A mixed-methods approach to elucidate SARS-CoV-2 transmission routes and clustering in outbreaks in native workers and labour migrants in the fruit and vegetable packaging industry in South Holland, the Netherlands, May to July 2020.

OBJECTIVES: To obtain insight into SARS-CoV-2 clustering and transmission routes during outbreaks in the predominantly migrant workforce of the fruit and vegetable packaging industry of South Holland, the Netherlands, May to July 2020. DESIGN: This mixed-methods study applied direct observation and interviews, epidemiologic investigation, source and contact data analysis and whole-genome sequencing. RESULTS: We detected 46 SARS-CoV-2 cases and 4 outbreaks with a proportional representation of labour migrant and native workers in 6 unrelated facilities. Complete viral genome sequences revealed at least 3 clusters of native workers and labour migrants, 2 within and 1 between facilities. On-site inspections found adequate implementation of preventative measures to which both native workers and labour migrants showed suboptimal adherence. Being a labour migrant was associated with living in shared housing, but not with more contacts or different sources. CONCLUSIONS: The fruit and vegetable packaging industry gave the impression of sufficient preparedness and control. Suboptimal adherence to the facilities' preventative guidelines could have facilitated work floor transmission. Community and household transmission are likely to have contributed to outbreaks. We encourage further research into risk factors for transmission in labour migrants and application of these insights into targeted public health policy.

Participant selection for preventive Regenerative Medicine trials: ethical challenges of selecting individuals at risk.

The innovative field of Regenerative Medicine (RM) is expected to extend the possibilities of prevention or early treatment in healthcare. Increasingly, clinical trials will be developed for people at risk of disease to investigate these RM interventions. These individuals at risk are characterised by their susceptibility for developing clinically manifest disease in future due to the existence of degenerative abnormalities. So far, there has been little debate about the ethical appropriateness of including such individuals at risk in clinical trials. We discuss three main challenges of selecting this participant model for testing RM interventions: the challenge of achieving a proportional risk-benefit balance; complexities in the trial design in terms of follow-up and sample size; and the difficulty of obtaining informed consent due to the many uncertainties. We conclude that selecting the model is not ethically justifiable for first-in-man trials with RM interventions due to the high risks and uncertainties. However, the model can be ethically appropriate for testing the efficacy of RM interventions under the following conditions: interventions should be low risk; the degenerative abnormalities (and other risk factors) should be strongly related with disease within a short time frame; robust preclinical evidence of efficacy needs to be present; and the informed consent procedure should contain extra safeguards with regard to communication on uncertainties.

Reconsidering the ethics of sham interventions in an era of emerging technologies.

BACKGROUND: Our aim was to ethically evaluate the arguments in favor and against sham interventions, as presented in literature. Two developments underscore the need to reconsider the ethics of sham interventions. First, the number of clinical trials investigating interventions in the field of regenerative medicine are increasing, in which the choice for a placebo requires an invasive intervention. Second, the increased awareness of the lack of systematic research in surgery stresses the need to discuss the necessity and acceptability of sham-controlled clinical trials. METHODS: A systematic search in Medline was performed, of which 104 articles were considered relevant. RESULTS: Arguments in favor of a sham controlled design are that it increases the scientific validity and the benefits to society while at the same time the risks and harm can be acceptable. Arguments against sham controls include that they pose unacceptable risks to participants, present difficulties with informed consent, that the use of deceptive tactics is unethical, and that the feasibility of such controls is compromised because of a lack of public support. CONCLUSION: None of the published literature fully rejects sham interventions, and many regard sham interventions acceptable provided the conditions of scientific necessity, reasonable risks, and valid informed consent are fulfilled. Further debate should no longer address whether a sham control is ethically acceptable but rather when these conditions are fulfilled.

Societal impacts of regenerative medicine: reflections on the views of orthopedic professionals.

As the amount of clinical studies in orthopedic regenerative medicine (RM) is increasing, it is time to take into account its impact on society. A total of 36 biomedical professionals working at the front row of orthopedic RM were interviewed to explore their attitudes, opinions and expectations regarding the societal impacts of RM. Professionals mainly recognized the societal impacts of counteraction of aging, prevention of disease and social justice. The 'soft' sides of these impacts were hardly mentioned. Whereas they did not perceive themselves in the position to mitigate these impacts, professionals should take up their role as actor and become involved in the societal debate. This is important as they can co-shape the societal impacts during the developmental process of technologies and thereby stimulate responsible innovation.

Stem cell trials for cardiovascular medicine: ethical rationale.

Stem cell-based interventions provide new treatment prospects for many disease conditions, including cardiovascular disorders. Clinical trials are necessary to collect adequate evidence on (long-term) safety and efficacy of novel interventions such as stem cells, but the design and launch of clinical trials, from first-in-human studies to larger randomized controlled trials (RCTs), is scientifically and ethically challenging. Stem cells are different from traditional pharmaceuticals, surgical procedures, and medical devices in the following ways: the novelty and complexity of stem cells, the invasiveness of the procedures, and the novel aim of regeneration. These specifics, combined with the characteristics of the study population, will have an impact on the design and ethics of RCTs. The recently closed JUVENTAS trial will serve as an example to identify the (interwoven) scientific and ethical challenges in the design and launch of stem cell RCTs. The JUVENTAS trial has investigated the efficacy of autologous bone marrow cells in end-stage vascular patients, in a double-blind sham-controlled design. We first describe the choices, considerations, and experiences of the JUVENTAS team. Subsequently, we identify the main ethical and scientific challenges and discuss what is important to consider in the design of future stem cell RCTs: assessment of risks and benefits, the choice for outcome measures, the choice for the comparator, the appropriate selection of participants, and adequate informed consent. Additionally, the stem cell field is highly in the spotlight due to the (commercial) interests and expectations. This warrants a cautious pace of translation and scrupulous set up of clinical trials, as failures could put the field in a negative light. At the same time, knowledge from clinical trials is necessary for the field to progress. We conclude that in the scientifically and ethically challenging field of stem cell RCTs, researchers and clinicians have to maneuver between the Skylla of hyper accelerated translation without rigorously conducted RCTs and the Charybdis of the missed opportunity of valuable knowledge.

Ethical implications of regenerative medicine in orthopedics: an empirical study with surgeons and scientists in the field.

BACKGROUND CONTEXT: Regenerative medicine (RM) interventions, such as (stem) cell transplantation, scaffolds, gene transfer, and tissue engineering, are likely to change the field of orthopedics considerably. These strategies will significantly differ from treatments in current orthopedic practice, as they treat the underlying cause of disease and intervene at a biological level, preferably in an earlier stage. Whereas most of the RM interventions for orthopedics are still in the preclinical phase of research, the number of clinical studies is expected to increase rapidly in the future. The debate about the challenging scientific and ethical issues of translating these innovative interventions into (early) clinical studies is developing. However, no empirical studies that have systematically described the attitudes, opinions, and experiences of experts in the field of orthopedic RM concerning these challenges exist. PURPOSE: The aim of this study was to identify ethical issues that experts in the area of RM for musculoskeletal disorders consider to be relevant to address so as to properly translate RM interventions into (early) clinical studies. STUDY DESIGN/SETTING: In-depth qualitative interviews were conducted with 36 experts in the field, mainly spine surgeons and musculoskeletal scientists from The Netherlands and the United Kingdom. METHODS: A topic list of open questions, based on existing literature and pilot interviews, was used to guide the interviews. Data analysis was based on the constant comparative method, which means going back and forth from the data to develop codes, concepts, and themes. RESULTS: Four ethical themes emerged from the interview data. First, the risks to study participants. Second, the appropriate selection of study participants. Third, setting relevant goal(s) for measuring outcome, varying from regenerating tissue to improving well-being of patients. Finally, the need for evidence-based medicine and scientific integrity, which is considered challenging in orthopedics. DISCUSSION: The overall attitude toward the development of RM was positive, especially because current surgical treatments for spine disorders lack satisfactory effectiveness. However, efforts should be taken to adequately address the ethical and scientific issues in the translation of RM interventions into clinical research. This is required to prevent unnecessary risks to study participants, to prevent exposure of future patients to useless clinical applications, as well as to prevent this young field from developing a negative reputation. Not only will the orthopedic RM field benefit from ethically and scientifically sound clinical studies, but the rise of RM also provides an opportunity to stimulate evidence-based practice in orthopedics and address hype- and profit-driven practices in orthopedics.

Regenerative medicine interventions for orthopedic disorders: ethical issues in the translation into patients.

Regenerative medicine (RM) technologies, such as cell therapy, gene transfer and tissue engineering, are expected to move the field of orthopedics into a new era. Now that more and more attempts are underway to translate preclinical research into clinical studies, it is time to proactively discuss the ethical issues associated with first-in-human applications of RM interventions for musculoskeletal disorders. The design and launch of early clinical trials will be ethically challenging due to the specific features of RM in general, and the application for musculoskeletal disorders specifically. In this paper, we identify three sets of ethical issues that need to be addressed when considering initiating early clinical trials: assessment of risks and benefits; designing a study in terms of outcome measures and comparators; and participant selection. These issues are particularly emphasized in RM research that aims to apply these approaches in an early stage of degenerative musculoskeletal disorders.

Anosmia after coiling of ruptured aneurysms: prevalence, prognosis, and risk factors.

BACKGROUND AND PURPOSE: Anosmia occurs frequently in patients with subarachnoid hemorrhage (SAH) from a ruptured aneurysm treated with clipping. We analyzed prevalence, prognosis, and potential risk factors for anosmia after coiling for SAH. METHODS: We interviewed all patients who resumed independent living after SAH treated with coiling between 1997 and 2007. We assessed by means of logistic regression analyses whether risk of anosmia was influenced by site of the ruptured aneurysm, neurological condition on admission, amount of extravasated blood, hydrocephalus, and treatment for hydrocephalus. RESULTS: Of 197 patients, 35 (18%; 95%CI:12 to 23) experienced anosmia. Anosmia had improved in 23 (66%) of them; in 20 the recovery had been complete after a median period of 6 weeks (SD +/-6.5). Intraventricular hemorrhage was a risk factor for anosmia (OR 2.4; 95%CI:1.0 to 5.9). Anterior aneurysm location (OR 1.1; 95%CI:0.5 to 2.3) and high amount of extravasated blood (OR 0.9; 95%CI:0.4 to 2.1) were not related to anosmia. CONCLUSIONS: Anosmia occurs after coiling in 1 of every 6 SAH patients, but has a good prognosis in most patients. The cause of anosmia after coiling for ruptured aneurysms remains elusive; severity of the initial hemorrhage or long lasting hydrocephalus may be contributing factors.