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Background: Numerous studies support a bidirectional association between rheumatoid arthritis (RA), a chronic autoimmune degenerative inflammatory joint disease, and periodontitis, a chronic inflammatory disease caused by the immune reaction to bacteria organized in biofilms. RA and periodontitis are both multifactorial chronic inflammatory diseases that share common modifiable and non‐modifiable risk factors. There is no cure for RA; treatment is based on lifestyle modifications and a variety of medications: nonsteroidal anti‐inflammatory drugs (NSAID), glucocorticoids, and disease‐modifying antirheumatic drugs (DMARDs, e.g., conventional synthetic DMARDs [csDMARDs]; biological DMARDs [bDMARD] and targeted synthetic DMARDs). There are molecular pathways of inflammation that are common to both RA and periodontitis. Thus, there is a potential effect of RA treatments on periodontitis. This systematic review aims to assess the impact of antirheumatic agents on periodontal conditions of patients suffering from both RA and periodontitis. Methods: PubMed/MEDLINE, Cochrane Library, and Embase online databases were systematically explored, and a manual search was performed to identify relevant studies published until January 2023. This review is registered in the PROSPERO database (CRD42023409006). Results: A total of 2827 articles were identified, and 35 fulfilled the inclusion criteria. The included studies generally show a consensus that, at normal dosage, NSAID and corticosteroids have negligible impact on periodontium. Similarly, csDMARD alone or in combination with other csDMARD demonstrated no adverse effect on periodontium. Monotherapy with bDMARD had a positive effect on periodontal pocket depths and gingival inflammation in the longitudinal studies up to 6 months but showed negligible effect on the periodontium in interventional studies with a longer follow‐up (9 months and 15.1 months). However, the combination of tumor necrosis factor (TNF)‐α inhibitors + methotrexate (MTX) was associated with a rise in gingival inflammation. Due to the considerable heterogeneity of the study designs, a meta‐analysis could not reasonably be performed. Conclusion: Within the limitations of the available studies, there is evidence to suggest that bDMARD monotherapy may improve the periodontal condition of RA patients with periodontal disease to a certain extent; the concomitant medication of TNF inhibitor + MTX could worsen gingival inflammation. More data are required to understand the impact of RA therapies on periodontal health. [ABSTRACT FROM AUTHOR]

Neurodegeneration, the decline of nerve cells in the brain, is a common feature of neurodegenerative disorders (NDDs). Oxidative stress, a key factor in NDDs such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and Huntington's disease can lead to neuronal cell death, mitochondria impairment, excitotoxicity, and Ca2+ stress. Environmental factors compromising stress response lead to cell damage, necessitating novel therapeutics for preventing or treating brain disorders in older individuals and an aging population. Synthetic medications offer symptomatic benefits but can have adverse effects. This research explores the potential of flavonoids derived from plants in treating NDDs. Flavonoids compounds, have been studied for their potential to enter the brain and treat NDDs. These compounds have diverse biological effects and are currently being explored for their potential in the treatment of central nervous system disorders. Flavonoids have various beneficial effects, including antiviral, anti-allergic, antiplatelet, anti-inflammatory, anti-tumor, anti-apoptotic, and antioxidant properties. Their potential to alleviate symptoms of NDDs is significant. [ABSTRACT FROM AUTHOR]

Simple Summary: For decades, a blood test showing elevated prostate-specific antigen (PSA) has been the mainstay for detecting prostate cancer. However, the PSA is often elevated in the absence of cancer. Here, we show that the neuroendocrine marker (NEM) outperforms the PSA test, both for sensitivity and for the exclusion of false-positive results. The purpose of this study was to assess the efficacy, specificity, and predictive value of a newly discovered biomarker, Zinc finger-like1 protein (referred to as neuroendocrine marker, NEM) for the detection of prostate cancer (PCa). We retrospectively analyzed banked plasma samples from 508 men, with a median age of 67 years (range 48–97), to compare the performance of NEM and PSA in predicting subsequent histologic PCa. The cohort consisted of four groups of patients visiting a urology clinic: (1) patients not diagnosed with either benign prostatic disease or prostate cancer (PCa) were defined as normal; (2) patients diagnosed with benign hyperplasia (BPH) but not PCa; (3) patients with confirmed PCa; and (4) patients with cancer other than PCa. The normal men displayed a mean NEM plasma level of 0.948 ± 0.051 ng/mL, which increased to 1.813 ± 0.315 ng/mL in men with BPH, 86.49 ± 15.51 ng/mL in men with PCa, and 10.47 ± 1.029 ng/mL in men with other Ca. The corresponding concentrations of prostate-specific antigen (PSA) in these subjects were 1.787 ± 0.135, 5.405 ± 0.699, 35.77 ± 11.48 ng/mL, and 8.036 ± 0.518, respectively. Receiver operating characteristic (ROC) curve analysis was performed to compare NEM and PSA performance, and the Jouden Index for each biomarker was calculated to determine cut-off points for each biomarker. The area under the ROC curve to predict PCa was 0.99 for NEM and 0.81 for PSA (p < 0.0001). The cut-off for NEM was at 1.9 ng/mL, with sensitivity of 98% and specificity of 97%. The corresponding PSA values were 4.4 ng/mL, with sensitivity of 76% and specificity of 95%. The predictive value of each biomarker in a patient was matched with his pathologic data to determine the accuracy of each biomarker. NEM was more accurate than PSA in differentiating cancer from benign conditions, such as BPH or prostatitis. In conclusion, NEM was a better predictor of PCa than PSA in patients visiting urology clinics. NEM tests, either alone or in conjunction with other biomarkers, provide a reliable, non-invasive, and inexpensive test to remarkably reduce false positives and thereby reduce the number of diagnostic biopsies and associated painful procedures and the loss of quality of life. [ABSTRACT FROM AUTHOR]

Background: In binary classification for clinical studies, an imbalanced distribution of cases to classes and an extreme association level between the binary dependent variable and a subset of independent variables can create significant classification problems. These crucial issues, namely class imbalance and complete separation, lead to classification inaccuracy and biased results in clinical studies. Method: To deal with class imbalance and complete separation problems, we propose using a fuzzy logistic regression framework for binary classification. Fuzzy logistic regression incorporates combinations of triangular fuzzy numbers for the coefficients, inputs, and outputs and produces crisp classification results. The fuzzy logistic regression framework shows strong classification performance due to fuzzy logic's better handling of imbalance and separation issues. Hence, classification accuracy is improved, mitigating the risk of misclassified conditions and biased insights for clinical study patients. Results: The performance of the fuzzy logistic regression model is assessed on twelve binary classification problems with clinical datasets. The model has consistently high sensitivity, specificity, F1, precision, and Mathew's correlation coefficient scores across all clinical datasets. There is no evidence of impact from the imbalance or separation that exists in the datasets. Furthermore, we compare the fuzzy logistic regression classification performance against two versions of classical logistic regression and six different benchmark sources in the literature. These six sources provide a total of ten different proposed methodologies, and the comparison occurs by calculating the same set of classification performance scores for each method. Either imbalance or separation impacts seven out of ten methodologies. The remaining three produce better classification performance in their respective clinical studies. However, these are all outperformed by the fuzzy logistic regression framework. Conclusion: Fuzzy logistic regression showcases strong performance against imbalance and separation, providing accurate predictions and, hence, informative insights for classifying patients in clinical studies. [ABSTRACT FROM AUTHOR]

Objective: The objective of this study was to evaluate the discoverability of supporting research materials, including supporting documents, individual participant data (IPD), and associated publications, in US federally funded COVID-19 clinical study records in ClinicalTrials.gov (CTG). Methods: Study registration records were evaluated for (1) links to supporting documents, including protocols, informed consent forms, and statistical analysis plans; (2) information on how unaffiliated researchers may access IPD and, when applicable, the linking of the IPD record back to the CTG record; and (3) links to associated publications and, when applicable, the linking of the publication record back to the CTG record. Results: 206 CTG study records were included in the analysis. Few records shared supporting documents, with only 4% of records sharing all 3 document types. 27% of records indicated they intended to share IPD, with 45% of these providing sufficient information to request access to the IPD. Only 1 dataset record was located, which linked back to its corresponding CTG record. The majority of CTG records did not have links to publications (61%), and only 21% linked out to at least 1 results publication. All publication records linked back to their corresponding CTG records. Conclusion: With only 4% of records sharing all supporting document types, 12% sufficient information to access IPD, and 21% results publications, improvements can be made to the discoverability of research materials in federally funded, COVID-19 CTG records. Sharing these materials on CTG can increase their discoverability, therefore increasing the validity, transparency, and reusability of clinical research. [ABSTRACT FROM AUTHOR]

Recognising the need for objective imaging‐based technologies to assess wound healing in clinical studies, the suction blister wound model offers an easily accessible wound model that creates reproducible epidermal wounds that heal without scarring. This study provides a comprehensive methodology for implementing and evaluating photography‐based imaging techniques utilising the suction blister wound model. Our method encompasses a protocol for capturing consistent, high‐quality photographs and procedures for quantifying these images via a visual wound healing score and a computer‐assisted colour analysis of wound exudation and wound redness. We employed this methodology on 16 suction blister wounds used as controls in a clinical phase‐1 trial. Our method enabled us to discern and quantify subtle differences between individual wounds concerning healing progress, erythema and wound exudation. The wound healing score exhibited a high inter‐rater agreement. There was a robust correlation between the spectrophotometer‐measured erythema index and photography‐based wound redness, as well as between dressing protein content and photography‐based dressing yellowness. In conclusion, this study equips researchers conducting clinical wound studies with reproducible methods that may support future wound research and aid in the development of new treatments. [ABSTRACT FROM AUTHOR]

Intermittent fasting (IF), one of the most popular diets, can regulate inflammation and promote health; however, the detailed molecular mechanisms are not fully understood. The present review aims to provide an overview of recent preclinical and clinical studies that have examined the effect of IF on inflammasome signaling, and to discuss the translational gap between preclinical and clinical studies. Three databases (PubMed, Web of Science, and Embase) were searched to identify all relevant preclinical and clinical studies up to October 30, 2022. A total of 1544 studies were identified through the database searches, and 29 preclinical and 10 clinical studies were included. Twenty-three of the 29 preclinical studies reported that IF treatment could reduce inflammasome activation in neurological diseases, metabolic and cardiovascular diseases, immune and inflammatory diseases, gastrointestinal diseases, and pulmonary diseases, and 7 of the 10 clinical studies demonstrated reduced inflammasome activation after IF intervention in both healthy and obese participants. Among various IF regimens, time-restricted eating seemed to be the most effective one in terms of inflammasome regulation, and the efficacy of IF might increase over time. This review highlights the regulatory effect of IF on inflammasome activation in health and disease. Future studies using different IF regimens, in various populations, are needed in order to evaluate its potential to be used alone or as an adjunct therapy in humans to improve health and counteract diseases. [ABSTRACT FROM AUTHOR]

Nowadays, it has become clear that extracellular vesicles (EVs) are not a cellular waste disposal vesicle but are an essential part of an intercellular communication system. Besides the use of EVs in biomarker studies and diagnostics, the potential of EV‐therapeutics has been seen by many. They provide unique properties for disease therapy, including strong immune‐modulatory actions, the possibility of engineering, low immunogenicity, and the capability of crossing biological barriers. Proof‐of‐concept of EV‐therapeutics for various pathologies has been achieved in preclinical studies. However, clinical trials with EVs have only been emerging slowly. Here, we aim to provide a comprehensive overview of the current state‐of‐the‐art concerning clinical studies using EVs in human therapy. By approaching the current knowledge in a systematic manner, we were able to include 21 reports for meta‐analysis of safety and evaluation of efficacy outcomes. Overall, we have shown that EV‐based therapy is safe with a low incidence of serious adverse events (SAE; 0.7% (95%‐CI: 0.1–5.2%), and adverse events (AE; 4.4% (95%‐CI: 0.7–22.2%). Subgroup analysis showed no significant difference in SAE when comparing autologous versus allogeneic administration, as well as engineered versus non‐engineered EV products. A significantly higher number of AE was seen in autologous versus allogeneic administration. However, the clinical relevance remains questionable. Evaluation of the clinical outcomes of immunostimulatory, immunosuppressive or regenerative EV‐therapies indicated improvement in the majority of treated patients. Despite these promising results, data need to be approached with caution due to a high heterogeneity in the EVs manufacturing methods, study design, and reporting of (S)AE. Overall, we conclude that EV‐based therapy is safe and presents a promising opportunity in therapy. More efforts are needed in the standardization and harmonization of reporting of EV isolation and characterization data as well as in the reporting of (S)AE to allow inter‐study comparison. [ABSTRACT FROM AUTHOR]

Trust in the power of knowledge. Reliability in choosing treatment. Loyalty to a mission that prioritizes health above all. These are the values that have been the foundation of Krka for 70 years. Our main purpose is to be a reliable global partner in health for doctors, pharmacists, and patients, while pursuing our mission to develop high-quality, safe, and effective medicines. The importance of the vertically integrated production model has been recently demonstrated. This model allows us to have complete oversight of the entire production process, from the active ingredient to the finished product, ensuring high-quality. Our innovations demonstrate our dedication to the well-being of consumers. In recent years, we have launched several valuable single-pill combinations. These include widely used combinations of antihypertensives, as well as other combinations for which we were pioneers among pharmaceutical producers. Our extensive portfolio of medicines addresses most common diseases, providing healthcare professionals with a variety of treatment options. We are also one of the few generic pharmaceutical companies whose medicines are supported by numerous postregistration clinical studies, demonstrating their effectiveness and safety in clinical practice. For 70 years, we have been committed to the health of current and future generations. [ABSTRACT FROM AUTHOR]

Human milk is universally regarded as the gold standard to fulfill nutrition needs of infants. Lactoferrin (LF) is a major multiple bioactive glycoprotein in human milk but little is presented in infant formula. LF can resist digestion in the infant gastrointestinal tract and is absorbed into the bloodstream in an intact form to perform physiological functions. Evidence suggest that LF prevents pathogen infection, promotes immune system development, intestinal development, brain development and bone health, as well as ameliorates iron deficiency anemia. However, more clinical studies of LF need to be further elucidated to determine an appropriate dosage for application in infant formula. LF is sensitive to denaturation induced by processing of infant formula such as heat treatments and spay drying. Thus, further studies should be focus on maximizing the retention of LF activity in the infant formula process. This review summarizes the structural features of LF. Then the digestion, absorption and metabolism of LF in infants are discussed, followed by the function of LF for infants. Further, we summarize LF in infant formula and effects of processing of infant formula on bioactivities of LF, as well as future perspectives of LF research. [ABSTRACT FROM AUTHOR]

Vitamin B12, a water‐soluble essential micronutrient, plays a pivotal role in numerous physiological processes in the human body. This review meticulously examines the structural complexity and the diverse mechanisms through which vitamin B12 exerts its preventive effects against a spectrum of health conditions, including pernicious anaemia, neurological disorders, obesity, diabetes, dyslipidaemia and complications in foetal development. The selection of articles for this review was conducted through a systematic search across multiple scientific databases, including PubMed, Scopus and Web of Science. Criteria for inclusion encompassed relevance to the biochemical impact of vitamin B12 on health, peer‐reviewed status and publication within the last decade. Exclusion criteria were non‐English articles and studies lacking empirical evidence. This stringent selection process ensured a comprehensive analysis of vitamin B12's multifaceted impact on health, covering its structure, bioavailable forms and mechanisms of action. Clinical studies highlighting its therapeutic potential, applications in food fortification and other utilizations are also discussed, underscoring the nutrient's versatility. This synthesis aims to provide a clear understanding of the integral role of vitamin B12 in maintaining human health and its potential in clinical and nutritional applications. © 2024 The Author(s). Journal of The Science of Food and Agriculture published by John Wiley & Sons Ltd on behalf of Society of Chemical Industry. [ABSTRACT FROM AUTHOR]

Summary: Although progression‐free survival (PFS) is a commonly used surrogate end‐point for clinical trials of follicular lymphoma (FL), no analyses have evaluated the strength of surrogacy for PFS with overall survival (OS). A systematic review was performed and 20 studies (total participants, 10 724) met final inclusion criteria. PFS was weakly associated with OS (correlation coefficient; 0.383, p < 0.001). The coefficient of determination was 0.15 (95% CI: 0.002–0.35) suggesting 15% of OS variance could be explained by changes in PFS. This challenges the role for PFS as a surrogate end‐point for clinical trials and drug approvals. [ABSTRACT FROM AUTHOR]

Fair allocation of funding in multi-centre clinical studies is challenging. Models commonly used in Germany - the case fees (“fixed-rate model”, FRM) and up-front staffing and consumables (“up-front allocation model”, UFAM) lack transparency and fail to suitably accommodate variations in centre performance. We developed a performance-based reimbursement model (PBRM) with automated calculation of conducted activities and applied it to the cohorts of the National Pandemic Cohort Network (NAPKON) within the Network of University Medicine (NUM). The study protocol activities, which were derived from data management systems, underwent validation through standardized quality checks by multiple stakeholders. The PBRM output (first funding period) was compared among centres and cohorts, and the cost-efficiency of the models was evaluated. Cases per centre varied from one to 164. The mean case reimbursement differed among the cohorts (1173.21€ [95% CI 645.68–1700.73] to 3863.43€ [95% CI 1468.89–6257.96]) and centres and mostly fell short of the expected amount. Model comparisons revealed higher cost-efficiency of the PBRM compared to FRM and UFAM, especially for low recruitment outliers. In conclusion, we have developed a reimbursement model that is transparent, accurate, and flexible. In multi-centre collaborations where heterogeneity between centres is expected, a PBRM could be used as a model to address performance discrepancies. Trial registration: ; ; . [ABSTRACT FROM AUTHOR]

Acute ischemic stroke (AIS) and traumatic brain injury (TBI) are two severe neurological events, both being major causes of death and prolonged impairment. Their incidence continues to rise due to the global increase in the number of people at risk, representing a significant burden on those remaining impaired, their families, and society. These molecular and cellular mechanisms of both stroke and TBI present similarities that can be targeted by treatments with a multimodal mode of action, such as traditional Chinese medicine. Therefore, we performed a detailed review of the preclinical and clinical development of MLC901 (NeuroAiDTMII), a natural multi-herbal formulation targeting several biological pathways at the origin of the clinical deficits. The endogenous neurobiological processes of self-repair initiated by the brain in response to the onset of brain injury are often insufficient to achieve complete recovery of impaired functions. This review of MLC901 and its parent formulation MLC601 confirms that it amplifies the natural self-repair process of brain tissue after AIS or TBI. Following AIS and TBI where "time is brain", many patients enter the post-acute phase with their functions still impaired, a period when "the brain needs time to repair itself". The treatment goal must be to accelerate recovery as much as possible. MLC901/601 demonstrated a significant reduction by 18 months of recovery time compared to a placebo, indicating strong potential for facilitating the improvement of health outcomes and the more efficient use of healthcare resources. [ABSTRACT FROM AUTHOR]

Cannabis sativa is a plant of the Cannabaceae family, whose molecular composition is known for its vast pharmacological properties. Cannabinoids are the molecules responsible for Cannabis sativa potential effects, especially tetrahydrocannabinol and cannabidiol. Scientific development has shown interest in the potential of cannabidiol in various health conditions, as it has demonstrated lower adverse events and great pharmacological potential, especially when administered topically. The present study aims to carry out a scoping review, focusing on the use of cannabidiol, in vivo models, for topical administration. Thus, the methodological approach used by the Joanna Briggs Institute was applied, and the studies were selected based on previously established inclusion criteria. Even though more information regarding the dose to achieve pharmacological potential is still needed, cannabidiol demonstrated potential in treating and preventing different conditions, such as glaucoma, atopic dermatitis, epidermolysis bullosa, and pyoderma gangrenosum. [ABSTRACT FROM AUTHOR]

The multifaceted nature of osteoarthritis (OA) pain presents a challenge in understanding and managing the condition. The diverse pain experiences, progression rates, individual responses to treatments, and complex disease mechanisms contribute to heterogeneity in the clinical studies outcomes. The lack of a standardized methodology for assessing and classifying OA pain challenges healthcare practitioners. This complicates the establishment of universally applicable protocols or standardized guidelines for treatment. This article explores the heterogeneity observed in clinical studies evaluating OA pain treatments, highlighting the necessity for refined methodologies, personalized patient categorization, and consistent outcome measures. It discusses the role of the multidimensional nature of OA pain, underlying pain mechanisms, and other contributing factors to the heterogeneity in outcome measures. Addressing these variations is crucial to establishing a more consistent framework for evidence-based treatments and advancing care of the patient with OA pain. [ABSTRACT FROM AUTHOR]

Extracellular vesicles (EVs) are nano-sized, membranous transporters of various active biomolecules with inflicting phenotypic capabilities, that are naturally secreted by almost all cells with a promising vantage point as a potential leading drug delivery platform. The intrinsic characteristics of their low toxicity, superior structural stability, and cargo loading capacity continue to fuel a multitude of research avenues dedicated to loading EVs with therapeutic and diagnostic cargos (pharmaceutical compounds, nucleic acids, proteins, and nanomaterials) in attempts to generate superior natural nanoscale delivery systems for clinical application in therapeutics. In addition to their well-known role in intercellular communication, EVs harbor microRNAs (miRNAs), which can alter the translational potential of receiving cells and thus act as important mediators in numerous biological and pathological processes. To leverage this potential, EVs can be structurally engineered to shuttle therapeutic miRNAs to diseased recipient cells as a potential targeted 'treatment' or 'therapy'. Herein, this review focuses on the therapeutic potential of EV-coupled miRNAs; summarizing the biogenesis, contents, and function of EVs, as well as providing both a comprehensive discussion of current EV loading techniques and an update on miRNA-engineered EVs as a next-generation platform piloting benchtop studies to propel potential clinical translation on the forefront of nanomedicine. [ABSTRACT FROM AUTHOR]

Clinical and preclinical studies have provided conflicting data on the postulated beneficial effects of vitamin D in patients with prostate cancer. In this opinion piece, we discuss reasons for discrepancies between preclinical and clinical vitamin D studies. Different criteria have been used as evidence for the key roles of vitamin D. Clinical studies report integrative cancer outcome criteria such as incidence and mortality in relation to vitamin D status over time. In contrast, preclinical vitamin D studies report molecular and cellular changes resulting from treatment with the biologically active vitamin D metabolite, 1,25-dihydroxyvitamin D3 (calcitriol) in tissues. However, these reported changes in preclinical in vitro studies are often the result of treatment with biologically irrelevant high calcitriol concentrations. In typical experiments, the used calcitriol concentrations exceed the calcitriol concentrations in normal and malignant prostate tissue by 100 to 1000 times. This raises reasonable concerns regarding the postulated biological effects and mechanisms of these preclinical vitamin D approaches in relation to clinical relevance. This is not restricted to prostate cancer, as detailed data regarding the tissue-specific concentrations of vitamin D metabolites are currently lacking. The application of unnaturally high concentrations of calcitriol in preclinical studies appears to be a major reason why the results of preclinical in vitro studies hardly match up with outcomes of vitamin D-related clinical studies. Regarding future studies addressing these concerns, we suggest establishing reference ranges of tissue-specific vitamin D metabolites within various cancer entities, carrying out model studies on human cancer cells and patient-derived organoids with biologically relevant calcitriol concentrations, and lastly improving the design of vitamin D clinical trials where results from preclinical studies guide the protocols and endpoints within these trials. [ABSTRACT FROM AUTHOR]

Bone is a metabolically dynamic structure that is generally remodeled throughout the lifetime of an individual but often causes problems with increasing age. A key player for bone development and homeostasis, but also under pathological conditions, is the bone vasculature. This complex system of arteries, veins, and capillaries forms distinct structures where each subset of endothelial cells has important functions. Starting with the basic process of angiogenesis and bone-specific blood vessel formation, coupled with initial bone formation, the importance of different vascular structures is highlighted with respect to how these structures are maintained or changed during homeostasis, aging, and pathological conditions. After exemplifying the current knowledge on bone vasculature, this review will move on to exosomes, a novel hotspot of scientific research. Exosomes will be introduced starting from their discovery via current isolation procedures and state-of-the-art characterization to their role in bone vascular development, homeostasis, and bone regeneration and repair while summarizing the underlying signal transduction pathways. With respect to their role in these processes, especially mesenchymal stem cell-derived extracellular vesicles are of interest, which leads to a discussion on patented applications and an update on ongoing clinical trials. Taken together, this review provides an overview of bone vasculature and bone regeneration, with a major focus on how exosomes influence this intricate system, as they might be useful for therapeutic purposes in the near future. [ABSTRACT FROM AUTHOR]

Melatonin is ubiquitously present in all animals and plants, where it exerts a variety of physiological activities thanks to its antioxidant properties and its key role as the first messenger of extracellular signaling functions. Most of the clinical studies on melatonin refer to its widespread oral use as a dietary supplement to improve sleep. A far smaller number of articles describe the clinical applications of topical melatonin to treat or prevent skin disorders by exploiting its antioxidant and anti-inflammatory activities. This review focuses on the clinical studies in which melatonin was applied on the skin as a photoprotective, anti-aging, or hair growth-promoting agent. The methodologies and results of such studies are discussed to provide an overall picture of the state of the art in this intriguing field of research. The clinical studies in which melatonin was applied on the skin before exposure to radiation (UV, sunlight, and high-energy beams) were all characterized by an appropriate design (randomized, double-blind, and placebo-controlled) and strongly support its clinical efficacy in preventing or reducing skin damage such as dermatitis, erythema, and sunburn. Most of the studies examined in this review do not provide a clear demonstration of the efficacy of topical melatonin as a skin anti-aging or as a hair growth-promoting agent owing to limitations in their design and/or to the use of melatonin combined with extra active ingredients, except for one trial that suggests a possible beneficial role of melatonin in treating some forms of alopecia in women. Further research efforts are required to reach definitive conclusions concerning the actual benefits of topical melatonin to counteract skin aging and hair loss. [ABSTRACT FROM AUTHOR]

Musculoskeletal disorders are among the main causes of disease‐associated disability. Moreover, the incidence and prevalence of osteoporosis and osteoarthritis, as well as the risk of bone fractures and the need for joint replacements, are expected to increase with longer life expectancy. New approaches based on electromagnetic stimulation have been developed, aiming to shorten bone healing time, attenuate osteoporosis and osteoarthritis, and increase implants' osseointegration. Inductive coupling (IC), a non‐invasive methodology to deliver magnetic stimuli, has reached clinical trials and some clinical practices but is not yet considered a standard procedure. Indeed, its feasibility in clinical use is still under discussion, and optimal stimulation parameters are fairly undefined. This comprehensive review describes the research trends and applicability of IC‐based therapeutics for musculoskeletal disorders, and starts identifying top‐performing magnetic stimulation parameters. Insights into the magnetic stimuli setups that promote osteogenesis are provided, based on pre‐clinical and clinical evidence from 117 in vivo studies in animal models and human patients. Potential cellular and molecular biomechanisms mediating IC‐induced effects on osteoblasts and osteoclasts are also explored. The transversal knowledge herein delivered will hopefully support innovative designs and medical devices that will implement IC stimulation as a clinical standard and effective therapeutic for musculoskeletal disorders. [ABSTRACT FROM AUTHOR]

Conventional therapy is commonly used for the treatment of inflammatory skin conditions, but undesirable effects, such as erythema, dryness, skin thinning, and resistance to treatment, may cause poor patient compliance. Therefore, patients may seek complementary treatment with herbal plant products including essential oils (EOs). This scoping review aims to generate a broad overview of the EOs used to treat inflammatory skin conditions, namely, acne vulgaris, dermatitis and eczema, psoriasis, and rosacea, in a clinical setting. The quality, efficacy, and safety of various EOs, as well as the way in which they are prepared, are reviewed, and the potential, as well as the limitations, of EOs for the treatment of inflammatory skin conditions are discussed. Twenty-nine eligible studies (case studies, uncontrolled clinical studies, and randomized clinical studies) on the applications of EOs for inflammatory skin conditions were retrieved from scientific electronic databases (PubMed, Embase, Scopus, and the Cochrane Library). As an initial result, tea tree (Melaleuca alternifolia) oil emerged as the most studied EO. The clinical studies with tea tree oil gel for acne treatment showed an efficacy with fewer adverse reactions compared to conventional treatments. The uncontrolled studies indicated the potential efficacy of ajwain (Trachyspermum ammi) oil, eucalyptus (Eucalyptus globulus) oil, and cedarwood (Cedrus libani) oil in the treatment of acne, but further research is required to reach conclusive evidence. The placebo-controlled studies revealed the positive effects of kānuka (Kunzea ericoides) oil and frankincense (Boswellia spp.) oil in the treatment of psoriasis and eczema. The quality verification of the EO products was inconsistent, with some studies lacking analyses and transparency. The quality limitations of some studies included a small sample size, a short duration, and the absence of a control group. This present review underscores the need for extended, well-designed clinical studies to further assess the efficacy and safety of EOs for treating inflammatory skin conditions with products of assured quality and to further elucidate the mechanisms of action involved. [ABSTRACT FROM AUTHOR]

Background: The dissemination of clinical trial results is an important scientific and ethical endeavour. This survey of completed interventional studies in a French academic center describes their reporting status. Methods: We explored all interventional studies sponsored by Rennes University Hospital identified on the French Open Science Monitor which tracks trials registered on EUCTR or clinicaltrials.gov, and provides an automatic assessment of the reporting of results. For each study, we ascertained the actual reporting of results using systematic searches on the hospital internal database, bibliographic databases (Google Scholar, PubMed), and by contacting all principal investigators (PIs). We describe several features (including total budget and numbers of trial participants) of the studies that did not report any results. Results: The French Open Science Monitor identified 93 interventional studies, among which 10 (11%) reported results. In contrast, our survey identified 36 studies (39%) reporting primary analysis results and an additional 18 (19%) reporting results for secondary analyses (without results for their primary analysis). The overall budget for studies that did not report any results was estimated to be €5,051,253 for a total of 6,735 trial participants. The most frequent reasons for the absence of results reported by PIs were lack of time for 18 (42%), and logistic difficulties (e.g. delay in obtaining results or another blocking factor) for 12 (28%). An association was found between non-publication and negative results (adjusted Odds Ratio = 4.70, 95% Confidence Interval [1.67;14.11]). Conclusions: Even allowing for the fact that automatic searches underestimate the number of studies with published results, the level of reporting was disappointingly low. This amounts to a waste of trial participants' implication and money. Corrective actions are needed. Trial registration: https://osf.io/q5hcs [ABSTRACT FROM AUTHOR]

Summary Large granular lymphocytic (LGL) leukaemia is a rare chronic lymphoproliferative disorder characterized by an expansion of cytotoxic T or NK cells. Despite a usually indolent evolution, most patients will require a treatment over the course of the disease because of cytopenia or symptomatic associated autoimmune disorders. First‐line treatment is based on immunosuppressive agents, namely cyclophosphamide, methotrexate and ciclosporin. However, relapses are frequent, and there is no consensus on the management of relapsed/refractory patients. The implication of the JAK/STAT pathway in the pathogenesis of this disease has prompted our group to propose treatment with ruxolitinib. A series of 21 patients who received this regimen is reported here. Ten patients (47.6%) were refractory to the three main immunosuppressive drugs at the time of ruxolitinib initiation. Ruxolitinib yielded an overall response rate of 86% (n = 18/21), including 3 complete responses and 15 partial responses. With a median follow‐up of 9 months, the median response duration was 4 months. One‐year event‐free survival and 1‐year overall survival were 57% and 83% respectively. Mild side effects were observed. Biological parameters, notably neutropenia and anaemia, improved significantly, and complete molecular responses were evidenced. This study supports ruxolitinib as a valid option for the treatment of relapsed/refractory LGL leukaemia. [ABSTRACT FROM AUTHOR]

Summary: Standard CHOP treatment includes a high cumulative dose of prednisone, and studies have shown increased fracture risk following CHOP. It is unclear whether reductions in bone mineral density (BMD) are caused by glucocorticoids or by the combination with chemotherapy. Our objective was to determine the effect of obinutuzumab (G)/rituximab (R)‐bendamustine versus G/R‐CHOP on BMD in follicular lymphoma patients. Patients in this GALLIUM post hoc study were ≥60 years old and in complete remission at induction treatment completion (ITC), following treatment with G or R in combination with bendamustine or CHOP. To assess BMD, Hounsfield units (HU) were measured in lumbar vertebra L1 on annual computed tomography. Furthermore, vertebral compression fractures were recorded. Of 173 patients included, 59 (34%) received CHOP and 114 (66%) received bendamustine. At baseline, there was no difference in HU between groups. The mean HU decrease from baseline to ITC was 27.8 after CHOP and 17.3 after bendamustine, corresponding to a difference of 10.4 (95% CI: 3.2–17.6). Vertebral fractures were recorded in 5/59 patients receiving CHOP and in 2/114 receiving bendamustine. CHOP was associated with a significant greater decrease in BMD and more frequent fractures. These results suggest that prophylaxis against BMD loss should be considered. [ABSTRACT FROM AUTHOR]

Objectives: This study aimed to systematize the Zhuang medicinal herbs of Ardisia (ZMHA) in China, to clarify the traditional use in Zhuang medicine and the dynamics of international research on phytochemistry, pharmacology, clinical application, and toxicity. Key findings: There are 25 species of ZMHA, approximately 938 compounds from the different part, including triterpenoids, phenolics, volatile oils, etc. Pharmacological activity studies have also shown that this genus has anti-tumour, anti-inflammatory, anti-oxidant, anti-bacterial, anti-microbial, etc., and significant effects on respiratory, digestive, urinary, and musculoskeletal system diseases without toxic side effects. Summary: The Ardisia has a medicinal history of nearly a thousand years, mainly for treating diseases of the injuries, musculoskeletal, and symptomatic system in Zhuang medicine. Some plants, such as A. crenata, A. gigantifolia, and A. japonica, are also commonly used in folk Zhuang medicine formulas, to treat musculoskeletal, injury, respiratory, and urinate systems disease. These diseases are related to inflammation. These could provide a new direction for future new drug development research. Therefore, species identification and resource investigation should be strengthened, and conducted in vitro mechanism, in vivo pharmacology, clinical efficacy, and toxicology studies and establish a perfect quality standard system. Graphical Abstract [ABSTRACT FROM AUTHOR]

Concerns around the impact of anesthesia on cognitive decline and dementia, including Alzheimer's Disease (AD), have been increasing and recently attracting considerable attention in the research community. One unanswered question is whether anesthesia is a risk factor of dementia, specifically AD type dementia. A large body of evidence, coming from in vivo and in vitro models, suggests that exposure to anesthetic agents may increase the risk of AD through mechanisms of action similar to AD's neuropathology. In terms of clinical studies, our knowledge of the relationship between anesthesia and dementia is based on limited data, with most studies suggesting that there is no association. The aim of this paper was therefore to outline recent clinical studies exploring this controversial relationship and discuss future directions in terms of study design and potential areas of study. As the aging population and the prevalence of dementia and AD increases, we need a better understanding of anesthesia as a risk factor for neurodegeneration through well-designed studies. Despite the controversy, there seems to be little evidence to support that anesthesia itself or other surgical and patient factors can cause or accelerate AD. [ABSTRACT FROM AUTHOR]

Summary: Trisomy karyotype occurs in 5%–10% of AML. Its mutational landscape and prognostic significance are not well defined. A cohort of 156 trisomy AML patients was analysed, with reference to 615 cytogenetically normal (CN) AML patients. Trisomy AML showed distinct mutational landscape with more prevalent SMC1A, N/KRAS, ASXL1 and BCOR but fewer CEBPAbZIP and NPM1 mutations in patients ≤60, and fewer NPM1 mutations in those >60. NRAS mutations were associated with poor outcome in trisomy AML, whereas DNMT3A and FLT3‐ITD mutations had neutral effect. Trisomy AML appeared biologically distinct from CN‐AML. [ABSTRACT FROM AUTHOR]

This case report describes the positive interference of the commonly used skin protective barrier cream used together with urine collection bags on the benzethonium chloride method for urine protein measurements in a 6-month-old female baby, leading to falsely elevated results. The interference was identified by both artificially mixing urine samples with this cream and comparing the results obtained using the benzethonium chloride method with those obtained using the pyrogallol red method. [ABSTRACT FROM AUTHOR]

Traumatic Brain Injury (TBI) remains a significant global health challenge, lacking effective pharmacological treatments. This shortcoming is attributed to TBI's heterogeneous and complex pathophysiology, which includes axonal damage, mitochondrial dysfunction, oxidative stress, and persistent neuroinflammation. The objective of this study is to analyze transcranial photobiomodulation (PBM), which employs specific red to near-infrared light wavelengths to modulate brain functions, as a promising therapy to address TBI's complex pathophysiology in a single intervention. This study reviews the feasibility of this therapy, firstly by synthesizing PBM's cellular mechanisms with each identified TBI's pathophysiological aspect. The outcomes in human clinical studies are then reviewed. The findings support PBM's potential for treating TBI, notwithstanding variations in parameters such as wavelength, power density, dose, light source positioning, and pulse frequencies. Emerging data indicate that each of these parameters plays a role in the outcomes. Additionally, new research into PBM's effects on the electrical properties and polymerization dynamics of neuronal microstructures, like microtubules and tubulins, provides insights for future parameter optimization. In summary, transcranial PBM represents a multifaceted therapeutic intervention for TBI with vast potential which may be fulfilled by optimizing the parameters. Future research should investigate optimizing these parameters, which is possible by incorporating artificial intelligence. [ABSTRACT FROM AUTHOR]

Background: Brain tumors represent a disease that causes both physical and psychological distress for those affected. The pharmacological treatment of depressive symptoms in particular has not been sufficiently researched in these patients. Depression can severely affect the quality of life and has an impact on the course of the disease. Objective: The aim of this work is to describe the diagnosis and treatment of depressive symptoms in brain tumor patients. Material and methods: For this work a comprehensive literature search was conducted to identify relevant studies addressing the topic of depressive symptoms in brain tumors. The included studies were critically appraised to ensure their quality and relevance. Results: The review of the literature revealed that depressive symptoms are a common complication in brain tumor patients. It was found that there are no studies to date on the efficacy of antidepressant medications in brain tumor patients. Discussion: The results of this work highlight the need to pay increased attention to mental health in brain tumor patients. It is important that healthcare professionals identify depression in these patients at an early stage and provide appropriate interventions to improve their quality of life. Future research should focus on further exploring the mechanisms behind the association between brain tumors and depression in order to develop targeted and effective intervention options. [ABSTRACT FROM AUTHOR]

Background: It is unclear how to disseminate the results of randomised controlled trials effectively to health professionals and policymakers to improve treatment, care or prevention through changing policy and practice. This systematic review examined the effectiveness of different methods of dissemination of clinical research results to professional audiences. Methods: We systematically reviewed the published and grey literature from 2000 to 2022 for studies assessing different approaches for disseminating clinical study results to professional audiences (health professionals, policymakers and guideline developers). Two reviewers assessed potentially relevant full texts for inclusion. We grouped studies by intervention type, synthesising findings using effect direction plots. Outcomes were grouped into out-takes (e.g. awareness, knowledge, understanding), outcomes (e.g. attitude changes) and impact (changes in policy/practice). The quality of evidence was assessed using GRADE. Results: Our search identified 13,264 unique records, of which 416 full texts were assessed for eligibility. Of 60 studies that were identified as eligible for inclusion, 20 evaluated the effectiveness of interventions to disseminate clinical research results (13 RCTs, 2 observational studies, 3 pre- and post-intervention surveys and 2 cross-sectional surveys). Studies were grouped by intervention: 7 studies that involved face-to-face meetings between the target audience and trained educators were classified as 'outreach interventions'; 5 studies that provided a summary format for systematic review findings (e.g. summary of findings tables) were grouped together. There was high certainty evidence of a small beneficial impact of outreach interventions on health and moderate certainty evidence of impact on practice (mostly prescribing). There was no evidence of impact on policy and very low certainty around benefits on outcomes and out-takes. We found no consistent benefits of summary formats for systematic review results on outcomes or out-takes (moderate quality evidence). Other interventions with less evidence are reported in the Additional Materials. Conclusions: Outreach interventions to disseminate clinical research results can lead to changes in practice and improvements in health. However, these interventions can be resource-intensive. Investment is vital to identify and implement effective and cost-effective ways to disseminate results, so that the potential benefits of trials to patients can be realised. Trial registration: International Prospective Register of Systematic Reviews (PROSPERO), CRD42019137364. [ABSTRACT FROM AUTHOR]

Autism spectrum disorder (ASD) is an increasingly prevalent neurodevelopmental condition characterized by social and communication deficits as well as patterns of restricted, repetitive behavior. Abnormal brain development has long been postulated to underlie ASD, but longitudinal studies aimed at understanding the developmental course of the disorder have been limited. More recently, abnormal development of the striatum in ASD has become an area of interest in research, partially due to overlap of striatal functions and deficit areas in ASD, as well as the critical role of the striatum in early development, when ASD is first detected. Focusing on the dorsal striatum and the associated symptom domain of restricted, repetitive behavior, we review the current literature on dorsal striatal abnormalities in ASD, including studies on functional connectivity, morphometry, and cellular and molecular substrates. We highlight that observed striatal abnormalities in ASD are often dynamic across development, displaying disrupted developmental trajectories. Important findings include an abnormal trajectory of increasing corticostriatal functional connectivity with age and increased striatal growth during childhood in ASD. We end by discussing striatal findings from animal models of ASD. In sum, the studies reviewed here demonstrate a key role for developmental disruptions of the dorsal striatum in the pathogenesis of ASD. Directing attention toward these findings will improve our understanding of ASD and of how associated deficits may be better addressed. [ABSTRACT FROM AUTHOR]

Background: Most colorectal cancers (CRCs) occur in individuals aged over 50 years; however, the incidence in younger age groups is increasing. Diagnosis in younger patients is frequently delayed due to non-specific symptoms and the relative frequency of benign disease. There is a need to identify patients who warrant further investigation for CRC. This study reviewed whether a faecal haemoglobin (f-Hb) ≥10 μg Hb/g faeces measured by the faecal immunochemical test for f-Hb (FIT) was associated with CRC in a local primary care population aged under 50 years. Methods: f-Hb results from symptomatic patients aged 18–49 years presenting to primary care during a 17-month period were extracted from local laboratory information systems. Colonoscopy lists were obtained from three local trusts. The Somerset Cancer Registry was searched to identify CRCs. f-Hb and outcomes were matched using NHS numbers. Results: A total of 3119 patients were included (median age 41 years); 313 of 2682 patients with f-Hb <10 μg/g (11.7%) and 305 of 437 patients with f-Hb ≥10 μg/g (69.8%) underwent colonoscopy. Twelve CRCs were detected. At a cut-off of 10 μg/g, the positivity rate was 14.0%, sensitivity was 100% (75.8–100%), specificity was 86.3% (85.1–87.5%), positive predictive value (PPV) was 2.7% (2.5–3.0%) and negative predictive value (NPV) was 100%. At a cut-off of 150 μg/g, sensitivity was 83.3% (55.2–95.3%), specificity was 95.2% (94.4–95.9%), PPV was 6.2% (4.7–8.2%) and NPV was 99.9% (99.8–100%). Conclusion: Our data supports the use of FIT to triage patients aged under 50 years presenting to primary care with symptoms suggestive of CRCs. [ABSTRACT FROM AUTHOR]

Vascular endothelial dysfunction is a major risk factor in the development of renal diseases. Recent studies pointed out a major interest for the inter-endothelial junction protein CD146, as its expression is modulated during renal injury. Indeed, some complex mechanisms involving this adhesion molecule and its multiple ligands are observed in a large number of renal diseases in fundamental or clinical research. The purpose of this review is to summarize the most recent literature on the role of CD146 in renal pathophysiology, from experimental nephropathy to clinical trials. [ABSTRACT FROM AUTHOR]

This work aimed to show which treatments showed efficacy against coronavirus disease 2019 (COVID-19); therefore, the results of 37 clinical trials started in 2020 and completed in 2021 are reviewed and discussed here. These were selected from databases, excluding vaccines, computational studies, in silico, in vitro, and those with hyperimmune sera from recovered patients. We found 34 drugs, one vitamin, and one herbal remedy with pharmacological activity against symptomatic COVID-19. They reduced mortality, disease progression, or recovery time. For each treatment, the identifier and type of trial, the severity of the disease, the sponsor, the country where the trial was conducted, and the trial results are presented. The drugs were classified according to their mechanism of action. Several drugs that reduced mortality also reduced inflammation in the most severe cases. These include some that are not considered anti-inflammatory, such as Aviptadil, pyridostigmine bromide, anakinra, imatinib, baricitinib, and bevacizumab, as well as the combination of ivermectin, aspirin, dexamethasone, and enoxaparin. Nigella sativa seeds with honey have also been reported to have therapeutic activity. On the other hand, tofacitinib, novaferon with ritonavir, and lopinavir were also effective, as well as in combination with antiviral therapies such as danoprevir with ritonavir. The natural products colchicine and Vitamin D3 were only effective in patients with mild-to-moderate COVID-19, as was hydroxychloroquine. Drug repositioning has been the main tool in the search for effective therapies by expanding the pharmacological options available to patients. [ABSTRACT FROM AUTHOR]

Cancer is a main cause of death and preferred methods of therapy depend on the type of tumor and its location. Gliomas are the most common primary intracranial tumor, accounting for 81% of malignant brain tumors. Although relatively rare, they cause significant mortality. Traditional methods include surgery, radiotherapy and chemotherapy; they also have significant associated side effects that cause difficulties related to tumor excision and recurrence. Photodynamic therapy has potentially fewer side effects, less toxicity, and is a more selective treatment, and is thus attracting increasing interest as an advanced therapeutic strategy. Photodynamic treatment of malignant glioma is considered to be a promising additional therapeutic option that is currently being extensively investigated in vitro and in vivo. This review describes the application of photodynamic therapy for treatment of brain cancer. The mechanism of photodynamic action is also described in this work as it applies to treatment of brain cancers such as glioblastoma multiforme. The pros and cons of photodynamic therapy for brain cancer are also discussed. [ABSTRACT FROM AUTHOR]

Scalp acupuncture, a specialized branch of traditional Chinese medicine, integrates classical acupuncture principles with modern neuroanatomy. Developed primarily in the 1970s, it has evolved into various styles, each offering unique methodologies and clinical applications. This review paper delves into the origins, definitions, and different styles of scalp acupuncture, including Huang’s, Fang’s, Tang’s, Jiao’s, Zhu’s, Yu’s, Lin’s, and Yamamoto’s Scalp Acupuncture, along with the International Standardized Scalp Acupuncture system. It explores the anatomical basis of scalp acupuncture, detailing the skull’s structure, surface landmarks, and the scalp’s tissues, while examining the cerebral hemispheres and lobes’ functional aspects. The paper emphasizes the therapeutic potential of scalp acupuncture in treating a wide range of conditions, from neurological disorders and chronic pain to mental health issues. Clinical studies are reviewed, highlighting the modality’s effectiveness in managing various medical conditions, such as autism spectrum disorder, post-stroke depression, ischemic stroke, and Parkinson’s disease. The mechanism of action, involving the nervous system and the release of neurotransmitters, is explored to understand the biological processes underlying scalp acupuncture’s therapeutic effects. The review also addresses the contraindications of scalp acupuncture, ensuring patient safety and treatment appropriateness. Overall, the paper presents scalp acupuncture as a holistic, non-invasive treatment option, reflecting the integration of ancient wisdom and modern scientific understanding in healthcare. [ABSTRACT FROM AUTHOR]

The convergence of an interdisciplinary team of neurocritical care specialists to organize the Curing Coma Campaign is the first effort of its kind to coordinate national and international research efforts aimed at a deeper understanding of disorders of consciousness (DoC). This process of understanding includes translational research from bench to bedside, descriptions of systems of care delivery, diagnosis, treatment, rehabilitation, and ethical frameworks. The description and measurement of varying confounding factors related to hospital care was thought to be critical in furthering meaningful research in patients with DoC. Interdisciplinary hospital care is inherently varied across geographical areas as well as community and academic medical centers. Access to monitoring technologies, specialist consultation (medical, nursing, pharmacy, respiratory, and rehabilitation), staffing resources, specialty intensive and acute care units, specialty medications and specific surgical, diagnostic and interventional procedures, and imaging is variable, and the impact on patient outcome in terms of DoC is largely unknown. The heterogeneity of causes in DoC is the source of some expected variability in care and treatment of patients, which necessitated the development of a common nomenclature and set of data elements for meaningful measurement across studies. Guideline adherence in hemorrhagic stroke and severe traumatic brain injury may also be variable due to moderate or low levels of evidence for many recommendations. This article outlines the process of the development of common data elements for hospital course, confounders, and medications to streamline definitions and variables to collect for clinical studies of DoC. [ABSTRACT FROM AUTHOR]

Identification of a subset of patients who may be sensitive to a specific treatment is an important step towards personalized medicine. We consider the case where the effect of a treatment is assessed by longitudinal measurements, which may be continuous or categorical, such as quality of life scores assessed over the duration of a clinical trial. We assume that multiple baseline covariates, such as age and expression levels of genes, are available, and propose a generalized single‐index linear threshold model to identify the treatment‐sensitive subset and assess the treatment‐by‐subset interaction after combining these covariates. Because the model involves an indicator function with unknown parameters, conventional procedures are difficult to apply for inferences of the parameters in the model. We define smoothed generalized estimating equations and propose an inference procedure based on these equations with an efficient spectral algorithm to find their solutions. The proposed procedure is evaluated through simulation studies and an application to the analysis of data from a randomized clinical trial in advanced pancreatic cancer. [ABSTRACT FROM AUTHOR]

Simple Summary: Cancer is a major global health concern, with the Mitogen-activated protein kinase (MAPK) pathway playing a crucial role in cancerous diseases. Indole alkaloids, such as vincristine and evodiamine, have been extensively studied for their potential in cancer treatment. These naturally occurring indole alkaloids have strong anticancer properties, and research is ongoing to develop new anticancer small molecules. The current review aims to evaluate how indole alkaloids affect the MAPK signaling pathway in cancer treatment and focus on advancements in the role of indole alkaloids. The review also highlights clinical trials with indole alkaloids in cancer treatment. Cancer is the leading cause of morbidity and mortality in people throughout the world. There are many signaling pathways associated with cancerous diseases, from which the Mitogen-activated protein kinase (MAPK) pathway performs a significant role in this regard. Apoptosis and proliferation are correlated with MAPK signaling pathways. Plenty of experimental investigations were carried out to assess the role of indole alkaloids in MAPK-mediated cancerous diseases. Previous reports established that indole alkaloids, such as vincristine and evodiamine are useful small molecules in cancer treatment via the MAPK signaling system. Indole alkaloids have the anticancer potential through different pathways. Vincristine and evodiamine are naturally occurring indole alkaloids that have strong anticancer properties. Additionally, much research is ongoing or completed with molecules belonging to this group. The current review aims to evaluate how indole alkaloids affect the MAPK signaling pathway in cancer treatment. Additionally, we focused on the advancement in the role of indole alkaloids, with the intention of modifying the MAPK signaling pathways to investigate potential new anticancer small molecules. Furthermore, clinical trials with indole alkaloids in cancer treatment are also highlighted. [ABSTRACT FROM AUTHOR]

Curcumin (CUR) is a natural hydrophobic compound, which is available in turmeric rhizome. It has several bioactivities including antioxidant, anti-obesity, anti-diabetic, cardioprotective, anti-inflammatory, antimicrobial, anticancer, and other activities. Despite its medical and biological benefits, it is using in limitations because of its hydrophobicity and sensitivity. These unfavorable conditions further reduced the bioavailability (BA) and biological efficacy of CUR. This review summarizes the stability and BA of free- and encapsulated-CUR, as well as comprehensively discusses the potential biological activity of CUR-loaded various micro-/nano-encapsulation systems. The stability and BA of CUR can be improved via loading in different encapsulation systems, including nanoemulsions, liposomes, niosomes, biopolymer-based nanoparticles, nano-hydrogel, and others. Biopolymer-based nanoparticles (especially poly lactic-co-glycolic acid (PLGA), zein, and chitosan) and nano-gels are the best carriers for encapsulating and delivering CUR. Both delivery systems are suitable because of their excellent functional properties such as high encapsulation efficiency, well-stability against unfavorable conditions, and can be coated using other encapsulation systems. Based on available evidences, encapsulated-CUR exerted greater biological activities especially anticancer (breast cancer), antioxidant, antidiabetic, and neuroprotective effects. [ABSTRACT FROM AUTHOR]

Acute myocardial infarction (AMI) has been responsible for 8.5 million deaths worldwide each year over the past decade and is the leading cause of death. It is a severe illness worldwide and can happen in multiple age categories. Despite the significant progress in fundamental and clinical studies of AMI, biomarkers for AMI development have not been adequately investigated. The present research aimed to characterize potential new biomarkers of AMI by comprehensive analysis and to explore the immune infiltration characteristics of this pathophysiological process. In this study, we identified 68 DEGs and performed gene set enrichment analysis, GO, disease oncology, and KEGG analysis, and the results suggested that several functional signaling pathways and essential genes were strongly related to the onset and progression of AMI. In addition, combining multiple algorithms, FCER1G, CLEC4D, SRGN, and SLC11A1 were determined to be prospective biomarkers of AMI and showed good diagnostic value. Immuno‐infiltration analysis suggested that neutrophils, CD8+ T cells, monocytes, and M0 macrophages might be involved in the onset and progress of AMI. In conclusion, a combined approach was employed to select biomarkers associated with AMI and to probe the critical function of immune cells in the progression of AMI. In addition, clinical studies were applied to analyze the correlation between the occurrence of AMI and lipid dysregulation. [ABSTRACT FROM AUTHOR]

Purpose: Osteoarthritis (OA) is one of the most common chronic diseases in the world. It is frequently accompanied by high levels of persistent pain, as well as substantial impairments in function and functional capacity. This review aims to systematically analyze the changes in proprioception and related mechanoreceptors in OA patients. Methods: Studies from September 2013 to September 2023 were identified by conducting searches on the PubMed, Web of Science, and Scopus electronic databases following the PRISMA statement. One reviewer independently assessed and screened the literature, extracted the data, and graded the studies. The body of evidence underwent an evaluation and grading process using the ROBINS-I tool, which was specifically designed to assess the risk of bias in non-randomized studies of interventions. Results were summarized using descriptive methods. Results: A search through 37 studies yielded 14 clinical studies that were ultimately included. The primary focus of the studies was on the knee joint, particularly the posterior cruciate ligament (PCL). The studies found that PCL in OA patients had impaired proprioceptive accuracy, possibly due to changes in mechanoreceptors (Ruffini, Pacini, and Golgi Mazzoni corpuscles). This suggests that dysfunctional articular mechanoreceptors, especially in severe cases of OA, may contribute to reduced proprioception. Dynamic stabilometry also identified significant proprioceptive deficits in patients with knee articular cartilage lesions, underscoring the impact of such lesions on knee proprioception. Conclusions: Literature data have shown that proprioceptive accuracy may play an important role in OA, particularly in the knee PCL and cartilage. However, the role of proprioception and related mechanoreceptors needs to be further clarified. Future studies focusing on the relationship between proprioception, OA disease, and symptoms, considering age and gender differences, and exploring OA joints other than the knee should be conducted to improve clinical and surgical outcomes in cases where proprioception and mechanoreceptors are impaired in OA patients. [ABSTRACT FROM AUTHOR]

• We provide a critical analysis of hesperidin in the prevention and treatment of lifestyle disorders such as diabetes, hypertension, Alzheimer's disease, Parkinson's disease, congestive heart failure, obesity, and cancer. • Hesperidin extraction, bioavailability, and the toxicological study were discussed. • Preclinical and clinical study of hesperidin in lifestyle disorders was evaluated. • Responsible mechanism of hesperidin was explored in the context of lifestyle disorders. Lifestyle disorders such as diabetes, hypertension, Alzheimer's disease, Parkinson's disease, congestive heart failure, obesity, and cancer are a growing concern for the modern healthcare system. Dietary modifications, herbal medicines, and fortified foods are proven to be one of the best ways to deal with these disorders and are significantly captivating scientists' attention all over the world. In this context, hesperidin, a flavonoid found in citrus fruits was selected based on its numerous in vivo and in vitro studies, hesperidin showed broad-spectrum therapeutic potential against several diseases such as cardiovascular disease, cancer, diabetes, hypertension, and neurodegenerative disorders. Numerous databases, including Scopus, PubMed, and Science Direct were used to pursuit and collect appropriate literature. The Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) criteria for drafting methodical reviews were followed and represents that hesperidin acts by different mechanisms including reducing oxidative stress and lowering the apoptotic protein like caspase, Bax, TNF-α, and NF-MB as well as the inflammatory markers such as IL-6, and LOX-2 in preclinical studies. Clinical studies showed that its consumption can remarkably prevent these lifestyle disorders. Although it has poor bioavailability when administered orally, various novel drug delivery approaches are used nowadays to resolve shortcomings associated with hesperidin. Hesperidin acts as a potential bioactive molecule for the prevention and treatment of lifestyle problems due to its wide therapeutic applications. Therefore, in this comprehensive review, an attempt has been made to explore the preclinical and clinical study of hesperidin in lifestyle disorders including cardiovascular disorder, diabetes, obesity, neurological disorders like Parkinson's disease, Alzheimer's disease, Huntington's disease, cancer, etc. with insights on its extraction, bioavailability, and safety profile. In conclusion, hesperidin acts as a potential molecule in the treatment of lifestyle disorders. Moreover, well-designed, high-quality, large-scale, and multicenter randomized clinical studies are required to establish the safety and clinical utility of hesperidin. [ABSTRACT FROM AUTHOR]

For pharmaceutical companies, it is essential to define their long-term corporate strategy. This especially involves the pipeline progress of pharmaceuticals and portfolio management. The objective of this study was to give a broad overview of study durations of the clinical trials from the top 30 pharmaceutical companies worldwide and to investigate what could possibly impact these study durations (e.g., indication areas, companies themselves, etc.) We worked with the clinicaltrials.gov database to examine the pipeline (phase 1–3) and portfolio (after regulatory approval) of the top 30 pharma companies worldwide over 20 years (from 2000–2020). We further calculated the study duration of each clinical study as the difference between the start date and end date. To analyze changes in our measure we estimated multiple linear regression to evaluate the impact of indication areas and companies on the study duration. Most of the clinical studies were conducted in the areas of ONCIM (N = 2720), and META (N = 1993). The indication with the highest study duration was ONCIM (on average 3.9 years per clinical study, SD: 0.8). Values for the study duration vary widely across companies. Mostly they range between 1 and 4 years (e.g., Merck Sharp & Dohme (MSD) on average 2.2 years per clinical study, SD: 1.0). Correlation analysis showed that study phases were positively correlated with the study duration (+ 0.36, p < 0.000), i.e., the higher the study phase, the higher the study duration. Furthermore, we found that indication areas influenced the study duration significantly (+ 0.17, p < 0.000). However, there were wide variations in effect sizes across indications. The results suggest that different indication areas influence the study duration to different extents. Pipeline progress and portfolio management differ widely between indications, companies and over the years. Research findings could help corporate strategy managers to make more informed decisions regarding their business development strategy. Highlights: Pipeline and portfolio management differ widely between companies. Most clinical studies were conducted in the area of oncology. Study duration varies mostly between 1–4 years across companies. Different indications influenced the study duration to different extents. [ABSTRACT FROM AUTHOR]

Pancreatic cancer is the third leading cause of cancer‐related deaths in the United States, owing to its aggressive nature and suboptimal treatment options, emphasizing the need for novel therapeutic approaches. Emerging studies have exhibited promising results regarding the therapeutic utility of plant‐derived compounds (phytochemicals) in pancreatic cancer. The purpose of this review is to evaluate the potential of phytochemicals in the treatment and prevention of pancreatic cancer. The Preferred Reporting Items for Systematic Reviews and Meta‐Analyses was applied to collect articles for this review. Scholarly databases, including PubMed, Scopus and ScienceDirect, were queried for relevant studies using the following keywords: phytochemicals, phenolics, terpenoids, alkaloids, sulfur‐containing compounds, in vitro, in vivo, clinical studies, pancreatic cancer, tumour, treatment and prevention. Aggregate results pooled from qualified studies indicate phytochemicals can inhibit pancreatic cancer cell growth or decrease tumour size and volume in animal models. These effects have been attributed to various mechanisms, such as increasing proapoptotic factors, decreasing antiapoptotic factors, or inducing cell death and cell cycle arrest. Notable signalling pathways modulated by phytochemicals include the rat sarcoma/mitogen activated protein kinase, wingless‐related integration site/β‐catenin and phosphoinositide 3‐kinase/protein kinase B/mammalian target of rapamycin signal transduction pathways. Clinically, phytochemicals have been found to increase survival while being well‐tolerated and safe, though research is scarce. While these promising results have produced great interest in this field, further in‐depth studies are required to characterize the anticancer activities of phytochemicals before they can be utilized to prevent or treat pancreatic cancer in clinical practice. [ABSTRACT FROM AUTHOR]

Simple Summary: Modulated electro-hyperthermia (mEHT) is a heating therapy that uses synergized thermal and nonthermal effects to heat and destroy malignant cells selectively without damaging healthy cells. This article presents the clinical validation of mEHT. The therapy is dominantly applied for such advanced malignancies when the conventional oncotherapies fail to apply. Survival results of mEHT were collected and compared with other methods. The results demonstrate the superiority of the mEHT method. The mEHT method uses tissues' thermal and bioelectromagnetic heterogeneity for the selective mechanisms. The success of the therapy for advanced, relapsed, and metastatic aggressive tumors can only be demonstrated by measuring survival time and quality of life (QoL). The complication is that mEHT-treated patients cannot be curatively treated any longer with "gold standards", where the permanent progression of the disease, the refractory, relapsing situation, the organ failure, the worsening of blood counts, etc., block them. Collecting a cohort of these patients is frequently impossible. Only an intent-to-treat (ITT) patient group was available. Due to the above limitations, many studies have single-arm data collection. The Phase III trial of advanced cervix tumors subgrouping of HIV-negative and -positive patients showed the stable efficacy of mEHT in all patients' subgroups. The single-arm represents lower-level evidence, which can be improved by comparing the survival data of various studies from different institutes. The Kaplan–Meier probability comparison had no significant differences, so pooled data were compared to other methods. Following this approach, we demonstrate the feasibility and superiority of mEHT in the cases of glioblastoma multiform, pancreas carcinomas, lung tumors, and colorectal tumors. [ABSTRACT FROM AUTHOR]

Purpose: Volatile organic compounds (VOCs) have shown great potential as novel biomarkers for cancer detection; however, comprehensive quantitative analysis is lacking. In this study, we performed a bibliometric analysis of non-invasive cancer diagnosis using VOCs to better characterise international trends and to predict future hotspots in this field, and then we focussed on human studies to analyse clinical characteristics for presenting the current controversies and future perspectives of further clinical work. Methods: Publications, from 2002 to 2022, were retrieved from the Web of Science Core Collection database. CiteSpace and VOSviewer were used to generate network maps and identify the annual publications, top countries, authors, institutions, journals, references, and keywords. Then, we further screened clinical trials, and the key information was extracted into Microsoft Excel for further systematical analysis. Results: Six hundred and forty-one articles were identified to evaluate research trends, of which 301 clinical trials were selected for further systematical analysis. Overall, the annual publications in this area increased, with an overall upward trend, while the quality of clinical research remains remarkably uneven. Conclusion: The study of non-invasive cancer diagnosis using VOCs would continue to be an active field. However, without stringent clinical design criteria, most suitable acquisition and analysis devices and statistical approaches, a list of exclusive, specific, reliable and reproducible VOCs to identify a disease and these VOCs appearing in a breath at detectable levels at early stage disease, the clinical utility of VOC tests will be difficult to have any breakthroughs. [ABSTRACT FROM AUTHOR]

Introduction: Polycystic Ovary Syndrome (PCOS) is a complex disorder with diverse clinical presentations. Women with PCOS use traditional, complementary, and integrative medicines, including Ayurveda (traditional Indian medicine) to manage their symptoms. Therefore, it is important to understand the current evidence base and the potential areas that require further research. Objective: This novel study aimed at providing a description of the Ayurveda studies conducted on women with PCOS and identifying gaps for future research. Methods: This scoping review was undertaken using the Joanna Briggs Institute scoping review guidelines. Relevant electronic databases were searched for any peer-reviewed original research that examined the role of Ayurveda (interventions using single/compound formula of herbs or minerals or metals, Panchakarma procedures and other therapies, and Ayurveda-based diet and lifestyle) for managing symptoms of PCOS in women of reproductive age. Two reviewers independently screened the records, extracted the data on population, intervention, comparator, and outcome characteristics and descriptively summarized the data. Results: Of the 1820 records identified, 57 articles met the inclusion criteria; 32 case studies, 13 randomized controlled trials, 9 pre-post trials, 2 case series, and 1 non-randomized trial. Most studies were conducted in India and used either a compound formula or a complex intervention (e.g., panchakarma therapies and lifestyle modifications). The majority of the case studies/series used an Ayurvedic diagnostic approach that influenced the choice of Ayurveda intervention. Among the interventions, shatapushpa (dill seeds) and krishnatila (black sesame seeds) were the most used single herbs whereas kanchanara guggulu and rajapravartini vati were the most used compound formulas. Basti karma (therapeutic enema) was the most used complex intervention. Reproductive outcomes were the most studied; menstruation, PCOS-related infertility, and polycystic ovary morphology. Conclusions: There are a number of clinical studies on Ayurveda interventions for PCOS with a promising role in managing symptoms of PCOS. However, a few gaps were identified. Future research should aim at: (1) exploring a wider range of interventions, including Ayurvedic diet and lifestyle in different settings/locations; (2) exploring the effectiveness of Ayurveda treatments as an adjunct to biomedical treatments (3) a greater range of outcome measures such as obesity, type 2 diabetes, anxiety, depression, and quality of life needs to be further explored in women with PCOS; and (4) finally, safety and adverse event reporting needs to be undertaken rigorously and systematically. [ABSTRACT FROM AUTHOR]