Myelin bilayer mapping in the human brain in vivo.

PURPOSE: To quantitatively map the myelin lipid-protein bilayer in the live human brain. METHODS: This goal was pursued by integrating a multi-TE acquisition approach targeting ultrashort T2 signals with voxel-wise fitting to a three-component signal model. Imaging was performed at 3 T in two healthy volunteers using high-performance RF and gradient hardware and the HYFI sequence. The design of a suitable imaging protocol faced substantial constraints concerning SNR, imaging volume, scan time, and RF power deposition. Model fitting to data acquired using the proposed protocol was made feasible through simulation-based optimization, and filtering was used to condition noise presentation and overall depiction fidelity. RESULTS: A multi-TE protocol (11 TEs of 20-780 µs) for in vivo brain imaging was developed in adherence with applicable safety regulations and practical scan time limits. Data acquired using this protocol produced accurate model fitting results, validating the suitability of the protocol for this purpose. Structured, grainy texture of myelin bilayer maps was observed and determined to be a manifestation of correlated image noise resulting from the employed acquisition strategy. Map quality was significantly improved by filtering to uniformize the k-space noise distribution and simultaneously extending the k-space support. The final myelin bilayer maps provided selective depiction of myelin, reconciling competitive resolution (1.4 mm) with adequate SNR and benign noise texture. CONCLUSION: Using the proposed technique, quantitative maps of the myelin bilayer can be obtained in vivo. These maps offer unique information content with potential applications in basic research, diagnosis, disease monitoring, and drug development.

Societal costs of illegal drug use in Sweden.

BACKGROUND: Illegal drug use is a public health concern with far-reaching consequences for people who use them and for society. In Sweden, the reported use of illegal drugs has been growing and the number of drug-induced deaths is among the highest in Europe. The aim of this study was to provide a comprehensive and up-to-date estimation of the societal costs of illegal drug use in Sweden, relying as much as possible on registry and administrative data. METHODS: A prevalence-based cost-of-illness study of illegal drug use in Sweden in 2020 was conducted. A societal approach was chosen and included direct costs (such as costs of health care, social services, and the criminal justice system), indirect costs (such as lost productivity due to unemployment and drug-induced death), and intangible costs (such as reduced quality of life among people who use drugs and their family members). Costs were estimated by combining registry, administrative, and survey data with unit cost data. RESULTS: The estimated societal costs of illegal drug use were 3.7 billion euros in 2020. This corresponded to 355 euros per capita and 0.78 % of the gross domestic product. The direct and intangible costs were of similar sizes, each contributing to approximately 40 % of total costs, whereas indirect costs contributed to approximately 20 %. The largest individual cost components were reduced quality of life among people who use drugs and costs of the criminal justice system. CONCLUSION: Illegal drug use has a negative impact on the societal aim to create good and equitable health in Sweden. The findings call for evidence-based prevention of drug use and treatment for those addicted. It is important to address the co-morbidity of mental ill-health and drug dependence, to develop low-threshold services and measures for early prevention among children and young adults, as well as to evaluate laws and regulations connected to illegal drug use.

Emergency Regulatory Procedures, Pharmaceutical Regulatory Politics, and the Political Economy of Vaccine Regulation in the COVID-19 Pandemic.

CONTEXT: Regulatory approaches to COVID-19 vaccine authorizations varied substantially across countries. Facing a common public health threat, what accounts for regulatory variation? This study focuses on emergency pharmaceutical and vaccine regulatory procedures and whether and how regulators' emergency pharmaceutical regulatory procedures going into the pandemic shaped regulatory processes and decisions during the pandemic. METHODS: The authors conducted an analysis of seven high-impact national and international pharmaceutical regulators with case studies from Brazil, China, India, Russia, the United Kingdom, the United States, and the European Medicines Agency. The authors analyzed evidence from primary source executive and legislative branch regulations and statutes as well as national and international scientific and general press reporting; they also drew on the secondary analysis of scholars, practitioners, and international organizations. FINDINGS: Inherited emergency pharmaceutical and vaccine regulatory procedures substantially shaped COVID-19 vaccine regulation during the pandemic. Variation in the presence and content of emergency regulatory procedures affected the quality of pandemic regulatory processes, outcomes, and procedural updates and differentially empowered policy-making experts and elected politicians. CONCLUSIONS: Emergency regulatory procedures affect key features of regulatory political economy and public health practices during crises. To improve future public health crisis responses, the authors provide policy recommendations for (1) establishing clear emergency pharmaceutical regulatory procedures, and (2) international collaboration.

Comprehensive, Evidence-Based, Consensus Guidelines for Prescription of Opioids for Chronic Non-Cancer Pain from the American Society of Interventional Pain Physicians (ASIPP).

BACKGROUND: Opioid prescribing in the United States is decreasing, however, the opioid epidemic is continuing at an uncontrollable rate. Available data show a significant number of opioid deaths, primarily associated with illicit fentanyl use. It is interesting to also note that the data show no clear correlation between opioid prescribing (either number of prescriptions or morphine milligram equivalent [MME] per capita), opioid hospitalizations, and deaths. Furthermore, the data suggest that the 2016 guidelines from the Centers for Disease Control and Prevention (CDC) have resulted in notable problems including increased hospitalizations and mental health disorders due to the lack of appropriate opioid prescribing as well as inaptly rapid tapering or weaning processes. Consequently, when examined in light of other policies and complications caused by COVID-19, a fourth wave of the opioid epidemic has been emerging. OBJECTIVES: In light of this, we herein seek to provide guidance for the prescription of opioids for the management of chronic non-cancer pain. These clinical practice guidelines are based upon a systematic review of both clinical and epidemiological evidence and have been developed by a panel of multidisciplinary experts assessing the quality of the evidence and the strength of recommendations and offer a clear explanation of logical relationships between various care options and health outcomes. METHODS: The methods utilized included the development of objectives and key questions for the various facets of opioid prescribing practice. Also utilized were employment of trustworthy standards, and appropriate disclosures of conflicts of interest(s). The literature pertaining to opioid use, abuse, effectiveness, and adverse consequences was reviewed. The recommendations were developed after the appropriate review of text and questions by a panel of multidisciplinary subject matter experts, who tabulated comments, incorporated changes, and developed focal responses to questions posed. The multidisciplinary panel finalized 20 guideline recommendations for prescription of opioids for chronic non-cancer pain. Summary of the results showed over 90% agreement for the final 20 recommendations with strong consensus. The consensus guidelines included 4 sections specific to opioid therapy with 1) ten recommendations particular to initial steps of opioid therapy; 2) five recommendations for assessment of effectiveness of opioid therapy; 3) three recommendations regarding monitoring adherence and side effects; and 4) two general, final phase recommendations. LIMITATIONS: There is a continued paucity of literature of long-term opioid therapy addressing chronic non-cancer pain. Further, significant biases exist in the preparation of guidelines, which has led to highly variable rules and regulations across various states. CONCLUSION: These guidelines were developed based upon a comprehensive review of the literature, consensus among expert panelists, and in alignment with patient preferences, and shared decision-making so as to improve the long-term pain relief and function in patients with chronic non-cancer pain. Consequently, it was concluded - and herein recommended - that chronic opioid therapy should be provided in low doses with appropriate adherence monitoring and understanding of adverse events only to those patients with a proven medical necessity, and who exhibit stable improvement in both pain relief and activities of daily function, either independently or in conjunction with other modalities of treatments.

Synthetic biomedical data generation in support of In Silico Clinical Trials.

Living in the era of Big Data, one may advocate that the additional synthetic generation of data is redundant. However, to be able to truly say whether it is valid or not, one needs to focus more on the meaning and quality of data than on the quantity. In some domains, such as biomedical and translational sciences, data privacy still holds a higher importance than data sharing. This by default limits access to valuable research data. Intensive discussion, agreements, and conventions among different medical research players, as well as effective techniques and regulations for data anonymization, already made a big step toward simplification of data sharing. However, the situation with the availability of data about rare diseases or outcomes of novel treatments still requires costly and risky clinical trials and, thus, would greatly benefit from smart data generation. Clinical trials and tests on animals initiate a cyclic procedure that may involve multiple redesigns and retesting, which typically takes two or three years for medical devices and up to eight years for novel medicines, and costs between 10 and 20 million euros. The US Food and Drug Administration (FDA) acknowledges that for many novel devices, practical limitations require alternative approaches, such as computer modeling and engineering tests, to conduct large, randomized studies. In this article, we give an overview of global initiatives advocating for computer simulations in support of the 3R principles (Replacement, Reduction, and Refinement) in humane experimentation. We also present several research works that have developed methodologies of smart and comprehensive generation of synthetic biomedical data, such as virtual cohorts of patients, in support of In Silico Clinical Trials (ISCT) and discuss their common ground.

mRNA: Vaccine or Gene Therapy? The Safety Regulatory Issues.

COVID-19 vaccines were developed and approved rapidly in response to the urgency created by the pandemic. No specific regulations existed at the time they were marketed. The regulatory agencies therefore adapted them as a matter of urgency. Now that the pandemic emergency has passed, it is time to consider the safety issues associated with this rapid approval. The mode of action of COVID-19 mRNA vaccines should classify them as gene therapy products (GTPs), but they have been excluded by regulatory agencies. Some of the tests they have undergone as vaccines have produced non-compliant results in terms of purity, quality and batch homogeneity. The wide and persistent biodistribution of mRNAs and their protein products, incompletely studied due to their classification as vaccines, raises safety issues. Post-marketing studies have shown that mRNA passes into breast milk and could have adverse effects on breast-fed babies. Long-term expression, integration into the genome, transmission to the germline, passage into sperm, embryo/fetal and perinatal toxicity, genotoxicity and tumorigenicity should be studied in light of the adverse events reported in pharmacovigilance databases. The potential horizontal transmission (i.e., shedding) should also have been assessed. In-depth vaccinovigilance should be carried out. We would expect these controls to be required for future mRNA vaccines developed outside the context of a pandemic.

Informed consent in cancer clinical drug trials in China: a narrative literature review of the past 20 years.

BACKGROUND: Although the number of cancer clinical drug trials is increasing rapidly in China, issues concerning informed consent in this research context are understudied. By performing a narrative literature review, we aim to describe the current situation and identify the most salient challenges affecting informed consent in cancer clinical drug trials among adult patients in China since 2000. METHODS: We searched Web of Science (WOS), PubMed, Scopus, EMBASE, the Cochrane Library databases, China National Knowledge Infrastructure (CNKI), China Biomedical Literature Database on Disc (CBMdisc), Chinese Scientific Journals Fulltext Database (CQVIP), and WANFANG Data to identify relevant publications since 2000. Data were extracted by three reviewers on six items pertaining to study type, theme, and challenges. RESULTS: We identified 37 unique manuscripts, from which 19 full texts were obtained and six were included in the review. All six studies were published in Chinese journals, and the publication years of the majority (five out of six) of the studies were 2015 or later. The authors of the six studies were all from clinical departments or ethical review committees at five hospitals in China. All of the included publications were descriptive studies. Publications reported challenges related to the following aspects of informed consent: information disclosure, patient understanding, voluntariness, authorization, and procedural steps. CONCLUSION: Based on our analysis of publications over the past two decades, there are currently frequent challenges related to various aspects of informed consent in cancer clinical drug trials in China. Furthermore, only a limited number of high-quality research studies on informed consent in cancer clinical drug trials in China are available to date. Efforts toward improvement of informed consent practice, in the form of guidelines or further regulations in China, should draw on both experience from other countries and high-quality local evidence.

Provider experiences with relaxing restrictions on take-home medications for opioid use disorder during the COVID-19 pandemic: A qualitative systematic review.

BACKGROUND: Historical restrictions on take-home medications for opioid use disorder have generated considerable debate. The COVID-19 pandemic shifted the perceived risks and benefits of daily clinic attendance and led to widespread policy reform, creating an unprecedented opportunity to explore the impact of more flexible prescribing. We conducted a qualitative systematic review to synthesize the evidence on providers' experiences with relaxing restrictions on take-home doses of medications prescribed for opioid use disorder during the COVID-19 pandemic. METHODS: The protocol for this systematic review was registered in PROSPERO (CRD42022360589; https://www.crd.york.ac.uk/prospero/). From Sept.-Nov. 2022, we searched Medline, Embase, CINAHL, PsycInfo, Web of Science, the Cochrane Register of Controlled Trials, and the grey literature from 2020 onward. Studies were eligible for inclusion if they used qualitative methods to investigate providers' experiences with relaxed restrictions on take-home medications for opioid use disorder during the COVID-19 pandemic. We appraised study quality using the CASP qualitative checklist and used thematic synthesis and GRADE-CERQual to synthesize the results. RESULTS: We retrieved 13 articles representing 11 studies. Six were conducted in the United States and most focused on changes to methadone treatment. Providers' experiences with increased flexibilities around take-homes were broadly positive, despite widespread initial concern over client safety and the potential for medication misuse. For a small number of providers, concerns about diversion were a specific manifestation of more general unease with loss of control over clients and the treatment process. Most providers appreciated increased flexibilities and described them as enabling more individualized, person-centered care. CONCLUSION: Our findings support the continuation of flexibilities around take-homes and demonstrate that regulations and policies that reduce flexibility around take-homes conflict with person-centered approaches to care. Stronger guidance and support from professional regulatory agencies may help increase uptake of flexibilities around take-homes.

State Variation in Antipsychotic Use Among Assisted Living Residents With Dementia.

OBJECTIVES: More than two-thirds of assisted living (AL) residents have dementia or cognitive impairment and antipsychotics are commonly prescribed for behavioral disturbances. As AL communities are regulated by state-level policies, which vary significantly regarding the care for people with dementia, we examined how antipsychotic prescribing varied across states among AL residents with dementia. DESIGN: This was an observational study using 20% sample of national Medicare data in 2017. SETTING AND PARTICIPANTS: The study cohort included Medicare beneficiaries with dementia aged 65 years or older who resided in larger (≥25-bed) ALs in 2017. METHODS: The study outcome was the percentage of eligible AL person-months in which antipsychotics were prescribed for each state. We used a random intercept linear regression model to shrink estimates toward the overall mean use of antipsychotics addressing unstable estimates due to small sample sizes in some states. RESULTS: A total of 20,867 AL residents with dementia were included in the analysis, contributing to 194,718 person-months of observation. On average, AL residents with dementia were prescribed antipsychotics during 12.6% of their person-months. This rate varied significantly by state, with a low of 7.8% (95% CI 5.9%-10.3%) for Hawaii to a high of 20.5% (95% CI 16.4%-25.3%) for Wyoming. CONCLUSIONS AND IMPLICATIONS: We observed significant state variation in the prescribing of antipsychotics among AL residents with dementia using national data. These variations may reflect differences in state regulations regarding the care for AL residents with dementia and suggest the need for further investigation to ensure high quality of care.

Implementation of a centralized pharmacovigilance system in academic pan-European clinical trials: Experience from EU-Response and conect4children consortia.

Setting-up a high quality, compliant and efficient pharmacovigilance (PV) system in multi-country clinical trials can be more challenging for academic sponsors than for companies. To ensure the safety of all participants in academic studies and that the PV system fulfils all regulations, we set up a centralized PV system that allows sponsors to delegate work on PV. This initiative was put in practice by our Inserm-ANRS MIE PV department in two distinct multinational European consortia with 19 participating countries: conect4children (c4c) for paediatrics research and EU-Response for Covid-19 platform trials. The centralized PV system consists of some key procedures to harmonize the complex safety processes, creation of a local safety officer (LSO) network and centralization of all safety activities. The key procedures described the safety management plan for each trial and how tasks were shared and delegated between all stakeholders. Processing of serious adverse events (SAEs) in a unique database guaranteed the full control of the safety data and continuous evaluation of the risk-benefit ratio. The LSO network participated in efficient regulatory compliance across multiple countries. In total, there were 1312 SAEs in EU-Response and 83 SAEs in c4c in the four trials. We present here the lessons learnt from our experience in four clinical trials. We managed heterogeneous European local requirements and implemented efficient communication with all trial teams. Our approach builds capacity for PV that can be used by multiple academic sponsors.

Delta-8 tetrahydrocannabinol: a scoping review and commentary.

BACKGROUND AND AIMS: Delta-8 tetrahydrocannabinol (THC) is a psychoactive substance from the Cannabis plant that has been rising in popularity in the United States since the 2018 US Farm Bill implicitly legalized it. This study reviewed research from peer-reviewed and non-peer-reviewed (e.g. anecdotal and news) reports related to delta-8 THC to summarize current knowledge and implications for public health and safety. METHODS: A scoping review was conducted using PubMed, Scopus, Google Scholar and Google as search engines, leading to the identification of 103 documents that were summarized. The themes that emerged were (1) legality, (2) use (popularity, motives, psychoactivity/potency, benefits/consequences), (3) synthesis (byproducts, laboratory testing) and (4) retail (availability, price, packaging, youth-oriented marketing). A second author independently coded 20% of the documents, which verified the categorization of articles by these emergent themes. RESULTS: Most research used animal/cell models or focused upon ways to identify the chemical structure of delta-8 THC in various products. Findings suggest that people often use delta-8 THC as a substitute for other substances. Anecdotally, delta-8 THC is a less potent psychoactive than delta-9 THC; however, several negative consequences have been reported. There is no federal age restriction for purchase/possession of delta-8 THC products. Delta-8 THC is readily accessible on-line, is typically less expensive than delta-9 THC and is often marketed in ways that would seemingly appeal to children. There are no regulations on synthesis, resulting in products being contaminated and/or yielding inconsistent effects. There have been thousands of calls to US poison control centers due to accidental delta-8 THC exposure among minors. CONCLUSIONS: Most research on delta-8 THC is largely anecdotal, not peer-reviewed and does not involve human subjects. Future research should examine delta-8 THC use using nationally representative samples to more clearly understand the prevalence and consequences of use. Laws are needed to mitigate the risks of using delta-8 THC, particularly quality control of synthesis and minimum purchase age.

[Clinical trials with investigational medicinal products-initial experiences with the new EU clinical trial regulation 536/2014 and challenges and opportunities for contract research organisations]. / Klinische Prüfung von Arzneimitteln ­ erste Erfahrungen mit der neuen EU-Verordnung 536/2014, Herausforderungen und Chancen für Auftragsforschungsinstitute.

The new authorisation procedure for clinical trials on medicinal products according to Regulation (EU) No 536/2014 (Clinical Trial Regulation - CTR) became applicable in the European Union and the European Economic Area on 31 January 2022. All involved parties communicate digitally via a specially programmed IT system, the Clinical Trial Information System (CTIS), provided by the European Medicines Agency (EMA). This article highlights the cooperation between sponsors and Contract Research Organisations (CROs) when applying the CTR and CTIS.First experiences and observed trends are described focusing on user administration in CTIS and on activities related to the protection of personal data and commercially confidential information (CCI) when clinical trials are published. Challenges for CROs are multifaceted and are discussed from different angles. For example, it is necessary for CROs to temporarily maintain a Quality Management System that serves both "systems": clinical trials under the EU-Directive 2001/20 as well as under the CTR. CTR and CTIS offer not only new tasks for CROs; they often become advisors for sponsors on the basis of their extensive experience, for example, regarding the cooperation model between sponsors and CROs and/or the strategic model for submission of a clinical trial. The article concludes with a look into possible future sponsor outsourcing strategies.

Invited review: Shelf-stable dairy protein beverages-Scientific and technological aspects.

Consumer focus on health and wellness is driving the growth in high-protein dairy beverages. The review discusses shelf-stable ready-to-drink beverages that are primarily dominated by sports nutrition and the "better for you" beverage categories. Both of these categories tend to have a "high in protein" claim. Because of their functionality, sensorial attributes, and protein quality, dairy protein ingredients are the ingredients of choice to meet protein claims. Due to the higher protein content of the beverages, the functionality of dairy protein ingredients plays a critical role in final product quality and stability. In the United States, Food and Drug Administration regulations classify shelf-stable foods into acid/acidified and low-acid foods. The differentiation is based on pH and water activity (aw). In the context of shelf-stable high-protein dairy beverages, any beverage with aw of >0.85 and with a finished equilibrium pH of >4.6 is classified as low acid. Beverages to which acids or acid foods are added and have a finished equilibrium pH of ≤4.6 and aw >0.85 are classified as acidified food. Acid foods have a natural pH of ≤4.6. The final pH requirement of these shelf-stable products will affect the type of dairy protein used in these applications. In acidified dairy protein beverages, the go-to ingredient is whey protein. In low-acid beverages, the protein ingredients of choice are milk protein ingredients (with a casein-to-whey protein ratio of 80:20, as found in typical bovine milk) and casein-enriched ingredients. Rendering the product shelf-stable depends on whether the product is classified as acidified or low acid. Low-acid, shelf-stable beverages, in general, have 2 manufacturing options: retort and UHT processing, followed by hermetic sealing. Pasteurization is the standard processing choice for shelf-stable acidified beverages, followed by hot fill. Because of differences in pH and heat loads during the manufacture of high-protein dairy beverages, the functionality of protein ingredients will play an essential role in determining the final beverage quality. Two of the most important functional properties of dairy protein ingredients that have a role in producing these beverages are solubility and heat stability. This review elucidates the physicochemical properties of dairy protein ingredients for low- and high-acid shelf-stable dairy protein applications, analytical techniques to characterize protein ingredients, beverage processing conditions, and quality defects observed.

Perspectives for licensing vaccines in Mexico.

Vaccine products represent one of the most successful public health measure to this day. This has been reflected during the current COVID-19 pandemic where more than 4.87 billion people have received at least one vaccine dose. In Latin America, Mexico occupies the second position in terms of the number of vaccinated people with 83.97 million people receiving at least a single dose. As in other countries, regulatory approval in Mexico is one of the key aspects that influences the public access to vaccines. This creates an active interplay between regulatory authorities establishing a regulatory framework to assure the quality, safety and efficacy of the vaccines, and applicants fulfilling this information. Mexico is a member of the International Council for Harmonisation (ICH) and it has adopted the Common Technical Document (CTD) for providing this information. This is particularly useful for vaccines developed abroad where it is expected to speed the evaluation of the new product. The Secretariat of Health of Mexico (SALUD) has published guidelines and laws or regulations related to GMP, labeling, stability, clinical trials, biocomparability and pharmacovigilance for drug products including vaccines which are classified as biological products. SALUD has also established guidelines and international homologating agreements to facilitate the application process for vaccine approval. Nevertheless, technical and scientific information and administrative processes for vaccine approval might be relatively concealed. Therefore, we aim to enable researchers and manufacturers in Mexico and overseas to better understand these requirements. To our knowledge, this is the most up-to-date and comprehensive attempt to present this information, also including information for COVID-19 vaccines. Here we describe the current requirements and processes by COFEPRIS, the national regulatory agency, for vaccine licensing and for emergency use authorization for COVID-19 vaccines in Mexico.

Comparison of Teleconsultations and In-Person Consultations from Outpatients with Rheumatoid Arthritis, During the COVID-19 Pandemic: An Internal Audit of Medical Notes.

Introduction: The objectives of this study were to compare the quality-of-care and compliance with medical record regulations between in-person consultations (QIP and CIP) and telephone consultations (QTP and CTP), from rheumatoid arthritis (RA) outpatients, during the COVID-19 pandemic, and to explore the impact of the consultation modality on the treatment. Methods: Data from 324 medical notes corresponding to rheumatic consultations between July and December 2020 were abstracted. Notes were selected considering a stratified (in-person and telephone consultations) random sampling strategy. QIP, CIP, QTP, and CTP were scored based on prespecified criteria as percentages, where higher numbers translated into better standards. Logistic regression analysis investigated the association between the consultation modality and the treatment recommendation (dependent variable). Results: There were 208 (64.2%) medical notes related to in-person consultations and 114 (35.2%) to telephone consultations. Overall, medical notes corresponded to middle-aged women with long-standing disease. QIP was superior to QTP (median, interquartile range): 60% (60-75%) versus 50% (25-60%), p ≤ 0.001, and differences were related to disease activity and prognosis documentation (81.3% vs. 34.5% and 55.8% vs. 33.6%, respectively, p ≤ 0.001) and the prolonged prescription of glucocorticoids with a documented management plan (58.5% vs. 30.4%, p = 0.045). Meanwhile, CIP and CTP were similar. Telephone consultation was a significant risk factor for no changes in the treatment recommendation (odds ratio: 2.113, 95% confidence interval: 1.284-3.479, p = 0.003), and results were consistent in the 142 medical notes with documented absence of disease activity. Conclusions: In the clinical context of RA, the quality-of-care provided by telephone consultations is below the standard of care and impacts the treatment.

Application of PDCA Process Management in Day Operation Ward and the Influence of Nursing Quality and Safety.

Objective: To survey the application of PDCA (plan, do, check, and action) process management in day operation ward and the influence of nursing quality and safety. Methods: The routine nursing management was carried out in our hospital from March 2019 to March 2020, which was set as the control group (N = 20), and the PDCA process management was implemented from March 2020 to March 2021 as the research group (N = 20). Twenty nurses and patients were selected as subjects in two periods of time. The nursing quality, the score of individual quality control examination in clinical department, the nursing quality of operating room, the incidence of adverse events and nursing errors, the number of problems existing in the quality management of nursing documents, and the score of nursing satisfaction were accessed. Results: In the comparison of nursing quality, the nursing safety, specialty quality, and nursing norms of the study group were higher compared to the control (P < 0.05). In terms of the scores of individual quality control examination in clinical departments, the scores of ward management, rescue, therapeutic articles, drug management, first-level nursing, nursing documents, and head nurses in the study group were greater compared to the control (P < 0.05). In terms of the operating room nursing quality score, the instrument management, instrument preparation, nurses' cooperation skills, disinfection and isolation quality, and the total score of the study group were above the control (P < 0.05). In terms of the incidence of operative adverse events and nursing errors, the incidence of nosocomial infection, iatrogenic injury, information check error, equipment failure, violation of operation regulations, ECG monitoring error, infusion operation error, and medication error in the study group was lower compared to the control (P < 0.05). According to the comparison of the number of problems existing in the quality management of nursing documents, the number of problems in temperature sheet, medical order, evaluation sheet, nursing record, and other nursing documents in the study group was lower than the control (P < 0.05). The scores of nursing communication, professional technology, nursing service attitude, nursing environment, and knowledge education in the study group were higher in contrast to the control (P < 0.05). Conclusion: The application of PDCA management can effectively enhance the nursing quality and safety of the day operation ward, further facilitate the quality of hospital nursing work, and improve patient satisfaction, which exert great potential, and application value in the management of day ward in the future.

Activation of Investigator-Initiated Clinical Trials with a Pharmaceutical for Cancer Patients before and after Post-Millennial Changes of Regulations in Germany and Europe.

Shortly after the beginning of the year 2000, multiple legal changes with impacts on the regulatory framework of clinical trials became effective almost simultaneously. They included the European Union (EU) Clinical Trial Directive (CTD) 2001/20 followed by major changes in national drug laws, the change in the legal status of German University Hospitals (1998), and a new disease-related groups (DRG)-based reimbursement system for hospitals in Germany (2000). Together, these changes created enormous bureaucratic and financial inhibition of activation and conduct of academic investigator-initiated clinical trials (IIT). Examples for activating clinical trials in oncology before and after 2004 are outlined and discussed, focussing on extended time frames, the establishment of centralized responsibility structures and the exploding financial consequences. In addition, the evolution of trial numbers and the distribution of trial initiators between "commercial" and "academic" over time are discussed together with the occurrence of clinical registries. At the same time, progress in molecular biology led to a plethora of new targets for effective pharmacological therapy of life-threatening diseases such as cancer, and the overall number of clinical trials has not decreased. Yet, judging the regulatory and administrative hurdles between scientific study design and first-patient on trial before and after 2004 and weighing these against the lack of evidence that this regulation has achieved its goal to enhance patient safety and trial quality, the necessity to completely overhaul this CTD becomes obvious. A main goal of such an initiative should be to minimize bureaucracy. For the specific situation in Germany, relocation of responsibility and freedom to operate in University Hospitals and Medical Faculties back to the physician-scientists and reduction in interference by legal divisions should be a goal as well as increasing the public financial support for IITs.

PAciFy Cough-a multicentre, double-blind, placebo-controlled, crossover trial of morphine sulphate for the treatment of pulmonary Fibrosis Cough.

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a progressive disease that leads to lung scarring. Cough is reported by 85% of patients with IPF and can be a distressing symptom with a significant impact on patients' quality of life. There are no proven effective therapies for IPF-related cough. Whilst morphine is frequently used as a palliative agent for breathlessness in IPF, its effects on cough have never been tested. PAciFy Cough is a multicenter, double-blind, placebo-controlled, crossover trial of morphine sulphate for the treatment of cough in IPF. METHODS: We will recruit 44 subjects with IPF prospectively from three interstitial lung disease units in the UK, namely the Royal Brompton Hospital, Manchester University NHS Foundation Trust (MFT) and Aintree University Hospital NHS Foundation Trust. Patients will be randomised (1:1) to either placebo twice daily or morphine sulphate 5 mg twice daily for 14 days. They will then crossover after a 7-day washout period. The primary endpoint is the percent change in daytime cough frequency (coughs per hour) from baseline as assessed by objective cough monitoring at day 14 of treatment. DISCUSSION: This multicentre, randomised trial will assess the effect of opioids on cough counts and cough associated quality of life in IPF subjects. If proven to be an effective intervention, it represents a readily available treatment for patients. TRIAL REGISTRATION: The study was approved by the UK Medicines and Healthcare Regulatory Agency (Ref: CTA 21268/0224/001-0001 - EUDRACT 2019-003571-19 - Protocol Number RBH2019/001) on 08 April 2020, in compliance with the European Clinical Trials Directive and the Medicines for Human Use (Clinical Trials) Regulations 2004 and its subsequent amendments. The study was provided with ethical approval by the London Brent Research Ethics Committee (Ref: 20/LO/0368) on 21 May 2020 and is registered with clinicaltrials.gov (NCT04429516) on 12 June 2020, available at https://clinicaltrials.gov/ct2/show/NCT04429516.

Meeting report: an exploration into the scientific and regulatory aspects of pharmaceutical drug quality in the United States.

INTRODUCTION: The University of Florida College of Pharmacy, Department of Pharmaceutical Outcomes and Policy hosted a seminar 6-7 March 2021, on the quality of pharmaceutical products in the United States. This meeting report summarizes the topics presented at the seminar and highlights the expert opinions offered by the presenters. AREAS COVERED: The seminar, held virtually due to the COVID-19 pandemic, included slide presentations and faculty-moderated panel discussions from experts in the field. These experts from regulatory, academic, and private sectors discussed bioequivalence standards, existing and emerging efforts to promote quality in brand and generic manufacturing, as well as market-based solutions throughout the drug supply chain. EXPERT OPINION: The time spent understanding bioequivalence standards during the seminar felt especially important and relevant in our current pandemic environment, given the present need to have confidence in the science of drug development and to advocate for the safety of pharmaceuticals. Also an important point to emphasize from the seminar, was that every stakeholder along the drug supply chain has a responsibility to do their part to maintain its quality. And those in attendance, many of whom were students of healthcare sciences, were encouraged to be leaders in their fields and develop strategies to advance innovative improvements.

Innovative medicine development.

BACKGROUND: In recent years the global landscape of pharmaceutical development has evolved drastically in order to adapt to innovative products such as immunotherapy, regenerative medicines and cell and gene therapy, all offering the hope to cure numerous untreated diseases. The global COVID-19 pandemic also led competent authorities in charge of approval of new medicines to implement adapted regulatory pathways allowing early access to innovative treatments and vaccines. New challenges are to be overcome, it is the short development time, or the small patient populations, or again drug product features requiring complete new production, testing and distribution strategies. OBJECTIVE: This paper provides a short overview of the different adaptations required to allow the development of such innovative medicines. METHOD: Several drug development strategies for products under clinical development or recently approved were assessed. RESULTS: Fully integrated strategies encompassing research, non-clinical, clinical and product manufacturing development along with adapted regulatory pathways, anticipation of market access and supported by risk based are important. In such fast pace, the development of relevant manufacturing processes and test methods assessing quality, safety and efficacy of new drugs falls on the critical path and requires particular attention, anticipation and detailed planning as early as possible in order to ensure successful filing and approval. CONCLUSION: Insights within innovative products approved recently reveal the importance of defining a solid chemistry manufacturing and control strategy early on as part of clinical development. Interactions with agencies at key milestones of development are also essential to reduce risks, prioritize development to support safety and allow early access to patients.