Core Legal Challenges for Medical 3D Printing in the EU.

3D printing has been adopted into routine use for certain medical applications, but more widespread usage has been hindered by, among other things, unclear legislation. We performed an analysis, using legal doctrinal study and legal informatics, of relevant EU legislation and case law in four issues relevant to medical 3D printing (excluding bioprinting or pharmacoprinting): pre-market approval, post-market liability, intellectual property rights, and data protection. Several gaps and uncertainties in the current legislation and interpretations were identified. In particular, we regard the current EU regulatory framework to be quite limiting and inflexible, exemplifying a cautionary approach common in EU law. Though the need to establish high safety standards in order to protect patients as a disadvantaged population is understood, both legal uncertainties and overregulation are seen as harmful to innovation. Hence, more adaptive legislation is called for to ensure continuous innovation efforts and enhanced patient outcomes.

Low-dose buprenorphine initiation and treatment continuation among hospitalized patients with opioid dependence: A retrospective cohort study.

BACKGROUND: Buprenorphine is an effective treatment for both opioid use disorder (OUD) and chronic pain, but buprenorphine's pharmacology complicates treatment initiation for some patients. Low-dose buprenorphine initiation is a novel strategy that may reduce precipitated withdrawal. Few studies describe what patient populations benefit most from low-dose initiations and the clinical parameters that impact treatment continuation. This study aimed to 1) describe experiences with low-dose buprenorphine initiation, including both successes and failures among hospitalized patients in an urban underserved community; 2) identify patient- and treatment-related characteristics associated with unsuccessful initiation and treatment discontinuation; and 3) assess buprenorphine treatment continuation after discharge. METHODS: This is a retrospective cohort study with opioid-dependent (meaning OUD or receiving long-term opioid therapy for chronic pain) patients who underwent low-dose buprenorphine initiation during hospital admission from October 2021 through April 2022. The primary outcome was successful completion of low-dose initiation. Bivariate analysis identified patient- and treatment-related factors associated with unsuccessful initiation. Secondary outcomes were buprenorphine treatment discontinuation at post-discharge follow-up, 30- and 90-days. RESULTS: Of 28 patients who underwent low-dose buprenorphine initiation, 68 % successfully completed initiation. Unsuccessful initiation was associated with receipt of methadone during admission and higher morphine milligram equivalents (MME) of supplemental opioids. Of 22 patients with OUD, the percent receiving a buprenorphine prescription at a follow-up visit, 30 days, and 90 days, respectively, was 46 %, 36 %, and 36 %. Of 6 patients with chronic pain, the percent receiving a buprenorphine prescription at a follow-up visit, 30 days, and 90 days, respectively, was 100 %, 100 %, and 83 %. CONCLUSION: Low-dose buprenorphine initiation can be successful in opioid-dependent hospitalized patients. Patients taking methadone or requiring higher MME of supplemental opioids may have more difficulty with the low-dose buprenorphine initiation approach, but these findings should be replicated in larger studies. This study suggests patient- and treatment-related factors that clinicians could consider when determining the optimal treatment strategy for patients wishing to transition to buprenorphine.

Learning From Experience and Finding the Right Balance in the Governance of Artificial Intelligence and Digital Health Technologies.

Artificial intelligence (AI) and machine learning medical tools have the potential to be transformative in care delivery; however, this change will only be realized if accompanied by effective governance that ensures patient safety and public trust. Recent digital health initiatives have called for tighter governance of digital health. A correct balance must be found between ensuring product safety and performance while also enabling the innovation needed to deliver better approaches for patients and affordable efficient health care for society. This requires innovative, fit-for-purpose approaches to regulation. Digital health technologies, particularly AI-based tools, pose specific challenges to the development and implementation of functional regulation. The approaches of regulatory science and "better regulation" have a critical role in developing and evaluating solutions to these problems and ensuring effective implementation. We describe the divergent approaches of the European Union and the United States in the implementation of new regulatory approaches in digital health, and we consider the United Kingdom as a third example, which is in a unique position of developing a new post-Brexit regulatory framework.

Integrating Water Purification with Electrochemical Aptamer Sensing for Detecting SARS-CoV-2 in Wastewater.

Wastewater analysis of pathogens, particularly SARS-CoV-2, is instrumental in tracking and monitoring infectious diseases in a population. This method can be used to generate early warnings regarding the onset of an infectious disease and predict the associated infection trends. Currently, wastewater analysis of SARS-CoV-2 is almost exclusively performed using polymerase chain reaction for the amplification-based detection of viral RNA at centralized laboratories. Despite the development of several biosensing technologies offering point-of-care solutions for analyzing SARS-CoV-2 in clinical samples, these remain elusive for wastewater analysis due to the low levels of the virus and the interference caused by the wastewater matrix. Herein, we integrate an aptamer-based electrochemical chip with a filtration, purification, and extraction (FPE) system for developing an alternate in-field solution for wastewater analysis. The sensing chip employs a dimeric aptamer, which is universally applicable to the wild-type, alpha, delta, and omicron variants of SARS-CoV-2. We demonstrate that the aptamer is stable in the wastewater matrix (diluted to 50%) and its binding affinity is not significantly impacted. The sensing chip demonstrates a limit of detection of 1000 copies/L (1 copy/mL), enabled by the amplification provided by the FPE system. This allows the integrated system to detect trace amounts of the virus in native wastewater and categorize the amount of contamination into trace (<10 copies/mL), medium (10-1000 copies/mL), or high (>1000 copies/mL) levels, providing a viable wastewater analysis solution for in-field use.

Legal issues and underexplored data protection in medical 3D printing: A scoping review.

Introduction: 3D printing has quickly found many applications in medicine. However, as with any new technology the regulatory landscape is struggling to stay abreast. Unclear legislation or lack of legislation has been suggested as being one hindrance for wide-scale adoption. Methods: A scoping review was performed in PubMed, Web of Science, SCOPUS and Westlaw International to identify articles dealing with legal issues in medical 3D printing. Results: Thirty-four articles fulfilling inclusion criteria were identified in medical/technical databases and fifteen in the legal database. The majority of articles dealt with the USA, while the EU was also prominently represented. Some common unresolved legal issues were identified, among them terminological confusion between custom-made and patient-matched devices, lack of specific legislation for patient-matched products, and the undefined legal role of CAD files both from a liability and from an intellectual property standpoint. Data protection was mentioned only in two papers and seems an underexplored topic. Conclusion: In this scoping review, several relevant articles and several common unresolved legal issues were identified including a need for terminological uniformity in medical 3D printing. The results of this work are planned to inform our own deeper legal analysis of these issues in the future.

Biomodifying the 'natural': from Adaptive Regulation to Adaptive Societal Governance.

Biomodifying technologies-such as gene editing, induced pluripotent stem cells, and bioprinting-are being developed for a wide range of applications, from pest control to lab-grown meat. In medicine, regulators have responded to the challenge of evaluating modified 'natural' material as a therapeutic 'product' by introducing more flexible assessment schemes. Attempts have also been made to engage stakeholders across the globe on the acceptable parameters for these technologies, particularly in the case of gene editing. Regulatory flexibility and stakeholder engagement are important, but a broader perspective is also needed to respond to the potential disruption of biomodification. Our case-study technologies problematize basic ideas-such as 'nature', 'product', and 'donation'-that underpin the legal categories used to regulate biotechnology. Where such foundational concepts are rendered uncertain, a socially responsive and sustainable solution would involve exploring evolutions in these concepts across different societies. We suggest that the global observatory model is a good starting point for this 'Adaptive Societal Governance' approach, in which a self-organizing network of scholars and interested parties could carry out the multi-modal (meta)analyses needed to understand societal constructions of ideas inherent to our understanding of 'life'.

Rescuing activity of oxygen-damaged pyruvate formate-lyase by a spare part protein.

Pyruvate formate-lyase (PFL) is a glycyl radical enzyme (GRE) that converts pyruvate and coenzyme A into acetyl-CoA and formate in a reaction that is crucial to the primary metabolism of many anaerobic bacteria. The glycyl radical cofactor, which is posttranslationally installed by a radical S-adenosyl-L-methionine (SAM) activase, is a simple and effective catalyst, but is also susceptible to oxidative damage in microaerobic environments. Such damage occurs at the glycyl radical cofactor, resulting in cleaved PFL (cPFL). Bacteria have evolved a spare part protein termed YfiD that can be used to repair cPFL. Previously, we obtained a structure of YfiD by NMR spectroscopy and found that the N-terminus of YfiD was disordered and that the C-terminus of YfiD duplicates the structure of the C-terminus of PFL, including a ß-strand that is not removed by the oxygen-induced cleavage. We also showed that cPFL is highly susceptible to proteolysis, suggesting that YfiD rescue of cPFL competes with protein degradation. Here, we probe the mechanism by which YfiD can bind and restore activity to cPFL through enzymatic and spectroscopic studies. Our data show that the disordered N-terminal region of YfiD is important for YfiD glycyl radical installation but not for catalysis, and that the duplicate ß-strand does not need to be cleaved from cPFL for YfiD to bind. In fact, truncation of this PFL region prevents YfiD rescue. Collectively our data suggest the molecular mechanisms by which YfiD activation is precluded both when PFL is not damaged and when it is highly damaged.

Framing and legitimating EU legal regulation of human gene-editing technologies: key facets and functions of an imaginary.

Gene-editing technologies, ie those able to make changes in the DNA of an organism, are the object of global competition and a regulatory race between countries and regions. There is an attempt to craft legal frameworks protective enough for users, but flexible enough for developers of gene-editing technologies. This article examines the imaginary built into the framing of EU-level legal regulation of human gene-editing technologies and identifies its three key related facets: the tension around naturalness; safeguarding morality and ethics; and the pursuit of medical objectives for the protection of human health. Concerns around the use of gene-editing technologies in relation to eugenics and human enhancement have produced a multifaceted imaginary. We argue that this imaginary not only places a limit on EU-level regulation, despite a strong EU competence in respect of the internal market, but also seeks to ensure its legitimation.

Digital readiness in 3D bioprinting: software, governance and hospitals' proto-clinical interfaces.

Aim: To understand the process through which some hospitals have become ready to assimilate the digital technologies required for 3D bioprinting. By enhancing their digital readiness, hospitals will be able to develop the current proto-clinical potentialities of bioprinting. Materials & methods: We conducted interviews with bioprinting researchers, entrepreneurs and regulators in three countries (United Kingdom, Italy and Brazil). We analyzed bioprinting papers in which hospital-based researchers participated. We also analyzed the international bioprinting market. Results: Digital readiness is more advanced in some hospitals and countries, which have noticed the strategic relevance of bioprinting. Furthermore, it is strengthened by the reformulation of the relations between hospitals and other institutions, a phenomenon that is here interpreted with the concept of interfaces.

Use of maximum-dose simvastatin or atorvastatin in an ethnically diverse population.

PURPOSE: The use of maximum-dose simvastatin or atorvastatin in an ethnically diverse population was studied. METHODS: This retrospective analysis was conducted at a publicly funded teaching institution whose predominant patient population consists of Hispanics and Asians. A computer-generated report was used to identify outpatients who received a prescription for maximum-dose simvastatin or atorvastatin between January 1, 2002, and January 1, 2004. Data evaluated included demographic information; metabolic syndrome elements; coronary heart disease (CHD) risk equivalents; clinical characteristics placing patients at very high risk of having a CHD event; 10-year Framingham risk score; documentation of hepatotoxicity, myalgia, myositis, or rhabdomyolysis during maximum-dose therapy; concomitant medication during maximumdose therapy; relevant laboratory test values; and physician response to biochemical abnormalities or adverse events associated with maximum-dose therapy. RESULTS: Of the 232 outpatients identified, 173 were eligible for study inclusion. A total of 135 patients were classified as having a high or very-high risk of developing CHD (68 and 67, respectively). The success rates for low-density-lipoprotein (LDL) cholesterol goal attainment by very-high-risk patients and high-risk patients were 19.4% and 44.1%, respectively. Thirteen patients developed myalgia. Alanine transaminase levels were monitored for 38.8% of the study patients. Approximately 9% of patients were prescribed one interacting medication while on maximum-dose simvastatin or atorvastatin. The most commonly prescribed interacting drug was gemfibrozil. CONCLUSION: Despite the use of maximum-dose simvastatin or atorvastatin, target LDL cholesterol goals were not achieved and statin use was not adequately monitored in an ethnically diverse population with a high or very high risk of developing CHD.