Search Results (1,091)

Nonsense mutations, responsible for ~11% of gene lesions causing human monogenic diseases, introduce premature termination codons (PTCs) that lead to truncated proteins and nonsense-mediated mRNA decay (NMD). In the central nervous system (CNS), these mutations drive severe, progressive neurological conditions such as spinal muscular atrophy, Rett syndrome, and Duchenne muscular dystrophy. Readthrough therapies—strategies to override PTCs and restore full-length protein expression—have evolved from early aminoglycosides to modern precision tools including suppressor tRNAs, RNA editing, and CRISPR-based platforms. Yet clinical translation remains hampered by inefficient CNS delivery, variable efficacy, and the absence of personalized stratification. In this review, we propose a translational framework—the 4 Ds of Readthrough Therapy—to systematically address these barriers. The framework dissects the pipeline into Detection (precision patient identification and biomarker profiling), Delivery (engineered vectors for CNS targeting), Decoding (context-aware molecular correction), and Durability (long-term safety and efficacy). By integrating advances in machine learning, nanocarriers, base editing, and adaptive trial designs, this roadmap provides a structured strategy to bridge the translational gap. We advocate that a synergistic, modality-tailored approach will transform nonsense suppression from palliative care to durable, precision-based cures for once-untreatable neurological disorders. Full article

Amblyopia affects 1–4% of the population and remains a leading cause of unilateral visual impairment, with adherence and residual deficits limiting outcomes of standard therapies. This systematic review and meta-analysis compared the effectiveness of conventional and emerging amblyopia treatments in children, adolescents, and adults with anisometropic, strabismic, or mixed amblyopia. Following PRISMA guidelines and PROSPERO registration (CRD420251123552), PubMed, Web of Science, and Scopus were searched up to 5 August 2025 for randomized controlled trials. Sixty-six trials (sample sizes 7–404) were included, with thirty-six contributing to the meta-analysis. Primary outcomes were best-corrected visual acuity (logMAR) and stereopsis. Risk of bias was assessed using the Cochrane tool, and certainty of evidence was assessed using GRADE. Atropine penalization and occlusion demonstrated equivalent effects on visual acuity (mean difference 0.04 logMAR; 95% CI −0.04 to 0.12; moderate-certainty evidence). Digital, dichoptic, binocular, and virtual reality therapies showed a statistically significant but small improvement over patching (mean difference 0.02 logMAR; 95% CI 0.00–0.04; low-certainty evidence). Pharmacological adjuvants combined with patching yielded slightly larger gains (mean difference 0.08 logMAR; 95% CI 0.03–0.13; low-to-moderate certainty). No consistent benefit was observed for stereopsis outcomes. Overall, the certainty of evidence ranged from low to moderate, and most pooled effects were below commonly accepted thresholds for clinically meaningful visual acuity improvement (≈0.1 logMAR, one line). Atropine and occlusion remain equivalent first-line treatments, while adjunctive and multimodal approaches may offer limited additional benefit in selected patients when adherence, tolerability, and engagement are prioritized. Full article

Background: The relationship between alcohol consumption and vascular function remains controversial. This study aimed to examine the association between total alcohol intake, type of alcoholic beverage, and arterial stiffness across different vascular territories in young Spanish adults, with special attention to sex-specific patterns. Methods: A descriptive cross-sectional study was conducted. Using consecutive non-probability sampling, 501 participants (222 men and 279 women) aged 18–34 years, were recruited from the urban population of Salamanca. Alcohol consumption was assessed using a standardized questionnaire and quantified in grams per week overall and by different types of drinks (wine, beer or spirits drinks). Arterial stiffness was evaluated using pulse pressure (PP), carotid–femoral pulse wave velocity (cf-PWV), brachial–ankle pulse wave velocity (ba-PWV), cardio–ankle vascular index (CAVI), and central augmentation index corrected to a heart rate of 75 beats per minute (CAIx75). Results: The mean age of the sample was 26.58 ± 4.40 years, and was significantly higher in men than in women (27.04 ± 4.41 vs. 26.22 ± 4.37 years; p = 0.040). The mean values for vascular function parameters were as follows: PP 42.86 ± 8.45 mmHg, cf-PWV 5.60 ± 1.29 m/s, ba-PWV 38 10.80 ± 1.01 m/s, CAVI 6.13 ± 0.75, and CAIx75 7.71 ± 19.74. Participants reporting alcohol consumption showed lower ba-PWV values compared with abstainers, while no consistent associations were observed for central arterial stiffness parameters. In sex-stratified analyses, higher total alcohol intake (β = −0.002, 95% CI: −0.004–−0.001), as well as beer (β = −0.004, 95% CI: −0.007–−0.001), and spirit consumption (β = −0.004, 95% CI: −0.006–−0.001), were inversely associated with ba-PWV exclusively in men. In women, spirit consumption was positively associated with CAIx75 (β = 0.044, 95% CI: 0.006–0.081). The magnitude of the observed differences in ba-PWV was modest and occurred in a predominantly low-risk population. Conclusions: In young adults, alcohol consumption was associated with differences in peripheral arterial stiffness, primarily reflected by ba-PWV, with clear sex-specific patterns. These findings do not support a causal or protective effect of alcohol consumption and should be interpreted cautiously due to the cross-sectional design of the study. The results highlight the importance of considering sex and vascular territory when evaluating early markers of vascular aging in young populations. Clinical trial registration: [ClinicalTrials.gov], identifier [NCT05819840]. Full article

This study aimed to identify metabolomic biomarkers for diabetes progression and validate their response to lifestyle intervention. A two-phase design was employed: first, untargeted metabolomics distinguished normoglycemic, prediabetic (PDM), and diabetic (DM) individuals, identifying 1,5-anhydroglucitol (1,5-AG) as the most significant biomarker for differentiating PDM from DM (apparent AUC = 0.97, 95% CI: 0.95–1.00; corrected AUC = 0.94, 95% CI: 0.83–1.00; q < 0.001). Second, in a 3-month randomized controlled trial involving 300 adults with PDM, the combined diet and exercise intervention significantly improved fasting blood glucose and glycated hemoglobin levels, while concurrently elevating serum 1,5-AG levels compared with the control group, though it did not yield significant improvements in other cardiovascular disease-related risk factors including body mass index, waist circumference, systolic blood pressure, and diastolic blood pressure. The intervention also showed a trend toward reduced diabetes incidence. Integrated analysis establishes 1,5-AG as a sensitive biomarker of dysglycemia that is responsive to lifestyle modification, supporting its potential as a mechanistic tool for monitoring intervention efficacy in diabetes prevention. Full article

Background: Protein–energy wasting (PEW) is a major predictor of morbidity and mortality in patients with chronic kidney disease (CKD), even before the initiation of dialysis. Its multifactorial pathogenesis includes reduced dietary intake, chronic inflammation, metabolic acidosis, hormonal disturbances, and dysbiosis of the gut microbiota. Early recognition and targeted management are crucial for preventing muscle loss, functional decline, and adverse outcomes. Methods: This narrative review summarises and integrates current evidence from the literature on nutritional and metabolic interventions to prevent and treat protein–energy wasting in patients with nondialysis chronic kidney disease. Relevant clinical trials, meta-analyses, and experimental studies published up to date were evaluated, focusing on dietary strategies, metabolic modulation, physical exercise, and gut microbiome-targeted therapies. Results: Adequate energy and protein intake remain the cornerstone of PEW management, based on available clinical and observational evidence. Individualised diets emphasising high-quality and plant-based proteins, oral nutritional supplements, and ketoanalogues can attenuate muscle wasting. Correction of metabolic acidosis and inflammation enhances protein anabolism and nitrogen balance. Physical exercise acts synergistically with dietary interventions to preserve muscle mass and function. Novel approaches—such as modulating the gut–kidney axis with pre-, pro-, and postbiotics or supplementing with short-chain fatty acids—show promise in improving metabolic and inflammatory profiles. Conclusions: The management of PEW in nondialysis CKD requires a personalised approach that integrates nutrition, physical activity, metabolic correction and microbiome modulation. Early, coordinated intervention may help to slow the progression of CKD and improve patient survival and quality of life. Full article

Background: Perceptual decision-making requires transforming sensory inputs into goal-directed actions under uncertainty. Neural oscillations in the theta band (3–7 Hz), particularly within frontal regions, have been implicated in cognitive control and decision confidence. However, whether changes in theta oscillations reflect greater effort during ambiguous decisions or more efficient control during clear conditions remains debated, and theta’s relationship to stimulus clarity is incompletely understood. Purpose: This study’s purpose was to examine how task difficulty modulates theta activity and how theta dynamics evolve across the decision-making process using two complementary analytical approaches. Methods: Electroencephalography (EEG) data were acquired from 26 healthy adults performing a face/house categorization task with images containing three levels of scrambled phase and Gaussian noise: clear (0%), moderate (40%), and high (55%). Theta dynamics were assessed from current source density (CSD) time courses of event-related potentials (ERPs) and single-trials. Statistical comparisons used Wilcoxon signed-rank tests with false discovery rate (FDR) correction for multiple comparisons. Results: Frontal theta power was greater for clear than noisy face stimuli (corrected p < 0.001), suggesting that theta activity reflects cognitive control effectiveness and decision confidence rather than processing difficulty. Connectivity decomposition revealed that frontoparietal theta coupling was modulated by stimulus clarity through both phase-locked (evoked: corrected p = 0.0085, dz = −0.61) and ongoing (induced: corrected p = 0.049, dz = −0.36) synchronization, with phase-locked coordination dominating the effect and showing opposite directionality to the induced components. Conclusions: Theta oscillations support perceptual decision-making through stimulus clarity modulation of both phase-locked and ongoing synchronization, with evoked component dominating. These findings underscore the importance of methodological choices in EEG-based connectivity research, as different analytical approaches capture different aspects of the same neural dynamics. The pattern of stronger theta activity for clear stimuli is consistent with neural processes related to decision confidence, though confidence was not measured behaviorally. Full article

This structured narrative review compared the efficacy, durability, and safety of anti-vascular endothelial growth factor (anti-VEGF) agents and intravitreal corticosteroids for the treatment of diabetic macular edema (DME), with the aim of identifying patient- and disease-specific factors to guide individualize therapy. A comprehensive search of PubMed, Embase, the Cochrane Library, and ClinicalTrials.gov was conducted for studies published between January 2009 and November 2025, including randomized controlled trials, meta-analyses, and large observational cohorts with at least six months of follow-up. Visual acuity, anatomical outcomes, treatment burden, durability, and safety were extracted, and evidence quality was assessed using the GRADE framework. Eleven studies encompassing 1341 eyes were included. Anti-VEGF therapy consistently produced greater improvements in best-corrected visual acuity, particularly in treatment-naïve eyes and in patients with worse baseline vision, whereas corticosteroids achieved larger reductions in central macular thickness and significantly reduced injection burden because of longer durability. However, corticosteroid therapy was associated with higher rates of intraocular pressure elevation and cataract progression. In pseudophakic patients and in chronic or refractory DME, functional and anatomical outcomes were generally comparable between the two therapeutic classes. Combination therapy resulted in the greatest anatomical improvement but at the cost of increased ocular adverse events. Overall, anti-VEGF agents remain the preferred first-line treatment for most patients with DME owing to superior visual outcomes and a more favorable safety profile, while corticosteroids represent valuable alternatives in pseudophakic eyes, chronic or anti-VEGF–refractory DME, and cases with prominent inflammatory features, provided that careful monitoring for ocular adverse events is maintained. Full article

Background/Objectives: Severe COVID-19 is marked by IL-6-driven inflammation, endothelial injury, and dysregulated coagulation. Although IL-6 antagonists improve clinical outcomes, their effects on the temporal evolution of coagulation and fibrinolysis remain insufficiently defined. This study characterizes inflammatory, endothelial, coagulation, and fibrinolytic trajectories following IL-6 receptor blockade in critically ill COVID-19 patients. Methods: In this prospective, exploratory multicenter case series (ClinicalTrials.gov NCT05218369), 15 ICU patients with PCR- or antigen-confirmed COVID-19 received tocilizumab per protocol. Serial sampling at five timepoints (T0–T4) included routine laboratories, comprehensive viscoelastic hemostatic assays (ClotPro^®), and ELISA-based endothelial and fibrinolytic biomarkers. Analyses were primarily descriptive, emphasizing temporal patterns through boxplots; paired Wilcoxon tests with FDR correction contextualized within-patient changes. Results: Patients exhibited marked inflammation, hyperfibrinogenemia, endothelial activation, and delayed fibrinolysis at baseline. IL-6 blockade induced rapid suppression of CRP and PCT, progressive declines in fibrinogen, and modest platelet increases. In contrast, vWF antigen and activity further increased, indicating persistent endothelial dysfunction. Viscoelastic testing showed preserved thrombin generation and sustained high clot firmness, while biochemical markers (rising PAI-1, modest PAP increase, and progressively increasing D-dimer) and VHA indices suggested ongoing antifibrinolytic activity despite resolution of systemic inflammation. Conclusions: IL-6 antagonism was associated with rapid attenuation of systemic inflammation but was not accompanied by normalization of endothelial activation or fibrinolytic resistance. The observed hemostatic profile was consistent with attenuation of inflammation-associated coagulation features, while endothelial and prothrombotic alterations appeared to persist during follow-up, warranting further investigation in larger controlled studies. Full article

Controlling pre-analytical conditions for medical biology tests, particularly during transport, is crucial for complying with the ISO 15189 standard and ensuring high-quality medical services. The use of drones, also known as unmanned aerial vehicles, to transport clinical samples is growing in scale, but requires prior validation to verify that there is no negative impact on the test results provided to doctors. This study aimed to establish a secure, high-quality solution for transporting biological samples by drone in a coastal region of France. The 80 km routes passed over several densely populated urban areas, with take-off and landing points within hospital grounds. The analytical and clinical impact of this mode of transport was compared according to two protocols: an interventional clinical trial on 30 volunteers compared to the reference transport by car, and an observational study on samples from 126 hospitalized patients compared to no transport. The system enabled samples to be transported without damage by maintaining freezing, refrigerated, and room temperatures throughout the flight, without any significant gain in travel time. Analytical variations were observed for sodium, folate, GGT, and platelet levels, with no clinical impact on the interpretation of the results. There is a risk of time-dependent alterations of blood glucose measurements in heparin tubes, which can be corrected by using fluoride tubes. This demonstrated the feasibility and security of transporting biological samples over long distances in line with the ISO 15189 standard. Controlling transport times remains crucial to assessing the quality of analyses. It is imperative to devise contingency plans for backup solutions to ensure the continuity of transportation in the event of inclement weather. Full article

The gut microbiome is a modifiable factor in cancer survivorship. Diet represents the most practical intervention for modulating the gut microbiome. However, diet–microbiome relationships in prostate-cancer survivors remain poorly characterized. We conducted a comprehensive analysis of diet–microbiome associations in 79 prostate-cancer survivors (ages 62–81) enrolled in a randomized exercise intervention trial, 59.5% of whom still have active metastatic disease. Dietary intake was assessed using the Diet History Questionnaire (201 variables) and analyzed using three validated dietary pattern scores: Mediterranean Diet Adherence Score (MEDAS), Healthy Eating Index-2015 (HEI-2015), and the Mediterranean-Dash Intervention for Neurodegenerative Delay (MIND) diet score. Gut microbiome composition was characterized via 16S rRNA sequencing. Dimensionality reduction strategies, including theory-driven diet scores and data-driven machine learning (Random Forest, and Least Absolute Shrinkage and Selection Operator (LASSO)), were used. Statistical analyses included beta regression for alpha diversity, Permutational Multivariate Analysis of Variance (PERMANOVA) for beta diversity (both Bray–Curtis and Sørensen metrics), and Microbiome Multivariable Associations with Linear Models (MaAsLin2) with negative binomial regression for taxa-level associations. All models tested interactions with exercise intervention, APOLIPOPROTEIN E (APOE) genotype, and testosterone levels. There was an interaction between MEDAS and exercise type on gut alpha diversity (Shannon: p = 0.0022), with stronger diet–diversity associations in strength training and Tai Chi groups than flexibility controls. All three diet-quality scores predicted beta diversity (HEI p = 0.002; MIND p = 0.025; MEDAS p = 0.034) but not Bray–Curtis (abundance-weighted) distance, suggesting diet shapes community membership rather than relative abundances. Taxa-level analysis revealed 129 genera with diet associations or diet × host factor interactions. Among 297 dietary variables tested for cognitive outcomes, only caffeine significantly predicted Montreal Cognitive Assessment (MoCA) scores after False Discovery Rate (FDR) correction (p = 0.0009, q = 0.014) through direct pathways beneficial to cognitive performance without notable gut microbiome modulation. In cancer survivors, dietary recommendations should be tailored to exercise habits, genetic background, and hormonal status. Full article

Accurate egocentric distance estimation in vista space depends on the interaction between perceptual encoding and cognitive recalibration. This study examined how iterative, feedback-based learning modulates spatial accuracy, perceptual bias, and task efficiency in large-scale environments. A total of 133 participants (mean age = 26.3 ± 7.44 years) performed distance estimations on three outdoor targets (134 m, 575 m, 1463 m) using a mobile web application providing immediate corrective feedback (too short/too long). Six variables were analyzed: first estimate (FE), error of first estimate (EFE), mean estimate (ME), error of mean estimate (EME), number of attempts (NAs), and trial duration (TD). Given the non-normal data distribution, nonparametric tests were applied (Friedman and Wilcoxon signed-rank tests with Bonferroni correction). All variables showed significant within-subject effects across distances (p < 0.001). Post hoc analyses indicated that EFE and EME differed significantly between all target pairs (p < 0.0167), revealing a shift from slight overestimation at 134 m to increasing underestimation at 575 m and 1463 m. NA was significantly higher for the farthest target (p < 0.0167), indicating greater cognitive load and iterative correction effort. TD differed significantly only between consecutive distances (p < 0.0167), suggesting non-linear temporal adaptation. These results demonstrate that iterative feedback improves perceptual stability and efficiency but does not remove distance compression. The consistent bias and adaptive response patterns support a feedback-driven, binary search-like recalibration mechanism. The proposed mobile paradigm offers a scalable and valid approach for assessing perceptual–cognitive calibration in both natural and virtual spatial contexts. Full article

Background/Objectives: To compare the clinical outcomes following cataract surgery with implantation of a new partial depth of field (DOFi) intraocular lens (IOL) versus a monofocal IOL of identical material, platform, and haptic design. Methods: Single-center, non-randomized trial including 55 patients randomly assigned to be implanted either with the partial-DOFi IOL Tecnis PureSee (partial-DOFi group, 29 patients) or the Tecnis monofocal IOL DCB00/ZCU (both Johnson & Johnson Surgical Vision) (monofocal group, 26 patients). Monocular visual acuity (VA), refractive, binocular defocus curve, and patient-reported outcomes (QoV and Catquest 9SF questionnaires) were evaluated during a 3-month follow-up. Results: No significant differences between monofocal and partial-DOFi groups were found in monocular postoperative uncorrected- (0.03 ± 0.08 vs. 0.05 ± 0.10, p = 0.419) and corrected-distance VA (−0.03 ± 0.04 vs. −0.03 ± 0.05, p = 0.642). Significantly better distance-corrected intermediate VA was found in the partial-DOFi group (0.29 ± 0.08 vs. 0.10 ± 0.06, p < 0.001). Similarly, postoperative monocular distance-corrected near VA was better in the partial-DOFi group (0.51 ± 0.10 vs. 0.31 ± 0.09, p < 0.001). In the defocus curve, significantly better distance-corrected VAs compared to monofocal were found for all defocus levels from −1.50 to −4.00 D. Minor reports of starbursts were found in both IOL groups. With the Catquest questionnaire, some significant differences were found between groups including reduced difficulty reading newspapers (p < 0.001), improved visibility of prices while shopping (p < 0.001) and enhanced performance of hobbies (p = 0.030) and needlework (p < 0.001). Conclusions: The partial-DOFi IOL evaluated demonstrates superior intermediate and near visual performance compared to a monofocal IOL, while maintaining equivalent distance vision and visual quality. Full article

Drones are increasingly used to conduct wildlife surveys in complex environments as they can be used in inaccessible areas, quickly survey large areas, and surveys can be reviewed post hoc, often leveraging AI technology. Double-observer methods applied to drone surveys, such as post-survey double-observer review of footage, improve inferences from drone-based wildlife surveys by correcting for individual perceptibility biases of observers. However, occlusion still affects the availability of individuals for detection, especially in complex environments. We explore the possibility that the availability of individuals may be increased by conducting a consecutive repeat survey with a parallel or rotated flight path in a double-observer survey design where individuals are largely stationary. We hypothesized that running this secondary flight would increase the availability of individuals for detection, thereby improving count accuracy, with the most prominent improvement in most complex (e.g., highly vegetated) environments. We explored this using (1) an in-field test of object detectability in environments with differing vegetation, and (2) a simulation of drone wildlife surveys in different levels of occlusion. In both trials, we tested a double-observer detectability estimator tool to correct survey counts. In the field, conducting a secondary flight from a different angle resulted in more accurate counts, with a post-count correction further increasing accuracy. The simulation highlighted detectability benefits from the secondary observer in nearly all trials (99%), and these benefits were generally greater in environments with denser canopies, and from flights paths rotated 90° compared to parallel paths. Full article

Amino acid availability is central for the synthesis of macromolecules and numerous bioactive compounds. Amino acids are also involved in ATP production, cell signaling, and the epigenetic regulation of gene expression in human cells. From clinical and experimental studies, it appears that supplementation with specific amino acids may be relevant to correct for amino acid deficiency in the case of insufficient supply from dietary proteins with regards to the amounts needed for optimal metabolism and physiological functions. Clinical and experimental arguments suggest that amino acid supplementation may be indicated in specific situations under a specific nutritional context. However, it is essential not to overdose with excessive quantities of amino acids in supplements beyond the upper levels of safe intake (ULSI). In this narrative review, I recapitulate the protein and amino acid requirements for the general population and for subgroups of the population, and these requirements are compared to the usual consumption. Typical examples of clinical trials showing the benefits from amino acid supplementation in different physiological and pathophysiological contexts are presented together with results obtained from experimental studies. Parameters such as the no-observed-adverse-effect-level (NOAEL) values used to determine the ULSI for amino acid supplementation are defined, and values determined in clinical trials are given and discussed. Finally, prospects for future research in the field are proposed. Full article