The implementation of Regulation (EU) No. 536/2014 (CTR) introduced a reformed clinical trial governance system in Italy, based on a single national ethics opinion, replacing the previous decentralized model. This transition has raised important questions regarding how sponsors orient their choice of Ethics Committees (ECs) within the new regulatory framework. The aim of this study is to evaluate geographical trends in sponsor-proposed ECs for clinical trials in Italy between January 2022 and January 2025, and to examine their association with therapeutic area, trial phase, and population characteristics. We conducted a retrospective three-year nationwide analysis based on data from the Italian Medicines Agency (AIFA) and the Clinical Trials Information System (CTIS). Adopting a longitudinal approach, descriptive and comparative evaluations were performed. A total of 1,462 Clinical Trials (CTs) were identified, of which 1,135 (77.8%) involved sponsor-proposed Ethics Committees (ECs), including both legacy ECs operating under Directive 2001/20/EC and Territorial Ethics Committees (TECs) active since June 2023. A marked geographical imbalance emerged in sponsor proposals: 60.2% targeted ECs located in Northern Italy, 26.4% in Central Italy, and 13.4% in Southern Italy and the Islands, with additional intra-regional disparities. Non-commercial sponsors often chose TECs within their own region (64.7%), frequently within the same institution. The results show a concentration of sponsor-proposed ECs in Northern Italy, together with marked intra-regional concentration patterns in regions hosting multiple ECs. The distribution of proposals also indicates that non-commercial sponsors frequently select TECs located within their own region and institution. In the most recent part of the observation period, a modest increase in proposals to Central TECs has been recorded. This nationwide analysis provides a descriptive overview of sponsor-driven EC selection in Italy under the CTR, identifying inter-regional and intra-regional imbalances. While some changes in sponsor behavior are observed in the latest data, continued monitoring over time is required. The observed patterns may be potentially influenced by contextual and organisational factors, as well as by additional variables not directly assessed in the analysis. Future studies incorporating these variables will be important to confirm whether the trends identified here persist over time and to better clarify the factors contributing to their distribution.
Attention-Deficit/Hyperactivity Disorder (ADHD) is a common neurodevelopmental condition that affects attention, impulse control, and the ability to remain still. These challenges can make it harder for individuals with ADHD to succeed at school, work, and in social situations. Stimulant medications, such as methylphenidate and amphetamines, are commonly used as first-line treatments and are effective at reducing symptoms. However, their use can be limited by side effects, such as insomnia, appetite loss, cardiovascular risks, potential for misuse, and variability in individual response. Since current treatments have drawbacks, many people are exploring nonstimulant options, such as behavioral therapy, dietary changes, and neurofeedback. These approaches may be safer and easier to maintain, but research on their effectiveness remains uncertain. This systematic review and meta-analysis aim to compare the effectiveness of pharmacological and nonpharmacological therapies for ADHD. We systematically searched PubMed, PsycINFO, Cochrane Library, ClinicalTrials.gov, and IEEE Xplore for randomized controlled trials (2008-2023) evaluating pharmacological (e.g., stimulant medications), non-pharmacological (e.g., behavioral therapy, cognitive training), or combined interventions in children and adolescents with ADHD. The search yielded 318 records. After screening titles and abstracts, 249 were excluded. Sixty-nine full-text articles were assessed, and 18 RCTs met the inclusion criteria for analysis. Primary outcomes were reductions in ADHD symptoms measured by standardized rating scales; secondary outcomes included academic performance, social functioning, and clinical global impression. Eighteen RCTs were pooled. ADHD symptoms were consistently reduced with stimulant medications (methylphenidate and amphetamines), although effects on academic performance were modest. Non-stimulants, such as viloxazine and guanfacine, showed significant improvements on ADHD-RS scores, but these improvements were only clinically modest. In contrast, some nutritional supplements, particularly iron and omega-3 fatty acids, showed more pronounced benefits in symptom reduction and social functioning. Behavioral and cognitive interventions were not very effective in achieving consistent outcomes. Combined approaches were somewhat more effective in achieving all identified outcomes, particularly social and functional outcomes. Stimulants, such as amphetamines and methylphenidate, consistently showed efficacy in reducing core ADHD symptoms, whereas non-pharmacological interventions showed mixed results. A comprehensive, individualized treatment plan that may combine pharmacological and non-pharmacological approaches often yields the best outcomes in managing ADHD. This review was conducted in accordance with the PRISMA recommendation. The review was entered into the Prospective International Registry of Systematic Reviews (PROSPERO 2024 CRD42024590678).
Primary Amoebic Meningoencephalitis (PAM), caused by Naegleria fowleri, is a rare but highly devastating infection with a mortality rate exceeding 98%. Although historically sporadic, recent emerging cases and localized outbreaks have raised global concern. The disease's rapid progression and diagnostic complexity demand immediate and precise therapeutic intervention, as even minor medication errors can critically impact patient survival. Such medication errors, ranging from incorrect dosing to delayed administration,Primary Amoebic Meningoencephalitis (PAM), caused by Naegleria fowleri, is a rare but devastating infection with a mortality rate exceeding 98%. Although historically sporadic, recent emerging cases and localized outbreaks have heightened global concern. The disease's rapid progression and diagnostic complexity necessitate immediate, precise therapeutic intervention, where even minor medication discrepancies can critically affect survival outcomes. Medication errors ranging from incorrect dosing to delayed administration pose significant clinical and economic challenges, underscoring the need for robust strategic safeguards. Within this context, clinical pharmacists emerge as pivotal agents of patient safety. Their expertise in pharmacotherapy, drug interactions, and adherence to treatment protocols enables them to implement strategic solutions such as: Standardized treatment algorithms for anti-amoebic therapy to minimize dosing errors. Real-time medication reconciliation systems to prevent delays and ensure timely administration. Multidisciplinary coordination frameworks integrating pharmacists with physicians, microbiologists, and intensivists for rapid decision-making. Continuous training and simulation exercises to prepare healthcare teams for rare but high-stakes infections. Digital monitoring and AI-driven alerts to detect potential drug interactions or deviations from protocol. This article synthesizes case reports from the United States, Pakistan, and India, highlighting both historical and recent PAM instances. These narratives emphasize the evolving role of clinical pharmacists in identifying, preventing, and correcting medication-related issues. By bridging clinical insight with pharmaceutical precision, pharmacists not only enhance therapeutic accuracy but also strengthen institutional preparedness against rare infections. As global awareness grows, embedding clinical pharmacy into multidisciplinary care models represents a strategic solution essential not only for PAM but also for other emerging infectious threats where survival hinges on therapeutic precision.
Rheumatoid arthritis (RA) is a chronic, systemic autoimmune disorder and one of the leading causes of disability globally. It affects approximately 1% of the population, significantly impairing quality of life and contributing to increased mortality. The disease is characterized by persistent synovial inflammation, progressive joint destruction, and extra-articular manifestations. This review aims to summarize current management insights into RA pathogenesis, and highlights significant clinical advances, and explore recent patented innovations. A comprehensive narrative review was carried out using PubMed, Google Scholar, Web of Science, ClinicalTrials.gov, and patent databases (Google patent, USPTO) to collect information on pathogenesis, treatment options, clinical trials, and RA-related patents published between 2012 and 2025. Relevance to the treatment of RA, novelty, and translational potential were important inclusion criteria. The cornerstone of managing RA remains conventional and biologic therapies, while JAK inhibitors, epigenetic modulators, and cell- based therapies have recently gained attention. Clinical trials show continued research into combinational therapy approaches, predictive biomarkers, and personalized medicine. Innovation in IL-6, TNF-α, and 14-3-3 pathway targeting agents, as well as natural formulations and new diagnostic tools are also revealed by patent study. Despite advances in disease-modifying antirheumatic drugs (DMARDs) and biologic agents, unmet needs persist, particularly in refractory cases, in biomarker identification and in the development of personalized treatment strategies. Future therapeutic development and individualized intervention strategies can benefit from the integration of new drug targets, clinical trials, and emerging patent trends. This review provides an updated and comprehensive understanding of RA research and development.
Controlling bleeding is one of the most closely monitored aspects of surgery and is considered both a potential complication and a possible source of malpractice, representing a significant risk for the surgeon. Floseal (Baxter Healthcare Corporation) is a hemostatic matrix composed of gelatin and thrombin, designed to control bleeding in surgical settings where standard techniques are ineffective or impractical. This study aimed to provide a comprehensive overview of the use of Floseal kits across a variety of surgical procedures. Particular attention was given to the ergonomic characteristics, usability, and effectiveness of the device in relation to procedural complexity and the associated risk of hemorrhage. Data from 95 clinical cases were collected through a survey of a sample of surgeons from three hospitals in the Tuscany Region (Italy). The survey gathered information on the use of Floseal kits across different types of surgeries, as well as the ergonomic aspects of their application. Additionally, a qualitative ergonomic analysis was performed through indirect observation of videos showing Floseal's use during surgical procedures. Based on these findings, potential medico-legal implications were also evaluated. The survey results indicated that 93% of procedures required only one Floseal kit, with the highest usage observed in open surgeries (76%). The device was rated as highly effective, receiving scores of 4-5 on a Likert scale, and demonstrated excellent ease of use in 73% of cases. In terms of ergonomics, Floseal showed outstanding ease of application without significant difficulties, even in complex procedures such as robotic and laparoscopic surgeries. Attention to proper usage is essential to avoid errors, such as application in non-expandable areas or the risk of intravascular thrombosis. Proper preparation of the device is necessary to ensure rapid intervention times. Additionally, some considerations are discussed regarding the potential role of AI in improving device ergonomics and its applications in surgical practice. Floseal is a highly effective and user-friendly hemostatic device with broad applicability across various surgical specialties. The limited kit consumption per procedure (93% of surgeries required only one kit) contributes to waste reduction and optimal hemorrhage management. Moreover, the ergonomic design and usability of the device enhance its effectiveness in controlling bleeding during surgery.
The management of clinical trial data is an essential component of medical research, where accuracy, security, and transparency directly impact the validity of outcomes. However, conventional methods often face challenges in maintaining data integrity and compliance with regulatory standards. The transformative role of Artificial Intelligence (AI) in enhancing these aspects by leveraging machine learning and analytics offers promising capabilities to improve data validation, detect inconsistencies, and secure sensitive information, thereby increasing credibility among researchers, participants, and regulators. The aim of this study is to explore the transformative potential of artificial intelligence in enhancing clinical trial data management. It specifically investigates whether AI can improve data integrity, transparency, and security, thus making the results credible to the researcher, participant, and regulatory bodies involved. The study employs machine learning algorithms and advanced analytics to investigate the role of AI in identifying data anomalies, verifying the accuracy of information, and validating data processes. Case studies and real-world applications are presented to highlight how AI enables real-time monitoring, reporting, and verification of regulatory compliance. It also analyzes encryption and access control systems powered by AI, ensuring that sensitive clinical trial data is protected against breaches and unlawful access. The findings demonstrate that AI significantly streamlines the management of clinical trial data through automated data validation processes, the detection of inconsistent data, and the capability for real-time data monitoring. AI encryptions and access control systems minimize data security risks to safeguard sensitive information. Case studies demonstrate that transparency, regulatory compliance, and stakeholder trust improve when AI is integrated into clinical trial processes. The study shows AI significantly enhances clinical trial data management through automated validation, real-time monitoring, and anomaly detection. Throughout the trial process, these capabilities reduce errors, ensure regulatory compliance, and improve transparency. Additionally, AI-driven encryption and access control systems offer robust protection against data breaches, reinforcing participant confidentiality and stakeholder trust. Case study analysis demonstrates that AI not only streamlines data workflows but also fosters greater confidence in trial outcomes, signaling a shift toward more efficient, secure, and credible AI-enabled clinical trials. The study highlights the potential of AI to revolutionize the management of clinical trial data with aspects such as data integrity, transparency, and security. The incorporation of AI ensures the credibility of trial outcomes among all stakeholders. This study advocates for a paradigm shift toward AI-enabled clinical trials, shedding light on the revolutionary approach it proposes for healthcare data management practices.
Central nervous system and peripheral clocks regulate the rhythms of life. Main zeitgebers are light-darkness, nutrition, and fasting cycles. There is a fine interaction among human body clocks, and different stimuli can affect and modulate biorhythms. Nutrition is one of these. Its role is still under investigation, especially in healthy status balance maintenance of critical and noncritical patients. For these reasons, a narrative review of the current literature on the definition of circadian clocks, their regulation, and the role of diet in their fine-tuning in critical and non-critical care patients was conducted. A search was conducted on PubMed and Medline for original articles, reviews, meta-analyses, and case series matching the following keywords and associations: enteral nutrition; circadian rhythms; chrononutrition; critically ill patient; personalized nutrition. A total of 1188 manuscripts were identified according to keywords. Subsequently, 579 articles were removed due to duplication, 208 due to non-English language, book chapter publications, and non-matching keyword combinations. The remaining 401 papers were checked for eligibility, and 170 manuscripts were accepted. Human central and peripheral circadian clocks are affected by several zeitgebers. Food micro- and macronutrients and time of administration can all affect peripheral clocks and interact with central ones. In critical and non-critical care patients, route and timing of artificial nutrition administration should consider the behaviour of different central and peripheral circadian clocks. This is also affected by inherited genetic biotypes. In detail, specific macronutrient patterns modulate peripheral clock gene expression and influence metabolic recovery in critically ill patients. In fact, timed and/or time-restricted setups of enteral nutrition administration (namely, timed enteral nutrition refers to administration according to circadian rhythms) show promising and yet incomplete data on their efficacy for restoring healthy status in the patients. Human circadian rhythms recognize nutrition as one of the main regulators. Both food composition and administration schemes can help to establish effective cycles in critical and non-critical admitted patients.
The pharmaceutical industry has undergone significant regulatory evolution, particularly in India, with the replacement of Schedule Y by the New Drugs and Clinical Trial (NDCT) Rules. These changes reflect India's commitment to ensuring the efficacy, safety, and quality of drugs while aligning with global standards. To conduct the literature search for the review, we employed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) approach from 2013 to 2024 for selecting titles and abstracts. The following keywords were used: Clinical Trial Regulations, CDSCO, FDA, and EMA. Further, the databases, such as Medline, PubMed, Embase, and Scopus, were explored for the searches. The clinical trial framework of India, overseen by the Central Drugs Standard Control Organization (CDSCO), emphasizes expedited approval pathways, ethical oversight by Institutional Ethics Committees (IECs), and cost-effectiveness. Its large and diverse patient pool, along with adherence to Good Clinical Practice (GCP) standards, makes it attractive for multinational trials. Regulatory reforms, such as mandatory trial registration and digital initiatives, further enhance transparency and efficiency. While India shares common ground with the USA and Europe on many regulatory aspects, it stands out for its efficient processes and accessibility, positioning itself as a key hub for global clinical research. Comparisons reveal India's focus on improving efficiency through digitalization and continuous reforms, underscoring its role in advancing clinical trial practices worldwide. The regulatory evolution of India demonstrates a strong commitment to medical innovation, patient safety, and ethical standards, positioning it as a competitive player in global clinical research. Ongoing collaboration among industry, academia, and regulatory bodies is crucial for addressing emerging challenges and promoting a harmonized, patient-centric approach to clinical trials.
Messenger RNA (mRNA) vaccine technology has recently emerged as a revolutionary platform in modern immunology and vaccinology. Unlike conventional vaccines that rely on attenuated pathogens or protein subunits, mRNA vaccines deliver genetic instructions to host cells to produce antigenic proteins that trigger robust immune responses. The widespread success during the COVID-19 pandemic accelerated global interest in this platform. However, challenges such as mRNA instability, degradation by extracellular RNases, and delivery barriers still limit its broader application in other therapeutic areas. This review provides an in-depth analysis of current advancements in mRNA vaccine development, focusing on mRNA structure stabilization, innovative carrier systems, immunogenicity modulation, and potential clinical applications beyond infectious diseases. It also compares mRNA vaccines to traditional vaccine platforms and highlights their advantages and future prospects. A comprehensive literature survey was conducted using databases such as PubMed, Google Scholar, ScienceDirect, and Web of Science with keywords "mRNA vaccine", "lipid nanoparticles", "delivery systems", "immunogenicity", "cancer vaccines", "stability enhancement techniques", and "COVID-19". Research articles, clinical trial reports, patents, and review papers published between 2000 and 2025 were screened. Out of more than 300 publications, 126 relevant articles were selected based on novelty, scientific contribution, and relevance to vaccine development and delivery. The gathered information was critically organized and summarized. The review highlights formulation strategies such as nucleoside-modified mRNA, selfamplifying mRNA, and circular mRNA to enhance stability and translation efficiency. Delivery vectors including lipid nanoparticles (LNPs), polymeric nanoparticles, and lipid-polymer hybrids are discussed, emphasizing their role in protecting mRNA from degradation and enabling targeted delivery. In addition to infectious diseases, the use of mRNA vaccines for cancer immunotherapy and personalized medicine is examined. Clinical findings confirm high efficacy and potent immune responses, although reactogenicity and cold-chain dependence remain major limitations. This review offers a comprehensive overview of mRNA vaccine development and highlights key scientific innovations addressing the inherent challenges of mRNA instability and delivery. By comparing current delivery strategies and formulation methods, it provides valuable insights for researchers designing next-generation mRNA vaccines with improved safety, efficacy, and broader applicability. mRNA vaccines represent a transformative approach in vaccine science, with tremendous potential for rapid adaptation against emerging pathogens and personalized treatment strategies. Ongoing research aimed at improving thermostability, reducing adverse immune responses, and expanding disease coverage may further strengthen global acceptance of mRNA technology. Continued advances in delivery systems and regulatory approval frameworks will be essential for expanding its application across therapeutic domains.
The pharmaceutical industry operates within a complex regulatory environment, requiring strict compliance with global guidelines. Regulatory affairs (RA) departments are pivotal in ensuring drug approvals and compliance. However, the increasing complexity and volume of regulatory requirements have put a strain on traditional processes, driving the adoption of automation tools to streamline these operations. This review aims to explore the key automation tools used in regulatory affairs, focusing on their role in streamlining submissions, ensuring compliance, centralizing data, and reducing human error. It also aims to examine the emerging technologies in the field and their potential for enhancing automation. A comprehensive review of current automation tools in regulatory affairs was conducted. The key tools explored include Submission Management Systems (SMS), Regulatory Information Management (RIM) systems, Electronic Document Management Systems (EDMS), and Regulatory Intelligence Tools. Additionally, the role of emerging technologies like Artificial Intelligence (AI) and Machine Learning (ML) in automating regulatory processes was evaluated. Automation tools such as SMS, RIM, EDMS, and Regulatory Intelligence Tools have been found to significantly improve the efficiency of regulatory affairs operations. These tools streamline submissions, centralize data, and ensure compliance. AI and ML technologies further enhance automation by enabling predictive analytics and automating risk assessments. Despite the advantages, challenges remain, including high implementation costs, data security concerns, and the need to adapt to varying global regulations. However, overcoming the challenges and limitations associated with these technologies in adopting regulatory automation is crucial. This study highlights that automation tools are important for modernizing regulatory affairs by improving efficiency, accuracy, and compliance. The integration of Artificial Intelligence (AI) and Machine Learning (ML) adds predictive and adaptive capabilities, transforming static processes into dynamic systems. These technologies hold immense potential to reshape regulatory operations globally. Automation tools are becoming essential in the pharmaceutical industry to maintain regulatory compliance, reduce time-to-market, and manage the increasing complexity of drug development in a globalized industry. As emerging technologies like AI, ML, and blockchain continue to evolve, they promise to further revolutionize regulatory affairs processes.
In cancer treatment, immunotherapy can be used as an adjuvant therapy in combination with chemotherapy. This review article provides a comprehensive analysis of immunotherapeutics used in combination with chemotherapy that are in clinical trials, focusing on their synergy and applications. An in-depth literature search was conducted across various scientific databases, including PubMed, ClinicalTrials.gov, Scopus, and Web of Science, using relevant keywords. Both research studies and relevant data from clinical trials were thoroughly analyzed to provide a comprehensive overview of the field. The analysis indicated that immunotherapy, when used as an adjunct to established chemotherapy regimens, is more effective than when used as a standalone treatment. Immunotherapeutics enhance the body's defenses against malignant cells, while chemotherapy directly targets rapidly dividing cancer cells. Moreover, interesting recent findings have suggested that certain chemotherapy agents at low doses selectively inhibit regulatory and suppressor cells, thereby enhancing the body's immune response against cancer cells. The findings further underscore the potential synergy between chemotherapy and immunotherapy. This review delves into the concept of integrating chemotherapy and radiotherapy, which induces cell death, with immunotherapy. Specifically, emphasis is placed on ongoing clinical trials investigating immunotherapeutics in combination with chemotherapeutic agents, offering a glimpse into the future landscape of cancer treatment. Immuno-chemotherapeutic combinations offer an immense opportunity, as demonstrated by numerous clinical trials. In the future, a deeper understanding of their interactions and mechanisms, identifying the optimal combination, and careful assessment of clinical responses are key to successful product development.
Natural bioactive compounds have significant potential for the development of therapeutic interventions, but the success of their discovery and use is greatly influenced by the development of efficient methods for their extraction, structural determination, quantification, and validation. Existing reviews have failed to adequately address the analytical approaches for the efficient determination of bioactive compounds, which is the main purpose of this systematic review: to comprehensively evaluate the current methods used in the extraction, determination of the structure, quantification, validation, and dose-response relationship in the assessment of natural bioactive compounds, which may be derived from plant and marine sources, with the aim of determining their structures for the development of new drugs, as well as validating the results obtained from the use of these compounds. An extensive simulated search was carried out on prominent scientific information sources, such as PubMed, Scopus, and Google Scholar, to gather literature published from 2000 to 2024. The literature selected for the study was based on the information provided on the extraction methods, structural elucidation mechanisms, analytical validation, and pharmacological investigation of bioactive compounds derived from plants. The information on 40 bioactive compounds and the analytical mechanisms was gathered and synthesized. Extraction is normally carried out using techniques such as Soxhlet extraction, MicrowaveAssisted Extraction (MAE), and maceration. For structural analysis, the most preferred methods include Nuclear Magnetic Resonance (NMR), Mass Spectrometry (MS), Fourier Transform Infrared Spectroscopy (FTIR), Ultraviolet-Visible Spectroscopy (UV-Vis), and X-ray crystallography. Validation indicates excellent linearity (R² > 0.99), specificity, and accuracy with %RSD < 2. Dose-response curves for compounds such as curcumin, quercetin, and silymarin indicate excellent potency, as indicated by IC50 values < 50 µM. However, drawbacks include issues such as interference in the matrix, the high cost of equipment, and the lack of universal standardization methods. The evidence is sound: modern spectroscopy and chromatography techniques provide impressive accuracy. However, disparities in standardization practices and expenses make it difficult to fully embrace the approach. This review highlights the importance of blending eco-friendly solvents and cost-effective approaches to fill the gap. For the purpose of precise characterization of bioactive compounds, it is necessary to integrate extraction techniques with analytical validation and spectroscopy. This review offers a useful guide to help researchers in selecting the best possible strategies depending on the nature of the compound and the objectives of the research. It also emphasizes the need to standardize analytical techniques and the feasibility of using green solvents.
The advent of decentralized clinical trials (DCTs) has altered the usual trends in clinical trials, and this presents an ethical, regulatory, and operational dilemma, particularly to the low-and middle-income countries (LMICs). This review critically examines the ethical preparedness of countries in South Asia to transform to the DCT paradigm. We consider the readiness of such nations as India, Bangladesh, Pakistan, Sri Lanka, Nepal, Bhutan, and the Maldives by weighing the local regulatory environments and establishing a difference in ethical safeguards, cyber infrastructure, and protection of participants. The paper specifically focuses on some of the fundamental themes, including the concept of informed consent in the virtual world, data security, the digital literacy problem, and the evolving nature of the local ethics committees. Case studies allow us to identify systemic gaps, especially the ones that were provoked by the COVID-19 pandemic, and propose ways to harmonize ethics with the comparative regulatory matrix. The focus is on regionalization of international standards, including ICH-GCP, and intergovernmental cooperation, as well as the effective construction of strong and inclusive systems of governance. This review offers strategic suggestions that policymakers may implement to enhance ethical resilience in the South Asian passage to a decentralized, data-driven future of clinical research.
In the context of metastatic disease, most studies have focused on ConRT for oligo-progressive disease, while data on outcomes with radical Con-RT in oligopersistent disease remain limited. We have been practicing Con-RT in patients who responded to first-line systemic therapy, including both oncogene addicted and non-addicted patients. To gain insight into the outcomes with Con-RT, we audited our real-world data in a resource-constrained setting. Metastatic NSCLC (2016-2022) who responded to first-line chemotherapy or targeted therapy and had oligo-persistent disease were offered radical chest RT (60Gy/30#/55Gy/20# or 45Gy/25#). The primary endpoint was Overall Survival (OS) and progression-free survival, which was derived with KM survival curves. Prognostic factors affecting OS were analyzed with a Cox regression model. A Propensity Score Analysis (PSA) was performed to adjust for potential confounding factors. Among 190 patients (71% males), 54% had adenocarcinoma. Metastatic staging included M1a (30%), M1b (13.6%), M1c (47.8%), and Mx (10%). First-line treatment comprised chemotherapy (50%), targeted therapy (14%), or CT/targeted therapy followed by Con-RT (21%); 3% received palliative RT alone, and 15% did not receive further treatment. Factors significant on univariate analysis for OS were smokers with median OS (4 mo. vs 6 mo., p =0.01), women (8 mo. vs 5 mo., p =0.05), M status (M1a 8 mo; M1b 6 mo; M1c 4 mo., p =0.05), type of treatment (No treatment 2 mo.; CT 4 mo; targeted 6 mo; Con RT 18 mo, p =0.001), and Con RT 18 mo vs No-RT 4 mo, p =0.001). On multivariate analysis, factors retained as significant were smokers HR 1.7 (95%CI, 1.2-2.5 p =0.004) and Con RT [HR 0.28 (95%CI 0.14-0.55) p=0.001]. On univariate analysis, factors significantly affecting the Progression-Free Survival (PFS) were females with median PFS (05 mo. vs 0 mo., p =0.02), type of treatment (No treatment 0 mo.; CT 0 mo.; targeted therapy 4 mo.; Con-RT 8 mo, palliative RT 6 mo., p =0.001), and Con-RT [Yes vs No] (10 mo. vs 0 mo, p =0.001). In the multivariate analysis, factors retained significant were females with HR 1.5 (95% CI 1.08-2.1, p =0.01), and Con-RT with HR 0.42 (95% CI 0.22-0.82, p <0.01). The OS benefit was similar even after PSA (Mean OS 21 mo. [Con-RT] vs 7 mo. [No-RT], p =<0.001). Local failures were significantly reduced, and the ratio of local versus distant recurrences was 1:4. The rates of grade 3 pneumonitis and grade 3 esophagitis were 7% and 2%, respectively. Our results show that radical intent Con-RT in responders to first-line systemic therapy yields a favorable survival benefit at no added cost of toxicity. Our real-world data demonstrates that Radical Con RT significantly improves OS and PFS in oligo-persistent metastatic NSCLC. These results are practice-changing and should be further evaluated in extensive prospective studies.
Type 1 diabetes mellitus (T1DM) results from progressive damage to pancreatic β- cells, leading to insufficient insulin production and impaired glucose regulation. The autoimmune destruction of β-cells reduces their functional mass, causing chronic hyperglycemia and associated complications. Recently, microRNAs (miRNAs) have emerged as important regulators of gene expression and play key roles in various cellular processes and pathways. This review aims to provide a comprehensive overview of how miRNA-375 influences β-cell biology and to explore its potential as a therapeutic target in T1DM. By examining the complex interplay between miRNA-375, β-cell function, and autoimmunity, this article contributes to the development of strategies for early detection, prevention, and potential treatment of T1DM. Electronic databases, including PubMed/Medline, Scopus, and Google Scholar, were searched for case reports and series, case-control, cohort, and cross-sectional studies, as well as reviews, from the inception of the databases to December 2024. The role of miRNAs in the onset and progression of T1DM has received considerable attention in recent years. Among them, miRNA- 375 is particularly significant due to its influence on β-cell function and apoptosis. Alterations in miRNA-375 levels have been observed during both the preclinical and clinical stages of T1DM. Developing reliable, non-invasive methods for monitoring miRNA-375 is critical for translating these findings into clinical applications. Future research should focus on establishing highly sensitive and specific assays for its measurement.
Urinary tract infections (UTIs) caused by multidrug-resistant, biofilmforming Klebsiella pneumoniae represent a serious global health concern. Conventional antibiotics often fail due to resistance and biofilm-associated tolerance, necessitating novel diagnostic and therapeutic strategies. This study investigated interleukin-8 (IL-8) as a diagnostic marker and evaluated the anti-virulence potential of ellagic acid against extended-spectrum β-lactamase (ESBL)-producing K. pneumoniae. This study was a cross-sectional, experimental, and analytical investigation conducted from August 2023 to March 2024. Serum IL-8 levels were quantified in patients and healthy controls using ELISA. The antibiotic susceptibility of K. pneumoniae isolates was assessed according to CLSI guidelines, and ESBL activity was determined by the nitrocefin hydrolysis test. Biofilm formation was quantified using the crystal violet assay, with and without ellagic acid treatment. In silico docking studies were conducted using AutoDock Vina to predict interactions between ellagic acid and the CTX-M-15 β-lactamase, Wza, FabH, and SdiA proteins. IL-8 levels were significantly higher in patients (223.8 ± 43.5 pg/mL) compared with controls (47.9 ± 17.3 pg/mL; p < 0.0001). All isolates were resistant to ampicillin and showed broad resistance to other antibiotics. Ellagic acid significantly reduced biofilm biomass (p = 0.0002) but concurrently increased ESBL activity (p = 0.0001). Docking demonstrated that ellagic acid was strongly bound to CTX-M-15 (-8.3 kcal/mol), had moderate interactions with Wza and SdiA, whereas the interaction with FabH was relatively low. The high concentration of IL-8 supports its use as a biomarker to detect K. pneumoniae infections. The elevated resistance profile of K. pneumoniae to antibiotics highlights the urgent need for alternative treatment approaches. Though ellagic acid increased ESBL activity, it showed distinct antibiofilm activity and responses with virulence-related proteins, indicating a modulatory action that may reduce bacterial pathogenicity. Limitations include the lack of in vivo validation and the need to mechanistically elucidate the modulation of ESBL. IL-8 is a valuable biomarker for ESBL-producing K. pneumoniae infection. Ellagic acid reduces biofilm formation and targets bacterial resistance and virulence proteins, supporting its potential as a natural anti-virulence agent against multidrug-resistant K. pneumoniae.
Virtual clinical trials (VCTs) represent an innovative approach to clinical research, using computer simulations and digital modeling rather than traditional human participants. These trials harness computational power and artificial intelligence to model the effects of medical treatments, drastically reducing costs, time, and logistical complexities. As this technology advances, VCTs offer the potential to streamline drug development, enhance precision, and make clinical research more accessible and efficient. However, the shift away from traditional human-based trials raises significant ethical concerns, particularly regarding the validity of results, regulatory oversight, and the potential reduction of human involvement in the research process. This paper explores the economic, ethical, and practical aspects of VCTs in clinical medicine, with a focus on their potential to revolutionize clinical trials and the challenges they present. Future lines of research will also be proposed to address these issues.
Chronic osteomyelitis is a complex and persistent orthopedic infection. Antibiotic-loaded calcium sulfate (CS) has promoted the eradication of infection and bone regeneration. To evaluate the early and mid-term clinical outcomes of antibiotic-impregnated CS in the management of chronic osteomyelitis following internal fixation. A prospective interventional case series included (n=15) patients with chronic osteomyelitis treated at Al Yarmouk Teaching Hospital. The patient's medical, surgical history, Additionally, patients' and physical examination were recorded. inflammatory markers and microbiological culture from sinus discharge. Imaging was performed to classify the type of infection according to the Cierny and Mader classification. All patients underwent extensive surgical debridement and implantation of CS loaded with vancomycin or tobramycin, and systemic antibiotics were administered according to culture results. Patients were followed up for 1 year to assess functional scores and infection eradication. The mean age was 36.86±9.41 years, with 66.7% male and 33.3% female. Tibia was involved in (46.7%). Methicillin-Resistant Staphylococcus Aureus was isolated in (66.67%) of all cases. After a one-year follow-up, all cases achieved infection resolution. Functional scores improved significantly, from 26.8 to 64.2 (P < 0.001). Antibiotic-loaded CS as an adjuvant to surgical debridement and systemic antibiotics shows promising results with higher rates of infection eradication and significant functional improvement. Using CS loaded with antibiotics as complementary therapy with systemic antibiotics demonstrated significant infection control and functional recovery in patients with chronic osteomyelitis following internal fixation during the early and mid-term follow up. Future studies need a larger sample and a longer follow up.
Disinfection of the root canal system is crucial for the effectiveness of root canal treatment. Lasers and photoactivated disinfection (PAD) have emerged as preferred methods for eliminating pathogens from the root canal. Sixty intact, freshly extracted adult human uniradicular mature teeth with a single root canal were collected. The crowns were removed, resulting in canals measuring 14 mm in length. The root canals were prepared, sterilized, and then inoculated with broth containing Enterococcus faecalis (E. faecalis), followed by incubation for 30 days in an aerobic environment at 37°C. Biofilm formation was verified using a scanning electron microscope. The samples were randomly divided into six experimental groups (n = 10). Group 1 consisted of teeth treated only with distilled water. Group 2 teeth received 3% NaOCl and 17% EDTA as part of Conventional Chemomechanical Debridement (CCMD) but no additional treatment. Groups 3-6 also received CCMD followed by additional laser disinfection as follows: Group 3 underwent photoactivated disinfection (PAD) using riboflavin with a 450 nm laser; Group 4 underwent PAD using toluidine blue O (TBO) with a 635 nm laser; Group 5 underwent conventional laser endodontics (CLE) with an 808 nm laser; and Group 6 underwent CLE using triple wavelengths of 450 nm, 635 nm, and 808 nm. The Kruskal-Wallis test revealed significant differences in colony-forming units (CFUs) among the groups after treatment (p < 0.001). Subsequent analysis showed that the difference in mean CFUs between the PAD groups and the CLE groups was not statistically significant. The group treated with the triple laser wavelength exhibited the lowest average CFUs/mL, while the distilled water group had the highest mean value. The study confirms that diode laser-assisted disinfection significantly enhances bacterial reduction compared with conventional irrigation alone. Although PAD methods reduced E. faecalis, their effect was not statistically superior to conventional laser endodontics (CLE). The triplewavelength diode laser group achieved the greatest bacterial reduction, likely due to the synergistic effects of thermal and photochemical interactions. These findings support the adjunctive use of laser disinfection to improve root canal decontamination, particularly when combined with chemomechanical preparation. This study demonstrates that combining an irrigating solution with a diode laser enhances the effectiveness of reducing pathogenic numbers.
The recently published article reported that approximately 500 million individuals live with diabetes and cardiovascular disease (CVD) worldwide. It is well known that individuals with systemic diseases have a higher risk of developing dental problems. This review aims to update the association between dental problems in people with cardiovascular disease and diabetes. By searching PubMed, Web of Science, and Scopus, an evaluation of scientific texts (n=120) was conducted based on the subject of attention. The strong association between periodontitis and atherosclerotic CVD suggested that patients with severe periodontitis are at an increased risk of developing CVD. In such conditions, dentists should be aware of dysfunctions associated with the saliva, which can individually increase the incidence of caries. The conditions related to the extraction sockets could be worsened due to inflammation, immune, endocrine, and neural aspects in patients with hyperglycemia. Periodontal disease is the sixth most common complication of diabetes. Diabetes mellitus is considered the most common cause of hospital admission. There is a higher chance of periodontal disease and tooth loss in patients with diabetes. Periodontitis could be associated with glycemic control. Using subgingival instrumentation, accompanied by indigenous or total antimicrobials, and occasionally by surgical intervention to remove gum tissue when periodontitis is severe, restores glycaemic control in individuals with both periodontitis and diabetes. Oral dysbiosis could be associated with the aortic valve due to bacteria. Intervention and routine dental check-ups are recommended in patients with CVD and diabetes to reduce periodontal inflammation.