US state laws on medical freedom and investigational stem cell procedures: a call to focus on state-based legislation.

The premature marketing of investigational stem cell interventions (SCIs) is a growing market in the US. Several US states have passed legislation to permit and promote unproven and experimental SCIs for individuals with terminal or chronic diseases. These SCI medical freedom laws, which are largely based on right-to-try legislation, increase access to experimental SCIs with little to no oversight. They undermine federal regulatory authority and can compromise patient safety and informed decision-making. SCI medical freedom laws have gone largely unnoticed by scientific societies interested in the responsible translation of stem cell medicine. In this article, we analyze state SCI medical freedom laws and describe their detrimental impact on patients and society. We contend that scientific and medical societies are uniquely poised to advocate against state-based policy promoting unproven SCIs but recognize resource and other constraints to advocate for or against legislation in 50 states. We recommend societies establish coalitions and share resources to address state-based SCI medical freedom laws and other legislation surrounding unproven SCIs.

Repurposing DailyQA3 for an efficient and spot position sensitive daily quality assurance tool for proton therapy.

INTRODUCTION: Daily quality assurance is an integral part of a radiotherapy workflow to ensure the dose is delivered safely and accurately to the patient. It is performed before the first treatment of the day and needs to be time and cost efficient for a multiple gantries proton center. In this study, we introduced an efficient method to perform QA for output constancy, range verification, spot positioning accuracy and imaging and proton beam isocenter coincidence with DailyQA3. METHODS: A stepped acrylic block of specific dimensions is fabricated and placed on top of the DailyQA3 device. Treatment plans comprising of two different spread-out Bragg peaks and five individual spots of 1.0 MU each are designed to be delivered to the device. A mathematical framework to measure the 2D distance between the detectors and individual spot is introduced and play an important role in realizing the spot positioning and centering QA. Lastly, a 5 months trends of the QA for two gantries are presented. RESULTS: The outputs are monitored by two ion chambers in the DailyQA3 and a tolerance of ± 3 % $ \pm 3\% $ are used. The range of the SOBPs are monitored by the ratio of ion chamber signals and a tolerance of ± 1 mm $ \pm 1\ {\mathrm{mm}}$ is used. Four diodes at ± 10 cm $ \pm 10\ {\mathrm{cm}}$ from the central ion chambers are used for spot positioning QA, while the central ion chamber is used for imaging and proton beam isocenter coincidence QA. Using the framework, we determined the absolute signal threshold corresponding to the offset tolerance between the individual proton spot and the detector. A 1.5 mm $1.5\ {\mathrm{mm}}$ tolerances are used for both the positioning and centering QA. No violation of the tolerances is observed in the 5 months trends for both gantries. CONCLUSION: With the proposed approach, we can perform four QA items in the TG224 within 10 min.

Modern-era radiotherapy and ischaemic heart disease-related mortality outcomes in Asian breast-cancer patients.

Introduction: Left-sided breast-cancer patients treated with adjuvant radiotherapy (RT) before the 1990s were associated with increased risk of cardiac mortality. Modern RT techniques have since improved, resulting in lower radiation doses to the heart. However, concerns regarding cardiac toxicity remain. In a retrospective cohort study, we compare the ischaemic heart disease (IHD)-related mortality of left-sided versus right-sided breast-cancer patients. We present the results of the cardiac mortality and all-cause mortality risk of Asian breast-cancer survivors treated with RT in Singapore. Material and methods: A total of 14,419 Asian women from a single institution were treated for breast cancer from 2000 to 2016. A systematic mortality follow-up was conducted until December 2015. The effect of breast cancer laterality on IHD-related mortality and on overall mortality was investigated. Mean heart doses were recorded for patients from 2010-2016. Results: In the irradiated group (n = 9556), we found no difference in IHD-related mortality or overall mortality when comparing the left- and right-sided breast cancers. The hazard ratio of cardiac mortality for left-sided versus right-sided RT was 0.94 (95% CI: 0.64-1.38). The hazard ratio for all-cause mortality was 1.03 (95% CI: 0.94-1.13). Conclusions: Our study of Asian cancer patients did not reveal a significant increase in the risk of IHD-related mortality or overall mortality comparing left- vs. right-sided breast cancers in modern-era RT.

Academic physician specialists' views toward the unproven stem cell intervention industry: areas of common ground and divergence.

BACKGROUND AND AIMS: Premature commercialization of unproven stem cell interventions (SCIs) has received significant attention within the regenerative medicine community. Patients considering SCIs may encounter misinformation and seek out guidance from their physicians who are trusted brokers of health information. However, little is known about the perspectives of academic physician specialists toward the SCI industry. The purpose of this study was to capture the attitudes of physician specialists with experience addressing patient questions about unproven SCIs. METHODS: The authors undertook 25 semi-structured interviews with academic physicians in cardiology, ophthalmology, orthopedics, pulmonology and neurology primarily from one academic center. RESULTS: The authors identified two major themes: concerns and mediators of appropriateness of offering SCIs as therapies to patients. Specialists were generally aware of the industry and reported scientific and commercial concerns, including the scientific uncertainty of SCIs, medical harms to patients, misleading marketing and its impact on patient informed consent and economic harms due to large out-of-pocket costs for patients. All specialists outside of orthopedics voiced that it was inappropriate to be offering SCIs to patients today. These views were informed by previously expressed concerns surrounding safety and properly informing patients, levels of evidence needed prior to offering SCIs therapeutically and desired qualifications for clinicians. Among the specialties, orthopedists reported that under certain conditions, SCIs may be appropriate for patients with limited clinical options but only when safety is adequate, expectations are managed and patients are well informed about the risks and chances of benefit. Most participants expressed a desire for phase 3 studies and Food and Drug Administration approval prior to marketing SCIs, but some also shared the challenges associated with upholding these thresholds of evidence, especially when caring for out-of-option patients. CONCLUSIONS: The authors' results suggest that medical specialists are aware of the industry and express several concerns surrounding SCIs but differ in their views on the appropriateness and clinical evidence necessary for offering SCIs currently to patients. Additional educational tools may help physicians with patient engagement and expectation management surrounding SCIs.

American Medical Society for Sports Medicine Position Statement: Principles for the Responsible Use of Regenerative Medicine in Sports Medicine.

ABSTRACT: Many sports medicine physicians are currently considering introducing regenerative medicine into their practice. Regenerative medicine and the subclassification of orthobiologics are a complicated topic and have produced widely varying opinions. Although there is concern by government regulators, clinicians, scientists, patient advocacy organizations, and the media regarding the use of regenerative medicine products, there is also excitement about the potential benefits with growing evidence that certain regenerative medicine products are safe and potentially efficacious in treating musculoskeletal conditions. Sports medicine physicians would benefit from decision-making guidance about whether to introduce orthobiologics into their practice and how to do it responsibly. The purpose of this position statement is to provide sports medicine physicians with information regarding regenerative medicine terminology, a brief review of basic science and clinical studies within the subclassification of orthobiologics, regulatory considerations, and best practices for introducing regenerative medicine into clinical practice. This information will help sports medicine physicians make informed and responsible decisions about the role of regenerative medicine and orthobiologics in their practice.

How to Handle Co-authorship When Not Everyone's Research Contributions Make It into the Paper.

While much of the scholarly work on ethics relating to academic authorship examines the fair distribution of authorship credit, none has yet examined situations where a researcher contributes significantly to the project, but whose contributions do not make it into the final manuscript. Such a scenario is commonplace in collaborative research settings in many disciplines and may occur for a number of reasons, such as excluding research in order to provide the paper with a clearer focus, tell a particular story, or exclude negative results that do not fit the hypothesis. Our concern in this paper is less about the reasons for including or excluding data from a paper and more about distributing credit in this type of scenario. In particular, we argue that the notion 'substantial contribution', which is part of the International Committee of Medical Journal Editors (ICMJE) authorship criteria, is ambiguous and that we should ask whether it concerns what ends up in the paper or what is a substantial contribution to the research process leading up to the paper. We then argue, based on the principles of fairness, due credit, and ensuring transparency and accountability in research, that the latter interpretation is more plausible from a research ethics point of view. We conclude that the ICMJE and other organizations interested in authorship and publication ethics should consider including guidance on authorship attribution in situations where researchers contribute significantly to the research process leading up to a specific paper, but where their contribution is finally omitted.

Duration-dependent margins for prostate radiotherapy-a practical motion mitigation strategy.

BACKGROUND AND OBJECTIVE: The magnitude of intra-fractional prostate displacement (change from initial position over time) is associated with the duration of the patient lying on the radiotherapy treatment couch. This study reports a minute-by-minute association and calculates the impact of this displacement on duration-dependent margins using real-time intra-fractional position data monitored by four-dimensional transperineal ultrasound (4D TPUS). MATERIALS AND METHODS: A total of 55 patients were recruited prospectively. Intra-fractional position of the prostate was monitored in real-time using a 4D TPUS Clarity® system. A total of 1745 monitoring sessions were analysed. Van Herk's margin recipe (2.5∑ + 1.64((σ2 + σp2)1/2 - σp)) was used to estimate the duration-dependant margins for every minute, up to the 15th minute. Linear regression analysis was then performed on the overall margins against time and direction. RESULTS: The mean intra-fractional position was 0.76 mm Inferior (Inf), 0 mm Lateral (Lat) and 0.94 mm Posterior (Post) at the 15th minute. A minimum margin expansion of 2.42 mm (Superior/Inf), 1.02 mm (Left/Right) and 2.65 mm (Anterior/Post) was required for an 8­minute treatment compared to 4.29 mm (Sup/Inf), 1.84 mm (Lt/Rt) and 4.63 mm (Ant/Post) for a 15-minute treatment. The required margin expansion increased linearly (R2 = 0.99) in all directions (p < 0.01). However, while there was no statistically significant difference (p = 0.10) in the required margin expansion in the Sup/Inf and Ant/Post directions respective of the time duration, the margins were much bigger compared to those in the Lt/Rt direction (p < 0.01). CONCLUSION: We report our experience in deriving the minimum duration-dependant margin to generate the required planning target volume for prostate radiotherapy. The required margin increases linearly in all directions within the 15-min duration; thus, the margin will depend on the duration of the technique chosen (IMRT/VMAT/3DCRT/proton).

Misconduct and Misbehavior Related to Authorship Disagreements in Collaborative Science.

Scientific authorship serves to identify and acknowledge individuals who "contribute significantly" to published research. However, specific authorship norms and practices often differ within and across disciplines, labs, and cultures. As a consequence, authorship disagreements are commonplace in team research. This study aims to better understand the prevalence of authorship disagreements, those factors that may lead to disagreements, as well as the extent and nature of resulting misbehavior. Methods include an international online survey of researchers who had published from 2011 to 2015 (8364 respondents). Of the 6673 who completed the main questions pertaining to authorship disagreement and misbehavior, nearly half (46.6%) reported disagreements regarding authorship naming; and discipline, rank, and gender had significant effects on disagreement rates. Paradoxically, researchers in multidisciplinary teams that typically reflect a range of norms and values, were less likely to have faced disagreements regarding authorship. Respondents reported having witnessed a wide range of misbehavior including: instances of hostility (24.6%), undermining of a colleague's work during meetings/talks (16.4%), cutting corners on research (8.3%), sabotaging a colleague's research (6.4%), or producing fraudulent work to be more competitive (3.3%). These findings suggest that authorship disputes may contribute to an unhealthy competitive dynamic that can undermine researchers' wellbeing, team cohesion, and scientific integrity.

Researchers' Perceptions of Ethical Authorship Distribution in Collaborative Research Teams.

Authorship is commonly used as the basis for the measurement of research productivity. It influences career progression and rewards, making it a valued commodity in a competitive scientific environment. To better understand authorship practices amongst collaborative teams, this study surveyed authors on collaborative journal articles published between 2011 and 2015. Of the 8364 respondents, 1408 responded to the final open-ended question, which solicited additional comments or remarks regarding the fair distribution of authorship in research teams. This paper presents the analysis of these comments, categorized into four main themes: (1) disagreements, (2) questionable behavior, (3) external influences regarding authorship, and (4) values promoted by researchers. Results suggest that some respondents find ways to effectively manage disagreements in a collegial fashion. Conversely, others explain how distribution of authorship can become a "blood sport" or a "horror story" which can negatively affect researchers' wellbeing, scientific productivity and integrity. Researchers fear authorship discussions and often try to avoid openly discussing the situation which can strain team interactions. Unethical conduct is more likely to result from deceit, favoritism, and questionable mentorship and may become more egregious when there is constant bullying and discrimination. Although values of collegiality, transparency and fairness were promoted by researchers, rank and need for success often overpowered ethical decision-making. This research provides new insight into contextual specificities related to fair authorship distribution that can be instrumental in developing applicable training tools to identify, prevent, and mitigate authorship disagreement.

CRISPR in the North American popular press.

PURPOSE: CRISPR is often called one of the century's most important discoveries and is commonly discussed in terms of its momentous potential impacts. This study analyzed how CRISPR is discussed in the North American popular press, including how it is defined, and which benefits and risks/concerns are attributed to the technology. METHODS: Using the Factiva database, we identified 228 relevant, nonduplicated articles containing either "CRISPR" or "C.R.I.S.P.R.," published in popular US and Canadian news sources between 1 January 2012 and 12 July 2017. Content analysis was performed on the articles. RESULTS: CRISPR is most often discussed in the context of human health (83.8%), compared with animals (26.3%) and plants (20.6%). Nearly all articles (96.1%) presented CRISPR's potential benefits; 61.4% of articles presented CRISPR-related risks/concerns, the vast majority of which focused on the uncertainty surrounding CRISPR, specifically with respect to germline modifications. CONCLUSIONS: Overall, the discourse suggests a strong promotion of CRISPR, but an element of caution is also evident. Technical as well as ethical, legal, and social risks/concerns play a prominent role. This media portrayal of CRISPR might help facilitate more sophisticated and balanced policy responses, where the scientific potential of the technology is highlighted alongside broader social considerations.

Non-invasive Prenatal Testing and the Unveiling of an Impaired Translation Process.

Non-invasive prenatal testing (NIPT) is an exciting technology with the potential to provide a variety of clinical benefits, including a reduction in miscarriages, via a decline in invasive testing. However, there is also concern that the economic and near-future clinical benefits of NIPT have been overstated and the potential limitations and harms underplayed. NIPT, therefore, presents an opportunity to explore the ways in which a range of social pressures and policies can influence the translation, implementation, and use of a health care innovation. NIPT is often framed as a potential first tier screen that should be offered to all pregnant women, despite concerns over cost-effectiveness. Multiple forces have contributed to a problematic translational environment in Canada, creating pressure towards first tier implementation. Governments have contributed to commercialization pressure by framing the publicly funded research sector as a potential engine of economic growth. Members of industry have an incentive to frame clinical value as beneficial to the broadest possible cohort in order to maximize market size. Many studies of NIPT were directly funded and performed by private industry in laboratories lacking strong independent oversight. Physicians' fear of potential liability for failing to recommend NIPT may further drive widespread uptake. Broad social endorsement, when combined with these translation pressures, could result in the "routinization" of NIPT, thereby adversely affecting women's reproductive autonomy. Policymakers should demand robust independent evidence of clinical and public health utility relevant to their respective jurisdictions before making decisions regarding public funding for NIPT.

Authorship ethics in global health research partnerships between researchers from low or middle income countries and high income countries.

BACKGROUND: Over the past two decades, the promotion of collaborative partnerships involving researchers from low and middle income countries with those from high income countries has been a major development in global health research. Ideally, these partnerships would lead to more equitable collaboration including the sharing of research responsibilities and rewards. While collaborative partnership initiatives have shown promise and attracted growing interest, there has been little scholarly debate regarding the fair distribution of authorship credit within these partnerships. DISCUSSION: In this paper, we identify four key authorship issues relevant to global health research and discuss their ethical and practical implications. First, we argue that authorship guidance may not adequately apply to global health research because it requires authors to write or substantially revise the manuscript. Since most journals of international reputation in global health are written in English, this would systematically and unjustly exclude non-English speaking researchers even if they have substantially contributed to the research project. Second, current guidance on authorship order does not address or mitigate unfair practices which can occur in global health research due to power differences between researchers from high and low-middle income countries. It also provides insufficient recognition of "technical tasks" such as local participant recruitment. Third, we consider the potential for real or perceived editorial bias in medical science journals in favour of prominent western researchers, and the risk of promoting misplaced credit and/or prestige authorship. Finally, we explore how diverse cultural practices and expectations regarding authorship may create conflict between researchers from low-middle and high income countries and contribute to unethical authorship practices. To effectively deal with these issues, we suggest: 1) undertaking further empirical and conceptual research regarding authorship in global health research; 2) raising awareness on authorship issues in global health research; and 3) developing specific standards of practice that reflect relevant considerations of authorship in global health research. SUMMARY: Through review of the bioethics and global health literatures, and examination of guidance documents on ethical authorship, we identified a set of issues regarding authorship in collaborative partnerships between researchers from low-middle income countries and high income countries. We propose several recommendations to address these concerns.

Pulsed low-dose rate radiotherapy for recurrent bone sarcomas: case reports and brief review.

PURPOSE: Re-irradiation for bulky recurrent sarcoma carries significant risks. Pulsed low-dose rate radiotherapy (PLDR) is an attractive option for re-irradiation due to inherent radiobiological advantages. MATERIALS AND METHODS: We present two patients who underwent reirradiation using PLDR technique, followed by a literature review. RESULTS: The first case is that of a 76-year-old male who developed an in-field recurrence of a bulky pelvic bone high-grade chondrosarcoma after he was treated with definitive radiotherapy using helical TomoTherapy with a total dose of 66 Gy. The patient was re-irradiated using PLDR with a shrinking field technique; 50 Gy in 2 Gy fractions followed by a boost of 20 Gy in 2 Gy fractions. The patient remains disease-free without significant toxicity 60 months post-irradiation. The second case is that of an 82-year-old female who was treated with a definitive irradiation of 66 Gy in 33 fractions for a right shoulder grade II chondrosarcoma. She developed an in-field recurrence 28 months later and presented with bulky disease causing brachial plexopathy and lymphedema. The patient was re-irradiated with a palliative intent to a total dose of 50 Gy in 2 Gy fractions over 5 weeks using PLDR. Brachial plexopathy resolved shortly after re-irradiation, but local progression near the surface was evident 8 months later. She passed away from unrelated causes 11 months later. CONCLUSION: We present two cases highlighting our early experience with PLDR, which was effective in the reirradiation of recurrent bony sarcoma. Our study highlights PLDR as an option for reirradiation in recurrent unresectable tumors.