Divergent roles for STAT4 in shaping differentiation of cytotoxic ILC1 and NK cells during gut inflammation.

Natural killer (NK) cells and type 1 innate lymphoid cells (ILC1) require signal transducer and activator of transcription 4 (STAT4) to elicit rapid effector responses and protect against pathogens. By combining genetic and transcriptomic approaches, we uncovered divergent roles for STAT4 in regulating effector differentiation of these functionally related cell types. Stat4 deletion in Ncr1-expressing cells led to impaired NK cell terminal differentiation as well as to an unexpected increased generation of cytotoxic ILC1 during intestinal inflammation. Mechanistically, Stat4-deficient ILC1 exhibited upregulation of gene modules regulated by STAT5 in vivo and an aberrant effector differentiation upon in vitro stimulation with IL-2, used as a prototypical STAT5 activator. Moreover, STAT4 expression in NCR+ innate lymphocytes restrained gut inflammation in the dextran sulfate sodium-induced colitis model limiting pathogenic production of IL-13 from adaptive CD4+ T cells in the large intestine. Collectively, our data shed light on shared and distinctive mechanisms of STAT4-regulated transcriptional control in NK cells and ILC1 required for intestinal inflammatory responses.

Emerging roles for endogenous retroviruses in immune epigenetic regulation.

In recent years, there has been significant progress toward understanding the transcriptional networks underlying mammalian immune responses, fueled by advances in regulatory genomic technologies. Epigenomic studies profiling immune cells have generated detailed genome-wide maps of regulatory elements that will be key to deciphering the regulatory networks underlying cellular immune responses and autoimmune disorders. Unbiased analyses of these genomic maps have uncovered endogenous retroviruses as an unexpected ally in the regulation of human immune systems. Despite their parasitic origins, studies are finding an increasing number of examples of retroviral sequences having been co-opted for beneficial immune function and regulation by the host cell. Here, we review how endogenous retroviruses have given rise to numerous regulatory elements that shape the epigenetic landscape of host immune responses. We will discuss the implications of these elements on the function, dysfunction, and evolution of innate immunity.

Aquaporin Modulation by Cations, a Review.

Aquaporins (AQPs) are transmembrane channels initially discovered for their role in water flux facilitation through biological membranes. Over the years, a much more complex and subtle picture of these channels appeared, highlighting many other solutes accommodated by AQPs and a dense regulatory network finely tuning cell membranes' water permeability. At the intersection between several transduction pathways (e.g., cell volume regulation, calcium signaling, potassium cycling, etc.), this wide and ancient protein family is considered an important therapeutic target for cancer treatment and many other pathophysiologies. However, a precise and isoform-specific modulation of these channels function is still challenging. Among the modulators of AQPs functions, cations have been shown to play a significant contribution, starting with mercury being historically associated with the inhibition of AQPs since their discovery. While the comprehension of AQPs modulation by cations has improved, a unifying molecular mechanism integrating all current knowledge is still lacking. In an effort to extract general trends, we reviewed all known modulations of AQPs by cations to capture a first glimpse of this regulatory network. We paid particular attention to the associated molecular mechanisms and pinpointed the residues involved in cation binding and in conformational changes tied up to the modulation of the channel function.

Post-marketing surveillance framework of cell and gene therapy products in the European Union, the United States, Japan, South Korea and China: a comparative study.

BACKGROUND: Cell and gene therapy products (CGTPs) often receive accelerated approvals, lacking comprehensive long-term safety and efficacy data, which can raise significant safety concerns. This research aims to study the post-marketing surveillance (PMS) of CGTPs in the European Union (EU), the United States (US), Japan, South Korea, and China, to offer insights for the development of a secure and standardized post-marketing regulatory framework for CGTPs. METHODS: Related regulations and the implementation effect of PMS for approved CGTPs were studied searching PubMed, CNKI, and the official websites of the European Medicines Agency, the US Food and Drug Administration, Japan's Pharmaceuticals and Medical Device Agency, South Korea's Ministry of Food and Drug Safety, and the National Medical Products Administration of China. RESULTS: Compared to those in China, the guidelines of PMS for CGTPs in the EU, the US, Japan, and South Korea was more comprehensive. Notably, the EU had dedicated regulations and supporting guidelines of PMS. Of the 26 CGTPs approved in the EU, 88% were under additional monitoring, 38% received conditional marketing authorization, and 12% were authorized under exceptional circumstances, with 77% designated as orphan drugs. The US had released 34 guidelines specifically for CGTPs which, forming the foundation of post-marketing risk management. Among the 27 CGTPs approved in the US, 22% were required to perform risk evaluation and mitigation strategies, 37% added black box warnings in the package inserts, 63% mandated to post-marketing requirements, and 15% subject to post-marketing commitments. In Japan, stringent supervision measures encompassing all-case surveillance (79%) and re-examination (53%) were applied to the 19 approved CGTPs, with 21% approved through conditional and time-limited approval. The PMS for CGTPs in South Korea, mainly included PSUR, re-examination, and re-evaluation. China had introduced several relevant regulations, which consisted of general statements and lacked detailed guidance. CONCLUSIONS: This study demonstrates that the regulatory policies of PMS for CGTPs in the EU, the US, Japan, and South Korea were comprehensive. The implementation of PMS for CGTPs in the EU, the US, and Japan was well developed. This knowledge holds valuable insights for China's future learning and development in this field.

Advancements in genetically modified insect pest-resistant crops in India.

MAIN CONCLUSION: The review offers insights into the current state of research on insect pest-resistant GM crops and the regulations governing the cultivation of GM crops in India. India has a rich crop diversity of more than 160 major and minor crops through its diverse agroclimatic conditions. Insect pests alone cause around USD 36 billion in crop loss annually in India. The last two decades witnessed considerable progress in managing insect pests by adopting innovative techniques including transgenics. In research, significant advancement has been brought in insect pest-resistant transgenics in India since its inception in 2002. However, any events have not been endorsed owing to biosafety impediments, except Bt cotton reaching the commercial release stage. A landmark decision to exempt certain types of gene-edited plants from genetically modified organism (GMO) regulations offers great promise for developing novel insect-resistant crops in India. The article reviews the current research on insect pest-resistant transgenics and its regulations in India.

Regulatory Aspects of AI-ML.

In the realm of healthcare, numerous generative and non-generative artificial intelligence and machine learning (AI-ML) tools have been developed and deployed. Simultaneously, manufacturers of medical devices are leveraging AI-ML. However, the adoption of AI in healthcare raises several concerns, including safety, security, ethical biases, accountability, trust, economic impact, and environmental effects. Effective regulation can mitigate some of these risks, promote fairness, establish standards, and advocate for more sustainable AI practices. Regulating AI tools not only ensures their safe and effective adoption but also fosters public trust. It is important that regulations remain flexible to accommodate rapid advances in this field to support innovation and also not to add additional burden to some of our preexisting and well-established frameworks. This article covers regional and global regulatory aspects of AI-ML including data privacy, Software as a Medical device (SaMD), agency approval and clearance pathways, reimbursement, and laboratory developed tests (LDTs).

US businesses engaged in direct-to-consumer marketing of perinatal stem cell interventions following the Food and Drug Administration's enforcement discretion era.

BACKGROUND AIMS: The goal of this study was to analyze online marketing representations made by 300 US businesses selling allogeneic perinatal stem cell products. The study was conducted after a period of enforcement discretion by the US Food and Drug Administration (FDA). METHODS: Data mining and content analysis were used to identify, analyze and categorize marketing claims made on the websites of 300 businesses selling perinatal stem cell interventions. RESULTS: The study identified types of perinatal interventions companies advertised, geographic locations of clinics selling such products, types of companies operating in this space, diseases and injuries such businesses claim to treat, prices companies charge for such interventions, brand names of advertised perinatal cell products and identities of suppliers. CONCLUSIONS: A substantial number of US businesses market unapproved perinatal stem cell products for various indications. This widespread commercial activity occurred following the conclusion of a period of enforcement discretion by the FDA and suggests the need for more robust and comprehensive regulatory responses to businesses selling unapproved perinatal stem cell products.

Guardians of precision: advancing radiation protection, safety, and quality systems in nuclear medicine.

BACKGROUND: In the rapidly evolving field of nuclear medicine, the paramount importance of radiation protection, safety, and quality systems cannot be overstated. This document provides a comprehensive analysis of the intricate regulatory frameworks and guidelines, meticulously crafted and updated by national and international regulatory bodies to ensure the utmost safety and efficiency in the practice of nuclear medicine. METHODS: We explore the dynamic nature of these regulations, emphasizing their adaptability in accommodating technological advancements and the integration of nuclear medicine with other medical and scientific disciplines. RESULTS: Audits, both internal and external, are spotlighted for their pivotal role in assessing and ensuring compliance with established standards, promoting a culture of continuous improvement and excellence. We delve into the significant contributions of entities like the International Atomic Energy Agency (IAEA) and relevant professional societies in offering universally applicable guidelines that amalgamate the latest in scientific research, ethical considerations, and practical applicability. CONCLUSIONS: The document underscores the essence of international collaborations in pooling expertise, resources, and insights, fostering a global community of practice where knowledge and innovations are shared. Readers will gain an in-depth understanding of the practical applications, challenges, and opportunities presented by these regulatory frameworks and audit processes. The ultimate goal is to inspire and inform ongoing efforts to enhance safety, quality, and effectiveness in nuclear medicine globally.

Innovative solution or cause for concern? The use of continuous glucose monitors in people not living with diabetes: A narrative review.

AIMS: Continuous glucose monitors (CGMs) have expanded their scope beyond indicated uses for diabetes management and are gaining traction among people not living with diabetes (PNLD). CGMs track in time glucose levels and are proposed as tools for the early detection of abnormal glucose and a potential solution for its normalisation through behavioural change, particularly, diet personalisation and motivation of physical activity. This becomes relevance given the growing incidence of metabolic conditions, such as type 2 diabetes mellitus (T2DM). Clinical guidelines, however, do not recommend CGMs in contexts outside type 1 diabetes (T1DM) or insulin-treated T2DM. Therefore, there is a visible disconnect between the indicated and real-world usage of these medical devices. While the commercial market for CGMs in PNLD is expanding rapidly, a comprehensive and evidence-based evaluation of the devices' utility in this population has not been done. Therefore, this review aims to formulate a working model for CGM utility in PNLD as proposed by the 'health and wellness' market that advertises and distributes it to these individuals. METHODS: We aim to critically analyse the available research addressing components of the working model, that is (1) detection of abnormal glucose; (2) behavioural change, and (3) metabolic health improvement. RESULTS: We find a lack of consistent and high-quality evidence to support the utility of CGMs for these purposes. We identify significantly under-reserved areas including clinical benchmarks and scoring procedures for CGM measures, device acceptability, and potential adverse effects of CGMs on eating habits in PNLD. We also raise concerns about the robustness of available CGM research. CONCLUSION: In the face of these research gaps, we urge for the commercial claims suggesting the utility of the device in PNLD to be labelled as misleading. We argue that there is a regulatory inadequacy that fuels 'off-label' CGM distribution and calls for the strengthening of post-market clinical follow-up oversight for CGMs. We hope this will help to avert the continued misinformation risk to PNLD and 'off-label' exacerbation of health disparities.

A Critical Review on Hydrogen Based Fuel Cell Technology and Applications.

The research in energy storage and conversion is playing a critical role in energy policy as the innovation and technological progress are essential for achieving the energy transition and climate neutrality goals. Hydrogen Fuel Cell technology is considered a strategic element in the pursuit of sustainable and clean energy solutions. This technology is increasingly gaining attention in recent years as a potential substitute to conventional non-renewable energy sources. Fuel cell technology can be employed for domestic/commercial use along with powering the transportation sector which currently employs the use of conventional battery systems. However, these systems pose severe limitations with respect to longer charging times and limited distance range. This review article aims at providing a comprehensive methodical overview of hydrogen-based fuel cell technology along with key concepts, present day scenarios, including overview of the market and industry trends, government policies and initiatives, along with major stakeholders involved in scaling up the technology for mass consumption. The outlook of fuel cells, including their capability to revolutionise the energy sector is discussed. The technological advancements and breakthroughs on the horizon along with the challenges and safety concerns related to the widespread acceptance of fuel cells are analysed.

The dynamic feasibility of resisting (R), accepting (A), or directing (D) ecological change.

Ecological transformations are occurring as a result of climate change, challenging traditional approaches to land management decision-making. The resist-accept-direct (RAD) framework helps managers consider how to respond to this challenge. We examined how the feasibility of the choices to resist, accept, and direct shifts in complex and dynamic ways through time. We considered 4 distinct types of social feasibility: regulatory, financial, public, and organizational. Our commentary is grounded in literature review and the examples that exist but necessarily has speculative elements because empirical evidence on this newly emerging management strategy is scarce. We expect that resist strategies will become less feasible over time as managers encounter situations where resisting is ecologically, by regulation, financially, or publicly not feasible. Similarly, we expect that as regulatory frameworks increasingly permit their use, if costs decrease, and if the public accepts them, managers will increasingly view accept and direct strategies as more viable options than they do at present. Exploring multiple types of feasibility over time allows consideration of both social and ecological trajectories of change in tandem. Our theorizing suggested that deepening the time horizon of decision-making allows one to think carefully about when one should adopt different approaches and how to combine them over time.

La viabilidad dinámica de resistir (R), aceptar (A) o dirigir (D) el cambio ecológico Resumen Las transformaciones ecológicas ocurren por el cambio climático, lo que representa un reto para los enfoques tradicionales para decidir en torno a la gestión de tierras. El marco resistir­aceptar­dirigir (RAD) ayuda a los gestores a considerar cómo responder a este reto. Analizamos cómo la viabilidad de las opciones para resistir, aceptar y dirigir cambia de manera compleja y dinámica con el tiempo. Consideramos cuatro tipos distintos de viabilidad: regulatoria, económica, pública y de organización. Nuestro comentario está basado en la revisión bibliográfica y los ejemplos que existen, pero por necesidad tiene elementos especulativos ya que la evidencia empírica sobre esta estrategia emergente de gestión es escasa. Esperamos que las estrategias de resistir se vuelvan menos viables con el tiempo conforme los gestores encuentren situaciones en las que resistir no es viable de forma ecológica, económica, pública o por regulación. Al igual esperamos que cada vez más los marcos regulatorios permitan su uso, si el costo disminuye, y si el público los acepta, los gestores verán cada vez más viables las estrategias de aceptar y dirigir que las que utilizan actualmente. La exploración de varios tipos de viabilidad a lo largo del tiempo permite considerar las trayectorias sociales y ecológicas del cambio en conjunto. Nuestra teoría sugiere que profundizar en el horizonte temporal de las decisiones permite que se analice con cuidado sobre cuando se deben adoptar enfoques diferentes y cómo combinarlos con el tiempo.

The Elusive Truth of Cannabinoids for Rheumatic Pain.

PURPOSE OF REVIEW: Medical cannabis (MC) has entered mainstream medicine by a unique route. Regulatory acceptance as a medical product in many jurisdictions has bypassed the traditional evidence-based pathway required for therapies. Easier access to MC, especially related to recreational legalization of cannabis, has led to widespread use by patients for symptom relief of a variety of medical conditions and often without medical oversight. Musculoskeletal pain remains the most common reason for MC use. This review examines real-world issues pertaining to MC and offers some guidance for clinical care of patients with rheumatic diseases being treated with MC. RECENT FINDINGS: Controlled clinical studies of cannabis products in patients with rheumatic diseases have been small and tested a range of compounds, routes of administration, and clinical populations, limiting our ability to generate conclusions on MC's effectiveness in this population. Observational cohort studies and surveys suggest that use of MC and related products in patients with rheumatic diseases improves pain and associated symptoms but is commonly accompanied by mild to moderate side effects. Conflicting evidence contributes to practitioner and patient uncertainty regarding the use of MC for rheumatic disease-related pain. Despite promising preclinical and observational evidence that MC and cannabis-derived compounds are useful in the management of rheumatic disease-related pain, there remains limited high-quality clinical evidence to substantiate these findings. There are a significant number of clinical trials on this topic currently planned or underway, however, suggesting the next decade may yield more clarity. Nevertheless, given that many people with rheumatic diseases are using cannabis products, healthcare professionals must remain apprised of the evidence pertaining to cannabinoids, communicate such evidence to patients in a meaningful way that is free from personal bias and stigma, and maintain strong collaborative clinical care pertaining to MC.

The Future of Municipal Wastewater Reuse Concentrate Management: Drivers, Challenges, and Opportunities.

Water reuse is rapidly becoming an integral feature of resilient water systems, where municipal wastewater undergoes advanced treatment, typically involving a sequence of ultrafiltration (UF), reverse osmosis (RO), and an advanced oxidation process (AOP). When RO is used, a concentrated waste stream is produced that is elevated in not only total dissolved solids but also metals, nutrients, and micropollutants that have passed through conventional wastewater treatment. Management of this RO concentrate─dubbed municipal wastewater reuse concentrate (MWRC)─will be critical to address, especially as water reuse practices become more widespread. Building on existing brine management practices, this review explores MWRC management options by identifying infrastructural needs and opportunities for multi-beneficial disposal. To safeguard environmental systems from the potential hazards of MWRC, disposal, monitoring, and regulatory techniques are discussed to promote the safety and affordability of implementing MWRC management. Furthermore, opportunities for resource recovery and valorization are differentiated, while economic techniques to revamp cost-benefit analysis for MWRC management are examined. The goal of this critical review is to create a common foundation for researchers, practitioners, and regulators by providing an interdisciplinary set of tools and frameworks to address the impending challenges and emerging opportunities of MWRC management.

How informal environmental regulations constrain carbon dioxide emissions under pollution control and carbon reduction: Evidence from China.

Exploring whether informal environmental regulations (INER) can achieve carbon reduction in the context of pollution reduction and carbon reduction, as well as how to achieve carbon reduction, can help solve the dual failures of the market and government in environmental protection. Based on the polycentric governance theory and considering the characteristics of social subject environmental participation, the Stackelberg game is used to demonstrate the impact mechanism of INER on CO2. In addition, using the panel data of China's 30 provinces from 2003 to 2018, this paper validates the effectiveness of INER by Pooled Ordinary Least Square (POLS) and threshold panel model. Then, the mediating effect model is used to test the mechanism of INER's effect on carbon reduction. The results show that corruption is not conducive to CO2 reduction. The reduction effect of INER on CO2 exhibits heterogeneity with changes in other non-greenhouse gas pollutants. While INER effectively reduces local corruption, its more substantial indirect impact on CO2 reduction is prominent when levels of other pollutants are lower. Comparative analysis reveals that there are still biased governance behaviors to cope with INER's pressure in some regions nowadays. The findings show that for countries facing the dual task of pollution control and carbon reduction, the key to leveraging the supervisory role of INER should be focused on mitigating information asymmetry caused by the characteristics of CO2. Therefore, in the process of environmental protection, the public environmental participation system should be improved, and the process of disclosing polluters' carbon information should be accelerated.

Opportunity and challenges in recovering and functionalizing anode graphite from spent lithium-ion batteries: A review.

Recent concerns have emerged regarding the improper disposal of spent lithium-ion batteries (LIBs), which has garnered widespread societal attention. Graphite materials accounted for 12-21 wt % of LIBs' mass, typically contain heavy metals, binders, and residual electrolytes. Regenerating spent graphite not only alleviated the shortage of plumbago, but also contributed to the supports environmental protection as well as national carbon peak and neutrality ("dual carbon" goals). Despite significant advancements in recycling spent LIBs had been made, a comprehensive overview of the processes for pretreatment, regeneration, and functionalization of spent graphite from retired LIBs, along with the associated technical standards and industry regulations enabling their smooth implementation still needed to be mentioned. Hence, we conducted the following research work. Firstly, the pre-treatment process of spent graphite, including discharging, crushing, and screening was summed up. Next,. Subsequently, graphite recovery methods, such as acid leaching, pyrometallurgy, and combined methods were summarized. Moreover, the modification and doping approach was used to enhance the electrochemical properties of graphite. Afterwards, we reviewed the functionalization of anode graphite from an economically and environmentally friendly view. Meanwhile, the technical standards and industry regulations of spent LIBs in domestic and oversea industries were described. Finally, we provided an overview of the technical challenges and development bottlenecks in graphite recycling, along with future prospects Overall, this study outlined the opportunities and challenges in recovering and functionalizing of anode materials via a efficient and sustainable processes.

How do different marine engine fuels and wet scrubbing affect gaseous air pollutants and ozone formation potential from ship emissions?

Sulphur Emission Control Areas (SECAs), mandated by the International Maritime Organization (IMO), regulate fuel sulphur content (FSC) to mitigate the environmental and health impact of shipping emissions in coastal areas. Currently, FSC is limited to 0.1% (w/w) within and 0.5% (w/w) outside SECAs, with exceptions for ships employing wet sulphur scrubbers. These scrubbers enable vessels using non-compliant fuels such as high-sulphur heavy fuel oils (HFOs) to enter SECAs. However, while sulphur reduction via scrubbers is effective, their efficiency in capturing other potentially harmful gases remains uncertain. Moreover, emerging compliant fuels like highly aromatic fuels or low-sulphur blends lack characterisation and may pose risks. Over three years, we assessed emissions from an experimental marine engine at 25% and 75% load, representative of manoeuvring and cruising, respectively. First, characterizing emissions from five different compliant and non-compliant fuels (marine gas oil MGO, hydro-treated vegetable oil HVO, high-, low- and ultra-low sulphur HFOs), we calculated emission factors (EF). Then, the wet scrubber gas-phase capture efficiency was measured using compliant and non-compliant HFOs. NOx EF varied among fuels (5200-19700 mg/kWh), with limited scrubber reduction. CO (EF 750-13700 mg/kWh) and hydrocarbons (HC; EF 122-1851 mg/kWh) showed also insufficient abatement. Carcinogenic benzene was notably higher at 25% load and about an order of magnitude higher with HFOs compared to MGO and HVO, with no observed scrubber reduction. In contrast, carbonyls such as carcinogenic formaldehyde and acetaldehyde, acting as ozone precursors, were effectively scrubbed due to their polarity and water solubility. The ozone formation potential (OFP) of all fuels was examined. Significant EF differences between fuels and engine loads were observed, with the wet scrubber providing limited or no reduction of gaseous emissions. We suggest enhanced regulations and emission abatements in the marine sector to mitigate gaseous pollutants harmful to human health and the environment.

Lifecycle of surgical devices: Global, environmental, and regulatory considerations.

BACKGROUND: Technological advancements, improved surgical access, and heightened demand for surgery have fueled unprecedented device and supply turnover impelling wealthy hospitals to upgrade continually and sell, donate, recycle, or dispose of used, expired, antiquated, or surplus goods. This paper reviews the issues related to device and supply lifecycles and discusses the opportunities and challenges they present for sustainable surgical growth in low- and middle-income (LMICs) countries. OBSERVATIONS: This review found, in LMICs countries, regulatory disparities persist that limit effective harmonization secondary to highly variable national policies and a lack of prioritized enforcement. Heterogeneity in the regulatory landscape, specifically in the classification, nomenclature, and identification of medical devices, encumbers effective regulation and distribution. Once devices are sold, donated, or reused in LMICs countries, complexities arise in regulatory compliance, maintenance, and appropriate use of these technologies. At the end of the lifecycle, waste management poses significant obstacles with limited resources hindering the implementation of best practices. CONCLUSION: There are major disparities in access to quality surgical equipment and supplies around the world. Improved communication between relevant stakeholders and harmonization of manufacture and disposal regulations will be needed to ensure adequate and appropriate responses to these challenges. TRIAL REGISTRATION NUMBER: Not applicable.

A comparative analysis of the doctoral regulations at the medical faculties in Germany.

Objective: In order to be allowed to use the title "Dr. med." in Germany, an independent scientific achievement under the supervision of an established scientist is necessary. The research question, analysis and results are essentially carried out and developed independently by the doctoral student. The doctorate serves as proof that the doctoral candidate is capable of independent academic work. The acquisition of scientific skills and knowledge is of particular importance in medicine, as Germany´s international competitiveness is based on the education of today´s young academics. Fair conditions and uniform quality standards for doctoral studies are therefore indispensable to attract future young scientists at an early stage. Methods: The currently valid doctoral regulations of the medical faculties in Germany were analysed with regards to the following target criteria; update date, dissertation language, possibility of publication-based dissertation and its details (number of first and total authorships, publication organ), knowledge of methods and consideration of "Good Medical Practice" (GMP), plagiarism check, review process and disputation. Results: All faculties with the right to award doctorates, and, thus 40 valid regulations were included in the analysis. This revealed a great divergence in the requirements for doctoral candidates. Although a publication-based doctorate is now possible at 93% (n=37) of the faculties, in addition to the monographic dissertation, the required first and total authorships vary from one required first authorship (n=26, 70%) to two or three first authorships (n=5, 14%), as well as some faculties having no information regarding the number of publications (n=6, 16%). The quality of the publication organ was not described in detail in seven faculties (19%). To ensure quality, requirements have increasingly been anchored in the regulations, so that 22 regulations (56%) now stipulate participation in courses on GMP or qualification programmes. The regulations leave a lot of room for manoeuvre in terms of content and do not allow for comparability of the conditions for preparing doctoral researchers. The specifications range from mere mention, to instruction, to compulsory course participation. Another means of quality assurance is the prevention of plagiarism through the applications of software systems. However, this simple and effective means is not yet mentioned in 65% of the regulations (n=26). While the other regulations make use of this possibility, it is not an obligatory application. A total of 34 regulations provide for the regular drawing up of a supervision agreement to define the rights and obligations of the actors involved. Conclusion: The analysis showed a divergent picture. Although imprecise regulations or gaps in information allow scope for design, they also prevent transparency. Despite revisions of many regulations in the past, these revisions have not led to any significant harmonisation. The implementation of standardised and structured doctoral programmes is desirable and could be tackled within the framework of the planned amendment of medical studies. This opens up the possibility of dealing efficiently with the scarce resource of time in the face of competing curriculum content and of making a doctoral project more attractive to potential young scientists at an early stage.

Morin reverses P-glycoprotein-mediated multidrug-resistance in KBChR-8-5 cancer cell lines.

Multidrug resistance (MDR) during clinical chemotherapy for cancer has been considered a major obstacle to treatment efficacy. The involvement of adenosine triphosphate-binding cassette (ABC) transporters in the MDR mechanism significantly reduces the efficacy of chemotherapeutics. This study investigates the potential of morin, a dietary bioflavonoid, to overcome colchicine resistance in KBChR-8-5 MDR cells. The P-gp inhibitory activity by morin was measured by calcein-AM drug efflux assay. Western blot analysis was employed to evaluate P-gp messenger RNA and protein expressions following morin treatment. Flow cytometry analysis and acridine orange/ethidium bromide fluorescence staining were utilised to investigate the induction of apoptosis and cell cycle arrest upon treatment with morin and paclitaxel in combination. Additionally, polymerase chain reaction (PCR) array analysis was conducted to study the gene expression profiles related to MDR, apoptosis and cell cycle arrest during treatment with morin, paclitaxel or their combination. Morin exhibited a strong binding interaction with human P-gp. This was corroborated by drug efflux assays, which showed a reduction in P-gp efflux function with increasing morin concentration. Furthermore, morin and paclitaxel combination potentiated the induction of apoptosis and G2/M phase cell cycle arrest. Morin treatment significantly downregulated the gene expression of ABCB1 and P-gp membrane expressions in MDR cells. Additionally, PCR array gene expression analysis revealed that the combination treatment with morin and paclitaxel upregulated proapoptotic and cell cycle arrest genes while downregulating ABCB1 gene and antiapoptotic genes. Thus, morin effectively reversed paclitaxel resistance in KBChR-8-5 drug-resistant cancer cells and concluded that morin resensitized the paclitaxel resistance in KBChR8-5 drug-resistant cancer cells.

Understanding the secondary outcomes of international travel measures during the covid-19 pandemic: a scoping review of social impact evidence.

BACKGROUND: Assessment of the effective use of international travel measures during the COVID-19 pandemic has focused on public health goals, namely limiting virus introduction and onward transmission. However, risk-based approaches includes the weighing of public health goals against potential social, economic and other secondary impacts. Advancing risk-based approaches thus requires fuller understanding of available evidence on such impacts. METHODS: We conducted a scoping review of existing studies of the social impacts of international travel measures during the COVID-19 pandemic. Applying a standardized typology of travel measures, and five categories of social impact, we searched 9 databases across multiple disciplines spanning public health and the social sciences. We identified 26 studies for inclusion and reviewed their scope, methods, type of travel measure, and social impacts analysed. RESULTS: The studies cover a diverse range of national settings with a strong focus on high-income countries. A broad range of populations are studied, hindered in their outbound or inbound travel. Most studies focus on 2020 when travel restrictions were widely introduced, but limited attention is given to the broader effects of their prolonged use. Studies primarily used qualitative or mixed methods, with adaptations to comply with public health measures. Most studies focused on travel restrictions, as one type of travel measure, often combined with domestic public health measures, making it difficult to determine their specific social impacts. All five categories of social impacts were observed although there was a strong emphasis on negative social impacts including family separation, decreased work opportunities, reduced quality of life, and inability to meet cultural needs. A small number of countries identified positive social impacts such as restored work-life balance and an increase in perceptions of safety and security. CONCLUSIONS: While international travel measures were among the most controversial interventions applied during the COVID-19 pandemic, given their prolonged use and widespread impacts on individuals and populations, there remains limited study of their secondary impacts. If risk-based approaches are to be advanced, involving informed choices between public health and other policy goals, there is a need to better understand such impacts, including their differential impacts across diverse populations and settings.