The endocannabinoid system in appetite regulation and treatment of obesity.

The endocannabinoid system (ECS) is a complex cell-signaling system that is responsible for maintaining homeostasis by modulating various regulatory reactions in response to internal and environmental changes. The influence of ECS on appetite regulation has been a subject of much recent research, however, the full extent of its impact remains unknown. Current evidence links human obesity to ECS activation, increased endocannabinoid levels in both central and peripheral tissues, along with cannabinoid receptor type 1 (CBR1) up-regulation. These findings imply the potential pharmacological use of the ECS in the treatment of obesity. Here, we present various pathophysiological processes in obesity involving the ECS, highlighting different pharmacological options for modulating endocannabinoid activity to treat obesity. However, the potential of those pharmacological possibilities remains under investigation and requires further research.

Effectiveness and Safety of mRNA Vaccines in the Therapy of Glioblastoma.

Glioblastoma (GBM) is the most common and most malignant primary brain tumor, presenting significant treatment challenges due to its heterogeneity, invasiveness, and resistance to conventional therapies. Despite aggressive treatment protocols, the prognosis remains poor, with a median survival time of approximately 15 months. Recent advancements in mRNA vaccine technology, particularly the development of lipid nanoparticles (LNPs), have revitalized interest in mRNA-based therapies. These vaccines offer unique advantages, including rapid production, personalization based on tumor-specific mutations, and a strong induction of both humoral and cellular immune responses. mRNA vaccines have demonstrated potential in preclinical models, showing significant tumor regression and improved survival rates. Early-phase clinical trials have indicated that mRNA vaccines are safe and can induce robust immune responses in GBM patients. Combining mRNA vaccines with other immunotherapeutic approaches, such as checkpoint inhibitors, has shown synergistic effects, further enhancing their efficacy. However, challenges such as optimizing delivery systems and overcoming the immunosuppressive tumor microenvironment remain. Future research should focus on addressing these challenges and exploring combination therapies to maximize therapeutic benefits. Large-scale, randomized clinical trials are essential to validate the efficacy and safety of mRNA vaccines in GBM therapy. The potential to reshape the tumor microenvironment and establish long-term immunological memory underscores the transformative potential of mRNA vaccines in cancer immunotherapy.

Bridging healthcare gaps: a scoping review on the role of artificial intelligence, deep learning, and large language models in alleviating problems in medical deserts.

"Medical deserts" are areas with low healthcare service levels, challenging the access, quality, and sustainability of care. This qualitative narrative review examines how artificial intelligence (AI), particularly large language models (LLMs), can address these challenges by integrating with e-Health and the Internet of Medical Things to enhance services in under-resourced areas. It explores AI-driven telehealth platforms that overcome language and cultural barriers, increasing accessibility. The utility of LLMs in providing diagnostic assistance where specialist deficits exist is highlighted, demonstrating AI's role in supplementing medical expertise and improving outcomes. Additionally, the development of AI chatbots offers preliminary medical advice, serving as initial contact points in remote areas. The review also discusses AI's role in enhancing medical education and training, supporting the professional development of healthcare workers in these regions. It assesses AI's strategic use in data analysis for effective resource allocation, identifying healthcare provision gaps. AI, especially LLMs, is seen as a promising solution for bridging healthcare gaps in "medical deserts," improving service accessibility, quality, and distribution. However, continued research and development are essential to fully realize AI's potential in addressing the challenges of medical deserts.

Novel Pharmaceuticals in Appetite Regulation: Exploring emerging gut peptides and their pharmacological prospects.

Obesity, a global health challenge, necessitates innovative approaches for effective management. Targeting gut peptides in the development of anti-obesity pharmaceuticals has already demonstrated significant efficacy. Ghrelin, peptide YY (PYY), cholecystokinin (CCK), and amylin are crucial in appetite regulation offering promising targets for pharmacological interventions in obesity treatment using both peptide-based and small molecule-based pharmaceuticals. Ghrelin, a sole orexigenic gut peptide, has a potential for anti-obesity therapies through various approaches, including endogenous ghrelin neutralization, ghrelin receptor antagonists, ghrelin O-acyltransferase, and functional inhibitors. Anorexigenic gut peptides, peptide YY, cholecystokinin, and amylin, have exhibited appetite-reducing effects in animal models and humans. Overcoming substantial obstacles is imperative for translating these findings into clinically effective pharmaceuticals. Peptide YY and cholecystokinin analogues, characterized by prolonged half-life and resistance to proteolytic enzymes, present viable options. Positive allosteric modulators emerge as a novel approach for modulating the cholecystokinin pathway. Amylin is currently the most promising, with both amylin analogues and dual amylin and calcitonin receptor agonists (DACRAs) progressing to advanced stages of clinical trials. Despite persistent challenges, innovative pharmaceutical strategies provide a glimpse into the future of anti-obesity therapies.

Medical deserts in Spain-Insights from an international project.

INTRODUCTION: Medical deserts are a growing phenomenon across many European countries. They are usually defined as (i) rural areas, (ii) underserved areas or (iii) by applying a measure of distance/time to a facility or a combination of the three characteristics. The objective was to define medical deserts in Spain as well as map their driving factors and approaches to mitigate them. METHODS: A mixed methods approach was applied following the project "A Roadmap out of medical deserts into supportive health workforce initiatives and policies" work plan. It included the following elements: (i) a scoping literature review; (ii) a questionnaire survey; (iii) national stakeholders' workshop; (iv) a descriptive case study on medical deserts in Spain. RESULTS: Medical deserts in Spain exist in the form of mostly rural areas with limited access to health care. The main challenge in their identification and monitoring is local data availability. Diversity of both factors contributing to medical deserts and solutions applied to eliminate or mitigate them can be identified in Spain. They can be related to demand for or supply of health care services. More national data, analyses and/or initiatives seem to be focused on the health care supply dimension. CONCLUSIONS: Addressing medical deserts in Spain requires a comprehensive and multidimensional approach. Effective policies are needed to address both the medical staff education and planning system, working conditions, as well as more intersectoral approach to the population health management.

Artificial intelligence in clinical pharmacology: A case study and scoping review of large language models and bioweapon potential.

This paper aims to explore the possibility of employing large language models (LLMs) - a type of artificial intelligence (AI) - in clinical pharmacology, with a focus on its possible misuse in bioweapon development. Additionally, ethical considerations, legislation and potential risk reduction measures are analysed. The existing literature is reviewed to investigate the potential misuse of AI and LLMs in bioweapon creation. The search includes articles from PubMed, Scopus and Web of Science Core Collection that were identified using a specific protocol. To explore the regulatory landscape, the OECD.ai platform was used. The review highlights the dual-use vulnerability of AI and LLMs, with a focus on bioweapon development. Subsequently, a case study is used to illustrate the potential of AI manipulation resulting in harmful substance synthesis. Existing regulations inadequately address the ethical concerns tied to AI and LLMs. Mitigation measures are proposed, including technical solutions (explainable AI), establishing ethical guidelines through collaborative efforts, and implementing policy changes to create a comprehensive regulatory framework. The integration of AI and LLMs into clinical pharmacology presents invaluable opportunities, while also introducing significant ethical and safety considerations. Addressing the dual-use nature of AI requires robust regulations, as well as adopting a strategic approach grounded in technical solutions and ethical values following the principles of transparency, accountability and safety. Additionally, AI's potential role in developing countermeasures against novel hazardous substances is underscored. By adopting a proactive approach, the potential benefits of AI and LLMs can be fully harnessed while minimizing the associated risks.

Evolving Trends and Economic Burden of Benzodiazepine Use: Insights From a 10-Year Predictive Model.

OBJECTIVES: Benzodiazepines (BZDs) are widely prescribed in Croatia to treat anxiety, insomnia, mood disorders, and epileptic seizures. Long-term BZD use is associated with memory loss, Alzheimer's disease, dependence, addiction, falls in elderly populations, and increased traffic accident risk. METHODS: Drug consumption data were obtained from the Agency for Medicinal Products and Medical Devices of Croatia website. Autoregressive integrated moving average models, constructed using R programming language, forecasted diazepam, alprazolam, and overall BZD utilization and financial costs at a national level over 10 years. RESULTS: BZD consumption increased by up to 18.6% between 2012 and 2020. During the same period, diazepam utilization rose by 29.1%, and alprazolam consumption increased by 19.4%. Our model predicts that, by 2032, BZD, diazepam, and alprazolam utilization will increase substantially. The total projected financial expenditure for BZDs in 2032 is estimated at 14.22 million euros, with diazepam and alprazolam expenditures at 7.39 and 4.12 million euros, respectively. These increases will result in significant growth in healthcare spending and a rise in adverse effects related to long-term use. CONCLUSIONS: National healthcare decision makers should consider implementing regulatory and legislative measures to quantify, specify, and limit monthly BZD use for each patient. This would help control the negative side effects of prolonged BZD use while continuing to provide treatment for patients who genuinely need it.

The European List of Key Medicines for Medical Education: A Modified Delphi Study.

Rational prescribing is essential for the quality of health care. However, many final-year medical students and junior doctors lack prescribing competence to perform this task. The availability of a list of medicines that a junior doctor working in Europe should be able to independently prescribe safely and effectively without supervision could support and harmonize teaching and training in clinical pharmacology and therapeutics (CPT) in Europe. Therefore, our aim was to achieve consensus on such a list of medicines that are widely accessible in Europe. For this, we used a modified Delphi study method consisting of three parts. In part one, we created an initial list based on a literature search. In part two, a group of 64 coordinators in CPT education, selected via the Network of Teachers in Pharmacotherapy of the European Association for Clinical Pharmacology and Therapeutics, evaluated the accessibility of each medicine in his or her country, and provided a diverse group of experts willing to participate in the Delphi part. In part three, 463 experts from 24 European countries were invited to participate in a 2-round Delphi study. In total, 187 experts (40%) from 24 countries completed both rounds and evaluated 416 medicines, 98 of which were included in the final list. The top three Anatomical Therapeutic Chemical code groups were (1) cardiovascular system (n = 23), (2) anti-infective (n = 21), and (3) musculoskeletal system (n = 11). This European List of Key Medicines for Medical Education could be a starting point for country-specific lists and could be used for the training and assessment of CPT.

Using artificial intelligence to create diverse and inclusive medical case vignettes for education.

AIMS: Medical case vignettes play a crucial role in medical education, yet they often fail to authentically represent diverse patients. Moreover, these vignettes tend to oversimplify the complex relationship between patient characteristics and medical conditions, leading to biased and potentially harmful perspectives among students. Displaying aspects of patient diversity, such as ethnicity, in written cases proves challenging. Additionally, creating these cases places a significant burden on teachers in terms of labour and time. Our objective is to explore the potential of artificial intelligence (AI)-assisted computer-generated clinical cases to expedite case creation and enhance diversity, along with AI-generated patient photographs for more lifelike portrayal. METHODS: In this study, we employed ChatGPT (OpenAI, GPT 3.5) to develop diverse and inclusive medical case vignettes. We evaluated various approaches and identified a set of eight consecutive prompts that can be readily customized to accommodate local contexts and specific assignments. To enhance visual representation, we utilized Adobe Firefly beta for image generation. RESULTS: Using the described prompts, we consistently generated cases for various assignments, producing sets of 30 cases at a time. We ensured the inclusion of mandatory checks and formatting, completing the process within approximately 60 min per set. CONCLUSIONS: Our approach significantly accelerated case creation and improved diversity, although prioritizing maximum diversity compromised representativeness to some extent. While the optimized prompts are easily reusable, the process itself demands computer skills not all educators possess. To address this, we aim to share all created patients as open educational resources, empowering educators to create cases independently.

Comparison of reporting rates of arthritis and arthralgia following AstraZeneca, Pfizer-BioNTech, Moderna, and Janssen vaccine administration against SARS-CoV-2 in 2021: analysis of European pharmacovigilance large-scale data.

This study aimed to investigate the reporting rates of arthritis and arthralgia following the administration of four vaccines against SARS-CoV-2: Pfizer-BioNTech (Tozinameran), Moderna (CX-024414), AstraZeneca (Chadox1 NCOV-19), and Janssen (AD26.COV2.S) in 2021. We used data from the EudraVigilance database, specifically analyzing spontaneous reports of suspected adverse reactions (ADRs) from the European Union (EU)/European Economic Area (EEA) region. Age-group-specific reporting rates were calculated by dividing the number of arthralgia and arthritis reports per 1,000,000 vaccine doses administered per age group. Reporting rates were compared using a rate ratio among the four vaccines, using the AstraZeneca vaccine as a comparator. The AstraZeneca vaccine was associated with the highest rate of arthralgia across all age groups. Arthritis reporting rates were significantly lower, with the AstraZeneca vaccine having the highest rates in most age groups, except the 60-69 and 80+ groups, where the Janssen and Pfizer-BioNTech vaccines demonstrated higher reporting rates, respectively. The distribution of arthritis rates did not follow the arthralgia pattern, being higher in the 50-79 age group. This study is the first spontaneous reporting system analysis of arthritis reporting rates post-SARS-CoV-2 vaccination at a European level, revealing a higher reporting of suspected musculoskeletal adverse reactions after AstraZeneca vaccination. The findings underscore the need to consider commonly reported events like arthralgia in risk-benefit assessments prior to vaccination against SARS-CoV-2. Given the high prevalence of rheumatic and musculoskeletal diseases and vaccine hesitancy in this population, our results could influence vaccine choice and acceptance.

The relationship between vaccine acceptance and COVID-19 mortality in Europe: A Cross-Country analysis of public opinion and Epidemiological data.

Introduction: More than two years after SARS-CoV-2 emerged in Wuhan, China, COVID-19 has become one of the most severe pandemics in modern human history. Prior to the widespread availability of specific vaccines in 2021, public opinion surveys indicated significant vaccine hesitancy in 26 European countries. Materials and methods: Epidemiological data on COVID-19 morbidity and mortality for 26 European countries were collected in November 2021 and compared with the proportions of people willing to receive the SARS-CoV-2 vaccine according to public opinion surveys analysed in 2020. Correlations between various variables were calculated using the Pearson correlation test and visualized with the R programming language. Results: Paired Student's t-test revealed no significant differences between survey results and actual vaccination rates (p = 0.9546), suggesting that the polls were good predictors. The percentage of people willing to receive the SARS-CoV-2 vaccine was significantly positively correlated with actual vaccination rates (R = 0.72, p = 0.00003) and significantly negatively correlated with the number of cumulative deaths per million people (R = -0.78, p = 0.0000024). However, there was no significant correlation with the number of cumulative cases per million people (R = -0.27, p = 0.18). These findings indicate that vaccines used in Europe were particularly effective at preventing severe COVID-19 and disease-related deaths, but did not necessarily provide strong protection against SARS-CoV-2 infection itself. Conclusion: Encouraging widespread immunization through vaccination was crucial for rapidly improving the epidemiological situation in Europe.

Antimicrobial Prescribing Preparedness of Croatian Medical Students-Did It Change between 2015 and 2019?

BACKGROUND: Antimicrobials are some of the most prescribed drugs by junior doctors, but studies suggest most medical graduates feel unprepared for their future prescribing tasks. The aim of the present study was to compare the self-reported preparedness to prudently prescribe antimicrobials of final-year medical students in Croatia in 2015 and 2019. METHODS: The same self-reported web-based survey on the preparedness to prescribe antibiotics was used in both 2015 and 2019. All final-year students at all four medical schools in Croatia (Osijek, Rijeka, Split, and Zagreb) were invited to participate in both 2015 and 2019. Preparedness scores were divided into "topic preparedness scores" and "global preparedness scores". Topic preparedness scores represented the percentage of students at a medical school who felt sufficiently prepared for each topic. They were first established at a medical school level and then at the national level. Global preparedness scores were determined for each student separately and then calculated at the medical school and national levels. RESULTS: The country's global preparedness score, representing the average proportion of topics in which students felt sufficiently prepared, was slightly higher in 2015 compared with the 2019 results (62.7% vs. 56.5%; p = 0.191). Croatian students reported higher preparedness in 2015 than in 2019 for 25 out of 27 topics included in the survey. The majority of students reported a need for more education on antibiotic use both in 2015 and 2019 (78.0% vs. 83.0%; p = 0.199). CONCLUSIONS: Despite increasing antimicrobial stewardship activities in various healthcare settings, medical students who are about to start prescribing antibiotics on their own do not feel sufficiently prepared to do so. Antimicrobial stewardship programs should be designed to incorporate undergraduate medical student education, for instance, as a specific, mandatory course or integrated into other courses, such as clinical pharmacology.

Characteristics of medical deserts and approaches to mitigate them: a scoping review.

INTRODUCTION: Medical deserts are increasingly considered problematic and many countries employ a multitude of actions and initiatives to achieve a better distribution of the health workforce (HWF). This study systematically maps research and provides an overview of the definitions/characteristics of medical deserts. It also identifies contributing factors and approaches to mitigate medical deserts. METHODS: Embase, MEDLINE, CINAHL, Web of Science Core Collection, Google Scholar and The Cochrane Library were searched from inception to May 2021. Studies reporting primary research on definitions, characteristics, contributing factors and approaches to mitigate medical deserts were included. Two independent reviewers assessed studies for eligibility, extracted data and clustered studies. RESULTS: Two-hundred and forty studies were included (49% Australia/New Zealand, 43% North America, 8% Europe). All used observational designs except for five quasi-experimental studies. Studies provided definitions (n=160), characteristics (n=71), contributing/associated factors (n=113), and approaches to mitigate medical deserts (n=94). Most medical deserts were defined by the density of the population in an area. Contributing/associated factors consisted in sociodemographic/characteristics of HWF (n=70), work-related factors (n=43) and lifestyle conditions (n=34). Approaches focused on training adapted to the scope of rural practice (n=79), HWF distribution (n=3), support and infrastructure (n=6) and innovative models of care (n=7). DISCUSSION: Our study provides the first scoping review on definitions, characteristics, contributing/associated factors and approaches to mitigate medical deserts. We identified gaps such as the scarcity of longitudinal studies to investigate factors contributing to medical deserts, and interventional studies to evaluate the effectiveness of approaches to mitigate medical deserts.