Search Results (19)

Background: Spirulina supplementation combined with structured exercise may improve obesity-related metabolic dysfunctions. This research examined whether this combination enhances body composition, glucose levels, lipid profile, and cardiorespiratory fitness in overweight and obese adults. Methods: Following PRISMA 2020 guidelines, a systematic search of Scopus, PubMed, and Web of Science identified randomized controlled trials (RCTs) evaluating spirulina (1–6 g/day) combined with structured exercise in individuals with overweight and obesity (BMI ≥ 25). The search retrieved 91 records, of which 10 studies met the inclusion criteria and were included in the systematic review. Nine studies provided sufficient post-intervention data and were included in the quantitative meta-analysis using a random-effects model, with heterogeneity assessed using τ², Q, and I² statistics. Publication bias was evaluated using rank correlation, regression-based tests, trim-and-fill, and fail-safe N analyses. Results: Combined spirulina supplementation and structured exercise (6–12 weeks) was associated with reductions in BMI (−1.34 kg/m²), body fat percentage (−3.03%), fasting glucose (−14.47 mg/dL), LDL-C (−12.68 mg/dL), and triglycerides (−9.81 mg/dL), along with increases in VO2max (3.25 mL/kg/min) and HDL-C (4.21 mg/dL). Effect estimates were generally larger in combined exercise–spirulina subgroups, particularly in HIITsupp and R-AEsupp conditions, whereas supplementation-only comparisons demonstrated smaller and less consistent changes. Inflammatory markers and adipokines (CRP, TNF-α, MCP-1, IL-6, IL-8) showed favorable directional changes in individual trials. Conclusions: Spirulina combined with structured exercise was associated with changes in anthropometric, glycemic, cardiorespiratory, and lipid parameters in individuals with overweight or obesity. Full article

Background: Innovative methods to test healthcare interventions have recently emerged to help provide more targeted, effective, and scalable interventions. Given the importance of the early years for children’s development, improved interventions for vulnerable children and families have become public health imperatives. Traditional randomized control trials (RCTs), considered the gold standards, have serious limitations due to high costs, time demands, and issues with the generalizability of the results. Indeed, new accelerated methods are being considered to improve the efficiency of RCTs. Thus, we compared innovative methods with RCTs in their ability to test and implement interventions. We also provided recommendations for best practices in the child-health research. Methods: A realist review was undertaken to identify and make recommendations on what works for whom and under what circumstances. This realist meta-review was conducted as an umbrella review of reviews, supplemented by a synthesis of the targeted grey-literature, to report both peer-reviewed and practice-based evidence on evaluation methods for community child-health interventions. We searched electronic databases, including MEDLINE, PubMed, EMBASE, PsycINFO, CINAHL, and the grey literature, and provided references. We identified, selected, and appraised sources if they were (1) written in English, (2) answered our research question, (3) described/criticized a method for intervention evaluation, and (4) focused on community-based health interventions. Results: For our final analysis, out of 5167 identified documents, we selected those that criticized or reviewed RCTs (n = 13) and innovative methods (n = 31). Following Pawson’s recommendations, we developed an extraction tool to promote a consistent approach and assessed to what degree each method enabled evaluation, was theory driven, offered clear guidelines, provided clear methods or tools, fostered innovation, was fast and generalizable, worked for who and under what circumstances, and focused on children and child-related research. Conclusions: Innovative and accelerated methods offer promising alternatives to the traditional RCTs for evaluating community-based child health interventions. Among these, the Innovate, Develop, Evaluate, Adapt, and Scale (IDEAS) method emerged as the most integrative and context-sensitive approach to evaluate early interventions in a variety of settings. Other innovative methods were not well-developed, compromising the internal validity of studies focused on promoting children’s health in community settings. Graphical abstract synthesizes the phases of RCTs and contrasts them with IDEAS. Full article

Chronic low back pain (cLBP) is a pervasive and debilitating condition that can result in motor control deficits and often leads to opioid dependence. Conventional rehabilitation approaches generally rely on internally driven tasks, which fail to capture adaptive motor responses to external perturbations. This study focuses on the design and evaluation of a pneumatic-actuated active balance board integrating pneumatic artificial muscles (PAMs), electromyography (EMG), and inertial measurement units (IMUs) to assess seated postural control responses. With PAM-powered perturbations, the balance board introduces controlled challenges to evaluate postural control dynamics and motor adaptation. EMG sensors monitor muscle activity in key postural muscles, while IMU systems track movement responses. The system was evaluated through an experimental trial with 15 healthy participants performing balance tasks on both a passive and active balance board. The active balance board’s effectiveness is assessed using signal processing techniques, including root mean square (RMS) analysis, Fast Fourier Transform (FFT), autoregressive (AR) modeling, and the Welch t-test. Experimental trials were conducted with healthy participants to establish baseline performance. Results demonstrate that the active balance board successfully induces adaptive motor responses, with higher EMG activation levels compared to passive boards. Frequency-domain analyses confirm significant differences in muscle activation patterns, supporting the hypothesis that external perturbations enhance postural control retraining. The pneumatic-actuated balance board presented in this study represents a novel approach to postural control assessment that may be applied in future rehabilitation studies involving individuals with cLBP, addressing the limitations of traditional methods. Future research will focus on clinical trials with cLBP patients to further evaluate its therapeutic efficacy and long-term benefits in rehabilitation. Full article

Background: Melanoma, one of the most aggressive forms of skin cancer, has seen significant therapeutic advances with immune checkpoint inhibitors (ICIs). However, many patients fail to respond or develop resistance, creating the need for adjunct strategies. Objective: The objective of this study is to critically evaluate how specific dietary patterns and nutrient-derived metabolites modulate melanoma metabolism and immunotherapy outcomes, emphasizing translational implications. Methods: We performed an integrative review of preclinical and clinical studies investigating dietary interventions in melanoma models and ICI-treated patients. Mechanistic insights were extracted from studies on nutrient transport, immunometabolism, and microbiome–immune interactions, including data from ongoing nutritional clinical trials. Results: Diets rich in fermentable fibers, plant polyphenols, and unsaturated lipids, such as Mediterranean and ketogenic diets, seem to contribute to the reprogramming of tumor metabolism and enhance CD8+ T-cell activity. Fasting-mimicking and methionine-restricted diets modulate T-cell fitness and tumor vulnerability via nutrient stress sensors (e.g., UPR, mTOR). High fiber intake correlates with favorable gut microbiota and improved ICI efficacy, while excess protein, methionine, or refined carbohydrates impair immune surveillance via lactate accumulation and immunosuppressive myeloid recruitment. Several dietary molecules act as network-level modulators of host and microbial proteins, with parallels to known drug scaffolds. Conclusions: Integrating dietary interventions into melanoma immunotherapy can significantly influence metabolic reprogramming by targeting metabolic vulnerabilities and reshaping the tumor–immune–microbiome axis. When combined with AI-driven nutrient–protein interaction mapping, this approach offers a precision nutrition paradigm that supports both physicians and patients, emerging as a novel layer to enhance and consolidate existing therapeutic strategies. Full article

Background and objectives: Hypertension remains a leading global cause of cardiovascular morbidity and mortality, with suboptimal blood pressure (BP) control despite available treatments. Monotherapy often fails to achieve target BP, necessitating combination therapies. Quadruple low-dose combination therapy (quadpill) has emerged as a potential strategy to enhance efficacy while minimizing side effects. This systematic review evaluates the effectiveness and safety of quadpill therapy compared to standard monotherapy and dual therapy. Methods: A systematic search was conducted in PubMed, Web of Science, and Scopus from inception till January 2025 for randomized controlled trials (RCTs) investigating quadruple therapy in hypertensive patients. Studies comparing quadpill therapy with monotherapy, dual therapy, or placebo were included. Data on BP reduction, achievement of target BP, and adverse events were extracted and analyzed. The Cochrane Risk of Bias tool (RoB-2) was used to assess study quality. Results: Five RCTs were included in the current systematic review. Quadpill therapy resulted in greater reductions in systolic BP (SBP and diastolic BP (DBP) compared to monotherapy and dual therapy across all time points. The proportion of patients achieving target BP (<140/90 mmHg) was significantly higher in the quadpill group. The safety profile was favorable, with adverse event rates comparable to those in monotherapy and dual therapy groups. Notable adverse effects included mild dizziness, edema, and biochemical alterations (elevated fasting glucose and uric acid levels), but these did not lead to significant treatment discontinuation. Conclusions: Quadruple low-dose combination therapy is a promising approach for improving BP control while maintaining a favorable safety profile. Early initiation of quadpill therapy could mitigate treatment inertia and improve long-term cardiovascular outcomes. Full article

Introduction: Patients with NRAS-mutant metastatic melanoma often have an aggressive disease requiring a fast-acting, effective therapy. The MEK inhibitor binimetinib shows an overall response rate of 15% in patients with NRAS-mutant melanoma, providing a backbone for combination strategies. Our previous studies demonstrated that in NRAS-mutant melanoma, the antitumor activity of the MEK inhibitor binimetinib was significantly potentiated by the BRAFV600E/K inhibitor encorafenib through the induction of ER stress, leading to melanoma cell death by apoptotic mechanisms. Encorafenib combined with binimetinib was well tolerated in a phase III trial showing potent antitumor activity in BRAF-mutant melanoma, making a rapid evaluation in NRAS-mutant melanoma imminently feasible. These data provide a mechanistic rationale for the evaluation of binimetinib combined with encorafenib in preclinical and clinical studies on NRAS-mutant metastatic melanoma. Methods: The combination of BRAFi plus MEKi was tested in a monolayer culture of patient-derived cell lines and in corresponding patient-derived tissue slice cultures of NRAS-mutant melanoma. To investigate the treatment in vivo, NSG (NOD. Cg-Prkdc^scid Il2rg^tm1Wjl/SzJ) mice were subcutaneously injected with three different BRAF wild-type melanoma models harboring oncogenic NRAS mutations and treated orally with encorafenib (6 mg/kg body weight, daily) with or without binimetinib (8 mg/kg body weight, twice daily). In parallel, an individual healing attempt was carried out by treating one patient with an NRAS-mutated tumor. Results: Encorafenib was able to enhance the inhibitory effect on cell growth of binimetinib only in the cell line SKMel147 in vitro. It failed to enhance the apoptotic effect found in two other NRAS-mutated cell lines. Encorafenib led to a hyperactivation of ERK which could be reduced with the combinational treatment. In two of the three patient-derived tissue slice culture models of NRAS-mutant melanomas, a slight tendency of a combinatorial effect was seen which was not significant. Encorafenib showed a slight induction of the ER stress genes ATF4, CHOP, and NUPR1. The combinational treatment was able to enhance this effect, but not significantly. In the mouse model, the combination therapy of encorafenib with binimetinib resulted in reduced tumor growth compared to the control and encorafenib groups; however, the best effect in terms of tumor growth inhibition was measured in the binimetinib therapy group. The therapy showed no effect in an individual healing attempt for a patient suffering from metastatic, therapy-refractory NRAS-mutated melanoma. Conclusion: In in vitro and ex vivo settings, the combination therapy was observed to elicit a response; however, it did not amplify the efficacy observed with binimetinib alone, whereas in a patient, the combinational treatment remained ineffective. The preclinical in vivo data showed no increased combinatorial effect. However, the in vivo effect of binimetinib as monotherapy was unexpectedly high in the tested regimen. Nevertheless, binimetinib proved to be advantageous in the treatment of melanoma in vivo and led to high rates of apoptosis in vitro; hence, it still seems to be a good base for combination with other substances in the treatment of patients with NRAS-mutant melanoma. Full article

Global rates of adolescent obesity have led the World Health Organization to consider the disease a pandemic that needs focus. In search of new anti-obesity agents, Crocus sativus, popularly known as saffron, is a nutraceutical agent, praised for its beneficial effects. The study aimed to investigate the possible effect of Kozanis saffron administration on weight management of obese prediabetic adolescents. Seventy-four obese prediabetic adolescents participated in a double-blind placebo-controlled trial of three arms, randomly assigned to receive either Kozanis saffron (n = 25, 60 mg/day), metformin (n = 25, 1000 mg/day) or a placebo (n = 24), for twelve weeks. Anthropometry, glycemic markers and lipid profiles were investigated at baseline and post-intervention. Saffron supplementation significantly reduced the weight z-score, BMI, BMI z-score and waist circumference (WC) of obese adolescents; however, this reduction was less significant compared to the effect of metformin. Metformin administration offered a significantly more profound improvement in anthropometry compared to saffron administration. Saffron administration also provided significant improvements in weight, weight z-scores, BMI values, BMI z-scores and WCs compared to the placebo. Saffron supplementation failed to change any glycemic marker, but provided a significant reduction in fasting triglyceride levels and also a significant increase in fasting HDL levels. Saffron Kozanis constitutes a promising nutraceutical option for adolescents and children with obesity and prediabetes in need of weight management. Full article

Traditional contact heat flux sensors suffer from a lack of dynamic performance, and existing non-contact optical heat measurement equipment fails to detect convective heat transfer effectively. This limitation precludes the effective testing of composite heat flux in explosive fields. This study introduces an ultra-responsive atomic layer thermopile (ALTP) heat flux sensor, developed and employed for the first time, to evaluate the transient heat flux associated with thermobaric explosions. Measurements reveal that the ALTP sensor’s temporal resolution surpasses that of the thermal resistance thin film heat flux sensor (TFHF), attaining a spectral response time of 10 μs under pulsed laser irradiation. Beyond these radiation-based tests, the present work also conducted novel simulation analyses of high-temperature jet impacts using COMSOL software. Static simulation discovered that fluid velocity significantly influences ALTP’s sensitivity, resulting in an error of 71%. Conversely, dynamic simulation demonstrated that an increase in fluid velocity reduces the ALTP’s time constant, whereas other factors such as fluid temperature exert minimal impact on its dynamic characteristics. This confirms that the simulation model compensates for the cost and accuracy deficiencies of convection heating tests. It also provides a new way to analyze the error of explosive heat flux measurement caused by sensitivity fluctuation and insufficient dynamic performance. In thermobaric explosive trials, the maximum heat fluxes recorded were 202 kW/m² in semi-enclosed environments and 526 kW/m² in open environments. A distinctive double-wave phenomenon was evident in the test curve. By a fast-response thermocouple, the study was able to differentiate between radiation and convective heat flux in the explosion field. The findings substantiate that the ALTP sensor amalgamates the benefits of optical thermal measurement tools with those of traditional contact heat flux sensors, thereby facilitating composite heat flux measurements in the challenging conditions of an explosive field. Full article

Excessive platelet reactivity plays a pivotal role in the pathogenesis of acute myocardial infarction. Today, the vast majority of patients presenting with acute coronary syndromes qualify for invasive treatment strategy and thus require fast and efficient platelet inhibition. Since 2008, in cases of ST-elevation myocardial infarction, the European Society of Cardiology guidelines have recommended pretreatment with a P2Y₁₂ inhibitor. This approach has become the standard of care in the majority of centers worldwide. Nevertheless, the latest guidelines for the management of patients presenting with acute coronary syndrome without persisting ST-elevation preclude routine pretreatment with the P2Y₁₂ receptor inhibitor. Those who oppose pretreatment support their stance with trials failing to prove the benefits of this strategy at the cost of an increased risk of major bleeding, especially in individuals inappropriately diagnosed with an acute coronary syndrome, thus having no indication for platelet inhibition. However, adequate platelet inhibition requires even up to several hours after application of a loading dose of P2Y₁₂ receptor inhibitors. Omission of data from pharmacokinetic and pharmacodynamic studies in the absence of data from clinical studies makes generalization of the pretreatment recommendations difficult to accept. We aimed to review the scientific evidence supporting the current recommendations regarding pretreatment with P2Y₁₂ inhibitors. Full article

Background: Observational studies have indicated beneficial effects of whole grain consumption on human health. However, no evidence based on randomized controlled trials has been established. Our objective was to perform a systematic review and meta-analysis of randomized controlled trials to assess the effects of whole grain consumption in glycaemic control of diabetic patients. Methods: A comprehensive search in four databases (Web of Science, Pubmed, Scopus and Cochrane library) was conducted to collect potential articles which measured the roles of whole grain consumption on glycaemic control up to October 2021. Results: A total of 16 eligible trials involving 1068 subjects were identified to evaluate the pooled effect. The overall results indicated that compared with the control group, whole grain intake presented a significantly reduced concentration in fast plasma glucose (WMD = −0.51 mmol/L, 95% CI: −0.73, −0.28; $I^2$ = 88.6%, p < 0.001), a homeostasis model assessment of insulin resistance (WMD = −0.39 μU × mol/L², 95% CI: −0.73, −0.04; $I^2$ = 58.4%, p = 0.014), and glycosylated haemoglobin (WMD = −0.56%, 95% CI: −0.88, −0.25, $I^2$ = 88.5%, p < 0.001), while no significant difference was observed in fast plasma insulin level between groups (SMD = −0.05, 95% CI: −0.25, 0.14; $I^2$ = 40.7%, p = 0.120). In terms of incremental area under the curve (iAUC), data suggested that whole grain effected a significant decrease in Glucose-iAUC (WMD = −233.09 min × mmol/L, 95% CI: −451.62, −14.57; $I^2$ = 96.1%, p < 0.001) and Insulin-iAUC (SMD = −4.80, 95% CI: −8.36, −1.23; $I^2$ = 89.9%, p = 0.002), although only in a small number of studies. Of note, there is evidence for modest unexplained heterogeneity in the present meta-analysis. Conclusion: Whole grain consumption confers a beneficial effect on glucose metabolism in patients with diabetes. Regrettably, since relevant studies were scarce, we failed to provide confident evidence of whole grain consumption on acute effects including Glucose-iAUC and Insulin-iAUC, which should be addressed in further trials. Full article

A glucose-lowering medication that acts by a different mechanism than metformin, or other approved diabetes medications, can supplement monotherapies when patients fail to meet blood glucose goals. We examined the actions underlying the effects of an insulin sensitizer, tolimidone (MLR-1023) and investigated its effects on body weight. Diet-induced obesity (CD1/ICR) and type 2 diabetes (db/db) mouse models were used to study the effect of MLR-1023 on metabolic outcomes and to explore its synergy with menthol. We also examined the efficacy of MLR-1023 alone in a clinical trial (NCT02317796), as well as in combination with menthol in human adipocytes. MLR-1023 produced weight loss in humans in four weeks, and in mice fed a high-fat diet it reduced weight gain and fat mass without affecting food intake. In human adipocytes from obese donors, the upregulation of Uncoupling Protein 1, Glucose (UCP)1, adiponectin, Glucose Transporter Type 4 (GLUT4), Adipose Triglyceride Lipase (ATGL), Carnitine palmitoyltransferase 1 beta (CPT1β), and Transient Receptor Potential Melastin (TRPM8) mRNA expression suggested the induction of thermogenesis. The TRPM8 agonist, menthol, potentiated the effect of MLR-1023 on the upregulation of genes for energy expenditure and insulin sensitivity in human adipocytes, and reduced fasting blood glucose in mice. The amplification of the thermogenic program by MLR-1023 and menthol in the absence of adrenergic activation will likely be well-tolerated, and bears investigation in a clinical trial. Full article

The use of MEK inhibitors in the therapy of uveal melanoma (UM) has been investigated widely but has failed to show benefits in clinical trials due to fast acquisition of resistance. In this study, we investigated a variety of therapeutic compounds in primary-derived uveal melanoma cell lines and found monosomy of chromosome 3 (M3) and mutations in BAP1 to be associated with higher resistance to MEK inhibition. However, reconstitution of BAP1 in a BAP1-deficient UM cell line was unable to restore sensitivity to MEK inhibition. We then compared UM tumors from The Cancer Genome Atlas (TCGA) with mutations in BAP1 with tumors with wild-type BAP1. Principal component analysis (PCA) clearly differentiated both groups of tumors, which displayed disparate overall and progression-free survival data. Further analysis provided insight into differential expression of genes involved in signaling pathways, suggesting that the downregulation of the eukaryotic translation initiation factor 2A (EIF2A) observed in UM tumors with BAP1 mutations and M3 UM cell lines might lead to a decrease in ribosome biogenesis while inducing an adaptive response to stress. Taken together, our study links loss of chromosome 3 with decreased sensitivity to MEK inhibition and gives insight into possible related mechanisms, whose understanding is fundamental to overcome resistance in this aggressive tumor. Full article

Visual search becomes challenging when the time to find the target is limited. Here we focus on how performance in visual search can be improved via a subtle saliency-aware modulation of the scene. Specifically, we investigate whether blurring salient regions of the scene can improve participant’s ability to find the target faster when the target is located in non-salient areas. A set of real-world omnidirectional images were displayed in virtual reality with a search target overlaid on the visual scene at a pseudorandom location. Participants performed a visual search task in three conditions defined by blur strength, where the task was to find the target as fast as possible. The mean search time, and the proportion of trials where participants failed to find the target, were compared across different conditions. Furthermore, the number and duration of fixations were evaluated. A significant effect of blur on behavioral and fixation metrics was found using linear mixed models. This study shows that it is possible to improve the performance by a saliency-aware subtle scene modulation in a challenging realistic visual search scenario. The current work provides an insight into potential visual augmentation designs aiming to improve user’s performance in everyday visual search tasks. Full article

The clinical failure rate for disease-modifying treatments (DMTs) that slow or stop disease progression has been nearly 100% for the major neurodegenerative disorders (NDDs), with many compounds failing in expensive and time-consuming phase 2 and 3 trials for lack of efficacy. Here, we critically review the use of pharmacological and mechanistic biomarkers in early phase clinical trials of DMTs in NDDs, and propose a roadmap for providing early proof-of-concept to increase R&D productivity in this field of high unmet medical need. A literature search was performed on published early phase clinical trials aimed at the evaluation of NDD DMT compounds using MESH terms in PubMed. Publications were selected that reported an early phase clinical trial with NDD DMT compounds between 2010 and November 2020. Attention was given to the reported use of pharmacodynamic (mechanistic and physiological response) biomarkers. A total of 121 early phase clinical trials were identified, of which 89 trials (74%) incorporated one or multiple pharmacodynamic biomarkers. However, only 65 trials (54%) used mechanistic (target occupancy or activation) biomarkers to demonstrate target engagement in humans. The most important categories of early phase mechanistic and response biomarkers are discussed and a roadmap for incorporation of a robust biomarker strategy for early phase NDD DMT clinical trials is proposed. As our understanding of NDDs is improving, there is a rise in potentially disease-modifying treatments being brought to the clinic. Further increasing the rational use of mechanistic biomarkers in early phase trials for these (targeted) therapies can increase R&D productivity with a quick win/fast fail approach in an area that has seen a nearly 100% failure rate to date. Full article

Bergamot flavonoids counteract dyslipidemia and hyperglycemia but fail to induce a significant weight loss. Here, we evaluated the efficacy of bergamot polyphenol extract complex (BPE-C), a novel bergamot juice-derived formulation enriched with flavonoids and pectins, on several metabolic syndrome parameters. Obese patients with atherogenic index of plasma (AIP) over 0.34 and mild hyperglycemia were recruited to a double-blind randomized trial comparing two doses of BPE-C (650 and 1300 mg daily) with placebo. Fifty-two subjects met the inclusion criteria and were assigned to three experimental groups. Fifteen subjects per group completed 90 days-trial. BPE-C reduced significantly fasting glucose by 18.1%, triglycerides by 32% and cholesterol parameters by up to 41.4%, leading to a powerful reduction of AIP (below 0.2) in the high dose group. The homeostasis model assessment of insulin resistance (HOMA-IR) and insulin levels were also reduced. Moreover, BPE-C decreased body weight by 14.8% and body mass index by 15.9% in BPE-C high group. This correlated with a significant reduction of circulating hormones balancing caloric intake, including leptin, ghrelin and upregulation of adiponectin. All effects showed a dose-dependent tendency. This study suggests that food supplements, containing full spectrum of bergamot juice components, such as BPE-C efficiently induce a combination of weight loss and insulin sensitivity effects together with a robust reduction of atherosclerosis risk. Full article