism, [7] trigger debates regarding the destruction of human embryos, creating a complex regulatory environment. For example, the 1996 Dickey-Wicker Amendment prohibited federal funding for the creation of embryos for research and the destruction of embryos for “more than allowed for research on fetuses in utero.” [8] Following suit, in 2001, the Bush Administration heavily restricted stem cell lines for research. However, the Stem Cell Research Enhancement Act of 2005 was proposed to help develop ESC research but was ultimately vetoed. [9] Under the Obama administration, in 2009, an executive order lifted restrictions allowing for more development in this field. [10] The flux of research capacity and funding parallels the different cultural perceptions of human dignity of the embryo and how it is socially presented within the country’s research culture. [11]

b.     Ubuntu and Collective Cultures

African bioethics differs from Western individualism because of the different traditions and values. African traditions, as described by individuals from South Africa and supported by some studies in other African countries, including Ghana and Kenya, follow the African moral philosophies of Ubuntu or Botho and Ukama , which “advocates for a form of wholeness that comes through one’s relationship and connectedness with other people in the society,” [12] making autonomy a socially collective concept. In this context, for the community to act autonomously, individuals would come together to decide what is best for the collective. Thus, stem cell research would require examining the value of the research to society as a whole and the use of the embryos as a collective societal resource. If society views the source as part of the collective whole, and opposes using stem cells, compromising the cultural values to pursue research may cause social detachment and stunt research growth. [13] Based on local culture and moral philosophy, the permissibility of stem cell research depends on how embryo, stem cell, and cell line therapies relate to the community as a whole . Ubuntu is the expression of humanness, with the person’s identity drawn from the “’I am because we are’” value. [14] The decision in a collectivistic culture becomes one born of cultural context, and individual decisions give deference to others in the society.

Consent differs in cultures where thought and moral philosophy are based on a collective paradigm. So, applying Western bioethical concepts is unrealistic. For one, Africa is a diverse continent with many countries with different belief systems, access to health care, and reliance on traditional or Western medicines. Where traditional medicine is the primary treatment, the “’restrictive focus on biomedically-related bioethics’” [is] problematic in African contexts because it neglects bioethical issues raised by traditional systems.” [15] No single approach applies in all areas or contexts. Rather than evaluating the permissibility of ESC research according to Western concepts such as the four principles approach, different ethics approaches should prevail.

Another consideration is the socio-economic standing of countries. In parts of South Africa, researchers have not focused heavily on contributing to the stem cell discourse, either because it is not considered health care or a health science priority or because resources are unavailable. [16] Each country’s priorities differ given different social, political, and economic factors. In South Africa, for instance, areas such as maternal mortality, non-communicable diseases, telemedicine, and the strength of health systems need improvement and require more focus. [17] Stem cell research could benefit the population, but it also could divert resources from basic medical care. Researchers in South Africa adhere to the National Health Act and Medicines Control Act in South Africa and international guidelines; however, the Act is not strictly enforced, and there is no clear legislation for research conduct or ethical guidelines. [18]

Some parts of Africa condemn stem cell research. For example, 98.2 percent of the Tunisian population is Muslim. [19] Tunisia does not permit stem cell research because of moral conflict with a Fatwa. Religion heavily saturates the regulation and direction of research. [20] Stem cell use became permissible for reproductive purposes only recently, with tight restrictions preventing cells from being used in any research other than procedures concerning ART/IVF.  Their use is conditioned on consent, and available only to married couples. [21] The community's receptiveness to stem cell research depends on including communitarian African ethics.

c.     Asia

Some Asian countries also have a collective model of ethics and decision making. [22] In China, the ethics model promotes a sincere respect for life or human dignity, [23] based on protective medicine. This model, influenced by Traditional Chinese Medicine (TCM), [24] recognizes Qi as the vital energy delivered via the meridians of the body; it connects illness to body systems, the body’s entire constitution, and the universe for a holistic bond of nature, health, and quality of life. [25] Following a protective ethics model, and traditional customs of wholeness, investment in stem cell research is heavily desired for its applications in regenerative therapies, disease modeling, and protective medicines. In a survey of medical students and healthcare practitioners, 30.8 percent considered stem cell research morally unacceptable while 63.5 percent accepted medical research using human embryonic stem cells. Of these individuals, 89.9 percent supported increased funding for stem cell research. [26] The scientific community might not reflect the overall population. From 1997 to 2019, China spent a total of $576 million (USD) on stem cell research at 8,050 stem cell programs, increased published presence from 0.6 percent to 14.01 percent of total global stem cell publications as of 2014, and made significant strides in cell-based therapies for various medical conditions. [27] However, while China has made substantial investments in stem cell research and achieved notable progress in clinical applications, concerns linger regarding ethical oversight and transparency. [28] For example, the China Biosecurity Law, promoted by the National Health Commission and China Hospital Association, attempted to mitigate risks by introducing an institutional review board (IRB) in the regulatory bodies. 5800 IRBs registered with the Chinese Clinical Trial Registry since 2021. [29] However, issues still need to be addressed in implementing effective IRB review and approval procedures.

The substantial government funding and focus on scientific advancement have sometimes overshadowed considerations of regional cultures, ethnic minorities, and individual perspectives, particularly evident during the one-child policy era. As government policy adapts to promote public stability, such as the change from the one-child to the two-child policy, [30] research ethics should also adapt to ensure respect for the values of its represented peoples.

Japan is also relatively supportive of stem cell research and therapies. Japan has a more transparent regulatory framework, allowing for faster approval of regenerative medicine products, which has led to several advanced clinical trials and therapies. [31] South Korea is also actively engaged in stem cell research and has a history of breakthroughs in cloning and embryonic stem cells. [32] However, the field is controversial, and there are issues of scientific integrity. For example, the Korean FDA fast-tracked products for approval, [33] and in another instance, the oocyte source was unclear and possibly violated ethical standards. [34] Trust is important in research, as it builds collaborative foundations between colleagues, trial participant comfort, open-mindedness for complicated and sensitive discussions, and supports regulatory procedures for stakeholders. There is a need to respect the culture’s interest, engagement, and for research and clinical trials to be transparent and have ethical oversight to promote global research discourse and trust.

d.     Middle East

Countries in the Middle East have varying degrees of acceptance of or restrictions to policies related to using embryonic stem cells due to cultural and religious influences. Saudi Arabia has made significant contributions to stem cell research, and conducts research based on international guidelines for ethical conduct and under strict adherence to guidelines in accordance with Islamic principles. Specifically, the Saudi government and people require ESC research to adhere to Sharia law. In addition to umbilical and placental stem cells, [35] Saudi Arabia permits the use of embryonic stem cells as long as they come from miscarriages, therapeutic abortions permissible by Sharia law, or are left over from in vitro fertilization and donated to research. [36] Laws and ethical guidelines for stem cell research allow the development of research institutions such as the King Abdullah International Medical Research Center, which has a cord blood bank and a stem cell registry with nearly 10,000 donors. [37] Such volume and acceptance are due to the ethical ‘permissibility’ of the donor sources, which do not conflict with religious pillars. However, some researchers err on the side of caution, choosing not to use embryos or fetal tissue as they feel it is unethical to do so. [38]

Jordan has a positive research ethics culture. [39] However, there is a significant issue of lack of trust in researchers, with 45.23 percent (38.66 percent agreeing and 6.57 percent strongly agreeing) of Jordanians holding a low level of trust in researchers, compared to 81.34 percent of Jordanians agreeing that they feel safe to participate in a research trial. [40] Safety testifies to the feeling of confidence that adequate measures are in place to protect participants from harm, whereas trust in researchers could represent the confidence in researchers to act in the participants’ best interests, adhere to ethical guidelines, provide accurate information, and respect participants’ rights and dignity. One method to improve trust would be to address communication issues relevant to ESC. Legislation surrounding stem cell research has adopted specific language, especially concerning clarification “between ‘stem cells’ and ‘embryonic stem cells’” in translation. [41] Furthermore, legislation “mandates the creation of a national committee… laying out specific regulations for stem-cell banking in accordance with international standards.” [42] This broad regulation opens the door for future global engagement and maintains transparency. However, these regulations may also constrain the influence of research direction, pace, and accessibility of research outcomes.

e.     Europe

In the European Union (EU), ethics is also principle-based, but the principles of autonomy, dignity, integrity, and vulnerability are interconnected. [43] As such, the opportunity for cohesion and concessions between individuals’ thoughts and ideals allows for a more adaptable ethics model due to the flexible principles that relate to the human experience The EU has put forth a framework in its Convention for the Protection of Human Rights and Dignity of the Human Being allowing member states to take different approaches. Each European state applies these principles to its specific conventions, leading to or reflecting different acceptance levels of stem cell research. [44]

For example, in Germany, Lebenzusammenhang , or the coherence of life, references integrity in the unity of human culture. Namely, the personal sphere “should not be subject to external intervention.” [45]  Stem cell interventions could affect this concept of bodily completeness, leading to heavy restrictions. Under the Grundgesetz, human dignity and the right to life with physical integrity are paramount. [46] The Embryo Protection Act of 1991 made producing cell lines illegal. Cell lines can be imported if approved by the Central Ethics Commission for Stem Cell Research only if they were derived before May 2007. [47] Stem cell research respects the integrity of life for the embryo with heavy specifications and intense oversight. This is vastly different in Finland, where the regulatory bodies find research more permissible in IVF excess, but only up to 14 days after fertilization. [48] Spain’s approach differs still, with a comprehensive regulatory framework. [49] Thus, research regulation can be culture-specific due to variations in applied principles. Diverse cultures call for various approaches to ethical permissibility. [50] Only an adaptive-deliberative model can address the cultural constructions of self and achieve positive, culturally sensitive stem cell research practices. [51]

II.     Religious Perspectives on ESC

Embryonic stem cell sources are the main consideration within religious contexts. While individuals may not regard their own religious texts as authoritative or factual, religion can shape their foundations or perspectives.

The Qur'an states:

“And indeed We created man from a quintessence of clay. Then We placed within him a small quantity of nutfa (sperm to fertilize) in a safe place. Then We have fashioned the nutfa into an ‘alaqa (clinging clot or cell cluster), then We developed the ‘alaqa into mudgha (a lump of flesh), and We made mudgha into bones, and clothed the bones with flesh, then We brought it into being as a new creation. So Blessed is Allah, the Best of Creators.” [52]

Many scholars of Islam estimate the time of soul installment, marked by the angel breathing in the soul to bring the individual into creation, as 120 days from conception. [53] Personhood begins at this point, and the value of life would prohibit research or experimentation that could harm the individual. If the fetus is more than 120 days old, the time ensoulment is interpreted to occur according to Islamic law, abortion is no longer permissible. [54] There are a few opposing opinions about early embryos in Islamic traditions. According to some Islamic theologians, there is no ensoulment of the early embryo, which is the source of stem cells for ESC research. [55]

In Buddhism, the stance on stem cell research is not settled. The main tenets, the prohibition against harming or destroying others (ahimsa) and the pursuit of knowledge (prajña) and compassion (karuna), leave Buddhist scholars and communities divided. [56] Some scholars argue stem cell research is in accordance with the Buddhist tenet of seeking knowledge and ending human suffering. Others feel it violates the principle of not harming others. Finding the balance between these two points relies on the karmic burden of Buddhist morality. In trying to prevent ahimsa towards the embryo, Buddhist scholars suggest that to comply with Buddhist tenets, research cannot be done as the embryo has personhood at the moment of conception and would reincarnate immediately, harming the individual's ability to build their karmic burden. [57] On the other hand, the Bodhisattvas, those considered to be on the path to enlightenment or Nirvana, have given organs and flesh to others to help alleviate grieving and to benefit all. [58] Acceptance varies on applied beliefs and interpretations.

Catholicism does not support embryonic stem cell research, as it entails creation or destruction of human embryos. This destruction conflicts with the belief in the sanctity of life. For example, in the Old Testament, Genesis describes humanity as being created in God’s image and multiplying on the Earth, referencing the sacred rights to human conception and the purpose of development and life. In the Ten Commandments, the tenet that one should not kill has numerous interpretations where killing could mean murder or shedding of the sanctity of life, demonstrating the high value of human personhood. In other books, the theological conception of when life begins is interpreted as in utero, [59] highlighting the inviolability of life and its formation in vivo to make a religious point for accepting such research as relatively limited, if at all. [60] The Vatican has released ethical directives to help apply a theological basis to modern-day conflicts. The Magisterium of the Church states that “unless there is a moral certainty of not causing harm,” experimentation on fetuses, fertilized cells, stem cells, or embryos constitutes a crime. [61] Such procedures would not respect the human person who exists at these stages, according to Catholicism. Damages to the embryo are considered gravely immoral and illicit. [62] Although the Catholic Church officially opposes abortion, surveys demonstrate that many Catholic people hold pro-choice views, whether due to the context of conception, stage of pregnancy, threat to the mother’s life, or for other reasons, demonstrating that practicing members can also accept some but not all tenets. [63]

Some major Jewish denominations, such as the Reform, Conservative, and Reconstructionist movements, are open to supporting ESC use or research as long as it is for saving a life. [64] Within Judaism, the Talmud, or study, gives personhood to the child at birth and emphasizes that life does not begin at conception: [65]

“If she is found pregnant, until the fortieth day it is mere fluid,” [66]

Whereas most religions prioritize the status of human embryos, the Halakah (Jewish religious law) states that to save one life, most other religious laws can be ignored because it is in pursuit of preservation. [67] Stem cell research is accepted due to application of these religious laws.

We recognize that all religions contain subsets and sects. The variety of environmental and cultural differences within religious groups requires further analysis to respect the flexibility of religious thoughts and practices. We make no presumptions that all cultures require notions of autonomy or morality as under the common morality theory , which asserts a set of universal moral norms that all individuals share provides moral reasoning and guides ethical decisions. [68] We only wish to show that the interaction with morality varies between cultures and countries.

III.     A Flexible Ethical Approach

The plurality of different moral approaches described above demonstrates that there can be no universally acceptable uniform law for ESC on a global scale. Instead of developing one standard, flexible ethical applications must be continued. We recommend local guidelines that incorporate important cultural and ethical priorities.

While the Declaration of Helsinki is more relevant to people in clinical trials receiving ESC products, in keeping with the tradition of protections for research subjects, consent of the donor is an ethical requirement for ESC donation in many jurisdictions including the US, Canada, and Europe. [69] The Declaration of Helsinki provides a reference point for regulatory standards and could potentially be used as a universal baseline for obtaining consent prior to gamete or embryo donation.

For instance, in Columbia University’s egg donor program for stem cell research, donors followed standard screening protocols and “underwent counseling sessions that included information as to the purpose of oocyte donation for research, what the oocytes would be used for, the risks and benefits of donation, and process of oocyte stimulation” to ensure transparency for consent. [70] The program helped advance stem cell research and provided clear and safe research methods with paid participants. Though paid participation or covering costs of incidental expenses may not be socially acceptable in every culture or context, [71] and creating embryos for ESC research is illegal in many jurisdictions, Columbia’s program was effective because of the clear and honest communications with donors, IRBs, and related stakeholders.  This example demonstrates that cultural acceptance of scientific research and of the idea that an egg or embryo does not have personhood is likely behind societal acceptance of donating eggs for ESC research. As noted, many countries do not permit the creation of embryos for research.

Proper communication and education regarding the process and purpose of stem cell research may bolster comprehension and garner more acceptance. “Given the sensitive subject material, a complete consent process can support voluntary participation through trust, understanding, and ethical norms from the cultures and morals participants value. This can be hard for researchers entering countries of different socioeconomic stability, with different languages and different societal values. [72]

An adequate moral foundation in medical ethics is derived from the cultural and religious basis that informs knowledge and actions. [73] Understanding local cultural and religious values and their impact on research could help researchers develop humility and promote inclusion.

IV.     Concerns

Some may argue that if researchers all adhere to one ethics standard, protection will be satisfied across all borders, and the global public will trust researchers. However, defining what needs to be protected and how to define such research standards is very specific to the people to which standards are applied. We suggest that applying one uniform guide cannot accurately protect each individual because we all possess our own perceptions and interpretations of social values. [74] Therefore, the issue of not adjusting to the moral pluralism between peoples in applying one standard of ethics can be resolved by building out ethics models that can be adapted to different cultures and religions.

Other concerns include medical tourism, which may promote health inequities. [75] Some countries may develop and approve products derived from ESC research before others, compromising research ethics or drug approval processes. There are also concerns about the sale of unauthorized stem cell treatments, for example, those without FDA approval in the United States. Countries with robust research infrastructures may be tempted to attract medical tourists, and some customers will have false hopes based on aggressive publicity of unproven treatments. [76]

For example, in China, stem cell clinics can market to foreign clients who are not protected under the regulatory regimes. Companies employ a marketing strategy of “ethically friendly” therapies. Specifically, in the case of Beike, China’s leading stem cell tourism company and sprouting network, ethical oversight of administrators or health bureaus at one site has “the unintended consequence of shifting questionable activities to another node in Beike's diffuse network.” [77] In contrast, Jordan is aware of stem cell research’s potential abuse and its own status as a “health-care hub.” Jordan’s expanded regulations include preserving the interests of individuals in clinical trials and banning private companies from ESC research to preserve transparency and the integrity of research practices. [78]

The social priorities of the community are also a concern. The ISSCR explicitly states that guidelines “should be periodically revised to accommodate scientific advances, new challenges, and evolving social priorities.” [79] The adaptable ethics model extends this consideration further by addressing whether research is warranted given the varying degrees of socioeconomic conditions, political stability, and healthcare accessibilities and limitations. An ethical approach would require discussion about resource allocation and appropriate distribution of funds. [80]

While some religions emphasize the sanctity of life from conception, which may lead to public opposition to ESC research, others encourage ESC research due to its potential for healing and alleviating human pain. Many countries have special regulations that balance local views on embryonic personhood, the benefits of research as individual or societal goods, and the protection of human research subjects. To foster understanding and constructive dialogue, global policy frameworks should prioritize the protection of universal human rights, transparency, and informed consent. In addition to these foundational global policies, we recommend tailoring local guidelines to reflect the diverse cultural and religious perspectives of the populations they govern. Ethics models should be adapted to local populations to effectively establish research protections, growth, and possibilities of stem cell research.

For example, in countries with strong beliefs in the moral sanctity of embryos or heavy religious restrictions, an adaptive model can allow for discussion instead of immediate rejection. In countries with limited individual rights and voice in science policy, an adaptive model ensures cultural, moral, and religious views are taken into consideration, thereby building social inclusion. While this ethical consideration by the government may not give a complete voice to every individual, it will help balance policies and maintain the diverse perspectives of those it affects. Embracing an adaptive ethics model of ESC research promotes open-minded dialogue and respect for the importance of human belief and tradition. By actively engaging with cultural and religious values, researchers can better handle disagreements and promote ethical research practices that benefit each society.

This brief exploration of the religious and cultural differences that impact ESC research reveals the nuances of relative ethics and highlights a need for local policymakers to apply a more intense adaptive model.

[1] Poliwoda, S., Noor, N., Downs, E., Schaaf, A., Cantwell, A., Ganti, L., Kaye, A. D., Mosel, L. I., Carroll, C. B., Viswanath, O., & Urits, I. (2022). Stem cells: a comprehensive review of origins and emerging clinical roles in medical practice.  Orthopedic reviews ,  14 (3), 37498. https://doi.org/10.52965/001c.37498

[2] Poliwoda, S., Noor, N., Downs, E., Schaaf, A., Cantwell, A., Ganti, L., Kaye, A. D., Mosel, L. I., Carroll, C. B., Viswanath, O., & Urits, I. (2022). Stem cells: a comprehensive review of origins and emerging clinical roles in medical practice.  Orthopedic reviews ,  14 (3), 37498. https://doi.org/10.52965/001c.37498

[3] International Society for Stem Cell Research. (2023). Laboratory-based human embryonic stem cell research, embryo research, and related research activities . International Society for Stem Cell Research. https://www.isscr.org/guidelines/blog-post-title-one-ed2td-6fcdk ; Kimmelman, J., Hyun, I., Benvenisty, N.  et al.  Policy: Global standards for stem-cell research.  Nature   533 , 311–313 (2016). https://doi.org/10.1038/533311a

[4] International Society for Stem Cell Research. (2023). Laboratory-based human embryonic stem cell research, embryo research, and related research activities . International Society for Stem Cell Research. https://www.isscr.org/guidelines/blog-post-title-one-ed2td-6fcdk

[5] Concerning the moral philosophies of stem cell research, our paper does not posit a personal moral stance nor delve into the “when” of human life begins. To read further about the philosophical debate, consider the following sources:

Sandel M. J. (2004). Embryo ethics--the moral logic of stem-cell research.  The New England journal of medicine ,  351 (3), 207–209. https://doi.org/10.1056/NEJMp048145 ; George, R. P., & Lee, P. (2020, September 26). Acorns and Embryos . The New Atlantis. https://www.thenewatlantis.com/publications/acorns-and-embryos ; Sagan, A., & Singer, P. (2007). The moral status of stem cells. Metaphilosophy , 38 (2/3), 264–284. http://www.jstor.org/stable/24439776 ; McHugh P. R. (2004). Zygote and "clonote"--the ethical use of embryonic stem cells.  The New England journal of medicine ,  351 (3), 209–211. https://doi.org/10.1056/NEJMp048147 ; Kurjak, A., & Tripalo, A. (2004). The facts and doubts about beginning of the human life and personality.  Bosnian journal of basic medical sciences ,  4 (1), 5–14. https://doi.org/10.17305/bjbms.2004.3453

[6] Vazin, T., & Freed, W. J. (2010). Human embryonic stem cells: derivation, culture, and differentiation: a review.  Restorative neurology and neuroscience ,  28 (4), 589–603. https://doi.org/10.3233/RNN-2010-0543

[7] Socially, at its core, the Western approach to ethics is widely principle-based, autonomy being one of the key factors to ensure a fundamental respect for persons within research. For information regarding autonomy in research, see: Department of Health, Education, and Welfare, & National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research (1978). The Belmont Report. Ethical principles and guidelines for the protection of human subjects of research.; For a more in-depth review of autonomy within the US, see: Beauchamp, T. L., & Childress, J. F. (1994). Principles of Biomedical Ethics . Oxford University Press.

[8] Sherley v. Sebelius , 644 F.3d 388 (D.C. Cir. 2011), citing 45 C.F.R. 46.204(b) and [42 U.S.C. § 289g(b)]. https://www.cadc.uscourts.gov/internet/opinions.nsf/6c690438a9b43dd685257a64004ebf99/$file/11-5241-1391178.pdf

[9] Stem Cell Research Enhancement Act of 2005, H. R. 810, 109 th Cong. (2001). https://www.govtrack.us/congress/bills/109/hr810/text ; Bush, G. W. (2006, July 19). Message to the House of Representatives . National Archives and Records Administration. https://georgewbush-whitehouse.archives.gov/news/releases/2006/07/20060719-5.html

[10] National Archives and Records Administration. (2009, March 9). Executive order 13505 -- removing barriers to responsible scientific research involving human stem cells . National Archives and Records Administration. https://obamawhitehouse.archives.gov/the-press-office/removing-barriers-responsible-scientific-research-involving-human-stem-cells

[11] Hurlbut, W. B. (2006). Science, Religion, and the Politics of Stem Cells.  Social Research ,  73 (3), 819–834. http://www.jstor.org/stable/40971854

[12] Akpa-Inyang, Francis & Chima, Sylvester. (2021). South African traditional values and beliefs regarding informed consent and limitations of the principle of respect for autonomy in African communities: a cross-cultural qualitative study. BMC Medical Ethics . 22. 10.1186/s12910-021-00678-4.

[13] Source for further reading: Tangwa G. B. (2007). Moral status of embryonic stem cells: perspective of an African villager. Bioethics , 21(8), 449–457. https://doi.org/10.1111/j.1467-8519.2007.00582.x , see also Mnisi, F. M. (2020). An African analysis based on ethics of Ubuntu - are human embryonic stem cell patents morally justifiable? African Insight , 49 (4).

[14] Jecker, N. S., & Atuire, C. (2021). Bioethics in Africa: A contextually enlightened analysis of three cases. Developing World Bioethics , 22 (2), 112–122. https://doi.org/10.1111/dewb.12324

[15] Jecker, N. S., & Atuire, C. (2021). Bioethics in Africa: A contextually enlightened analysis of three cases. Developing World Bioethics, 22(2), 112–122. https://doi.org/10.1111/dewb.12324

[16] Jackson, C.S., Pepper, M.S. Opportunities and barriers to establishing a cell therapy programme in South Africa.  Stem Cell Res Ther   4 , 54 (2013). https://doi.org/10.1186/scrt204 ; Pew Research Center. (2014, May 1). Public health a major priority in African nations . Pew Research Center’s Global Attitudes Project. https://www.pewresearch.org/global/2014/05/01/public-health-a-major-priority-in-african-nations/

[17] Department of Health Republic of South Africa. (2021). Health Research Priorities (revised) for South Africa 2021-2024 . National Health Research Strategy. https://www.health.gov.za/wp-content/uploads/2022/05/National-Health-Research-Priorities-2021-2024.pdf

[18] Oosthuizen, H. (2013). Legal and Ethical Issues in Stem Cell Research in South Africa. In: Beran, R. (eds) Legal and Forensic Medicine. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-32338-6_80 , see also: Gaobotse G (2018) Stem Cell Research in Africa: Legislation and Challenges. J Regen Med 7:1. doi: 10.4172/2325-9620.1000142

[19] United States Bureau of Citizenship and Immigration Services. (1998). Tunisia: Information on the status of Christian conversions in Tunisia . UNHCR Web Archive. https://webarchive.archive.unhcr.org/20230522142618/https://www.refworld.org/docid/3df0be9a2.html

[20] Gaobotse, G. (2018) Stem Cell Research in Africa: Legislation and Challenges. J Regen Med 7:1. doi: 10.4172/2325-9620.1000142

[21] Kooli, C. Review of assisted reproduction techniques, laws, and regulations in Muslim countries.  Middle East Fertil Soc J   24 , 8 (2020). https://doi.org/10.1186/s43043-019-0011-0 ; Gaobotse, G. (2018) Stem Cell Research in Africa: Legislation and Challenges. J Regen Med 7:1. doi: 10.4172/2325-9620.1000142

[22] Pang M. C. (1999). Protective truthfulness: the Chinese way of safeguarding patients in informed treatment decisions. Journal of medical ethics , 25(3), 247–253. https://doi.org/10.1136/jme.25.3.247

[23] Wang, L., Wang, F., & Zhang, W. (2021). Bioethics in China’s biosecurity law: Forms, effects, and unsettled issues. Journal of law and the biosciences , 8(1).  https://doi.org/10.1093/jlb/lsab019 https://academic.oup.com/jlb/article/8/1/lsab019/6299199

[24] Wang, Y., Xue, Y., & Guo, H. D. (2022). Intervention effects of traditional Chinese medicine on stem cell therapy of myocardial infarction.  Frontiers in pharmacology ,  13 , 1013740. https://doi.org/10.3389/fphar.2022.1013740

[25] Li, X.-T., & Zhao, J. (2012). Chapter 4: An Approach to the Nature of Qi in TCM- Qi and Bioenergy. In Recent Advances in Theories and Practice of Chinese Medicine (p. 79). InTech.

[26] Luo, D., Xu, Z., Wang, Z., & Ran, W. (2021). China's Stem Cell Research and Knowledge Levels of Medical Practitioners and Students.  Stem cells international ,  2021 , 6667743. https://doi.org/10.1155/2021/6667743

[27] Luo, D., Xu, Z., Wang, Z., & Ran, W. (2021). China's Stem Cell Research and Knowledge Levels of Medical Practitioners and Students.  Stem cells international ,  2021 , 6667743. https://doi.org/10.1155/2021/6667743

[28] Zhang, J. Y. (2017). Lost in translation? accountability and governance of Clinical Stem Cell Research in China. Regenerative Medicine , 12 (6), 647–656. https://doi.org/10.2217/rme-2017-0035

[29] Wang, L., Wang, F., & Zhang, W. (2021). Bioethics in China’s biosecurity law: Forms, effects, and unsettled issues. Journal of law and the biosciences , 8(1).  https://doi.org/10.1093/jlb/lsab019 https://academic.oup.com/jlb/article/8/1/lsab019/6299199

[30] Chen, H., Wei, T., Wang, H.  et al.  Association of China’s two-child policy with changes in number of births and birth defects rate, 2008–2017.  BMC Public Health   22 , 434 (2022). https://doi.org/10.1186/s12889-022-12839-0

[31] Azuma, K. Regulatory Landscape of Regenerative Medicine in Japan.  Curr Stem Cell Rep   1 , 118–128 (2015). https://doi.org/10.1007/s40778-015-0012-6

[32] Harris, R. (2005, May 19). Researchers Report Advance in Stem Cell Production . NPR. https://www.npr.org/2005/05/19/4658967/researchers-report-advance-in-stem-cell-production

[33] Park, S. (2012). South Korea steps up stem-cell work.  Nature . https://doi.org/10.1038/nature.2012.10565

[34] Resnik, D. B., Shamoo, A. E., & Krimsky, S. (2006). Fraudulent human embryonic stem cell research in South Korea: lessons learned.  Accountability in research ,  13 (1), 101–109. https://doi.org/10.1080/08989620600634193 .

[35] Alahmad, G., Aljohani, S., & Najjar, M. F. (2020). Ethical challenges regarding the use of stem cells: interviews with researchers from Saudi Arabia. BMC medical ethics, 21(1), 35. https://doi.org/10.1186/s12910-020-00482-6

[36] Association for the Advancement of Blood and Biotherapies.  https://www.aabb.org/regulatory-and-advocacy/regulatory-affairs/regulatory-for-cellular-therapies/international-competent-authorities/saudi-arabia

[37] Alahmad, G., Aljohani, S., & Najjar, M. F. (2020). Ethical challenges regarding the use of stem cells: Interviews with researchers from Saudi Arabia.  BMC medical ethics ,  21 (1), 35. https://doi.org/10.1186/s12910-020-00482-6

[38] Alahmad, G., Aljohani, S., & Najjar, M. F. (2020). Ethical challenges regarding the use of stem cells: Interviews with researchers from Saudi Arabia. BMC medical ethics , 21(1), 35. https://doi.org/10.1186/s12910-020-00482-6

Culturally, autonomy practices follow a relational autonomy approach based on a paternalistic deontological health care model. The adherence to strict international research policies and religious pillars within the regulatory environment is a great foundation for research ethics. However, there is a need to develop locally targeted ethics approaches for research (as called for in Alahmad, G., Aljohani, S., & Najjar, M. F. (2020). Ethical challenges regarding the use of stem cells: interviews with researchers from Saudi Arabia. BMC medical ethics, 21(1), 35. https://doi.org/10.1186/s12910-020-00482-6), this decision-making approach may help advise a research decision model. For more on the clinical cultural autonomy approaches, see: Alabdullah, Y. Y., Alzaid, E., Alsaad, S., Alamri, T., Alolayan, S. W., Bah, S., & Aljoudi, A. S. (2022). Autonomy and paternalism in Shared decision‐making in a Saudi Arabian tertiary hospital: A cross‐sectional study. Developing World Bioethics , 23 (3), 260–268. https://doi.org/10.1111/dewb.12355 ; Bukhari, A. A. (2017). Universal Principles of Bioethics and Patient Rights in Saudi Arabia (Doctoral dissertation, Duquesne University). https://dsc.duq.edu/etd/124; Ladha, S., Nakshawani, S. A., Alzaidy, A., & Tarab, B. (2023, October 26). Islam and Bioethics: What We All Need to Know . Columbia University School of Professional Studies. https://sps.columbia.edu/events/islam-and-bioethics-what-we-all-need-know

[39] Ababneh, M. A., Al-Azzam, S. I., Alzoubi, K., Rababa’h, A., & Al Demour, S. (2021). Understanding and attitudes of the Jordanian public about clinical research ethics.  Research Ethics ,  17 (2), 228-241.  https://doi.org/10.1177/1747016120966779

[40] Ababneh, M. A., Al-Azzam, S. I., Alzoubi, K., Rababa’h, A., & Al Demour, S. (2021). Understanding and attitudes of the Jordanian public about clinical research ethics.  Research Ethics ,  17 (2), 228-241.  https://doi.org/10.1177/1747016120966779

[41] Dajani, R. (2014). Jordan’s stem-cell law can guide the Middle East.  Nature  510, 189. https://doi.org/10.1038/510189a

[42] Dajani, R. (2014). Jordan’s stem-cell law can guide the Middle East.  Nature  510, 189. https://doi.org/10.1038/510189a

[43] The EU’s definition of autonomy relates to the capacity for creating ideas, moral insight, decisions, and actions without constraint, personal responsibility, and informed consent. However, the EU views autonomy as not completely able to protect individuals and depends on other principles, such as dignity, which “expresses the intrinsic worth and fundamental equality of all human beings.” Rendtorff, J.D., Kemp, P. (2019). Four Ethical Principles in European Bioethics and Biolaw: Autonomy, Dignity, Integrity and Vulnerability. In: Valdés, E., Lecaros, J. (eds) Biolaw and Policy in the Twenty-First Century. International Library of Ethics, Law, and the New Medicine, vol 78. Springer, Cham. https://doi.org/10.1007/978-3-030-05903-3_3

[44] Council of Europe. Convention for the protection of Human Rights and Dignity of the Human Being with regard to the Application of Biology and Medicine: Convention on Human Rights and Biomedicine (ETS No. 164) https://www.coe.int/en/web/conventions/full-list?module=treaty-detail&treatynum=164 (forbidding the creation of embryos for research purposes only, and suggests embryos in vitro have protections.); Also see Drabiak-Syed B. K. (2013). New President, New Human Embryonic Stem Cell Research Policy: Comparative International Perspectives and Embryonic Stem Cell Research Laws in France.  Biotechnology Law Report ,  32 (6), 349–356. https://doi.org/10.1089/blr.2013.9865

[45] Rendtorff, J.D., Kemp, P. (2019). Four Ethical Principles in European Bioethics and Biolaw: Autonomy, Dignity, Integrity and Vulnerability. In: Valdés, E., Lecaros, J. (eds) Biolaw and Policy in the Twenty-First Century. International Library of Ethics, Law, and the New Medicine, vol 78. Springer, Cham. https://doi.org/10.1007/978-3-030-05903-3_3

[46] Tomuschat, C., Currie, D. P., Kommers, D. P., & Kerr, R. (Trans.). (1949, May 23). Basic law for the Federal Republic of Germany. https://www.btg-bestellservice.de/pdf/80201000.pdf

[47] Regulation of Stem Cell Research in Germany . Eurostemcell. (2017, April 26). https://www.eurostemcell.org/regulation-stem-cell-research-germany

[48] Regulation of Stem Cell Research in Finland . Eurostemcell. (2017, April 26). https://www.eurostemcell.org/regulation-stem-cell-research-finland

[49] Regulation of Stem Cell Research in Spain . Eurostemcell. (2017, April 26). https://www.eurostemcell.org/regulation-stem-cell-research-spain

[50] Some sources to consider regarding ethics models or regulatory oversights of other cultures not covered:

Kara MA. Applicability of the principle of respect for autonomy: the perspective of Turkey. J Med Ethics. 2007 Nov;33(11):627-30. doi: 10.1136/jme.2006.017400. PMID: 17971462; PMCID: PMC2598110.

Ugarte, O. N., & Acioly, M. A. (2014). The principle of autonomy in Brazil: one needs to discuss it ...  Revista do Colegio Brasileiro de Cirurgioes ,  41 (5), 374–377. https://doi.org/10.1590/0100-69912014005013

Bharadwaj, A., & Glasner, P. E. (2012). Local cells, global science: The rise of embryonic stem cell research in India . Routledge.

For further research on specific European countries regarding ethical and regulatory framework, we recommend this database: Regulation of Stem Cell Research in Europe . Eurostemcell. (2017, April 26). https://www.eurostemcell.org/regulation-stem-cell-research-europe   

[51] Klitzman, R. (2006). Complications of culture in obtaining informed consent. The American Journal of Bioethics, 6(1), 20–21. https://doi.org/10.1080/15265160500394671 see also: Ekmekci, P. E., & Arda, B. (2017). Interculturalism and Informed Consent: Respecting Cultural Differences without Breaching Human Rights.  Cultura (Iasi, Romania) ,  14 (2), 159–172.; For why trust is important in research, see also: Gray, B., Hilder, J., Macdonald, L., Tester, R., Dowell, A., & Stubbe, M. (2017). Are research ethics guidelines culturally competent?  Research Ethics ,  13 (1), 23-41.  https://doi.org/10.1177/1747016116650235

[52] The Qur'an  (M. Khattab, Trans.). (1965). Al-Mu’minun, 23: 12-14. https://quran.com/23

[53] Lenfest, Y. (2017, December 8). Islam and the beginning of human life . Bill of Health. https://blog.petrieflom.law.harvard.edu/2017/12/08/islam-and-the-beginning-of-human-life/

[54] Aksoy, S. (2005). Making regulations and drawing up legislation in Islamic countries under conditions of uncertainty, with special reference to embryonic stem cell research. Journal of Medical Ethics , 31: 399-403.; see also: Mahmoud, Azza. "Islamic Bioethics: National Regulations and Guidelines of Human Stem Cell Research in the Muslim World." Master's thesis, Chapman University, 2022. https://doi.org/10.36837/ chapman.000386

[55] Rashid, R. (2022). When does Ensoulment occur in the Human Foetus. Journal of the British Islamic Medical Association , 12 (4). ISSN 2634 8071. https://www.jbima.com/wp-content/uploads/2023/01/2-Ethics-3_-Ensoulment_Rafaqat.pdf.

[56] Sivaraman, M. & Noor, S. (2017). Ethics of embryonic stem cell research according to Buddhist, Hindu, Catholic, and Islamic religions: perspective from Malaysia. Asian Biomedicine,8(1) 43-52.  https://doi.org/10.5372/1905-7415.0801.260

[57] Jafari, M., Elahi, F., Ozyurt, S. & Wrigley, T. (2007). 4. Religious Perspectives on Embryonic Stem Cell Research. In K. Monroe, R. Miller & J. Tobis (Ed.),  Fundamentals of the Stem Cell Debate: The Scientific, Religious, Ethical, and Political Issues  (pp. 79-94). Berkeley: University of California Press.  https://escholarship.org/content/qt9rj0k7s3/qt9rj0k7s3_noSplash_f9aca2e02c3777c7fb76ea768ba458f0.pdf https://doi.org/10.1525/9780520940994-005

[58] Lecso, P. A. (1991). The Bodhisattva Ideal and Organ Transplantation.  Journal of Religion and Health ,  30 (1), 35–41. http://www.jstor.org/stable/27510629 ; Bodhisattva, S. (n.d.). The Key of Becoming a Bodhisattva . A Guide to the Bodhisattva Way of Life. http://www.buddhism.org/Sutras/2/BodhisattvaWay.htm

[59] There is no explicit religious reference to when life begins or how to conduct research that interacts with the concept of life. However, these are relevant verses pertaining to how the fetus is viewed. (( King James Bible . (1999). Oxford University Press. (original work published 1769))

Jerimiah 1: 5 “Before I formed thee in the belly I knew thee; and before thou camest forth out of the womb I sanctified thee…”

In prophet Jerimiah’s insight, God set him apart as a person known before childbirth, a theme carried within the Psalm of David.

Psalm 139: 13-14 “…Thou hast covered me in my mother's womb. I will praise thee; for I am fearfully and wonderfully made…”

These verses demonstrate David’s respect for God as an entity that would know of all man’s thoughts and doings even before birth.

[60] It should be noted that abortion is not supported as well.

[61] The Vatican. (1987, February 22). Instruction on Respect for Human Life in Its Origin and on the Dignity of Procreation Replies to Certain Questions of the Day . Congregation For the Doctrine of the Faith. https://www.vatican.va/roman_curia/congregations/cfaith/documents/rc_con_cfaith_doc_19870222_respect-for-human-life_en.html

[62] The Vatican. (2000, August 25). Declaration On the Production and the Scientific and Therapeutic Use of Human Embryonic Stem Cells . Pontifical Academy for Life. https://www.vatican.va/roman_curia/pontifical_academies/acdlife/documents/rc_pa_acdlife_doc_20000824_cellule-staminali_en.html ; Ohara, N. (2003). Ethical Consideration of Experimentation Using Living Human Embryos: The Catholic Church’s Position on Human Embryonic Stem Cell Research and Human Cloning. Department of Obstetrics and Gynecology . Retrieved from https://article.imrpress.com/journal/CEOG/30/2-3/pii/2003018/77-81.pdf.

[63] Smith, G. A. (2022, May 23). Like Americans overall, Catholics vary in their abortion views, with regular mass attenders most opposed . Pew Research Center. https://www.pewresearch.org/short-reads/2022/05/23/like-americans-overall-catholics-vary-in-their-abortion-views-with-regular-mass-attenders-most-opposed/

[64] Rosner, F., & Reichman, E. (2002). Embryonic stem cell research in Jewish law. Journal of halacha and contemporary society , (43), 49–68.; Jafari, M., Elahi, F., Ozyurt, S. & Wrigley, T. (2007). 4. Religious Perspectives on Embryonic Stem Cell Research. In K. Monroe, R. Miller & J. Tobis (Ed.),  Fundamentals of the Stem Cell Debate: The Scientific, Religious, Ethical, and Political Issues  (pp. 79-94). Berkeley: University of California Press.  https://escholarship.org/content/qt9rj0k7s3/qt9rj0k7s3_noSplash_f9aca2e02c3777c7fb76ea768ba458f0.pdf https://doi.org/10.1525/9780520940994-005

[65] Schenker J. G. (2008). The beginning of human life: status of embryo. Perspectives in Halakha (Jewish Religious Law).  Journal of assisted reproduction and genetics ,  25 (6), 271–276. https://doi.org/10.1007/s10815-008-9221-6

[66] Ruttenberg, D. (2020, May 5). The Torah of Abortion Justice (annotated source sheet) . Sefaria. https://www.sefaria.org/sheets/234926.7?lang=bi&with=all&lang2=en

[67] Jafari, M., Elahi, F., Ozyurt, S. & Wrigley, T. (2007). 4. Religious Perspectives on Embryonic Stem Cell Research. In K. Monroe, R. Miller & J. Tobis (Ed.),  Fundamentals of the Stem Cell Debate: The Scientific, Religious, Ethical, and Political Issues  (pp. 79-94). Berkeley: University of California Press.  https://escholarship.org/content/qt9rj0k7s3/qt9rj0k7s3_noSplash_f9aca2e02c3777c7fb76ea768ba458f0.pdf https://doi.org/10.1525/9780520940994-005

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[69] World Medical Association (2013). World Medical Association Declaration of Helsinki: ethical principles for medical research involving human subjects. JAMA , 310(20), 2191–2194. https://doi.org/10.1001/jama.2013.281053 Declaration of Helsinki – WMA – The World Medical Association .; see also: National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research. (1979).  The Belmont report: Ethical principles and guidelines for the protection of human subjects of research . U.S. Department of Health and Human Services.  https://www.hhs.gov/ohrp/regulations-and-policy/belmont-report/read-the-belmont-report/index.html

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Mifrah Hayath

SM Candidate Harvard Medical School, MS Biotechnology Johns Hopkins University

Olivia Bowers

MS Bioethics Columbia University (Disclosure: affiliated with Voices in Bioethics)

Article Details

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Enhanced homing of mesenchymal stem cells for in situ niche remodeling and bone regeneration

• Research Article
• Published: 21 May 2024

Cite this article

• Yin Yuan 1 , 2   na1 ,
• Lijun Chen 1 , 3   na1 ,
• Jing Yang 1 ,
• Sining Zhou 1 ,
• Yangxin Fang 1 ,
• Qi Zhang 1 ,
• Ning Zhang 1 ,
• Yifei Li 1 ,
• Li Yuan 4 ,
• Fan Jia 5 , 6 ,
• Shuo Ni 7 , 8 &
• Charlie Xiang 1 , 3  

Mesenchymal stem cells (MSCs) transplantation is a promising strategy for osteoporosis treatment. However, limited sources and poor tissue-homing efficiency limit their clinical capabilities. In this study, we isolated a kind of MSCs from women’s menstrual blood (MenSCs) noninvasively and established a novel MSCs bone marrow-targeted delivery system by utilizing water-in-oil-in-water droplet microfluidics. MenSCs were encapsulated within β -cyclodextrin-functionalized alginate microcapsules loaded with zoledronates, which has a high affinity for bone. With this delivery system, MenSCs could be preferentially delivered to the bone marrow tissues via intravenous infusion, and restored bone mass by remodeling the bone marrow niche in situ in ovariectomized mouse models. Moreover, scRNA-seq analysis demonstrated that those MenSCs homed to the bone marrow recruited CD4 + FOXP3 + natural regulatory T (nT reg ) cells by secreting CCL28. The recruited nT reg promoted CD8 + T cells to secret Wnt family member 10B (WNT10B), activating the Wnt signaling in osteoblasts and thus promoting bone formation in situ in the bone marrow. This study reveals a promising application of MenSCs in postmenopausal osteoporosis treatment and highlights the clinical value of MenSCs by encouraging women to reserve autologous MenSCs before menopause to prevent and alleviate postmenopausal osteoporosis.

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Reid, I. R. Extensive expertise in endocrinology: Osteoporosis management. Eur. J. Endocrinol. 2022 , 187 , R65–R80.

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Jiang, Y. H.; Zhang, P.; Zhang, X.; Lv, L. W.; Zhou, Y. S. Advances in mesenchymal stem cell transplantation for the treatment of osteoporosis. Cell Prolif. 2021 , 54 , e12956.

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Acknowledgements

We thank Prof. Robert Langer and his group members at Koch Institute for their help on optimizing the microfluidics. Specially, thanks to Tuanzi and Yuanyuan, the loveliest doggies in the world, for companionship and spiritual support. This work was supported by the National Key R&D Program of China (No. 2022YFA1105603), the Fundamental Research Funds for the Central Universities (No. 2022ZFJH003), National Science & Technology Major Project “Key New Drug Creation and Manufacturing Program” (No. 2018ZX09201002-005), the National Natural Science Foundation of China (Nos. 82200994 and 81900563), CAMS Innovation Fund for Medical Sciences (No. 2019-I2M-5-045) and Shanghai Post-doctoral Excellence Program (No. 2022428).

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Yin Yuan and Lijun Chen contributed equally to this work .

Authors and Affiliations

State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, China

Yin Yuan, Lijun Chen, Jing Yang, Sining Zhou, Yangxin Fang, Qi Zhang, Ning Zhang, Yifei Li & Charlie Xiang

Department of Biology, The David H. Koch Institute for Integrative Cancer Research at MIT, Massachusetts Institute of Technology, Cambridge, MA, 02139, USA

Research Units of Infectious disease and Microecology, Chinese Academy of Medical Sciences, Hangzhou, 310003, China

Lijun Chen & Charlie Xiang

Innovative Precision Medicine (IPM) Group, Hangzhou, 311215, China

MOE Key Laboratory of Macromolecule Synthesis and Functionalization of Ministry of Education, Department of Polymer Science and Engineering, Zhejiang University, Hangzhou, 310027, China

Key Laboratory of Cardiovascular Intervention and Regenerative Medicine of Zhejiang Province, Department of Cardiology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, 310016, China

Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Immunology, Harvard Medical School, Boston, MA, 02115, USA

Department of Orthopedic Surgery and Shanghai Institute of Microsurgery on Extremities, Shanghai Sixth People’s Hospital Affiliated to Shanghai Jiaotong University School of Medicine, Shanghai, 200233, China

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Correspondence to Fan Jia , Shuo Ni or Charlie Xiang .

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Yuan, Y., Chen, L., Yang, J. et al. Enhanced homing of mesenchymal stem cells for in situ niche remodeling and bone regeneration. Nano Res. (2024). https://doi.org/10.1007/s12274-024-6715-1

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DOI : https://doi.org/10.1007/s12274-024-6715-1

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Competing interests, does propofol improve polyp detection during colonoscopy the promise and peril of clinical registry data.

Accepted for publication March 22, 2024. Published online first on April 17, 2024.

This editorial accompanies the article on p. 1088.

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Douglas A. Colquhoun , Ma Somsouk , Catherine L. Chen; Does Propofol Improve Polyp Detection during Colonoscopy? The Promise and Peril of Clinical Registry Data. Anesthesiology 2024; 140:1062–1064 doi: https://doi.org/10.1097/ALN.0000000000004987

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“Despite these limitations, this study still calls attention to the importance of preserving access to routine propofol use in patients undergoing screening and surveillance colonoscopy.”

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In this month’s issue of Anesthesiology, Quaye et al . report findings of their investigation into differences in type of sedation and the detection of polyps during colonoscopy for screening and surveillance. 1   Their study uses data from the New Hampshire Colonoscopy Registry to compare patients who received propofol for their procedure versus moderate sedation with benzodiazepines and opioids. Although the authors hypothesized that the use of propofol would improve the detection of polyps that might progress to colon cancer, in their final analysis, they found no association between sedation type and overall detection of adenomas (adjusted odds ratio, 1.00; 95% CI, 0.95 to 1.05) or any neoplasia (adjusted odds ratio, 1.03; 95% CI, 0.98 to 1.08). However, they reported a modest statistically and clinically significant association between propofol use and detection of serrated polyps (adjusted odds ratio, 1.13; 95% CI, 1.07 to 1.19).

Serrated polyps comprise a heterogeneous family of polyps grouped based on a histologic feature, including both hyperplastic polyps and the less common—but clinically more concerning for malignant transformation—serrated adenomas. The latter are typically located in the right colon and are flat and more difficult to detect, particularly with suboptimal bowel preparation. Given the heterogeneity of these lesions, serrated polyps as a class are a secondary consideration in current colonoscopy quality metrics, which emphasize greater importance of adenoma detection rates over serrated lesion detection. 2   Small hyperplastic polyps are specifically excluded from these definitions. Hyperplastic polyps larger than 10 mm should be removed during colonoscopy, and their presence may impact subsequent screening intervals. 2  

While previous work has demonstrated improvements in patient satisfaction and recovery times when propofol is used for sedation, the literature around adenoma detection is mixed, 3   making a robustly conducted study an important contribution to the literature. Unfortunately, because the current analysis grouped both serrated adenomas and hyperplastic polyps within the single serrated polyp variable, it is not possible to infer whether propofol is associated with increased detection of serrated adenomas. Future analyses should separate these specific lesion types.

Nevertheless, the analysis contains a number of important design features. The first is the setting of the study within a statewide registry. This design is generally positive, as it ensures that a breadth of clinical practice is captured and provides important definitional consistency of key covariates and outcomes across sites. Registry designs attempt to limit selection bias by including all or a specific sample of procedures across a group of facilities rather than those in a specific setting. As such, they can identify differences in care outcomes that may be attributable to differential care practices.

Second, the authors have taken a causal inference–informed approach to their experimental design. Causal inference as a field has emerged simultaneously from multiple fields including economics, computing science, and epidemiology. This field uses observed data, including practice variation as the basis of natural experiments, to make statements around causation. Fundamental to this approach is the careful assessment of the proposed causal pathway: How could propofol use increase the rate of serrated polyp detection? The authors surmised that deeper sedation achieved with propofol might lead to improved procedural conditions, allowing the endoscopist to more effectively detect serrated polyps. 4  

Third, informed by this framework, the authors employed a statistical technique known as inverse probability of treatment weighting to try to address differences in the likelihood of receiving the propofol, a source of residual confounding. In an ideal experiment, patients would be randomly assigned to sedation at the same facility with the same equipment and endoscopists to receive either propofol or moderate sedation with a benzodiazepine and opioids. Inverse probability of treatment weighting creates a balanced analytic population where the patients are at equipoise of receiving each treatment and increases the rigor of the analysis.

Some important limitations of this study remain. We note that propofol sedation may not always equate to anesthesiologist-led care. The study’s authors also avoided making this assumption. While the Food and Drug Administration (Silver Spring, Maryland)–approved package labeling 5   for propofol recommends administration “only by persons trained in the administration of general anesthesia and not involved in the conduct of the surgical/diagnostic procedure,” nonanesthesiologist-administered propofol is widely accepted among gastroenterologists. Despite the medicolegal considerations, 6   multiple gastroenterology professional societies have released position statements supporting this practice. 3 , 4 , 7   Therefore, we cannot conclude with certainty that anesthesiologist-led care improves polyp detection.

In addition, propofol use may be associated with providers and systems that are inherently different from those using moderate sedation. The initial study cohort included a large number of facilities that showed exclusive use of propofol and a few centers with exclusive use of moderate sedation. The authors subsequently identified facilities in which both sedation types were used during the study period for a restricted analysis; however, even in these centers, proceduralists might prefer propofol for medically complex patients, who are more likely to have comorbid conditions such as diabetes, smoking, and obesity, which have been linked to a greater risk of polyps. Proceduralists may also be motivated by quality metrics or financial incentives associated with polyp removal. Given this context, after applying propensity methods to adjust for treatment assignment and clustering patients by the endoscopist performing the procedure in this restricted cohort, there was a substantial attenuation in the effect size of receiving propofol sedation from an adjusted odds ratio of 1.51 (95% CI, 1.46 to 1.57) to an adjusted odds ratio of 1.13 (95% CI, 1.07 to 1.19). While the resultant effect size still suggests a clinically meaningful improvement in serrated polyp detection, the results must be interpreted with caution due to the inherent limitations present when analyzing registry data mentioned above.

Despite these limitations, this study still calls attention to the importance of preserving access to routine propofol use in patients undergoing screening and surveillance colonoscopy. The marked increase in the provision of anesthesiologist-led sedation for endoscopic procedures has been widely documented in both the Veterans Affairs and U.S. commercial insurance market. 8–10   In recent years, payers have proposed to stop reimbursing anesthesiologists providing sedation for healthy patients undergoing low-risk procedures such as cataract surgery and screening colonoscopy. 11 , 12   To date, these proposals have been unsuccessful due to opposition from patients and physicians. 13 , 14   In the case of screening colonoscopy, these coverage decisions could adversely impact early diagnosis, patient outcomes, and access to care due to reduced clinical throughput; this is alarming in the context of the increased care demand driven by recent consensus guidelines that lower the recommended age for initial screening. 15   Additional rigorously conducted studies evaluating the impact of anesthesia care on outcomes will be important to determine the value of anesthesia care for patients undergoing screening and surveillance colonoscopy.

Research reported in this publication was supported by National Heart, Lung, and Blood Institute of the National Institutes of Health (Bethesda, Maryland) under award No. K08HL159327 (Dr. Colquhoun) and the National Institute on Aging under award No. K23AG072035 (Dr. Chen). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Dr. Colquhoun declares research support from Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc. (Rahway, New Jersey), and Chiesi, USA (Cary, North Carolina) paid to the University of Michigan (Ann Arbor, Michigan) unrelated to the presented work. Dr. Colquhoun reports receiving an honorarium from Medscape, Inc. Dr. Somsouk has received research support from Freenome, Inc. (South San Francisco, California) and Genentech (South San Francisco, California) and consulted for Guardant Health (Palo Alto, California). Dr. Chen is not supported by, nor maintains any financial interest in, any commercial activity that may be associated with the topic of this article.

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Autosomal dominant Weill-Marchesani-like syndrome in a Chinese family due to novel haplotypic mutations in LTBP2

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Juan Chen , Jifeng Wan , Jiayi Jin , Guangming Jin , Yongxin Zheng , Danying Zheng , Liuxueying Zhong; Autosomal dominant Weill-Marchesani-like syndrome in a Chinese family due to novel haplotypic mutations in LTBP2. Ophthalmic Res 2024; https://doi.org/10.1159/000538844

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Introduction: Weill-Marchesani syndrome (WMS) is a hereditary connective tissue disorder with substantial heterogeneity in clinical features and genetic etiology, so it is essential to define the full mutation spectrum for earlier diagnosis. In this study, we report Weill-Marchesani-like syndrome (WMS-like) change to autosomal dominance inheritance caused by novel haplotypic mutations in latent transforming growth factor beta-binding protein 2 (LTBP2). Methods: Twenty-five members from a 4-generation Chinese family were recruited from Guangzhou, of whom nine were diagnosed with WMS-like disease, nine were healthy, and seven were of “uncertain” clinical status because of their young age. All members received detailed physical and ocular examinations. Whole exome sequencing, Sanger sequencing, and real-time PCR were used to identify and verify the causative mutations in family members. Results: Genetic sequencing revealed novel haplotypic mutations on the same LTBP2 chromosome associated with WMS-like, c. 2657C>A/p.T886K in exon 16 and deletion of exons 25-36. Real-time PCR and Sanger sequencing verified both mutations in patients with clinically diagnosed WMS-like, and in one “uncertain” child. In these patients, the haplotypic mutations led to ectopia lentis, short stature and obesity. Conclusion: Our study revealed that WMS-like may be associated with haplotypic LTBP2 mutations with autosomal dominant inheritance.

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